FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Leopoldino, AM Squarize, CH Garcia, CB Almeida, LO Pestana, CR Sobral, LM Uyemura, SA Tajara, EH Gutkind, JS Curti, C AF Leopoldino, Andreia M. Squarize, Cristiane H. Garcia, Cristiana B. Almeida, Luciana O. Pestana, Cezar R. Sobral, Lays M. Uyemura, Sergio A. Tajara, Eloiza H. Gutkind, J. Silvio Curti, Carlos TI SET protein accumulates in HNSCC and contributes to cell survival: Antioxidant defense, Akt phosphorylation and AVOs acidification SO ORAL ONCOLOGY LA English DT Article DE I2PP2A; Oral cancer; HNSCC; Oxidative stress; NM23-H1; Akt phosphorylation; Acidic vesicular organelles ID OXIDATIVE STRESS; CANCER-CELLS; PROTEOMIC ANALYSIS; MYELOID-LEUKEMIA; HEAD; NECK; CARCINOMA; APOPTOSIS; AUTOPHAGY; TARGET AB Objectives: Determination of the SET protein levels in head and neck squamous cell carcinoma (HNSCC) tissue samples and the SET role in cell survival and response to oxidative stress in HNSCC cell lineages. Materials and Methods: SET protein was analyzed in 372 HNSCC tissue samples by immunohistochemistry using tissue microarray and HNSCC cell lineages. Oxidative stress was induced with the pro-oxidant tert-butylhydroperoxide (50 and 250 mu M) in the HNSCC HN13 cell lineage either with (siSET) or without (siNC) SET knockdown. Cell viability was evaluated by trypan blue exclusion and annexin V/propidium iodide assays. It was assessed caspase-3 and -9, PARP-1, DNA fragmentation, NM23-H1, SET, Akt and phosphorylated Akt (p-Akt) status. Acidic vesicular organelles (AVOs) were assessed by the acridine orange assay. Glutathione levels and transcripts of antioxidant genes were assayed by fluorometry and real time PCR, respectively. Results: SET levels were up-regulated in 97% tumor tissue samples and in HNSCC cell lineages. SiSET in HN13 cells (i) promoted cell death but did not induced caspases, PARP-1 cleavage or DNA fragmentation, and (ii) decreased resistance to death induced by oxidative stress, indicating SET involvement through caspase-independent mechanism. The red fluorescence induced by siSET in HN13 cells in the acridine orange assay suggests SET-dependent prevention of AVOs acidification. NM23-H1 protein was restricted to the cytoplasm of siSET/siNC HN13 cells under oxidative stress, in association with decrease of cleaved SET levels. In the presence of oxidative stress, siNC HN13 cells showed lower GSH antioxidant defense (GSH/GSSG ratio) but higher expression of the antioxidant genes PRDX6, SOD2 and TXN compared to siSET HN13 cells. Still under oxidative stress, p-Akt levels were increased in siNC HN13 cells but not in siSET HN13, indicating its involvement in HN13 cell survival. Similar results for the main SET effects were observed in HN12 and CAL 27 cell lineages, except that HN13 cells were more resistant to death. Conclusion: SET is potential (i) marker for HNSCC associated with cancer cell resistance and (ii) new target in cancer therapy. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Leopoldino, Andreia M.; Garcia, Cristiana B.; Almeida, Luciana O.; Sobral, Lays M.; Uyemura, Sergio A.] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, BR-14040930 Ribeirao Preto, SP, Brazil. [Squarize, Cristiane H.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Div Oral Pathol Med Radiol, Ann Arbor, MI 48109 USA. [Pestana, Cezar R.; Curti, Carlos] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, BR-14040930 Ribeirao Preto, SP, Brazil. [Tajara, Eloiza H.] Fac Med Sao Jose do Rio Preto, Dept Biol Mol, Sao Jose do Rio Preto, Brazil. [Tajara, Eloiza H.] Univ Sao Paulo, Inst Ciencias Biol, Dept Biol, BR-14040930 Ribeirao Preto, SP, Brazil. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Leopoldino, AM (reprint author), Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, Av Cafe S-N, BR-14040930 Ribeirao Preto, SP, Brazil. EM andreiaml@usp.br RI Pestana, Cezar/K-6250-2012; Uyemura, Sergio/B-4656-2011; Sobral, Lays/G-4831-2012; Inov Farmaceutica, Inct/K-2313-2013; Leopoldino, Andreia/E-9926-2012; Curti, Carlos/H-6982-2016; OI Uyemura, Sergio/0000-0001-5505-9817; Sobral, Lays/0000-0002-8731-850X; Leopoldino, Andreia/0000-0002-8313-4754; Curti, Carlos/0000-0001-8154-5595; Oliveira de Almeida, Luciana/0000-0002-5342-0434 FU FAPESP [2005/03380-2, 2006/06334-4, 2010/20384-0, 2009/52228-0]; CNPq; CAPES; NIH, National Institute of Dental and Craniofacial Research FX Supported by FAPESP (PD Fellowship 2005/03380-2, Young Project 2006/06334-4, Research Project 2010/20384-0, Tematic Project 2009/52228-0), CNPq, CAPES and the Intramural Research Program of NIH, National Institute of Dental and Craniofacial Research. NR 58 TC 11 Z9 12 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD NOV PY 2012 VL 48 IS 11 BP 1106 EP 1113 DI 10.1016/j.oraloncology.2012.05.014 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 028OX UT WOS:000310433000014 PM 22739068 ER PT J AU Dencker, D Weikop, P Sorensen, G Woldbye, DPD Wortwein, G Wess, J Fink-Jensen, A AF Dencker, Ditte Weikop, Pia Sorensen, Gunnar Woldbye, David P. D. Wortwein, Gitta Wess, Juergen Fink-Jensen, Anders TI An allosteric enhancer of M-4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine SO PSYCHOPHARMACOLOGY LA English DT Article DE Muscarinic acetylcholine (ACh) M-4 receptor; Positive allosteric modulator (PAM); Cocaine; Psychostimulants; Dopamine; Striatum ID ANTIPSYCHOTIC-LIKE ACTIVITY; AGONIST XANOMELINE; RAT-BRAIN; DOPAMINE; MICE; EXPRESSION; ADDICTION; STRIATUM; D1; SUBPOPULATION AB The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M-4 acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M-4 receptors could be a novel target for modulating psychostimulant effects of cocaine. For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M-4 receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice. To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition, the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated. We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M-4 receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M-4 receptor knockout mice. Furthermore, selective deletion of the M-4 receptor gene in dopamine D-1 receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M-4 receptors co-localized with D-1 receptors. These results show that positive allosteric modulators of the M-4 receptor deserve attention as agents in the future treatment of cocaine abuse. C1 [Dencker, Ditte; Weikop, Pia; Sorensen, Gunnar; Woldbye, David P. D.; Wortwein, Gitta; Fink-Jensen, Anders] Copenhagen Univ Hosp, Lab Neuropsychiat, Psychiat Ctr Copenhagen, DK-2100 Copenhagen, Denmark. [Dencker, Ditte; Weikop, Pia; Sorensen, Gunnar; Woldbye, David P. D.; Wortwein, Gitta; Fink-Jensen, Anders] Univ Copenhagen, Dept Neurosci & Pharmacol, DK-2100 Copenhagen, Denmark. [Woldbye, David P. D.] Univ Copenhagen, Prot Lab, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. [Wortwein, Gitta] Univ Copenhagen, Dept Publ Hlth, Psychiat Ctr Copenhagen, DK-2100 Copenhagen, Denmark. [Wess, Juergen] NIDDK, Mol Signaling Sect, NIH, Bethesda, MD 20892 USA. RP Fink-Jensen, A (reprint author), Copenhagen Univ Hosp, Lab Neuropsychiat, Psychiat Ctr Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. EM a.fink-jensen@dadlnet.dk OI Wortwein, Gitta/0000-0001-6981-7885 FU Ivan Nielsen Foundation; Aase and Einar Danielsens Foundation; Butcher Max Worzner and wife Inger Worzner Foundation; A.P. Moller Foundation for the Advancement of Medical Science; Lundbeck Foundation FX The Ivan Nielsen Foundation, Aase and Einar Danielsens Foundation, Butcher Max Worzner and wife Inger Worzner Foundation, A.P. Moller Foundation for the Advancement of Medical Science, and Lundbeck Foundation supported the present work. We thank Birgit H. Hansen for expert technical assistance. NR 40 TC 17 Z9 19 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2012 VL 224 IS 2 BP 277 EP 287 DI 10.1007/s00213-012-2751-8 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 026ZK UT WOS:000310321400006 PM 22648127 ER PT J AU Tejeda, HA Natividad, LA Orfila, JE Torres, OV O'Dell, LE AF Tejeda, Hugo A. Natividad, Luis A. Orfila, James E. Torres, Oscar V. O'Dell, Laura E. TI Dysregulation of kappa-opioid receptor systems by chronic nicotine modulate the nicotine withdrawal syndrome in an age-dependent manner SO PSYCHOPHARMACOLOGY LA English DT Article DE Adolescent; Anxiety; Conditioned place aversion; Development; Dopamine; Elevated plus maze; Nicotinic; Mesolimbic; Microdialysis; Nucleus accumbens ID CONDITIONED PLACE PREFERENCE; MESOLIMBIC DOPAMINE RELEASE; NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; PREFRONTAL CORTEX; ADULT RATS; ADOLESCENT; COCAINE; REWARD; ABSTINENCE AB Mechanisms that mediate age differences during nicotine withdrawal are unclear. This study compared kappa-opioid receptor (KOR) activation in na < ve and nicotine-treated adolescent and adult rats using behavioral and neurochemical approaches to study withdrawal. The behavioral models used to assess withdrawal included conditioned place and elevated plus maze procedures. Deficits in dopamine transmission in the nucleus accumbens (NAcc) were examined using microdialysis procedures. Lastly, the effects of KOR stimulation and blockade on physical signs produced upon removal of nicotine were examined in adults. Nicotine-treated adults displayed a robust aversion to an environment paired with a KOR agonist versus na < ve adults. Neither of the adolescent groups displayed a place aversion. KOR activation produced an increase in anxiety-like behavior that was highest in nicotine-treated adults versus all other groups. KOR activation produced a decrease in NAcc dopamine that was largest in nicotine-treated adults versus all other groups. Lastly, KOR activation facilitated physical signs of withdrawal upon removal of nicotine and KOR blockade reduced this effect. Chronic nicotine enhanced the affective, anxiogenic, and neurochemical effects produced by KOR activation in adult rats. Our data suggest that chronic nicotine elicits an increase in KOR function, and this may contribute to nicotine withdrawal since KOR activation facilitated and KOR blockade prevented withdrawal signs upon removal of nicotine. Given that chronic nicotine facilitated the neurochemical effects of KOR agonists in adults but not in adolescents, it is suggested that KOR regulation of mesolimbic dopamine may contribute to age differences in nicotine withdrawal. C1 [Tejeda, Hugo A.; Natividad, Luis A.; Orfila, James E.; Torres, Oscar V.; O'Dell, Laura E.] Univ Texas El Paso, Dept Psychol, El Paso, TX 79968 USA. [Tejeda, Hugo A.] Natl Inst Drug Abuse, Integrat Neurosci Sect, Integrat Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP O'Dell, LE (reprint author), Univ Texas El Paso, Dept Psychol, 500 W Univ Ave, El Paso, TX 79968 USA. EM lodell@utep.edu FU NIDA [R01-DA021274]; UTEP BBRC-RCMI [5G12RR008124]; NIMH [MH 019978-08; HAT]; Ford Foundation; National Science Foundation; NIH [F31-DA021133]; APA Diversity Program in Neuroscience [T32-MH018882] FX The authors thank Ivan Torres, Evelyn Escalante, and Arturo Orona for technical assistance. This research was supported by NIDA (R01-DA021274) and the UTEP BBRC-RCMI (5G12RR008124). Funds for student training were also provided by the NIMH Career Opportunities in Research Program (MH 019978-08; HAT), the Ford Foundation (HAT), the National Science Foundation (HAT), the NIH Ruth L. Kirschstein pre-doctoral fellowship program (F31-DA021133; LAN), and the APA Diversity Program in Neuroscience (T32-MH018882; LAN). NR 52 TC 17 Z9 17 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2012 VL 224 IS 2 BP 289 EP 301 DI 10.1007/s00213-012-2752-7 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 026ZK UT WOS:000310321400007 PM 22659976 ER PT J AU Jhou, TC Xu, SP Lee, MR Gallen, CL Ikemoto, S AF Jhou, Thomas C. Xu, Sheng-Ping Lee, Mary R. Gallen, Courtney L. Ikemoto, Satoshi TI Mapping of reinforcing and analgesic effects of the mu opioid agonist Endomorphin-1 in the ventral midbrain of the rat SO PSYCHOPHARMACOLOGY LA English DT Article DE Opioids; Reward; Pain; Endomorphin; RMTg; tVTA; Habenula ID CONDITIONED PLACE PREFERENCE; ROSTROMEDIAL TEGMENTAL NUCLEUS; VENTROLATERAL PREOPTIC NUCLEUS; FORMALIN TEST; DOPAMINE NEURONS; PERIAQUEDUCTAL GRAY; OLFACTORY TUBERCLE; MORPHINE ANALGESIA; BRAIN SITES; AREA AB Agonists at the mu opioid receptor (MOR) are widely recognized for their effects on reward and pain. Although prior studies have attributed some of these effects to MORs on GABA neurons in the ventral tegmental area (VTA), recent studies have identified a region of particularly strong MOR immunostaining residing caudal to the VTA, in a region denoted the rostromedial tegmental nucleus (RMTg). Hence, we examined whether rats would self-administer small doses (50-250 pmol) of the selective MOR agonist endomorphin-1 (EM1) into the RMTg and adjacent sites. EM1 was chosen due to its short half-life, thus limiting drug spread, and due to its presence endogenously in brain neurons, including some afferents to the RMTg. The highest rates of EM1 self-administration occurred within 0.5 mm of the RMTg center, in a region roughly 0.8-1.6 mm caudal to the majority of VTA DA neurons. In contrast, self-administration rates were much lower in the adjacent VTA, interpeduncular nucleus, central linear nucleus, or median raphe nucleus. Furthermore, EM1 infusions into the RMTg, but not surrounding regions, produced conditioned place preference, while EM1 infusions into the RMTg but not anterior VTA markedly reduced formalin-induced pain behaviors. EM1 effects were mimicked by infusions of the GABA agonist muscimol into the same region, consistent with EM1 having inhibitory actions on its target neurons. These results implicate a novel brain region in modulating MOR influences on both appetitive and aversive behavior. C1 [Jhou, Thomas C.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Jhou, Thomas C.; Xu, Sheng-Ping; Ikemoto, Satoshi] Natl Inst Drug Abuse, Behav Neurosci Branch, NIH, US Dept HHS, Baltimore, MD USA. [Lee, Mary R.; Gallen, Courtney L.] Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, US Dept HHS, Baltimore, MD USA. RP Jhou, TC (reprint author), Med Univ S Carolina, Dept Neurosci, 173 Ashley Ave, Charleston, SC 29425 USA. EM tomjhou@gmail.com OI Ikemoto, Satoshi/0000-0002-0732-7386 FU National Institute on Drug Abuse, National Institutes of Health FX We acknowledge Toni Shippenberg and Vicky Minney for helpful technical advice. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 53 TC 24 Z9 25 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2012 VL 224 IS 2 BP 303 EP 312 DI 10.1007/s00213-012-2753-6 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 026ZK UT WOS:000310321400008 PM 22669129 ER PT J AU Fayad, LM Jacobs, MA Wang, X Carrino, JA Bluemke, DA AF Fayad, Laura M. Jacobs, Michael A. Wang, Xin Carrino, John A. Bluemke, David A. TI Musculoskeletal Tumors: How to Use Anatomic, Functional, and Metabolic MR Techniques SO RADIOLOGY LA English DT Article ID SOFT-TISSUE TUMORS; CONTRAST-ENHANCED MR; MAGNETIC-RESONANCE-SPECTROSCOPY; DIFFUSION-WEIGHTED MRI; ISOLATED LIMB PERFUSION; PRIMARY BONE-TUMORS; IN-VIVO ASSESSMENT; DIFFERENTIAL-DIAGNOSIS; VERTEBRAL METASTASES; MONITORING RESPONSE AB Although the function of magnetic resonance (MR) imaging in the evaluation of musculoskeletal tumors has traditionally been to help identify the extent of disease prior to treatment, its role continues to evolve as new techniques emerge. Conventional pulse sequences remain heavily used and useful, but with the advent of chemical shift imaging, diffusion-weighted imaging, perfusion imaging and MR spectroscopy, additional quantitative metrics have become available that may help expand the role of MR imaging to include detection, characterization, and reliable assessment of treatment response. This review discusses a multiparametric approach to the evaluation of musculoskeletal tumors, with a focus on the utility and potential added value of various pulse sequences in helping establish a diagnosis, assess pretreatment extent, and evaluate a tumor in the posttreatment setting for recurrence and treatment response. C1 [Fayad, Laura M.; Jacobs, Michael A.; Wang, Xin; Carrino, John A.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Fayad, LM (reprint author), Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 601 N Wolfe St, Baltimore, MD 21287 USA. EM lfayad1@jhmi.edu RI Jacobs, Michael/G-2901-2010; wang, xin/I-3395-2013; OI wang, xin/0000-0002-9519-8413; Bluemke, David/0000-0002-8323-8086 FU AUR GE Radiology Research Academic Fellowship; SCBT-MR Young Investigator Award; William M. G. Gatewood Fellowship; National Institutes of Health [R01 CA118371, R01EB009367, 2R01CA112163, NIH R01CA100184, P50CA103175, 5P30CA06973, P50CA88843, U01CA140204]; Siemens Medical Systems; Carestream Health; Toshiba; Integra FX L.M.F. supported by the AUR GE Radiology Research Academic Fellowship (2008), SCBT-MR Young Investigator Award (2004), and the William M. G. Gatewood Fellowship.; This research was supported by the National Institutes of Health (grants R01 CA118371, R01EB009367, 2R01CA112163, NIH R01CA100184, P50CA103175, 5P30CA06973, P50CA88843, and U01CA140204). D. A. B. is an employee of the National Institutes of Health.; L.M.F. No relevant conflicts of interest to disclose. M.A.J. No relevant conflicts of interest to disclose. X. W. No relevant conflicts of interest to disclose. J.A.C. Financial activities related to the present article: received a grant from Siemens Medical Systems. Financial activities not related to the present article: served as consultant to Quality Medical Metrics and Medtronics; has grants or grants pending from Siemens Medical Systems, Carestream Health, Toshiba, and Integra. Other relationships: none to disclose. D. A. B. No relevant conflicts of interest to disclose. NR 120 TC 46 Z9 48 U1 0 U2 8 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2012 VL 265 IS 2 BP 340 EP 356 DI 10.1148/radiol.12111740 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 029PN UT WOS:000310508000006 PM 23093707 ER PT J AU Ernande, L Thibault, H Bergerot, C Moulin, P Wen, H Derumeaux, G Croisille, P AF Ernande, Laura Thibault, Helene Bergerot, Cyrille Moulin, Phillippe Wen, Han Derumeaux, Genevieve Croisille, Pierre TI Systolic Myocardial Dysfunction in Patients with Type 2 Diabetes Mellitus: Identification at MR Imaging with Cine Displacement Encoding with Stimulated Echoes SO RADIOLOGY LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; HEART-DISEASE; DENSE MRI; ASYMPTOMATIC PATIENTS; MAGNETIC-RESONANCE; TISSUE TRACKING; STRAIN; INFARCTION; MOTION; ECHOCARDIOGRAPHY AB Purpose: To determine if cine displacement encoding with stimulated echoes (DENSE) can help to identify and determine the patterns of subclinical myocardial systolic dysfunction in patients with type 2 diabetes mellitus (DM) when compared with cine DENSE in control patients. Materials and Methods: After obtaining approval from the institutional ethics committee and written informed consent from the patients, 37 patients with type 2 DM without overt heart disease and 23 age-matched control patients were prospectively included in the study. The patients underwent standard cine magnetic resonance (MR) imaging with two-dimensional cine DENSE acquisitions. Circumferential (Ecc) and radial (Err) systolic strains were measured on short-axis views at basal, mid, and apical left ventricular levels. Longitudinal strain (Ell) was measured on four-and two-chamber views. Statistical testing included the intraclass correlation coefficient and multiple linear regression analysis. Results: The intraobserver intraclass correlation coefficient values were 0.85, 0.95, and 0.90, and the interobserver intraclass correlation coefficient values were 0.79, 0.91 and 0.80 for Ecc, Err, and Ell, respectively. The left ventricular ejection fraction was in the reference range and similar between the groups, and the patients with DM showed a decrease in Ecc (-14.4% +/- 1.6 vs -17.0% +/- 1.6, P < .001), Err (36.2% +/- 10.9 vs 44.4% +/- 9.9, P = .006) and Ell (-12.9% +/- 2.1 vs -15.5% +/- 1.6, P < .001) compared with the control patients. Finally, DM was independently associated with Ecc (P < .001), Err (P = .05) and Ell (P = .01) after adjustment for age, sex, hypertension, body mass index, and left ventricular mass. Conclusion: Cine DENSE, a motion-encoding MR imaging technique for myocardial strain assessment with high spatial resolution, appears to be useful in the identification of subclinical myocardial dysfunction in patients with DM. C1 [Croisille, Pierre] Univ Lyon, Univ St Etienne, CHU St Etienne, CREATIS,CNRS,UMR 5220,INSERM,U1044, Lyon, France. [Ernande, Laura; Thibault, Helene; Bergerot, Cyrille; Derumeaux, Genevieve] Louis Pradel Hosp, Serv Explorat Fonct Cardiovascu, F-69500 Bron, France. [Ernande, Laura; Thibault, Helene; Derumeaux, Genevieve] Univ Lyon, CarMeN, INSERM, U 1060, Lyon, France. [Wen, Han] NHLBI, NIH, Bethesda, MD 20892 USA. [Moulin, Phillippe] Louis Pradel Hosp, Dept Endocrinol, Lyon, France. RP Croisille, P (reprint author), Univ Lyon, Univ St Etienne, CHU St Etienne, CREATIS,CNRS,UMR 5220,INSERM,U1044, Lyon, France. EM croisille@creatis.univ-lyon1.fr RI Croisille, Pierre/H-4928-2014; Wen, Han/G-3081-2010 OI Croisille, Pierre/0000-0003-4019-3460; Wen, Han/0000-0001-6844-2997 FU institutional grant "Programme Hospitalier Regional de Recherche Clinique" (PHRC 27-9, Interegion Rhone Alpes Auvergne, France); Programme Hospitalier de Recherche Clinique; French Society of Cardiology; Sanofi; ANR FX Supported by an institutional grant "Programme Hospitalier Regional de Recherche Clinique" (PHRC 27-9, Interegion Rhone Alpes Auvergne, France).; L.E. Financial activities related to the present article: Received a government agency grant from Programme Hospitalier de Recherche Clinique. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. H. T. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: Institution received a grant from the French Society of Cardiology; institution received payment for lecture at the Toshiba symposium in January 2012. Other relationships: none to disclose. C. B. No relevant conflicts of interest to disclose. P. M. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: Received payment for consultancy from BMS, GSK, Lilly, and Novo Nordisk; payment to author and institution for board membership of BMS-Astra Zenica. Other relationships: Grants/grants pending from Sanofi, author and institution received payment for lectures from Novo Nordisk and MSD; author receive payment for travel and accomodations from Astra Zenica, MSD, Servier, Solvay, and Takeda; Author was a clinical trial co-investigator for Astra Zenica, GSK, Lilly, Merk Lipha, MSD, Novo Nordisk, Novartis, Olympus, Sanofi, Servier, and Takeda. H. W. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: Institution holds a patent on an MR imaging technique; author and institution have received royalties from Siemens and General Electric. Other relationships: none to disclose. G. D. Financial activities related to the present article: received a government agency grant from Programme Hospitalier de Recherche Clinique. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. P. C. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution has grants/grants pending from ANR; author received payment for lectures from Siemens, Guerbet, and Novartis. Other relationships: none to disclose. NR 40 TC 16 Z9 16 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2012 VL 265 IS 2 BP 402 EP 409 DI 10.1148/radiol.12112571 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 029PN UT WOS:000310508000012 PM 22929334 ER PT J AU Ouwerkerk, R Pettigrew, RI Gharib, AM AF Ouwerkerk, Ronald Pettigrew, Roderic I. Gharib, Ahmed M. TI Liver Metabolite Concentrations Measured with H-1 MR Spectroscopy SO RADIOLOGY LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; GLYCOGEN IN-VIVO; SPINNING H-1-NMR SPECTROSCOPY; C-13 NMR; PROTON SPECTROSCOPY; LIPID SUPPRESSION; STORAGE-DISEASE; TIME-DOMAIN; 3 TESLA; QUANTIFICATION AB Purpose: To determine the feasibility of measuring choline and glycogen concentrations in normal human liver in vivo with proton (hydrogen 1 [H-1]) magnetic resonance (MR) spectroscopy. Materials and Methods: Signed consent to participate in an institutional review board-approved and HIPAA-compliant study was obtained from 46 subjects (mean age, 46 years 6 17 [standard deviation]; 24 women) consecutively recruited during 285 days. Navigator-gated MR images were used to select 8-mL volumes for point-resolved spectroscopy (PRESS) with a 35-msec echo time. Line widths were minimized with fast breath-hold B0 field mapping and further manual shimming. Navigator-gated spectra were recorded with and without water suppression to determine metabolite concentrations with water signals as an internal reference. In three subjects, echo time was varied to determine the glycogen and choline T2. Linear regression analysis was used to examine relations between choline, hepatic lipid content, body mass index, glycogen content, and age. Results: Choline concentrations could be determined in 46 of 48 studies and was found to be 8.6 mmol per kilogram of wet weight +/- 3.1 (range, 3.8-17.6; n = 44). Twenty-seven spectra in 25 individuals with narrow line widths and low lipid content were adequate for quantitation of glycogen. The glycogen (glucosyl unit) concentration was 38.1 mmol/kg wet weight +/- 14.4. The T2 of combined glycogen peaks in the liver of three subjects was 36 msec +/- 8. Choline levels showed a weak but significant correlation with glycogen (r(2) = 0.15; P < .05) but not with lipid content. Conclusion: Navigator-gated and gradient-echo shimmed PRESS 1H MR spectroscopy may allow quantification of liver metabolites that are important for understanding and identifying disorders of glucose and lipid metabolism. C1 [Ouwerkerk, Ronald; Pettigrew, Roderic I.; Gharib, Ahmed M.] NIDDKD, Biomed & Metab Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Ouwerkerk, R (reprint author), NIDDKD, Biomed & Metab Imaging Branch, NIH, 10 Ctr Dr,CRC Bldg 10,Room 3-5340,MSC 1263, Bethesda, MD 20892 USA. EM ouwerkerkr@niddk.nih.gov RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X NR 43 TC 9 Z9 9 U1 0 U2 13 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2012 VL 265 IS 2 BP 565 EP 575 DI 10.1148/radiol.12112344 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 029PN UT WOS:000310508000030 PM 22891360 ER PT J AU Aronow, ME Adamus, G Abu-Asab, M Wang, YJ Chan, CC Zakov, ZN Singh, AD AF Aronow, Mary E. Adamus, Grazyna Abu-Asab, Mones Wang, Yujuan Chan, Chi-Chao Zakov, Z. Nicholas Singh, Arun D. TI Paraneoplastic Vitelliform Retinopathy: Clinicopathologic Correlation and Review of the Literature SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE paraneoplastic vitelliform retinopathy; melanoma; uveal; cutaneous; MAR; CAR; autoantibodies; retina; autoimmune; retinopathy ID MELANOMA-ASSOCIATED RETINOPATHY; CANCER-ASSOCIATED RETINOPATHY; MALIGNANT-MELANOMA; RETINAL DETACHMENTS; AUTOANTIBODIES; PATIENT; AUTOIMMUNITY AB Traditionally, the paraneoplastic retinopathies have been classified into two groups: melanoma-associated retinopathy (MAR) and cancer-associated retinopathy. MAR occurs in individuals with metastatic cutaneous or uveal melanoma and is characterized by nyctalopia, photopsias, and variable vision loss. In most cases, the fundus is essentially normal in appearance. More recently, there have been multiple reports of a MAR-like retinopathy with associated detachments of the retinal pigment epithelium and neurosensory retina. Such a clinical presentation has been termed paraneoplastic vitelliform retinopathy. We describe an 80-year-old man with metastatic cutaneous melanoma who developed paraneoplastic vitelliform retinopathy. For the first time, histopathology from enucleation specimens provides a clinicopathologic disease correlation with focal abnormalities in the inner nuclear and outer plexiform layers. (Surv Ophthalmol 57:558-564, 2012. (C) 2012 Elsevier Inc. All rights reserved.) C1 [Aronow, Mary E.; Singh, Arun D.] Cleveland Clin, Dept Ophthalm Oncol, Cole Eye Inst, Cleveland, OH 44195 USA. [Adamus, Grazyna] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Abu-Asab, Mones; Wang, Yujuan; Chan, Chi-Chao] NEI, Sect Immunopathol, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zakov, Z. Nicholas] Retina Associates Cleveland, Cleveland, OH USA. RP Singh, AD (reprint author), Cleveland Clin, Dept Ophthalm Oncol, Cole Eye Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM singha@ccf.org RI wang, yujuan/C-8428-2016; OI Abu-Asab, Mones/0000-0002-4047-1232 FU Intramural NIH HHS [ZIA EY000222-26, ZIC EY000461-04]; NEI NIH HHS [R01 EY013053] NR 19 TC 10 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD NOV-DEC PY 2012 VL 57 IS 6 BP 558 EP 564 DI 10.1016/j.survophthal.2012.02.004 PG 7 WC Ophthalmology SC Ophthalmology GA 027XI UT WOS:000310387000006 PM 22784677 ER PT J AU Tornero-Velez, R Davis, J Scollon, EJ Starr, JM Setzer, RW Goldsmith, MR Chang, DT Xue, JP Zartarian, V DeVito, MJ Hughes, MF AF Tornero-Velez, Rogelio Davis, Jimena Scollon, Edward J. Starr, James M. Setzer, R. Woodrow Goldsmith, Michael-Rock Chang, Daniel T. Xue, Jianping Zartarian, Valerie DeVito, Michael J. Hughes, Michael F. TI A Pharmacokinetic Model of cis- and trans-Permethrin Disposition in Rats and Humans With Aggregate Exposure Application SO TOXICOLOGICAL SCIENCES LA English DT Article DE pyrethroids; PBPK; aggregate exposure model ID IN-VITRO METABOLISM; HUMAN DOSE-EXCRETION; SUBURBAN CHILDRENS EXPOSURE; PYRETHROID INSECTICIDES; DRUG-METABOLISM; RISK-ASSESSMENT; CARE-CENTERS; DELTAMETHRIN; HYDROLYSIS; LIVER AB Permethrin is a broad-spectrum pyrethroid insecticide and among the most widely used insecticides in homes and crops. Managing the risks for pesticides such as permethrin depends on the ability to consider diverse exposure scenarios and their relative risks. Physiologically based pharmacokinetic models of delta methrin disposition were modified to describe permethrin kinetics in the rat and human. Unlike formulated deltamethrin which consists of a single stereoisomer, permethrin is formulated as a blend of cis- and trans-diastereomers. We assessed time courses for cis-permethrin and trans-permethrin in several tissues (brain, blood, liver, and fat) in the rat following oral administration of 1 and 10mg/kg permethrin (cis/trans: 40/60). Accurate simulation of permethrin in the rat suggests that a generic model structure is promising for modeling pyrethroids. Human in vitro data and appropriate anatomical information were used to develop a provisional model of permethrin disposition with structures for managing oral, dermal, and inhalation routes of exposure. The human permethrin model was used to evaluate dietary and residential exposures in the U.S. population as estimated by EPA's Stochastic Human Exposure and Dose Simulation model. Simulated cis- and trans-DCCA, metabolites of permethrin, were consistent with measured values in the National Health and Nutrition Examination Survey, indicating that the model holds promise for assessing population exposures and quantifying dose metrics. C1 [Tornero-Velez, Rogelio] US EPA, Natl Exposure Res Lab, NERL ORD, Res Triangle Pk, NC 27711 USA. [Davis, Jimena; Setzer, R. Woodrow] US EPA, NCCT ORD, Res Triangle Pk, NC 27711 USA. [Scollon, Edward J.; Hughes, Michael F.] US EPA, NHEERL ORD, Res Triangle Pk, NC 27711 USA. [DeVito, Michael J.] NIEHS NTP, Res Triangle Pk, NC USA. RP Tornero-Velez, R (reprint author), US EPA, Natl Exposure Res Lab, NERL ORD, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. EM tornero-velez.rogelio@epa.gov FU United States Environmental Protection Agency through its Office of Research and Development FX The United States Environmental Protection Agency through its Office of Research and Development funded and managed the research described here. NR 61 TC 20 Z9 20 U1 1 U2 40 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2012 VL 130 IS 1 BP 33 EP 47 DI 10.1093/toxsci/kfs236 PG 15 WC Toxicology SC Toxicology GA 025CV UT WOS:000310163200004 PM 22859315 ER PT J AU Liang, YH Gao, R Su, XD AF Liang, Yu-He Gao, Rong Su, Xiao-Dong TI Structural insights into the broadened substrate profile of the extended-spectrum beta-lactamase OXY-1-1 from Klebsiella oxytoca SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID STREPTOMYCES-ALBUS-G; CRYSTAL-STRUCTURE; ANTIBIOTIC-RESISTANCE; BACTERIAL-RESISTANCE; CATALYTIC MECHANISM; ANGSTROM RESOLUTION; PROTEIN-STRUCTURE; SEQUENCE; ENZYMES; TOHO-1 AB Klebsiella oxytoca is a pathogen that causes serious infections in hospital patients. It shows resistance to many clinically used beta-lactam antibiotics by producing chromosomally encoded OXY-family beta-lactamases. Here, the crystal structure of an OXY-family beta-lactamase, OXY-1-1, determined at 1.93 angstrom resolution is reported. The structure shows that the OXY-1-1 beta-lactamase has a typical class A beta-lactamase fold and exhibits greater similarity to CTX-M-type beta-lactamases than to TEM-family or SHV-family beta-lactamases. It is also shown that the enzyme provides more space around the active cavity for the R-1 and R-2 substituents of beta-lactam antibiotics. The half-positive/half-negative distribution of surface electrostatic potential in the substrate-binding pocket indicates the preferred properties of substrates or inhibitors of the enzyme. The results reported here provide a structural basis for the broadened substrate profile of the OXY-family beta-lactamases. C1 Peking Univ, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China. Peking Univ, Biodynam Opt Imaging Ctr BIOPIC, Beijing 100871, Peoples R China. RP Liang, YH (reprint author), NCI, Ctr Macromol Crystallog, Frederick, MD 21702 USA. EM liangyh@pku.edu.cn; xdsu@pku.edu.cn RI LIANG, YUHE/B-6704-2012 FU Fok Ying Tong Education Foundation [94017]; Peking University FX This project was supported by a Fok Ying Tong Education Foundation grant (94017). Peking University's 985 and 211 grants are also greatly acknowledged. We thank the beamline staff of MAX-lab, Lund, Sweden for their kind help with data collection. We also thank Dr Xinhua Ji for critical reading of the manuscript. NR 58 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD NOV PY 2012 VL 68 BP 1460 EP 1467 DI 10.1107/S090744491203466X PN 11 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 023XA UT WOS:000310069500004 PM 23090395 ER PT J AU Soeiro-de-Souza, MG Dias, VV Figueira, ML Forlenza, OV Gattaz, WF Zarate, CA Machado-Vieira, R AF Soeiro-de-Souza, M. G. Dias, V. V. Figueira, M. L. Forlenza, O. V. Gattaz, W. F. Zarate, C. A., Jr. Machado-Vieira, R. TI Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Review DE brain-derived neurotrophic factor; Bcl-2; mitogen-activated protein kinases; neuroprotection; calcium; bipolar disorder; mania; depression ID GLYCOGEN-SYNTHASE KINASE-3; INTRACELLULAR CALCIUM-CONCENTRATION; RETICULUM STRESS-RESPONSE; CHRONIC LITHIUM TREATMENT; WNT SIGNALING PATHWAY; GRAY-MATTER VOLUME; MOOD DISORDERS; PREFRONTAL CORTEX; MITOCHONDRIAL DYSFUNCTION; HUMAN BRAIN AB Soeiro-de-Souza MG, Dias VV, Figueira ML, Forlenza OV, Gattaz WF, Zarate Jr CA, Machado-Vieira R. Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder. Objective: Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. Methods: We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were brain-derived neurotrophic factor,Bcl-2,mitogen-activated protein kinases,neuroprotection,calcium,bipolar disorder,mania, and depression. Results: The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. Conclusion: Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder. C1 [Soeiro-de-Souza, M. G.; Dias, V. V.] Univ Sao Paulo HC FMUSP, Sch Med, Dept & Inst Psychiat, Mood Disorders Unit GRUDA, Sao Paulo, Brazil. [Forlenza, O. V.; Gattaz, W. F.; Machado-Vieira, R.] Univ Sao Paulo HC FMUSP, Sch Med, Dept & Inst Psychiat, Lab Neurosci LIM 27, Sao Paulo, Brazil. [Figueira, M. L.] Univ Lisbon, Hosp Santa Maria, Bipolar Disorder Res Program, Fac Med,FMUL, P-1699 Lisbon, Portugal. [Zarate, C. A., Jr.] NIMH, Sect Neurobiol & Treatment Mood Disorders, Intramural Res Program, Bethesda, MD 20892 USA. RP Machado-Vieira, R (reprint author), Inst Psychiat, LIM 27, Mood Disorders Program, Rua Dr Ovidio Pires de Campos 785,3rd Floor N, BR-05403010 Sao Paulo, Brazil. EM machadovieirar@gmail.com RI Forlenza, Orestes/B-8848-2013; Gattaz, Wagner/C-4456-2012; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural NIH HHS [Z01 MH002828-05, Z99 MH999999] NR 104 TC 34 Z9 34 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD NOV PY 2012 VL 126 IS 5 BP 332 EP 341 DI 10.1111/j.1600-0447.2012.01889.x PG 10 WC Psychiatry SC Psychiatry GA 019CI UT WOS:000309714200003 PM 22676371 ER PT J AU Rice, JP Hartz, SM Agrawal, A Almasy, L Bennett, S Breslau, N Bucholz, KK Doheny, KF Edenberg, HJ Goate, AM Hesselbrock, V Howells, WB Johnson, EO Kramer, J Krueger, RF Kuperman, S Laurie, C Manolio, TA Neuman, RJ Nurnberger, JI Porjesz, B Pugh, E Ramos, EM Saccone, N Saccone, S Schuckit, M Bierut, LJ AF Rice, John P. Hartz, Sarah M. Agrawal, Arpana Almasy, Laura Bennett, Siiri Breslau, Naomi Bucholz, Kathleen K. Doheny, Kimberly F. Edenberg, Howard J. Goate, Alison M. Hesselbrock, Victor Howells, William B. Johnson, Eric O. Kramer, John Krueger, Robert F. Kuperman, Samuel Laurie, Cathy Manolio, Teri A. Neuman, Rosalind J. Nurnberger, John I. Porjesz, Bernice Pugh, Elizabeth Ramos, Erin M. Saccone, Nancy Saccone, Scott Schuckit, Marc Bierut, Laura J. CA GENEVA Consortium TI CHRNB3 is more strongly associated with Fagerstrom Test for Cigarette Dependence-based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results SO ADDICTION LA English DT Article DE CHRNB3; genome-wide association studies; meta-analysis; phenotype definitions ID NATIONALLY REPRESENTATIVE SAMPLE; RECEPTOR GENES; HEAVY SMOKING; LUNG-CANCER; RISK; SUSCEPTIBILITY; ALCOHOLISM; VARIANTS; TOBACCO; SNPS AB Aims Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerstrom Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence. Design Genome-wide association study. Setting Community sample. Participants A total of 3365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2267 were European Americans, 999 were African Americans. Measurements Nicotine dependence defined by FTCD score >= 4, CPD. Findings The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR)= 0.65, P=2.4 X 10-8]. This association was further strengthened in a meta-analysis with a previously published data set (combined P?=?6.7 x 10-16, total n?=?4200). When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (beta?=?-0.08, P?=?0.0004). Conclusions Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci. C1 [Rice, John P.; Hartz, Sarah M.; Agrawal, Arpana; Bucholz, Kathleen K.; Goate, Alison M.; Howells, William B.; Neuman, Rosalind J.; Saccone, Scott; Bierut, Laura J.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Almasy, Laura] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Bennett, Siiri; Laurie, Cathy] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Breslau, Naomi] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Doheny, Kimberly F.; Pugh, Elizabeth] Johns Hopkins Sch Med, Ctr Inherited Dis Res, Baltimore, MD USA. [Edenberg, Howard J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA. [Hesselbrock, Victor] Univ Connecticut, Dept Psychiat, Farmington, CT 06107 USA. [Johnson, Eric O.] Res Triangle Inst Int, Div Hlth Social & Econ Res, Res Triangle Pk, NC USA. [Kramer, John] Univ Iowa, Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. [Kuperman, Samuel] Univ Iowa Hosp, Div Child Psychiat, Iowa City, IA USA. [Manolio, Teri A.; Ramos, Erin M.] NHGRI, Bethesda, MD 20892 USA. [Nurnberger, John I.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA. [Porjesz, Bernice] SUNY, Dept Psychiat & Behav Sci, Brooklyn, NY USA. [Saccone, Nancy] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Schuckit, Marc] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Rice, JP (reprint author), Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. EM john@zork.wustl.edu OI Nurnberger, John/0000-0002-7674-1767; Hartz, Sarah/0000-0002-5429-3799; Edenberg, Howard/0000-0003-0344-9690 FU NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422]; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH [HHSN268200782096C, K02DA021237, UL1RR024992, KL2RR024994, T32MH014677]; NIH from the National Cancer Institute [P01 CA089392]; NIDA [HHSN271200477451C] FX Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423, R01 DA019963). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The Collaborative Genetic Study of Nicotine Dependence (COGEND) project is a collaborative research group and part of the NIDA Genetics Consortium. Subject collection was supported by NIH grant P01 CA089392 (L.J. Bierut) from the National Cancer Institute. Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C (J. Tischfield and J. Rice). Lead investigators directing data collection are L.J. Bierut, N. Breslau, D. Hatsukami, and E.O. Johnson. The authors thank Heidi Kromrei and Tracey Richmond for their assistance in data collection. Additional funding was provided by NIH grants UL1RR024992, K02DA021237, UL1RR024992, KL2RR024994 and T32MH014677. John P. Rice, Scott Saccone, Alison Goate and Laura J. Bierut are listed as inventors on Issued U.S. Patent 8,080,371, 'Markers for Addiction' covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Laura J. Bierut acted as a consultant for Pfizer in 2008. NR 33 TC 31 Z9 32 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 J9 ADDICTION JI Addiction PD NOV PY 2012 VL 107 IS 11 BP 2019 EP 2028 DI 10.1111/j.1360-0443.2012.03922.x PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 017NM UT WOS:000309596900021 PM 22524403 ER PT J AU Boyd, SJ Fang, LJ Medoff, DR Dixon, LB Gorelick, DA AF Boyd, Susan J. Fang, Li Juan Medoff, Deborah R. Dixon, Lisa B. Gorelick, David A. TI METHADONE TREATMENT CENTERS AND CRIME Response SO ADDICTION LA English DT Letter C1 [Boyd, Susan J.; Fang, Li Juan; Medoff, Deborah R.] Univ Maryland, Sch Med, Dept Psychiat, Div Res Serv, Baltimore, MD 21201 USA. [Dixon, Lisa B.] Columbia Univ, Dept Psychiat, Ctr Practice Innovat, New York, NY USA. [Gorelick, David A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Boyd, SJ (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Div Res Serv, Baltimore, MD 21201 USA. EM sboyd@psych.umaryland.eu NR 2 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 J9 ADDICTION JI Addiction PD NOV PY 2012 VL 107 IS 11 BP 2052 EP 2053 DI 10.1111/j.1360-0443.2012.04060.x PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 017NM UT WOS:000309596900026 ER PT J AU Lenoir, M Guillem, K Koob, GF Ahmed, SH AF Lenoir, Magalie Guillem, Karyn Koob, George F. Ahmed, Serge H. TI Drug specificity in extended access cocaine and heroin self-administration SO ADDICTION BIOLOGY LA English DT Article DE Cross-sensitization; cross-tolerance; drug of choice; escalation of drug use; polydrug abuse; self-medication ID NUCLEUS-ACCUMBENS DOPAMINE; SOCIAL-DEFEAT STRESS; KNOCK-OUT MICE; SEEKING BEHAVIOR; INDUCED REINSTATEMENT; ADMINISTERED COCAINE; INTRAVENOUS COCAINE; BASOLATERAL AMYGDALA; EXCITOTOXIC LESIONS; SESSION DURATION AB Increased drug availability can precipitate a rapid escalation of drug consumption in both vulnerable humans and laboratory animals. Drug intake escalation is observed across a broad spectrum of drugs of abuse, including stimulants, opiates, ethanol and phencyclidine. Whether and to what extent the processes underlying escalated levels of drug intake vary across different substances is poorly understood. The present study sought to address this question in rats self-administering both cocaine and herointwo addictive drugs with both common and different neurobiological effects. In experiment 1, we determined how cocaine intake is initially related to heroin intake in non-escalated rats with a limited access to both drugs. In experiment 2, two groups of rats were initially allowed to self-administer either cocaine or heroin for 1 hour per day and then after behavioral stabilization, for 6 hours per day to precipitate drug intake escalation. In each group, dose-injection functions for cocaine and heroin self-administration were generated. In experiment 1, regardless of the dose, rats with a high intake of one drug did not necessarily have a high intake of the alternate drug. In experiment 2, escalated levels of heroin or cocaine self-administration did not generalize to the other drug. This outcome was confirmed in a third drug substitution experiment following different access lengths to cocaine self-administration (i.e. 1, 4 and 8 hours). The processes underlying spontaneous and escalated drug overconsumption appear thus to vary across different drugs of abuse. More research should be devoted in the future to these differences. C1 [Ahmed, Serge H.] Univ Bordeaux 2, CNRS, Inst Malad Neurodegenerat, UMR 5293, F-33076 Bordeaux, France. [Guillem, Karyn; Ahmed, Serge H.] Univ Bordeaux, Inst Malad Neurodegenerat, Bordeaux, France. [Lenoir, Magalie] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD USA. [Koob, George F.; Ahmed, Serge H.] Scripps Res Inst, Comm Neurobiol Addict Disorder, La Jolla, CA 92037 USA. RP Ahmed, SH (reprint author), Univ Bordeaux 2, CNRS, Inst Malad Neurodegenerat, UMR 5293, 146 Rue Leo Saignat, F-33076 Bordeaux, France. EM sahmed@u-bordeaux2.fr RI Ahmed, Serge/D-5236-2014; koob, george/P-8791-2016 FU French Research Council (CNRS); Mission Interministerielle de Lutte contre les Drogues et la Toxicomanie (MILDT); Universite Victor Segalen-Bordeaux 2; Conseil Regional d'Aquitaine FX We thank Anne Fayoux and Stephane Lelgouach for animal care, Pierre Gonzalez for technical assistance, Marie-Helene Bruyeres for administrative assistance, Christian Darrack for his help with data extraction and Alain Labarriere for house-keeping assistance. We also thank Dr Gerald Zernig and the reviewers for their helpful comments on a previous version of the manuscript. This work was supported by the French Research Council (CNRS), the Mission Interministerielle de Lutte contre les Drogues et la Toxicomanie (MILDT), the Universite Victor Segalen-Bordeaux 2 and the Conseil Regional d'Aquitaine. NR 76 TC 6 Z9 6 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD NOV PY 2012 VL 17 IS 6 BP 964 EP 976 DI 10.1111/j.1369-1600.2011.00385.x PG 13 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 023UY UT WOS:000310063100003 PM 21995515 ER PT J AU Moeller, SJ Tomasi, D Woicik, PA Maloney, T Alia-Klein, N Honorio, J Telang, F Wang, GJ Wang, RL Sinha, R Carise, D Astone-Twerell, J Bolger, J Volkow, ND Goldstein, RZ AF Moeller, Scott J. Tomasi, Dardo Woicik, Patricia A. Maloney, Thomas Alia-Klein, Nelly Honorio, Jean Telang, Frank Wang, Gene-Jack Wang, Ruiliang Sinha, Rajita Carise, Deni Astone-Twerell, Janetta Bolger, Joy Volkow, Nora D. Goldstein, Rita Z. TI Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with reduced drug-related choice SO ADDICTION BIOLOGY LA English DT Article DE Cocaine addiction; dopamine; drug Stroop; fMRI; midbrain; thalamus ID ANTERIOR CINGULATE CORTEX; SELF-ADMINISTER COCAINE; BRAIN ACTIVATION; METHAMPHETAMINE ABUSERS; DEPENDENT INDIVIDUALS; DOPAMINE TRANSPORTERS; PROTRACTED ABSTINENCE; COGNITIVE CONTROL; DECISION-MAKING; FRONTAL-CORTEX AB Drug addiction is characterized by dysregulated dopamine neurotransmission. Although dopamine functioning appears to partially recover with abstinence, the specific regions that recover and potential impact on drug seeking remain to be determined. Here we used functional magnetic resonance imaging (fMRI) to study an ecologically valid sample of 15 treatment-seeking cocaine addicted individuals at baseline and 6-month follow-up. At both study sessions, we collected fMRI scans during performance of a drug Stroop task, clinical self-report measures of addiction severity and behavioral measures of cocaine seeking (simulated cocaine choice); actual drug use in between the two study sessions was also monitored. At 6-month follow-up (compared with baseline), we predicted functional enhancement of dopaminergically innervated brain regions, relevant to the behavioral responsiveness toward salient stimuli. Consistent with predictions, whole-brain analyses revealed responses in the midbrain (encompassing the ventral tegmental area/substantia nigra complex) and thalamus (encompassing the mediodorsal nucleus) that were higher (and more positively correlated) at follow-up than baseline. Increased midbrain activity from baseline to follow-up correlated with reduced simulated cocaine choice, indicating that heightened midbrain activations in this context may be marking lower approach motivation for cocaine. Normalization of midbrain function at follow-up was also suggested by exploratory comparisons with active cocaine users and healthy controls (who were assessed only at baseline). Enhanced self-control at follow-up was suggested by a trend for the commonly hypoactive dorsal anterior cingulate cortex to increase response during a drug-related context. Together, these results suggest that fMRI could be useful in sensitively tracking follow-up outcomes in drug addiction. C1 [Moeller, Scott J.; Woicik, Patricia A.; Maloney, Thomas; Alia-Klein, Nelly; Wang, Gene-Jack; Wang, Ruiliang; Bolger, Joy; Goldstein, Rita Z.] Brookhaven Natl Lab, Upton, NY 11973 USA. [Tomasi, Dardo; Telang, Frank; Volkow, Nora D.] NIAAA, Bethesda, MD USA. [Honorio, Jean] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Sinha, Rajita] Yale Univ, Sch Med, New Haven, CT USA. [Carise, Deni] Phoenix House Fdn Inc, New York, NY USA. [Carise, Deni] Univ Penn, Philadelphia, PA 19104 USA. [Astone-Twerell, Janetta] Samaritan Village Inc, Briarwood, NY USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, 30 Bell Ave,Bldg 490, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Tomasi, Dardo/J-2127-2015; Moeller, Scott/L-5549-2016 OI Moeller, Scott/0000-0002-4449-0844 FU National Institute on Drug Abuse [1R01DA023579, 1F32DA030017-01]; U.S. Department of Energy [DE-AC02-98CHI-886] FX This study was supported by grants from the National Institute on Drug Abuse (to R.Z.G.: 1R01DA023579; to S.J.M.: 1F32DA030017-01).; Notice: This manuscript has been authored by Brookhaven Science Associates, LLC, under Contract No. DE-AC02-98CHI-886 with the U.S. Department of Energy. The United States Government retains, and the publisher, by accepting the article for publication, acknowledges, a world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for the United States Government purposes. NR 65 TC 18 Z9 18 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD NOV PY 2012 VL 17 IS 6 BP 1013 EP 1025 DI 10.1111/j.1369-1600.2012.00440.x PG 13 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 023UY UT WOS:000310063100008 PM 22458423 ER PT J AU Hoofnagle, JH AF Hoofnagle, J. H. TI Letter: renal tubular dysfunction during nucleotide analogue therapy in chronic hepatitis B - author's reply SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter C1 NIDDKD, Liver Dis Branch, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDKD, Liver Dis Branch, Bethesda, MD 20892 USA. EM hoofnaglej@extra.niddk.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD NOV PY 2012 VL 36 IS 10 BP 993 EP 993 DI 10.1111/apt.12074 PG 1 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 023VN UT WOS:000310065000015 ER PT J AU Lee, RWY McGready, J Conley, SK Yanjanin, NM Nowaczyk, MJM Porter, FD AF Lee, Ryan W. Y. McGready, John Conley, Sandra K. Yanjanin, Nicole M. Nowaczyk, Malgorzata J. M. Porter, Forbes D. TI Growth charts for individuals with Smith-Lemli-Opitz syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Smith-Lemli-Opitz Syndrome; SLOS; growth; height; weight; head circumference; anthropometry ID DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; CARRIER FREQUENCY; REDUCTASE GENE; SYNDROME SLOS; SUPPLEMENTATION; MUTATIONS; SIMVASTATIN; CHILDREN; TRIAL; DHCR7 AB SmithLemliOpitz syndrome (SLOS) is a rare multiple congenital anomaly neurodevelopmental syndrome of impaired cholesterol synthesis. Growth restriction and developmental delay are very common clinical manifestations of SLOS. The degree, etiology, and consequences of growth restriction in SLOS remain an area of limited knowledge to the scientific community. There have been no studies describing the growth parameters and providing reference growth charts for individuals with SLOS. Our longitudinal data from 78 patients between the ages of 0.1 and 16 years with SLOS show a growth restriction of about two standard deviations below the Centers for Disease Control (CDC) norms for age. This study represents comprehensive anthropometric data from the largest cohort available, and proposes growth charts for widespread use in the management and study of individuals with SLOS. (c) 2012 Wiley Periodicals, Inc. C1 [Lee, Ryan W. Y.] Kennedy Krieger Inst, Baltimore, MD 21205 USA. [Lee, Ryan W. Y.; Conley, Sandra K.; Yanjanin, Nicole M.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Lee, Ryan W. Y.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [McGready, John] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Nowaczyk, Malgorzata J. M.] McMaster Univ, Med Ctr, Hamilton, ON, Canada. RP Lee, RWY (reprint author), Kennedy Krieger Inst, 716 N Broadway St, Baltimore, MD 21205 USA. EM leer@kennedykrieger.org FU Eunice Kennedy Shriver National Institute of Health; Institute for Clinical and Translational Research at Johns Hopkins University FX This work is supported by the Intramural research program of the Eunice Kennedy Shriver National Institute of Health, and the Institute for Clinical and Translational Research at Johns Hopkins University. NR 27 TC 4 Z9 4 U1 0 U2 0 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 NOV PY 2012 VL 158A IS 11 BP 2707 EP 2713 DI 10.1002/ajmg.a.35376 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 023XT UT WOS:000310071700012 PM 22615010 ER PT J AU Fu, R Yanjanin, NM Elrick, MJ Ware, C Lieberman, AP Porter, FD AF Fu, Rao Yanjanin, Nicole M. Elrick, Matthew J. Ware, Christopher Lieberman, Andrew P. Porter, Forbes D. TI Apolipoprotein E genotype and neurological disease onset in Niemann-Pick disease, type C1 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE neurodegenerative disease; lysosomal storage disease; apolipoprotein E; tau ID ALZHEIMERS-DISEASE; NEUROFIBRILLARY TANGLES; NEURITIC PLAQUES; GENE; APOE; ALLELE; ASSOCIATION; METABOLISM; NEURONS; PROTEIN AB NiemannPick disease, type C1 (NPC1) is a lipid storage disorder that results in progressive neurological impairment. The NPC1 phenotype is extremely variable and at the individual level is likely influenced by other genetic traits. In addition to residual function of NPC1 protein, we hypothesize that modifier genes, as frequently observed with other autosomal recessive diseases, influence the NPC phenotype. The NPC1 phenotype includes progressive dementia, and the NPC pathology has some overlap with the pathology of Alzheimer disease (AD). Thus, we examined apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) polymorphisms in a cohort of 15 NPC1 patients with well characterized longitudinal disease progression. Although we did not find any correlations between disease severity and tau polymorphisms, we found significant associations between ApoE polymorphisms and phenotypic severity. Specifically, ApoE4 and ApoE2 alleles were associated, respectively, with increased and decreased disease severity in this cohort of NPC1 patients. These data support the hypothesis that ApoE may play a role in modulating NPC1 neuropathology. (c) 2012 Wiley Periodicals, Inc. C1 [Fu, Rao; Yanjanin, Nicole M.; Porter, Forbes D.] NICHD, Sect Mol Dysmorphol, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Fu, Rao] Peking Univ, Sch Basic Med Sci, Beijing 100871, Peoples R China. [Elrick, Matthew J.; Ware, Christopher; Lieberman, Andrew P.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. RP Porter, FD (reprint author), NICHD, Sect Mol Dysmorphol, Program Dev Endocrinol & Genet, NIH,DHHS, Bld 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov FU NIH [NS063967, NS065662]; NICHD; Office of Rare Disease; Ara Parseghian Medical Research Foundation; Dana Angel's Research Trust FX Grant sponsor: NIH; Grant numbers: NS063967, NS065662.; This work was supported by the intramural research program of NICHD and a Bench-to-Bedside award from the Office of Rare Disease. This work was also supported by grants from the NIH (NS063967 to A. P. L. and NS065662 to M.J.E.). We acknowledge the support from the Ara Parseghian Medical Research Foundation and Dana Angel's Research Trust. NR 26 TC 12 Z9 12 U1 0 U2 1 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 NOV PY 2012 VL 158A IS 11 BP 2775 EP 2780 DI 10.1002/ajmg.a.35395 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 023XT UT WOS:000310071700022 PM 23023945 ER PT J AU Hooten, NN Ejiogu, N Zonderman, AB Evans, MK AF Hooten, Nicole Noren Ejiogu, Ngozi Zonderman, Alan B. Evans, Michele K. TI Association of Oxidative DNA Damage and C-Reactive Protein in Women at Risk for Cardiovascular Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE 8-oxo-7,8-dihydro-2 ' deoxyguanosine; DNA damage; oxidative stress; C-reactive protein; inflammation; women's health; cardiovascular disease ID CALCIUM-CHANNEL BLOCKER; BREAK REPAIR CAPACITY; DIABETIC-NEPHROPATHY; HEART-DISEASE; COMET ASSAY; IN-VIVO; STRESS; ATHEROSCLEROSIS; CELLS; INTERLEUKIN-6 AB Objective-The aim of the current study was to examine the relationship between clinical markers of inflammation and 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxodG), an oxidative stress marker, in middle-aged women drawn from the HANDLS study, a longitudinal epidemiological study. Methods and Results-We examined commonly assayed markers of inflammation, the DNA base adduct 8-oxodG, a marker of oxidative stress, and cardiovascular risk factors in a cohort of women matched on age and race in 3 groups (n=39 per group) who had low (<3 mg/L) high-sensitivity C-reactive protein (hsCRP), mid (>3-20 mg/L), and high (>20 mg/L) hsCRP. We found a significant relationship between hsCRP level and the oxidative stress marker, 8-oxodG. 8-oxodG was positively correlated with systolic blood pressure, pulse pressure, and interleukin-23. hsCRP was associated with obesity variables, high-density lipoprotein, serum insulin levels, interleukin-12p70 and intracellular adhesion molecule-1. Incubation of primary human endothelial cells with hsCRP generated reactive oxygen species in vitro. Furthermore, hsCRP specifically induced DNA base lesions, but not other forms of DNA damage, including single and double strand breaks. Conclusion-These data suggest that in women 8-oxodG is associated with hsCRP and is independently related to select cardiovascular risk factors. Our data in women suggest that hsCRP may contribute to cardiovascular disease by increasing oxidative stress. (Arterioscler Thromb Vasc Biol. 2012;32:2776-2784.) C1 [Hooten, Nicole Noren; Ejiogu, Ngozi; Zonderman, Alan B.; Evans, Michele K.] NIA, Hlth Dispar Res Sect, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIA, Hlth Dispar Res Sect, NIH, Baltimore, MD 21224 USA. EM me42v@nih.gov OI Noren Hooten, Nicole/0000-0002-1683-3838; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 53 TC 12 Z9 12 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2012 VL 32 IS 11 BP 2776 EP + DI 10.1161/ATVBAHA.112.300276 PG 15 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 023TP UT WOS:000310058900033 ER PT J AU Ioannou, C Talbot, K Ohuma, E Sarris, I Villar, J Conde-Agudelo, A Papageorghiou, AT AF Ioannou, C. Talbot, K. Ohuma, E. Sarris, I. Villar, J. Conde-Agudelo, A. Papageorghiou, A. T. TI Systematic review of methodology used in ultrasound studies aimed at creating charts of fetal size SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Review DE Biometry; fetal growth; guideline; methodology; quality; review; ultrasound ID ABDOMINAL CIRCUMFERENCE MEASUREMENTS; INTRAUTERINE GROWTH RESTRICTION; BIPARIETAL DIAMETER; FEMUR LENGTH; MENSTRUAL AGE; NORMAL-PREGNANCY; HEAD CIRCUMFERENCE; LIMB BONES; SINGLETON PREGNANCIES; CRITICAL REEVALUATION AB Please cite this paper as: Ioannou C, Talbot K, Ohuma E, Sarris I, Villar J, Conde-Agudelo A, Papageorghiou A. Systematic review of methodology used in ultrasound studies aimed at creating charts of fetal size. BJOG 2012;119:14251439. Background Reliable ultrasound charts are necessary for the prenatal assessment of fetal size, yet there is a wide variation of methodologies for the creation of such charts. Objective To evaluate the methodological quality of studies of fetal biometry using a set of predefined quality criteria of study design, statistical analysis and reporting methods. Search strategy Electronic searches in MEDLINE, EMBASE and CINAHL, and references of retrieved articles. Selection criteria Observational studies whose primary aim was to create ultrasound size charts for bi-parietal diameter, head circumference, abdominal circumference and femur length in fetuses from singleton pregnancies. Data collection and analysis Studies were scored against a predefined set of independently agreed methodological criteria and an overall quality score was given to each study. Multiple regression analysis between quality scores and study characteristics was performed. Main results Eighty-three studies met the inclusion criteria. The highest potential for bias was noted in the following fields: Inclusion/exclusion criteria, as none of the studies defined a rigorous set of antenatal or fetal conditions which should be excluded from analysis; Ultrasound quality control measures, as no study demonstrated a comprehensive quality assurance strategy; and Sample size calculation, which was apparent in six studies only. On multiple regression analysis, there was a positive correlation between quality scores and year of publication: quality has improved with time, yet considerable heterogeneity in study methodology is still observed today. Conclusions There is considerable methodological heterogeneity in studies of fetal biometry. Standardisation of methodologies is necessary in order to make correct interpretations and comparisons between different charts. A checklist of recommended methodologies is proposed. C1 [Ioannou, C.; Talbot, K.; Ohuma, E.; Sarris, I.; Villar, J.; Papageorghiou, A. T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford OX1 2JD, England. [Villar, J.; Papageorghiou, A. T.] Univ Oxford, Green Templeton Coll, Oxford Maternal & Perinatal Hlth Inst, Oxford OX1 2JD, England. [Conde-Agudelo, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Conde-Agudelo, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. RP Papageorghiou, AT (reprint author), John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Oxford OX3 9DU, England. EM aris.papageorghiou@obs-gyn.ox.ac.uk FU INTERGROWTH-21st from the Bill & Melinda Gates Foundation [49038]; Oxford Partnership Comprehensive Biomedical Research Centre; Department of Health NIHR Biomedical Research Centres FX This project was supported by INTERGROWTH-21st (Grant ID# 49038) from the Bill & Melinda Gates Foundation to the University of Oxford, for which we are very grateful. CI and ATP are supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health NIHR Biomedical Research Centres funding scheme. NR 108 TC 29 Z9 30 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 J9 BJOG-INT J OBSTET GY JI BJOG PD NOV PY 2012 VL 119 IS 12 BP 1425 EP 1439 DI 10.1111/j.1471-0528.2012.03451.x PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 019OP UT WOS:000309749500002 PM 22882780 ER PT J AU Reeve, BB Stover, AM Alfano, CM Smith, AW Ballard-Barbash, R Bernstein, L McTiernan, A Baumgartner, KB Piper, BF AF Reeve, Bryce B. Stover, Angela M. Alfano, Catherine M. Smith, Ashley Wilder Ballard-Barbash, Rachel Bernstein, Leslie McTiernan, Anne Baumgartner, Kathy B. Piper, Barbara F. TI The Piper Fatigue Scale-12 (PFS-12): psychometric findings and item reduction in a cohort of breast cancer survivors SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Review DE Fatigue; Breast cancer survivors; Patient-reported outcomes; Piper Fatigue Scale; Psychometrics ID QUALITY-OF-LIFE; FIT INDEXES; DEPENDENCE; IMPACT; BANKS AB Brief, valid measures of fatigue, a prevalent and distressing cancer symptom, are needed for use in research. This study's primary aim was to create a shortened version of the revised Piper Fatigue Scale (PFS-R) based on data from a diverse cohort of breast cancer survivors. A secondary aim was to determine whether the PFS captured multiple distinct aspects of fatigue (a multidimensional model) or a single overall fatigue factor (a unidimensional model). Breast cancer survivors (n = 799; stages in situ through IIIa; ages 29-86 years) were recruited through three SEER registries (New Mexico, Western Washington, and Los Angeles, CA) as part of the Health, Eating, Activity, and Lifestyle (HEAL) study. Fatigue was measured approximately 3 years post-diagnosis using the 22-item PFS-R that has four subscales (Behavior, Affect, Sensory, and Cognition). Confirmatory factor analysis was used to compare unidimensional and multidimensional models. Six criteria were used to make item selections to shorten the PFS-R: scale's content validity, items' relationship with fatigue, content redundancy, differential item functioning by race and/or education, scale reliability, and literacy demand. Factor analyses supported the original 4-factor structure. There was also evidence from the bi-factor model for a dominant underlying fatigue factor. Six items tested positive for differential item functioning between African-American and Caucasian survivors. Four additional items either showed poor association, local dependence, or content validity concerns. After removing these 10 items, the reliability of the PFS-12 subscales ranged from 0.87 to 0.89, compared to 0.90-0.94 prior to item removal. The newly developed PFS-12 can be used to assess fatigue in African-American and Caucasian breast cancer survivors and reduces response burden without compromising reliability or validity. This is the first study to determine PFS literacy demand and to compare PFS-R responses in African-Americans and Caucasian breast cancer survivors. Further testing in diverse populations is warranted. C1 [Reeve, Bryce B.] Univ N Carolina, Dept Hlth Policy & Management, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Reeve, Bryce B.; Stover, Angela M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Stover, Angela M.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Chapel Hill, NC 27599 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Smith, Ashley Wilder; Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Div Canc Etiol, Dept Populat Sci, Beckman Res Inst, Duarte, CA 91010 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Prevent Ctr, Seattle, WA 98109 USA. [Baumgartner, Kathy B.] Univ Louisville, Louisville, KY 40292 USA. [Piper, Barbara F.] Univ Arizona, Sch Nursing, Scottsdale, AZ 85259 USA. RP Reeve, BB (reprint author), Univ N Carolina, Dept Hlth Policy & Management, Gillings Sch Global Publ Hlth, 1101-D McGavran Greenberg Hall,135 Dauer Dr,CB 74, Chapel Hill, NC 27599 USA. EM bbreeve@email.unc.edu FU National Cancer Institute [HHSN261201000642P] FX Dr. Reeve's work was supported under a National Cancer Institute contract: HHSN261201000642P. NR 37 TC 13 Z9 13 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2012 VL 136 IS 1 BP 9 EP 20 DI 10.1007/s10549-012-2212-4 PG 12 WC Oncology SC Oncology GA 022FF UT WOS:000309940300002 PM 22933027 ER PT J AU Bertrand, KA Eliassen, AH Hankinson, SE Gierach, GL Xu, X Rosner, B Ziegler, RG Tamimi, RM AF Bertrand, Kimberly A. Eliassen, A. Heather Hankinson, Susan E. Gierach, Gretchen L. Xu, Xia Rosner, Bernard Ziegler, Regina G. Tamimi, Rulla M. TI Urinary estrogens and estrogen metabolites and mammographic density in premenopausal women SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Estradiol; Estrogen metabolites; Mammographic density; Breast cancer; Epidemiology ID BREAST-CANCER RISK; CHROMATOGRAPHY-MASS SPECTROMETRY; POSTMENOPAUSAL WOMEN; PARENCHYMAL PATTERNS; ENDOGENOUS ESTROGEN; UNITED-STATES; REPRODUCIBILITY; METAANALYSIS; AREA AB Mammographic density is a strong and independent risk factor for breast cancer and is considered an intermediate marker of risk. The major predictors of premenopausal mammographic density, however, have yet to be fully elucidated. To test the hypothesis that urinary estrogen metabolism profiles are associated with mammographic density, we conducted a cross-sectional study among 352 premenopausal women in the Nurses' Health Study II (NHSII). We measured average percent mammographic density using a computer-assisted method. In addition, we assayed 15 estrogens and estrogen metabolites (jointly termed EM) in luteal-phase urine samples. We used multivariable linear regression to quantify the association of average percent density with quartiles of each individual EM as well as the sum of all EM (total EM), EM groups defined by metabolic pathway, and pathway ratios. In multivariable models controlling for body mass index and other predictors of breast density, women in the top quartile of total EM had an average percent density 3.4 percentage points higher than women in the bottom quartile (95 % confidence interval: -1.1, 8.0; p trend = 0.08). A non-significant positive association was noted for the 2-hydroxylation pathway catechols (breast density was 4.0 percentage points higher in top vs. bottom quartile; p trend = 0.06). In general, we observed no associations with parent estrogens or the 4- or 16-hydroxylation pathways or pathway ratios. These results suggest that urinary luteal estrogen profiles are not strongly associated with premenopausal mammographic density. If these profiles are associated with breast cancer risk, they may not act through influences on breast density. C1 [Bertrand, Kimberly A.; Hankinson, Susan E.; Tamimi, Rulla M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bertrand, Kimberly A.; Eliassen, A. Heather; Hankinson, Susan E.; Rosner, Bernard; Tamimi, Rulla M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bertrand, Kimberly A.; Eliassen, A. Heather; Hankinson, Susan E.; Rosner, Bernard; Tamimi, Rulla M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Gierach, Gretchen L.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Xu, Xia] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21701 USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Bertrand, KA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM kbertran@hsph.harvard.edu RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Breast Cancer Research Foundation; National Institutes of Health, National Cancer Institute (NCI) [CA124865, CA67262, CA50385]; Intramural Research Program of the NCI Division of Cancer Epidemiology and Genetics; federal funds of the NCI [HHSN261200800001E]; Nutritional Epidemiology of Cancer Training Grant [R25 CA098566] FX We thank Barbara DeSouza and Divya Prithviraj for their assistance with data collection. This work was supported in part by the Breast Cancer Research Foundation, the National Institutes of Health, National Cancer Institute (NCI) (CA124865, CA67262, and CA50385), the Intramural Research Program of the NCI Division of Cancer Epidemiology and Genetics, and with federal funds of the NCI awarded under Contract HHSN261200800001E to SAIC-Frederick. K.A.B. was supported by the Nutritional Epidemiology of Cancer Training Grant (R25 CA098566). The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services; nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 35 TC 11 Z9 11 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2012 VL 136 IS 1 BP 277 EP 287 DI 10.1007/s10549-012-2240-0 PG 11 WC Oncology SC Oncology GA 022FF UT WOS:000309940300026 PM 23053640 ER PT J AU Stevens, KN Wang, XS Fredericksen, Z Pankratz, VS Greene, MH Andrulis, IL Thomassen, M Caligo, M Nathanson, KL Jakubowska, A Osorio, A Hamann, U Godwin, AK Stoppa-Lyonnet, D Southey, M Buys, SS Singer, CF Hansen, TVO Arason, A Offit, K Piedmonte, M Montagna, M Imyanitov, E Tihomirova, L Sucheston, L Beattie, M Neuhausen, SL Szabo, CI Simard, J Spurdle, AB Healey, S Chen, XQ Rebbeck, TR Easton, DF Chenevix-Trench, G Antoniou, AC Couch, FJ AF Stevens, Kristen N. Wang, Xianshu Fredericksen, Zachary Pankratz, Vernon S. Greene, Mark H. Andrulis, Irene L. Thomassen, Mads Caligo, Maria Nathanson, Katherine L. Jakubowska, Anna Osorio, Ana Hamann, Ute Godwin, Andrew K. Stoppa-Lyonnet, Dominique Southey, Melissa Buys, Saundra S. Singer, Christian F. Hansen, Thomas V. O. Arason, Adalgeir Offit, Kenneth Piedmonte, Marion Montagna, Marco Imyanitov, Evgeny Tihomirova, Laima Sucheston, Lara Beattie, Mary Neuhausen, Susan L. Szabo, Csilla I. Simard, Jacques Spurdle, Amanda B. Healey, Sue Chen, Xiaoqing Rebbeck, Timothy R. Easton, Douglas F. Chenevix-Trench, Georgia Antoniou, Antonis C. Couch, Fergus J. CA Sweden SWE-BRCA HEreditary Breast Ovarian Canc Grp GC HBOC CONSIT Team KConFab TI Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE BRCA1; BRCA2; Genetic modifier; Association study ID COMMON VARIANTS; ALLELES; COHORT AB Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 x 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations. C1 [Wang, Xianshu; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Coll Med, Rochester, MN 55905 USA. [Stevens, Kristen N.; Fredericksen, Zachary; Pankratz, Vernon S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Greene, Mark H.] US Natl Canc Inst, Clin Genet Branch, Rockville, MD USA. [Andrulis, Irene L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet, New York, NY 10029 USA. [Andrulis, Irene L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Caligo, Maria] Univ Pisa, Dept Oncol, Div Surg Mol & Ultrastruct Pathol, Pisa, Italy. [Nathanson, Katherine L.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Jakubowska, Anna] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Osorio, Ana] Spanish Natl Canc Res Ctr, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain. [Osorio, Ana] Spanish Network Rare Dis CIBERER, Madrid, Spain. [Hamann, Ute] Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany. [Godwin, Andrew K.] Kansas Med Ctr, Dept Pathol & Lab Med, Kansas City, KS USA. [Stoppa-Lyonnet, Dominique] Univ Paris 05, INSERM, U509, Serv Genet Oncol,Inst Curie, Paris, France. [Stoppa-Lyonnet, Dominique] Federat Natl Ctr Lutte Canc, GEMO Study Canc Genet Network Grp Genet & Canc, Paris, France. [Southey, Melissa] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic, Australia. [Buys, Saundra S.] Univ Utah, Dept Oncol Sci, Huntsman Canc Inst, Salt Lake City, UT USA. [Singer, Christian F.] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Ctr Genom Med, Rigshosp, Copenhagen, Denmark. [Arason, Adalgeir] Landspitali LSH, Dept Pathol, Reykjavik, Iceland. [Arason, Adalgeir] Univ Iceland, Fac Med, Reykjavik, Iceland. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Montagna, Marco] Ist Oncol Veneto IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Imyanitov, Evgeny] NN Petrov Oncol Res Inst, Mol Oncol Lab, St Petersburg, Russia. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Sucheston, Lara] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Beattie, Mary] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Szabo, Csilla I.] Univ Delaware, Dept Biol Sci, Newark, DE USA. [Spurdle, Amanda B.; KConFab] Peter MacCallum Canc Ctr, Kathleen Cuningham Consortium Res Familial Breast, Melbourne, Vic, Australia. [Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Spurdle, Amanda B.; Healey, Sue; Chen, Xiaoqing; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Rebbeck, Timothy R.] Belfast City Hosp, No Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland. [Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Simard, Jacques] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Andrulis, Irene L.] Canc Care Ontario, Ontario Canc Genet Network OCGN, Toronto, ON, Canada. [Caligo, Maria] Pisa Univ Hosp, Pisa, Italy. [Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Singer, Christian F.] Med Univ Vienna, Comprehens Canc Ctr MUW, Vienna, Austria. RP Couch, FJ (reprint author), Mayo Clin, Dept Lab Med & Pathol, Coll Med, 200 1st St SW, Rochester, MN 55905 USA. EM Couch@mayo.edu RI montagna, marco/E-2225-2012; Andrulis, Irene/E-7267-2013; Osorio, Ana/I-4324-2014; Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; Spurdle, Amanda/A-4978-2011 OI montagna, marco/0000-0002-4929-2150; Osorio, Ana/0000-0001-8124-3984; Ehrencrona, Hans/0000-0002-5589-3622; Arason, Adalgeir/0000-0003-0480-886X; Nordling, Margareta/0000-0002-4047-4994; Nathanson, Katherine/0000-0002-6740-0901; Spurdle, Amanda/0000-0003-1337-7897 FU Cancer Research UK [C12292/A11174, C1287/A10118]; National Institutes of Health [CA128978]; Komen Foundation for the Cure; Breast Cancer Research Foundation (BCRF); NIH [CA128978, CA74415, R01-CA083855, R01-CA9677, CA122340]; City of Hope Clinical Cancer Genetics Community Network; Hereditary Cancer Research Registry from the National Cancer Institute [RC4CA153828]; Office of the Director, National Institutes of Health; Susan G. Komen for the Cure; Mayo Clinic Breast Cancer SPORE [P50-CA116201]; Fondazione Italiana per la Ricerca sul Cancro; Associazione Italiana per la Ricerca sul Cancro [8713]; Italian Ministry of Health; Italian Ministry of Education, University and Research; Fondazione IRCCS Istituto Nazionale Tumori; Mayo Rochester Early Career Development Award for Non-Clinician Scientists; Grant Agency of the Czech Republic [GP301/08/P103]; Fund for Scientific Research Flanders (FWO) [1.5.150.07]; Ghent University [12051203]; Fund for Scientific Research of Flanders (FWO-Vlaanderen); Vlaamse Liga tegen Kanker through a grant of the Foundation Emmanuel van der Schueren; Ministry of Health [CR-MZ0 MOU 2005]; Intramural Research Program of the US National Cancer Institute; Israel Cancer Association (ICA); Cancer Genetics Network; Marjorie Cohen Foundation; Fundacion Mutua Madrilena; Asociacion Espanola Contra el Cancer; Spanish Ministry of Science and Innovation [FIS PI08 1120, FIS 09/00859, RD06/0020/0021]; Basque Foundation for Health Innovation and Research (BIOEF) [BIO07/CA/006]; DKFZ; Cancer Research-UK [C1287/A10118, C1287/A8874, C8197/A10123]; Dutch Cancer Society [NKI19981854, NKI2004-3088, NKI2007-3756]; NWO [91109024]; Pink Ribbon Grant [110005]; BBMRI Grant [CP46/NWO]; National Cancer Institute, National Institutes of Health [RFACA-06-503]; Ligue National Contre le Cancer; Association for International Cancer Research [AICR-07-0454]; Association "Le cancer du sein, parlons-en!" Award; National Cancer Institute [CA 27469]; GOG Tissue Bank [CA 27469]; Gynecologic Oncology Group Statistical and Data Center [CA 37517, CA 101165]; OSU Comprehensive Cancer Center; Ministero dell'Universita e della Ricerca; Ministero della Salute; Alleanza Contro il Cancro; Russian Foundation for Basic Research [08-04-00369-a, 09-04-90402, 10-04-92110-a]; Commission of the European Communities [PITN-GA-2009-238132]; Royal Society International Joint Grant [JP090615]; Latvian Science Council Grant [10.0010.08]; American Cancer Society Early Detection Professorship; Entertainment Industry Foundation; German Cancer Aid [107054]; Helsinki University Central Hospital Research Fund, Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; Canadian Institutes of Health Research; Canadian Breast Cancer Research Alliance [019511]; NHMRC [145684, 288704, 454508]; National Breast Cancer Foundation; Cancer Australia [628333]; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Councils of Tasmania; Cancer Councils of South Australia; Cancer Foundation of Western Australia; Landspitali University Hospital Research Fund; Icelandic association; Sandra Taub Research Fund of the BCRF; [NO2-CP-11019-50]; [N02-CP-65504]; [PBZ_ KBN_122/P05/2004] FX This study, by the Consortium of Investigators of Modifiers of BRCA1/2, was supported by grants from Cancer Research UK and by National Institutes of Health Grant CA128978, the Komen Foundation for the Cure and the Breast Cancer Research Foundation and by grants from Cancer Research UK (C12292/A11174 and C1287/A10118). All study-specific grants are: Cancer Research UK provided financial support for this work. A. C. A. is a Senior Cancer Research UK Cancer Research Fellow. D. F. E. is Cancer Research UK Principal Research Fellow. S.L.N., the Morris and Horowitz Families Endowed Professor, and Y.C.D. were supported by NIH CA74415. The MAGIC study is supported by NIH Grants R01-CA083855 and R01-CA9677. City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J.N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The Mayo Clinic study was supported in part by the Breast Cancer Research Foundation (BCRF), a grant from Susan G. Komen for the Cure, the Mayo Clinic Breast Cancer SPORE (P50-CA116201), and NIH Grants CA122340 and CA128978 to F.J.C. KNS is a Mayo Cancer Genetic Epidemiology Training Program (CA92049-09) fellow. The Italian study (CONsorzio Studi Italiani Tumori Ereditari Alla Mammella, CONSIT TEAM) is funded in part by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumors"), Associazione Italiana per la Ricerca sul Cancro (8713), Italian Ministry of Health (Extraordinary National Cancer Program 2006 "Alleanza contro il Cancro" and "Progetto Tumori Femminili"), Italian Ministry of Education, University and Research (Prin 2008) and by funds from Italian citizens who allocated the 5 9 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000"). CONSIT TEAM acknowledges Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Bernardo Bonanni and Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy; Riccardo Dolcetti of the Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy; Liliana Varesco of the AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Laura Ottini of the University "La Sapienza," Rome, Italy; Laura Papi of the University of Florence, Florence, Italy; and the personnel of the Cogentech, Cancer Genetic Test Laboratory, Milan, Italy. C. I. S. is supported by the Mayo Rochester Early Career Development Award for Non-Clinician Scientists. We acknowledge the contributions of Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic) and the support of the Grant Agency of the Czech Republic, project No. GP301/08/P103 (to M.Z.). We acknowledge the contribution of Kim De Leeneer and Anne De Paepe. This research was supported by Grant 1.5.150.07 from the Fund for Scientific Research Flanders (FWO) to Kathleen Claes and by Grant 12051203 from the Ghent University to Anne De Paepe. Bruce Poppe is Senior Clinical Investigator of the Fund for Scientific Research of Flanders (FWO-Vlaanderen). Kim De Leeneer is supported by the Vlaamse Liga tegen Kanker through a grant of the Foundation Emmanuel van der Schueren. L. F., Machackova Eva, and Lukesova Miroslava's are supported through the Ministry of Health Grant CR-MZ0 MOU 2005. The research of P. L. Mai and M. H.; Greene was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. Genotyping of NCI DNA samples was performed by NCI's Core Genotyping Facility, Gaithersburg, MD. We thank the investigators of the Australia New Zealand Gynaecological Oncology Group (ANZGOG). Ontario Cancer Genetics Network (OCGN) thanks Mona Gill, Lucine Collins, Nalan Gokgoz, Teresa Selander, Nayana Weerasooriya, and members of the Ontario Cancer Genetics Network for their contributions to the study. The SMC study was supported in part by the Israel Cancer Association (ICA). SWE-BRCA acknowledge collaborators Per Karlsson, Margareta Nordling, Annika Bergman, and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Sigrun Liedgren, Linkoping University Hospital; Niklas Loman, Ha kan Olsson, Ulf Kristoffersson, Helena Jernstrom, Katja Harbst, and Karin Henriksson, Lund University Hospital; Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, and Gisela Barbany-Bustinza, Stockholm, Karolinska University Hospital; Henrik Gro nberg, Eva-Lena Stattin, and Monica Emanuelsson, Umea University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell, and Niklas Dahl, Uppsala University Hospital. University of Pennsylvania (UPENN) was supported by Breast Cancer Research Foundation (to K. L. N.); Cancer Genetics Network (to S. M. D.), Marjorie Cohen Foundation (to S. M. D.). IHCC was supported by Grant PBZ_ KBN_122/P05/2004. Spanish National Cancer Center (CNIO) thanks R. M. Alonso, G Pita, and R. M. Milne for their assistance. This study was partially supported by Fundacion Mutua Madrilena, Asociacion Espanola Contra el Cancer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120). Funded in part by the Basque Foundation for Health Innovation and Research (BIOEF): BIO07/CA/006. The DKFZ study was supported by the DKFZ. Douglas F. Easton is the PI of the EMBRACE study and acknowledges collaborators: North of Scotland Regional Genetics Service, Aberdeen: Helen Gregory, Zosia Miedzybrodzka. West Midlands Regional Clinical Genetics Service, Birmingham: Carole McKeown, Laura Boyes. South West Regional Genetics Service, Bristol: Alan Donaldson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark Rogers, Emma McCann. St James's Hospital, Dublin & National Center for Medical Genetics, Dublin: David Barton. Peninsula Clinical Genetics Service. Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman. West of Scotland Regional Genetics Service, Glasgow: Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Carol Chu, Tim Bishop, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: Felicity Holt. North East Thames Regional Genetics Service, NE Thames: Alison Male, Lucy Side, Anne Robinson. Nottingham Center for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber. Oxford Regional Genetics Service, Oxford: Diane McLeod, Dorothy Halliday, Sarah Durrell, Barbara Stayner.; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Sheila Goff, Glen Brice, Lizzie Winchester. Wessex Clinical Genetics Service. Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Emma Tyler, Donna McBride. D. F. E., S. P., M. C., D. F. and C. O. are funded by Cancer Research-UK Grants C1287/A10118 and C1287/A8874. D. C. is supported by Cancer Research-UK Grant C8197/A10123. HEBON stands for The Hereditary Breast and Ovarian Cancer Research Group Netherlands and consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M. A. Rookus, F. B. L. Hogervorst, F. E. van Leeuwen, S. Verhoef, M. K. Schmidt, J. L. de Lange; Erasmus Medical Center, Rotterdam, NL: J. M. Collee, A. M. W. van den Ouweland, M. J. Hooning, C. Seynaeve, C. H. M. van Deurzen; Leiden University Medical Center, NL: C. J. van Asperen, J. T. Wijnen, R. A. Tollenaar, P. Devilee, T. C. T. E. F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C. M. Kets, A. R. Mensenkamp; University Medical Center Utrecht, NL: M. G. E. M. Ausems, R. B. van der Luijt; Amsterdam Medical Center, NL: C. M. Aalfs, T. A. M. van Os; VU University Medical Center, Amsterdam, NL: J. J. P. Gille, Q. Waisfisz, H. E. J. Meijers-Heijboer; University Hospital Maastricht, NL: E. B. Gomez-Garcia, M. J. Blok; University Medical Center Groningen, NL: J. C. Oosterwijk, A. H. van der Hout, M. J. Mourits, G. H. de Bock. The Netherlands Foundation for the detection of hereditary tumour, Leiden, NL: H. F. Vasen. The HEBON study is supported by the Dutch Cancer Society Grants NKI19981854, NKI2004-3088, NKI2007-3756, the NWO Grant 91109024, the Pink Ribbon Grant 110005 and the BBMRI Grant CP46/NWO. The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health under RFACA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). Samples from the CPIC, FCCC, HCI, and were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government or the BCFR. The GEMO study is supported by the Ligue National Contre le Cancer, Association for International Cancer Research Grant AICR-07-0454, and the Association "Le cancer du sein, parlons-en!" Award. We wish to thank all the GEMO collaborating groups for their contribution to this study.; GEMO Collaborating Centers are: Coordinating Centres, Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Centre Hospitalier Universitaire de Lyon/Centre Leon Berard, and UMR5201 CNRS, Universite de Lyon, Lyon: Laure Barjhoux, Sophie Giraud, Melanie Leone, Sylvie; and INSERM U509, Service de Genetique Oncologique, Institut Curie, Paris: Marion Gauthier-Villars, Claude Houdayer, Virginie Moncoutier, Muriel Belotti. Institut Gustave Roussy, Villejuif: Brigitte Bressacde-Paillerets, Audrey Remenieras, Veronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont-Ferrand:Yves-Jean Bignon, Nancy Uhrhammer. Institut Paoli Calmettes, Marseille: Violaine Bourdon, Francois Eisinger. Groupe Hospitalier Pitie ' -Salpetriere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joe " lle Fournier, Franc, oise Re ' villion, Philippe Vennin, Claude Adenis. Centre Rene ' Huguenin, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange. Centre Paul Strauss, Strasbourg: Danie le Muller, Jean-Pierre Fricker. Institut Bergonie ', Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Christine Rebischung. CHU de Dijon: Cecile Cassini. CHU de St-Etienne: Fabienne Prieur. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. CBCS thanks Mette K. Andersen and Susanne Kjaergaard for clinical data. The work was supported by the Neye Foundation. GOG was supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469), the GOG Tissue Bank (CA 27469), and the Gynecologic Oncology Group Statistical and Data Center (CA 37517 and CA 101165). GOG's participation was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program-COPTRG) NCI programs. Genotyping of GOG DNA samples was performed by NCI's Core Genotyping Facility. The technical expertise of Tim Sheehy and Amy Hutchinson is gratefully acknowledged. OSU CCG was funded by the OSU Comprehensive Cancer Center. We thank Kevin Sweet and Caroline Craven for patient accrual and data management, the Human Genetics Sample Bank for sample preparation, and the OSU Nucleic Acids Shared Resource for plate reads. IOVHBOCS was supported by the Ministero dell'Universita e della Ricerca, Ministero della Salute, and Alleanza Contro il Cancro. N. N. Petrov Institute of Oncology (NNPIO) was supported by the Russian Foundation for Basic Research (Grants 08-04-00369-a, 09-04-90402, and 10-04-92110-a), the Commission of the European Communities (Grant PITN-GA-2009-238132), and through a Royal Society International Joint Grant (JP090615). BFBOCC was supported by Latvian Science Council Grant Nr. 10.0010.08. BFBOCC also acknowledges the Genome Database of Latvian Population, Latvian Biomedical Research and Study Centre for providing data and DNA samples for BFBOCC (L. V.), and Ramunas Janavicius (Vilnius University Hospital Santariskiu Clinics, Lithuania) for data and DNA samples for BFBOCC (L. T.). UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Carole Pye and Patricia Harrington for family recruitment and technical support. We would like to acknowledge the Roswell Park Alliance Foundation for their continued support of the Gilda Radner Ovarian Family Cancer Registry.; GRFOCR qould like to acknowledge Kirsten Moysich (Department of Cancer Prevention and Control) and Kunle Odunsi (Departments Gynecologic Oncology and Immunology). WCRI was supported by the American Cancer Society Early Detection Professorship and Entertainment Industry Foundation. GC-HBOC is supported by a grant of the German Cancer Aid (Grant 107054). We thank Juliane Kohler for her excellent technical assistance, Ellen Kirsch, Isabell Eisenhauer, Hans-Jorg Plendl, Thomas Neumann, Ulrike SiebersRehnelt, Doris Steinemann, Britta Skawran, Patricia Steiner, and the 12 centers of the GC-HBOC for providing samples and clinical data. HEBCS thanks Tuomas Heikkinen and Dr. Carl Blomqvist for their help with the patient data and samples. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation. Trinidad Caldes and Miguel de la Hoya were supported by FIS 09/00859 and RD06/0020/ 0021 (RTICC; ISCIII) Spanish Ministry of Science and Innovation. Dumont, Martine Tranchant for sample management and skillful technical assistance. Jacques Simard-J. S. is Chairholder of the Canada Research Chair in Oncogenetics. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer'' program and by the Canadian Breast Cancer Research Alliance-Grant # 019511. kConFab thanks Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by NHMRC Grants 145684, 288704, and 454508 and currently by the National Breast Cancer Foundation and Cancer Australia # 628333) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia, Amanda Spurdle is supported by an NHMRC Senior Research Fellowship, and Georgia Chenevix-Trench by an NHMRC Senior Principal Research Fellowship. ILUH was funded by the Landspitali University Hospital Research Fund and by the Icelandic association: "Walking for Breast Cancer Research". MSKCC acknowledges support of the Sandra Taub Research Fund of the BCRF. NR 11 TC 1 Z9 1 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2012 VL 136 IS 1 BP 295 EP 302 DI 10.1007/s10549-012-2255-6 PG 8 WC Oncology SC Oncology GA 022FF UT WOS:000309940300028 PM 23011509 ER PT J AU Fang, ZZ Krausz, KW Li, F Cheng, J Tanaka, N Gonzalez, FJ AF Fang, Zhong-Ze Krausz, Kristopher W. Li, Fei Cheng, Jie Tanaka, Naoki Gonzalez, Frank J. TI Metabolic map and bioactivation of the anti-tumour drug noscapine SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE noscapine; metabolic map; bioactivation ID UDP-GLUCURONOSYLTRANSFERASES UGTS; MESSENGER-RNA EXPRESSION; HUMAN LIVER-MICROSOMES; CELL LUNG-CANCER; ANTICANCER ACTIVITY; ARRIVE GUIDELINES; RATIONAL DESIGN; IN-VIVO; AGENT; IDENTIFICATION AB BACKGROUND AND PURPOSE Noscapine is a promising anti-tumour agent. The purpose of the present study was to describe the metabolic map and investigate the bioactivation of noscapine. EXPERIMENTAL APPROACH Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics was used to analyse the in vitro incubation mixtures, urine and faeces samples from mice treated with noscapine. Recombinant drug-metabolizing enzymes were employed to identify those involved in noscapine metabolism. Hepatic GSH levels and serum biochemistry were also carried out to determine reactive metabolites of noscapine. KEY RESULTS Several novel phase I metabolites of noscapine were detected after oral gavage of mice, including an N-demethylated metabolite, two hydroxylated metabolites, one metabolite undergoing both demethylation and cleavage of the methylenedioxy group and a bis-demethylated metabolite. Additionally, several novel glucuronides were detected, and their structures were elucidated through MS/MS fragmentology. Recombinant enzymes screening showed the involvement of several cytochromes P450, flavin-containing mono-oxygenase 1 and the UDP-glucuronosyltransferases UGT1A1, UGT1A3, UGT1A9 and UGT2B7, in noscapine metabolism. In vitro glutathione trapping revealed the existence of an ortho-quinone reactive intermediate formed through further oxidation of a catechol metabolite. However, this bioactivation process of noscapine does not occur in vivo. Similar to this result, altered glutathione levels in liver and serum biochemistry revealed no evidence of hepatic damage, thus indicating that, at least in mice, noscapine does not induce hepatotoxicity through bioactivation. CONCLUSIONS AND IMPLICATIONS A comprehensive metabolic map and bioactivation evaluation provides important information for the development of noscapine as an anti-tumour drug. C1 [Fang, Zhong-Ze; Krausz, Kristopher W.; Li, Fei; Cheng, Jie; Tanaka, Naoki; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov RI Li, Fei/F-6849-2013 NR 43 TC 45 Z9 45 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD NOV PY 2012 VL 167 IS 6 BP 1271 EP 1286 DI 10.1111/j.1476-5381.2012.02067.x PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 024AR UT WOS:000310080300009 PM 22671862 ER PT J AU Portevin, D Via, LE Eum, S Young, D AF Portevin, Damien Via, Laura E. Eum, Seokyong Young, Douglas TI Natural killer cells are recruited during pulmonary tuberculosis and their ex vivo responses to mycobacteria vary between healthy human donors in association with KIR haplotype SO CELLULAR MICROBIOLOGY LA English DT Article ID HUMAN NK CELLS; MHC CLASS-I; NKP46 RECEPTOR; IFN-GAMMA; ACTIVATION; INFECTION; DISEASE; INNATE; BOVIS; INDIVIDUALS AB Humans vary widely in their susceptibility to tuberculosis. While only a minority will progress to disease, the majority of healthy individuals exposed to Mycobacterium tuberculosis mount an immune response that can clear or contain the infection in a quiescent form. Using immunofluorescence on human clinical samples, we identified natural killer (NK) cells infiltrating granulomatous pulmonary lesions during active disease. In order to compare the NK cell ability to react to free mycobacteria in the context of tuberculosis infection and Mycobacterium bovis BCG vaccination, NK cells were isolated from the peripheral blood of anonymous healthy human donors, and stimulated with M.?tuberculosis H37Rv or M.?bovis BCG. Extracellular M.?tuberculosis and M.?bovis BCG could equally trigger the release of IFN? and TNFa from NK cells in the presence of IL-2. However, we found that this response varied 1000-fold between individuals (n?=?52), with differences in KIR haplotype providing a significant criterion to distinguish between low and high responders. Our findings suggest that variations at the KIR locus and therefore of the NK cell repertoire may affect cytokine production in response to mycobacteria and we propose that this innate variability couldsustain different levels of susceptibility to M.?tuberculosis infection. C1 [Portevin, Damien; Young, Douglas] MRC Natl Inst Med Res, Div Mycobacterial Res, London NW7 1AA, England. [Via, Laura E.] NIAID, TB Res Sect, LCID, NIH, Bethesda, MD 20892 USA. [Eum, Seokyong] Int TB Res Ctr, Masan, Changwon, South Korea. RP Portevin, D (reprint author), MRC Natl Inst Med Res, Div Mycobacterial Res, Mill Hill, London NW7 1AA, England. EM dportev@nimr.mrc.ac.uk OI Via, Laura/0000-0001-6074-9521 FU MRC [U117581288]; National Institute of Allergy and Infectious Disease, National Institutes of Health, USA; Korean Ministry of Health, Welfare and Family FX We would like to thank NIMR Histology Services and especially Dr Radma Mahmood for her technical support, Dr Helene Royo for fruitful briefing on fluorescence microscopy and Dr Andreas Wack for critical reading of the manuscript. We would also like to thank the patients and staff of NMTH for their kind participation in the research protocols at ITRC and NMTH. This work was entirely supported by the MRC core funds (U117581288). D. P. was holding a Career Development Fellowship from the MRC. The tissue collection, L. E. V. and S. E. were supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, USA, and in part by the Korean Ministry of Health, Welfare and Family. NR 44 TC 20 Z9 22 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD NOV PY 2012 VL 14 IS 11 BP 1734 EP 1744 DI 10.1111/j.1462-5822.2012.01834.x PG 11 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 023XY UT WOS:000310072400007 PM 22788220 ER PT J AU Forbes, CE Poore, JC Barbey, AK Krueger, F Solomon, J Lipsky, RH Hodgkinson, CA Goldman, D Grafman, J AF Forbes, Chad E. Poore, Joshua C. Barbey, Aron K. Krueger, Frank Solomon, Jeffrey Lipsky, Robert H. Hodgkinson, Colin A. Goldman, David Grafman, Jordan TI BDNF Polymorphism-Dependent OFC and DLPFC Plasticity Differentially Moderates Implicit and Explicit Bias SO CEREBRAL CORTEX LA English DT Article DE BDNF; implicit and explicit bias; PFC plasticity; social neuroscience; TBI ID VAL66MET GENE POLYMORPHISM; PENETRATING HEAD-INJURY; NEUROTROPHIC-FACTOR; PREFRONTAL CORTEX; COLLEGE-STUDENTS; SOCIAL COGNITION; ASSOCIATION TEST; EPISODIC MEMORY; WOMEN SCALE; ATTITUDES AB This study examined the role of orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) plasticity in controlling implicit and explicit social biases. Normal controls and patients with varied OFC and DLPFC lesion size and single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, which promotes (methionine-valine [Met/Val] SNP) or stifles (valine-valine [Val/Val] SNP) plasticity in damaged PFC regions, completed measures of implicit and explicit social bias. Patients and controls demonstrated comparable levels of implicit bias, but patients with Met/Val SNPs exhibited less implicit bias when they had smaller OFC lesions compared with Val/Val patients with similar size lesions and those with large OFC lesions. Both patients and controls demonstrated patterns of explicit bias consistent with hypotheses. Patients with Met/Val SNPs exhibited less explicit bias when they had smaller DLPFC lesions sizes compared with Val/Val patients with similar size lesions and those with large DLPFC lesions. OFC lesion size and BDNF SNP type did not moderate explicit bias; DLPFC lesion size and BDNF SNP type did not moderate implicit bias (nor did other medial or lateral regions). Findings suggest that plasticity within specific PFC regions modulates the type and degree of social bias that individuals' exhibit. C1 [Forbes, Chad E.] Univ Delaware, Dept Psychol, Newark, DE 19716 USA. [Forbes, Chad E.] Natl Inst Neurol Disorders & Stroke, Imaging Sci Training Program, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Forbes, Chad E.] Natl Inst Neurol Disorders & Stroke, Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Forbes, Chad E.; Poore, Joshua C.; Krueger, Frank; Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Barbey, Aron K.] Univ Illinois, Decis Neurosci Lab, Champaign, IL 61820 USA. [Barbey, Aron K.] Univ Illinois, Beckman Inst Adv Sci & Technol, Champaign, IL 61820 USA. [Barbey, Aron K.] Univ Illinois, Neurosci Program, Champaign, IL 61820 USA. [Barbey, Aron K.] Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL 61820 USA. [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Solomon, Jeffrey] Med Numer Inc, Germantown, MD 20876 USA. [Lipsky, Robert H.] Inova Fairfax Hosp, Dept Neurosci, Falls Church, VA 22042 USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Forbes, CE (reprint author), Univ Delaware, Dept Psychol, 220 Wolf Hall, Newark, DE 19716 USA. EM cforbes@psych.udel.edu RI Barbey, Aron/L-7312-2015; Goldman, David/F-9772-2010; OI Barbey, Aron/0000-0002-6092-0912; Goldman, David/0000-0002-1724-5405; Grafman, Jordan H./0000-0001-8645-4457; Lipsky, Robert/0000-0001-7753-1473 FU Imaging Sciences Training Program, Radiology and Imaging Sciences, Clinical Center and National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke, National Institutes of Health; U.S. Army Medical Research and Material Command [DAMD17-01-1-0675] FX This work was supported by the Imaging Sciences Training Program, Radiology and Imaging Sciences, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and a project grant from the U.S. Army Medical Research and Material Command administrated by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: A 30-year postinjury follow-up study: Grant number: DAMD17-01-1-0675). NR 56 TC 8 Z9 8 U1 0 U2 6 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 NOV PY 2012 VL 22 IS 11 BP 2602 EP 2609 DI 10.1093/cercor/bhr337 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 018XH UT WOS:000309700700013 PM 22123938 ER PT J AU Kaphingst, KA Facio, FM Cheng, MR Brooks, S Eidem, H Linn, A Biesecker, BB Biesecker, LG AF Kaphingst, K. A. Facio, F. M. Cheng, M-R Brooks, S. Eidem, H. Linn, A. Biesecker, B. B. Biesecker, L. G. TI Effects of informed consent for individual genome sequencing on relevant knowledge SO CLINICAL GENETICS LA English DT Article DE genomic knowledge; genome sequencing; informed consent; knowledge ID BREAST-CANCER SUSCEPTIBILITY; MYELOID-LEUKEMIA GENOME; GENETIC INFORMATION; ATTITUDES; MEDICINE; HEALTH; OUTCOMES; CAPTURE; PATIENT; CHOICE AB Kaphingst KA, Facio FM, Cheng M-R, Brooks S, Eidem H, Linn A, Biesecker BB, Biesecker LG. Effects of informed consent for individual genome sequencing on relevant knowledge. Increasing availability of individual genomic information suggests that patients will need knowledge about genome sequencing to make informed decisions, but prior research is limited. In this study, we examined genome sequencing knowledge before and after informed consent among 311 participants enrolled in the ClinSeq (TM) sequencing study. An exploratory factor analysis of knowledge items yielded two factors (sequencing limitations knowledge; sequencing benefits knowledge). In multivariable analysis, high pre-consent sequencing limitations knowledge scores were significantly related to education [odds ratio (OR): 8.7, 95% confidence interval (CI): 2.45-31.10 for post-graduate education, and OR: 3.9; 95% CI: 1.05, 14.61 for college degree compared with less than college degree] and race/ethnicity (OR: 2.4, 95% CI: 1.09, 5.38 for non-Hispanic Whites compared with other racial/ethnic groups). Mean values increased significantly between pre- and post-consent for the sequencing limitations knowledge subscale (6.97.7, p < 0.0001) and sequencing benefits knowledge subscale (7.07.5, p < 0.0001); increase in knowledge did not differ by sociodemographic characteristics. This study highlights gaps in genome sequencing knowledge and underscores the need to target educational efforts toward participants with less education or from minority racial/ethnic groups. The informed consent process improved genome sequencing knowledge. Future studies could examine how genome sequencing knowledge influences informed decision making. C1 [Kaphingst, K. A.; Cheng, M-R] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Facio, F. M.; Brooks, S.; Eidem, H.; Biesecker, B. B.; Biesecker, L. G.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Linn, A.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Kaphingst, KA (reprint author), Washington Univ, Sch Med, Div Publ Hlth Sci, 660 S Euclid Ave, St Louis, MO 63110 USA. EM kkaphingst@gwbmail.wustl.edu FU National Human Genome Research Institute, National Institutes of Health; Barnes-Jewish Hospital Foundation FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. KAK was supported by funding from the Barnes-Jewish Hospital Foundation. The authors thank the ClinSeq (TM) participants who completed the surveys for this analysis. NR 35 TC 22 Z9 22 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD NOV PY 2012 VL 82 IS 5 BP 408 EP 415 DI 10.1111/j.1399-0004.2012.01909.x PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 019DT UT WOS:000309718000002 PM 22694298 ER PT J AU Valli, M Barnes, AM Gallanti, A Cabral, WA Viglio, S Weis, MA Makareeva, E Eyre, D Leikin, S Antoniazzi, F Marini, JC Mottes, M AF Valli, M. Barnes, A. M. Gallanti, A. Cabral, W. A. Viglio, S. Weis, M. A. Makareeva, E. Eyre, D. Leikin, S. Antoniazzi, F. Marini, J. C. Mottes, M. TI Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix SO CLINICAL GENETICS LA English DT Article DE cartilage-associated protein; collagen; matrix insufficiency; osteogenesis imperfecta ID PROLYL 3-HYDROXYLATION COMPLEX; CARTILAGE-ASSOCIATED PROTEIN; CYCLOPHILIN-B; MUTATIONS; LETHAL AB Valli M, Barnes AM, Gallanti A, Cabral WA, Viglio S, Weis MA, Makareeva E, Eyre D, Leikin S, Antoniazzi F, Marini JC, Mottes M. Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix. Deficiency of any component of the ER-resident collagen prolyl 3-hydroxylation complex causes recessive osteogenesis imperfecta (OI). The complex modifies the a1(I)Pro986 residue and contains cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and cyclophilin B (CyPB). Fibroblasts normally secrete about 10% of CRTAP. Most CRTAP mutations cause a null allele and lethal type VII OI. We identified a 7-year-old Egyptian boy with non-lethal type VII OI and investigated the effects of his null CRTAP mutation on collagen biochemistry, the prolyl 3-hydroxylation complex, and collagen in extracellular matrix. The proband is homozygous for an insertion/deletion in CRTAP (c.118_133del16insTACCC). His dermal fibroblasts synthesize fully overmodified type I collagen, and 3-hydroxylate only 5% of a1(I)Pro986. CRTAP transcripts are 10% of control. CRTAP protein is absent from proband cells, with residual P3H1 and normal CyPB levels. Dermal collagen fibril diameters are significantly increased. By immunofluorescence of long-term cultures, we identified a severe deficiency (1015% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborate deficiency of matrix deposition, rather than increased matrix turnover. We conclude that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of type VII OI. C1 [Mottes, M.] Univ Verona, Div Biol & Genet, Dept Life & Reprod Sci, I-37134 Verona, Italy. [Valli, M.; Gallanti, A.; Viglio, S.] Univ Pavia, Dept Biochem A, I-27100 Pavia, Italy. [Barnes, A. M.; Cabral, W. A.; Marini, J. C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA. [Weis, M. A.; Eyre, D.] Univ Washington, Orthopaed Res Labs, Seattle, WA 98195 USA. [Makareeva, E.; Leikin, S.] NICHD, Sect Phys Biochem, NIH, Bethesda, MD USA. [Antoniazzi, F.] Univ Verona, Div Pediat, Dept Life & Reprod Sci, I-37134 Verona, Italy. RP Mottes, M (reprint author), Univ Verona, Div Biol & Genet, Dept Life & Reprod Sci, Str Grazie 8, I-37134 Verona, Italy. EM monica.mottes@univr.it RI Makareeva, Elena/F-5183-2011; Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU MIUR (Italian Ministry of Education and Research); Azienda Ospedaliera Universitaria Integrata; NICHD FX This work was supported by MIUR (Italian Ministry of Education and Research) (M. V. and M. M.), intramural funding by Azienda Ospedaliera Universitaria Integrata (F. A.), and by NICHD intramural funding (J. C. M. and S. L.). NR 23 TC 12 Z9 14 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD NOV PY 2012 VL 82 IS 5 BP 453 EP 459 DI 10.1111/j.1399-0004.2011.01794.x PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 019DT UT WOS:000309718000008 PM 21955071 ER PT J AU Yeh, S Sen, HN Colyer, M Zapor, M Wroblewski, K AF Yeh, Steven Sen, Hatice N. Colyer, Marcus Zapor, Michael Wroblewski, Keith TI Update on ocular tuberculosis SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Review DE HIV; latent tuberculosis infection; Mycobacterium tuberculosis; tuberculin skin testing; PCR ID SERPIGINOUS-LIKE CHOROIDITIS; EALES-DISEASE; MYCOBACTERIUM-TUBERCULOSIS; FUNDUS AUTOFLUORESCENCE; CLINICAL PRESENTATIONS; SCLERITIS; UVEITIS; FEATURES; PATIENT; SERUM AB Purpose of review Despite recent downtrends, tuberculosis remains a worldwide public health concern. This review provides an update on recent demographic data, clinical and experimental data, and diagnostic modalities. Recent findings Quantitative PCR showing mycobacterial load in intraocular fluids may have an emerging role in the diagnosis of ocular tuberculosis when used in combination with ophthalmic features of tuberculosis. Recent investigations in porcine models of ocular tuberculosis have provided valuable insight into the microbiologic, histologic, and clinical features of Mycobacterium tuberculosis infection of the choroid. Differentiating features between sarcoidosis and tuberculosis include tuberculin skin test status, the presence of ocular surface disease, and the anatomic relationship between vasculitis and choroiditis. Summary The diagnosis of presumed ocular tuberculosis remains a clinical challenge with currently available diagnostic modalities. Although newer interferon-gamma release assays can distinguish exposure to M. tuberculosis from the Bacille-Calmette-Guerin vaccine strain, they currently lack the specificity to distinguish between latent tuberculosis infection and active tuberculosis. Continued improvement in the currently available molecular diagnostic techniques including quantitative PCR may be valuable in our ability to establish an earlier etiologic diagnosis and institute appropriate antimycobacterial therapy. C1 [Colyer, Marcus; Wroblewski, Keith] Walter Reed Natl Mil Med Ctr, Ophthalmol Serv, Bethesda, MD 20892 USA. [Yeh, Steven] Emory Univ, Sch Med, Dept Ophthalmol, Div Uveitis Vitreoretinal Dis & Surg,Emory Eye Ct, Atlanta, GA 30322 USA. [Sen, Hatice N.] NEI, Dept Ocular Immunol & Uveitis, NIH, Bethesda, MD 20892 USA. [Colyer, Marcus] Walter Reed Natl Mil Med Ctr, Ocular Trauma Serv, Bethesda, MD 20892 USA. [Zapor, Michael] Walter Reed Natl Mil Med Ctr, Dept Infect Dis, Bethesda, MD 20892 USA. RP Wroblewski, K (reprint author), Walter Reed Natl Mil Med Ctr, Ophthalmol Serv, 8901 Wisconsin Ave, Bethesda, MD 20892 USA. EM keith.wroblewski@med.navy.mil FU Research to Prevent Blindness FX This manuscript is supported in part by an unrestricted grant from Research to Prevent Blindness to the Emory Eye Center, Emory University School of Medicine (S.Y.) The authors of this manuscript have no conflicts of interest to disclose in reference to the research presented herein. NR 36 TC 14 Z9 15 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD NOV PY 2012 VL 23 IS 6 BP 551 EP 556 DI 10.1097/ICU.0b013e328358ba01 PG 6 WC Ophthalmology SC Ophthalmology GA 020NL UT WOS:000309818000017 PM 23047173 ER PT J AU Zeng, XK Hou, SX AF Zeng, Xiankun Hou, Steven X. TI Broad relays hormone signals to regulate stem cell differentiation in Drosophila midgut during metamorphosis SO DEVELOPMENT LA English DT Article DE Drosophila; Adult midgut progenitors; Intestinal stem cells; Hormone; Broad; Differentiation ID JUVENILE-HORMONE; PROTHORACIC GLAND; GENE DISRUPT; DEATH; COMPLEX; MELANOGASTER; MECHANISMS; EXPRESSION; MUTATIONS; EGFR AB Like the mammalian intestine, the Drosophila adult midgut is constantly replenished by multipotent intestinal stem cells (ISCs). Although it is well known that adult ISCs arise from adult midgut progenitors (AMPs), relatively little is known about the mechanisms that regulate AMP specification. Here, we demonstrate that Broad (Br)-mediated hormone signaling regulates AMP specification. Br is highly expressed in AMPs temporally during the larva-pupa transition stage, and br loss of function blocks AMP differentiation. Furthermore, Br is required for AMPs to develop into functional ISCs. Conversely, br overexpression drives AMPs toward premature differentiation. In addition, we found that Br and Notch (N) signaling function in parallel pathways to regulate AMP differentiation. Our results reveal a molecular mechanism whereby Br-mediated hormone signaling directly regulates stem cells to generate adult cells during metamorphosis. C1 [Zeng, Xiankun; Hou, Steven X.] NIH, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Zeng, XK (reprint author), NIH, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM zengx2@mail.nih.gov; hous@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Deposited in PMC for release after 12 months. NR 50 TC 7 Z9 7 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD NOV PY 2012 VL 139 IS 21 BP 3917 EP 3925 DI 10.1242/dev.083030 PG 9 WC Developmental Biology SC Developmental Biology GA 018XN UT WOS:000309701300004 PM 23048182 ER PT J AU Louis, GMB Peterson, CM Chen, Z Hediger, ML Croughan, MS Sundaram, R Stanford, JB Fujimoto, VY Varner, MW Giudice, LC Kennedy, A Sun, LP Wu, Q Kannan, K AF Louis, Germaine M. Buck Peterson, C. Matthew Chen, Zhen Hediger, Mary L. Croughan, Mary S. Sundaram, Rajeshwari Stanford, Joseph B. Fujimoto, Victor Y. Varner, Michael W. Giudice, Linda C. Kennedy, Anne Sun, Liping Wu, Qian Kannan, Kurunthachalam TI Perfluorochemicals and Endometriosis The ENDO Study SO EPIDEMIOLOGY LA English DT Article ID PERFLUORINATED COMPOUNDS PFCS; DIOXIN-LIKE COMPOUNDS; PERFLUOROOCTANOIC ACID; HUMAN BLOOD; EXPOSURE; WOMEN; ASSOCIATION; PREGNANCY; CHEMICALS; RISK AB Background: Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues. Methods: We formulated two samples. The first was an operative sample comprising 495 women aged 18-44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007-2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity. Results: Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17-3.06]) and perfluorononanoic acid (2.20 [1.02-4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99-2.66] and 1.99 [0.91-4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05-3.30]) and PFOA (2.58 [1.18-5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively). Conclusions: Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration. C1 [Louis, Germaine M. Buck; Chen, Zhen; Hediger, Mary L.; Sundaram, Rajeshwari; Sun, Liping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol, Rockville, MD 20852 USA. [Louis, Germaine M. Buck; Chen, Zhen; Hediger, Mary L.; Sundaram, Rajeshwari; Sun, Liping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Stat, Rockville, MD 20852 USA. [Louis, Germaine M. Buck; Chen, Zhen; Hediger, Mary L.; Sundaram, Rajeshwari; Sun, Liping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Prevent Res, Rockville, MD 20852 USA. [Peterson, C. Matthew] Univ Utah, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Salt Lake City, UT USA. [Croughan, Mary S.; Fujimoto, Victor Y.; Giudice, Linda C.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Croughan, Mary S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Stanford, Joseph B.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT USA. [Kennedy, Anne] Univ Utah, Dept Radiol, Salt Lake City, UT 84132 USA. [Wu, Qian; Kannan, Kurunthachalam] Wadsworth Ctr, Div Environm Hlth Sci, Albany, NY USA. [Wu, Qian; Kannan, Kurunthachalam] SUNY Albany, Dept Hlth & Environm Hlth Sci, Albany, NY 12222 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM louisg@mail.nih.gov RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health [NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02] FX Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (contracts NO1-DK-6-3428; NO1-DK-6-3427; 10001406-02; 10001406-02). NR 39 TC 18 Z9 18 U1 4 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2012 VL 23 IS 6 BP 799 EP 805 DI 10.1097/EDE.0b013e31826cc0cf PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 022NJ UT WOS:000309965800007 PM 22992575 ER PT J AU Beebe-Dimmer, JL Colt, JS Ruterbusch, JJ Keele, GR Purdue, MP Wacholder, S Graubard, BI Davis, F Chow, WH Schwartz, KL AF Beebe-Dimmer, Jennifer L. Colt, Joanne S. Ruterbusch, Julie J. Keele, Gregory R. Purdue, Mark P. Wacholder, Sholom Graubard, Barry I. Davis, Faith Chow, Wong-Ho Schwartz, Kendra L. TI Body Mass Index and Renal Cell Cancer The Influence of Race and Sex SO EPIDEMIOLOGY LA English DT Article ID NUTRITION EXAMINATION SURVEY; SELF-REPORTED HEIGHT; 3RD NATIONAL-HEALTH; PHYSICAL-ACTIVITY; KIDNEY CANCER; UNITED-STATES; RISK-FACTORS; METABOLIC-SYNDROME; ATTRIBUTABLE RISK; CARCINOMA AB Background: Obesity is a risk factor for renal cell (or renal) cancer. The increasing prevalence of obesity may be contributing to the rising incidence of this cancer over the past several decades. The effects of early-age obesity and change in body mass index (BMI) on renal cancer have been studied less thoroughly, and the influence of race has never been formally investigated. Methods: Using data gathered as part of a large case-control study of renal cancer (1214 cases and 1234 controls), we investigated associations with BMI at several time points, as well as with height. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression modeling. Race- and sex-stratified analyses were conducted to evaluate subgroup differences. Results: Obesity (BMI >= 30 kg/m(2)) early in adulthood (OR = 1.6 [95% CI = 1.1 to 2.4]) and 5 years before diagnosis (1.6 [1.1 to 2.2]) was associated with renal cancer. The association with early- adult obesity was stronger among whites than blacks (test for interaction, P = 0.006), whereas the association with obesity near diagnosis was marginally stronger in women than men (test for interaction, P = 0.08). The strongest association with renal cancer was observed for obese whites both in early adulthood and before interview (2.6 [1.5 to 4.4]); this association was not present among blacks. Estimates of the annual excess rate of renal cancer (per 100,000 persons) attributed to both overweight and obesity (BMI > 25 kg/m(2)) ranged from 9.9 among black men to 5.6 among white women. Conclusion: Obesity, both early and later in life, is associated with an increased risk of renal cancer. The association with early obesity seems to be stronger among whites than blacks. C1 [Beebe-Dimmer, Jennifer L.; Ruterbusch, Julie J.; Keele, Gregory R.; Schwartz, Kendra L.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48201 USA. [Beebe-Dimmer, Jennifer L.; Ruterbusch, Julie J.; Keele, Gregory R.; Schwartz, Kendra L.] Wayne State Univ, Sch Med, Dept Family Med, Detroit, MI 48201 USA. [Beebe-Dimmer, Jennifer L.; Schwartz, Kendra L.] Karmanos Canc Inst, Detroit, MI 48201 USA. [Colt, Joanne S.; Purdue, Mark P.; Wacholder, Sholom; Graubard, Barry I.; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Davis, Faith] Univ Illinois, Div Epidemiol & Biostat, Chicago, IL USA. RP Beebe-Dimmer, JL (reprint author), Wayne State Univ, Sch Med, Dept Oncol, 4100 John R, Detroit, MI 48201 USA. EM dimmerj@karmanos.org RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services [N02-CP-10128, N02-CP-11004, N02-CP-11161] FX Supported, in part, with federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract Nos. N02-CP-10128, N02-CP-11004, and N02-CP-11161. NR 37 TC 8 Z9 8 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2012 VL 23 IS 6 BP 821 EP 828 DI 10.1097/EDE.0b013e31826b7fe9 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 022NJ UT WOS:000309965800010 PM 23007040 ER PT J AU Goldstein, E Viboud, C Charu, V Lipsitch, M AF Goldstein, Edward Viboud, Cecile Charu, Vivek Lipsitch, Marc TI Improving the Estimation of Influenza-Related Mortality Over a Seasonal Baseline SO EPIDEMIOLOGY LA English DT Article ID INVASIVE PNEUMOCOCCAL DISEASE; RESPIRATORY SYNCYTIAL VIRUS; UNITED-STATES; CONJUGATE VACCINE; WINTER-MORTALITY; OLDER-ADULTS; DEATHS; REGRESSION; SUMMER AB Background: Existing methods for estimation of mortality attributable to influenza are limited by methodological and data uncertainty. We have used proxies for disease incidence of the three influenza cocirculating subtypes (A/H3N2, A/H1N1, and B) that combine data on influenza-like illness consultations and respiratory specimen testing to estimate influenza-associated mortality in the United States between 1997 and 2007. Methods: Weekly mortality rate for several mortality causes potentially affected by influenza was regressed linearly against subtype-specific influenza incidence proxies, adjusting for temporal trend and seasonal baseline, modeled by periodic cubic splines. Results: Average annual influenza-associated mortality rates per 100,000 individuals were estimated for the following underlying causes of death: for pneumonia and influenza, 1.73 (95% confidence interval = 1.53-1.93); for chronic lower respiratory disease, 1.70 (1.48-1.93); for all respiratory causes, 3.58 (3.04-4.14); for myocardial infarctions, 1.02 (0.85-1.2); for ischemic heart disease, 2.7 (2.23-3.16); for heart disease, 3.82 (3.21-4.4); for cerebrovascular deaths, 0.65 (0.51-0.78); for all circulatory causes, 4.6 (3.79-5.39); for cancer, 0.87 (0.68-1.05); for diabetes, 0.33 (0.26-0.39); for renal disease, 0.19 (0.14-0.24); for Alzheimer disease, 0.41 (0.3-0.52); and for all causes, 11.92 (10.17-13.67). For several underlying causes of death, baseline mortality rates changed after the introduction of the pneumococcal conjugate vaccine. Conclusions: The proposed methodology establishes a linear relation between influenza incidence proxies and excess mortality, rendering temporally consistent model fits, and allowing for the assessment of related epidemiologic phenomena such as changes in mortality baselines. C1 [Goldstein, Edward; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Viboud, Cecile; Charu, Vivek] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Charu, Vivek] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Goldstein, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, 677 Huntington Ave,Kresge Room 506, Boston, MA 02115 USA. EM egoldste@hsph.harvard.edu OI Lipsitch, Marc/0000-0003-1504-9213 FU US National Institutes of Health Models of Infectious Disease Agent Study program [1 U54 GM088558]; US National Institutes of Health K01 award [1K01AI101010-01]; influenza research program of the Fogarty International Center, US NIH FX Supported, in part, by the US National Institutes of Health Models of Infectious Disease Agent Study program through cooperative agreement 1 U54 GM088558 (M.L., E.G.), by the US National Institutes of Health K01 award 1K01AI101010-01 (E.G.), and by the influenza research program of the Fogarty International Center, US NIH (C.V., V.C.). NR 30 TC 44 Z9 44 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2012 VL 23 IS 6 BP 829 EP 838 DI 10.1097/EDE.0b013e31826c2dda PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 022NJ UT WOS:000309965800011 PM 22992574 ER PT J AU Goldstein, E Viboud, C Lipsitch, M AF Goldstein, Edward Viboud, Cecile Lipsitch, Marc TI Time-Series Analyses of Count Data to Estimate the Burden of Seasonal Infectious Diseases Respond SO EPIDEMIOLOGY LA English DT Editorial Material ID RESPIRATORY SYNCYTIAL VIRUS; UNITED-STATES; INFLUENZA; DEATHS C1 [Goldstein, Edward; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Goldstein, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, 677 Huntington Ave,Kresge Room 506, Boston, MA 02115 USA. EM egoldste@hsph.harvard.edu NR 10 TC 1 Z9 1 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2012 VL 23 IS 6 BP 843 EP 844 DI 10.1097/EDE.0b013e31826e12c1 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 022NJ UT WOS:000309965800013 ER PT J AU Ilkhanoff, L Liu, K Ning, HY Nazarian, S Bluemke, DA Soliman, EZ Lloyd-Jones, DM AF Ilkhanoff, Leonard Liu, Kiang Ning, Hongyan Nazarian, Saman Bluemke, David A. Soliman, Elsayed Z. Lloyd-Jones, Donald M. TI Association of QRS duration with left ventricular structure and function and risk of heart failure in middle-aged and older adults: the Multi-Ethnic Study of Atherosclerosis (MESA) SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Electrocardiogram; Heart failure; Magnetic resonance imaging; QRS duration ID LIFE; MASS AB Prolonged QRS duration (QRSd) on the electrocardiogram (ECG) has been associated with cardiac structural and functional abnormalities by echocardiography and an increased risk of heart failure (HF). Data are sparse on these relationships in middle-aged and elderly individuals free of baseline cardiovascular disease with respect to cardiac magnetic resonance imaging (MRI). We sought to determine whether QRSd is associated with incident HF and measures of cardiac structure and function by cardiac MRI. We analysed baseline ECGs in the Multi-Ethnic Study of Atherosclerosis (MESA) to determine whether QRSd 100 ms was associated with incident HF. We adjusted for demographic and clinical risk factors, as well as MRI measures of left ventricular (LV) structure and function. Among 4591 eligible participants (51 women; 39 white; mean age 61 years), 75 developed incident HF over a mean follow-up of 7.1 years. QRSd 100 ms was significantly associated with MRI measures of cardiac structure and function, as well as incident HF, even after adjustment for demographic covariates [hazard ratio (HR) 2.10, 95 confidence interval (CI) 1.293.42; P 0.003] and clinical risk factors (HR 1.86, 95 CI 1.143.03; P 0.01). With further adjustment for individual LV structural measures, findings were attenuated to non-significance. Separate adjustment for LV functional measures yielded only mild attenuation. In middle-aged and older adults without cardiovascular disease, a QRSd 100 ms was significantly associated with incident HF. After adjustment for LV structural measures, the association was attenuated to non-significance, suggesting that prolonged QRSd is potentially a useful marker of LV structure that may predispose to HF risk. C1 [Ilkhanoff, Leonard; Lloyd-Jones, Donald M.] Northwestern Univ, Dept Med, Div Cardiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Ilkhanoff, Leonard; Lloyd-Jones, Donald M.] Northwestern Univ, Bluhm Cardiovasc Inst, Feinberg Sch Med, Chicago, IL 60611 USA. [Liu, Kiang; Ning, Hongyan; Lloyd-Jones, Donald M.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Nazarian, Saman] Johns Hopkins Univ, Johns Hopkins Hosp, Div Cardiol, Dept Med, Baltimore, MD USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. [Soliman, Elsayed Z.] Wake Forest Univ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. RP Ilkhanoff, L (reprint author), NW Mem Hosp, Div Cardiol, Dept Med, Electrophysiol Sect, Chicago, IL 60611 USA. EM l-ilkhanoff@northwestern.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169] FX The National Heart, Lung, and Blood Institute (contracts N01-HC-95159 through N01-HC-95169). NR 17 TC 10 Z9 12 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD NOV PY 2012 VL 14 IS 11 BP 1285 EP 1292 DI 10.1093/eurjhf/hfs112 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025EL UT WOS:000310168200013 PM 22791081 ER PT J AU Ngamskulrungroj, P Chang, Y Hansen, B Bugge, C Fischer, E Kwon-Chung, KJ AF Ngamskulrungroj, Popchai Chang, Yun Hansen, Bryan Bugge, Cliff Fischer, Elizabeth Kwon-Chung, Kyung J. TI Cryptococcus neoformans Yop1, an endoplasmic reticulum curvature-stabilizing protein, participates with Sey1 in influencing fluconazole-induced disomy formation SO FEMS YEAST RESEARCH LA English DT Article DE Cryptococcus neoformans; disomy formation; fluconazole; antifungal resistance; heteroresistance; endoplasmic reticulum ID CELL-DIVISION; YEAST; GENE; RESISTANCE; ER; HETERORESISTANCE; IDENTIFICATION; TRANSFORMATION; MEMBRANE; TUBULES AB Cryptococcus neoformans, an opportunistic fungal pathogen, manifests an intrinsic adaptive mechanism of resistance toward fluconazole (FLC) termed heteroresistance. Heteroresistance is characterized by the emergence of minor resistant subpopulations at levels of FLC that are higher than the strain's minimum inhibitory concentration. The heteroresistant clones that tolerate high concentrations of FLC often contain disomic chromosome 4 (Chr4). SEY1 , GLO3 , and GCS2 on Chr4 are responsible for endoplasmic reticulum (ER) integrity and important for Chr4 disomy formation under FLC stress. We sought an evidence of a direct relationship between ER morphology and Chr4 disomy formation. Deletion of the YOP1 gene on Chr7, which encodes an ER curvature-stabilizing protein that interacts with Sey1 , perturbed ER morphology without affecting FLC susceptibility or the frequency of FLC-induced disomies. However, deletion of both YOP1 and SEY1 , not only perturbed ER morphology more severely than in sey1? or yop1? strains, but also abrogated the FLC-induced disomy. Although the heteroresistance phenotype was retained in the sey1?yop1? strains, tolerance to FLC appeared to have resulted not from chromosome duplication but from gene amplification restricted to the region surrounding ERG11 on Chr1. These data support the importance of ER integrity in C.similar to neoformans for the formation of disomy under FLC stress. C1 [Ngamskulrungroj, Popchai; Chang, Yun; Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Ngamskulrungroj, Popchai] Mahidol Univ, Dept Microbiol, Fac Med, Siriraj Hosp, Bangkok 10700, Thailand. [Hansen, Bryan; Fischer, Elizabeth] NIAID, Electron Microscopy Unit, Rocky Mt Labs, NIH, Hamilton, MT USA. [Bugge, Cliff] FEI Co, Hillsboro, OR USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. EM June_kwon-chung@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by funds from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank A. Varma for critical discussions and reading of the manuscript. NR 29 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1567-1356 J9 FEMS YEAST RES JI FEMS Yeast Res. PD NOV PY 2012 VL 12 IS 7 BP 748 EP 754 DI 10.1111/j.1567-1364.2012.00824.x PG 7 WC Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biotechnology & Applied Microbiology; Microbiology; Mycology GA 021YK UT WOS:000309921700003 PM 22731401 ER PT J AU Mathews, CA Stoner, JA Wentzensen, N Moxley, KM Tenney, ME Tuller, ER Myers, T Landrum, LM Lanneau, G Zuna, RE Gold, MA Wang, SS Walker, JL AF Mathews, Cara A. Stoner, Julie A. Wentzensen, Nicolas Moxley, Katherine M. Tenney, Meaghan E. Tuller, Erin R. Myers, Tashanna Landrum, Lisa M. Lanneau, Grainger Zuna, Rosemary E. Gold, Michael A. Wang, Sophia S. Walker, Joan L. TI Tubal ligation frequency in Oklahoma women with cervical cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Tubal ligation; Pap screening; Cervical cancer; Cervical dysplasia ID HUMAN-PAPILLOMAVIRUS; UNITED-STATES; SCREENING HISTORIES; NATURAL-HISTORY; RISK-FACTORS; IN-SITU; NEOPLASIA; PROGRESSION; COHORT; TESTS AB Objective. Infrequent Pap screening is an important risk factor for cervical cancer. We studied the association between contraceptive methods, screening frequency, and cancer. Methods. Women (n=2004) enrolled in the cross-sectional Study to Understand Cervical Cancer Endpoints and Determinants (SUCCEED) underwent colposcopy to evaluate an abnormal Pap test. Questionnaire data were compared between those with cervical intraepithelial neoplasia (CIN) 3/adenocarcinoma in situ (AIS) and those with invasive cancer to identify factors associated with cancer. Logistic regression was used to calculate age-stratified measures of association between contraceptive method and Pap frequency as well as tubal ligation (TL) and cancer risk. Results. In all age groups, women with TL were more likely to have had no Pap screening in the previous 5 years compared to women using other contraception: 26-35 years (OR 4.6, 95% Cl 2.4-8.6; p<0.001), 36-45 years (OR 3.8,95% Cl 2.1-7.0; p<0.001), and 46-55 years (OR 2.2, 95% Cl 1.0-4.9; p=0.050). Subjects with cancer (n=163) were more likely to have had a TL (41% vs. 21%, p<0.001) than those with ON 3/AIS (n=370). Age-stratified analyses showed increased odds of tubal ligation in women with cancer versus those with CIN 3/AIS between 25 and 45 years, with a significant increase in women 26 to 35 years old (OR 3.3, 95% CI 1.4-8.1; p=0.009). Adjusting for Pap frequency changed the effect only slightly, suggesting that increased risk was not fully mediated by lack of screening. Conclusion. Contraceptive type is associated with Pap screening. Women with TLs obtain less frequent Pap testing and may be at an increased risk for cervical cancer. (C) 2012 Elsevier Inc. All rights reserved. C1 [Mathews, Cara A.; Moxley, Katherine M.; Landrum, Lisa M.; Lanneau, Grainger; Walker, Joan L.] Univ Oklahoma, Hlth Sci Ctr, Div Gynecol Oncol, Oklahoma City, OK 73104 USA. [Stoner, Julie A.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK 73104 USA. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Tenney, Meaghan E.] Univ Chicago, Div Gynecol Oncol, Chicago, IL 60637 USA. [Tuller, Erin R.] Univ Missouri, Div Gynecol Oncol, Columbia, MO USA. [Myers, Tashanna] Baystate Med Ctr, Div Gynecol Oncol, Springfield, MA USA. [Zuna, Rosemary E.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Gold, Michael A.] Vanderbilt Univ, Div Gynecol Oncol, Nashville, TN USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. RP Mathews, CA (reprint author), Univ Oklahoma, Hlth Sci Ctr, Div Gynecol Oncol, 800 NE 10th St, Oklahoma City, OK 73104 USA. EM Cara-Mathews@ouhsc.edu FU Intramural Research Program of the NIH; National Cancer Institute FX The research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. NR 25 TC 3 Z9 3 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD NOV PY 2012 VL 127 IS 2 BP 278 EP 282 DI 10.1016/j.ygyno.2012.07.119 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 024GN UT WOS:000310097800004 PM 22858904 ER PT J AU Biesecker, L AF Biesecker, Leslie TI Improving the rigor of mutation reports: Biologic parentage and de novo mutations SO HUMAN MUTATION LA English DT Editorial Material DE mutation analysis; mutation databases; de novo mutations; human genetic disease ID GENE AB The accurate determination and dissemination of the causality or pathogenicity of human DNA sequence variants is a crucial function of genetics journals. Published reports of pathogenic mutations are a common source of information for mutation databases, which are in turn used to make recommendations to patients. One of the strongest pieces of evidence in support of causality or pathogenicity for mutation reports is the occurrence of a de novo mutation. Yet, many publications describing such changes do not demonstrate that the mutation is truly de novo, by performing biologic parentage testing. I argue here that all mutation reports that describe such mutations should include biologic parentage testing, or in the absence of such testing, the mutation should be described as apparently de novo. This proposed standard should improve the transparency of the evidence that underlies our literature, and ultimately improve the databases of mutations in human disease. Hum Mutat 33:15011502, 2012. Published 2012 Wiley Periodicals, Inc.* C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Biesecker, L (reprint author), NHGRI, NIH, 49 Convent Dr,Room 4A56, Bethesda, MD 20892 USA. EM lesb@helix.nih.gov FU Intramural Research Program of the National Human Genome Research Institute FX Contract grant sponsor: Intramural Research Program of the National Human Genome Research Institute. NR 12 TC 3 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2012 VL 33 IS 11 BP 1501 EP 1502 DI 10.1002/humu.22131 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 019RA UT WOS:000309755800002 PM 22715147 ER PT J AU Hashimoto, K Rogozin, IB Panchenko, AR AF Hashimoto, Kosuke Rogozin, Igor B. Panchenko, Anna R. TI Oncogenic potential is related to activating effect of cancer single and double somatic mutations in receptor tyrosine kinases SO HUMAN MUTATION LA English DT Article DE cancer mutation; receptor tyrosine kinase; protein structure; kinase activation; mutation spectra; double mutations ID GROWTH-FACTOR RECEPTOR; LUNG-CANCER; MULTIPLE MUTATIONS; MISSENSE MUTATIONS; DNA-POLYMERASE; EGFR MUTANTS; TRANSIENT HYPERMUTABILITY; CHRONOCOORDINATE EVENTS; INHIBITOR SENSITIVITY; PROTEIN INTERACTIONS AB Aberrant activation of receptor tyrosine kinases (RTKs) is a common feature of many cancer cells. It was previously suggested that the mechanisms of kinase activation in cancer might be linked to transitions between active and inactive states. Here, we estimate the effects of single and double cancer mutations on the stability of active and inactive states of the kinase domains from different RTKs. We show that singleton cancer mutations destabilize active and inactive states; however, inactive states are destabilized more than the active ones, leading to kinase activation. We show that there exists a relationship between the estimate of oncogenic potential of cancer mutation and kinase activation. Namely, more frequent mutations have a higher activating effect, which might allow us to predict the activating effect of the mutations from the mutation spectra. Independent evolutionary analysis of mutation spectra complements this observation and finds the same frequency threshold defining mutation hotspots. We analyze double mutations and report a positive epistasis and additional advantage of doublets with respect to cancer cell fitness. The activation mechanisms of double mutations differ from those of single mutations and double mutation spectrum is found to be dissimilar to the mutation spectrum of singletons. Hum Mutat 33:15661575, 2012. Published 2012 Wiley Periodicals, Inc.* C1 [Hashimoto, Kosuke; Rogozin, Igor B.; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike,Bldg 38A 8S814, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at the US National Institutes of Health; JSPS Research Fellowship from the Japan Society for the Promotion of Science FX Contract grant sponsors: Intramural Research Program of the National Library of Medicine at the US National Institutes of Health; K.H. was supported by a JSPS Research Fellowship from the Japan Society for the Promotion of Science. NR 71 TC 15 Z9 15 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2012 VL 33 IS 11 BP 1566 EP 1575 DI 10.1002/humu.22145 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 019RA UT WOS:000309755800010 PM 22753356 ER PT J AU Barnes, AM Cabral, WA Weis, M Makareeva, E Mertz, EL Leikin, S Eyre, D Trujillo, C Marini, JC AF Barnes, Aileen M. Cabral, Wayne A. Weis, MaryAnn Makareeva, Elena Mertz, Edward L. Leikin, Sergey Eyre, David Trujillo, Carlos Marini, Joan C. TI Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix SO HUMAN MUTATION LA English DT Article DE osteogenesis imperfecta; Bruck syndrome; FKBP65; FKBP10; PPIB; peptidylprolyl isomerase ID FK506-BINDING PROTEIN FKBP65; BRUCK SYNDROME; ENDOPLASMIC-RETICULUM; CYCLOPHILIN-B; I COLLAGEN; BIOCHEMICAL-CHARACTERIZATION; SECRETORY PATHWAY; CHAIN ASSOCIATION; TRIPLE-HELIX; MUTATIONS AB Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with similar to 10% overmodification. Normal chain incorporation, helix folding, and collagen Tm support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix. Hum Mutat 33:15891598, 2012. Published 2012 Wiley Periodicals, Inc. C1 [Barnes, Aileen M.; Cabral, Wayne A.; Marini, Joan C.] Natl Inst Child Hlth & Human Dev NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [Weis, MaryAnn; Eyre, David] Univ Washington, Orthopaed Res Labs, Seattle, WA 98195 USA. [Makareeva, Elena; Mertz, Edward L.; Leikin, Sergey] NICHD, Sect Phys Biochem, NIH, Bethesda, MD USA. [Trujillo, Carlos] Dr Erfan & Bagedo Gen Hosp, Genet Unit, Jeddah, Saudi Arabia. RP Marini, JC (reprint author), NICHHD, Bone & Extracellular Matrix Branch, NIH, Bldg 10,Room 10N260,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov RI Makareeva, Elena/F-5183-2011; Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU NICHD; NIH [AR37318, AR36794]; Burgess Chair endowment FX Contract grant sponsors: NICHD Intramural Funding (to J.C.M. and S.L.); NIH grants AR37318 and AR36794; the Burgess Chair endowment. NR 42 TC 44 Z9 45 U1 0 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2012 VL 33 IS 11 BP 1589 EP 1598 DI 10.1002/humu.22139 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 019RA UT WOS:000309755800012 PM 22718341 ER PT J AU Jiang, LQ Zhang, J Monticone, RE Telljohann, R Wu, J Wang, MY Lakatta, EG AF Jiang, Liqun Zhang, Jing Monticone, Robert E. Telljohann, Richard Wu, James Wang, Mingyi Lakatta, Edward G. TI Calpain-1 Regulation of Matrix Metalloproteinase 2 Activity in Vascular Smooth Muscle Cells Facilitates Age-Associated Aortic Wall Calcification and Fibrosis SO HYPERTENSION LA English DT Article DE aging; matrix metalloproteinase 2; vascular calcification; calpain-1; fibrosis ID CARDIOVASCULAR-DISEASE ENTERPRISES; SUBCLINICAL ARTERIAL-DISEASE; ANGIOTENSIN-II; ALKALINE-PHOSPHATASE; ELASTIN CALCIFICATION; EXTRACELLULAR-MATRIX; MAJOR SHAREHOLDERS; UP-REGULATION; MECHANISMS; ACTIVATION AB Age-associated central arterial wall stiffness is linked to extracellular matrix remodeling, including fibrosis and vascular calcification. Angiotensin II induces both matrix metalloproteinase 2 (MMP2) and calpain-1 expression and activity in the arterial wall. However, the role of calpain-1 in MMP2 activation and extracellular matrix remodeling remains unknown. Dual histo-immunolabeling demonstrates colocalization of calpain-1 and MMP2 within old rat vascular smooth muscle cells. Overexpression of calpain-1 induces MMP2 transcripts, protein levels, and activity, in part, by increasing the ratio of membrane type 1 MMPs to tissue inhibitor of metalloproteinases 2. These effects of calpain-1 overexpression-induced MMP2 activation are linked to increased collagen I and III production and vascular calcification. In addition, overexpression of calpain-1 also induces transforming growth factor-beta 1/Smad signaling, elastin degradation, alkaline phosphatase activation, and total calcium content but reduces the expression of calcification inhibitors, osteopontin, and osteonectin, in cultured vascular smooth muscle cells in vitro and in carotid artery rings ex vivo. Furthermore, both calpain-1 and collagen II increase with aging within human aortic intima. Interestingly, in aged human aortic wall, both calpain-1 and collagen II are highly expressed in artherosclerotic plaque areas compared with grossly normal areas. Cross-talk of 2 proteases, calpain-1 and MMP2, leads to secretion of active MMP2, which modulates extracellular matrix remodeling via enhancing collagen production and facilitating vascular calcification. These results establish calpain-1 as a novel molecular candidate to retard age-associated extracellular matrix remodeling and its attendant risk for hypertension and atherosclerosis. (Hypertension. 2012;60:1192-1199.). Online Data Supplement C1 [Jiang, Liqun; Zhang, Jing; Monticone, Robert E.; Telljohann, Richard; Wu, James; Wang, Mingyi; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Jiang, LQ (reprint author), NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM jiangli@mail.nih.gov; mingyiw@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. NR 38 TC 32 Z9 36 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2012 VL 60 IS 5 BP 1192 EP + DI 10.1161/HYPERTENSIONAHA.112.196840 PG 20 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 023TX UT WOS:000310059800022 PM 23006733 ER PT J AU Lu, JH Marjon, KD Mold, C Du Clos, TW Sun, PD AF Lu, Jinghua Marjon, Kristopher D. Mold, Carolyn Du Clos, Terry W. Sun, Peter D. TI Pentraxins and Fc receptors SO IMMUNOLOGICAL REVIEWS LA English DT Review ID C-REACTIVE PROTEIN; AMYLOID-P COMPONENT; SYSTEMIC-LUPUS-ERYTHEMATOSUS; SMALL NUCLEAR RIBONUCLEOPROTEIN; CRYSTAL-STRUCTURE; GAMMA-RECEPTOR; GENETIC-VARIATION; STRUCTURAL BASIS; APOPTOTIC CELLS; EPSILON-RI AB Pentraxins are innate pattern recognition molecules whose major function is to bind microbial pathogens or cellular debris during infection and inflammation and, by doing so, contribute to the clearance of necrotic cells as well as pathogens through complement activations. Fc receptors are the cellular mediators of antibody functions. Although conceptually separated, both pentraxins and antibodies are important factors in controlling acute and chronic inflammation and infections. In recent years, increasing experimental evidence suggests a direct link between the innate pentraxins and humoral Fc receptors. Specifically, both human and mouse pentraxins recognize major forms of Fc receptors in solution and on cell surfaces with affinities similar to antibodies binding to their low affinity Fc receptors. Like immune complex, pentraxin aggregation and opsonization of pathogen result in Fc receptor and macrophage activation. The recently published crystal structure of human serum amyloid P (SAP) in complex with Fc?RIIA further illustrated similarities to antibody recognition. These recent findings implicate a much broader role than complement activation for pentraxins in immunity. This review summarizes the structural and functional work that bridge the innate pentraxins and the adaptive Fc receptor functions. In many ways, pentraxins can be regarded as innate antibodies. C1 [Lu, Jinghua; Sun, Peter D.] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Marjon, Kristopher D.; Mold, Carolyn; Du Clos, Terry W.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Marjon, Kristopher D.; Mold, Carolyn; Du Clos, Terry W.] Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Du Clos, Terry W.] VA Med Ctr, Albuquerque, NM USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM psun@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [R21AI085414] FX The authors do not have conflicts of interests to declare. The work was supported in part by the Intramural Research Funding of National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by an National Institutes of Health Grant R21AI085414. NR 65 TC 33 Z9 34 U1 1 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD NOV PY 2012 VL 250 SI SI BP 230 EP 238 DI 10.1111/j.1600-065X.2012.01162.x PG 9 WC Immunology SC Immunology GA 019PR UT WOS:000309752300015 PM 23046133 ER PT J AU Tsutsuki, H Yahiro, K Suzuki, K Suto, A Ogura, K Nagasawa, S Ihara, H Shimizu, T Nakajima, H Moss, J Noda, M AF Tsutsuki, Hiroyasu Yahiro, Kinnosuke Suzuki, Kotaro Suto, Akira Ogura, Kohei Nagasawa, Sayaka Ihara, Hideshi Shimizu, Takeshi Nakajima, Hiroshi Moss, Joel Noda, Masatoshi TI Subtilase Cytotoxin Enhances Escherichia coli Survival in Macrophages by Suppression of Nitric Oxide Production through the Inhibition of NF-kappa B Activation SO INFECTION AND IMMUNITY LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; SHIGA-TOXIN; DOWN-REGULATION; BACTERIAL LIPOPOLYSACCHARIDE; MOUSE MACROPHAGES; INTERFERON-GAMMA; GENE-EXPRESSION; REACTIVE OXYGEN; VERO CELLS AB Subtilase cytotoxin (SubAB), which is produced by certain strains of Shiga-toxigenic Escherichia coli (STEC), cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress and caspase-dependent apoptosis. SubAB alters the innate immune response. SubAB pretreatment of macrophages inhibited lipopolysaccharide (LPS)-induced production of both monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor alpha (TNF-alpha). We investigated here the mechanism by which SubAB inhibits nitric oxide (NO) production by mouse macrophages. SubAB suppressed LPS-induced NO production through inhibition of inducible NO synthase (iNOS) mRNA and protein expression. Further, SubAB inhibited LPS-induced I kappa B-alpha phosphorylation and nuclear localization of the nuclear factor-kappa B (NF-kappa B) p65/p50 heterodimer. Reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that SubAB reduced LPS-induced NF-kappa B p65/p50 heterodimer binding to an NF-kappa B binding site on the iNOS promoter. In contrast to the native toxin, a catalytically inactivated SubAB mutant slightly enhanced LPS-induced iNOS expression and binding of NF-kappa B subunits to the iNOS promoter. The SubAB effect on LPS-induced iNOS expression was significantly reduced in macrophages from NF-kappa B1 (p50)-deficient mice, which lacked a DNA-binding subunit of the p65/p50 heterodimer, suggesting that p50 was involved in SubAB-mediated inhibition of iNOS expression. Treatment of macrophages with an NOS inhibitor or expression of SubAB by E. coli increased E. coli survival in macrophages, suggesting that NO generated by macrophages resulted in efficient killing of the bacteria and SubAB contributed to E. coli survival in macrophages. Thus, we hypothesize that SubAB might represent a novel bacterial strategy to circumvent host defense during STEC infection. C1 [Tsutsuki, Hiroyasu; Yahiro, Kinnosuke; Ogura, Kohei; Shimizu, Takeshi; Noda, Masatoshi] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chiba, Japan. [Suzuki, Kotaro; Suto, Akira; Nakajima, Hiroshi] Chiba Univ, Grad Sch Med, Dept Mol Genet, Chiba, Japan. [Nagasawa, Sayaka] Chiba Univ, Grad Sch Med, Dept Legal Med, Chiba, Japan. [Ihara, Hideshi] Osaka Prefecture Univ, Grad Sch Sci, Dept Biol Sci, Osaka, Japan. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Yahiro, K (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chiba, Japan. EM yahirok@faculty.chiba-u.jp FU Ministry of Education, Science, and Culture of Japan; Japan Science and Technology Agency; National Institutes of Health, National Heart, Lung, and Blood Institute FX This work was supported by grants in aid for scientific research from the Ministry of Education, Science, and Culture of Japan and Improvement of Research Environment for Young Researchers from Japan Science and Technology Agency. Joel Moss was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. NR 62 TC 14 Z9 15 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2012 VL 80 IS 11 BP 3939 EP 3951 DI 10.1128/IAI.00581-12 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 022PK UT WOS:000309971600022 PM 22949549 ER PT J AU Bosio, CF Jarrett, CO Gardner, D Hinnebusch, BJ AF Bosio, Christopher F. Jarrett, Clayton O. Gardner, Donald Hinnebusch, B. Joseph TI Kinetics of Innate Immune Response to Yersinia pestis after Intradermal Infection in a Mouse Model SO INFECTION AND IMMUNITY LA English DT Article ID NECROSIS-FACTOR-ALPHA; PRIMARY PNEUMONIC PLAGUE; FLEA-BORNE PLAGUE; V-ANTIGEN; BUBONIC PLAGUE; LYMPH-NODE; PASTEURELLA-PESTIS; DENDRITIC CELLS; FUSION PEPTIDE; III SECRETION AB A hallmark of Yersinia pestis infection is a delayed inflammatory response early in infection. In this study, we use an intradermal model of infection to study early innate immune cell recruitment. Mice were injected intradermally in the ear with wild-type (WT) or attenuated Y. pestis lacking the pYV virulence plasmid (pYV(-)). The inflammatory responses in ear and draining lymph node samples were evaluated by flow cytometry and immunohistochemistry. As measured by flow cytometry, total neutrophil and macrophage recruitment to the ear in WT-infected mice did not differ from phosphate-buffered saline (PBS) controls or mice infected with pYV(-), except for a transient increase in macrophages at 6 h compared to the PBS control. Limited inflammation was apparent even in animals with high bacterial loads (10(5) to 10(6) CFU). In addition, activation of inflammatory cells was significantly reduced in WT-infected mice as measured by CD11b and major histocompatibility complex class II (MHC-II) expression. When mice infected with WT were injected 12 h later at the same intradermal site with purified LPS, Y. pestis did not prevent recruitment of neutrophils. However, significant reduction in neutrophil activation remained compared to that of PBS and pYV(-) controls. Immunohistochemistry revealed qualitative differences in neutrophil recruitment to the skin and draining lymph node, with WT-infected mice producing a diffuse inflammatory response. In contrast, focal sites of neutrophil recruitment were sustained through 48 h postinfection in pYV(-)-infected mice. Thus, an important feature of Y. pestis infection is reduced activation and organization of inflammatory cells that is at least partially dependent on the pYV virulence plasmid. C1 [Bosio, Christopher F.; Jarrett, Clayton O.; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Gardner, Donald] NIAID, Vet Pathol Sect, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Bosio, CF (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. EM bosioch@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was supported by the Division of Intramural Research, NIAID, NIH. NR 54 TC 17 Z9 17 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2012 VL 80 IS 11 BP 4034 EP 4045 DI 10.1128/IAI.00606-12 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 022PK UT WOS:000309971600031 PM 22966041 ER PT J AU Henderson, DK AF Henderson, David K. TI Changing Times, Changing Landscapes: Comparing the Society for Healthcare Epidemiology of America's Infected Provider Guidelines with the Centers for Disease Control and Prevention's Guidelines for Managing Providers Infected with Hepatitis B Virus SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; HBV DNA LEVELS; C VIRUS; PATIENT TRANSMISSION; DENTAL PRACTICE; WORKERS; MANAGEMENT; ANESTHESIOLOGIST; PATHOGENS; SURGEON C1 [Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), Bldg 10,Room 6-1480,10 Ctr Dr, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 36 TC 1 Z9 1 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD NOV PY 2012 VL 33 IS 11 BP 1152 EP 1155 DI 10.1086/668038 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 018MU UT WOS:000309665800014 PM 23041815 ER PT J AU Lewis-Morrarty, E Degnan, KA Chronis-Tuscano, A Rubin, KH Cheah, CSL Pine, DS Henderon, HA Fox, NA AF Lewis-Morrarty, Erin Degnan, Kathryn A. Chronis-Tuscano, Andrea Rubin, Kenneth H. Cheah, Charissa S. L. Pine, Daniel S. Henderon, Heather A. Fox, Nathan A. TI Maternal Over-Control Moderates the Association Between Early Childhood Behavioral Inhibition and Adolescent Social Anxiety Symptoms SO JOURNAL OF ABNORMAL CHILD PSYCHOLOGY LA English DT Article DE Behavioral inhibition; Parenting; Maternal over-control; Social anxiety ID MIDDLE CHILDHOOD; PRESCHOOL-CHILDREN; FAMILY ENVIRONMENT; FOLLOW-UP; TEMPERAMENT; DISORDERS; RISK; WITHDRAWAL; TODDLERS; SHYNESS AB Behavioral inhibition (BI) and maternal over-control are early risk factors for later childhood internalizing problems, particularly social anxiety disorder (SAD). Consistently high BI across childhood appears to confer risk for the onset of SAD by adolescence. However, no prior studies have prospectively examined observed maternal over-control as a risk factor for adolescent social anxiety (SA) among children initially selected for BI. The present prospective longitudinal study examines the direct and indirect relations between these early risk factors and adolescent SA symptoms and SAD, using a multi-method approach. The sample consisted of 176 participants initially recruited as infants and assessed for temperamental reactivity to novel stimuli at age 4 months. BI was measured via observations and parent-report across multiple assessments between the ages of 14 months and 7 years. Maternal over-control was assessed observationally during parent-child interaction tasks at 7 years. Adolescents (ages 14-17 years) and parents provided independent reports of adolescent SA symptoms. Results indicated that higher maternal over-control at 7 years predicted higher SA symptoms and lifetime rates of SAD during adolescence. Additionally, there was a significant interaction between consistently high BI and maternal over-control, such that patterns of consistently high BI predicted higher adolescent SA symptoms in the presence of high maternal over-control. High BI across childhood was not significantly associated with adolescent SA symptoms when children experienced low maternal over-control. These findings have the potential to inform prevention and early intervention programs by indentifying particularly at-risk youth and specific targets of treatment. C1 [Lewis-Morrarty, Erin; Chronis-Tuscano, Andrea] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Degnan, Kathryn A.; Rubin, Kenneth H.; Fox, Nathan A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Cheah, Charissa S. L.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. [Pine, Daniel S.] NIMH, Div Intramural Res, Bethesda, MD 20892 USA. [Henderon, Heather A.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. RP Chronis-Tuscano, A (reprint author), Univ Maryland, Dept Psychol, 1123K Biol Psychol Bldg, College Pk, MD 20742 USA. EM achronis@umd.edu FU NICHD NIH HHS [R37HD17899]; NIMH NIH HHS [R01MH07454] NR 65 TC 31 Z9 32 U1 3 U2 55 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0627 J9 J ABNORM CHILD PSYCH JI J. Abnorm. Child Psychol. PD NOV PY 2012 VL 40 IS 8 BP 1363 EP 1373 DI 10.1007/s10802-012-9663-2 PG 11 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 021GB UT WOS:000309872200013 PM 22821448 ER PT J AU Hoppin, JA Long, S Umbach, DM Lubin, JH Starks, SE Gerr, F Thomas, K Hines, CJ Weichenthal, S Kamel, F Koutros, S Alavanja, M Freeman, LEB Sandler, DP AF Hoppin, Jane A. Long, Stuart Umbach, David M. Lubin, Jay H. Starks, Sarah E. Gerr, Fred Thomas, Kent Hines, Cynthia J. Weichenthal, Scott Kamel, Freya Koutros, Stella Alavanja, Michael Freeman, Laura E. Beane Sandler, Dale P. TI Lifetime organophosphorous insecticide use among private pesticide applicators in the Agricultural Health Study SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE pesticide use; farming; organophosphorous insecticide AB Organophosphorous insecticides (OPs) are the most commonly used insecticides in US agriculture, but little information is available regarding specific OP use by individual farmers. We describe OP use for licensed private pesticide applicators from Iowa and North Carolina in the Agricultural Health Study (AHS) using lifetime pesticide use data from 701 randomly selected male participants collected at three time periods. Of 27 OPs studied, 20 were used by >1%. Overall, 95% had ever applied at least one OP. The median number of different OPs used was 4 (maximum = 13). Malathion was the most commonly used OP (74%) followed by chlorpyrifos (54%). OP use declined over time. At the first interview (1993-1997), 68% of participants had applied OPs in the past year; by the last interview (2005-2007), only 42% had. Similarly, median annual application days of OPs declined from 13.5 to 6 days. Although OP use was common, the specific OPs used varied by state, time period, and individual. Much of the variability in OP use was associated with the choice of OP, rather than the frequency or duration of application. Information on farmers' OP use enhances our ability to characterize and understand the potential health effects of multiple OP exposures. C1 [Hoppin, Jane A.; Kamel, Freya; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Long, Stuart] WESTAT Corp, Durham, NC USA. [Umbach, David M.] NIEHS, Biost Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Lubin, Jay H.] NCI, Biostat Branch, NIH, DHHS, Rockville, MD USA. [Starks, Sarah E.; Gerr, Fred] Univ IA, Coll Publ Hlth, Iowa City, IA USA. [Thomas, Kent] US EPA, Human Exposure & Atmosphere Sci Div, Res Triangle Pk, NC 27711 USA. [Hines, Cynthia J.] NIOSH, Div Surveillance Hazard Evaluat & Field Studies, Cincinnati, OH 45226 USA. [Weichenthal, Scott] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Koutros, Stella; Alavanja, Michael; Freeman, Laura E. Beane] NCI, OEEB, DCEG, Rockville, MD USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, DHHS, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01-ES049030]; National Cancer Institute [Z01-CP010119]; National Institute for Occupational Safety and Health FX We thank Dr. Joe Coble for his efforts to create the AHS pesticide use data base. This work was supported by the intramural research program of the National Institutes of Health, the National Institute of Environmental Health Sciences (Z01-ES049030), National Cancer Institute (Z01-CP010119), and the National Institute for Occupational Safety and Health. The United States Environmental Protection Agency through its Office of Research and Development collaborated in the research described here; it has been subjected to Agency review and approved for publication. NR 17 TC 5 Z9 5 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD NOV-DEC PY 2012 VL 22 IS 6 BP 584 EP 592 DI 10.1038/jes.2012.79 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 022US UT WOS:000309989900006 PM 22854518 ER PT J AU Yang, DM Lyashkov, AE Li, Y Ziman, BD Lakatta, EG AF Yang, Dongmei Lyashkov, Alexey E. Li, Yue Ziman, Bruce D. Lakatta, Edward G. TI RGS2 overexpression or G(i) inhibition rescues the impaired PKA signaling and slow AP firing of cultured adult rabbit pacemaker cells SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Cultured adult rabbit sinoatrial node cells; Action potential firing rate; PKA-dependent protein phosphorylation; Type2 regulator of G-protein signaling ID SINOATRIAL NODAL CELLS; CARDIAC MYOCYTES; DIASTOLIC DEPOLARIZATION; HEARTS PACEMAKER; CA2+ RELEASES; SINUS NODE; CHANNEL; OSCILLATIONS; AUTOMATICITY; ACTIVATION AB Freshly isolated adult rabbit sinoatrial node cells (f-SANC) are an excellent model for studies of autonomic signaling, but are not amenable to genetic manipulation. We have developed and characterized a stable cultured rabbit SANC (c-SANC) model that is suitable for genetic manipulation to probe mechanisms of spontaneous action potential (AP) firing. After 48 h in culture, c-SANC generate stable, rhythmic APs at 34+/-0.5 degrees C, at a rate that is 50% less than f-SANC. In c-vs. f-SANC: AP duration is prolonged; phosphorylation of phospholamban at Ser(16) and type2 ryanodine receptor (RyR2) at Ser(2809) are reduced; and the level of type2 regulator of G-protein signaling (RGS2), that facilitates adenylyl cyclases/cAMP/protein kinase A (PKA) via G(i) inhibition, is substantially reduced. Consistent with the interpretation that cAMP/PKA signaling becomes impaired in c-SANC, acute beta-adrenergic receptor stimulation increases phospholamban and RyR2 phosphorylation, enhances RGS2-labeling density, and accelerates the AP firing rate to the similar maximum in c- and f-SANC. Specific PKA inhibition completely inhibits all beta-adrenergic receptor effects. Adv-RGS2 infection, or pertussis toxin treatment to disable G(i)-signaling, each partially rescues the c-SANC spontaneous AP firing rate. Thus, a G(i)-dependent reduction in PKA-dependent protein phosphorylation, including that of Ca2+ cycling proteins, reduces the spontaneous AP firing rate of c-SANC, and can be reversed by genetic or pharmacologic manipulation of PKA signaling. Published by Elsevier Ltd. C1 [Yang, Dongmei; Lyashkov, Alexey E.; Li, Yue; Ziman, Bruce D.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, IRP, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Lab Cardiovasc Sci, IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging, NIH; Oak Ridge Associated Universities' Research Associates/Specialists Program at NIH FX This work was supported by the Intramural Research Program of the National Institute on Aging, NIH. D.Y. was supported in part by an appointment to the Oak Ridge Associated Universities' Research Associates/Specialists Program at NIH. NR 32 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD NOV PY 2012 VL 53 IS 5 BP 687 EP 694 DI 10.1016/j.yjmcc.2012.08.007 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 028AC UT WOS:000310394200013 PM 22921807 ER PT J AU Jin, J Cheng, Y Zhang, YQ Wood, W Peng, Q Hutchison, E Mattson, MP Becker, KG Duan, WZ AF Jin, Jing Cheng, Yong Zhang, Yongqing Wood, William Peng, Qi Hutchison, Emmette Mattson, Mark P. Becker, Kevin G. Duan, Wenzhen TI Interrogation of brain miRNA and mRNA expression profiles reveals a molecular regulatory network that is perturbed by mutant huntingtin SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE gene array; Huntington's disease; miR-200; miRNA array; Trim2 ID TYROSINE-PHOSPHATASE-DELTA; CYSTEINE-STRING PROTEIN; DOPAMINE-RECEPTOR D2; GENE-EXPRESSION; NEUROTROPHIC FACTOR; MOUSE MODEL; PTP-SIGMA; DISEASE; NEURONS; MICE AB Emerging evidence indicates that microRNAs (miRNAs) may play an important role in the pathogenesis of Huntington's disease (HD). To identify the individual miRNAs that are altered in HD and may therefore regulate a gene network underlying mutant huntingtin-induced neuronal dysfunction in HD, we performed miRNA array analysis combined with mRNA profiling in the cerebral cortex from N171-82Q HD mice. Expression profiles of miRNAs as well as mRNAs in HD mouse cerebral cortex were analyzed and confirmed at different stages of disease progression; the most significant changes of miRNAs in the cerebral cortex were also detected in the striatum of HD mice. Our results revealed a significant alteration of miR-200 family members, miR-200a, and miR-200c in the cerebral cortex and the striatum, at the early stage of disease progression in N171-82Q HD mice. We used a coordinated approach to integrate miRNA and mRNA profiling, and applied bioinformatics to predict a target gene network potentially regulated by these significantly altered miRNAs that might be involved in HD disease progression. Interestingly, miR-200a and miR-200c are predicted to target genes regulating synaptic function, neurodevelopment, and neuronal survival. Our results suggest that altered expression of miR-200a and miR-200c may interrupt the production of proteins involved in neuronal plasticity and survival, and further investigation of the involvement of perturbed miRNA expression in HD pathogenesis is warranted, and may lead to reveal novel approaches for HD therapy. C1 [Jin, Jing; Cheng, Yong; Peng, Qi; Duan, Wenzhen] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Neurobiol, Baltimore, MD 21205 USA. [Zhang, Yongqing; Wood, William; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Hutchison, Emmette; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Duan, Wenzhen] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD USA. RP Duan, WZ (reprint author), Johns Hopkins Sch Med, Div Neurobiol, Dept Psychiat & Behav Sci, CMSC 8-121,600 N Wolfe St, Baltimore, MD 21287 USA. EM wduan2@jhmi.edu OI Becker, Kevin/0000-0002-6794-6656 FU NINDS; CHDI; NIA FX We thank Dr. Stephen Elledge at Harvard University for providing us pPRIME-CMV-GFP-FF3 vector and we acknowledge Dr. Pamela Talalay for dedicated editorial assistance. Dr. Marcy Macdonald provided us striatal cells. This work was supported by NINDS (WD), CHDI (W. D.), NIA Intramural Research Program (M. P. M, K. G. B). All authors have no conflict of interest to declare. NR 62 TC 23 Z9 23 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2012 VL 123 IS 4 BP 477 EP 490 DI 10.1111/j.1471-4159.2012.07925.x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 021WU UT WOS:000309916900003 PM 22906125 ER PT J AU Yu, X Erzinger, MM Pietsch, KE Cervoni-Curet, FN Whang, J Niederhuber, J Sturla, SJ AF Yu, Xiang Erzinger, Melanie M. Pietsch, Kathryn E. Cervoni-Curet, Frances N. Whang, John Niederhuber, John Sturla, Shana J. TI Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID IN-VIVO; ALKENAL/ONE OXIDOREDUCTASE; ANTICANCER AGENTS; TUMOR-CELLS; PRECLINICAL EVALUATION; CHEMOPREVENTIVE AGENT; ENZYME INDUCERS; DT-DIAPHORASE; CANCER-CELLS; MITOMYCIN-C AB Prostaglandin reductase 1 (PTGR1) is a highly inducible enzyme with enone reductase activity. Previous studies demonstrated the role of rat PTGR1 in the activation of acylfulvene analogs, a class of antitumor natural product derivatives. Of these, hydroxymethylacylfulvene (HMAF) was in advanced clinical development for the treatment of advanced solid tumors, including prostate, ovarian, and pancreatic cancers. However, the efficiency of human PTGR1 in activating acylfulvenes and its potential to enhance therapeutic efficacy have remained uncharacterized. In this study, human PTGR1 was polymerase chain reaction-cloned and purified. Conversion of HMAF to its cellular metabolite by the purified enzyme proceeded at a 20-fold higher rate than with the rat variant of the enzyme. The K-m was 4.9 mu M, which was 40-fold lower than for the rat variant and similar to the therapeutic dose. Human cell lines, including colon cancer lines, were transfected with a vector containing rat PTGR1 or human PTGR1, and cell viability was examined after dosing with HMAF. New data obtained in this study suggest that transfection with human PTGR1, or its induction in colon and liver cancer cell lines with 1,2-dithiol-3-thione, enhances susceptibility to the cytotoxic influences of HMAF by 2- to 10-fold. Furthermore, similar or enhanced enzyme induction and HMAF toxicity results from preconditioning cancer cells with the bioactive food components curcumin and resveratrol. The functional impact of PTGR1 induction in human cells and chemical-based strategies for its activation can provide important knowledge for the design of clinical strategies involving reductively activated cytotoxic chemotherapeutics. C1 [Yu, Xiang; Cervoni-Curet, Frances N.; Whang, John; Niederhuber, John] NCI, Canc Cell & Biol Branch, NIH, Bethesda, MD 20892 USA. [Erzinger, Melanie M.; Pietsch, Kathryn E.; Sturla, Shana J.] ETH, Inst Food Nutr & Hlth, Zurich, Switzerland. RP Yu, X (reprint author), NCI, Canc Cell & Biol Branch, NIH, Bethesda, MD 20892 USA. EM xshawnyu@gmail.com RI Sturla, Shana/B-4028-2015 FU National Institutes of Health National Cancer Institute [CA123007]; Swiss National Science Foundation [CRSII3_136247]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the National Institutes of Health National Cancer Institute [Grant CA123007]; the Swiss National Science Foundation [Grant CRSII3_136247]; and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 41 TC 13 Z9 14 U1 0 U2 17 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD NOV PY 2012 VL 343 IS 2 BP 426 EP 433 DI 10.1124/jpet.112.195768 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 022RK UT WOS:000309979400019 PM 22895897 ER PT J AU Goldstein, RB Dawson, DA Chou, P Grant, BF AF Goldstein, Rise B. Dawson, Deborah A. Chou, Patricia Grant, Bridget F. TI Sex Differences in Prevalence and Comorbidity of Alcohol and Drug Use Disorders: Results From Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID SUBSTANCE USE DISORDERS; PSYCHIATRIC DIAGNOSTIC MODULES; GENERAL-POPULATION SAMPLE; IV AUDADIS-IV; GENDER-DIFFERENCES; UNITED-STATES; PERSONALITY-DISORDERS; TREATMENT-SEEKING; ANXIETY DISORDERS; MENTAL-DISORDERS AB Objective: The present study examined sex differences in lifetime Axis I and II psychiatric comorbidity of DSM-1V alcohol use disorders (AUDs) and drug use disorders (DUDS) among general population U.S. adults. Method: Using data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions, Wave 2 lifetime prevalences of each disorder comorbid with alcohol abuse, alcohol dependence, drug abuse, and drug dependence were compared between men and women. Sex-specific associations of alcohol, any drug, and cannabis- and cocaine-specific abuse and dependence with each comorbid disorder were examined using logistic regression, first with adjustment for sociodemographic variables and then with additional adjustment for all other psychiatric disorders. Results: Prevalences of most comorbid disorders differed significantly by sex among respondents with each AUD and DUD. However, after adjustment for sociodemographic characteristics and additional co-occurring psychiatric diagnoses, there were few sex differences in unique comorbid associations of specific AUDs and DUDs with specific psychiatric disorders. Conclusions: Rates of psychiatric disorders comorbid with AUDs and DUDs indicate large burdens of morbidity in both sexes, highlighting the need for careful assessment and appropriate treatment of both substance use and mental health disorders. The unique comorbid associations with AUDs and DUDs identified in this study further indicate the need for prospective etiological research to characterize these associations, their underlying mechanisms, and the possible sex specificity of those mechanisms. (J Stud. Alcohol Drugs, 73, 938-950, 2012) C1 [Goldstein, Rise B.; Dawson, Deborah A.; Chou, Patricia; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Goldstein, RB (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Room 3071,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse; National Institutes of Health, NIAAA FX The National Epidemiologic Survey on Alcohol and Related Conditions is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support from the National Institute on Drug Abuse. This research was supported in part by the Intramural Program of the National Institutes of Health, NIAAA. A preliminary version of parts of this article was presented at the Joint Research Society on Alcoholism/International Society for Biomedical Research on Alcoholism Scientific Conference, June 2008, Washington, DC. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of sponsoring organizations, agencies, or the U.S. government. NR 63 TC 27 Z9 28 U1 1 U2 25 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD NOV PY 2012 VL 73 IS 6 BP 938 EP 950 PG 13 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 023NO UT WOS:000310041900010 PM 23036212 ER PT J AU Khozin, S Roth, MJ Rajan, A Smith, K Thomas, A Berman, A Giaccone, G AF Khozin, Sean Roth, Mark J. Rajan, Arun Smith, Karen Thomas, Anish Berman, Arlene Giaccone, Giuseppe TI Hepatoid Carcinoma of the Lung with Anaplastic Lymphoma Kinase Gene Rearrangement SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article ID FEATURES C1 [Khozin, Sean; Rajan, Arun; Thomas, Anish; Berman, Arlene; Giaccone, Giuseppe] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Roth, Mark J.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Smith, Karen] Medstar Washington Hosp Ctr, Dept Med, Div Hematol & Oncol, Washington, DC USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program, National Cancer Institute, National Institutes of Health FX Financial support for this study was provided by Intramural Research Program, National Cancer Institute, National Institutes of Health. NR 5 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2012 VL 7 IS 11 BP E29 EP E31 DI 10.1097/JTO.0b013e3182697a23 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 023SZ UT WOS:000310057000002 PM 23070248 ER PT J AU Agochukwu, NQ Metwalli, AR Kutikov, A Pinto, PA Linehan, WM Bratslavsky, G AF Agochukwu, Nnenaya Q. Metwalli, Adam R. Kutikov, Alexander Pinto, Peter A. Linehan, W. Marston Bratslavsky, Gennady TI Economic Burden of Repeat Renal Surgery on Solitary Kidney-Do the Ends Justify the Means? A Cost Analysis SO JOURNAL OF UROLOGY LA English DT Article DE kidney; neoplasm recurrence, local; nephrectomy; reoperation; costs and cost analysis ID QUALITY-OF-LIFE; PARTIAL NEPHRECTOMY; DIALYSIS PATIENTS; ESRD PATIENTS; HEMODIALYSIS; OUTCOMES; BELIEFS; ACCESS; FEASIBILITY; DISEASE AB Purpose: Despite the high morbidity of repeat renal surgery in patients with multifocal recurrent renal carcinoma, in most patients adequate renal function is preserved to obviate the need for dialysis. To our knowledge the economic burden of repeat renal surgery has not been evaluated. We provide a cost analysis for patients requiring repeat renal surgery on a solitary kidney. Materials and Methods: We reviewed the charts of patients treated at the National Cancer Institute who required repeat renal surgery from 1989 to 2010. Functional, oncological and surgical outcomes were evaluated and the costs of repeat renal surgery were calculated. We then compared costs in a cohort of 33 patients who underwent repeat renal surgery on a solitary kidney and in a hypothetical patient cohort treated with uncomplicated nephrectomy, fistula placement and dialysis. All costs were calculated based on Medicare reimbursement rates derived from CPT codes. Cost analysis was performed. Results: Despite a high 45% complication rate, 87% of patients maintained renal function that was adequate to avoid dialysis and 96% remained metastasis free at an average followup of 3.12 years (range 0.3 to 16.4). Compared to the hypothetical dialysis cohort, the financial benefit of repeat renal surgery was reached at 0.68 years. Conclusions: Repeat renal surgery is a viable alternative for patients with multifocal renal cell carcinoma requiring multiple surgical interventions, especially when left with a solitary kidney. Despite the high complication rate, renal function is preserved in most patients and they have an excellent oncological outcome. The financial benefit of repeat renal surgery is reached at less than 1 year. C1 [Bratslavsky, Gennady] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. [Agochukwu, Nnenaya Q.; Metwalli, Adam R.; Pinto, Peter A.; Linehan, W. Marston; Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kutikov, Alexander] Fox Chase Canc Ctr, Dept Urol, Philadelphia, PA 19111 USA. RP Bratslavsky, G (reprint author), SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. EM bratslag@upstate.edu RI Kutikov, Alexander/L-8707-2014 FU Intramural NIH HHS [ZIA BC011038-05, ZIA BC011043-05, ZIE BC011023-05, ZIA BC011028-05] NR 19 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD NOV PY 2012 VL 188 IS 5 BP 1695 EP 1700 DI 10.1016/j.juro.2012.07.029 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 028QY UT WOS:000310438600011 PM 22998899 ER PT J AU Tolea, MI Costa, PT Terracciano, A Ferrucci, L Faulkner, K Coday, MC Ayonayon, HN Simonsick, EM AF Tolea, Magdalena I. Costa, Paul T., Jr. Terracciano, Antonio Ferrucci, Luigi Faulkner, Kimberly Coday, Mathilda (Mace) C. Ayonayon, Hilsa N. Simonsick, Eleanor M. CA Hlth Aging Boby Composition Study TI Associations of Openness and Conscientiousness With Walking Speed Decline: Findings From the Health, Aging, and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Chronic conditions; Conscientiousness; Lifestyle factors; Openness to experience; Walking speed ID ALL-CAUSE MORTALITY; PERSONALITY-TRAITS; 5-FACTOR MODEL; OLDER-ADULTS; PRIMARY-CARE; PREDICTORS; COMMUNITY; METAANALYSIS; POPULATION; STABILITY AB Objectives. The objective of this study was to explore the associations between openness to experience and conscientiousness, two dimensions of the five-factor model of personality, and usual gait speed and gait speed decline. Method. Baseline analyses were conducted on 907 men and women aged 71-82 years participating in the Cognitive Vitality substudy of the Health, Aging, and Body Composition study. The longitudinal analytic sample consisted of 740 participants who had walking speed assessed 3 years later. Results. At baseline, gait speed averaged 1.2 m/s, and an average decline of 5% over the 3-year follow-up period was observed. Higher conscientiousness was associated with faster initial walking speed and less decline in walking speed over the study period, independent of sociodemographic characteristics. Lifestyle factors and disease status appear to play a role in the baseline but not the longitudinal association between conscientiousness and gait speed. Openness was not associated with either initial or decline in gait speed. Discussion. These findings extend the body of evidence suggesting a protective association between conscientiousness and physical function to performance-based assessment of gait speed. Future studies are needed to confirm these associations and to explore mechanisms that underlie the conscientiousness mobility connection in aging adults. C1 [Tolea, Magdalena I.] Univ Missouri, Gerontol Program, Sch Social Work, St Louis, MO 63121 USA. [Costa, Paul T., Jr.; Terracciano, Antonio] NIA, Lab Cognit & Personal, Baltimore, MD 21224 USA. [Ferrucci, Luigi; Simonsick, Eleanor M.] NIA, Longitudinal Studies Sect, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Faulkner, Kimberly] NIOSH, Natl Personal Protect Technol Lab OD, Atlanta, GA USA. [Coday, Mathilda (Mace) C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Tolea, MI (reprint author), Univ Missouri, Gerontol Program, Sch Social Work, St Louis, MO 63121 USA. EM toleam@umsl.edu OI Costa, Paul/0000-0003-4375-1712 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA); NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NEO-PI-R FX This work was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA). The Health ABC Study is funded by NIA contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. H.N.A. was partly supported by one of these contracts. P. T. C. receives royalties from the NEO-PI-R. NR 32 TC 9 Z9 9 U1 2 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD NOV PY 2012 VL 67 IS 6 BP 705 EP 711 DI 10.1093/geronb/gbs030 PG 7 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 027QQ UT WOS:000310368500007 PM 22451484 ER PT J AU Tolea, MI Ferrucci, L Costa, PT Faulkner, K Rosano, C Satterfield, S Ayonayon, HN Simonsick, EM AF Tolea, Magdalena I. Ferrucci, Luigi Costa, Paul T. Faulkner, Kimberly Rosano, Caterina Satterfield, Suzanne Ayonayon, Hilsa N. Simonsick, Eleanor M. CA Hlth Aging Body Composition Study TI Personality and Reduced Incidence of Walking Limitation in Late Life: Findings From the Health, Aging, and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Conscientiousness; Functional limitations; Openness to experience; Personality ID ALL-CAUSE MORTALITY; OLDER-ADULTS; MOBILITY LIMITATION; PREDICTIVE-VALIDITY; FUNCTIONAL STATUS; PHYSICAL-ACTIVITY; STYLE FACTORS; DISABILITY; COMMUNITY; RISK AB To examine the association between openness to experience and conscientiousness and incident reported walking limitation. The study population consisted of 786 men and women aged 71-81 years (M = 75 years, SD = 2.7) participating in the Health, Aging, and Body Composition-Cognitive Vitality Substudy. Nearly 20% of participants (155/786) developed walking limitation during 6 years of follow-up. High openness was associated with a reduced risk of walking limitation (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.69-0.98), independent of sociodemographic factors, health conditions, and conscientiousness. This association was not mediated by lifestyle factors and was not substantially modified by other risk factors for functional disability. Conscientiousness was not associated with risk of walking limitation (HR = 0.91, 95% CI = 0.77-1.07). Findings suggest that personality dimensions, specifically higher openness to experience, may contribute to functional resilience in late life. C1 [Tolea, Magdalena I.] Univ Missouri, Gerontol Program, Sch Social Work, St Louis, MO 63121 USA. [Ferrucci, Luigi; Simonsick, Eleanor M.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Costa, Paul T.] NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. [Faulkner, Kimberly] NIOSH, Natl Personal Protect Technol Lab OD, Atlanta, GA USA. [Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Tolea, MI (reprint author), Univ Missouri, Gerontol Program, Sch Social Work, 1 Univ Blvd,107 Bellerive Hall, St Louis, MO 63121 USA. EM toleam@umsl.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Costa, Paul/0000-0003-4375-1712 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; Intramural Research Program of the National Institutes of Health, NIA; NEO-PI-R FX The Health ABC Study is funded by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. H.N. Ayonayon was partly supported by one of these contracts. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, NIA. P. T. Costa receives royalties from the NEO-PI-R. NR 46 TC 9 Z9 9 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD NOV PY 2012 VL 67 IS 6 BP 712 EP 719 DI 10.1093/geronb/gbs001 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 027QQ UT WOS:000310368500008 PM 22437204 ER PT J AU Weil, EJ Lemley, KV Mason, CC Yee, B Jones, LI Blouch, K Lovato, T Richardson, M Myers, BD Nelson, RG AF Weil, E. Jennifer Lemley, Kevin V. Mason, Clinton C. Yee, Berne Jones, Lois I. Blouch, Kristina Lovato, Tracy Richardson, Meghan Myers, Bryan D. Nelson, Robert G. TI Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy SO KIDNEY INTERNATIONAL LA English DT Article DE diabetic glomerulopathy; electron microscopy; endothelial cells; glomerular filtration rate; podocytes ID STAGE RENAL-DISEASE; VEGF-A EXPRESSION; PIMA-INDIANS; FILTRATION-RATE; PROTEINURIA; MELLITUS; INJURY; DYSFUNCTION; NUMBER; MICROALBUMINURIA AB Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from 10 kidney donors (not American Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study. Kidney International (2012) 82, 1010-1017; doi:10.1038/ki.2012.234; published online 20 June 2012 C1 [Weil, E. Jennifer; Mason, Clinton C.; Jones, Lois I.; Lovato, Tracy; Richardson, Meghan; Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ 85014 USA. [Lemley, Kevin V.] Univ So Calif, Keck Sch Med, Dept Pediat, Div Nephrol,Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA. [Yee, Berne] SW Kidney Inst, Phoenix, AZ USA. [Blouch, Kristina; Myers, Bryan D.] Stanford Univ, Sch Med, Div Nephrol, Stanford, CA 94305 USA. RP Nelson, RG (reprint author), NIDDK, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM rnelson@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association [1-08-CR-42] FX We are indebted to the participants of this investigation and to the doctors, nurses, and support staff involved in collecting and processing the data. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the American Diabetes Association (Clinical Science Award 1-08-CR-42). NR 40 TC 71 Z9 78 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD NOV PY 2012 VL 82 IS 9 BP 1010 EP 1017 DI 10.1038/ki.2012.234 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 022SD UT WOS:000309981700010 PM 22718189 ER PT J AU Levy, MA Freymann, JB Kirby, JS Fedorov, A Fennessy, FM Eschrich, SA Berglund, AE Fenstermacher, DA Tan, YQ Guo, XT Casavant, TL Brown, BJ Braun, TA Dekker, A Roelofs, E Mountz, JM Boada, F Laymon, C Oborski, M Rubin, DL AF Levy, Mia A. Freymann, John B. Kirby, Justin S. Fedorov, Andriy Fennessy, Fiona M. Eschrich, Steven A. Berglund, Anders E. Fenstermacher, David A. Tan, Yongqiang Guo, Xiaotao Casavant, Thomas L. Brown, Bartley J. Braun, Terry A. Dekker, Andre Roelofs, Erik Mountz, James M. Boada, Fernando Laymon, Charles Oborski, Matt Rubin, Daniel L. TI Informatics methods to enable sharing of quantitative imaging research data SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Quantitative Imaging Network; Data sharing; Imaging informatics; Research informatics; Image repository; Image meta-data repository; Clinical data repository; System architecture AB Introduction: The National Cancer Institute Quantitative Research Network (QIN) is a collaborative research network whose goal is to share data, algorithms and research tools to accelerate quantitative imaging research. A challenge is the variability in tools and analysis platforms used in quantitative imaging. Our goal was to understand the extent of this variation and to develop an approach to enable sharing data and to promote reuse of quantitative imaging data in the community. Methods: We performed a survey of the current tools in use by the QIN member sites for representation and storage of their QIN research data including images, image meta-data and clinical data. We identified existing systems and standards for data sharing and their gaps for the QIN use case. We then proposed a system architecture to enable data sharing and collaborative experimentation within the QIN. Results: There are a variety of tools currently used by each QIN institution. We developed a general information system architecture to support the QIN goals. We also describe the remaining architecture gaps we are developing to enable members to share research images and image meta-data across the network. Conclusions: As a research network, the QIN will stimulate quantitative imaging research by pooling data, algorithms and research tools. However, there are gaps in current functional requirements that will need to be met by future informatics development. Special attention must be given to the technical requirements needed to translate these methods into the clinical research workflow to enable validation and qualification of these novel imaging biomarkers. (C) 2012 Elsevier Inc. All rights reserved. C1 [Levy, Mia A.] Vanderbilt Univ, Dept Biomed Informat & Med, Div Hematol & Oncol, Sch Med, Nashville, TN 37232 USA. [Freymann, John B.; Kirby, Justin S.] SAIC Frederick Inc, NCI Frederick, Clin Res Directorate CMRP, Ft Detrick, MD 21702 USA. [Fedorov, Andriy; Fennessy, Fiona M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Eschrich, Steven A.; Berglund, Anders E.; Fenstermacher, David A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Tan, Yongqiang; Guo, Xiaotao] Columbia Univ, New York, NY USA. [Casavant, Thomas L.; Brown, Bartley J.; Braun, Terry A.] Univ Iowa, Holden Comprehens Canc Ctr, Ctr Bioinformat & Computat Biol, Iowa City, IA USA. [Dekker, Andre; Roelofs, Erik] Maastricht Univ, Med Ctr, Dept Radiat Oncol MAASTRO, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands. [Mountz, James M.; Boada, Fernando; Laymon, Charles; Oborski, Matt] Univ Pittsburgh, Pittsburgh, PA USA. [Rubin, Daniel L.] Stanford Univ, Dept Radiol & Med Biomed Informat Res, Sch Med, Stanford, CA 94305 USA. RP Levy, MA (reprint author), Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. EM mia.levy@vanderbilt.edu; freymannj@mail.nih.gov; kirbyju@mail.nih.gov; fedorov@bwh.harvard.edu; ffennessy@partners.org; steven.eschrich@moffitt.org; anders.berglund@moffiit.org; david.fenstermacher@moffitt.org; yt2314@columbia.edu; xg2145@columbia.edu; tomc@eng.uiowa.edu; bbrown@eng.uiowa.edu; tabraun@eng.uiowa.edu; andre.dekker@maastro.nl; erik.roelofs@maastro.nl; mountzjm@upmc.edu; boadfe@upmc.edu; cml14@pitt.edu; oborskimj@upmc.edu; dlrubin@stanford.edu RI Eschrich, Steven/K-6848-2013; Guo, Xiaotao /L-7680-2014; OI Roelofs, Erik/0000-0003-2172-8669; Dekker, Andre/0000-0002-0422-7996; Fedorov, Andrey/0000-0003-4806-9413 FU NIH/NCI [PAR-11-150]; NCI [HHSN261200800001E]; caBIG Imaging Workspace [98411XSB2] FX NIH/NCI PAR-11-150, NCI contract no. HHSN261200800001E, caBIG Imaging Workspace contract no. 98411XSB2. NR 16 TC 3 Z9 5 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD NOV PY 2012 VL 30 IS 9 SI SI BP 1249 EP 1256 DI 10.1016/j.mri.2012.04.007 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 022GO UT WOS:000309946000006 PM 22770688 ER PT J AU Chang, LC Walker, L Pierpaoli, C AF Chang, Lin-Ching Walker, Lindsay Pierpaoli, Carlo TI Informed RESTORE: A method for robust estimation of diffusion tensor from low redundancy datasets in the presence of physiological noise artifacts SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE RESTORE; diffusion tensor; robust estimation; artifact; outlier; trace; fractional anisotropy ID DISTORTION CORRECTION; HUMAN BRAIN; B-MATRIX; MRI DATA; SCHEMES; TISSUES; MOTION; ECHO; EPI AB Physiological noise artifacts, especially those originating from cardiac pulsation and subject motion, are common in clinical Diffusion tensor-MRI acquisitions. Previous works show that signal perturbations produced by artifacts can be severe and neglecting to account for their contribution can result in erroneous diffusion tensor values. The Robust Estimation of Tensors by Outlier Rejection (RESTORE) method has been shown to be an effective strategy for improving tensor estimation on a voxel-by-voxel basis in the presence of artifactual data points in diffusion-weighted images. In this article, we address potential instabilities that may arise when using RESTORE and propose practical constraints to improve its usability. Moreover, we introduce a method, called informed RESTORE designed to remove physiological noise artifacts in datasets acquired with low redundancy (less than 3040 diffusion-weighted image volumes)a condition in which the original RESTORE algorithm may converge to an incorrect solution. This new method is based on the notion that physiological noise is more likely to result in signal dropouts than signal increases. Results from both Monte Carlo simulation and clinical diffusion data indicate that informed RESTORE performs very well in removing physiological noise artifacts for low redundancy diffusion-weighted image datasets. Magn Reson Med, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Chang, Lin-Ching] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. [Walker, Lindsay] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Walker, Lindsay; Pierpaoli, Carlo] NICHHD, NIH, Bethesda, MD 20892 USA. RP Chang, LC (reprint author), Catholic Univ Amer, Dept Elect Engn & Comp Sci, 620 Michigan Ave NE, Washington, DC 20064 USA. EM changl@cua.edu FU Department of Defense through the Center for Neuroscience and Regenerative Medicine; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Grant sponsors: The Department of Defense through the Center for Neuroscience and Regenerative Medicine, the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 35 TC 36 Z9 36 U1 4 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD NOV PY 2012 VL 68 IS 5 BP 1654 EP 1663 DI 10.1002/mrm.24173 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 023UR UT WOS:000310062300034 PM 22287298 ER PT J AU Machado-Vieira, R Mallinger, AG AF Machado-Vieira, Rodrigo Mallinger, Alan G. TI Abnormal function of monoamine oxidase-A in comorbid major depressive disorder and cardiovascular disease: Pathophysiological and therapeutic implications (Review) SO MOLECULAR MEDICINE REPORTS LA English DT Article DE depression; cardiovascular disease; MAO; noradrenaline; comorbidity; oxidative stress; inflammation ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; CENTRAL-NERVOUS-SYSTEM; OXIDATIVE STRESS; ARTERY-DISEASE; MAO-A; TRYPTOPHAN DEPLETION; GENE PROMOTER; RISK-FACTOR; REGULATORY POLYMORPHISM AB The association between major depressive disorder (MDD) and cardiovascular disease (CVD) is among the best described medical comorbidities. The presence of MDD increases the risk of cardiac admissions and mortality and increases healthcare costs in patients with CVD, and similarly, CVD affects the course and outcome of MDD. The potential shared biological mechanisms involved in these comorbid conditions are not well known. However, the enzyme monoamine oxidase-A (MAO-A), which has a key role in the degradation of catecholamines, has been associated with the pathophysiology and therapeutics of both MDD and CVD. Increased MAO-A activity results in the dysregulation of downstream targets of this enzyme and thus affects the pathophysiology of the two diseases. These deleterious effects include altered noradrenaline turnover, with a direct elevation in oxidative stress parameters, as well as increased platelet activity and cytokine levels. These effects were shown to be reversed by MAO inhibitors. Here, a model describing a key role for the MAO-A in comorbid MDD and CVD is proposed, with focus on the shared pathophysiological mechanisms and the potential therapeutic relevance of agents targeting this enzyme. C1 [Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, Lab Neurosci, LIM27, BR-01060970 Sao Paulo, Brazil. [Mallinger, Alan G.] NIMH, NIH, Bethesda, MD 20892 USA. [Mallinger, Alan G.] Dept Vet Affairs, Off Inspector Gen, Washington, DC USA. RP Machado-Vieira, R (reprint author), Univ Sao Paulo, Inst & Dept Psychiat, Lab Neurosci, LIM27, Rua Ovidio Pires de Campos 785, BR-01060970 Sao Paulo, Brazil. EM rvieira@usp.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 NR 120 TC 6 Z9 6 U1 0 U2 6 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 J9 MOL MED REP JI Mol. Med. Rep. PD NOV PY 2012 VL 6 IS 5 BP 915 EP 922 DI 10.3892/mmr.2012.1062 PG 8 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA 023MN UT WOS:000310039200001 PM 22948532 ER PT J AU Vecchiarelli, AG Mizuuchi, K Funnell, BE AF Vecchiarelli, Anthony G. Mizuuchi, Kiyoshi Funnell, Barbara E. TI Surfing biological surfaces: exploiting the nucleoid for partition and transport in bacteria SO MOLECULAR MICROBIOLOGY LA English DT Review ID PROKARYOTIC DNA SEGREGATION; CELL-WALL SYNTHESIS; ESCHERICHIA-COLI; BACILLUS-SUBTILIS; CHROMOSOME SEGREGATION; PLASMID PARTITION; PATTERN-FORMATION; F-PLASMID; POLAR LOCALIZATION; HELICAL FILAMENTS AB The ParA family of ATPases is responsible for transporting bacterial chromosomes, plasmids and large protein machineries. ParAs pattern the nucleoid in vivo, but how patterning functions or is exploited in transport is of considerable debate. Here we discuss the process of self-organization into patterns on the bacterial nucleoid and explore how it relates to the molecular mechanism of ParA action. We review ParA-mediated DNA partition as a general mechanism of how ATP-driven protein gradients on biological surfaces can result in spatial organization on a mesoscale. We also discuss how the nucleoid acts as a formidable diffusion barrier for large bodies in the cell, and make the case that the ParA family evolved to overcome the barrier by exploiting the nucleoid as a matrix for movement. C1 [Funnell, Barbara E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Vecchiarelli, Anthony G.; Mizuuchi, Kiyoshi] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Funnell, BE (reprint author), Univ Toronto, Dept Mol Genet, 100 Coll St, Toronto, ON M5S 1A8, Canada. EM b.funnell@utoronto.ca FU Canadian Institutes of Health Research [37997]; intramural research fund FX We thank James Havey and Ling Chin Hwang for critical reading of this paper. This work was supported by grant 37997 from the Canadian Institutes of Health Research (to B. E. F.), and by intramural research fund for NIDDK, NIH, HHS, US Government (to K. M.). NR 87 TC 53 Z9 53 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD NOV PY 2012 VL 86 IS 3 BP 513 EP 523 DI 10.1111/mmi.12017 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 025ZW UT WOS:000310238200002 PM 22934804 ER PT J AU De Lay, N Gottesman, S AF De Lay, Nicholas Gottesman, Susan TI A complex network of small non-coding RNAs regulate motility in Escherichia coli SO MOLECULAR MICROBIOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; DEPENDENT SMALL RNA; MESSENGER-RNA; FLAGELLAR EXPRESSION; 2-COMPONENT SYSTEM; RIBOSOME-BINDING; GENE-EXPRESSION; OUTER-MEMBRANE; HFQ; TRANSLATION AB Small Hfq-dependent non-coding regulatory RNAs (sRNAs) that alter mRNA stability and expression by pairing with target mRNAs have increasingly been shown to be important in influencing the behaviour of bacteria. In Escherichia coli, flhD and flhC, which encode the master regulator of flagellar synthesis, are co-transcribed from a promoter that is regulated by multiple transcription factors that respond to different environmental cues. Here, we show that the 5' untranslated region (5' UTR) of the flhDC mRNA also serves as a hub to integrate additional environmental cues into the decision to make flagella. Four sRNAs, ArcZ, OmrA, OmrB and OxyS, negatively regulated and one sRNA, McaS, positively regulated motility and flhDC expression by base-pairing with the 5' UTR of this mRNA. Another sRNA, MicA, positively regulated motility independent of regulation of flhDC. Furthermore, we demonstrate that the regulation of motility by the ArcB/A two component system is in part due to its regulation of ArcZ. flhDC is the first mRNA that has been shown to be both positively and negatively regulated by direct pairing to sRNAs. Moreover, both positive regulation by McaS and negative regulation by ArcZ require the same binding site in the flhDC mRNA. C1 [De Lay, Nicholas; Gottesman, Susan] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM Gottesms@helix.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Gisela Storz, Maude Guillier, Karl Thompson, Maureen Thomason and members of our laboratory including Nadim Majdalani, Hyun-Jung Lee, Daniel Schu, Aurelia Battesti, and Tong Song for their comments on this manuscript and their advice. We thank Gisela Storz, Caroline Ranquet and Maude Guillier for providing strains. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 48 TC 48 Z9 49 U1 1 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD NOV PY 2012 VL 86 IS 3 BP 524 EP 538 DI 10.1111/j.1365-2958.2012.08209.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 025ZW UT WOS:000310238200003 PM 22925049 ER PT J AU Shaffer, AL Staudt, LM AF Shaffer, Arthur L., III Staudt, Louis M. TI The case of the missing c-Myc SO NATURE IMMUNOLOGY LA English DT Editorial Material ID B-CELL LYMPHOMAS AB A fundamental mystery of the biology of germinal center B cells is why it seems that these rapidly dividing B cells lack expression of c-Myc, a transcriptional regulator intimately linked to cell metabolism and proliferation. This mystery has now been resolved. C1 [Shaffer, Arthur L., III; Staudt, Louis M.] Ctr Canc Res, Natl Canc Inst, Metab Branch, Bethesda, MD USA. RP Shaffer, AL (reprint author), Ctr Canc Res, Natl Canc Inst, Metab Branch, Bethesda, MD USA. EM lstaudt@mail.nih.gov NR 12 TC 2 Z9 2 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2012 VL 13 IS 11 BP 1029 EP 1031 PG 3 WC Immunology SC Immunology GA 024EO UT WOS:000310091700003 PM 23080195 ER PT J AU Yamane, H Paul, WE AF Yamane, Hidehiro Paul, William E. TI Cytokines of the gamma(c) family control CD4(+) T cell differentiation and function SO NATURE IMMUNOLOGY LA English DT Review ID FOLLICULAR HELPER-CELL; TRANSCRIPTION FACTOR GATA-3; CXC CHEMOKINE RECEPTOR-5; NF-KAPPA-B; RETINOIC-ACID; TGF-BETA; IN-VIVO; DENDRITIC CELLS; MOLECULAR-MECHANISMS; TH2 DIFFERENTIATION AB Naive CD4(+) T cells undergo massive proliferation and differentiation into at least four distinct helper T cell subsets after recognition of foreign antigen-derived peptides presented by dendritic cells. Each helper T cell subset expresses a distinct set of genes that encode unique transcription factor(s), as well as hallmark cytokines. The cytokine environment created by activated CD4(+) T cells, dendritic cells and/or other cell types during the course of differentiation is a major determinant for the helper T cell fate. This Review focuses on the role of cytokines of the common gamma-chain (gamma(c)) family in the determination of the effector helper T cell phenotype that naive CD4(+) T cells adopt after being activated and in the function of these helper T cells. C1 [Yamane, Hidehiro; Paul, William E.] NIAID, Cytokine Biol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Yamane, H (reprint author), NIAID, Cytokine Biol Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hyamane@niaid.nih.gov; wpaul@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (US National Institutes of Health) FX Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (US National Institutes of Health). NR 100 TC 59 Z9 59 U1 0 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2012 VL 13 IS 11 BP 1037 EP 1044 DI 10.1038/ni.2431 PG 8 WC Immunology SC Immunology GA 024EO UT WOS:000310091700006 PM 23080204 ER PT J AU Biesecker, LG Burke, W Kohane, I Plon, SE Zimmern, R AF Biesecker, Leslie G. Burke, Wylie Kohane, Isaac Plon, Sharon E. Zimmern, Ron TI Next-generation sequencing in the clinic: are we ready? SO NATURE REVIEWS GENETICS LA English DT Article ID GENOMIC MEDICINE; CANCER-SUSCEPTIBILITY; GENETIC COUNSELORS; NATIONAL SOCIETY; CLINSEQ PROJECT; RARE DISEASES; HEALTH-CARE; RISK; RECOMMENDATIONS; INCIDENTALOME AB We are entering an era in which the cost of clinical whole-genome and targeted sequencing tests is no longer prohibitive to their application. However, currently the infrastructure is not in place to support both the patient and the physicians that encounter the resultant data. Here, we ask five experts to give their opinions on whether clinical data should be treated differently from other medical data, given the potential use of these tests, and on the areas that must be developed to improve patient outcome. C1 [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Burke, Wylie] Univ Washington, Dept Bioeth & Humanities, Seattle, WA 98195 USA. [Kohane, Isaac] Boston Childrens Hosp, Boston, MA 02115 USA. [Plon, Sharon E.] Texas Childrens Hosp, Baylor Coll Med, Baylor Canc Genet Clin, Human Genome Sequencing Ctr,Dept Pediat, Houston, TX 77030 USA. [Plon, Sharon E.] Texas Childrens Hosp, Baylor Coll Med, Baylor Canc Genet Clin, Human Genome Sequencing Ctr,Dept Hematol Oncol, Houston, TX 77030 USA. [Plon, Sharon E.] Texas Childrens Hosp, Baylor Coll Med, Baylor Canc Genet Clin, Human Genome Sequencing Ctr,Dept Mol & Human Gene, Houston, TX 77030 USA. [Zimmern, Ron] PHG Fdn, Cambridge CB1 8RN, England. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, 49 Convent Dr,Room 4A56, Bethesda, MD 20892 USA. EM lesb@helix.nih.gov; wburke@u.washington.edu; isaac_kohane@harvard.edu; splon@bcm.edu; ron.zimmern@phgfoundation.org RI Kohane, Isaac Kohane/K-3716-2012 OI Kohane, Isaac Kohane/0000-0003-2192-5160 FU US National Human Genome Research Institute; [1 U01 HG006485] FX L.G.B. and the ClinSeq program are supported by the Intramural Research Program of the US National Human Genome Research Institute. S. E. P. acknowledges grant 1 U01 HG006485. R.Z. would like to thank M. Kroese and A. Hall, both of the PHG Foundation, for helpful discussion. The opinions expressed are the authors' own and do not necessarily reflect the views of the institutions with which they are affiliated. NR 36 TC 66 Z9 68 U1 3 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD NOV PY 2012 VL 13 IS 11 BP 818 EP 824 DI 10.1038/nrg3357 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 025TS UT WOS:000310218200011 PM 23076269 ER PT J AU Volkow, ND AF Volkow, Nora D. TI Long-Term Safety of Stimulant Use for ADHD: Findings from Nonhuman Primates SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID MEDICATION; METHYLPHENIDATE; ABUSE C1 NIDA, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, 6001 Execut Blvd,Rm 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 8 TC 6 Z9 8 U1 0 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2012 VL 37 IS 12 BP 2551 EP 2552 DI 10.1038/npp.2012.127 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 023SD UT WOS:000310054700001 PM 23070200 ER PT J AU Cottone, P Wang, XF Park, JW Valenza, M Blasio, A Kwak, J Iyer, MR Steardo, L Rice, KC Hayashi, T Sabino, V AF Cottone, Pietro Wang, Xiaofan Park, Jin Won Valenza, Marta Blasio, Angelo Kwak, Jina Iyer, Malliga R. Steardo, Luca Rice, Kenner C. Hayashi, Teruo Sabino, Valentina TI Antagonism of Sigma-1 Receptors Blocks Compulsive-Like Eating SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE binge eating disorder; food intake; eating disorders; addiction; palatability; risk-taking behavior ID CONDITIONED PLACE PREFERENCE; ALCOHOL-PREFERRING RATS; PREFRONTAL CORTEX; BINDING-SITES; NEUROPSYCHIATRIC DISORDERS; EXTRACELLULAR GLUTAMATE; SIGMA(1)-BINDING SITE; PRELIMBIC CORTEX; DRUG-ADDICTION; LIMITED ACCESS AB Binge eating disorder is an addiction-like disorder characterized by episodes of rapid and excessive food consumption within discrete periods of time which occur compulsively despite negative consequences. This study was aimed at determining whether antagonism of Sigma-1 receptors (Sig-1Rs) blocked compulsive-like binge eating. We trained male wistar rats to obtain a sugary, highly palatable diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day under fixed ratio 1 operant conditioning. Following intake stabilization, we evaluated the effects of the selective Sig-1R antagonist BD-1063 on food responding. Using a light/dark conflict test, we also tested whether BD-1063 could block the time spent and the food eaten in an aversive, open compartment, where the palatable diet was offered. Furthermore, we measured Sig-1R mRNA and protein expression in several brain areas of the two groups, 24 h after the last binge session. Palatable rats rapidly developed binge-like eating, escalating the 1 h intake by four times, and doubling the eating rate and the regularity of food responding, compared to Chow rats. BD-1063 dose-dependently reduced binge-like eating and the regularity of food responding, and blocked the increased eating rate in Palatable rats. In the light/dark conflict test, BD-1063 antagonized the increased time spent in the aversive compartment and the increased intake of the palatable diet, without affecting motor activity. Finally, Palatable rats showed reduced Sig-1R mRNA expression in prefrontal and anterior cingulate cortices, and a two-fold increase in Sig-1R protein expression in anterior cingulate cortex compared to control Chow rats. These findings suggest that the Sig-1R system may contribute to the neurobiological adaptations driving compulsive-like eating, opening new avenues of investigation towards pharmacologically treating binge eating disorder. Neuropsychopharmacology (2012) 37, 2593-2604; doi:10.1038/npp.2012.89; published online 20 June 2012 C1 [Cottone, Pietro; Wang, Xiaofan; Park, Jin Won; Valenza, Marta; Blasio, Angelo; Kwak, Jina; Sabino, Valentina] Boston Univ, Dept Pharmacol, Lab Addict Disorders, Sch Med, Boston, MA 02118 USA. [Cottone, Pietro; Wang, Xiaofan; Park, Jin Won; Valenza, Marta; Blasio, Angelo; Kwak, Jina; Sabino, Valentina] Boston Univ, Dept Psychiat, Sch Med, Boston, MA 02118 USA. [Valenza, Marta] Univ Bari, Sch Med, Dept Pharmacol & Human Physiol, Bari, Italy. [Blasio, Angelo; Steardo, Luca] Univ Roma La Sapienza, Dept Physiol & Pharmacol, Rome, Italy. [Iyer, Malliga R.; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Iyer, Malliga R.; Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. [Hayashi, Teruo] NIDA, Cellular Stress Signaling Unit, Intramural Res Program, NIH, Baltimore, MD USA. RP Cottone, P (reprint author), Boston Univ, Dept Pharmacol & Psychiat, Lab Addict Disorders, Sch Med, 72 E Concord St,R-618, Boston, MA 02118 USA. EM cottone@bu.edu; vsabino@bu.edu RI Cottone, Pietro/F-5291-2012; Sabino, Valentina/F-5290-2012; OI Cottone, Pietro/0000-0003-1320-1672; Sabino, Valentina/0000-0002-6680-1279; Steardo, Luca/0000-0003-3570-2195 FU National Institute on Drug Abuse (NIDA) [DA023680, DA030425, MH091945, MH093650A1, AA016731]; National Institute of Mental Health (NIMH); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Peter Paul Career Development Professorship (PC) FX We thank Stephen St Cyr, Aditi R Narayan, Esther Kim, Alexander Su, and Vamsee Neerukonda for the technical assistance. This publication was made possible by Grant numbers DA023680, DA030425, MH091945, MH093650A1, and AA016731 from the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and by the Peter Paul Career Development Professorship (PC). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 86 TC 25 Z9 26 U1 1 U2 30 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 NOV PY 2012 VL 37 IS 12 BP 2593 EP 2604 DI 10.1038/npp.2012.89 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 023SD UT WOS:000310054700006 PM 22713906 ER PT J AU Agochukwu, NB Solomon, BD Gropman, AL Muenke, M AF Agochukwu, Nneamaka B. Solomon, Benjamin D. Gropman, Andrea L. Muenke, Maximilian TI Epilepsy in Muenke Syndrome: FGFR3-Related Craniosynostosis SO PEDIATRIC NEUROLOGY LA English DT Article ID MYOCLONIC EPILEPSY; RECEPTOR-3 GENE; APERT-SYNDROME; MUTATION; DISORDER; SEIZURES; GROWTH; CHILDREN; FEATURES; HYPOXIA AB Epilepsy, a neurologic disorder characterized by the predisposition to recurrent unprovoked seizures, is reported in more than 300 genetic syndromes. Muenke syndrome is an autosomal-dominant craniosynostosis syndrome characterized by unilateral or bilateral coronal craniosynostosis, hearing loss, intellectual disability, and relatively subtle limb findings such as carpal bone fusion and tarsal bone fusion. Muenke syndrome is caused by a single defining point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Epilepsy rarely occurs in individuals with Muenke syndrome, and little detail is reported on types of epilepsy, patient characteristics, and long-term outcomes. We present seven patients with Muenke syndrome and seizures. A review of 789 published cases of Muenke syndrome, with a focus on epilepsy and intracranial anomalies in Muenke syndrome, revealed epilepsy in six patients, with intracranial anomalies in five. The occurrence of epilepsy in Muenke syndrome within our cohort of 58 patients, of whom seven manifested epilepsy, and the intracranial anomalies and epilepsy reported in the literature, suggest that patients with Muenke syndrome may be at risk for epilepsy and intracranial anomalies. Furthermore, the impact of Muenke syndrome on the central nervous system may be greater than previously thought. (C) 2012 Elsevier Inc. All rights reserved. C1 [Agochukwu, Nneamaka B.; Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Agochukwu, Nneamaka B.] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Gropman, Andrea L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Gropman, Andrea L.] George Washington Univ Hlth Sci, Dept Neurol, Washington, DC USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, Bldg 35,Room 1B-203,MSC 3717, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Division of Intramural Research of the National Human Genome Research Institute at the National Institutes of Health; Department of Health and Human Services FX The authors thank the individuals described in this article for their participation. This study was supported by the Division of Intramural Research of the National Human Genome Research Institute at the National Institutes of Health and the Department of Health and Human Services. NR 30 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD NOV PY 2012 VL 47 IS 5 BP 355 EP 361 DI 10.1016/j.pediatrneurol.2012.07.004 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 023OJ UT WOS:000310044000008 PM 23044018 ER PT J AU Hill, SC Dwyer, AJ Kaler, SG AF Hill, Suvimol C. Dwyer, Andrew J. Kaler, Stephen G. TI Cervical spine anomalies in Menkes disease: a radiologic finding potentially confused with child abuse SO PEDIATRIC RADIOLOGY LA English DT Article DE Menkes disease; Cervical spine; Bone abnormalities; Copper metabolism ID HORN-SYNDROME; DIAGNOSIS; DEFECTS; INJURY AB Menkes disease is an X-linked recessive disorder of copper transport caused by mutations in ATP7A, a copper-transporting ATPase. Certain radiologic findings reported in this condition overlap with those caused by child abuse. However, cervical spine defects simulating cervical spine fracture, a known result of nonaccidental pediatric trauma, have not been reported previously in this illness. To assess the frequency of cervical spine anomalies in Menkes disease after discovery of an apparent C2 posterior arch defect in a child participating in a clinical trial. We examined cervical spine radiographs obtained in 35 children with Menkes disease enrolled in a clinical trial at the National Institutes of Health Clinical Center. Four of the 35 children with Menkes disease had apparent C2 posterior arch defects consistent with spondylolysis or incomplete/delayed ossification. Defects in C2 were found in 11% of infants and young children with Menkes disease. Discovery of cervical spine defects expands the spectrum of radiologic findings associated with this condition. As with other skeletal abnormalities, this feature simulates nonaccidental trauma. In the context of Menkes disease, suspicions of child abuse should be considered cautiously and tempered by these findings to avoid unwarranted accusations. C1 [Hill, Suvimol C.; Dwyer, Andrew J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bldg 10,Rm 10N313,10 Ctr Dr,MSC 1853, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU Intramural NIH HHS [ZIA HD008768-08] NR 23 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD NOV PY 2012 VL 42 IS 11 BP 1301 EP 1304 DI 10.1007/s00247-012-2457-4 PG 4 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 026ZV UT WOS:000310322500003 PM 22825777 ER PT J AU Gangjee, A Pavana, RK Li, W Hamel, E Westbrook, C Mooberry, SL AF Gangjee, Aleem Pavana, Roheeth K. Li, Wei Hamel, Ernest Westbrook, Cara Mooberry, Susan L. TI Novel Water-Soluble Substituted Pyrrolo[3,2-d]pyrimidines: Design, Synthesis, and Biological Evaluation as Antitubulin Antitumor Agents SO PHARMACEUTICAL RESEARCH LA English DT Article DE antitubulin; colchicine-site binders; drug design; microtubule depolymerizer; pyrrolo[3,2-d]pyrimidines ID III BETA-TUBULIN; OVARIAN-CANCER PATIENTS; CELL LUNG-CANCER; COLCHICINE SITE; BREAST-CANCER; RESISTANCE; OVEREXPRESSION; MECHANISMS; DISCOVERY; ANALOGS AB To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents. Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and inhibit colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel. Pyrrolo[3,2-d]pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound tested in the NCI 60 cell line is a 2-digit nanomolar (GI(50)) inhibitor of 8 tumor cell lines. We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization. C1 [Gangjee, Aleem; Pavana, Roheeth K.; Li, Wei] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Westbrook, Cara; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. RP Gangjee, A (reprint author), Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. EM gangjee@duq.edu RI Pavana, Roheeth/F-5839-2017 OI Pavana, Roheeth/0000-0001-6256-3683 FU National Institute of Health, National Cancer Institute [CA142868]; NSF [NMR: CHE 0614785]; CTRC Cancer Center [P30 CA054174] FX Grant from the National Institute of Health, National Cancer Institute, CA142868 (AG,SLM).; NSF equipment grant for the NMR (NMR: CHE 0614785) and the CTRC Cancer Center Support Grant, P30 CA054174 NR 24 TC 7 Z9 8 U1 0 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES-DORDR JI Pharm. Res. PD NOV PY 2012 VL 29 IS 11 BP 3033 EP 3039 DI 10.1007/s11095-012-0816-3 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 025QG UT WOS:000310206100008 PM 22814902 ER PT J AU Urban, TJ Shen, YF Stolz, A Chalasani, N Fontana, RJ Rochon, J Ge, DL Shianna, KV Daly, AK Lucena, MI Nelson, MR Molokhia, M Aithal, GP Floratos, A Pe'er, I Serrano, J Bonkovsky, H Davern, TJ Lee, WM Navarro, VJ Talwalkar, JA Goldstein, DB Watkins, PB AF Urban, Thomas J. Shen, Yufeng Stolz, Andrew Chalasani, Naga Fontana, Robert J. Rochon, James Ge, Dongliang Shianna, Kevin V. Daly, Ann K. Isabel Lucena, M. Nelson, Matthew R. Molokhia, Mariam Aithal, Guruprasad P. Floratos, Aris Pe'er, Itsik Serrano, Jose Bonkovsky, Herbert Davern, Timothy J. Lee, William M. Navarro, Victor J. Talwalkar, Jayant A. Goldstein, David B. Watkins, Paul B. CA Drug-Induced Liver Injury Network DILIGEN EUDRAGENE Spanish DILI Registry Int Serious Adverse Events Consort TI Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE drug-induced liver injury; genome-wide association study; pharmacogenetics ID WHOLE-GENOME ASSOCIATION; ACTIVATED RECEPTOR-GAMMA; WIDE ASSOCIATION; POPULATION; DICLOFENAC; SAMPLE; POWER; SET AB Background and aims Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs. Methods DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases. Results After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5 x 10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5 x 10(-5) for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables. Conclusion Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study. Pharmacogenetics and Genomics 22:784-795 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Watkins, Paul B.] Univ N Carolina, Sch Med, Hamner Univ N Carolina, Inst Drug Safety Sci, Res Triangle Pk, NC 27709 USA. [Urban, Thomas J.; Rochon, James; Ge, Dongliang; Shianna, Kevin V.; Goldstein, David B.] Duke Univ, Ctr Human Genome Variat, Durham, NC 27706 USA. [Nelson, Matthew R.] GlaxoSmithKline, Res Triangle Pk, NC USA. [Bonkovsky, Herbert] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Bonkovsky, Herbert; Watkins, Paul B.] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Stolz, Andrew] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Davern, Timothy J.] Univ Calif San Francisco, Calif Pacific Med Ctr, Dept Transplantat, San Francisco, CA 94143 USA. [Shen, Yufeng; Floratos, Aris] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USA. [Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. [Chalasani, Naga] Indiana Univ, Div Gastroenterol Hepatol, Sch Med, Indianapolis, IN USA. [Fontana, Robert J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Serrano, Jose] NIDDKD, Bethesda, MD 20892 USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Gastroenterol Hepatol & Nutr, Dallas, TX 75390 USA. [Navarro, Victor J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Talwalkar, Jayant A.] Mayo Clin, Rochester, MN USA. [Daly, Ann K.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Molokhia, Mariam] Kings Coll London, London WC2R 2LS, England. [Aithal, Guruprasad P.] Univ Nottingham Hosp, NIHR Biomed Res Unit Gastrointestinal & Liver Dis, Nottingham NG7 2UH, England. [Aithal, Guruprasad P.] Univ Nottingham, Nottingham NG7 2RD, England. [Isabel Lucena, M.] Univ Malaga, IBIMA, CIBERehd, Hosp Univ Virgen Victoria, E-29071 Malaga, Spain. [Bonkovsky, Herbert; Watkins, Paul B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. RP Watkins, PB (reprint author), Univ N Carolina, Sch Med, Hamner Univ N Carolina, Inst Drug Safety Sci, 6 Davis Dr,POB 12137, Res Triangle Pk, NC 27709 USA. EM pwatkins@thehamner.org RI Daly, Ann/H-3144-2011; Pirmohamed, Munir/H-6004-2011; Wadelius, Mia/C-7740-2016; OI Daly, Ann/0000-0002-7321-0629; Pirmohamed, Munir/0000-0002-7534-7266; Lapeyre-Mestre, Maryse/0000-0002-5494-5873; Wadelius, Mia/0000-0002-6368-2622; Lucena Gonzalez, Maria Isabel/0000-0001-9586-4896; Eliasson, Erik/0000-0002-4707-4256; Bondon-Guitton, Emmanuelle/0000-0002-1212-3898 FU Wellcome Trust [076113, 085475]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [2U01-DK065176-06, 2U01-DK065201-06, 2U01-DK065184-06, 2U01-DK065211-06, 5U01DK065193-04, 5U01-DK065238-08]; CTSA [UL1 RR025761, UL1 RR025747, UL1 UL1 RR024986]; UK Department of Health (Pharmacogenetics Initiative) [PHGX10A]; UK NIHR; EC 5th Framework program [QLRI-CT-2002- 02757]; iSAEC; UK NIHR [ICT-215847, HEALTH-241679]; Spanish Medicine Agency; Instituto de Salud Carlos III; NIDDK [2U01-DK065176-06]; Abbott; Daiichi-Sankyo; GSK; J J; Novartis; Pfizer; Roche; Sanofi-Aventis; Takeda; Wellcome Trust; Wyeth FX The authors acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection and UK National Blood Service control cohorts. 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 award 076113 and 085475.; The DILIN network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1 RR025747 (UNC), and UL1 UL1 RR024986 (UMich).; The DILIGEN sample collection was partly funded by the UK Department of Health (Pharmacogenetics Initiative ref PHGX10A), UK NIHR funding to the Nottingham Digestive Diseases Centre, and the iSAEC. The EUDRAGENE collaboration has received support from the EC 5th Framework program (QLRI-CT-2002- 02757) and the iSAEC. M. M. has received funding from a UK NIHR postdoctoral award and is an investigator for the FP7 EU-ADR (ICT-215847) and ARITMO (HEALTH-241679) projects on drug safety. The Spanish DILI Registry is partly funded by the Spanish Medicine Agency and has received support from the iSAEC. CIBERehd is funded by Instituto de Salud Carlos III.; The genome-wide genotyping of DILIN cases was funded by the NIDDK under grant 2U01-DK065176-06. Genome-wide genotyping of the DILIGEN, Dundee, EUDRAGENE, Spanish DILI Registry and GSK POPRES controls was funded by iSAEC, with support from Abbott, Daiichi-Sankyo, GSK, J & J, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, the Wellcome Trust and Wyeth. NR 29 TC 51 Z9 51 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD NOV PY 2012 VL 22 IS 11 BP 784 EP 795 DI 10.1097/FPC.0b013e3283589a76 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 022QS UT WOS:000309977100003 PM 22968431 ER PT J AU Wadt, K Choi, J Chung, JY Kiilgaard, J Heegaard, S Drzewiecki, KT Trent, JM Hewitt, SM Hayward, NK Gerdes, AM Brown, KM AF Wadt, Karin Choi, Jiyeon Chung, Joon-Yong Kiilgaard, Jens Heegaard, Steffen Drzewiecki, Krzysztof T. Trent, Jeffrey M. Hewitt, Stephen M. Hayward, Nicholas K. Gerdes, Anne-Marie Brown, Kevin M. TI A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE BAP1; splice mutation; melanoma; paraganglioma ID PREDISPOSE AB Inactivating germ line BRCA1-associated protein-1 (BAP1) mutations have recently been reported in families with uveal or cutaneous malignant melanoma (UMM, CMM), mesothelioma, and meningioma. Although apparently predisposing to a wide range of tumors, the exact tumor spectrum associated with germ line BAP1 mutations has yet to be established. Here, we report a novel germ line BAP1 splice mutation, c.1708C>G (p.Leu570fs*40), in a multiple-case Danish UMM family with a spectrum of other tumors. Whole-exome sequencing identified an apparent missense mutation of BAP1 in UMM, CMM, as well as paraganglioma, breast cancer, and suspected mesothelioma cases in the family. Bioinformatic analysis and splicing assays demonstrated that this mutation creates a strong cryptic splice donor, resulting in aberrant splicing and a truncating frameshift of the BAP1 transcript. Somatic loss of the wild-type allele was also confirmed in the UMM and paraganglioma tumors. Our findings further support BAP1 as a melanoma susceptibility gene and extend the potential predisposition spectrum to paraganglioma. C1 [Wadt, Karin; Gerdes, Anne-Marie] Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Kiilgaard, Jens; Heegaard, Steffen] Glostrup Univ Hosp, Dept Ophthalmol, Glostrup, Denmark. [Heegaard, Steffen] Univ Copenhagen, Eye Pathol Sect, Dept Neurosci & Pharmacol, Copenhagen, Denmark. [Drzewiecki, Krzysztof T.] Rigshosp, Dept Plast Surg, Breast Surg & Burns Unit, DK-2100 Copenhagen, Denmark. [Trent, Jeffrey M.; Brown, Kevin M.] Translat Genom Res Inst, Phoenix, AZ USA. [Hayward, Nicholas K.] Queensland Inst Med Res, Oncogen Lab, Brisbane, Qld 4006, Australia. [Choi, Jiyeon; Brown, Kevin M.] NCI, Lab Translat Genom, Bethesda, MD 20892 USA. RP Brown, KM (reprint author), Adv Technol Ctr ATC, 8717 Grovemont Circle, Bethesda, MD USA. EM brownkm2@mail.nih.gov RI hayward, nicholas/C-1367-2015; OI hayward, nicholas/0000-0003-4760-1033; Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982; Kiilgaard, Jens Folke/0000-0003-1054-1460 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute; Center for Cancer Research of the National Cancer Institute; Melanoma Research Alliance Team Science Award; National Health and Medical Research Council of Australia FX This work was funded by Division of Cancer Epidemiology and Genetics (K. M. B and J.C.) and Center for Cancer Research (S. M. H and J-Y.C.) of the National Cancer Institute, and a Melanoma Research Alliance Team Science Award to J.M.T (J.M.T., N.K.H, and K. M. B.). N.K.H. is the recipient of a Senior Principal Research Fellowship from the National Health and Medical Research Council of Australia. We thank Nina Hastrup for help with pathology. The authors are extremely grateful to the family for their participation in this project. NR 8 TC 48 Z9 49 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD NOV PY 2012 VL 25 IS 6 BP 815 EP 818 DI 10.1111/pcmr.12006 PG 4 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 023XE UT WOS:000310070000020 PM 22889334 ER PT J AU Hou, Y Ouyang, X Wan, RQ Cheng, HP Mattson, MP Cheng, AW AF Hou, Yan Ouyang, Xin Wan, Ruiqian Cheng, Heping Mattson, Mark P. Cheng, Aiwu TI Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development SO STEM CELLS LA English DT Article DE cpYFP; Manganese superoxide dismutase; Extracellular signal-regulated kinases; Mitochondrial permeability transition pore; Neural progenitor cells; Self-renewal; Proliferation; Neurospheres ID DISMUTASE-DEFICIENT MICE; NEUROTROPHIC FACTOR; CELL PROLIFERATION; OXIDATIVE-STRESS; SELF-RENEWAL; STEM-CELLS; PERMEABILITY TRANSITION; HYDROGEN-PEROXIDE; OXYGEN-TOXICITY; FACTOR-RECEPTOR AB Although high amounts of reactive oxygen species (ROS) can damage cells, ROS can also play roles as second messengers, regulating diverse cellular processes. Here, we report that embryonic mouse cerebral cortical neural progenitor cells (NPCs) exhibit intermittent spontaneous bursts of mitochondrial superoxide (SO) generation (mitochondrial SO flashes) that require transient opening of membrane permeability transition pores (mPTP). This quantal SO production negatively regulates NPC self-renewal. Mitochondrial SO scavengers and mPTP inhibitors reduce SO flash frequency and enhance NPC proliferation, whereas prolonged mPTP opening and SO generation increase SO flash incidence and decrease NPC proliferation. The inhibition of NPC proliferation by mitochondrial SO involves suppression of extracellular signal-regulated kinases. Moreover, mice lacking SOD2 (SOD2-/- mice) exhibit significantly fewer proliferative NPCs and differentiated neurons in the embryonic cerebral cortex at midgestation compared with wild-type littermates. Cultured SOD2-/- NPCs exhibit a significant increase in SO flash frequency and reduced NPC proliferation. Taken together, our findings suggest that mitochondrial SO flashes negatively regulate NPC self-renewal in the developing cerebral cortex. STEM CELLS2012;30:25352547 C1 [Hou, Yan; Ouyang, Xin; Wan, Ruiqian; Mattson, Mark P.; Cheng, Aiwu] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Cheng, Heping] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Cheng, Heping] Peking Univ, Natl Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. [Mattson, Mark P.] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov; chengai@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging; National Natural Science Foundation; National Basic Research Program of China [2011CB809100] FX This work was supported by the Intramural Research Program of the National Institute on Aging, and by the National Natural Science Foundation and National Basic Research Program of China (2011CB809100). NR 51 TC 30 Z9 31 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD NOV PY 2012 VL 30 IS 11 BP 2535 EP 2547 DI 10.1002/stem.1213 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 023ZP UT WOS:000310077000017 PM 22949407 ER PT J AU Collins, M Riascos, D Kovalik, T An, JY Krupa, K Krupa, K Hood, BL Conrads, TP Renton, AE Traynor, BJ Bowser, R AF Collins, Mahlon Riascos, David Kovalik, Tina An, Jiyan Krupa, Kelly Krupa, Kristin Hood, Brian L. Conrads, Thomas P. Renton, Alan E. Traynor, Bryan J. Bowser, Robert TI The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients SO ACTA NEUROPATHOLOGICA LA English DT Article DE Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; TDP-43; RNA-binding protein; RBM45; C9ORF72 ID HEXANUCLEOTIDE REPEAT EXPANSION; ALZHEIMERS-DISEASE; MESSENGER-RNA; UBIQUITIN IMMUNOHISTOCHEMISTRY; NUCLEAR SPECKLES; C9ORF72; PATHOLOGY; DIAGNOSIS; DEMENTIA; GENE AB RNA-binding protein pathology now represents one of the best characterized pathologic features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration patients with TDP-43 or FUS pathology (FTLD-TDP and FTLD-FUS). Using liquid chromatography tandem mass spectrometry, we identified altered levels of the RNA-binding motif 45 (RBM45) protein in the cerebrospinal fluid (CSF) of ALS patients. This protein contains sequence similarities to TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) that are contained in cytoplasmic inclusions of ALS and FTLD-TDP or FTLD-FUS patients. To further characterize RBM45, we first verified the presence of RBM45 in CSF and spinal cord tissue extracts of ALS patients by immunoblot. We next used immunohistochemistry to examine the subcellular distribution of RBM45 and observed in a punctate staining pattern within nuclei of neurons and glia in the brain and spinal cord. We also detected RBM45 cytoplasmic inclusions in 91 % of ALS, 100 % of FTLD-TDP and 75 % of Alzheimer's disease (AD) cases. The most extensive RBM45 pathology was observed in patients that harbor the C9ORF72 hexanucleotide repeat expansion. These RBM45 inclusions were observed in spinal cord motor neurons, glia and neurons of the dentate gyrus. By confocal microscopy, RBM45 co-localizes with ubiquitin and TDP-43 in inclusion bodies. In neurons containing RBM45 cytoplasmic inclusions we often detected the protein in a punctate pattern within the nucleus that lacked either TDP-43 or ubiquitin. We identified RBM45 using a proteomic screen of CSF from ALS and control subjects for candidate biomarkers, and link this RNA-binding protein to inclusion pathology in ALS, FTLD-TDP and AD. C1 [Riascos, David; Kovalik, Tina; An, Jiyan; Bowser, Robert] Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA. [Collins, Mahlon; Krupa, Kelly; Krupa, Kristin; Bowser, Robert] Univ Pittsburgh, Dept Neurobiol & Pathol, Pittsburgh, PA USA. [Hood, Brian L.; Conrads, Thomas P.] Inova Hlth Syst, Womens Hlth Integrated Res Ctr, Annandale, VA USA. [Renton, Alan E.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Bowser, R (reprint author), Barrow Neurol Inst, Div Neurol, NRC 4th Floor,350 Thomas Rd, Phoenix, AZ 85013 USA. EM robert.bowser@dignityhealth.org RI Traynor, Bryan/G-5690-2010 FU National Institutes of Health [NS061867, NS068179]; Walter S. & Lucienne Driskill Foundation; Intramural Research Programs of the National Institute on Aging [Z01-AG000949-02]; Achievement Rewards for College Scientists Foundation, Inc. Pittsburgh Chapter FX This work was supported by National Institutes of Health grants NS061867 and NS068179 to RB, a grant from the Walter S. & Lucienne Driskill Foundation to RB, and by the Achievement Rewards for College Scientists Foundation, Inc. Pittsburgh Chapter to MC. This work was also supported in part by the Intramural Research Programs of the National Institute on Aging (Z01-AG000949-02) to BJT. We thank Dr. Ronald Hamilton for neuropathologic assessment of all cases and Jonette Werley for technical assistance. The authors wish to thank the NEALS Biofluid Repository for CSF samples and all patients for their participation in this study. NR 45 TC 29 Z9 31 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD NOV PY 2012 VL 124 IS 5 BP 717 EP 732 DI 10.1007/s00401-012-1045-x PG 16 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 021CO UT WOS:000309863100009 PM 22993125 ER PT J AU Cao, HP Chapital, DC Howard, OD Deterding, LJ Mason, CB Shockey, JM Klasson, KT AF Cao, Heping Chapital, Dorselyn C. Howard, O. D., Jr. Deterding, Leesa J. Mason, Catherine B. Shockey, Jay M. Klasson, K. Thomas TI Expression and purification of recombinant tung tree diacylglycerol acyltransferase 2 SO APPLIED MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE Diacylglycerol acyltransferase; Protein expression; Protein purification; E. coli (Escherichia coli); Tung tree (Vernicia fordii) ID SITE-DIRECTED MUTAGENESIS; ACYL-COA; ESCHERICHIA-COLI; TRIACYLGLYCEROL BIOSYNTHESIS; TRIGLYCERIDE SYNTHESIS; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM; BINDING-PROTEIN; SKELETAL-MUSCLE; MESSENGER-RNA AB Diacylglycerol acyltransferases (DGATs) esterify sn-1,2-diacylglycerol with a long-chain fatty acyl-CoA, the last and rate-limiting step of triacylglycerol (TAG) biosynthesis in eukaryotic organisms. At least 74 DGAT2 sequences from 61 organisms have been identified, but the expression of any DGAT2 as a partial or full-length protein in Escherichia coli had not been reported. The main objective of this study was to express and purify recombinant DGAT2 (rDGAT2) from E. coli for antigen production with a minor objective to compare rDGAT2 expression in yeast. A plasmid was engineered to express tung tree DGAT2 fused to maltose binding protein and poly-histidine (His) affinity tags. Immunoblotting showed that rDGAT2 was detected in the soluble, insoluble, and membrane fractions. The rDGAT2 in the soluble fraction was partially purified by amylose resin, nickel-nitrilotriacetic agarose (Ni-NTA) beads, and tandem affinity chromatography. Multiple proteins co-purified with rDGAT2. Size exclusion chromatography estimated the size of the rDGAT2-enriched fraction to be approximately eight times the monomer size. Affinity-purified rDGAT2 fractions had a yellow tint and contained fatty acids. The rDGAT2 in the insoluble fraction was partially solubilized by seven detergents with SDS being the most effective. Recombinant DGAT2 was purified to near homogeneity by SDS solubilization and Ni-NTA affinity chromatography. Mass spectrometry identified rDGAT2 as a component in the bands corresponding to the monomer and dimer forms as observed by SDS-PAGE. Protein bands with monomer and dimer sizes were also observed in the microsomal membranes of Saccharomyces cerevisiae expressing hemagglutinin-tagged DGAT2. Nonradioactive assay showed TAG synthesis activity of DGAT2 from yeast but not E. coli. The results suggest that rDGAT2 is present as monomer and dimer forms on SDS-PAGE, associated with other proteins, lipids, and membranes, and that post-translational modification of rDGAT2 may be required for its enzymatic activity and/or the E. coli protein is misfolded. C1 [Cao, Heping; Chapital, Dorselyn C.; Mason, Catherine B.; Shockey, Jay M.; Klasson, K. Thomas] Agr Res Serv, Commod Utilizat Res Unit, So Reg Res Ctr, USDA, New Orleans, LA 70124 USA. [Howard, O. D., Jr.] Alcorn State Univ, Ctr Genom & Biotechnol, Lorman, MS 39069 USA. [Howard, O. D., Jr.] Alcorn State Univ, Dept Biol, Lorman, MS 39069 USA. [Deterding, Leesa J.] NIEHS, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Cao, HP (reprint author), Agr Res Serv, Commod Utilizat Res Unit, So Reg Res Ctr, USDA, 1100 Robert E Lee Blvd, New Orleans, LA 70124 USA. EM Heping.Cao@ars.usda.gov OI Klasson, K. Thomas/0000-0003-3358-3081; Shockey, Jay/0000-0002-5057-5457 FU USDA-ARS; NIH, NIEHS [ES050171] FX This work was supported by USDA-ARS Quality and Utilization of Agricultural Products Research Program and, in part, by the Intramural Research Program of the NIH, NIEHS (project ES050171). O.D. Howard Jr. is a graduate student from the Center for Genomics and Biotechnology and Department of Biology at Alcorn State University working on his thesis at USDA-ARS. The authors thank Ms. Katina Johnson of the Protein Microcharacterization Core Facility (NIH-NIEHS) for the mass spectrometry analyses, Drs. Kandan Sethumadhavan and Soheila J. Maleki for technical help, and Drs. John M. Dyer, Thomas J. Caperna, Jeffrey W. Cary, Stephanie A. Boone, Kenneth B. Tomer, and Jeffrey F. Kuhn for helpful comments on the manuscript. A preliminary report was presented at the Plant Biology 2010 in Montreal, Canada, on July 31-August 4, 2010 (Cao et al. 2010). Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. USDA is an equal opportunity provider and employer. NR 65 TC 10 Z9 10 U1 1 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7598 J9 APPL MICROBIOL BIOT JI Appl. Microbiol. Biotechnol. PD NOV PY 2012 VL 96 IS 3 BP 711 EP 727 DI 10.1007/s00253-012-3869-7 PG 17 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 019AI UT WOS:000309708900011 PM 22270236 ER PT J AU Darbari, DS Desai, D Arnaldez, F Desai, K Kallen, J Strouse, J Streiff, MB Hong, K Takemoto, CM AF Darbari, Deepika S. Desai, Devarshi Arnaldez, Fernanda Desai, Kruti Kallen, Joshua Strouse, John Streiff, Michael B. Hong, Kelvin Takemoto, Clifford M. TI Safety and efficacy of catheter directed thrombolysis in children with deep venous thrombosis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE paediatric thrombosis; anticoagulation; paediatric haemostasis C1 [Darbari, Deepika S.] Childrens Natl Med Ctr, Div Hematol, Washington, DC 20010 USA. [Desai, Devarshi; Desai, Kruti; Strouse, John; Takemoto, Clifford M.] Johns Hopkins Univ Hosp, Div Pediat Hematol, Baltimore, MD 21287 USA. [Desai, Devarshi; Kallen, Joshua; Hong, Kelvin] Johns Hopkins Univ Hosp, Dept Radiol, Baltimore, MD 21287 USA. [Arnaldez, Fernanda] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Streiff, Michael B.] Johns Hopkins Univ Hosp, Dept Med, Div Hematol, Baltimore, MD 21287 USA. RP Darbari, DS (reprint author), Childrens Natl Med Ctr, Div Hematol, Washington, DC 20010 USA. EM ctakemot@jhmi.edu NR 9 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD NOV PY 2012 VL 159 IS 3 BP 376 EP U11 DI 10.1111/bjh.12025 PG 5 WC Hematology SC Hematology GA 019DO UT WOS:000309717500016 PM 22934795 ER PT J AU Poole, EM Gates, MA High, BA Chanock, SJ Cramer, DW Cunningham, JM Fridley, BL Gayther, SA Goode, EL Iversen, ES Lissowska, J Weber, RTP Pharoah, PDP Phelan, CM Ramus, SJ Schildkraut, JM Sutphen, R Tsai, YY Tyrer, J Vierkant, RA Wentzensen, N Yang, HP Terry, KL Tworoger, SS AF Poole, Elizabeth M. Gates, Margaret A. High, Brigit A. Chanock, Stephen J. Cramer, Daniel W. Cunningham, Julie M. Fridley, Brooke L. Gayther, Simon A. Goode, Ellen L. Iversen, Edwin S. Lissowska, Jolanta Weber, Rachel T. Palmieri Pharoah, Paul D. P. Phelan, Catherine M. Ramus, Susan J. Schildkraut, Joellen M. Sutphen, Rebecca Tsai, Ya-Yu Tyrer, Jonathan Vierkant, Robert A. Wentzensen, Nicolas Yang, Hannah P. Terry, Kathryn L. Tworoger, Shelley S. TI ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium SO CANCER CAUSES & CONTROL LA English DT Article DE Ovarian cancer; ABO blood group; Ovarian Cancer Association Consortium (OCAC); Genetic epidemiology ID COHORT CONSORTIUM; GROUP ALLELES; SELECTIN; DISEASE AB Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results. In eight studies participating in the Ovarian Cancer Association Consortium, we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios and 95 % confidence intervals were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis. Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95 % CI: 1.01-1.18; p = 0.03). In diplotype analysis, the AO, but not the AA diplotype, was associated with increased risk (AO: OR: 1.11; 95 % CI: 1.01-1.22; p = 0.03; AA: OR: 1.03; 95 % CI: 0.87-1.21; p = 0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes. Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted. C1 [Poole, Elizabeth M.; Gates, Margaret A.; High, Brigit A.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Gates, Margaret A.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chanock, Stephen J.; Wentzensen, Nicolas; Yang, Hannah P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cunningham, Julie M.; Fridley, Brooke L.; Goode, Ellen L.; Vierkant, Robert A.] Mayo Clin, Coll Med, Rochester, MN USA. [Gayther, Simon A.; Ramus, Susan J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. [Weber, Rachel T. Palmieri; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Pharoah, Paul D. P.; Tyrer, Jonathan] Univ Cambridge, Cambridge, England. [Phelan, Catherine M.; Tsai, Ya-Yu] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Sutphen, Rebecca] Univ S Florida, Coll Med, Tampa, FL USA. RP Poole, EM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, 181 Longwood Ave,3rd Floor, Boston, MA 02115 USA. EM nhlip@channing.harvard.edu RI Fridley, Brooke/D-8315-2015; OI Fridley, Brooke/0000-0001-7739-7956; Poole, Elizabeth/0000-0002-4680-4587; Vierkant, Robert/0000-0001-6242-5221; Tworoger, Shelley/0000-0002-6986-7046; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799 FU Ovarian Cancer Research Fund; Mayo Foundation; Department of Defense [DAMD17-02-1-0666, W81XWH-10-1-0280, DAMD17-98-1-8659]; NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Center for Cancer Research; Celma Mastry Ovarian Cancer Foundation; Canadian Cancer Society [NIH R01 CA63682, NIH R01 CA63678, NIH R01 CA080978]; Oak Foundation; Cancer Research UK [C8804/A7058]; Medical Research Council [MRC28209]; European Commission [223175, HEALTH-F2-2009-223175]; UK Department of Health's National Institute for Health Research Biomedical Research Centre funding scheme; [NIH R01 CA122443]; [NIH P50 CA136393]; [NCO: NIH R01 CA76016]; [NEC: NIH R01 CA54419]; [NIH P50 CA105009]; [NHS: NIH T32 CA009001]; [NIH P01 CA87969]; [NIH R01 CA49449]; [NIH R01 CA50383]; [NIH R01 CA67262]; [NIH R01 CA106414]; [ACS CRTG-00-196-01-CCE] FX We thank all members of the UKOPS research team, including research nurses, research scientists, data entry personnel, and consultant gynecological oncologists for their help in establishing the UKOPS case-control collection. In particular, we thank Aleksandra Gentry Maharaj, Usha Menon, Ian Jacobs, Eva Wozniak, Andy Ryan, and Jeremy Ford. The NHS and NHSII thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The MAY study thanks Christopher Hilker and Jason Vollenweider for iSelect genotyping. OCAC: funded through the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith; MAY: NIH R01 CA122443 and NIH P50 CA136393, funding from the Mayo Foundation; NCO: NIH R01 CA76016 and Department of Defense DAMD17-02-1-0666; NEC: NIH R01 CA54419, NIH P50 CA105009, and Department of Defense grant W81XWH-10-1-0280; NHS: NIH T32 CA009001, NIH P01 CA87969, NIH R01 CA49449, NIH R01 CA50383, and NIH R01 CA67262; POL: supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research; TBO: NIH R01 CA106414, ACS CRTG-00-196-01-CCE, Department of Defense grant DAMD17-98-1-8659, and the Celma Mastry Ovarian Cancer Foundation.; TOR: grants from the Canadian Cancer Society, NIH R01 CA63682, NIH R01 CA63678, and NIH R01 CA080978; UKG: The UKOPS ovarian cancer case-control study is funded by a grant from the Oak Foundation. Additional research was funded by a charitable donation from UCLH special trustees, The Eve Appeal, Cancer Research UK project grant (no. C8804/A7058), a Medical Research Council Grant (MRC28209), and a European Commission Seventh Framework Program grant agreement #223175 (HEALTH-F2-2009-223175). Some of this work was undertaken at University College Hospital, London, which receives a proportion of its funding from the UK Department of Health's National Institute for Health Research Biomedical Research Centre funding scheme.. NR 19 TC 16 Z9 19 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2012 VL 23 IS 11 BP 1805 EP 1810 DI 10.1007/s10552-012-0059-y PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 018OQ UT WOS:000309671300006 PM 22961099 ER PT J AU Murphy, MA Trabert, B Yang, HP Park, Y Brinton, LA Hartge, P Sherman, ME Hollenbeck, A Wentzensen, N AF Murphy, Megan A. Trabert, Britton Yang, Hannah P. Park, Yikyung Brinton, Louise A. Hartge, Patricia Sherman, Mark E. Hollenbeck, Albert Wentzensen, Nicolas TI Non-steroidal anti-inflammatory drug use and ovarian cancer risk: findings from the NIH-AARP Diet and Health Study and systematic review SO CANCER CAUSES & CONTROL LA English DT Article DE Aspirin; Non-steroidal anti-inflammatory drugs; Inflammation; Ovarian cancer; Prospective study ID SERVICES-TASK-FORCE; IOWA WOMENS HEALTH; LOW-DOSE ASPIRIN; ENDOMETRIAL CANCER; COLORECTAL-CANCER; PRIMARY PREVENTION; CIGARETTE-SMOKING; MEDICATION USE; UNITED-STATES; ANALGESIC USE AB Chronic inflammation has been proposed as a risk factor for ovarian cancer. Some data suggest that anti-inflammatory medications may be protective against ovarian cancer; however, results have been inconsistent. We evaluated the risk of epithelial ovarian cancer with regular use of NSAIDs prospectively in the NIH-AARP Diet and Health Study, using Cox proportional hazard models. We also examined the risk of common subtypes of epithelial ovarian cancer (serous, mucinous, endometrioid, clear cell, and other epithelial) with regular use of NSAIDs. In addition, we performed meta-analyses summarizing the risk of ovarian cancer with "regular use" of NSAIDs in previously published studies. We did not observe a significant association between regular use of NSAIDs with ovarian cancer risk in the AARP cohort (aspirin: RR 1.06, 95 % CI 0.87-1.29; non-aspirin NSAIDs: RR 0.93, 95 % CI 0.74-1.15); however, summary estimates from prospective cohort studies demonstrated that use of non-aspirin NSAIDs may reduce the risk of ovarian cancer (RR 0.88, 95 % CI 0.77-1.01). Although not significant, we found that mucinous tumors were inversely associated with non-aspirin NSAID use (RR 0.69, 95 % CI 0.23-2.10) in the AARP cohort, which was supported by the meta-analysis (RR 0.69, CI 0.50-0.94.) Although results from the NIH-AARP cohort study were not statistically significant, our meta-analysis suggests that non-aspirin NSAIDs may be protective against ovarian cancer. Additional analyses, focusing on dose, duration, and frequency of NSAID use and accounting for ovarian cancer heterogeneity are necessary to further elucidate the association between NSAID use and ovarian cancer risk. C1 [Wentzensen, Nicolas] NCI, Rockville, MD 20852 USA. [Hollenbeck, Albert] AARP, Org & Tracking Res Dept, Washington, DC USA. [Murphy, Megan A.; Trabert, Britton; Yang, Hannah P.; Brinton, Louise A.; Sherman, Mark E.; Wentzensen, Nicolas] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Murphy, Megan A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Murphy, Megan A.] Harvard Univ, Sch Med, Boston, MA USA. [Murphy, Megan A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. RP Wentzensen, N (reprint author), NCI, 6120 Execut Blvd,EPS 5012, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov RI Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015; OI Brinton, Louise/0000-0003-3853-8562; Park, Yikyung/0000-0002-6281-489X FU NIH, National Cancer Institute; National Cancer Institute; [T32 CA09001] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract to the Department of Health (DOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or DOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. Finally, we thank and remember the founder of the NIH-AARP Diet and Health Study, Dr. Arthur Schatzkin, who was a visionary and a dedicated investigator. The research project was supported by the Intramural Research Program of the National Cancer Institute. Megan A. Murphy is supported in part by training grant T32 CA09001. NR 55 TC 14 Z9 15 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2012 VL 23 IS 11 BP 1839 EP 1852 DI 10.1007/s10552-012-0063-2 PG 14 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 018OQ UT WOS:000309671300010 PM 22972000 ER PT J AU Lindell, SG Yuan, QP Zhou, ZF Goldman, D Thompson, RC Lopez, JF Suomi, SJ Higley, JD Barr, CS AF Lindell, Stephen G. Yuan, Qiaoping Zhou, Zhifeng Goldman, David Thompson, Robert C. Lopez, Juan F. Suomi, Stephen J. Higley, J. Dee Barr, Christina S. TI The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: Potential roles in genetic selection and Gene x Environment interactions SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID NONHUMAN PRIMATE MODEL; OPIOID-RECEPTOR GENE; LINKED POLYMORPHIC REGION; EARLY-LIFE STRESS; ALCOHOL-CONSUMPTION; PROMOTER POLYMORPHISM; REARING CONDITION; EARLY EXPERIENCE; BEHAVIOR; MONKEYS AB In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/ long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 bindingwere determined. We found effects of age and stress exposure. Therewas a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders. C1 [Barr, Christina S.] NIAAA, Sect Comparat Behav Genom, Neurogenet Lab, DICBR,NIH, Rockville, MD 20852 USA. [Thompson, Robert C.; Lopez, Juan F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Suomi, Stephen J.] NICHD, NIH, Bethesda, MD 20892 USA. [Higley, J. Dee] Brigham Young Univ, Provo, UT 84602 USA. RP Barr, CS (reprint author), NIAAA, Sect Comparat Behav Genom, Neurogenet Lab, DICBR,NIH, 5625 Fishers Lane,Room 3S-32, Rockville, MD 20852 USA. EM cbarr@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-09] NR 51 TC 12 Z9 12 U1 2 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD NOV PY 2012 VL 24 IS 4 SI SI BP 1391 EP 1400 DI 10.1017/S0954579412000788 PG 10 WC Psychology, Developmental SC Psychology GA 021ZX UT WOS:000309925800018 PM 23062305 ER PT J AU Murphy, G Kamangar, F Albanes, D Stanczyk, FZ Weinstein, SJ Taylor, PR Virtamo, J Abnet, CC Dawsey, SM Freedman, ND AF Murphy, Gwen Kamangar, Farin Albanes, Demetrius Stanczyk, Frank Z. Weinstein, Stephanie J. Taylor, Philip R. Virtamo, Jarmo Abnet, Christian C. Dawsey, Sanford M. Freedman, Neal D. TI Serum ghrelin is inversely associated with risk of subsequent oesophageal squamous cell carcinoma SO GUT LA English DT Article ID HELICOBACTER-PYLORI; GASTRIC ATROPHY; PROSTATE-CANCER; IMMUNE-SYSTEM; EXPRESSION; HORMONE; ADENOCARCINOMAS; METAANALYSIS; PEPSINOGENS; PEPTIDE AB Background Gastric atrophy, as determined by a low serum pepsinogen I:II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, is also produced in the gastric fundic glands may be a marker of gastric atrophy, but its association with OSCC is not known. Methods To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, the authors conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. ORs and 95% CIs were calculated using conditional logistic regression with adjustment for potential confounders. Results For individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate OR of subsequent OSCC was 6.83 (95% CI 1.46 to 31.84). These associations were dose dependent (p value for trend =0.005 for both), and independent of the effects of low pepsinogen I:II ratio and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, although they become attenuated after 10 years. Conclusion Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC. C1 [Murphy, Gwen; Albanes, Demetrius; Weinstein, Stephanie J.; Taylor, Philip R.; Abnet, Christian C.; Dawsey, Sanford M.; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Stanczyk, Frank Z.] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Murphy, G (reprint author), NCI, Nutr Epidemiol Branch, DCEG, 6120 Execut Blvd,EPS 3034, Rockville, MD 20892 USA. EM murphygw@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Abnet, Christian/C-4111-2015; Murphy, Gwen/G-7443-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU Intramural Research Program of the National Cancer Institute; US Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was supported by funding provided by the Intramural Research Program of the National Cancer Institute and US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004). NR 39 TC 7 Z9 7 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD NOV PY 2012 VL 61 IS 11 BP 1533 EP 1537 DI 10.1136/gutjnl-2011-300653 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 017PN UT WOS:000309602800004 PM 22180062 ER PT J AU Amaral, AFS Porta, M Silverman, DT Milne, RL Kogevinas, M Rothman, N Cantor, KP Jackson, BP Pumarega, JA Lopez, T Carrato, A Guarner, L Real, FX Malats, N AF Amaral, Andre F. S. Porta, Miquel Silverman, Debra T. Milne, Roger L. Kogevinas, Manolis Rothman, Nathaniel Cantor, Kenneth P. Jackson, Brian P. Pumarega, Jose A. Lopez, Tomas Carrato, Alfredo Guarner, Luisa Real, Francisco X. Malats, Nuria TI Pancreatic cancer risk and levels of trace elements SO GUT LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; NICKEL-REFINERY WORKERS; CADMIUM BATTERY WORKERS; OXIDATIVE DNA-DAMAGE; K-RAS MUTATIONS; ARSENIC EXPOSURE; DRINKING-WATER; BLADDER-CANCER; LUNG-CANCER; ORGANOCHLORINE COMPOUNDS AB Background and Aims Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. Methods The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. Results Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; p(trend)=5x10(-6)), arsenic (OR 2.02, 95% CI 1.08 to 3.78; p(trend)=0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; p(trend)=3x10(-5)) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; p(trend)=8x10(-11)) and nickel (OR 0.27, 95% CI 0.12 to 0.59; p(trend)=2x10(-4)) were inversely associated with the risk of EPC. Conclusion Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis. C1 [Amaral, Andre F. S.; Milne, Roger L.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid 28029, Spain. [Porta, Miquel; Pumarega, Jose A.; Lopez, Tomas] Univ Autonoma Barcelona, IMIM, E-08193 Barcelona, Spain. [Porta, Miquel; Pumarega, Jose A.; Lopez, Tomas] CIBERESP, Barcelona, Spain. [Silverman, Debra T.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kogevinas, Manolis] Ctr Recerca Epidemiol Ambiental, Barcelona, Spain. [Cantor, Kenneth P.] KP Cantor Environm LLC, Silver Spring, MD USA. [Jackson, Brian P.] Dartmouth Coll, Dept Earth Sci, Trace Element Anal Core, Hanover, NH 03755 USA. [Carrato, Alfredo] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Carrato, Alfredo] Hosp Gen Elche, Alicante, Spain. [Guarner, Luisa] Hosp Gen Valle Hebron, Barcelona, Spain. [Real, Francisco X.] Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid 28029, Spain. [Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM nuria@cnio.es RI Porta, Miquel/B-5787-2008; Malats, Nuria/H-7041-2015; Real Arribas, Francisco/H-5275-2015; Kogevinas, Manolis/C-3918-2017; Amaral, Andre/A-7662-2008; OI Porta, Miquel/0000-0003-1684-7428; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Amaral, Andre/0000-0002-0369-9449; Lopez-Jimenez, Tomas/0000-0001-8255-4936 FU Association for International Cancer Research [AICR09-0780]; Fondo de Investigacion Sanitaria, Spain [PI09-02102]; Red Tematica de Investigacion Cooperativa en Cancer (RTICC); CIBER de Epidemiologia y Salud Publica (CIBERESP); Instituto de Salud Carlos III; Ministry of Health, Spain; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA; NIH from the National Institute of Environmental Health Sciences [P42 ES007373] FX This work was partly supported by the Association for International Cancer Research (AICR09-0780), Fondo de Investigacion Sanitaria, Spain (# PI09-02102), Red Tematica de Investigacion Cooperativa en Cancer (RTICC) and CIBER de Epidemiologia y Salud Publica (CIBERESP), Instituto de Salud Carlos III, Ministry of Health, Spain, Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC) and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. The Dartmouth Trace Element Core is partly supported by NIH grant number P42 ES007373 from the National Institute of Environmental Health Sciences. NR 70 TC 27 Z9 28 U1 0 U2 29 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD NOV PY 2012 VL 61 IS 11 BP 1583 EP 1588 DI 10.1136/gutjnl-2011-301086 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 017PN UT WOS:000309602800011 PM 22184070 ER PT J AU Posligua, L Silva, EG Deavers, MT Merino, MJ Malpica, A AF Posligua, Lorena Silva, Elvio G. Deavers, Michael T. Merino, Maria J. Malpica, Anais TI Low-grade Smooth Muscle Tumors of the Primary and the Secondary Mullerian System: A Proposed Concept of Multicentricity SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Uterus; Ovary; Peritoneum; Retroperitoneum; Female genital tract; Leiomyosarcoma; Low-grade leiomyosarcoma; Smooth muscle tumor of uncertain malignant potential; Smooth muscle tumor ID LEIOMYOMATOSIS PERITONEALIS DISSEMINATA; X-CHROMOSOME INACTIVATION; DEEP SOFT-TISSUE; HEREDITARY LEIOMYOMATOSIS; METASTASIZING LEIOMYOMA; UTERINE LEIOMYOMAS; FUMARATE-HYDRATASE; OVARIAN; ORIGIN; CANCER AB Some patients with bland smooth muscle tumors in the uterus have synchronous or asynchronous smooth muscle tumors in the peritoneum and/or the retroperitoneum. It is usually assumed that the uterine tumor is the primary lesion, and the extrauterine neoplasm represents its metastasis. Thus, they are designated as low-grade leiomyosarcomas because they lack the diagnostic features of a conventional spindle cell leiomyosarcoma. Nineteen such cases were retrieved from the files of the Department of Pathology at The University of Texas M.D. Anderson Cancer Center, covering a period of 18 yr. Institutional Review Board approval was obtained before the initiation of this study. In addition, 31 cases of conventional uterine leiomyosarcomas of a high grade were reviewed for comparison. Clinicopathologic features such as patients' age, tumor location, histologic features, stage, treatment, and follow-up were recorded. Immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and WT-1 were performed in the initially detected tumor and the subsequent neoplasm of all cases with available material in the low-grade group and selected cases in the high-grade group. Compared with high-grade leiomyosarcomas, the low-grade group cases were found at an early age (45 vs. 52.8 yr), had a longer median time of "recurrence" (42 mo for the low-grade group vs. 12 mo for high-grade leiomyosarcomas), longer median survival (165 mo for the low-grade group vs. 41 mo for the high-grade group), and a much better overall survival (84% vs. 13%). Three (16%) patients died of disease in the low-grade group versus 27 (87%) patients in the high-grade leiomyosarcoma group. We also found a difference in the location of the extrauterine tumors. Most cases of low-grade tumors were found in the pelvis, abdomen, or retroperitoneum, whereas most high-grade leiomyosarcomas involved the lung. In the low-grade tumors, there were some differences in the immunophenotype between the uterine and the extrauterine neoplasms, but in the high-grade tumors, there were no differences in the immunohistochemistry between the primary tumor and the metastasis. In addition to these differences between the 2 groups in the age of the patients, sites of recurrences, and the immunophenotype of the uterine and extrauterine tumor, neither the uterine nor the extrauterine low-grade lesions had histologic features of malignancy. On the basis of these differences, the possibility that the extrauterine lesions in the low-grade group represent independent primaries involving the secondary mullerian system is proposed. C1 [Posligua, Lorena; Silva, Elvio G.; Deavers, Michael T.; Malpica, Anais] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Merino, Maria J.] NIH, Bethesda, MD 20892 USA. RP Silva, EG (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Pathol, 1515 Holcombe Blvd,Unit 0085, Houston, TX 77030 USA. EM esilva@mdanderson.org NR 31 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD NOV PY 2012 VL 31 IS 6 BP 547 EP 555 DI 10.1097/PGP.0b013e31824d3539 PG 9 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 020NS UT WOS:000309818800010 PM 23018207 ER PT J AU Steffen-Smith, EA Venzon, DJ Bent, RS Hipp, SJ Warren, KE AF Steffen-Smith, Emilie A. Venzon, David J. Bent, Robyn S. Hipp, Sean J. Warren, Katherine E. TI Single- and Multivoxel Proton Spectroscopy in Pediatric Patients With Diffuse Intrinsic Pontine Glioma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Brainstem; Children; Glioma; Pontine; Tumor ID MAGNETIC-RESONANCE-SPECTROSCOPY; BRAIN-STEM GLIOMAS; MR SPECTROSCOPY; CHILDREN; METABOLITES; SURVIVAL AB Purpose: To determine the feasibility of two magnetic resonance spectroscopy (MRS) techniques for treating pediatric patients with diffuse intrinsic pontine gliomas (DIPGs) and to evaluate the relationship of metabolic profiles determined by each technique. Utility of each technique for improving patient management is also discussed. Methods and Materials: Children with DIPG (n = 36) were evaluated using single-voxel spectroscopy (SVS) and magnetic resonance spectroscopic imaging (MRSI) during the same imaging session. Patients were followed longitudinally (n = 150 total studies). Technical feasibility was defined by sufficient water and lipid suppression for detection of metabolites. Correlation of metabolic data obtained by SVS and MRSI was determined using the Spearman rank method. Metabolite ratios, including choline: N-acetyl-aspartate (Cho:NAA) and Cho: creatine (Cho:Cr), were obtained from SVS and MRSI. Results: SVS and MRSI acquisitions were feasible in >90% of studies. Maximum Cho: NAA and Cho: Cr from MRSI analysis were strongly associated with Cho: NAA and Cho: Cr obtained by SVS (r = 0.67 and 0.76, respectively). MRSI Cho: NAA values were more heterogeneous than Cho: Cr values within the same lesion, and a strong linear relationship between the range and maximum Cho: NAA values was observed. Conclusions: SVS and MRSI acquisitions were feasible, with a strong correlation in metabolic data. Both techniques may improve diagnostic evaluation and management of DIPG. SVS is recommended for global assessment of tumor metabolism before and after therapy. MRSI showed heterogeneous patterns of metabolic activity within these tumors and is recommended for planning and monitoring targeted therapies and evaluating nearby tissue for tumor invasion. (C) 2012 Elsevier Inc. C1 [Steffen-Smith, Emilie A.; Bent, Robyn S.; Hipp, Sean J.; Warren, Katherine E.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Hipp, Sean J.] Walter Reed Natl Mil Med Ctr, Dept Pediat, Bethesda, MD USA. [Hipp, Sean J.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Warren, KE (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1-5750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov OI Steffen-Smith, Emilie/0000-0002-4966-3046 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The views expressed in this article are those of the authors and do not reflect the official policy of the National Institutes of Health, Department of Army, Department of Defense, or U.S. Government. NR 20 TC 8 Z9 8 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2012 VL 84 IS 3 BP 774 EP 779 DI 10.1016/j.ijrobp.2012.01.032 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 017AI UT WOS:000309560600064 PM 22445531 ER PT J AU Delattre, BMA Viallon, M Wei, HJ Zhu, YM Feiweier, T Pai, VM Wen, H Croisille, P AF Delattre, Benedicte M. A. Viallon, Magalie Wei, Hongjiang Zhu, Yuemin M. Feiweier, Thorsten Pai, Vinay M. Wen, Han Croisille, Pierre TI In Vivo Cardiac Diffusion-Weighted Magnetic Resonance Imaging Quantification of Normal Perfusion and Diffusion Coefficients With Intravoxel Incoherent Motion Imaging SO INVESTIGATIVE RADIOLOGY LA English DT Article DE diffusion-weighted imaging; heart; IVIM; PCA; temporal MIP; in vivo ID PRELIMINARY-EXPERIENCE; CLASSICAL PERFUSION; MOTION-CORRECTION; B-VALUES; IVIM; CIRRHOSIS; LESIONS; TISSUE; HEART; T-1 AB Objectives: Diffusion-weighted imaging (DWI) and the introduction of the intravoxel incoherent motion (IVIM) model have provided a unique method for evaluating perfusion and diffusion within a tissue without the need for a contrast agent. Despite its relevance, cardiac DWI has thus far been limited by low b values because of signal loss induced by physiological motion. The goal of this study was to develop a methodology for estimating IVIM parameters of in vivo cardiac magnetic resonance imaging using an efficient DWI acquisition framework. This was achieved by investigating various acquisition strategies (principal component analysis [PCA] filtering and temporal maximum intensity projection [PCATMIP] and single trigger delay [TD]) and fitting methods. Material and Methods: Simulations were performed on a synthetic dataset of diffusion-weighted signal intensity (SI) to determine the fitting method that would yield IVIM parameters with the greatest accuracy. The required number of b values to correctly estimate IVIM parameters was also investigated. Breath-hold DWI scans were performed for 12 volunteers to collect several TD values during diastole. Thirteen b values ranging from 0 to 550 s/mm(2) were used. The IVIM parameters derived using the data from all the acquired TDs (PCATMIP technique) were compared with those derived using a single acquisition performed at an optimized diastolic time point (1TD). Results: The main result of this study was that PCATMIP, when combined with a fitting model that accounted for T1 and T2 relaxation, provided IVIM parameters with less variability. However, an acquisition performed with 1 optimized diastolic TD provided results that were as good as those provided using PCATMIP if the R-R variability during the acquisition was sufficiently low (T5%). Furthermore, the use of only 9 b values (that could be acquired in 2 breath-holds), instead of 13 b values (requiring 3 breath-holds), was sufficient to determine the IVIM parameters. Conclusions: This study demonstrates that IVIM is technically feasible invivo and reports for the first time the perfusion fraction, f, and the diffusion coefficients, D and D*, for the cardiac DWI of healthy volunteers. Motion-induced signal loss, which is the main problem associated with cardiac DWI, could be avoided with the combined use of sliding acquisition during the cardiac cycle and image postprocessing with the PCATMIP algorithm. This study provides new perspectives for perfusion imaging without a contrast agent and demonstrates that IVIM parameters can act as promising tools to further characterize microvascular abnormalities or dysfunction. C1 [Delattre, Benedicte M. A.; Wei, Hongjiang; Zhu, Yuemin M.; Croisille, Pierre] CREATIS, Lyon, France. [Delattre, Benedicte M. A.; Wei, Hongjiang; Zhu, Yuemin M.; Croisille, Pierre] CNRS, UMR 5220, Lyon, France. [Delattre, Benedicte M. A.; Wei, Hongjiang; Zhu, Yuemin M.; Croisille, Pierre] INSERM, U1044, Lyon, France. [Delattre, Benedicte M. A.; Wei, Hongjiang; Zhu, Yuemin M.; Croisille, Pierre] INSA Lyon, Lyon, France. [Delattre, Benedicte M. A.; Wei, Hongjiang; Zhu, Yuemin M.; Croisille, Pierre] Univ Lyon, Lyon, France. [Viallon, Magalie] Univ Hosp Geneva, Dept Radiol, Geneva, Switzerland. [Feiweier, Thorsten] Siemens AG, Healthcare Sect, Erlangen, Germany. [Pai, Vinay M.; Wen, Han] NHLBI, Imaging Phys Lab, Biochem & Biophys Core, NIH, Bethesda, MD 20892 USA. [Croisille, Pierre] Univ St Etienne, CHU St Etienne, Hop Nord, Dept Radiol, St Etienne, France. RP Croisille, P (reprint author), CHU Hop Nord, Serv Radiol, Ave Albert Raimond, F-42270 St Priest En Jarez, France. EM croisille@creatis.insa-lyon.fr RI Croisille, Pierre/H-4928-2014; Magalie, Viallon/H-4471-2014; Wen, Han/G-3081-2010 OI Croisille, Pierre/0000-0003-4019-3460; Magalie, Viallon/0000-0001-9118-0438; Wen, Han/0000-0001-6844-2997 FU French ANR FX Y. Zhu, P. Croisille, and B. M. A. Delattre received support from French ANR grant. T. Feiweier is employed by Siemens AG. NR 28 TC 16 Z9 16 U1 1 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD NOV PY 2012 VL 47 IS 11 BP 662 EP 670 DI 10.1097/RLI.0b013e31826ef901 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 018JC UT WOS:000309655300007 PM 23001045 ER PT J AU Wakschlag, LS Choi, SW Carter, AS Hullsiek, H Burns, J McCarthy, K Leibenluft, E Briggs-Gowan, MJ AF Wakschlag, Lauren S. Choi, Seung W. Carter, Alice S. Hullsiek, Heide Burns, James McCarthy, Kimberly Leibenluft, Ellen Briggs-Gowan, Margaret J. TI Defining the developmental parameters of temper loss in early childhood: implications for developmental psychopathology SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Developmental psychopathology; temper tantrums; disruptive behavior; preschool psychopathology; dimensional ID DISRUPTIVE-BEHAVIOR; CONDUCT DISORDER; TANTRUMS; PRESCHOOLERS; PREVALENCE; FRAMEWORK; CRITERIA AB Background: Temper modulation problems are both a hallmark of early childhood and a common mental health concern. Thus, characterizing specific behavioral manifestations of temper loss along a dimension from normative misbehaviors to clinically significant problems is an important step toward identifying clinical thresholds. Methods: Parent-reported patterns of temper loss were delineated in a diverse community sample of preschoolers (n = 1,490). A developmentally sensitive questionnaire, the Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB), was used to assess temper loss in terms of tantrum features and anger regulation. Specific aims were: (a) document the normative distribution of temper loss in preschoolers from normative misbehaviors to clinically concerning temper loss behaviors, and test for sociodemographic differences; (b) use Item Response Theory (IRT) to model a Temper Loss dimension; and (c) examine associations of temper loss and concurrent emotional and behavioral problems. Results: Across sociodemographic subgroups, a unidimensional Temper Loss model fit the data well. Nearly all (83.7%) preschoolers had tantrums sometimes but only 8.6% had daily tantrums. Normative misbehaviors occurred more frequently than clinically concerning temper loss behaviors. Milder behaviors tended to reflect frustration in expectable contexts, whereas clinically concerning problem indicators were unpredictable, prolonged, and/or destructive. In multivariate models, Temper Loss was associated with emotional and behavioral problems. Conclusions: Parent reports on a developmentally informed questionnaire, administered to a large and diverse sample, distinguished normative and problematic manifestations of preschool temper loss. A developmental, dimensional approach shows promise for elucidating the boundaries between normative early childhood temper loss and emergent psychopathology. C1 [Wakschlag, Lauren S.; Choi, Seung W.; Burns, James] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Carter, Alice S.] Univ Massachusetts, Dept Psychol, Boston, MA 02125 USA. [Hullsiek, Heide; McCarthy, Kimberly; Briggs-Gowan, Margaret J.] Univ Connecticut, Ctr Hlth, Dept Psychiat, Farmington, CT 06032 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Wakschlag, LS (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Abbott Hall,Suite 729,710 N,Lake Shore Dr, Chicago, IL 60611 USA. EM lauriew@northwestern.edu FU NIMH [R01MH082830, R01MH090301]; Walden & Jean Young Shaw Foundation FX Lauren Wakschlag, Margaret Briggs-Gowan, Alice Carter, and Seung Choi are supported by NIMH grants R01MH082830 and R01MH090301. Lauren Wakschlag was also supported by the Walden & Jean Young Shaw Foundation. The contributions of Patrick Tolan, Ph.D., Robert Gibbons, Ph.D., Barbara Danis, Ph.D., and Carri Hill, Ph.D. to the development of the MAP-DB are gratefully acknowledged. We express heartfelt thanks to participating pediatric clinics and families from Rush University, the University of Illinois at Chicago, and the following Northwestern University Pediatric Practice Research Group practices for their participation: Healthlinc in Valparaiso, IN, Healthlinc in Michigan City, IN, and Associated Pediatricians in Valparaiso, IN. We also thank David Cella, Ph.D. for his inspiring leadership and scientific support. NR 35 TC 30 Z9 30 U1 6 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD NOV PY 2012 VL 53 IS 11 BP 1099 EP 1108 DI 10.1111/j.1469-7610.2012.02595.x PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 022AP UT WOS:000309927700002 PM 22928674 ER PT J AU Stringaris, A Goodman, R Ferdinando, S Razdan, V Muhrer, E Leibenluft, E Brotman, MA AF Stringaris, Argyris Goodman, Robert Ferdinando, Sumudu Razdan, Varun Muhrer, Eli Leibenluft, Ellen Brotman, Melissa A. TI The Affective Reactivity Index: a concise irritability scale for clinical and research settings SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Mood dysregulation; Affective Reactivity Index; irritability; depression; bipolar ID SEVERE MOOD DYSREGULATION; OPPOSITIONAL DEFIANT DISORDER; PEDIATRIC BIPOLAR DISORDER; DIFFICULTIES QUESTIONNAIRE; PSYCHOMETRIC PROPERTIES; DISRUPTIVE BEHAVIOR; CONDUCT DISORDER; CHILDREN; YOUTH; DIMENSIONS AB Background: Irritable mood has recently become a matter of intense scientific interest. Here, we present data from two samples, one from the United States and the other from the United Kingdom, demonstrating the clinical and research utility of the parent- and self-report forms of the Affective Reactivity Index (ARI), a concise dimensional measure of irritability. Methods: The US sample (n = 218) consisted of children and adolescents recruited at the National Institute of Mental Health meeting criteria for bipolar disorder (BD, n = 39), severe mood dysregulation (SMD, n = 67), children at family risk for BD (n = 35), or were healthy volunteers (n = 77). The UK sample (n = 88) was comprised of children from a generic mental health setting and healthy volunteers from primary and secondary schools. Results: Parent- and self-report scales of the ARI showed excellent internal consistencies and formed a single factor in the two samples. In the US sample, the ARI showed a gradation with irritability significantly increasing from healthy volunteers through to SMD. Irritability was significantly higher in SMD than in BD by parent-report, but this did not reach significance by self-report. In the UK sample, parent-rated irritability was differentially related to emotional problems. Conclusions: Irritability can be measured using a concise instrument both in a highly specialized US, as well as a general UK child mental health setting. C1 [Stringaris, Argyris; Goodman, Robert; Ferdinando, Sumudu] Kings Coll London, Inst Psychiat, London SE5 8AF, England. [Razdan, Varun; Muhrer, Eli; Leibenluft, Ellen; Brotman, Melissa A.] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Stringaris, A (reprint author), Kings Coll London, Inst Psychiat, Denmark Hill, London SE5 8AF, England. EM argyris.stringaris@kcl.ac.uk RI Brotman, Melissa/H-7409-2013 FU Wellcome Trust FX The authors have declared that they have no competing or potential conflicts of interest. This manuscript is based on material funded by the Wellcome Trust. Argyris Stringaris gratefully acknowledges the support of the Wellcome Trust. NR 42 TC 38 Z9 38 U1 2 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD NOV PY 2012 VL 53 IS 11 BP 1109 EP 1117 DI 10.1111/j.1469-7610.2012.02561.x PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 022AP UT WOS:000309927700003 PM 22574736 ER PT J AU Adleman, NE Fromm, SJ Razdan, V Kayser, R Dickstein, DP Brotman, MA Pine, DS Leibenluft, E AF Adleman, Nancy E. Fromm, Stephen J. Razdan, Varun Kayser, Reilly Dickstein, Daniel P. Brotman, Melissa A. Pine, Daniel S. Leibenluft, Ellen TI Cross-sectional and longitudinal abnormalities in brain structure in children with severe mood dysregulation or bipolar disorder SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Severe mood dysregulation; bipolar disorder; pediatric; longitudinal; neuroimaging; voxel-based morphometry ID VOXEL-BASED MORPHOMETRY; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CORTICAL GRAY-MATTER; YOUNG-ADULTS; ADOLESCENTS; SCHIZOPHRENIA; REGIONS; METAANALYSIS; AMYGDALA; ADHD AB Background: There is debate as to whether chronic irritability (operationalized as severe mood dysregulation, SMD) is a developmental form of bipolar disorder (BD). Although structural brain abnormalities in BD have been demonstrated, no study compares neuroanatomy among SMD, BD, and healthy volunteers (HV) either cross-sectionally or over time. Furthermore, the developmental trajectories of structural abnormalities in BD or SMD are unknown. This study provides such data in BD, SMD, and HV. Methods: An optimized, modulated voxel-based morphometry (VBM) analysis was conducted on structural MRI scans from 201 children (78 SMD, 55 BD, and 68 HV). In addition, 92 children (31 SMD, 34 BD, and 27 HV) were rescanned after 2 years (mean interval 1.99 +/- 0.94 years), to compare time-related changes among the three groups. Results: Cross-sectionally, the groups differed in gray matter (GM) volume in presupplementary motor area (pre-SMA), dorsolateral prefrontal cortex (DLPFC), insula, and globus pallidus. The cortical differences were driven mainly by increased GM volume in HV compared with BD and SMD. In globus pallidus, there was increased GM in BD compared with HV and SMD. Longitudinally, group-by-time interactions were evident in two clusters in the superior/inferior parietal lobule (R SPL/IPL) and in the precuneus. In both clusters, the interactions were driven by an abnormal increase in volume in BD. Conclusions: Cross-sectionally, both BD and SMD are associated with structural abnormalities in frontal cortex, insula, and basal ganglia. Although some of these deficits overlap (insula and DLPFC), others differentiate SMD and BD (pre-SMA and globus pallidus). Abnormal developmental trajectories in lateral parietal cortex and precuneus are present in, and unique to, BD. Because of the high proportion of co-occurring ADHD in the SMD subjects, we could not separate effects of ADHD from those of SMD, and future research including a nonirritable ADHD group must address this issue. C1 [Adleman, Nancy E.; Fromm, Stephen J.; Razdan, Varun; Kayser, Reilly; Brotman, Melissa A.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Emot & Dev Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Dickstein, Daniel P.] Brown Univ, Bradley Hosp, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Adleman, NE (reprint author), NIMH, Emot & Dev Branch, NIH, US Dept HHS, 9000 Rockville Pike,Bldg 15K,Room 204, Bethesda, MD 20892 USA. EM adlemann@mail.nih.gov RI Brotman, Melissa/H-7409-2013; Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU National Institute of Mental Health (NIMH), National Institutes of Health (NIH) FX This research was supported by the Intramural Program of the National Institute of Mental Health (NIMH), National Institutes of Health (NIH). NR 46 TC 16 Z9 17 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD NOV PY 2012 VL 53 IS 11 BP 1149 EP 1156 DI 10.1111/j.1469-7610.2012.02568.x PG 8 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 022AP UT WOS:000309927700007 PM 22650379 ER PT J AU Berger, VW AF Berger, Vance W. TI De facto masking and other measures to prevent contamination SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Letter C1 [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 2 TC 5 Z9 5 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 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD NOV PY 2012 VL 65 IS 11 BP 1236 EP 1236 DI 10.1016/j.jclinepi.2012.04.016 PG 1 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 017DY UT WOS:000309571500014 PM 23017642 ER PT J AU Berger, VW AF Berger, Vance W. TI Conservative handling of missing information SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Letter ID RANDOMIZED-TRIALS C1 [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 5 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD NOV PY 2012 VL 65 IS 11 BP 1237 EP 1238 DI 10.1016/j.jclinepi.2012.04.017 PG 2 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 017DY UT WOS:000309571500016 PM 23017643 ER PT J AU Kloverpris, HN Harndahl, M Leslie, AJ Carlson, JM Ismail, N van der Stok, M Huang, KHG Chen, FB Riddell, L Steyn, D Goedhals, D van Vuuren, C Frater, J Walker, BD Carrington, M Ndung'u, T Buus, S Goulder, P AF Kloverpris, Henrik N. Harndahl, Mikkel Leslie, Alasdair J. Carlson, Jonathan M. Ismail, Nasreen van der Stok, Mary Huang, Kuan-Hsiang Gary Chen, Fabian Riddell, Lynn Steyn, Dewald Goedhals, Dominique van Vuuren, Cloete Frater, John Walker, Bruce D. Carrington, Mary Ndung'u, Thumbi Buus, Soren Goulder, Philip TI HIV Control through a Single Nucleotide on the HLA-B Locus SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL RESPONSES; CLASS-I ALLELES; IMMUNE CONTROL; ANTIGEN PRESENTATION; SELECTION PRESSURE; MICROPOLYMORPHISM; EPITOPES; AIDS; ASSOCIATIONS AB Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here, we exploit an experiment of nature involving two recently diverged HLA alleles, HLA-B(star)42:01 and HLA-B(star)42:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay (P = 2 x 10(-10)) and functionally through CTL escape mutation (P = 2 x 10(-8)). HLA-B(star)42:01, which presents multiple Gag epitopes, is associated with a 0.52 log(10) lower viral-load set point than HLA-B(star)42:02 (P = 0.02), which presents no p24 Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A(star)30:01/B(star)42/Cw(star)17:01 haplotype is equivalent to 75% of that of HLA-B(star)57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of a particular HIV-specific CTL on disease control. C1 [Kloverpris, Henrik N.; Leslie, Alasdair J.; Goulder, Philip] Univ Oxford, Dept Paediat, Oxford, England. [Harndahl, Mikkel; Buus, Soren] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Copenhagen, Denmark. [Ismail, Nasreen; van der Stok, Mary; Walker, Bruce D.; Ndung'u, Thumbi; Goulder, Philip] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Program, Durban, South Africa. [Walker, Bruce D.; Carrington, Mary; Ndung'u, Thumbi; Goulder, Philip] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Chen, Fabian] Royal Berkshire Hosp, Dept Sexual Hlth, Reading RG1 5AN, Berks, England. [Riddell, Lynn] Northampton Gen Hosp, Northamptonshire Healthcare Natl Hlth Serv Trust, Dept Genitourinary Med, Northampton, England. [Huang, Kuan-Hsiang Gary; Frater, John] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Carlson, Jonathan M.] Microsoft Res, eSci Grp, Los Angeles, CA USA. [Steyn, Dewald; Goedhals, Dominique; van Vuuren, Cloete] Univ Orange Free State, Bloemfontein, South Africa. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Carrington, Mary] SAIC Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kloverpris, HN (reprint author), Univ Oxford, Dept Paediat, Oxford, England. EM henrik.kloverpris@paediatrics.ox.ac.uk RI Buus, Soren/F-5446-2010; OI Buus, Soren/0000-0001-8363-1999; Ndung'u, Thumbi/0000-0003-2962-3992 FU Wellcome Trust; National Institutes of Health [RO1 AI46995]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Laboratory, Center for Cancer Research FX This work was supported by the Wellcome Trust (P.G.) and National Institutes of Health grant RO1 AI46995. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. NR 52 TC 20 Z9 20 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11493 EP 11500 DI 10.1128/JVI.01020-12 PG 8 WC Virology SC Virology GA 018JT UT WOS:000309657100008 PM 22896606 ER PT J AU Sette, P Dussupt, V Bouamr, F AF Sette, Paola Dussupt, Vincent Bouamr, Fadila TI Identification of the HIV-1 NC Binding Interface in Alix Bro1 Reveals a Role for RNA SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTIOUS-ANEMIA VIRUS; ESCRT-III; L-DOMAINS; RETROVIRUS; GAG; ALIX/AIP1; APOBEC3G; HOMOLOG; TSG101 AB HIV-1 recruits members of ESCRT, the cell membrane fission machinery that promotes virus exit. HIV-1 Gag protein gains access to ESCRT directly by binding Alix, an ESCRT-associated protein that promotes budding. The Alix Bro1 and V domains bind Gag NC and p6 regions, respectively. Whereas V-p6 binding and function are well characterized, residues in Bro1 that interact with NC and their functional contribution to Alix-mediated HIV-1 budding are unknown. We mapped Bro1 residues that constitute the NC binding interface and found that they are critical for function. Intriguingly, residues involved in interactions on both sides of the Bro1-NC interface are positively charged, suggesting the involvement of a negatively charged cellular factor serving as a bridge. Nuclease treatment eliminated Bro1-NC interactions, revealing the involvement of RNA. These findings establish a direct role for NC in mediating interactions with ESCRT necessary for virus release and report the first evidence of RNA involvement in such recruitments. C1 [Sette, Paola; Dussupt, Vincent; Bouamr, Fadila] NIAID, Viral Budding Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Bouamr, F (reprint author), NIAID, Viral Budding Unit, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bouamrf@mail.nih.gov FU NIAID; Office of AIDS Research (OAR), NIH FX This work was supported by the Intramural Research Program of the NIAID and in part by funds from the Office of AIDS Research (OAR), NIH. NR 45 TC 13 Z9 13 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11608 EP 11615 DI 10.1128/JVI.01260-12 PG 8 WC Virology SC Virology GA 018JT UT WOS:000309657100019 PM 22896625 ER PT J AU Nemecek, D Qiao, J Mindich, L Steven, AC Heymann, JB AF Nemecek, Daniel Qiao, Jian Mindich, Leonard Steven, Alasdair C. Heymann, J. Bernard TI Packaging Accessory Protein P7 and Polymerase P2 Have Mutually Occluding Binding Sites inside the Bacteriophage phi 6 Procapsid SO JOURNAL OF VIROLOGY LA English DT Article ID STRANDED-RNA BACTERIOPHAGES; 3-DIMENSIONAL STRUCTURE; PURIFIED PROTEIN; PORTAL VERTEX; COMPLEX; VIRUS; REPLICATION; MICROSCOPY; PARTICLES; MOTOR AB Bacteriophage phi 6 is a double-stranded RNA (dsRNA) virus whose genome is packaged sequentially as three single-stranded RNA (ssRNA) segments into an icosahedral procapsid which serves as a compartment for genome replication and transcription. The procapsid shell consists of 60 copies each of P1(A) and P1(B), two nonequivalent conformers of the P1 protein. Hexamers of the packaging ATPase P4 are mounted over the 5-fold vertices, and monomers of the RNA-dependent RNA polymerase (P2) attach to the inner surface, near the 3-fold axes. A fourth protein, P7, is needed for packaging and also promotes assembly. We used cryo-electron microscopy to localize P7 by difference mapping of procapsids with different protein compositions. We found that P7 resides on the interior surface of the P1 shell and appears to be monomeric. Its binding sites are arranged around the 3-fold axes, straddling the interface between two P1(A) subunits. Thus, P7 may promote assembly by stabilizing an initiation complex. Only about 20% of the 60 P7 binding sites were occupied in our preparations. P7 density overlaps P2 density similarly mapped, implying mutual occlusion. The known structure of the phi 12 homolog fits snugly into the P7 density. Both termini-which have been implicated in RNA binding-are oriented toward the adjacent 5-fold vertex, the entry pathway of ssRNA segments. Thus, P7 may promote packaging either by interacting directly with incoming RNA or by modulating the structure of the translocation pore. C1 [Nemecek, Daniel; Steven, Alasdair C.; Heymann, J. Bernard] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Qiao, Jian; Mindich, Leonard] Univ Med & Dent New Jersey, Dept Microbiol, Publ Hlth Res Inst Ctr, Newark, NJ 07103 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov FU NIAMS; National Institutes of Health [GM34352] FX This work was supported by the Intramural Research Program of NIAMS and by grant GM34352 to L. M. from the National Institutes of Health. NR 37 TC 13 Z9 14 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11616 EP 11624 DI 10.1128/JVI.01347-12 PG 9 WC Virology SC Virology GA 018JT UT WOS:000309657100020 PM 22896624 ER PT J AU Abend, JR Ramalingam, D Kieffer-Kwon, P Uldrick, TS Yarchoan, R Ziegelbauer, JM AF Abend, Johanna R. Ramalingam, Dhivya Kieffer-Kwon, Philippe Uldrick, Thomas S. Yarchoan, Robert Ziegelbauer, Joseph M. TI Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Target IRAK1 and MYD88, Two Components of the Toll-Like Receptor/Interleukin-1R Signaling Cascade, To Reduce Inflammatory-Cytokine Expression SO JOURNAL OF VIROLOGY LA English DT Article ID RECEPTOR-ASSOCIATED KINASE; NF-KAPPA-B; INTERFERON-ALPHA INDUCTION; PRIMARY EFFUSION LYMPHOMA; VIRUS-ENCODED MICRORNAS; INNATE IMMUNITY; PROTEIN EXPRESSION; MICE LACKING; IN-VIVO; KSHV AB Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is the causative agent of KS, an important AIDS-associated malignancy. KSHV expresses at least 18 different mature microRNAs (miRNAs). We identified interleukin-1 receptor (IL-1R)-associated kinase 1 (IRAK1) as a potential target of miR-K12-9 (miR-K9) in an array data set examining changes in cellular gene expression levels in the presence of KSHV miRNAs. Using 3'-untranslated region (3'UTR) luciferase reporter assays, we confirmed that miR-K9 and other miRNAs inhibit IRAK1 expression. In addition, IRAK1 expression is downregulated in cells transfected with miR-K9 and during de novo KSHV infection. IRAK1 is an important component of the Toll-like receptor (TLR)/IL-1R signaling cascade. The downregulation of IRAK1 by miR-K9 resulted in the decreased stimulation of NF-kappa B activity in endothelial cells treated with IL-1 alpha and in B cells treated with a TLR7/8 agonist. Interestingly, miR-K9 had a greater effect on NF-kappa B activity than did a small interfering RNA (siRNA) targeting IRAK1 despite the more efficient downregulation of IRAK1 expression with the siRNA. We hypothesized that KSHV miRNAs may also be regulating a second component of the TLR/IL-1R signaling cascade, resulting in a stronger phenotype. Reanalysis of the array data set identified myeloid differentiation primary response protein 88 (MYD88) as an additional potential target. 3'UTR luciferase reporter assays and Western blot analysis confirmed the targeting of MYD88 by miR-K5. The presence of miR-K9 and miR-K5 inhibited the production of IL-6 and IL-8 upon the IL-1 alpha stimulation of endothelial cells. These results demonstrate KSHV-encoded miRNAs regulating the TLR/IL-1R signaling cascade at two distinct points and suggest the importance of these pathways during viral infection. C1 [Abend, Johanna R.; Ramalingam, Dhivya; Kieffer-Kwon, Philippe; Uldrick, Thomas S.; Yarchoan, Robert; Ziegelbauer, Joseph M.] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ziegelbauer, JM (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM ziegelbauerjm@mail.nih.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; intramural AIDS research fellowship FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. J.R.A. was supported by an intramural AIDS research fellowship. NR 55 TC 53 Z9 54 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11663 EP 11674 DI 10.1128/JVI.01147-12 PG 12 WC Virology SC Virology GA 018JT UT WOS:000309657100025 PM 22896623 ER PT J AU Schneemann, A Speir, JA Tan, GS Khayat, R Ekiert, DC Matsuoka, Y Wilson, IA AF Schneemann, Anette Speir, Jeffrey A. Tan, Gene S. Khayat, Reza Ekiert, Damian C. Matsuoka, Yumiko Wilson, Ian A. TI A Virus-Like Particle That Elicits Cross-Reactive Antibodies to the Conserved Stem of Influenza Virus Hemagglutinin SO JOURNAL OF VIROLOGY LA English DT Article ID NEUTRALIZING ANTIBODY; EPITOPE-SCAFFOLDS; A VIRUSES; INDUCTION; PEPTIDE; VACCINE; DESIGN; NANOPARTICLES; RECOGNITION; MICROSCOPY AB The discovery of broadly neutralizing antibodies that recognize highly conserved epitopes in the membrane-proximal region of influenza virus hemagglutinin (HA) has revitalized efforts to develop a universal influenza virus vaccine. This effort will likely require novel immunogens that contain these epitopes but lack the variable and immunodominant epitopes located in the globular head of HA. As a first step toward developing such an immunogen, we investigated whether the 20-residue A-helix of the HA2 chain that forms the major component of the epitope of broadly neutralizing antibodies CR6261, F10, and others is sufficient by itself to elicit antibodies with similarly broad antiviral activity. Here, we report the multivalent display of the A-helix on icosahedral virus-like particles (VLPs) derived from the capsid of Flock House virus. Mice immunized with VLPs displaying 180 copies/particle of the A-helix produced antibodies that recognized trimeric HA and the elicited antibodies had binding characteristics similar to those of CR6261 and F10: they recognized multiple HA subtypes from group 1 but not from group 2. However, the anti-A-helix antibodies did not neutralize influenza virus. These results indicate that further engineering of the transplanted peptide is required and that display of additional regions of the epitope may be necessary to achieve protection. C1 [Schneemann, Anette; Speir, Jeffrey A.; Khayat, Reza; Ekiert, Damian C.; Wilson, Ian A.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Tan, Gene S.] Mt Sinai Sch Med, Dept Microbiol, New York, NY USA. [Matsuoka, Yumiko] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Schneemann, A (reprint author), Scripps Res Inst, Dept Mol Biol, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM aschneem@scripps.edu; speir@scrippps.edu OI Ekiert, Damian/0000-0002-2570-0404 FU National Institutes of Health [AI92280, AI058113, GM080209]; Achievements Rewards for College Scientists Foundation; Skaggs Institute for Chemical Biology; National Institutes of Health through the National Center for Research Resource P41 program [RR17573] FX This study was supported by grants from the National Institutes of Health to A. S. (AI92280) and to I. A. W. (AI058113), a predoctoral fellowship from the Achievements Rewards for College Scientists Foundation and the NIH Molecular Evolution Training Program GM080209 (D. C. E.), and the Skaggs Institute for Chemical Biology. Cryo-EM and image reconstructions were conducted at the National Resource for Automated Molecular Microscopy, which is supported by the National Institutes of Health through the National Center for Research Resource P41 program (RR17573). NR 45 TC 34 Z9 35 U1 0 U2 30 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11686 EP 11697 DI 10.1128/JVI.01694-12 PG 12 WC Virology SC Virology GA 018JT UT WOS:000309657100027 PM 22896619 ER PT J AU Ilyushina, NA Ikizler, MR Kawaoka, Y Rudenko, LG Treanor, JJ Subbarao, K Wright, PF AF Ilyushina, Natalia A. Ikizler, Mine R. Kawaoka, Yoshihiro Rudenko, Larisa G. Treanor, John J. Subbarao, Kanta Wright, Peter F. TI Comparative Study of Influenza Virus Replication in MDCK Cells and in Primary Cells Derived from Adenoids and Airway Epithelium SO JOURNAL OF VIROLOGY LA English DT Article ID COLD-ADAPTED INFLUENZA; LIVE ATTENUATED VACCINES; YOUNG-CHILDREN; REASSORTANT VIRUS; A VIRUS; PANDEMIC INFLUENZA; SEASONAL INFLUENZA; RESPIRATORY-TRACT; ADULT VOLUNTEERS; HEALTHY-ADULTS AB Although clinical trials with human subjects are essential for determination of safety, infectivity, and immunogenicity, it is desirable to know in advance the infectiousness of potential candidate live attenuated influenza vaccine strains for human use. We compared the replication kinetics of wild-type and live attenuated influenza viruses, including H1N1, H3N2, H9N2, and B strains, in Madin-Darby canine kidney (MDCK) cells, primary epithelial cells derived from human adenoids, and human bronchial epithelium (NHBE cells). Our data showed that despite the fact that all tissue culture models lack a functional adaptive immune system, differentiated cultures of human epithelium exhibited the greatest restriction for all H1N1, H3N2, and B vaccine viruses studied among three cell types tested and the best correlation with their levels of attenuation seen in clinical trials with humans. In contrast, the data obtained with MDCK cells were the least predictive of restricted viral replication of live attenuated vaccine viruses in humans. We were able to detect a statistically significant difference between the replication abilities of the U. S. (A/Ann Arbor/6/60) and Russian (A/Leningrad/134/17/57) cold-adapted vaccine donor strains in NHBE cultures. Since live attenuated pandemic influenza vaccines may potentially express a hemagglutinin and neuraminidase from a non-human influenza virus, we assessed which of the three cell cultures could be used to optimally evaluate the infectivity and cellular tropism of viruses derived from different hosts. Among the three cell types tested, NHBE cultures most adequately reflected the infectivity and cellular tropism of influenza virus strains with different receptor specificities. NHBE cultures could be considered for use as a screening step for evaluating the restricted replication of influenza vaccine candidates. C1 [Ilyushina, Natalia A.; Wright, Peter F.] Geisel Med Sch Dartmouth, Dept Pediat, Lebanon, NH USA. [Ikizler, Mine R.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Dept Microbiol & Immunol, Tokyo, Japan. [Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Dept Special Pathogens, Tokyo, Japan. [Kawaoka, Yoshihiro] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. [Kawaoka, Yoshihiro] Japan Sci & Technol Agcy, ERATO Infect Induced Host Responses Project, Saitama, Japan. [Rudenko, Larisa G.] RAMS, Inst Expt Med, Dept Virol, St Petersburg, Russia. [Treanor, John J.] Univ Rochester, Dept Microbiol & Immunol, Div Infect Dis, Rochester, NY USA. [Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Ilyushina, NA (reprint author), Geisel Med Sch Dartmouth, Dept Pediat, Lebanon, NH USA. EM natalia.a.ilyushina@dartmouth.edu RI Rudenko, Larisa/B-5169-2015 OI Rudenko, Larisa/0000-0002-0107-9959 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900026C]; ARRA; NIAID, NIH FX This study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200900026C and ARRA funding and by the Intramural Research Program of NIAID, NIH. NR 54 TC 17 Z9 17 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11725 EP 11734 DI 10.1128/JVI.01477-12 PG 10 WC Virology SC Virology GA 018JT UT WOS:000309657100030 PM 22915797 ER PT J AU Raymond, GJ Race, B Hollister, JR Offerdahl, DK Moore, RA Kodali, R Raymond, LD Hughson, AG Rosenke, R Long, D Dorward, DW Baron, GS AF Raymond, Gregory J. Race, Brent Hollister, Jason R. Offerdahl, Danielle K. Moore, Roger A. Kodali, Ravindra Raymond, Lynne D. Hughson, Andrew G. Rosenke, Rebecca Long, Dan Dorward, David W. Baron, Gerald S. TI Isolation of Novel Synthetic Prion Strains by Amplification in Transgenic Mice Coexpressing Wild-Type and Anchorless Prion Proteins SO JOURNAL OF VIROLOGY LA English DT Article ID STRAUSSLER-SCHEINKER-DISEASE; MISFOLDING CYCLIC AMPLIFICATION; IN-VITRO GENERATION; MAMMALIAN PRIONS; DIFFERENT CONFORMATIONS; INFECTIOUS PRIONS; AMYLOID FIBRILS; SCRAPIE; RESISTANT; PRP AB Mammalian prions are thought to consist of misfolded aggregates (protease-resistant isoform of the prion protein [PrPres]) of the cellular prion protein (PrPC). Transmissible spongiform encephalopathy (TSE) can be induced in animals inoculated with recombinant PrP (rPrP) amyloid fibrils lacking mammalian posttranslational modifications, but this induction is inefficient in hamsters or transgenic mice overexpressing glycosylphosphatidylinositol (GPI)-anchored PrPC. Here we show that TSE can be initiated by inoculation of misfolded rPrP into mice that express wild-type (wt) levels of PrPC and that synthetic prion strain propagation and selection can be affected by GPI anchoring of the host's PrPC. To create prions de novo, we fibrillized mouse rPrP in the absence of molecular cofactors, generating fibrils with a PrPres-like protease-resistant banding profile. These fibrils induced the formation of PrPres deposits in transgenic mice coexpressing wt and GPI-anchorless PrPC (wt/GPI(-)) at a combined level comparable to that of PrPC expression in wt mice. Secondary passage into mice expressing wt, GPI(-), or wt plus GPI(-) PrPC induced TSE disease with novel clinical, histopathological, and biochemical phenotypes. Contrary to laboratory-adapted mouse scrapie strains, the synthetic prion agents exhibited a preference for conversion of GPI(-) PrPC and, in one case, caused disease only in GPI(-) mice. Our data show that novel TSE agents can be generated de novo solely from purified mouse rPrP after amplification in mice coexpressing normal levels of wt and anchorless PrPC. These observations provide insight into the minimal elements required to create prions in vitro and suggest that the PrPC GPI anchor can modulate the propagation of synthetic TSE strains. C1 [Raymond, Gregory J.; Race, Brent; Hollister, Jason R.; Offerdahl, Danielle K.; Moore, Roger A.; Kodali, Ravindra; Raymond, Lynne D.; Hughson, Andrew G.; Baron, Gerald S.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Rosenke, Rebecca; Long, Dan] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Dorward, David W.] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Baron, GS (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM gbaron@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 63 TC 22 Z9 22 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11763 EP 11778 DI 10.1128/JVI.01353-12 PG 16 WC Virology SC Virology GA 018JT UT WOS:000309657100034 PM 22915801 ER PT J AU Hoenen, T Shabman, RS Groseth, A Herwig, A Weber, M Schudt, G Dolnik, O Basler, CF Becker, S Feldmann, H AF Hoenen, Thomas Shabman, Reed S. Groseth, Allison Herwig, Astrid Weber, Michaela Schudt, Gordian Dolnik, Olga Basler, Christopher F. Becker, Stephan Feldmann, Heinz TI Inclusion Bodies Are a Site of Ebolavirus Replication SO JOURNAL OF VIROLOGY LA English DT Article ID GREEN FLUORESCENT PROTEIN; VIRUS-LIKE PARTICLES; MARBURG-VIRUS; NUCLEOCAPSID FORMATION; VIRAL TRANSCRIPTION; CELLS; VP40; INFECTION; VP35; NUCLEOPROTEIN AB Inclusion bodies are a characteristic feature of ebolavirus infections in cells. They contain large numbers of preformed nucleocapsids, but their biological significance has been debated, and they have been suggested to be aggregates of viral proteins without any further biological function. However, recent data for other viruses that produce similar structures have suggested that inclusion bodies might be involved in genome replication and transcription. In order to study filovirus inclusion bodies, we fused mCherry to the ebolavirus polymerase L, which is found in inclusion bodies. The resulting L-mCherry fusion protein was functional in minigenome assays and incorporated into virus-like particles. Importantly, L-mCherry fluorescence in transfected cells was readily detectable and distributed in a punctate pattern characteristic for inclusion bodies. A recombinant ebolavirus encoding L-mCherry instead of L was rescued and showed virtually identical growth kinetics and endpoint titers to those for wild-type virus. Using this virus, we showed that the onset of inclusion body formation corresponds to the onset of viral genome replication, but that viral transcription occurs prior to inclusion body formation. Live-cell imaging further showed that inclusion bodies are highly dynamic structures and that they can undergo dramatic reorganization during cell division. Finally, by labeling nascent RNAs using click technology we showed that inclusion bodies are indeed the site of viral RNA synthesis. Based on these data we conclude that, rather than being inert aggregates of nucleocapsids, ebolavirus inclusion bodies are in fact complex and dynamic structures and an important site at which viral RNA replication takes place. C1 [Hoenen, Thomas; Groseth, Allison; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Hoenen, Thomas; Groseth, Allison; Herwig, Astrid; Weber, Michaela; Schudt, Gordian; Dolnik, Olga; Becker, Stephan] Univ Marburg, Inst Virol, D-3550 Marburg, Germany. [Shabman, Reed S.; Basler, Christopher F.] Mt Sinai Sch Med, Dept Microbiol, New York, NY USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM feldmannh@niaid.nih.gov RI Becker, Stephan/A-1065-2010; OI Becker, Stephan/0000-0002-2794-5659; Hoenen, Thomas/0000-0002-5829-6305 FU NIH, NIAID; NIH [AI059536, AI093786]; Deutsche Forschungsgemeinschaft [SFB 593, TP B12]; Initiative for Excellence in Science and Technology of the state of Hessen (LOEWE) FX This research was supported in part by the Intramural Research Program of the NIH, NIAID. Further, this work was supported in part by NIH grants AI059536 and AI093786 to C. F. B., as well as by the Deutsche Forschungsgemeinschaft through the SFB 593, TP B12, and the Initiative for Excellence in Science and Technology of the state of Hessen (LOEWE). NR 45 TC 35 Z9 36 U1 1 U2 23 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11779 EP 11788 DI 10.1128/JVI.01525-12 PG 10 WC Virology SC Virology GA 018JT UT WOS:000309657100035 PM 22915810 ER PT J AU Woloshin, S Schwartz, LM Black, WC Kramer, BS AF Woloshin, Steven Schwartz, Lisa M. Black, William C. Kramer, Barnett S. TI Cancer Screening Campaigns - Getting Past Uninformative Persuasion SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Woloshin, Steven; Schwartz, Lisa M.] VA Outcomes Grp, White River Jct, VT USA. [Woloshin, Steven; Schwartz, Lisa M.] Dartmouth Inst Hlth Policy & Clin Practice, Ctr Med & Media, Lebanon, NH USA. [Woloshin, Steven; Schwartz, Lisa M.; Black, William C.] Norris Cotton Canc Ctr, Lebanon, NH USA. [Black, William C.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Woloshin, S (reprint author), VA Outcomes Grp, White River Jct, VT USA. NR 5 TC 31 Z9 31 U1 1 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 1 PY 2012 VL 367 IS 18 BP 1677 EP 1679 DI 10.1056/NEJMp1209407 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 028RS UT WOS:000310440800001 PM 23113476 ER PT J AU Neta, G Stewart, PA Rajaraman, P Hein, MJ Waters, MA Purdue, MP Samanic, C Coble, JB Linet, MS Inskip, PD AF Neta, Gila Stewart, Patricia A. Rajaraman, Preetha Hein, Misty J. Waters, Martha A. Purdue, Mark P. Samanic, Claudine Coble, Joseph B. Linet, Martha S. Inskip, Peter D. TI Occupational exposure to chlorinated solvents and risks of glioma and meningioma in adults SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; BRAIN-TUMORS; EPIDEMIOLOGIC EVIDENCE; CANCER; TRICHLOROETHYLENE; MORTALITY; STATES; WOMEN; MEN AB Objectives Chlorinated solvents are classified as probable or possible carcinogens. It is unknown whether exposure to these agents increases the risk of malignant or benign brain tumours. Our objective was to evaluate associations of brain tumour risk with occupational exposure to six chlorinated solvents (ie, dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, trichloroethylene and perchloroethylene). Methods 489 glioma cases, 197 meningioma cases and 799 controls were enrolled in a hospital-based case-control study conducted at three USA hospitals in Arizona, Massachusetts and Pennsylvania. Information about occupational history was obtained through a detailed inperson interview that included job-specific modules of questions such that the interview was tailored to each individual's particular work history. An industrial hygienist assessed potential solvent exposure based on this information and an exhaustive review of the relevant industrial hygiene literature. Unconditional logistic regression models were used to calculate OR and 95% CI for each solvent for ever/never, duration, cumulative, average weekly and highest exposure. Results Overall, we found no consistent evidence of an increased risk of glioma or meningioma related to occupational exposure to the six chlorinated solvents evaluated. There was some suggestion of an association between carbon tetrachloride and glioma in analyses restricted to exposed subjects, with average weekly exposure above the median associated with increased risk compared with below the median exposure (OR = 7.1, 95% CI 1.1 to 45.2). Conclusions We found no consistent evidence for increased brain tumour risk related to chlorinated solvents. C1 [Neta, Gila; Stewart, Patricia A.; Rajaraman, Preetha; Purdue, Mark P.; Samanic, Claudine; Coble, Joseph B.; Linet, Martha S.; Inskip, Peter D.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Hein, Misty J.] NIOSH, Div Surveillance Hazard Evaluat & Field Studies, Cincinnati, OH 45226 USA. [Waters, Martha A.] NIOSH, Div Appl Res & Technol, Cincinnati, OH 45226 USA. RP Neta, G (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv,EPS, Room 7092,6120 Execut Blvd, Bethesda, MD 20852 USA. EM netagil@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health FX This research was supported, in part, by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health. NR 38 TC 5 Z9 5 U1 2 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD NOV PY 2012 VL 69 IS 11 BP 793 EP 801 DI 10.1136/oemed-2012-100742 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 020KF UT WOS:000309806700004 PM 22864249 ER PT J AU Guha, R AF Guha, Rajarshi TI Exploring structure-activity data using the landscape paradigm SO WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE LA English DT Article AB In this article, we present an overview of the origin and applications of the activity landscape view of structureactivity relationship (SAR) data as conceived by Shanmugasundaram and Maggiora. Within this landscape, different regions exemplify different aspects of SAR trendsranging from smoothly varying trends to discontinuous trends (also termed activity cliffs). We discuss the various definitions of landscapes and cliffs that have been proposed as well as different approaches to the numerical quantification of a landscape. We then highlight some of the landscape visualization approaches that have been developed, followed by a review of the various applications of activity landscapes and cliffs to topics in medicinal chemistry and SAR analysis. (c) 2012 John Wiley & Sons, Ltd. C1 NIH, Ctr Translat Therapeut, Rockville, MD USA. RP Guha, R (reprint author), NIH, Ctr Translat Therapeut, Rockville, MD USA. EM guhar@mail.nih.gov OI Guha, Rajarshi/0000-0001-7403-8819 NR 50 TC 15 Z9 15 U1 0 U2 3 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1759-0876 J9 WIRES COMPUT MOL SCI JI Wiley Interdiscip. Rev.-Comput. Mol. Sci. PD NOV-DEC PY 2012 VL 2 IS 6 BP 829 EP 841 DI 10.1002/wcms.1087 PG 13 WC Chemistry, Multidisciplinary; Mathematical & Computational Biology SC Chemistry; Mathematical & Computational Biology GA 017LX UT WOS:000309592500002 ER PT J AU Wang, YJ Shen, DF Wang, VM Yu, CR Wang, RX Tuo, JS Chan, CC AF Wang, Yujuan Shen, Defen Wang, Vinson M. Yu, Cheng-Rong Wang, Ren-Xi Tuo, Jingsheng Chan, Chi-Chao TI Enhanced apoptosis in retinal pigment epithelium under inflammatory stimuli and oxidative stress SO APOPTOSIS LA English DT Article DE Apoptosis; Retinal pigment epithelium (RPE); Inflammation; Oxidative stress; Fas ligand (FasL); Decoy receptor 3 (DcR3) ID PHOTORECEPTOR CELL-DEATH; MACULAR DEGENERATION; FAS LIGAND; GENE-EXPRESSION; DNA-DAMAGE; MODELS; MICE; RPE; AMPLIFICATION; ACTIVATION AB Age-related macular degeneration (AMD) is a neurodegenerative disease that causes irreversible central vision loss in the elderly. Retinal pigment epithelium (RPE) has been found to be a key component in AMD pathogenesis. The Ccl2 (-/-) /Cx3cr1 (-/-) (DKO) mouse on Crb1 (rd8) background is created as an AMD model, developing AMD-like retinal lesions. Our study aimed to examine RPE apoptosis in DKO mouse and human ARPE-19 cell line. DKO RPE expressed higher apoptotic proteins when compared with age-matched wild type (WT) RPE in physiological conditions. Apoptosis of primary cultured mouse RPE was evaluated under stimulation with lipopolysaccharide for inflammatory stimulation and 2,3,7,8-tetrachlorodibenzo-p-dioxin or H2O2 for oxidative stress. Compared with WT RPE, DKO RPE was more susceptible to Fas ligand (FasL)-mediated apoptosis under both inflammatory and oxidative stress, with less cell viability and higher expression of apoptotic transcripts and proteins. Decreased cell viability was also observed in ARPE-19 cells under each stimulus. Furthermore, we also investigated the anti-apoptotic effects of decoy receptor 3 (DcR3), a decoy receptor for FasL, on ARPE-19 cells under inflammatory and oxidative stress. DcR3 pre-incubated ARPE-19 cells showed decreased apoptosis, with increased cell viability and decreased expression of apoptotic transcripts and proteins under the stimuli. On the contrary, knockdown of DcR3 in ARPE-19 cells showed totally opposite results. Our study demonstrates that FasL-mediated RPE apoptosis may play a pivotal role in AMD pathogenesis. C1 [Wang, Yujuan; Shen, Defen; Wang, Vinson M.; Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Yujuan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. [Yu, Cheng-Rong; Wang, Ren-Xi] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov RI wang, yujuan/C-8428-2016; OI Tuo, Jingsheng/0000-0002-1372-7810 FU National Eye Institute Intramural Research Program FX The National Eye Institute Intramural Research Program supported the study. NR 45 TC 15 Z9 17 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD NOV PY 2012 VL 17 IS 11 BP 1144 EP 1155 DI 10.1007/s10495-012-0750-1 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 016VL UT WOS:000309547700002 PM 22911474 ER PT J AU Croteau, DL Rossi, ML Ross, J Dawut, L Dunn, C Kulikowicz, T Bohr, VA AF Croteau, Deborah L. Rossi, Marie L. Ross, Jennifer Dawut, Lale Dunn, Christopher Kulikowicz, Tomasz Bohr, Vilhelm A. TI RAPADILINO RECQL4 mutant protein lacks helicase and ATPase activity SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE RecQ helicase; RECQL4; RAPADILINO; Rothmund-Thomson syndrome; ATPase ID ROTHMUND-THOMSON-SYNDROME; STRAND-ANNEALING ACTIVITIES; SYNDROME GENE-PRODUCT; UNWINDING ACTIVITIES; DNA HELICASE; HUMAN-CELLS; LOCALIZES; STABILITY; REPAIR; MITOCHONDRIA AB The RecQ family of helicases has been shown to play an important role in maintaining genomic stability. In humans, this family has five members and mutations in three of these helicases, BLM, WRN and RECQL4, are associated with disease. Alterations in RECQL4 are associated with three diseases, Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILINO syndrome. One of the more common mutations found in RECQL4 is the RAPADILINO mutation, c.1390+2delT which is a splice-site mutation leading to an in-frame skipping of exon 7 resulting in 44 amino acids being deleted from the protein (p.Ala420-Ala463del). In order to characterize the RAPADILINO RECQL4 mutant protein, it was expressed in bacteria and purified using an established protocol. Strand annealing, helicase, and ATPase assays were conducted to characterize the protein's activities relative to WT RECQL4. Here we show that strand annealing activity in the absence of ATP is unchanged from that of WT RECQL4. However, the RAPADILINO protein variant lacks helicase and ssDNA-stimulated ATPase activity. These observations help explain the underlying molecular etiology of the disease and our findings provide insight into the genotype and phenotype association among RECQL4 syndromes. Published by Elsevier B.V. C1 [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM BohrV@grc.nia.nih.gov FU National Institute on Aging, NIH [Z01 AG000726-20] FX We would like to thank Dr. Avik Ghosh and Martin Jensen for their assistance with the purification of WT RECQL4 and for editing the article. We would like to thank Robert Brosh for critically reading the article. We would like to thank Patrick Sung (Yale, CT) for the pGEX-RECQL4-His bacterial expression vector and Dr. Sharon Plon (Baylor College of Medicine, TX) for the pGFP-Delta exon 7 RECQL4 mammalian expression vector. This work was supported by the intramural research program of the National Institute on Aging, NIH, Z01 AG000726-20. NR 35 TC 9 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD NOV PY 2012 VL 1822 IS 11 BP 1727 EP 1734 DI 10.1016/j.bbadis.2012.07.014 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 017BX UT WOS:000309566200009 PM 22885111 ER PT J AU Benson, PJ Beedie, SA Shephard, E Giegling, I Rujescu, D St Clair, D AF Benson, Philip J. Beedie, Sara A. Shephard, Elizabeth Giegling, Ina Rujescu, Dan St Clair, David TI Simple Viewing Tests Can Detect Eye Movement Abnormalities That Distinguish Schizophrenia Cases from Controls with Exceptional Accuracy SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Classification; eye-movement phenotype; neural network; predictive model; risk marker; schizophrenia ID VISUAL SCAN PATHS; SMOOTH-PURSUIT; TRACKING DYSFUNCTION; FIXATION STABILITY; 1ST-DEGREE RELATIVES; SIBLINGS; MARKER; GENE; SPECIFICITY; IMPAIRMENT AB Background: We have investigated which eye-movement tests alone and combined can best discriminate schizophrenia cases from control subjects and their predictive validity. Methods: A training set of 88 schizophrenia cases and 88 controls had a range of eye movements recorded; the predictive validity of the tests was then examined on eye-movement data from 34 9-month retest cases and controls, and from 36 novel schizophrenia cases and 52 control subjects. Eye movements were recorded during smooth pursuit, fixation stability, and free-viewing tasks. Group differences on performance measures were examined by univariate and multivariate analyses. Model fitting was used to compare regression, boosted tree, and probabilistic neural network approaches. Results: As a group, schizophrenia cases differed from control subjects on almost all eye-movement tests, including horizontal and Lissajous pursuit, visual scanpath, and fixation stability; fixation dispersal during free viewing was the best single discriminator. Effects were stable over time, and independent of sex, medication, or cigarette smoking. A boosted tree model achieved perfect separation of the 88 training cases from 88 control subjects; its predictive validity on retest assessments and novel cases and control subjects was 87.8%. However, when we examined the whole data set of 298 assessments, a cross-validated probabilistic neural network model was superior and could discriminate all cases from controls with near perfect accuracy at 98.3%. Conclusions: Simple viewing patterns can detect eye-movement abnormalities that can discriminate schizophrenia cases from control subjects with exceptional accuracy. C1 [Benson, Philip J.; Beedie, Sara A.; Shephard, Elizabeth] Univ Aberdeen, Sch Psychol, Kings Coll, Aberdeen AB24 3UB, Scotland. [Giegling, Ina; Rujescu, Dan] Univ Munich, Dept Psychiat & Psychotherapy, D-80539 Munich, Germany. [St Clair, David] Univ Aberdeen, Dept Mental Hlth, Royal Cornhill Hosp, Aberdeen AB24 3UB, Scotland. [St Clair, David] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Benson, PJ (reprint author), Univ Aberdeen, Sch Psychol, Kings Coll, Aberdeen AB24 3UB, Scotland. EM philip.benson@abdn.ac.uk FU Royal Society of London; Millar-Mackenzie Trust; National Institute of Mental Health Genome-Wide Association Study; University of Aberdeen; European Framework 6 (SGENE); Scottish Chief Scientist Office [CZB 4/734] FX All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. This work was partially supported by the Royal Society of London, Millar-Mackenzie Trust, National Institute of Mental Health Genome-Wide Association Study, and the University of Aberdeen, and by grants from European Framework 6 (SGENE) and Scottish Chief Scientist Office (Grant No. CZB 4/734). NR 58 TC 27 Z9 30 U1 2 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD NOV 1 PY 2012 VL 72 IS 9 BP 716 EP 724 DI 10.1016/j.biopsych.2012.04.019 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 017SF UT WOS:000309610500003 PM 22621999 ER PT J AU Alarcon, SV Mollapour, M Lee, MJ Tsutsumi, S Lee, S Kim, YS Prince, T Apolo, AB Giaccone, G Xu, W Neckers, LM Trepel, JB AF Alarcon, S. V. Mollapour, M. Lee, M-J. Tsutsumi, S. Lee, S. Kim, Y. S. Prince, T. Apolo, A. B. Giaccone, G. Xu, W. Neckers, L. M. Trepel, J. B. TI Tumor-Intrinsic and Tumor-Extrinsic Factors Impacting Hsp90-Targeted Therapy SO CURRENT MOLECULAR MEDICINE LA English DT Review DE Heat shock protein 90; host; phosphorylation; posttranslational; reactive oxygen species; stroma; systems ID HEAT-SHOCK-PROTEIN; HSP90 MOLECULAR CHAPERONE; IN-VITRO PHOSPHORYLATION; E3 UBIQUITIN LIGASE; KAPPA-B ACTIVATION; BREAST-CANCER; 90 INHIBITOR; ATPASE ACTIVITY; HSP90-SPECIFIC INHIBITOR; HETEROPROTEIN COMPLEX AB In 1994 the first heat shock protein 90 (Hsp90) inhibitor was identified and Hsp90 was reported to be a target for anticancer therapeutics. In the past 18 years there have been 17 distinct Hsp90 inhibitors entered into clinical trial, and the small molecule Hsp90 inhibitors have been highly valuable as probes of the role of Hsp90 and its client proteins in cancer. Although no Hsp90 inhibitor has achieved regulatory approval, recently there has been significant progress in Hsp90 inhibitor clinical development, and in the past year RECIST responses have been documented in HER2-positive breast cancer and EML4-ALK-positive non-small cell lung cancer. All of the clinical Hsp90 inhibitors studied to date are specific in their target, i.e. they bind exclusively to Hsp90 and two related heat shock proteins. However, Hsp90 inhibitors are markedly pleiotropic, causing degradation of over 200 client proteins and impacting critical multiprotein complexes. Furthermore, it has only recently been appreciated that Hsp90 inhibitors can, paradoxically, cause transient activation of the protein kinase clients they are chaperoning, resulting in initiation of signal transduction and significant physiological events in both tumor and tumor microenvironment. An additional area of recent progress in Hsp90 research is in studies of the posttranslational modifications of Hsp90 itself and Hsp90 co-chaperone proteins. Together, a picture is emerging in which the impact of Hsp90 inhibitors is shaped by the tumor intracellular and extracellular milieu, and in which Hsp90 inhibitors impact tumor and host on a microenvironmental and systems level. Here we review the tumor intrinsic and extrinsic factors that impact the efficacy of small molecules engaging the Hsp90 chaperone machine. C1 [Trepel, J. B.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20816 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20816 USA. RP Trepel, JB (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 12N230,10 Ctr Dr, Bethesda, MD 20816 USA. EM trepel@nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU NCI Intramural Program, Center for Cancer Research FX The authors of this work received funding from the NCI Intramural Program, Center for Cancer Research. NR 167 TC 20 Z9 20 U1 1 U2 16 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD NOV PY 2012 VL 12 IS 9 BP 1125 EP 1141 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 018KD UT WOS:000309658100004 PM 22804236 ER PT J AU Prosser, LA Curatalo, LA Alter, KE Damiano, DL AF Prosser, Laura A. Curatalo, Lindsey A. Alter, Katharine E. Damiano, Diane L. TI Acceptability and potential effectiveness of a foot drop stimulator in children and adolescents with cerebral palsy SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID FUNCTIONAL ELECTRICAL-STIMULATION; GAIT; CLASSIFICATION; STRENGTHEN; WALKING; MUSCLE AB Aim Anklefoot orthoses are the standard of care for foot drop in cerebral palsy (CP), but may overly constrain ankle movement and limit function in those with mild CP. Functional electrical stimulation (FES) may be a less restrictive and more effective alternative, but has rarely been used in CP. The primary objective of this study was to conduct the first trial in CP examining the acceptability and clinical effectiveness of a novel, commercially available device that delivers FES to stimulate ankle dorsiflexion. Method Twenty-one individuals were enrolled (Gross Motor Function Classification System [GMFCS] levels I and II, mean age 13y 2mo). Gait analyses in FES and non-FES conditions were performed at two walking speeds over a 4 month period of device use. Measures included ankle kinematics and spatiotemporal variables. Differences between conditions were revealed using repeated measures multivariate analyses of variance. Results Nineteen individuals (nine females, 10 males; mean age 12y 11mo, range 7y 5mo to 19y 11mo; 11 at GMFCS level I, eight at level II) completed the FES intervention, with all but one choosing to continue using FES beyond that phase. Average daily use was 5.6 hours (SD 2.3). Improved dorsiflexion was observed during swing (mean and peak) and at footfloor contact, with partial preservation of ankle plantarflexion at toe-off when using the FES at self-selected and fast walking speeds. Gait speed was unchanged. Interpretation This FES device was well accepted and effective for foot drop in those with mild gait impairments from CP. C1 [Curatalo, Lindsey A.; Alter, Katharine E.; Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Hlth Clin Ctr, Bethesda, MD 20814 USA. [Prosser, Laura A.] Childrens Hosp Philadelphia, Ctr Rehabil, Philadelphia, PA 19104 USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Baltimore, MD USA. RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Hlth Clin Ctr, 10 Ctr Dr,MSC 1604, Bethesda, MD 20814 USA. EM damianod@cc.nih.gov RI Prosser, Laura/C-1242-2009; Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Intramural Research Program of the National Institutes of Health Clinical Center FX We acknowledge Chris Stanley, Cristiane Zampieri-Gallagher, and Laurie Ohlrich, for their assistance with data collection and entry, and Sara Sadeghi for her assistance with scheduling and protocol management. This research was supported by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 22 TC 12 Z9 12 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD NOV PY 2012 VL 54 IS 11 BP 1044 EP 1049 DI 10.1111/j.1469-8749.2012.04401.x PG 6 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 017OB UT WOS:000309598500021 PM 22924431 ER PT J AU Liu, CT Ng, MCY Rybin, D Adeyemo, A Bielinski, SJ Boerwinkle, E Borecki, I Cade, B Chen, YDI Djousse, L Fornage, M Goodarzi, MO Grant, SFA Guo, X Harris, T Kabagambe, E Kizer, JR Liu, Y Lunetta, KL Mukamal, K Nettleton, JA Pankow, JS Patel, SR Ramos, E Rasmussen-Torvik, L Rich, SS Rotimi, CN Sarpong, D Shriner, D Sims, M Zmuda, JM Redline, S Kao, WH Siscovick, D Florez, JC Rotter, JI Dupuis, J Wilson, JG Bowden, DW Meigs, JB AF Liu, C-T Ng, M. C. Y. Rybin, D. Adeyemo, A. Bielinski, S. J. Boerwinkle, E. Borecki, I. Cade, B. Chen, Y. D. I. Djousse, L. Fornage, M. Goodarzi, M. O. Grant, S. F. A. Guo, X. Harris, T. Kabagambe, E. Kizer, J. R. Liu, Y. Lunetta, K. L. Mukamal, K. Nettleton, J. A. Pankow, J. S. Patel, S. R. Ramos, E. Rasmussen-Torvik, L. Rich, S. S. Rotimi, C. N. Sarpong, D. Shriner, D. Sims, M. Zmuda, J. M. Redline, S. Kao, W. H. Siscovick, D. Florez, J. C. Rotter, J. I. Dupuis, J. Wilson, J. G. Bowden, D. W. Meigs, J. B. TI Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource SO DIABETOLOGIA LA English DT Article DE African ancestry; Genetics; Genome-wide association; LD mapping; Minorities; Type 2 diabetes ID GENOME-WIDE ASSOCIATION; LARGE-SCALE ASSOCIATION; AFRICAN-AMERICANS; FASTING GLUCOSE; SUSCEPTIBILITY LOCI; ATHEROSCLEROSIS RISK; DIABETES-MELLITUS; TCF7L2 GENE; TYPE-2; VARIANTS AB Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs. We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within +/- 250 kb around each EuA SNP in AfAs. Allele frequency differences ranged from 0.6% to 54%. F-st exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were < 2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 x 10(-8); MTNR1B, p = 8.5 x 10(-9); and FADS1, p = 2.2 x 10(-4)) or FI (GCKR, p = 5.9 x 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r (2) < 0.2), suggesting allelic heterogeneity for association with FG at these loci. Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping. C1 [Djousse, L.; Mukamal, K.; Florez, J. C.; Meigs, J. B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Liu, C-T; Lunetta, K. L.; Dupuis, J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ng, M. C. Y.; Liu, Y.; Bowden, D. W.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Diabet Res, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Rybin, D.] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Adeyemo, A.; Ramos, E.; Rotimi, C. N.; Shriner, D.] NHGRI, Bethesda, MD 20892 USA. [Bielinski, S. J.] Mayo Clin, Rochester, MN USA. [Boerwinkle, E.; Fornage, M.; Nettleton, J. A.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Borecki, I.] Washington Univ, St Louis, MO USA. [Cade, B.; Djousse, L.; Patel, S. R.; Redline, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chen, Y. D. I.; Goodarzi, M. O.; Guo, X.; Rotter, J. I.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Djousse, L.] Boston VA Healthcare Syst, Boston, MA USA. [Grant, S. F. A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Kabagambe, E.] Univ Alabama Birmingham, Birmingham, AL USA. [Kizer, J. R.] Cornell Univ, New York, NY 10021 USA. [Liu, Y.] Wake Forest Univ, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Lunetta, K. L.; Dupuis, J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pankow, J. S.] Univ Minnesota, Minneapolis, MN USA. [Rasmussen-Torvik, L.] Northwestern Univ, Chicago, IL 60611 USA. [Rich, S. S.] Univ Virginia, Charlottesville, VA USA. [Sarpong, D.] Jackson State Univ, Jackson, MS USA. [Zmuda, J. M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Kao, W. H.] Johns Hopkins Univ, Baltimore, MD USA. [Siscovick, D.] Univ Washington, Seattle, WA 98195 USA. [Florez, J. C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, J. C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, J. C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Bowden, D. W.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA. [Bowden, D. W.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Meigs, J. B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Sims, M.; Wilson, J. G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RP Meigs, JB (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. EM jmeigs@partners.org RI Bielinski, Suzette/A-2238-2009; Djousse, Luc/F-5033-2017; OI Bielinski, Suzette/0000-0002-2905-5430; Djousse, Luc/0000-0002-9902-3047; Lunetta, Kathryn/0000-0002-9268-810X; Rybin, Denis/0000-0002-3657-4829; Dupuis, Josee/0000-0003-2871-3603; Adeyemo, Adebowale/0000-0002-3105-3231; Patel, Sanjay/0000-0002-9142-5172 FU NIDDK [R01 2 DK078616, K24 DK080140]; Doris Duke Charitable Foundation; NHLBI MESA [N01HC95165-21-0-1]; NHBLI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; CFS: Case Western Reserve University [NIH HL 46380, M01RR00080]; Jackson State University [N01-HC-95170]; University of Mississippi [N01-HC-95171]; Tougaloo College [N01-HC-95172]; University of Alabama at Birmingham [N01-HC-48047, N01-HC-95095]; University of Minnesota [N01-HC-48048]; Northwestern University [N01-HC-48049]; Kaiser Foundation Research Institute [N01-HC-48050]; Tufts-New England Medical Center [N01-HC-45204]; Wake Forest University [N01-HC-45205]; Harbor-UCLA Research and Education Institute [N01-HC-05187]; University of California Irvine [N01-HC-45134, N01-HC-95100]; [RO1 DK066358]; [5RC1HL099911-025UC2HL103010-02]; [N01-HD-95159]; [N01-HC-95169]; [RR-024156]; [R01-HL-071205] FX This work was supported by NIDDK R01 2 DK078616 and NIDDK K24 DK080140 to J. B. Meigs, a Doris Duke Charitable Foundation Clinical Scientist Development Award to J. C. Florez, RO1 DK066358 to D. W. Bowden, 5RC1HL099911-025UC2HL103010-02 and the NHLBI MESA contract N01HC95165-21-0-1 to S. S. Rich.; ARIC is carried out as a collaborative study supported by NHBLI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. CFS: Case Western Reserve University (NIH HL 46380, M01RR00080).; JHS is carried out as a collaborative study supported by Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172);; MESA is conducted and supported by the NHLBI in collaboration with MESA investigators. Support is provided by grants and contracts N01-HD-95159 through N01-HC-95169, RR-024156, and R01-HL-071205.; CARDIA is carried out as a collaborative study supported by University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California Irvine (N01-HC-45134, N01-HC-95100). NR 57 TC 12 Z9 12 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2012 VL 55 IS 11 BP 2970 EP 2984 DI 10.1007/s00125-012-2656-4 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 017AR UT WOS:000309561600013 PM 22893027 ER PT J AU Palmer, AJ Lochhead, P Hold, GL Rabkin, CS Chow, WH Lissowska, J Vaughan, TL Berry, S Gammon, M Risch, H El-Omar, EM AF Palmer, Andrew J. Lochhead, Paul Hold, Georgina L. Rabkin, Charles S. Chow, Wong-Ho Lissowska, Jolanta Vaughan, Thomas L. Berry, Susan Gammon, Marilie Risch, Harvey El-Omar, Emad M. TI Genetic variation in C20orf54, PLCE1 and MUC1 and the risk of upper gastrointestinal cancers in Caucasian populations SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE cancer susceptibility; gastric cancer; genetic polymorphism; oesophageal cancer ID SQUAMOUS-CELL CARCINOMA; GENOME-WIDE ASSOCIATION; PHOSPHOLIPASE C-EPSILON; GASTRIC-CANCER; SUSCEPTIBILITY LOCI; CHINESE POPULATION; STOMACH-CANCER; EXPRESSION; VARIANTS; ALCOHOL AB Recently, two large genome-wide association studies, conducted in Chinese populations, have reported associations between upper gastrointestinal cancer and the rs2274223, rs13042395 and rs4072037 polymorphisms in PLCE1, C20orf54 and MUC1, respectively. We aimed to determine whether similar associations existed for Caucasian populations. We genotyped two population-based, case-control studies of upper gastrointestinal cancer; the first study included 290 gastric cancer (GC) cases and 376 controls and the second study included 306 GC cases, 107 oesophageal adenocarcinoma cancer cases, 52 oesphageal squamous cell cancer cases and 211 controls. Odds ratios (OR) and 95% confidence intervals (CIs) were computed from logistic models and adjusted for confounding variables. The rs4072037 polymorphism in MUC1 was associated with a reduced risk of GC of intestinal histological type (OR 0.4; 95% CI 0.2-0.9) and a reduced risk of oesophageal squamous cell cancer (OR 0.5; 95% CI 0.2-1.0), but not oesphageal adenocarcinoma. Similarly, rs2274223 in PLCE1 was associated with a reduced risk of oesophageal squamous cell cancer (OR 0.5; 95% CI 0.3-1.0), but not oesphageal adenocarcinoma. We observed no association between rs13042395 in Corf54 and the risk of gastric or oesphageal cancer in either of the two studies. Our findings for rs4072037 and the risk of GC are in agreement with one previous report for a Caucasian population. To the best of our knowledge, this is the first study to report an association between rs2274223 and rs4072037 and the risk of oesophageal squamous cell carcinoma in a Caucasian population. European Journal of Cancer Prevention 21: 541-544 (C) 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [El-Omar, Emad M.] Univ Aberdeen, Inst Med Sci, Sch Med & Dent, Div Appl Med,GI Res Grp, Aberdeen AB25 2ZD, Scotland. [Rabkin, Charles S.; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Washington, DC USA. [Gammon, Marilie] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Risch, Harvey] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP El-Omar, EM (reprint author), Univ Aberdeen, Inst Med Sci, Sch Med & Dent, Div Appl Med,GI Res Grp, Foresterhill, Aberdeen AB25 2ZD, Scotland. EM e.el-omar@abdn.ac.uk OI Lissowska, Jolanta/0000-0003-2695-5799 FU Scottish Government Chief Scientist Office; United States Public Health Service [U01-CA57983, U01-CA57949, U01-CA57923, P30ES10126]; National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services [N02-CP40501, N01-CN05230] FX Paul Lochhead is funded by a fellowship from the Scottish Government Chief Scientist Office. The US multicentre oesophageal and gastric cancer study was supported by the United States Public Health Service (U01-CA57983, U01-CA57949, U01-CA57923, P30ES10126) and by the National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services (N02-CP40501, N01-CN05230). NR 23 TC 37 Z9 39 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD NOV PY 2012 VL 21 IS 6 BP 541 EP 544 DI 10.1097/CEJ.0b013e3283529b79 PG 4 WC Oncology SC Oncology GA 016TS UT WOS:000309543000006 PM 22805490 ER PT J AU Jiao, J Zheng, TZ Lan, Q Chen, YT Deng, Q Bi, XF Kim, C Holford, T Leaderer, B Boyle, P Ba, Y Xia, ZL Chanock, SJ Rothman, N Zhang, YW AF Jiao, Jie Zheng, Tongzhang Lan, Qing Chen, Yingtai Deng, Qian Bi, Xiaofeng Kim, Christopher Holford, Theodore Leaderer, Brian Boyle, Peter Ba, Yue Xia, Zhaolin Chanock, Stephen J. Rothman, Nathaniel Zhang, Yawei TI Occupational solvent exposure, genetic variation of DNA repair genes, and the risk of non-Hodgkin's lymphoma SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE DNA repair genes; non-Hodgkin's lymphoma; occupational exposure; single nucleotide polymorphism; solvents ID NIJMEGEN BREAKAGE SYNDROME; CHROMOSOMAL INSTABILITY; ORGANIC-SOLVENTS; POLYMORPHISMS; NBS1; METHYLTRANSFERASE; SUSCEPTIBILITY; LOCALIZATION; CONNECTICUT; POPULATION AB The main objective of this study was to test the hypothesis that genetic variations in DNA repair genes may modify the association between occupational exposure to solvents and the risk of non-Hodgkin's lymphoma (NHL). A population-based case-control study was conducted on Connecticut women including 518 histologically confirmed incident NHL cases and 597 controls. Unconditional logistic regression models were used to estimate the odds ratios and effect modification from the 30 single nucleotide polymorphisms in 16 DNA repair genes of the association between solvent exposure and the risk of NHL overall and subtypes. Single nucleotide polymorphisms in MGMT (rs12917) and NBS1 (rs1805794) significantly modified the association between exposure to chlorinated solvents and the risk of NHL (P-for interaction = 0.0003 and 0.0048, respectively). After stratification by major NHL histological subtypes, MGMT (rs12917) modified the association between chlorinated solvents and the risk of diffuse large B-cell lymphoma (P-for interaction = 0.0027) and follicular lymphoma (P-for interaction = 0.0024). A significant interaction was also observed between occupational exposure to benzene and BRCA2 (rs144848) for NHL overall (P-for interaction = 0.0042). Our study results suggest that genetic variations in DNA repair genes modify the association between occupational exposure to solvents and the risk of NHL. European Journal of Cancer Prevention 21: 580-584 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Jiao, Jie; Zheng, Tongzhang; Chen, Yingtai; Bi, Xiaofeng; Kim, Christopher; Holford, Theodore; Leaderer, Brian; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Jiao, Jie] Henan Prov Inst Occupat Hlth, Zhengzhou, Peoples R China. [Ba, Yue] Zhengzhou Univ, Sch Publ Hlth, Zhengzhou, Peoples R China. [Jiao, Jie; Xia, Zhaolin] Fudan Univ, Sch Publ Hlth, Shanghai 200433, Peoples R China. [Chen, Yingtai; Bi, Xiaofeng] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100730, Peoples R China. [Deng, Qian] Sichuan Univ, Sch Publ Hlth, Chengdu 610064, Peoples R China. [Lan, Qing; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,DHHS, Gaithersburg, MD USA. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St,LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU National Institutes of Health [CA62006, 1D43TW008323-01, 1D43TW007864-01, CA105666, HD70324-01]; Intramural Research Program of the National Institutes of Health, the National Cancer Institute FX This work was supported by the National Institutes of Health Research Grant CA62006, the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the National Institutes of Health Training Grants 1D43TW008323-01, 1D43TW007864-01, CA105666, and HD70324-01. NR 40 TC 10 Z9 11 U1 2 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-8278 EI 1473-5709 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD NOV PY 2012 VL 21 IS 6 BP 580 EP 584 DI 10.1097/CEJ.0b013e328351c762 PG 5 WC Oncology SC Oncology GA 016TS UT WOS:000309543000012 PM 22430443 ER PT J AU Werner-Lin, A Hoskins, LM Doyle, MH Greene, MH AF Werner-Lin, Allison Hoskins, Lindsey M. Doyle, Maya H. Greene, Mark H. TI 'Cancer doesn't have an age': Genetic testing and cancer risk management in BRCA1/2 mutation-positive women aged 18-24 SO HEALTH LA English DT Article DE BRCA1/2 genetic mutations; family relations; human development; risk management; risk perceptions ID BREAST-CANCER; OVARIAN-CANCER; HEREDITARY BREAST; YOUNG-WOMEN; PROPHYLACTIC SURGERY; MULTICENTER; ADULTHOOD; FAMILIES; SUPPORT; IMPACT AB Increasingly, 18-24-year-old women from hereditary breast/ovarian cancer (HBOC) families are pursuing genetic testing, despite their low absolute risks of breast and ovarian cancer and the fact that evidence-based management options used with older high-risk women are not generally available. Difficult clinical decisions in older carriers take on substantially more complexity and value-laden import in very young carriers. As a result, many of the latter receive highly personal and emotionally charged cancer risk information in a life context where management strategies are not well defined. We analyzed 32 in-depth interviews with BRCA1/2 mutation-positive women aged 18-24 using techniques of grounded theory and interpretive description. Participants described feeling vulnerable to a cancer diagnosis but in a quandary regarding their care because evidence-based approaches to management have not been developed and clinical trials have not been undertaken. Our participants demonstrated a wide range of genetic and health literacy. Inconsistent recommendations, surveillance fatigue, and the unpredictability of their having health insurance coverage for surgical risk-reducing procedures led several to contemplate risk-reducing mastectomy before age 25. Parents remained a primary source of emotional and financial support, slowing age-appropriate independence and complicating patient privacy. Our findings suggest that, for 18-24-year-olds, readiness to autonomously elect genetic testing, to fully understand and act on genetic information, and to confidently make decisions with life-long implications are all evolving processes. We comment on the tensions between informed consent, privacy, and the unique developmental needs of BRCA1/2 mutation-positive women just emerging into their adult years. C1 [Werner-Lin, Allison; Doyle, Maya H.] NYU, Silver Sch Social Work, New York, NY 10003 USA. [Greene, Mark H.] NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD 20892 USA. RP Werner-Lin, A (reprint author), NYU, Silver Sch Social Work, 1 Washington Sq N, New York, NY 10003 USA. EM awernerlin@nyu.edu NR 54 TC 8 Z9 8 U1 2 U2 15 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1363-4593 EI 1461-7196 J9 HEALTH-LONDON JI Health PD NOV PY 2012 VL 16 IS 6 BP 636 EP 654 DI 10.1177/1363459312442420 PG 19 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 018SN UT WOS:000309683400005 PM 22547552 ER PT J AU Deye, JA AF Deye, James A. TI NCI SUPPORT FOR PARTICLE THERAPY: PAST, PRESENT, FUTURE SO HEALTH PHYSICS LA English DT Article DE National Council on Radiation Protection and Measurements; National Cancer Institute; protons; radiation therapy AB In light of the rising worldwide interest in particle therapy, and proton therapy specifically in the United States, the National Cancer Institute (NCI) is being asked more often about funding for such research and facilities. Many of the questions imply that NCI is naive to the exciting possibilities inherent in particle therapies, and thus they wish to encourage NCI to initiate and underwrite such programs. In fact, NCI has a long track record of support for the translation of hadrons from the physics laboratory to the therapy clinic by way of technology development and scientific investigations of physical and biological processes as well as clinical outcomes. Early work has included continuous funding since 1961 of proton treatments for more than 15,000 patients and facility construction at the Harvard/Massachusetts General Hospital (MGH) site; treatment of 227 patients with the pi-meson facility at Los Alamos between 1974 and 1981; funding of more than $69M for seven neutron therapy centers between 1971 and 1989; many funded projects in boron neutron capture radiation therapy through the present time; and numerous radiobiology projects over the past 50 y. NCI continues to play an active role in the incorporation of protons into randomized clinical trials through the Children's Oncology Group, Radiation Therapy Oncology Group, and the Program Project Grant (P01), which is co-directed by the MGH and MD Anderson Cancer Center. This has required funding development and implementation of guidelines that enable intercomparison of dosimetry and treatment between facilities. NCI has also funded recent efforts to develop new physical processes for the production of particles such as protons. With regard to the future, while it is true that there are no specific funding opportunity announcements directed to particle therapy research, it is also true that NCI remains open to reviewing any research that is compatible with an established mechanism. However, given the very substantial resources that these facilities currently require along with the highly competitive economic environment that now exists, it is clear that scientific review of such grant applications will look to leverage the scientific pursuits that are the NCI mandate with the reality of the clinical practices, just as is the case for photon radiation research. Such leveraging should be enhanced by the growing opportunities and need for international collaborations. On the other hand, these collaborations are complicated by the fact that these particle therapies are now fully reimbursable modalities, which makes it difficult to separate research (the NCI mission) from clinical practice development. This paper seeks to illuminate these new realities in order to encourage the pursuit and funding of the scientific underpinnings of physical methods, radiobiology, and clinical practice with particle therapy. Health Phys. 103(5):662-666; 2012 C1 NCI, Radiat Res Programs, Rockville, MD 20892 USA. RP Deye, JA (reprint author), NCI, Radiat Res Programs, 6130 Execut Blvd,MSC 7440, Rockville, MD 20892 USA. EM deyej@mail.nih.gov NR 7 TC 6 Z9 6 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD NOV PY 2012 VL 103 IS 5 BP 662 EP 666 DI 10.1097/HP.0b013e3182609bb7 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 016MI UT WOS:000309522300020 PM 23032896 ER PT J AU Venuti, P Caria, A Esposito, G De Pisapia, N Bornstein, MH de Falco, S AF Venuti, Paola Caria, Andrea Esposito, Gianluca De Pisapia, Nicola Bornstein, Marc H. de Falco, Simona TI Differential brain responses to cries of infants with autistic disorder and typical development: An fMRI study SO RESEARCH IN DEVELOPMENTAL DISABILITIES LA English DT Article DE Autism; Infant cry; fMRI; Autistic disorder; Brain imaging; Parenting; Typical development ID PHYSIOLOGICAL CONDITION; ACOUSTIC FEATURES; CORTICAL ACTIVITY; YOUNG-CHILDREN; HUMAN AMYGDALA; PERCEPTION; CRY; DISTRESS; BEHAVIOR; EMPATHY AB This study used fMRI to measure brain activity during adult processing of cries of infants with autistic disorder (AD) compared to cries of typically developing (TD) infants. Using whole brain analysis, we found that cries of infants with AD compared to those of TD infants elicited enhanced activity in brain regions associated with verbal and prosodic processing, perhaps because altered acoustic patterns of AD cries render them especially difficult to interpret, and increased activity in brain regions associated with emotional processing, indicating that AD cries also elicit more negative feelings and may be perceived as more aversive and/or arousing. Perceived distress engendered by AD cries related to increased activation in brain regions associated with emotional processing. This study supports the hypothesis that cry is an early and meaningful anomaly displayed by children with AD. It could be that cries associated with AD alter parent-child interactions much earlier than the time that reliable AD diagnosis normally occurs. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Venuti, Paola; Caria, Andrea; Esposito, Gianluca; De Pisapia, Nicola; de Falco, Simona] Univ Trent, Dept Cognit Sci & Educ, Trento, Italy. [Caria, Andrea] Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. [Esposito, Gianluca] RIKEN Brain Sci Inst, Unit Affiliat Social Behav, Saitama, Japan. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Eunice, LA USA. RP Venuti, P (reprint author), Dept Cognit Sci & Educ, Via Matteo Del Ben 5, I-38068 Rovereto, TN, Italy. EM paola.venuti@unitn.it RI Esposito, Gianluca/B-1374-2012; Esposito, Gianluca/K-9353-2013; OI Esposito, Gianluca/0000-0002-9442-0254; Esposito, Gianluca/0000-0002-9442-0254; De Pisapia, Nicola/0000-0002-1089-8841 FU Intramural NIH HHS [ZIA HD001119-25] NR 77 TC 10 Z9 10 U1 3 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-4222 J9 RES DEV DISABIL JI Res. Dev. Disabil. PD NOV-DEC PY 2012 VL 33 IS 6 BP 2255 EP 2264 DI 10.1016/j.ridd.2012.06.011 PG 10 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 009JL UT WOS:000309022000061 PM 22835685 ER PT J AU Jenko, KJ Hirvonen, J Henter, ID Anderson, KB Zoghbi, SS Hyde, TM Deep-Soboslay, A Innis, RB Kleinman, JE AF Jenko, Kimberly J. Hirvonen, Jussi Henter, Ioline D. Anderson, Kacey B. Zoghbi, Sami S. Hyde, Thomas M. Deep-Soboslay, Amy Innis, Robert B. Kleinman, Joel E. TI Binding of a tritiated inverse agonist to cannabinoid CB1 receptors is increased in patients with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Cannabinoid; CB1; Schizophrenia; Dorsolateral prefrontal cortex; [H-3]MePPEP ID ANTERIOR CINGULATE CORTEX; PREFRONTAL CORTEX; EXPRESSION; DISORDER; DENSITY AB This study sought to determine whether cannabinoid-1 (CB1) receptor binding was altered in the postmortem dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (schizophrenia; n = 47) compared to controls (n = 43). The CB1 receptor inverse agonist radioligand [H-3]MePPEP was used to measure specific binding to CB1 receptors. The specific binding of [H-3]MePPEP to CB1 receptors was 20% higher in patients with schizophrenia than in controls. Power analyses suggested that 53 subjects per group would be needed to detect a similar difference in vivo with positron emission tomography (PET) and the structurally related inverse agonist radioligand [F-18]FMPEP-d(2) (80% statistical power, p<0.05). Published by Elsevier B.V. C1 [Jenko, Kimberly J.; Hirvonen, Jussi; Henter, Ioline D.; Anderson, Kacey B.; Zoghbi, Sami S.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Hyde, Thomas M.; Deep-Soboslay, Amy; Kleinman, Joel E.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Hyde, Thomas M.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr,Room B1D43-10,MSC 1026, Bethesda, MD 20892 USA. EM innisr@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This study was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). The NIMH had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 17 TC 13 Z9 13 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2012 VL 141 IS 2-3 BP 185 EP 188 DI 10.1016/j.schres.2012.07.021 PG 4 WC Psychiatry SC Psychiatry GA 016IN UT WOS:000309511300011 PM 22910406 ER PT J AU Ballester, L Aung, PP Walter-Rodriguez, BA Garcia-Macias, C Ballester, LY Merino, M AF Ballester, Leomar Aung, Phyu P. Walter-Rodriguez, Beatriz A. Garcia-Macias, C. Ballester, Leomar Y. Merino, Maria TI Overexpression of HER-2/neu Can Be Determined by a New HistoSonda Probe: A Comparison With Traditional Methods, FISH, CISH, and IHC, in Urothelial Carcinoma SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Aung, Phyu P.; Walter-Rodriguez, Beatriz A.; Ballester, Leomar Y.] NCI, NIH, Bethesda, MD 20892 USA. [Garcia-Macias, C.] Univ Salamanca, Salamanca, Spain. [Merino, Maria] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD NOV 1 PY 2012 VL 138 SU 2 MA 158 BP A158 EP A158 PG 1 WC Pathology SC Pathology GA V45XH UT WOS:000209848800120 ER PT J AU Ballester, L Ballester, LY Aung, PP Siddiqui, S Stetler-Stevenson, M Kreitman, RJ Roth, MJ Filie, A AF Ballester, Leomar Ballester, Leomar Y. Aung, Phyu P. Siddiqui, Sarwat Stetler-Stevenson, Maryalice Kreitman, Robert J. Roth, Mark J. Filie, Armando TI Relapsed Hairy Cell Leukemia: Cytologic and Immunophenotypic Findings of an Unusual Presentation in Pleural Effusion SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Ballester, Leomar Y.; Aung, Phyu P.; Siddiqui, Sarwat; Stetler-Stevenson, Maryalice; Kreitman, Robert J.; Roth, Mark J.; Filie, Armando] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD NOV 1 PY 2012 VL 138 SU 2 MA 14 BP A014 EP A014 PG 1 WC Pathology SC Pathology GA V45XH UT WOS:000209848800014 ER PT J AU Flatley, E Jaffe, ES Lawce, H Olson, S Fan, G AF Flatley, Ellen Jaffe, Elaine S. Lawce, Helen Olson, Susan Fan, Guang TI B-Cell Prolymphocytic Leukemia With t(8;14) Translocation SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Flatley, Ellen; Lawce, Helen; Olson, Susan; Fan, Guang] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Jaffe, Elaine S.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD NOV 1 PY 2012 VL 138 SU 2 MA 95 BP A095 EP A095 PG 1 WC Pathology SC Pathology GA V45XH UT WOS:000209848800071 ER PT J AU Przysiecki, C Lucas, B Mitchell, R Carapau, D Wen, ZY Xu, H Wang, XM Nahas, D Wu, CW Hepler, R Ottinger, E ter Meulen, J Kaslow, D Shiver, J Nardin, E AF Przysiecki, Craig Lucas, Bob Mitchell, Robert Carapau, Daniel Wen, Zhiyun Xu, Hui Wang, Xin-Min Nahas, Debbie Wu, Chengwei Hepler, Robert Ottinger, Elizabeth ter Meulen, Jan Kaslow, David Shiver, John Nardin, Elizabeth TI Sporozoite neutralizing antibodies elicited in mice and rhesus macaques immunized with a Plasmodium falciparum repeat peptide conjugated to rneningococcal outer membrane protein complex SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE P falciparum; vaccine; sporozoites; peptide-OMPC; mice; rhesus; antibody ID MALARIA-NAIVE ADULTS; PHASE 2A TRIAL; CIRCUMSPOROZOITE PROTEIN; CUTTING EDGE; VACCINE; IMMUNOGENICITY; RESPONSES; ADJUVANT; BERGHEI; SAFETY AB Antibodies that neutralize Infectivity of malaria sporozoites target the central repeat region of the circumsporozoite (CS) protein, which in Plasmodium falciparum is comprised primarily of 30-40 tandem NANP tetramer repeats. We evaluated immunogenicity of an alum-adsorbed (NANP)(6) peptide conjugated to an outer membrane protein complex (OMPC) derived from Neisseria meningitidis, a carrier protein used in a licensed Haemophilus influenzae pediatric vaccine. Mice immunized with (NANP)(6)-OMPC adsorbed to Merck's alum adjuvant (MAA), with or without Iscomatrix (R) as co-adjuvant, developed high levels of anti-repeat peptide antibody that inhibited in vitro invasion of human hepatoma cells by transgenic P berghei sporozoites that express P falciparum CS repeats (PfPb). Inhibition of sporozoite invasion in vitro correlated with in vivo resistance to challenge by the bites of PfPb-infected mosquitoes. Challenged mice had >90% reduction of hepatic stage parasites as measured by real-time PCR, and either sterile immunity, i.e., no detectable blood stage parasites, or delayed prepatent periods which indicate neutralization of a majority, but not all, sporozoites. Rhesus macaques immunized with two doses of (NANP)(6)-OMPC/MAA formulated with lscomatrix (R) developed anti-repeat antibodies that persisted for similar to 2 years. A third dose of (NANP)(6)-OMPC/MAA+ Iscomatrixe (R) at that time elicited strong anamnestic antibody responses. Rhesus macaque immune sera obtained post second and third dose of vaccine displayed high levels of sporozoite neutralizing activity in vitro that correlated with presence of high anti-repeat antibody titers. These preclinical studies in mice of different MHC haplotypes and a non-human primate support use of CS peptide-OMPC conjugates as a highly immunogenic platform to evaluate CS protective epitopes. Potential pro erythrocytic vaccines can be combined with sexual blood stage vaccines as a multi-antigen malaria vaccine to block invasion and transmission of Plasmodium parasites. C1 [Przysiecki, Craig; Lucas, Bob; Wen, Zhiyun; Xu, Hui; Wang, Xin-Min; Nahas, Debbie; Wu, Chengwei; Hepler, Robert; ter Meulen, Jan; Shiver, John] Merck Res Labs, Vaccine Res, West Point, PA USA. [Mitchell, Robert; Carapau, Daniel; Nardin, Elizabeth] NYU, Sch Med, Dept Microbiol, Div Med Parasitol, New York, NY 10010 USA. [Ottinger, Elizabeth] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Kaslow, David] Merck Res Labs, Res Med, Upper Gwynedd, PA USA. RP Nardin, E (reprint author), NYU, Sch Med, Dept Microbiol, Div Med Parasitol, 341 East 25th St, New York, NY 10010 USA. EM elizabeth.nardin@nyumc.org RI Carapau, Daniel/J-3966-2012 OI Carapau, Daniel/0000-0001-8888-6333 FU NIH NIAID [R01 AI45138, R56 AI083655] FX We gratefully acknowledge the excellent technical assistance of Rita Altszuler and Sandra Gonzalez and we thank Leyda Cordoba for ELISA. Research at NYU was supported by NIH NIAID R01 AI45138 and R56 AI083655 to Elizabeth Nardin. NR 32 TC 7 Z9 7 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD NOV PY 2012 VL 2 AR UNSP 146 DI 10.3389/fcimb.2012.00146 PG 11 WC Immunology; Microbiology SC Immunology; Microbiology GA 221DP UT WOS:000324638100014 PM 23226683 ER PT J AU Roiser, JP Levy, J Fromm, SJ Goldman, D Hodgkinson, CA Hasler, G Sahakian, BJ Drevets, WC AF Roiser, Jonathan P. Levy, Jamey Fromm, Stephen J. Goldman, David Hodgkinson, Colin A. Hasler, Gregor Sahakian, Barbara J. Drevets, Wayne C. TI Serotonin transporter genotype differentially modulates neural responses to emotional words following tryptophan depletion in patients recovered from depression and healthy volunteers SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Depression; serotonin transporter polymorphism (5-HTTLPR); acute tryptophan depletion; functional magnetic resonance imaging (fMRI); emotional processing ID MAJOR DEPRESSION; PROMOTER POLYMORPHISM; 5-HTTLPR GENOTYPE; BEHAVIORAL-RESPONSES; UNMEDICATED PATIENTS; PREFRONTAL CORTEX; MOOD DISORDERS; GENE; METAANALYSIS; ASSOCIATION AB Previous studies have suggested that polymorphism in the serotonin transporter gene (5-HTTLPR) influences responses to serotonergic manipulation, with opposite effects in patients recovered from depression (rMDD) and controls. Here we sought to clarify the neurocognitive mechanisms underpinning these surprising results. Twenty controls and 23 rMDD subjects completed the study; functional magnetic resonance imaging (fMRI) and genotype data were available for 17 rMDD subjects and 16 controls. Following tryptophan or sham depletion, subjects performed an emotional-processing task during fMRI. Although no genotype effects on mood were identified, significant genotype(star)diagnosis(star)depletion interactions were observed in the hippocampus and subgenual cingulate in response to emotionally valenced words. In both regions, tryptophan depletion increased responses to negative words, relative to positive words, in high-expression controls, previously identified as being at low-risk for mood change following this procedure. By contrast, in higher-risk low-expression controls and high-expression rMDD subjects, tryptophan depletion had the opposite effect. Increased neural responses to negative words following tryptophan depletion may reflect an adaptive mechanism promoting resilience to mood change following perturbation of the serotonin system, which is reversed in sub-groups vulnerable to developing depressive symptoms. However, this interpretation is complicated by our failure to replicate previous findings of increased negative mood following tryptophan depletion. C1 [Roiser, Jonathan P.] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Roiser, Jonathan P.; Levy, Jamey; Fromm, Stephen J.; Hasler, Gregor; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Roiser, Jonathan P.; Sahakian, Barbara J.] Univ Cambridge, Addenbrookes Hosp, Dept Psychiat, Cambridge CB2 2QQ, England. [Goldman, David; Hodgkinson, Colin A.] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Sahakian, Barbara J.] Wellcome Trust Behav & Clin Neurosci Inst, MRC, Cambridge, England. [Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. RP Roiser, JP (reprint author), UCL, Inst Cognit Neurosci, 17 Queen Sq, London WC1N 3AR, England. EM j.roiser@ucl.ac.uk RI Hasler, Gregor/E-4845-2012; Goldman, David/F-9772-2010; OI Hasler, Gregor/0000-0002-8311-0138; Goldman, David/0000-0002-1724-5405; Levy, Jamey/0000-0002-7434-7213 FU Intramural Research Program of the NIMH; NIH-Cambridge Health Science Scholars Program FX This research was supported by the Intramural Research Program of the NIMH. JPR was supported by the NIH-Cambridge Health Science Scholars Program. NR 47 TC 3 Z9 4 U1 1 U2 16 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD NOV PY 2012 VL 26 IS 11 BP 1434 EP 1442 DI 10.1177/0269881112442789 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 020UC UT WOS:000309839100005 PM 22495688 ER PT J AU Lal-Nag, M Battis, M Santin, AD Morin, PJ AF Lal-Nag, M. Battis, M. Santin, A. D. Morin, P. J. TI Claudin-6: a novel receptor for CPE-mediated cytotoxicity in ovarian cancer SO ONCOGENESIS LA English DT Article DE ovarian cancer; clostridium perfringens enterotoxin; claudin; therapy AB Claudins are integral tight junction proteins that are responsible for maintaining the integrity of epithelial cell architecture and cell polarity. Claudin-3 and -4 are overexpressed in several cancers and have been shown to act as receptors for the Clostridium perfringens enterotoxin (CPE), a toxin that causes rapid cell lysis. CPE has demonstrated effectiveness in treating several different cancers in mouse models, provided that these cancers express claudin-3 or claudin-4. Here, we show that claudin-3/4 expression is not an absolute requirement for CPE action and, through overexpression and knockdown experiments, we identify claudin-6 as a novel functional receptor for CPE. Indeed, UCI-101, an ovarian cancer cell line highly sensitive to CPE, does not express claudin-3/4 and knockdown of claudin-6 in these cells decreases CPE sensitivity. Moreover, two different ovarian cell lines that are resistant to the effects of CPE can be made sensitive through claudin-6 overexpression. Binding assays show that CPE can indeed bind claudin-6 in cells and that this binding is associated with CPE cytotoxicity. Multicellular tumor spheroids experiments demonstrate that claudin-6 can also be a target of CPE in three-dimensional cultures. Our data establish claudin-6 as a novel receptor for CPE and introduces the possibility of a novel targeted therapeutic for ovarian and other cancers that express claudin-6. C1 [Lal-Nag, M.; Battis, M.; Morin, P. J.] NIA, Lab Mol Biol & Immunol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Santin, A. D.] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Morin, P. J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Morin, PJ (reprint author), NIA, Cellular & Mol Biol Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Room 6C228, Baltimore, MD 21224 USA. EM patjmorin@excite.com FU NIH, National Institute on Aging; NIH [R01 CA122728-01A4, R01 CA154460-01A1]; Honorable Tina Brozman Foundation; Deborah Bunn Alley Ovarian Cancer Research Foundation FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. ADS is Supported in part by grants from NIH R01 CA122728-01A4 and R01 CA154460-01A1, the Honorable Tina Brozman Foundation and Deborah Bunn Alley Ovarian Cancer Research Foundation. We thank the members of our laboratory for helpful comments on the manuscript. NR 37 TC 12 Z9 12 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2157-9024 J9 ONCOGENESIS JI Oncogenesis PD NOV PY 2012 VL 1 AR UNSP e33 DI 10.1038/oncsis.2012.32 PG 8 WC Oncology SC Oncology GA V36NY UT WOS:000209219600002 PM 23552466 ER PT J AU Ji, BT Gao, YT Shu, XO Yang, G Yu, K Xue, SZ Li, HL Liao, LDM Blair, A Rothman, N Zheng, W Chow, WH AF Ji, Bu-Tian Gao, Yu-Tang Shu, Xiao-Ou Yang, Gong Yu, Kai Xue, Shou-Zheng Li, Hong-Lan Liao, Linda M. Blair, Aaron Rothman, Nathaniel Zheng, Wei Chow, Wong-Ho TI Night shift work job exposure matrices and urinary 6-sulfatoxymelatonin levels among healthy Chinese women SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE aMT6s; cancer; China; job exposure matrix; melatonin; nighttime work; shift work; urine sample AB Objective Six-sulfatoxymelatonin (aMT6s) is a primary urinary metabolite of melatonin. We examined the association between aMT6s levels and shift work estimated by a job exposure matrix (JEM) among healthy participants of the Shanghai Women's Health Study. Methods Creatinine-adjusted aMT6s levels were measured in the urine samples of 300 women and related to JEM shift work categories. Results Adjusted geometric means of aMT6s levels from urine samples collected before 08:00 hours were lower among persons holding nighttime shift work jobs. The adjusted aMT6s levels (ng/mg creatinine) were 8.36 [95% confidence intervals (95% CI) 4.47-15.6], 6.37 (95% CI 3.53-11.5), 6.20 (95% CI 3.33-11.5), 3.81 (95% CI 2.02-7.19), and 3.70 (95% CI 1.92-7.11) from the lowest (never held a shift work job) to the highest (current job likely involved all-night shift work) shift work JEM scores (P=0.05). Conclusion Our results indicate that night shift work JEM scores were significantly and inversely associated with aMT6s levels in early morning spot urine samples collected between 07:00-08:00 hours. C1 [Ji, Bu-Tian; Xue, Shou-Zheng; Liao, Linda M.; Blair, Aaron; Rothman, Nathaniel; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Gao, Yu-Tang; Li, Hong-Lan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Shu, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. RP Ji, BT (reprint author), 6120 Execut Blvd,EPS 8104, Bethesda, MD 20852 USA. EM jib@mail.nih.gov OI Liao, Linda/0000-0002-1923-5294 FU US National Institutes of Health (NIH) [R37 CA070867]; Intramural Research Program of the NIH, Division of Cancer Epidemiology and Genetics [NO2-CP-11010-66]; National Center for Research Resources (NCRR) [UL1 RR 025005] FX This study was supported by the US National Institutes of Health (NIH) (grant R37 CA070867) and the Intramural Research Program of the NIH, Division of Cancer Epidemiology and Genetics (contract NO2-CP-11010-66). This publication was also made possible by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on re-engineering the clinical research enterprise can be obtained from http://nihroadmap.nih.gov/clinical research/overview-translational.asp. The authors also thank Ying Ni at the Johns Hopkins University Bayview Medical Center Core Laboratory for laboratory analyses and David Check at the National Cancer Institute for development of figures. NR 39 TC 6 Z9 6 U1 1 U2 3 PU SCANDINAVIAN JOURNAL WORK ENVIRONMENT & HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 EI 1795-990X J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD NOV PY 2012 VL 38 IS 6 BP 553 EP 559 DI 10.5271/sjweh.3322 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V31KY UT WOS:000208883700008 PM 22975884 ER PT J AU Fijalkowska, IJ Schaaper, RM Jonczyk, P AF Fijalkowska, Iwona J. Schaaper, Roel M. Jonczyk, Piotr TI DNA replication fidelity in Escherichia coli: a multi-DNA polymerase affair SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE DNA replication fidelity; accessory DNA polymerases; polymerase switching; untargeted mutagenesis; leading and lagging DNA replication; exonucleolytic proofreading ID SOS MUTATOR ACTIVITY; LAGGING-STRAND SYNTHESIS; COORDINATED LEADING-STRAND; UNIQUE C-TERMINUS; SYNTHESIS IN-VIVO; III HOLOENZYME; TRANSLESION SYNTHESIS; SLIDING-CLAMP; POL-IV; SPONTANEOUS MUTAGENESIS AB High accuracy (fidelity) of DNA replication is important for cells to preserve the genetic identity and to prevent the accumulation of deleterious mutations. The error rate during DNA replication is as low as 10-9 to 10-11 errors per base pair. How this low level is achieved is an issue of major interest. This review is concerned with the mechanisms underlying the fidelity of the chromosomal replication in the model system Escherichia coli by DNA polymerase III holoenzyme, with further emphasis on participation of the other, accessory DNA polymerases, of which E.similar to coli contains four (Pols I, II, IV, and V). Detailed genetic analysis of mutation rates revealed that (1) Pol II has an important role as a back-up proofreader for Pol III, (2) Pols IV and V do not normally contribute significantly to replication fidelity, but can readily do so under conditions of elevated expression, (3) participation of Pols IV and V, in contrast to that of Pol II, is specific to the lagging strand, and (4) Pol I also makes a lagging-strand-specific fidelity contribution, limited, however, to the faithful filling of the Okazaki fragment gaps. The fidelity role of the Pol III t subunit is also reviewed. C1 [Fijalkowska, Iwona J.; Jonczyk, Piotr] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. [Schaaper, Roel M.] NIEHS, Mol Genet Lab, Durham, NC USA. RP Jonczyk, P (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Pawinskiego 5A, PL-02106 Warsaw, Poland. EM piotrekj@ibb.waw.pl RI Fijalkowska, Iwona/I-7796-2016 FU Polish Ministry of Science and Higher Education [2 PO4A 061 30]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES065086]; Foundation for Polish Science TEAM Program FX The authors thank Drs K. Bebenek and A. Clausen for their careful reading of the manuscript for this paper. The work described in this review was supported by grant 2 PO4A 061 30 (to I.J.F. and P.J.) from the Polish Ministry of Science and Higher Education, and project number Z01 ES065086 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (to RMS), and by the Foundation for Polish Science TEAM Program (to I.J.F.). NR 159 TC 27 Z9 28 U1 5 U2 49 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0168-6445 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD NOV PY 2012 VL 36 IS 6 BP 1105 EP 1121 DI 10.1111/j.1574-6976.2012.00338.x PG 17 WC Microbiology SC Microbiology GA 015LT UT WOS:000309448200004 PM 22404288 ER PT J AU Shallom, SJ Tae, H Sarmento, L Preston, D McIver, L Franck, C Dickerman, A Adams, LG Garner, HR AF Shallom, Shamira J. Tae, Hongseok Sarmento, Luciana Preston, Dale McIver, Lauren Franck, Christopher Dickerman, Allan Adams, L. Garry Garner, Harold R. TI Comparison of genome diversity of Brucella spp. field isolates using Universal Bio-signature Detection Array and whole genome sequencing reveals limitations of current diagnostic methods SO GENE LA English DT Article DE Brucella; Diagnostics; UBDA; PCR; Serology ID LINKED-IMMUNOSORBENT-ASSAY; BOVINE BRUCELLOSIS; ALIGNMENT; PCR; LIPOPOLYSACCHARIDE; CLASSIFICATION; OVIS; TOOL AB The detection and identification of bio-threat agents and the study of host-pathogen interactions require a high-resolution detection platform capable of discerning closely related species. Diverse analysis methods are used to identify pathogens, specifically Brucella species or biovars. In this study, we compared four diagnostic approaches including serology-based biochemical test, PCR assay, microarray analysis using a Universal Bio-signature Detection Array (UBDA) and whole genome "deep" sequencing for Brucella organisms including a number of field isolates. We found that although there was frequent agreement among the different tests, some tests gave compound/contradictory results that were a consequence of species diversity due to mixed infections or minor contaminants as measured by UBDA and validated from whole genome sequence. By comparing these analysis techniques, we demonstrate that standard diagnostics used in the field are limited in their ability to identify genomic DNA contaminants in field isolates while UBDA and sequencing analysis are highly sensitive in tracing genomic differences among the isolates. (C) 2012 Elsevier B.V. All rights reserved. C1 [Garner, Harold R.] Virginia Tech, Virginia Bioinformat Inst, Med Informat & Syst Div, Blacksburg, VA 24061 USA. [Sarmento, Luciana] Texas A&M Univ, Coll Vet Med, Dept Vet Pathobiol, College Stn, TX 77843 USA. [Preston, Dale] Texas Anim Hlth Commiss, State Federal Diagnost Lab, Austin, TX USA. [Franck, Christopher] Virginia Tech, Dept Stat, LISA, Blacksburg, VA 24061 USA. [Shallom, Shamira J.] NIH Clin Ctr, Dept Lab Med, Bethesda, MD USA. RP Garner, HR (reprint author), Virginia Tech, Virginia Bioinformat Inst, Med Informat & Syst Div, Blacksburg, VA 24061 USA. EM garner@vbi.vt.edu RI Tae, Hongseok/K-2497-2012 FU U.S. Department of Homeland Security-National Center of Excellence for Foreign Animal and Zoonotic Disease Defense at Texas AM University [DHS 2007-ST-061-000002, 570636]; Director's funds at Virginia Bioinformatics Institute, Virginia Tech; SREB (Southern Regional Education Board) FX This project was funded by subaward 570636 from DHS 2007-ST-061-000002 from the U.S. Department of Homeland Security-National Center of Excellence for Foreign Animal and Zoonotic Disease Defense at Texas A&M University and by the Director's funds at Virginia Bioinformatics Institute, Virginia Tech. S. Shallom received funding from SREB (Southern Regional Education Board) state doctoral scholar award. Dr. Nammalwar Sriranganathan and Hamzeh Al Qublan from Biomedical and Veterinary Sciences at Virginia Tech kindly provided B. abortus 2308 genomic DNA. F. tularensis LVS genomic DNA was kindly provided by Dr. Abey Bandara and Dr. Tom Inzana from the Department of Biology at Virginia Tech. We would like to extend special thanks to Greg Thorne and Shaukat Rangwala at MoGene for their valuable technical assistance. The field isolates were sequenced by the Virginia Bioinformatics Institute's Core Laboratory Facility at Virginia Tech. NR 29 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD NOV 1 PY 2012 VL 509 IS 1 BP 142 EP 148 DI 10.1016/j.gene.2012.07.073 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 015GW UT WOS:000309435400018 PM 22967710 ER PT J AU Benninger, DH Iseki, K Kranick, S Luckenbaugh, DA Houdayer, E Hallett, M AF Benninger, David H. Iseki, Kazumi Kranick, Sarah Luckenbaugh, David A. Houdayer, Elise Hallett, Mark TI Controlled Study of 50-Hz Repetitive Transcranial Magnetic Stimulation for the Treatment of Parkinson Disease SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE Parkinson disease; repetitive transcranial magnetic stimulation (rTMS); 50-Hz rTMS; noninvasive brain stimulation; therapeutic study; rehabilitation ID HIGH-FREQUENCY STIMULATION; MOTOR CORTEX; SUBTHALAMIC NUCLEUS; CORTICAL INHIBITION; BRAIN-STIMULATION; SILENT PERIOD; EXCITABILITY; PERFORMANCE; IMPROVEMENT; SYNCHRONIZATION AB Objective. To investigate the safety and efficacy of 50-Hz repetitive transcranial magnetic stimulation (rTMS) in the treatment of motor symptoms in Parkinson disease (PD). Background. Progression of PD is characterized by the emergence of motor deficits that gradually respond less to dopaminergic therapy. rTMS has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. Prior controlled studies suggest that an increase in stimulation frequency might enhance therapeutic efficacy. Methods. In this randomized, double blind, sham-controlled study, the authors investigated the safety and efficacy of 50-Hz rTMS of the motor cortices in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neurophysiological, and neuropsychological parameters. In addition, the safety of 50-Hz rTMS was tested with electromyography-electroencephalogram (EMG-EEG) monitoring during and after stimulation. Results. The authors investigated 26 patients with mild to moderate PD: 13 received 50-Hz rTMS and 13 sham stimulation. The 50-Hz rTMS did not improve gait, bradykinesia, and global and motor UPDRS, but there appeared a short-lived "on"-state improvement in activities of daily living (UPDRS II). The 50-Hz rTMS lengthened the cortical silent period, but other neurophysiological and neuropsychological measures remained unchanged. EMG/EEG recorded no pathological increase of cortical excitability or epileptic activity. There were no adverse effects. Conclusion. It appears that 50-Hz rTMS of the motor cortices is safe, but it fails to improve motor performance and functional status in PD. Prolonged stimulation or other techniques with rTMS might be more efficacious but need to be established in future research. C1 [Benninger, David H.] CHU Vaudois, Dept Neurol, CH-1011 Lausanne, Switzerland. [Benninger, David H.] NIH, Bethesda, MD 20892 USA. RP Benninger, DH (reprint author), CHU Vaudois, Dept Neurol, Rue Bugnon 46, CH-1011 Lausanne, Switzerland. EM David.Benninger@chuv.ch RI Benninger, David/A-8157-2015 OI Benninger, David/0000-0002-1049-9533 FU National Institutes of Health for the H-coil, a type of coil for magnetic stimulation; Intramural Research Program of the NINDS, NIH; USAMRMC [W81XWH-06-1-0534] FX The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Hallett has received personal compensation or travel expenses for activities with Neurotoxin Institute, Parkinson's and Ageing Research Foundation, Columbia University, Blackwell Publishers, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, and Elsevier as an advisory board member, an editor, a writer, or a speaker. He has also received license fee payments from the National Institutes of Health for the H-coil, a type of coil for magnetic stimulation.; The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Intramural Research Program of the NINDS, NIH, and in part by a grant from the USAMRMC (W81XWH-06-1-0534). NR 33 TC 13 Z9 15 U1 2 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD NOV-DEC PY 2012 VL 26 IS 9 BP 1096 EP 1105 DI 10.1177/1545968312445636 PG 10 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 014ER UT WOS:000309358400009 PM 22593114 ER PT J AU Kato, GJ AF Kato, Gregory J. TI Anemia, age, desaturation, and impaired neurocognition in sickle cell anemia SO PEDIATRIC BLOOD & CANCER LA English DT Article ID HEMOGLOBIN OXYGEN-SATURATION; BLOOD-FLOW-VELOCITY; DISEASE; CHILDREN; DYSFUNCTION; AFFINITY C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, Hematol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health [1 ZIA HL006014-03] FX Grant sponsor: Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health; Grant number: 1 ZIA HL006014-03. NR 12 TC 0 Z9 1 U1 0 U2 4 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2012 VL 59 IS 5 BP 773 EP 774 DI 10.1002/pbc.24276 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 004BW UT WOS:000308656100001 PM 22949104 ER PT J AU Salzer, WL Jones, TL Devidas, M Hilden, JM Winick, N Hunger, S Carroll, WL Camitta, B Dreyer, ZE AF Salzer, Wanda L. Jones, Tamekia L. Devidas, Meenakshi Hilden, Joanne M. Winick, Naomi Hunger, Stephen Carroll, William L. Camitta, Bruce Dreyer, ZoAnn E. TI Modifications to induction therapy decrease risk of early death in infants with acute lymphoblastic leukemia treated on Children's Oncology Group P9407 SO PEDIATRIC BLOOD & CANCER LA English DT Article DE infant acute lymphoblastic leukemia; mortality ID CONTINUOUS INTRAVENOUS-INFUSION; CANCER-STUDY-GROUP; PROGNOSTIC-FACTORS; STANDARD-RISK; CONSECUTIVE TRIALS; CHILDHOOD-LEUKEMIA; RANDOMIZED-TRIAL; DEXAMETHASONE; DOXORUBICIN; PROTOCOL AB Background Infants (<366 days of age) with acute lymphoblastic leukemia (ALL) have a poor prognosis. Most treatment failures occur within 69 months of diagnosis, primarily from relapse. Procedure The Children's Oncology Group P9407 study was designed to test if early intensified treatment would improve outcome for infants with ALL. Due to a significant number of early deaths (90 days of age at diagnosis, early death occurred in 7/51 (13.7%) in Cohorts 1?+?2 and 4/114 (3.5%) in Cohort 3 (P?=?0.036). Bacterial, viral, and fungal infections were more common in Cohorts 1?+?2 versus Cohort 3. Conclusions Early morbidity and mortality for infants with ALL were reduced by substitution of prednisone (40?mg/m2/day) for dexamethasone (10?mg/m2/day), the delivery of daunorubicin over 30 minutes instead of a continuous infusion for 48 hours, and the provision of more specific supportive care measures. Pediatr Blood Cancer 2012; 59: 834839. (C) 2012 Wiley Periodicals, Inc. C1 [Salzer, Wanda L.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Jones, Tamekia L.; Devidas, Meenakshi] Univ Florida, Coll Med, Dept Biostat, Gainesville, FL USA. [Jones, Tamekia L.; Devidas, Meenakshi] Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Biostat, Gainesville, FL USA. [Hilden, Joanne M.; Hunger, Stephen] Univ Colorado, Childrens Hosp, Dept Pediat, Aurora, CO USA. [Winick, Naomi] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Camitta, Bruce] Med Coll Wisconsin, Midwest Ctr Canc & Blood Disorders, Milwaukee, WI 53226 USA. [Camitta, Bruce] Childrens Hosp, Milwaukee, WI USA. [Dreyer, ZoAnn E.] Texas Childrens Hosp, Houston, TX 77030 USA. RP Salzer, WL (reprint author), 1335 EW Hwy,9th Floor, Silver Spring, MD 20910 USA. EM salzerw@mail.nih.gov FU National Institutes of Health [CA30969, CA29139, CA13539, CA98543, CA98413] FX Grant sponsor: National Institutes of Health; Grant numbers: CA30969, CA29139, CA13539, CA98543, CA98413. NR 47 TC 12 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 NOV PY 2012 VL 59 IS 5 BP 834 EP 839 DI 10.1002/pbc.24132 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 004BW UT WOS:000308656100013 PM 22488662 ER PT J AU Chuk, MK Aikin, A Whitcomb, T Widemann, BC Zannikos, P Bayever, E Balis, FM Fox, E AF Chuk, Meredith K. Aikin, Alberta Whitcomb, Trish Widemann, Brigitte C. Zannikos, Peter Bayever, Eliel Balis, Frank M. Fox, Elizabeth TI A phase I trial and pharmacokinetic study of a 24-hour infusion of trabectedin (Yondelis (R), ET-743) in children and adolescents with relapsed or refractory solid tumors SO PEDIATRIC BLOOD & CANCER LA English DT Article DE pediatrics; pharmacokinetics; phase I clinical trial; trabectedin ID SOFT-TISSUE SARCOMAS; HOMOLOGOUS RECOMBINATION; NUCLEOTIDE-EXCISION; ONCOLOGY GROUP; ECTEINASCIDIN-743; HEPATOTOXICITY; DEXAMETHASONE; TRANSCRIPTION; CHEMOTHERAPY; COMPOUND AB Background The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors. Procedure Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle. Pharmacokinetic studies were conducted during cycle 1. Results Patients (n?=?12) median (range) age 14.5 (816) years received trabectedin at 1.1 (n?=?3), 1.5 (n?=?6), or 1.7 (n?=?3) mg/m2. At the 1.5?mg/m2 dose level, one patient had dose limiting anorexia and fatigue. At 1.7?mg/m2, two patients experienced dose limiting toxicity, dehydration, and gamma-glutamyl transpeptidase elevation. Non-dose limiting toxicities included elevated serum transaminases, myelosuppression, nausea, emesis, and fatigue. Plasma pharmacokinetic parameters were similar to historical data in adults. One partial response was observed in a patient with neuroendocrine carcinoma. Stable disease (=6 cycles) was achieved in three patients (osteosarcoma n?=?2, desmoplastic small round cell tumor n?=?1). Conclusions The MTD of trabectedin in pediatric patients with refractory solid tumors is 1.5?mg/m2 IV over 24?hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required. Pediatr Blood Cancer 2012; 59: 865869. (C) 2012 Wiley Periodicals, Inc. C1 [Chuk, Meredith K.] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA. [Aikin, Alberta; Whitcomb, Trish; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Zannikos, Peter] Johnson & Johnson Pharmaceut R&D LLC, Titusville, NJ USA. [Bayever, Eliel] Johnson & Johnson Pharmaceut R&D LLC, Raritan, NJ USA. [Balis, Frank M.; Fox, Elizabeth] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Chuk, MK (reprint author), UPMC, Childrens Hosp Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224 USA. EM meredith.chuk@chp.edu FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsor: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 10 Z9 10 U1 0 U2 9 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 NOV PY 2012 VL 59 IS 5 BP 865 EP 869 DI 10.1002/pbc.24201 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 004BW UT WOS:000308656100018 PM 22847981 ER PT J AU Rochowski, A Olson, SB Alonzo, TA Gerbing, RB Lange, BJ Alter, BP AF Rochowski, Andrzej Olson, Susan B. Alonzo, Todd A. Gerbing, Robert B. Lange, Beverly J. Alter, Blanche P. TI Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute myelogenous leukemia; cytogenetics; clones; Fanconi anemia; sporadic AML ID MARROW FAILURE SYNDROMES; ACUTE MYELOID-LEUKEMIA; CANCER; REGISTRY; GAINS; RISK AB Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9), and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management. Pediatr Blood Cancer 2012; 59: 922924. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Rochowski, Andrzej; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Rochowski, Andrzej; Alter, Blanche P.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Olson, Susan B.] Oregon Hlth & Sci Univ, Clin Cytogenet Lab, Portland, OR 97201 USA. [Alonzo, Todd A.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Gerbing, Robert B.] Childrens Oncol Grp, Arcadia, CA USA. [Lange, Beverly J.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Execut Plaza S,Room 7020, Bethesda, MD 20852 USA. EM alterb@mail.nih.gov FU Children's National Medical Center; Children's Oncology Group from the National Cancer Institute (NCI) [U10 CA98543, U10 CA98413]; National Institutes of Health (NIH); Intramural Research Program of the NIH; NCI; National Cancer Institute [U10 CA98543, U10 CA98413] FX This research was supported in part by Children's National Medical Center, the Children's Oncology Group Grants U10 CA98543 and U10 CA98413 from the National Cancer Institute (NCI), National Institutes of Health (NIH), and the Intramural Research Program of the NIH and the NCI.; Grant sponsor: Children's National Medical Center; Grant sponsor: National Cancer Institute; Grant numbers: U10 CA98543, U10 CA98413; Grant sponsor: National Institutes of Health; Grant sponsor: Intramural Research Program of the NIH and the NCI. NR 14 TC 7 Z9 8 U1 0 U2 2 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2012 VL 59 IS 5 BP 922 EP 924 DI 10.1002/pbc.24168 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 004BW UT WOS:000308656100028 PM 22517793 ER PT J AU Desta, Z Moaddel, R Ogburn, ET Xu, C Ramamoorthy, A Venkata, SLV Sanghvi, M Goldberg, ME Torjman, MC Wainer, IW AF Desta, Zeruesenay Moaddel, Ruin Ogburn, Evan T. Xu, Cong Ramamoorthy, Anuradha Venkata, Swarajya Lakshmi Vattem Sanghvi, Mitesh Goldberg, Michael E. Torjman, Marc C. Wainer, Irving W. TI Stereoselective and regiospecific hydroxylation of ketamine and norketamine SO XENOBIOTICA LA English DT Article DE Ketamine; hydroxynorketamine; dehydronorketamine; hydroxyketamine; cytochrome P450s; complex regional pain syndrome; depression ID REGIONAL PAIN SYNDROME; LIVER MICROSOMAL PREPARATIONS; HEALTHY-VOLUNTEERS; DIABETES-MELLITUS; DRUG-METABOLISM; RAT; IDENTIFICATION; PLASMA; BIOTRANSFORMATION; PHARMACOKINETICS AB 1. The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). 2. The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis-Menten, Hill or substrate inhibition equation. 3. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 4. 5a and 4b were detected in plasma samples from patients receiving (R, S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response. C1 [Wainer, Irving W.] NIA, Lab Clin Investigat, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Desta, Zeruesenay; Ogburn, Evan T.; Xu, Cong] Indiana Univ Sch Med, Div Clin Pharmacol, Dept Med, Indianapolis, IN USA. [Goldberg, Michael E.; Torjman, Marc C.] Rowan Univ, Cooper Med Sch, Cooper Univ Hosp & Hlth Syst, Camdem, NJ USA. RP Wainer, IW (reprint author), NIA, Lab Clin Investigat, NIH, Biomed Res Ctr, 251 Bayview Blvd,Room 8B133, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov RI Sanghvi, Mitesh/C-6740-2013; Xu, Cong/I-3291-2014 FU National Institute of General Medical Sciences, National Institutes of Health (Bethesda, MD) [R01GM078501, 3R01GM078501-04S1]; Intramural Research Program of the NIH, National Institute on Aging FX This project was supported in part by Award Number R01GM078501 and 3R01GM078501-04S1 from the National Institute of General Medical Sciences, National Institutes of Health (Bethesda, MD) (ZD). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (IWW). IWW, MEG, MCT and RM have submitted a patent, assigned to the US government, for use of ketamine metabolites in treatment of neuropathic pain and bipolar disorder and major depression. NR 35 TC 18 Z9 19 U1 0 U2 17 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD NOV PY 2012 VL 42 IS 11 BP 1076 EP 1087 DI 10.3109/00498254.2012.685777 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 015VL UT WOS:000309474400004 PM 22612619 ER PT J AU Rebois, RV Maki, K Meeks, JA Fishman, PH Hebert, TE Northup, JK AF Rebois, R. Victor Maki, Karl Meeks, Julie A. Fishman, Peter H. Hebert, Terence E. Northup, John K. TI D-2-like dopamine and p-adrenergic receptors forma signaling complex that integrates G(s)- and G(i)-mediated regulation of adenylyl cyclase SO CELLULAR SIGNALLING LA English DT Article DE beta-Adrenergic receptors; D-2-like dopamine receptors; Heterotrimeric G proteins; Adenylyl cyclase; Signaling complexes; Bioluminescence resonance energy transfer; Alprenolol-Sepharose ID RESONANCE ENERGY-TRANSFER; HETEROTRIMERIC G-PROTEINS; LIVING CELLS; SUBUNIT DISSOCIATION; POTASSIUM CHANNELS; COUPLED RECEPTORS; STABLE COMPLEXES; PLASMA-MEMBRANE; D-4 RECEPTOR; ACTIVATION AB beta 3-Adrenergic receptors (beta AR) and D-2-like dopamine receptors (which include D-2-, D-3- and D-4-dopamine receptors) activate G(s) and G(i), the stimulatory and inhibitory heterotrimeric G proteins, respectively, which in turn regulate the activity of adenylyl cyclase (AC). beta(2)-Adrenergic receptors (beta(2)AR) and D-4-dopamine receptors (D4DR) co-immunoprecipitated when co-expressed in HEK 293 cells, suggesting the existence of a signaling complex containing both receptors. In order to determine if these receptors are closely associated with each other, and with other components involved in G protein-mediated signal transduction, beta(2)AR, D4DR, G protein subunits (Ga-i1 and the G beta(1)gamma(2) heterodimer) and AC were tagged so that bioluminescence resonance energy transfer (BRET) could be used to monitor their interactions. All of the tagged proteins retained biological function. For the first time. FlAsH-labeled proteins were used in BRET experiments as fluorescent acceptors for the energy transferred from Renilla luciferase-tagged donor proteins. Our experiments revealed that beta(2)AR, D4DR. G proteins and AC were closely associated in a functional signaling complex in cellulo. Furthermore. BRET experiments indicated that although activation of G(i) caused a conformational change within the heterotrimeric protein, it did not cause the G beta gamma heterodimer to dissociate from the Ga-i1 subunit. Evidence for the presence of a signaling complex in vivo was obtained by purifying beta AR from detergent extracts of mouse brain with alprenolol-Sepharose and showing that the precipitate also contained both D-2-like dopamine receptors and AC. Published by Elsevier Inc. C1 [Rebois, R. Victor; Maki, Karl; Meeks, Julie A.; Northup, John K.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Rebois, R. Victor; Fishman, Peter H.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Hebert, Terence E.] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada. RP Rebois, RV (reprint author), Natl Inst Deafness & Other Communicat Disorders, Lab Cellular Biol, NIH, 5 Res Court,Room 2A11, Rockville, MD 20850 USA. EM reboisv@nidcd.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute on Deafness and Other Communication Disorders; National Institute of Neurological Disorders and Stroke; Canadian Institutes for Health Research FX We thank Maya Mamarbachi for making the recombinant plasmid coding for D4DR-PGCC, and Drs. Jurgen Wess and David R. Sibley for reviewing the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, the National Institute on Deafness and Other Communication Disorders and the National Institute of Neurological Disorders and Stroke, and by grants to TEH from the Canadian Institutes for Health Research. TEH is a Chercheur National of the Fonds de la Recherche en Sante du Quebec (FRSQ). NR 56 TC 9 Z9 9 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD NOV PY 2012 VL 24 IS 11 BP 2051 EP 2060 DI 10.1016/j.cellsig.2012.06.011 PG 10 WC Cell Biology SC Cell Biology GA 013MI UT WOS:000309309100009 PM 22759790 ER PT J AU Bonacci, TM Hirsch, DS Shen, Y Dokmanovic, M Wu, WJ AF Bonacci, Tabetha M. Hirsch, Dianne S. Shen, Yi Dokmanovic, Milos Wu, Wen Jin TI Small GTPase Rho regulates R-cadherin through Dia1/profilin-1 SO CELLULAR SIGNALLING LA English DT Article DE R-cadherin; Rho; Dia1; Profilin-1; Adherens junction ID CELL-CELL-ADHESION; BREAST-CANCER CELLS; ADHERENS JUNCTIONS; RECEPTOR DEGRADATION; TUMOR PROGRESSION; P120 CATENIN; EXPRESSION; PROFILIN; ESTABLISHMENT; PROTEINS AB R-cadherin is a member of the classical cadherins. Though much is known about E-cadherin in adherens junction formation in epithelial cells, the role of R-cadherin in epithelial cells remains elusive. This study examines regulation of R-cadherin adherens junctions by the small GTPase Rho and its downstream effectors in MDA-MB-231 breast cancer cells, MDA-MB-231 cells stably expressing the N-terminus of c-Cbl, and MCF10A normal breast epithelial cells. We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dial (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells. Importantly. R-cadherin adherens junction formation facilitates a mesenchymal to epithelial-like transition in MDA-MB-231 cells. Additionally, our data suggest an inverse relationship between EGFR signaling and R-cadherin adherens junction formation. Taken together, results from this study indicate that R-cadherin is a critical regulator of epithelial phenotype. Published by Elsevier Inc. C1 [Bonacci, Tabetha M.; Hirsch, Dianne S.; Shen, Yi; Dokmanovic, Milos; Wu, Wen Jin] US FDA, Div Monoclonal Antibodies, OBP, OPS,CDER, Bethesda, MD 20892 USA. RP Wu, WJ (reprint author), US FDA, Div Monoclonal Antibodies, OBP, OPS,CDER, HFD-123,29 Lincoln Dr,NIH Bldg 29B,Room 3NN-15, Bethesda, MD 20892 USA. EM wen.wu@fda.hhs.gov FU Interagency Oncology Task Force Joint Fellowship Program; U.S. Food and Drug Administration; National Cancer Institute, NIH FX Grant support: Interagency Oncology Task Force Joint Fellowship Program sponsored by the U.S. Food and Drug Administration and the National Cancer Institute, NIH. NR 42 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD NOV PY 2012 VL 24 IS 11 BP 2102 EP 2110 DI 10.1016/j.cellsig.2012.07.015 PG 9 WC Cell Biology SC Cell Biology GA 013MI UT WOS:000309309100015 PM 22820501 ER PT J AU Paiva, TM Ishida, MA Benega, MA Constantino, CRA Silva, DBB Santos, KCO Oliveira, MI Barbosa, HA Carvalhanas, TRMP Schuck-Paim, C Alonso, WJ AF Paiva, Terezinha M. Ishida, Maria A. Benega, Margarete A. Constantino, Clovis R. A. Silva, Daniela B. B. Santos, Katia C. O. Oliveira, Maria I. Barbosa, Helena A. Carvalhanas, Telma R. M. P. Schuck-Paim, Cynthia Alonso, Wladimir J. TI Shift in the timing of respiratory syncytial virus circulation in a subtropical megalopolis: Implications for immunoprophylaxis SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE respiratory syncytial virus; palivizumab; acute respiratory infections; Brazil ID SOUTHEAST BRAZIL; IMMUNE GLOBULIN; INFECTIONS; CHILDREN; PALIVIZUMAB; PREVENTION AB Respiratory syncytial virus (RSV) is the most common cause of severe respiratory infections worldwide, and an important cause of childhood bronchiolitis, pneumonia, and mortality. Although prevention of RSV infection by immunoprophylaxis with palivizumab has proved effective, a precise understanding of the timing of RSV outbreaks is necessary to ensure that infants are protected when RSV is circulating. In this study a consistent shift in the seasonal patterns of RSV circulation in southeast Brazil (Sao Paulo) is reported based on the analysis of 15 years of viral surveillance. Surveillance was conducted from 1996 to 2010 and involved the collection of samples from children with symptoms of acute respiratory infection. Putative changes in school terms, in the proportion of RSV genotypes infecting children and in the seasonal dynamics of several climatic parameters during the period were also investigated. The results revealed a progression in the timing of RSV seasons, with a shift in the onset and peak of RSV epidemics from 2007 onwards. Although lower rainfall and temperatures were associated with the onset of outbreaks, there was no evidence of changes in climate, school terms or in the relative proportion of genotypes in the period analyzed. These findings have direct implications for improving the prophylactic use of palivizumab, and stress the importance of fine tuning prophylaxis with recent surveillance data. In the case of Sao Paulo, palivizumab prophylaxis should be initiated earlier than suggested currently. Similar adjustments may be necessary in other regions. J. Med. Virol. 84:18251830, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Alonso, Wladimir J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Paiva, Terezinha M.; Ishida, Maria A.; Benega, Margarete A.; Constantino, Clovis R. A.; Silva, Daniela B. B.; Santos, Katia C. O.; Oliveira, Maria I.] Adolfo Lutz Inst, Ctr Resp Dis, Sao Paulo, Brazil. [Barbosa, Helena A.; Carvalhanas, Telma R. M. P.] Sao Paulo State Secretariat Hlth, Sao Paulo, Brazil. [Schuck-Paim, Cynthia] Univ Oxford, Wolfson Coll, Oxford, England. RP Alonso, WJ (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr,Bldg 16,Stone House, Bethesda, MD 20892 USA. EM wladimir.j.alonso@gmail.com FU Fogarty International Center, National Institutes of Health, US; Adolfo Lutz Institute, Brazil; State Secretariat for Health, Sao Paulo, Brazil; Brazilian Ministry of Health FX Grant sponsor: Fogarty International Center, National Institutes of Health, US (to W.J.A.); Grant sponsor: Financial support was also received from Adolfo Lutz Institute, Brazil; Grant sponsor: State Secretariat for Health, Sao Paulo, Brazil; Grant sponsor: Brazilian Ministry of Health. NR 23 TC 4 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD NOV PY 2012 VL 84 IS 11 BP 1825 EP 1830 DI 10.1002/jmv.23347 PG 6 WC Virology SC Virology GA 010AM UT WOS:000309066800017 PM 22997087 ER PT J AU Moody, TW Di Florio, A Jensen, RT AF Moody, Terry W. Di Florio, Alessia Jensen, Robert T. TI PYK-2 is Tyrosine Phosphorylated after Activation of Pituitary Adenylate Cyclase Activating Polypeptide Receptors in Lung Cancer Cells SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE PACAP; Signal transduction; Tyrosine phosphorylation; PYK-2 ID FOCAL ADHESION KINASE; VASOACTIVE INTESTINAL POLYPEPTIDE; FUNCTIONAL EXPRESSION; SIGNAL-TRANSDUCTION; PHOSPHOLIPASE-C; SPLICE VARIANTS; PROTEIN-KINASE; I RECEPTOR; GROWTH; PROLIFERATION AB The signal transduction mechanisms of pituitary adenylate cyclase activating polypeptide (PACAP) were investigated in lung cancer cells. Previously, PACAP-27 addition to NCI-H838 cells increased phosphatidylinositol turnover and intracellular cAMP leading to proliferation of lung cancer cells. Also, PACAP receptors (PAC1) regulated the tyrosine phosphorylation of ERK, focal adhesion kinase, and paxillin. In this communication, the effects of PACAP on cytosolic Ca2+ and PYK-2 tyrosine phosphorylation were investigated. PACAP-27 increased cytosolic Ca2+ within seconds after addition to FURA-2 AM loaded NCI-H838 cells. The increase in cytosolic Ca2+ caused by PACAP was inhibited by PACAP(6-38) (PAC1 antagonist), U73122 (phospholipase C inhibitor), or BAPTA (calcium chelator), but not H89 (PKA inhibitor). PACAP-38, but not vasoactive intestinal peptide (VIP), addition to NCI-H838 or H1299 cells significantly increased the tyrosine phosphorylation of PYK-2 after 2 min. The increase in PYK-2 tyrosine phosphorylation caused by PACAP was inhibited by PACAP(6-38), U73122, or BAPTA, but not H89. The results suggest that PAC1 regulates PYK-2 tyrosine phosphorylation in a calcium-dependent manner. C1 [Moody, Terry W.] NCI, NCI Off Director, Ctr Canc Res, Bethesda, MD 20892 USA. [Di Florio, Alessia; Jensen, Robert T.] NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Moody, TW (reprint author), NCI, NCI Off Director, Ctr Canc Res, 31 Ctr Dr,Bldg 31,Rm 4A48, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov FU NCI; NIDDK of NIH FX This research is supported in part by intramural funds of the NCI and NIDDK of NIH. NR 36 TC 1 Z9 1 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD NOV PY 2012 VL 48 IS 3 BP 660 EP 666 DI 10.1007/s12031-012-9785-6 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 008LS UT WOS:000308959100022 PM 22581436 ER PT J AU White, TA Kwon, EM Fu, R Lucas, JM Ostrander, EA Stanford, JL Nelson, PS AF White, Thomas A. Kwon, Erika M. Fu, Rong Lucas, Jared M. Ostrander, Elaine A. Stanford, Janet L. Nelson, Peter S. TI The Monoamine Oxidase A gene promoter repeat and prostate cancer risk SO PROSTATE LA English DT Article DE MAOA; polymorphism; prostate cancer ID CLORGYLINE; MALONATE; CELLS AB BACKGROUND Amine catabolism by monoamine oxidase A (MAOA) contributes to oxidative stress, which plays a role in prostate cancer (PCa) development and progression. An upstream variable-number tandem repeat (uVNTR) in the MAOA promoter influences gene expression and activity, and may thereby affect PCa susceptibility. METHODS Caucasian (n?=?2,572) men from two population-based case-control studies of PCa were genotyped for the MAOA-VNTR. Logistic regression was used to assess PCa risk in relation to genotype. RESULTS Common alleles of the MAOA-VNTR were not associated with the relative risk of PCa, nor did the relationship differ by clinical features of the disease. The rare 5-copy variant (frequency: 0.5% in cases; 1.8% in controls), however, was associated with a reduced PCa risk (odds ratio, OR?=?0.30, 95% CI 0.130.71). CONCLUSIONS A rare polymorphism of the MAOA promoter previously shown to confer low expression was associated with a reduced risk of developing PCa. This novel finding awaits confirmation in other study populations. Prostate 72:16221627, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [White, Thomas A.; Lucas, Jared M.; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [White, Thomas A.; Fu, Rong; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [White, Thomas A.] Univ Washington, Grad Program Mol & Cellular Biol, Seattle, WA 98195 USA. [Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Nelson, PS (reprint author), Fred Hutchinson Canc Res Ctr, Div Human Biol, Mailstop D4-100 1100,Fairview Ave N, Seattle, WA 98109 USA. EM pnelson@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU NIH [T32 CA80416]; National Cancer Institute [RO1 CA056678, RO1 CA082664, RO1 CA092579, P50 CA097186]; Fred Hutchinson Cancer Research Center; Prostate Cancer Foundation; National Human Genome Research Institute FX Grant sponsor: Interdisciplinary Dual Mentorship Training Grant Program NIH; Grant number: T32 CA80416; Grant sponsor: National Cancer Institute grants; Grant numbers: RO1 CA056678, RO1 CA082664, RO1 CA092579, P50 CA097186; Grant sponsor: Fred Hutchinson Cancer Research Center; Grant sponsor: Prostate Cancer Foundation; Grant sponsor: Intramural Program of the National Human Genome Research Institute. NR 17 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD NOV PY 2012 VL 72 IS 15 BP 1622 EP 1627 DI 10.1002/pros.22515 PG 6 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 014WG UT WOS:000309405800003 PM 22473857 ER PT J AU Jin, MG Memarzadeh, F Lee, K Chen, QY AF Jin, Mingang Memarzadeh, Farhad Lee, Kisup Chen, Qingyan TI Experimental study of ventilation performance in laboratories with chemical spills SO BUILDING AND ENVIRONMENT LA English DT Article DE Chemical spills; Ventilation performance; Bench hood exhaust; Laboratory ventilation ID MORTALITY; CHEMISTS AB Chemical spills occur frequently in laboratories. The current ventilation code for laboratories recommends a ventilation rate of 12 ACH for maintaining a safe laboratory environment. On the other hand, the energy saving potential encourages a reduction of the ventilation rate. But the effect of reducing the ventilation rate on the indoor air quality in a laboratory with chemical spills has not been well studied. This experimental study investigated the ventilation performance under different ventilation rates in a chemistry laboratory mockup. The impact of wall exhaust locations and chemical spill positions was examined related to the contaminant concentration distribution in the laboratory. This investigation also studied the ventilation performance with and without the use of bench hood exhausts. The results showed that the contaminant concentration was not linearly proportional to the ventilation rate. If the chemical spill position was close to an exhaust, the contaminant concentration in the laboratory could be rather low. The bench hood exhaust had the potential to effectively reduce the contaminant concentration. The results indicated that the ventilation rate in a chemistry laboratory may be reduced without increasing the safety risk if the ventilation system is properly designed. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Jin, Mingang; Lee, Kisup; Chen, Qingyan] Purdue Univ, Sch Mech Engn, W Lafayette, IN 47907 USA. [Memarzadeh, Farhad] NIH, Div Tech Resources, Bethesda, MD 20892 USA. [Chen, Qingyan] Tianjin Univ, Sch Environm Sci & Engn, Tianjin 300072, Peoples R China. RP Chen, QY (reprint author), Purdue Univ, Sch Mech Engn, W Lafayette, IN 47907 USA. EM yanchen@purdue.edu NR 21 TC 2 Z9 2 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0360-1323 J9 BUILD ENVIRON JI Build. Environ. PD NOV PY 2012 VL 57 BP 327 EP 335 DI 10.1016/j.buildenv.2012.04.022 PG 9 WC Construction & Building Technology; Engineering, Environmental; Engineering, Civil SC Construction & Building Technology; Engineering GA 990GL UT WOS:000307618900032 ER PT J AU Glenn, CR Klein, DN Lissek, S Britton, JC Pine, DS Hajcak, G AF Glenn, Catherine R. Klein, Daniel N. Lissek, Shmuel Britton, Jennifer C. Pine, Daniel S. Hajcak, Greg TI The development of fear learning and generalization in 8-13 year-olds SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE fear learning; fear generalization; aversive conditioning; startle reflex; development ID ANXIETY DISORDERS; POTENTIATED STARTLE; CONDITIONED FEAR; ANXIOUS RESPONSES; CHILDREN; ADOLESCENTS; HUMANS; REFLEX; THREAT; REPRESENTATION AB The current study examined developmental changes in fear learning and generalization in 40 healthy 813 year-olds using an aversive conditioning paradigm adapted from Lau et al. [Lau et al. [2008] Journal of the American Academy of Child and Adolescent Psychiatry 47:94102]. In this task, the conditioned stimuli (CS+/CS-) are two neutral female faces, and the unconditioned stimulus is a fearful, screaming face. The second phase of the study also included a generalization stimulus (GS): a 50% blend of the CS +/- faces. The eye-blink startle reflex was utilized to measure defensive responding. Patterns of fear learning and generalization were qualified by child age. Older children demonstrated greater fear learning (i.e., larger startle during CS+ than CS-) than younger children. In addition, older children exhibited the typical pattern of generalization observed in adults, whereas younger children did not. Finally, fear learning also related to contingency awareness; only children who correctly identified the CS+ demonstrated fear-potentiated startle to the CS+. Clinical implications and future directions are discussed. (C) 2011 Wiley Periodicals,Inc. Dev Psychobiol 54: 675684, 2012. C1 [Glenn, Catherine R.; Klein, Daniel N.; Hajcak, Greg] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Lissek, Shmuel] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Britton, Jennifer C.; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Glenn, CR (reprint author), SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. EM cassie.glenn@gmail.com RI Britton, Jennifer/J-4501-2013 FU NIMH [RO1 MH069942]; NIH [F31 MH086197] FX Contract grant sponsor: NIMH; Contract grant number: RO1 MH069942; Contract grant sponsor: NIH; Contract grant number: F31 MH086197 NR 39 TC 30 Z9 30 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1630 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD NOV PY 2012 VL 54 IS 7 BP 675 EP 684 DI 10.1002/dev.20616 PG 10 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA 008CJ UT WOS:000308934600001 PM 22072276 ER PT J AU Peluso, CE Jang, W Drager, UC Schwob, JE AF Peluso, Carolyn E. Jang, Woochan Draeger, Ursula C. Schwob, James E. TI Differential expression of components of the retinoic acid signaling pathway in the adult mouse olfactory epithelium SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE retinoic acid; olfactory epithelium; regeneration; retinaldehyde dehydrogenase; cellular retinoic acid binding protein ID ODORANT RECEPTOR EXPRESSION; BINDING PROTEIN-II; GENE-EXPRESSION; SENSORY NEURONS; BASAL-CELLS; MICE; PROLIFERATION; INACTIVATION; INHIBITION; INDUCTION AB Position within a tissue often correlates with cellular phenotype, for example, differential expression of odorant receptors and cell adhesion molecules across the olfactory mucosa (OM). The association between position and phenotype is often paralleled by gradations in the concentration of retinoic acid (RA), caused by differential expression of the RA synthetic enzymes, the retinaldehyde dehydrogenases (RALDH). We show here that RALDH-1, -2, and -3 are enriched in the sustentacular cells, deep fibroblasts of the lamina propria, and the superficial fibroblasts, respectively, of the ventral and lateral OM as compared to the dorsomedial OM. The shift from high to low expression of the RALDHs matches the boundary defined by the differential expression of OCAM/mamFasII. Further, we found that RA-binding proteins are expressed in the epithelium overlying the RALDH-3 expressing fibroblasts of the lamina propria. Both findings suggest that local alterations in RA concentration may be more important than a gradient of RA across the epithelial plane, per se. In addition, RALDH-3 is found in a small population of basal cells in the ventral and lateral epithelium, which expand and contribute to the neuronal lineage following MeBr lesion. Indeed, transduction with a retrovirus expressing a dominant negative form of retinoic acid receptor type alpha blocks the reappearance of mature, olfactory marker protein (OMP) (+) olfactory neurons as compared to empty vector. These results support the notion of a potential role for RA, both in maintaining the spatial organization of the normal olfactory epithelium and in reestablishing the neuronal population during regeneration after injury. J. Comp. Neurol. 520:37073726, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Peluso, Carolyn E.; Jang, Woochan; Schwob, James E.] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. [Peluso, Carolyn E.] Tufts Univ, Sackler Sch Grad Biomed Sci, Program Cell Mol & Dev Biol, Boston, MA 02111 USA. [Peluso, Carolyn E.] NICHHD, Unit Cellular Commun, Program Cell Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Draeger, Ursula C.] Univ Massachusetts, Sch Med, Eunice Kennedy Shriver Ctr, Dept Psychiat, Waltham, MA 02452 USA. RP Schwob, JE (reprint author), Tufts Univ, Sch Med, Dept Anat & Cellular Biol, 136 Harrison Ave, Boston, MA 02111 USA. EM jim.schwob@tufts.edu OI Drager, Ursula C/0000-0003-1815-190X FU National Institute on Deafness and Other Communication Disorders [F31 DC007373, R01 DC000467, R01 DC002167] FX Grant sponsor: National Institute on Deafness and Other Communication Disorders; Grant numbers: F31 DC007373, R01 DC000467, R01 DC002167. NR 44 TC 7 Z9 7 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD NOV 1 PY 2012 VL 520 IS 16 BP 3707 EP 3726 DI 10.1002/cne.23124 PG 20 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 000RT UT WOS:000308406400009 PM 22522724 ER PT J AU Lynch, CD Jackson, LW Kostyniak, PJ McGuinness, BM Louis, GMB AF Lynch, Courtney D. Jackson, Leila W. Kostyniak, Paul J. McGuinness, Bridget M. Louis, Germaine M. Buck TI The effect of prenatal and postnatal exposure to polychlorinated biphenyls and child neurodevelopment at age twenty four months SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Polychlorinated biphenyls; Growth and development; Pregnancy; Breast feeding; Environmental exposure ID 3,3',4,4',5-PENTACHLOROBIPHENYL PCB 126; MATERNAL SERUM; ENVIRONMENTAL EXPOSURE; CRITICAL WINDOWS; ANGLER COHORT; BIRTH COHORT; INFANTS; MILK; RATS; CONTAMINANTS AB We examined the association between prenatal and postnatal exposure to PCBs and development at age 24 months as measured by the Bayley Scales of Infant Development II. 44 (85%) of 52 children had information available. When prenatal and postnatal exposure were modeled together, we found no association between total PCB exposure and the mental development index (MDI) or the physical development index (PDI). In examining PCB 153, we found no association between PCB 153 and MDI, while higher levels of postnatal exposure was associated with a decrease in PDI after adjustment [beta for highest tertile = -24.9; 95% CI (-44.3, -5.5)]. Higher levels of prenatal PCB 153 exposure were associated with a statistically significant increased odds of screening positive for a motor delay. In sum, when prenatal and postnatal exposures were considered together, breast milk exposure to PCB 153 appears to be associated with decrements in motor development; however, we cannot rule out that the finding was due to chance. (C) 2012 Elsevier Inc. All rights reserved. C1 [Lynch, Courtney D.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Columbus, OH 43210 USA. [Jackson, Leila W.] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Kostyniak, Paul J.] SUNY Buffalo, Toxicol Res Ctr, Sch Med & Biomed Sci, Buffalo, NY 14214 USA. [Kostyniak, Paul J.; McGuinness, Bridget M.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Lynch, CD (reprint author), Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, 395 W 12th Ave, Columbus, OH 43210 USA. EM courtney.lynch@osumc.edu OI Buck Louis, Germaine/0000-0002-1774-4490 FU Great Lakes Protection Fund [RM 791-3021]; Agency for Toxic Substances and Disease Registry [H75/ATH 298328]; Gerber Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported in part by the Great Lakes Protection Fund (RM 791-3021); the Agency for Toxic Substances and Disease Registry (H75/ATH 298328): the Gerber Foundation; and intramural funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 40 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 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD NOV PY 2012 VL 34 IS 3 BP 451 EP 456 DI 10.1016/j.reprotox.2012.04.013 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 003NU UT WOS:000308619400022 PM 22569275 ER PT J AU Arbyn, M de Sanjose, S Saraiya, M Sideri, M Palefsky, J Lacey, C Gillison, M Bruni, L Ronco, G Wentzensen, N Brotherton, J Qiao, YL Denny, L Bornstein, J Abramowitz, L Giuliano, A Tommasino, M Monsonego, J AF Arbyn, Marc de Sanjose, Silvia Saraiya, Mona Sideri, Mario Palefsky, Joel Lacey, Charles Gillison, Maura Bruni, Laia Ronco, Guglielmo Wentzensen, Nicolas Brotherton, Julia Qiao, You-Lin Denny, Lynnette Bornstein, Jacob Abramowitz, Laurent Giuliano, Anna Tommasino, Massimo Monsonego, Joseph TI EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE cervical cancer; vulvar cancer; anal cancer; penile cancer; head and neck cancer; genital warts; incidence; mortality; human papillomavirus; HPV; screening; vaccination ID VULVAR INTRAEPITHELIAL NEOPLASIA; SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS INFECTION; CERVICAL-CANCER PREVENTION; GENITAL WARTS; UNITED-STATES; ANAL CANCER; NECK-CANCER; BURDEN; LESIONS AB The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes similar to 600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease. C1 [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, B-1050 Brussels, Belgium. [de Sanjose, Silvia; Bruni, Laia] CIBER Epidemiol & Salut Publ, Barcelona, Spain. [Saraiya, Mona] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Sideri, Mario] European Inst Oncol, Gynecol Div, Prevent Gynecol Unit, Milan, Italy. [Palefsky, Joel] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Lacey, Charles] Univ York, Hull York Med Sch, York YO10 5DD, N Yorkshire, England. [Gillison, Maura] Kimmel Canc Ctr, Div Viral Oncol, Baltimore, MD USA. [Ronco, Guglielmo] Ctr Prevenz Oncol, Canc Epidemiol Unit, Turin, Italy. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Brotherton, Julia] Victorian Cytol Serv, Victorian Cytol Serv Registries, Melbourne, Vic, Australia. [Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Beijing 100021, Peoples R China. [Denny, Lynnette] Univ Cape Town, Dept Obstet & Gynaecol, Cape Town, South Africa. [Denny, Lynnette] Groote Schuur Hosp, ZA-7925 Cape Town, South Africa. [Bornstein, Jacob] Bar Ilan Univ, Fac Med, IL-52100 Ramat Gan, Israel. [Bornstein, Jacob] Western Galilee Hosp, Dept Obstet & Gynecol, Nahariyya, Israel. [Abramowitz, Laurent] Hop Xavier Bichat, Dept Gastroenterol & Proctol, Paris, France. [Giuliano, Anna] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Tommasino, Massimo] Int Agcy Res Canc, F-69372 Lyon, France. [Monsonego, Joseph] Inst Cervix, Paris, France. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Canc Epidemiol Unit, J Wytsmanst 14, B-1050 Brussels, Belgium. EM marc.arbyn@wiv-isp.be RI de Sanjose Llongueras, Silvia/H-6339-2014; Bruni, Laia/N-5816-2014; Qiao, You-Lin/B-4139-2012; OI Qiao, You-Lin/0000-0001-6380-0871; Bruni, Laia/0000-0003-3943-0326 FU Merck; GSK; MSD; Qiagen; SPMSD; Australian Research Council; Cooperative Research Centre for Aboriginal Health; CSL Limited; Directorate of SANCO of the European Commission, Luxembourg; Grand-Duchy of Luxembourg through the IARC, Lyon, France; Grand-Duchy of Luxembourg through the EUROCHIP-3 Network (Istituto Nazionale dei Tumori, Milan, Italy); Belgian Foundation Against Cancer (Brussels, Belgium); European Commission [242061]; HPV-AHEAD Project [FP7-HEALTH-2011-282562]; National Cancer Institute (Bethesda, USA) FX MA: Participation at Eurogin conference (Lisbon 2011) funded by organizers of the conference. SdS has an unrestricted grant from Merck and has had occasional grants for assistance to scientific meetings from GSK, MSD and Qiagen. MSi: consultancy with salary to IEO with the following companies: Qiagen, GSK, Sanofi Pasteur, MTM labs, Roche Diagnostics, Innogenetics. CL has acted as a consultant for SPMSD and received travel grants from SPMSD & GSK. MG: Merck (funding and consulting), GSK (consulting). JBr: investigator on an Australian Research Council Linkage Grant, for which CSL Biotherapies is a partner organization and was a chief investigator on a study of HPV prevalence in Australian women, which was funded by a grant from the Cooperative Research Centre for Aboriginal Health, as well as education grants in aid from GlaxoSmithKline and CSL Limited. LD has received honoraria from Merck and Glaxosmithkline for appearing on various speaker fora and has conducted research funded by both organizations. AG: Merck (Speaker Bureau, consult, grant funding), GSK (grant funding). JM has participated to Steering Committees at Merck and to the Advisory Board of Sanofi Pasteur MSD, Gen-Probe, Qiagen and Roche Diagnostics.; Grant sponsors: Directorate of SANCO of the European Commission, Luxembourg, Grand-Duchy of Luxembourg [through the ECCG project (European Cooperation on Development and Implementation of Cancer Screening and Prevention Guidelines), the IARC, Lyon, France and through the EUROCHIP-3 Network (Istituto Nazionale dei Tumori, Milan, Italy)]. The Belgian Foundation Against Cancer (Brussels, Belgium). The 7th Framework Programme of DG Research of the European Commission (PREHDICT Project, coordinated by the Vrije Universiteit Amsterdam, the Netherlands), Grant number: 242061; the HPV-AHEAD Project (coordinated by IARC), Grant number: FP7-HEALTH-2011-282562. The Intramural Research Program of the National Cancer Institute (Bethesda, USA). NR 98 TC 66 Z9 73 U1 1 U2 20 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 NOV 1 PY 2012 VL 131 IS 9 BP 1969 EP 1982 DI 10.1002/ijc.27650 PG 14 WC Oncology SC Oncology GA 993XP UT WOS:000307893600003 PM 22623137 ER PT J AU Balansky, R Ganchev, G Iltcheva, M Kratchanova, M Denev, P Kratchanov, C Polasa, K D'Agostini, F Steele, VE De Flora, S AF Balansky, Roumen Ganchev, Gancho Iltcheva, Marietta Kratchanova, Maria Denev, Petko Kratchanov, Christo Polasa, Kalpagam D'Agostini, Francesco Steele, Vernon E. De Flora, Silvio TI Inhibition of lung tumor development by berry extracts in mice exposed to cigarette smoke SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE berries; cigarette smoke; chemoprevention; lung tumors ID LYOPHILIZED BLACK-RASPBERRIES; FREEZE-DRIED STRAWBERRIES; CANCER PREVENTION; TOBACCO-SMOKE; COLON-CANCER; ESOPHAGEAL TUMORIGENESIS; INTESTINAL TUMORIGENESIS; MAMMARY TUMORIGENESIS; ESTROGEN METABOLISM; APC(MIN) MICE AB Cigarette smoke (CS) and dietary factors play a major role in cancer epidemiology. At the same time, however, the diet is the richest source of anticancer agents. Berries possess a broad array of health protective properties and were found to attenuate the yield of tumors induced by individual carcinogens in the rodent digestive tract and mammary gland but failed to prevent lung tumors induced by typical CS components in mice. We exposed whole-body Swiss ICR mice to mainstream CS, starting at birth and continuing daily for 4 months. Aqueous extracts of black chokeberry and strawberry were given as the only source of drinking water, starting after weaning and continuing for 7 months, thus mimicking an intervention in current smokers. In the absence of berries, CS caused a loss of body weight, induced early cytogenetical damage in circulating erythrocytes and histopathological alterations in lung (emphysema, blood vessel proliferation, alveolar epithelial hyperplasia and adenomas), liver (parenchymal degeneration) and urinary bladder (epithelial hyperplasia). Both berry extracts inhibited the CS-related body weight loss, cytogenetical damage, liver degeneration, pulmonary emphysema and lung adenomas. Protective effects were more pronounced in female mice, which may be ascribed to modulation by berry components of the metabolism of estrogens implicated in lung carcinogenesis. Interestingly, both the carcinogen and the chemopreventive agents tested are complex mixtures that contain a multitude of components working through composite mechanisms. C1 [Balansky, Roumen; D'Agostini, Francesco; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta] Natl Oncol Ctr, BU-1157 Sofia, Bulgaria. [Kratchanova, Maria; Denev, Petko; Kratchanov, Christo] Bulgarian Acad Sci, Ctr Phytochem, Inst Organ Chem, Plovdiv, Bulgaria. [Polasa, Kalpagam] Natl Inst Nutr, Food & Drug Toxicol Ctr, Hyderabad 500007, Andhra Pradesh, India. [Steele, Vernon E.] NCI, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it RI Denev, Petko/I-7274-2012 FU Bulgarian Ministry of Education, Youth and Science (National Research Fund), Bulgarian Innovation Fund [IF-02-66/2007]; US National Cancer Institute [N01-CN53301] FX Grant sponsor: The Bulgarian Ministry of Education, Youth and Science (National Research Fund), Bulgarian Innovation Fund; Grant number: IF-02-66/2007; Grant sponsor: The US National Cancer Institute; Grant number: N01-CN53301 NR 49 TC 17 Z9 17 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV 1 PY 2012 VL 131 IS 9 BP 1991 EP 1997 DI 10.1002/ijc.27486 PG 7 WC Oncology SC Oncology GA 993XP UT WOS:000307893600005 PM 22328465 ER PT J AU Persson, EC Graubard, BI Evans, AA London, WT Weber, JP LeBlanc, A Chen, G Lin, WY McGlynn, KA AF Persson, E. Christina Graubard, Barry I. Evans, Alison A. London, W. Thomas Weber, Jean-Philippe LeBlanc, Alain Chen, Gang Lin, Wenyao McGlynn, Katherine A. TI Dichlorodiphenyltrichloroethane and risk of hepatocellular carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE DDT; DDE; hepatocellular carcinoma; cohort study; China; epidemiology ID ORGANOCHLORINE PESTICIDES; ANDROGEN RECEPTOR; CANCER INCIDENCE; LIVER-CANCER; BREAST-MILK; HAIMEN-CITY; CF-1 MICE; FOLLOW-UP; DDT; CHINA AB Dichlorodiphenyltrichloroethane (p,p'-DDT), an organochlorine pesticide known to have deleterious health effects in humans, has been linked to hepatocellular carcinoma (HCC) in rodents. A recent study has reported that p,p'-DDT and its most persistent metabolite, dichlorodiphenyldichloroethylene (p,p'-DDE), may also be associated with HCC in humans. To examine whether there is an association between p,p'-DDT and/or p,p'-DDE in a population at high-risk of developing HCC, a nested casecontrol study was conducted within the 83,794 person Haimen City Cohort in China. Sera and questionnaire data were collected from all participants between 1992 and 1993. This study included 473 persons who developed HCC and 492 who did not, frequency matched on sex, age and area of residence. p,p'-DDT and p,p'-DDE levels were determined by mass spectrometry. Hepatitis B viral infection status (based on hepatitis B virus surface antigen; HBsAg) was also determined. p,p'-DDT and/or p,p'-DDE serum levels were significantly associated with sex, area of residence, occupation, alcohol consumption and cigarette smoking. Adjusting for age, sex, area of residence, HBsAg, family history of HCC, history of acute hepatitis, smoking, alcohol, occupation (farmer vs. other) and levels of p,p'-DDT or p,p'-DDE, odds ratios (OR) and 95% confidence intervals (CI) were calculated via unconditional logistic regression. Overall, the highest quintile of p,p'-DDT was associated with an increased risk of HCC, OR = 2.96 95% CI; 1.197.40. There were no statistically significant associations with p,p'-DDE. Overall, these results suggest that recent exposure to p,p'-DDT may increase risk of HCC. C1 [Persson, E. Christina] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. [Evans, Alison A.] Drexel Sch Publ Hlth, Philadelphia, PA USA. [Evans, Alison A.; Chen, Gang] Hepatitis B Fdn, Doylestown, PA USA. [London, W. Thomas] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Weber, Jean-Philippe; LeBlanc, Alain] Inst Natl Sante Publ Quebec, Quebec City, PQ, Canada. [Lin, Wenyao] Haimen City Ctr Dis Control, Haimen City, Peoples R China. RP Persson, EC (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS Suite 550,Room 5008, Rockville, MD 20852 USA. EM christina.persson@nih.gov RI Evans, Alison/I-4970-2013 FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX Grant sponsors: Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services NR 37 TC 13 Z9 13 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV 1 PY 2012 VL 131 IS 9 BP 2078 EP 2084 DI 10.1002/ijc.27459 PG 7 WC Oncology SC Oncology GA 993XP UT WOS:000307893600014 PM 22290210 ER PT J AU Kalra, N Zhang, JL Yu, YK Ho, M Merino, M Cao, L Hassan, R AF Kalra, Neetu Zhang, Jingli Yu, Yunkai Ho, Mitchell Merino, Maria Cao, Liang Hassan, Raffit TI Efficacy of anti-insulin-like growth factor I receptor monoclonal antibody cixutumumab in mesothelioma is highly correlated with insulin growth factor-I receptor sites/cell SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE malignant mesothelioma; IGF-IR; cixutumumab; ADCC; pleural mesothelioma ID MALIGNANT PLEURAL MESOTHELIOMA; CELL-LINES; PHASE-II; INHIBITION; PATHWAY; COMBINATION; CISPLATIN; CETUXIMAB; IMC-A12; IGF-1R AB Insulin growth factor-I receptor (IGF-IR) is expressed in mesothelioma and therefore an attractive target for therapy. The antitumor activity of cixutumumab, a humanized monoclonal antibody to IGF-IR, in mesothelioma and relationship to IGF-IR expression was investigated using eight early passage tumor cells obtained from patients, nine established cell lines and an in vivo human mesothelioma tumor xenograft model. Although IGF-IR expression at the mRNA and protein level was present in all mesothelioma cells, using a quantitative ELISA immunoassay, there was considerable variability of IGF-IR expression ranging from 1 to 14 ng/mg of lysate. Using flow cytometry, the number of IGF-IR surface receptors varied from similar to 2,000 to 50,000 sites/cell. Cells expressing >10,000 sites/cell had greater than 10% growth inhibition when treated with cixutumumab (100 mu g/ml). Cixutumumab also induced antibody-dependent cell-mediated toxicity (>10% specific lysis) in cell lines, which had >20,000 IGF-IR sites/cell. Treatment with cixutumumab decreased phosphorylation of IGF-IR, Akt and Erk in cell lines, H226 and H28 having 24,000 and 51,000 IGF-IR sites/cell, respectively, but not in the cell line H2052 with 3,000 IGF-IR sites/cell. In vivo, cixutumumab treatment delayed growth of H226 mesothelioma tumor xenografts in mice and improved the overall survival of these mice compared to mice treated with saline (p < 0.004). Our results demonstrate that the antitumor efficacy of cixutumumab including inhibition of IGF-IR downstream signaling is highly correlated with IGF-IR sites/cell. A phase II clinical trial of cixutumumab is currently ongoing for the treatment of patients with mesothelioma. C1 [Kalra, Neetu; Zhang, Jingli; Ho, Mitchell; Hassan, Raffit] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Yunkai; Cao, Liang] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merino, Maria] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research NR 25 TC 14 Z9 16 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV 1 PY 2012 VL 131 IS 9 BP 2143 EP 2152 DI 10.1002/ijc.27471 PG 10 WC Oncology SC Oncology GA 993XP UT WOS:000307893600021 PM 22323052 ER PT J AU Chang, CM Landgren, O Koshiol, J Bjorkholm, M Love, TJ Kristinsson, SY AF Chang, Cindy M. Landgren, Ola Koshiol, Jill Bjoerkholm, Magnus Loeve, Thorvardur J. Kristinsson, Sigurdur Y. TI Borrelia and subsequent risk of solid tumors and hematologic malignancies in Sweden SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID B-CELL LYMPHOMA; INFECTION C1 [Chang, Cindy M.; Koshiol, Jill] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Rockville, MD USA. [Landgren, Ola] NCI, Metab Branch, Ctr Canc Res, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Bjoerkholm, Magnus; Kristinsson, Sigurdur Y.] Karolinska Univ Hosp Solna, Div Hematol, Dept Med, Stockholm, Sweden. [Loeve, Thorvardur J.] Landspitali Univ Hosp, Reykjavik, Iceland. RP Chang, CM (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Rockville, MD USA. RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Intramural NIH HHS NR 5 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV 1 PY 2012 VL 131 IS 9 BP 2208 EP 2209 DI 10.1002/ijc.27483 PG 2 WC Oncology SC Oncology GA 993XP UT WOS:000307893600029 PM 22322900 ER PT J AU Choi, KY Saravanakumar, G Park, JH Park, K AF Choi, Ki Young Saravanakumar, Gurusamy Park, Jae Hyung Park, Kinam TI Hyaluronic acid-based nanocarriers for intracellular targeting: Interfacial interactions with proteins in cancer SO COLLOIDS AND SURFACES B-BIOINTERFACES LA English DT Article DE Hyaluronic acid; Tumor targeting; Intracellular targeting; Nanocarrier; Drug delivery; Tumor imaging ID RECEPTOR-MEDIATED ENDOCYTOSIS; HUMAN BREAST-CANCER; ANCHORAGE-INDEPENDENT GROWTH; TUMOR-DERIVED HYALURONIDASE; CD44 SPLICE VARIANTS; IN-VIVO; DRUG-DELIVERY; PROSTATE-CANCER; BLADDER-CANCER; EXTRACELLULAR-MATRIX AB The therapeutic efficacy of most drugs is greatly depends on their ability to cross the cellular barrier and reach their intracellular target sites. To transport the drugs effectively through the cellular membrane and to deliver them into the intracellular environment, several interesting smart carrier systems based on both synthetic or natural polymers have been designed and developed. In recent years, hyaluronic acid (HA) has emerged as a promising candidate for intracellular delivery of various therapeutic and imaging agents because of its innate ability to recognize specific cellular receptors that overexpressed on diseased cells. The aim of this review is to highlight the significance of HA in cancer, and to explore the recent advances of HA-based drug carriers towards cancer imaging and therapeutics. (C) 2011 Elsevier B.V. All rights reserved. C1 [Park, Kinam] Purdue Univ, Weldon Sch Biomed Engn, Dept Biomed Engn, W Lafayette, IN 47907 USA. [Choi, Ki Young; Park, Kinam] Purdue Univ, Dept Pharmaceut, W Lafayette, IN 47907 USA. [Choi, Ki Young] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Saravanakumar, Gurusamy; Park, Jae Hyung] Sungkyunkwan Univ, Dept Polymer Sci & Engn, Suwon 440746, South Korea. RP Park, K (reprint author), Purdue Univ, Weldon Sch Biomed Engn, Dept Biomed Engn, 2065 S Martin Jischke Dr, W Lafayette, IN 47907 USA. EM kpark@purdue.edu RI byun, jaehyun/G-5584-2014; CHOI, KI YOUNG/Q-7177-2016 FU NIH [CA129287]; Showalter Trust Research Trust Fund FX This study was supported in part by the grant from NIH (CA129287) and Showalter Trust Research Trust Fund. NR 165 TC 79 Z9 83 U1 10 U2 73 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7765 J9 COLLOID SURFACE B JI Colloid Surf. B-Biointerfaces PD NOV 1 PY 2012 VL 99 SI SI BP 82 EP 94 DI 10.1016/j.colsurfb.2011.10.029 PG 13 WC Biophysics; Chemistry, Physical; Materials Science, Biomaterials SC Biophysics; Chemistry; Materials Science GA 990FG UT WOS:000307615800012 PM 22079699 ER PT J AU Fang, EF Zhang, CZY Wong, JH Shen, JY Li, CH Ng, TB AF Fang, Evandro Fei Zhang, Chris Zhi Yi Wong, Jack Ho Shen, Jia Yun Li, Chuan Hao Ng, Tzi Bun TI The MAP30 protein from bitter gourd (Momordica charantia) seeds promotes apoptosis in liver cancer cells in vitro and in vivo SO CANCER LETTERS LA English DT Article DE MAP30; Bitter gourd; Momordica charantia; Hepatocellular carcinoma; Apoptosis ID RIBOSOME-INACTIVATING PROTEINS; ANTI-HIV; HEPATOCELLULAR-CARCINOMA; ANTITUMOR-ACTIVITY; RECOMBINANT MAP30; GAP31; MELON; PROLIFERATION; INHIBITION; EXPRESSION AB Human hepatocellular carcinoma Hop G2 cells and Hep G2-bearing mice were used as in vitro and in vivo models to assess the efficacy and safety of MAP30, a natural component from Momordica charantia, as an anticancer agent against liver cancer. Molecular studies disclosed the contribution of both caspase-8 regulated extrinsic and caspase-9 regulated intrinsic caspase cascades in MAP30-induced cell apoptosis. The antitumor potential was also effective in Hep G2-bearing nude mice. Since bitter gourd is a staple in many Asian countries, MAP30 would serve as a novel and relatively safe agent for prophylaxis and treatment of liver cancer. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Fang, Evandro Fei; Wong, Jack Ho; Ng, Tzi Bun] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Zhang, Chris Zhi Yi] Sun Yat Sen Univ, State Key Lab Oncol So China, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Zhang, Chris Zhi Yi] Sun Yat Sen Univ, Ctr Canc, Dept Pathol, Guangzhou 510275, Guangdong, Peoples R China. [Shen, Jia Yun] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China. [Shen, Jia Yun] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Li, Chuan Hao] Chinese Univ Hong Kong, Fac Sci, Dept Chem, Hong Kong, Hong Kong, Peoples R China. RP Ng, TB (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM b021770@mailserv.cuhk.edu.hk RI Li, Chuanhao/B-2193-2016 NR 42 TC 24 Z9 30 U1 1 U2 29 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD NOV 1 PY 2012 VL 324 IS 1 BP 66 EP 74 DI 10.1016/j.canlet.2012.05.005 PG 9 WC Oncology SC Oncology GA 987MC UT WOS:000307420200007 PM 22579806 ER PT J AU Lupu-Meiri, M Geras-Raaka, E Lupu, R Shapira, H Sandbank, J Segal, L Gershengorn, MC Oron, Y AF Lupu-Meiri, Monica Geras-Raaka, Elizabeth Lupu, Ruth Shapira, Hagit Sandbank, Judith Segal, Liora Gershengorn, Marvin C. Oron, Yoram TI Knock-down of plasminogen-activator inhibitor-1 enhances expression of E-cadherin and promotes epithelial differentiation of human pancreatic adenocarcinoma cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID UROKINASE RECEPTOR; BREAST-CANCER; MESENCHYMAL TRANSITION; IN-VIVO; TUMOR; TARGET; GROWTH; PROGRESSION; METASTASIS; CARCINOMA AB High levels of plasminogen activator inhibitor-1 (PAI-1), which is produced by stromal, endothelial, and cancer cells and has multiple complex effects on cancers, correlate with poor cancer prognosis. To more definitively study the role of endogenously produced PAI-1 in human pancreatic adenocarcinoma (PAC) PANC-1 cell line biology, we used anti-PAI-1 shRNA to create stable PAI-1 deficient cells (PD-PANC-1s). PD-PANC-1s exhibited a heterogeneous morphology. While the majority of cells exhibited a cuboidal shape similar to the parental PANC-1 or the vector-infected control cells, numerous large cells with long filopodia and a neuronal-like appearance were observed. Although both Vector-control cells and PD-PANC-1s expressed mRNAs that are characteristic of mesenchymal, neural, and epithelial phenotypes, epithelial marker RNAs were up-regulated (e.g., E-cadherin, 32-fold) whereas mesenchymal marker RNAs were down-regulated (e.g., Thy1, ninefold) in PD-PANC-1s, suggesting mesenchymal-to-epithelial transition. Neural markers exhibited both up- and down-regulation. Immunocytochemistry indicated that epithelial-like PD-PANC-1s expressed E-cadherin and beta-catenin in significantly more cells, while neural-like cells exhibited robust expression of organized beta-3-tubulin. PAI-1 and E-cadherin were rarely co-expressed in the same cells. Indeed, examination of PAI-1 and E-cadherin mRNAs expression in additional cell lines yielded clear inverse correlation. Indeed, infection of Colo357 PAC cells (that exhibit high expression of E-cadherin) with PAI-1-expressing adenovirus led to a marked decrease in E-cadherin expression and to enhanced migration of cells from clusters. Our results suggest that endogenous PAI-1 suppresses expression of E-cadherin and differentiation in PAC cells in vitro, supporting its negative impact on tumor prognosis. J. Cell. Physiol. 227: 36213628, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Lupu-Meiri, Monica; Segal, Liora; Oron, Yoram] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. [Geras-Raaka, Elizabeth; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Lupu, Ruth] Mayo Clin, Div Expt Pathol & Lab Med, Rochester, MN 55905 USA. [Shapira, Hagit; Sandbank, Judith] Maccabi, Inst Pathol, Cent Lab, IL-76703 Rehovot, Israel. [Sandbank, Judith] Assaf Harofe Hosp, Inst Pathol, IL-70300 Zerifin, Israel. [Sandbank, Judith] Tel Aviv Univ, Sackler Fac Med, Dept Pathol, IL-69978 Ramat Aviv, Israel. RP Oron, Y (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. EM medfair@post.tau.ac.il FU Intramural NIH HHS [ZIA DK011007-11] NR 29 TC 3 Z9 3 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD NOV PY 2012 VL 227 IS 11 BP 3621 EP 3628 DI 10.1002/jcp.24068 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 976UD UT WOS:000306610200011 PM 22331587 ER PT J AU Hudson, TS Carlson, BA Hoeneroff, MJ Young, HA Sordillo, L Muller, WJ Hatfield, DL Green, JE AF Hudson, Tamaro S. Carlson, Bradley A. Hoeneroff, Mark J. Young, Heather A. Sordillo, Lorraine Muller, William J. Hatfield, Dolph L. Green, Jeffrey E. TI Selenoproteins reduce susceptibility to DMBA-induced mammary carcinogenesis SO CARCINOGENESIS LA English DT Article ID CANCER PREVENTION; BREAST-CANCER; GLUTATHIONE PEROXIDASE-1; SELENIUM BIOCHEMISTRY; THIOREDOXIN REDUCTASE; PROSTATE-CANCER; ALLELIC LOSS; EXPRESSION; CHEMOPREVENTION; SELENOCYSTEINE AB Selenium is an essential micronutrient in the diet of humans and other mammals. Based largely on animal studies and epidemiological evidence, selenium is purported to be a promising cancer chemopreventive agent. However, the biological mechanisms by which chemopreventive activity takes place are poorly understood. It remains unclear whether selenium acts in its elemental form, through incorporation into organic compounds, through selenoproteins or any combination of these. The purpose of this study was to determine whether selenoproteins mitigate the risk of developing chemically induced mammary cancer. Selenoprotein expression was ablated in mouse mammary epithelial cells through genetic deletion of the selenocysteine (Sec) tRNA gene (Try), whose product, designated selenocysteine tRNA, is required for selenoprotein translation. Try foxed and mouse mammary tumor virus (MMTV)-cre mice were crossed to achieve tissue-specific excision of Trsp in targeted mammary glands. Eight- to twelve-week-old second generation Trsp(fi+);wt., Trspft(/+;)MMTV-cre, Trsp(fl/fl) and Trsp(fl/fl);MMTV-cre female mice were administered standard doses of the carcinogen, 7,12-dimethylbenzylbenz[a]antracene. Our results revealed that heterozygous, Trsp(fl+);MMTV-cre mice showed no difference in tumor incidence, tumor rate and survival compared with the Trsplu+;wt mice. However, 54.8% of homozygous Trsp(fl/fl);MMTV-cre mice developed mammary tumors and exhibited significantly shorter survival than the corresponding Trsp(fi/fl);wt mice, where only 36.4% developed tumors. Loss of the homozygous Trsp alleles was associated with the reduction of selenoprotein expression. The results suggest that mice with reduced selenoprotein expression have increased susceptibility to developing carcinogen-induced mammary tumors and that a major protective mechanism against carcinogen-induced mammary cancer requires the expression of these selenoproteins. C1 [Green, Jeffrey E.] NCI, Transgen Oncogenesis & Genom Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Sect Mol Biol Selenium, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. [Hoeneroff, Mark J.] NIEHS, Natl Toxicol Program, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Young, Heather A.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC 20037 USA. [Sordillo, Lorraine] Michigan State Univ, Coll Vet Med, Ctr Vet Med, E Lansing, MI 48824 USA. [Muller, William J.] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada. RP Green, JE (reprint author), NCI, Transgen Oncogenesis & Genom Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM jegreen@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This study was funded by the intramural research program of NIH, National Cancer Institute, Center for Cancer Research. NR 49 TC 13 Z9 13 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2012 VL 33 IS 6 BP 1225 EP 1230 DI 10.1093/carcin/bgs129 PG 6 WC Oncology SC Oncology GA 970MW UT WOS:000306135800014 PM 22436612 ER PT J AU Burghardt, PR Love, TM Stohler, CS Hodgkinson, C Shen, PH Enoch, MA Goldman, D Zubieta, JK AF Burghardt, Paul R. Love, Tiffany M. Stohler, Christian S. Hodgkinson, Colin Shen, Pei-Hong Enoch, Mary-Anne Goldman, David Zubieta, Jon-Kar TI Leptin Regulates Dopamine Responses to Sustained Stress in Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL FRONTAL-CORTEX; VISUAL FOOD STIMULI; NUCLEUS-ACCUMBENS; INTRAVENTRICULAR INSULIN; AFFECTIVE DIMENSIONS; CONTINUOUS-INFUSION; STRIATAL RESPONSE; MUSCLE PAIN; HUMAN BRAIN; REWARD AB Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [C-11]raclopride PET at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of dopamine release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance-use disorders, eating disorders, and obesity. C1 [Burghardt, Paul R.; Love, Tiffany M.; Zubieta, Jon-Kar] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Burghardt, Paul R.; Zubieta, Jon-Kar] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Zubieta, Jon-Kar] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Hodgkinson, Colin; Shen, Pei-Hong; Enoch, Mary-Anne; Goldman, David] NIAAA, NIH, Bethesda, MD 20892 USA. [Stohler, Christian S.] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. RP Burghardt, PR (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, 209 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM pburghar@umich.edu RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Love, Tiffany/0000-0001-9299-3190 FU NIDA [R01 DA 016423, R01 DA 022520, UL1RR024986]; NIAAA Intramural Program FX This work was supported by NIDA Grants R01 DA 016423, R01 DA 022520, and UL1RR024986 and the NIAAA Intramural Program. We thank the technologists in the PET center in the Department of Nuclear Medicine at the University of Michigan for their contribution to this work. NR 70 TC 19 Z9 19 U1 3 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 OCT 31 PY 2012 VL 32 IS 44 BP 15369 EP 15376 DI 10.1523/JNEUROSCI.2521-12.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 030LY UT WOS:000310573400014 PM 23115175 ER PT J AU Murase, S Kim, E Lin, L Hoffman, DA McKay, RD AF Murase, Sachiko Kim, Eunyoung Lin, Lin Hoffman, Dax A. McKay, Ronald D. TI Loss of Signal Transducer and Activator of Transcription 3 (STAT3) Signaling during Elevated Activity Causes Vulnerability in Hippocampal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HOMEOSTATIC SYNAPTIC PLASTICITY; SERINE PHOSPHORYLATION; TYROSINE PHOSPHORYLATION; KINASE; PROTEIN; SURVIVAL; COMPLEX; DEATH; CREB; NEUROPROTECTION AB Chronically altered levels of network activity lead to changes in the morphology and functions of neurons. However, little is known of how changes in neuronal activity alter the intracellular signaling pathways mediating neuronal survival. Here, we use primary cultures of rat hippocampal neurons to show that elevated neuronal activity impairs phosphorylation of the serine/threonine kinase, Erk1/2, and the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation of serine 727. Chronically stimulated neurons go through apoptosis when they fail to activate another serine/threonine kinase, Akt. Gain-and loss-of-function experiments show that STAT3 plays the key role directly downstream from Erk1/2 as the alternative survival pathway. Elevated neuronal activity resulted in increased expression of a tumor suppressor, p53, and its target gene, Bax. These changes are observed in Kv4.2 knock-out mouse hippocampal neurons, which are also sensitive to the blockade of TrkB signaling, confirming that the alteration occurs in vivo. Thus, this study provides new insight into a mechanism by which chronic elevation of activity may cause neurodegeneration. C1 [Murase, Sachiko; McKay, Ronald D.] NINDS, Lab Mol Biol, Bethesda, MD 20892 USA. [Kim, Eunyoung; Lin, Lin; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [McKay, Ronald D.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP Murase, S (reprint author), NINDS, Lab Mol Biol, Bethesda, MD 20892 USA. EM sachikom@ninds.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU National Institute of Neurological Disorders and Stroke-National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke-National Institutes of Health. We thank Dr. Yukiko Gotoh for wild-type and mutant STAT3 IRES EGFP/pMX plasmids. NR 55 TC 9 Z9 12 U1 0 U2 2 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 OCT 31 PY 2012 VL 32 IS 44 BP 15511 EP 15520 DI 10.1523/JNEUROSCI.2940-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 030LY UT WOS:000310573400027 PM 23115188 ER PT J AU Allen, M Dietz, M Blair, KS van Beek, M Rees, G Vestergaard-Poulsen, P Lutz, A Roepstorff, A AF Allen, Micah Dietz, Martin Blair, Karina S. van Beek, Martijn Rees, Geraint Vestergaard-Poulsen, Peter Lutz, Antoine Roepstorff, Andreas TI Cognitive-Affective Neural Plasticity following Active-Controlled Mindfulness Intervention SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SHORT-TERM MEDITATION; SOCIAL SUPPORT; COMPASSION MEDITATION; ANTERIOR CINGULATE; DEFAULT NETWORK; WORKING-MEMORY; ATTENTION; METAANALYSIS; EXPERIENCE; AWARENESS AB Mindfulness meditation is a set of attention-based, regulatory, and self-inquiry training regimes. Although the impact of mindfulness training (MT) on self-regulation is well established, the neural mechanisms supporting such plasticity are poorly understood. MT is thought to act through interoceptive salience and attentional control mechanisms, but until now conflicting evidence from behavioral and neural measures renders difficult distinguishing their respective roles. To resolve this question we conducted a fully randomized 6 week longitudinal trial of MT, explicitly controlling for cognitive and treatment effects with an active-control group. We measured behavioral metacognition and whole-brain blood oxygenation level-dependent (BOLD) signals using functional MRI during an affective Stroop task before and after intervention in healthy human subjects. Although both groups improved significantly on a response-inhibition task, only the MT group showed reduced affective Stroop conflict. Moreover, the MT group displayed greater dorsolateral prefrontal cortex responses during executive processing, consistent with increased recruitment of top-down mechanisms to resolve conflict. In contrast, we did not observe overall group-by-time interactions on negative affect-related reaction times or BOLD responses. However, only participants with the greatest amount of MT practice showed improvements in response inhibition and increased recruitment of dorsal anterior cingulate cortex, medial prefrontal cortex, and right anterior insula during negative valence processing. Our findings highlight the importance of active control in MT research, indicate unique neural mechanisms for progressive stages of mindfulness training, and suggest that optimal application of MT may differ depending on context, contrary to a one-size-fits-all approach. C1 [Allen, Micah; Dietz, Martin; Vestergaard-Poulsen, Peter; Roepstorff, Andreas] Aarhus Univ, Ctr Functionally Integrat Neurosci, MINDLab, DK-8000 Aarhus, Denmark. [Blair, Karina S.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [van Beek, Martijn; Roepstorff, Andreas] Aarhus Univ, Interacting Minds Ctr, DK-8000 Aarhus, Denmark. [Rees, Geraint] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Lutz, Antoine] Univ Wisconsin, Waisman Lab Brain Imaging & Behav, Madison, WI 53705 USA. [Lutz, Antoine] Univ Lyon 1, CNRS, Lyon Neurosci Res Ctr, INSERM,U1028,UMR5292, F-69365 Lyon, France. RP Allen, M (reprint author), Aarhus Univ Hosp, Ctr Functionally Integrat Neurosci, Norrebrogade 44,Bldg 10G,5th Floor, DK-8000 Aarhus C, Denmark. EM micah@cfin.dk RI Rees, Geraint/C-1493-2008; LUTZ, Antoine/E-2197-2015; OI Rees, Geraint/0000-0002-9623-7007; LUTZ, Antoine/0000-0002-0258-3233; Allen, Micah/0000-0001-9399-4179 FU ViFAB (Knowledge and Research Center for Alternative Medicine), Ministry of Health, Denmark; National Center for Complementary and Alternative Medicine [P01-AT004952]; Adam J. Weissman Foundation; Velux Foundation; Wellcome Trust [082334]; MINDlab Investment Capital for University Research fund FX This work was supported by a grant from ViFAB (Knowledge and Research Center for Alternative Medicine), Ministry of Health, Denmark, project "Mechanisms of mindfulness training," by grants from the National Center for Complementary and Alternative Medicine (P01-AT004952) and the Adam J. Weissman Foundation (A. L.), by the Velux Foundation (Technologies of the Mind; A. R., M. v. B.), and by a grant from the Wellcome Trust (082334; G. R.). The authors acknowledge the support of the MINDlab Investment Capital for University Research fund. We thank Torben Lund, Christian Gaden Jensen, Ryota Kanai, Chris Frith, and Uta Frith for helpful discussions on the design, analysis, and manuscript. We also thank Mette Steenberg, Karsten Skipper, and Hannah Jakobsen for running the reading and meditation courses. We are deeply grateful to our contemplative collaborators, Jes Bertelsen and Michael Stubberup, whose guidance on the content and aims of meditation training informed this research. NR 55 TC 71 Z9 71 U1 24 U2 126 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 OCT 31 PY 2012 VL 32 IS 44 BP 15601 EP 15610 DI 10.1523/JNEUROSCI.2957-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 030LY UT WOS:000310573400034 PM 23115195 ER PT J AU Provencal, N Suderman, MJ Guillemin, C Massart, R Ruggiero, A Wang, DS Bennett, AJ Pierre, PJ Friedman, DP Cote, SM Hallett, M Tremblay, RE Suomi, SJ Szyf, M AF Provencal, Nadine Suderman, Matthew J. Guillemin, Claire Massart, Renaud Ruggiero, Angela Wang, Dongsha Bennett, Allyson J. Pierre, Peter J. Friedman, David P. Cote, Sylvana M. Hallett, Michael Tremblay, Richard E. Suomi, Stephen J. Szyf, Moshe TI The Signature of Maternal Rearing in the Methylome in Rhesus Macaque Prefrontal Cortex and T Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NONHUMAN PRIMATE MODEL; DIFFERENTIAL DNA METHYLATION; EARLY-LIFE STRESS; SOCIOECONOMIC POSITION; ADVERSE EXPERIENCES; MICROARRAY DATA; BRAIN STRUCTURE; CANCER-CELLS; COPY-NUMBER; GENE AB Early-life adversity is associated with a broad scope of life-long health and behavioral disorders. Particularly critical is the role of the mother. A possible mechanism is that these effects are mediated by "epigenetic" mechanisms. Studies in rodents suggest a causal relationship between early-life adversity and changes in DNA methylation in several "candidate genes" in the brain. This study examines whether randomized differential rearing (maternal vs surrogate-peer rearing) of rhesus macaques is associated with differential methylation in early adulthood. The data presented here show that differential rearing leads to differential DNA methylation in both prefrontal cortex and T cells. These differentially methylated promoters tend to cluster by both chromosomal region and gene function. The broad impact of maternal rearing on DNA methylation in both the brain and T cells supports the hypothesis that the response to early-life adversity is system-wide and genome-wide and persists to adulthood. Our data also point to the feasibility of studying the impact of the social environment in peripheral T-cell DNA methylation. C1 [Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Provencal, Nadine; Suderman, Matthew J.; Guillemin, Claire; Szyf, Moshe] McGill Univ, Sackler Program Epigenet & Dev Psychobiol, Montreal, PQ H3A 0G4, Canada. [Provencal, Nadine; Suderman, Matthew J.; Guillemin, Claire; Massart, Renaud; Wang, Dongsha; Szyf, Moshe] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3A 0G4, Canada. [Suderman, Matthew J.; Hallett, Michael] McGill Univ, McGill Ctr Bioinformat, Montreal, PQ H3A 0G4, Canada. [Provencal, Nadine; Guillemin, Claire; Wang, Dongsha; Cote, Sylvana M.; Tremblay, Richard E.] Univ Montreal, Res Unit Childrens Psychosocial Maladjustment, Montreal, PQ H3C 3J7, Canada. [Provencal, Nadine; Guillemin, Claire; Wang, Dongsha; Cote, Sylvana M.; Tremblay, Richard E.] Univ Montreal, St Justine Hosp Res Ctr, Montreal, PQ H3C 3J7, Canada. [Cote, Sylvana M.] Univ Montreal, Sch Social & Prevent Med, Montreal, PQ H3C 3J7, Canada. [Tremblay, Richard E.] Univ Montreal, Dept Psychol & Pediat, Montreal, PQ H3C 3J7, Canada. [Tremblay, Richard E.] Natl Univ Ireland Univ Coll Dublin, Sch Publ Hlth Physiotherapy & Populat Sci, Dublin 4, Ireland. [Pierre, Peter J.] Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Behav Management Unit, Madison, WI 53715 USA. [Bennett, Allyson J.] Univ Wisconsin, Psychol Dept, Madison, WI 53715 USA. [Bennett, Allyson J.] Univ Wisconsin, Harlow Ctr Biol Psychol, Madison, WI 53715 USA. [Bennett, Allyson J.; Pierre, Peter J.; Friedman, David P.] Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. RP Suomi, SJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM suomis@lce.nichd.nih.gov; moshe.szyf@mcgill.ca RI Tremblay, Richard/O-1360-2014; Cote, Silvana Maria/O-1356-2014 FU Canadian Institute of Health Research; McGill University; European Research Area Neuron Network; Division of Intramural Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development; National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health; FRSQ FX This work was supported by a grant from the Canadian Institute of Health Research (M. S.), the Sackler Program in Psychobiology and Epigenetics at McGill University (M. S.), a grant from the European Research Area Neuron Network (M. S.), and by funds from the Division of Intramural Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development (S.J.S.) and National Institute on Alcohol Abuse and Alcoholism (D. P. F.), National Institutes of Health. M. S. and S.J.S. are fellows of the Canadian Institute for Advanced Research. N.P. was supported by a grant to R. E. T. from the Canadian Institute of Health Research. C. G. and D. W. were supported by grants to S. M. C. from FRSQ. NR 92 TC 114 Z9 116 U1 2 U2 39 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 OCT 31 PY 2012 VL 32 IS 44 BP 15626 EP 15642 DI 10.1523/JNEUROSCI.1470-12.2012 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 030LY UT WOS:000310573400036 PM 23115197 ER PT J AU Wong, G Richardson, JS Pillet, S Patel, A Qiu, XG Alimonti, J Hogan, J Zhang, Y Takada, A Feldmann, H Kobinger, GP AF Wong, Gary Richardson, Jason S. Pillet, Stephane Patel, Ami Qiu, Xiangguo Alimonti, Judie Hogan, Jeff Zhang, Yi Takada, Ayato Feldmann, Heinz Kobinger, Gary P. TI Immune Parameters Correlate with Protection Against Ebola Virus Infection in Rodents and Nonhuman Primates SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID EQUINE ENCEPHALITIS-VIRUS; CYTOTOXIC T-LYMPHOCYTES; VACCINE PROTECTS; GUINEA-PIGS; HEMORRHAGIC-FEVER; RECOMBINANT ADENOVIRUSES; MONOCLONAL-ANTIBODIES; CELL RESPONSES; TH2 RESPONSES; IMMUNIZATION AB Ebola virus causes severe hemorrhagic fever in susceptible hosts. Currently, no licensed vaccines or treatments are available; however, several experimental vaccines have been successful in protecting rodents and nonhuman primates (NHPs) from the lethal Zaire ebolavirus (ZEBOV) infection. The objective of this study was to evaluate immune responses correlating with survival in these animals after lethal challenge with ZEBOV. Knockout mice with impaired ability to generate normal T and/or B cell responses were vaccinated and challenged with ZEBOV. Vaccine-induced protection in mice was mainly mediated by B cells and CD4(+) T cells. Vaccinated, outbred guinea pigs and NHPs demonstrated the highest correlation between survival and levels of total immunoglobulin G (IgG) specific to the ZEBOV glycoprotein (ZGP). These results highlight the relevance of total ZGP-specific IgG levels as a meaningful correlate of protection against ZEBOV exposure. C1 [Wong, Gary; Richardson, Jason S.; Pillet, Stephane; Patel, Ami; Qiu, Xiangguo; Alimonti, Judie; Kobinger, Gary P.] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB R3E 3R2, Canada. [Wong, Gary; Patel, Ami; Feldmann, Heinz; Kobinger, Gary P.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J9, Canada. [Hogan, Jeff] Univ Georgia, Dept Anat & Radiol, Dept Infect Dis, Athens, GA 30602 USA. [Zhang, Yi] Univ Michigan, Dept Immunol, Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Takada, Ayato] Hokkaido Univ, Div Global Epidemiol, Res Ctr Zoonosis Control, Sapporo, Hokkaido 0010020, Japan. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Kobinger, Gary P.] Univ Manitoba, Dept Immunol, Winnipeg, MB R3E 0T5, Canada. RP Kobinger, GP (reprint author), Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB R3E 3R2, Canada. EM gary_kobinger@phac-aspc.gc.ca RI Takada, Ayato/A-6679-2012 FU PHAC; Chemical, Biological, Radiological and Nuclear Research and Technology Initiative; Japan Initiative for Global Research Network on Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology; Canadian Institute for Health Research FX Funding: This research was supported by the PHAC and funded by a grant from the Chemical, Biological, Radiological and Nuclear Research and Technology Initiative to G. P. K. and the Japan Initiative for Global Research Network on Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology to A. T. G. W. is the recipient of a Doctoral Research Award from the Canadian Institute for Health Research. NR 47 TC 31 Z9 32 U1 2 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 31 PY 2012 VL 4 IS 158 AR 158ra146 DI 10.1126/scitranslmed.3004582 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 030MX UT WOS:000310575900008 PM 23115355 ER PT J AU Scadding, GW Calderon, MA Bellido, V Koed, GK Nielsen, NC Lund, K Togias, A Phippard, D Turka, LA Hansel, TT Durham, SR Wurtzen, PA AF Scadding, Guy W. Calderon, Moises A. Bellido, Virginia Koed, Gitte Konsgaard Nielsen, Niels-Christian Lund, Kaare Togias, Alkis Phippard, Deborah Turka, Laurence A. Hansel, Trevor T. Durham, Stephen R. Wurtzen, Peter Adler TI Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Nasal allergen provocation; Nasal allergen challenge; Seasonal allergic rhinitis; Grass pollen; Biomarker; Nasal cytokines ID COLONY-STIMULATING FACTOR; INFLAMMATORY MEDIATORS; ANTIGEN CHALLENGE; CYTOKINE LEVELS; RHINITIS; SECRETIONS; IMMUNOTHERAPY; PROVOCATION; CELLS; IL-5 AB Nasal allergen challenge can be used to assess the clinical and immunological aspects of rhinitis due to inhalant allergens. We aimed to develop a reproducible technique for grass pollen nasal allergen challenge and to study biomarkers within nasal secretions. 20 Grass pollen allergic individuals underwent nasal challenges with purified Timothy grass allergen. An initial dose-titration challenge was used to determine dose-response characteristics. Subsequently, volunteers underwent 3 further challenges using individualised threshold doses. Symptom scores, visual analogue scores, and peak nasal inspiratory flow (PNIF) were recorded at baseline and up to 6 h after challenge. Nasal secretions were collected at each time point using synthetic filter papers or absorptive polyurethane sponges and analysed for IL-4, -5, -10, -13, IFN-gamma, Tryptase and Eosinophil Cationic Protein (ECP). Challenges gave reproducible symptom scores and decreased PNIF. Tryptase levels in nasal fluid peaked at 5 min after challenge and returned to baseline levels at 1 h. ECP, IL-5, IL-13 and IL-4 levels were increased from 2-3 h and showed progressive increases to 5-6 h. Sponges proved the superior nasal fluid sampling technique. We have developed a reproducible nasal allergen challenge technique. This may be used as a surrogate clinical endpoint in trials assessing the efficacy of treatments for allergic rhinitis. Tryptase in local nasal secretions is a potential biomarker of the early phase response; ECP and the Th2 cytokines IL-5, -13 and 4 markers of late phase allergic responses. Our model allows correlation between clinical responses and local biomarkers following nasal allergen challenge. (C) 2012 Elsevier B.V. All rights reserved. C1 [Scadding, Guy W.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Fac Med, Sect Allergy & Clin Immunol, London SW3 6LY, England. [Koed, Gitte Konsgaard; Nielsen, Niels-Christian; Lund, Kaare; Wurtzen, Peter Adler] ALK Abello, Vaccine Res & Discovery, Horsholm, Denmark. [Togias, Alkis] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Phippard, Deborah] Immune Tolerance Network, Bethesda, MD USA. [Turka, Laurence A.] Beth Israel Deaconess Med Ctr, Immune Tolerance Network, Boston, MA 02215 USA. [Turka, Laurence A.] Harvard Univ, Sch Med, Boston, MA USA. RP Scadding, GW (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Fac Med, Sect Allergy & Clin Immunol, Dovehouse St, London SW3 6LY, England. EM g.scadding@imperial.ac.uk FU Medical Research Council [G1000758] NR 36 TC 33 Z9 33 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD OCT 31 PY 2012 VL 384 IS 1-2 BP 25 EP 32 DI 10.1016/j.jim.2012.06.013 PG 8 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 017EG UT WOS:000309572300004 PM 22759401 ER PT J AU Mondul, AM Weinstein, SJ Bosworth, T Remaley, AT Virtamo, J Albanes, D AF Mondul, Alison M. Weinstein, Stephanie J. Bosworth, Tracey Remaley, Alan T. Virtamo, Jarmo Albanes, Demetrius TI Circulating Thyroxine, Thyroid-Stimulating Hormone, and Hypothyroid Status and the Risk of Prostate Cancer SO PLOS ONE LA English DT Article ID NUTRITION EXAMINATION SURVEY; NATIONAL-HEALTH; CARCINOMA-CELLS; FOLLOW-UP; TRIIODOTHYRONINE; SMOKING; MEN AB Background: Thyroid hormones may influence risk of cancer through their role in cell differentiation, growth, and metabolism. One study of circulating thyroid hormones supports this hypothesis with respect to prostate cancer. We undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: Within the ATBC Study, a randomized controlled trial of alpha-tocopherol and beta-carotene supplements and cancer incidence in male smokers, 402 prostate cancer cases were sampled. Controls were matched 2:1 to cases on age and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer were estimated for quintiles of serum total and free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroid-binding globulin (TBG), and by categories of thyroid status. Results: Men with serum higher TSH had a decreased risk of prostate cancer compared to men with lower TSH (Q5 vs. Q1-4: OR = 0.70, 95% CI: 0.51-0.97, p = 0.03). When the T4 and TSH measurements were combined to define men as hypothyroid, euthyroid or hyperthyroid, hypothyroid men had a lower risk of prostate cancer compared to euthyroid men (OR = 0.48, 95% CI = 0.28-0.81, p = 0.006). We observed no association between hyperthyroid status and risk, although the number of hyperthyroid men with prostate cancer was small (n = 9). Conclusions: In this prospective study of smokers, men with elevated TSH and those classified as being in a hypothyroid state were at decreased risk of prostate cancer. Future studies should examine the association in other populations, particularly non-smokers and other racial/ethnic groups. C1 [Mondul, Alison M.; Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bosworth, Tracey; Remaley, Alan T.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Mondul, AM (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mondulam@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mondul, Alison/0000-0002-8843-1416 FU United States Public Health Service from the National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; Intramural Research Program of the National Cancer Institute FX This work was was supported by the United States Public Health Service (contract numbers N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services, and by funding from the Intramural Research Program of the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 18 Z9 20 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 30 PY 2012 VL 7 IS 10 AR e47730 DI 10.1371/journal.pone.0047730 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HJ UT WOS:000310705600016 PM 23118893 ER PT J AU Taha, AY Gao, F Ramadan, E Cheon, Y Rapoport, SI Kim, HW AF Taha, Ameer Y. Gao, Fei Ramadan, Epolia Cheon, Yewon Rapoport, Stanley I. Kim, Hyung-Wook TI Upregulated expression of brain enzymatic markers of arachidonic and docosahexaenoic acid metabolism in a rat model of the metabolic syndrome SO BMC NEUROSCIENCE LA English DT Article DE Arachidonic acid; Docosahexaenoic acid; BDNF; Brain; Polyunsaturated fatty acids (PUFA); Metabolic syndrome; Drebrin; Sucrose; Insulin resistance ID CYTOSOLIC PHOSPHOLIPASE A(2); INDUCED INSULIN-RESISTANCE; ESSENTIAL FATTY-ACIDS; HIGH-SUCROSE DIET; SYNAPTIC PLASTICITY; ALZHEIMER-DISEASE; LIPID-METABOLISM; GENE-EXPRESSION; FRONTAL-CORTEX; FOOD-INTAKE AB Background: In animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with phospholipase (PLA(2)) enzymes that regulate arachidonic (AA, 20: 4n-6) and docosahexaenoic (DHA, 22: 6n-6) acid metabolism, major polyunsaturated fatty acids in brain. Male Wistar rats were fed a control or high-sucrose diet for 8 weeks. Brains were assayed for markers of AA metabolism (calcium-dependent cytosolic cPLA(2) IVA and cyclooxygenases), DHA metabolism (calcium-independent iPLA(2) VIA and lipoxygenases), brain-derived neurotrophic factor (BDNF), and synaptic integrity (drebrin and synaptophysin). Lipid concentrations were measured in brains subjected to high-energy microwave fixation. Results: The high-sucrose compared with control diet induced insulin resistance, and increased phosphorylatedc-PLA(2) protein, cPLA(2) and iPLA(2) activity and 12-lipoxygenase mRNA, but decreased BDNF mRNA and protein, and drebrin mRNA. The concentration of several n-6 fatty acids in ethanolamine glycerophospholipids and lysophosphatidylcholine was increased, as was unesterified AA concentration. Eicosanoid concentrations (prostaglandin E-2, thromboxane B-2 and leukotriene B-4) did not change. Conclusion: These findings show upregulated brain AA and DHA metabolism and reduced BDNF and drebrin, but no changes in eicosanoids, in an animal model of the metabolic syndrome. These changes might contribute to altered synaptic plasticity and cognitive impairment in rats and humans with the metabolic syndrome. C1 [Taha, Ameer Y.; Gao, Fei; Ramadan, Epolia; Cheon, Yewon; Rapoport, Stanley I.; Kim, Hyung-Wook] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Kim, Hyung-Wook] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. RP Kim, HW (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM peterkhw@gmail.com RI Taha, Ameer/E-1979-2013 FU National Institute on Aging, NIH FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. NR 82 TC 4 Z9 4 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD OCT 30 PY 2012 VL 13 AR 131 DI 10.1186/1471-2202-13-131 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 060UR UT WOS:000312804200001 PM 23110484 ER PT J AU Tang, SW Ducroux, A Jeang, KT Neuveut, C AF Tang, Sai-Wen Ducroux, Aurelie Jeang, Kuan-Teh Neuveut, Christine TI Impact of cellular autophagy on viruses: Insights from hepatitis B virus and human retroviruses SO JOURNAL OF BIOMEDICAL SCIENCE LA English DT Review ID NF-KAPPA-B; PROTEIN CONJUGATION SYSTEM; HIV-1 REPLICATION; MAMMALIAN AUTOPHAGY; C VIRUS; T-CELLS; ENDOPLASMIC-RETICULUM; ATG12-ATG5 CONJUGATE; SELECTIVE AUTOPHAGY; SUPPRESSOR ACTIVITY AB Autophagy is a protein degradative process important for normal cellular metabolism. It is apparently used also by cells to eliminate invading pathogens. Interestingly, many pathogens have learned to subvert the cell's autophagic process. Here, we review the interactions between viruses and cells in regards to cellular autophagy. Using findings from hepatitis B virus and human retroviruses, HIV-1 and HTLV-1, we discuss mechanisms used by viruses to usurp cellular autophagy in ways that benefit viral replication. C1 [Tang, Sai-Wen; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Ducroux, Aurelie; Neuveut, Christine] Inst Pasteur, Lab Hepacivirus & Innate Immun, F-75015 Paris, France. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kjeang@nih.gov; cneuveut@pasteur.fr FU Ministere de l'Enseignement Superieur et de la Recherche; Institut National de la Sante et de la Recherche Medicale; Agence Nationale de la Recherche sur le Sida et les Hepatites Virales (ANRS); Institut National du Cancer (INCa); NIAID; office of the Director, NIH FX AD is supported by a fellowship from the Ministere de l'Enseignement Superieur et de la Recherche, CN is supported by the Institut National de la Sante et de la Recherche Medicale. Work in the Neuveut laboratory is supported by grants from the Agence Nationale de la Recherche sur le Sida et les Hepatites Virales (ANRS) and by the Institut National du Cancer (INCa). Work in the Jeang laboratory is supported by NIAID Intramural funding and by the Intramural AIDS Targeted Antiviral Program (IATAP) from the office of the Director, NIH. We thank members of the Jeang laboratory for critical readings of the manuscript and Swathi Nuli for assistance with Figure 3. NR 151 TC 13 Z9 13 U1 0 U2 23 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1021-7770 J9 J BIOMED SCI JI J. Biomed. Sci. PD OCT 30 PY 2012 VL 19 AR 92 DI 10.1186/1423-0127-19-92 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 039ZH UT WOS:000311287200001 PM 23110561 ER PT J AU Kitanaka, J Kitanaka, N Hall, FS Uhl, GR Tanaka, K Nishiyama, N Takemura, M AF Kitanaka, Junichi Kitanaka, Nobue Hall, F. Scott Uhl, George R. Tanaka, Koh-ichi Nishiyama, Nobuyoshi Takemura, Motohiko TI Straub tail reaction in mice treated with sigma(1) receptor antagonist in combination with methamphetamine SO BRAIN RESEARCH LA English DT Article DE Methamphetamine; Sigma ligand; Straub tail reaction; Opioid receptor system ID BEHAVIORAL EVIDENCE; OPIOID RECEPTOR; MECHANISM; ACTIVATION; TOLERANCE; ANALGESIA; SYSTEM; TARGET; AGENTS AB Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific a receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative sigma(1) receptor agonist) and partially by PB 28 (a putative sigma(2) receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative sigma(1) receptor antagonist), but not SM-21, a putative sigma(2) receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective kappa-agonist), suggesting that the STR may be mediated by activation of opioid receptor system. (C) 2012 Elsevier B.V. All rights reserved. C1 [Kitanaka, Junichi; Kitanaka, Nobue; Takemura, Motohiko] Hyogo Coll Med, Dept Pharmacol, Nishinomiya, Hyogo 6638501, Japan. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Tanaka, Koh-ichi; Nishiyama, Nobuyoshi] Hyogo Univ Hlth Sci, Div Pharmacol, Dept Pharm, Sch Pharm, Kobe, Hyogo 6508530, Japan. RP Kitanaka, J (reprint author), Hyogo Coll Med, Dept Pharmacol, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan. EM kitanaka-hyg@umin.net RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Hyogo College of Medicine; National Institute on Drug Abuse, USA FX The authors are grateful to Ms. A. Yoshioka of the Department of Pharmacology, Hyogo College of Medicine, for preparing the animal study proposal. We also thank Mr. T. Nakajima of Joint-Use Research Facilities, Hyogo College of Medicine, for constructing the acrylic test boxes. This research was supported, in part, by a Grant-in-Aid for Researchers, Hyogo College of Medicine (2011 to NK), and intramural funding from the National Institute on Drug Abuse, USA (GRU and FSH). NR 32 TC 2 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 30 PY 2012 VL 1482 BP 40 EP 46 DI 10.1016/j.brainres.2012.09.001 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 038KX UT WOS:000311174700005 PM 22981417 ER PT J AU Metais, JY Winkler, T Geyer, JT Calado, RT Aplan, PD Eckhaus, MA Dunbar, CE AF Metais, Jean-Yves Winkler, Thomas Geyer, Julia T. Calado, Rodrigo T. Aplan, Peter D. Eckhaus, Michael A. Dunbar, Cynthia E. TI BCL2A1a Over-Expression in Murine Hematopoietic Stem and Progenitor Cells Decreases Apoptosis and Results in Hematopoietic Transformation SO PLOS ONE LA English DT Article ID RETROVIRAL VECTOR INTEGRATION; ACUTE MYELOID-LEUKEMIA; BCL-2 FAMILY-MEMBER; NF-KAPPA-B; GENE-THERAPY; HEMATOLOGICAL MALIGNANCIES; TRANSCRIPTIONAL TARGET; MOUSE MODEL; A1; MICE AB We previously reported the development of a lethal myeloid sarcoma in a non-human primate model utilizing retroviral vectors to genetically modify hematopoietic stem and progenitor cells. This leukemia was characterized by insertion of the vector provirus into the BCL2A1 gene, with resultant BCL2A1 over-expression. There is little information on the role of this anti-apoptotic member of the BCL2 family in hematopoiesis or leukemia induction. Therefore we studied the impact of Bcl2a1a lentiviral over-expression on murine hematopoietic stem and progenitor cells. We demonstrated the anti-apoptotic function of this protein in hematopoietic cells, but did not detect any impact of Bcl2a1a on in vitro cell growth or cell cycle kinetics. In vivo, we showed a higher propensity of HSCs over-expressing Bcl2a1a to engraft and contribute to hematopoiesis. Mice over-expressing Bcl2a1a in the hematologic compartment eventually developed an aggressive malignant disease characterized as a leukemia/lymphoma of B-cell origin. Secondary transplants carried out to investigate the primitive origin of the disease revealed the leukemia was transplantable. Thus, Bcl2a1 should be considered as a protooncogene with a potential role in both lymphoid and myeloid leukemogenesis, and a concerning site for insertional activation by integrating retroviral vectors utilized in hematopoietic stem cell gene therapy. C1 [Metais, Jean-Yves; Winkler, Thomas; Calado, Rodrigo T.; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Geyer, Julia T.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Calado, Rodrigo T.] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, BR-14049 Ribeirao Preto, Brazil. [Aplan, Peter D.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael A.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011; Aplan, Peter/K-9064-2016 FU intramural research programs of the National Heart Lung and Blood Institute (CED) of the National Institutes of Health FX This work was supported by the intramural research programs of the National Heart Lung and Blood Institute (CED) of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 6 Z9 6 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 OCT 30 PY 2012 VL 7 IS 10 AR e48267 DI 10.1371/journal.pone.0048267 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HJ UT WOS:000310705600037 PM 23118966 ER PT J AU Zieman, SJ Kamineni, A Ix, JH Barzilay, J Djousse, L Kizer, JR Biggs, ML de Boer, IH Chonchol, M Gottdiener, JS Selvin, E Newman, AB Kuller, LH Siscovick, DS Mukamal, KJ AF Zieman, Susan J. Kamineni, Aruna Ix, Joachim H. Barzilay, Joshua Djousse, Luc Kizer, Jorge R. Biggs, Mary L. de Boer, Ian H. Chonchol, Michel Gottdiener, John S. Selvin, Elizabeth Newman, Anne B. Kuller, Lewis H. Siscovick, David S. Mukamal, Kenneth J. TI Hemoglobin A1c and Arterial and Ventricular Stiffness in Older Adults SO PLOS ONE LA English DT Article ID CARDIOVASCULAR-HEALTH; ATHEROSCLEROSIS RISK; DIABETES-MELLITUS; CARDIAC STRUCTURE; GLYCEMIC CONTROL; DISEASE; GLYCATION; COMMUNITIES; MORTALITY; PRESSURE AB Objective: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA(1c), an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes. Research Design & Methods: Baseline HbA(1c) was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged >= 65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA(1c) and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures. Results: HbA(1c) was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p < 0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA(1c) was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, endarterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM. Conclusions: In this sample of older adults without diabetes, HbA(1c) was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers. C1 [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Zieman, Susan J.; Selvin, Elizabeth] NIA, NIH, Bethesda, MD 20892 USA. [Kamineni, Aruna] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol Hypertens, La Jolla, CA 92093 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA. [Barzilay, Joshua] Kaiser Permanente, Div Endocrinol, Tucker, GA USA. [Djousse, Luc] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging, Boston, MA 02115 USA. [Djousse, Luc] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Kizer, Jorge R.] Cornell Univ, Weill Med Coll, Dept Med & Publ Hlth, New York, NY 10021 USA. [Biggs, Mary L.; de Boer, Ian H.; Siscovick, David S.] Univ Washington, Dept Biostat & Med, Seattle, WA 98195 USA. [Chonchol, Michel] Univ Colorado Denver, Dept Med, Hlth Sci Ctr, Denver, CO USA. [Gottdiener, John S.] Univ Maryland, Sch Med, Div Cardiol, Baltimore, MD 21201 USA. [Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Newman, Anne B.; Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. RP Mukamal, KJ (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. EM kmukamal@bidmc.harvard.edu RI Newman, Anne/C-6408-2013; Djousse, Luc/F-5033-2017 OI Newman, Anne/0000-0002-0106-1150; Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute (NHLBI) [R01HL094555]; NIDDK [K01DK076595]; NHLBI [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295] FX The research reported in this article was supported by grant R01HL094555 from the National Heart, Lung, and Blood Institute (NHLBI) (KM, LD, JI and JK), NIDDK grant K01DK076595 (ES) and contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 5 Z9 6 U1 1 U2 4 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 OCT 30 PY 2012 VL 7 IS 10 AR e47941 DI 10.1371/journal.pone.0047941 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HJ UT WOS:000310705600020 PM 23118911 ER PT J AU Wolynes, PG Eaton, WA Fersht, AR AF Wolynes, Peter G. Eaton, William A. Fersht, Alan R. TI Chemical physics of protein folding SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID INTERNAL-FRICTION; ENERGY LANDSCAPE; TRANSITION-STATE; KINETICS; PATHWAY C1 [Wolynes, Peter G.] Rice Univ, Dept Chem, Houston, TX 77005 USA. [Wolynes, Peter G.] Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 USA. [Eaton, William A.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Fersht, Alan R.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. RP Wolynes, PG (reprint author), Rice Univ, Dept Chem, POB 1892, Houston, TX 77005 USA. EM pwolynes@rice.edu NR 26 TC 28 Z9 28 U1 8 U2 98 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 OCT 30 PY 2012 VL 109 IS 44 BP 17770 EP 17771 DI 10.1073/pnas.1215733109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900023 PM 23112193 ER PT J AU Mandl, JN Liou, R Klauschen, F Vrisekoop, N Monteiro, JP Yates, AJ Huang, AY Germain, RN AF Mandl, Judith N. Liou, Rachel Klauschen, Frederick Vrisekoop, Nienke Monteiro, Joao P. Yates, Andrew J. Huang, Alex Y. Germain, Ronald N. TI Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naive CD4(+) and CD8(+) T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE trafficking; migration; immune recognition ID DENDRITIC CELLS; MIGRATION BEHAVIOR; SELF-RECOGNITION; LYMPHOCYTES; MOTILITY; EGRESS; ORGANS; ENTRY; TCR; CHEMOKINES AB Naive T cells continually recirculate between blood and secondary lymphoid organs, scanning dendritic cells (DC) for foreign antigen. Despite its importance for understanding how adaptive immune responses are efficiently initiated from rare precursors, a detailed quantitative analysis of this fundamental process has not been reported. Here we measure lymph node (LN) entry, transit, and exit rates for naive CD4(+) and CD8(+) T cells, then use intravital imaging and mathematical modeling to relate cell-cell interaction dynamics to population behavior. Our studies reveal marked differences between CD4(+) vs. CD8(+) T cells. CD4(+) T cells recirculate more rapidly, homing to LNs more efficiently, traversing LNs twice as quickly, and spending similar to 1/3 of their transit time interacting with MHCII on DC. In contrast, adoptively transferred CD8(+) T cells enter and leave the LN more slowly, with a transit time unaffected by the absence of MHCI molecules on host cells. Together, these data reveal an unexpectedly asymmetric role for MHC interactions in controlling CD4(+) vs. CD8(+) T lymphocyte recirculation, as well as distinct contributions of T cell receptor (TCR)-independent factors to the LN transit time, exposing the divergent surveillance strategies used by the two lymphocyte populations in scanning for foreign antigen. C1 [Mandl, Judith N.; Vrisekoop, Nienke; Monteiro, Joao P.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Liou, Rachel; Huang, Alex Y.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Klauschen, Frederick] Charite, Inst Pathol, D-10117 Berlin, Germany. [Yates, Andrew J.] Albert Einstein Coll Med, Dept Syst & Computat Biol, Bronx, NY 10461 USA. [Yates, Andrew J.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. RP Mandl, JN (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mandlj@niaid.nih.gov; rgermain@nih.gov RI Klauschen, Frederick/C-5637-2015; OI Huang, Alex/0000-0002-5701-4521 FU National Institutes of Health (NIH) Office of AIDS Research; NIH [R01 AI093870-01, R21 AI092299-01, R01 CA154656-01]; St. Baldrick's Foundation; National Institute of Allergy and Infectious Diseases, NIH FX We thank I. Stefanova, J. Egen, and H. Qi for technical advice and I. Ifrim, P. Torabi-Parizi, D. Barkauskas, and C. Su for help with large experiments. This work was supported by the National Institutes of Health (NIH) Office of AIDS Research (J.N.M.), NIH Grant R01 AI093870-01 (to A.J.Y.), NIH Grants R21 AI092299-01 and R01 CA154656-01, the St. Baldrick's Foundation (A.Y.H.), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 41 TC 52 Z9 52 U1 0 U2 14 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 OCT 30 PY 2012 VL 109 IS 44 BP 18036 EP 18041 DI 10.1073/pnas.1211717109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900073 PM 23071319 ER PT J AU Panicker, LM Miller, D Park, TS Patel, B Azevedo, JL Awad, O Masood, MA Veenstra, TD Goldin, E Stubblefield, BK Tayebi, N Polumuri, SK Vogel, SN Sidransky, E Zambidis, ET Feldman, RA AF Panicker, Leelamma M. Miller, Diana Park, Tea Soon Patel, Brijesh Azevedo, Judi L. Awad, Ola Masood, M. Athar Veenstra, Timothy D. Goldin, Ehud Stubblefield, Barbara K. Tayebi, Nahid Polumuri, Swamy K. Vogel, Stefanie N. Sidransky, Ellen Zambidis, Elias T. Feldman, Ricardo A. TI Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Gaucher model; Gaucher macrophages; lipid storage disease; glucosylsphingolipids; erythrophagocytosis ID ACID BETA-GLUCOSIDASE; ISOFAGOMINE INCREASES; GLUCOCEREBROSIDASE; FIBROBLASTS; MECHANISMS; LYSOSOMES; SPECTRUM; FORM AB Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid beta-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/N370S), type 2 (L444P/RecNcil), and type 3 (L444P/L444P) GD. Pluripotency was demonstrated by the ability of GD hiPSC to differentiate to all three germ layers and to form teratomas in vivo. GD hiPSC differentiated efficiently to the cell types most affected in GD, i.e., macrophages and neuronal cells. GD hiPSC-macrophages expressed macrophage-specific markers, were phagocytic, and were capable of releasing inflammatory mediators in response to LPS. Moreover, GD hiPSC-macrophages recapitulated the phenotypic hallmarks of the disease. They exhibited low glucocerebrosidase (GC) enzymatic activity and accumulated sphingolipids, and their lysosomal functions were severely compromised. GD hiPSC-macrophages had a defect in their ability to clear phagocytosed RBC, a phenotype of tissue-infiltrating GD macrophages. The kinetics of RBC clearance by types 1, 2, and 3 GD hiPSC-macrophages correlated with the severity of the mutations. Incubation with recombinant GC completely reversed the delay in RBC clearance from all three types of GD hiPSC-macrophages, indicating that their functional defects were indeed caused by GC deficiency. However, treatment of induced macrophages with the chaperone isofagomine restored phagocytosed RBC clearance only partially, regardless of genotype. These findings are consistent with the known clinical efficacies of recombinant GC and isofagomine. We conclude that cell types derived from GD hiPSC can effectively recapitulate pathologic hallmarks of the disease. C1 [Panicker, Leelamma M.; Miller, Diana; Patel, Brijesh; Azevedo, Judi L.; Awad, Ola; Polumuri, Swamy K.; Vogel, Stefanie N.; Feldman, Ricardo A.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Park, Tea Soon; Zambidis, Elias T.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. [Park, Tea Soon; Zambidis, Elias T.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Masood, M. Athar; Veenstra, Timothy D.] SAIC Frederick Inc, Lab Prote & Analyt Technol, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Goldin, Ehud; Stubblefield, Barbara K.; Tayebi, Nahid; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Feldman, RA (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM rfeldman@umaryland.edu FU Maryland Stem Cell Research Fund (MSCRF) [2009-MSCRFII-0082-00, 2007-MSCRFE-0110-00, 2011-MSCRF II-0008-00, 2007-MSCRF II-0379-00]; March of Dimes [6-FY10-334]; National Institutes of Health [1U01HL099775, U01HL100397] FX We thank Gustavo Mostoslavsky (Boston University) for providing the STEMCCA vector and Avital Shimanovich and Vivek Bose for expert technical assistance. This work was supported by Grants 2009-MSCRFII-0082-00 (to R.A.F.), 2007-MSCRFE-0110-00 (to R.A.F.), 2011-MSCRF II-0008-00 (to E.T.Z.), and 2007-MSCRF II-0379-00 (to E.T.Z.) from the Maryland Stem Cell Research Fund (MSCRF), Grant 6-FY10-334 (to R.A.F.) from the March of Dimes, and Grants 1U01HL099775 and U01HL100397 (both to E.T.Z.) from the National Institutes of Health. T.S.P. and O.A. are recipients of MSCRF postdoctoral fellowship grants. NR 37 TC 39 Z9 39 U1 0 U2 8 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 OCT 30 PY 2012 VL 109 IS 44 BP 18054 EP 18059 DI 10.1073/pnas.1207889109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900076 PM 23071332 ER PT J AU Desnues, C La Scola, B Yutin, N Fournous, G Robert, C Azza, S Jardot, P Monteil, S Campocasso, A Koonin, EV Raoult, D AF Desnues, Christelle La Scola, Bernard Yutin, Natalya Fournous, Ghislain Robert, Catherine Azza, Said Jardot, Priscilla Monteil, Sonia Campocasso, Angelique Koonin, Eugene V. Raoult, Didier TI Provirophages and transpovirons as the diverse mobilome of giant viruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ROLLING-CIRCLE TRANSPOSONS; RETICULOENDOTHELIOSIS VIRUS; DNA TRANSPOSONS; LIFE-STYLE; GENOME; EVOLUTION; SEQUENCE; PROTEIN; MIMIVIRUS; VIROPHAGE AB A distinct class of infectious agents, the virophages that infect giant viruses of the Mimiviridae family, has been recently described. Here we report the simultaneous discovery of a giant virus of Acanthamoeba polyphaga (Lentille virus) that contains an integrated genome of a virophage (Sputnik 2), and a member of a previously unknown class of mobile genetic elements, the transpovirons. The transpovirons are linear DNA elements of similar to 7 kb that encompass six to eight protein-coding genes, two of which are homologous to virophage genes. Fluorescence in situ hybridization showed that the free form of the transpoviron replicates within the giant virus factory and accumulates in high copy numbers inside giant virus particles, Sputnik 2 particles, and amoeba cytoplasm. Analysis of deep-sequencing data showed that the virophage and the transpoviron can integrate in nearly any place in the chromosome of the giant virus host and that, although less frequently, the transpoviron can also be linked to the virophage chromosome. In addition, integrated fragments of transpoviron DNA were detected in several giant virus and Sputnik genomes. Analysis of 19 Mimivirus strains revealed three distinct transpovirons associated with three subgroups of Mimiviruses. The virophage, the transpoviron, and the previously identified self-splicing introns and inteins constitute the complex, interconnected mobilome of the giant viruses and are likely to substantially contribute to interviral gene transfer. C1 [Desnues, Christelle; La Scola, Bernard; Fournous, Ghislain; Robert, Catherine; Azza, Said; Jardot, Priscilla; Monteil, Sonia; Campocasso, Angelique; Raoult, Didier] Aix Marseille Univ, Ctr Natl Rech Sci 7278, Inst Natl Sante & Rech Med 1095,Inst Rech Dev 198, Unite Rech Malad Infect & Trop Emergentes,Unite M, F-13005 Marseille, France. [Yutin, Natalya; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Raoult, D (reprint author), Aix Marseille Univ, Ctr Natl Rech Sci 7278, Inst Natl Sante & Rech Med 1095,Inst Rech Dev 198, Unite Rech Malad Infect & Trop Emergentes,Unite M, F-13005 Marseille, France. EM didier.raoult@gmail.com RI Desnues, Christelle/B-1383-2010; LA SCOLA, Bernard/P-6477-2016 OI Desnues, Christelle/0000-0002-2178-0355; LA SCOLA, Bernard/0000-0001-8006-7704 FU Centre National de la Recherche Scientifique; US Department of Health and Human Services (National Library of Medicine, National Institutes of Health) FX This work was funded by the Centre National de la Recherche Scientifique (credits recurrent). N.Y. and E.V.K. are supported by the intramural funds of the US Department of Health and Human Services (National Library of Medicine, National Institutes of Health). NR 46 TC 81 Z9 86 U1 3 U2 36 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 OCT 30 PY 2012 VL 109 IS 44 BP 18078 EP 18083 DI 10.1073/pnas.1208835109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900080 PM 23071316 ER PT J AU Renz, M Daniels, BR Vamosi, G Arias, IM Lippincott-Schwartz, J AF Renz, Malte Daniels, Brian R. Vamosi, Gyoergy Arias, Irwin M. Lippincott-Schwartz, Jennifer TI Plasticity of the asialoglycoprotein receptor deciphered by ensemble FRET imaging and single-molecule counting PALM imaging SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RESONANCE ENERGY-TRANSFER; ISOLATED RAT HEPATOCYTES; LIVER; PROTEINS; SUBUNIT; FORMS; COMPLEX; DOMAIN; H1 AB The stoichiometry and composition of membrane protein receptors are critical to their function. However, the inability to assess receptor subunit stoichiometry in situ has hampered efforts to relate receptor structures to functional states. Here, we address this problem for the asialoglycoprotein receptor using ensemble FRET imaging, analytical modeling, and single-molecule counting with photoactivated localization microscopy (PALM). We show that the two subunits of asialoglycoprotein receptor [rat hepatic lectin 1 (RHL1) and RHL2] can assemble into both homo-and hetero-oligomeric complexes, displaying three forms with distinct ligand specificities that coexist on the plasma membrane: higher-order homo-oligomers of RHL1, higher-order hetero-oligomers of RHL1 and RHL2 with two-to-one stoichiometry, and the homo-dimer RHL2 with little tendency to further homo-oligomerize. Levels of these complexes can be modulated in the plasma membrane by exogenous ligands. Thus, even a simple two-subunit receptor can exhibit remarkable plasticity in structure, and consequently function, underscoring the importance of deciphering oligomerization in single cells at the single-molecule level. C1 [Renz, Malte; Daniels, Brian R.; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Organelle Biol, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. [Renz, Malte; Arias, Irwin M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Cellular Polar, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. [Vamosi, Gyoergy] Univ Debrecen, Dept Biophys & Cell Biol, Med & Hlth Sci Ctr, H-4012 Debrecen, Hungary. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Organelle Biol, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov FU German Research Foundation Fellowship DFG [2893/1-1]; American Liver Foundation; Hungarian Scientific Research Foundation OTKA [K77600, TAMOP-4.2.1/B-09/1/KONV-2010-0007]; European Social Fund; European Regional Development Fund FX We thank Dr. Ramanujan Hegde, Dr. Alexander Gansen, and Dr. Christian Wunder for critical discussion and reading of the manuscript. M. R. was supported by German Research Foundation Fellowship DFG 2893/1-1 and the Charles Trey, MD Memorial Postdoctoral Research Award from the American Liver Foundation. G. V. was supported by the Hungarian Scientific Research Foundation OTKA K77600 and TAMOP-4.2.1/B-09/1/KONV-2010-0007 cofinanced by the European Social Fund and European Regional Development Fund. NR 27 TC 30 Z9 30 U1 3 U2 32 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 OCT 30 PY 2012 VL 109 IS 44 BP E2989 EP E2997 DI 10.1073/pnas.1211753109 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900008 PM 23043115 ER PT J AU Oertell, K Wu, Y Zakharova, VM Kashemirov, BA Shock, DD Beard, WA Wilson, SH McKenna, CE Goodman, MF AF Oertell, Keriann Wu, Yue Zakharova, Valeria M. Kashemirov, Boris A. Shock, David D. Beard, William A. Wilson, Samuel H. McKenna, Charles E. Goodman, Myron F. TI Effect of beta,gamma-CHF- and beta,gamma-CHCl-dGTP Halogen Atom Stereochemistry on the Transition State of DNA Polymerase beta SO BIOCHEMISTRY LA English DT Article ID TERNARY COMPLEX; GENE MUTATION; CANCER; EXCISION; REPAIR; FIDELITY; DIFLUOROTOLUENE; REPLICATION; CARCINOMAS; CHEMISTRY AB Recently, we synthesized the first individual beta,gamma-CHX-dGTP diastereomers [(R)- or (S)-CHX, where X is F or Cl] and determined their structures in ternary complexes with DNA polymerase beta (pot beta). We now report stereospecificity by pol beta on the mixed beta,gamma-CHX diastereomer pairs using nuclear magnetic resonance and on the separate diastereomers using transient kinetics. For both the F and Cl diastereomers, the R isomer is favored over the S isomer for GC correct incorporation, with stereospecificities [(k(pol)/K-d)(R)/(kp(ol)/K-d)(S)] of 3.8 and 6.3, respectively, and also for GT misincorporation, with stereospecificities of 11 and 7.8, respectively. Stereo-preference for the (R)-CHF-dGTP diastereomer was abolished for k(pol) but not K-d with mutant pol beta (R183A). These compounds constitute a new class of stereochemical probes for active site interactions involving halogen atoms. As Arg183 is unique in family X pols, the design of CXY deoxyribonucleotide analogues to enhance interaction is a possible strategy for inhibiting BER selectively in cancer cells. C1 [Oertell, Keriann; Wu, Yue; Zakharova, Valeria M.; Kashemirov, Boris A.; McKenna, Charles E.; Goodman, Myron F.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Shock, David D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. EM mgoodman@usc.edu FU National Cancer Institute of the National Institutes of Health [5-U19-CA105010]; National Institutes of Health [R01-GM21422]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159] FX This research was supported, in part, by the National Cancer Institute of the National Institutes of Health via Grant 5-U19-CA105010, by the National Institutes of Health via Grant R01-GM21422 (to M.F.G.) and by Research Project Numbers Z01-ES050158 and Z01-ES050159 from the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 38 TC 8 Z9 8 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 30 PY 2012 VL 51 IS 43 BP 8491 EP 8501 DI 10.1021/bi3010335 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 029GX UT WOS:000310483900003 PM 23043620 ER PT J AU Gail, MH AF Gail, Mitchell H. TI Comment on Principles of research' by Jerome Cornfield SO STATISTICS IN MEDICINE LA English DT Article C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8032, Rockville, MD 20892 USA. EM gailm@mail.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 30 PY 2012 VL 31 IS 24 SI SI BP 2771 EP 2772 DI 10.1002/sim.5390 PG 2 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 017MF UT WOS:000309593300005 PM 23037137 ER PT J AU Ghysels, A Miller, BT Pickard, FC Brooks, BR AF Ghysels, An Miller, Benjamin T. Pickard, Frank C. Brooks, Bernard R. TI Comparing normal modes across different models and scales: Hessian reduction versus coarse-graining SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE effective Hessian; NMA; normal mode analysis; vibrational analysis; chemical kinetics; entropy; free energy; coarse-grained models; coarse-graining; kinetic tensor; elastic network model; heat capacity; CG ID FREQUENCY NORMAL-MODES; ELASTIC NETWORK MODEL; MOLECULAR-DYNAMICS; HARMONIC-ANALYSIS; PROTEIN DYNAMICS; LARGE SYSTEMS; VIBRATIONAL ANALYSIS; SINGLE-PARAMETER; FORCE-FIELDS; MACROMOLECULES AB Dimension reduction is often necessary when attempting to reach longer length and time scales in molecular simulations. It is realized by constraining degrees of freedom or by coarse-graining the system. When evaluating the accuracy of a dimensional reduction, there is a practical challenge: the models yield vectors with different lengths, making a comparison by calculating their dot product impossible. This article investigates mapping procedures for normal mode analysis. We first review a horizontal mapping procedure for the reduced Hessian techniques, which projects out degrees of freedom. We then design a vertical mapping procedure for the implosion of the all-atom (AA) Hessian to a coarse-grained scale that is based upon vibrational subsystem analysis. This latter method derives both effective force constants and an effective kinetic tensor. Next, a series of metrics is presented for comparison across different scales, where special attention is given to proper mass-weighting. The dimension-dependent metrics, which require prior mapping for proper evaluation, are frequencies, overlap of normal mode vectors, probability similarity, Hessian similarity, collectivity of modes, and thermal fluctuations. The dimension-independent metrics are shape derivatives, elastic modulus, vibrational free energy differences, heat capacity, and projection on a predefined basis set. The power of these metrics to distinguish between reasonable and unreasonable models is tested on a toy alpha helix system and a globular protein; both are represented at several scales: the AA scale, a Go-like model, a canonical elastic network model, and a network model with intentionally unphysical force constants. Published 2012 Wiley Periodicals, Inc. C1 [Ghysels, An] Univ Ghent, Ctr Mol Modeling, B-9052 Ghent, Belgium. [Miller, Benjamin T.; Pickard, Frank C.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Ghysels, A (reprint author), Univ Ghent, Ctr Mol Modeling, Technol Pk 903, B-9052 Ghent, Belgium. EM an.ghysels@ugent.be; btmiller@nhlbi.nih.gov RI Ghysels, An/M-9095-2015; OI Miller, Benjamin/0000-0003-1647-0122 FU Intramural Research Program of NIH, National Heart, Lung and Blood Institute FX Contract/grant sponsor: Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. NR 79 TC 7 Z9 7 U1 2 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD OCT 30 PY 2012 VL 33 IS 28 BP 2250 EP 2275 DI 10.1002/jcc.23076 PG 26 WC Chemistry, Multidisciplinary SC Chemistry GA 009ZY UT WOS:000309065400005 PM 22941785 ER PT J AU Gaudet, P Arighi, C Bastian, F Bateman, A Blake, JA Cherry, MJ D'Eustachio, P Finn, R Giglio, M Hirschman, L Kania, R Klimke, W Martin, MJ Karsch-Mizrachi, I Munoz-Torres, M Natale, D O'Donovan, C Ouellette, F Pruitt, KD Robinson-Rechavi, M Sansone, SA Schofield, P Sutton, G Van Auken, K Vasudevan, S Wu, C Young, J Mazumder, R AF Gaudet, Pascale Arighi, Cecilia Bastian, Frederic Bateman, Alex Blake, Judith A. Cherry, Michael J. D'Eustachio, Peter Finn, Robert Giglio, Michelle Hirschman, Lynette Kania, Renate Klimke, William Martin, Maria Jesus Karsch-Mizrachi, Ilene Munoz-Torres, Monica Natale, Darren O'Donovan, Claire Ouellette, Francis Pruitt, Kim D. Robinson-Rechavi, Marc Sansone, Susanna-Assunta Schofield, Paul Sutton, Granger Van Auken, Kimberly Vasudevan, Sona Wu, Cathy Young, Jasmine Mazumder, Raja TI Recent advances in biocuration: Meeting Report from the fifth International Biocuration Conference SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article AB The 5th International Biocuration Conference brought together over 300 scientists to exchange on their work, as well as discuss issues relevant to the International Society for Biocuration's (ISB) mission. Recurring themes this year included the creation and promotion of gold standards, the need for more ontologies, and more formal interactions with journals. The conference is an essential part of the ISB's goal to support exchanges among members of the biocuration community. Next year's conference will be held in Cambridge, UK, from 7 to 10 April 2013. In the meanwhile, the ISB website provides information about the society's activities (http://biocurator.org), as well as related events of interest. C1 [Gaudet, Pascale] Int Soc Biocurat, Geneva, Switzerland. [Gaudet, Pascale] Swiss Inst Bioinformat, CALIPHO Grp, Geneva, Switzerland. [Arighi, Cecilia; Wu, Cathy] Univ Delaware, Newark, DE USA. [Bastian, Frederic; Robinson-Rechavi, Marc] Univ Lausanne, Swiss Inst Bioinformat, Lausanne, Switzerland. [Bastian, Frederic; Robinson-Rechavi, Marc] Univ Lausanne, Dept Ecol & Evolut, Lausanne, Switzerland. [Bateman, Alex] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Blake, Judith A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Cherry, Michael J.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [D'Eustachio, Peter] NYU, Sch Med, New York, NY USA. [Finn, Robert] HHMI, Ashburn, VA USA. [Giglio, Michelle] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Hirschman, Lynette] Mitre Corp, Bedford, MA 01730 USA. [Kania, Renate] Heidelberg Inst Theoret Studies, Heidelberg, Germany. [Klimke, William; Karsch-Mizrachi, Ilene; Pruitt, Kim D.] NCBI NLM NIH DHHS, Bethesda, MD USA. [Martin, Maria Jesus; O'Donovan, Claire] European Bioinformat Inst, Hinxton, Cambs, England. [Munoz-Torres, Monica; Natale, Darren; Vasudevan, Sona] Georgetown Univ, Washington, DC USA. [Ouellette, Francis] Univ Toronto, Ontario Inst Canc Res, Toronto, ON, Canada. [Ouellette, Francis] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON, Canada. [Sansone, Susanna-Assunta] Univ Oxford, Oxford, England. [Schofield, Paul] Univ Cambridge, Cambridge, England. [Sutton, Granger] J Craig Venter Inst, Rockville, MD USA. [Van Auken, Kimberly] CALTECH, Pasadena, CA 91125 USA. [Young, Jasmine] Rutgers State Univ, RCSB Prot Data Bank, Piscataway, NJ 08855 USA. [Mazumder, Raja] George Washington Univ, Int Biocurat Conf Organizing Comm 5, Washington, DC 20037 USA. [Mazumder, Raja] George Washington Univ, Dept Biochem & Mol Biol, Washington, DC 20037 USA. RP Gaudet, P (reprint author), Int Soc Biocurat, 1 Rue Michel Servet, Geneva, Switzerland. EM pascale.gaudet@isb-sib.ch; mazumder@gwu.edu RI Munoz Torres, Manuel/O-2330-2016; OI Munoz Torres, Manuel/0000-0002-9645-3260; Bateman, Alex/0000-0002-6982-4660; Finn, Robert/0000-0001-8626-2148; Robinson-Rechavi, Marc/0000-0002-3437-3329; Ouellette, B. F. Francis/0000-0003-4676-675X; D'Eustachio, Peter/0000-0002-5494-626X; Arighi, Cecilia/0000-0002-0803-4817; Martin, Maria-Jesus/0000-0001-5454-2815; O'Donovan, Claire/0000-0001-8051-7429 FU International Biocuration Conference committee; International Society for Biocuration; Intramural Research Program of the National Library of Medicine, NIH FX The publication fees of this article has been paid by the 2012 International Biocuration Conference committee and the International Society for Biocuration. This research was supported in part by the Intramural Research Program of the National Library of Medicine, NIH. NR 15 TC 6 Z9 6 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD OCT 29 PY 2012 AR bas036 DI 10.1093/database/bas036 PG 8 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 105ZG UT WOS:000316110600001 ER PT J AU Ames, NJ Sulima, P Ngo, T Barb, J Munson, PJ Paster, BJ Hart, TC AF Ames, Nancy J. Sulima, Pawel Ngo, Thoi Barb, Jennifer Munson, Peter J. Paster, Bruce J. Hart, Thomas C. TI A Characterization of the Oral Microbiome in Allogeneic Stem Cell Transplant Patients SO PLOS ONE LA English DT Article ID BONE-MARROW-TRANSPLANTATION; INTENSIVE-CARE-UNIT; DENTAL PLAQUE; RESPIRATORY PATHOGENS; INFECTIOUS COMPLICATIONS; NOSOCOMIAL INFECTIONS; HOST DISEASE; COLONIZATION; MICROARRAY; PNEUMONIA AB Background: The mouth is a complex biological structure inhabited by diverse bacterial communities. The purpose of this study is to describe the effects of allogeneic stem cell transplantation on the oral microbiota and to examine differences among those patients who acquired respiratory complications after transplantation. Methodology/Principal Findings: All patients were consented at the National Institutes of Health, Clinical Center. Bacterial DNA was analyzed from patients' oral specimens using the Human Oral Microbe Identification Microarray. The specimens were collected from four oral sites in 45 allogeneic transplantation patients. Specimens were collected at baseline prior to transplantation, after transplantation at the nadir of the neutrophil count and after myeloid engraftment. If respiratory signs and symptoms developed, additional specimens were obtained. Patients were followed for 100 days post transplantation. Eleven patients' specimens were subjected to further statistical analysis. Many common bacterial genera, such as Streptococcus, Veillonella, Gemella, Granulicatella and Camplyobacter were identified as being present before and after transplantation. Five of 11 patients developed respiratory complications following transplantation and there was preliminary evidence that the oral microbiome changed in their oral specimens. Cluster analysis and principal component analysis revealed this change in the oral microbiota. Conclusions/Significance: After allogeneic transplantation, the oral bacterial community's response to a new immune system was not apparent and many of the most common core oral taxa remained unaffected. However, the oral microbiome was affected in patients who developed respiratory signs and symptoms after transplantation. The association related to the change in the oral microbiota and respiratory complications after transplantation will be validated by future studies using high throughput molecular methods. C1 [Ames, Nancy J.; Ngo, Thoi] NIH, Ctr Clin, Nursing Serv, Bethesda, MD 20892 USA. [Ames, Nancy J.; Ngo, Thoi] NIH, Ctr Clin, Patient Care Serv, Bethesda, MD 20892 USA. [Sulima, Pawel; Hart, Thomas C.] Natl Inst Dent & Craniofacial Res, Human Craniofacial Genet Sect, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. [Barb, Jennifer; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Paster, Bruce J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Ames, NJ (reprint author), NIH, Ctr Clin, Nursing Serv, Bethesda, MD 20892 USA. EM names@nih.gov FU National Institute of Dental and Craniofacial Research of the National Institutes of Health, Bethesda, MD; Clinical Center Nursing and Patient Care Services of the National Institutes of Health, Bethesda, MD FX The authors acknowledge support from the Intramural Program of the National Institute of Dental and Craniofacial Research and the Clinical Center Nursing and Patient Care Services of the National Institutes of Health, Bethesda, MD. NR 45 TC 6 Z9 6 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 OCT 29 PY 2012 VL 7 IS 10 AR e47628 DI 10.1371/journal.pone.0047628 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300015 PM 23144704 ER PT J AU Cologna, SM Jiang, XS Backlund, PS Cluzeau, CVM Dail, MK Yanjanin, NM Siebel, S Toth, CL Jun, HS Wassif, CA Yergey, AL Porter, FD AF Cologna, Stephanie M. Jiang, Xiao-Sheng Backlund, Peter S. Cluzeau, Celine V. M. Dail, Michelle K. Yanjanin, Nicole M. Siebel, Stephan Toth, Cynthia L. Jun, Hyun-sik Wassif, Christopher A. Yergey, Alfred L. Porter, Forbes D. TI Quantitative Proteomic Analysis of Niemann-Pick Disease, Type C1 Cerebellum Identifies Protein Biomarkers and Provides Pathological Insight SO PLOS ONE LA English DT Article ID ACID-BINDING PROTEINS; LOW-DENSITY-LIPOPROTEIN; ALZHEIMERS-DISEASE; CHOLESTEROL TRAFFICKING; STATISTICAL-MODEL; MIGLUSTAT THERAPY; OXIDATIVE STRESS; ESCRT-III; NEURODEGENERATION; MICE AB Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disorder for which there is no definitive therapy. In NPC1, a pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While the genetic cause of NPC1 is known, we sought to gain a further understanding into the pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis and mass spectrometry, 77 differentially expressed proteins were identified in Npc1 mutant mice cerebella compared to controls. These include proteins involved in glucose metabolism, detoxification/oxidative stress and Alzheimer disease-related proteins. Furthermore, members of the fatty acid binding protein family, including FABP3, FABP5 and FABP7, were found to have altered expression in the Npc1 mutant cerebellum relative to control. Translating our findings from the murine model to patients, we confirm altered expression of glutathione s-transferase alpha, superoxide dismutase, and FABP3 in cerebrospinal fluid of NPC1 patients relative to pediatric controls. A subset of NPC1 patients on miglustat, a glycosphingolipid synthesis inhibitor, showed significantly decreased levels of FABP3 compared to patients not on miglustat therapy. This study provides an initial report of dysregulated proteins in NPC1 which will assist with further investigation of NPC1 pathology and facilitate implementation of therapeutic trials. C1 [Cologna, Stephanie M.; Jiang, Xiao-Sheng; Cluzeau, Celine V. M.; Dail, Michelle K.; Yanjanin, Nicole M.; Siebel, Stephan; Toth, Cynthia L.; Jun, Hyun-sik; Wassif, Christopher A.; Porter, Forbes D.] NICHHD, Program Dev Endocrinol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Backlund, Peter S.; Yergey, Alfred L.] NICHHD, Biomed Mass Spectrometry Facil, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), NICHHD, Program Dev Endocrinol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov RI Jun, Hyun Sik/C-6799-2013; Cluzeau, Celine/E-6873-2016; OI Cluzeau, Celine/0000-0002-7791-6223; Wassif, Christopher/0000-0002-2524-1420 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Human Genome Research Institute; National Institutes of Health (NIH) Clinical Center; NIH Office of Rare Diseases; Ara Parsegian Medical Research Foundation; Dana Angels Research Trust; National Center for Advancement of Therapeutics; Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD [HHSN275200900011c, N01-HD-9-0011] FX This work was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Therapeutics of Rare and Neglected Disease Program of National Human Genome Research Institute, and a Bench to Bedside award from the National Institutes of Health (NIH) Clinical Center and the NIH Office of Rare Diseases. Support for NY and the collection of control CSF was provide by the Ara Parsegian Medical Research Foundation and Dana Angels Research Trust. Support has also been provided by the Therapeutics and Rare Diseases Program of the National Center for Advancement of Therapeutics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, contract HHSN275200900011c, Ref. No. N01-HD-9-0011. The authors would also like to express our gratitude to the families and patients that have participated in the clinical trial. NR 69 TC 21 Z9 21 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 OCT 29 PY 2012 VL 7 IS 10 AR e47845 DI 10.1371/journal.pone.0047845 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300021 PM 23144710 ER PT J AU Doka, NI Jacob, ST Banura, P Moore, CC Meya, D Mayanja-Kizza, H Reynolds, SJ Scheld, WM Yuan, W AF Doka, Najah I. Jacob, Shevin T. Banura, Patrick Moore, Christopher C. Meya, David Mayanja-Kizza, Harriet Reynolds, Steven J. Scheld, W. Michael Yuan, Wen TI Enrichment of HIV-1 Subtype AD Recombinants in a Ugandan Cohort of Severely Septic Patients SO PLOS ONE LA English DT Article ID BLOOD-STREAM INFECTIONS; DISEASE PROGRESSION; INTENSIVE-CARE; ANTIRETROVIRAL THERAPY; RAKAI DISTRICT; SEVERE SEPSIS; TYPE-1; POPULATION; MANAGEMENT; PATTERNS AB Background: Several population-wide HIV-1 subtype distribution studies in Uganda have evaluated relatively healthy clinic patients. Given the differences in HIV-1 disease progression based on subtype, we examined HIV-1 subtype distribution and disease outcomes among hospitalized patients with severe sepsis. Methods: Patients with severe sepsis were enrolled at two hospitals in Uganda. Data collected included demographics, Karnofsky scores, highly active antiretroviral therapy (HAART) use, HIV-1 serostatus, CD4+ T cell concentration, whole blood lactate concentration, and blood cultures. HIV-1 subtypes were determined by sequencing parts of the gag and env genes, followed by phylogenetic analysis. Results: Of the 267 patients evaluated, 228 (85.4%) were HIV infected. The predominant HIV-1 subtypes were A (46%), D (17%), and AD recombinants (30%). HIV-1 subtypes B, C, and other recombinants were uncommon. Patients infected with HIV-1 subtypes A, D and AD viruses were similar in demographics, CD4(+) T cell concentration, HAART use, Karnofsky scores, whole blood lactate concentration, and positive blood cultures. There was no difference in 30-day mortality from severe sepsis between the 3 groups (p = 0.99). Conclusion: A high proportion of HIV-1 subtypes A and AD recombinants was observed in this cohort of severely septic patients. The proportion of AD recombinants was higher in this cohort than in previous cohorts of Ugandan HIV-1 patients. No difference in baseline demographics, clinical factors or 30-day mortality was seen across HIV-subtypes. C1 [Doka, Najah I.; Moore, Christopher C.; Scheld, W. Michael; Yuan, Wen] Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22903 USA. [Doka, Najah I.; Yuan, Wen] Univ Virginia, Myles H Thaler Ctr AIDS & Human Retroviruses Res, Charlottesville, VA USA. [Jacob, Shevin T.] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA USA. [Jacob, Shevin T.] Univ Washington, Dept Med, Int Resp & Severe Illness Ctr INTERSECT, Seattle, WA USA. [Banura, Patrick] Masaka Reg Referral Hosp, Dept Community Hlth, Masaka, Uganda. [Meya, David; Mayanja-Kizza, Harriet] Makerere Univ, Infect Dis Inst, Dept Med, Kampala, Uganda. [Reynolds, Steven J.] NIAID, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.] Johns Hopkins Sch Med, Baltimore, MD USA. RP Yuan, W (reprint author), Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22903 USA. EM wy5e@virginia.edu RI Andrade, Hugo/M-6631-2013; OI Andrade, Hugo/0000-0001-6781-6125; Mayanja-Kizza, Harriet/0000-0002-9297-6208; Meya, David/0000-0002-4138-240X FU Pfizer Initiative in International Health at the University of Virginia [GA 9001SZ] FX This work was supported by the Pfizer Initiative in International Health at the University of Virginia [GA 9001SZ]. Additional non-grant support was provided by the Rakai Health Sciences Program through the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 2 Z9 2 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 OCT 29 PY 2012 VL 7 IS 10 AR e48356 DI 10.1371/journal.pone.0048356 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300065 PM 23144755 ER PT J AU Heacock, M Poltoratsky, V Prasad, R Wilson, SH AF Heacock, Michelle Poltoratsky, Vladimir Prasad, Rajendra Wilson, Samuel H. TI Evidence for Abasic Site Sugar Phosphate-Mediated Cytotoxicity in Alkylating Agent Treated Saccharomyces cerevisiae SO PLOS ONE LA English DT Article ID DNA-POLYMERASE-BETA; ACTIVE-SITE; DIRECTED MUTAGENESIS; LYASE ACTIVITY; BUDDING YEAST; REPAIR; ENCODES; PURIFICATION; INHIBITORS; HOMOLOG AB To better understand alkylating agent-induced cytotoxicity and the base lesion DNA repair process in Saccharomyces cerevisiae, we replaced the RAD27(FEN1) open reading frame (ORF) with the ORF of the bifunctional human repair enzyme DNA polymerase (Pol) beta. The aim was to probe the effect of removal of the incised abasic site 59-sugar phosphate group (i.e., 5'-deoxyribose phosphate or 5'-dRP) in protection against methyl methanesulfonate (MMS)-induced cytotoxicity. In S. cerevisiae, Rad27(Fen1) was suggested to protect against MMS-induced cytotoxicity by excising multinucleotide flaps generated during repair. However, we proposed that the repair intermediate with a blocked 5'-end, i.e., 5'-dRP group, is the actual cytotoxic lesion. In providing a 5'-dRP group removal function mediated by dRP lyase activity of Pol beta, the effects of the 5'-dRP group were separated from those of the multinucleotide flap itself. Human Pol beta was expressed in S. cerevisiae, and this partially rescued the MMS hypersensitivity observed with rad27(fen1) - null cells. To explore this rescue effect, altered forms of Pol beta with site-directed eliminations of either the 5'-dRP lyase or polymerase activity were expressed in rad27(fen1) null cells. The 5'-dRP lyase, but not the polymerase activity, conferred the resistance to MMS. These results suggest that after MMS exposure, the 5'-dRP group in the repair intermediate is cytotoxic and that Rad27(Fen1) protection against MMS in wild-type cells is due to elimination of the 5'-dRP group. C1 [Heacock, Michelle; Poltoratsky, Vladimir; Prasad, Rajendra; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, 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, National Institute of Environmental Health Sciences [Z01ES050159] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [project number Z01ES050159]. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 3 Z9 3 U1 0 U2 0 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 OCT 29 PY 2012 VL 7 IS 10 AR e47945 DI 10.1371/journal.pone.0047945 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300027 PM 23144716 ER PT J AU Navarathna, DHMLP Lionakis, MS Lizak, MJ Munasinghe, J Nickerson, KW Roberts, DD AF Navarathna, Dhammika H. M. L. P. Lionakis, Michail S. Lizak, Martin J. Munasinghe, Jeeva Nickerson, Kenneth W. Roberts, David D. TI Urea Amidolyase (DUR1,2) Contributes to Virulence and Kidney Pathogenesis of Candida albicans SO PLOS ONE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE SYNTHASE; HELICOBACTER-PYLORI; MOUSE MODEL; IMMUNE-RESPONSES; EPITHELIAL-CELLS; AMMONIA; EXPRESSION; GENE; INDUCTION AB The intracellular enzyme urea amidolyase (Dur1,2p) enables C. albicans to utilize urea as a sole nitrogen source. Because deletion of the DUR1,2 gene reduces survival of C. albicans co-cultured with a murine macrophage cell line, we investigated the role of Dur1,2p in pathogenesis using a mouse model of disseminated candidiasis. A dur1,2 Delta/dur1,2 Delta strain was significantly less virulent than the wild-type strain, showing significantly higher survival rate, better renal function, and decreased and less sustained fungal colonization in kidney and brain. Complementation of the mutant restored virulence. DUR1,2 deletion resulted in a milder host inflammatory reaction. Immunohistochemistry, flow cytometry, and magnetic resonance imaging showed decreased phagocytic infiltration into infected kidneys. Systemic cytokine levels of wild-type mice infected with the dur1,2 mutant showed a more balanced systemic pro-inflammatory cytokine response. Host gene expression and protein analysis in infected kidneys revealed parallel changes in the local immune response. Significant differences were observed in the kidney IL-1 inflammatory pathway, IL-15 signaling, MAP kinase signaling, and the alternative complement pathway. We conclude that Dur1,2p is important for kidney colonization during disseminated candidiasis and contributes to an unbalanced host inflammatory response and subsequent renal failure. Therefore, this Candida-specific enzyme may represent a useful drug target to protect the host from kidney damage associated with disseminated candidiasis. C1 [Navarathna, Dhammika H. M. L. P.; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lizak, Martin J.; Munasinghe, Jeeva] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Nickerson, Kenneth W.] Univ Nebraska, Sch Biol Sci, Lincoln, NE USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, 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; University of Nebraska Tobacco Settlement Biomedical Research Enhancement Fund; John C. and Nettie V. David Memorial Trust Fund; University of Nebraska Foundation FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (DDR), the University of Nebraska Tobacco Settlement Biomedical Research Enhancement Fund (KWN), the John C. and Nettie V. David Memorial Trust Fund (KWN), Ann L. Kelsall and the Farnesol and Candida albicans Research Fund, University of Nebraska Foundation (KWN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 12 Z9 13 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 OCT 29 PY 2012 VL 7 IS 10 AR e48475 DI 10.1371/journal.pone.0048475 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300074 PM 23144764 ER PT J AU Jiao, XD Wang, PF Li, SQ Li, AR Guo, XM Zhang, QJ Hejtmancik, JF AF Jiao, Xiaodong Wang, Panfeng Li, Shiqiang Li, Anren Guo, Xiangming Zhang, Qingjiong Hejtmancik, J. Fielding TI Association of markers at chromosome 15q14 in Chinese patients with moderate to high myopia SO MOLECULAR VISION LA English DT Article ID GENOME-WIDE ASSOCIATION; DOMINANT HIGH MYOPIA; HIGH-GRADE MYOPIA; SINGLE NUCLEOTIDE POLYMORPHISMS; SAMPLE-SIZE CALCULATIONS; RECESSIVE HIGH MYOPIA; REFRACTIVE ERROR; SUSCEPTIBILITY LOCUS; GENETIC ASSOCIATION; LINKAGE AB Purpose: To investigate the association of two reported regions on chromosome 15 with moderate to high myopia in two Chinese cohorts from southern China. Methods: Two candidate regions on 15q14 and 15q25 were selected based on reported association with refractive error in the literature. Five single nucleotide polymorphisms (SNPs) were genotyped in 300 university students with high myopia at Guangzhou and 308 without refractive error, and 96 university students of Chaoshan Chinese origin with moderate to high myopia and 96 without refractive error. Genotypes were evaluated using direct sequencing and analyzed with chi-square, Armitage trend, and Mantel-Haenszel tests, and regression analysis. Results: Of the five SNPs screened, alleles of rs634990 and rs524952 in the 15q14 region showed evidence of allelic association with moderate to high myopia (p<8.81x10(-7) and p<1.57x10(-6), respectively) in the Guangzhou group, but not in the Chaoshan group. The SNPs at 15q25 did not show significant association in any group. Association of rs634990 and rs524952 were still significant when both groups were combined into a single analysis (p<1.66x10(-6) and p<2.72x10(-6), respectively), and for genotypic, additive, and dominant models. Conclusions: This study confirms the significant association of rs634990 and rs524952 on chromosome 15q14 previously reported in European and Japanese populations with high myopia in the Guangzhou but not the Chaoshan Chinese populations, suggesting that genetic contributors to high myopia in the Chaoshan population might be different from other Chinese populations. C1 [Wang, Panfeng; Li, Shiqiang; Guo, Xiangming; Zhang, Qingjiong] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [Jiao, Xiaodong; Li, Anren; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, QJ (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, 54 Xianlie Rd, Guangzhou 510060, Guangdong, Peoples R China. EM zhangqji@mail.sysu.edu.cn FU National Science Fund for Distinguished Young Scholars [30,725,044]; Fundamental Research Funds of State Key Lab of Ophthalmology, Sun Yat-sen University FX The authors like to thank all the participants for their kind cooperation in this study. Grant information: This study was supported by National Science Fund for Distinguished Young Scholars (30,725,044 to Q.Z.) and the Fundamental Research Funds of State Key Lab of Ophthalmology, Sun Yat-sen University. NR 56 TC 8 Z9 9 U1 0 U2 5 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD OCT 26 PY 2012 VL 18 IS 271-72 BP 2633 EP 2645 PG 13 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 052VK UT WOS:000312226400002 PM 23170057 ER PT J AU Liu, TF Xiao, N Liu, YX Wilson, B Li, J Wang, YY Cao, X Liu, ZQ AF Liu, Tengfei Xiao, Nan Liu, Yuxin Wilson, Belinda Li, Jing Wang, Yuanyuan Cao, Xu Liu, Zhiqin TI The anti-inflammatory effects of ethyl acetate on Lipopolysaccharide/D-galactosamine challenged mice and Lipopolysaccharide activated RAW264.7 cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Ethyl acetate; LPS; Endotoxic shock; Anti-inflammatory; RAW264.7 ID CHAIN FATTY-ACIDS; OXIDE SYNTHASE EXPRESSION; NITRIC-OXIDE; KAPPA-B; INFLAMMATORY DISEASES; CYTOKINES; ETHANOL; PHOSPHORYLATION; NEUTROPHILS; MEDIATORS AB Ethyl acetate (EA) is an ordinary organic compound in fruits, wine and cosmetics, and used as a solvent frequently. With the recent observation in our experiment, we suspected that EA could affect immune function, in particular macrophage activity. In this paper, we tested EA's protect effect against death in Lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced endotoxic shock model in mice. And also found EA decreased the LPS-induced mRNA expression of mediators of inflammation including cyclooxygenase 2 (COX2), inducible NOS (iNOS), and tumor necrosis factor alpha (TNF alpha) in RAW264.7 cells. Consequently, EA decreased the production of, TNF alpha and the inflammatory agent nitric oxide (NO) in RAW264.7 cells treated with LPS. Other pro-inflammatory cytokines such as IL-1h and IL-6 were similarly decreased by EA treatment of RAW264.7 cells. The potential mechanism may associate with NF-kappa B activity as we shown. Taken together, these results suggest that EA has anti-inflammatory properties. (C) 2012 Elsevier Inc. All rights reserved. C1 [Liu, Tengfei; Xiao, Nan; Liu, Yuxin; Li, Jing; Cao, Xu] Hebei Univ, Coll Pharmaceut Sci, Lab Cell Pharmacol, Baoding 071002, Peoples R China. [Liu, Yuxin; Liu, Zhiqin] Hebei Univ, Drug Qual Control Key Lab Hebei Prov, Baoding 071002, Peoples R China. [Wilson, Belinda] Natl Inst Environm Hlth Sci, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. [Wang, Yuanyuan] Hebei Univ, Sch Biol, Mol Biol Lab, Baoding 071002, Peoples R China. RP Liu, YX (reprint author), Hebei Univ, Coll Pharmaceut Sci, Lab Cell Pharmacol, 180 E Wusi Rd, Baoding 071002, Peoples R China. EM yuxinliu@hbu.edu.cn FU Hebei University [y2008118]; National Sciences and Technology subject for Returned Overseas Chinese Scholars [2008-199]; Key Project of Science and Technology for Universities in Hebei Province [ZD2010234]; Key Basic Applied Research Program of Hebei Province [11966411D] FX This research was supported by the Hebei University grant (y2008118), the National Sciences and Technology subject for Returned Overseas Chinese Scholars (2008-199), the Key Project of Science and Technology for Universities in Hebei Province (ZD2010234), and the Key Basic Applied Research Program of Hebei Province (11966411D). NR 41 TC 4 Z9 4 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 26 PY 2012 VL 427 IS 3 BP 518 EP 524 DI 10.1016/j.bbrc.2012.09.088 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 039RC UT WOS:000311263200015 PM 23022187 ER PT J AU Loven, J Orlando, DA Sigova, AA Lin, CY Rahl, PB Burge, CB Levens, DL Lee, TI Young, RA AF Loven, Jakob Orlando, David A. Sigova, Alla A. Lin, Charles Y. Rahl, Peter B. Burge, Christopher B. Levens, David L. Lee, Tong Ihn Young, Richard A. TI Revisiting Global Gene Expression Analysis SO CELL LA English DT Article ID C-MYC; MOLECULAR CLASSIFICATION; BREAST-CANCER; RNA-SEQ; NORMALIZATION; ARRAYS; PREDICTION; DISCOVERY; ADENOCARCINOMA; MICROARRAYS AB Gene expression analysis is a widely used and powerful method for investigating the transcriptional behavior of biological systems, for classifying cell states in disease, and for many other purposes. Recent studies indicate that common assumptions currently embedded in experimental and analytical practices can lead to misinterpretation of global gene expression data. We discuss these assumptions and describe solutions that should minimize erroneous interpretation of gene expression data from multiple analysis platforms. C1 [Loven, Jakob; Orlando, David A.; Sigova, Alla A.; Lin, Charles Y.; Rahl, Peter B.; Lee, Tong Ihn; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Lin, Charles Y.] MIT, Computat & Syst Biol Program, Cambridge, MA 02139 USA. [Burge, Christopher B.; Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Levens, David L.] NCI, Gene Regulat Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Lee, TI (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM tlee@wi.mit.edu; young@wi.mit.edu RI Young, Richard/F-6495-2012; Levens, David/C-9216-2009 OI Young, Richard/0000-0001-8855-8647; Levens, David/0000-0002-7616-922X FU National Institutes of Health [HG002668, CA146445]; American Cancer Society [PF-11-042-01-DMC]; Swedish Research Council [VR-B0086301] FX We thank Tom Volkert, Jeong-Ah Kwen, Jennifer Love, and Sumeet Gupta at the Whitehead Genome Technologies Core for Solexa sequencing and microarray processing and Ziv Bar-Joseph for critical comments. This work was supported by National Institutes of Health grants HG002668 (R. A. Y.) and CA146445 (R. A. Y., T. I. L.), an American Cancer Society Postdoctoral Fellowship PF-11-042-01-DMC (P. B. R.) and a Swedish Research Council Postdoctoral Fellowship VR-B0086301 (J.L.). NR 44 TC 191 Z9 192 U1 4 U2 84 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 26 PY 2012 VL 151 IS 3 BP 476 EP 482 DI 10.1016/j.cell.2012.10.012 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 029WY UT WOS:000310529300006 PM 23101621 ER PT J AU Jia, JL Zheng, XB Hu, GQ Cui, KR Zhang, JQ Zhang, AY Jiang, H Lu, BW Yates, J Liu, CY Zhao, KJ Zheng, YX AF Jia, Junling Zheng, Xiaobin Hu, Gangqing Cui, Kairong Zhang, Junqi Zhang, Anying Jiang, Hao Lu, Bingwen Yates, John, III Liu, Chengyu Zhao, Keji Zheng, Yixian TI Regulation of Pluripotency and Self-Renewal of ESCs through Epigenetic-Threshold Modulation and mRNA Pruning SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; CORE TRANSCRIPTIONAL NETWORK; DEVELOPMENTAL REGULATORS; TROPHECTODERM DIFFERENTIATION; GENE-EXPRESSION; POLYMERASE-II; TARGET GENES; CHROMATIN; POLYCOMB; PROTEIN AB Embryonic stem cell (ESC) pluripotency requires bivalent epigenetic modifications of key developmental genes regulated by various transcription factors and chromatin-modifying enzymes. How these factors coordinate with one another to maintain the bivalent chromatin state so that ESCs can undergo rapid self-renewal while retaining pluripotency is poorly understood. We report that Utf1, a target of Oct4 and Sox2, is a bivalent chromatin component that buffers poised states of bivalent genes. By limiting PRC2 loading and histone 3 lysine-27 trimethylation, Utf1 sets proper activation thresholds for bivalent genes. It also promotes nuclear tagging of messenger RNAs (mRNAs) transcribed from insufficiently silenced bivalent genes for cytoplasmic degradation through mRNA decapping. These opposing functions of Utf1 promote coordinated differentiation. The mRNA degradation function also ensures rapid cell proliferation by blocking the Myc-Arf feedback control. Thus, Utf1 couples the core pluripotency factors with Myc and PRC2 networks to promote the pluripotency and proliferation of ESCs. C1 [Jia, Junling; Zheng, Xiaobin; Zhang, Junqi; Zhang, Anying; Jiang, Hao; Zheng, Yixian] Carnegie Inst Sci, Dept Embryol, Baltimore, MD 21218 USA. [Jia, Junling; Zheng, Yixian] NHLBI, Howard Hughes Med Inst, NIH, Bethesda, MD 20892 USA. [Hu, Gangqing; Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. [Lu, Bingwen; Yates, John, III] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. RP Zheng, YX (reprint author), Carnegie Inst Sci, Dept Embryol, 3520 San Martin Dr, Baltimore, MD 21218 USA. EM zheng@ciwemb.edu RI HU, GANGQING/K-5849-2012 FU NIH [GM56312, MH067880, P41 RR011823]; NHLBI; HHMI [P41 RR011823, R01 HL079442-08]; Cystic Fibrosis Foundation Therapeutics, Inc. [BALCH05X5]; [R01 GM056312] FX We thank Allison Pinder for deep-seq; Nick Ingolia for advice on data analyses; and Chen-ming Fan, Nick Ingolia, Xin Chen, Haiqing Zhao, Dong Yang, Ma Wan, Max Guo, and members of the Zheng lab for comments. This work was supported by NIH (GM56312 to Y. Z.; MH067880 and P41 RR011823 to J. R. Y.) and by NHLBI intramural research (G. H., K. C., C. L., and K. Z.). This work was also supported by R01 GM056312 (Y. Z., J. Z., A. Z.), HHMI (J. J., Y. Z.), P41 RR011823 and R01 HL079442-08 (J. Y.), and Cystic Fibrosis Foundation Therapeutics, Inc. BALCH05X5 (B.L.). NR 54 TC 30 Z9 30 U1 6 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 26 PY 2012 VL 151 IS 3 BP 576 EP 589 DI 10.1016/j.cell.2012.09.023 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 029WY UT WOS:000310529300014 PM 23101626 ER PT J AU Kohr, MJ Aponte, A Sun, JH Gucek, M Steenbergen, C Murphy, E AF Kohr, Mark J. Aponte, Angel Sun, Junhui Gucek, Marjan Steenbergen, Charles Murphy, Elizabeth TI Measurement of S-Nitrosylation Occupancy in the Myocardium With Cysteine-Reactive Tandem Mass Tags Short Communication SO CIRCULATION RESEARCH LA English DT Article DE S-nitrosylation; oxidation; occupancy; ischemic preconditioning ID PROTEINS AB Rationale: S-nitrosylation (SNO) is a reversible, thiol-based protein modification that plays an important role in the myocardium by protecting critical cysteine residues from oxidation. However, little is known with regard to the percentage of a given protein that is modified by SNO (ie, SNO occupancy). Current methods allow for the relative quantification of SNO levels, but not for the determination of SNO occupancy. Objective: To develop a method for the measurement of SNO occupancy, and apply this methodology to determine SNO occupancy in the myocardium. Methods and Results: We developed a differential cysteine-reactive tandem mass tag (cysTMT) labeling procedure for the measurement of SNO occupancy. To validate this cysTMT labeling method, we treated whole-heart homogenates with the S-nitrosylating agent S-nitrosoglutathione and determined maximal SNO occupancy. We also examined SNO occupancy under more physiological conditions and observed that SNO occupancy is low for most protein targets at baseline. Following ischemic preconditioning, SNO occupancy increased to an intermediate level compared to baseline and S-nitrosoglutathione treatment, and this is consistent with the ability of SNO to protect against cysteine oxidation. Conclusions: This novel cysTMT labeling approach provides a method for examining SNO occupancy in the myocardium. Using this approach, we demonstrated that IPC-induced SNO occupancy levels are sufficient to protect against oxidation. (Circ Res. 2012;111:1308-1312.) C1 [Murphy, Elizabeth] NHLBI, Lab Cardiac Physiol, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Aponte, Angel; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Kohr, Mark J.; Steenbergen, Charles] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Murphy, E (reprint author), NHLBI, Lab Cardiac Physiol, Syst Biol Ctr, NIH, Bldg 10,Room 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@nhlbi.nih.gov OI Kohr, Mark/0000-0002-6034-5962 FU National Institutes of Health (NIH) [1F32HL096142, 5R01HL039752]; NHLBI/NIH Intramural Program FX This work was supported by National Institutes of Health (NIH) grants 1F32HL096142 (to M.J.K.) and 5R01HL039752 (to C. S.), and the NHLBI/NIH Intramural Program (to A. A., J.S., M. G., & E.M.). NR 11 TC 34 Z9 34 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD OCT 26 PY 2012 VL 111 IS 10 BP 1308 EP U166 DI 10.1161/CIRCRESAHA.112.271320 PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 029NA UT WOS:000310501300012 PM 22865876 ER PT J AU Sassa, A Beard, WA Prasad, R Wilson, SH AF Sassa, Akira Beard, William A. Prasad, Rajendra Wilson, Samuel H. TI DNA Sequence Context Effects on the Glycosylase Activity of Human 8-Oxoguanine DNA Glycosylase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; THYMINE GLYCOL RESIDUE; DUAL-REACTION MODE; POLYMERASE-BETA; SACCHAROMYCES-CEREVISIAE; MUTATIONAL HOTSPOT; TANDEM MUTATIONS; AP-ENDONUCLEASE; BOVINE TESTIS; HUMAN-CELLS AB Human 8-oxoguanine DNA glycosylase (OGG1) is a key enzyme involved in removing 7,8-dihydro-8-oxoguanine (8-oxoG), a highly mutagenic DNA lesion generated by oxidative stress. The removal of 8-oxoG by OGG1 is affected by the local DNA sequence, and this feature most likely contributes to observed mutational hot spots in genomic DNA. To elucidate the influence of local DNA sequence on 8-oxoG excision activity of OGG1, we conducted steady-state, pre-steady-state, and single turnover kinetic evaluation of OGG1 in alternate DNA sequence contexts. The sequence context effect was studied for a mutational hot spot at a CpG dinucleotide. Altering either the global DNA sequence or the 5'-flanking unmodified base pair failed to influence the excision of 8-oxoG. Methylation of the cytosine 5' to 8-oxoG also did not affect 8-oxoG excision. In contrast, a 5'-neighboring mismatch strongly decreased the rate of 8-oxoG base removal. Substituting the 5'-C in the CpG dinucleotide with T, A, or tetrahydrofuran (i.e. T:G, A:G, and tetrahydrofuran: G mispairs) resulted in a 10-, 13-, and 4-fold decrease in the rate constant for 8-oxoG excision, respectively. A greater loss in activity was observed when T:C or A:C was positioned 5' of 8-oxoG (59- and 108-fold, respectively). These results indicate that neighboring structural abnormalities 5' to 8-oxoG deter its repair thereby enhancing its mutagenic potential. C1 [Sassa, Akira; Beard, William A.; Prasad, Rajendra; Wilson, Samuel H.] NIEHS, NIH, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Beard, WA (reprint author), 111 TW Alexander Dr,POB 12233,MD F3-01, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU National Institutes of Health Research Project in the Intramural Research Program, NIEHS [Z01-ES050158] FX This work was supported, in whole or in part, by National Institutes of Health Research Project Grant Z01-ES050158 in the Intramural Research Program, NIEHS. NR 69 TC 17 Z9 17 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 26 PY 2012 VL 287 IS 44 BP 36702 EP 36710 DI 10.1074/jbc.M112.397786 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 030RT UT WOS:000310588500008 PM 22989888 ER PT J AU Rogers, H Wang, L Yu, XB Alnaeeli, M Cui, KR Zhao, KJ Bieker, JJ Prchal, J Huang, SM Weksler, B Noguchi, CT AF Rogers, Heather Wang, Li Yu, Xiaobing Alnaeeli, Mawadda Cui, Kairong Zhao, Keji Bieker, James J. Prchal, Josef Huang, Suming Weksler, Babette Noguchi, Constance Tom TI T-cell Acute Leukemia 1 (TAL1) Regulation of Erythropoietin Receptor and Association with Excessive Erythrocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; TRANSCRIPTION FACTOR GATA-1; ERYTHROID-CELLS; HEMATOPOIETIC DEVELOPMENT; FAMILIAL ERYTHROCYTOSIS; CHROMATIN OCCUPANCY; OXYGEN HOMEOSTASIS; POLYCYTHEMIA-VERA; GENE-EXPRESSION; POSITIVE ROLE AB During erythropoiesis, erythropoietin stimulates induction of erythroid transcription factors that activate expression of erythroid genes including the erythropoietin receptor (EPO-R) that results in increased sensitivity to erythropoietin. DNA binding of the basic helix-loop-helix transcription factor, TAL1/SCL, is required for normal erythropoiesis. A link between elevated TAL1 and excessive erythrocytosis is suggested by erythroid progenitor cells from a patient that exhibits unusually high sensitivity to erythropoietin with concomitantly elevated TAL1 and EPO-R expression. We found that TAL1 regulates EPO-R expression mediated via three conserved E-box binding motifs (CAGCTG) in the EPO-R 5' untranslated transcribed region. TAL1 increases association of the GATA-1.TAL1.LMO2.LDB1 transcription activation complex to the region that includes the transcription start site and the 5' GATA and 3' E-box motifs flanking the EPO-R transcription start site suggesting that TAL1 promotes accessibility of this region. Nucleosome shifting has been demonstrated to facilitate TAL1 but not GATA-1 binding to regulate target gene expression. Accordingly, we observed that with induced expression of EPO-R in hemotopoietic progenitor cells, nucleosome phasing shifts to increase the linker region containing the EPO-R transcription start site and TAL1 binds to the flanking 5' GATA and 3' E-box regions of the promoter. These data suggest that TAL1 binds to the EPO-R promoter to activate EPO-R expression and provides a potential link to elevated EPO-R expression leading to hypersensitivity to erythropoietin and the resultant excessive erythrocytosis. C1 [Rogers, Heather; Wang, Li; Yu, Xiaobing; Alnaeeli, Mawadda; Noguchi, Constance Tom] NIDDK, Mol Med Branch, Bethesda, MD 20892 USA. [Cui, Kairong; Zhao, Keji] NHLBI, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. [Bieker, James J.] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. [Prchal, Josef] Univ Utah, Div Hematol, Salt Lake City, UT 84132 USA. [Prchal, Josef] VAH, Salt Lake City, UT 84132 USA. [Huang, Suming] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL USA. [Huang, Suming] Univ Florida, Coll Med, Shands Canc Ctr, Gainesville, FL USA. [Weksler, Babette] Cornell Univ, Weill Med Coll, Div Hematol Oncol, New York, NY 10065 USA. RP Noguchi, CT (reprint author), Bldg 10,Rm 9N319,10 Ctr Dr,MSC 1822, Bethesda, MD 20892 USA. EM connien@helix.nih.gov RI cheng, yong/I-4270-2012 FU National Institutes of Health Intramural Research Program of the NIDDK FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIDDK. NR 53 TC 4 Z9 8 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 26 PY 2012 VL 287 IS 44 BP 36720 EP 36731 DI 10.1074/jbc.M112.378398 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 030RT UT WOS:000310588500010 PM 22982397 ER PT J AU Nakaya, N Sultana, A Lee, HS Tomarev, SI AF Nakaya, Naoki Sultana, Afia Lee, Hee-Sheung Tomarev, Stanislav I. TI Olfactomedin 1 Interacts with the Nogo A Receptor Complex to Regulate Axon Growth SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MYELIN-ASSOCIATED GLYCOPROTEIN; REGENERATION; EXPRESSION; GENE; INHIBITION; PANCORTINS; MUTATIONS; A2-PANCORTINS; PROTEINS; EPILEPSY AB Olfm1, a secreted highly conserved glycoprotein, is detected in peripheral and central nervous tissues and participates in neural progenitor maintenance, cell death in brain, and optic nerve arborization. In this study, we identified Olfm1 as a molecule promoting axon growth through interaction with the Nogo A receptor (NgR1) complex. Olfm1 is coexpressed with NgR1 in dorsal root ganglia and retinal ganglion cells in embryonic and postnatal mice. Olfm1 specifically binds to NgR1, as judged by alkaline phosphatase assay and coimmunoprecipitation. The addition of Olfm1 inhibited the growth cone collapse of dorsal root ganglia neurons induced by myelin-associated inhibitors, indicating that Olfm1 attenuates the NgR1 receptor functions. Olfm1 caused the inhibition of NgR1 signaling by interfering with interaction between NgR1 and its coreceptors p75NTR or LINGO-1. In zebrafish, inhibition of optic nerve extension by olfm1 morpholino oligonucleotides was partially rescued by dominant negative ngr1 or lingo-1. These data introduce Olfm1 as a novel NgR1 ligand that may modulate the functions of the NgR1 complex in axonal growth. C1 [Nakaya, Naoki; Sultana, Afia; Lee, Hee-Sheung; Tomarev, Stanislav I.] NEI, Sect Mol Mech Glaucoma, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, Sect Mol Mech Glaucoma, Retinal Cell & Mol Biol Lab, NIH, Bldg 6,Room 212,6 Ctr Dr,MSC 0606, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov FU National Eye Institute, National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 36 TC 26 Z9 30 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 26 PY 2012 VL 287 IS 44 BP 37171 EP 37184 DI 10.1074/jbc.M112.389916 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 030RT UT WOS:000310588500051 PM 22923615 ER PT J AU Gupta, V Bhinge, KN Hosain, SB Xiong, K Gu, X Shi, RH Ho, MY Khoo, KH Li, SC Li, YT Ambudkar, SV Jazwinski, SM Liu, YY AF Gupta, Vineet Bhinge, Kaustubh N. Hosain, Salman B. Xiong, Katherine Gu, Xin Shi, Runhua Ho, Ming-Yi Khoo, Kay-Hooi Li, Su-Chen Li, Yu-Teh Ambudkar, Suresh V. Jazwinski, S. Michal Liu, Yong-Yu TI Ceramide Glycosylation by Glucosylceramide Synthase Selectively Maintains the Properties of Breast Cancer Stem Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAMMARY PROGENITOR CELLS; DRUG-RESISTANCE; SELF-RENEWAL; STEM/PROGENITOR CELLS; CARCINOMA-CELLS; BONE-MARROW; IN-VITRO; EXPRESSION; GLYCOSPHINGOLIPIDS; DIFFERENTIATION AB Cancer stem cells are distinguished from normal adult stem cells by their stemness without tissue homeostasis control. Glycosphingolipids (GSLs), particularly globo-series GSLs, are important markers of undifferentiated embryonic stem cells, but little is known about whether or not ceramide glycosylation, which controls glycosphingolipid synthesis, plays a role in modulating stem cells. Here, we report that ceramide glycosylation catalyzed by glucosylceramide synthase, which is enhanced in breast cancer stem cells (BCSCs) but not in normal mammary epithelial stem cells, maintains tumorous pluripotency of BCSCs. Enhanced ceramide glycosylation and globotriosylceramide (Gb3) correlate well with the numbers of BCSCs in breast cancer cell lines. In BCSCs sorted with CD44(+)/ESA(+)/CD24(-) markers, Gb3 activates c-Src/beta-catenin signaling and up-regulates the expression of FGF-2, CD44, and Oct-4 enriching tumorigenesis. Conversely, silencing glucosylceramide synthase expression disrupts Gb3 synthesis and selectively kills BCSCs through deactivation of c-Src/beta-catenin signaling. These findings highlight the unexploited role of ceramide glycosylation in selectively maintaining the tumorous pluripotency of cancer stem cells. It speculates that disruption of ceramide glycosylation or globo-series GSL is a useful approach to specifically target BCSCs specifically. C1 [Gupta, Vineet; Bhinge, Kaustubh N.; Hosain, Salman B.; Xiong, Katherine; Liu, Yong-Yu] Univ Louisiana Monroe, Dept Basic Pharmaceut Sci, Monroe, LA 71209 USA. [Gu, Xin] Louisiana State Univ, Hlth Sci Ctr, Dept Pathol, Shreveport, LA 71130 USA. [Shi, Runhua; Khoo, Kay-Hooi] Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, Shreveport, LA 71130 USA. [Ho, Ming-Yi] Acad Sinica, Inst Biol Chem, Taipei 115, Taiwan. [Li, Su-Chen; Li, Yu-Teh] Tulane Univ, Sch Med, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA. [Jazwinski, S. Michal] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Jazwinski, S. Michal] Tulane Univ, Sch Med, Tulane Ctr Aging, New Orleans, LA 70112 USA. [Ambudkar, Suresh V.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Liu, YY (reprint author), Univ Louisiana Monroe, Dept Basic Pharmaceut Sci, 700 Univ Ave, Monroe, LA 71209 USA. EM yliu@ulm.edu RI Liu, Yong-Yu/H-8593-2014; OI Liu, Yong-Yu/0000-0002-7968-0162 FU National Institutes of Health, National Center for Research Resources [5P20RR016456-11]; National Institute of General Medical Sciences [8 P20 GM103424-11]; Mizutani Foundation for Glycoscience, Japan; Center for Cancer Research, NCI, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants 5P20RR016456-11 from the National Center for Research Resources and 8 P20 GM103424-11 from the National Institute of General Medical Sciences (to Y.-Y. L.). This work was also supported by funds from the Mizutani Foundation for Glycoscience, Japan (to Y.-Y. L.).; Supported by the Intramural Research Program, Center for Cancer Research, NCI, National Institutes of Health. NR 71 TC 19 Z9 20 U1 0 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 26 PY 2012 VL 287 IS 44 BP 37195 EP 37205 DI 10.1074/jbc.M112.396390 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 030RT UT WOS:000310588500053 PM 22936806 ER PT J AU Varma, S Cao, YX Tagne, JB Lakshminarayanan, M Li, J Friedman, TB Morell, RJ Warburton, D Kotton, DN Ramirez, MI AF Varma, Saaket Cao, Yuxia Tagne, Jean-Bosco Lakshminarayanan, Meenakshi Li, Jun Friedman, Thomas B. Morell, Robert J. Warburton, David Kotton, Darrell N. Ramirez, Maria I. TI The Transcription Factors Grainyhead-like 2 and NK2-Homeobox 1 Form a Regulatory Loop That Coordinates Lung Epithelial Cell Morphogenesis and Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; PROBE LEVEL DATA; FACTOR-I; GENE-EXPRESSION; EPIDERMAL DIFFERENTIATION; BRANCHING MORPHOGENESIS; STEM-CELLS; TELOMERASE; PROTEIN; MOUSE AB The Grainyhead family of transcription factors controls morphogenesis and differentiation of epithelial cell layers in multicellular organisms by regulating cell junction- and proliferation-related genes. Grainyhead-like 2 (Grhl2) is expressed in developing mouse lung epithelium and is required for normal lung organogenesis. The specific epithelial cells expressing Grhl2 and the genes regulated by Grhl2 in normal lungs are mostly unknown. In these studies we identified the NK2-homeobox 1 transcription factor (Nkx2-1) as a direct transcriptional target of Grhl2. By binding and transcriptional assays and by confocal microscopy we showed that these two transcription factors form a positive feedback loop in vivo and in cell lines and are co-expressed in lung bronchiolar and alveolar type II cells. The morphological changes observed in flattening lung alveolar type II cells in culture are associated with down-regulation of Grhl2 and Nkx2-1. Reduction of Grhl2 in lung epithelial cell lines results in lower expression levels of Nkx2-1 and of known Grhl2 target genes. By microarray analysis we identified that in addition to Cadherin1 and Claudin4, Grhl2 regulates other cell interaction genes such as semaphorins and their receptors, which also play a functional role in developing lung epithelium. Impaired collective cell migration observed in Grhl2 knock-down cell monolayers is associated with reduced expression of these genes and may contribute to the altered epithelial phenotype reported in Grhl2 mutant mice. Thus, Grhl2 functions at the nexus of a novel regulatory network, connecting lung epithelial cell identity, migration, and cell-cell interactions. C1 [Varma, Saaket; Cao, Yuxia; Tagne, Jean-Bosco; Lakshminarayanan, Meenakshi; Li, Jun; Kotton, Darrell N.; Ramirez, Maria I.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. [Warburton, David] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [Friedman, Thomas B.; Morell, Robert J.] NIDCD, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. RP Ramirez, MI (reprint author), 72 E Concord St,R304, Boston, MA 02118 USA. EM mramirez@bu.edu OI Tagne, Jean-Bosco/0000-0003-1830-9156; Morell, Robert/0000-0003-1537-7356; Kotton, Darrell/0000-0002-9604-8476 FU National Institutes of Health Grant [R01 HL0833034, P01 HL47049]; California Institute of Regenerative Medicine [TG2-01168]; NIDCD, National Institutes of Health, Intramural Funds [DC000039-15] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 HL0833034 (NHLBI; to M. I. R., D. N. K., and S. V.) and in part by P01 HL47049 (NHLBI; to M. I. R. and D. N. K.). This work was also supported by the California Institute of Regenerative Medicine TG2-01168 (to S. V. and D. W.).; Supported by NIDCD, National Institutes of Health, Intramural Funds DC000039-15. NR 60 TC 27 Z9 30 U1 0 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 26 PY 2012 VL 287 IS 44 BP 37282 EP 37295 DI 10.1074/jbc.M112.408401 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 030RT UT WOS:000310588500060 PM 22955271 ER PT J AU McDonald, M Box, H Bian, W Kendall, A Tycko, R Stubbs, G AF McDonald, Michele Box, Hayden Bian, Wen Kendall, Amy Tycko, Robert Stubbs, Gerald TI Fiber Diffraction Data Indicate a Hollow Core for the Alzheimer's A beta 3-Fold Symmetric Fibril SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE amyloid structure; amyloid beta peptide; X-ray fiber diffraction; solid-state NMR; Alzheimer's disease ID TOBACCO-MOSAIC-VIRUS; X-RAY-DIFFRACTION; SOLID-STATE NMR; AMYLOID FIBRILS; INTENSITY DISTRIBUTION; NONCRYSTALLINE FIBERS; MOLECULAR-DYNAMICS; STRUCTURAL BASIS; A-BETA(1-40); DISEASE AB Amyloid beta protein (A beta), the principal component of the extracellular plaques found in the brains of patients with Alzheimer's disease, forms fibrils well suited to structural study by X-ray fiber diffraction. Fiber diffraction patterns from the 40-residue form A beta(1-40) confirm a number of features of a 3-fold symmetric A beta model from solid-state NMR (ssNMR) but suggest that the fibrils have a hollow core not present in the original ssNMR models. Diffraction patterns calculated from a revised 3-fold hollow model with a more regular beta-sheet structure are in much better agreement with the observed diffraction data than patterns calculated from the original ssNMR model. Refinement of a hollow-core model against ssNMR data led to a revised ssNMR model, similar to the fiber diffraction model. (C 2012 Elsevier Ltd. All rights reserved. C1 [McDonald, Michele; Box, Hayden; Bian, Wen; Kendall, Amy; Stubbs, Gerald] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. [Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Stubbs, G (reprint author), Vanderbilt Univ, Dept Biol Sci, 221 Kirkland Hall, Nashville, TN 37235 USA. EM gerald.stubbs@vanderbilt.edu RI Kendall, Amy/F-6780-2013; ID, BioCAT/D-2459-2012 OI Kendall, Amy/0000-0002-6176-9177; FU US National Institutes of Health (NIH) [AG002132]; National Institute of Diabetes and Digestive and Kidney Diseases; Department of Energy, Office of Biological and Environmental Research; NIH National Center for Research Resources; US Department of Energy; NIH FX This work was supported by the US National Institutes of Health (NIH) grants AG002132 and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Stanford Synchrotron Radiation Laboratory is a national user facility operated by Stanford University on behalf of the US Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the NIH National Center for Research Resources. Use of the Advanced Photon Source was supported by the US Department of Energy. BioCAT and BioCARS are Research Centers RR-007707 and RR-008630 supported by NIH. We thank Sarah Tiggelaar and Adrianne Eyman for assistance with preliminary fiber diffraction experiments. NR 42 TC 22 Z9 22 U1 3 U2 49 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 26 PY 2012 VL 423 IS 3 BP 454 EP 461 DI 10.1016/j.jmb.2012.08.004 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 028IG UT WOS:000310415400014 PM 22903058 ER PT J AU Rouquette-Jazdanian, AK Sommers, CL Kortum, RL Morrison, DK Samelson, LE AF Rouquette-Jazdanian, Alexandre K. Sommers, Connie L. Kortum, Robert L. Morrison, Deborah K. Samelson, Lawrence E. TI LAT-Independent Erk Activation via Bam32-PLC-gamma 1-Pak1 Complexes: GTPase-Independent Pak1 Activation SO MOLECULAR CELL LA English DT Article ID RECEPTOR-MEDIATED ACTIVATION; T-CELL-ACTIVATION; ADAPTER PROTEIN; SH3 DOMAIN; PHOSPHOLIPASE C-GAMMA-1; ANTIGEN RECEPTOR; BAM32; SLP-76; PHOSPHORYLATION; KINASES AB In T cells, the adaptor Bam32 is coupled to Erk activation downstream of the TCR by an unknown mechanism. We characterized in Jurkat cells and primary T lymphocytes a pathway dependent on Bam32-PLC-gamma 1-Pak1 complexes, in which Pak1 kinase activates Raf-1 and Mek-1, both upstream of Erk. In the Bam32-PLC-gamma 1-Pak1 complex, catalytically inactive PLC-gamma 1 is used as a scaffold linking Bam32 to Pak1. PLC-gamma 1(C-SH2) directly binds S141 of Bam32, preventing LAT-mediated activation of Ras by PLC-gamma 1. The Bam32-PLC-gamma 1 interaction enhances the binding of the SH3 domain of the phospholipase with Pak1. The PLC-gamma 1(SH3)-Pak1 interaction activates Pak1 independently of the small GTPases Rac1/Cdc42, previously described as being the only activators of Pak1 in T cells. Direct binding of the SH3 domain of PLC-gamma 1 to Pak1 dissociates inactive Pak1 homodimers, a mechanism required for Pak1 activation. We have thus uncovered a LAT/Ras-independent, Bam32-nucleated pathway that activates Erk signaling in T cells. C1 [Rouquette-Jazdanian, Alexandre K.; Sommers, Connie L.; Kortum, Robert L.; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morrison, Deborah K.] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM samelsonl@helix.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank B. Rellahan and K. DeBell for PLC-gamma 1 constructs, P.-W. Chen and P.A. Randazzo for recombinant ASAP protein, B. Taylor for cell sorting, and C. Regan and C. Hatheway for technical help. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 37 TC 13 Z9 13 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 26 PY 2012 VL 48 IS 2 BP 298 EP 312 DI 10.1016/j.molcel.2012.08.011 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 028LM UT WOS:000310423800015 PM 22981863 ER PT J AU McBain, CJ AF McBain, Chris J. TI Decoding the Neuronal Tower of Babel SO SCIENCE LA English DT Editorial Material ID EXPRESSION; RELEASE C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Porter Neurosci Ctr, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Porter Neurosci Ctr, Room 3C903,Lincoln Dr, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov FU Intramural NIH HHS [ZIA HD001205-21] NR 6 TC 1 Z9 1 U1 3 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 26 PY 2012 VL 338 IS 6106 BP 482 EP 483 DI 10.1126/science.1230338 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025NH UT WOS:000310195800044 PM 23112322 ER PT J AU Bjorkstrom, NK Beziat, V Cichocki, F Liu, LL Levine, J Larsson, S Koup, RA Anderson, SK Ljunggren, HG Malmberg, KJ AF Bjorkstrom, Niklas K. Beziat, Vivien Cichocki, Frank Liu, Lisa L. Levine, Jeffrey Larsson, Stella Koup, Richard A. Anderson, Stephen K. Ljunggren, Hans-Gustaf Malmberg, Karl-Johan TI CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells SO BLOOD LA English DT Article ID IG-LIKE RECEPTOR; IMMUNOGLOBULIN-LIKE RECEPTORS; CHRONIC HEPATITIS-C; INHIBITORY RECEPTORS; VIRUS-INFECTION; GROUP-A; MHC; HLA; REPERTOIRE; ACQUISITION AB Epistatic interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate HLA class I ligands have important implications for reproductive success, antiviral immunity, susceptibility to autoimmune conditions and cancer, as well as for graft-versus-leukemia reactions in settings of allogeneic stem cell transplantation. Although CD8 T cells are known to acquire KIRs when maturing from naive to terminally differentiated cells, little information is available about the constitution of KIR repertoires on human CD8 T cells. Here, we have performed a high-resolution analysis of KIR expression on CD8 T cells. The results show that most CD8 T cells possess a restricted KIR expression pattern, often dominated by a single activating or inhibitory KIR. Furthermore, the expression of KIR, and its modulation of CD8 T-cell function, was independent of expression of self-HLA class I ligands. Finally, despite similarities in the stochastic regulation of KIRs by the bidirectional proximal promoter, the specificity of inhibitory KIRs on CD8 T cells was often distinct from that of natural killer cells in the same individual. The results provide new insight into the formation of KIR repertoires on human T cells. (Blood. 2012;120(17):3455-3465) C1 [Bjorkstrom, Niklas K.; Beziat, Vivien; Cichocki, Frank; Liu, Lisa L.; Levine, Jeffrey; Ljunggren, Hans-Gustaf; Malmberg, Karl-Johan] Karolinska Univ Hosp Hudding, Karolinska Inst, Dept Med, Ctr Infect Med, S-14186 Stockholm, Sweden. [Bjorkstrom, Niklas K.] Karolinska Univ Hosp Hudding, Karolinska Inst, Dept Med, Div Gastroenterol & Hepatol,Liver Immunol Lab, S-14186 Stockholm, Sweden. [Cichocki, Frank; Anderson, Stephen K.] NCI, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Cichocki, Frank; Anderson, Stephen K.] NCI, Inflammat Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Larsson, Stella] Karolinska Univ Hosp Hudding, Karolinska Inst, Dept Clin Immunol & Transfus Med, S-14186 Stockholm, Sweden. [Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Malmberg, Karl-Johan] Oslo Univ Hosp, Inst Canc Res, Oslo, Norway. [Malmberg, Karl-Johan] Univ Oslo, Inst Clin Med, Inst Canc Res, Oslo, Norway. RP Bjorkstrom, NK (reprint author), Karolinska Univ Hosp Hudding, Karolinska Inst, Dept Med, Ctr Infect Med, F59, S-14186 Stockholm, Sweden. EM niklas.bjorkstrom@ki.se; kalle.malmberg@ki.se RI Beziat, Vivien/G-2971-2011; OI Beziat, Vivien/0000-0002-4020-824X; Malmberg, Karl-Johan/0000-0002-8718-9373; Bjorkstrom, Niklas/0000-0002-0967-076X FU Swedish Research Council; Swedish Cancer Society; Royal Swedish Academy of Sciences; Tobias Foundation; Wenner-Gren Foundation; Karolinska Institutet FX This work was supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Royal Swedish Academy of Sciences, the Tobias Foundation, the Wenner-Gren Foundation, and the Karolinska Institutet. NR 49 TC 26 Z9 26 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 25 PY 2012 VL 120 IS 17 BP 3455 EP 3465 DI 10.1182/blood-2012-03-416867 PG 11 WC Hematology SC Hematology GA 044MN UT WOS:000311623800012 PM 22968455 ER PT J AU Davids, MS Deng, J Wiestner, A Lannutti, BJ Wang, LL Wu, CJ Wilson, WH Brown, JR Letai, A AF Davids, Matthew S. Deng, Jing Wiestner, Adrian Lannutti, Brian J. Wang, Lili Wu, Catherine J. Wilson, Wyndham H. Brown, Jennifer R. Letai, Anthony TI Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID B-CELLS; CHEMOKINE RECEPTORS; EXPRESSION; INHIBITOR; CAL-101; DISEASE; SIGNALS; MECHANISMS; SURVIVAL; CXCR4 AB Stroma induces treatment resistance in chronic lymphocytic leukemia (CLL), possibly because of alterations in the BCL-2 family of proteins, which are key regulators of apoptosis. We previously developed BH3 profiling, a functional assay that assesses mitochondrial depolarization in response to BH3-only peptides, to measure "apoptotic priming," the proximity of a cell to the apoptotic threshold. In the present study, we use BH3 profiling to show that CLL cells from the PB are highly primed. Increased priming is associated with improved clinical response and, unexpectedly, with unmutated IGHV status. Coculturing CLL cells in vitro with stroma decreases priming. Using matched PB, BM, and lymph node compartment samples, we found in vivo that BM-derived CLL cells are the least primed. CLL cells cocultured with stroma were treated with the PI3K delta-isoform inhibitor CAL-101 (GS1101). CAL-101 caused CLL cell de-adhesion, leading to increased CLL cell priming. Stimulation of CLL cells with anti-IgM or CXCL12 caused decreased priming that could be reversed by CAL-101. Our results show that inhibition of stromal interactions leading to displacement of CLL cells into the blood by CAL-101 in vivo may increase CLL cell priming, suggesting a mechanism by which agents inducing lymphocyte redistribution might facilitate improved clinical response when used in combination with other therapies. (Blood. 2012;120(17):3501-3509) C1 [Davids, Matthew S.; Deng, Jing; Wang, Lili; Wu, Catherine J.; Brown, Jennifer R.; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lannutti, Brian J.] Gilead Sci Inc, Seattle, WA USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM anthony_letai@dfci.harvard.edu FU FLAMES Fund of the Pan-Mass Challenge; National Institutes of Health [RO1CA129974]; Ruth L. Kirschstein National Research Service Award T32 National Cancer Institute grant; Friends of the Dana-Farber Cancer Institute; National Institutes of Health; National Heart, Lung, and Blood Institute; National Cancer Institute; American Association of Cancer Research/Stand Up To Cancer Innovative Research Grant; Gilead Sciences FX This work was funded by the FLAMES Fund of the Pan-Mass Challenge, the National Institutes of Health (RO1CA129974), a Ruth L. Kirschstein National Research Service Award T32 National Cancer Institute grant, and the Friends of the Dana-Farber Cancer Institute. M. S. D. is a Leukemia & Lymphoma Society Special Fellow in Clinical Research and a recipient of an National Institutes of Health Loan Repayment Program award. A. W. and W. H. W. are supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the National Cancer Institute, respectively. C. J. W. is a Damon Runyon Cancer Research Foundation Clinical Investigator and a recipient of an American Association of Cancer Research/Stand Up To Cancer Innovative Research Grant. J. R. B. is a Leukemia & Lymphoma Society Scholar in Clinical Research and a Scholar of the American Society of Hematology. A. L. is a Leukemia & Lymphoma Society Scholar and a Scholar of the American Society of Hematology.; B.J.L. is an employee of Gilead Sciences. J.R.B. was a paid consultant for Calistoga Pharmaceuticals before its acquisition by Gilead Sciences. A. L. is a cofounder of, and formerly a paid advisor to, Eutropics Pharmaceuticals, which has purchased a license to BH3 profiling from Dana-Farber Cancer Institute. A. L. and the Dana-Farber Cancer Institute have a patent relating to the use of BH3 profiling in predicting chemosensitivity. The remaining authors declare no competing financial interests. NR 28 TC 51 Z9 51 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 25 PY 2012 VL 120 IS 17 BP 3501 EP 3509 DI 10.1182/blood-2012-02-414060 PG 9 WC Hematology SC Hematology GA 044MN UT WOS:000311623800017 PM 22955911 ER PT J AU Yocum, AO Steiner, LA Seidel, NE Cline, AP Rout, ED Lin, JY Wong, C Garrett, LJ Gallagher, PG Bodine, DM AF Yocum, Ashley O. Steiner, Laurie A. Seidel, Nancy E. Cline, Amanda P. Rout, Emily D. Lin, Jolinta Y. Wong, Clara Garrett, Lisa J. Gallagher, Patrick G. Bodine, David M. TI A tissue-specific chromatin loop activates the erythroid ankyrin-1 promoter SO BLOOD LA English DT Article ID HEMATOLOGICALLY IMPORTANT MUTATIONS; RECESSIVE HEREDITARY SPHEROCYTOSIS; GENE-EXPRESSION; CELLS; INSULATORS; ORGANIZATION; VARIANTS; SPECTRIN; SUGGESTS; ROLES AB The human ankyrin-1 gene (ANK1) contains 3 tissue-specific alternative promoters. We have shown previously that the erythroid-specific ankyrin 1 (ANK1E) core promoter contains a 5' DNase I hypersensitive site (HS) with barrier insulator function that prevents gene silencing in vitro and in vivo. Mutations in the ANK1E barrier region lead to decreased ANK1 mRNA levels and hereditary spherocytosis. In this report, we demonstrate a second ANK1E regulatory element located in an adjacent pair of DNase I HS located 5.6 kb 3' of the ANK1E promoter at the 3' boundary of an erythroid-specific DNase I-sensitive chromatin domain. The 3' regulatory element exhibits enhancer activity in vitro and in transgenic mice, and it has the histone modifications associated with an enhancer element. One of the ANK1E 3' HS contains an NF-E2 binding site that is required for enhancer function. We show that a chromatin loop brings the 3' enhancer and NF-E2 into proximity with the 5' barrier region including the ANK1E core promoter. These observations demonstrate a model for the tissue-specific activation of alternative promoters that may be applicable to the similar to 30% of mammalian genes with alternative promoters that exhibit distinct expression patterns. (Blood. 2012;120(17):3586-3593) C1 [Yocum, Ashley O.; Seidel, Nancy E.; Cline, Amanda P.; Rout, Emily D.; Lin, Jolinta Y.; Bodine, David M.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Steiner, Laurie A.; Wong, Clara; Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Steiner, Laurie A.; Wong, Clara; Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Steiner, Laurie A.; Wong, Clara; Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Garrett, Lisa J.] NHGRI, Embryon Stem Cell & Transgen Mouse Core Facil, NIH, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bldg 49,Rm 4A04,49 Convent Dr,MSC 4442, Bethesda, MD 20892 USA. EM tedyaz@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health [HL65448, DK62039] FX This study was supported by intramural funds from National Human Genome Research Institute (D. M. B.) and grants HL65448 and DK62039 from the National Institutes of Health (P.G.G.). NR 36 TC 3 Z9 4 U1 0 U2 7 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 OCT 25 PY 2012 VL 120 IS 17 BP 3586 EP 3593 DI 10.1182/blood-2012-08-450262 PG 8 WC Hematology SC Hematology GA 044MN UT WOS:000311623800025 PM 22968456 ER PT J AU Blanford, S Jenkins, NE Christian, R Chan, BHK Nardini, L Osae, M Koekemoer, L Coetzee, M Read, AF Thomas, MB AF Blanford, Simon Jenkins, Nina E. Christian, Riann Chan, Brian H. K. Nardini, Luisa Osae, Michael Koekemoer, Lizette Coetzee, Maureen Read, Andrew F. Thomas, Matthew B. TI Storage and persistence of a candidate fungal biopesticide for use against adult malaria vectors SO MALARIA JOURNAL LA English DT Article ID THURINGIENSIS VAR. ISRAELENSIS; ANOPHELES-GAMBIAE-S.S.; METARHIZIUM-ANISOPLIAE; ENTOMOPATHOGENIC FUNGUS; BEAUVERIA-BASSIANA; AEDES-AEGYPTI; 1ST REPORT; INSECTICIDE RESISTANCE; MOSQUITO-CONTROL; INFECTION AB Background: New products aimed at augmenting or replacing chemical insecticides must have operational profiles that include both high efficacy in reducing vector numbers and/or blocking parasite transmission and be long lasting following application. Research aimed at developing fungal spores as a biopesticide for vector control have shown considerable potential yet have not been directly assessed for their viability after long-term storage or following application in the field. Methods: Spores from a single production run of the entomopathogenic fungi Beauveria bassiana were dried and then stored under refrigeration at 7 degrees C. After 585 days these spores were sub-sampled and placed at either 22 degrees C, 26 degrees C or 32 degrees C still sealed in packaging (closed storage) or in open beakers and exposed to the 80% relative humidity of the incubator they were kept in. Samples were subsequently taken from these treatments over a further 165 days to assess viability. Spores from the same production run were also used to test their persistence following application to three different substrates, clay, cement and wood, using a hand held sprayer. The experiments were conducted at two different institutes with one using adult female Anopheles stephensi and the other adult female Anopheles gambiae. Mosquitoes were exposed to the treated substrates for one hour before being removed and their survival monitored for the next 14 days. Assays were performed at monthly intervals over a maximum seven months. Results: Spore storage under refrigeration resulted in no loss of spore viability over more than two years. Spore viability of those samples kept under open and closed storage was highly dependent on the incubation temperature with higher temperatures decreasing viability more rapidly than cooler temperatures. Mosquito survival following exposure was dependent on substrate type. Spore persistence on the clay substrate was greatest achieving 80% population reduction for four months against An. stephensi and for at least five months against Anopheles gambiae. Cement and wood substrates had more variable mortality with the highest spore persistence being two to three months for the two substrates respectively. Conclusions: Spore shelf-life under refrigeration surpassed the standard two year shelf-life expected of a mosquito control product. Removal to a variety of temperatures under either closed or open storage indicated that samples sent out from refrigeration should be deployed rapidly in control operations to avoid loss of viability. Spore persistence following application onto clay surfaces was comparable to a number of chemical insecticides in common use. Persistence on cement and wood was shorter but in one assay still comparable to some organophosphate and pyrethroid insecticides. Optimized formulations could be expected to improve spore persistence still further. C1 [Blanford, Simon; Chan, Brian H. K.; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, Mueller Lab, University Pk, PA 16802 USA. [Blanford, Simon; Jenkins, Nina E.; Chan, Brian H. K.; Read, Andrew F.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, Merkle Lab, University Pk, PA 16802 USA. [Christian, Riann; Nardini, Luisa; Osae, Michael; Koekemoer, Lizette; Coetzee, Maureen] NHLS, Natl Inst Communicable Dis, Vector Control Reference Unit, ZA-2131 Johannesburg, South Africa. [Christian, Riann; Nardini, Luisa; Koekemoer, Lizette; Coetzee, Maureen; Thomas, Matthew B.] Univ Witwatersrand, Malaria Entomol Res Unit, Sch Pathol, Fac Hlth Sci, Johannesburg, South Africa. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Blanford, S (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, Mueller Lab, University Pk, PA 16802 USA. EM stb13@psu.edu OI Chan, Brian/0000-0002-9451-4621 FU Gates Grand Challenges Explorations [53066]; National Institutes of Health [AI088094-01]; Innovative Vector Control Consortium; Research and Policy for Infectious Disease Dynamics (RAPIDD) program; Pennsylvania Department of Health using Tobacco Settlement Funds FX This research was part-funded by grants from Gates Grand Challenges Explorations (No. 53066), the National Institutes of Health (AI088094-01), the Innovative Vector Control Consortium and by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program. This project was also funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 7 Z9 7 U1 3 U2 33 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD OCT 25 PY 2012 VL 11 AR 354 DI 10.1186/1475-2875-11-354 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 044EL UT WOS:000311602100002 PM 23098323 ER PT J AU Sirivolu, VR Vernekar, SKV Marchand, C Naumova, A Chergui, A Renaud, A Stephen, AG Chen, F Sham, YY Pommier, Y Wang, ZQ AF Sirivolu, Venkata Ramana Vernekar, Sanjeev Kumar V. Marchand, Christophe Naumova, Alena Chergui, Adel Renaud, Amelie Stephen, Andrew G. Chen, Feng Sham, Yuk Y. Pommier, Yves Wang, Zhengqiang TI 5-Arylidenethioxothiazolidinones as Inhibitors of Tyrosyl-DNA Phosphodiesterase I SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHOLIPASE-D SUPERFAMILY; TOPOISOMERASE-I; CRYSTAL-STRUCTURE; TDP1; DAMAGE; DERIVATIVES; DRUGS; THIAZOLIDINEDIONES; REPAIR; MECHANISM AB Tyrosyl-DNA phosphodiesterase I (Tdp1) is a cellular enzyme that repairs the irreversible topoisomerase I (Top1)-DNA complexes and confers chemotherapeutic resistance to Top1 inhibitors. Inhibiting Tdp1 provides an attractive approach to potentiating clinically used Top1 inhibitors. However, despite recent efforts in studying Tdp1 as a therapeutic target, its inhibition remains poorly understood and largely underexplored. We describe herein the discovery of arylidene thioxothiazolidinone as a scaffold for potent Tdp1 inhibitors based on an initial tyrphostin lead compound 8. Through structure-activity relationship (SAR) studies we demonstrated that arylidene thioxothiazolidinones inhibit Tdp1 and identified compound 50 as a submicromolar inhibitor of Tdp1 (IC50 = 0.87 mu M). Molecular modeling provided insight into key interactions essential for observed activities. Some derivatives were also active against endogenous Tdp1 in whole cell extracts. These findings contribute to advancing the understanding on Tdp1 inhibition. C1 [Marchand, Christophe; Naumova, Alena; Chergui, Adel; Renaud, Amelie; Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Sirivolu, Venkata Ramana; Vernekar, Sanjeev Kumar V.; Chen, Feng; Sham, Yuk Y.; Wang, Zhengqiang] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. [Stephen, Andrew G.] SAIC Frederick Inc, Prot Chem Lab, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov; wangx472@umn.edu RI Vernekar, Sanjeev Kumar/F-7011-2015 FU Center for Drug Design at the University of Minnesota; Center for Cancer Research, Intramural Program of the National Cancer Institute, National Institutes of Health FX This research was supported by the Center for Drug Design at the University of Minnesota and by the Center for Cancer Research, Intramural Program of the National Cancer Institute, National Institutes of Health. We thank the University of Minnesota Supercomputing Institute for providing the computational resources. NR 62 TC 19 Z9 22 U1 2 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 25 PY 2012 VL 55 IS 20 BP 8671 EP 8684 DI 10.1021/jm3008773 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 024PI UT WOS:000310120700009 PM 23006064 ER PT J AU McDowell, EN Kisielewski, AE Pike, JW Franco, HL Yao, HHC Johnson, KJ AF McDowell, Erin N. Kisielewski, Anne E. Pike, Jack W. Franco, Heather L. Yao, Humphrey H. -C. Johnson, Kamin J. TI A Transcriptome-Wide Screen for mRNAs Enriched in Fetal Leydig Cells: CRHR1 Agonism Stimulates Rat and Mouse Fetal Testis Steroidogenesis SO PLOS ONE LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; IMPAIRED STRESS-RESPONSE; GENE-EXPRESSION; FACTOR RECEPTORS; MICROARRAY DATA; PROBE LEVEL; HORMONE; DIFFERENTIATION; UROCORTIN; DISRUPTION AB Fetal testis steroidogenesis plays an important role in the reproductive development of the male fetus. While regulators of certain aspects of steroidogenesis are known, the initial driver of steroidogenesis in the human and rodent fetal testis is unclear. Through comparative analysis of rodent fetal testis microarray datasets, 54 candidate fetal Leydig cell-specific genes were identified. Fetal mouse testis interstitial expression of a subset of these genes with unknown expression (Crhr1, Gramd1b, Itih5, Vgll3, and Vsnl1) was verified by whole-mount in situ hybridization. Among the candidate fetal Leydig cell-specific factors, three receptors (CRHR1, PRLR, and PROKR2) were tested for a steroidogenic function using ex vivo fetal testes treated with receptor agonists (CRH, PRL, and PROK2). While PRL and PROK2 had no effect, CRH, at low (approximately 1 to 10) nM concentration, increased expression of the steroidogenic genes Cyp11a1, Cyp17a1, Scarb1, and Star in GD15 mouse and GD17 rat testes, and in conjunction, testosterone production was increased. Exposure of GD15 fetal mouse testis to a specific CRHR1 antagonist blunted the CRH-induced steroidogenic gene expression and testosterone responses. Similar to ex vivo rodent fetal testes, >= 10 nM CRH exposure of MA-10 Leydig cells increased steroidogenic pathway mRNA and progesterone levels, showing CRH can enhance steroidogenesis by directly targeting Leydig cells. Crh mRNA expression was observed in rodent fetal hypothalamus, and CRH peptide was detected in rodent amniotic fluid. Together, these data provide a resource for discovering factors controlling fetal Leydig cell biology and suggest that CRHR1 activation by CRH stimulates rat and mouse fetal Leydig cell steroidogenesis in vivo. C1 [McDowell, Erin N.; Kisielewski, Anne E.; Pike, Jack W.; Johnson, Kamin J.] Alfred I Dupont Hosp Children, Wilmington, DE USA. [Franco, Heather L.; Yao, Humphrey H. -C.] NIEHS, NIH, Reprod Dev Biol Grp, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. RP Johnson, KJ (reprint author), Alfred I Dupont Hosp Children, Wilmington, DE USA. EM johnson@nemoursresearch.org RI Yao, Humphrey Hung-Chang/B-4795-2010 OI Yao, Humphrey Hung-Chang/0000-0003-2944-8469 FU National Institutes of Health [P20 RR020173]; National Institute of Environmental and Health Sciences branch of the National Institutes of Health; Eunice Kennedy Shriver NICHD/NIH (SCCPIR) [U54-HD28934] FX This research was supported by the National Institutes of Health grant P20 RR020173 and in part by the Intramural Research Program of the National Institute of Environmental and Health Sciences branch of the National Institutes of Health. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Lab is supported by the Eunice Kennedy Shriver NICHD/NIH (SCCPIR) grant U54-HD28934. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 7 Z9 7 U1 0 U2 9 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 OCT 25 PY 2012 VL 7 IS 10 AR e47359 DI 10.1371/journal.pone.0047359 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026GE UT WOS:000310261800005 PM 23133512 ER PT J AU Roelens, J Reuschenbach, M Doeberitz, MV Wentzensen, N Bergeron, C Arbyn, M AF Roelens, Jolien Reuschenbach, Miriam Doeberitz, Magnus von Knebel Wentzensen, Nicolas Bergeron, Christine Arbyn, Marc TI p16INK4a immunocytochemistry versus human papillomavirus testing for triage of women with minor cytologic abnormalities SO CANCER CYTOPATHOLOGY LA English DT Review DE cervical cancer; cervical intraepithelial neoplasia; atypical squamous cells of undetermined significance; low-grade squamous intraepithelial lesions; triage; p16INK4a; cytoimmunochemistry; human papillomavirus testing; diagnostic accuracy; systematic review ID ATYPICAL SQUAMOUS-CELLS; CERVICAL INTRAEPITHELIAL NEOPLASIA; EQUIVOCAL PAP-SMEARS; UNDETERMINED SIGNIFICANCE; P16(INK4A) EXPRESSION; DIAGNOSTIC-ACCURACY; RANDOMIZED-TRIAL; FOLLOW-UP; MILD DYSKARYOSIS; CANCER AB The best method for identifying women who have minor cervical lesions that require diagnostic workup remains unclear. The authors of this report performed a meta-analysis to assess the accuracy of cyclin-dependent kinase inhibitor 2A (p16INK4a) immunocytochemistry compared with high-risk human papillomavirus DNA testing with Hybrid Capture 2 (HC2) to detect grade 2 or greater cervical intraepithelial neoplasia (CIN2+) and CIN3+ among women who had cervical cytology indicating atypical squamous cells of undetermined significance (ASC-US) or low-grade cervical lesions (LSIL). A literature search was performed in 3 electronic databases to identify studies that were eligible for this meta-analysis. Seventeen studies were included in the meta-analysis. The pooled sensitivity of p16INK4a to detect CIN2+ was 83.2% (95% confidence interval [CI], 76.8%-88.2%) and 83.8% (95% CI, 73.5%-90.6%) in ASC-US and LSIL cervical cytology, respectively, and the pooled specificities were 71% (95% CI, 65%-76.4%) and 65.7% (95% CI, 54.2%-75.6%), respectively. Eight studies provided both HC2 and p16INK4a triage data. p16INK4a and HC2 had similar sensitivity, and p16INK4a has significantly higher specificity in the triage of women with ASC-US (relative sensitivity, 0.95 [95% CI, 0.89-1.01]; relative specificity, 1.82 [95% CI, 1.57-2.12]). In the triage of LSIL, p16INK4a had significantly lower sensitivity but higher specificity compared with HC2 (relative sensitivity, 0.87 [95% CI, 0.81-0.94]; relative specificity, 2.74 [95% CI, 1.99-3.76]). The published literature indicated the improved accuracy of p16INK4a compared with HC2 testing in the triage of women with ASC-US. In LSIL triage, p16INK4a was more specific but less sensitive. Cancer (Cancer Cytopathol) 2012. (c) 2012 American Cancer Society. C1 [Roelens, Jolien; Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, B-1050 Brussels, Belgium. [Reuschenbach, Miriam; Doeberitz, Magnus von Knebel] Univ Heidelberg, Inst Pathol, Dept Appl Tumor Biol, D-6900 Heidelberg, Germany. [Reuschenbach, Miriam; Doeberitz, Magnus von Knebel] German Canc Res Ctr, Clin Cooperat Unit, D-6900 Heidelberg, Germany. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Bergeron, Christine] Lab Cerba, Cergy Pontoise, France. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Canc Epidemiol Unit, J Wytsmanstraat 14, B-1050 Brussels, Belgium. EM marc.arbyn@wiv-isp.be RI von Knebel Doeberitz, Magnus/D-2372-2016 OI von Knebel Doeberitz, Magnus/0000-0002-0498-6781 FU European Commission through the Prevention Strategies for HPV-Related Diseases in European Countries (PREHDICT) Network; DG Research (Brussels, Belgium); European Cooperation on Development and Implementation of Cancer screening and prevention guidelines; Directorate of SANCO (Luxembourg, Grand-Duchy of Luxembourg); Belgian Foundation Against Cancer (Brussels, Belgium); Gynaecological Cancer Cochrane Review Collaboration (Bath, United Kingdom) FX Financial support was received from: 1) the European Commission through the Prevention Strategies for HPV-Related Diseases in European Countries (PREHDICT) Network, coordinated by the Free University of Amsterdam (the Netherlands), funded by the seventh Framework program of DG Research (Brussels, Belgium), and through the European Cooperation on Development and Implementation of Cancer screening and prevention guidelines (coordinated by the International Agency for Research on Cancer [Lyon, France]), funded by the Directorate of SANCO (Luxembourg, Grand-Duchy of Luxembourg); 2) The Belgian Foundation Against Cancer (Brussels, Belgium); and 3) the Gynaecological Cancer Cochrane Review Collaboration (Bath, United Kingdom). NR 46 TC 33 Z9 38 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2012 VL 120 IS 5 BP 294 EP 307 DI 10.1002/cncy.21205 PG 14 WC Oncology; Pathology SC Oncology; Pathology GA 021WC UT WOS:000309915100005 PM 22700382 ER PT J AU Tussiwand, R Lee, WL Murphy, TL Mashayekhi, M Wumesh, KC Albring, JC Satpathy, AT Rotondo, JA Edelson, BT Kretzer, NM Wu, XD Weiss, LA Glasmacher, E Li, P Liao, W Behnke, M Lam, SSK Aurthur, CT Leonard, WJ Singh, H Stallings, CL Sibley, LD Schreiber, RD Murphy, KM AF Tussiwand, Roxane Lee, Wan-Ling Murphy, Theresa L. Mashayekhi, Mona Wumesh, K. C. Albring, Joern C. Satpathy, Ansuman T. Rotondo, Jeffrey A. Edelson, Brian T. Kretzer, Nicole M. Wu, Xiaodi Weiss, Leslie A. Glasmacher, Elke Li, Peng Liao, Wei Behnke, Michael Lam, Samuel S. K. Aurthur, Cora T. Leonard, Warren J. Singh, Harinder Stallings, Christina L. Sibley, L. David Schreiber, Robert D. Murphy, Kenneth M. TI Compensatory dendritic cell development mediated by BATF-IRF interactions SO NATURE LA English DT Article ID INTERFERON-REGULATORY FACTOR-4; CLASS-SWITCH RECOMBINATION; IN-VIVO; NEGATIVE REGULATOR; T-CELLS; B-ATF; CD8-ALPHA(+); TRANSCRIPTION; EXPRESSION; INFECTION AB The AP1 transcription factor Batf3 is required for homeostatic development of CD8 alpha(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8 alpha(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-gamma. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines. C1 [Tussiwand, Roxane; Lee, Wan-Ling; Murphy, Theresa L.; Mashayekhi, Mona; Wumesh, K. C.; Albring, Joern C.; Satpathy, Ansuman T.; Rotondo, Jeffrey A.; Edelson, Brian T.; Kretzer, Nicole M.; Wu, Xiaodi; Lam, Samuel S. K.; Aurthur, Cora T.; Schreiber, Robert D.; Murphy, Kenneth M.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Weiss, Leslie A.; Behnke, Michael; Stallings, Christina L.; Sibley, L. David] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Glasmacher, Elke; Singh, Harinder] Genentech Inc, Dept Discovery Immunol, San Francisco, CA 94080 USA. [Li, Peng; Liao, Wei; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Li, Peng; Liao, Wei; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Murphy, Kenneth M.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Murphy, KM (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, 660 S Euclid Ave, St Louis, MO 63110 USA. EM kmurphy@wustl.edu RI Schreiber, Robert/A-1276-2013; Glasmacher, Elke/B-8939-2015; Behnke, Michael/R-8839-2016; OI Schreiber, Robert/0000-0001-6311-0432; Glasmacher, Elke/0000-0003-1265-2543; Behnke, Michael/0000-0002-4668-8109; Albring, Jorn/0000-0002-5534-7250 FU Howard Hughes Medical Institute; National Institutes of Health [AI076427-02]; Department of Defense [W81XWH-09-1-0185]; American Heart Association [12PRE8610005]; German Research Foundation [AL 1038/1-1]; American Society of Hematology; Cancer Research Institute; NCI Cancer Center [P30 CA91842] FX This work was supported by the Howard Hughes Medical Institute, National Institutes of Health (AI076427-02) and Department of Defense (W81XWH-09-1-0185) (K.M.M.), the American Heart Association (12PRE8610005) (A.T.S.), German Research Foundation (AL 1038/1-1) (J.C.A), American Society of Hematology Scholar Award and Burroughs Welcome Fund Career Award for Medical Scientists (B.T.E.), and Cancer Research Institute predoctoral fellowship (W.-L.L.). We thank the ImmGen consortium34, M. White for blastocyst injections and generation of mouse chimaeras, the Alvin J. Siteman Cancer Center at Washington University School of Medicine for use of the Center for Biomedical Informatics and Multiplex Gene Analysis Genechip Core Facility. The Siteman Cancer Center is supported in part by the NCI Cancer Center Support Grant P30 CA91842. IL-12 was a gift from Pfizer. NR 46 TC 124 Z9 131 U1 0 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 25 PY 2012 VL 490 IS 7421 BP 502 EP + DI 10.1038/nature11531 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025NK UT WOS:000310196200034 PM 22992524 ER PT J AU White, JF Noinaj, N Shibata, Y Love, J Kloss, B Xu, F Gvozdenovic-Jeremic, J Shah, P Shiloach, J Tate, CG Grisshammer, R AF White, Jim F. Noinaj, Nicholas Shibata, Yoko Love, James Kloss, Brian Xu, Feng Gvozdenovic-Jeremic, Jelena Shah, Priyanka Shiloach, Joseph Tate, Christopher G. Grisshammer, Reinhard TI Structure of the agonist-bound neurotensin receptor SO NATURE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; MEMBRANE-PROTEINS; CRYSTAL-STRUCTURE; OPIOID RECEPTOR; BINDING-SITE; MACROMOLECULAR CRYSTALS; RADIATION-DAMAGE; ACTIVE STATE; PEPTIDE; ACTIVATION AB Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 angstrom resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS8-13, the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity. C1 [White, Jim F.; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Grisshammer, Reinhard] Natl Inst Neurol Disorders & Stroke, Membrane Prot Struct Funct Unit, NIH, US Dept HHS, Rockville, MD 20852 USA. [Noinaj, Nicholas] NIDDKD, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Shibata, Yoko; Tate, Christopher G.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. [Love, James; Kloss, Brian] New York Struct Biol Ctr, New York Consortium Membrane Prot Struct, Prot Prod Facil, New York, NY 10027 USA. [Shiloach, Joseph] NIDDKD, Biotechnol Core Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Grisshammer, R (reprint author), Natl Inst Neurol Disorders & Stroke, Membrane Prot Struct Funct Unit, NIH, US Dept HHS, Rockville, MD 20852 USA. EM rkgriss@helix.nih.gov RI Grisshammer, Reinhard/C-3089-2015; OI Tate, Christopher/0000-0002-2008-9183 FU National Institutes of Health (National Institute of Neurological Disorders and Stroke); National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases); Pfizer Global Research and Development; MRCT Development Gap Fund; UK Medical Research Council [MRC U105197215]; National Institutes of Health [U54GM075026]; NIH Roadmap grant [P50 GM073197]; US Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357] FX This research was supported by the Intramural Research Program of the National Institutes of Health (J.F.W., J.G.-J., P.S. and R.G.: National Institute of Neurological Disorders and Stroke; N.N. and J.S.: National Institute of Diabetes and Digestive and Kidney Diseases) and a joint grant from Pfizer Global Research and Development and the MRCT Development Gap Fund in addition to core funding from the UK Medical Research Council MRC U105197215 (Y.S., C.G.T.). The Protein Production Facility of the New York Consortium on Membrane Protein Structure was supported by the National Institutes of Health grant U54GM075026 (J.L., B.K.). We acknowledge the NIH Roadmap grant P50 GM073197 for technology development (to R. C. Stevens) for visitor support at The Scripps Research Institute. We thank the staff at the General Medicine and Cancer Institute's Collaborative Access Team (GM/CA-CAT) beamline at the Advanced Photon Source, Argonne National Laboratory for their assistance during data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357. NR 59 TC 213 Z9 219 U1 9 U2 76 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 25 PY 2012 VL 490 IS 7421 BP 508 EP + DI 10.1038/nature11558 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025NK UT WOS:000310196200035 PM 23051748 ER PT J AU Li, P Spolski, R Liao, W Wang, L Murphy, TL Murphy, KM Leonard, WJ AF Li, Peng Spolski, Rosanne Liao, Wei Wang, Lu Murphy, Theresa L. Murphy, Kenneth M. Leonard, Warren J. TI BATF-JUN is critical for IRF4-mediated transcription in T cells SO NATURE LA English DT Article ID INTERFERON-REGULATORY FACTOR-4; TERNARY COMPLEX; GENE-EXPRESSION; FACTOR PU.1; B-ATF; DIFFERENTIATION; IL-21; MODULATION; ACTIVATION; INFLAMMATION AB Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response(1,2). IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity(3), allowing IRF4 to regulate genes containing ETS-IRF composite elements (EICEs; 5'-GGAAnnGAAA-3')(1). Here we show that in mouse CD4(+) T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1-IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1-IRF composite elements (AICEs). Moreover, BATF-JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4(+) T cells stimulated with IL-21 and in T(H)17 differentiated cells. Importantly, BATF binding was diminished in Irf4(-/-) T cells and IRF4 binding was diminished in Batf(-/-) T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in T(H)17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription. C1 [Li, Peng; Spolski, Rosanne; Liao, Wei; Wang, Lu; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Li, Peng; Spolski, Rosanne; Liao, Wei; Wang, Lu; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Murphy, Theresa L.; Murphy, Kenneth M.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Murphy, Kenneth M.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Li, P (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lip3@nhlbi.nih.gov; wjl@helix.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH; Howard Hughes Medical Institute FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH (P.L., R.S., W.L., L.W. and W.J.L.) and the Howard Hughes Medical Institute (T.L.M. and K.M.M.). We thank J.-X. Lin for valuable suggestions, critical comments and RNA-Seq data for pro-B/pre-B-enriched populations. We thank J. Zhu and Y. Wakabayashi, NHLBI DNA Sequencing Core, for excellent services, K. Ozato and Y. Hiroaki, NICHD, for Irf4-/- mice, and J. Thierry-Mieg and D. Thierry-Mieg, NCBI, for early analysis of ChIP-Seq data from ref. 14. NR 33 TC 112 Z9 117 U1 0 U2 13 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 OCT 25 PY 2012 VL 490 IS 7421 BP 543 EP + DI 10.1038/nature11530 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025NK UT WOS:000310196200043 PM 22992523 ER PT J AU Yang, Y Tao-Cheng, JH Reese, TS Dosemeci, A AF Yang, Y. Tao-Cheng, J-H Reese, T. S. Dosemeci, A. TI SYNGAP MOVES OUT OF THE CORE OF THE POSTSYNAPTIC DENSITY UPON DEPOLARIZATION (vol 192, pg 132, 2011) SO NEUROSCIENCE LA English DT Correction C1 [Yang, Y.; Reese, T. S.; Dosemeci, A.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Tao-Cheng, J-H] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. RP Yang, Y (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM yyijung@med.umich.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 25 PY 2012 VL 223 BP 487 EP 487 DI 10.1016/j.neuroscience.2012.08.006 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 018VM UT WOS:000309694700048 ER PT J AU Kramer, H Sempos, C Cao, GC Luke, A Shoham, D Cooper, R Durazo-Arvizu, R AF Kramer, Holly Sempos, Chris Cao, Guichan Luke, Amy Shoham, David Cooper, Richard Durazo-Arvizu, Ramon TI Mortality Rates Across 25-Hydroxyvitamin D (25[OH] D) Levels among Adults with and without Estimated Glomerular Filtration Rate < 60 ml/min/1.73 m(2) : The Third National Health and Nutrition Examination Survey SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; VITAMIN-D DEFICIENCY; SERUM PARATHYROID-HORMONE; CARDIOVASCULAR-DISEASE; HYPOVITAMINOSIS-D; D SUPPLEMENTATION; D INSUFFICIENCY; US POPULATION; UNITED-STATES; OLDER MEN AB Background: Previous studies exploring the association between 25[OH]D levels and mortality in adults with and without kidney disease utilized 25[OH]D thresholds that have recently been scrutinized by the Institute of Medicine Committee to Review Dietary References Intakes for Vitamin D and Calcium. Objective: We explored all-cause mortality rates across the spectrum of 25[OH]D levels over an eighteen-year follow-up among adults with and without an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). Design: The study included 1,097 U.S. adults with eGFR <60 ml/min/1.73 m(2) and 14, 002 adults with eGFR >= 60 ml/min/1.73 m2. Mortality rates and rate ratios (RR) across 25[OH]D groups were calculated with Poisson regression and restricted cubic splines while adjusting for covariates. Results: Prevalence of 25[OH]D levels <30 and <20 ng/ml among adults with eGFR <60 ml/min/1.73 m(2) was 76.5% (population estimate 6.2 million) and 35.4% (population estimate 2.9 million), respectively. Among adults with eGFR >= 60 ml/min/1.73 m(2), 70.5% had 25[OH] D levels <30 ng/ml (population estimate 132.2 million) while 30.3% had 25[OH]D levels <20 ng/ml (population estimate 56.8 million). Significantly higher mortality rates were noted among individuals with 25[OH]D levels <12 ng/ml compared to referent group (24 to <30 ng/ml): RR1.41 (95% CI 1.17, 1.71) among individuals with eGFR <60 ml/min/1.73 m(2) and RR 1.32 (95% CI 1.13, 1.56) among individuals with eGFR >= 60 ml/min/1.73 m(2) after adjustment for covariates including co-morbid conditions. Mortality rates were fairly similar across all 25[OH]D groups with levels >20 ng/ml after adjustment for all covariates. Conclusions: Regardless of presence of eGFR <60 ml/min/1.73 m(2), mortality rates across groups with 25[OH] D levels 2040 ng/ml are similar. C1 [Kramer, Holly; Cao, Guichan; Luke, Amy; Shoham, David; Cooper, Richard; Durazo-Arvizu, Ramon] Loyola Univ, Med Ctr, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [Kramer, Holly] Loyola Univ, Med Ctr, Dept Med, Maywood, IL 60153 USA. [Kramer, Holly] Loyola Univ, Med Ctr, Div Nephrol & Hypertens, Maywood, IL 60153 USA. [Sempos, Chris] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Kramer, H (reprint author), Loyola Univ, Med Ctr, Dept Prevent Med & Epidemiol, 2160 S 1st Ave, Maywood, IL 60153 USA. EM hkramer@lumc.edu OI Kramer, Holly/0000-0002-6374-837X FU National Institutes of Health [1R01DK90360-1A1] FX This study was funded by a grant from the National Institutes of Health (1R01DK90360-1A1). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 41 TC 9 Z9 9 U1 0 U2 4 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 OCT 24 PY 2012 VL 7 IS 10 AR e47458 DI 10.1371/journal.pone.0047458 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026VC UT WOS:000310310200041 PM 23112816 ER PT J AU Nasr, S Tootell, RBH AF Nasr, Shahin Tootell, Roger B. H. TI A Cardinal Orientation Bias in Scene-Selective Visual Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PERCEPTION; PARAHIPPOCAMPAL; DISCRIMINATION; ROLES AB It has long been known that human vision is more sensitive to contours at cardinal (horizontal and vertical) orientations, compared with oblique orientations; this is the "oblique effect." However, the real-world relevance of the oblique effect is not well understood. Experiments here suggest that this effect is linked to scene perception, via a common bias in the image statistics of scenes. This statistical bias for cardinal orientations is found in many "carpentered environments" such as buildings and indoor scenes, and some natural scenes. In Experiment 1, we confirmed the presence of a perceptual oblique effect in a specific set of scene stimuli. Using those scenes, we found that a well known "scene-selective" visual cortical area (the parahippocampal place area; PPA) showed distinctively higher functional magnetic resonance imaging (fMRI) activity to cardinal versus oblique orientations. This fMRI-based oblique effect was not observed in other cortical areas (including scene-selective areas transverse occipital sulcus and retrosplenial cortex), although all three scene-selective areas showed the expected inversion effect to scenes. Experiments 2 and 3 tested for an analogous selectivity for cardinal orientations using computer-generated arrays of simple squares and line segments, respectively. The results confirmed the preference for cardinal orientations in PPA, thus demonstrating that the oblique effect can also be produced in PPA by simple geometrical images, with statistics similar to those in scenes. Thus, PPA shows distinctive fMRI selectivity for cardinal orientations across a broad range of stimuli, which may reflect a perceptual oblique effect. C1 [Nasr, Shahin; Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinioula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Tootell, Roger B. H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Tootell, Roger B. H.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Nasr, S (reprint author), Massachusetts Gen Hosp, Athinioula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM shahin@nmr.mgh.harvard.edu FU NIH [R01 MH67529, R01 EY017081]; Martinos Center for Biomedical Imaging; National Center for Research Resources; MIND Institute; NIMH Intramural Research Program FX This study was supported by NIH Grants R01 MH67529 and R01 EY017081 to R. B. H. T., the Martinos Center for Biomedical Imaging, the National Center for Research Resources, the MIND Institute, and the NIMH Intramural Research Program. We thank Ali Amin-Mansour for help with data collection, and Dr. Dara Manoach for support measuring eye movements. NR 25 TC 27 Z9 27 U1 4 U2 17 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 OCT 24 PY 2012 VL 32 IS 43 BP 14921 EP 14926 DI 10.1523/JNEUROSCI.2036-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 029VD UT WOS:000310523900009 PM 23100415 ER PT J AU Yokogawa, T Hannan, MC Burgess, HA AF Yokogawa, Tohei Hannan, Markus C. Burgess, Harold A. TI The Dorsal Raphe Modulates Sensory Responsiveness during Arousal in Zebrafish SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; LARVAL ZEBRAFISH; SEROTONERGIC NEURONS; ATTENTIONAL PROCESSES; DEPENDENT MODULATION; INFERIOR COLLICULUS; SUPERIOR COLLICULUS; NEURAL CIRCUITS; OLFACTORY-BULB; OPTIC TECTUM AB During waking behavior, animals adapt their state of arousal in response to environmental pressures. Sensory processing is regulated in aroused states, and several lines of evidence imply that this is mediated at least partly by the serotonergic system. However, there is little information directly showing that serotonergic function is required for state-dependent modulation of sensory processing. Here we find that zebrafish larvae can maintain a short-term state of arousal during which neurons in the dorsal raphe modulate sensory responsiveness to behaviorally relevant visual cues. After a brief exposure to water flow, larvae show elevated activity and heightened sensitivity to perceived motion. Calcium imaging of neuronal activity after flow revealed increased activity in serotonergic neurons of the dorsal raphe. Genetic ablation of these neurons abolished the increase in visual sensitivity during arousal without affecting baseline visual function or locomotor activity. We traced projections from the dorsal raphe to a major visual area, the optic tectum. Laser ablation of the tectum demonstrated that this structure, like the dorsal raphe, is required for improved visual sensitivity during arousal. These findings reveal that serotonergic neurons of the dorsal raphe have a state-dependent role in matching sensory responsiveness to behavioral context. C1 [Yokogawa, Tohei; Hannan, Markus C.; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. RP Burgess, HA (reprint author), Bldg 6B,Room 3B 308,6 Ctr Dr, Bethesda, MD 20892 USA. EM burgessha@mail.nih.gov RI Burgess, Harold/B-8474-2015 OI Burgess, Harold/0000-0003-1966-7801 FU National Institute of Child Health and Human Development; Japan Society of the Promotion of Science FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development and a research fellowship from the Japan Society of the Promotion of Science (T.Y.). NR 83 TC 35 Z9 35 U1 1 U2 9 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 OCT 24 PY 2012 VL 32 IS 43 BP 15205 EP 15215 DI 10.1523/JNEUROSCI.1019-12.2012 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 029VD UT WOS:000310523900035 PM 23100441 ER PT J AU Mondal, P Tatem, AJ AF Mondal, Pinki Tatem, Andrew J. TI Uncertainties in Measuring Populations Potentially Impacted by Sea Level Rise and Coastal Flooding SO PLOS ONE LA English DT Article ID CLIMATE-CHANGE; ZONES; MAPS AB A better understanding of the impact of global climate change requires information on the locations and characteristics of populations affected. For instance, with global sea level predicted to rise and coastal flooding set to become more frequent and intense, high-resolution spatial population datasets are increasingly being used to estimate the size of vulnerable coastal populations. Many previous studies have undertaken this by quantifying the size of populations residing in low elevation coastal zones using one of two global spatial population datasets available - LandScan and the Global Rural Urban Mapping Project (GRUMP). This has been undertaken without consideration of the effects of this choice, which are a function of the quality of input datasets and differences in methods used to construct each spatial population dataset. Here we calculate estimated low elevation coastal zone resident population sizes from LandScan and GRUMP using previously adopted approaches, and quantify the absolute and relative differences achieved through switching datasets. Our findings suggest that the choice of one particular dataset over another can translate to a difference of more than 7.5 million vulnerable people for countries with extensive coastal populations, such as Indonesia and Japan. Our findings also show variations in estimates of proportions of national populations at risk range from,0.1% to 45% differences when switching between datasets, with large differences predominantly for countries where coarse and outdated input data were used in the construction of the spatial population datasets. The results highlight the need for the construction of spatial population datasets built on accurate, contemporary and detailed census data for use in climate change impact studies and the importance of acknowledging uncertainties inherent in existing spatial population datasets when estimating the demographic impacts of climate change. C1 [Mondal, Pinki; Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Mondal, P (reprint author), Columbia Univ, Dept Ecol Evolut & Environm Biol, New York, NY USA. EM pm2658@columbia.edu FU Bill & Melinda Gates Foundation [49446, OPP1032350]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX AJT is supported by grants from the Bill & Melinda Gates Foundation (#49446 and #OPP1032350) and also acknowledges funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 14 Z9 15 U1 3 U2 37 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 OCT 24 PY 2012 VL 7 IS 10 AR e48191 DI 10.1371/journal.pone.0048191 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026VC UT WOS:000310310200156 PM 23110208 ER PT J AU Offerdahl, DK Dorward, DW Hansen, BT Bloom, ME AF Offerdahl, Danielle K. Dorward, David W. Hansen, Bryan T. Bloom, Marshall E. TI A Three-Dimensional Comparison of Tick-Borne Flavivirus Infection in Mammalian and Tick Cell Lines SO PLOS ONE LA English DT Article ID JAPANESE ENCEPHALITIS-VIRUS; HEMORRHAGIC-FEVER VIRUS; CULTURED MOSQUITO CELLS; VIRAL-RNA SYNTHESIS; DOUBLE-STRANDED-RNA; DENGUE VIRUS; KUNJIN VIRUS; ENDOPLASMIC-RETICULUM; PERSISTENT INFECTION; NONSTRUCTURAL PROTEINS AB Tick-borne flaviviruses (TBFV) are sustained in nature through cycling between mammalian and tick hosts. In this study, we used African green monkey kidney cells (Vero) and Ixodes scapularis tick cells (ISE6) to compare virus-induced changes in mammalian and arthropod cells. Using confocal microscopy, transmission electron microscopy (TEM), and electron tomography (ET), we examined viral protein distribution and the ultrastructural changes that occur during TBFV infection. Within host cells, flaviviruses cause complex rearrangement of cellular membranes for the purpose of virus replication. Virus infection was accompanied by a marked expansion in endoplasmic reticulum (ER) staining and markers for TBFV replication were localized mainly to the ER in both cell lines. TEM of Vero cells showed membrane-bound vesicles enclosed in a network of dilated, anastomosing ER cisternae. Virions were seen within the ER and were sometimes in paracrystalline arrays. Tubular structures or elongated vesicles were occasionally noted. In acutely and persistently infected ISE6 cells, membrane proliferation and vesicles were also noted; however, the extent of membrane expansion and the abundance of vesicles were lower and no viral particles were observed. Tubular profiles were far more prevalent in persistently infected ISE6 cells than in acutely infected cells. By ET, tubular profiles, in persistently infected tick cells, had a cross-sectional diameter of 60-100 nm, reached up to 800 nm in length, were closed at the ends, and were often arranged in fascicle-like bundles, shrouded with ER membrane. Our experiments provide analysis of viral protein localization within the context of both mammalian and arthropod cell lines as well as both acute and persistent arthropod cell infection. Additionally, we show for the first time 3D flavivirus infection in a vector cell line and the first ET of persistent flavivirus infection. C1 [Offerdahl, Danielle K.; Bloom, Marshall E.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Dorward, David W.; Hansen, Bryan T.] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Bloom, ME (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM mbloom@nih.gov FU Intramural Research Program of National Institutes of Health/National Institute of Allergy and Infectious Disease FX These studies were supported by the Intramural Research Program of National Institutes of Health/National Institute of Allergy and Infectious Disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 27 Z9 28 U1 0 U2 11 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 OCT 24 PY 2012 VL 7 IS 10 AR e47912 DI 10.1371/journal.pone.0047912 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026VC UT WOS:000310310200107 PM 23112871 ER PT J AU Ong, HL Jang, SI Ambudkar, IS AF Ong, Hwei Ling Jang, Shyh-Ing Ambudkar, Indu Suresh TI Distinct Contributions of Orai1 and TRPC1 to Agonist-Induced [Ca2+](i) Signals Determine Specificity of Ca2+-Dependent Gene Expression SO PLOS ONE LA English DT Article ID OPERATED CALCIUM-CHANNELS; ACTIVATES CRAC CHANNELS; CA2+ INFLUX; PLASMA-MEMBRANE; STIM1 GATES; STORE; OSCILLATIONS; CELLS; ENTRY; ELEMENTARY AB Regulation of critical cellular functions, including Ca2+-dependent gene expression, is determined by the temporal and spatial aspects of agonist-induced Ca2+ signals. Stimulation of cells with physiological concentrations of agonists trigger increases [Ca2+](i) due to intracellular Ca2+ release and Ca2+ influx. While Orai1-STIM1 channels account for agonist-stimulated [Ca2+](i) increase as well as activation of NFAT in cells such as lymphocytes, RBL and mast cells, both Orai1-STIM1 and TRPC1-STIM1 channels contribute to [Ca2+](i) increases in human submandibular gland (HSG) cells. However, only Orai1-mediated Ca2+ entry regulates the activation of NFAT in HSG cells. Since both TRPC1 and Orai1 are activated following internal Ca2+ store depletion in these cells, it is not clear how the cells decode individual Ca2+ signals generated by the two channels for the regulation of specific cellular functions. Here we have examined the contributions of Orai1 and TRPC1 to carbachol (CCh)-induced [Ca2+](i) signals and activation of NFAT in single cells. We report that Orai1-mediated Ca2+ entry generates [Ca2+](i) oscillations at different [CCh], ranging from very low to high. In contrast, TRPC1-mediated Ca2+ entry generates sustained [Ca2+](i) elevation at high [CCh] and contributes to frequency of [Ca2+](i) oscillations at lower [agonist]. More importantly, the two channels are coupled to activation of distinct Ca2+ dependent gene expression pathways, consistent with the different patterns of [Ca2+](i) signals mediated by them. Nuclear translocation of NFAT and NFAT-dependent gene expression display "all-or-none" activation that is exclusively driven by local [Ca2+](i) generated by Orai1, independent of global [Ca2+](i) changes or TRPC1-mediated Ca2+ entry. In contrast, Ca2+ entry via TRPC1 primarily regulates NF kappa B-mediated gene expression. Together, these findings reveal that Orai1 and TRPC1 mediate distinct local and global Ca2+ signals following agonist stimulation of cells, which determine the functional specificity of the channels in activating different Ca2+-dependent gene expression pathways. C1 [Ong, Hwei Ling; Jang, Shyh-Ing; Ambudkar, Indu Suresh] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov NR 42 TC 19 Z9 19 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 OCT 24 PY 2012 VL 7 IS 10 AR e47146 DI 10.1371/journal.pone.0047146 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026VC UT WOS:000310310200027 PM 23115638 ER PT J AU Rulli, T Wendler, D AF Rulli, Tina Wendler, David TI Requirement to Purchase Health Insurance Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Rulli, Tina; Wendler, David] NIH, Dept Bioeth, Clin Ctr, Bethesda, MD 20892 USA. RP Rulli, T (reprint author), NIH, Dept Bioeth, Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 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 OCT 24 PY 2012 VL 308 IS 16 BP 1629 EP 1629 DI 10.1001/jama.2012.12628 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 028PI UT WOS:000310434100012 ER PT J AU de Heer, HD Wilkinson, AV Strong, LL Bondy, ML Koehly, LM AF de Heer, Hendrik D. Wilkinson, Anna V. Strong, Larkin L. Bondy, Melissa L. Koehly, Laura M. TI Sitting time and health outcomes among Mexican origin adults: obesity as a mediator SO BMC PUBLIC HEALTH LA English DT Article DE Sitting time; Diabetes; Obesity; Hypertension; Hispanic ID CARDIOVASCULAR-DISEASE RISK; TYPE-2 DIABETES-MELLITUS; TELEVISION VIEWING TIME; PHYSICAL-ACTIVITY; METABOLIC SYNDROME; SEDENTARY TIME; LIFE-STYLE; ENERGY-EXPENDITURE; PLASMA-GLUCOSE; UNITED-STATES AB Background: Sitting time and sedentary behaviors have been associated with adverse health outcomes including obesity, diabetes and cardiovascular disease (CVD) within non-Hispanic White populations. Similar associations have not been described within Hispanic populations despite their high CVD risk profile. This study aimed to assess the association between sitting time and obesity, self-reported diagnosed diabetes, hypertension and high cholesterol among a large cohort (N= 11,268) of Mexican origin adults and to assess whether obesity mediated these associations. Methods: Using a cross-sectional design, data collected between 2004 and 2010 were analyzed in late 2010. Regression analyses evaluated associations between self-reported daily sitting hours and disease outcomes, controlling for demographics, employment status, family disease history, and light, moderate and strenuous physical activity. Results: Participants were mostly female (81.1%) Mexican origin adults. Sitting time was associated with increased odds of being obese, having diabetes and having hypertension, but not high cholesterol. Adjusted odds ratios of participants who reported sitting > 4 hours/day compared to those sitting 1-2 hours/day were for obesity OR=1.55 (95% CI 1.39, 1.73), p<.001, for diabetes OR=1.29 (95% CI, 1.09, 1.52), p=.003, for hypertension OR=1.17 (95% CI, 1.01, 1.37), p=.041. Associations controlled for physical activity and employment status. Effects on hypertension and diabetes were mediated by obesity. Conclusions: Sitting time was significantly associated with detrimental health outcomes, independent of physical activity. Obesity mediated these relationships for diabetes and hypertension. Future research should assess whether interventions addressing sitting time are feasible and effective among Mexican origin populations. C1 [de Heer, Hendrik D.] Univ Arizona, Dept Phys Therapy & Athlet Training, Flagstaff, AZ 86011 USA. [Wilkinson, Anna V.] Univ Texas Sch Publ Hlth Austin Reg Campus, Michael & Susan Dell Ctr Hlth Living, Austin, TX USA. [Strong, Larkin L.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar, Houston, TX 77030 USA. [Bondy, Melissa L.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Koehly, Laura M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP de Heer, HD (reprint author), Univ Arizona, Dept Phys Therapy & Athlet Training, 208 E Pine Knoll Dr,Bldg 66,Rm 112,POB 15105, Flagstaff, AZ 86011 USA. EM hendrik.deheer@nau.edu RI de Heer, Hendrik/D-3192-2013 OI de Heer, Hendrik/0000-0002-9241-5021 FU Comprehensive Tobacco Settlement of 1998; Caroline W. Law Fund for Cancer Prevention; Dan Duncan Family Institute for Cancer Prevention and Risk Assessment; National Cancer Institute [CA126988]; Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health [Z01HG200335] FX We would like to extend our gratitude to our research participants, without whom this project would not have been possible. The Mano a Mano cohort was funded by the Comprehensive Tobacco Settlement of 1998, the Caroline W. Law Fund for Cancer Prevention, and the Dan Duncan Family Institute for Cancer Prevention and Risk Assessment. Anna V. Wilkinson is funded by the National Cancer Institute [CA126988]. This study was supported by the Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health [Z01HG200335 to LMK]. NR 43 TC 8 Z9 8 U1 3 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD OCT 23 PY 2012 VL 12 AR 896 DI 10.1186/1471-2458-12-896 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 059ZJ UT WOS:000312744000001 PM 23092387 ER PT J AU Hammond, GRV AF Hammond, Gerald R. V. TI Membrane Biology: Making Light Work of Lipids SO CURRENT BIOLOGY LA English DT Editorial Material ID PLASMA-MEMBRANE; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; LIVING CELLS; PROTEINS AB A clever genetic trick allows the lipid composition of the plasma membrane to be manipulated using light, paving the way for new investigations into the many membrane interactions that dictate cell shape, movement and communication. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Hammond, GRV (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM gerald.hammond@nih.gov RI Hammond, Gerald/A-5759-2016 OI Hammond, Gerald/0000-0002-6660-3272 NR 11 TC 0 Z9 0 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD OCT 23 PY 2012 VL 22 IS 20 BP R869 EP R871 DI 10.1016/j.cub.2012.09.005 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 048AM UT WOS:000311882600009 PM 23098593 ER PT J AU Welbourn, S Miyagi, E White, TE Diaz-Griffero, F Strebel, K AF Welbourn, Sarah Miyagi, Eri White, Tommy E. Diaz-Griffero, Felipe Strebel, Klaus TI Identification and characterization of naturally occurring splice variants of SAMHD1 SO RETROVIROLOGY LA English DT Article DE Vpx; SAMHD1; Splicing; Gene regulation ID RESTRICTION FACTOR SAMHD1; IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 RESTRICTION; DENDRITIC CELLS; MYELOID CELLS; VPX; PROTEIN; MACROPHAGES; GENE; REPLICATION AB Background: Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1) is a recently identified host factor that restricts HIV-1 replication in dendritic and myeloid cells. SAMHD1 is a dNTPase that presumably reduces the cellular dNTP levels to levels too low for retroviral reverse transcription to occur. However, HIV-2 and SIV encoded Vpx counteracts the antiviral effects of SAMHD1 by targeting the protein for proteasomal degradation. SAMHD1 is encoded by a multiply spliced mRNA and consists of 16 coding exons. Results: Here, we identified two naturally occurring splice variants lacking exons 8-9 and 14, respectively. Like wildtype SAMHD1, both splice variants localize primarily to the nucleus, interact with Vpx, and retain some sensitivity to Vpx-dependent degradation. However, the splice variants differ from full-length SAMHD1 in their metabolic stability and catalytic activity. While full-length SAMHD1 is metabolically stable in uninfected cells, both splice variants were inherently metabolically unstable and were rapidly degraded even in the absence of Vpx. Vpx strongly increased the rate of degradation of full-length SAMHD1 and further accelerated the degradation of the splice variants. However, the effect of Vpx on the splice variants was more modest due to the inherent instability of these proteins. Analysis of dNTPase activity indicates that neither splice variant is catalytically active. Conclusions: The identification of SAMHD1 splice variants exposes a potential regulatory mechanism that could enable the cell to control its dNTPase activity on a post-transcriptional level. C1 [Welbourn, Sarah; Miyagi, Eri; Strebel, Klaus] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [White, Tommy E.; Diaz-Griffero, Felipe] Albert Einstein Coll Med Bronx, Dept Microbiol & Immunol, New York, NY 10461 USA. RP Strebel, K (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bldg 4,Room 310,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU NIH, NIAID; Canadian Institutes of Health Research (C.I.H.R); NIH [R01 AI087390] FX We thank Amy Andrew, Takeshi Yoshida, Sandra Kao, and Haruka Yoshii-Kamiyama for helpful discussions and critical reading of the manuscript. This work was supported in part by the Intramural Research Program of the NIH, NIAID. SW was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (C.I.H.R) and an Intramural AIDS Research Fellowship from NIH. TEW and FD-G were funded by a NIH R01 AI087390 to FD-G. NR 35 TC 19 Z9 20 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD OCT 23 PY 2012 VL 9 AR 86 DI 10.1186/1742-4690-9-86 PG 10 WC Virology SC Virology GA 043PY UT WOS:000311557700001 PM 23092512 ER PT J AU Lei, Y Guo, XG Liu, Y Cao, Y Deng, Y Chen, XF Cheng, CHK Dawid, IB Chen, YL Zhao, H AF Lei, Yong Guo, Xiaogang Liu, Yun Cao, Yang Deng, Yi Chen, Xiongfeng Cheng, Christopher H. K. Dawid, Igor B. Chen, Yonglong Zhao, Hui TI Efficient targeted gene disruption in Xenopus embryos using engineered transcription activator-like effector nucleases (TALENs) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genome editing; heritable mutagenesis; mutagenesis detection; reverse genetics; genome engineering ID DNA-BINDING SPECIFICITY; III EFFECTORS; RESTRICTION ENZYMES; FINGER; CLEAVAGE; RECOGNITION; PANCREAS; EXOCRINE; BREAKING; CODE AB Transcription activator-like effector nucleases (TALENs) are an approach for directed gene disruption and have been proved to be effective in various animal models. Here, we report that TALENs can induce somatic mutations in Xenopus embryos with reliably high efficiency and that such mutations are heritable through germ-line transmission. We modified the Golden Gate method for TALEN assembly to make the product suitable for RNA transcription and microinjection into Xenopus embryos. Eight pairs of TALENs were constructed to target eight Xenopus genes, and all resulted in indel mutations with high efficiencies of up to 95.7% at the targeted loci. Furthermore, mutations induced by TALENs were highly efficiently passed through the germ line to F-1 frogs. Together with simple and reliable PCR-based approaches for detecting TALEN-induced mutations, our results indicate that TALENs are an effective tool for targeted gene editing/knockout in Xenopus. C1 [Lei, Yong; Liu, Yun; Cheng, Christopher H. K.; Zhao, Hui] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Guo, Xiaogang; Cao, Yang; Chen, Yonglong] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China. [Deng, Yi] S Univ Sci & Technol China, Dept Biol, Shenzhen 518055, Peoples R China. [Chen, Xiongfeng] NCI, Adv Biomed Comp Ctr, NIH, Frederick, MD 21702 USA. [Cheng, Christopher H. K.; Zhao, Hui] Chinese Univ Hong Kong, Shenzhen Res Inst, Shenzhen 518057, Peoples R China. [Dawid, Igor B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Cheng, CHK (reprint author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. EM chkcheng@cuhk.edu.hk; idawid@nih.gov; chen_yonglong@gibh.ac.cn; zhaohui@cuhk.edu.hk RI Zhao, Hui/B-8429-2016 FU Research Grants Council of Hong Kong [CUHK480709]; National Basic Research Program of China [2009CB941202]; Chinese Academy of Sciences [KSCX2-YW-R-083]; National Institute of Child Health and Human Development, National Institutes of Health; National Natural Science Foundation of China [31172394]; Chinese University of Hong Kong FX We thank Dr. Thomas Cermak, Dr. Daniel Voytas, and Addgene for making the Golden Gate TALEN constructs accessible to the research community. This work was supported by grants from the Research Grants Council of Hong Kong (CUHK480709) (to H.Z.); and in part by funds from the National Basic Research Program of China (2009CB941202) and funds from the Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-YW-R-083) (to Y. Chen), the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health (I. B. D.), and the National Natural Science Foundation of China (31172394) (to C. H. K. C.). Y. Lei is supported by the Graduate Studentships from The Chinese University of Hong Kong. NR 24 TC 137 Z9 151 U1 6 U2 54 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 OCT 23 PY 2012 VL 109 IS 43 BP 17484 EP 17489 DI 10.1073/pnas.1215421109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800040 PM 23045671 ER PT J AU Oakley, RH Revollo, J Cidlowski, JA AF Oakley, Robert H. Revollo, Javier Cidlowski, John A. TI Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BETA-ARRESTINS; BETA-ARRESTIN-2; DESENSITIZATION; ACTIVATION; DISEASE; ASTHMA AB G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, beta-arrestin-1 and beta-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, beta-arrestins terminateG protein-dependent responses (desensitization) and stimulate beta-arrestin-dependent signaling pathways. Alterations in the cellular complement of beta-arrestin-1 and beta-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control beta-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate beta-arrestin-1 and beta-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of beta-arrestin-1 and repress the expression of beta-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the beta-arrestin-1 gene and intron-11 of the beta-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of beta-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing beta-arrestin-1-dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in beta-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs. C1 [Oakley, Robert H.; Revollo, Javier; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health FX We thank Dr. Robert J. Lefkowitz (Duke University) for providing the mouse embryonic fibroblasts and Dr. JoAnn Trejo (University of California at San Diego) for providing the FLAG-PAR1 expression vector. This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 26 TC 12 Z9 12 U1 1 U2 8 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 OCT 23 PY 2012 VL 109 IS 43 BP 17591 EP 17596 DI 10.1073/pnas.1209411109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800058 PM 23045642 ER PT J AU Guo, CC Chang, CC Wortham, M Chen, LH Kernagis, DN Qin, XX Cho, YW Chi, JT Grant, GA McLendon, RE Yan, H Ge, K Papadopoulos, N Bigner, DD He, YP AF Guo, Changcun Chang, Chun-Chi Wortham, Matthew Chen, Lee H. Kernagis, Dawn N. Qin, Xiaoxia Cho, Young-Wook Chi, Jen-Tsan Grant, Gerald A. McLendon, Roger E. Yan, Hai Ge, Kai Papadopoulos, Nickolas Bigner, Darell D. He, Yiping TI Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumor suppressor; somatic targeting; S100A gene cluster ID HISTONE H3K4 TRIMETHYLATION; B-CELL LYMPHOMA; SOMATIC MUTATIONS; CHROMATIN IMMUNOPRECIPITATION; METHYLTRANSFERASE ACTIVITY; ENDOGENOUS PROTEINS; ESTROGEN-RECEPTOR; MODIFYING GENES; LEUKEMIA-CELLS; TARGET GENES AB Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations. C1 [Guo, Changcun; Chang, Chun-Chi; Wortham, Matthew; Chen, Lee H.; Grant, Gerald A.; McLendon, Roger E.; Yan, Hai; Bigner, Darell D.; He, Yiping] Duke Univ, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA. [Guo, Changcun; Chang, Chun-Chi; Wortham, Matthew; Chen, Lee H.; Grant, Gerald A.; McLendon, Roger E.; Yan, Hai; Bigner, Darell D.; He, Yiping] Duke Univ, Pediat Brain Tumor Fdn Inst, Durham, NC 27710 USA. [Guo, Changcun; Chang, Chun-Chi; Wortham, Matthew; Chen, Lee H.; Kernagis, Dawn N.; McLendon, Roger E.; Yan, Hai; Bigner, Darell D.; He, Yiping] Duke Univ, Dept Pathol, Durham, NC 27710 USA. [Qin, Xiaoxia; Chi, Jen-Tsan] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27710 USA. [Grant, Gerald A.] Duke Univ, Dept Surg, Durham, NC 27710 USA. [Cho, Young-Wook; Ge, Kai] NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Papadopoulos, Nickolas] Sidney Kimmel Comprehens Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. RP He, YP (reprint author), Duke Univ, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA. EM yiping.he@duke.edu OI Ge, Kai/0000-0002-7442-5138 FU Pediatric Brain Tumor Foundation; Preston Robert Tisch Brain Tumor Center at Duke; Duke Cancer Institute FX We thank Zhenghe Wang (Case Western Reserve University) for the somatic knockin construct and advice on generating somatic knockin cell lines and the Duke Microarray Core Facility (a Duke National Cancer Institute and Duke Institute for Genome Sciences and Policy shared-resource facility) for technical support, microarray data management, and feedback on the generation of the microarray data reported in this manuscript. This work was supported by the Pediatric Brain Tumor Foundation and The Preston Robert Tisch Brain Tumor Center at Duke (Y.H.) and the Duke Cancer Institute (Y.H.). NR 51 TC 36 Z9 36 U1 0 U2 11 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 OCT 23 PY 2012 VL 109 IS 43 BP 17603 EP 17608 DI 10.1073/pnas.1208807109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800060 PM 23045699 ER PT J AU Wang, P Lazarus, BD Forsythe, ME Love, DC Krause, MW Hanover, JA AF Wang, Peng Lazarus, Brooke D. Forsythe, Michele E. Love, Dona C. Krause, Michael W. Hanover, John A. TI O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neurodegeneration; Alzheimer's disease; Huntington disease; insulin ID LINKED N-ACETYLGLUCOSAMINE; BETA-AMYLOID PEPTIDE; ALZHEIMERS-DISEASE; INSULIN-RESISTANCE; AUTOPHAGY GENES; PROTEIN-TAU; POLYGLUTAMINE; AGGREGATION; PROTEASOME; EXPRESSION AB O-GlcNAcylation is an abundant posttranslational modification in the brain implicated in human neurodegenerative diseases. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized Caenorhabditis elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatically modulated the severity of the phenotype in transgenic models of tauopathy, amyloid beta-peptide, and polyglutamine expansion. Intriguingly, loss of function of O-GlcNAc transferase alleviated, whereas loss of O-GlcNAcase enhanced, the phenotype of multiple neurodegenerative disease models. The O-GlcNAc cycling mutants act in part by altering DAF-16-dependent transcription and modulating the protein degradation machinery. These findings suggest that O-GlcNAc levels may directly influence neurodegenerative disease progression, thus making the enzymes of O-GlcNAc cycling attractive targets for neurodegenerative disease therapies. C1 [Wang, Peng; Lazarus, Brooke D.; Forsythe, Michele E.; Love, Dona C.; Hanover, John A.] NIDDKD, NIH, Lab Cell & Mol Biol, Bethesda, MD 20892 USA. [Krause, Michael W.] NIDDKD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDKD, NIH, Lab Cell & Mol Biol, Bethesda, MD 20892 USA. EM jah@helix.nih.gov OI Krause, Michael/0000-0001-6127-3940 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); NIH National Center for Research Resources FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). We thank Drs. A. Hart, C. Link, and B. Kraemer for transgenic strains and the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources. NR 56 TC 35 Z9 35 U1 0 U2 18 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 OCT 23 PY 2012 VL 109 IS 43 BP 17669 EP 17674 DI 10.1073/pnas.1205748109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800071 PM 22988095 ER PT J AU Song, R Zhang, HY Li, X Bi, GH Gardner, EL Xi, ZX AF Song, Rui Zhang, Hai-Ying Li, Xia Bi, Guo-Hua Gardner, Eliot L. Xi, Zheng-Xiong TI Increased vulnerability to cocaine in mice lacking dopamine D-3 receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE etiology of addiction; susceptibility to cocaine; reinforcement; extinction; reinstatement ID SEEKING BEHAVIOR; NUCLEUS-ACCUMBENS; PROGRESSIVE-RATIO; TRAIT IMPULSIVITY; DEFICIENT MICE; D2 RECEPTORS; D3 RECEPTORS; MUTANT MICE; HUMAN BRAIN; DRUG-ABUSE AB Neuroimaging studies using positron emission tomography suggest that reduced dopamine D-2 receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D-3 receptors (D(3)Rs) in the neurobiology of addiction remains unclear, however. Here we report that D3R KO (D-3(-/-)) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D-3(-/-) mice. In addition, D-3(-/-) mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D3R deletion increases vulnerability to cocaine, and that reduced D3R availability in the brainmay constitute a risk factor for the development of cocaine addiction. C1 [Song, Rui; Zhang, Hai-Ying; Li, Xia; Bi, Guo-Hua; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Neuropsychopharmacol Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Song, Rui] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. [Li, Xia] Univ Calif San Diego, Sch Med, Dept Psychiat, La Jolla, CA 92093 USA. RP Xi, ZX (reprint author), NIDA, Neuropsychopharmacol Sect, Intramural Res Program, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov OI Zhang, Haiying/0000-0003-0593-5940 FU US National Institute on Drug Abuse's Intramural Research Program; National Basic Research Program of China [2009CB522008] FX This work was supported by the US National Institute on Drug Abuse's Intramural Research Program and by the National Basic Research Program of China (Grant 2009CB522008). NR 59 TC 28 Z9 28 U1 2 U2 20 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 OCT 23 PY 2012 VL 109 IS 43 BP 17675 EP 17680 DI 10.1073/pnas.1205297109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800072 PM 23045656 ER PT J AU Walogorsky, M Mongeon, R Wen, H Nelson, NR Urban, JM Ono, F Mandel, G Brehm, P AF Walogorsky, Michael Mongeon, Rebecca Wen, Hua Nelson, Nathan R. Urban, Jason M. Ono, Fumihito Mandel, Gail Brehm, Paul TI Zebrafish model for congenital myasthenic syndrome reveals mechanisms causal to developmental recovery SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuromuscular; quinidine; nicotinic receptor ID ACETYLCHOLINE-RECEPTOR DEFICIENCY; AGONIST BINDING-AFFINITY; EPSILON-SUBUNIT; ALPHA-SUBUNIT; GAMMA-SUBUNIT; MUSCLE; MUTATIONS; DESENSITIZATION; BLOCKADE; RAPSYN AB Mutations in muscle ACh receptors cause slow-channel syndrome (SCS) and Escobar syndrome, two forms of congenital myasthenia. SCS is a dominant disorder with mutations reported for all receptor subunits except gamma. Escobar syndrome is distinct, with mutations located exclusively in gamma, and characterized by developmental improvement of muscle function. The zebrafish mutant line, twister, models SCS in terms of a dominant mutation in the alpha subunit (alpha(twi)) but shows the behavioral improvement associated with Escobar syndrome. Here, we present a unique electrophysiological study into developmental improvement for a myasthenic syndrome. The embryonic alpha(twi)beta delta gamma receptor isoform produces slowly decaying synaptic currents typical of SCS that transit to a much faster decay upon the appearance of adult epsilon, despite the atwi mutation. Thus, the continued expression of alpha(twi) into adulthood is tolerated because of the e expression and associated recovery, raising the likelihood of unappreciated myasthenic cases that benefit from the gamma-epsilon switch. C1 [Walogorsky, Michael; Mongeon, Rebecca; Wen, Hua; Nelson, Nathan R.; Mandel, Gail; Brehm, Paul] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Mongeon, Rebecca; Nelson, Nathan R.; Mandel, Gail] Oregon Hlth & Sci Univ, Howard Hughes Med Inst, Portland, OR 97239 USA. [Urban, Jason M.; Ono, Fumihito] NIAAA, NIH, Rockville, MD 20852 USA. RP Mandel, G (reprint author), Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. EM mandelg@ohsu.edu FU National Institutes of Health; Muscular Dystrophy Association FX We thank Dr. Geng-Lin Li for providing the Igor routine for fit of synaptic current. This research was supported by grants from the National Institutes of Health and the Muscular Dystrophy Association (to P.B). NR 24 TC 7 Z9 7 U1 0 U2 4 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 OCT 23 PY 2012 VL 109 IS 43 BP 17711 EP 17716 DI 10.1073/pnas.1215858109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800078 PM 23045675 ER PT J AU Mondul, AM Weinstein, SJ Virtamo, J Albanes, D AF Mondul, A. M. Weinstein, S. J. Virtamo, J. Albanes, D. TI Influence of vitamin D binding protein on the association between circulating vitamin D and risk of bladder cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE urinary bladder neoplasms; 25-hydroxyvitamin D; vitamin D binding protein; case-control study ID 25-HYDROXYVITAMIN D; GC-GLOBULIN; OSTEOPOROSIS; POLYMORPHISM; COHORT; TRIAL AB BACKGROUND: There is little research investigating the role of vitamin D binding protein (DBP) in the association between 25-hydroxyvitamin D (25(OH)D) and disease risk. METHODS: Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, 250 bladder cancer cases were randomly sampled and matched 1:1 to controls on age and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer were estimated by quartiles of DBP (measured by ELISA), 25(OH)D and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. Analyses were also conducted stratifying 25(OH)D by DBP (median split) and vice versa. RESULTS: We found no direct association between circulating DBP levels and bladder cancer risk (P-trend = 0.83). The inverse association between 25(OH)D and bladder cancer risk was unchanged after adjustment for DBP (Q4 vs Q1 OR = 0.61, 95% CI = 0.36-1.05; P-trend = 0.04), and was stronger among men with lower DBP (low DBP: 25(OH)D Q4 vs Q1 OR = 0.47, 95% CI = 0.23-1.00; high DBP: 25(OH)D Q4 vs Q1 OR = 0.83, 95% CI = 0.40-1.75; P for interaction = 0.11). CONCLUSION: Our findings provide additional support for an aetiologic role for vitamin D in bladder cancer and suggest that free, rather than total, circulating vitamin D may be a more relevant exposure when examining bladder and, perhaps, other cancers. British Journal of Cancer (2012) 107, 1589-1594. doi:10.1038/bjc.2012.417 www.bjcancer.com Published online 18 September 2012 (C) 2012 Cancer Research UK C1 [Mondul, A. M.; Weinstein, S. J.; Albanes, D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Rockville, MD USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. RP Mondul, AM (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, 6120 Execut Blvd,Suite 320, Rockville, MD USA. EM mondulam@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mondul, Alison/0000-0002-8843-1416 FU US Public Health Service from the National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; Intramural Research Program of the National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We would like to thank William C Kopp and Helen Rager from the Clinical Support Laboratory, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA for their measurement of DBP. This work was supported by US Public Health Service (contract numbers N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services, and by funding from the Intramural Research Program of the National Cancer Institute. This project has been funded, in whole or in part, with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 23 TC 21 Z9 22 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 23 PY 2012 VL 107 IS 9 BP 1589 EP 1594 DI 10.1038/bjc.2012.417 PG 6 WC Oncology SC Oncology GA 029OS UT WOS:000310505800021 PM 22990651 ER PT J AU Dorjsuren, D Kim, D Vyjayanti, VN Maloney, DJ Jadhav, A Wilson, DM Simeonov, A AF Dorjsuren, Dorjbal Kim, Daemyung Vyjayanti, Vaddadi N. Maloney, David J. Jadhav, Ajit Wilson, David M., III Simeonov, Anton TI Diverse Small Molecule Inhibitors of Human Apurinic/Apyrimidinic Endonuclease APE1 Identified from a Screen of a Large Public Collection SO PLOS ONE LA English DT Article ID BASE EXCISION-REPAIR; ENHANCES CELLULAR-SENSITIVITY; HUMAN ABASIC ENDONUCLEASE; DNA-REPAIR; MAJOR HUMAN; STATISTICAL PARAMETER; SITE RECOGNITION; CANCER; DAMAGE; CELLS AB The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER) pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), as well as additional public collections, with each compound tested as a 7-concentration series in a 4 mu L reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment. C1 [Vyjayanti, Vaddadi N.; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Dorjsuren, Dorjbal; Maloney, David J.; Jadhav, Ajit; Simeonov, Anton] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD USA. [Vyjayanti, Vaddadi N.] Cheongju Univ, Dept Gen Engn, Cheongju, South Korea. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov; asimeono@mail.nih.gov FU Molecular Libraries Initiative of the National Institutes of Health (NIH) Roadmap for Medical Research [1 R03 MH092154-01, U54MH084681]; Intramural Research Program of NIA, NIH FX This research was supported in part by the Molecular Libraries Initiative of the National Institutes of Health (NIH) Roadmap for Medical Research (grants 1 R03 MH092154-01 (DMWIII) and U54MH084681 (AS)) and the Intramural Research Program of NIA, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 9 Z9 10 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 23 PY 2012 VL 7 IS 10 AR e47974 DI 10.1371/journal.pone.0047974 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025MO UT WOS:000310193600041 PM 23110144 ER PT J AU Nachega, JB Uthman, OA Anderson, J Peltzer, K Wampold, S Cotton, MF Mills, EJ Ho, YS Stringer, JSA McIntyre, JA Mofenson, LM AF Nachega, Jean B. Uthman, Olalekan A. Anderson, Jean Peltzer, Karl Wampold, Sarah Cotton, Mark F. Mills, Edward J. Ho, Yuh-Shan Stringer, Jeffrey S. A. McIntyre, James A. Mofenson, Lynne M. TI Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis SO AIDS LA English DT Article; Proceedings Paper CT 19th Conference on Retroviruses and Opportunistic Infections (CROI) CY MAR 05-08, 2012 CL Seattle, WA DE adherence; antiretroviral therapy; HIV infection; prevention of mother-to-child HIV transmission; pregnancy ID CHILD HIV TRANSMISSION; SINGLE-DOSE NEVIRAPINE; RANDOMIZED CONTROLLED-TRIAL; HUMAN-IMMUNODEFICIENCY-VIRUS; SHORT-COURSE ZIDOVUDINE; WOMENS INTERAGENCY HIV; INFECTED WOMEN; SOUTH-AFRICA; PROSPECTIVE COHORT; GREATER ADHERENCE AB Objective: To estimate anti retroviral therapy (ART) adherence rates during pregnancy and postpartum in high-income, middle-income, and low-income countries. Design: Systematic review and meta-analysis. Methods: MEDLINE, EMBASE, SCI Web of Science, NLM Gateway, and Google scholar databases were searched. We included all studies reporting adherence rates as a primary or secondary outcome among HIV-infected pregnant women. Two independent reviewers extracted data on adherence and study characteristics. A random-effects model was used to pool adherence rates; sensitivity, heterogeneity, and publication bias were assessed. Results: Of 72 eligible articles, 51 studies involving 20153 HIV-infected pregnant women were included. Most studies were from United States (n = 14, 27%) followed by Kenya (n = 6, 12%), South Africa (n = 5, 10%), and Zambia (n = 5, 10%). The threshold defining good adherence to ART varied across studies (>80, >90, >95, 100%). A pooled analysis of all studies indicated a pooled estimate of 73.5% [95% confidence interval (Cl) 69.3-77.5%] of pregnant women who had adequate (>80%) ART adherence. The pooled proportion of women with adequate adherence levels was higher during the antepartum (75.7%, 95% Cl 71.5-79.7%) than during postpartum (53.0%, 95% Cl 32.8-72.7%; P=0.005). Selected reported barriers for nonadherence included physical, economic and emotional stresses, depression (especially postdelivery), alcohol or drug use, and ART dosing frequency or pill burden. Conclusion: Our findings indicate that only 73.5% of pregnant women achieved optimal ART adherence. Reaching adequate ART adherence levels was a challenge in pregnancy, but especially during the postpartum period. Further research to investigate specific barriers and interventions to address them is urgently needed globally. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Nachega, Jean B.; Wampold, Sarah] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Nachega, Jean B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Nachega, Jean B.] Univ Stellenbosch, Fac Hlth Sci, Dept Med, Cape Town, South Africa. [Nachega, Jean B.; Cotton, Mark F.] Univ Stellenbosch, Fac Hlth Sci, Ctr Infect Dis, Cape Town, South Africa. [Uthman, Olalekan A.] Univ Stellenbosch, Fac Hlth Sci, Ctr Evidence Based Healthcare, Cape Town, South Africa. [Uthman, Olalekan A.] Keele Univ, Dept Primary Care Sci, Keele, Staffs, England. [Anderson, Jean] Johns Hopkins Univ Hosp, Dept Gynecol & Obstet, Baltimore, MD 21287 USA. [Peltzer, Karl] Human Sci Res Council, Pretoria, South Africa. [Peltzer, Karl] Univ Orange Free State, Bloemfontein, South Africa. [Cotton, Mark F.] Univ Stellenbosch, Fac Hlth Sci, Tygerbergs Children Hosp, Dept Pediat & Child Hlth, Cape Town, South Africa. [Mills, Edward J.] Univ Ottawa, Fac Hlth Sci, Ottawa, ON, Canada. [Ho, Yuh-Shan] Asia Univ, Trend Res Ctr, Taichung, Taiwan. [Stringer, Jeffrey S. A.] Ctr Infect Dis Res, Lusaka, Zambia. [Stringer, Jeffrey S. A.] Univ Alabama Birmingham, Birmingham, AL USA. [McIntyre, James A.] Anova Hlth Inst, Johannesburg, South Africa. [McIntyre, James A.] Univ Cape Town, Sch Publ Hlth & Family Med, ZA-7925 Cape Town, South Africa. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. RP Nachega, JB (reprint author), Johns Hopkins Univ, Dept Int Hlth, Bloomberg Sch Publ Hlth, Global Dis Epidemiol & Control Program, 615N Wolfe St,Suite W5031, Baltimore, MD 21205 USA. EM jnachega@jhsph.edu RI Ho, Yuh-Shan/C-8624-2009; OI Mofenson, Lynne/0000-0002-2818-9808; Uthman, Olalekan/0000-0002-8567-3081 FU NIAID NIH HHS [K23 AI 068582-01, K23 AI068582, R01 AI005535901]; NIMH NIH HHS [R21 MH083592, R34 MH083592-01A1]; Wellcome Trust [WT087537MA] NR 101 TC 121 Z9 121 U1 0 U2 31 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD OCT 23 PY 2012 VL 26 IS 16 BP 2039 EP 2052 DI 10.1097/QAD.0b013e328359590f PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 021OB UT WOS:000309894000006 PM 22951634 ER PT J AU Weinert, LA Welch, JJ Suchard, MA Lemey, P Rambaut, A Fitzgerald, JR AF Weinert, Lucy A. Welch, John J. Suchard, Marc A. Lemey, Philippe Rambaut, Andrew Fitzgerald, J. Ross TI Molecular dating of human-to-bovid host jumps by Staphylococcus aureus reveals an association with the spread of domestication SO BIOLOGY LETTERS LA English DT Article DE Bayesian phylogenetics; molecular clocks; bacterial evolution; host switching ID EVOLUTION; INSIGHTS; ORIGINS AB Host species switches by bacterial pathogens leading to new endemic infections are important evolutionary events that are difficult to reconstruct over the long term. We investigated the host switching of Staphylococcus aureus over a long evolutionary timeframe by developing Bayesian phylogenetic methods to account for uncertainty about past host associations and using estimates of evolutionary rates from serially sampled whole-genome data. Results suggest multiple jumps back and forth between human and bovids with the first switch from humans to bovids taking place around 5500 BP, coinciding with the expansion of cattle domestication throughout the Old World. The first switch to poultry is estimated at around 275 BP, long after domestication but still preceding large-scale commercial farming. These results are consistent with a central role for anthropogenic change in the emergence of new endemic diseases. C1 [Weinert, Lucy A.; Welch, John J.] Univ Montpellier 2, Montpellier, France. [Weinert, Lucy A.; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Welch, John J.] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, UCLA Felding Sch Publ Hlth, Dept Biostat, Los Angeles, CA USA. [Lemey, Philippe] Katholieke Univ Leuven, Dept Microbiol & Immunol, Louvain, Belgium. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD USA. [Fitzgerald, J. Ross] Univ Edinburgh, Roslin Inst & Edinburgh Infect Dis, Edinburgh, Midlothian, Scotland. RP Weinert, LA (reprint author), UCL Genet Inst, Dept Genet Environm & Evolut, Darwin Bldg,Gower St, London WC1E 6BT, England. EM lucy.weinert@gmail.com OI Rambaut, Andrew/0000-0003-4337-3707 FU MRC; BBSRC; NSF; NIH; NESCent; European Community's Seventh Framework Programme (FP7) [278433, 260864] FX We thank Michael Stanhope for S. simiae sequences, Francois Balloux and Andrew Leigh Brown for support, two anonymous reviewers for comments and the MRC and BBSRC (L.W. and J.R.F.), the NSF and NIH (M.A.S.) and the NESCent (M.A.S., A.R. and P.L.) for funding. Initial research received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 278433 and ERC grant agreement no. 260864. NR 26 TC 23 Z9 24 U1 0 U2 22 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1744-9561 EI 1744-957X J9 BIOL LETTERS JI Biol. Lett. PD OCT 23 PY 2012 VL 8 IS 5 BP 829 EP 832 DI 10.1098/rsbl.2012.0290 PG 4 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 005ZP UT WOS:000308789200039 PM 22628096 ER PT J AU Nahin, RL Byrd-Clark, D Stussman, BJ Kalyanaraman, N AF Nahin, Richard L. Byrd-Clark, Danita Stussman, Barbara J. Kalyanaraman, Nilesh TI Disease severity is associated with the use of complementary medicine to treat or manage type-2 diabetes: data from the 2002 and 2007 National Health Interview Survey SO BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Article DE Complementary medicine; Diabetes; Disease severity; Logistic regression; Survey ID ALTERNATIVE MEDICINE; UNITED-STATES; RISK-FACTORS; CLINICAL CHARACTERISTICS; COST-EFFECTIVENESS; YOUTH PREVALENCE; SELF-MANAGEMENT; BLOOD-GLUCOSE; OLDER-ADULTS; MELLITUS AB Background: The overall prevalence of complementary medicine (CM) use among adults in the United States with diabetes has been examined both in representative national samples and in more restricted populations. However, none of these earlier studies attempted to identify predictors of CM use to treat diabetes among the populations sampled, nor looked for a relationship between CM use and diabetes severity. Methods: Combining data from the 2002 and 2007 National Health Interview Survey (NHIS), we constructed a nationally representative sample of 3,978 U. S. adults aged >= 18 years with self-reported diabetes. Both the 2002 and 2007 NHIS contained extensive questions on the use of CM. We used logistic regression to examine the association between diabetes severity and overall CM use, as well as the use of specific categories of CM. Results: In adults with type-2 diabetes, 30.9% used CM for any reason, but only 3.4% used CM to treat or manage their type-2 diabetes versus 7.1% of those with type-1 diabetes. Among those using CM to treat/manage their type-2 diabetes, 77% used both CM and conventional prescription medicine for their diabetes. The most prevalent types of CM therapies used were diet-based interventions (35.19%, S.E. 5.11) and non-vitamin/non-mineral dietary supplements (33.74%, S.E. 5.07). After controlling for sociodemographic factors, we found that, based on a count of measures of diabetes severity, persons with the most severe diabetes had nearly twice the odds of using CM as those with less severe disease (OR=1.9, 95%CI 1.2-3.01). Persons who had diabetes 10 years or more (OR=1.66, 95%CI 1.04-3.66) and those that had a functional limitation resulting from their diabetes (OR=1.74, 95%CI 1.09-2.8) had greater odds of using CM than those not reporting these measures. No significant associations were observed between overall CM use and other individual measures of diabetes severity: use of diabetic medications, weak or failing kidneys, coronary heart disease, or severe vision problems. Conclusions: Our results demonstrate that individuals with more severe diabetes are more likely to use CM independent of sociodemographic factors. Further studies are essential to determine if CM therapies actually improve clinical outcomes when used to treat/manage diabetes. C1 [Nahin, Richard L.; Stussman, Barbara J.; Kalyanaraman, Nilesh] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Byrd-Clark, Danita] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. RP Nahin, RL (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM nahinr@mail.nih.gov OI Nahin, Richard/0000-0002-3682-4816 NR 54 TC 8 Z9 8 U1 6 U2 23 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6882 J9 BMC COMPLEM ALTERN M JI BMC Complement. Altern. Med. PD OCT 22 PY 2012 VL 12 AR 193 DI 10.1186/1472-6882-12-193 PG 17 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 059RZ UT WOS:000312724200001 PM 23088705 ER PT J AU Qiu, YF Davis, MJ Dayrit, JK Hadd, Z Meister, DL Osterholzer, JJ Williamson, PR Olszewski, MA AF Qiu, Yafeng Davis, Michael J. Dayrit, Jeremy K. Hadd, Zachary Meister, Daniel L. Osterholzer, John J. Williamson, Peter R. Olszewski, Michal A. TI Immune Modulation Mediated by Cryptococcal Laccase Promotes Pulmonary Growth and Brain Dissemination of Virulent Cryptococcus neoformans in Mice SO PLOS ONE LA English DT Article ID CD8+ T-CELLS; INTERFERON-GAMMA; MACROPHAGE ACTIVATION; HOST-RESISTANCE; AFFERENT PHASE; INFECTION; STRAIN; INTERLEUKIN-4; INFLAMMATION; EXPRESSION AB C. neoformans is a leading cause of fatal mycosis linked to CNS dissemination. Laccase, encoded by the LAC1 gene, is an important virulence factor implicated in brain dissemination yet little is known about the mechanism(s) accounting for this observation. Here, we investigated whether the presence or absence of laccase altered the local immune response in the lungs by comparing infections with the highly virulent strain, H99 (which expresses laccase) and mutant strain of H99 deficient in laccase (lac1 Delta) in a mouse model of pulmonary infection. We found that LAC1 gene deletion decreased the pulmonary fungal burden and abolished CNS dissemination at weeks 2 and 3. Furthermore, LAC1 deletion lead to: 1) diminished pulmonary eosinophilia; 2) increased accumulation of CD4+ and CD8+ T cells; 3) increased Th1 and Th17 cytokines yet decreased Th2 cytokines; and 4) lung macrophage shifting of the lung macrophage phenotype from M2-towards M1-type activation. Next, we used adoptively transferred CD4+ T cells isolated from pulmonary lymph nodes of mice infected with either lac1 Delta or H99 to evaluate the role of laccase-induced immunomodulation on CNS dissemination. We found that in comparison to PBS treated mice, adoptively transferred CD4+ T cells isolated from lac1 Delta-infected mice decreased CNS dissemination, while those isolated from H99-infected mice increased CNS dissemination. Collectively, our findings reveal that immune modulation away from Th1/Th17 responses and towards Th2 responses represents a novel mechanism through which laccase can contribute to cryptococcal virulence. Furthermore, our data support the hypothesis that laccase-induced changes in polarization of CD4+ T cells contribute to CNS dissemination. C1 [Qiu, Yafeng; Davis, Michael J.; Dayrit, Jeremy K.; Osterholzer, John J.; Olszewski, Michal A.] Vet Adm Ann Arbor Hlth Syst, Res Serv, Ann Arbor, MI USA. [Qiu, Yafeng; Davis, Michael J.; Dayrit, Jeremy K.; Hadd, Zachary; Meister, Daniel L.; Osterholzer, John J.; Olszewski, Michal A.] Univ Michigan, Sch Med, Dept Internal Med, Div Pulm & Crit Care Med, Ann Arbor, MI USA. [Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Williamson, Peter R.] Univ Illinois, Coll Med, Sect Infect Dis Immunol & Int Med, Chicago, IL USA. RP Olszewski, MA (reprint author), Vet Adm Ann Arbor Hlth Syst, Res Serv, Ann Arbor, MI USA. EM olszewsm@umich.edu FU VA [1I01BX000656-01A1]; VA CDA-2; Multidisciplinary Training Program in Pulmonary Diseases [PHS T32-HL07749-19]; Intramural Research Program of the NIH, NIAID; Undergraduate Research Opportunity Program at the University of Michigan FX This Research has been supported by VA Merit Review funding (1I01BX000656-01A1, MAO), VA CDA-2 funding (JJO), and the Multidisciplinary Training Program in Pulmonary Diseases (MJD, PHS T32-HL07749-19). This research was also supported, in part, by the Intramural Research Program of the NIH, NIAID (PRW). Undergraduate Research Opportunity Program at the University of Michigan supported undergraduate students (DLM, ZH) during their work in the authors' laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 23 Z9 25 U1 0 U2 4 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 OCT 22 PY 2012 VL 7 IS 10 AR e47853 DI 10.1371/journal.pone.0047853 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025MM UT WOS:000310193400020 PM 23110112 ER PT J AU Tauseef, M Knezevic, N Chava, KR Smith, M Sukriti, S Gianaris, N Obukhov, AG Vogel, SM Schraufnagel, DE Dietrich, A Birnbaumer, L Malik, AB Mehta, D AF Tauseef, Mohammad Knezevic, Nebojsa Chava, Koteswara R. Smith, Monica Sukriti, Sukriti Gianaris, Nicholas Obukhov, Alexander G. Vogel, Stephen M. Schraufnagel, Dean E. Dietrich, Alexander Birnbaumer, Lutz Malik, Asrar B. Mehta, Dolly TI TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID LIGHT-CHAIN KINASE; NF-KAPPA-B; INCREASED ENDOTHELIAL PERMEABILITY; PATTERN-RECOGNITION RECEPTORS; C REGULATES ACTIVATION; TOLL-LIKE RECEPTOR-4; PHOSPHOLIPASE-C; CA2+ ENTRY; IN-VIVO; MICROVASCULAR PERMEABILITY AB Lung vascular endothelial barrier disruption and the accompanying inflammation are primary pathogenic features of acute lung injury (ALI); however, the basis for the development of both remains unclear. Studies have shown that activation of transient receptor potential canonical (TRPC) channels induces Ca2+ entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca2+ signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca2+ entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6 renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. TRPC6 induces Ca2+ entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca2+ entry mediated by TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the inter-action of myeloid differentiation factor 88 and IL-1R-associated kinase 4, which are required for NF-kappa B activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca2+ entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin. C1 [Tauseef, Mohammad; Knezevic, Nebojsa; Chava, Koteswara R.; Smith, Monica; Sukriti, Sukriti; Vogel, Stephen M.; Malik, Asrar B.; Mehta, Dolly] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 61605 USA. [Tauseef, Mohammad; Knezevic, Nebojsa; Chava, Koteswara R.; Smith, Monica; Sukriti, Sukriti; Vogel, Stephen M.; Malik, Asrar B.; Mehta, Dolly] Univ Illinois, Coll Med, Ctr Lung & Vasc Biol, Chicago, IL 61605 USA. [Schraufnagel, Dean E.] Univ Illinois, Coll Med, Dept Med, Chicago, IL 61605 USA. [Gianaris, Nicholas; Obukhov, Alexander G.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Dietrich, Alexander] Univ Munich, Walther Straub Inst Pharmacol & Toxicol, D-80336 Munich, Germany. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Mehta, D (reprint author), Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 61605 USA. EM dmehta@uic.edu RI Dietrich, Alexander/G-8619-2013; Obukhov, Alexander/C-7246-2008; OI Obukhov, Alexander/0000-0002-3862-6004; Schraufnagel, Dean/0000-0003-0063-7223; Dietrich, Alexander/0000-0002-1168-8707 FU National Institutes of Health [HL71794, HL84153, P01-HL60678]; American Heart Association postdoctoral fellowship [10POST2600336]; Intramural Research Division of the National Institutes of Health [Z01-ES-101684] FX This work was supported by National Institutes of Health grants HL71794 (D. Mehta), HL84153 (D. Mehta) and P01-HL60678 (D. Mehta and A.B. Malik), American Heart Association postdoctoral fellowship to M. Tauseef (10POST2600336), and in part by the Intramural Research Division of the National Institutes of Health (project Z01-ES-101684 to LB). NR 66 TC 62 Z9 64 U1 1 U2 23 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 22 PY 2012 VL 209 IS 11 BP 1953 EP 1968 DI 10.1084/jem.20111355 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 027QT UT WOS:000310368800005 PM 23045603 ER PT J AU Prasad, V AF Prasad, Vinay TI An Unmeasured Harm of Screening SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID AORTIC-ANEURYSM; REPAIR C1 [Prasad, Vinay] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 8 TC 3 Z9 3 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 22 PY 2012 VL 172 IS 19 BP 1442 EP 1443 DI 10.1001/2013.jamainternmed.682 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 023XG UT WOS:000310070200002 PM 22987011 ER PT J AU Ito, T Cadiot, G Jensen, RT AF Ito, Tetsuhide Cadiot, Guillaume Jensen, Robert T. TI Diagnosis of Zollinger-Ellison syndrome: Increasingly difficult SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Zollinger-Ellison syndrome; Gastrinoma; Hypergastrinemia; Secretin test; Serum gastrin; Gastrin; Neuroendocrine tumor ID SOMATOSTATIN RECEPTOR SCINTIGRAPHY; PANCREATIC ENDOCRINE TUMORS; SERUM CHROMOGRANIN-A; PROTON-PUMP INHIBITORS; INSTITUTES-OF-HEALTH; NEOPLASIA-TYPE-I; LONG-TERM; GASTRIN-CONCENTRATIONS; NEUROENDOCRINE-TUMORS; SYSTEMIC MASTOCYTOSIS AB In the present paper the increasing difficulty of diagnosis of Zollinger-Ellison syndrome (ZES) due to issues raised in two recent papers is discussed. These issues involve the difficulty and need to withdraw patients suspected of ZES from treatment with Proton Pump Inhibitors (omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole) and the unreliability of many gastrin radioimmunoassays. The clinical context of each of these important issues is reviewed and the conclusions in these articles commented from the perspective of clinical management. (C) 2012 Baishideng. All rights reserved. C1 [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Ito, Tetsuhide] Kyushu Univ, Dept Med & Bioregulatory Sci, Grad Sch Med Sci, Fukuoka 8128582, Japan. [Cadiot, Guillaume] Hosp Robert Debre, Serv Hepatogastroenterol, Ctr Hosp Univ Reims, F-51092 Reims, France. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov NR 112 TC 10 Z9 11 U1 0 U2 3 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD OCT 21 PY 2012 VL 18 IS 39 BP 5495 EP 5503 DI 10.3748/wjg.v18.i39.5495 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 033TG UT WOS:000310823400002 PM 23112541 ER PT J AU Wang, VM Rosen, RB Meyerle, CB Kurup, SK Ardeljan, D Agron, E Tai, K Pomykala, M Chew, EY Chan, CC Tuo, J AF Wang, Vinson M. Rosen, Richard B. Meyerle, Catherine B. Kurup, Shree K. Ardeljan, Daniel Agron, Elvira Tai, Katy Pomykala, Matthew Chew, Emily Y. Chan, Chi-Chao Tuo, Jingsheng TI Suggestive association between PLA2G12A single nucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration SO MOLECULAR VISION LA English DT Article ID FACTOR-H Y402H; EYE DISEASE; PHOSPHOLIPASE A(2); INTRAVITREAL BEVACIZUMAB; NEOVASCULAR AMD; RISK-FACTORS; RANIBIZUMAB; ANGIOGENESIS; AREDS; ROLES AB Purpose: The use of anti-vascular endothelial growth factor (anti-VEGF) therapy, with drugs such as ranibizumab and bevacizumab, to treat neovascular age-related macular degeneration (nAMD) produces an effective but widely variable response. Identifying markers that predict differentiated response could serve as a valuable assay in developing more personalized medicine. This study aimed to identify single nucleotide polymorphisms (SNPs) that influence the outcome of treatment with anti-VEGF therapy for AMD. Methods: One hundred six patients with nAMD were treated with either ranibizumab or bevacizumab as needed over a period of 12 months. Visual acuity and the presence of macular fluid were measured with optical coherence tomography at baseline, six months, and 12 months. Patients were then classified as good or poor responders based on change in visual acuity and macular fluid on follow-up visits. DNA extracted from blood was genotyped with a TaqMan-based allelic discrimination SNP assay for 21 SNPs in six candidate genes (PLAG12A, IL23R, STAT3, VEGFA, KDR, and HIF1A). The SNPs were primarily selected based on previously reported associations with AMD and functional involvement in angiogenesis pathways. SNPs shown to be promising for association with anti-VEGF therapy were then assessed in an independent AMD case-control cohort. Results: Of the 106 patients with nAMD, 77 were classified as good responders and 29 as poor responders. For rs2285714 (PLA2G12A), the frequency of minor allele T was 40.1% for good responders compared to 51.7% for poor responders (odds ratio: 1.60, 95% confidence interval of odds ratio: 0.87-2.94, p=0.13). Genetic model analysis of rs2285714 (PLA2G12A) demonstrated an association between rs2285714 (PLA2G12A) and therapy response in a dominant genotypic model. Patients carrying at least one T allele of rs2285714 were 2.79 times (95% confidence interval=1.02-7.69, p < 0.05) more likely to be poor responders (79.3% of poor responders) than good responders (57.3% of good responders). However, after adjusting for multiple testing by the false discovery rate or Bonferroni correction, the initially observed association was no longer statistically significant. No association was identified between the remaining SNPs and response status. The SNP rs2285714 of PLA2G12A was not significantly associated with AMD in an independent AMD case-control cohort. Conclusions: Data suggest a possible weak association between rs2285714 (PLA2G12A) and response to anti-VEGF therapy, but the association must be confirmed in additional cohorts with larger patient samples. Identifying factors that predict the differentiated response could provide a valuable assay for developing approaches in personalized medicine. C1 [Wang, Vinson M.; Ardeljan, Daniel; Chan, Chi-Chao; Tuo, Jingsheng] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Vinson M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Rosen, Richard B.; Tai, Katy; Pomykala, Matthew] New York Eye & Ear Infirm, Dept Ophthalmol, New York, NY 10003 USA. [Meyerle, Catherine B.; Agron, Elvira; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Kurup, Shree K.] Wake Forest Univ, Dept Ophthalmol, Winston Salem, NC 27109 USA. RP Tuo, J (reprint author), NEI, Immunol Lab, NIH, 10-10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM tuoj@nei.nih.gov FU Intramural Research Program of National Eye Institute FX The project was supported by Intramural Research Program of National Eye Institute. The authors thank the study participants and their families for enrolling in this study, and Ms. Kathy Chu (NEI) for English editing. NR 40 TC 11 Z9 12 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD OCT 20 PY 2012 VL 18 IS 267-70 BP 2578 EP 2585 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 052VH UT WOS:000312226100001 PM 23112570 ER PT J AU Dalton, T Cegielski, P Akksilp, S Asencios, L Caoili, JC Cho, SN Erokhin, VV Ershova, J Gler, MT Kazennyy, BY Kim, HJ Kliiman, K Kurbatova, E Kvasnovsky, C Leimane, V van der Walt, M Via, LE Volchenkov, GV Yagui, MA Kang, H AF Dalton, Tracy Cegielski, Peter Akksilp, Somsak Asencios, Luis Campos Caoili, Janice Cho, Sang-Nae Erokhin, Vladislav V. Ershova, Julia Tarcela Gler, Ma Kazennyy, Boris Y. Kim, Hee Jin Kliiman, Kai Kurbatova, Ekaterina Kvasnovsky, Charlotte Leimane, Vaira van der Walt, Martie Via, Laura E. Volchenkov, Grigory V. Yagui, Martin A. Kang, Hyungseok CA Global PETTS Investigators TI Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study SO LANCET LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; INDIA; TB AB Background The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries. Methods From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis. Findings Among 1278 patients, 43.7% showed resistance to at least one second-line drug, 20.0% to at least one second-line injectable drug, and 12.9% to at least one fluoroquinolone. 6.7% of patients had XDR tuberculosis (range across study sites 0.8-15.2%). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries. Interpretation Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies. C1 [Dalton, Tracy; Cegielski, Peter; Ershova, Julia; Kurbatova, Ekaterina; Kvasnovsky, Charlotte] Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA 30333 USA. [Akksilp, Somsak] Off Dis Prevent & Control Reg 7, Ubon Ratchathani, Thailand. [Asencios, Luis] Natl TB Reference Lab, Lima, Peru. [Campos Caoili, Janice; Tarcela Gler, Ma] Trop Dis Fdn, Manila, Philippines. [Cho, Sang-Nae] Int TB Res Ctr, Masan, South Korea. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Seoul, South Korea. [Erokhin, Vladislav V.] Russian Acad Med Sci, Cent TB Res Inst, Moscow, Russia. [Kazennyy, Boris Y.] Orel Oblast TB Dispensary, Oryol, Russia. [Kim, Hee Jin] Korean Inst TB, Seoul, South Korea. [Kliiman, Kai] Tartu Univ Hosp, Tartu, Estonia. [Leimane, Vaira] State Agcy, Infectol Ctr Latvia, TB & Lung Dis Clin, Riga, Latvia. [van der Walt, Martie] MRC, Pretoria, South Africa. [Via, Laura E.] NIAID, NIH, Bethesda, MD 20892 USA. [Volchenkov, Grigory V.] Vladimir Oblast TB Dispensary, Vladimir, Russia. [Yagui, Martin A.] Natl Inst Hlth, Lima, Peru. [Kang, Hyungseok] Natl Masan TB Hosp, Masan, South Korea. RP Dalton, T (reprint author), Ctr Dis Control & Prevent, Div TB Eliminat, 1600 Clifton Rd NE,Mailstop F08, Atlanta, GA 30333 USA. EM tldalton@cdc.gov RI Barry, III, Clifton/H-3839-2012; Kuznetsova, Tatiana/I-6882-2013; OI Kuznetsova, Tatiana/0000-0003-3564-7405; Via, Laura/0000-0001-6074-9521 FU US Agency for International Development; Centers for Disease Control and Prevention; National Institutes of Health/National Institute of Allergy and Infectious Diseases; Korean Ministry of Health and Welfare; Centers for Disease Control and Prevention Division of Tuberculosis Elimination; National Institute of Allergy and Infectious Diseases; North Estonia Regional Hospital; Tartu University Hospital, Estonia National Tuberculosis Registry; Estonia National Institute for Health Development; State Agency Infectology Centre of Latvia; Riga Tuberculosis and Lung Disease Clinic; Lima Ciudad and Lima Este Health Districts and reference laboratories; Philippines Tropical Disease Foundation; Orel and Vladimir Oblast Tuberculosis Dispensaries; Central Tuberculosis Research Institute of the Russian Academy of Medical Sciences; South Africa Medical Research Council; KwaZulu-Natal King George V Hospital; Klerksdorp Hospital; Witbank Specialised Tuberculosis Hospital; Jose Pearson Hospital; Korean Institute of Tuberculosis; National Masan Tuberculosis Hospital; Thai Office of Disease Prevention and Control; WHO in Switzerland, Denmark, Peru, and Russia FX US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare.; The findings and conclusions in this Article are those of the authors and do not necessarily represent the views of the US CDC. We thank the patients who gave their time and energy to contribute to this study and the doctors, nurses, and microbiologists at each of the enrolment sites for their contributions to this work. We thank the people in the following countries and organisations for support and contributions: Centers for Disease Control and Prevention Division of Tuberculosis Elimination, US Agency for International Development, National Institute of Allergy and Infectious Diseases, North Estonia Regional Hospital, Tartu University Hospital, Estonia National Tuberculosis Registry, Estonia National Institute for Health Development, State Agency Infectology Centre of Latvia, Riga Tuberculosis and Lung Disease Clinic, Lima Ciudad and Lima Este Health Districts and reference laboratories, Philippines Tropical Disease Foundation, Orel and Vladimir Oblast Tuberculosis Dispensaries, Central Tuberculosis Research Institute of the Russian Academy of Medical Sciences, South Africa Medical Research Council, KwaZulu-Natal King George V Hospital, Klerksdorp Hospital, Witbank Specialised Tuberculosis Hospital, Jose Pearson Hospital, Korean Institute of Tuberculosis, National Masan Tuberculosis Hospital, Thai Office of Disease Prevention and Control, and WHO in Switzerland, Denmark, Peru, and Russia. We also thank medical and nursing staff in the Ubon Ratchathani, Srisaket, Sakon Nakon, Yasothon Provinces, Thailand. NR 23 TC 98 Z9 101 U1 3 U2 41 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD OCT 20 PY 2012 VL 380 IS 9851 BP 1406 EP 1417 DI 10.1016/S0140-6736(12)60734-X PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 025NM UT WOS:000310196500030 PM 22938757 ER PT J AU Boja, E Hiltke, T Kinsinger, C Mesri, M Rivers, R Rodriguez, H AF Boja, Emily Hiltke, Tara Kinsinger, Chris Mesri, Mehdi Rivers, Robert Rodriguez, Henry CA Off Canc Clinical Proteomics Res TI Development of open-access mock 510(k) regulatory documents on multiplex proteomic technologies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Boja, Emily; Hiltke, Tara; Kinsinger, Chris; Mesri, Mehdi; Rivers, Robert; Rodriguez, Henry; Off Canc Clinical Proteomics Res] 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 OCT 20 PY 2012 VL 30 IS 30 SU S MA 99 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100092 ER PT J AU Chen, JQ Heldman, M Herrmann, M Kedei, N Blumberg, P Goldsmith, P AF Chen, Jin-Qiu Heldman, Madeleine Herrmann, Michelle Kedei, Noemi Blumberg, Peter Goldsmith, Paul TI A fully automated capillary western system for absolute quantitation of endogenous PKC proteins: An approach to correlate protein quantity with function SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Collaborat Prot Technol Resource, Cell Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Off Sci & Technol Partnership, Off Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2012 VL 30 IS 30 SU S MA 31 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100031 ER PT J AU Chen, JQ Lee, JH Herrmann, M Wang, YS Park, KS Heldman, M Goldsmith, P Giaccone, G AF Chen, Jin-Qiu Lee, Jih-hsiang Herrmann, Michelle Wang, Yisong Park, Kang-Seo Heldman, Madeleine Goldsmith, Paul Giaccone, Giuseppe TI A nanofluidic immunoassay system to develop proteomic responsive biomarkers in non-small cell lung cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Collaborat Prot Technol Resource, Cell Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Off Sci & Technol Partnership, Off Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2012 VL 30 IS 30 SU S MA 27 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100027 ER PT J AU Conley, BA Cavenagh, MM Rohan, JP Lively, TG Lih, CJ Williams, PM AF Conley, Barbara A. Cavenagh, Margaret M. Rohan, JoyAnn Phillips Lively, Tracy G. Lih, Chih-Jian Williams, P. Mickey TI Clinical assay development program SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. SAIC Frederick Inc, Frederick, 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 OCT 20 PY 2012 VL 30 IS 30 SU S MA 98 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100091 ER PT J AU Lih, CJ Forbes, T Mehaffey, M Sause, E Sims, D McGregor, P Conley, BA Kummar, S Williams, PM AF Lih, Chih-Jian Forbes, Thomas Mehaffey, Michele Sause, Eric Sims, David McGregor, Paul Conley, Barbara A. Kummar, Shivaani Williams, Paul M. TI Moving next-generation sequencing into the clinical realm: Detection of somatic mutations in cancer by targeted amplicon sequencing SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 SAIC Frederick Inc, Frederick, MD USA. NCI, Frederick, MD 21701 USA. NCI, Bethesda, MD 20892 USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2012 VL 30 IS 30 SU S MA 60 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100056 ER PT J AU McShane, LA Conley, BA Cavenagh, MM Lively, TG Eberhard, DA Williams, PM Bigbee, WL Mesirov, JP Polley, MYC Kim, KY Tricoli, JV AF McShane, Lisa A. Conley, Barbara A. Cavenagh, Margaret M. Lively, Tracy G. Eberhard, David A. Williams, Paul M. Bigbee, William L. Mesirov, Jill P. Polley, Mei-Yin C. Kim, Kelly Y. Tricoli, James V. TI Criteria for use of omics-based predictors in NCI-sponsored clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. SAIC Frederick Inc, Frederick, MD USA. NCI, Frederick, MD 21701 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. Broad Inst MIT & Harvard, Cambridge, MA 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 OCT 20 PY 2012 VL 30 IS 30 SU S MA 58 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100054 ER PT J AU Parekh, PR Redon, CE Weyemi, U Bonner, W AF Parekh, Palak R. Redon, Christophe E. Weyemi, Urbain Bonner, William TI Examining the reliability of surrogate tissue predictability of drug efficacy in reconstituted human 3D skin models containing melanomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RI Parekh, Palak/B-7042-2015; Weyemi, Urbain/E-2083-2016 OI Parekh, Palak/0000-0001-9201-5194; 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 OCT 20 PY 2012 VL 30 IS 30 SU S MA 49 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100046 ER PT J AU Petryshyn, RA Seidel, GD Prindiville, SA AF Petryshyn, Ray A. Seidel, Geoffrey David Prindiville, Sheila Ann TI Funding of biomarker, imaging, quality-of-life (QOL), and cost-effectiveness analysis (CEA) studies by NCI SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Coordinating Ctr Clin Trials, Bethesda, MD 20892 USA. SAIC Frederick Inc, Clin Monitoring Res Progam, Bethesda, 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 OCT 20 PY 2012 VL 30 IS 30 SU S MA 104 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100097 ER PT J AU Pogue-Geile, KL Tanaka, N Gavin, P Yothers, G Colangelo, LH Kim, C Kim, SR Fumagalli, D Taniyama, Y Sharif, S O'Connell, MJ Paik, S AF Pogue-Geile, Katherine L. Tanaka, Noriko Gavin, Patrick Yothers, Greg Colangelo, Linda H. Kim, Chungyeul Kim, Seong-Rim Fumagalli, Debora Taniyama, Yusuke Sharif, Saima O'Connell, Michael J. Paik, Soonmyung TI DNA mismatch repair deficiency and benefit from adjuvant bevacizumab in NSABP C-08: Molecular profiling results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 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 OCT 20 PY 2012 VL 30 IS 30 SU S MA 55 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100051 ER PT J AU Rotunno, M Hu, N Su, H Wang, CY Bertazzi, PA Caporaso, N Taylor, PR Landi, MT AF Rotunno, Melissa Hu, Nan Su, Hua Wang, Chaoyu Bertazzi, Pier Alberto Caporaso, Neil Taylor, Phil R. Landi, Maria Teresa TI A blood-based gene expression signature of early-stage nonsmall cell lung cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ Milan, Milan, Italy. 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 OCT 20 PY 2012 VL 30 IS 30 SU S MA 69 PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100063 ER PT J AU Vorholter, FJ Wiggerich, HG Scheidle, H Sidhu, VK Mrozek, K Kuster, H Puhler, A Niehaus, K AF Vorhoelter, Frank-Joerg Wiggerich, Heinrich-Guenter Scheidle, Heiko Sidhu, Vishaldeep Kaur Mrozek, Kalina Kuester, Helge Puehler, Alfred Niehaus, Karsten TI Involvement of bacterial TonB-dependent signaling in the generation of an oligogalacturonide damage-associated molecular pattern from plant cell walls exposed to Xanthomonas campestris pv. campestris pectate lyases SO BMC MICROBIOLOGY LA English DT Article DE TonB system; Damage-associate molecular pattern; DAMP; Oligogalacturonide; Trans-envelope signaling; Molecular plant-microbe interaction; Pathogen; Xanthomonas campestris ID HOST-PATHOGEN INTERACTIONS; ELICITS PHYTOALEXIN ACCUMULATION; COMPLETE GENOME SEQUENCE; F-SP GLYCINEA; HYPERSENSITIVE RESPONSE; INNATE IMMUNITY; DISEASE RESISTANCE; OXIDATIVE BURST; POLYGALACTURONATE LYASE; TRANSDUCTION SYSTEMS AB Background: Efficient perception of attacking pathogens is essential for plants. Plant defense is evoked by molecules termed elicitors. Endogenous elicitors or damage-associated molecular patterns (DAMPs) originate from plant materials upon injury or pathogen activity. While there are comparably well-characterized examples for DAMPs, often oligogalacturonides (OGAs), generated by the activity of fungal pathogens, endogenous elicitors evoked by bacterial pathogens have been rarely described. In particular, the signal perception and transduction processes involved in DAMP generation are poorly characterized. Results: A mutant strain of the phytopathogenic bacterium Xanthomonas campestris pv. campestris deficient in exbD2, which encodes a component of its unusual elaborate TonB system, had impaired pectate lyase activity and caused no visible symptoms for defense on the non-host plant pepper (Capsicum annuum). A co-incubation of X. campestris pv. campestris with isolated cell wall material from C. annuum led to the release of compounds which induced an oxidative burst in cell suspension cultures of the non-host plant. Lipopolysaccharides and proteins were ruled out as elicitors by polymyxin B and heat treatment, respectively. After hydrolysis with trifluoroacetic acid and subsequent HPAE chromatography, the elicitor preparation contained galacturonic acid, the monosaccharide constituent of pectate. OGAs were isolated from this crude elicitor preparation by HPAEC and tested for their biological activity. While small OGAs were unable to induce an oxidative burst, the elicitor activity in cell suspension cultures of the non-host plants tobacco and pepper increased with the degree of polymerization (DP). Maximal elicitor activity was observed for DPs exceeding 8. In contrast to the X. campestris pv. campestris wild type B100, the exbD2 mutant was unable to generate elicitor activity from plant cell wall material or from pectin. Conclusions: To our knowledge, this is the second report on a DAMP generated by bacterial features. The generation of the OGA elicitor is embedded in a complex exchange of signals within the framework of the plant-microbe interaction of C. annuum and X. campestris pv. campestris. The bacterial TonB-system is essential for the substrate-induced generation of extracellular pectate lyase activity. This is the first demonstration that a TonB-system is involved in bacterial trans-envelope signaling in the context of a pathogenic interaction with a plant. C1 [Vorhoelter, Frank-Joerg; Scheidle, Heiko; Sidhu, Vishaldeep Kaur; Mrozek, Kalina; Niehaus, Karsten] Univ Bielefeld, Fac Biol, Dept Proteome & Metabolome Res, D-33615 Bielefeld, Germany. [Vorhoelter, Frank-Joerg; Wiggerich, Heinrich-Guenter; Kuester, Helge; Puehler, Alfred] Univ Bielefeld, CeBiTec, D-33615 Bielefeld, Germany. [Sidhu, Vishaldeep Kaur] NIAAA, Mol Signalling Lab, NIH, Rockville, MD 20852 USA. [Kuester, Helge] Leibniz Univ Hannover, D-30419 Hannover, Germany. RP Vorholter, FJ (reprint author), Univ Bielefeld, Fac Biol, Dept Proteome & Metabolome Res, Univ Str 25, D-33615 Bielefeld, Germany. EM frank@cebitec.uni-bielefeld.de RI Kuster, Helge/A-4487-2013 FU BMBF program "GenoMik Plus"; Deutsche Forschungsgemeinschaft; Bielefeld University FX We gratefully acknowledge Dorothee Steinmann for providing the X. campestris pv. campestris mutant strain B100-Bac2. Also, we want to thank Dr. Bruno Moerschbacher from the Institut fur Biochemie und Biotechnologie in Munster, Germany for the kind permission to use his HPAEC system. At Bielefeld University, the project benefitted from work carried out by, Julia Voss, Sergej Wendler, Anna Kopfer, and Tim Steffens. Jannis Harfmann provided supportive transcriptomics data. Completing the project successfully benefited substantially from oxidative burst measurements carried out by Barbara Samenfeld. This work was financially supported by the BMBF program "GenoMik Plus". We acknowledge support of the publication fee by Deutsche Forschungsgemeinschaft and by the Open Access Publication Funds of Bielefeld University. NR 105 TC 12 Z9 12 U1 0 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD OCT 19 PY 2012 VL 12 AR 239 DI 10.1186/1471-2180-12-239 PG 18 WC Microbiology SC Microbiology GA 075JO UT WOS:000313881600002 PM 23082751 ER PT J AU Carpenter, AC Grainger, JR Xiong, YM Kanno, Y Chu, HH Wang, L Naik, S dos Santos, L Wei, L Jenkins, MK O'Shea, JJ Belkaid, Y Bosselut, R AF Carpenter, Andrea C. Grainger, John R. Xiong, Yumei Kanno, Yuka Chu, H. Hamlet Wang, Lie Naik, Shruti dos Santos, Liliane Wei, Lai Jenkins, Marc K. O'Shea, John J. Belkaid, Yasmine Bosselut, Remy TI The Transcription Factors Thpok and LRF Are Necessary and Partly Redundant for T Helper Cell Differentiation SO IMMUNITY LA English DT Article ID ZINC-FINGER PROTEIN; LEISHMANIA-MAJOR INFECTION; LINEAGE FATE; GENE-EXPRESSION; DEFICIENT MICE; LYMPHOCYTE DEVELOPMENT; POSITIVE SELECTION; MEDIATED-IMMUNITY; CD4 EXPRESSION; COMMITMENT AB T helper (Th) cells are critical for defenses against infection and recognize peptides bound to class II major histocompatibility complex (MHC II) molecules. Although transcription factors have been identified that direct Th cells into specific effector fates, whether a "master" regulator controls the developmental program common to all Th cells remains unclear. Here, we showed that the two transcription factors Thpok and LRF share this function. Although disruption of both factors did not prevent the generation of MHC II-specific T cells, these cells failed to express Th cell genes or undergo Th cell differentiation in vivo. In contrast, T cells lacking Thpok, which only displayed LRF-dependent functions, contributed to multiple effector responses, both in vitro and in vivo, with the notable exception of Th2 cell responses that control extracellular parasites. These findings identify the Thpok-LRF pair as a core node of Th cell differentiation and function. C1 [Carpenter, Andrea C.; Xiong, Yumei; Wang, Lie; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grainger, John R.; Naik, Shruti; dos Santos, Liliane; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Kanno, Yuka; Wei, Lai; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Chu, H. Hamlet; Jenkins, Marc K.] Univ Minnesota, Sch Med, Ctr Immunol, Dept Microbiol, Minneapolis, MN 55455 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM remy@helix.nih.gov RI Kanno, Yuka/B-5802-2013; Jenkins, Marc/G-1063-2012; Wei, Lai/D-1088-2014; OI Jenkins, Marc/0000-0001-8009-7655; Kanno, Yuka/0000-0001-5668-9319; Grainger, John/0000-0002-4052-5923 FU Intramural Research Programs of the National Cancer Institute; Center for Cancer Research, of the National Institute of Allergy and Infectious Diseases; National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health FX We thank P.P. Pandolfi for Zbtb7a mutant mice, N. Bouladoux for assistance with L. major experiments, B. Taylor and S. Banerjee for cell sorting, L. Williams and Q. Xiao for help with experiments, K. Beacht, E. Castro, and L. Stepanian for expert mouse technical support, M. Mehaffey, B. Tran, and Y. Zhao for assistance with Chipseq analyses, and J. Ashwell, A. Gegonne, J. Konkel, P. Schwartzberg, and M. Vacchio for reading the manuscript. This work benefitted from data assembled by the ImmGen consortium. This work was supported by the Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, of the National Institute of Allergy and Infectious Diseases, and of the National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health. NR 60 TC 18 Z9 18 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 19 PY 2012 VL 37 IS 4 BP 622 EP 633 DI 10.1016/j.immuni.2012.06.019 PG 12 WC Immunology SC Immunology GA 025JQ UT WOS:000310185400008 PM 23041065 ER PT J AU Zhu, JF Jankovic, D Oler, AJ Wei, G Sharma, S Hu, GQ Guo, LY Yagi, R Yamane, H Punkosdy, G Feigenbaum, L Zhao, KJ Paul, WE AF Zhu, Jinfang Jankovic, Dragana Oler, Andrew J. Wei, Gang Sharma, Suveena Hu, Gangqing Guo, Liying Yagi, Ryoji Yamane, Hidehiro Punkosdy, George Feigenbaum, Lionel Zhao, Keji Paul, William E. TI The Transcription Factor T-bet Is Induced by Multiple Pathways and Prevents an Endogenous Th2 Cell Program during Th1 Cell Responses SO IMMUNITY LA English DT Article ID IN-VIVO; LINEAGE COMMITMENT; GENE-EXPRESSION; IL-4 PRODUCTION; FACTOR GATA-3; DIFFERENTIATION; BASOPHILS; IMMUNITY; PLAYS; GAMMA AB T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T-bet-ZsGreen reporter mouse strain. We determined that interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) were redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet did not contribute to its own expression when induced by IL-12 and IFN-gamma. By contrast, T-bet and the transcription factor Stat4 were critical for IFN-gamma production whereas IFN-gamma signaling was dispensable for inducing IFN-gamma. Loss of T-bet resulted in activation of an endogenous program driving Th2 cell differentiation in cells expressing T-bet-ZsGreen. Genome-wide analyses indicated that T-bet directly induced many Th1 cell-related genes but indirectly suppressed Th2 cell-related genes. Our study revealed redundancy and synergy among several Th1 cell-inducing pathways in regulating the expression of T-bet and IFN-gamma, and a critical role of T-bet in suppressing an endogenous Th2 cell-associated program. C1 [Zhu, Jinfang; Sharma, Suveena; Guo, Liying; Yagi, Ryoji; Yamane, Hidehiro; Punkosdy, George; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Jankovic, Dragana] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Oler, Andrew J.] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Wei, Gang; Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Frederick, MD 21702 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov RI HU, GANGQING/K-5849-2012; Oler, Andrew/B-5053-2013; Zhu, Jinfang/B-7574-2012 OI Oler, Andrew/0000-0002-6310-0434; FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX We thank A. Sher, R. Germain, J. O'Shea, and P. Schwartzberg for their critical reading of our manuscript; J. Edwards for her excellent assistance in cell sorting; J. O'Shea, Y. Kanno and M. Kaplan for providing Stat4-/- mice on C57BL/6 background. The work is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 46 TC 81 Z9 85 U1 1 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 19 PY 2012 VL 37 IS 4 BP 660 EP 673 DI 10.1016/j.immuni.2012.09.007 PG 14 WC Immunology SC Immunology GA 025JQ UT WOS:000310185400011 PM 23041064 ER PT J AU Singh, NJ Bando, JK Schwartz, RH AF Singh, Nevil J. Bando, Jennifer K. Schwartz, Ronald H. TI Subsets of Nonclonal Neighboring CD4(+) T Cells Specifically Regulate the Frequency of Individual Antigen-Reactive T Cells SO IMMUNITY LA English DT Article ID HOMEOSTATIC PROLIFERATION; ADAPTIVE TOLERANCE; CLONAL COMPETITION; GAMMA-CHAIN; SURVIVAL; NAIVE; MEMORY; LYMPHOCYTES; MOLECULES; SELECTION AB After an immune response, the expanded population of antigen-specific CD4(+) T cells contract to steady state levels. We have found that the contraction is neither cell-autonomous nor mediated by competition for generic trophic factors, but regulated by relatively rare subsets of neighboring CD4(+) T cells not necessarily of a conventional regulatory T cell lineage. These regulators, referred to as deletors, specifically limit the frequency of particular antigen-specific T cells even though they are not reactive to the same agonist as their targets. Instead, an isolated deletor could outcompete the target for recognition of a shared, nonstimulatory endogenous peptide-MHC ligand. This mechanism was sufficient to prevent even agonist-driven autoimnnune disease in a lymphopenic environment. Such a targeted regulation of homeostasis within narrow colonies of T cells with related TCR specificities for subthreshold ligands might help to prevent the loss of unrelated TCRs during multiple responses, preserving the valuable diversity of the repertoire. C1 [Singh, Nevil J.; Schwartz, Ronald H.] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bando, Jennifer K.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. RP Singh, NJ (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. EM ns117r@nih.gov FU NIH, NIAID FX We thank C. Chen and E. Chuang for assistance with experiments, C. Henry and C. Eigsti for FACS sorting, Q. Su and T. Myers for microarray hybridization, P. Chappert for hearty discussions, and R. Germain and Y. Belkaid for comments on improving the manuscript. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 40 TC 18 Z9 18 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 19 PY 2012 VL 37 IS 4 BP 735 EP 746 DI 10.1016/j.immuni.2012.08.008 PG 12 WC Immunology SC Immunology GA 025JQ UT WOS:000310185400017 PM 23021952 ER PT J AU Farina, AR Cappabianca, L Ruggeri, P Di Ianni, N Ragone, M Merolle, S Sano, K Stracke, ML Horowitz, JM Gulino, A Mackay, AR AF Farina, Antonietta R. Cappabianca, Lucia Ruggeri, Pierdomenico Di Ianni, Natalia Ragone, Marzia Merolle, Stefania Sano, Kimihiko Stracke, Mary L. Horowitz, Jonathan M. Gulino, Alberto Mackay, Andrew R. TI Constitutive autotaxin transcription by Nmyc-amplified and non-amplified neuroblastoma cells is regulated by a novel AP-1 and SP-mediated mechanism and abrogated by curcumin SO FEBS LETTERS LA English DT Article DE Autotaxin; Transcription; Neuroblastoma; AP-1; SP; Internally initiated SP3; Curcumin ID LYSOPHOSPHOLIPASE-D ACTIVITY; NF-KAPPA-B; LYSOPHOSPHATIDIC ACID; ANGIOGENIC FACTOR; MOTILITY FACTOR; EXPRESSION; PROTEIN; CANCER; CARCINOMA; GROWTH AB The motility, angiogenesis and metastasis-stimulating factor Autotaxin (Atx), over expressed by human neuroblastomas (NB), is constitutively expressed by human Nmyc-amplified SK-N-BE and non-Nmyc-amplified SH-SY5Y NB cells. Here, we characterise a novel Atx transcriptional mechanism, utilised by both cell lines, that is restricted to the first 285 bp of the Atx promoter and involves AP-1 and SP transcription factors, acting through a CRE/AP-1-like element at position -142 to -149 and a GAbox at position -227 to -235 relative to the Atx translational start site. This novel transcriptional mechanism can be inhibited by internally initiated SP-3 and the natural phenol curcumin. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Farina, Antonietta R.; Cappabianca, Lucia; Ruggeri, Pierdomenico; Di Ianni, Natalia; Ragone, Marzia; Merolle, Stefania; Mackay, Andrew R.] Univ Aquila, Dept Expt Med, Sect Mol Pathol, I-67100 Laquila, Italy. [Sano, Kimihiko] Kobe Univ, Sch Med, Dept Pediat, Kobe, Hyogo 650, Japan. [Stracke, Mary L.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Horowitz, Jonathan M.] N Carolina State Univ, Dept Anat Physiol Sci & Radiol, Raleigh, NC 27606 USA. [Gulino, Alberto] Univ Roma La Sapienza, Dept Expt Med & Pathol, I-00161 Rome, Italy. RP Mackay, AR (reprint author), Univ Aquila, Dept Expt Med, Sect Mol Pathol, I-67100 Laquila, Italy. EM andrewreay.mackay@univaq.it OI cappabianca, lucia/0000-0002-9112-1750; Mackay, Andrew Reay/0000-0001-7096-3759; FARINA, Antonietta Rosella/0000-0003-0962-6088 FU AIRC; COFIN; Maugeri Foundation FX Supported by AIRC, COFIN and Maugeri Foundation. NR 42 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 19 PY 2012 VL 586 IS 20 BP 3681 EP 3691 DI 10.1016/j.febslet.2012.08.026 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 028BG UT WOS:000310397200022 PM 22975311 ER PT J AU Bayer, H Essig, K Stanzel, S Frank, M Gildersleeve, JC Berger, MR Voss, C AF Bayer, Helene Essig, Katharina Stanzel, Sven Frank, Martin Gildersleeve, Jeffrey C. Berger, Martin R. Voss, Cristina TI Evaluation of Riproximin Binding Properties Reveals a Novel Mechanism for Cellular Targeting SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RIBOSOME-INACTIVATING PROTEINS; BOVINE SUBMAXILLARY MUCIN; PROSTATE-SPECIFIC ANTIGEN; BREAST-CANCER PATIENTS; HUMAN COLON; XIMENIA-AMERICANA; SEMINAL PLASMA; CARCINOMA; SERUM; GLYCOSYLATION AB Riproximin is a cytotoxic type II ribosome-inactivating protein showing high selectivity for tumor cell lines. Its binding to cell surface glycans is crucial for subsequent internalization and cytotoxicity. In this paper, we describe a unique mechanism of interaction and discuss its implications for the cellular targeting and cytotoxicity of riproximin. On a carbohydrate microarray, riproximin specifically bound to two types of asialo-glycans, namely to bi- and triantennary complex N-glycan structures (NA2/NA3) and to repetitive N-acetyl-D-galactosamine (GalNAc), the so-called clustered Tn antigen, a cancer-specific O-glycan on mucins. Two glycoproteins showing high riproximin binding, the NA3-presenting asialofetuin and the clustered Tn-rich asialo-bovine submaxillary mucin, were subsequently chosen as model glycoproteins to mimic the binding interactions of riproximin with the two types of glycans. ELISA analyses were used to relate the two binding specificities of riproximin to its two sugar binding sites. The ability of riproximin to cross-link the two model proteins revealed that binding of the two types of glycoconjugates occurs within different binding sites. The biological implications of these binding properties were analyzed in cellular assays. The cytotoxicity of riproximin was found to depend on its specific and concomitant interaction with the two glycoconjugates as well as on dynamic avidity effects typical for lectins binding to multivalent glycoproteins. The presence of definite, cancer-related structures on the cells to be targeted determines the therapeutic potency of riproximin. Due to its cross-linking ability, riproximin is expected to show a high degree of specificity for cells exposing both NA2/NA3 and clustered Tn structures. C1 [Voss, Cristina] Heidelberg Pharma GmbH, Dept Biochem, D-68526 Ladenburg, Germany. [Bayer, Helene; Essig, Katharina; Berger, Martin R.] German Canc Res Ctr, Toxicol & Chemotherapy Unit, D-69120 Heidelberg, Germany. [Stanzel, Sven] German Canc Res Ctr, Dept Biostat, D-69120 Heidelberg, Germany. [Frank, Martin] BIOGNOS AB, S-41705 Gothenburg, Sweden. [Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Voss, C (reprint author), Heidelberg Pharma GmbH, Dept Biochem, Schriesheimer Str 101, D-68526 Ladenburg, Germany. EM c.voss@hdpharma.com RI Gildersleeve, Jeffrey/N-3392-2014 FU National Institutes of Health, NCI, Intramural Research Program; German Federal Ministry of Economics and Technology [Pro Inno II KF0425101UL6, ZIM KF2301002AJ0] FX This work was supported, in whole or in part, by the National Institutes of Health, NCI, Intramural Research Program.; Supported by German Federal Ministry of Economics and Technology Grants Pro Inno II KF0425101UL6 and ZIM KF2301002AJ0. NR 61 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 19 PY 2012 VL 287 IS 43 BP 35873 EP 35886 DI 10.1074/jbc.M112.368548 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 027PA UT WOS:000310364000010 PM 22872642 ER PT J AU Wang, RX Yu, CR Mahdi, RM Egwuagu, CE AF Wang, Ren-Xi Yu, Cheng-Rong Mahdi, Rashid M. Egwuagu, Charles E. TI Novel IL27p28/IL12p40 Cytokine Suppressed Experimental Autoimmune Uveitis by Inhibiting Autoreactive Th1/Th17 Cells and Promoting Expansion of Regulatory T Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; IL-12 P40 HOMODIMER; INTERLEUKIN-2 PRODUCTION; TH1 DIFFERENTIATION; HELPER-CELLS; DISEASE; IL-27; INFLAMMATION; STAT3; MICE AB IL-12 family cytokines are important in host immunity. Whereas some members (IL-12, IL-23) play crucial roles in pathogenesis of organ-specific autoimmune diseases by inducing the differentiation of Th1 and Th17 lymphocytes, others (IL-27 and IL-35) suppress inflammatory responses and limit tissue injury induced by these T cell subsets. In this study, we have genetically engineered a novel IL27p28/IL12p40 heterodimeric cytokine (p28/p40) that antagonizes signaling downstream of the gp130 receptor. We investigated whether p28/p40 can be used to ameliorate uveitis, a CNS inflammatory disease. Experimental autoimmune uveitis (EAU) is the mouse model of human uveitis and is mediated by Th1 and Th17 cells. We show here that p28/p40 suppressed EAU by inhibiting the differentiation and inflammatory responses of Th1 and Th17 cells while promoting expansion of IL-10(+)- and Foxp3(+)-expressing regulatory T cells. Lymph node cells from mice treated with p28/p40 blocked adoptive transfer of EAU to naive syngeneic mice by immunopathogenic T cells and suppressive effects of p28/p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6. Interestingly, IL27p28 also suppressed EAU, but to a lesser extent than p28/p40. The inhibition of uveitogenic lymphocyte proliferation and suppression of EAU by p28/p40 and IL27p28 establish efficacy of single chain and heterodimeric IL-12 family cytokines in treatment of a CNS autoimmune disease. Creation of the biologically active p28/p40 heterodimeric cytokine represents an important proof-of-concept experiment, suggesting that cytokines comprising unique IL-12 alpha- and beta-subunit pairing may exist in nature and may constitute a new class of therapeutic cytokines. C1 [Wang, Ren-Xi; Yu, Cheng-Rong; Mahdi, Rashid M.; Egwuagu, Charles E.] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, Bldg 10,Rm 10N109A,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Institutes of Health through the Intramural Research Programs of the NEI FX This work was supported, in whole or in part, by the National Institutes of Health through the Intramural Research Programs of the NEI. NR 47 TC 29 Z9 32 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 19 PY 2012 VL 287 IS 43 BP 36012 EP 36021 DI 10.1074/jbc.M112.390625 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 027PA UT WOS:000310364000023 PM 22936807 ER PT J AU Sobhany, M Kakuta, Y Sugiura, N Kimata, K Negishi, M AF Sobhany, Mack Kakuta, Yoshimitsu Sugiura, Nobuo Kimata, Koji Negishi, Masahiko TI The Structural Basis for a Coordinated Reaction Catalyzed by a Bifunctional Glycosyltransferase in Chondroitin Biosynthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SULFATE BIOSYNTHESIS; CRYSTAL-STRUCTURE; POLYMERASE; PROTEOGLYCANS; MECHANISM; EXTL2; K4 AB Bifunctional chondroitin synthase K4CP catalyzes glucuronic acid and N-acetylgalactosamine transfer activities and polymerizes a chondroitin chain. Here we have determined that an N-terminal region (residues 58-134) coordinates two transfer reactions and enables K4CP to catalyze polymerization. When residues 58-107 are deleted, K4CP loses polymerase activity while retaining both transfer activities. Peptide (DWPSDL118)-D-113 within this N-terminal region interacts with C-terminal peptide (YTWEKI682)-Y-677. The deletion of either sequence abolishes glucuronic acid but not N-acetylgalactosamine transfer activity in K4CP. Both donor bindings and transfer activities are lost by mutating (YTWEKI682)-Y-677 to (677)DAWEDI(682). On the other hand, acceptor substrates retain their binding to K4CP mutants. The characteristics of these K4CP mutants highlight different states of the enzyme reaction, providing an underlying structural basis for how these peptides play essential roles in coordinating the two glycosyltransferase activities for K4CP to elongate the chondroitin chain. C1 [Sobhany, Mack; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Kakuta, Yoshimitsu] Kyushu Univ, Fac Agr, Dept Biochem, Fukuoka 8128581, Japan. [Sugiura, Nobuo; Kimata, Koji] Aichi Med Univ, Inst Mol Sci Med, Nagakute, Aichi 4801195, Japan. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU National Institutes of Health (Intramural Research Program of NIEHS) [Z01ES1005-01] FX This work was supported, in whole or in part, by National Institutes of Health Grant Z01ES1005-01 (Intramural Research Program of NIEHS). NR 13 TC 9 Z9 9 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 19 PY 2012 VL 287 IS 43 BP 36022 EP 36028 DI 10.1074/jbc.M112.375873 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 027PA UT WOS:000310364000024 PM 22936799 ER PT J AU Kim, JC Crary, B Chang, YC Kwon-Chung, KJ Kim, KJ AF Kim, Jong-Chul Crary, Benjamin Chang, Yun C. Kwon-Chung, Kyung J. Kim, Kee J. TI Cryptococcus neoformans Activates RhoGTPase Proteins Followed by Protein Kinase C, Focal Adhesion Kinase, and Ezrin to Promote Traversal across the Blood-Brain Barrier SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MICROVASCULAR ENDOTHELIAL-CELLS; ESCHERICHIA-COLI K1; CENTRAL-NERVOUS-SYSTEM; RHO-GTPASES; IN-VITRO; INVASION; CYTOSKELETON; MENINGITIS; STRATEGIES; INTERNALIZATION AB Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis. Previous studies have demonstrated that Cryptococcus binding and invasion of human brain microvascular endothelial cells (HBMEC) is a prerequisite for transmigration across the blood-brain barrier. However, the molecular mechanism involved in the cryptococcal blood-brain barrier traversal is poorly understood. In this study we examined the signaling events in HBMEC during interaction with C. neoformans. Analysis with inhibitors revealed that cryptococcal association, invasion, and transmigration require host actin cytoskeleton rearrangement. Rho pulldown assays revealed that Cryptococcus induces activation of three members of RhoGTPases, e.g. RhoA, Rac1, and Cdc42, and their activations are required for cryptococcal transmigration across the HBMEC monolayer. Western blot analysis showed that Cryptococcus also induces phosphorylation of focal adhesion kinase (FAK), ezrin, and protein kinase C alpha (PKC alpha), all of which are involved in the rearrangement of host actin cytoskeleton. Down-regulation of FAK, ezrin, or PKC alpha by shRNA knockdown, dominant-negative transfection, or inhibitors significantly reduces cryptococcal ability to traverse the HBMEC monolayer, indicating their positive role in cryptococcal transmigration. In addition, activation of RhoGTPases is the upstream event for phosphorylation of FAK, ezrin, and PKC alpha during C. neoformans-HBMEC interaction. Taken together, our findings demonstrate that C. neoformans activates RhoGTPases and subsequently FAK, ezrin, and PKC alpha to promote their traversal across the HBMEC monolayer, which is the critical step for cryptococcal brain infection and development of meningitis. C1 [Kim, Jong-Chul; Crary, Benjamin; Kim, Kee J.] Univ Kansas, Dept Microbiol Mol Genet & Immunol, Med Ctr, Kansas City, KS 66160 USA. [Chang, Yun C.; Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, Mol Microbiol Sect, NIH, Bethesda, MD 20892 USA. RP Kim, KJ (reprint author), Univ Kansas, Dept Microbiol Mol Genet & Immunol, Med Ctr, Kansas City, KS 66160 USA. EM kkim@kumc.edu FU National Institutes of Health [P20RR016443, R01DA027729]; NIAID FX This work was supported, in whole or in part, by National Institutes of Health Grants P20RR016443 and R01DA027729 (to K.J.K.) and NIAID intramural grants (to Y.C.C. and K.J.K.-C.). NR 50 TC 16 Z9 19 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 19 PY 2012 VL 287 IS 43 BP 36147 EP 36157 DI 10.1074/jbc.M112.389676 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 027PA UT WOS:000310364000036 PM 22898813 ER PT J AU Schlebusch, CM Skoglund, P Sjodin, P Gattepaille, LM Hernandez, D Jay, F Li, S De Jongh, M Singleton, A Blum, MGB Soodyall, H Jakobsson, M AF Schlebusch, Carina M. Skoglund, Pontus Sjodin, Per Gattepaille, Lucie M. Hernandez, Dena Jay, Flora Li, Sen De Jongh, Michael Singleton, Andrew Blum, Michael G. B. Soodyall, Himla Jakobsson, Mattias TI Genomic Variation in Seven Khoe-San Groups Reveals Adaptation and Complex African History SO SCIENCE LA English DT Article ID HUMAN-POPULATIONS; HUNTER-GATHERERS; MODERN HUMANS; DIVERSITY; SEQUENCES; GENOTYPE; ORIGINS AB The history of click-speaking Khoe-San, and African populations in general, remains poorly understood. We genotyped similar to 2.3 million single-nucleotide polymorphisms in 220 southern Africans and found that the Khoe-San diverged from other populations >= 100,000 years ago, but population structure within the Khoe-San dated back to about 35,000 years ago. Genetic variation in various sub-Saharan populations did not localize the origin of modern humans to a single geographic region within Africa; instead, it indicated a history of admixture and stratification. We found evidence of adaptation targeting muscle function and immune response; potential adaptive introgression of protection from ultraviolet light; and selection predating modern human diversification, involving skeletal and neurological development. These new findings illustrate the importance of African genomic diversity in understanding human evolutionary history. C1 [Schlebusch, Carina M.; Skoglund, Pontus; Sjodin, Per; Gattepaille, Lucie M.; Li, Sen; Jakobsson, Mattias] Uppsala Univ, Dept Evolutionary Biol, S-75236 Uppsala, Sweden. [Hernandez, Dena; Singleton, Andrew] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Jay, Flora] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [De Jongh, Michael] Univ S Africa, Dept Anthropol & Archaeol, ZA-0001 Pretoria, South Africa. [Blum, Michael G. B.] Univ Grenoble 1, Ctr Natl Rech Sci, Lab TIMC IMAG UMR 5525, Grenoble, France. [Soodyall, Himla] Univ Witwatersrand, Human Genom Divers & Dis Res Unit, Div Human Genet, Sch Pathol,Fac Hlth Sci, Johannesburg, South Africa. [Soodyall, Himla] Natl Hlth Lab Serv, Johannesburg, South Africa. [Jakobsson, Mattias] Uppsala Univ, Sci Life Lab, S-75236 Uppsala, Sweden. RP Schlebusch, CM (reprint author), Uppsala Univ, Dept Evolutionary Biol, Norbyvagen 18D, S-75236 Uppsala, Sweden. EM carina.schlebusch@ebc.uu.se; mattias.jakobsson@ebc.uu.se RI Jakobsson, Mattias/A-6116-2011; BLUM, Michael/F-9978-2010; Singleton, Andrew/C-3010-2009; Schlebusch, Carina/B-3411-2010; OI Jakobsson, Mattias/0000-0001-7840-7853; BLUM, Michael/0000-0003-4174-7373; Schlebusch, Carina/0000-0002-8160-9621; Skoglund, Pontus/0000-0002-3021-5913 FU Wenner-Gren Foundation; Intramural Research Program of the National Institute on Aging; NIH; U.S. Department of Health and Human Services [Z01 AG000932-04]; Medical Research Council of South Africa; National Health Laboratory Service; STINT; Swedish Research Council; Erik Philip Sorensen Foundation FX We thank participants who donated blood samples, T. Jenkins, and B. Henn. Approved by the Working Group of Indigenous Minorities in Southern Africa (WIMSA) and the South African San Council; we thank them for facilitating sampling trips. Computations were performed at the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) in Uppsala, Sweden (project number p2011187). This work was supported by the Wenner-Gren Foundation (C. S.); the Intramural Research Program of the National Institute on Aging, NIH, U.S. Department of Health and Human Services, grant Z01 AG000932-04 (A. S.); the Medical Research Council of South Africa and National Health Laboratory Service (H. S.); STINT (M. B. and M.J.); the Swedish Research Council (M.J.); and the Erik Philip Sorensen Foundation (M.J.). H. S. retains governance of the DNA samples. Author contributions were as follows: conception and design of study: C. M. S., P.Sk., and M.J.; sample collection, preparation, and description: C. M. S., M.D.J., and H. S.; genotyping: D. H. and A. S.; data preparation: C. M. S., P.Sk., D. H., and M.J.; population structure analysis: C. M. S., P.Sk., L. M. G., S. L., F.J., M. B., and M.J.; model-based inference: P.Sk. and M.J.; language/geography comparisons: F.J., C. M. S., and M. B.; diversity statistics: C. M. S., P.Sk., L. M. G., P.Sj., and M.J.; Selection scans: P.Sj., P.Sk., C. M. S., and M.J.. The paper was written by C. M. S., P.Sk., and M.J. with contributions from all authors. Genotype data are available at the Arrayexpress database (www.ebi.ac.uk/arrayexpress/, accession no. E-MTAB-1259) and at www.ebc.uu.se/Research/IEG/evbiol/research/Jakobsson/data/. NR 29 TC 96 Z9 98 U1 3 U2 48 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 OCT 19 PY 2012 VL 338 IS 6105 BP 374 EP 379 DI 10.1126/science.1227721 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022JS UT WOS:000309955800039 PM 22997136 ER PT J AU Roche, B Dobson, AP Guegan, JF Rohani, P AF Roche, Benjamin Dobson, Andrew P. Guegan, Jean-Francois Rohani, Pejman TI Linking community and disease ecology: the impact of biodiversity on pathogen transmission SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE community epidemiology; density-dependent infectious diseases; community ecology; mathematical modelling ID INFECTIOUS-DISEASES; LYME-DISEASE; MATHEMATICAL-THEORY; SPECIES-DIVERSITY; BODY-SIZE; RISK; POPULATIONS; EMERGENCE; DYNAMICS; WILDLIFE AB The increasing number of zoonotic diseases spilling over from a range of wild animal species represents a particular concern for public health, especially in light of the current dramatic trend of biodiversity loss. To understand the ecology of these multi-host pathogens and their response to environmental degradation and species extinctions, it is necessary to develop a theoretical framework that takes into account realistic community assemblages. Here, we present a multi-host species epidemiological model that includes empirically determined patterns of diversity and composition derived from community ecology studies. We use this framework to study the interaction between wildlife diversity and directly transmitted pathogen dynamics. First, we demonstrate that variability in community composition does not affect significantly the intensity of pathogen transmission. We also show that the consequences of community diversity can differentially impact the prevalence of pathogens and the number of infectious individuals. Finally, we show that ecological interactions among host species have a weaker influence on pathogen circulation than inter-species transmission rates. We conclude that integration of a community perspective to study wildlife pathogens is crucial, especially in the context of understanding and predicting infectious disease emergence events. C1 [Roche, Benjamin] Ctr IRD France Nord, UMI UMMISCO IRD UPMC 209, F-93143 Bondy, France. [Dobson, Andrew P.; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48105 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48105 USA. [Roche, Benjamin; Guegan, Jean-Francois] Univ Montpellier I, CNRS, UMR MIVEGEC IRD, F-34394 Montpellier 5, France. [Roche, Benjamin; Guegan, Jean-Francois] Univ Montpellier 2, Ctr IRD Montpellier, F-34394 Montpellier 5, France. [Dobson, Andrew P.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Guegan, Jean-Francois] French Sch Publ Hlth, Interdisciplinary Ctr Biodivers Climate Change &, Montpellier, France. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Roche, B (reprint author), Ctr IRD France Nord, UMI UMMISCO IRD UPMC 209, F-93143 Bondy, France. EM benjamin.roche@ird.fr OI Roche, Benjamin/0000-0001-7975-4232 FU Institut de Recherche pour le Developpement; Centre National de la Recherche Scientifique; French School of Public Health; EDEN project (EU grant) [GOCE2003010284 EDEN]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We sincerely acknowledge the many colleagues who reviewed and improved this manuscript. In particular, we thank Marc Choisy, Camille Lebarbenchon, Andrew Park, John Drake, Krisztian Magori, Peter Daszak, Rick Ostfeld, the Rohani and King laboratories at the University of Michigan for their helpful comments. B. R. and J.F.G. are sponsored by the Institut de Recherche pour le Developpement and the Centre National de la Recherche Scientifique, the French School of Public Health and acknowledge support from the EDEN project (EU grant GOCE2003010284 EDEN). P. R. was supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. This publication is catalogued by the EDEN Steering Committee as EDEN089 (http://www.edenfp6project.net/). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. This work is a contribution from DIVERSITAS-EcoHealth Alliance ecoHEALTH research working group and the LABEX CEBA ANR-10-LABX-25-01. NR 46 TC 33 Z9 33 U1 4 U2 109 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 OCT 19 PY 2012 VL 367 IS 1604 BP 2807 EP 2813 DI 10.1098/rstb.2011.0364 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 006HZ UT WOS:000308811400002 PM 22966136 ER PT J AU Cong, WN Cai, H Wang, R Daimon, CM Maudsley, S Raber, K Canneva, F von Horsten, S Martin, B AF Cong, Wei-na Cai, Huan Wang, Rui Daimon, Caitlin M. Maudsley, Stuart Raber, Kerstin Canneva, Fabio von Hoersten, Stephan Martin, Bronwen TI Altered Hypothalamic Protein Expression in a Rat Model of Huntington's Disease SO PLOS ONE LA English DT Article ID EXPANDED CAG REPEAT; NEUROENDOCRINE CHANGES; GLUCOSE-HOMEOSTASIS; ALZHEIMERS-DISEASE; STRIATAL ATROPHY; RODENT MODELS; BODY-WEIGHT; WHOLE-BODY; BRAIN; MICE AB Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD. C1 [Cong, Wei-na; Cai, Huan; Wang, Rui; Daimon, Caitlin M.; Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Raber, Kerstin; Canneva, Fabio; von Hoersten, Stephan] Univ Erlangen Nurnberg, Dept Expt Therapy, D-91054 Erlangen, Germany. RP Martin, B (reprint author), NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov RI Cai, Huan/B-6578-2016; von Horsten, Stephan/G-9005-2015 OI Cai, Huan/0000-0001-7731-8891; von Horsten, Stephan/0000-0001-6409-0664 FU Intramural NIH HHS NR 82 TC 8 Z9 8 U1 0 U2 4 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 OCT 18 PY 2012 VL 7 IS 10 AR e47240 DI 10.1371/journal.pone.0047240 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054ZN UT WOS:000312384500007 PM 23094041 ER PT J AU Lee, YJ Johnson, KR Hallenbeck, JM AF Lee, Yang-ja Johnson, Kory R. Hallenbeck, John M. TI Global Protein Conjugation by Ubiquitin-Like-Modifiers during Ischemic Stress Is Regulated by MicroRNAs and Confers Robust Tolerance to Ischemia SO PLOS ONE LA English DT Article ID ARCTIC GROUND-SQUIRRELS; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; DOWN-REGULATION; CELLS; INVASION; SUPPRESSION; TORPOR; SYSTEM; TISSUE AB Hibernation torpor provides an excellent model of natural tolerance to ischemia. We have previously shown that massive global SUMOylation occurs during hibernation torpor in ground squirrels. We have also shown that overexpression of Ubc9, SUMO-1, or SUMO-2/3 provides protection against ischemic damage in cell lines and cortical neurons exposed to oxygen/glucose deprivation, and in mice exposed to middle cerebral artery occlusion. We have now extended our study to other Ubiquitin-Like-Modifiers (ULMs), which have multiple cellular functions during stress, in order to assess the possibility that they also have roles in tolerance to ischemia. We found that not only SUMO conjugation, but also global protein conjugation by other ULMs including NEDD8, ISG15, UFM1 and FUB1 were significantly increased in the brains of hibernating ground squirrels during torpor. By means of miRNA microarrays of ground squirrel brain samples (from active and torpor phase) we found that the miR-200 family (miR-200a,b,c/miR-141/miR-429) and the miR-182 family (miR-182/miR-183/miR-96) were among the most consistently depressed miRNAs in the brain during the torpor phase as compared to active animals. In addition, we showed that these miRNAs are involved in the expression of various ULM proteins and their global conjugation to proteins. We observed that inhibition of the miR-200 family and/or miR-182 family miRNA activities in SHSY5Y cells increases global protein conjugation by the above ULMs and makes these cells more tolerant to OGD-induced cell death. This is the first report to describe that the natural tolerance to brain ischemia in hibernators is linked to regulation by microRNAs of a broad range of ubiquitin-like modifiers. C1 [Lee, Yang-ja; Hallenbeck, John M.] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. [Johnson, Kory R.] NINDS, Bioinformat Sect, Informat Technol & Bioinformat Program, DIR,NIH, Bethesda, MD 20892 USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM hallenbj@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke/National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke/National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 27 Z9 28 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 OCT 18 PY 2012 VL 7 IS 10 AR e47787 DI 10.1371/journal.pone.0047787 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054ZN UT WOS:000312384500023 PM 23094087 ER PT J AU de Latour, RP Calado, RT Busson, M Abrams, J Adoui, N Robin, M Larghero, J Dhedin, N Xhaard, A Clave, E Charron, D Toubert, A Loiseau, P Socie, G Young, NS AF de Latour, Regis Peffault Calado, Rodrigo T. Busson, Marc Abrams, Jeffrey Adoui, Nadir Robin, Marie Larghero, Jerome Dhedin, Nathalie Xhaard, Alienor Clave, Emmanuel Charron, Dominique Toubert, Antoine Loiseau, Pascale Socie, Gerard Young, Neal S. TI Age-adjusted recipient pretransplantation telomere length and treatment-related mortality after hematopoietic stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTS; HIGH-DOSE CHEMOTHERAPY; ACUTE MYELOID-LEUKEMIA; PREDICTIVE FACTORS; SERUM FERRITIN; BLOOD; FIBROBLASTS; SURVIVORS; FAILURE; DISEASE AB Telomere attrition induces cell senescence and apoptosis. We hypothesized that age-adjusted pretransplantation telomere length might predict treatment-related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donors after myeloablative conditioning regimens, mainly for hematologic malignancies (n = 153). Blood lymphocytes' telomere length was measured by real-time quantitative PCR before HSCT. Age-adjusted pretransplantation telomere lengths were analyzed for correlation with clinical outcomes. After age adjustment, patients' telomere-length distribution was similar among all 4 quartiles except for disease stage. There was no correlation between telomere length and engraftment, GVHD, or relapse. The overall survival was 62% at 5 years (95% confidence interval [CI], 54-70). After a median follow-up of 51 months (range, 1-121 months), 43 patients died because of TRM. The TRM rate inversely correlated with telomere length. TRM in patients in the first (lowest telomere length) quartile was significantly higher than in patients with longer telomeres (P = .017). In multivariate analysis, recipients' age (hazard ratio, 1.1; 95% CI, .0-1.1; P = .0001) and age-adjusted telomere length (hazard ratio, 0.4; 95% CI; 0.2-0.8; P = .01) were independently associated with TRM. In conclusion, age-adjusted recipients' telomere length is an independent biologic marker of TRM after HSCT. (Blood. 2012;120(16):3353-3359) C1 [de Latour, Regis Peffault; Robin, Marie; Dhedin, Nathalie; Xhaard, Alienor; Socie, Gerard] Hop St Louis, AP HP, Serv Hematol Greffe, Paris, France. [de Latour, Regis Peffault; Socie, Gerard] INSERM, U728, Paris, France. [Calado, Rodrigo T.; Abrams, Jeffrey; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Calado, Rodrigo T.] Univ Sao Paulo, Sch Med, Dept Internal Med, BR-14049 Ribeirao Preto, Brazil. [Busson, Marc; Clave, Emmanuel; Charron, Dominique; Toubert, Antoine; Loiseau, Pascale] Hop St Louis, AP HP, Lab Immunol & Histocompatibilite, INSERM,UMR 940,Inst Univ Hematol, Paris, France. [Adoui, Nadir] Hop St Louis, AP HP, Biochim Lab, Paris, France. [Larghero, Jerome; Charron, Dominique; Toubert, Antoine] Hop St Louis, AP HP, Unite Therapie Cellulaire & CIC Biotherapies, Paris, France. [Larghero, Jerome; Socie, Gerard] Univ Paris Diderot, Paris, France. RP de Latour, RP (reprint author), Hop St Louis, AP HP, Serv Hematol Greffe, Paris, France. EM regis.peffaultdelatour@sls.aphp.fr RI Calado, Rodrigo/G-2619-2011; OI Clave, Emmanuel/0000-0001-8217-5039 FU National Institutes of Health Intramural Research Program, National Heart, Lung, and Blood Institute; AA and Myelodysplastic Syndrome International Foundation; France HPN; Fapesp FX This work was supported by the National Institutes of Health Intramural Research Program, National Heart, Lung, and Blood Institute. R.P.d.L. received a bursary award from the AA and Myelodysplastic Syndrome International Foundation and a grant from France HPN. R.T.C. was supported in part by Fapesp. NR 37 TC 10 Z9 10 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 18 PY 2012 VL 120 IS 16 BP 3353 EP 3359 DI 10.1182/blood-2012-01-403337 PG 7 WC Hematology SC Hematology GA 044KX UT WOS:000311619200027 ER PT J AU Shen, Y Torchia, MLG Lawson, GW Karp, CL Ashwell, JD Mazmanian, SK AF Shen, Yue Torchia, Maria Letizia Giardino Lawson, Gregory W. Karp, Christopher L. Ashwell, Jonathan D. Mazmanian, Sarkis K. TI Outer Membrane Vesicles of a Human Commensal Mediate Immune Regulation and Disease Protection SO CELL HOST & MICROBE LA English DT Article ID TNBS-INDUCED COLITIS; BACTEROIDES-FRAGILIS; INTESTINAL INFLAMMATION; DEMYELINATING DISEASE; DNA INVERSIONS; T-CELLS; MICROBIOTA; POLYSACCHARIDE; COLONIZATION; BACTERIA AB Commensal bacteria impact host health and immunity through various mechanisms, including the production of immunomodulatory molecules. Bacteroides fragilis produces a capsular polysaccharide (PSA), which induces regulatory T cells and mucosal tolerance. However, unlike pathogens, which employ secretion systems, the mechanisms by which commensal bacteria deliver molecules to the host remain unknown. We reveal that Bacteroides fragilis releases PSA in outer membrane vesicles (OMVs) that induce immunomodulatory effects and prevent experimental colitis. Dendritic cells (DCs) sense OMV-associated PSA through TLR2, resulting in enhanced regulatory T cells and anti-inflammatory cytokine production. OMV-induced signaling in DCs requires growth arrest and DNA-damage-inducible protein (Gadd45 alpha). DCs treated with PSA-containing OMVs prevent experimental colitis, whereas Gadd45 alpha(-/-) DCs are unable to promote regulatory T cell responses or suppress proinflammatory cytokine production and host pathology. These findings demonstrate that OMV-mediated delivery of a commensal molecule prevents disease, uncovering a mechanism of interkingdom communication between the microbiota and mammals. C1 [Shen, Yue; Mazmanian, Sarkis K.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Torchia, Maria Letizia Giardino; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lawson, Gregory W.] Univ Calif Los Angeles, David Geffen Sch Med, Div Lab Anim Med, Los Angeles, CA 90095 USA. [Karp, Christopher L.] Univ Cincinnati, Coll Med, Cincinnati, OH 45229 USA. [Karp, Christopher L.] Cincinnati Childrens Hosp Med Ctr, Div Mol Immunol, Cincinnati, OH 45229 USA. RP Mazmanian, SK (reprint author), CALTECH, Div Biol, Pasadena, CA 91125 USA. EM sarkis@caltech.edu OI Karp, Christopher/0000-0002-0832-2659; Mazmanian, Sarkis/0000-0003-2713-1513 FU National Institutes of Health (NIH) predoctoral training grant [GM007616]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; NIH [DK078938]; Crohn's and Colitis Foundation of America FX We are indebted to M. Kuehn (Duke University) for helpful discussions regarding OMVs. We thank P. Webster (House Ear Institute) for help with electron microscopy. Proteomic mass spectrometry of OMVs was performed and analyzed at Proteome Exploration Laboratory (Caltech). Mouse whole-genome microarray was performed at Millard and Muriel Jacobs Genetics and Genomics Laboratory (Caltech). We are grateful to members of the Mazmanian laboratory for their critical review of the manuscript. Y.S. acknowledges support from a National Institutes of Health (NIH) predoctoral training grant (GM007616). M.L.G.T. and J.D.A. were supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. This work was funded by grants from the NIH (DK078938) and the Crohn's and Colitis Foundation of America to S.K.M. NR 38 TC 100 Z9 102 U1 2 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD OCT 18 PY 2012 VL 12 IS 4 SI SI BP 509 EP 520 DI 10.1016/j.chom.2012.08.004 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 032LI UT WOS:000310719700013 PM 22999859 ER PT J AU Lavzin, M Rapoport, S Polsky, A Garion, L Schiller, J AF Lavzin, Maria Rapoport, Sophia Polsky, Alon Garion, Liora Schiller, Jackie TI Nonlinear dendritic processing determines angular tuning of barrel cortex neurons in vivo SO NATURE LA English DT Article ID PRIMARY VISUAL-CORTEX; 5 PYRAMIDAL NEURONS; BASAL DENDRITES; THALAMOCORTICAL SYNAPSES; DIRECTION SELECTIVITY; SOMATOSENSORY CORTEX; NMDA SPIKES; LAYER-IV; CELLS; ORGANIZATION AB Layer 4 neurons in primary sensory cortices receive direct sensory information from the external world(1,2). A general feature of these neurons is their selectivity to specific features of the sensory stimulation(3-5). Various theories try to explain the manner in which these neurons are driven by their incoming sensory information(6-11). In all of these theories neurons are regarded as simple elements summing small biased inputs to create tuned output through the axosomatic amplification mechanism(12). However, the possible role of active dendritic integration(13-15) in further amplifying the sensory responses and sharpening the tuning curves of neurons(16-19) is disregarded. Our findings show that dendrites of layer 4 spiny stellate neurons in the barrel cortex can generate local and global multi-branch N-methyl-D-aspartate (NMDA) spikes, which are the main regenerative events in these dendrites. In turn, these NMDA receptor (NMDAR) regenerative mechanisms can sum supralinearly the coactivated thalamocortical and corticocortical inputs. Using in vivo whole-cell recordings combined with an intracellular NMDAR blocker and membrane hyperpolarization, we show that dendritic NMDAR-dependent regenerative responses contribute substantially to the angular tuning of layer 4 neurons by preferentially amplifying the preferred angular directions over non-preferred angles. Taken together, these findings indicate that dendritic NMDAR regenerative amplification mechanisms contribute markedly to sensory responses and critically determine the tuning of cortical neurons. C1 [Lavzin, Maria; Rapoport, Sophia; Garion, Liora; Schiller, Jackie] Technion Israel Inst Technol, Rappaport Fac Med, Dept Physiol, IL-31096 Haifa, Israel. [Lavzin, Maria; Rapoport, Sophia; Garion, Liora; Schiller, Jackie] Technion Israel Inst Technol, Res Inst, IL-31096 Haifa, Israel. [Polsky, Alon] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Schiller, J (reprint author), Technion Israel Inst Technol, Rappaport Fac Med, Dept Physiol, IL-31096 Haifa, Israel. EM Jackie@tx.technion.ac.il OI Poleg-Polsky, Alon/0000-0003-1327-5129 FU Israel Science Foundation (ISF); Rappaport Foundation FX We thank Y. Schiller and G. Major for their helpful comments and discussions on the manuscript. We thank A. Korngreen and C. de Kock for help with Neurolucida reconstructions, U. Dubin for help in programming the stimulus and analysis programs, O. Schiff for help with Igor software and R. Azouz for help with the passive stimulus. We thank I. Reiter for her technical help, particularly with histology. We also thank R. Bruno for sharing his knowledge of in vivo patch clamp recordings. This study was supported by the Israel Science Foundation (ISF) and the Rappaport Foundation (J.S.). NR 29 TC 71 Z9 72 U1 0 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 18 PY 2012 VL 490 IS 7420 BP 397 EP 401 DI 10.1038/nature11451 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 021XI UT WOS:000309918500045 PM 22940864 ER PT J AU Rolland, M Edlefsen, PT Larsen, BB Tovanabutra, S Sanders-Buell, E Hertz, T deCamp, AC Carrico, C Menis, S Magaret, CA Ahmed, H Juraska, M Chen, L Konopa, P Nariya, S Stoddard, JN Wong, K Zhao, H Deng, WJ Maust, BS Bose, M Howell, S Bates, A Lazzaro, M O'Sullivan, A Lei, E Bradfield, A Ibitamuno, G Assawadarachai, V O'Connell, RJ deSouza, MS Nitayaphan, S Rerks-Ngarm, S Robb, ML McLellan, JS Georgiev, I Kwong, PD Carlson, JM Michael, NL Schief, WR Gilbert, PB Mullins, JI Kim, JH AF Rolland, Morgane Edlefsen, Paul T. Larsen, Brendan B. Tovanabutra, Sodsai Sanders-Buell, Eric Hertz, Tomer deCamp, Allan C. Carrico, Chris Menis, Sergey Magaret, Craig A. Ahmed, Hasan Juraska, Michal Chen, Lennie Konopa, Philip Nariya, Snehal Stoddard, Julia N. Wong, Kim Zhao, Hong Deng, Wenjie Maust, Brandon S. Bose, Meera Howell, Shana Bates, Adam Lazzaro, Michelle O'Sullivan, Annemarie Lei, Esther Bradfield, Andrea Ibitamuno, Grace Assawadarachai, Vatcharain O'Connell, Robert J. deSouza, Mark S. Nitayaphan, Sorachai Rerks-Ngarm, Supachai Robb, Merlin L. McLellan, Jason S. Georgiev, Ivelin Kwong, Peter D. Carlson, Jonathan M. Michael, Nelson L. Schief, William R. Gilbert, Peter B. Mullins, James I. Kim, Jerome H. TI Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2 SO NATURE LA English DT Article ID COMPETING RISKS; SUBTYPE-C; TRIAL; NEUTRALIZATION; PROTECTION; INFECTION; SEQUENCES; EPITOPES; THAILAND; AIDSVAX AB The RV144 trial demonstrated 31% vaccine efficacy at preventing human immunodeficiency virus (HIV)-1 infection(1). Antibodies against the HIV-1 envelope variable loops 1 and 2 (Env V1 and V2) correlated inversely with infection risk(2). We proposed that vaccine-induced immune responses against V1/V2 would have a selective effect against, or sieve, HIV-1 breakthrough viruses. A total of 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V2 at amino acid positions 169 and 181. Vaccine efficacy against viruses matching the vaccine at position 169 was 48% (confidence interval 18% to 66%; P = 0.0036), whereas vaccine efficacy against viruses mismatching the vaccine at position 181 was 78% (confidence interval 35% to 93%; P = 0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signature sites (21 +/- 7 angstrom) and their match/mismatch dichotomy indicate that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2-binding antibodies and reduced risk of HIV-1 acquisition, and provide evidence that vaccine-induced V2 responses plausibly had a role in the partial protection conferred by the RV144 regimen. C1 [Rolland, Morgane; Tovanabutra, Sodsai; Sanders-Buell, Eric; Bose, Meera; Howell, Shana; Bates, Adam; Lazzaro, Michelle; O'Sullivan, Annemarie; Lei, Esther; Bradfield, Andrea; Ibitamuno, Grace; O'Connell, Robert J.; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.] US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Edlefsen, Paul T.; Hertz, Tomer; deCamp, Allan C.; Magaret, Craig A.; Ahmed, Hasan; Juraska, Michal; Gilbert, Peter B.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98109 USA. [Larsen, Brendan B.; Chen, Lennie; Konopa, Philip; Nariya, Snehal; Stoddard, Julia N.; Wong, Kim; Zhao, Hong; Deng, Wenjie; Maust, Brandon S.; Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Carrico, Chris; Menis, Sergey; Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Carrico, Chris; Menis, Sergey; Schief, William R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Carrico, Chris; Menis, Sergey; Schief, William R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Assawadarachai, Vatcharain; deSouza, Mark S.; Nitayaphan, Sorachai] Royal Thai Army Component, AFRIMS, Bangkok 10400, Thailand. [Rerks-Ngarm, Supachai] Thai Minist Publ Hlth, Nonthaburi 11000, Thailand. [McLellan, Jason S.; Georgiev, Ivelin; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Carlson, Jonathan M.] Microsoft Res, Redmond, WA 98052 USA. RP Rolland, M (reprint author), US Mil HIV Res Program, Silver Spring, MD 20910 USA. EM mrolland@hivresearch.org RI Hertz, Tomer/S-5744-2016; OI Hertz, Tomer/0000-0002-0561-1578; Carrico, Chris/0000-0003-0939-9006 FU US Army Medical Research and Material Command (USAMRMC) [Y1-AI-2642-12]; National Institutes of Allergy and Infectious Diseases [Y1-AI-2642-12]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; US Department of Defense (DOD) [W81XWH-07-2-0067]; NIH [2R37AI05465-10] FX We thank B. F. Haynes and F. A. Matsen for advice and comments, and I. A. Wilson and R. L. Stanfield for assistance. This study was supported in part by an Interagency Agreement Y1-AI-2642-12 between US Army Medical Research and Material Command (USAMRMC) and the National Institutes of Allergy and Infectious Diseases. This work was also supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of Defense (DOD). Additional support was provided to P.B.G. through the NIH grant 2R37AI05465-10. The opinions herein are those of the authors and should not be construed as official or representing the views of the US Department of Defense or the Department of the Army. NR 30 TC 181 Z9 184 U1 2 U2 58 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 18 PY 2012 VL 490 IS 7420 BP 417 EP + DI 10.1038/nature11519 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 021XI UT WOS:000309918500049 PM 22960785 ER PT J AU Anasetti, C Logan, BR Lee, SJ Waller, EK Weisdorf, DJ Wingard, JR Cutler, CS Westervelt, P Woolfrey, A Couban, S Ehninger, G Johnston, L Maziarz, RT Pulsipher, MA Porter, DL Mineishi, S McCarty, JM Khan, SP Anderlini, P Bensinger, WI Leitman, SF Rowley, SD Bredeson, C Carter, SL Horowitz, MM Confer, DL AF Anasetti, Claudio Logan, Brent R. Lee, Stephanie J. Waller, Edmund K. Weisdorf, Daniel J. Wingard, John R. Cutler, Corey S. Westervelt, Peter Woolfrey, Ann Couban, Stephen Ehninger, Gerhard Johnston, Laura Maziarz, Richard T. Pulsipher, Michael A. Porter, David L. Mineishi, Shin McCarty, John M. Khan, Shakila P. Anderlini, Paolo Bensinger, William I. Leitman, Susan F. Rowley, Scott D. Bredeson, Christopher Carter, Shelly L. Horowitz, Mary M. Confer, Dennis L. CA Blood And Marrow Transplant Clinic TI Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VERSUS-HOST-DISEASE; COLONY-STIMULATING FACTOR; TERM-FOLLOW-UP; RANDOMIZED-TRIAL; CHRONIC GRAFT; PROGENITOR CELLS; ALLOGENEIC TRANSPLANTATION; LEUKEMIA; RECIPIENTS; MALIGNANCIES AB BACKGROUND Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1: 1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P = 0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P = 0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P = 0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.) C1 [Anasetti, Claudio] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Logan, Brent R.; Horowitz, Mary M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Lee, Stephanie J.; Woolfrey, Ann; Bensinger, William I.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Waller, Edmund K.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Khan, Shakila P.] Mayo Clin, Rochester, MN USA. [Confer, Dennis L.] Natl Marrow Donor Program, Minneapolis, MN USA. [Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Westervelt, Peter] Washington Univ, Siteman Canc Ctr, St Louis, MO USA. [Couban, Stephen] Dalhousie Univ, Halifax, NS, Canada. [Bredeson, Christopher] Ottawa Hosp, Ottawa, ON, Canada. [Ehninger, Gerhard] Univ Hosp Dresden, Dresden, Germany. [Johnston, Laura] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Pulsipher, Michael A.] Univ Utah, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Porter, David L.] Univ Penn, Philadelphia, PA 19104 USA. [Mineishi, Shin] Univ Michigan, Ann Arbor, MI 48109 USA. [McCarty, John M.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23284 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Leitman, Susan F.] NIH, Bethesda, MD 20892 USA. [Carter, Shelly L.] EMMES Corp, Rockville, MD USA. [Rowley, Scott D.] Hackensack Univ, John Theurer Canc Ctr, Hackensack, NJ USA. [Wingard, John R.] Univ Florida, Shands Canc Ctr, Gainesville, FL USA. RP Anasetti, C (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. EM claudio.anasetti@moffitt.org FU National Heart, Lung, and Blood Institute-National Cancer Institute; National Heart, Lung, and Blood Institute; National Cancer Institute [U10HL069294]; Office of Naval Research; National Marrow Donor Program FX Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.; Supported by a grant from the National Heart, Lung, and Blood Institute and the National Cancer Institute (U10HL069294), by the Office of Naval Research, and by the National Marrow Donor Program. NR 29 TC 212 Z9 216 U1 1 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 18 PY 2012 VL 367 IS 16 BP 1487 EP 1496 DI 10.1056/NEJMoa1203517 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 021SA UT WOS:000309904500006 PM 23075175 ER PT J AU Lee, M Lee, J Carroll, MW Choi, H Min, S Song, T Via, LE Goldfeder, LC Kang, E Jin, B Park, H Kwak, H Kim, H Jeon, HS Jeong, I Joh, JS Chen, RY Olivier, KN Shaw, PA Follmann, D Song, SD Lee, JK Lee, D Kim, CT Dartois, V Park, SK Cho, SN Barry, CE AF Lee, Myungsun Lee, Jongseok Carroll, Matthew W. Choi, Hongjo Min, Seonyeong Song, Taeksun Via, Laura E. Goldfeder, Lisa C. Kang, Eunhwa Jin, Boyoung Park, Hyeeun Kwak, Hyunkyung Kim, Hyunchul Jeon, Han-Seung Jeong, Ina Joh, Joon Sung Chen, Ray Y. Olivier, Kenneth N. Shaw, Pamela A. Follmann, Dean Song, Sun Dae Lee, Jong-Koo Lee, Dukhyoung Kim, Cheon Tae Dartois, Veronique Park, Seung-Kyu Cho, Sang-Nae Barry, Clifton E., III TI Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTRACTABLE MULTIDRUG-RESISTANT; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; OXAZOLIDINONE ANTIBACTERIAL; MURINE MODEL; PHARMACOKINETICS; TOLERABILITY; MOXIFLOXACIN; OFLOXACIN; EFFICACY AB BACKGROUND Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.) C1 [Carroll, Matthew W.; Via, Laura E.; Goldfeder, Lisa C.; Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Lee, Myungsun; Lee, Jongseok; Choi, Hongjo; Min, Seonyeong; Song, Taeksun; Kang, Eunhwa; Jin, Boyoung; Park, Hyeeun; Kwak, Hyunkyung; Kim, Hyunchul; Jeon, Han-Seung; Song, Sun Dae] Int TB Res Ctr, Chang Won, South Korea. [Jeong, Ina; Joh, Joon Sung] Natl Med Ctr, Dept Internal Med, Seoul, South Korea. [Lee, Jong-Koo] Seoul Natl Univ Hosp, Dept Family Med, Seoul 110744, South Korea. [Lee, Dukhyoung] Korea Ctr Dis Control & Prevent, Osong, South Korea. [Kim, Cheon Tae; Park, Seung-Kyu] Natl Masan Hosp, Masan, South Korea. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Inst Immunol & Immunol Dis, Seoul, South Korea. [Olivier, Kenneth N.] NIAID, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. [Chen, Ray Y.] NIAID, Lab Clin Infect Dis, Off Global Res, NIH, Bethesda, MD 20892 USA. [Shaw, Pamela A.; Follmann, Dean] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Dartois, Veronique] Novartis Inst Trop Dis, Singapore, Singapore. RP Barry, CE (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521; Chen, Ray/0000-0001-6344-1442 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Ministry of Health and Welfare, South Korea FX Supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the Ministry of Health and Welfare, South Korea. NR 45 TC 198 Z9 207 U1 5 U2 39 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 OCT 18 PY 2012 VL 367 IS 16 BP 1508 EP 1518 DI 10.1056/NEJMoa1201964 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 021SA UT WOS:000309904500008 PM 23075177 ER PT J AU Markowitz, N Lopardo, G Wentworth, D Gey, D Babiker, A Fox, L Tavel, J AF Markowitz, Norman Lopardo, Gustavo Wentworth, Deborah Gey, Daniela Babiker, Abdel Fox, Lawrence Tavel, Jorge CA STALWART Study Grp TI Long-Term Effects of Intermittent IL-2 in HIV Infection: Extended Follow-Up of the INSIGHT STALWART Study SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; INTERLEUKIN-2 THERAPY; RANDOMIZED-TRIAL; CELL COUNT; T-CELLS; CD4(+); EXPANSION; SURVIVAL; PLASMA; IMPACT AB Background: The Study of Aldesleukin with and without Antiretroviral Therapy (STALWART) was designed to evaluate whether intermittent IL-2 alone or with peri-cycle ART increased CD4+ cell counts (and so delayed initiation of ART) in HIV infected individuals having >= 300 CD4+ cells/mm(3) compared to untreated controls. When the results of two large clinical trials, ESPRIT and SILCAAT, showed no clinical benefit from IL-2 therapy, IL-2 administration was halted in STALWART. Because IL-2 recipients in STALWART experienced a greater number of opportunistic disease (OD) or death and adverse events (AEs), participants were asked to consent to an extended follow-up phase in order to assess persistence of IL-2 effects. Methodology: Participants in this study were followed for clinical events and AEs every 4 months for 24 months. Unadjusted Cox proportional hazards models were used to summarize death, death or first OD event, and first grade 3 or 4 AE. Principal Findings: A total of 267 persons were enrolled in STALWART (176 randomized to the IL-2 arms and 91 to the no therapy arm); 142 individuals in the IL-2 group and 80 controls agreed to enter the extended follow-up study. Initiation of continuous ART was delayed in the IL-2 groups, but once started, resulted in similar CD4+ cell and viral load responses compared to controls. The hazard ratios (95% CI) for IL-2 versus control during the extension phase for death or OD, grade 3 or 4 AE, and grade 4 AE were 1.45 (0.38, 5.45), 0.43 (0.24, 1.63) and 0.20 (0.04, 1.03), respectively. The hazard ratios for the AE outcomes were significantly lower during the extension than during the main study. Conclusions: Adverse events associated with IL-2 cycling did not persist upon discontinuation of IL-2. The use of IL-2 did not impact the subsequent response to initiation of cART. C1 [Markowitz, Norman] Henry Ford Hosp, Detroit, MI 48202 USA. [Lopardo, Gustavo] Fdn Ctr Estudios Infectol, Buenos Aires, DF, Argentina. [Wentworth, Deborah] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Gey, Daniela] Univ Copenhagen, Copenhagen HIV Programme, Copenhagen, Denmark. [Babiker, Abdel] MRC, London, England. [Fox, Lawrence; Tavel, Jorge] NIAID, Bethesda, MD 20892 USA. RP Markowitz, N (reprint author), Henry Ford Hosp, Detroit, MI 48202 USA. EM nmarkow1@hfhs.org RI Beral, Valerie/B-2979-2013 FU National Institutes of Health (NIH) [U01-AI068641, U01-AI46957] FX The work was supported by National Institutes of Health (NIH) grants U01-AI068641 and U01-AI46957. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 5 Z9 5 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 OCT 17 PY 2012 VL 7 IS 10 AR e47506 DI 10.1371/journal.pone.0047506 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AF UT WOS:000311146900069 PM 23082173 ER PT J AU Gasselhuber, A Dreher, MR Rattay, F Wood, BJ Haemmerich, D AF Gasselhuber, Astrid Dreher, Matthew R. Rattay, Frank Wood, Bradford J. Haemmerich, Dieter TI Comparison of Conventional Chemotherapy, Stealth Liposomes and Temperature-Sensitive Liposomes in a Mathematical Model SO PLOS ONE LA English DT Article ID INTENSITY FOCUSED ULTRASOUND; TARGETED DRUG-DELIVERY; HUMAN TUMOR XENOGRAFT; MICROVASCULAR PERMEABILITY; THERMOSENSITIVE LIPOSOMES; CONTENT RELEASE; CANCER-THERAPY; BEARING MICE; SOLID TUMORS; IN-VITRO AB Various liposomal drug carriers have been developed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX): conventional chemotherapy (Free-DOX), Stealth liposomes (Stealth-DOX), temperature sensitive liposomes (TSL) with intra-vascular triggered release (TSL-i), and TSL with extra-vascular triggered release (TSL-e). All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue-and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 mu g/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free-DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and <3 s, respectively. Optimal release time constants were shorter for MDR cells, with similar to 4 min for Stealth-DOX and for TSL-e. Tissue concentrations correlated well quantitatively with a prior in-vivo study. Mathematical models may thus allow optimization of drug delivery systems to achieve a better therapeutic index. C1 [Gasselhuber, Astrid; Haemmerich, Dieter] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Dreher, Matthew R.; Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Gasselhuber, Astrid; Rattay, Frank] Vienna Univ Technol, Inst Anal & Sci Comp, A-1040 Vienna, Austria. [Haemmerich, Dieter] Clemson Univ, Dept Bioengn, Clemson, SC USA. RP Haemmerich, D (reprint author), Med Univ S Carolina, Dept Pediat, 171 Ashley Ave, Charleston, SC 29425 USA. EM haemmer@musc.edu RI Rattay, Frank/A-2231-2015; OI Rattay, Frank/0000-0002-2819-8827; Haemmerich, Dieter/0000-0003-1127-7024 FU National Institutes of Health [R01CA118990, R21CA135519]; NIH Center for Interventional Oncology; NIH Intramural Research Program; Extramural Research Facilities Program of the National Center for Research Resources [C06 RR018823] FX This work was supported by National Institutes of Health grants R01CA118990, R21CA135519 to DH, and by the NIH Center for Interventional Oncology and NIH Intramural Research Program. The work was conducted in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 23 Z9 23 U1 2 U2 38 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 OCT 17 PY 2012 VL 7 IS 10 AR e47453 DI 10.1371/journal.pone.0047453 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AF UT WOS:000311146900064 PM 23082168 ER PT J AU Lopez-Rodriguez, A Holmgren, M AF Lopez-Rodriguez, Angelica Holmgren, Miguel TI Restoration of Proper Trafficking to the Cell Surface for Membrane Proteins Harboring Cysteine Mutations SO PLOS ONE LA English DT Article ID NUCLEOTIDE-GATED CHANNELS; SHAKER K+ CHANNEL; RENAL TUBULAR-ACIDOSIS; ION CHANNELS; FUNCTIONAL EXPRESSION; CHEMICAL CHAPERONES; POTASSIUM CHANNEL; COMPLEMENTARY-DNA; GAUCHER-DISEASE; CNGA3 MUTATIONS AB A common phenotype for many genetic diseases is that the cell is unable to deliver full-length membrane proteins to the cell surface. For some forms of autism, hereditary spherocytosis and color blindness, the culprits are single point mutations to cysteine. We have studied two inheritable cysteine mutants of cyclic nucleotide-gated channels that produce achromatopsia, a common form of severe color blindness. By taking advantage of the reactivity of cysteine's sulfhydryl group, we modified these mutants with chemical reagents that attach moieties with similar chemistries to the wild-type amino acids' side chains. We show that these modifications restored proper delivery to the cell membrane. Once there, the channels exhibited normal functional properties. This strategy might provide a unique opportunity to assess the chemical nature of membrane protein traffic problems. C1 [Lopez-Rodriguez, Angelica; Holmgren, Miguel] NINDS, Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Holmgren, M (reprint author), NINDS, Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM holmgren@ninds.nih.gov FU National Institutes of Health, National Institute Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute Neurological Disorders and Stroke. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 2 Z9 2 U1 2 U2 8 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 OCT 17 PY 2012 VL 7 IS 10 AR e47693 DI 10.1371/journal.pone.0047693 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AF UT WOS:000311146900090 PM 23082193 ER PT J AU Xia, HY Cao, Y Dai, XM Marelja, Z Zhou, D Mo, R Al-Mahdawi, S Pook, MA Leimkuehler, S Rouault, TA Li, KY AF Xia, Haiyan Cao, Yun Dai, Xiaoman Marelja, Zvonimir Zhou, Di Mo, Ran Al-Mahdawi, Sahar Pook, Mark A. Leimkuehler, Silke Rouault, Tracey A. Li, Kuanyu TI Novel Frataxin Isoforms May Contribute to the Pathological Mechanism of Friedreich Ataxia SO PLOS ONE LA English DT Article ID IN-VIVO; EXTRAMITOCHONDRIAL FRATAXIN; CLUSTER BIOGENESIS; REPEAT EXPANSION; IRON HOMEOSTASIS; SCAFFOLD PROTEIN; MOUSE MODEL; CELLS; COMPLEX; GENE AB Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum-specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA. C1 [Xia, Haiyan; Cao, Yun; Dai, Xiaoman; Zhou, Di; Mo, Ran; Li, Kuanyu] Nanjing Univ, Sch Med, Jiangsu Key Lab Mol Med, Nanjing, Jiangsu, Peoples R China. [Xia, Haiyan; Li, Kuanyu] Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing, Jiangsu, Peoples R China. [Marelja, Zvonimir; Leimkuehler, Silke] Univ Potsdam, Inst Biochem & Biol, Potsdam, Germany. [Al-Mahdawi, Sahar; Pook, Mark A.] Brunel Univ, Sch Hlth Sci & Social Care, Div Biosci, Uxbridge UB8 3PH, Middx, England. [Rouault, Tracey A.] NICHHD, Program Mol Med, Bethesda, MD 20892 USA. RP Li, KY (reprint author), Nanjing Univ, Sch Med, Jiangsu Key Lab Mol Med, Nanjing, Jiangsu, Peoples R China. EM likuanyu@nju.edu.cn FU National Institute of Child Health and Human Development, National Institutes of Health; Friedreich ataxia research association; National Nature Science Foundation of China (NSFC) [31071085]; Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry; State Key Laboratory of Pharmaceutical Biotechnology [ZZYJ-SN-201006]; Studienstiftung des Deutschen Volkes; Deutscher Akademischer Austauschdienst scholarship; Deutsche Forschungsgemeinschaft [SL1171/5-3] FX This work was supported by the intramural program of the National Institute of Child Health and Human Development, National Institutes of Health, and in part by Friedreich ataxia research association; by the National Nature Science Foundation of China (NSFC) (No. 31071085), by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, and by State Key Laboratory of Pharmaceutical Biotechnology (No. ZZYJ-SN-201006). Zvonimir Marelja was supported by a grant from the Studienstiftung des Deutschen Volkes and by Deutscher Akademischer Austauschdienst scholarship. Additional support was obtained from the Deutsche Forschungsgemeinschaft Grant SL1171/5-3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 19 Z9 20 U1 1 U2 16 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 OCT 17 PY 2012 VL 7 IS 10 AR e47847 DI 10.1371/journal.pone.0047847 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AF UT WOS:000311146900121 PM 23082224 ER PT J AU Feldhahn, N Ferretti, E Robbiani, DF Callen, E Deroubaix, S Selleri, L Nussenzweig, A Nussenzweig, MC AF Feldhahn, Niklas Ferretti, Elisabetta Robbiani, Davide F. Callen, Elsa Deroubaix, Stephanie Selleri, Licia Nussenzweig, Andre Nussenzweig, Michel C. TI The hSSB1 orthologue Obfc2b is essential for skeletogenesis but dispensable for the DNA damage response in vivo SO EMBO JOURNAL LA English DT Article DE apoptosis; DNA damage response; hSSB1; Obfc2b; skeletogenesis ID CLASS SWITCH RECOMBINATION; DOUBLE-STRAND BREAKS; GENOMIC STABILITY; MRN COMPLEX; MOUSE LIMB; C-MYC; MICE; TRANSLOCATIONS; REPAIR; 53BP1 AB Human single-stranded DNA-binding protein 1 (hSSB1), encoded by OBFC2B, was recently characterized as an essential factor for the initiation of DNA damage checkpoints and the maintenance of genomic stability. Here, we report that loss of Obfc2b in mice results in perinatal lethality characterized by growth delay and skeletal abnormalities. These abnormalities are associated with accumulation of gamma H2ax, apoptosis and defective pre-cartilage condensation, which is essential for normal bone formation. However, deficiency of Obfc2b does not affect the initiation of DNA damage checkpoints, Atm activation, or the maintenance of genomic stability in B lymphocytes and primary fibroblasts. Loss of Obfc2b results in increased expression of its homologue Obfc2a (hSSB2). In contrast to Obfc2b deficiency, depletion of Obfc2a in fibroblasts results in impaired proliferation, accumulation of gamma H2ax and increased genomic instability. Thus, the hSSB1 orthologue Obfc2b has a unique function during embryogenesis limited to cell types that contribute to bone formation. While being dispensable in most other cell lineages, its absence leads to a compensatory increase in Obfc2a protein, a homologue required for the maintenance of genomic integrity. The EMBO Journal (2012) 31, 4045-4056. doi:10.1038/emboj.2012.247; Published online 31 August 2012 C1 [Feldhahn, Niklas; Robbiani, Davide F.; Deroubaix, Stephanie; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Ferretti, Elisabetta; Selleri, Licia] Cornell Univ, Dept Cell & Dev Biol, Weill Med Coll, New York, NY 10021 USA. [Callen, Elsa; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Feldhahn, N (reprint author), Rockefeller Univ, Lab Mol Immunol, 1230 York Ave,Box 220, New York, NY 10065 USA. EM nfeldhahn@rockefeller.edu FU NIH grant [R01 AI037526-18, RO1 HD043997] FX All members of the Nussenzweig laboratory for discussions. Klara Velinzon for cell sorting. The Rockefeller University Gene Targeting Facility for the generation of mutant mice. The work was supported by an NIH grant to MCN (R01 AI037526-18) and an NIH grant to LS (RO1 HD043997). NF was a Fellow of the Leukemia and Lymphoma Society. MCN is a Howard Hughes Medical Institute Investigator. NR 53 TC 12 Z9 13 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 17 PY 2012 VL 31 IS 20 BP 4045 EP 4056 DI 10.1038/emboj.2012.247 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 023SJ UT WOS:000310055400011 PM 22940690 ER PT J AU Chu, HY Ito, W Li, JY Morozov, A AF Chu, Hong-Yuan Ito, Wataru Li, Jiayang Morozov, Alexei TI Target-Specific Suppression of GABA Release from Parvalbumin Interneurons in the Basolateral Amygdala by Dopamine SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LATERAL AMYGDALA; CONDITIONED FEAR; RAT AMYGDALA; NEURONS; COLOCALIZATION; INNERVATION; INHIBITION; FACILITATION; MODULATION; EXPRESSION AB Dopamine (DA) in the basolateral amygdala (BLA) promotes fear learning by disinhibiting principal neurons (PNs) and enabling synaptic plasticity in their sensory inputs. While BLA interneurons (INs) are heterogeneous, it is unclear which interneuron subtypes decrease GABAergic input to PNs in the presence of DA. Here, using cell type-selective photostimulation by channelrhodopsin 2 in BLA slices from mouse brain, we examined the role of parvalbumin-positive INs (PV-INs), the major interneuronal subpopulation in BLA, in the disinhibitory effect of DA. We found that DA selectively suppressed GABAergic transmission from PV-INs to PNs by acting on presynaptic D-2 receptors, and this effect was mimicked by Rp-cAMP, an inhibitor of cAMP-dependent signaling. In contrast, DA did not alter GABA release from PV-INs to INs. Furthermore, neither suppressing cAMP-dependent signaling by Rp-cAMP nor enhancing it by forskolin altered GABA release from PV-INs to BLA INs. Overall, DA disinhibits BLA, at least in part, by suppressing GABA release from PV-INs in the target cell-specific manner that results from differential control of this release by cAMP-dependent signaling. C1 [Chu, Hong-Yuan; Ito, Wataru; Li, Jiayang; Morozov, Alexei] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Morozov, Alexei] Virginia Tech, Caril Res Inst, Roanoke, VA 24016 USA. RP Morozov, A (reprint author), NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM hongyuan.chu@gmail.com; alexeim@vtc.vt.edu RI Chu, Hong-yuan/G-2380-2014 OI Chu, Hong-yuan/0000-0003-0923-683X FU National Institute of Mental Health FX This work was supported by the National Institute of Mental Health intramural research program. We thank Victor Luna for commenting on the manuscript. NR 34 TC 14 Z9 15 U1 4 U2 12 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 OCT 17 PY 2012 VL 32 IS 42 BP 14815 EP 14820 DI 10.1523/JNEUROSCI.2997-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 023RY UT WOS:000310054000034 PM 23077066 ER PT J AU Carroll, MD Kit, BK Lacher, DA Shero, ST Mussolino, ME AF Carroll, Margaret D. Kit, Brian K. Lacher, David A. Shero, Susan T. Mussolino, Michael E. TI Trends in Lipids and Lipoproteins in US Adults, 1988-2010 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; NUTRITION-EXAMINATION-SURVEYS; UNITED-STATES ADULTS; SERUM-CHOLESTEROL; RISK-FACTOR; NATIONAL-HEALTH; PREVALENCE; PLASMA; REDUCTION; OBESITY AB Context Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) contribute to atherosclerosis and its clinical consequences. Between the periods 1988-1994 and 1999-2002, mean TC and mean LDL-C declined in adults. During this time, there was an increase in the percentage of adults receiving lipid-lowering medications. Geometric mean triglyceride levels increased but mean high-density lipoprotein cholesterol (HDL-C) remained unchanged. Objective To examine trends in serum lipids in adults between 1988 and 2010. Design, Setting, and Participants Three distinct US cross-sectional National Health and Nutrition Examination Surveys, 1988-1994 (n=16 573), 1999-2002 (n=9471), and 2007-2010 (n=11 766). Main Outcome Measures Mean TC, LDL-C, HDL-C, non-HDL-C, and geometric mean triglyceride levels and the prevalence of lipid-lowering medication use. Results Mean TC declined from 206 (95% CI, 205-207) mg/dL in 1988-1994 to 196 (95% CI, 195-198) mg/dL in 2007-2010 (P<.001 for linear trend); mean LDL-C declined from 129 (95% CI, 127-130) mg/dL to 116 (95% CI, 114-117) mg/dL (P<.001 for linear trend). Mean non-HDL-C declined from 155 (95% CI, 153-157) mg/dL in 1988-1994 to 144 (95% CI, 143-145) mg/dL in 2007-2010 (P<.001 for linear trend). Mean HDL-C increased from 50.7 (95% CI, 50.0-51.0) mg/dL during 1988-1994 to 52.5 (95% CI, 51.8-53.2) mg/dL in 2007-2010 (P=.001 for linear trend). Geometric mean serum triglyceride levels increased from 118 (95% CI, 114-121) mg/dL in 1988-1994 to 123 (95% CI, 119-127) mg/dL in 1999-2002 and decreased to 110 (95% CI, 107-113) mg/dL in 2007-2010 (P<.001 for quadratic trend). The prevalence of lipid-lowering medication use increased from 3.4% (95% CI, 2.9%-3.9%) in 1988-1994 to 15.5% (95% CI, 14.7%-16.3%) in 2007-2010 (P<.001 for linear trend). Among adults not receiving lipid-lowering medications, trends in lipids were similar to those reported for adults overall. Among obese adults, mean TC, non-HDL-C, LDL-C, and geometric mean triglycerides declined between 1988 and 2010. Conclusion Between 1988 and 2010, favorable trends in lipid levels have occurred among adults in the United States. JAMA. 2012;308(15):1545-1554 www.jama.com C1 [Carroll, Margaret D.; Kit, Brian K.; Lacher, David A.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth & Nutr Examinat Surveys, Hyattsville, MD 20782 USA. [Shero, Susan T.] NHLBI, Div Applicat Res Discoveries, NIH, Bethesda, MD USA. [Mussolino, Michael E.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD USA. RP Carroll, MD (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth & Nutr Examinat Surveys, 3311 Toledo Rd,Room 4311, Hyattsville, MD 20782 USA. EM mdc3@cdc.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health [Y1-HC-8039] FX The laboratory analysis of lipids was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health (intra-agency agreement Y1-HC-8039). NR 38 TC 83 Z9 87 U1 0 U2 8 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 OCT 17 PY 2012 VL 308 IS 15 BP 1545 EP 1554 DI 10.1001/jama.2012.13260 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 021AQ UT WOS:000309858100021 PM 23073951 ER PT J AU Mitra, A Luo, J Zhang, HM Cui, KR Zhao, KJ Song, JZ AF Mitra, Apratim Luo, Juan Zhang, Huanming Cui, Kairong Zhao, Keji Song, Jiuzhou TI Marek's disease virus infection induces widespread differential chromatin marks in inbred chicken lines SO BMC GENOMICS LA English DT Article DE Histone modifications; Thymus; Differential marks; Bivalent domain; Chromatin signature; Marek's disease ID RNA-BINDING PROTEIN; GENE-EXPRESSION; IMMUNE-RESPONSES; CANCER-CELLS; HUMAN GENOME; STEM-CELLS; CRD-BP; HERPESVIRUS; GROWTH; P53 AB Background: Marek's disease (MD) is a neoplastic disease in chickens caused by the MD virus (MDV). Successful vaccine development against MD has resulted in increased virulence of MDV and the understanding of genetic resistance to the disease is, therefore, crucial to long-term control strategies. Also, epigenetic factors are believed to be one of the major determinants of disease response. Results: Here, we carried out comprehensive analyses of the epigenetic landscape induced by MDV, utilizing genome-wide histone H3 lysine 4 and lysine 27 trimethylation maps from chicken lines with varying resistance to MD. Differential chromatin marks were observed on genes previously implicated in the disease such as MX1 and CTLA-4 and also on genes reported in other cancers including IGF2BP1 and GAL. We detected bivalent domains on immune-related transcriptional regulators BCL6, CITED2 and EGR1, which underwent dynamic changes in both lines as a result of MDV infection. In addition, putative roles for GAL in the mechanism of MD progression were revealed. Conclusion: Our results confirm the presence of widespread epigenetic differences induced by MD in chicken lines with different levels of genetic resistance. A majority of observed epigenetic changes were indicative of increased levels of viral infection in the susceptible line symptomatic of lowered immunocompetence in these birds caused by early cytolytic infection. The GAL system that has known anti-proliferative effects in other cancers is also revealed to be potentially involved in MD progression. Our study provides further insight into the mechanisms of MD progression while revealing a complex landscape of epigenetic regulatory mechanisms that varies depending on host factors. C1 [Mitra, Apratim; Luo, Juan; Song, Jiuzhou] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Zhang, Huanming] ARS, USDA, Avian Dis & Oncol Lab, E Lansing, MI USA. [Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Song, JZ (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM songj88@umd.edu FU National Research Initiative Competitive Grant [USDA-NRI/NIFA 2008-35204-04660]; USDA National Institute of Food and Agriculture [USDA-NRI/NIFA 2010-65205-20588] FX This project was supported by National Research Initiative Competitive Grant no. USDA-NRI/NIFA 2008-35204-04660 and USDA-NRI/NIFA 2010-65205-20588 from the USDA National Institute of Food and Agriculture. NR 55 TC 6 Z9 6 U1 0 U2 8 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 OCT 16 PY 2012 VL 13 AR 557 DI 10.1186/1471-2164-13-557 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 051TP UT WOS:000312150600001 PM 23072359 ER PT J AU Dieter, KL Huestis, DL Lehmann, T AF Dieter, Kathryne L. Huestis, Diana L. Lehmann, Tovi TI The effects of oviposition-site deprivation on Anopheles gambiae reproduction SO PARASITES & VECTORS LA English DT Article DE Anopheles gambiae; Dry season; Drought; Hatch rate; Malaria; Reproduction; Seasonality; Vectorial capacity; Oviposition; Fecundity ID FORCED EGG-RETENTION; DRY SEASON; WESTERN KENYA; DIPTERA-CULICIDAE; METABOLIC-RATE; MOSQUITO; SURVIVAL; SAHEL; SUDAN; PERSISTENCE AB Background: The African malaria mosquito, Anopheles gambiae, depends on availability of suitable surface water for oviposition. Short and long dry spells occur throughout the year in many parts of its range that limit its access to oviposition sites. Although not well understood, oviposition-site deprivation has been found to rapidly reduce egg batch size and hatch rate of several mosquito species. We conducted laboratory experiments to assess these effects of oviposition-site deprivation on An. gambiae and to evaluate the role of nutrition and sperm viability as mediators of these effects. Methods: Anopheles gambiae adults (1-2 d old) from the G3 laboratory colony were assigned to the following treatment groups: oviposition-deprived (fed once and then deprived of oviposition site for 7 or 14 d), multiple-fed control (fed regularly once a week and allowed to lay eggs without delay), and age matched blood-deprived control (fed once, three days before water for oviposition was provided). Egg batch size and hatch rate were measured. In the second experiment two additional treatment groups were included: oviposition-deprived females that received either a second (supplemental) blood meal or virgin males (supplemental mating) 4 days prior to receiving water for oviposition. Results: An. gambiae was highly sensitive to oviposition-site deprivation. Egg batch size dropped sharply to 0-3.5 egg/female within 14 days, due to reduced oviposition rate rather than a reduced number of eggs/batch. Egg hatch rate also fell dramatically to 0-2% within 7 days. The frequency of brown eggs that fail to tan was elevated. A supplemental blood meal, but not 'supplemental insemination,' recovered the oviposition rate of females subjected to oviposition-site deprivation. Similarly, a supplemental blood meal, but not 'supplemental insemination,' partly recovered hatch rate, but this increase was marginally significant (P < 0.069). Conclusions: Even a short dry spell resulting in oviposition-site deprivation for several days may result in a dramatic decline of An. gambiae populations via reduced fecundity and fertility. However, females taking supplemental blood meals regain at least some reproductive success. If mosquitoes subjected to oviposition-site deprivation increase the frequency of blood feeding, malaria transmission may even increase during a short dry spell. The relevance of oviposition-site deprivation as a cue to alter the physiology of An. gambiae during the long dry season is not evident from these results because no reduction in hatch rate was evident in wild M-form An. gambiae collected in the dry season in the Sahel by previous studies. C1 [Dieter, Kathryne L.; Huestis, Diana L.; Lehmann, Tovi] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Lehmann, T (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Room 2W-09-C, Rockville, MD 20852 USA. EM TLehmann@niaid.nih.gov OI Huestis, Diana/0000-0001-6649-4785 FU NIAID, NIH FX We thank Ms. Monica Artis for technical assistance during the laboratory work, Mr. Andre Laughinghouse and Mr. Kevin Lee for assisting with mosquito cultures, and Dr. Gwadz for facilitating the project. This study was supported by the Intramural Research Program of NIAID, NIH. NR 25 TC 8 Z9 8 U1 1 U2 20 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 OCT 16 PY 2012 VL 5 AR 235 DI 10.1186/1756-3305-5-235 PG 8 WC Parasitology SC Parasitology GA 049FY UT WOS:000311969100001 PM 23072301 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI A measure of success SO CELL AND BIOSCIENCE LA English DT Editorial Material ID BIOSCIENCE; TIME AB Cell and Bioscience is on track to receive its first Impact Factor in mid-2013. What is the role of the Impact Factor as a measure of a journal's success? C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kjeang@nih.gov NR 6 TC 1 Z9 1 U1 0 U2 2 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 OCT 16 PY 2012 VL 2 AR 35 DI 10.1186/2045-3701-2-35 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 040KK UT WOS:000311321200001 PM 23072434 ER PT J AU Carlson, LA Hurley, JH AF Carlson, Lars-Anders Hurley, James H. TI In vitro reconstitution of the ordered assembly of the endosomal sorting complex required for transport at membrane-bound HIV-1 Gag clusters SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE confocal microscopy; host-pathogen interaction; membrane traffic; virus budding ID ESCRT-III COMPLEX; MULTIVESICULAR BODY; PLASMA-MEMBRANE; LATE DOMAINS; STRUCTURAL BASIS; MATRIX PROTEIN; VIRUS; P6; SCISSION; RELEASE AB Most membrane-enveloped viruses depend on host proteins of the endosomal sorting complex required for transport (ESCRT) machinery for their release. HIV-1 is the prototypic ESCRT-dependent virus. The direct interactions between HIV-1 and the early ESCRT factors TSG101 and ALIX have been mapped in detail. However, the full pathway of ESCRT recruitment to HIV-1 budding sites, which culminates with the assembly of the late-acting CHMP4, CHMP3, CHMP2, and CHMP1 subunits, is less completely understood. Here, we report the biochemical reconstitution of ESCRT recruitment to viral assembly sites, using purified proteins and giant unilamellar vesicles. The myristylated full-length Gag protein of HIV-1 was purified to monodispersity. Myr-Gag forms clusters on giant unilamellar vesicle membranes containing the plasma membrane lipid PI(4,5)P-2. These Gag clusters package a fluorescent oligonucleotide, and recruit early ESCRT complexes ESCRT-I or ALIX with the appropriate dependence on the Gag PTAP and LYP(X)(n)L motifs. ALIX directly recruits the key ESCRT-III subunit CHMP4. ESCRT-I can only recruit CHMP4 when ESCRT-II and CHMP6 are present as intermediary factors. Downstream of CHMP4, CHMP3 and CHMP2 assemble synergistically, with the presence of both subunits required for efficient recruitment. The very late-acting factor CHMP1 is not recruited unless the pathway is completed through CHMP3 and CHMP2. These findings define the minimal sets of components needed to complete ESCRT assembly at HIV-1 budding sites, and provide a starting point for in vitro structural and biophysical dissection of the system. C1 [Carlson, Lars-Anders; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM james.hurley@nih.gov FU European Molecular Biology Organization; Human Frontier Science Program; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Office of the Director, National Institutes of Health FX We thank E. Freed for critically reading the manuscript, E. Tyler for Fig. 5, E. Boura for providing ESCRT-II, and Hurley lab members for constructive discussions. L.-A. C. was supported by a European Molecular Biology Organization long-term fellowship and a Human Frontier Science Program long-term fellowship. This work was supported by the Intramural Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director, National Institutes of Health. NR 52 TC 43 Z9 44 U1 0 U2 21 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 OCT 16 PY 2012 VL 109 IS 42 BP 16928 EP 16933 DI 10.1073/pnas.1211759109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 029SK UT WOS:000310515800042 PM 23027949 ER PT J AU Soto-Pantoja, DR Miller, TW Frazier, WA Roberts, DD AF Soto-Pantoja, David R. Miller, Thomas W. Frazier, William A. Roberts, David D. TI Inhibitory signaling through signal regulatory protein-alpha is not sufficient to explain the antitumor activities of CD47 antibodies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID RECEPTOR C1 [Soto-Pantoja, David R.; Miller, Thomas W.; Roberts, David D.] NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frazier, William A.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Frazier, William A.] Washington Univ, Sch Med, Dept Cell Biol, St Louis, MO 63110 USA. [Frazier, William A.] Washington Univ, Sch Med, Dept Physiol, St Louis, MO 63110 USA. RP Roberts, DD (reprint author), NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; Miller, Thomas/G-1215-2011 OI Roberts, David/0000-0002-2481-2981; Miller, Thomas/0000-0001-8645-2785 NR 5 TC 13 Z9 13 U1 0 U2 5 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 OCT 16 PY 2012 VL 109 IS 42 BP E2842 EP E2842 DI 10.1073/pnas.1205441109 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 029SK UT WOS:000310515800001 PM 22923696 ER PT J AU Zhang, XW Zhao, XH Fiskus, W Lin, JH Lwin, T Rao, R Zhang, YZ Chan, JC Fu, K Marquez, VE Chen-Kiang, S Moscinski, LC Seto, E Dalton, WS Wright, KL Sotomayor, E Bhalla, K Tao, JG AF Zhang, Xinwei Zhao, Xiaohong Fiskus, Warren Lin, Jianhong Lwin, Tint Rao, Rekha Zhang, Yizhuo Chan, John C. Fu, Kai Marquez, Victor E. Chen-Kiang, Selina Moscinski, Lynn C. Seto, Edward Dalton, William S. Wright, Kenneth L. Sotomayor, Eduardo Bhalla, Kapil Tao, Jianguo TI Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas SO CANCER CELL LA English DT Article ID MANTLE-CELL; EXPRESSION; CANCER; DEACETYLASE; REPRESSION; TUMORIGENESIS; RECRUITMENT; LEUKEMIA; MODEL AB We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies. C1 [Zhang, Xinwei; Zhao, Xiaohong; Lwin, Tint; Moscinski, Lynn C.; Dalton, William S.; Sotomayor, Eduardo; Tao, Jianguo] H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33613 USA. [Zhang, Xinwei; Zhao, Xiaohong; Lwin, Tint; Moscinski, Lynn C.; Dalton, William S.; Sotomayor, Eduardo; Tao, Jianguo] H Lee Moffitt Canc Ctr & Res Inst, Expt Therapeut Program, Tampa, FL 33613 USA. [Seto, Edward] H Lee Moffitt Canc Ctr & Res Inst, Mol Oncol Program, Tampa, FL 33613 USA. [Wright, Kenneth L.] H Lee Moffitt Canc Ctr & Res Inst, Immunol Program, Tampa, FL 33613 USA. [Zhang, Xinwei; Zhang, Yizhuo] Tianjin Canc Hosp, Dept Immunol & Malignant Hematol, Tianjin 300060, Peoples R China. [Fiskus, Warren; Rao, Rekha; Bhalla, Kapil] Univ Kansas, Ctr Canc, Kansas City, KS 66160 USA. [Lin, Jianhong] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chan, John C.; Fu, Kai] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE 68198 USA. [Marquez, Victor E.] NCI, Chem Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Chen-Kiang, Selina] Weill Cornell Med Coll, Dept Pathol, New York, NY 10065 USA. RP Tao, JG (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33613 USA. EM jianguo.tao@moffitt.org FU National Cancer Institute [R01 CA137123]; Maher Fund; Susan and John Sykes Lymphoma Research Fund; Lymphoma Research Foundation FX We are grateful to the Tissue Procurement and Molecular Core Laboratory at Moffitt Cancer Center for providing specimens and molecular analysis. We thank Rasa Hamilton for editorial assistance. This work was supported by grants from the National Cancer Institute (Grant R01 CA137123 to J.T.), the Maher Fund (to J.T.), the Susan and John Sykes Lymphoma Research Fund (to J.T.) and the Lymphoma Research Foundation (to J.T.). NR 21 TC 109 Z9 114 U1 2 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 16 PY 2012 VL 22 IS 4 BP 506 EP 523 DI 10.1016/j.ccr.2012.09.003 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 024MS UT WOS:000310113900011 PM 23079660 ER PT J AU Jiang, X Huang, H Li, ZJ Li, YY Wang, X Gurbuxani, S Chen, P He, CJ You, DW Zhang, SD Wang, JH Arnovitz, S Elkahloun, A Price, C Hong, GM Ren, HM Kunjamma, RB Neilly, MB Matthews, JM Xu, MY Larson, RA Le Beau, MM Slany, RK Liu, PP Lu, J Zhang, JW He, C Chen, JJ AF Jiang, Xi Huang, Hao Li, Zejuan Li, Yuanyuan Wang, Xiao Gurbuxani, Sandeep Chen, Ping He, Chunjiang You, Dewen Zhang, Shuodan Wang, Jinhua Arnovitz, Stephen Elkahloun, Abdel Price, Colles Hong, Gia-Ming Ren, Haomin Kunjamma, Rejani B. Neilly, Mary Beth Matthews, Jonathan M. Xu, Mengyi Larson, Richard A. Le Beau, Michelle M. Slany, Robert K. Liu, Paul P. Lu, Jun Zhang, Jiwang He, Chuan Chen, Jianjun TI Blockade of miR-150 Maturation by MLL-Fusion/MYC/LIN-28 Is Required for MLL-Associated Leukemia SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; FACTOR C-MYB; HISTONE MODIFICATIONS; CELL-DIFFERENTIATION; REARRANGED LEUKEMIA; THERAPEUTIC TARGET; STEM-CELLS; MICRORNA; EXPRESSION; FLT3 AB Expression of microRNAs (miRNAs) is under stringent regulation at both transcriptional and posttranscriptional levels. Disturbance at either level could cause dysregulation of miRNAs. Here, we show that MLL fusion proteins negatively regulate production of miR-150, an miRNA widely repressed in acute leukemia, by blocking miR-150 precursors from being processed to mature miRNAs through MYC/LIN28 functional axis. Forced expression of miR-150 dramatically inhibited leukemic cell growth and delayed MLL-fusion-mediated leukemogenesis, likely through targeting FLT3 and MYB and thereby interfering with the HOXA9/MEIS1/FLT3/MYB signaling network, which in turn caused downregulation of MYC/LIN28. Collectively, we revealed a MLL-fusion/MYC/LIN28 (sic)miR-150 (sic)FLT3/MYB/HOXA9/MEIS1 signaling circuit underlying the pathogenesis of leukemia, where miR-150 functions as a pivotal gatekeeper and its repression is required for leukemogenesis. C1 [Jiang, Xi; Huang, Hao; Li, Zejuan; Li, Yuanyuan; Chen, Ping; He, Chunjiang; Zhang, Shuodan; Wang, Jinhua; Arnovitz, Stephen; Price, Colles; Hong, Gia-Ming; Ren, Haomin; Kunjamma, Rejani B.; Neilly, Mary Beth; Matthews, Jonathan M.; Xu, Mengyi; Larson, Richard A.; Le Beau, Michelle M.; Chen, Jianjun] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Wang, Xiao; He, Chuan] Univ Chicago, Dept Chem, Chicago, IL 60637 USA. [Wang, Xiao; He, Chuan] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA. [Gurbuxani, Sandeep] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [You, Dewen; Zhang, Jiwang] Loyola Univ, Med Ctr, Cardinal Bernardin Canc Ctr, Inst Oncol, Maywood, IL 60153 USA. [Zhang, Jiwang] Loyola Univ, Med Ctr, Dept Pathol, Maywood, IL 60153 USA. [Slany, Robert K.] Univ Erlangen Nurnberg, Dept Genet, D-91058 Erlangen, Germany. [Lu, Jun] Yale Univ, Dept Genet, Yale Stem Cell Ctr, New Haven, CT 06520 USA. [Elkahloun, Abdel; Liu, Paul P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, JJ (reprint author), Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. EM jchen@medicine.bsd.uchicago.edu RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; He, Chunjiang/0000-0002-4868-331X; Larson, Richard/0000-0001-9168-3203 FU National Institutes of Health (NIH) [CA127277]; American Cancer Society (ACS); University of Chicago Committee on Cancer Biology (CCB); LLS Special Fellowship; Gabrielle's Angel Foundation for Cancer Research; Leukemia & Lymphoma Society (LLS); Fidelity Foundation; Intramural Research Program of the National Human Genome Research Institute, NIH [NIH P01 CA40046, P30 CA014599]; [R01 HL95896] FX The authors thank Dr. Janet D. Rowley for her support and constructive suggestions/comments and Dr. Peter Breslin for critical reading and constructive comments. We are also grateful to Drs. Gregory Hannon, Scott Hammond, Lin He, Scott Armstrong, and Michael Thirman for providing retroviral constructs. This work was supported in part by the National Institutes of Health (NIH) R01 Grant CA127277 (J.C.), American Cancer Society (ACS) Research Scholar grant (J.C.), The University of Chicago Committee on Cancer Biology (CCB) Fellowship Program (X.J.), LLS Special Fellowship (Z.L.), Gabrielle's Angel Foundation for Cancer Research (J.C., Z.L., and H.H.), Leukemia & Lymphoma Society (LLS) Translational Research Grant (J.D.R. and J.C.), the Fidelity Foundation (J.D.R. and J.C.), R01 HL95896 (J.Z.), and the Intramural Research Program of the National Human Genome Research Institute, NIH (A.E. and P.P.L.), NIH P01 CA40046 (M.M.L.B), and P30 CA014599 (CCSG) (M.M.L.B). NR 48 TC 71 Z9 75 U1 1 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 16 PY 2012 VL 22 IS 4 BP 524 EP 535 DI 10.1016/j.ccr.2012.08.028 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 024MS UT WOS:000310113900012 PM 23079661 ER PT J AU Davis, J Burr, AR Davis, GF Birnbaumer, L Molkentin, JD AF Davis, Jennifer Burr, Adam R. Davis, Gregory F. Birnbaumer, Lutz Molkentin, Jeffery D. TI A TRPC6-Dependent Pathway for Myofibroblast Transdifferentiation and Wound Healing In Vivo SO DEVELOPMENTAL CELL LA English DT Article ID SERUM RESPONSE FACTOR; ACTIVATED T-CELLS; TGF-BETA; TRANSCRIPTION FACTOR; CARDIAC-HYPERTROPHY; NUCLEAR FACTOR; TRPC CHANNELS; UP-REGULATION; DIFFERENTIATION; FIBROSIS AB After injury or cytokine stimulation, fibroblasts transdifferentiate into myofibroblasts, contractile cells that secrete extracellular matrix for wound healing and tissue remodeling. Here, a genome-wide screen identified TRPC6, a Ca2+ channel necessary and sufficient for myofibroblast transformation. TRPC6 overexpression fully activated myofibroblast transformation, while fibroblasts lacking Trpc6 were refractory to transforming growth factor beta (TGF-beta) and angiotensin II-induced transdifferentiation. Trpc6 gene-deleted mice showed impaired dermal and cardiac wound healing after injury. The profibrotic ligands TGF-beta and angiotensin II induced TRPC6 expression through p38 mitogen-activated protein kinase (MAPK) serum response factor (SRF) signaling via the TRPC6 promoter. Once induced, TRPC6 activates the Ca2+-responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPC6-dependent transdifferentiation and dermal wound healing. These results demonstrate an obligate function for TRPC6 and calcineurin in promoting myofibroblast differentiation, suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-beta, p38 MAPK, and SRF. C1 [Davis, Jennifer; Burr, Adam R.; Davis, Gregory F.; Molkentin, Jeffery D.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Molkentin, Jeffery D.] Howard Hughes Med Inst, Cincinnati, OH 45229 USA. RP Molkentin, JD (reprint author), Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. EM jeff.molkentin@cchmc.org FU National Institutes of Health [5F32HL095353-03]; Intramural Research Program of the NIH National Institute of Environmental Health Sciences; Howard Hughes Medical Institute FX This work was supported by grants from the National Institutes of Health (J.D.M.), the equivalent of support in part by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences (L.B.), and by the Howard Hughes Medical Institute (J.D.M). J.D. was supported by a National Service Award from the NIH (5F32HL095353-03). NR 36 TC 77 Z9 78 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD OCT 16 PY 2012 VL 23 IS 4 BP 705 EP 715 DI 10.1016/j.devcel.2012.08.017 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 023LR UT WOS:000310036200008 PM 23022034 ER PT J AU Hashkes, PJ Spalding, SJ Giannini, EH Huang, B Johnson, A Park, G Barron, KS Weisman, MH Pashinian, N Reiff, AO Samuels, J Wright, DA Kastner, DL Lovell, DJ AF Hashkes, Philip J. Spalding, Steven J. Giannini, Edward H. Huang, Bin Johnson, Anne Park, Grace Barron, Karyl S. Weisman, Michael H. Pashinian, Noune Reiff, Andreas O. Samuels, Jonathan Wright, Dowain A. Kastner, Daniel L. Lovell, Daniel J. TI Rilonacept for Colchicine-Resistant or -Intolerant Familial Mediterranean Fever A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID DOUBLE-BLIND; ANAKINRA; THERAPY; PYRIN; MUTATIONS; EFFICACY; PROTEIN; AMYLOIDOSIS; ADOLESCENT; PATIENT AB Background: Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory cytokine in FMF. Objective: To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF. Design: Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907). Setting: 6 U. S. sites. Patients: Patients with FMF aged 4 years or older with 1 or more attacks per month. Intervention: One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo. Measurements: Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo. Results: 8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 [95% CI, -3.4 to -0.1]; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [-0.5 and 2.4 days in the first and third quartiles, respectively]; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of -4 and 0 in the first and third quartiles, respectively]; P = 0.047), but no differences were seen in other adverse events. Limitation: Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations. Conclusion: Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF. C1 [Hashkes, Philip J.] Shaare Zedek Med Ctr, Pediat Rheumatol Unit, IL-91031 Jerusalem, Israel. Cleveland Clin Fdn, Cleveland, OH USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. NIAID, NIAMSD, Bethesda, MD 20892 USA. NHGRI, Bethesda, MD 20892 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Childrens Hosp Cent Calif, Madera, CA USA. NYU, Langone Hosp Joint Dis, New York, NY USA. RP Hashkes, PJ (reprint author), Shaare Zedek Med Ctr, Pediat Rheumatol Unit, POB 3235, IL-91031 Jerusalem, Israel. EM hashkesp@szmc.org.il RI Huang, bin/G-2468-2014; OI samuels, jonathan/0000-0002-1513-770X FU U.S. Food and Drug Administration, Office of Orphan Products Development; U.S. Food and Drug Administration, Office of Orphan Products Development [R01 FD003435]; Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Human Genome Research Institute; Cleveland Clinic Foundation FX U.S. Food and Drug Administration, Office of Orphan Products Development.; Grant Support: By the U.S. Food and Drug Administration, Office of Orphan Products Development (R01 FD003435). This trial was also supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Human Genome Research Institute, and the Cleveland Clinic Foundation. Rilonacept and placebo were supplied by Regeneron Pharmaceuticals. Target Health provided and partially subsidized the electronic data capture system and electronic database. NR 46 TC 68 Z9 69 U1 0 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 16 PY 2012 VL 157 IS 8 BP 533 EP + DI 10.7326/0003-4819-157-8-201210160-00003 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 021SP UT WOS:000309906000013 PM 23070486 ER PT J AU Wu, LC Grabaud, BI Gail, MH AF Wu, Lindsey C. Grabaud, Barry I. Gail, Mitchell H. TI Tipping the Balance of Benefits and Harms to Favor Screening Mammography Starting at Age 40 Years SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID RISK C1 [Wu, Lindsey C.; Grabaud, Barry I.; Gail, Mitchell H.] NIH, Bethesda, MD 20814 USA. RP Wu, LC (reprint author), NIH, Bethesda, MD 20814 USA. NR 5 TC 3 Z9 3 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 16 PY 2012 VL 157 IS 8 BP 597 EP 597 DI 10.7326/0003-4819-157-8-201210160-00019 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 021SP UT WOS:000309906000025 PM 23070497 ER PT J AU Elinoff, JM Danner, RL AF Elinoff, Jason M. Danner, Robert L. TI Hydroxyethyl starch 130/0.42 increased death at 90 days compared with Ringer's acetate in severe sepsis SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID RESUSCITATION C1 [Elinoff, Jason M.; Danner, Robert L.] NIH, Bethesda, MD 20892 USA. RP Elinoff, JM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 1 U1 1 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 16 PY 2012 VL 157 IS 8 AR JC4-6 DI 10.7326/0003-4819-157-8-201210160-02006 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 021SP UT WOS:000309906000005 PM 23070508 ER PT J AU Bates, SE AF Bates, Susan E. TI Reinventing Cancer Cell Metabolism SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 2 Z9 2 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2012 VL 18 IS 20 BP 5536 EP 5536 DI 10.1158/1078-0432.CCR-12-2884 PG 1 WC Oncology SC Oncology GA 048JW UT WOS:000311908500004 PM 23071354 ER PT J AU Teicher, BA Linehan, WM Helman, LJ AF Teicher, Beverly A. Linehan, W. Marston Helman, Lee J. TI Targeting Cancer Metabolism SO CLINICAL CANCER RESEARCH LA English DT Article ID PYRUVATE-KINASE M2; FUMARATE-HYDRATASE DEFICIENCY; RENAL-CELL CARCINOMA; IDH2 MUTATIONS; SUCCINATE-DEHYDROGENASE; BREAST-CANCER; GLUTAMINE-METABOLISM; GLUCOSE-METABOLISM; TUMOR SUPPRESSORS; MAFFUCCI SYNDROME AB The understanding that oncogenes can have profound effects on cellular metabolism and the discovery of mutations and alterations in several metabolism-related enzymes-isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2)-has renewed interest in cancer metabolism and renewed hope of taking therapeutic advantage of cancer metabolism. Otto Warburg observed that aerobic glycolysis was a characteristic of cancer cells. More than 50 years later, we understand that aerobic glycolysis and uptake of glutamine and glycine allow cancer cells to produce energy (ATP) and the nucleotides, amino acids, and lipids required for proliferation. Expression of the MYC oncogene drives the increase in cellular biomass facilitating proliferation. PKM2 expression in cancer cells stimulates aerobic glycolysis. Among intermediary metabolism enzymes, mutations in SDH occur in gastointestinal stromal tumors and result in a pseudohypoxic metabolic milieu. FH mutations lead to a characteristic renal cell carcinoma. Isocitrate dehydrogenase (IDH1/2) mutations have been found in leukemias, gliomas, prostate cancer, colon cancer, thyroid cancer, and sarcomas. These recently recognized oncogenic metabolic lesions may be selective targets for new anticancer therapeutics. Clin Cancer Res; 18(20); 5537-45. (C) 2012 AACR. C1 [Teicher, Beverly A.; Linehan, W. Marston; Helman, Lee J.] NCI, Bethesda, MD 20892 USA. RP Teicher, BA (reprint author), NCI, Mol Pharmacol Branch, Dev Therapeut Program, MSC 7458,Room 8156,6130 Execut Blvd, Rockville, MD 20852 USA. EM Beverly.Teicher@nih.gov FU Intramural NIH HHS [Z99 CA999999, ZIA BC011028-05, ZIA BC011038-05] NR 95 TC 47 Z9 50 U1 1 U2 40 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2012 VL 18 IS 20 BP 5537 EP 5545 DI 10.1158/1078-0432.CCR-12-2587 PG 9 WC Oncology SC Oncology GA 048JW UT WOS:000311908500005 PM 23071355 ER PT J AU Kim, HJ Zhong, Q Sheng, ZH Yoshimori, T Liang, CY Jung, JU AF Kim, Hee Jin Zhong, Qing Sheng, Zu-Hang Yoshimori, Tamotsu Liang, Chengyu Jung, Jae U. TI Beclin-1-interacting autophagy protein Atg14L targets the SNARE-associated protein Snapin to coordinate endocytic trafficking SO JOURNAL OF CELL SCIENCE LA English DT Article DE Atg14L; Snapin; Autophagosome maturation; Endosome maturation; Autophagy ID PHOSPHATIDYLINOSITOL 3-KINASE COMPLEXES; C-VPS COMPLEX; UNANSWERED QUESTIONS; BECLIN 1; MEMBRANE; FUSION; MATURATION; UVRAG; IDENTIFICATION; INTERACTS AB Autophagy is a highly regulated membrane remodeling process that allows the lysosome-mediated degradation of cytoplasmic entities by sequestrating them in double-membrane autophagosomes. Autophagy is hence highly intertwined with the endocytic trafficking pathway, sharing similar molecular machinery. Atg14L, also known as Beclin 1-associated autophagy-related key regulator (Barkor), directly interacts with Beclin 1 through its coiled-coil domain and enhances phosphatidylinositol 3-phosphate kinase class III (PI3KC3) activity to induce autophagosome membrane nucleation, highlighting its essential role in the early stage of mammalian autophagy. Here, we report a novel function of Atg14L in the endocytic trafficking pathway wherein Atg14L binds to and colocalizes with the fusogenic SNARE effector protein Snapin to facilitate endosome maturation. Atg14L specifically binds to Snapin and this interaction effectively facilitates endosomal maturation without affecting autophagic cargo degradation. Consequently, atg14l knockdown significantly delayed the late stage of endocytic trafficking, as evidenced by the retarded kinetics of internalized surface receptor degradation. This phenotype was effectively complemented by wild-type Atg14L or Beclin 1-binding mutant, but not by its Snapin-binding mutant. Taken together, our study demonstrates that Atg14L functions as a multivalent trafficking effector that regulates endosome maturation as well as autophagosome formation, reflecting the complexity of the crosstalk between autophagic and endocytic vesicle trafficking in higher eukaryotes. C1 [Kim, Hee Jin; Liang, Chengyu; Jung, Jae U.] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Zhong, Qing] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Sheng, Zu-Hang] NINDS, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. [Yoshimori, Tamotsu] Osaka Univ, Grad Sch Med, Dept Genet, Osaka, Japan. RP Jung, JU (reprint author), Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. EM jaeujung@usc.edu OI LIANG, CHENGYU/0000-0001-6082-2143 FU Hastings Foundation [22-2107-1000]; Fletcher Jones Foundation [22-2101-1003]; Global Reaserch Laboratory Program from National Research Foundation of Korea [K20815000001]; National Institute Health [CA82057, CA31363, DE019085, AI073099, AI083025, CA140964, AI083841]; American Cancer Society [RGS-11-121-01-CCG] FX This work was partly supported by the Hastings Foundation (grant number 22-2107-1000 to J.U.J.), the Fletcher Jones Foundation [grant number 22-2101-1003 to J.U.J.], the Global Reaserch Laboratory Program from National Research Foundation of Korea (grant number K20815000001 to JUJ), and National Institute Health [grant numbers CA82057, CA31363, DE019085, AI073099, and AI083025 to J.U.J; CA140964 and AI083841 to C. L.], and American Cancer Society (grant number RGS-11-121-01-CCG to C. L.). Deposited in PMC for release after 12 month. NR 34 TC 20 Z9 20 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD OCT 15 PY 2012 VL 125 IS 20 BP 4740 EP 4750 DI 10.1242/jcs.100339 PG 11 WC Cell Biology SC Cell Biology GA 050XN UT WOS:000312088200007 PM 22797916 ER PT J AU Voss, C Lahiri, S Young, BP Loewen, CJ Prinz, WA AF Voss, Christiane Lahiri, Sujoy Young, Barry P. Loewen, Christopher J. Prinz, William A. TI ER-shaping proteins facilitate lipid exchange between the ER and mitochondria in S. cerevisiae SO JOURNAL OF CELL SCIENCE LA English DT Article DE Endoplasmic reticulum; Mitochondria; Lipid trafficking; Membrane contact sites; Reticulons; ERMES complex; Sey1p ID ORGANELLE CONTACT SITES; OUTER-MEMBRANE PROTEIN; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM; PHOSPHATIDYLSERINE DECARBOXYLASE; PHOSPHOLIPID-SYNTHESIS; NULL ALLELE; YEAST; GENE; INHERITANCE AB The endoplasmic reticulum (ER) forms a network of sheets and tubules that extends throughout the cell. Proteins required to maintain this complex structure include the reticulons, reticulon-like proteins, and dynamin-like GTPases called atlastins in mammals and Sey1p in Saccharomyces cerevisiae. Yeast cells missing these proteins have abnormal ER structure, particularly defects in the formation of ER tubules, but grow about as well as wild-type cells. We screened for mutations that cause cells that have defects in maintaining ER tubules to grow poorly. Among the genes we found were members of the ER mitochondria encounter structure (ERMES) complex that tethers the ER and mitochondria. Close contacts between the ER and mitochondria are thought to be sites where lipids are moved from the ER to mitochondria, a process that is required for mitochondrial membrane biogenesis. We show that ER to mitochondria phospholipid transfer slows significantly in cells missing both ER-shaping proteins and the ERMES complex. These cells also have altered steady-state levels of phospholipids. We found that the defect in ER to mitochondria phospholipid transfer in a strain missing ER-shaping proteins and a component of the ERMES complex was corrected by expression of a protein that artificially tethers the ER and mitochondria. Our findings indicate that ER-shaping proteins play a role in maintaining functional contacts between the ER and mitochondria and suggest that the shape of the ER at ER-mitochondria contact sites affects lipid exchange between these organelles. C1 [Voss, Christiane; Lahiri, Sujoy; Prinz, William A.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Young, Barry P.; Loewen, Christopher J.] Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC V6T 1Z3, Canada. RP Prinz, WA (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM wprinz@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; CIHR; NSERC; CFI; MSFHR; Tula Foundation FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. B.P.Y and C.J.L were supported by CIHR, NSERC, CFI, MSFHR and the Tula Foundation. Deposited in PMC for release after 12 months. NR 43 TC 56 Z9 57 U1 0 U2 12 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD OCT 15 PY 2012 VL 125 IS 20 BP 4791 EP 4799 DI 10.1242/jcs.105635 PG 9 WC Cell Biology SC Cell Biology GA 050XN UT WOS:000312088200012 PM 22797914 ER PT J AU Van Itallie, CM Tietgens, AJ LoGrande, K Aponte, A Gucek, M Anderson, JM AF Van Itallie, Christina M. Tietgens, Amber Jean LoGrande, Kirsten Aponte, Angel Gucek, Marjan Anderson, James M. TI Phosphorylation of claudin-2 on serine 208 promotes membrane retention and reduces trafficking to lysosomes SO JOURNAL OF CELL SCIENCE LA English DT Article DE Tight junction; Claudin; Claudin-2; Phosphorylation ID EPIDERMAL-GROWTH-FACTOR; PROTEIN-KINASE-A; PARACELLULAR CHLORIDE PERMEABILITY; EPITHELIAL TIGHT JUNCTIONS; OVARIAN-CANCER CELLS; BARRIER FUNCTION; POSTTRANSLATIONAL MODIFICATIONS; EXTRACELLULAR DOMAINS; SELECTIVE CHANNELS; CYCLIC-AMP AB Claudins are critical components of epithelial and endothelial tight junction seals, but their post-transcriptional regulation remains poorly understood. Several studies have implicated phosphorylation in control of claudin localisation and/or function, but these have focused on single sites or pathways with differing results, so that it has been difficult to draw general functional conclusions. In this study, we used mass spectrometry (MS) analysis of purified claudin-2 from MDCK II cells and found that the cytoplasmic tail is multiply phosphorylated on serines, a threonine and tyrosines. Phos-tag SDS PAGE revealed that one site, S208, is heavily constitutively phosphorylated in MDCK II cells and in mouse kidney; this site was targeted for further study. Mutational analysis revealed that the phosphomimetic mutant of claudin-2, S208E, was preferentially localised to the plasma membrane while claudin-2 S208A, which could not be phosphorylated at this site, both immunolocalized and co-fractionated with lysosomal markers. Mutations at sites that were previously reported to interfere with plasma membrane targeting of claudin-2 reduced phosphorylation at S208, suggesting that membrane localisation is required for phosphorylation; however phosphorylation at S208 did not affect binding to ZO-1 or ZO-2 Administration of forskolin or PGE2 resulted in dephosphorylation at S208 and transient small increases in transepithelial electrical resistance (TER). Together these data are consistent with phosphorylation at S208 playing a major role in the retention of claudin-2 at the plasma membrane. C1 [Van Itallie, Christina M.; Tietgens, Amber Jean; LoGrande, Kirsten; Aponte, Angel; Gucek, Marjan; Anderson, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Van Itallie, CM (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Christina.vanitallie@nih.gov FU Office of the Director through the Intramural Research Program of the National Institutes of Health FX This research was funded by the Office of the Director through the Intramural Research Program of the National Institutes of Health. Deposited in PMC for release after 12 months. NR 67 TC 26 Z9 27 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 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD OCT 15 PY 2012 VL 125 IS 20 BP 4902 EP 4912 DI 10.1242/jcs.111237 PG 11 WC Cell Biology SC Cell Biology GA 050XN UT WOS:000312088200022 PM 22825868 ER PT J AU Liu, X Zhu, XH Qiu, PH Chen, W AF Liu, Xiao Zhu, Xiao-Hong Qiu, Peihua Chen, Wei TI A correlation-matrix-based hierarchical clustering method for functional connectivity analysis SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Resting-state functional connectivity; Spontaneous BOLD fluctuations; Clustering method; Thalamocortical connections ID INDEPENDENT COMPONENT ANALYSIS; RESTING-STATE; HUMAN BRAIN; FMRI; FLUCTUATIONS; NETWORK; SIGNAL; SYSTEMS; IMAGES; CORTEX AB In this study, a correlation matrix based hierarchical clustering (CMBHC) method is introduced to extract multiple correlation patterns from resting-state functional magnetic resonance imaging (fMRI) data. It was applied to spontaneous fMRI signals acquired from anesthetized rats, and the results were then compared with those obtained using independent component analysis (ICA), one of the most popular multivariate analysis method for analyzing spontaneous fMRI signals. It was demonstrated that the CMBHC has a higher sensitivity than the ICA, particularly on a single run data, for identifying correlation structures with relatively weak connections, for instance, the thalamocortical connections. Compared to the seed-based correlation analysis, the CMBHC does not require a priori information and thus can avoid potential biases caused by seed selection, and multiple patterns can be extracted at one time. In contrast to other multivariate methods, the CMBHC is based on spatiotemporal correlations of fMRI signals and its analysis outcomes are easy to interpret as the strength of functional connectivity. Moreover, its sensitivity of detecting patterns remains relatively high even for a single dataset. In conclusion, the CMBHC method could be a useful tool for investigating resting-state brain connectivity and function. (C) 2012 Elsevier B.V. All rights reserved. C1 [Liu, Xiao; Zhu, Xiao-Hong; Chen, Wei] Univ Minnesota, Dept Radiol, Ctr Magnet Resonance Res, Minneapolis, MN 55455 USA. [Liu, Xiao; Qiu, Peihua] Univ Minnesota, Sch Stat, Minneapolis, MN 55455 USA. RP Liu, X (reprint author), NINDS, NIH, LFMI, 10 Ctr Dr,Bldg 10,RM B1D728,MSC 1065, Bethesda, MD 20892 USA. EM liux15@ninds.nih.gov RI Liu, Xiao/C-5943-2016 FU NIH [NS041262, NS041262S1, NS057560, NS070839, P41 RR08079, P30NS057091]; Keck Foundation FX This work was partially supported by NIH grants: NS041262, NS041262S1, NS057560, NS070839, P41 RR08079 and P30NS057091; and the Keck Foundation. NR 37 TC 12 Z9 12 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2012 VL 211 IS 1 BP 94 EP 102 DI 10.1016/j.jneumeth.2012.08.016 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 036IF UT WOS:000311018900013 PM 22939920 ER PT J AU Lehner, T AF Lehner, Thomas TI The Genes in the Major Histocompatibility Complex as Risk Factors for Schizophrenia: De Omnibus Dubitandum SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID EXPRESSION; DISORDERS; DISEASE C1 NIMH, Off Genom Res Coordinat, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lehner, T (reprint author), NIMH, Off Genom Res Coordinat, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM tlehner@mail.nih.gov NR 10 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2012 VL 72 IS 8 BP 615 EP 616 DI 10.1016/j.biopsych.2012.08.002 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 016UQ UT WOS:000309545400001 PM 22999335 ER PT J AU Ye, TZ Lipska, BK Tao, R Hyde, TM Wang, LQ Li, C Choi, KH Straub, RE Kleinman, JE Weinberger, DR AF Ye, Tianzhang Lipska, Barbara K. Tao, Ran Hyde, Thomas M. Wang, Liqin Li, Chao Choi, Kwang H. Straub, Richard E. Kleinman, Joel E. Weinberger, Daniel R. TI Analysis of Copy Number Variations in Brain DNA from Patients with Schizophrenia and Other Psychiatric Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Autism; copy number variations; gene expression; major depressive disorder; postmortem brain; prefrontal cortex; schizophrenia ID HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; GENE-EXPRESSION; MICROARRAY; RISK AB Background: Clinical studies have identified several regions of the genome with copy number variations (CNVs) associated with diverse neurodevelopmental behavioral disorders. Methods: We analyzed 1 million (M) single nucleotide polymorphism genotype arrays for evidence of previously reported recurrent CNVs and enriched genome-wide CNV burden in DNA from 600 brains, including 441 individuals with various psychiatric diagnoses. We explored gene expression in the dorsolateral prefrontal cortex in selected cases with CNVs and in other subjects with Illumina BeadArrays (568 subjects in total) and additionally in 66-92 subjects with quantitative real-time polymerase chain reaction. Results: The CNVs in previously reported genomic regions were identified in 4 of 193 patients with the diagnosis of schizophrenia (1q21.1, 11q25, 15q11.2, 22q11), 4 of 238 patients with mood disorders (11q25, 15q11.2, 22q11), and 1 of 10 patients with autism (2p16.3). No evidence of increased genome-wide CNV burden was observed in cases with schizophrenia or mood disorders, although the study is underpowered to observe rare events. Messenger RNA expression patterns suggested incomplete molecular penetrance of observed CNVs. Conclusions: Our data confirm in brain DNA the presence of certain recurrent CNVs in a small percentage of patients with psychiatric diagnoses. C1 [Ye, Tianzhang; Hyde, Thomas M.; Straub, Richard E.; Weinberger, Daniel R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Lipska, Barbara K.; Tao, Ran; Wang, Liqin; Li, Chao; Kleinman, Joel E.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Choi, Kwang H.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. [Choi, Kwang H.] Uniformed Serv Univ Hlth Sci, Program Neurosci, Bethesda, MD 20814 USA. RP Weinberger, DR (reprint author), Johns Hopkins Univ, Lieber Inst Brain Dev, Med Campus,855 N Wolfe St, Baltimore, MD 21205 USA. EM drweinberger@libd.org RI Tao, Ran/C-2662-2013; Tao, Ran/L-3460-2014; Lipska, Barbara/E-4569-2017 FU Intramural NIH HHS [Z01 MH002734-12] NR 17 TC 18 Z9 18 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2012 VL 72 IS 8 BP 651 EP 654 DI 10.1016/j.biopsych.2012.06.014 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 016UQ UT WOS:000309545400007 PM 22795968 ER PT J AU Bellizzi, KM Smith, A Schmidt, S Keegan, THM Zebrack, B Lynch, CF Deapen, D Shnorhavorian, M Tompkins, BJ Simon, M AF Bellizzi, Keith M. Smith, Ashley Schmidt, Steven Keegan, Theresa H. M. Zebrack, Brad Lynch, Charles F. Deapen, Dennis Shnorhavorian, Margarett Tompkins, Bradley J. Simon, Michael CA Adolescent Young Adult Hlth Outcom TI Positive and Negative Psychosocial Impact of Being Diagnosed With Cancer as an Adolescent or Young Adult SO CANCER LA English DT Article DE adolescent and young adult cancer; psychosocial impact; oncology; quality of life ID QUALITY-OF-LIFE; BREAST-CANCER; POSTTRAUMATIC GROWTH; CHILDHOOD-CANCER; BODY-IMAGE; LONG-TERM; FERTILITY PRESERVATION; PHYSICAL-ACTIVITY; CLINICAL-TRIALS; SURVIVORS AB BACKGROUND: The objective of this study was to explore the psychosocial impact of cancer on newly diagnosed adolescent and young adult (AYA) cancer patients. METHODS: This was a population-based, multicenter study of 523 newly diagnosed AYA survivors (ages 15-39 years) of germ cell cancer (n = 204), non-Hodgkin lymphoma (n = 131), Hodgkin lymphoma (n = 142), acute lymphocytic leukemia (n = 21), or sarcoma (n = 25) from 7 National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries. Age at diagnosis was categorized into 3 groups (ages 15-20 years, 21-29 years, and 30-39 years). RESULTS: Respondents (43% response rate), on average (+/- standard deviation), were aged 29 +/- 6.7 years, and most patients (80.1%) were not receiving treatment at the time the completed the survey. With modest differences between the age groups, the most prevalent areas of life impacted in a negative way were financial, body image, control over life, work plans, relationship with spouse/significant other, and plans for having children. Endorsement of positive life impact items also was evident across the 3 age groups, particularly with regard to relationships, future plans/goals, and health competence. CONCLUSIONS: The current results indicated that there will be future need for interventions targeting financial assistance, body image issues, relationships, and helping AYAs to attain their education objectives. Cancer 2012;118:5155-62. (C) 2012 American Cancer Society. C1 [Bellizzi, Keith M.; Schmidt, Steven] Univ Connecticut, Dept Human Dev & Family Studies, Storrs, CT 06269 USA. [Smith, Ashley] NCI, Outcomes Res Branch, Bethesda, MD 20892 USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Zebrack, Brad] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Deapen, Dennis] Univ So Calif, Dept Prevent Med, Los Angeles, CA USA. [Shnorhavorian, Margarett] Seattle Childrens Hosp, Seattle, WA USA. [Tompkins, Bradley J.] Vermont Dept Hlth, Burlington, VT 05402 USA. [Simon, Michael] Barbara Ann Karmanos Canc Inst, Detroit, MI USA. RP Bellizzi, KM (reprint author), Univ Connecticut, Dept Human Dev & Family Studies, 348 Mansfield Rd, Storrs, CT 06269 USA. EM keith.m.bellizzi@uconn.edu FU University of Iowa [N01PC-2010-00032]; Cancer Prevention Institute of California [N01PC-2010-00140]; Public Health Institute [N01PC-2010-00034]; University of Southern California [N01PC-2010-00035]; Fred Hutchinson Cancer Research Center [N01PC-2010-00029]; Wayne State University [N01PC-2010-00028]; Louisiana State University Health Sciences Center [N01PC-2010-00030] FX This work was supported by N01PC-2010-00032 (University of Iowa), N01PC-2010-00140 (Cancer Prevention Institute of California), N01PC-2010-00034 (Public Health Institute), N01PC-2010-00035 (University of Southern California), N01PC-2010-00029 (Fred Hutchinson Cancer Research Center), N01PC-2010-00028 (Wayne State University), and N01PC-2010-00030 (Louisiana State University Health Sciences Center). NR 45 TC 65 Z9 65 U1 3 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2012 VL 118 IS 20 BP 5155 EP 5162 DI 10.1002/cncr.27512 PG 8 WC Oncology SC Oncology GA 024BL UT WOS:000310082500030 PM 22415815 ER PT J AU Reeves, BN Dakhil, SR Sloan, JA Wolf, SL Burger, KN Kamal, A Le-Lindqwister, NA Soori, GS Jaslowski, AJ Kelaghan, J Novotny, PJ Lachance, DH Loprinzi, CL AF Reeves, Brandi N. Dakhil, Shaker R. Sloan, Jeff A. Wolf, Sherry L. Burger, Kelli N. Kamal, Arif Le-Lindqwister, Nguyet A. Soori, Gamini S. Jaslowski, Anthony J. Kelaghan, Joseph Novotny, Paul J. Lachance, Daniel H. Loprinzi, Charles L. TI Further Data Supporting That Paclitaxel-Associated Acute Pain Syndrome Is Associated With Development of Peripheral Neuropathy SO CANCER LA English DT Article DE paclitaxel; arthralgia; myalgia; paclitaxel-associated acute pain syndrome; neuropathy ID INDUCED ARTHRALGIAS; SENSORY NEURONS; CANCER; RATS; INFILTRATION; MINOCYCLINE; PREVENTION; ALLODYNIA; INFUSION; MYALGIAS AB BACKGROUND: Paclitaxel causes an acute pain syndrome (P-APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these 2 syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of PAPS and eventual peripheral neuropathy symptoms. METHODS: Patients entering this study were about to receive paclitaxel and carboplatin every 3 weeks. Daily questionnaires were completed for the first week after every chemotherapy dose, and European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Chemotherapy-Induced Peripheral Neuropathy 20-item instruments were completed weekly. RESULTS: The P-APS severity peaked on day 4 after the initial chemotherapy dose, with 12%, 29%, 23%, and 36% of patients having maximal pain scores of 0, 1 to 4, 5 or 6, or 7 to 10 during the first week after the first dose of therapy, respectively. Patients with P-APS scores of 0 to 4 with the first dose of chemotherapy had less eventual sensory neuropathy than did patients with P-APS scores of 5 to 10 (P = 0.001). With regard to the more peripheral neuropathy, sensory neuropathy was more problematic than was either motor or autonomic neuropathy. Numbness and tingling were more common components of the sensory neuropathy than was pain. CONCLUSIONS: Patients with worse P-APS severities appear to have more eventual chemotherapy-induced peripheral neuropathy. This provides support for the concept that P-APS is a form of nerve pathology. Cancer 2012;118:5171-8. (C) 2012 American Cancer Society. C1 [Reeves, Brandi N.; Sloan, Jeff A.; Wolf, Sherry L.; Burger, Kelli N.; Kamal, Arif; Novotny, Paul J.; Lachance, Daniel H.; Loprinzi, Charles L.] Mayo Clin Rochester, Rochester, MN USA. [Dakhil, Shaker R.] Wichita Community Clin Oncol Program CCOP, Wichita, KS USA. [Le-Lindqwister, Nguyet A.] Illinois Oncol Res Assoc CCOP, Peoria, IL USA. [Soori, Gamini S.] Missouri Valley Canc Consortium, Omaha, NE USA. [Jaslowski, Anthony J.] St Vincent Reg Canc Ctr CCOP, Green Bay, WI USA. [Kelaghan, Joseph] NCI, Bethesda, MD 20892 USA. RP Loprinzi, CL (reprint author), Mayo Clin, Dept Oncol, 200 1st St SW, Rochester, MN 55905 USA. EM cloprinzi@mayo.edu FU Public Health Service [CA-25224, CA-37404, CA-124477, CA-63848, CA-52352, CA-35090, CA-35101, CA-35269, CA-37417, CA-35448, CA-63844, CA-35267, CA-35272, CA-35113, CA-35103, CA-35415, CA-35431] FX This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-124477, CA-63848, CA-52352, CA-35090, CA-35101, CA-35269, CA-37417, CA-35448, CA-63844, CA-35267, CA-35272, CA-35113, CA-35103, CA-35415 and CA-35431. NR 29 TC 38 Z9 38 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2012 VL 118 IS 20 BP 5171 EP 5178 DI 10.1002/cncr.27489 PG 8 WC Oncology SC Oncology GA 024BL UT WOS:000310082500032 PM 22415454 ER PT J AU Yu, JH Kim, H AF Yu, Ji Hoon Kim, Hyeyoung TI Role of Janus Kinase/Signal Transducers and Activators of Transcription in the Pathogenesis of Pancreatitis and Pancreatic Cancer SO GUT AND LIVER LA English DT Article DE JAK/STAT; Pancreatitis; Pancreatic cancer; Oxidative stress ID ACINAR-CELLS; STAT3 ACTIVATION; CYTOKINE EXPRESSION; SIGNALING PATHWAY; TYROSINE KINASE; FREE-RADICALS; LUNG INJURY; RECEPTOR; INTERLEUKIN-6; ALPHA AB In the pathogenesis of pancreatitis, oxidative stress is involved in the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and cytokine expression. High serum levels of cholecystokinin (OCR) have been reported in patients with acute pancreatitis, and treatment with cerulein, a CCK analogue, induces acute pancreatitis in a rodent model. Recent studies have shown that cerulein-activated nicotinamide adenine dinucleotide phosphate oxidase elicits reactive oxygen species, which trigger the phosphorylation of the JAK1, STAT1, and STAT3 proteins and induce the production of inflammatory cytokines, such as tumor necrosis factor-a, interleukin (IL)-1 beta, and IL-6, in pancreatic acinar cells. The JAK/STAT pathway also stimulates cell proliferation and malignant transformation and inhibits apoptosis in the pancreas. This review discusses the possible role of the JAK/STAT pathway in the pathogenesis of pancreatitis and pancreatic cancer in response to oxidative stress. (Gut Liver 2012;6:417-422) C1 [Kim, Hyeyoung] Yonsei Univ, Dept Food & Nutr, Coll Human Ecol, Brain Korea Project 21, Seoul 120749, South Korea. [Yu, Ji Hoon] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Kim, H (reprint author), Yonsei Univ, Dept Food & Nutr, Coll Human Ecol, Brain Korea Project 21, 50 Yonsei Ro, Seoul 120749, South Korea. EM kim626@yonsei.ac.kr RI rchnds, rchnds/D-7595-2016; OI Kim, Hyeyoung/0000-0002-7019-917X FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0001177] FX This study was supported by the National Research Foundation of Korea (NRF) funded by Ministry of Education, Science and Technology (2011-0001177). Hyeyoung Kim is grateful to the Brain Korea 21 Project, Yonsei University College of Human Ecology. NR 46 TC 12 Z9 14 U1 0 U2 7 PU EDITORIAL OFFICE GUT & LIVER PI SEOUL PA 305 LOTTE GOLD ROSE II, 890-59, DAECHI 4-DONG, GANGNAM-GU, SEOUL, 135-839, SOUTH KOREA SN 1976-2283 J9 GUT LIVER JI Gut Liver PD OCT 15 PY 2012 VL 6 IS 4 BP 417 EP 422 DI 10.5009/gnl.2012.6.4.417 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 025FG UT WOS:000310170600003 PM 23170143 ER PT J AU Gazos-Lopes, F Mesquita, RD Silva-Cardoso, L Senna, R Silveira, AB Jablonka, W Cudischevitch, CO Carneiro, AB Machado, EA Lima, LG Monteiro, RQ Nussenzveig, RH Folly, E Romeiro, A Vanbeselaere, J Mendonca-Previato, L Previato, JO Valenzuela, JG Ribeiro, JMC Atella, GC Silva-Neto, MAC AF Gazos-Lopes, Felipe Mesquita, Rafael Dias Silva-Cardoso, Livia Senna, Raquel Silveira, Alan Barbosa Jablonka, Willy Cudischevitch, Cecilia Oliveira Carneiro, Alan Brito Machado, Ednildo Alcantara Lima, Luize G. Monteiro, Robson Queiroz Nussenzveig, Roberto Henrique Folly, Evelize Romeiro, Alexandre Vanbeselaere, Jorick Mendonca-Previato, Lucia Previato, Jose Osvaldo Valenzuela, Jesus G. Ribeiro, Jose Marcos Chaves Atella, Georgia Correa Cardoso Silva-Neto, Mario Alberto TI Glycoinositolphospholipids from Trypanosomatids Subvert Nitric Oxide Production in Rhodnius prolixus Salivary Glands SO PLOS ONE LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; BLOODSUCKING BUG; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORS; ANOPHELES-STEPHENSI; EPIMASTIGOTE FORMS; VECTOR SALIVA; RANGELI; CRUZI; INFECTION; SYNTHASE AB Background: Rhodnius prolixus is a blood-sucking bug vector of Trypanosoma cruzi and T. rangeli. T. cruzi is transmitted by vector feces deposited close to the wound produced by insect mouthparts, whereas T. rangeli invades salivary glands and is inoculated into the host skin. Bug saliva contains a set of nitric oxide-binding proteins, called nitrophorins, which deliver NO to host vessels and ensure vasodilation and blood feeding. NO is generated by nitric oxide synthases (NOS) present in the epithelium of bug salivary glands. Thus, T. rangeli is in close contact with NO while in the salivary glands. Methodology/Principal Findings: Here we show by immunohistochemical, biochemical and molecular techniques that inositolphosphate-containing glycolipids from trypanosomatids downregulate NO synthesis in the salivary glands of R. prolixus. Injecting insects with T. rangeli-derived glycoinositolphospholipids (Tr GIPL) or T. cruzi-derived glycoinositolphospholipids (Tc GIPL) specifically decreased NO production. Salivary gland treatment with Tc GIPL blocks NO production without greatly affecting NOS mRNA levels. NOS protein is virtually absent from either Tr GIPL-or Tc GIPL-treated salivary glands. Evaluation of NO synthesis by using a fluorescent NO probe showed that T. rangeli-infected or Tc GIPL-treated glands do not show extensive labeling. The same effect is readily obtained by treatment of salivary glands with the classical protein tyrosine phosphatase (PTP) inhibitor, sodium orthovanadate (SO). This suggests that parasite GIPLs induce the inhibition of a salivary gland PTP. GIPLs specifically suppressed NO production and did not affect other anti-hemostatic properties of saliva, such as the anti-clotting and anti-platelet activities. Conclusions/Significance: Taken together, these data suggest that trypanosomatids have overcome NO generation using their surface GIPLs. Therefore, these molecules ensure parasite survival and may ultimately enhance parasite transmission. C1 [Gazos-Lopes, Felipe; Silva-Cardoso, Livia; Senna, Raquel; Silveira, Alan Barbosa; Jablonka, Willy; Cudischevitch, Cecilia Oliveira; Carneiro, Alan Brito; Lima, Luize G.; Monteiro, Robson Queiroz; Atella, Georgia Correa; Cardoso Silva-Neto, Mario Alberto] Univ Fed Rio de Janeiro, Inst Bioquim Med, Rio De Janeiro, Brazil. [Mesquita, Rafael Dias] Inst Fed Educ Ciencia & Tecnol Rio de Janeiro, Rio De Janeiro, Brazil. [Machado, Ednildo Alcantara; Romeiro, Alexandre; Mendonca-Previato, Lucia; Previato, Jose Osvaldo] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Rio De Janeiro, Brazil. [Nussenzveig, Roberto Henrique] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Folly, Evelize] Univ Fed Fluminense, Inst Biol, Predio Inst Biol, Dept Biol Celular & Mol, Rio De Janeiro, Brazil. [Vanbeselaere, Jorick] Univ Lille 1, Unite Glycobiol Struct & Fonct, F-59655 Villeneuve Dascq, France. [Ribeiro, Jose Marcos Chaves] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Gazos-Lopes, Felipe; Mesquita, Rafael Dias; Silva-Cardoso, Livia; Senna, Raquel; Silveira, Alan Barbosa; Jablonka, Willy; Cudischevitch, Cecilia Oliveira; Carneiro, Alan Brito; Folly, Evelize; Atella, Georgia Correa; Cardoso Silva-Neto, Mario Alberto] INCT EM, Rio De Janeiro, Brazil. RP Silva-Neto, MAC (reprint author), Univ Fed Rio de Janeiro, Inst Bioquim Med, Rio De Janeiro, Brazil. EM maneto@bioqmed.ufrj.br RI Vacinas, Inct/J-9431-2013; Inbeb, Inct/K-2317-2013; Entomologiamolecular, Inct/J-8214-2013; Monteiro, Robson/B-8007-2014; das Chagas, Evelize/M-2409-2014; Ribeiro, Jose/J-7011-2015; Jablonka, Willy/D-2333-2017; OI das Chagas, Evelize/0000-0001-6313-2447; Vanbeselaere, Jorick/0000-0002-1949-4835; Jablonka, Willy/0000-0001-5380-7797; Ribeiro, Jose/0000-0002-9107-0818 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Fundacao de Amparo a Pesquisa de Estado do Rio de Janeiro (FAPERJ); Instituto Nacional de Ciencia e Tecnologia em Entomologia Molecular (INCT-Entomologia Molecular); International Foundation for Science (IFS-Sweden) [F/3619-1, F/2887-3] FX This work was supported by grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Fundacao de Amparo a Pesquisa de Estado do Rio de Janeiro (FAPERJ) and Instituto Nacional de Ciencia e Tecnologia em Entomologia Molecular (INCT-Entomologia Molecular). This work was also supported by two grants provided by the International Foundation for Science (IFS-Sweden) to Dr. G. C. Atella (F/3619-1) and to Dr. M. A. C. Silva-Neto (F/2887-3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 14 Z9 14 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 OCT 15 PY 2012 VL 7 IS 10 AR e47285 DI 10.1371/journal.pone.0047285 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022WO UT WOS:000309995100087 PM 23077586 ER PT J AU Kaneko, Y Tajiri, N Su, TP Wang, Y Borlongan, CV AF Kaneko, Yuji Tajiri, Naoki Su, Tsung-Ping Wang, Yun Borlongan, Cesar V. TI Combination Treatment of Hypothermia and Mesenchymal Stromal Cells Amplifies Neuroprotection in Primary Rat Neurons Exposed to Hypoxic-Ischemic-Like Injury In Vitro: Role of the Opioid System SO PLOS ONE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; STEM-CELLS; BRAIN-INJURY; DELTA; STROKE; HIBERNATION; ENCEPHALOPATHY; NEUROGENESIS; DISORDERS; THERAPY AB This study was designed to reveal the therapeutic regimen and mechanism of action underlying hypothermia treatment in combination with stem cell transplantation for ameliorating neonatal hypoxic-ischemic-like injury. Primary rat neurons were exposed to oxygen-glucose deprivation (OGD), which produced hypoxic-ischemic-like injury in vitro, then incubated at 25 degrees C (severe hypothermia), 34 degrees C (moderate hypothermia), and 37 degrees C (normothermia) with or without subsequent co-culture with mesenchymal stromal cells (MSCs). Combination treatment of moderate hypothermia and MSCs significantly improved cell survival and mitochondrial activity after OGD exposure. The exposure of delta opioid human embryonic kidney cells (HEK293) to moderate hypothermia attenuated OGD-mediated cell alterations, which were much more pronounced in HEK293 cells overexpressing the delta opioid receptor. Further, the addition of delta opioid peptide to 34 degrees C hypothermia and stem cell treatment in primary rat neurons showed synergistic neuroprotective effects against OGD which were significantly more robust than the dual combination of moderate hypothermia and MSCs, and were significantly reduced, but not completely abolished, by the opioid receptor antagonist naltrexone altogether implicating a ligand-receptor mechanism of neuroprotection. Further investigations into non-opioid therapeutic signaling pathways revealed growth factor mediation and anti-apoptotic function accompanying the observed therapeutic benefits. These results support combination therapy of hypothermia and stem cells for hypoxic-ischemic-like injury in vitro, which may have a direct impact on current clinical trials using stand-alone hypothermia or stem cells for treating neonatal encephalopathy. C1 [Kaneko, Yuji; Tajiri, Naoki; Borlongan, Cesar V.] Univ S Florida, Coll Med, Dept Neurosurg & Brain Repair, Tampa, FL 33620 USA. [Su, Tsung-Ping; Wang, Yun] NIDA, NIH, Baltimore, MD USA. RP Borlongan, CV (reprint author), Univ S Florida, Coll Med, Dept Neurosurg & Brain Repair, Tampa, FL 33620 USA. EM cborlong@health.usf.edu RI Tajiri, Naoki/K-1230-2012; OI Tajiri, Naoki/0000-0003-2189-662X; Borlongan, Cesar/0000-0002-2966-9782 FU National Institutes of Health; National Institute of Neurological Disorders and Stroke [1R01NS071956-01]; James and Esther King Foundation for Biomedical Research Program; SanBio Inc.; Celgene Cellular Therapeutics; KMPHC; NeuralStem Inc. FX CVB is supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke 1R01NS071956-01, James and Esther King Foundation for Biomedical Research Program, SanBio Inc., Celgene Cellular Therapeutics, KMPHC and NeuralStem Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 9 Z9 11 U1 0 U2 11 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 OCT 15 PY 2012 VL 7 IS 10 AR e47583 DI 10.1371/journal.pone.0047583 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022WO UT WOS:000309995100141 PM 23077646 ER PT J AU Kim, HK Prokunina-Olsson, L Chanock, SJ AF Kim, Hye Kyung Prokunina-Olsson, Ludmila Chanock, Stephen J. TI Common Genetic Variants in miR-1206 (8q24.2) and miR-612 (11q13.3) Affect Biogenesis of Mature miRNA Forms SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; PROSTATE-CANCER SUSCEPTIBILITY; MICRORNA-RELATED GENES; RENAL-CELL CARCINOMA; COLORECTAL-CANCER; CHROMOSOME 8Q24; BLADDER-CANCER; CERVICAL-CANCER; FRAGILE SITES; MULTIPLE LOCI AB Cancer genome-wide association studies (GWAS) have identified many common genetic markers located in non-coding regions of the genome. Two notable examples are the multi-cancer susceptibility regions, 8q24.2 and 11q13.3. Since these GWAS signals localize to gene-poor regions, we investigated genetic variants within pre-microRNA (pre-miRNA) transcripts as a possible link between the GWAS findings and the associated molecular phenotypes. Across the two regions, which contain 37 miRNAs genes, we explored genetic variants by surveying public databases and conducting targeted resequencing. Specifically, we investigated one common single nucleotide polymorphism (SNP) within miR-1206 on 8q24.2 and two SNPs within miR-612 on 11q13.3. Though these variants are not correlated with known GWAS signals, we conjectured that they might be important for function of corresponding miRNAs. To test the functional significance of these genetic variants, we cloned both allelic forms of miR-1206 and miR-612 pre-miRNA into expression vectors and assessed biogenesis of mature miRNA-forms. The two SNPs within miR-612 significantly affected expression of mature miR-612 in a cell-type specific manner; enhancement in prostate cancer cell lines, reduction in colon cancer cells, and no effect in breast cancer cell lines. The SNP within miR-1206 also affected expression of mature miR-1206, but not in a cell-type specific manner. Future studies should identify targets of miR-1206 and miR-612 and help understand the biological roles of these miRNAs and their possible role in carcinogenesis. C1 [Kim, Hye Kyung; Prokunina-Olsson, Ludmila; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU National Institutes of Health, National Cancer Institute (NCI); NCI FX This study was supported by the intramural research program of the National Institutes of Health, National Cancer Institute (NCI) and the NCI Director's Innovation Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 11 Z9 11 U1 1 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 OCT 15 PY 2012 VL 7 IS 10 AR e47454 DI 10.1371/journal.pone.0047454 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022WO UT WOS:000309995100117 PM 23077621 ER PT J AU Ott, M Litzenburger, UM Sahm, F Rauschenbach, KJ Tudoran, R Hartmann, C Marquez, VE von Deimling, A Wick, W Platten, M AF Ott, Martina Litzenburger, Ulrike M. Sahm, Felix Rauschenbach, Katharina J. Tudoran, Ruxandra Hartmann, Christian Marquez, Victor E. von Deimling, Andreas Wick, Wolfgang Platten, Michael TI Promotion of Glioblastoma Cell Motility by Enhancer of Zeste Homolog 2 (EZH2) Is Mediated by AXL Receptor Kinase SO PLOS ONE LA English DT Article ID POLYCOMB-REPRESSIVE COMPLEX-2; METHYLTRANSFERASE GENE EZH2; ACUTE-LEUKEMIA CELLS; GROUP PROTEIN EZH2; TYROSINE KINASE; BREAST-CANCER; TRANSCRIPTIONAL REPRESSION; COORDINATED REGULATION; THERAPEUTIC TARGET; PROLONGS SURVIVAL AB Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that epigenetically silences gene transcription through histone H3 lysine trimethylation (H3K27me3). EZH2 has been implicated in stem cell maintenance and is overexpressed in hematological and solid malignancie's including malignant glioma. EZH2 is thought to promote tumor progression by silencing tumor suppressor genes. Hence pharmacological disruption of the PRC2 is an attractive therapeutic strategy for cancer treatment. Here we show that EZH2 is expressed in human glioma and correlates with malignancy. Silencing of EZH2 reduced glioma cell proliferation and invasiveness. While we did not observe induction of cell cycle-associated tumor suppressor genes by silencing or pharmacological inhibition of EZH2, microarray analyses demonstrated a strong transcriptional reduction of the AXL receptor kinase. Neither histone nor DNA methylation appeared to be involved in the positive regulation of AXL by EZH2. Silencing AXL mimicked the antiinvasive effects of EZH2 knockdown. Finally, AXL expression is found in human gliomas with high EZH2 expression. Collectively these data suggest that EZH2 drives glioma invasiveness via transcriptional control of AXL independent of histone or DNA methylation. C1 [Ott, Martina; Litzenburger, Ulrike M.; Rauschenbach, Katharina J.; Tudoran, Ruxandra; Wick, Wolfgang; Platten, Michael] Univ Heidelberg Hosp, Dept Neurooncol, Heidelberg, Germany. [Sahm, Felix; Hartmann, Christian; von Deimling, Andreas] Univ Heidelberg Hosp, Inst Neuropathol, Heidelberg, Germany. [Ott, Martina; Litzenburger, Ulrike M.; Rauschenbach, Katharina J.; Tudoran, Ruxandra; Platten, Michael] German Canc Res Ctr, Clin Cooperat Unit, D-6900 Heidelberg, Germany. [Ott, Martina; Litzenburger, Ulrike M.; Rauschenbach, Katharina J.; Tudoran, Ruxandra; Platten, Michael] German Canc Res Ctr, Helmholtz Grp Expt Neuroimmunol, D-6900 Heidelberg, Germany. [Wick, Wolfgang] German Canc Res Ctr, Dept Neurooncol, D-6900 Heidelberg, Germany. [Sahm, Felix; Hartmann, Christian; von Deimling, Andreas] German Canc Res Ctr, Dept Neuropathol, D-6900 Heidelberg, Germany. [Hartmann, Christian] Hannover Med Sch, Inst Pathol, Dept Neuropathol, D-3000 Hannover, Germany. [Marquez, Victor E.] NCI, Biol Chem Lab, Frederick, MD 21701 USA. RP Platten, M (reprint author), Univ Heidelberg Hosp, Dept Neurooncol, Heidelberg, Germany. EM michael.platten@med.uni-heidelberg.de RI Platten, Michael/F-2902-2013; von Deimling, Andreas/F-7774-2013; Hartmann, Christian/D-1882-2010 OI von Deimling, Andreas/0000-0002-5863-540X; FU Helmholtz Association [VH-NG-306]; Hertie Foundation; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from the Helmholtz Association (VH-NG-306) to MP and the Hertie Foundation to WW and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research to VM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 16 Z9 16 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 OCT 15 PY 2012 VL 7 IS 10 AR e47663 DI 10.1371/journal.pone.0047663 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022WO UT WOS:000309995100151 PM 23077658 ER PT J AU Ogino, S King, EE Beck, AH Sherman, ME Milner, DA Giovannucci, E AF Ogino, Shuji King, Emily E. Beck, Andrew H. Sherman, Mark E. Milner, Danny A. Giovannucci, Edward TI Interdisciplinary Education to Integrate Pathology and Epidemiology: Towards Molecular and Population-Level Health Science SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE education; public health professional; health care reform; individualized medicine; interdisciplinary communication; molecular epidemiology; pathology ID ISLAND METHYLATOR PHENOTYPE; BODY-MASS INDEX; ONE-CARBON METABOLISM; TUMOR MICROSATELLITE INSTABILITY; COLORECTAL-CANCER RISK; LIFE-STYLE FACTORS; MLH1-93G-GREATER-THAN-A PROMOTER POLYMORPHISM; ACID SYNTHASE EXPRESSION; GREATER-THAN T; COLON-CANCER AB In recent decades, epidemiology, public health, and medical sciences have been increasingly compartmentalized into narrower disciplines. The authors recognize the value of integration of divergent scientific fields in order to create new methods, concepts, paradigms, and knowledge. Herein they describe the recent emergence of molecular pathological epidemiology (MPE), which represents an integration of population and molecular biologic science to gain insights into the etiologies, pathogenesis, evolution, and outcomes of complex multifactorial diseases. Most human diseases, including common cancers (such as breast, lung, prostate, and colorectal cancers, leukemia, and lymphoma) and other chronic diseases (such as diabetes mellitus, cardiovascular diseases, hypertension, autoimmune diseases, psychiatric diseases, and some infectious diseases), are caused by alterations in the genome, epigenome, transcriptome, proteome, metabolome, microbiome, and interactome of all of the above components. In this era of personalized medicine and personalized prevention, we need integrated science (such as MPE) which can decipher diseases at the molecular, genetic, cellular, and population levels simultaneously. The authors believe that convergence and integration of multiple disciplines should be commonplace in research and education. We need to be open-minded and flexible in designing integrated education curricula and training programs for future students, clinicians, practitioners, and investigators. C1 [Ogino, Shuji; Beck, Andrew H.; Giovannucci, Edward] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA 02215 USA. [Ogino, Shuji; King, Emily E.; Milner, Danny A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; King, Emily E.; Beck, Andrew H.; Milner, Danny A.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Milner, Danny A.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Ogino, S (reprint author), Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, 450 Brookline Ave,Room JF-215C, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU National Institutes of Health [R01 CA151993, K23 AI072033, P01 CA87969, P01 CA55075]; Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported in part by National Institutes of Health grants (grant R01 CA151993 to Shuji Ogino, grant K23 AI072033 to Danny A. Milner, grant P01 CA87969 to Susan E. Hankinson, and grant P01 CA55075 to Walter C. Willett) and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 86 TC 32 Z9 33 U1 0 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2012 VL 176 IS 8 BP 659 EP 667 DI 10.1093/aje/kws226 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 024ZW UT WOS:000310152800001 PM 22935517 ER PT J AU Ogino, S Beck, AH King, EE Sherman, ME Milner, DA Giovannucci, E AF Ogino, Shuji Beck, Andrew H. King, Emily E. Sherman, Mark E. Milner, Danny A. Giovannucci, Edward TI Ogino et al. Respond to "The 21st Century Epidemiologist" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID COLORECTAL-CANCER RISK; BODY-MASS INDEX; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; LIFE-STYLE FACTORS; MICROSATELLITE INSTABILITY; PHYSICAL-ACTIVITY; SURVIVAL; DIAGNOSIS; THERAPY; FIELD C1 [Ogino, Shuji; Beck, Andrew H.; Giovannucci, Edward] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA 02215 USA. [Ogino, Shuji; King, Emily E.; Milner, Danny A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Beck, Andrew H.; King, Emily E.; Milner, Danny A.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Milner, Danny A.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Ogino, S (reprint author), Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, 450 Brookline Ave,Room JF-215C, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU Intramural NIH HHS; NCI NIH HHS [P01 CA055075, P01 CA087969, P01 CA55075, P01 CA87969, R01 CA151993]; NIAID NIH HHS [K23 AI072033] NR 29 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2012 VL 176 IS 8 BP 672 EP 674 DI 10.1093/aje/kws229 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 024ZW UT WOS:000310152800003 PM 22935516 ER PT J AU Fojo, AT Noonan, A AF Fojo, Antonio T. Noonan, Anne TI RECIST: No Longer the Sharpest Tool in the Oncology Clinical Trials Toolbox Reply SO CANCER RESEARCH LA English DT Editorial Material C1 [Fojo, Antonio T.; Noonan, Anne] NCI, NIH, Med Branch, Bethesda, MD 20892 USA. RP Fojo, AT (reprint author), NCI, NIH, Med Branch, 10 Ctr Dr,MSC 1906,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2012 VL 72 IS 20 BP 5150 EP 5150 DI 10.1158/0008-5472.CAN-12-1989 PG 1 WC Oncology SC Oncology GA 022PR UT WOS:000309972700002 PM 22952222 ER PT J AU Fojo, AT Noonan, A AF Fojo, Antonio T. Noonan, Anne TI Why RECIST Works and Why It Should Stay Counterpoint SO CANCER RESEARCH LA English DT Review ID RENAL-CELL CARCINOMA; PHASE-III TRIAL; METASTATIC BREAST-CANCER; MALIGNANT PLEURAL MESOTHELIOMA; IXABEPILONE PLUS CAPECITABINE; ADVANCED COLORECTAL-CANCER; RESISTANT PROSTATE-CANCER; LUNG-CANCER; DOUBLE-BLIND; 1ST-LINE THERAPY AB Assessing that the efficacy of a cancer therapeutic is an integral part of its path to regulatory approval, we review the history that led to our current assessment method, Response Evaluation Criteria in Solid Tumors (RECIST). We describe the efforts of Moertel and Hanley to standardize response assessments in lymphoid malignancies and how this was adapted in the World Health Organization (WHO) criteria. Two decades later, RECIST was advanced to streamline WHO and improve its reproducibility. We describe the ways in which thresholds established by Moertel and Hanley to provide accuracy and reproducibility evolved to become measures of efficacy and why they have been valuable. While we recognize RECIST is far from perfect-in need of modification as a measure of efficacy for some agents and in some diseases-for the majority of solid tumors, it is very valuable. We argue that over time, the efficacy thresholds established by WHO and then RECIST have proved their worth, and we summarize 10 years of U.S. Food and Drug Administration (FDA) approvals in solid tumors to support our position that current RECIST thresholds should be retained. Cancer Res; 72(20); 5151-7. (C)2012 AACR. C1 [Fojo, Antonio T.; Noonan, Anne] NCI, NIH, Med Branch, Bethesda, MD 20892 USA. RP Fojo, AT (reprint author), NCI, NIH, Med Branch, 10 Ctr Dr,MSC 1906,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 82 TC 12 Z9 12 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2012 VL 72 IS 20 BP 5151 EP 5157 DI 10.1158/0008-5472.CAN-12-0733 PG 7 WC Oncology SC Oncology GA 022PR UT WOS:000309972700003 PM 22952221 ER PT J AU Navarro, A Clot, G Royo, C Jares, P Hadzidimitriou, A Agathangelidis, A Bikos, V Darzentas, N Papadaki, T Salaverria, I Pinyol, M Puig, X Palomero, J Vegliante, MC Amador, V Martinez-Trillos, A Stefancikova, L Wiestner, A Wilson, W Pott, C Calasanz, MJ Trim, N Erber, W Sander, B Ott, G Rosenwald, A Colomer, D Gine, E Siebert, R Lopez-Guillermo, A Stamatopoulos, K Bea, S Campo, E AF Navarro, Alba Clot, Guillem Royo, Cristina Jares, Pedro Hadzidimitriou, Anastasia Agathangelidis, Andreas Bikos, Vasilis Darzentas, Nikos Papadaki, Theodora Salaverria, Itziar Pinyol, Magda Puig, Xavier Palomero, Jara Carmela Vegliante, Maria Amador, Virgina Martinez-Trillos, Alejandra Stefancikova, Lenka Wiestner, Adrian Wilson, Wyndham Pott, Christiane Jose Calasanz, Maria Trim, Nicola Erber, Wendy Sander, Birgitta Ott, German Rosenwald, Andreas Colomer, Dolors Gine, Eva Siebert, Reiner Lopez-Guillermo, Armando Stamatopoulos, Kostas Bea, Silvia Campo, Elias TI Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features SO CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; V-H GENES; MARGINAL ZONE LYMPHOMA; SOMATIC HYPERMUTATION; STEREOTYPED PATTERNS; GOOD PROGNOSIS; IMMUNOGLOBULIN; RECEPTORS; AMPLIFICATIONS; PATHOGENESIS AB Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%-97%), 19% significantly mutated (96.9%-95%), and 17% hypermutated (<95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior. Cancer Res; 72(20); 5307-16. (C) 2012 AACR. C1 [Navarro, Alba; Clot, Guillem; Royo, Cristina; Jares, Pedro; Salaverria, Itziar; Pinyol, Magda; Palomero, Jara; Carmela Vegliante, Maria; Amador, Virgina; Martinez-Trillos, Alejandra; Colomer, Dolors; Gine, Eva; Lopez-Guillermo, Armando; Bea, Silvia; Campo, Elias] Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer IDIBAPS, Dept Pathol, E-08036 Barcelona, Spain. [Navarro, Alba; Clot, Guillem; Royo, Cristina; Jares, Pedro; Salaverria, Itziar; Pinyol, Magda; Palomero, Jara; Carmela Vegliante, Maria; Amador, Virgina; Martinez-Trillos, Alejandra; Colomer, Dolors; Gine, Eva; Lopez-Guillermo, Armando; Bea, Silvia; Campo, Elias] Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer IDIBAPS, Dept Hematol, E-08036 Barcelona, Spain. [Puig, Xavier] Tech Univ Catalonia, Dept Stat, Barcelona, Spain. [Jose Calasanz, Maria] Univ Navarra, Dept Genet, E-31080 Pamplona, Spain. [Hadzidimitriou, Anastasia; Agathangelidis, Andreas; Bikos, Vasilis; Darzentas, Nikos; Stamatopoulos, Kostas] Ctr Res & Technol Hellas, Inst Agrobiotechnol, Thessaloniki, Greece. [Agathangelidis, Andreas] Aristotle Univ Thessaloniki, Sch Biol, GR-54006 Thessaloniki, Greece. [Stamatopoulos, Kostas] G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece. [Stamatopoulos, Kostas] G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece. [Papadaki, Theodora] Evangelismos Med Ctr, Athens, Greece. [Salaverria, Itziar; Siebert, Reiner] Univ Kiel, Inst Human Genet, Kiel, Germany. [Pott, Christiane] Univ Med Ctr Schleswig Holstein, Dept Med, Kiel, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Rosenwald, Andreas] Univ Wurzburg, Wurzburg, Germany. [Stefancikova, Lenka] Masaryk Univ, Fac Sci, Dept Expt Biol, CS-61137 Brno, Czech Republic. [Wiestner, Adrian; Wilson, Wyndham] NHLBI, Hemathol Branch, Bethesda, MD 20892 USA. [Trim, Nicola] Addenbrookes Hosp, Cambridge, England. [Erber, Wendy] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia. [Sander, Birgitta] Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden. RP Bea, S (reprint author), Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer IDIBAPS, Dept Pathol, Villarroel 170, E-08036 Barcelona, Spain. EM sbea@clinic.ub.es; ecampo@clinic.ub.es RI Siebert, Reiner/A-8049-2010; Erber, Wendy/A-1955-2012; Bea, Silvia/K-7699-2014; Darzentas, Nikos/D-6889-2012; Navarro, Alba/H-2611-2015; Royo, Cristina/H-3193-2015; SALAVERRIA, ITZIAR/L-2246-2015; Calasanz, MJ/R-5813-2016 OI Bea, Silvia/0000-0001-7192-2385; COLOMER, DOLORS/0000-0001-7486-8484; Campo, elias/0000-0001-9850-9793; Darzentas, Nikos/0000-0002-6365-7515; Navarro, Alba/0000-0002-4041-0974; Royo, Cristina/0000-0002-1214-4656; SALAVERRIA, ITZIAR/0000-0002-2427-9822; Calasanz, MJ/0000-0002-0374-3008 FU European Science Foundation-Frontiers of Functional Genomics; Affymetrix; Illumina; Abbott; Spanish Ministry of Science [SAF 2008-03630]; Instituto de Salud Carlos III, Fondo Investigaciones Sanitarias [PI08/0077, PI11/01177]; Red Tematica de Investigacion Cooperativa de Cancer [RD06/0020/0039, RD06/0020/0014, RD06/0020/0051]; Formacion de Personal Investigador [BES-2007-16330]; Fondo Europeo de Desarrollo Regional. Union Europea; "Una manera de hacer Europa," European Mantle Cell Lymphoma Network, Generalitat de Catalunya [2009-SGR-992, 2009-SGR-967]; Cariplo Foundation; Associazione Italiana per la Ricerca sul Cancro (Italy); ENosAI project [09SYN-13-880]; EU; Hellenic General Secretariat for Research and Technology FX L. Stefancikova has other commercial research support from European Science Foundation-Frontiers of Functional Genomics. R. Siebert has commercial research grant from Affymetrix and Illumina, has other commercial research support from Abbott, has honoraria from speakers bureau of Abbott and Lilly, and is a consultant/advisory board member of various companies providing FISH probes. No potential conflicts of interest were disclosed by the other authors.; This work was supported by grants from Spanish Ministry of Science SAF 2008-03630 (E. Campo), "Instituto de Salud Carlos III, Fondo Investigaciones Sanitarias" (PI08/0077 and PI11/01177; S. Bea), "Red Tematica de Investigacion Cooperativa de Cancer" (RD06/0020/0039, RD06/0020/0014, and RD06/0020/0051), "Formacion de Personal Investigador" (BES-2007-16330; A. Navarro), Fondo Europeo de Desarrollo Regional. Union Europea. "Una manera de hacer Europa," European Mantle Cell Lymphoma Network, Generalitat de Catalunya (2009-SGR-992; 2009-SGR-967), European Science Foundation, "Frontiers of Functional Genomics" (L. Stefancikova), Cariplo Foundation and Associazione Italiana per la Ricerca sul Cancro (Italy), ENosAI project (09SYN-13-880), cofunded by the EU and the Hellenic General Secretariat for Research and Technology. NR 46 TC 75 Z9 77 U1 1 U2 21 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2012 VL 72 IS 20 BP 5307 EP 5316 DI 10.1158/0008-5472.CAN-12-1615 PG 10 WC Oncology SC Oncology GA 022PR UT WOS:000309972700020 PM 22915760 ER PT J AU Zhang, DP Aravind, L AF Zhang, Dapeng Aravind, L. TI Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment SO CELL CYCLE LA English DT Article DE ciliogenesis; transglutaminase-like; membrane; tubulin-tyrosine ligase; C2; transition zone; Y-shaped linkers; evolution; origin of eukaryotes; ciliopathy ID CAUSE JOUBERT-SYNDROME; TUBULIN HOMOLOG TUBZ; INTRAFLAGELLAR TRANSPORT; COMPARATIVE GENOMICS; PRIMARY CILIUM; TRANSITION ZONE; PLASMODIUM-FALCIPARUM; MECKEL-SYNDROME; CELL-DIVISION; PORE COMPLEX AB In addition to their role in motility, eukaryotic cilia serve as a distinct compartment for signal transduction and regulatory sequestration of biomolecules. Recent genetic and biochemical studies have revealed an extraordinary diversity of protein complexes involved in the biogenesis of cilia during each cell cycle. Mutations in components of these complexes are at the heart of human ciliopathies such as Nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), Bardet-Biedl syndrome (BBS) and Joubert syndrome (JBTS). Despite intense studies, proteins in some of these complexes, such as the NPHP1-4-8 and the MKS, remain poorly understood. Using a combination of computational analyses we studied these complexes to identify novel domains in them which might throw new light on their functions and evolutionary origins. First, we identified both catalytically active and inactive versions of transglutaminase-like (TGL) peptidase domains in key ciliary/centrosomal proteins CC2D2A/MKS6, CC2D2B, CEP76 and CCDC135. These ciliary TGL domains appear to have originated from prokaryotic TGL domains that act as peptidases, either in a prokaryotic protein degradation system with the MoxR AAA+ ATPase, the precursor of eukaryotic dyneins and midasins, or in a peptide-ligase system with an ATP-grasp enzyme comparable to tubulin-modifying TT L proteins. We suggest that active ciliary TGL proteins are part of a cilia-specific peptidase system that might remove tubulin modifications or cleave cilia-localized proteins, while the inactive versions are likely to bind peptides and mediate key interactions during ciliogenesis. Second, we observe a vast radiation of C2 domains, which are key membrane-localization modules, in multiple ciliary proteins, including those from the NPHP1-4-8 and the MKS complexes, such as CC2D2A/MKS6, RPGRIP1, RPGRIP1L, NPHP1, NPHP4, C2CD3, AHI1/Jouberin and CEP76, most of which can be traced back to the last eukaryotic ancestor. Identification of these TGL and C2 domains aid in the proper reconstruction of the Y-shaped linkers, which are key structures in the transitional zone of cilia, by allowing precise prediction of the multiple membrane-contacting and protein-protein interaction sites in these structures. These findings help decipher key events in the evolutionary separation of the ciliary and nuclear compartments in course of the emergence of the eukaryotic cell. C1 [Zhang, Dapeng; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM aravind@ncbi.nlm.nih.gov NR 85 TC 14 Z9 15 U1 1 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2012 VL 11 IS 20 BP 3861 EP 3875 DI 10.4161/cc.22068 PG 15 WC Cell Biology SC Cell Biology GA 020ML UT WOS:000309814300027 PM 22983010 ER PT J AU Riou, C Treurnicht, F Abrahams, MR Mlisana, K Liu, MKP Goonetilleke, N Koup, R Roederer, M Karim, SA de Bruyn, G Williamson, C Gray, CM Burgers, WA AF Riou, Catherine Treurnicht, Florette Abrahams, Melissa-Rose Mlisana, Koleka Liu, Michael K. P. Goonetilleke, Nilu Koup, Richard Roederer, Mario Karim, Salim Abdool de Bruyn, Guy Williamson, Carolyn Gray, Clive M. Burgers, Wendy A. CA CAPRISA 002 Acute Infection Study Team TI Increased Memory Differentiation Is Associated with Decreased Polyfunctionality for HIV but Not for Cytomegalovirus-Specific CD8(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL LOAD; FUNCTIONAL PROFILE; SET-POINT; INFECTION; RESPONSES; PHENOTYPE; CD4(+); LYMPHOCYTES; EXHAUSTION AB The generation of polyfunctional CD8(+) T cells, in response to vaccination or natural infection, has been associated with improved protective immunity. However, it is unclear whether the maintenance of polyfunctionality is related to particular cellular phenotypic characteristics. To determine whether the cytokine expression profile is linked to the memory differentiation stage, we analyzed the degree of polyfunctionality of HIV-specific CD8(+) T cells within different memory subpopulations in 20 antiretroviral therapy-naive HIV-1-infected individuals at similar to 34 wk postinfection. These profiles were compared with CMV-specific CD8(+) T cell responses in HIV-uninfected control subjects and in individuals chronically infected with HIV. Our results showed that the polyfunctional abilities of HIV-specific CD8(+) T cells differed according to their memory phenotype. Early-differentiated cells (CD45RO(+)CD27(+)) exhibited a higher proportion of cells positive for three or four functions (p < 0.001), and a lower proportion of monofunctional cells (p < 0.001) compared with terminally differentiated (TD; CD45RO(-)CD27(-)) HIV-specific CD8(+) T cells. The majority of TD HIV-specific CD8(+) T cells were monofunctional (median 69% [interquartile range: 57-83]), producing predominantly CD107a or MIP1 beta. Moreover, proportions of HIV-specific monofunctional CD8(+) T cells positively associated with proportions of TD HIV-specific CD8(+) T cells (p = 0.019, r = 0.54). In contrast, CMV-specific CD8(+) T cell polyfunctional capacities were similar across all memory subpopulations, with terminally and early-differentiated cells endowed with comparable polyfunctionality. Overall, these data show that the polyfunctional abilities of HIV-specific CD8(+) T cells are influenced by the stage of memory differentiation, which is not the case for CMV-specific responses. The Journal of Immunology, 2012, 189:3838-3847. C1 [Treurnicht, Florette; Abrahams, Melissa-Rose; Williamson, Carolyn; Burgers, Wendy A.] Univ Cape Town, Inst Infect Dis & Mol Med, Fac Hlth Sci, Div Med Virol, ZA-7925 Cape Town, Western Cape, South Africa. [Riou, Catherine; Gray, Clive M.] Univ Cape Town, Inst Infect Dis & Mol Med, Fac Hlth Sci, Div Immunol, ZA-7925 Cape Town, Western Cape, South Africa. [Mlisana, Koleka; Karim, Salim Abdool] Univ KwaZulu Natal, Ctr AIDS Program Res S Africa, ZA-4013 Durban, South Africa. [Mlisana, Koleka] Univ KwaZulu Natal, Sch Lab Med & Med Sci, Dept Med Microbiol, ZA-4013 Durban, South Africa. [Liu, Michael K. P.; Goonetilleke, Nilu] Univ Oxford, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [Koup, Richard] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [de Bruyn, Guy] Univ Witwatersrand, Perinatal HIV Res Unit, ZA-1864 Johannesburg, South Africa. RP Burgers, WA (reprint author), Univ Cape Town, Inst Infect Dis & Mol Med, Fac Hlth Sci, Div Med Virol, ZA-7925 Cape Town, Western Cape, South Africa. EM wendy.burgers@uct.ac.za RI Abdool Karim, Salim Safurdeen/N-5947-2013; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; , Carolyn/0000-0003-0125-1226; Mlisana, Koleka/0000-0002-8436-3268; Burgers, Wendy/0000-0003-3396-9398 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services [U19 A151794, R01 AI084387]; Canada-Africa Prevention Trials Network; Bill and Melinda Gates Comprehensive T Cell Vaccine Immune Monitoring Consortium award; Columbia University Fogarty AIDS International Training Research Fellowship; Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine FX This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services (Grant U19 A151794 to S.A.K., Grant R01 AI084387 to W.A.B.); the Canada-Africa Prevention Trials Network; a Bill and Melinda Gates Comprehensive T Cell Vaccine Immune Monitoring Consortium award; a Columbia University Fogarty AIDS International Training Research Fellowship (to W.A.B.); and a Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine (to W.A.B.). NR 58 TC 6 Z9 6 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2012 VL 189 IS 8 BP 3838 EP 3847 DI 10.4049/jimmunol.1201488 PG 10 WC Immunology SC Immunology GA 017LH UT WOS:000309590900011 PM 22966086 ER PT J AU Munster, VJ Prescott, JB Bushmaker, T Long, D Rosenke, R Thomas, T Scott, D Fischer, ER Feldmann, H de Wit, E AF Munster, Vincent J. Prescott, Joseph B. Bushmaker, Trenton Long, Dan Rosenke, Rebecca Thomas, Tina Scott, Dana Fischer, Elizabeth R. Feldmann, Heinz de Wit, Emmie TI Rapid Nipah virus entry into the central nervous system of hamsters via the olfactory route SO SCIENTIFIC REPORTS LA English DT Article ID CLINICAL-FEATURES; ENCEPHALITIS; INFECTION; HOST; TRANSMISSION; BANGLADESH; OUTBREAK; PATHWAY AB Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Here, we performed a spatio-temporal analysis of NiV entry into the CNS of hamsters. NiV initially predominantly targeted the olfactory epithelium in the nasal turbinates. From there, NiV infected neurons were visible extending through the cribriform plate into the olfactory bulb, providing direct evidence of rapid CNS entry. Subsequently, NiV disseminated to the olfactory tubercle and throughout the ventral cortex. Transmission electron microscopy on brain tissue showed extravasation of plasma cells, neuronal degeneration and nucleocapsid inclusions in affected tissue and axons, providing further evidence for axonal transport of NiV. NiV entry into the CNS coincided with the occurrence of respiratory disease, suggesting that the initial entry of NiV into the CNS occurs simultaneously with, rather than as a result of, systemic virus replication. C1 [Munster, Vincent J.; Prescott, Joseph B.; Bushmaker, Trenton; Thomas, Tina; Feldmann, Heinz; de Wit, Emmie] NIAID, Virol Lab, NIH, Hamilton, MT USA. [Long, Dan; Rosenke, Rebecca; Scott, Dana] NIAID, Rocky Mt Vet Branch, NIH, Hamilton, MT USA. [Fischer, Elizabeth R.] NIAID, Res Technol Branch, Microscopy Unit, Div Intramural Res,NIH, Hamilton, MT USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Munster, VJ (reprint author), NIAID, Virol Lab, NIH, Hamilton, MT USA. EM vincent.munster@nih.gov; emmie.dewit@nih.gov OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors would like to thank Anita Mora and Heather Murphy for help with graphics and Lin-Fa Wang for providing Nipah virus antiserum. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 25 TC 26 Z9 27 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 OCT 15 PY 2012 VL 2 AR 736 DI 10.1038/srep00736 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022KH UT WOS:000309957800003 PM 23071900 ER PT J AU Cheng, HW Mollica, MY Lee, SH Wang, L Velazquez-Martinez, CA Wu, SY AF Cheng, Huiwen Mollica, Molly Y. Lee, Shin Hee Wang, Lei Velazquez-Martinez, Carlos A. Wu, Shiyong TI Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE NONO-NASAIDs; Melanoma; Cell adhesion; Integrin ID BIOLOGICAL EVALUATION; FLOW CONDITIONS; METASTASIS; ASPIRIN; INDOMETHACIN; INHIBITION; PRODRUGS; DESIGN; MOIETY; INJURY AB A new class of nitric oxide (NO center dot)-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) were developed in recent years and have shown promising potential as NSAID substitutes due to their gentle nature on cardiovascular and gastrointestinal systems. Since nitric oxide plays a role in regulation of cell adhesion, we assessed the potential use of NONO-NSAIDs as anti-metastasis drugs. In this regard, we compared the effects of NONO-aspirin and a novel NONO-naproxen to those exerted by their respective parent NSAIDs on avidities of human melanoma M624 cells. Both NONO-NSAIDs, but not the corresponding parent NSAIDs, reduced M624 adhesion on vascular cellular adhesion molecule-1 (VCAM-1) by 20-30% and fibronectin by 25-44% under fluid flow conditions and static conditions, respectively. Only NONO-naproxen reduced (similar to 56%) the activity of beta 1 integrin, which binds to alpha 4 integrin to form very late antigen-4 (VLA-4), the ligand of VCAM-1. These results indicate that the diazeniumdiolate (NO center dot)-donor moiety is critical for reducing the adhesion between VLA-4 and its ligands, while the NSAID moiety can impact the regulation mechanism of melanoma cell adhesion. (c) 2012 Elsevier Inc. All rights reserved. C1 [Velazquez-Martinez, Carlos A.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. [Cheng, Huiwen; Mollica, Molly Y.; Lee, Shin Hee; Wang, Lei; Wu, Shiyong] Ohio Univ, Edison Biotechnol Inst, Athens, OH 45701 USA. [Cheng, Huiwen; Wang, Lei; Wu, Shiyong] Ohio Univ, Dept Chem & Biochem, Athens, OH 45701 USA. [Velazquez-Martinez, Carlos A.] NCI, Chem Sect, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. [Velazquez-Martinez, Carlos A.] NCI, Basic Res Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. RP Velazquez-Martinez, CA (reprint author), Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. EM velazque@ualberta.ca; wus1@ohio.edu RI Wu, Shiyong/I-3359-2013 OI Wu, Shiyong/0000-0002-4104-4160 FU NIH [RO1CA086928, RO1CA086928-08S1/09S2]; National Cancer Institute, Intramural Research Program of the NIH, Center for Cancer Research FX The authors thank Dr. Monica M. Burdick for her insightful discussion and technical assistance during this study. This work was partially supported by NIH RO1CA086928 (to S. Wu), NIH RO1CA086928-08S1/09S2 (to M.Y. Mollica) and graduate assistantship (to H. Cheng) from the Department of Chemistry and Biochemistry, Ohio University. Part of this work was done using federal funds to the Laboratory of Comparative Carcinogenesis (Chief, L.K. Keefer) from the National Cancer Institute, Intramural Research Program of the NIH, Center for Cancer Research. NR 26 TC 10 Z9 10 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 15 PY 2012 VL 264 IS 2 BP 161 EP 166 DI 10.1016/j.taap.2012.07.029 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 020XM UT WOS:000309849900003 PM 22889880 ER PT J AU Bricceno, KV Sampognaro, PJ Van Meerbeke, JP Sumner, CJ Fischbeck, KH Burnett, BG AF Bricceno, Katherine V. Sampognaro, Paul J. Van Meerbeke, James P. Sumner, Charlotte J. Fischbeck, Kenneth H. Burnett, Barrington G. TI Histone deacetylase inhibition suppresses myogenin-dependent atrogene activation in spinal muscular atrophy mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID FOXO TRANSCRIPTION FACTORS; SKELETAL-MUSCLE ATROPHY; E3 LIGASE MURF1; MOUSE MODEL; UBIQUITIN LIGASES; NEUROMUSCULAR-JUNCTIONS; DIFFERENT MECHANISMS; PROTEIN BREAKDOWN; SINGLE NUCLEOTIDE; SMN PROTEIN AB Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by mutations in the survival of motor neuron 1 (SMN1) gene and deficient expression of the ubiquitously expressed SMN protein. Pathologically, SMA is characterized by motor neuron loss and severe muscle atrophy. During muscle atrophy, the E3 ligase atrogenes, atrogin-1 and muscle ring finger 1 (MuRF1), mediate muscle protein breakdown through the ubiquitin proteasome system. Atrogene expression can be induced by various upstream regulators. During acute denervation, they are activated by myogenin, which is in turn regulated by histone deacetylases 4 and 5. Here we show that atrogenes are induced in SMA model mice and in SMA patient muscle in association with increased myogenin and histone deacetylase-4 (HDAC4) expression. This activation during both acute denervation and SMA disease progression is suppressed by treatment with a histone deacetylase inhibitor; however, this treatment has no effect when atrogene induction occurs independently of myogenin. These results indicate that myogenin-dependent atrogene induction is amenable to pharmacological intervention with histone deacetylase inhibitors and help to explain the beneficial effects of these agents on SMA and other denervating diseases. C1 [Bricceno, Katherine V.; Fischbeck, Kenneth H.; Burnett, Barrington G.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Bricceno, Katherine V.] George Washington Univ, Inst Biomed Sci, Washington, DC USA. [Sampognaro, Paul J.; Van Meerbeke, James P.; Sumner, Charlotte J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Sumner, Charlotte J.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD USA. RP Burnett, BG (reprint author), 35 Convent Dr,Bldg 35,Room 2A1008, Bethesda, MD 20892 USA. EM burnettb@mail.nih.gov FU NINDS; NINDS [R01NS062869]; Spinal Muscular Atrophy Foundation FX We thank Dr Stewart Lecker (Beth Israel Deaconess Medical Center) and Dr Eric Olson (University of Texas Southwestern Medical Center) for providing the atrogin-1 and MuRF1 reporter plasmids and Dr Peter Macpherson (University of Michigan) for the Dach2 primer sequences. Human tissue was obtained from the NICHD brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. This work was supported by intramural NINDS research funds. C.J.S. was supported by NINDS grant R01NS062869 and funds from the Spinal Muscular Atrophy Foundation. NR 45 TC 18 Z9 18 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2012 VL 21 IS 20 BP 4448 EP 4459 DI 10.1093/hmg/dds286 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 015QF UT WOS:000309460300007 PM 22798624 ER PT J AU Chen, GJ Bentley, A Adeyemo, A Shriner, D Zhou, J Doumatey, A Huang, HX Ramos, E Erdos, M Gerry, N Herbert, A Christman, M Rotimi, C AF Chen, Guanjie Bentley, Amy Adeyemo, Adebowale Shriner, Daniel Zhou, Jie Doumatey, Ayo Huang, Hanxia Ramos, Edward Erdos, Michael Gerry, Norman Herbert, Alan Christman, Michael Rotimi, Charles TI Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans SO HUMAN MOLECULAR GENETICS LA English DT Article ID OBESITY; POPULATION; INFLAMMATION; HOMEOSTASIS; VARIANTS; GLUCOSE; GENES; CELLS; MODEL AB Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n 12) with P 5 10(6) in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P 1.7 10(8) and 2.9 10(8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P 7.5 10(9) and 4.9 10(10) for FI and IR, respectively). In silico replication in the MAGIC study (n 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes. C1 [Chen, Guanjie; Bentley, Amy; Adeyemo, Adebowale; Shriner, Daniel; Zhou, Jie; Doumatey, Ayo; Huang, Hanxia; Ramos, Edward; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Erdos, Michael] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Gerry, Norman; Christman, Michael] Coriell Inst Med Res, Camden, NJ 08103 USA. [Herbert, Alan] Boston Univ, Sch Med, Dept Genet & Genom, Boston, MA 02118 USA. RP Chen, GJ (reprint author), 12 South Dr,Bldg 12A,Room 4047, Bethesda, MD 20878 USA. EM chengu@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU NIGMS/MBRS/SCORE Program [S06GM008016-320107, S06GM008016-380111]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [2M01RR010284]; Intramural Research Program of the Center for Research in Genomics and Global Health, NHGRI/NIH; Coriell Institute for Medical Research FX The study was supported by grants S06GM008016-320107 to C.R. and S06GM008016-380111 to A.A., both from the NIGMS/MBRS/SCORE Program. Participant enrollment was carried out at the Howard University General Clinical Research Center (GCRC), which is supported by grant number 2M01RR010284 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Additional support was provided by the Coriell Institute for Medical Research. This research was supported in part by the Intramural Research Program of the Center for Research in Genomics and Global Health, NHGRI/NIH. In silico replication in European populations was performed in the MAGIC study (www.magicinvestigators.org). NR 34 TC 21 Z9 23 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2012 VL 21 IS 20 BP 4530 EP 4536 DI 10.1093/hmg/dds282 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 015QF UT WOS:000309460300014 PM 22791750 ER PT J AU Rimbault, M Ostrander, EA AF Rimbault, Maud Ostrander, Elaine A. TI So many doggone traits: mapping genetics of multiple phenotypes in the domestic dog SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME; HAPLOTYPE; HEIGHT; ASSOCIATION; VARIANTS; SEQUENCE; ORIGINS; WOLVES; GROWTH; ADULT AB The worldwide dog population is fragmented into 350 domestic breeds. Breeds share a common ancestor, the gray wolf. The intense artificial selection imposed by humans to develop breeds with particular behaviors and phenotypic traits has occurred primarily in the last 200300 years. As a result, the number of genes controlling the major differences in body size, leg length, head shape, etc. that define each dog is small, and genetically tractable. This is in comparison to many human complex traits where small amounts of variance are controlled by literally hundreds of genes. We have been interested in disentangling the genetic mechanisms controlling breed-defining morphological traits in the domestic dog. The structure of the dog population, comprised large numbers of pure breeding populations, makes this task surprisingly doable. In this review, we summarize recent work on the genetics of body size, leg length and skull shape, while setting the stage for tackling other traits. It is our expectation that these results will contribute to a better understanding of mammalian developmental processes overall. C1 [Rimbault, Maud; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Ostrander, EA (reprint author), 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU National Human Genome Research Institute (NHGRI) at NIH FX E.A.O. and M. R. are funded by the Intramural Program of the National Human Genome Research Institute (NHGRI) at NIH. NR 45 TC 11 Z9 11 U1 18 U2 93 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2012 VL 21 SI 1 BP R52 EP R57 DI 10.1093/hmg/dds323 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 015QP UT WOS:000309461300008 PM 22878052 ER PT J AU Malachowa, N Kobayashi, SD Braughton, KR Whitney, AR Parnell, MJ Gardner, DJ DeLeo, FR AF Malachowa, Natalia Kobayashi, Scott D. Braughton, Kevin R. Whitney, Adeline R. Parnell, Michael J. Gardner, Donald J. DeLeo, Frank R. TI Staphylococcus aureus Leukotoxin GH Promotes Inflammation SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; HUMAN NEUTROPHILS; POLYMORPHONUCLEAR LEUKOCYTES; VIRULENCE DETERMINANT; INFECTION; USA300; MODEL; PATHOGENESIS; HEMOLYSIN; DISEASE AB Background. Staphylococcus aureus produces numerous molecules that facilitate survival in the host. We recently identified a novel S. aureus leukotoxin (leukotoxin GH [LukGH]) using proteomics, but its role in virulence remains unclear. Here we investigated the role of LukGH in vivo. Methods. We tested cytotoxicity of LukGH toward polymorphonuclear leukocytes (PMNs) from mice, rabbits, monkeys, and humans. LukGH was administered to mice, rabbits, and a cynomolgus monkey by subcutaneous or intradermal injection to assess cytotoxicity or host response in vivo. The effects of LukGH in vivo were compared with those of Panton-Valentine leukocidin (PVL), a well-characterized S. aureus leukotoxin. The contribution of LukGH to S. aureus infection was tested using mouse and rabbit infection models. Results. Susceptibility of PMNs to LukGH was similar between humans and cynomolgus monkeys, and was greater than that of rabbits, which in turn was greater than that of mice. LukGH or PVL caused skin inflammation in rabbits and a monkey, but deletion of neither lukGH nor lukGH and lukS/F-PV reduced severity of USA300 infections in rabbits or mice. Rather, some disease parameters (eg, rabbit abscess size) were increased following infection with a lukGH and lukS/F-PV deletion strain. Conclusions. Our findings indicate that S. aureus leukotoxins enhance the host inflammatory response and influence the outcome of infection. C1 [Malachowa, Natalia; Kobayashi, Scott D.; Braughton, Kevin R.; Whitney, Adeline R.; Parnell, Michael J.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Gardner, Donald J.] NIAID, Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 28 TC 34 Z9 34 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2012 VL 206 IS 8 BP 1185 EP 1193 DI 10.1093/infdis/jis495 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 015RH UT WOS:000309463200006 PM 22872735 ER PT J AU Vazquez, N Rekka, S Gliozzi, M Feng, CG Amarnath, S Orenstein, JM Wahl, SM AF Vazquez, Nancy Rekka, Sofia Gliozzi, Maria Feng, Carl G. Amarnath, Shoba Orenstein, Jan M. Wahl, Sharon M. TI Modulation of Innate Host Factors by Mycobacterium avium Complex in Human Macrophages Includes Interleukin 17 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID T-CELLS; GENE-EXPRESSION; CYTOKINE PRODUCTION; HIV-INFECTION; PROGRAMMED DEATH-1; HUMAN MONOCYTES; I INTERFERON; IL-17; IL-21; ACTIVATION AB Background. Although opportunistic infections due to Mycobacterium avium complex (MAC) have been less common since the introduction of highly active antiretroviral therapy, globally, human immunodeficiency virus-1 (HIV-1)-positive patients remain predisposed to these infections. Absence of a properly functioning acquired immune response allows MAC persistence within macrophages localized in lymph nodes coinfected with HIV and MAC. Although a deficiency in interferon. appears to play a part in the ability of MAC to deflect the macrophage-associated antimicrobial attack, questions about this process remain. Our study examines the ability of MAC to regulate interleukin 17 (IL-17), a proinflammatory cytokine involved in host cell recruitment. Methods. Coinfected lymph nodes were examined for IL-17 by immunohistochemical analysis. In vitro, macrophages exposed to mycobacteria were evaluated for transcription activities, proteins, and signaling pathways responsible for IL-17 expression. Infected macrophages were also analyzed for expression of interleukin 21 (IL-21) and negative regulators of immune responses. Results. Infection of macrophages triggered synthesis of IL-17, correlating with IL-17 expression by macrophages in coinfected lymph nodes. Infected macrophages exposed to exogenous IL-17 expressed CXCL10, which favors recruitment of new macrophages as targets for infection. Blockade of nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase pathways suppressed mycobacteria-induced IL-17 expression. MAC triggered expression of IL-21, IRF4, and STAT3 genes related to IL-17 regulation, as well as expression of the negative immunoregulators CD274(PD-L1) and suppressors of cytokine signaling. Conclusions. MAC-infected macrophages can provide an alternative source for IL-17 that favors accumulation of new targets for perpetuating bacterial and viral infection while suppressing host antimicrobial immune responses. C1 [Vazquez, Nancy; Rekka, Sofia; Gliozzi, Maria; Wahl, Sharon M.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Feng, Carl G.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Orenstein, Jan M.] George Washington Univ, Dept Pathol, Washington, DC USA. RP Vazquez, N (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. EM nvazquez@mail.nih.gov FU National Institute of Dental and Craniofacial Research, NIH FX This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH. NR 50 TC 2 Z9 2 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2012 VL 206 IS 8 BP 1206 EP 1217 DI 10.1093/infdis/jis492 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 015RH UT WOS:000309463200008 PM 22930805 ER PT J AU Budde, MD Frank, JA AF Budde, Matthew D. Frank, Joseph A. TI Examining brain microstructure using structure tensor analysis of histological sections SO NEUROIMAGE LA English DT Article DE Anisotropy; Diffusion tensor imaging; Structure tensor; Crossing fibers; Histology; Fiber orientation ID MOUSE-BRAIN; FIBER-TRACKING; NERVOUS-SYSTEM; DIFFUSION MRI; RAT-BRAIN; TRACTOGRAPHY; VALIDATION; RESOLUTION; TISSUE; MICROSCOPY AB The mammalian central nervous system has a tremendous structural complexity, and diffusion tensor imaging (DTI) is unique in its ability to extract microstructural tissue properties at a macroscopic scale. However, despite its widespread use and applications in clinical and research settings, accurate validation of DTI has notoriously lagged the advances in image acquisition and analysis. In this report, we demonstrate an approach to visualize and quantify the microscopic features of histological sections on multiple length scales using techniques derived from image texture analysis. Structure tensor (ST) analysis was applied to fluorescence microscopy images of rat brain sections to visualize and quantify tissue microstructure. Images were digitally color-coded based on the local orientation in the pixelwise ST implementation, which allowed direct visualization of white matter complexity at the microscopic level. A piecewise ST algorithm was also employed to quantify anisotropy and orientation at a resolution comparable to that typically acquired with DTI. Anisotropy measured with ST analysis of stained histological sections was highly correlated with anisotropy measured by ex vivo DTI of the same brains (R-2 = 0.92). Furthermore, angular histograms, or Fiber Orientation Distributions (FODs), were computed to mimic similar measures derived from high angular resolution diffusion imaging methods. The FODs for each pixel were fit to a mixture of von Mises distributions to identify putative regions of multiple fiber populations (i.e. crossing fibers). Despite its current application to two-dimensional microscopy, the ST analysis is a novel approach to visualize and quantify microstructure in the central nervous system in both health and disease, and advances the available set of tools for validating DTI and other diffusion MRI techniques. (C) 2012 Published by Elsevier Inc. C1 [Budde, Matthew D.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Budde, Matthew D.; Frank, Joseph A.] Ctr Clin, Frank Lab Radiol & Imaging Sci, Bethesda, MD USA. [Frank, Joseph A.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Budde, MD (reprint author), 8701 Watertown Plank Rd,C1890 Neurosci Res Ctr, Milwaukee, WI 53226 USA. EM mdbudde@mcw.edu FU Research and Education Initiative Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin [5520207]; Center for Neuroscience and Regenerative Medicine [300604-8.01-60855]; Intramural Research Program of the Clinical Center, National Institutes of Health FX This project was partially funded through the Research and Education Initiative Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin (5520207 to M.D.B.), the Center for Neuroscience and Regenerative Medicine (300604-8.01-60855 to J.A.F), and the Intramural Research Program of the Clinical Center, National Institutes of Health. NR 43 TC 40 Z9 40 U1 0 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2012 VL 63 IS 1 BP 1 EP 10 DI 10.1016/j.neuroimage.2012.06.042 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005SN UT WOS:000308770300001 PM 22759994 ER PT J AU Yang, Z Zuo, XN Wang, PP Li, ZH LaConte, SM Bandettini, PA Hu, XPP AF Yang, Zhi Zuo, Xi-Nian Wang, Peipei Li, Zhihao LaConte, Stephen M. Bandettini, Peter A. Hu, Xiaoping P. TI Generalized RAICAR: Discover homogeneous subject (sub)groups by reproducibility of their intrinsic connectivity networks SO NEUROIMAGE LA English DT Article DE Independent component analysis; Reproducibility; Group discovery; Sample homogeneity; Exploratory analysis; Resting state ID INDEPENDENT COMPONENT ANALYSIS; BRAINS DEFAULT NETWORK; RESTING-STATE NETWORKS; RESONANCE-IMAGING DATA; FUNCTIONAL CONNECTIVITY; FMRI DATA; MODE; VISUALIZATION; INFERENCES; ICA AB Existing spatial independent component analysis (ICA) methods for multi-subject fMRI datasets have mainly focused on detecting common components across subjects, under the assumption that all the subjects in a group share the same (identical) components. However, as a data-driven approach, ICA could potentially serve as an exploratory tool at multi-subject level, and help us uncover inter-subject differences in patterns of connectivity (e.g., find subtypes in patient populations). In this work, we propose a methodology named gRAICAR that exploits the data-driven nature of ICA to allow discovery of sub-groupings of subjects based on reproducibility of their ICA components. This technique allows us not only to find highly reproducible common components across subjects but also to explore (without a priori subject groupings) components that could classify all subjects into sub-groups. gRAICAR generalizes the reproducibility framework previously developed for single subjects (Ranking and averaging independent component analysis by reproducibility-RAICAR-Yang et al., Hum Brain Mapp, 2008) to multiple-subject analysis. For each group-level component, gRAICAR generates its reproducibility matrix and further computes two metrics, inter-subject consistency and intra-subject reliability, to characterize inter-subject variability and reflect contributions from individual subjects. Nonparametric tests are employed to examine the significance of both the inter-subject consistency and the separation of subject groups reflected in the component. Our validations based on simulated and experimental resting-state fMRI datasets demonstrated the advantage of gRAICAR in extracting features reflecting potential subject groupings. It may facilitate discovery of the underlying brain functional networks with substantial potential to inform our understandings of development, neurodegenerative conditions, and psychiatric disorders. (C) 2012 Elsevier Inc. All rights reserved. C1 [Yang, Zhi; Zuo, Xi-Nian] Chinese Acad Sci, Inst Psychol, Lab Funct Connectome & Dev, Key Lab Behav Sci, Beijing 100101, Peoples R China. [Yang, Zhi; Zuo, Xi-Nian] Chinese Acad Sci, Inst Psychol, Magnet Resonance Imaging Res Ctr, Beijing 100101, Peoples R China. [Yang, Zhi; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Wang, Peipei] Capital Med Univ, Ctr Higher Brain Funct Res, Sch Basic Med Sci, Beijing, Peoples R China. [Li, Zhihao; Hu, Xiaoping P.] Emory Univ, Dept Biomed Engn, Biomed Imaging Technol Ctr, Atlanta, GA 30322 USA. RP Yang, Z (reprint author), 4A Datun Rd, Beijing 100101, Peoples R China. EM yangz@psych.ac.cn OI Li, Zhihao/0000-0002-6009-7903; Zuo, Xi-Nian/0000-0001-9110-585X; Yang, Zhi/0000-0002-2222-2312 FU National Natural Science Foundation of China [30900366, 81171409, 30973164, 30670674]; National Basic Research Program of China (973 Program) [2007CB512300]; National Institutes of Health of the United States [RO1B002009]; Youth Foundation [O9CX012001]; Institute of Psychology, Chinese Academy of Sciences [Y0CX492S03] FX We acknowledge Dr. Anna B. Moore for sharing the resting-state fMRI dataset and Dr. R. Cameron Craddock for his efforts in improving the paper. This work was supported by the National Natural Science Foundation of China (Nos. 30900366, 81171409, 30973164, and 30670674), the National Basic Research Program of China (973 Program, 2007CB512300), the National Institutes of Health of the United States (RO1B002009), the Youth Foundation (O9CX012001, ZY) and the Startup Foundation for Distinguished Research Professor (Y0CX492S03, XNZ) of the Institute of Psychology, Chinese Academy of Sciences. NR 43 TC 20 Z9 21 U1 2 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2012 VL 63 IS 1 BP 403 EP 414 DI 10.1016/j.neuroimage.2012.06.060 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005SN UT WOS:000308770300042 PM 22789741 ER PT J AU Frank, EG McDonald, JP Karata, K Huston, D Woodgate, R AF Frank, Ekaterina G. McDonald, John P. Karata, Kiyonobu Huston, Donald Woodgate, Roger TI A strategy for the expression of recombinant proteins traditionally hard to purify SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Recombinant protein expression; Protein purification; DNA polymerase eta; DNA polymerase iota; DNA polymerase nu ID HUMAN DNA-POLYMERASE; ESCHERICHIA-COLI; TRANSLESION SYNTHESIS; INCLUSION-BODIES; IN-VITRO; IOTA; BYPASS; PURIFICATION; REPLICATION; FIDELITY AB We have developed a series of plasmid vectors for the soluble expression and subsequent purification of recombinant proteins that have historically proven to be extremely difficult to purify from Escherichia coli. Instead of dramatically overproducing the target protein, it is expressed at a low basal level that facilitates the correct folding of the recombinant protein and increases its solubility. Highly active recombinant proteins that are traditionally difficult to purify are readily purified using standard affinity tags and conventional chromatography. To demonstrate the utility of these vectors, we have expressed and purified full-length human DNA polymerases eta, iota, and nu from E. coli and show that the purified DNA polymerases are catalytically active in vitro. Published by Elsevier Inc. C1 [Frank, Ekaterina G.; McDonald, John P.; Karata, Kiyonobu; Huston, Donald; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program; Special Coordination Funds for Promoting Science and Technology of the Japanese Ministry of Education, Culture, Sports, Science, and Technology FX This work was supported in part by the National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program (to R.W., E.G.F., D.H., and J.P.M.) and the Special Coordination Funds for Promoting Science and Technology of the Japanese Ministry of Education, Culture, Sports, Science, and Technology (to K.K.). NR 24 TC 15 Z9 16 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 15 PY 2012 VL 429 IS 2 BP 132 EP 139 DI 10.1016/j.ab.2012.07.016 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 004LM UT WOS:000308683200008 PM 22828411 ER PT J AU Talbot, GH Powers, JH Fleming, TR Siuciak, JA Bradley, J Boucher, H AF Talbot, George H. Powers, John H. Fleming, Thomas R. Siuciak, Judith A. Bradley, John Boucher, Helen CA CABP-ABSSSI Project Team TI Progress on Developing Endpoints for Registrational Clinical Trials of Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infections: Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID PNEUMOCOCCIC PNEUMONIA; COMPLICATED SKIN; DOUBLE-BLIND; INTEGRATED ANALYSIS; CONTROLLED SERIES; 2-PHASE 3; SULFAPYRIDINE; EFFICACY; MULTICENTER; VANCOMYCIN AB Efficacy endpoints for previous registrational trials of antimicrobials for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP) were based on nonstandardized, clinician-based observations and decisions, as well as on patient reports. More quantifiable, reproducible, and externally verifiable endpoints could improve the design of future noninferiority trials. At the request of the Food and Drug Administration, the Foundation for the National Institutes of Health convened a broadly representative scientific project team to evaluate potential endpoints for such registrational trials. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent early in therapy; later outcomes provide important supportive information. Although evidence is incomplete, early response endpoints can anchor noninferiority hypotheses in ABSSSI and CABP registrational trials, thereby allowing evidence-based drug development to continue. Further research is underway to establish which short- and long-term outcomes are well-defined, reliable, and reflective of how patients feel, function, or survive. C1 [Talbot, George H.] Talbot Advisors, Anna Maria, FL 34216 USA. [Powers, John H.] SAIC Frederick, Bethesda, MD USA. [Siuciak, Judith A.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Fleming, Thomas R.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Bradley, John] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Bradley, John] Rady Childrens Hosp San Diego, Dept Pediat, San Diego, CA USA. [Boucher, Helen] Tufts Med Ctr, Boston, MA USA. [Boucher, Helen] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Talbot, GH (reprint author), Talbot Advisors, POB 2121, Anna Maria, FL 34216 USA. EM ghtalbot@gmail.com RI Siuciak, Judith/K-2759-2016 OI Siuciak, Judith/0000-0002-3945-3555 FU National Cancer Institute [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Actelion Pharmaceuticals; Basilea Pharmaceutica International; Cempra Pharmaceuticals; Cerexa; Actelion; Basilea; Bayer; Cempra; Durata; Cubist-Calixa; FAB Pharma; JJ; Kalidex; Meiji; Merada; Merck; Nabriva; Wyeth/Pfizer FX This work was supported by the National Cancer Institute (contract HHSN261200800001E) and the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Actelion Pharmaceuticals; Basilea Pharmaceutica International; Cempra Pharmaceuticals; Cerexa, a wholly owned subsidiary of Forest Laboratories; Cubist Pharmaceuticals; Merck; Nabriva Therapeutics; and Trius Therapeutics. Clinical trial data were also contributed to the project by Cerexa, Cubist Pharmaceuticals, Durata Therapeutics, and Pfizer.; Within the past 36 months, G. H. T., through Talbot Advisors, has received board compensation and/or consultancy fees from Actelion, Basilea, Bayer, Cempra, Cerexa, Durata, Cubist-Calixa, FAB Pharma, J&J, Kalidex, Meiji, Merada, Merck, Nabriva, and Wyeth/Pfizer (data safety monitoring board). G. H. T. also has equity interests in Durata, Calixa, Cerexa, Kalidex, and Nabriva; he did not receive compensation for work on the PT, including manuscript preparation, but travel expenses to PT meetings were reimbursed by the Infectious Diseases Society of America and the FNIH. In past 36 months, J. P. served as consultant for Advanced Life Sciences, Astra-Zeneca, Cardeas, Contrafect, Gilead, Johnson and Johnson, LEO, Methylgene, Novartis, Optimer, Pfizer, Trius, Warner Chilcott, and Wyeth. J. S. is an employee of the FNIH. In the last 3 years, H. B. provided advice or consultation to Basilea, Cerexa, Cubist, Durata, Merck (adjudication committee), J&J, Rib-X, Targanta/The Medicines Company, and Wyeth/Pfizer (data safety monitoring board). All other authors: No reported conflicts. NR 36 TC 45 Z9 45 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2012 VL 55 IS 8 BP 1114 EP 1121 DI 10.1093/cid/cis566 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 010BX UT WOS:000309070500018 PM 22744885 ER PT J AU Giese, AP Ezan, J Wang, LY Lasvaux, L Lembo, F Mazzocco, C Richard, E Reboul, J Borg, JP Kelley, MW Sans, N Brigande, J Montcouquiol, M AF Giese, Arnaud P. Ezan, Jerome Wang, Lingyan Lasvaux, Lea Lembo, Frederique Mazzocco, Claire Richard, Elodie Reboul, Jerome Borg, Jean-Paul Kelley, Matthew W. Sans, Nathalie Brigande, John Montcouquiol, Mireille TI Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear SO DEVELOPMENT LA English DT Article DE Polarity; Traffic; Actin; Cochlea; Van Gogh-like 2; Gipc1; Myosin VI; Planar polarity; Mouse; Rat ID PLANAR CELL-POLARITY; NMDA RECEPTOR TRAFFICKING; NEURAL-TUBE DEFECTS; MYOSIN-VI; ASYMMETRIC LOCALIZATION; UNCONVENTIONAL MYOSIN; ENDOCYTIC VESICLES; SENSORY EPITHELIA; MAMMALIAN COCHLEA; GENE-TRANSFER AB Vangl2 is one of the central proteins controlling the establishment of planar cell polarity in multiple tissues of different species. Previous studies suggest that the localization of the Vangl2 protein to specific intracellular microdomains is crucial for its function. However, the molecular mechanisms that control Vangl2 trafficking within a cell are largely unknown. Here, we identify Gipc1 (GAIP C-terminus interacting protein 1) as a new interactor for Vangl2, and we show that a myosin VI-Gipc1 protein complex can regulate Vangl2 traffic in heterologous cells. Furthermore, we show that in the cochlea of MyoVI mutant mice, Vangl2 presence at the membrane is increased, and that a disruption of Gipc1 function in hair cells leads to maturation defects, including defects in hair bundle orientation and integrity. Finally, stimulated emission depletion microscopy and overexpression of GFP-Vangl2 show an enrichment of Vangl2 on the supporting cell side, adjacent to the proximal membrane of hair cells. Altogether, these results indicate a broad role for Gipc1 in the development of both stereociliary bundles and cell polarization, and suggest that the strong asymmetry of Vangl2 observed in early postnatal cochlear epithelium is mostly a 'tissue' polarity readout. C1 [Giese, Arnaud P.; Ezan, Jerome; Lasvaux, Lea; Mazzocco, Claire; Richard, Elodie; Sans, Nathalie; Montcouquiol, Mireille] Neuroctr Magendie, Inserm U862, Planar Polar & Plast Grp, Bordeaux, France. [Giese, Arnaud P.; Ezan, Jerome; Sans, Nathalie; Montcouquiol, Mireille] Univ Bordeaux, F-33000 Bordeaux, France. [Wang, Lingyan; Brigande, John] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. [Lembo, Frederique; Reboul, Jerome; Borg, Jean-Paul] CRCM, INSERM, U1068, F-13009 Marseille, France. [Lembo, Frederique; Reboul, Jerome; Borg, Jean-Paul] Inst J Paoli I Calmettes, F-13009 Marseille, France. [Lembo, Frederique; Reboul, Jerome; Borg, Jean-Paul] Aix Marseille Univ, F-13284 Marseille, France. [Lembo, Frederique; Reboul, Jerome; Borg, Jean-Paul] CNRS, UMR7258, F-75700 Paris, France. [Kelley, Matthew W.] NIDCD, Lab Cochlear Dev, NIH, Bethesda, MD USA. RP Montcouquiol, M (reprint author), Neuroctr Magendie, Inserm U862, Planar Polar & Plast Grp, Bordeaux, France. EM mireille.montcouquiol@inserm.fr RI Reboul, Jerome/P-9103-2016; OI Reboul, Jerome/0000-0002-5513-4546; montcouquiol, mireille/0000-0001-8739-6519 FU French National Institute of Health and Medical Research (INSERM) AVENIR [R04208GS, R04210GS]; Conseil Regional d'Aquitaine; La Fondation pour la Recherche Medicale; Agence Nationale de la Recherche [ANR-08-, MNPS-040-01, ANR-07-NEUR-031-01]; Aquitaine-INSERM Fellowship; International Reintegration Grants (IRG) Marie-Curie action; European Commission Coordination Action; Network of European Neuroscience Institutes ENINET [LSHM-CT-2005-19063]; National Institute on Deafness and other Communication Disorders [DC R01 008595, DC R01 008595-03S2, P30 DC005983]; Ligue Nationale Contre le Cancer; European Consortium for Anticancer Antibody Development (EUCAAD); INCa; IBISa (Marseille Proteomic Platform) FX This research was supported by a French National Institute of Health and Medical Research (INSERM) AVENIR grant [R04208GS to M. M. and R04210GS to N.S.]; Conseil Regional d'Aquitaine [M.M. and N.S.]; La Fondation pour la Recherche Medicale [M.M., N.S., J.E.]; Agence Nationale de la Recherche [ANR-08-; MNPS-040-01 to M. M. and ANR-07-NEUR-031-01 to N.S.]; Aquitaine-INSERM Fellowship [A. P. G.]; International Reintegration Grants (IRG) Marie-Curie action [M. M.] and the European Commission Coordination Action and the Network of European Neuroscience Institutes ENINET [contract number LSHM-CT-2005-19063; N.S. and M. M.]; and the National Institute on Deafness and other Communication Disorders [DC R01 008595, DC R01 008595-03S2 (to J.B.) and P30 DC005983]. J.-P.B. is supported by Ligue Nationale Contre le Cancer [Label 2010 JPB], European Consortium for Anticancer Antibody Development (EUCAAD) (FP7 program), INCa and IBISa (Marseille Proteomic Platform). NR 57 TC 21 Z9 21 U1 0 U2 15 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT 15 PY 2012 VL 139 IS 20 BP 3775 EP 3785 DI 10.1242/dev.074229 PG 11 WC Developmental Biology SC Developmental Biology GA 008SH UT WOS:000308976300011 PM 22991442 ER PT J AU Heuer, LS Rose, M Ashwood, P Van de Water, J AF Heuer, Luke S. Rose, Melissa Ashwood, Paul Van de Water, Judy TI Decreased levels of total immunoglobulin in children with autism are not a result of B cell dysfunction SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Autism; B cell; Immunoglobulin; Immune system ID LYMPHOCYTE CYTOKINE PROFILES; SPECTRUM DISORDERS; IMMUNE ACTIVATION; GASTROINTESTINAL SYMPTOMS; T-CELLS; BRAIN; PREGNANCY; RESPONSES; GLOBULIN; INNATE AB Autism spectrum disorders are a heterogeneous group of behaviorally defined disorders having complex etiologies. We previously reported a direct correlation between lower plasma levels of the immunoglobulins (Ig) IgG and IgM and increased severity of behavioral symptoms in children with autism. Our current objective was to determine if these reduced plasma levels of IgG and IgM are the result of defective B cell development, activation, or function. Results suggest no differences in the B cell parameters measured, indicating that decreased Ig in autism is not a result of B cell dysfunction and other immune cells might be involved. (C) 2012 Elsevier B.V. All rights reserved. C1 [Heuer, Luke S.; Van de Water, Judy] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Rose, Melissa] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Ashwood, Paul] Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. [Heuer, Luke S.; Rose, Melissa; Ashwood, Paul; Van de Water, Judy] Univ Calif Davis, MIND Inst, Davis, CA 95616 USA. [Heuer, Luke S.; Rose, Melissa; Ashwood, Paul; Van de Water, Judy] Univ Calif Davis, NIEHS Ctr Childrens Environm Hlth, Davis, CA 95616 USA. RP Van de Water, J (reprint author), Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, 451 E Hlth Sci Dr, Davis, CA 95616 USA. EM javandewater@ucdavis.edu FU NIEHS [1P01ES11269-01]; U.S. EPA [R829388] FX Sponsors: NIEHS 1P01ES11269-01 and U.S. EPA Grant R829388. NR 37 TC 9 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 15 PY 2012 VL 251 IS 1-2 BP 94 EP 102 DI 10.1016/j.jneuroim.2012.07.001 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 013OM UT WOS:000309314700014 PM 22854260 ER PT J AU Gail, MH AF Gail, Mitchell H. TI Using multiple risk models with preventive interventions SO STATISTICS IN MEDICINE LA English DT Article DE absolute risk models; breast cancer; disease prevention; modeling multiple risks; risk-based prevention strategy; risk versus benefit ID BREAST-CANCER RISK; TAMOXIFEN; BENEFITS AB An ideal preventive intervention would have negligible side effects and could be applied to the entire population, thus achieving maximal preventive impact. Unfortunately, many interventions have adverse effects and beneficial effects. For example, tamoxifen reduces the risk of breast cancer by about 50% and the risk of hip fracture by 45%, but increases the risk of stroke by about 60%; other serious adverse effects include endometrial cancer and pulmonary embolus. Hence, tamoxifen should only be given to the subset of the population with high enough risks of breast cancer and hip fracture such that the preventive benefits outweigh the risks. Recommendations for preventive use of tamoxifen have been based primarily on breast cancer risk. Age-specific and race-specific rates were considered for other health outcomes, but not risk models. In this paper, we investigate the extent to which modeling not only the risk of breast cancer, but also the risk of stroke, can improve the decision to take tamoxifen. These calculations also give insight into the relative benefits of improving the discriminatory accuracy of such risk models versus improving the preventive effectiveness or reducing the adverse risks of the intervention. Depending on the discriminatory accuracies of the risk models, there may be considerable advantage to modeling the risks of more than one health outcome. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Gail, MH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, EPS 8032, Rockville, MD 20892 USA. EM gailm@mail.nih.gov FU National Institutes of Health; Division of Cancer Epidemiology and Genetics of the National Cancer Institute. FX This work was supported by the Intramural Research Program of the National Institutes of Health and Division of Cancer Epidemiology and Genetics of the National Cancer Institute. We thank Dr. Ruth M. Pfeiffer for detecting a previous error in the calculation of min loss. NR 15 TC 2 Z9 2 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 15 PY 2012 VL 31 IS 23 BP 2687 EP 2696 DI 10.1002/sim.5443 PG 10 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 007FP UT WOS:000308874500008 PM 22733645 ER PT J AU Kipnis, V Midthune, D Freedman, LS Carroll, RJ AF Kipnis, Victor Midthune, Douglas Freedman, Laurence S. Carroll, Raymond J. TI Regression calibration with more surrogates than mismeasured variables SO STATISTICS IN MEDICINE LA English DT Article DE attenuation; logistic regression; measurement error; reparameterization ID LOGISTIC-REGRESSION AB In a recent paper (Weller EA, Milton DK, Eisen EA, Spiegelman D. Regression calibration for logistic regression with multiple surrogates for one exposure. Journal of Statistical Planning and Inference 2007; 137: 449-461), the authors discussed fitting logistic regression models when a scalar main explanatory variable is measured with error by several surrogates, that is, a situation with more surrogates than variables measured with error. They compared two methods of adjusting for measurement error using a regression calibration approximate model as if it were exact. One is the standard regression calibration approach consisting of substituting an estimated conditional expectation of the true covariate given observed data in the logistic regression. The other is a novel two-stage approach when the logistic regression is fitted to multiple surrogates, and then a linear combination of estimated slopes is formed as the estimate of interest. Applying estimated asymptotic variances for both methods in a single data set with some sensitivity analysis, the authors asserted superiority of their two-stage approach. We investigate this claim in some detail. A troubling aspect of the proposed two-stage method is that, unlike standard regression calibration and a natural form of maximum likelihood, the resulting estimates are not invariant to reparameterization of nuisance parameters in the model. We show, however, that, under the regression calibration approximation, the two-stage method is asymptotically equivalent to a maximum likelihood formulation, and is therefore in theory superior to standard regression calibration. However, our extensive finite-sample simulations in the practically important parameter space where the regression calibration model provides a good approximation failed to uncover such superiority of the two-stage method. We also discuss extensions to different data structures. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Kipnis, Victor; Midthune, Douglas] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Freedman, Laurence S.] Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52621 Tel Hashomer, Israel. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Kipnis, V (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, Execut Plaza N,Room 3124,6130 Execut Blvd,MSC 735, Bethesda, MD 20892 USA. EM kipnisv@mail.nih.gov FU National Cancer Institute [CA57030]; King Abdullah University of Science and Technology (KAUST) [KUS-CI-016-04] FX We thank Dr. Weller for providing us with the data used in their original analysis. Carroll's research was supported by a grant from the National Cancer Institute (CA57030) and by Award Number KUS-CI-016-04, made by King Abdullah University of Science and Technology (KAUST). NR 5 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 15 PY 2012 VL 31 IS 23 BP 2713 EP 2732 DI 10.1002/sim.5435 PG 20 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 007FP UT WOS:000308874500010 PM 22744878 ER PT J AU Ahmet, I Lakatta, EG Talan, MI AF Ahmet, Ismayil Lakatta, Edward G. Talan, Mark I. TI Acute hemodynamic effects of erythropoietin do not mediate its cardioprotective properties SO BIOLOGY OPEN LA English DT Article DE Erythropoietin; Nitric oxide; Arterial blood pressure; Cardiac function; Myocardial infarction; Cardioprotection AB Activation of nitric oxide (NO) signaling is considered, at list partially, a mechanistic basis for EPO-induced cardioprotection. Surprisingly, hemodynamic response subsequent to NO activation after EPO administration has never been reported. The objectives of this study were to evaluate the acute hemodynamic and cardiovascular responses to EPO administration, to confirm their NO genesis, and to test the hypothesis that EPO-induced cardioprotection is mediated through cardiovascular changes related to NO activation. In Experiment 1, after 3000 U/kg of rhEPO was administered intravenously to Wistar rats, arterial blood pressure, monitored via indwelling catheter, progressively declined almost immediately until it leveled off 90 minutes after injection at 20% below control level. In Experiment 2 the 25% reduction of mean blood pressure, compared to control group, was observed 2 hours after intravenous injection of either 3000 or 150 U/kg of rhEPO. Detailed pressure-volume loop analyses of cardiac performance (Experiment 3) 2 hours after intravenous injection of human or rat recombinant EPO (3000 U/kg) revealed a significant reduction of systolic function (PRSW was 33% less than control). Reduction of arterial blood pressure and systolic cardiac function in response to rhEPO were blocked in rats pretreated with a non-selective inhibitor of nitric oxide synthase (L-NAME). In Experiment 4, 24 hours after a permanent ligation of a coronary artery, myocardial infarction (MI) measured 26 +/- 3.5% of left ventricle in untreated rats. MI in rats treated with 3000 U/kg of rhEPO immediately after coronary ligation was 56% smaller. Pretreatment with L-NAME did not attenuate the beneficial effect of rhEPO on MI size, while MI size in rats treated with L-NAME alone did not differ from control. Therefore, a single injection of rhEPO resulted in a significant, NO-mediated reduction of systemic blood pressure and corresponding reduction of cardiac systolic function. However, EPO-induced protection of myocardium from ischemic damage is not associated with NO activation or NO-mediated hemodynamic responses. (C) 2012. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0). C1 [Ahmet, Ismayil; Lakatta, Edward G.; Talan, Mark I.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Talan, MI (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM talanm@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health FX This work was fully funded by Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 39 TC 0 Z9 0 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD OCT 15 PY 2012 VL 1 IS 10 BP 1049 EP 1053 DI 10.1242/bio.20122378 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA V36IH UT WOS:000209205500014 PM 23213383 ER PT J AU Yi, JH Katagiri, Y Susarla, B Figge, D Symes, AJ Geller, HM AF Yi, Jae-Hyuk Katagiri, Yasuhiro Susarla, Bala Figge, David Symes, Aviva J. Geller, Herbert M. TI Alterations in sulfated chondroitin glycosaminoglycans following controlled cortical impact injury in mice SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE chondroitin sulfate proteoglycan; traumatic brain injury; extracellular ma-trix; perineuronal nets ID SPINAL-CORD-INJURY; TRAUMATIC BRAIN-INJURY; MONOCLONAL-ANTIBODY; GLIAL SCAR; PROTEOGLYCAN EXPRESSION; REACTIVE ASTROCYTES; PERINEURONAL NETS; NG2 PROTEOGLYCAN; ADULT-RAT; ARTICULAR-CARTILAGE AB Chondroitin sulfate proteoglycans (CSPGs) play a pivotal role in many neuronal growth mechanisms including axon guidance and the modulation of repair processes following injury to the spinal cord or brain. Many actions of CSPGs in the central nervous system (CNS) are governed by the specific sulfation pattern on the glycosaminoglycan (GAG) chains attached to CSPG core proteins. To elucidate the role of CSPGs and sulfated GAG chains following traumatic brain injury (TBI), controlled cortical impact injury of mild to moderate severity was performed over the left sensory motor cortex in mice. Using immunoblotting and immunostaining, we found that TBI resulted in an increase in the CSPGs neurocan and NG2 expression in a tight band surrounding the injury core, which overlapped with the presence of 4-sulfated CS GAGs but not with 6-sulfated GAGs. This increase was observed as early as 7 days post injury (dpi), and persisted for up to 28 dpi. Labeling with markers against microglia/macrophages, NG2+ cells, fibroblasts, and astrocytes showed that these cells were all localized in the area, suggesting multiple origins of chondroitin-4-sulfate increase. TBI also caused a decrease in the expression of aggrecan and phosphacan in the pericontusional cortex with a concomitant reduction in the number of perineuronal nets. In summary, we describe a dual response in CSPGs whereby they may be actively involved in complex repair processes following TBI. J. Comp. Neurol. 520:32953313, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Yi, Jae-Hyuk; Katagiri, Yasuhiro; Figge, David; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Yi, Jae-Hyuk; Susarla, Bala; Symes, Aviva J.; Geller, Herbert M.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Susarla, Bala; Symes, Aviva J.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Geller, HM (reprint author), NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM geller@helix.nih.gov RI Symes, Aviva/S-7471-2016; OI Symes, Aviva/0000-0003-2557-9939; Geller, Herbert/0000-0002-7048-6144 FU Center for Neuroscience and Regenerative Medicine [G175PD, G1709B] FX Grant sponsor: Center for Neuroscience and Regenerative Medicine; Grant numbers: G175PD (to H.M.G. and A.J.S.) and G1709B (postdoctoral fellowship to J.-H.Y.). NR 77 TC 29 Z9 29 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD OCT 15 PY 2012 VL 520 IS 15 BP 3295 EP 3313 DI 10.1002/cne.23156 PG 19 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 993HV UT WOS:000307849400001 PM 22628090 ER PT J AU Alimova, I Venkataraman, S Harris, P Marquez, VE Northcott, PA Dubuc, A Taylor, MD Foreman, NK Vibhakar, R AF Alimova, Irina Venkataraman, Sujatha Harris, Peter Marquez, Victor E. Northcott, Paul A. Dubuc, Adrian Taylor, Michael D. Foreman, Nicholas K. Vibhakar, Rajeev TI Targeting the enhancer of zeste homologue 2 in medulloblastoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE EZH2; medulloblastoma; polycomb repressive complex 2; histone lysine methylation; DZNEP ID PHARMACOLOGICAL DISRUPTION; CANCER-CELLS; EXPRESSION; EZH2; TUMORS; GENE; METHYLATION; PROSTATE; THERAPY; BREAST AB Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 that catalyzes the trimethylation of histone H3 on Lys 27, and represses gene transcription. EZH2 enhances cancer-cell proliferation and regulates stem cell maintenance and differentiation. Here, we demonstrate that EZH2 is highly expressed in medulloblastoma, a highly malignant brain tumor of childhood, and this altered expression is correlated with genomic gain of chromosome 7 in a subset of medulloblastoma. Inhibition of EZH2 by RNAi suppresses medulloblastoma tumor cell growth. We show that 3-deazaneplanocin A, a chemical inhibitor of EZH2, can suppress medulloblastoma cell growth partially by inducing apoptosis. Suppression of EZH2 expression diminishes the ability of tumor cells to form spheres in culture and strongly represses the ability of known oncogenes to transform neural stem cells. These findings establish a role of EZH2 in medulloblastoma and identify EZH2 as a potential therapeutic target especially in high-risk tumors. C1 [Alimova, Irina; Venkataraman, Sujatha; Harris, Peter; Foreman, Nicholas K.; Vibhakar, Rajeev] Univ Colorado, Boulder, CO 80309 USA. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD USA. [Northcott, Paul A.; Dubuc, Adrian; Taylor, Michael D.] Hosp Sick Children, Program Dev & Stem Cell Biol, Div Neurosurg, Toronto, ON M5G 1X8, Canada. RP Vibhakar, R (reprint author), Univ Colorado Denver, Dept Pediat, 12800 19th Ave,Mail Stop 4103, Aurora, CO 80045 USA. EM rajeev.vibhakar@ucdenver.edu OI Foreman, Nicholas/0000-0003-4848-4801 FU NIH [KO8NS59790-3]; Morgan Adams Foundation FX Grant sponsor: NIH; Grant number: KO8NS59790-3; Grant sponsor: Morgan Adams Foundation NR 32 TC 27 Z9 29 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2012 VL 131 IS 8 BP 1800 EP 1809 DI 10.1002/ijc.27455 PG 10 WC Oncology SC Oncology GA 993XN UT WOS:000307893400007 PM 22287205 ER PT J AU Rodriguez, AC Schiffman, M Herrero, R Hildesheim, A Bratti, C Sherman, ME Solomon, D Guillen, D Alfaro, M Morales, J Hutchinson, M Cheung, L Wacholder, S Burk, RD AF Cecilia Rodriguez, Ana Schiffman, Mark Herrero, Rolando Hildesheim, Allan Bratti, Concepcion Sherman, Mark E. Solomon, Diane Guillen, Diego Alfaro, Mario Morales, Jorge Hutchinson, Martha Cheung, Li Wacholder, Sholom Burk, Robert D. TI Low risk of type-specific carcinogenic HPV re-appearance with subsequent cervical intraepithelial neoplasia grade 2/3 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HPV infection re-appearance; CIN2+; risk after re-appearance; HPV infection epidemiology ID HUMAN-PAPILLOMAVIRUS INFECTION; YOUNG-WOMEN; NATURAL-HISTORY; COSTA-RICA; DURATION; GUANACASTE; INCIDENT; CANCER; COHORT; PCR AB Carcinogenic human papillomavirus (HPV) infections are very common after sexual debut and nearly all become undetectable (clear) within a few years. Following clearance, the long-term risks of type-specific HPV re-appearance and subsequent risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are not well defined. In the 7-year, population-based cohort study in Guanacaste, Costa Rica, we studied how often type-specific carcinogenic HPV infections re-appeared after clearance and how often re-appearance led to CIN2+. We considered 1,740 carcinogenic HPV infections detected by MY09/11 PCR among 2,805 women (1891 years old, median 34) who were actively followed at 6- or 12-month intervals. We identified women with one or more type-specific HPV infections that cleared and re-appeared and further defined a subgroup of definite clearance and re-appearance (=2 intervening negative results over a period of =1 year). We determined the absolute risk of CIN2+ among the different groups. p values are two-sided. Only 7.7% (81/1,052) of HPV-infected women had intervening negative results. Very few (3.7%, 39/1,052) had definite clearance and re-appearance, of which 5.1% (2/39) subsequently persisted to a diagnosis of CIN2. There were zero CIN3+ lesions. Extremely few women (2/2,805 of women in our cohort) had a type-specific carcinogenic HPV infection clear, re-appear and lead to CIN2+. If confirmed, this argues against vaccination to avoid re-appearance that leads to precursor lesions and against the need of frequent HPV screening after initial negative results. C1 [Cecilia Rodriguez, Ana; Bratti, Concepcion; Guillen, Diego; Alfaro, Mario; Morales, Jorge] INCIENSA Fdn, San Jose, Costa Rica. [Schiffman, Mark; Hildesheim, Allan; Sherman, Mark E.; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Herrero, Rolando] World Hlth Org, Int Agcy Res Canc, Prevent & Implementat Grp, Lyon, France. [Solomon, Diane] NCI, Canc Prevent Div, NIH, DHHS, Rockville, MD USA. [Hutchinson, Martha] Womens & Infants Hosp, Providence, RI USA. [Cheung, Li] Informat Management Serv Inc, Silver Spring, MD USA. [Burk, Robert D.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Rodriguez, AC (reprint author), Proyecto Epidemiol Guanacaste Fdn INCIENSA Torre, 7Mo Piso Sabana Norte, San Jose, Costa Rica. EM acrodriguez@racsa.co.cr RI Hildesheim, Allan/B-9760-2015; OI Hildesheim, Allan/0000-0003-0257-2363; Cheung, Li/0000-0003-1625-4331 FU National Institutes of Health [N01-CP-21081, N01-CP-33061, N01-CP-40542, N01-CP-50535, N01-CP-81023]; Intramural Program [CA78527] FX Grant sponsor: National Institutes of Health; Contract numbers: N01-CP-21081, N01-CP-33061, N01-CP-40542, N01-CP-50535, N01-CP-81023; Grant sponsor: Intramural Program; Grant number: CA78527 NR 26 TC 11 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2012 VL 131 IS 8 BP 1874 EP 1881 DI 10.1002/ijc.27418 PG 8 WC Oncology SC Oncology GA 993XN UT WOS:000307893400015 PM 22213126 ER PT J AU O'Rorke, MA Cantwell, MM Abnet, CC Brockman, JD Murray, LJ AF O'Rorke, Michael A. Cantwell, Marie M. Abnet, Christian C. Brockman, John D. Murray, Liam J. CA FINBAR Study Grp TI Toenail trace element status and risk of Barrett's oesophagus and oesophageal adenocarcinoma: Results from the FINBAR study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE trace elements; Barrett's oesophagus; oesophageal adenocarcinoma; selenium; case-control study ID CANCER-RISK; MYOCARDIAL-INFARCTION; ZINC CONCENTRATION; PROSTATE-CANCER; UNITED-STATES; SELENIUM; EXPOSURE; NAILS; NETHERLANDS; POPULATION AB Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. Our study aimed to examine toenail trace element status and risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using instrumental neutron activation analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% confidence intervals (CIs) were calculated within tertiles of trace element concentrations. A twofold increased risk of BO was observed, but not OAC, among individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI, 1.114.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI, 0.442.04) or BO OR 0.89 (95% CI, 0.372.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI, 1.013.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first casecontrol study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis. C1 [O'Rorke, Michael A.; Cantwell, Marie M.; Murray, Liam J.] Queens Univ Belfast, Ctr Publ Hlth, Inst Clin Sci, Canc Epidemiol & Hlth Serv Res Grp, Belfast BT12 6BA, Antrim, North Ireland. [Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Brockman, John D.] Univ Missouri Columbia, Res Reactor Ctr, Columbia, MO USA. RP O'Rorke, MA (reprint author), Queens Univ Belfast, Ctr Publ Hlth, Inst Clin Sci, Canc Epidemiol & Hlth Serv Res Grp, ICS-B Bldg,RVH Site,Grosvenor Rd, Belfast BT12 6BA, Antrim, North Ireland. EM m.ororke@qub.ac.uk RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Brockman, John/0000-0001-7419-5558 FU Centre for Health Improvement, Queen's University Belfast, Northern Ireland; Northern Ireland Research & Development Office: The Health Research Board, Ireland; Ulster Cancer Foundation; Charitable Fund of the Royal Groups of Hospitals, Belfast; Northern Ireland Cancer Registry; National Cancer Registry Ireland; NIH (National Cancer Institute) FX Grant sponsors: The Centre for Health Improvement, Queen's University Belfast, Northern Ireland, The Northern Ireland Research & Development Office: The Health Research Board, Ireland, The Ulster Cancer Foundation, The Charitable Fund of the Royal Groups of Hospitals, Belfast; The authors appreciate the contributions made by the study participants and their families. The authors thank the clinicians who were contacted throughout the study period and their secretaries for administrative support. The authors acknowledge the contribution of Miss Siobhan Reynolds, Ms. Majella Gallagher, Ms. Carol Anderson and Mr. Martin McAnaespie and Dr. Damian McManus. Thanks to the Ulster Cancer Foundation, the Northern Ireland Cancer Registry and the National Cancer Registry Ireland for their support and involvement in the research. This study was supported in part by the intramural research program of the NIH (National Cancer Institute). NR 50 TC 6 Z9 6 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2012 VL 131 IS 8 BP 1882 EP 1891 DI 10.1002/ijc.27434 PG 10 WC Oncology SC Oncology GA 993XN UT WOS:000307893400016 PM 22262413 ER PT J AU Lacey, JV Chia, VM Rush, BB Carreon, DJ Richesson, DA Ioffe, OB Ronnett, BM Chatterjee, N Langholz, B Sherman, ME Glass, AG AF Lacey, James V., Jr. Chia, Victoria M. Rush, Brenda B. Carreon, Danny J. Richesson, Douglas A. Ioffe, Olga B. Ronnett, Brigitte M. Chatterjee, Nilanjan Langholz, Bryan Sherman, Mark E. Glass, Andrew G. TI Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE uterine carcinoma; gynecologic oncology; joinpoint regression; epidemiology; atypical hyperplasia ID HORMONE REPLACEMENT THERAPY; UNITED-STATES; CARCINOMA; WOMEN; TRENDS; RISK; DIAGNOSIS; ESTROGEN; OBESITY; ADENOCARCINOMA AB Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 19802003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 19801990, -12.9% (95% CI = -15.6% to -10.1%) for 19901999 and 2.4% (95% CI = -6.6% to 12.2%) for 19992003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 19802000 and 24.5% (95% CI = -16.5% to 85.7%) for 20002003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 19801988 and 1.4% (95% CI = -0.2% to 3.0%) for 19882003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia. C1 [Lacey, James V., Jr.; Chia, Victoria M.; Carreon, Danny J.; Richesson, Douglas A.; Sherman, Mark E.] City Hope Natl Med Ctr, Div Canc Etiol, Duarte, CA 91010 USA. [Rush, Brenda B.; Glass, Andrew G.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Ioffe, Olga B.] Univ Maryland, Med Ctr, Dept Pathol, Baltimore, MD 21201 USA. [Ronnett, Brigitte M.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Langholz, Bryan] Univ So Calif, Keck Sch Med, Dept Prevent Med, Div Biostat, Los Angeles, CA 90033 USA. RP Lacey, JV (reprint author), City Hope Natl Med Ctr, Div Canc Etiol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM jlacey@coh.org FU NIH, National Cancer Institute FX Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute NR 41 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2012 VL 131 IS 8 BP 1921 EP 1929 DI 10.1002/ijc.27457 PG 9 WC Oncology SC Oncology GA 993XN UT WOS:000307893400020 PM 22290745 ER PT J AU Mohammed, A Qian, L Janakiram, NB Lightfoot, S Steele, VE Rao, CV AF Mohammed, Altaf Qian, Li Janakiram, Naveena B. Lightfoot, Stan Steele, Vernon E. Rao, Chinthalapally V. TI Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE PI3; AKT; atorvastatin; pancreatic cancer; p48Cre; +-LSL-Kras G12D; + mice ID 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE INHIBITORS; HMG-COA REDUCTASE; TUMOR-SPECIFIC APOPTOSIS; CANCER CELL INVASION; INTRAEPITHELIAL NEOPLASIA; MOUSE MODEL; IN-VITRO; LOVASTATIN; STATINS; GROWTH AB Pancreatic cancer is the one of most common causes of cancer deaths and has the worst prognosis. Clinical observational studies suggest that statins may reduce the risk of pancreatic cancer. The chemopreventive efficacy of the statin atorvastatin (Lipitor (R)) and the role of the phosphatidyl-inositol 3-kinase (PI3/AKT) signaling pathway were evaluated for the progression of pancreatic intraepithelial neoplasms (PanINs) to pancreatic ductal adenocarcinoma (PDAC) in conditional p48Cre/+-LSL-KrasG12D/+ transgenic mice. Six-week-old male p48Cre/+-LSL-KrasG12D/+ (20/group) mice were fed AIN-76A diets containing 0, 200 and 400 ppm atorvastatin for 35 weeks. At termination, pancreata were evaluated histopathologically for PanINs and PDAC, and for various PI3/AKT signaling markers, and inflammatory cytokines, by immunohistochemistry/immunohistoflourscence, ELISA, Western blotting and/or reverse transcription-PCR methods. Control diet-fed mice showed 85% incidence of PDAC; whereas, mice fed with atorvastatin showed PDAC incidence of 65 and 35%, respectively (p < 0.0001). Similarly, significant suppression of PanIN-3 (22.6%) was observed in mice fed 400 ppm atorvastatin. Importantly, pancreata from atorvastatin-treated mice were 68% free from ductal lesions. Furthermore, pancreas of mice administered with atorvastatin had significantly reduced expressions levels of PCNA, p2X7, p-ERK, RhoA, cyclin D1, survivin, Akt, pAKT, beta-catenin, cyclin E, cdK2 and caveolin-1. Also, atorvastatin-treated mice had shown dose-dependent suppression of inflammatory cytokines and a significant increase in tunnel-positive cells, p21 and PARP expression levels in pancreas. Atorvastatin significantly delays the progression of PanIN-1 and -2 lesions to PanIN-3 and PDAC by modulating PI3/AKT signal molecules in a preclinical model, suggesting potential clinical benefits of statins for high-risk pancreatic cancer patients. C1 [Mohammed, Altaf; Qian, Li; Janakiram, Naveena B.; Rao, Chinthalapally V.] Univ Oklahoma, PC Stephenson Oklahoma Canc Ctr, Ctr Chemoprevent & Canc Drug Dev, Hlth Sci Ctr,Hem Onc Sect,Dept Med, Oklahoma City, OK USA. [Lightfoot, Stan] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Steele, Vernon E.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), OUHSC, Ctr Chemoprevent & Canc Drug Dev, 975 NE 10th St,BRC Bldg 2,Room 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU National Cancer Institute [N01-CN-53300] FX Grant sponsor: National Cancer Institute; Grant number: N01-CN-53300 NR 51 TC 25 Z9 25 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2012 VL 131 IS 8 BP 1951 EP 1962 DI 10.1002/ijc.27456 PG 12 WC Oncology SC Oncology GA 993XN UT WOS:000307893400023 PM 22287227 ER PT J AU Handley, SA Thackray, LB Zhao, G Presti, R Miller, AD Droit, L Abbink, P Maxfield, LF Kambal, A Duan, E Stanley, K Kramer, J Macri, SC Permar, SR Schmitz, JE Mansfield, K Brenchley, JM Veazey, RS Stappenbeck, TS Wang, D Barouch, DH Virgin, HW AF Handley, Scott A. Thackray, Larissa B. Zhao, Guoyan Presti, Rachel Miller, Andrew D. Droit, Lindsay Abbink, Peter Maxfield, Lori F. Kambal, Amal Duan, Erning Stanley, Kelly Kramer, Joshua Macri, Sheila C. Permar, Sallie R. Schmitz, Joern E. Mansfield, Keith Brenchley, Jason M. Veazey, Ronald S. Stappenbeck, Thaddeus S. Wang, David Barouch, Dan H. Virgin, Herbert W. TI Pathogenic Simian Immunodeficiency Virus Infection Is Associated with Expansion of the Enteric Virome SO CELL LA English DT Article ID GUT MICROBIOME; IMMUNE ACTIVATION; HIV-INFECTION; GENE ATG16L1; METAGENOMICS; DISEASE; MOUSE; TRANSLOCATION; SEQUENCES; COLITIS AB Pathogenic simian immunodeficiency virus (SIV) infection is associated with enteropathy, which likely contributes to AIDS progression. To identify candidate etiologies for AIDS enteropathy, we used next-generation sequencing to define the enteric virome during SIV infection in nonhuman primates. Pathogenic, but not nonpathogenic, SIV infection was associated with significant expansion of the enteric virome. We identified at least 32 previously undescribed enteric viruses during pathogenic SIV infection and confirmed their presence by using viral culture and PCR testing. We detected unsuspected mucosal adenovirus infection associated with enteritis as well as parvovirus viremia in animals with advanced AIDS, indicating the pathogenic potential of SIV-associated expansion of the enteric virome. No association between pathogenic SIV infection and the family-level taxonomy of enteric bacteria was detected. Thus, enteric viral infections may contribute to AIDS enteropathy and disease progression. These findings underline the importance of metagenomic analysis of the virome for understanding AIDS pathogenesis. C1 [Abbink, Peter; Maxfield, Lori F.; Stanley, Kelly; Schmitz, Joern E.; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Handley, Scott A.; Thackray, Larissa B.; Zhao, Guoyan; Droit, Lindsay; Kambal, Amal; Duan, Erning; Stappenbeck, Thaddeus S.; Wang, David; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Zhao, Guoyan; Droit, Lindsay; Wang, David; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Presti, Rachel] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Miller, Andrew D.; Kramer, Joshua; Macri, Sheila C.; Mansfield, Keith] Harvard Univ, Sch Med, Dept Comparat Pathol, New England Primate Res Ctr, Southborough, MA 01772 USA. [Miller, Andrew D.; Kramer, Joshua; Macri, Sheila C.; Mansfield, Keith] Harvard Univ, Sch Med, Dept Vet Resources, New England Primate Res Ctr, Southborough, MA 01772 USA. [Permar, Sallie R.] Duke Univ, Med Ctr, Human Vaccine Inst, Durham, NC 27710 USA. [Brenchley, Jason M.] NIAID, Program Barrier Immun, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Repair & Immunopathogenesis Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Veazey, Ronald S.] Tulane Univ, Tulane Natl Primate Res Ctr, Sch Med, Covington, LA 70433 USA. [Barouch, Dan H.] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Barouch, Dan H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Barouch, DH (reprint author), Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu; virgin@wustl.edu RI zhou, zhenqing/H-4580-2014; Duan, Erning /H-4608-2014 FU Project 10 [U54 AI057160-08]; National Center for Research Resources [1R01 RR032309]; Office of Research Infrastructure Programs [OD11170-02]; Crohn's and Colitis Foundation [3132]; [AI066305]; [AI066924]; [AI078526]; [AI095985]; [AI65335]; [8P51OD011103-5] FX This work was supported by Project 10 of U54 AI057160-08 to D. W. for development of VirusHunter software, was initially funded by the National Center for Research Resources 1R01 RR032309, and is currently supported by the Office of Research Infrastructure Programs OD11170-02 to H. W. V. and D. H. B.; Crohn's and Colitis Foundation Grant 3132 to H. W. V. and T. S. S.; grants AI066305, AI066924, AI078526, and AI095985 to D. H. B.; AI65335 to J.E.S.; and grant 8P51OD011103-5 to A. D. M. and J.K. We would like to thank Angela Carville, Elizabeth Curran, and Vanessa Hirsch for assistance with these experiments. NR 38 TC 111 Z9 112 U1 1 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 12 PY 2012 VL 151 IS 2 BP 253 EP 266 DI 10.1016/j.cell.2012.09.024 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 022RX UT WOS:000309981000006 PM 23063120 ER PT J AU Wang, WF Guo, J Yu, DY Vorster, PJ Chen, WJ Wu, YT AF Wang, Weifeng Guo, Jia Yu, Dongyang Vorster, Paul J. Chen, WanJun Wu, Yuntao TI A Dichotomy in Cortical Actin and Chemotactic Actin Activity between Human Memory and Naive T Cells Contributes to Their Differential Susceptibility to HIV-1 Infection SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CCR7 LIGANDS CCL19; ANTIRETROVIRAL THERAPY; VIRAL REPLICATION; PREFERENTIAL REPLICATION; GASTROINTESTINAL-TRACT; IN-VITRO; LYMPHOCYTES; CHEMOKINE; TRANSCRIPTION AB Human memory and naive CD4 T cells can mainly be identified by the reciprocal expression of the CD45RO or CD45RA isoforms. In HIV-1 infection, blood CD45RO memory CD4 T cells are preferentially infected and serve as a major viral reservoir. The molecular mechanism dictating this differential susceptibility to HIV-1 remains largely obscure. Here, we report that the different susceptibility of memory and naive T cells to HIV is not determined by restriction factors such as Apobec3G or BST2. However, we observed a phenotypic distinction between human CD45RO and CD45RA resting CD4 T cells in their cortical actin density and actin dynamics. CD45RO CD4 T cells possess a higher cortical actin density and can be distinguished as CD45RO(+)Actin(high). In contrast, CD45RA T cells are phenotypically CD45RA(+)Actin(low). In addition, the cortical actin in CD45RO memory CD4 T cells is more dynamic and can respond to low dosages of chemotactic induction by SDF-1, whereas that of naive cells cannot, despite a similar level of the chemokine receptor CXCR4 present on both cells. We further demonstrate that this difference in the cortical actin contributes to their differential susceptibility to HIV-1; resting memory but not naive T cells are highly responsive to HIV-mediated actin dynamics that promote higher levels of viral entry and early DNA synthesis in resting memory CD4 T cells. Furthermore, transient induction of actin dynamics in resting naive T cells rescues HIV latent infection following CD3/CD28 stimulation. These results suggest a key role of chemotactic actin activity in facilitating HIV-1 latent infection of these T cell subsets. C1 [Wang, Weifeng; Guo, Jia; Yu, Dongyang; Vorster, Paul J.; Wu, Yuntao] George Mason Univ, Dept Mol & Microbiol, Natl Ctr Biodef & Infect Dis, Manassas, VA 20110 USA. [Chen, WanJun] NIDCR, Mucosal Immunol Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Wu, YT (reprint author), George Mason Univ, Dept Mol & Microbiol, Natl Ctr Biodef & Infect Dis, 10900 Univ Blvd, Manassas, VA 20110 USA. EM ywu8@gmu.edu RI Guo, Jia/L-2102-2013; wang, weifeng/N-4140-2013; Guo, Jia/C-8678-2014 FU National Institutes of Health USPHS Grant from NIAID [1R01AI081568]; National Institutes of Health Intramural Research Program of NIDCR FX This work was supported, in whole or in part, by National Institutes of Health USPHS Grant 1R01AI081568; Supported by National Institutes of Health Intramural Research Program of NIDCR. NR 69 TC 17 Z9 18 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 12 PY 2012 VL 287 IS 42 BP 35455 EP 35469 DI 10.1074/jbc.M112.362400 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 022OF UT WOS:000309968000055 PM 22879601 ER PT J AU Wesolowski, A Eagle, N Tatem, AJ Smith, DL Noor, AM Snow, RW Buckee, CO AF Wesolowski, Amy Eagle, Nathan Tatem, Andrew J. Smith, David L. Noor, Abdisalan M. Snow, Robert W. Buckee, Caroline O. TI Quantifying the Impact of Human Mobility on Malaria SO SCIENCE LA English DT Article ID ELIMINATION STRATEGIES; TRANSMISSION; KENYA; NAIROBI; SETTLEMENT; ZANZIBAR AB Human movements contribute to the transmission of malaria on spatial scales that exceed the limits of mosquito dispersal. Identifying the sources and sinks of imported infections due to human travel and locating high-risk sites of parasite importation could greatly improve malaria control programs. Here, we use spatially explicit mobile phone data and malaria prevalence information from Kenya to identify the dynamics of human carriers that drive parasite importation between regions. Our analysis identifies importation routes that contribute to malaria epidemiology on regional spatial scales. C1 [Eagle, Nathan; Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wesolowski, Amy] Carnegie Mellon Univ, Dept Engn & Publ Policy, Pittsburgh, PA 15221 USA. [Wesolowski, Amy] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15221 USA. [Eagle, Nathan] Northeastern Univ, Coll Comp & Informat Sci, Boston, MA 02115 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Tatem, Andrew J.; Smith, David L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32610 USA. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Malaria Res Inst, Baltimore, MD 21205 USA. [Noor, Abdisalan M.; Snow, Robert W.] Univ Oxford, Collaborat Programme, KEMRI Wellcome Trust, Malaria Publ Hlth & Epidemiol Grp,Ctr Geog Med, Nairobi, Kenya. [Noor, Abdisalan M.; Snow, Robert W.] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford OX3 7LJ, England. [Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. RP Buckee, CO (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM cbuckee@hsph.harvard.edu RI Smith, David/L-8850-2013; OI Smith, David/0000-0003-4367-3849; Snow, Robert/0000-0003-3725-6088 FU National Science Foundation Graduate Research Fellowship program [0750271]; Bill & Melinda Gates Foundation [49446, OPP1032350]; National Institute of Allergy and Infectious Disease, NIH [U19AI089674]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, NIH; Wellcome Trust [095127, 079080]; Wellcome Trust Major Overseas Programme grant [092654]; Models of Infectious Disease Agent Study program [1U54GM088558] FX A.W. was supported by the National Science Foundation Graduate Research Fellowship program (0750271). D. L. S. and A.J.T. acknowledge support from Bill & Melinda Gates Foundation grants (49446 and OPP1032350); National Institute of Allergy and Infectious Disease, NIH, grant (U19AI089674); and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; and the Fogarty International Center, NIH. A.M.N. is supported by the Wellcome Trust as an Intermediate Research Fellow (095127). R. W. S. is supported by the Wellcome Trust as Principal Research Fellow (079080). A.M.N. and R. W. S. also acknowledge programmatic support provided by the Wellcome Trust Major Overseas Programme grant to the Kenya Medical Research Institute-Wellcome Trust Programme (092654). C.O.B. was supported by the Models of Infectious Disease Agent Study program (cooperative agreement 1U54GM088558). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the NIH. Mobile phone data were provided by an anonymous service provider in Kenya and are not available for distribution. NR 20 TC 176 Z9 180 U1 9 U2 71 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 12 PY 2012 VL 338 IS 6104 BP 267 EP 270 DI 10.1126/science.1223467 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 019BQ UT WOS:000309712300049 PM 23066082 ER PT J AU Scolari, F Gomulski, LM Ribeiro, JMC Siciliano, P Meraldi, A Falchetto, M Bonomi, A Manni, M Gabrieli, P Malovini, A Bellazzi, R Aksoy, S Gasperi, G Malacrida, AR AF Scolari, Francesca Gomulski, Ludvik M. Ribeiro, Jose M. C. Siciliano, Paolo Meraldi, Alice Falchetto, Marco Bonomi, Angelica Manni, Mose Gabrieli, Paolo Malovini, Alberto Bellazzi, Riccardo Aksoy, Serap Gasperi, Giuliano Malacrida, Anna R. TI Transcriptional Profiles of Mating-Responsive Genes from Testes and Male Accessory Glands of the Mediterranean Fruit Fly, Ceratitis capitata SO PLOS ONE LA English DT Article ID SEMINAL FLUID PROTEINS; FEMALE DROSOPHILA-MELANOGASTER; PATHOGENESIS-RELATED PROTEINS; JUVENILE-HORMONE ESTERASE; RICH SECRETORY PROTEINS; DENGUE VECTOR MOSQUITO; REPRODUCTIVE PROTEINS; BINDING-PROTEIN; AEDES-AEGYPTI; HELICONIUS BUTTERFLIES AB Background: Insect seminal fluid is a complex mixture of proteins, carbohydrates and lipids, produced in the male reproductive tract. This seminal fluid is transferred together with the spermatozoa during mating and induces post-mating changes in the female. Molecular characterization of seminal fluid proteins in the Mediterranean fruit fly, Ceratitis capitata, is limited, although studies suggest that some of these proteins are biologically active. Methodology/Principal Findings: We report on the functional annotation of 5914 high quality expressed sequence tags (ESTs) from the testes and male accessory glands, to identify transcripts encoding putative secreted peptides that might elicit post-mating responses in females. The ESTs were assembled into 3344 contigs, of which over 33% produced no hits against the nr database, and thus may represent novel or rapidly evolving sequences. Extraction of the coding sequences resulted in a total of 3371 putative peptides. The annotated dataset is available as a hyperlinked spreadsheet. Four hundred peptides were identified with putative secretory activity, including odorant binding proteins, protease inhibitor domain-containing peptides, antigen 5 proteins, mucins, and immunity-related sequences. Quantitative RT-PCR-based analyses of a subset of putative secretory protein-encoding transcripts from accessory glands indicated changes in their abundance after one or more copulations when compared to virgin males of the same age. These changes in abundance, particularly evident after the third mating, may be related to the requirement to replenish proteins to be transferred to the female. Conclusions/Significance: We have developed the first large-scale dataset for novel studies on functions and processes associated with the reproductive biology of Ceratitis capitata. The identified genes may help study genome evolution, in light of the high adaptive potential of the medfly. In addition, studies of male recovery dynamics in terms of accessory gland gene expression profiles and correlated remating inhibition mechanisms may permit the improvement of pest management approaches. C1 [Scolari, Francesca; Gomulski, Ludvik M.; Siciliano, Paolo; Meraldi, Alice; Falchetto, Marco; Bonomi, Angelica; Manni, Mose; Gabrieli, Paolo; Gasperi, Giuliano; Malacrida, Anna R.] Univ Pavia, Dept Biol & Biotechnol, I-27100 Pavia, Italy. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, Rockville, MD USA. [Malovini, Alberto] Fdn Salvatore Maugeri, IRCCS, Pavia, Italy. [Malovini, Alberto] IUSS, Pavia, Italy. [Malovini, Alberto; Bellazzi, Riccardo] Univ Pavia, Dept Ind & Informat Engn, I-27100 Pavia, Italy. [Aksoy, Serap] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. RP Malacrida, AR (reprint author), Univ Pavia, Dept Biol & Biotechnol, Via Palestro 3, I-27100 Pavia, Italy. EM malacrid@unipv.it RI Ribeiro, Jose/J-7011-2015; scolari, francesca/L-9233-2015; Gabrieli, Paolo/A-3206-2016; OI scolari, francesca/0000-0003-3085-9038; Gabrieli, Paolo/0000-0002-4996-2468; Aksoy, Serap/0000-0001-9941-143X; Ribeiro, Jose/0000-0002-9107-0818 FU Italian Ministry of Universities and Research PRIN [2004053427, 2008FLZZ37]; International Atomic Energy Agency (IAEA) [16966]; Intramural Research Program of the Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health (JMCR) FX The study was partially funded by Italian Ministry of Universities and Research PRIN grants 2004053427 and 2008FLZZ37 (LMG, ARM, GG) and International Atomic Energy Agency (IAEA) contract 16966. The work was also carried out within the IAEA CRP programme "Development and evaluation of improved strains of insect pests for SIT'' (GG). It was also in part supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (JMCR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Because JMCR is a government employee and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the United States National Institutes of Health reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices, or establish rights outside of the U.S. subject to a government use license. NR 170 TC 18 Z9 18 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 OCT 11 PY 2012 VL 7 IS 10 AR e46812 DI 10.1371/journal.pone.0046812 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020KP UT WOS:000309807700034 PM 23071645 ER PT J AU Hansen, AM Jin, DJ AF Hansen, Anne-Marie Jin, Ding Jun TI SspA up-regulates gene expression of the LEE pathogenicity island by decreasing H-NS levels in enterohemorrhagic Escherichia coli SO BMC MICROBIOLOGY LA English DT Article DE Enterohemorrhagic Escherichia coli; LEE; SspA; H-NS ID STRINGENT STARVATION PROTEIN; TISSUE-CULTURE CELLS; LONG POLAR FIMBRIAE; TRANSCRIPTIONAL REGULATION; FOREIGN DNA; FRANCISELLA-TULARENSIS; VIRULENCE FACTORS; VIBRIO-CHOLERAE; RNA-POLYMERASE; NULL MUTATION AB Background: Enterohemorrhagic Escherichia coli (EHEC) colonizes the intestinal epithelium and causes attaching and effacing (A/E) lesions. Expression of virulence genes, particularly those from the locus of the enterocyte effacement (LEE) pathogenicity island is required for the formation of a type three secretion system, which induces A/E lesion formation. Like other horizontally acquired genetic elements, expression of the LEE is negatively regulated by H-NS. In the non-pathogenic Escherichia coli K-12 strain the stringent starvation protein A (SspA) inhibits accumulation of H-NS, and thereby allows de-repression of the H-NS regulon during the stationary phase of growth. However, the effect of SspA on the expression of H-NS-controlled virulence genes in EHEC is unknown. Results: Here we assess the effect of SspA on virulence gene expression in EHEC. We show that transcription of virulence genes including those of the LEE is decreased in an sspA mutant, rendering the mutant strain defective in forming A/E lesions. A surface exposed pocket of SspA is functionally important for the regulation of the LEE and for the A/E phenotype. Increased expression of ler alleviates LEE expression in an sspA mutant, suggesting that the level of Ler in the mutant is insufficient to counteract H-NS-mediated repression. We demonstrate that the H-NS level is two-fold higher in an sspA mutant compared to wild type, and that the defects of the sspA mutant are suppressed by an hns null mutation, indicating that hns is epistatic to sspA in regulating H-NS repressed virulence genes. Conclusions: SspA positively regulates the expression of EHEC virulence factors by restricting the intracellular level of H-NS. Since SspA is conserved in many bacterial pathogens containing horizontally acquired pathogenicity islands controlled by H-NS, our study suggests a common mechanism whereby SspA potentially regulates the expression of virulence genes in these pathogens. C1 [Hansen, Anne-Marie; Jin, Ding Jun] NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, Frederick Natl Lab Canc Res,NIH, Frederick, MD 21702 USA. RP Jin, DJ (reprint author), NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, Frederick Natl Lab Canc Res,NIH, Frederick, MD 21702 USA. EM jind@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Darren Sledjeski for the antiserum against H-NS. We also thank lab members for interaction and discussion during the course of the study. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 62 TC 7 Z9 7 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD OCT 11 PY 2012 VL 12 AR 231 DI 10.1186/1471-2180-12-231 PG 10 WC Microbiology SC Microbiology GA 071HI UT WOS:000313581400001 PM 23051860 ER PT J AU Castro, FA Koshiol, J Hsing, AW Gao, YT Rashid, A Chu, LW Shen, MC Wang, BS Han, TQ Zhang, BH Niwa, S Yu, K Zhang, H Chanock, S Andreotti, G AF Castro, Felipe A. Koshiol, Jill Hsing, Ann W. Gao, Yu-Tang Rashid, Asif Chu, Lisa W. Shen, Ming-Chang Wang, Bing-Shen Han, Tian-Qua Zhang, Bai-He Niwa, Shelley Yu, Kai Zhang, Hong Chanock, Stephen Andreotti, Gabriella TI Inflammatory gene variants and the risk of biliary tract cancers and stones: a population-based study in China SO BMC CANCER LA English DT Article DE Biliary tract cancer; Biliary stones; Inflammation; Genetic susceptibility ID NORTH INDIAN POPULATION; GALLBLADDER CANCER; POLYMORPHISMS; GALLSTONES; INFECTION; SHANGHAI; SUSCEPTIBILITY; SYSTEM AB Background: Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies. Methods: To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population-based case-control study in Shanghai, China. Results: Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate <= 0.2). Conclusion: These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation. C1 [Castro, Felipe A.; Koshiol, Jill; Hsing, Ann W.; Chu, Lisa W.; Yu, Kai; Chanock, Stephen; Andreotti, Gabriella] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Shen, Ming-Chang] Shanghai Tumor Hosp, Shanghai, Peoples R China. [Wang, Bing-Shen] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Han, Tian-Qua] Shanghai Med Univ 2, Ruijin Hosp, Dept Surg, Shanghai, Peoples R China. [Zhang, Bai-He] Second Mil Med Univ, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. [Niwa, Shelley] WESTAT Corp, Rockville, MD 20850 USA. [Zhang, Hong] Fudan Univ, Sch Life Sci, Inst Biostat, Shanghai 200433, Peoples R China. [Chanock, Stephen] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Adv Technol Ctr, Bethesda, MD 20892 USA. RP Castro, FA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7063, Rockville, MD 20892 USA. EM felipe.castro@nih.gov RI Castro, Felipe/N-4241-2013 FU Intramural Research Program of the National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA FX We thank the collaborating surgeons and pathologists in Shanghai for assistance in patient recruitment and pathology review; Chia-Rong Cheng, Lu Sun, and Kai Wu of the Shanghai Cancer Institute for coordinating data and specimen collection; and Shelley Niwa and Ann Truelove of Westat for support with study and data management. The study was funded by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA. NR 28 TC 9 Z9 9 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 11 PY 2012 VL 12 AR 468 DI 10.1186/1471-2407-12-468 PG 6 WC Oncology SC Oncology GA 059OV UT WOS:000312715800001 PM 23057767 ER PT J AU Huang, JP Jochems, C Talaie, T Anderson, A Jales, A Tsang, KY Madan, RA Gulley, JL Schlom, J AF Huang, Jianping Jochems, Caroline Talaie, Tara Anderson, Austin Jales, Alessandra Tsang, Kwong Y. Madan, Ravi A. Gulley, James L. Schlom, Jeffrey TI Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role SO BLOOD LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; METASTATIC PROSTATE-CANCER; SUPPRESSOR-CELLS; ENDOTHELIAL-CELLS; IMMUNE-SYSTEM; PLATELET ACTIVATION; IL-12 PRODUCTION; PLASMA-LEVELS; SURVIVAL; INVOLVEMENT AB Tumor cells can induce certain cytokines and soluble receptors that have a suppressive effect on the immune system. In this study, we showed that an extracellular portion of a membrane-bound ligand of CD40 (soluble CD40 ligand; sCD40L) was significantly elevated in the serum of cancer patients compared with healthy donors. In addition, PBMCs from cancer patients had a relatively larger population of myeloid-derived suppressor cells (MDSCs), defined as CD33(+)HLA-DR- cells, and these cells expressed higher levels of CD40. T-cell proliferation and IFN-gamma production decreased when stimulated T cells were cocultured with an increased amount of autologous MDSCs. The addition of recombinant monomeric sCD40L enriched MDSCs and had an additive inhibitory effect on T-cell proliferation. PBMCs cultured in vitro with sCD40L also showed an expansion of regulatory T cells (CD4+CD25(high)Foxp3(+)), as well as induction of cytokines, such as IL-10 and IL-6. Moreover, sCD40L-induced enrichment of programmed death-1-expressing T cells was greater in cancer patients than in healthy donors. Preexisting sCD40L also inhibited IL-12 production from monocytes on activation. These data suggest that the higher levels of sCD40L seen in cancer patients may have an immunosuppressive effect. These studies were registered at www.clinicaltrials.gov as NCT00060528, NCT00019695, NCT00179309, NCT00514072, NCT00081848, and NCT00436956. (Blood. 2012; 120(15):3030-3038) C1 [Huang, Jianping; Jochems, Caroline; Talaie, Tara; Anderson, Austin; Jales, Alessandra; Tsang, Kwong Y.; Madan, Ravi A.; Gulley, James L.; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Madan, Ravi A.; Gulley, James L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Rm 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 38 TC 37 Z9 39 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 11 PY 2012 VL 120 IS 15 BP 3030 EP 3038 DI 10.1182/blood-2012-05-427799 PG 9 WC Hematology SC Hematology GA 044KY UT WOS:000311619300020 PM 22932804 ER PT J AU Xu, HM Menendez, S Schlegelberger, B Bae, N Aplan, PD Gohring, G Deblasio, TR Nimer, SD AF Xu, Haiming Menendez, Silvia Schlegelberger, Brigitte Bae, Narae Aplan, Peter D. Goehring, Gudrun Deblasio, Tony R. Nimer, Stephen D. TI Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13-driven mouse model SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; SELF-RENEWAL; CHROMOSOMAL-ABNORMALITIES; TP53 MUTATIONS; GENE; MICE; MECHANISM; INDUCTION; EXPANSION AB The nucleoporin gene NUP98 is fused to several genes including HOXD13 in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myeloid leukemia, blast crisis. Genetically engineered mice that express a NUP98-HOXD13 (NHD13) transgene (Tg) display the phenotypic features of MDS, including cytopenias, bone marrow dysplasia, and transformation to acute leukemia. Here we show that short-term treatment with the p53 inhibitor Pifithrin-alpha partially and transiently rescued the myeloid and lymphoid abnormalities found in NHD13(+) Tg mice, with no improvement in the anemia, while the genetic deletion of 2 alleles of p53 rescued both the myeloid progenitor cell and long-term hematopoietic stem cell compartments. Nonetheless, loss of one or both alleles of p53 did not rescue the MDS phenotype, but instead exacerbated the MDS phenotype and accelerated the development of acute myeloid leukemia. Our studies suggest that while targeting p53 may transiently improve hematopoiesis in MDS, over the long-term, it has detrimental effects, raising caution about abrogating its function to treat the cytopenias that accompany this disease. (Blood. 2012; 120(15): 3089-3097) C1 [Nimer, Stephen D.] Univ Miami, Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Xu, Haiming; Menendez, Silvia; Bae, Narae; Deblasio, Tony R.; Nimer, Stephen D.] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10021 USA. [Schlegelberger, Brigitte; Goehring, Gudrun] Hannover Med Sch, Inst Cell & Mol Pathol, D-3000 Hannover, Germany. [Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nimer, SD (reprint author), Univ Miami, Sch Med, Sylvester Comprehens Canc Ctr, 1550 NW 10th Ave, Miami, FL 33136 USA. EM snimer@med.miami.edu RI Xu, Haiming/A-2238-2014; Aplan, Peter/K-9064-2016 FU Leukemia & Lymphoma Society SCOR grant; National Institutes of Health [DK52208]; Translational and Integrative Medicine Research Fund; National Institutes of Health, National Cancer Institute; National Institutes of Health Technology Transfer Office FX This work was supported by a Leukemia & Lymphoma Society SCOR grant (S.D.N.), National Institutes of Health RO1 grant (DK52208; S.D.N.), a Translational and Integrative Medicine Research Fund (S.D.N.), and the Intramural Research Program of the National Institutes of Health, National Cancer Institute (P.D.A.).; P.D.A. receives royalties from the National Institutes of Health Technology Transfer Office for the invention of NHD13 Tg mice. The remaining authors declare no competing financial interests. NR 36 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 11 PY 2012 VL 120 IS 15 BP 3089 EP 3097 DI 10.1182/blood-2012-01-405332 PG 9 WC Hematology SC Hematology GA 044KY UT WOS:000311619300026 PM 22927245 ER PT J AU Xu, JJ Wang, DD Liu, DY Fan, ZP Zhang, HY Liu, OS Ding, G Gao, RT Zhang, CM Ding, YZ Bromberg, JS Chen, WJ Sun, LY Wang, SL AF Xu, Junji Wang, Dandan Liu, Dayong Fan, Zhipeng Zhang, Huayong Liu, Ousheng Ding, Gang Gao, Runtao Zhang, Chunmei Ding, Yaozhong Bromberg, Jonathan S. Chen, Wanjun Sun, Lingyun Wang, Songlin TI Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome SO BLOOD LA English DT Article ID REGULATORY T-CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; STROMAL CELLS; DENDRITIC CELLS; SALIVARY-GLANDS; DOUBLE-BLIND; BONE-MARROW; TRANSPLANTATION; PATHOGENESIS; GENERATION AB Sjogren syndrome (SS) is a systemic autoimmune disease characterized by dry mouth and eyes, and the cellular and molecular mechanisms for its pathogenesis are complex. Here we reveal, for the first time, that bone marrow mesenchymal stem cells in SS-like NOD/Ltj mice and human patients were defective in immunoregulatory functions. Importantly, treatment with mesenchymal stem cells (MSCs) suppressed autoimmunity and restored salivary gland secretory function in both mouse models and SS patients. MSC treatment directed T cells toward Treg and Th2, while suppressing Th17 and Tfh responses, and alleviated disease symptoms. Infused MSCs migrated toward the inflammatory regions in a stromal cell-derived factor-1-dependent manner, as neutralization of stromal cell-derived factor-1 ligand CXCR4 abolished the effectiveness of bone marrow mesenchymal stem cell treatment. Collectively, our study suggests that immunologic regulatory functions of MSCs play an important role in SS pathogenesis, and allogeneic MSC treatment may provide a novel, effective, and safe therapy for patients with SS. This study was registered atwww.clinicaltrials.gov as NCT00953485. (Blood. 2012; 120(15): 3142-3151) C1 [Xu, Junji; Liu, Dayong; Fan, Zhipeng; Liu, Ousheng; Ding, Gang; Gao, Runtao; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. [Xu, Junji; Liu, Dayong; Fan, Zhipeng; Liu, Ousheng; Ding, Gang; Gao, Runtao; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Beijing 100050, Peoples R China. [Wang, Dandan; Zhang, Huayong; Sun, Lingyun] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Rheumatol & Immunol, Nanjing, Jiangsu, Peoples R China. [Liu, Ousheng] Cent S Univ, Xiangya Hosp, Dept Oral & Maxillofacial Surg, Changsha, Hunan, Peoples R China. [Ding, Yaozhong] Capital Med Univ, Dept Immunol, Beijing 100050, Peoples R China. [Ding, Yaozhong; Bromberg, Jonathan S.] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA. [Bromberg, Jonathan S.] Univ Maryland, Sch Med, Ctr Vasc Inflammatory Dis, Baltimore, MD 21201 USA. [Chen, Wanjun] Natl Inst Dent & Craniofacial Res, NIH, Baltimore, MD USA. [Wang, Songlin] Capital Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100050, Peoples R China. RP Wang, SL (reprint author), Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Tian Tan Xi Li 4, Beijing 100050, Peoples R China. EM slwang@ccmu.edu.cn OI Liu, Dayong/0000-0001-8511-2658 FU National Nature Science Foundation of China [30430690, 30972736]; National Basic Research Program of China [2007CB947304, 2010CB944801]; Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality [PHR20090510]; Funding Project to Science Facility in Institutions of Higher Learning Under the jurisdiction of Beijing Municipality [PXM 2009-014226-074691, PXM2011-014226-07-000066]; Major International (Regional) Joint Research Project [81120108021]; Jiangsu Province Natural Science Foundation [BK2009034]; Jiangsu Province Kejiao Xingwei Program; National Institutes of Health, National Institute of Dental and Craniofacial Research FX This work was supported by the National Nature Science Foundation of China (Key project grant 30430690, S. W.), the National Basic Research Program of China (2007CB947304 and 2010CB944801, S. W.), the Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (PHR20090510, S. W.), the Funding Project to Science Facility in Institutions of Higher Learning Under the jurisdiction of Beijing Municipality (PXM 2009-014226-074691, S. W.; PXM2011-014226-07-000066, Z.F.), Major International (Regional) Joint Research Project (81120108021, L. S.), the National Nature Science Foundation of China (30972736, L. S.), Jiangsu Province Natural Science Foundation (BK2009034, L. S.), Jiangsu Province Kejiao Xingwei Program (L. S.), and the Intramural Research Program of National Institutes of Health, National Institute of Dental and Craniofacial Research (W.C.). NR 45 TC 69 Z9 78 U1 3 U2 27 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 OCT 11 PY 2012 VL 120 IS 15 BP 3142 EP 3151 DI 10.1182/blood-2011-11-391144 PG 10 WC Hematology SC Hematology GA 044KY UT WOS:000311619300033 PM 22927248 ER PT J AU Keyvanfar, K Weed, J Swamy, P Kajigaya, S Calado, RT Young, NS AF Keyvanfar, Keyvan Weed, Jason Swamy, Prashanth Kajigaya, Sachiko Calado, Rodrigo T. Young, Neal S. TI Interphase Chromosome Flow-FISH SO BLOOD LA English DT Article ID IN-SITU HYBRIDIZATION; MYELODYSPLASTIC-SYNDROME; TELOMERE LENGTH; SCORING SYSTEM; REPETITIVE DNA; CYTOGENETICS; CYTOMETRY; LEUKEMIA; SUBPOPULATIONS; PROGNOSIS AB A 2-day method using flow cytometry and FISH for interphase cells was developed to detect monosomy 7 cells in myelodysplastic syndrome patients. The method, Interphase Chromosome Flow-FISH (IC Flow-FISH), involves fixation of leukocytes from blood, membrane permeabilization, hybridization of cellular DNA with peptide nucleic acid probes with cells intact, and analysis by flow cytometry. Hundreds to thousands of monosomy 7 cells were consistently detected from 10-20 mL of blood in patients with monosomy 7. Proportions of monosomy 7 cells detected in IC Flow-FISH were compared with results from conventional cytogenetics; identification of monosomy 7 populations was verified with FACS; and patient and donor cells were mixed to test for sensitivity. IC Flow-FISH allows for detecting monosomy 7 without requiring bone marrow procurement or the necessity of metaphase spreads, and wider applications to other chromosomal abnormalities are in development. (Blood. 2012; 120(15): e54-e59) C1 [Keyvanfar, Keyvan; Weed, Jason; Swamy, Prashanth; Kajigaya, Sachiko; Calado, Rodrigo T.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Calado, Rodrigo T.] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, BR-14049 Ribeirao Preto, SP, Brazil. RP Weed, J (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10-CRC,Rm 3E-5216,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jason.weed@nih.gov RI Calado, Rodrigo/G-2619-2011 FU National Institutes of Health Intramural Research Program; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo FX This work was supported by the National Institutes of Health Intramural Research Program. R.T.C. was supported in part by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo. NR 19 TC 1 Z9 1 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 11 PY 2012 VL 120 IS 15 BP E54 EP E59 DI 10.1182/blood-2012-05-434266 PG 6 WC Hematology SC Hematology GA 044KY UT WOS:000311619300001 PM 22932794 ER PT J AU Landis, SC Amara, SG Asadullah, K Austin, CP Blumenstein, R Bradley, EW Crystal, RG Darnell, RB Ferrante, RJ Fillit, H Finkelstein, R Fisher, M Gendelman, HE Golub, RM Goudreau, JL Gross, RA Gubitz, AK Hesterlee, SE Howells, DW Huguenard, J Kelner, K Koroshetz, W Krainc, D Lazic, SE Levine, MS Macleod, MR McCall, JM Moxley, RT Narasimhan, K Noble, LJ Perrin, S Porter, JD Steward, O Unger, E Utz, U Silberberg, SD AF Landis, Story C. Amara, Susan G. Asadullah, Khusru Austin, Chris P. Blumenstein, Robi Bradley, Eileen W. Crystal, Ronald G. Darnell, Robert B. Ferrante, Robert J. Fillit, Howard Finkelstein, Robert Fisher, Marc Gendelman, Howard E. Golub, Robert M. Goudreau, John L. Gross, Robert A. Gubitz, Amelie K. Hesterlee, Sharon E. Howells, David W. Huguenard, John Kelner, Katrina Koroshetz, Walter Krainc, Dimitri Lazic, Stanley E. Levine, Michael S. Macleod, Malcolm R. McCall, John M. Moxley, Richard T., III Narasimhan, Kalyani Noble, Linda J. Perrin, Steve Porter, John D. Steward, Oswald Unger, Ellis Utz, Ursula Silberberg, Shai D. TI A call for transparent reporting to optimize the predictive value of preclinical research SO NATURE LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; CONTROLLED CLINICAL-TRIALS; EXPERIMENTAL STROKE; EMPIRICAL-EVIDENCE; STATISTICAL-ANALYSIS; CONSORT STATEMENT; PUBLICATION BIAS; DRUG DEVELOPMENT; ANIMAL RESEARCH; CANCER-RESEARCH AB The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress. C1 [Landis, Story C.; Finkelstein, Robert; Gubitz, Amelie K.; Koroshetz, Walter; Porter, John D.; Utz, Ursula; Silberberg, Shai D.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Amara, Susan G.] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Asadullah, Khusru] Bayer HealthCare, D-13342 Berlin, Germany. [Austin, Chris P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20854 USA. [Blumenstein, Robi] CHDI Management CHDI Fdn, New York, NY 10001 USA. [Bradley, Eileen W.] NIH, Ctr Review, Bethesda, MD 20892 USA. [Crystal, Ronald G.] Weill Cornell Med Coll, Dept Genet Med, New York, NY 10021 USA. [Darnell, Robert B.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15213 USA. [Fillit, Howard] Alzheimers Drug Discovery Fdn, New York, NY 10019 USA. [Fisher, Marc] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01545 USA. [Gendelman, Howard E.] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68198 USA. [Golub, Robert M.] JAMA, Chicago, IL 60654 USA. [Goudreau, John L.] Michigan State Univ, Dept Neurol, E Lansing, MI 48824 USA. [Gross, Robert A.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Hesterlee, Sharon E.] Parent Project Muscular Dystrophy, Hackensack, NJ 07601 USA. [Howells, David W.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Heidelberg, Vic 3081, Australia. [Huguenard, John] Stanford Univ, Stanford, CA 94305 USA. [Kelner, Katrina] AAAS, Washington, DC USA. [Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Lazic, Stanley E.] F Hoffmann La Roche & Co Ltd, CH-4070 Basel, Switzerland. [Levine, Michael S.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Macleod, Malcolm R.] Univ Edinburgh, Western Gen Hosp, Dept Clin Neurosci, Edinburgh EH4 2XU, Midlothian, Scotland. [Moxley, Richard T., III] Univ Rochester, Med Ctr, Sch Med & Dent, Rochester, NY 14642 USA. [McCall, John M.] PharMac LLC, Boca Grande, FL 33921 USA. [Narasimhan, Kalyani] Nat Neurosci, New York, NY 10013 USA. [Noble, Linda J.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Perrin, Steve] ALS Therapy Dev Inst, Cambridge, MA 02139 USA. [Steward, Oswald] Univ Calif Irvine, Reeve Irvine Res Ctr, Irvine, CA 92697 USA. [Unger, Ellis] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Silberberg, SD (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. EM silberbs@ninds.nih.gov RI Lazic, Stanley/F-1160-2011; Huguenard, John/I-5016-2012; Darnell, Robert/B-9022-2008; OI Huguenard, John/0000-0002-6950-1191; Darnell, Robert/0000-0002-5134-8088; Steward, Oswald/0000-0001-7069-8756; Macleod, Malcolm Robert/0000-0001-9187-9839 FU NINDS FX Funded by NINDS. NR 64 TC 380 Z9 386 U1 8 U2 91 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 11 PY 2012 VL 490 IS 7419 BP 187 EP 191 DI 10.1038/nature11556 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 019IY UT WOS:000309733300036 PM 23060188 ER PT J AU Yang, J Loos, RJF Powell, JE Medland, SE Speliotes, EK Chasman, DI Rose, LM Thorleifsson, G Steinthorsdottir, V Maegi, R Waite, L Smith, AV Yerges-Armstrong, LM Monda, KL Hadley, D Mahajan, A Li, G Kapur, K Vitart, V Huffman, JE Wang, SR Palmer, C Esko, T Fischer, K Zhao, JH Demirkan, A Isaacs, A Feitosa, MF Luan, J Heard-Costa, NL White, C Jackson, AU Preuss, M Ziegler, A Eriksson, J Kutalik, Z Frau, F Nolte, IM Van Vliet-Ostaptchouk, JV Hottenga, JJ Jacobs, KB Verweij, N Goel, A Medina-Gomez, C Estrada, K Bragg-Gresham, JL Sanna, S Sidore, C Tyrer, J Teumer, A Prokopenko, I Mangino, M Lindgren, CM Assimes, TL Shuldiner, AR Hui, J Beilby, JP McArdle, WL Hall, P Haritunians, T Zgaga, L Kolcic, I Polasek, O Zemunik, T Oostra, BA Junttila, MJ Groenberg, H Schreiber, S Peters, A Hicks, AA Stephens, J Foad, NS Laitinen, J Pouta, A Kaakinen, M Willemsen, G Vink, JM Wild, SH Navis, G Asselbergs, FW Homuth, G John, U Iribarren, C Harris, T Launer, L Gudnason, V O'Connell, JR Boerwinkle, E Cadby, G Palmer, LJ James, AL Musk, AW Ingelsson, E Psaty, BM Beckmann, JS Waeber, G Vollenweider, P Hayward, C Wright, AF Rudan, I Groop, LC Metspalu, A Khaw, KT van Duijn, CM Borecki, IB Province, MA Wareham, NJ Tardif, JC Huikuri, HV Cupples, LA Atwood, LD Fox, CS Boehnke, M Collins, FS Mohlke, KL Erdmann, J Schunkert, H Hengstenberg, C Stark, K Lorentzon, M Ohlsson, C Cusi, D Staessen, JA Van der Klauw, MM Pramstaller, PP Kathiresan, S Jolley, JD Ripatti, S Jarvelin, MR de Geus, EJC Boomsma, DI Penninx, B Wilson, JF Campbell, H Chanock, SJ van der Harst, P Hamsten, A Watkins, H Hofman, A Witteman, JC Zillikens, MC Uitterlinden, AG Rivadeneira, F Zillikens, MC Kiemeney, LA Vermeulen, SH Abecasis, GR Schlessinger, D Schipf, S Stumvoll, M Toenjes, A Spector, TD North, KE Lettre, G McCarthy, MI Berndt, SI Heath, AC Madden, PAF Nyholt, DR Montgomery, GW Martin, NG McKnight, B Strachan, DP Hill, WG Snieder, H Ridker, PM Thorsteinsdottir, U Stefansson, K Frayling, TM Hirschhorn, JN Goddard, ME Visscher, PM AF Yang, Jian Loos, Ruth J. F. Powell, Joseph E. Medland, Sarah E. Speliotes, Elizabeth K. Chasman, Daniel I. Rose, Lynda M. Thorleifsson, Gudmar Steinthorsdottir, Valgerdur Maegi, Reedik Waite, Lindsay Smith, Albert Vernon Yerges-Armstrong, Laura M. Monda, Keri L. Hadley, David Mahajan, Anubha Li, Guo Kapur, Karen Vitart, Veronique Huffman, Jennifer E. Wang, Sophie R. Palmer, Cameron Esko, Toenu Fischer, Krista Zhao, Jing Hua Demirkan, Ayse Isaacs, Aaron Feitosa, Mary F. Luan, Jian'an Heard-Costa, Nancy L. White, Charles Jackson, Anne U. Preuss, Michael Ziegler, Andreas Eriksson, Joel Kutalik, Zoltan Frau, Francesca Nolte, Ilja M. Van Vliet-Ostaptchouk, Jana V. Hottenga, Jouke-Jan Jacobs, Kevin B. Verweij, Niek Goel, Anuj Medina-Gomez, Carolina Estrada, Karol Bragg-Gresham, Jennifer Lynn Sanna, Serena Sidore, Carlo Tyrer, Jonathan Teumer, Alexander Prokopenko, Inga Mangino, Massimo Lindgren, Cecilia M. Assimes, Themistocles L. Shuldiner, Alan R. Hui, Jennie Beilby, John P. McArdle, Wendy L. Hall, Per Haritunians, Talin Zgaga, Lina Kolcic, Ivana Polasek, Ozren Zemunik, Tatijana Oostra, Ben A. Junttila, M. Juhani Groenberg, Henrik Schreiber, Stefan Peters, Annette Hicks, Andrew A. Stephens, Jonathan Foad, Nicola S. Laitinen, Jaana Pouta, Anneli Kaakinen, Marika Willemsen, Gonneke Vink, Jacqueline M. Wild, Sarah H. Navis, Gerjan Asselbergs, Folkert W. Homuth, Georg John, Ulrich Iribarren, Carlos Harris, Tamara Launer, Lenore Gudnason, Vilmundur O'Connell, Jeffrey R. Boerwinkle, Eric Cadby, Gemma Palmer, Lyle J. James, Alan L. Musk, Arthur W. Ingelsson, Erik Psaty, Bruce M. Beckmann, Jacques S. Waeber, Gerard Vollenweider, Peter Hayward, Caroline Wright, Alan F. Rudan, Igor Groop, Leif C. Metspalu, Andres Khaw, Kay Tee van Duijn, Cornelia M. Borecki, Ingrid B. Province, Michael A. Wareham, Nicholas J. Tardif, Jean-Claude Huikuri, Heikki V. Cupples, L. Adrienne Atwood, Larry D. Fox, Caroline S. Boehnke, Michael Collins, Francis S. Mohlke, Karen L. Erdmann, Jeanette Schunkert, Heribert Hengstenberg, Christian Stark, Klaus Lorentzon, Mattias Ohlsson, Claes Cusi, Daniele Staessen, Jan A. Van der Klauw, Melanie M. Pramstaller, Peter P. Kathiresan, Sekar Jolley, Jennifer D. Ripatti, Samuli Jarvelin, Marjo-Riitta de Geus, Eco J. C. Boomsma, Dorret I. Penninx, Brenda Wilson, James F. Campbell, Harry Chanock, Stephen J. van der Harst, Pim Hamsten, Anders Watkins, Hugh Hofman, Albert Witteman, Jacqueline C. Zillikens, M. Carola Uitterlinden, Andre G. Rivadeneira, Fernando Zillikens, M. Carola Kiemeney, Lambertus A. Vermeulen, Sita H. Abecasis, Goncalo R. Schlessinger, David Schipf, Sabine Stumvoll, Michael Toenjes, Anke Spector, Tim D. North, Kari E. Lettre, Guillaume McCarthy, Mark I. Berndt, Sonja I. Heath, Andrew C. Madden, Pamela A. F. Nyholt, Dale R. Montgomery, Grant W. Martin, Nicholas G. McKnight, Barbara Strachan, David P. Hill, William G. Snieder, Harold Ridker, Paul M. Thorsteinsdottir, Unnur Stefansson, Kari Frayling, Timothy M. Hirschhorn, Joel N. Goddard, Michael E. Visscher, Peter M. TI FTO genotype is associated with phenotypic variability of body mass index SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; ENVIRONMENTAL SENSITIVITY; PHYSICAL-ACTIVITY; GENETIC-VARIATION; ADULT OBESITY; LOCI; VARIANTS; CHILDHOOD; SELECTION; TRAITS AB There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000. C1 [Yang, Jian; Powell, Joseph E.] Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. [Yang, Jian; Powell, Joseph E.; Medland, Sarah E.; Nyholt, Dale R.; Montgomery, Grant W.; Martin, Nicholas G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Loos, Ruth J. F.; Zhao, Jing Hua; Luan, Jian'an; Wareham, Nicholas J.] Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Loos, Ruth J. F.] Mt Sinai Sch Med, New York, NY 10029 USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur] deCODE Genet, IS-101 Reykjavik, Iceland. [Maegi, Reedik; Esko, Toenu; Fischer, Krista; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50410 Tartu, Estonia. [Maegi, Reedik; Mahajan, Anubha; Lindgren, Cecilia M.; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Waite, Lindsay; Frayling, Timothy M.] Hudson Alpha Inst Biotechnol, Huntsville, AL 35806 USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert Vernon] Univ Iceland, IS-101 Reykjavik, Iceland. [Yerges-Armstrong, Laura M.; O'Connell, Jeffrey R.] Univ Maryland, Dept Med, Sch Med, Baltimore, MD 21201 USA. [Monda, Keri L.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Hadley, David; Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England. [Li, Guo] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Kapur, Karen; Kutalik, Zoltan; Jacobs, Kevin B.] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Kapur, Karen; Kutalik, Zoltan; Jacobs, Kevin B.] Swiss Inst Bioinformat, CH-1005 Lausanne, Switzerland. [Vitart, Veronique; Huffman, Jennifer E.; Hayward, Caroline; Wright, Alan F.] Univ Edinburgh, MRC HGU, MRC IGMM, Edinburgh EH8 9AG, Midlothian, Scotland. [Wang, Sophie R.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Wang, Sophie R.; Palmer, Cameron] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Wang, Sophie R.; Palmer, Cameron] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Wang, Sophie R.; Palmer, Cameron] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Wang, Sophie R.; Palmer, Cameron; Hirschhorn, Joel N.] Broad Inst, Metab Initiat, Cambridge, MA 02142 USA. [Wang, Sophie R.; Palmer, Cameron; Hirschhorn, Joel N.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Demirkan, Ayse; Isaacs, Aaron; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Subdiv Genet Epidemiol, Rotterdam, Netherlands. [Feitosa, Mary F.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Preuss, Michael] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Preuss, Michael; Ziegler, Andreas; Van Vliet-Ostaptchouk, Jana V.] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23562 Lubeck, Germany. [Eriksson, Joel; Hottenga, Jouke-Jan; Lorentzon, Mattias; Ohlsson, Claes] Univ Gothenburg, Ctr Bone & Arthrit Res, Inst Med, Sahlgrenska Acad, S-41345 Gothenburg, Sweden. [Frau, Francesca; Verweij, Niek; Cusi, Daniele] Univ Milan, Dept Hlth Sci, I-20133 Milan, Italy. [Nolte, Ilja M.; Goel, Anuj; Snieder, Harold] Univ Groningen, Unit Genet Epidemiol & Bioinformat, Dept Epidemiol, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. [Medina-Gomez, Carolina; Van der Klauw, Melanie M.] Univ Groningen, Dept Endocrinol, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. [Medina-Gomez, Carolina] Univ Groningen, LifeLines Cohort Study, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. [Estrada, Karol; Kaakinen, Marika; Willemsen, Gonneke; Vink, Jacqueline M.; de Geus, Eco J. C.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Bragg-Gresham, Jennifer Lynn] SAIC Frederick Inc, Core Genotyping Facil, NCI Frederick, Frederick, MD 21702 USA. [van der Harst, Pim] Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. [Zillikens, M. Carola] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Witteman, Jacqueline C.; Rivadeneira, Fernando] Netherlands Consortiumfor Healthy Aging, Netherlands Genom Initiat, NL-2300 RC Leiden, Netherlands. [Sanna, Serena; Abecasis, Goncalo R.] Univ Michigan, Biostat Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Sidore, Carlo] CNR, Ist Ric Genet & Biomed, I-09042 Monserrato, Italy. [Sidore, Carlo] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Tyrer, Jonathan] Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England. [Teumer, Alexander; Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany. [Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7BN, England. [Mangino, Massimo; Toenjes, Anke] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA. [Hui, Jennie; Beilby, John P.] Univ Western Australia, PathWest Lab Med WA, Nedlands, WA 6009, Australia. [Hui, Jennie] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [Hall, Per; Groenberg, Henrik; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Haritunians, Talin] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA. [Zgaga, Lina; Wild, Sarah H.; Rudan, Igor; Wilson, James F.; Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Sch Med, Edinburgh EH16 4TJ, Midlothian, Scotland. [Zgaga, Lina] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia. [Kolcic, Ivana; Polasek, Ozren; Zemunik, Tatijana] Univ Split, Fac Med, Split 21000, Croatia. [Junttila, M. Juhani; Huikuri, Heikki V.] Univ Oulu, Dept Internal Med, Inst Clin Med, Oulu 90014, Finland. [Peters, Annette] Univ Kiel, Inst Klin Mol Biol, D-24098 Kiel, Germany. [Peters, Annette] Munich Heart Alliance, D-80802 Munich, Germany. [Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy. [Stephens, Jonathan] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England. [Stephens, Jonathan; Jolley, Jennifer D.] NHS Blood & Transplant, Cambridge CB2 0PT, England. [Foad, Nicola S.] Finnish Inst Occupat Hlth, Oulu 90220, Finland. [Laitinen, Jaana] Natl Inst Hlth & Welf, Oulu 90101, Finland. [Laitinen, Jaana] Univ Oulu, Dept Clin Sci Obstet & Gynecol, Oulu 90014, Finland. [Pouta, Anneli] Univ Oulu, Inst Hlth Sci, Bioctr, Oulu 90014, Finland. [Navis, Gerjan] Univ Groningen, Dept Internal Med, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, NL-3508 GA Utrecht, Netherlands. [John, Ulrich] Univ Med Greifswald, Inst Epidemiol & Social Med, D-17475 Greifswald, Germany. [Iribarren, Carlos] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Harris, Tamara; Launer, Lenore] NIA, NIH, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr, Houston, TX 77030 USA. [Cadby, Gemma; Palmer, Lyle J.] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. [James, Alan L.; Musk, Arthur W.] Univ Western Australia, Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Beckmann, Jacques S.] CHUV Univ Hosp, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Waeber, Gerard; Vollenweider, Peter] Univ Lausanne Hosp, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Groop, Leif C.] Lund Univ, Ctr Diabet, Dept Clin Sci, S-20502 Malmo, Sweden. [Khaw, Kay Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Borecki, Ingrid B.; Province, Michael A.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Tardif, Jean-Claude] Univ Montreal, Dept Med, Montreal, PQ H4J 1C5, Canada. [Tardif, Jean-Claude; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Fox, Caroline S.] Boston Univ, Framingham, MA 01702 USA. [Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Deutsch Zentrum Herz Kreislauf Forsch DZHK, D-23562 Lubeck, Germany. [Hengstenberg, Christian; Stark, Klaus] Klin & Poliklin Innere Med II, D-93053 Regensburg, Germany. [Staessen, Jan A.] Katholieke Univ Leuven, Dept Cardiovasc Dis, B-3000 Louvain, Belgium. [Cupples, L. Adrienne; Staessen, Jan A.] Maastricht Univ, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands. [Pramstaller, Peter P.] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, D-23562 Lubeck, Germany. [Kathiresan, Sekar] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Kathiresan, Sekar] MIT, Cambridge, MA 02142 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Ripatti, Samuli] Univ Helsinki, Inst Mol Med Finland, FIMM, FIN-00014 Helsinki, Finland. [Ripatti, Samuli] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki 00271, Finland. [Ripatti, Samuli] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, MRC HPA Ctr Environm & Hlth, London W2 1PG, England. [Penninx, Brenda] Univ Groningen, Dept Psychiat, Univ Med Ctr Groningen, NL-9713 GZ Groningen, Netherlands. [Chanock, Stephen J.; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Hamsten, Anders] Karolinska Inst, S-17177 Stockholm, Sweden. [Hamsten, Anders] Dept Med, Atherosclerosis Res Unit, S-17176 Stockholm, Sweden. [Kiemeney, Lambertus A.; Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, NL-6500 HB Nijmegen, Netherlands. [Schlessinger, David] NIA, NIH, Bethesda, MD 20892 USA. [Schipf, Sabine] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Stumvoll, Michael] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Stumvoll, Michael] Univ Leipzig, IFB Adipos Dis, D-04103 Leipzig, Germany. [Spector, Tim D.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Spector, Tim D.; North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27514 USA. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7LJ, England. [Heath, Andrew C.; Madden, Pamela A. F.] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA. [McKnight, Barbara] Washington Univ, Dept Biostat, St Louis, MO 63110 USA. [Hill, William G.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Frayling, Timothy M.] Univ Exeter, Inst Biomed & Clin Sci, Peninsula Med Sch, Exeter EX1 2LU, Devon, England. [Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic 3010, Australia. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Bundoora, Vic 3083, Australia. [Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. RP Yang, J (reprint author), Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. RI Erdmann, Jeanette/P-7513-2014; Verweij, Niek/A-4499-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Staessen, Jan/A-1065-2011; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Prokopenko, Inga/H-3241-2014; Peters, Annette/A-6117-2011; Vermeulen, H.H.M./L-4716-2015; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Yang, Jian/A-5852-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Medland, Sarah/C-7630-2013; Nyholt, Dale/C-8384-2013; Gudnason, Vilmundur/K-6885-2015; Beckmann, Jacques S /A-9772-2008; Abecasis, Goncalo/B-7840-2010; Colaus, PsyColaus/K-6607-2013; van der Klauw, Melanie/A-2138-2014; Kiemeney, Lambertus/D-3357-2009; Schreiber, Stefan/B-6748-2008; Powell, Joseph/G-3027-2014; Pramstaller, Peter/C-2357-2008; Palmer, Lyle/K-3196-2014 OI Visscher, Peter/0000-0002-2143-8760; Martin, Nicholas/0000-0003-4069-8020; Ziegler, Andreas/0000-0002-8386-5397; Rivadeneira, Fernando/0000-0001-9435-9441; Verweij, Niek/0000-0002-4303-7685; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; John, Ulrich/0000-0003-0587-5298; Watkins, Hugh/0000-0002-5287-9016; Medina-Gomez, Carolina/0000-0001-7999-5538; Esko, Tonu/0000-0003-1982-6569; Sidore, Carlo/0000-0001-7504-7477; Goddard, Michael/0000-0001-9917-7946; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Erdmann, Jeanette/0000-0002-4486-6231; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Wang, Sophie Ran/0000-0002-7897-8389; Heard-Costa, Nancy/0000-0001-9730-0306; Kaakinen, Marika/0000-0002-9228-0462; Cupples, L. Adrienne/0000-0003-0273-7965; Magi, Reedik/0000-0002-2964-6011; Zgaga, Lina/0000-0003-4089-9703; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Staessen, Jan/0000-0002-3026-1637; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Prokopenko, Inga/0000-0003-1624-7457; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Yang, Jian/0000-0003-2001-2474; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Medland, Sarah/0000-0003-1382-380X; Gudnason, Vilmundur/0000-0001-5696-0084; Beckmann, Jacques S /0000-0002-9741-1900; van der Klauw, Melanie/0000-0001-7178-009X; Kiemeney, Lambertus/0000-0002-2368-1326; Schreiber, Stefan/0000-0003-2254-7771; Powell, Joseph/0000-0001-9031-6356; Palmer, Lyle/0000-0002-1628-3055 FU Australian National Health and Medical Research Council (NHMRC) [241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601, 1011506]; US National Institutes of Health [AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, DA12854, GM057091]; Australian Research Council (ARC) [DP1093502] FX We acknowledge funding from the Australian National Health and Medical Research Council (NHMRC grants 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506), the US National Institutes of Health (grants AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, DA12854 and GM057091) and the Australian Research Council (ARC grant DP1093502). A detailed list of acknowledgements by study is provided in the Supplementary Information. We apologize to authors whose work we could not cite owing to space restrictions. NR 36 TC 121 Z9 130 U1 6 U2 106 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 11 PY 2012 VL 490 IS 7419 BP 267 EP + DI 10.1038/nature11401 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 019IY UT WOS:000309733300051 PM 22982992 ER PT J AU Okun, E Barak, B Saada-Madar, R Rothman, SM Griffioen, KJ Roberts, N Castro, K Mughal, MR Pita, MA Stranahan, AM Arumugam, TV Mattson, MP AF Okun, Eitan Barak, Boaz Saada-Madar, Ravit Rothman, Sarah M. Griffioen, Kathleen J. Roberts, Nicholas Castro, Kamilah Mughal, Mohamed R. Pita, Mario A. Stranahan, Alexis M. Arumugam, Thiruma V. Mattson, Mark P. TI Evidence for a Developmental Role for TLR4 in Learning and Memory SO PLOS ONE LA English DT Article ID TOLL-LIKE-RECEPTORS; ADULT HIPPOCAMPAL NEUROGENESIS; AMYGDALA; HMGB1 AB Toll-like receptors (TLRs) play essential roles in innate immunity and increasing evidence indicates that these receptors are expressed in neurons, astrocytes and microglia in the brain where they mediate responses to infection, stress and injury. Very little is known about the roles of TLRs in cognition. To test the hypothesis that TLR4 has a role in hippocampus-dependent spatial learning and memory, we used mice deficient for TLR4 and mice receiving chronic TLR4 antagonist infusion to the lateral ventricles in the brain. We found that developmental TLR4 deficiency enhances spatial reference memory acquisition and memory retention, impairs contextual fear-learning and enhances motor functions, traits that were correlated with CREB up-regulation in the hippocampus. TLR4 antagonist infusion into the cerebral ventricles of adult mice did not affect cognitive behavior, but instead affected anxiety responses. Our findings indicate a developmental role for TLR4 in shaping spatial reference memory, and fear learning and memory. Moreover, we show that central TLR4 inhibition using a TLR4 antagonist has no discernible physiological role in regulating spatial and contextual hippocampus-dependent cognitive behavior. C1 [Okun, Eitan; Saada-Madar, Ravit] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Leslie & Susan Gonda Multidisciplinary Brain Res, Ramat Gan, Israel. [Barak, Boaz] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [Barak, Boaz] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Rothman, Sarah M.; Griffioen, Kathleen J.; Roberts, Nicholas; Castro, Kamilah; Mughal, Mohamed R.; Pita, Mario A.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Stranahan, Alexis M.] Georgia Hlth Sci Univ, Dept Physiol, Augusta, GA USA. [Arumugam, Thiruma V.] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Okun, E (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Leslie & Susan Gonda Multidisciplinary Brain Res, Ramat Gan, Israel. EM eitan.okun@biu.ac.il RI Arumugam, Thiruma/B-4898-2011; okun, eitan/K-1314-2016; OI okun, eitan/0000-0001-8474-1487; Madar, Ravit/0000-0002-2025-8178; Castro, Kamilah/0000-0002-0176-0998 FU Intramural Research Program of the National Institute on Aging; Gonda Multidisciplinary Center for Brain Research; Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University FX This study was supported in part by the Intramural Research Program of the National Institute on Aging and in part by the Gonda Multidisciplinary Center for Brain Research and the Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 32 Z9 32 U1 1 U2 8 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 OCT 11 PY 2012 VL 7 IS 10 AR e47522 DI 10.1371/journal.pone.0047522 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020KP UT WOS:000309807700087 PM 23071817 ER PT J AU Tattersall, J Rao, GV Runac, J Hackstadt, T Grieshaber, SS Grieshaber, NA AF Tattersall, Jeremiah Rao, Geeta Vittal Runac, Justin Hackstadt, Ted Grieshaber, Scott S. Grieshaber, Nicole A. TI Translation Inhibition of the Developmental Cycle Protein HctA by the Small RNA IhtA Is Conserved across Chlamydia SO PLOS ONE LA English DT Article ID HISTONE-LIKE PROTEIN; TRACHOMATIS; HC1; DNA; EXPRESSION; TRANSCRIPTION; PURIFICATION; INFECTIONS; REPRESSION; PREDICTION AB The developmental cycle of the obligate intracellular pathogen Chlamydia trachomatis serovar L2 is controlled in part by the small non-coding RNA (sRNA), IhtA. All Chlamydia alternate in a regulated fashion between the infectious elementary body (EB) and the replicative reticulate body (RB) which asynchronously re-differentiates back to the terminal EB form at the end of the cycle. The histone like protein HctA is central to RB:EB differentiation late in the cycle as it binds to and occludes the genome, thereby repressing transcription and translation. The sRNA IhtA is a critical component of this regulatory loop as it represses translation of hctA until late in infection at which point IhtA transcription decreases, allowing HctA expression to occur and RB to EB differentiation to proceed. It has been reported that IhtA is expressed during infection by the human pathogens C. trachomatis serovars L2, D and L2b and C. pneumoniae. We show in this work that IhtA is also expressed by the animal pathogens C. caviae and C. muridarum. Expression of HctA in E. coli is lethal and co-expression of IhtA relieves this phenotype. To determine if regulation of HctA by IhtA is a conserved mechanism across pathogenic chlamydial species, we cloned hctA and ihtA from C. trachomatis serovar D, C. muridarum, C. caviae and C. pneumoniae and assayed for rescue of growth repression in E. coli co-expression studies. In each case, co-expression of ihtA with the cognate hctA resulted in relief of growth repression. In addition, expression of each chlamydial species IhtA rescued the lethal phenotype of C. trachomatis serovar L2 HctA expression. As biolayer interferometry studies indicate that IhtA interacts directly with hctA message for all species tested, we predict that conserved sequences of IhtA are necessary for function and/or binding. C1 [Tattersall, Jeremiah; Rao, Geeta Vittal; Runac, Justin; Grieshaber, Scott S.; Grieshaber, Nicole A.] Univ Florida, Coll Dent, Dept Oral Biol, Gainesville, FL 32610 USA. [Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Grieshaber, NA (reprint author), Univ Florida, Coll Dent, Dept Oral Biol, Gainesville, FL 32610 USA. EM ngriesha@ufl.edu FU National Institutes of Health grant [AI079193]; University of Florida Open-Access Publishing Fund FX This study was supported by National Institutes of Health grant AI079193 to NAG. Publication of this article was funded in part by the University of Florida Open-Access Publishing Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 7 Z9 7 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 OCT 11 PY 2012 VL 7 IS 10 AR e47439 DI 10.1371/journal.pone.0047439 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020KP UT WOS:000309807700080 PM 23071807 ER PT J AU Burks, AW Jones, SM Plaut, M AF Burks, A. Wesley Jones, Stacie M. Plaut, Marshall TI Oral Immunotherapy for Egg Allergy in Children REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Burks, A. Wesley] Univ N Carolina, Chapel Hill, NC 27515 USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Plaut, Marshall] NIH, Bethesda, MD 20892 USA. RP Burks, AW (reprint author), Univ N Carolina, Chapel Hill, NC 27515 USA. EM wburks@email.unc.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 11 PY 2012 VL 367 IS 15 BP 1472 EP 1473 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 018ID UT WOS:000309652700029 ER PT J AU Ananthan, S Saini, SK Dersch, CM Xu, H McGlinchey, N Giuvelis, D Bilsky, EJ Rothman, RB AF Ananthan, Subramaniam Saini, Surendra K. Dersch, Christina M. Xu, Heng McGlinchey, Nicholas Giuvelis, Denise Bilsky, Edward J. Rothman, Richard B. TI 14-Alkoxy- and 14-Acyloxypyridomorphinans: mu Agonist/delta Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BIOLOGICAL EVALUATION; RECEPTOR ANTAGONIST; MORPHINE-TOLERANCE; ANTINOCICEPTIVE TOLERANCE; SELECTIVE MU; DELTA; MICE; 14-ALKOXYMORPHINANS; BINDING; LIGANDS AB In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5 alpha-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects. C1 [Ananthan, Subramaniam; Saini, Surendra K.] So Res Inst, Dept Organ Chem, Birmingham, AL 35205 USA. [Dersch, Christina M.; Xu, Heng; Rothman, Richard B.] NIDA, Translat Pharmacol Sect, Chem Biol Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [McGlinchey, Nicholas; Giuvelis, Denise; Bilsky, Edward J.] Univ New England, Dept Biomed Sci, Coll Osteopath Med, Biddeford, ME 04005 USA. [McGlinchey, Nicholas; Giuvelis, Denise; Bilsky, Edward J.] Univ New England, Ctr Excellence Neurosci, Biddeford, ME 04005 USA. RP Ananthan, S (reprint author), So Res Inst, Dept Organ Chem, Birmingham, AL 35205 USA. EM ananthan@southernresearch.org FU NIH from the National Institute on Drug Abuse (NIDA) [R01DA008883]; NIDA FX This investigation was supported by NIH grant R01DA008883 from the National Institute on Drug Abuse (NIDA). Portions of this work were supported by the Intramural Research Program of NIDA. We thank Dr. James M. Riordan, Mr. Mark D. Richardson, Ms. Joan C. Bearden, and Ms. Jackie W. Truss for analytical and spectral data. We are grateful to Dr. John A. Secrist III for his encouragement, valuable comments, and suggestions during the course of this work. NR 48 TC 23 Z9 23 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 11 PY 2012 VL 55 IS 19 BP 8350 EP 8363 DI 10.1021/jm300686p PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 018ES UT WOS:000309643500014 PM 23016952 ER PT J AU Kim, MS Ryu, H Kang, DW Cho, SH Seo, S Park, YS Kim, MY Kwak, EJ Kim, YS Bhondwe, RS Kim, HS Park, SG Son, K Choi, S DeAndrea-Lazarus, IA Pearce, LV Blumberg, PM Frank, R Bahrenberg, G Stockhausen, H Kogel, BY Schiene, K Christoph, T Lee, J AF Kim, Myeong Seop Ryu, HyungChul Kang, Dong Wook Cho, Seong-Hee Seo, Sejin Park, Young Soo Kim, Mi-Yeon Kwak, Eun Joo Kim, Yong Soo Bhondwe, Rahul S. Kim, Ho Shin Park, Seul-gi Son, Karam Choi, Sun DeAndrea-Lazarus, Ian A. Pearce, Larry V. Blumberg, Peter M. Frank, Robert Bahrenberg, Gregor Stockhausen, Hannelore Koegel, Babette Y. Schiene, Klaus Christoph, Thomas Lee, Jeewoo TI 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure-Activity Relationships of 2-Amino Derivatives in the N-(6-Trifluoromethylpyridin-3-ylmethyl) C-Region SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CAPSAICIN RECEPTOR; PAIN SENSATION; RESINIFERATOXIN AB A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K-i(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region. C1 [Kim, Myeong Seop; Ryu, HyungChul; Kang, Dong Wook; Cho, Seong-Hee; Seo, Sejin; Park, Young Soo; Kim, Mi-Yeon; Kwak, Eun Joo; Kim, Yong Soo; Bhondwe, Rahul S.; Kim, Ho Shin; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. [Park, Seul-gi; Son, Karam; Choi, Sun] Ewha Womans Univ, Coll Pharm, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Park, Seul-gi; Son, Karam; Choi, Sun] Ewha Womans Univ, Natl Core Res Ctr Cell Signaling & Drug Discovery, Seoul 120750, South Korea. [DeAndrea-Lazarus, Ian A.; Pearce, Larry V.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Koegel, Babette Y.; Schiene, Klaus; Christoph, Thomas] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Grunenthal; National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; NLRL [2011-0028885]; 21st Century Frontier Research Program [2011-K000289]; NCRC [2012-0000952]; Ewha Global Top 5 Grant; NIH, Center for Cancer Research, NCI [Z1A BC 005270] FX This research was supported by research grants from Grunenthal, grants from the National Research Foundation of Korea (NRF) (Grant R11-2007-107-02001-0), grants from the NLRL program (Grant 2011-0028885), the 21st Century Frontier Research Program (Grant 2011-K000289), and NCRC program (Grant 2012-0000952), and the Ewha Global Top 5 Grant 2011 and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270). NR 26 TC 16 Z9 16 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 11 PY 2012 VL 55 IS 19 BP 8392 EP 8408 DI 10.1021/jm300780p PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 018ES UT WOS:000309643500017 PM 22957803 ER PT J AU Canchi, DR Jayasimha, P Rau, DC Makhatadze, GI Garcia, AE AF Canchi, Deepak R. Jayasimha, Pruthvi Rau, Donald C. Makhatadze, George I. Garcia, Angel E. TI Molecular Mechanism for the Preferential Exclusion of TMAO from Protein Surfaces SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TRIMETHYLAMINE-N-OXIDE; FORCE-FIELD; DYNAMICS SIMULATION; HYDROPHOBIC INTERACTIONS; UREA DENATURATION; OSMOTIC-STRESS; AQUEOUS UREA; TRP-CAGE; OSMOLYTE; WATER AB Trimethylamine N-oxide (TMAO) is a naturally occurring protecting osmolyte that stabilizes the folded state of proteins and also counteracts the destabilizing effect of urea on protein stability. Experimentally, it has been inferred that TMAO is preferentially excluded from the vicinity of protein surfaces. Here, we combine computer modeling and experimental measurements to gain an understanding of the mechanism of the protecting effect of TMAO on proteins. We have developed an all-atom molecular model for TMAO that captures the exclusion of TMAO from model compounds and protein surfaces, as a consequence of incorporating realistic TMAO water interactions through osmotic pressure measurements. Osmotic pressure measurements also suggest no significant attraction between urea and TMAO molecules in solution. To obtain an accurate potential for molecular simulations of protein stability in TMAO solutions, we have explored different ways of parametrizing the protein/osmolyte and osmolyte/osmolyte interactions by scaling charges and the strength of Leonard-Jones interactions and carried out equilibrium folding experiments of Trp-cage miniprotein in the presence of TMAO to guide the parametrization. Our calculations suggest a general principle for preferential interaction behavior of cosolvents with protein surfaces-preferentially excluded osmolytes have repulsive self-interaction given by osmotic coefficient phi > 1, while denaturants, in addition to having attractive interactions with the proteins, have favorable self-interaction given by osmotic coefficient phi < 1, to enable preferential accumulation in the vicinity of proteins. C1 [Makhatadze, George I.; Garcia, Angel E.] Rensselaer Polytech Inst, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY 12180 USA. [Canchi, Deepak R.] Rensselaer Polytech Inst, Dept Chem Engn, Troy, NY 12180 USA. [Jayasimha, Pruthvi; Makhatadze, George I.] Rensselaer Polytech Inst, Dept Biol, Troy, NY 12180 USA. [Rau, Donald C.] NICHHD, NIH, Bethesda, MD 20852 USA. [Garcia, Angel E.] Rensselaer Polytech Inst, Dept Phys Appl Phys & Astron, Troy, NY 12180 USA. RP Garcia, AE (reprint author), Rensselaer Polytech Inst, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY 12180 USA. EM angel@rpi.edu FU National Science Foundation (NSF) [MCB-1050966, MCB-0110396]; National Institutes of Health [GM086801]; National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work has been funded by the National Science Foundation (NSF MCB-1050966 to A.E.G. and MCB-0110396 to G.I.M.) and the National Institutes of Health (GM086801). This research was partially supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank M. T. Record and D. Thirumalai for comments and suggestions. NR 66 TC 57 Z9 57 U1 6 U2 73 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 11 PY 2012 VL 116 IS 40 BP 12095 EP 12104 DI 10.1021/jp304298c PG 10 WC Chemistry, Physical SC Chemistry GA 018GT UT WOS:000309648900004 PM 22970901 ER PT J AU Oh, J Conlan, S Polley, EC Segre, JA Kong, HH AF Oh, Julia Conlan, Sean Polley, Eric C. Segre, Julia A. Kong, Heidi H. TI Shifts in human skin and nares microbiota of healthy children and adults SO GENOME MEDICINE LA English DT Article ID PUBERTAL DEVELOPMENT; BODY HABITATS; DIVERSITY; PATTERN; LIPIDS; GIRLS; BOYS; SEX AB Background: Characterization of the topographical and temporal diversity of the microbial collective (microbiome) hosted by healthy human skin established a reference for studying disease-causing microbiomes. Physiologic changes occur in the skin as humans mature from infancy to adulthood. Thus, characterizations of adult microbiomes might have limitations when considering pediatric disorders such as atopic dermatitis (AD) or issues such as sites of microbial carriage. The objective of this study was to determine if microbial communities at several body sites in children differed significantly from adults. Methods: Using 16S-rRNA gene sequencing technology, we characterized and compared the bacterial communities of four body sites in relation to Tanner stage of human development. Body sites sampled included skin sites characteristically involved in AD (antecubital/popliteal fossae), a control skin site (volar forearm), and the nares. Twenty-eight healthy individuals aged from 2 to 40 years were evaluated at the outpatient dermatology clinic in the National Institutes of Health's Clinical Center. Exclusion criteria included the use of systemic antibiotics within 6 months, current/prior chronic skin disorders, asthma, allergic rhinitis, or other chronic medical conditions. Results: Bacterial communities in the nares of children (Tanner developmental stage 1) differed strikingly from adults (Tanner developmental stage 5). Firmicutes (Streptococcaceae), Bacteroidetes, and Proteobacteria (beta, gamma) were overrepresented in Tanner 1 compared to Tanner 5 individuals, where Corynebacteriaceae and Propionibacteriaceae predominated. While bacterial communities were significantly different between the two groups in all sites, the most marked microbial shifts were observed in the nares, a site that can harbor pathogenic species, including Staphylococcus aureus and Streptococcus pneumonia. Conclusions: Significant shifts in the microbiota associated with progressive sexual maturation as measured by Tanner staging suggest that puberty-dependent shifts in the skin and nares microbiomes may have significant implications regarding prevention and treatment of pediatric disorders involving microbial pathogens and colonization. C1 [Oh, Julia; Conlan, Sean; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20814 USA. [Polley, Eric C.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Rockville, MD 20852 USA. [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. RP Segre, JA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 49 Convent Dr, Bethesda, MD 20814 USA. EM jsegre@nhgri.nih.gov; konghe@mail.nih.gov RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Kong, Heidi/0000-0003-4424-064X FU NIH NHGRI; NCI; National Institutes of Health [1UH2AR057504-01, 4UH3AR057504-02]; [1K99AR059222] FX We thank Clay Deming, Effie Nomicos, and Deborah Schoenfeld for their underlying efforts; and Maria L Turner, Isaac Brownell, and Mark C Udey for helpful discussions. This work was supported by NIH NHGRI and NCI Intramural Research Programs and in part by 1K99AR059222 (HHK). Sequencing was funded by grants from the National Institutes of Health (1UH2AR057504-01 and 4UH3AR057504-02). NR 31 TC 63 Z9 64 U1 5 U2 45 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD OCT 10 PY 2012 VL 4 AR 77 DI 10.1186/gm378 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 084YR UT WOS:000314577700001 PM 23050952 ER PT J AU Conlan, S Kong, HH Segre, JA AF Conlan, Sean Kong, Heidi H. Segre, Julia A. TI Species-Level Analysis of DNA Sequence Data from the NIH Human Microbiome Project SO PLOS ONE LA English DT Article ID SPECTRUM BETA-LACTAMASE; STAPHYLOCOCCUS-AUREUS; KLEBSIELLA-PNEUMONIAE; NASAL COLONIZATION; UNITED-STATES; CARRIAGE; IDENTIFICATION; PREVALENCE; ARB AB Background: Outbreaks of antibiotic-resistant bacterial infections emphasize the importance of surveillance of potentially pathogenic bacteria. Genomic sequencing of clinical microbiological specimens expands our capacity to study cultivable, fastidious and uncultivable members of the bacterial community. Herein, we compared the primary data collected by the NIH's Human Microbiome Project (HMP) with published epidemiological surveillance data of Staphylococcus aureus. Methods: The HMP's initial dataset contained microbial survey data from five body regions (skin, nares, oral cavity, gut and vagina) of 242 healthy volunteers. A significant component of the HMP dataset was deep sequencing of the 16S ribosomal RNA gene, which contains variable regions enabling taxonomic classification. Since species-level identification is essential in clinical microbiology, we built a reference database and used phylogenetic placement followed by most recent common ancestor classification to look at the species distribution for Staphylococcus, Klebsiella and Enterococcus. Main Results: We show that selecting the accurate region of the 16S rRNA gene to sequence is analogous to carefully selecting culture conditions to distinguish closely related bacterial species. Analysis of the HMP data showed that Staphylococcus aureus was present in the nares of 36% of healthy volunteers, consistent with culture-based epidemiological data. Klebsiella pneumoniae and Enterococcus faecalis were found less frequently, but across many habitats. Conclusions: This work demonstrates that large 16S rRNA survey studies can be used to support epidemiological goals in the context of an increasing awareness that microbes flourish and compete within a larger bacterial community. This study demonstrates how genomic techniques and information could be critically important to trace microbial evolution and implement hospital infection control. C1 [Conlan, Sean; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Kong, Heidi/0000-0003-4424-064X FU National Human Genome Research Institute; Center for Cancer Research, National Cancer Institute; NIH [UH3-AR057504] FX This work was supported by the National Human Genome Research Institute and Center for Cancer Research, National Cancer Institute Intramural Research Programs and NIH Common Fund Human Microbiome Project grant UH3-AR057504. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 40 Z9 41 U1 0 U2 47 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 OCT 10 PY 2012 VL 7 IS 10 AR e47075 DI 10.1371/journal.pone.0047075 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054ZU UT WOS:000312385200076 PM 23071716 ER PT J AU O'Connor, CM Fiuzat, M Carson, PE Anand, IS Plehn, JF Gottlieb, SS Silver, MA Lindenfeld, J Miller, AB White, M Walsh, R Nelson, P Medway, A Davis, G Robertson, AD Port, JD Carr, J Murphy, GA Lazzeroni, LC Abraham, WT Liggett, SB Bristow, MR AF O'Connor, Christopher M. Fiuzat, Mona Carson, Peter E. Anand, Inder S. Plehn, Jonathan F. Gottlieb, Stephen S. Silver, Marc A. Lindenfeld, JoAnn Miller, Alan B. White, Michel Walsh, Ryan Nelson, Penny Medway, Allen Davis, Gordon Robertson, Alastair D. Port, J. David Carr, James Murphy, Guinevere A. Lazzeroni, Laura C. Abraham, William T. Liggett, Stephen B. Bristow, Michael R. TI Combinatorial Pharmacogenetic Interactions of Bucindolol and beta(1), alpha(2C) Adrenergic Receptor Polymorphisms SO PLOS ONE LA English DT Article ID CHRONIC HEART-FAILURE; BETA(1)-ADRENERGIC RECEPTOR; MERIT-HF; BLOCKER BUCINDOLOL; RANDOMIZED-TRIAL; CIBIS-II; SURVIVAL; MYOCARDIUM; CARVEDILOL; METOPROLOL AB Background: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a beta-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (beta(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (alpha(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. Methodology: In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of beta(1)389 and alpha(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for b1389 AR variants was measured in human explanted left ventricles. Principal Findings: The combination of beta(1)389 Arg+alpha(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in beta(1)389 Arg homozygotes+alpha(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in beta(1)389 Arg vs. Gly ARs, which converts alpha(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit. Conclusions: On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (beta(1)389 Arg homozygotes), intermediate (beta(1)389 Gly carriers+alpha(2C)322-325 Wt homozygotes), and no (beta(1)389 Gly carriers+alpha(2C)322-325 Del carriers) efficacy. C1 [O'Connor, Christopher M.; Fiuzat, Mona] Duke Univ, Med Ctr, Div Cardiol, Duke Clin Res Inst, Durham, NC 27710 USA. [Carson, Peter E.] Dept Vet Affairs, Div Cardiol, Washington, DC USA. [Anand, Inder S.] Dept Vet Affairs, Div Cardiol, Minneapolis, MN USA. [Plehn, Jonathan F.] NHLBI, NIH, Washington, DC USA. [Gottlieb, Stephen S.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Silver, Marc A.] Advocate Christ Med Ctr, Inst Heart & Vasc, Oak Lawn, IL USA. [Lindenfeld, JoAnn; Walsh, Ryan; Nelson, Penny; Medway, Allen; Robertson, Alastair D.; Port, J. David; Bristow, Michael R.] Univ Colorado, Div Cardiol, Cardiovasc Inst, Sch Med, Aurora, CO USA. [Miller, Alan B.] Univ Florida, Hlth Sci Ctr, Div Cardiol, Jacksonville, FL 32209 USA. [White, Michel] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Davis, Gordon; Port, J. David; Carr, James; Murphy, Guinevere A.; Bristow, Michael R.] ARCA Biopharma, Broomfield, CO USA. [Lazzeroni, Laura C.] Stanford Univ, Dept Psychiat & Behav US Amer, Stanford, CA 94305 USA. [Abraham, William T.] Ohio State Univ, Columbus, OH 43210 USA. [Liggett, Stephen B.] Univ S Florida, Ctr Personalized Med & Genom, Morsani Coll Med, Tampa, FL USA. RP O'Connor, CM (reprint author), Duke Univ, Med Ctr, Div Cardiol, Duke Clin Res Inst, Durham, NC 27710 USA. EM christophe.oconnor@duke.edu FU United States National Institutes of Health (NIH) [HL077101, 2R01 HL48013]; Department of Veterans Affairs Cooperative Studies Program; National Heart, Lung, and Blood Institute Division of Cardiovascular Sciences; ARCA biopharma; NIH/National Heart, Lung, and Blood Institute FX This study was supported by United States National Institutes of Health (NIH) grants HL077101, awarded to SB Liggett, and 2R01 HL48013, awarded to MR Bristow; the Department of Veterans Affairs Cooperative Studies Program; the National Heart, Lung, and Blood Institute Division of Cardiovascular Sciences; and ARCA biopharma. The BEST Trial and DNA substudy were funded by the NIH/National Heart, Lung, and Blood Institute. No other funding was used to support this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 16 Z9 16 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 OCT 10 PY 2012 VL 7 IS 10 AR e44324 DI 10.1371/journal.pone.0044324 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054ZU UT WOS:000312385200002 PM 23071495 ER PT J AU Sterling, J Fu, LZ Matsuura, K Shi, YB AF Sterling, Job Fu, Liezhen Matsuura, Kazuo Shi, Yun-Bo TI Cytological and Morphological Analyses Reveal Distinct Features of Intestinal Development during Xenopus tropicalis Metamorphosis SO PLOS ONE LA English DT Article ID THYROID-HORMONE RECEPTOR; RETINOIC ACID RECEPTORS; MOUSE SMALL-INTESTINE; AMPHIBIAN METAMORPHOSIS; STEM-CELLS; GENE-EXPRESSION; POSTEMBRYONIC DEVELOPMENT; FROG METAMORPHOSIS; CONNECTIVE-TISSUE; BINDING PROTEIN AB Background: The formation and/or maturation of adult organs in vertebrates often takes place during postembryonic development, a period around birth in mammals when thyroid hormone (T3) levels are high. The T3-dependent anuran metamorphosis serves as a model to study postembryonic development. Studies on the remodeling of the intestine during Xenopus (X.) laevis metamorphosis have shown that the development of the adult intestine involves de novo formation of adult stem cells in a process controlled by T3. On the other hand, X. tropicalis, highly related to X. laevis, offers a number of advantages for studying developmental mechanisms, especially at genome-wide level, over X. laevis, largely due to its shorter life cycle and sequenced genome. To establish X. tropicalis intestinal metamorphosis as a model for adult organogenesis, we analyzed the morphological and cytological changes in X. tropicalis intestine during metamorphosis. Methodology/Principal Findings: We observed that in X. tropicalis, the premetamorphic intestine was made of mainly a monolayer of larval epithelial cells surrounded by little connective tissue except in the single epithelial fold, the typhlosole. During metamorphosis, the larval epithelium degenerates and adult epithelium develops to form a multi-folded structure with elaborate connective tissue and muscles. Interestingly, typhlosole, which is likely critical for adult epithelial development, is present along the entire length of the small intestine in premetamorphic tadpoles, in contrast to X. laevis, where it is present only in the anterior 1/3. T3-treatment induces intestinal remodeling, including the shortening of the intestine and the typhlosole, just like in X. laevis. Conclusions/Significance: Our observations indicate that the intestine undergoes similar metamorphic changes in X. laevis and X. tropicalis, making it possible to use the large amount of information available on X. laevis intestinal metamorphosis and the genome sequence information and genetic advantages of X. tropicalis to dissect the pathways governing adult intestinal development. C1 [Sterling, Job; Fu, Liezhen; Matsuura, Kazuo; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD USA. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD USA. EM Shi@helix.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of National Institute of Child Health and Human Development, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 4 Z9 4 U1 2 U2 14 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 OCT 10 PY 2012 VL 7 IS 10 AR e47407 DI 10.1371/journal.pone.0047407 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054ZU UT WOS:000312385200117 PM 23071801 ER PT J AU Facio, FM Sapp, JC Linn, A Biesecker, LG AF Facio, Flavia M. Sapp, Julie C. Linn, Amy Biesecker, Leslie G. TI Approaches to informed consent for hypothesis-testing and hypothesis-generating clinical genomics research SO BMC MEDICAL GENOMICS LA English DT Article DE Whole genome sequencing; Whole exome sequencing; Informed consent ID GENETIC RESEARCH; WORKING GROUP; MEDICINE; RECOMMENDATIONS; PARTICIPANTS AB Background: Massively-parallel sequencing (MPS) technologies create challenges for informed consent of research participants given the enormous scale of the data and the wide range of potential results. Discussion: We propose that the consent process in these studies be based on whether they use MPS to test a hypothesis or to generate hypotheses. To demonstrate the differences in these approaches to informed consent, we describe the consent processes for two MPS studies. The purpose of our hypothesis-testing study is to elucidate the etiology of rare phenotypes using MPS. The purpose of our hypothesis-generating study is to test the feasibility of using MPS to generate clinical hypotheses, and to approach the return of results as an experimental manipulation. Issues to consider in both designs include: volume and nature of the potential results, primary versus secondary results, return of individual results, duty to warn, length of interaction, target population, and privacy and confidentiality. Summary: The categorization of MPS studies as hypothesis-testing versus hypothesis-generating can help to clarify the issue of so-called incidental or secondary results for the consent process, and aid the communication of the research goals to study participants. C1 [Facio, Flavia M.; Sapp, Julie C.; Linn, Amy; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov FU National Human Genome Research Institute FX This study was supported by funding from the Intramural Research Program of the National Human Genome Research Institute. The authors have no conflicts to declare. NR 23 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 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD OCT 10 PY 2012 VL 5 AR 45 DI 10.1186/1755-8794-5-45 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 038CB UT WOS:000311151700001 PM 23046515 ER PT J AU Zhu, L Huang, XL Choi, KY Ma, Y Zhang, F Liu, G Lee, S Chen, XY AF Zhu, Lei Huang, Xinglu Choi, Ki Young Ma, Ying Zhang, Fan Liu, Gang Lee, Seulki Chen, Xiaoyuan TI Real-time monitoring of caspase cascade activation in living cells SO JOURNAL OF CONTROLLED RELEASE LA English DT Article; Proceedings Paper CT 9th International Nanomedicine and Drug Delivery Symposium (NanoDDS) CY OCT 15-16, 2011 CL Salt Lake City, UT DE Caspase; Activatable probe; Fluorescence imaging; Peptide; Transfection agent ID ANNEXIN-V; IN-VIVO; APOPTOSIS; DIFFERENTIATION; NANOPARTICLES; EXPRESSION; DELIVERY; PEPTIDE; PROBES; DEATH AB We introduce a simple, versatile and robust one-step technique that enables real-time imaging of multiple intracellular caspase activities in living cells without the need for complicated synthetic protocols. Conventional fluorogenic probes or recently reported activatable probes have been designed to target various proteases but are limited to extracellular molecules. Only a few have been applied to image intracellular proteases in living cells because most of these probes have limited cell-permeability. Our platform does not need complicated synthetic processes; instead it involves a straightforward peptide synthesis and a simple mixing step with a commercial transfection agent. The transfection agent efficiently delivered the highly quenched fluorogenic probes, comprised of distinctive pairs of dyes and quenchers, to the initiator caspase-8 and the effector caspase-3 in MDA-MB-435 cells, allowing dual-imaging of the activities of both caspases during the apoptotic process induced by TNF-related apoptosis induced ligand (TRAIL). With the combination of multiple fluorogenic probes, this simple platform can be applied to multiplexed imaging of selected intracellular proteases to study apoptotic processes in pathologies or for cell-based high throughput screening systems for drug discovery. Published by Elsevier B.V. C1 [Zhu, Lei; Huang, Xinglu; Choi, Ki Young; Ma, Ying; Zhang, Fan; Liu, Gang; Lee, Seulki; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Zhu, Lei; Zhang, Fan; Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Lee, S (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM seulki.lee@nih.gov; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016; CHOI, KI YOUNG/Q-7177-2016 OI Zhu, Lei/0000-0002-1820-4795; FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-02]; NIBIB NIH HHS [R00 EB013450] NR 35 TC 11 Z9 11 U1 2 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD OCT 10 PY 2012 VL 163 IS 1 BP 55 EP 62 DI 10.1016/j.jconrel.2012.05.044 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 029PK UT WOS:000310507600008 PM 22664474 ER PT J AU Husain, FT Patkin, DJ Kim, J Braun, AR Horwitz, B AF Husain, Fatima T. Patkin, Debra J. Kim, Jieun Braun, Allen R. Horwitz, Barry TI Dissociating neural correlates of meaningful emblems from meaningless gestures in deaf signers and hearing non-signers SO BRAIN RESEARCH LA English DT Article DE ASL; Deaf; Gesture; Emblem; fMRI; Meaningful; Meaning; Normal hearing; Non-signer ID RECOGNITION; LANGUAGE; BRAIN; FMRI; COMPREHENSION; SPEECH; ERPS AB Emblems are meaningful, culturally-specific hand gestures that are analogous to words. In this fMRI study, we contrasted the processing of emblematic gestures with meaningless gestures by pre-lingually Deaf and hearing participants. Deaf participants, who used American Sign Language, activated bilateral auditory processing and associative areas in the temporal cortex to a greater extent than the hearing participants while processing both types of gestures relative to rest. The hearing non-signers activated a diverse set of regions, including those implicated in the mirror neuron system, such as premotor cortex (BA 6) and inferior parietal lobule (BA 40) for the same contrast. Further, when contrasting the processing of meaningful to meaningless gestures (both relative to rest), the Deaf participants, but not the hearing, showed greater response in the left angular and supramarginal gyri, regions that play important roles in linguistic processing. These results suggest that whereas the signers interpreted emblems to be comparable to words, the non-signers treated emblems as similar to pictorial descriptions of the world and engaged the mirror neuron system. (c) 2012 Elsevier B.V. All rights reserved. C1 [Husain, Fatima T.] Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL USA. [Husain, Fatima T.; Patkin, Debra J.; Kim, Jieun; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD USA. [Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD USA. RP Husain, FT (reprint author), Univ Illinois, Dept Speech & Hearing Sci, 901 S 6th St, Champaign, IL USA. EM husainf@illinois.edu FU NIH-NIDCD Intramural Research Program FX The research was supported by the NIH-NIDCD Intramural Research Program. The authors are grateful to Nathan Pajor for assistance with the analysis of behavioral data. NR 36 TC 7 Z9 7 U1 0 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 10 PY 2012 VL 1478 BP 24 EP 35 DI 10.1016/j.brainres.2012.08.029 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 028HU UT WOS:000310414200003 PM 22968047 ER PT J AU Barrot, M Sesack, SR Georges, F Pistis, M Hong, S Jhou, TC AF Barrot, Michel Sesack, Susan R. Georges, Francois Pistis, Marco Hong, Simon Jhou, Thomas C. TI Braking Dopamine Systems: A New GABA Master Structure for Mesolimbic and Nigrostriatal Functions SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; LATERAL HABENULA; SUBSTANTIA-NIGRA; SEEKING BEHAVIOR; CONTAINING NEURONS; NUCLEUS-ACCUMBENS; ANTAGONIST RIMONABANT; GLUTAMATERGIC NEURONS; CANNABINOID MECHANISM; GABAERGIC NEURONS AB A new mesopontine structure exerting a strong influence on dopamine systems has recently been defined: the tail of the ventral tegmental area/rostromedial tegmental nucleus (tVTA/RMTg). This review presents a neuroanatomical, physiological, and behavioral overview of some of the recent and ongoing research on this brain region and its relationship with dopamine systems. The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons. The inhibitory influence of tVTA/RMTg on dopamine neurons is supported by both neuroanatomical and electrophysiology data. The latter studies also reveal the tVTA/RMTg as a substrate for morphine and cannabinoid action on dopamine cells. In primates, the tVTA/RMTg has been implicated in reward prediction error signals, through a basal ganglia-lateral habenula-tVTA/RMTg-dopamine-basal ganglia circuit. In rodents, the tVTA/RMTg has been shown to play a critical role in aversive behaviors, particularly those involving behavioral inhibition, such as freezing and avoidance. These findings highlight the functional importance of the tVTA/RMTg as a major GABA brake for dopamine systems. C1 [Barrot, Michel] Univ Strasbourg, CNRS, Inst Neurosci Cellulaires & Integrat, F-67084 Strasbourg, France. [Sesack, Susan R.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15260 USA. [Sesack, Susan R.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Georges, Francois] Univ Bordeaux, Interdisciplinary Inst Neurosci, UMR 5297, F-33000 Bordeaux, France. [Georges, Francois] CNRS, Interdisciplinary Inst Neurosci, UMR 5297, F-33000 Bordeaux, France. [Pistis, Marco] Univ Cagliari, Dept Biomed Sci, I-09042 Monserrato, Italy. [Hong, Simon] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. [Jhou, Thomas C.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. RP Barrot, M (reprint author), Univ Strasbourg, CNRS, Inst Neurosci Cellulaires & Integrat, F-67084 Strasbourg, France. EM mbarrot@inci-cnrs.unistra.fr RI Pistis, Marco/A-3773-2013; OI Pistis, Marco/0000-0002-4622-3205; GEORGES, Francois/0000-0002-2628-2638 FU Centre National de la Recherche Scientifique; Universite de Strasbourg; Universite Bordeaux Segalen; Agence Nationale de la Recherche [ANT-11-bsv4-002]; U.S. Public Health Service [MH067937]; Italian Ministry of University [PRIN 200928EEX4]; National Eye Institute; National Institutes of Health [MH094489, DA034431]; State of California Research Program for Alcoholism and Addiction; NIH-NIDA; Medical University of South Carolina; Adir (Servier); Lilly France; Missions-Cadres FX This work was supported by the Centre National de la Recherche Scientifique (M.B., F.G.), the Universite de Strasbourg (M.B.), the Universite Bordeaux Segalen (F.G.), Agence Nationale de la Recherche Grant ANT-11-bsv4-002 (M.B., F.G.), U.S. Public Health Service Grant MH067937 (S.R.S.), Italian Ministry of University Grant PRIN 200928EEX4 (M.P.), the intramural research program of the National Eye Institute (S.H.), National Institutes of Health Grants MH094489 and DA034431 (T.J.), the State of California Research Program for Alcoholism and Addiction (T.J.), the Intramural Research Program of NIH-NIDA (T.J.), and the Medical University of South Carolina (T.J.).; M.B. has received lecture fees from Adir (Servier) and from Lilly France, a research contractor funding from Missions-Cadres, and reports a CNRS-filed patent for new pain treatments. Those were unrelated to the topic of this Mini-Symposium. The other authors declare no competing financial interests. NR 98 TC 70 Z9 70 U1 1 U2 24 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 OCT 10 PY 2012 VL 32 IS 41 BP 14094 EP 14101 DI 10.1523/JNEUROSCI.3370-12.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 022MO UT WOS:000309963700008 PM 23055478 ER PT J AU Grati, M Shin, JB Weston, MD Green, J Bhat, MA Gillespie, PG Kachar, B AF Grati, M'hamed Shin, Jung-Bum Weston, Michael D. Green, James Bhat, Manzoor A. Gillespie, Peter G. Kachar, Bechara TI Localization of PDZD7 to the Stereocilia Ankle-Link Associates this Scaffolding Protein with the Usher Syndrome Protein Network SO JOURNAL OF NEUROSCIENCE LA English DT Article ID COCHLEAR HAIR-CELLS; HEARING; CADHERIN-23; MUTATIONS; COMPONENT; HARMONIN; COMPLEX; BUNDLE; VLGR1; MICE AB Usher syndrome is the leading cause of genetic deaf-blindness. Monoallelic mutations in PDZD7 increase the severity of Usher type II syndrome caused by mutations in USH2A and GPR98, which respectively encode usherin and GPR98. PDZ domain-containing 7 protein (PDZD7) is a paralog of the scaffolding proteins harmonin and whirlin, which are implicated in Usher type 1 and type 2 syndromes. While usherin and GPR98 have been reported to form hair cell stereocilia ankle-links, harmonin localizes to the stereocilia upper tip-link density and whirlin localizes to both tip and ankle-link regions. Here, we used mass spectrometry to show that PDZD7 is expressed in chick stereocilia at a comparable molecular abundance to GPR98. We also show by immunofluorescence and by overexpression of tagged proteins in rat and mouse hair cells that PDZD7 localizes to the ankle-link region, overlapping with usherin, whirlin, and GPR98. Finally, we show in LLC-PK1 cells that cytosolic domains of usherin and GPR98 can bind to both whirlin and PDZD7. These observations are consistent with PDZD7 being a modifier and candidate gene for USH2, and suggest that PDZD7 is a second scaffolding component of the ankle-link complex. C1 [Grati, M'hamed; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Shin, Jung-Bum; Gillespie, Peter G.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. [Weston, Michael D.] Creighton Univ, Sch Dent, Dept Oral Biol, Omaha, NE 68178 USA. [Green, James; Bhat, Manzoor A.] Univ N Carolina, Lab Cell & Mol Physiol, Chapel Hill, NC 27599 USA. RP Kachar, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. EM Mgrati@aol.com; kacharb@nidcd.nih.gov OI Barr-Gillespie, Peter/0000-0002-9787-5860 FU Intramural Program of the National Institute on Deafness and Other Communication Disorders - National Institutes of Health [NIH DC002368, NIH DC011034, NIH GM063074]; State of North Carolina; Hearing Health Foundation FX This work was supported by the Intramural Program of the National Institute on Deafness and Other Communication Disorders - National Institutes of Health, NIH DC002368 (P. G. G.), NIH DC011034 (P. G. G.), NIH GM063074 (M. A. B.), the State of North Carolina (M. A. B.) and from the Hearing Health Foundation (M. D. W.). We thank Drs. Ronald Petralia, Mark Berryman, Lisa Dunbar and Bryan Millis for their critical reading of the manuscript. NR 24 TC 26 Z9 26 U1 2 U2 9 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 OCT 10 PY 2012 VL 32 IS 41 BP 14288 EP 14293 DI 10.1523/JNEUROSCI.3071-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 022MO UT WOS:000309963700029 PM 23055499 ER PT J AU Waterhouse, EG An, JJ Orefice, LL Baydyuk, M Liao, GY Zheng, K Lu, B Xu, BJ AF Waterhouse, Emily G. An, Juan Ji Orefice, Lauren L. Baydyuk, Maryna Liao, Guey-Ying Zheng, Kang Lu, Bai Xu, Baoji TI BDNF Promotes Differentiation and Maturation of Adult-born Neurons through GABAergic Transmission SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; MICROTUBULE-ASSOCIATED PROTEIN; GENERATED GRANULE CELLS; NEUROTROPHIC FACTOR; DENTATE GYRUS; SYNAPTIC PLASTICITY; HIPPOCAMPAL NEUROGENESIS; DEPENDENT REGULATION; DIETARY RESTRICTION; MESSENGER-RNAS AB Brain-derived neurotrophic factor (BDNF) has been implicated in regulating adult neurogenesis in the subgranular zone (SGZ) of the dentate gyrus; however, the mechanism underlying this regulation remains unclear. In this study, we found that Bdnf mRNA localized to distal dendrites of dentate gyrus granule cells isolated from wild-type (WT) mice, but not from Bdnf(klox/klox) mice where the long 3' untranslated region (UTR) of Bdnf mRNA is truncated. KCl-induced membrane depolarization stimulated release of dendritic BDNF translated from long 3' UTR Bdnf mRNA in cultured hippocampal neurons, but not from short 3' UTR Bdnf mRNA. Bdnf(klox/klox) mice exhibited reduced expression of glutamic acid decarboxylase 65 (a GABA synthase), increased proliferation of progenitor cells, and impaired differentiation and maturation of newborn neurons in the SGZ. These deficits in adult neurogenesis were rescued with administration of phenobarbital, an enhancer of GABA(A) receptor activity. Furthermore, we observed similar neurogenesis deficits in mice where the receptor for BDNF, TrkB, was selectively abolished in parvalbumin (PV)-expressing GABAergic interneurons. Thus, our data suggest that locally synthesized BDNF in dendrites of granule cells promotes differentiation and maturation of progenitor cells in the SGZ by enhancing GABA release, at least in part, from PV-expressing GABAergic interneurons. C1 [Waterhouse, Emily G.; An, Juan Ji; Orefice, Lauren L.; Baydyuk, Maryna; Liao, Guey-Ying; Xu, Baoji] Georgetown Univ, Med Ctr, Dept Physiol & Pharmacol, Washington, DC 20057 USA. [Zheng, Kang; Lu, Bai] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Xu, BJ (reprint author), Georgetown Univ, Med Ctr, Dept Physiol & Pharmacol, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM bx3@georgetown.edu FU National Institutes of Health [R01 NS050596, R01 NS073930, F30 DK084717, F31 NS074840] FX This work was supported by the National Institutes of Health Grants R01 NS050596 and R01 NS073930 (B. X.), F30 DK084717 (E. G. W.), and F31 NS074840 (L.L.O.). We thank Patrick Forcelli and Karen Gale for assistance in administration of phenobarbital. NR 54 TC 88 Z9 92 U1 0 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 OCT 10 PY 2012 VL 32 IS 41 BP 14318 EP 14330 DI 10.1523/JNEUROSCI.0709-12.2012 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 022MO UT WOS:000309963700033 PM 23055503 ER PT J AU Kim, E Hoffman, DA AF Kim, Eunyoung Hoffman, Dax A. TI Dynamic Regulation of Synaptic Maturation State by Voltage-Gated A-Type K+ Channels in CA1 Hippocampal Pyramidal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; RECEPTOR SUBUNIT COMPOSITION; MENTAL-RETARDATION PROTEIN; FRAGILE-X-SYNDROME; NMDA RECEPTORS; POTASSIUM CHANNELS; KNOCKOUT MICE; MEMORY; KV4.2; EXPRESSION AB Neuronal activity is critical for the formation and modification of neural circuits during brain development. In hippocampal CA1 pyramidal dendrites, A-type voltage-gated K+ currents, formed primarily by Kv4.2 subunits, control excitability. Here we used Kv4.2 knock-out (Kv4.2-KO) mice along with acute in vivo expression of Kv4.2 or its dominant-negative pore mutant to examine the role of Kv4.2 in the development of CA1 synapses. We found that Kv4.2 expression induces synaptic maturation in juvenile WT mice and rescues developmentally delayed synapses in adult Kv4.2-KO mice. In addition, we show that NMDAR subunit composition can be reverted back to the juvenile form in WT adult synapses by functionally downregulating Kv4.2 levels. These results suggest that Kv4.2 regulation of excitability determines synaptic maturation state, which can be bidirectionally adjusted into adulthood. C1 [Kim, Eunyoung; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Hoffman, DA (reprint author), 35 Lincoln Dr,MSC 3715,Bldg 35,Room 3C-905, Bethesda, MD 20892 USA. EM hoffmand@mail.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU National Institute of Child Health and Human Development Intramural Research Program FX This work was supported by the National Institute of Child Health and Human Development Intramural Research Program. We thank Drs. Katherine Roche (NINDS) and Wei Li (NEI) for their critical review of earlier versions of this manuscript. We thank Begum Choudhury, Lin Lin, and Michael (Martin) Hatch for technical and experimental assistance. NR 30 TC 8 Z9 8 U1 0 U2 8 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 OCT 10 PY 2012 VL 32 IS 41 BP 14427 EP 14432 DI 10.1523/JNEUROSCI.2373-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 022MO UT WOS:000309963700042 PM 23055512 ER PT J AU Insel, TR AF Insel, Thomas R. TI Next-Generation Treatments for Mental Disorders SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; DEEP BRAIN-STIMULATION; STAR-ASTERISK-D; ANTIDEPRESSANT ACTIONS; BIPOLAR DEPRESSION; SCHIZOPHRENIA; RISK; DISEASE; HUMANS; NEUROGENESIS AB There has been a steady retreat by the private sector away from developing medications for mental disorders. This retreat comes just as research is identifying new molecular targets, new clinical targets, and new uses of current treatments that may serve as the basis for the next generation of treatments for mental disorders. C1 NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Bethesda, MD 20892 USA. EM insel@mail.nih.gov NR 85 TC 26 Z9 27 U1 5 U2 28 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 10 PY 2012 VL 4 IS 155 AR 155ps19 DI 10.1126/scitranslmed.3004873 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 022NT UT WOS:000309966800002 PM 23052292 ER PT J AU Roth, N Wohlfarth, A Muller, M Auwarter, V AF Roth, Nadine Wohlfarth, Ariane Mueller, Michael Auwaerter, Volker TI Regioselective synthesis of isotopically labeled Delta 9-tetrahydrocannabinolic acid A (THCA-A-D-3) by reaction of Delta 9-tetrahydrocannabinol-D-3 with magnesium methyl carbonate SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE Delta 9-Tetrahydrocannabinolic acid A; Delta 9-Tetrahydrocannabinolic acid B; Delta 9-Tetrahydrocannabinol (THC); Deuterated internal standard; MMC; Cannabis consumption marker ID CANNABIS-SATIVA; MASS-SPECTROMETRY; LC-MS/MS; GC-MS; SERUM; DELTA(9)-TETRAHYDROCANNABINOL; METABOLITES; PLASMA; THC AB For the reliable quantification of Delta 9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of Delta 9-tetrahydrocannabinol (THC), in biological matrices by LC-MS/MS and GC-MS(/MS), an isotopically labeled internal standard was synthesized starting from Delta 9-tetrahydrocannabinol-D-3 (THC-D-3). Synthesis strategy was based on a method reported by Mechoulam et al. in 1969 using magnesium methyl carbonate (MMC) as carboxylation reagent for the synthesis of cannabinoid acids. Preliminary experiments with THC to optimize yield of the product (THCA-A) resulted in the synthesis of the positional isomer tetrahydrocannabinolic acid B (THCA-B) as a byproduct. Using the optimized conditions for the desired isomer, THCA-A-D-3 was prepared and isolated with a yield of approx. 10% after two synthesis cycles. Isotope purity was estimated to be >99% by relative abundance of the molecular ions. The synthesized compound proved to be suitable as an internal standard for quantification of THCA-A in serum and hair samples of cannabis consumers. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Roth, Nadine; Wohlfarth, Ariane; Auwaerter, Volker] Univ Med Ctr Freiburg, Inst Forens Med, D-79104 Freiburg, Germany. [Wohlfarth, Ariane] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Mueller, Michael] Univ Freiburg, Inst Pharmaceut Sci, D-79104 Freiburg, Germany. RP Auwarter, V (reprint author), Univ Med Ctr Freiburg, Inst Forens Med, Albertstr 9, D-79104 Freiburg, Germany. EM nadine.roth@uniklinik-freiburg.de; ariane.wohlfarth@nih.gov; michael.mueller@pharmazie.uni-freiburg.de; volker.auwaerter@uniklinik-freiburg.de FU Deutsche Forschungsgemeinschaft [DFG-AU: 324/3-1] FX The authors would like to thank Volker Brecht (Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Germany) for the acquisition of NMR-spectra. The project was funded by the "Deutsche Forschungsgemeinschaft" (DFG-AU: 324/3-1). NR 17 TC 6 Z9 6 U1 3 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD OCT 10 PY 2012 VL 222 IS 1-3 BP 368 EP 372 DI 10.1016/j.forsciint.2012.07.019 PG 5 WC Medicine, Legal SC Legal Medicine GA 004OI UT WOS:000308690600058 PM 22921834 ER PT J AU Easterbrook, JD Schwartzman, LM Gao, J Kash, JC Morens, DM Couzens, L Wan, HQ Eichelberger, MC Taubenberger, JK AF Easterbrook, Judith D. Schwartzman, Louis M. Gao, Jin Kash, John C. Morens, David M. Couzens, Laura Wan, Hongquan Eichelberger, Maryna C. Taubenberger, Jeffery K. TI Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice SO VIROLOGY LA English DT Article DE Cross-protection; Virus-like particle (VLP); Vaccine ID BROADER IMMUNE-RESPONSES; HEMAGGLUTININ; VACCINE; ANTIBODY; INFECTION; FERRETS; HUMANS; NA AB Highly pathogenic H5N1 influenza shares the same neuraminidase (NA) subtype with the 2009 pandemic (H1N1pdm09), and cross-reactive NA immunity might protect against or mitigate lethal H5N1 infection. In this study, mice were either infected with a sublethal dose of H1N1pdm09 or were vaccinated and boosted with virus-like particles (VLP) consisting of the NA and matrix proteins, standardized by NA activity and administered intranasally, and were then challenged with a lethal dose of HPAI H5N1 virus. Mice previously infected with H1N1pdm09 survived H5N1 challenge with no detectable virus or respiratory tract pathology on day 4. Mice immunized with H5N1 or H1N1pdm09 NA VLPs were also fully protected from death, with a 100-fold and 10-fold reduction in infectious virus, respectively, and reduced pathology in the lungs. Human influenza vaccines that elicit not only HA, but also NA immunity may provide enhanced protection against the emergence of seasonal and pandemic viruses. Published by Elsevier Inc. C1 [Easterbrook, Judith D.; Schwartzman, Louis M.; Kash, John C.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Gao, Jin; Couzens, Laura; Wan, Hongquan; Eichelberger, Maryna C.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU NIH; BARDA MCM Initiative IV: Influenza Vaccine Manufacturing Improvement; FDA CBER PanFlu funds; NIAID FX We thank the Comparative Medicine Branch (NIH/NIAID) for their assistance with animal studies. We would also like to thank Dr. David Dorward at the Rocky Mountain Laboratories, NIAID, NIH for the TEM images and Aline Sandouk for the IHC staining. This work was supported in part by the Intramural Research Program of the NIH and the NIAID, by the BARDA MCM Initiative IV: Influenza Vaccine Manufacturing Improvement (JKT), and by FDA CBER PanFlu funds (MCE). We want to further acknowledge Dr. Edwin Kilbourne's remarkable and important contributions to our understanding of neuraminidase immunity. NR 38 TC 27 Z9 27 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 0042-6822 J9 VIROLOGY JI Virology PD OCT 10 PY 2012 VL 432 IS 1 BP 39 EP 44 DI 10.1016/j.virol.2012.06.003 PG 6 WC Virology SC Virology GA 982FB UT WOS:000307027100005 PM 22727831 ER PT J AU Chowell, G Nishiura, H AF Chowell, Gerardo Nishiura, Hiroshi TI Toward unbiased assessment of treatment and prevention: modeling household transmission of pandemic influenza SO BMC MEDICINE LA English DT Editorial Material DE epidemic; estimation; household transmissibility; household transmission studies; mathematical model; outbreaks; pandemic; reproduction number; secondary attack rate; serial interval AB Providing valid and reliable estimates of the transmissibility and severity of pandemic influenza in real time is key to guide public health policymaking. In particular, early estimates of the transmissibility are indispensable for determining the type and intensity of interventions. A recent study by House and colleagues in BMC Medicine devised a stochastic transmission model to estimate the unbiased risk of transmission within households, applying the method to datasets of the 2009 A/H1N1 influenza pandemic. Here, we discuss future challenges in household transmission studies and underscore the need to systematically collect epidemiological data to decipher the household transmission dynamics. We emphasize the need to consider three critical issues for future improvements: (i) capturing age-dependent heterogeneity within households calls for intensive modeling efforts, (ii) the timeline of observation during the course of an epidemic and the length of follow-up should be aligned with study objectives, and (iii) the use of laboratory methods, especially molecular techniques, is encouraged to distinguish household transmissions from those arising in the community. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, Gerardo] Fogarty Int Ctr, Div Epidemiol & Populat Studies, NIH, Bethesda, MD USA. [Nishiura, Hiroshi] Univ Hong Kong, Sch Publ Hlth, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Nishiura, Hiroshi] Japan Sci & Technol Agcy, PRESTO, Saitama, Japan. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Nishiura, Hiroshi/0000-0003-0941-8537 FU NIGMS NIH HHS [R01 GM100471] NR 12 TC 1 Z9 1 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 9 PY 2012 VL 10 AR 118 DI 10.1186/1741-7015-10-118 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 055CR UT WOS:000312393300002 PM 23046539 ER PT J AU Delogu, LG Vidili, G Venturelli, E Menard-Moyon, C Zoroddu, MA Pilo, G Nicolussi, P Ligios, C Bedognetti, D Sgarrella, F Manetti, R Bianco, A AF Delogu, Lucia Gemma Vidili, Gianpaolo Venturelli, Enrica Menard-Moyon, Cecilia Zoroddu, Maria Antonietta Pilo, Giovannantonio Nicolussi, Paola Ligios, Ciriaco Bedognetti, Davide Sgarrella, Francesco Manetti, Roberto Bianco, Alberto TI Functionalized multiwalled carbon nanotubes as ultrasound contrast agents SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nanomaterials; biocompatibility; nanomedicine; nanobiotechnology; echography ID NEAR-INFRARED WINDOW; DRUG-DELIVERY; IMMUNE CELLS; LIVING MICE; LIVE CELLS; NANOPARTICLES; MICROBUBBLES; SPECTROSCOPY; FLUORESCENCE; FREQUENCIES AB Ultrasonography is a fundamental diagnostic imaging tool in everyday clinical practice. Here, we are unique in describing the use of functionalized multiwalled carbon nanotubes (MWCNTs) as hyperechogenic material, suggesting their potential application as ultrasound contrast agents. Initially, we carried out a thorough investigation to assess the echogenic property of the nanotubes in vitro. We demonstrated their long-lasting ultrasound contrast properties. We also showed that ultrasound signal of functionalized MWCNTs is higher than graphene oxide, pristine MWCNTs, and functionalized single-walled CNTs. Qualitatively, the ultrasound signal of CNTs was equal to that of sulfur hexafluoride (SonoVue), a commercially available contrast agent. Then, we found that MWCNTs were highly echogenic in liver and heart through ex vivo experiments using pig as an animal model. In contrast to the majority of ultrasound contrast agents, we observed in a phantom bladder that the tubes can be visualized within a wide variety of frequencies (i.e., 5.5-10 MHz) and 12.5 MHz using tissue harmonic imaging modality. Finally, we demonstrated in vivo in the pig bladder that MWCNTs can be observed at low frequencies, which are appropriate for abdominal organs. Importantly, we did not report any toxicity of CNTs after 7 d from the injection by animal autopsy, organ histology and immunostaining, blood count, and chemical profile. Our results reveal the enormous potential of CNTs as ultrasound contrast agents, giving support for their future applications as theranostic nanoparticles, combining diagnostic and therapeutic modalities. C1 [Delogu, Lucia Gemma; Zoroddu, Maria Antonietta; Sgarrella, Francesco] Univ Sassari, Dipartimento Chim & Farm, I-07100 Sassari, Italy. [Vidili, Gianpaolo; Manetti, Roberto] Univ Sassari, Dipartimento Med Clin Sperimentale & Oncol, I-07100 Sassari, Italy. [Venturelli, Enrica; Menard-Moyon, Cecilia; Bianco, Alberto] CNRS, Inst Biol Mol & Cellulaire, Lab Immunol & Chim Therapeut, Unite Propre Rech 9021, F-67000 Strasbourg, France. [Pilo, Giovannantonio; Nicolussi, Paola; Ligios, Ciriaco] Ist Zooprofilatt Sperimentale Sardegna, I-07100 Sassari, Italy. [Bedognetti, Davide] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bedognetti, Davide] Univ Genoa, Dipartimento Oncol Biol & Genet, I-16132 Genoa, Italy. [Bedognetti, Davide] Univ Genoa, Dipartimento Med Interna, I-16132 Genoa, Italy. [Bedognetti, Davide] NIH, Trans Natl Inst Hlth, Ctr Human Immunol, Bethesda, MD 20892 USA. RP Delogu, LG (reprint author), Univ Sassari, Dipartimento Chim & Farm, I-07100 Sassari, Italy. EM lgdelogu@uniss.it; a.bianco@ibmc-cnrs.unistra.fr OI Bedognetti, Davide/0000-0002-5857-773X; VIDILI, Gianpaolo/0000-0003-0003-1272 FU Fondazione Banco di Sardegna [994/2010.0410, 186/2011.0484]; University of Sassari; Centre National de la Recherche Scientifique; European Union Seventh Framework Programme FP7 [HEALTH-2007-201587]; Conquer Cancer Foundation of the American Society of Clinical Oncology; Sardinia Region FX We thank Giannella Cancedda and Simona Macioccu for technical assistance, and Renzo Tramaglino for graphic assistance; L.G.D. thanks Anna Marchesi for support in part of this project and the Sardinia Region for support thought an Invited Professorship (to A.B.). This work was supported in part by Fondazione Banco di Sardegna Grants 994/2010.0410 and 186/2011.0484 (to L.G.D.), the University of Sassari, the Centre National de la Recherche Scientifique, and the European Union Seventh Framework Programme FP7 (HEALTH-2007-201587, ANTICARB) program. D.B. was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology. Transmission electron microscopy images were recorded at the Microscopy Facility Platform of Esplanade Campus (Strasbourg, France). NR 52 TC 65 Z9 66 U1 4 U2 64 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 OCT 9 PY 2012 VL 109 IS 41 BP 16612 EP 16617 DI 10.1073/pnas.1208312109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026LQ UT WOS:000310280300050 PM 23012426 ER PT J AU Hobbs, EC Yin, XF Paul, BJ Astarita, JL Storz, G AF Hobbs, Errett C. Yin, Xuefeng Paul, Brian J. Astarita, Jillian L. Storz, Gisela TI Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE multidrug resistance; resistance-nodulation-division; RND superfamily ID ESCHERICHIA-COLI; TRANSPORTER ACRB; SUBSTRATE PATH; BINDING POCKET; MEMBRANE; MECHANISM; SYSTEM; GENES; RNA; PROMOTER AB The AcrAB-TolC multidrug efflux pump confers resistance to a wide variety of antibiotics and other compounds in Escherichia coli. Here we show that AcrZ (formerly named YbhT), a 49-amino-acid inner membrane protein, associates with the AcrAB-TolC complex. Co-purification of AcrZ with AcrB, in the absence of both AcrA and TolC, two-hybrid assays and suppressor mutations indicate that this interaction occurs through the inner membrane protein AcrB. The highly conserved acrZ gene is coregulated with acrAB through induction by the MarA, Rob, and SoxS transcription regulators. In addition, mutants lacking AcrZ are sensitive to many, but not all, of the antibiotics transported by AcrAB-TolC. This differential antibiotic sensitivity suggests that AcrZ may enhance the ability of the AcrAB-TolC pump to export certain classes of substrates. C1 [Hobbs, Errett C.; Yin, Xuefeng; Paul, Brian J.; Astarita, Jillian L.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Yin, Xuefeng] Peking Univ, Hlth Sci Ctr, Beijing 100191, Peoples R China. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM storzg@mail.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Pharmacology Research Associate Program of the National Institute of General Medical Sciences; National Research Council FX We thank P. Backlund and A. Yergey for conducting the mass spectrometric analysis; A. Battesti, N. Majdalani, H. Nikaido, L. Rosner, and A. Sharma for sharing antisera, strains, and plasmids; and M. Goulian, M. Machner, K. Ramamurthi, and L. Rosner for comments on the manuscript. Work in the laboratory of G.S. is supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. E.C.H. was additionally supported by the Pharmacology Research Associate Program of the National Institute of General Medical Sciences and B.J.P. was supported by a fellowship from the National Research Council. NR 38 TC 42 Z9 47 U1 1 U2 21 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 OCT 9 PY 2012 VL 109 IS 41 BP 16696 EP 16701 DI 10.1073/pnas.1210093109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026LQ UT WOS:000310280300064 PM 23010927 ER PT J AU Anticevic, A Gancsos, M Murray, JD Repovs, G Driesen, NR Ennis, DJ Niciu, MJ Morgan, PT Surti, TS Bloch, MH Ramani, R Smith, MA Wang, XJ Krystal, JH Corlett, PR AF Anticevic, Alan Gancsos, Mark Murray, John D. Repovs, Grega Driesen, Naomi R. Ennis, Debra J. Niciu, Mark J. Morgan, Peter T. Surti, Toral S. Bloch, Michael H. Ramani, Ramachandran Smith, Mark A. Wang, Xiao-Jing Krystal, John H. Corlett, Philip R. TI NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE default-mode network; task-based activation; task-based deactivation; pharmacological manipulation; fMRI ID CORTICAL NETWORK MODEL; WORKING-MEMORY; PREFRONTAL CORTEX; NEGATIVE SYMPTOMS; CONNECTIVITY MRI; BRAIN-FUNCTION; HEAD MOTION; KETAMINE; DYSFUNCTION; RESPONSES AB Glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain's global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate's role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans. C1 [Anticevic, Alan; Gancsos, Mark; Driesen, Naomi R.; Niciu, Mark J.; Morgan, Peter T.; Surti, Toral S.; Bloch, Michael H.; Krystal, John H.; Corlett, Philip R.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. [Anticevic, Alan; Krystal, John H.] Yale Univ, CTNA, NIAAA, New Haven, CT 06519 USA. [Anticevic, Alan; Gancsos, Mark; Driesen, Naomi R.; Niciu, Mark J.; Morgan, Peter T.; Surti, Toral S.; Bloch, Michael H.; Krystal, John H.; Corlett, Philip R.] Yale Univ, Dept Psychiat, Connecticut Mental Hlth Ctr, Abraham Ribicoff Res Facil, New Haven, CT 06519 USA. [Murray, John D.] Yale Univ, Dept Phys, New Haven, CT 06520 USA. [Repovs, Grega] Univ Ljubljana, Dept Psychol, SI-1000 Ljubljana, Slovenia. [Ennis, Debra J.] AstraZeneca, Study Management & Operat, Wilmington, DE 19803 USA. [Smith, Mark A.] AstraZeneca, Med Sci, Wilmington, DE 19803 USA. [Ramani, Ramachandran] Yale Univ, Sch Med, Dept Anesthesiol, New Haven, CT 06520 USA. [Krystal, John H.] Yale New Haven Med Ctr, Dept Psychiat, Psychiat Serv, New Haven, CT 06510 USA. [Krystal, John H.] VA Connecticut Healthcare Syst, Vet Affairs VA Natl Ctr Posttraumat Stress Disord, Clin Neurosci Div, West Haven, CT 06516 USA. RP Corlett, PR (reprint author), Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. EM philip.corlett@yale.edu RI Wang, Xiao-Jing/D-2722-2009; Anticevic, Alan/E-7868-2010; Niciu, Mark/J-1766-2014; Murray, John/B-2835-2009; OI Niciu, Mark/0000-0002-5612-3021; Murray, John/0000-0003-4115-8181; Repovs, Grega/0000-0003-1837-3879 FU AstraZeneca Pharmaceuticals; National Institutes of Health Grant [R01 MH062349]; Janssen Research Foundation FX We thank Gretchen Hermes and David Matuskey for their skill and time running subject infusions; the nursing staff, Core Laboratory, and support staff of the Human Research Unit at Yale-New Haven Hospital; the MRI technicians at the Anlyan Center for all their support; the Clinical Neuroscience Research Unit staff at the Connecticut Mental Health Center as well as Department of Mental Health and Addiction Services for their support throughout the study; and Megan Ichinose and Taylor McGuinness for assistance with the final dataset. We thank Dr. Eve Marder and Gabrielle Gutierrez for providing a framework for how to visualize complex multidimensional parameter space data. We thank two anonymous reviewers for their excellent and constructive critique, comments, and suggestions on how to improve the manuscript. This research was supported by AstraZeneca Pharmaceuticals and by National Institutes of Health Grant R01 MH062349 (to X.-J.W.). The Janssen Research Foundation provided drug and some study support to the Department of Veterans Affairs (J.H.K.). NR 51 TC 73 Z9 74 U1 2 U2 24 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 OCT 9 PY 2012 VL 109 IS 41 BP 16720 EP 16725 DI 10.1073/pnas.1208494109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026LQ UT WOS:000310280300068 PM 23012427 ER PT J AU Nayar, R Enos, M Prince, A Shin, H Hemmers, S Jiang, JK Klein, U Thomas, CJ Berg, LJ AF Nayar, Ribhu Enos, Megan Prince, Amanda Shin, HyunMu Hemmers, Saskia Jiang, Jian-kang Klein, Ulf Thomas, Craig J. Berg, Leslie J. TI TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8(+) T-cell differentiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T-cell receptor signal strength; T-cell signaling; ITK inhibitor ID TRANSCRIPTION FACTOR IRF4; TH2 CYTOKINES; EOMESODERMIN; EXPRESSION; EFFECTOR; FAMILY; BET; DEFICIENT; RESPONSES; SUBSETS AB CD8(+) T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of "innate" T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (TCR) signaling pathway produce increased numbers of innate CD8(+) T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor, Eomesodermin (Eomes). One component of this altered development is a non-CD8(+) T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8(+) T cells might also contribute to this pathway, we investigated the role of the transcription factor, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8(+) T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8(+) T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8(+) T cells. C1 [Nayar, Ribhu; Enos, Megan; Prince, Amanda; Shin, HyunMu; Berg, Leslie J.] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. [Hemmers, Saskia] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10065 USA. [Klein, Ulf] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA. [Jiang, Jian-kang; Thomas, Craig J.] NIH, Chem Genom Ctr, Rockville, MD 20850 USA. RP Berg, LJ (reprint author), Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. EM leslie.berg@umassmed.edu FU National Institutes of Health [AI084987, AI083505] FX We thank Regina Whitehead, Catherine Yin, and Sharlene Hubbard for technical assistance and Dr. Alexander Rudensky, John Evans III, and Dr. Iivari Kleino for the contribution of reagents. This work was supported by National Institutes of Health Grants AI084987 and AI083505. NR 40 TC 33 Z9 33 U1 0 U2 7 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 OCT 9 PY 2012 VL 109 IS 41 BP E2794 EP E2802 DI 10.1073/pnas.1205742109 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026LQ UT WOS:000310280300009 PM 23011795 ER PT J AU Schleiermacher, G Mosseri, V London, WB Maris, JM Brodeur, GM Attiyeh, E Haber, M Khan, J Nakagawara, A Speleman, F Noguera, R Tonini, GP Fischer, M Ambros, I Monclair, T Matthay, KK Ambros, P Cohn, SL Pearson, ADJ AF Schleiermacher, G. Mosseri, V. London, W. B. Maris, J. M. Brodeur, G. M. Attiyeh, E. Haber, M. Khan, J. Nakagawara, A. Speleman, F. Noguera, R. Tonini, G. P. Fischer, M. Ambros, I. Monclair, T. Matthay, K. K. Ambros, P. Cohn, S. L. Pearson, A. D. J. TI Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project SO BRITISH JOURNAL OF CANCER LA English DT Article DE neuroblastoma; genetic alterations; genomic profile; prognosis; INRG ID CLINICAL-RELEVANCE; HIGHER RISK; GAIN; AMPLIFICATION; RELAPSE; TUMORS; 1P; HETEROZYGOSITY; ACCUMULATION; PROGRESSION AB BACKGROUND: In the INRG dataset, the hypothesis that any segmental chromosomal alteration might be of prognostic impact in neuroblastoma without MYCN amplification (MNA) was tested. METHODS: The presence of any segmental chromosomal alteration (chromosome 1p deletion, 11q deletion and/ or chromosome 17q gain) defined a segmental genomic profile. Only tumours with a confirmed unaltered status for all three chromosome arms were considered as having no segmental chromosomal alterations. RESULTS: Among the 8800 patients in the INRG database, a genomic type could be attributed for 505 patients without MNA: 397 cases had a segmental genomic type, whereas 108 cases had an absence of any segmental alteration. A segmental genomic type was more frequent in patients > 18 months and in stage 4 disease (P < 0.0001). In univariate analysis, 11q deletion, 17q gain and a segmental genomic type were associated with a poorer event-free survival (EFS) (P < 0.0001, P = 0.0002 and P < 0.0001, respectively). In multivariate analysis modelling EFS, the parameters age, stage and a segmental genomic type were retained in the model, whereas the individual genetic markers were not (P < 0.0001 and RR = 2.56; P = 0.0002 and RR = 1.8; P = 0.01 and RR = 1.7, respectively). CONCLUSION: A segmental genomic profile, rather than the single genetic markers, adds prognostic information to the clinical markers age and stage in neuroblastoma patients without MNA, underlining the importance of pangenomic studies. British Journal of Cancer (2012) 107, 1418-1422. doi:10.1038/bjc.2012.375 www.bjcancer.com Published online 13 September 2012 (c) 2012 Cancer Research UK C1 [Schleiermacher, G.] Inst Curie, INSERM, U830, Lab Genet & Biol Canc, Paris, France. [Schleiermacher, G.] Inst Curie, Dept Pediat Oncol, F-75248 Paris 05, France. [Mosseri, V.] Inst Curie, Serv Biostat, Paris, France. [London, W. B.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Childrens Hosp Boston, Boston, MA 02115 USA. [Maris, J. M.; Brodeur, G. M.; Attiyeh, E.] Univ Penn, Ctr Childhood Canc Res, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Haber, M.] Univ New S Wales, Childrens Canc Inst Australia Med Res Lowy Canc R, Sydney, NSW, Australia. [Khan, J.] NCI, Oncogen Sect, Pediat Oncol Branch, NIH, Gaithersburg, MD USA. [Nakagawara, A.] Chiba Canc Ctr Res Inst, Lab Innovat Canc Therapeut, Chiba, Japan. [Speleman, F.] Ghent Univ Hosp, Ctr Med Genet, Dept Paediat Hematol & Oncol, Ghent, Belgium. [Tonini, G. P.] Natl Inst Canc Res, Genoa, Italy. [Noguera, R.] Univ Valencia, Dept Pathol, Valencia, Spain. [Fischer, M.] Univ Cologne, Childrens Hosp, Dept Pediat Oncol & Hematol, D-50931 Cologne, Germany. [Fischer, M.] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany. [Ambros, I.; Ambros, P.] St Anna Kinderkrebsforsch, CCRI, Vienna, Austria. [Monclair, T.] Aker Univ Hosp, Sect Paediat Surg, Div Surg, Rikshosp, Oslo, Norway. [Matthay, K. K.] UCSF Sch Med, San Francisco, CA USA. [Matthay, K. K.] Benioff Childrens Hosp, San Francisco, CA USA. [Cohn, S. L.] Univ Chicago, Sect Pediat Hematol Oncol, Comer Childrens Hosp, Chicago, IL 60637 USA. [Pearson, A. D. J.] Royal Marsden Hosp, Childrens Dept, Inst Canc Res, Sutton, Surrey, England. RP Schleiermacher, G (reprint author), Inst Curie, INSERM, U830, Lab Genet & Biol Canc, Paris, France. EM gudrun.schleiermacher@curie.net RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Ambros, Peter F./0000-0002-5507-7211; Cohn, Susan/0000-0001-5749-7650 FU Annenberg Foundation FX GS is supported by the Annenberg Foundation. The INRG database harbours biology data from different national groups and laboratories responsible for neuroblastoma genetics. For SIOPEN, the following members of the SIOPEN Biology group contributed data: Clare Bedwell, Newcastle, UK; Klaus Beiske, Oslo, Norway; Jean Benard, Villejuif, France; Nick Bown, Newcastle, UK; Valerie Combaret, Lyon, France; Jerome Couturier, Paris, France; Raffaella Defferrari, Genoa, Italy; Nicole Gross, Lausanne, Switzerland; Marta Jeison, Petah Tikva, Israel: John Lunec, Newcastle, UK; Tommy Martinsson, Goteborg, Sweden; Barbara Marques, Lisbon, Portugal; Katia Mazzocco, Genoa, Italy; Rosa Noguera, Valencia, Spain; Gianpaolo Tonini, Genoa, Italy; Deborah Tweddle, Newcastle, UK; Alexander Valent, Villejuif, France; Nadine Van Roy, Ghent, Belgium; Luigi Varesio, Genoa, Italy; Alex Vicha, Prague, Czech Republic; Eva Villamon, Valencia, Spain. For GPOH, the following biology group members contributed data: Franck Berthold, Cologne, Germany; Jessica Theissen, Cologne, Germany; Manfred Schwab, Heidelberg, Germany; Frank Westermann, Heidelberg, Germany; Freimut Schilling, Stuttgart, Germany; Sabine Stegmaier, Stuttgart, Germany; Felix Niggli, Zurich, Switzerland. For COG, the following biology group members contributed data: Michael Hogarty, Philadelphia, USA; Rochelle Bagatell, Philadelphia, USA. For Japan, the following biology group members contributed data: Miki Ohira, Chiba, Japan; Yasuhiko Kaneko, Saitama, Japan; Junko Takita, Tokyo, Japan; Hajime Ohkita, Tokyo, Japan (Ambros et al, 2009). NR 26 TC 39 Z9 40 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 9 PY 2012 VL 107 IS 8 BP 1418 EP 1422 DI 10.1038/bjc.2012.375 PG 5 WC Oncology SC Oncology GA 022MI UT WOS:000309963100028 PM 22976801 ER PT J AU Tortorella, LL Pipalia, NH Mukherjee, S Pastan, I Fitzgerald, D Maxfield, FR AF Tortorella, Lori L. Pipalia, Nina H. Mukherjee, Sushmita Pastan, Ira Fitzgerald, David Maxfield, Frederick R. TI Efficiency of Immunotoxin Cytotoxicity Is Modulated by the Intracellular Itinerary SO PLOS ONE LA English DT Article ID TRANS-GOLGI NETWORK; PSEUDOMONAS EXOTOXIN-A; ENDOCYTIC RECYCLING COMPARTMENT; CYTOPLASMIC DOMAIN; CELL-SURFACE; HEMATOLOGIC MALIGNANCIES; RECOMBINANT IMMUNOTOXINS; PROPROTEIN CONVERTASE; BETA-CHAIN; EN-ROUTE AB Pseudomonas exotoxin-based immunotoxins, including LMB-2 (antiTac(F-v)-PE38), are proposed to traffic to the trans-Golgi network (TGN) and move by a retrograde pathway to the endoplasmic reticulum, where they undergo translocation to the cytoplasm, a step that is essential for cytotoxicity. The retrograde transport pathways used by LMB-2 are not completely understood, so it is unclear if transit through specific organelles is critical for maximal cytotoxic activity. In this study, we used Chinese hamster ovary (CHO) cell lines that express chimeric constructs of CD25, the Tac antigen, attached to the cytoplasmic domain of the TGN-targeted transmembrane proteins, TGN38 and furin. These chimeras are both targeted to the TGN, but the itineraries they follow are quite different. LMB-2 was incubated with the two cell lines, and the efficiency of cell killing was determined using cell viability and cytotoxicity assays. LMB-2 that is targeted through the endocytic recycling compartment to the TGN via Tac-TGN38 kills the cells more efficiently than immunotoxins delivered through the late endosomes by Tac-furin. Although the processing to the 37 kDa active fragment was more efficient in Tac-furin cells than in Tac-TGN38 cells, this was not associated with enhanced cytotoxicity - presumably because the toxin was also degraded more rapidly in these cells. These data indicate that trafficking through specific organelles is an important factor modulating toxicity by LMB-2. C1 [Tortorella, Lori L.; Pipalia, Nina H.; Mukherjee, Sushmita; Maxfield, Frederick R.] Weill Cornell Med Coll, Dept Biochem, New York, NY USA. [Pastan, Ira; Fitzgerald, David] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Maxfield, FR (reprint author), Weill Cornell Med Coll, Dept Biochem, New York, NY USA. EM frmaxfie@med.cornell.edu OI Maxfield, Frederick/0000-0003-4396-8866 FU National Institutes of Health [R37-DK27083]; Center for Cancer Research, National Cancer Institute FX This work was supported by National Institutes of Health grant R37-DK27083 (FRM) and by the Center for Cancer Research, National Cancer Institute (DF, IP)(http://www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 7 Z9 7 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 OCT 9 PY 2012 VL 7 IS 10 AR e47320 DI 10.1371/journal.pone.0047320 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 021MR UT WOS:000309889400075 PM 23056628 ER PT J AU Vaught, J Lockhart, NC AF Vaught, Jim Lockhart, Nicole C. TI The evolution of biobanking best practices SO CLINICA CHIMICA ACTA LA English DT Review DE Biobanking; Biorepository; Best practices; Biospecimens; Tissue; Informed consent ID INFORMED-CONSENT; GENETIC RESEARCH; BIOSPECIMEN; CANCER; BIOREPOSITORIES; BIOBANKONOMICS; INSTITUTE; OPINIONS; MEDICINE; SCIENCE AB Biobanks and biospecimens are critical components for many areas of clinical and basic research. The quality of biospecimens and associated data must be consistent and collected according to standardized methods in order to prevent spurious analytical results that can lead to artifacts being interpreted as valid findings. A number of international institutions have taken the initiative to develop and publish best practices, which include technical recommendations for handling biospecimens as well as recommendations for ethical and regulatory practices in biobanking. These sources of guidance have been useful in raising the overall consistency and quality of research involving biospecimens. However, the lack of international harmonization, uneven adoption, and insufficient oversight of best practices are preventing further improvements in biospecimen quality and coordination among collaborators and biobanking networks. In contrast to the more straightforward technical and management issues, ethical and regulatory practices often involve issues that are more controversial and difficult to standardize. Published by Elsevier B.V. C1 [Vaught, Jim; Lockhart, Nicole C.] NCI, Off Biorepositories & Biospecimen Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Vaught, J (reprint author), NCI, Off Biorepositories & Biospecimen Res, NIH, US Dept HHS, 11400 Rockville Pike, Bethesda, MD 20892 USA. EM vaughtj@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 47 TC 44 Z9 46 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD OCT 9 PY 2012 VL 413 IS 19-20 BP 1569 EP 1575 DI 10.1016/j.cca.2012.04.030 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 994IL UT WOS:000307924000027 PM 22579478 ER PT J AU Yoshioka, M Couret, J Kim, F McMillan, J Burkot, TR Dotson, EM Kitron, U Vazquez-Prokopec, GM AF Yoshioka, Miho Couret, Jannelle Kim, Frances McMillan, Joseph Burkot, Thomas R. Dotson, Ellen M. Kitron, Uriel Vazquez-Prokopec, Gonzalo M. TI Diet and density dependent competition affect larval performance and oviposition site selection in the mosquito species Aedes albopictus (Diptera: Culicidae) SO PARASITES & VECTORS LA English DT Article DE Habitat selection; Oviposition; Diet; Conspecific density; Mosquito ID PLAGIORCHIS ELEGANS TREMATODA; AEGYPTI L DIPTERA; OFFSPRING PERFORMANCE; FEEDING-BEHAVIOR; GROWTH-RETARDANT; FECUNDITY; FIELD; DENGUE; POPULATIONS; STARVATION AB Background: Oviposition-site choice is an essential component of the life history of all mosquito species. According to the oviposition-preference offspring-performance (P-P) hypothesis, if optimizing offspring performance and fitness ensures high overall reproductive fitness for a given species, the female should accurately assess details of the heterogeneous environment and lay her eggs preferentially in sites with conditions more suitable to offspring. Methods: We empirically tested the P-P hypothesis using the mosquito species Aedes albopictus by artificially manipulating two habitat conditions: diet (measured as mg of food added to a container) and conspecific density (CD; number of pre-existing larvae of the same species). Immature development (larval mortality, development time to pupation and time to emergence) and fitness (measured as wing length) were monitored from first instar through adult emergence using a factorial experimental design over two ascending gradients of diet (2.0, 3.6, 7.2 and 20 mg food/300 ml water) and CD (0, 20, 40 and 80 larvae/300 ml water). Treatments that exerted the most contrasting values of larval performance were recreated in a second experiment consisting of single-female oviposition site selection assay. Results: Development time decreased as food concentration increased, except from 7.2 mg to 20.0 mg (Two-Way CR ANOVA Post-Hoc test, P > 0.1). Development time decreased also as conspecific density increased from zero to 80 larvae (Two-Way CR ANOVA Post-Hoc test, P < 0.5). Combined, these results support the role of density-dependent competition for resources as a limiting factor for mosquito larval performance. Oviposition assays indicated that female mosquitoes select for larval habitats with conspecifics and that larval density was more important than diet in driving selection for oviposition sites. Conclusions: This study supports predictions of the P-P hypothesis and provides a mechanistic understanding of the underlying factors driving mosquito oviposition site selection. C1 [Vazquez-Prokopec, Gonzalo M.] Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. [Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Burkot, Thomas R.; Dotson, Ellen M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Burkot, Thomas R.] James Cook Univ, Cairns, Australia. RP Vazquez-Prokopec, GM (reprint author), Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. EM gmvazqu@emory.edu RI Burkot, Thomas/C-6838-2013 FU Emory University (Department of Environmental Studies James G. Lester Research Grant); Scholarly Inquiry and Research at Emory (SIRE) program; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We gratefully thank Paul Howell for helping with mosquito bloodfeeding and colony maintenance. This study was supported by funds from Emory University (Department of Environmental Studies James G. Lester Research Grant) and the Scholarly Inquiry and Research at Emory (SIRE) program through a student fellowship to M.Y. Development of the ideas presented here was assisted by support from Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 50 TC 21 Z9 22 U1 4 U2 55 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 OCT 8 PY 2012 VL 5 AR 225 DI 10.1186/1756-3305-5-225 PG 11 WC Parasitology SC Parasitology GA 028YE UT WOS:000310461000003 PM 23044004 ER PT J AU Jamerson, KA Agodoa, L AF Jamerson, Kenneth A. Agodoa, Lawrence TI Hypertension as an Emerging Risk Factor for Acute Heart Failure in Africa SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID ISOSORBIDE DINITRATE; HYDRALAZINE; TRIAL C1 [Jamerson, Kenneth A.] Univ Michigan Hlth Syst, Div Cardiovasc Med, Ann Arbor, MI 48106 USA. [Agodoa, Lawrence] NIDDK, NIH, Bethesda, MD USA. RP Jamerson, KA (reprint author), Univ Michigan Hlth Syst, Div Cardiovasc Med, 24 Frank Lloyd Wright Dr,3rd Floor, Ann Arbor, MI 48106 USA. EM jamerson@umich.edu NR 9 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 8 PY 2012 VL 172 IS 18 BP 1395 EP 1396 DI 10.1001/archinternmed.2012.4491 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 016ST UT WOS:000309540500005 PM 22945627 ER PT J AU Parameswaran, S Balasubramanian, S Babai, N DelDebbio, CB Harms, DW Gurumurthy, CB Rao, MS Sharp, JG Ahmad, I AF Parameswaran, Sowmya Balasubramanian, Sudha Babai, Norbert DelDebbio, Carolina B. Harms, Donald W. Gurumurthy, Channabasavaiah B. Rao, Mahendra S. Sharp, John G. Ahmad, Iqbal TI Nucleic Acid and Non-Nucleic Acid-Based Reprogramming of Adult Limbal Progenitors to Pluripotency SO PLOS ONE LA English DT Article ID EMBRYONIC STEM-CELLS; SOMATIC-CELLS; GENERATION; MOUSE; DIFFERENTIATION; EFFICIENT; INDUCTION; MICRORNAS; MECHANISM; THERAPY AB Reprogramming somatic cells to a pluripotent state by nucleic acid based (NAB) approaches, involving the ectopic expression of transcription factors, has emerged as a standard method. We recently demonstrated that limbal progenitors that regenerate cornea are reprogrammable to pluripotency by a non-NAB approach through simple manipulation of microenvironment thus extending the possible therapeutic use of these readily accessible cells beyond the proven treatment of corneal diseases and injury. Therefore, to determine the validity and robustness of non-cell autonomous reprogramming of limbal progenitors for a wider clinical use, here, we have compared their reprogramming by non-NAB and NAB approaches. We observed that both approaches led to (1) the emergence of colonies displaying pluripotency markers, accompanied by a temporal reciprocal changes in limbal-specific and pluripotency gene expression, and (2) epigenetic alterations of Oct4 and Nanog, associated with the de-novo activation of their expression. While the efficiency of reprogramming and passaging of re-programmed cells were significantly better with the NAB approach, the non-NAB approach, in contrast, led to a regulated reprogramming of gene expression, and a significant decrease in the expression of Hormad1, a gene associated with immunogenic responses. The reprogramming efficiency by non-NAB approach was influenced by exosomes present in conditioned medium. Cells reprogrammed by both approaches were capable of differentiating along the three germ lineages and generating chimeras. The analysis suggests that both approaches are effective in reprogramming limbal progenitors but the non-NAB approach may be more suitable for potential clinical applications by averting the risk of insertional mutagenesis and immune responses associated with the NAB approach. C1 [Parameswaran, Sowmya; Balasubramanian, Sudha; Babai, Norbert; DelDebbio, Carolina B.; Ahmad, Iqbal] Univ Nebraska Med Ctr, Dept Ophthalmol & Visual Sci, Omaha, NE 68198 USA. [Harms, Donald W.; Gurumurthy, Channabasavaiah B.; Sharp, John G.] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Parameswaran, S (reprint author), Univ Nebraska Med Ctr, Dept Ophthalmol & Visual Sci, Omaha, NE 68198 USA. EM iahmad@unmc.edu RI Del Debbio, Carolina/C-4428-2012 FU Lincy Foundation; Pearson Foundation; Nebraska Department of Health and Human Services; Otis Glebe Foundation FX This work was supported by Lincy Foundation, Pearson Foundation, Nebraska Department of Health and Human Services, and Otis Glebe Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 5 Z9 6 U1 0 U2 11 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 OCT 8 PY 2012 VL 7 IS 10 AR e46734 DI 10.1371/journal.pone.0046734 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020RP UT WOS:000309831500066 PM 23056428 ER PT J AU Victor, TA Furey, ML Fromm, SJ Bellgowan, PSF Ohman, A Drevets, WC AF Victor, Teresa A. Furey, Maura L. Fromm, Stephen J. Bellgowan, Patrick S. F. Ohman, Arne Drevets, Wayne C. TI The Extended Functional Neuroanatomy of Emotional Processing Biases for Masked Faces in Major Depressive Disorder SO PLOS ONE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; HAPPY FACIAL EXPRESSIONS; ANTIDEPRESSANT TREATMENT; SUSTAINED ATTENTION; CLINICAL DEPRESSION; AMYGDALA ACTIVATION; MACAQUE MONKEYS; NEURAL RESPONSE; MOOD DISORDERS; INFORMATION AB Background: Major depressive disorder (MDD) is associated with a mood-congruent processing bias in the amygdala toward face stimuli portraying sad expressions that is evident even when such stimuli are presented below the level of conscious awareness. The extended functional anatomical network that maintains this response bias has not been established, however. Aims: To identify neural network differences in the hemodynamic response to implicitly presented facial expressions between depressed and healthy control participants. Method: Unmedicated-depressed participants with MDD (n = 22) and healthy controls (HC; n = 25) underwent functional MRI as they viewed face stimuli showing sad, happy or neutral face expressions, presented using a backward masking design. The blood-oxygen-level dependent (BOLD) signal was measured to identify regions where the hemodynamic response to the emotionally valenced stimuli differed between groups. Results: The MDD subjects showed greater BOLD responses than the controls to masked-sad versus masked-happy faces in the hippocampus, amygdala and anterior inferotemporal cortex. While viewing both masked-sad and masked-happy faces relative to masked-neutral faces, the depressed subjects showed greater hemodynamic responses than the controls in a network that included the medial and orbital prefrontal cortices and anterior temporal cortex. Conclusions: Depressed and healthy participants showed distinct hemodynamic responses to masked-sad and masked-happy faces in neural circuits known to support the processing of emotionally valenced stimuli and to integrate the sensory and visceromotor aspects of emotional behavior. Altered function within these networks in MDD may establish and maintain illness-associated differences in the salience of sensory/social stimuli, such that attention is biased toward negative and away from positive stimuli. C1 [Victor, Teresa A.; Furey, Maura L.; Fromm, Stephen J.; Drevets, Wayne C.] NIMH, NIH, Bethesda, MD 20892 USA. [Victor, Teresa A.; Bellgowan, Patrick S. F.; Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. [Victor, Teresa A.; Ohman, Arne] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Bellgowan, Patrick S. F.] Univ Tulsa, Fac Community Med, Tulsa, OK 74104 USA. RP Victor, TA (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM tvictor@laureateinstitute.org RI Furey, Maura/H-5273-2013 FU National Institute of Mental Health [Z01-MH002792]; William K. Warren Foundation FX This work was supported by National Institute of Mental Health: Grant number Z01-MH002792 "Functional Neuroimaging in Unipolar and Bipolar Depressed Patients'' (http://www.nimh.nih.gov/index.shtml) and William K. Warren Foundation (http://williamkwarrenfoundation.org/). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Dr. Furey and Dr. Drevets: for relevant financial activities outside the submitted work (money paid to them and their institution): a pending patent, US Patent Application No: 2006/0270,698 entitled "Scopolamine for the Treatment of Depression and Anxiety''. NIMH is the primary patent holder. Dr. Drevets: for the work under consideration for publication: grant money to his institution (NIMH DIRP) and for relevant financial activities outside the submitted work: consultancy (money paid to him) at Myriad, Esai, Johnson & Johnson and Pfizer; grant money to his institution from the William K. Warren Foundation in support of Laureate Institute for Brain Research; payment for development of educational presentations (lecture honoraria): University of PA, Washington University, UC-Davis, CME Incorporated. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. NR 63 TC 23 Z9 24 U1 2 U2 15 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 OCT 8 PY 2012 VL 7 IS 10 AR e46439 DI 10.1371/journal.pone.0046439 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020RP UT WOS:000309831500040 PM 23056309 ER PT J AU Yamanaka, K Dorjsuren, D Eoff, RL Egli, M Maloney, DJ Jadhav, A Simeonov, A Lloyd, RS AF Yamanaka, Kinrin Dorjsuren, Dorjbal Eoff, Robert L. Egli, Martin Maloney, David J. Jadhav, Ajit Simeonov, Anton Lloyd, R. Stephen TI A Comprehensive Strategy to Discover Inhibitors of the Translesion Synthesis DNA Polymerase kappa SO PLOS ONE LA English DT Article ID INTERSTRAND CROSS-LINKS; ERROR-FREE; REPAIR; REPLICATION; FAMILY; BYPASS; ADDUCTS; IOTA; MECHANISM; ACROLEIN AB Human DNA polymerase kappa (pol kappa) is a translesion synthesis (TLS) polymerase that catalyzes TLS past various minor groove lesions including N-2-dG linked acrolein-and polycyclic aromatic hydrocarbon-derived adducts, as well as N-2-dG DNA-DNA interstrand cross-links introduced by the chemotherapeutic agent mitomycin C. It also processes ultraviolet light-induced DNA lesions. Since pol kappa TLS activity can reduce the cellular toxicity of chemotherapeutic agents and since gliomas overexpress pol kappa, small molecule library screens targeting pol kappa were conducted to initiate the first step in the development of new adjunct cancer therapeutics. A high-throughput, fluorescence-based DNA strand displacement assay was utilized to screen similar to 16,000 bioactive compounds, and the 60 top hits were validated by primer extension assays using non-damaged DNAs. Candesartan cilexetil, manoalide, and MK-886 were selected as proof-of-principle compounds and further characterized for their specificity toward pol kappa by primer extension assays using DNAs containing a site-specific acrolein-derived, ring-opened reduced form of gamma-HOPdG. Furthermore, candesartan cilexetil could enhance ultraviolet light-induced cytotoxicity in xeroderma pigmentosum variant cells, suggesting its inhibitory effect against intracellular pol kappa. In summary, this investigation represents the first high-throughput screening designed to identify inhibitors of pol kappa, with the characterization of biochemical and biologically relevant endpoints as a consequence of pol kappa inhibition. These approaches lay the foundation for the future discovery of compounds that can be applied to combination chemotherapy. C1 [Yamanaka, Kinrin; Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97201 USA. [Yamanaka, Kinrin] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. [Dorjsuren, Dorjbal; Maloney, David J.; Jadhav, Ajit; Simeonov, Anton] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Eoff, Robert L.] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. [Egli, Martin] Vanderbilt Univ, Sch Med, Dept Biochem, Ctr Mol Toxicol, Nashville, TN 37212 USA. [Egli, Martin] Vanderbilt Univ, Sch Med, Vanderbilt Inst Chem Biol, Nashville, TN 37212 USA. RP Lloyd, RS (reprint author), Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97201 USA. EM lloydst@ohsu.edu FU National Institute of Environmental Health Sciences [ES05355]; National Cancer Institute [CA106858]; National Institute of Mental Health [R03 MH 094179]; National Institute of General Medical Sciences [R00 GM 084460] FX This work was supported by National Institute of Environmental Health Sciences [ES05355 to R. S. L.], National Cancer Institute [CA106858 to R. S. L.], National Institute of Mental Health [R03 MH 094179 to R. S. L.], and National Institute of General Medical Sciences [R00 GM 084460 to R. L. E.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 12 Z9 12 U1 0 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 OCT 8 PY 2012 VL 7 IS 10 AR e45032 DI 10.1371/journal.pone.0045032 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020RP UT WOS:000309831500011 PM 23056190 ER PT J AU Pigott, A Frescas, S McCorvy, JD Huang, XP Roth, BL Nichols, DE AF Pigott, Adam Frescas, Stewart McCorvy, John D. Huang, Xi-Ping Roth, Bryan L. Nichols, David E. TI trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT2 receptor family SO BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY LA English DT Article DE cyclopropanation; diazomethane; hallucinogen; 5-HT2A agonist; receptor probe; trans-2-phenylcyclopropylamines AB A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT2 family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (-)-(1R,2S)-configuration. Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased affinity at several sites in addition to the 5-HT2A and 5-HT2B receptors. Therefore, at appropriate doses - although (-)-4 and (-)-5 may be useful as tools to probe 5-HT2 receptor function - one would need to be mindful that their selectivity for 5-HT2A receptors is somewhat less than for DOI itself. C1 [Pigott, Adam; Frescas, Stewart; McCorvy, John D.; Nichols, David E.] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Natl Inst Mental Hlth,Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. RP Nichols, DE (reprint author), Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM drdave@purdue.edu RI Roth, Bryan/F-3928-2010 FU Robert C. and Charlotte P. Anderson endowment FX This research was supported by the Robert C. and Charlotte P. Anderson endowment. NR 9 TC 3 Z9 3 U1 0 U2 13 PU BEILSTEIN-INSTITUT PI FRANKFURT AM MAIN PA TRAKEHNER STRASSE 7-9, FRANKFURT AM MAIN, 60487, GERMANY SN 1860-5397 J9 BEILSTEIN J ORG CHEM JI Beilstein J. Org. Chem. PD OCT 8 PY 2012 VL 8 BP 1705 EP 1709 DI 10.3762/bjoc.8.194 PG 5 WC Chemistry, Organic SC Chemistry GA 017ML UT WOS:000309593900001 PM 23209503 ER PT J AU Tao, P Wu, XW Brooks, BR AF Tao, Peng Wu, Xiongwu Brooks, Bernard R. TI Maintain rigid structures in Verlet based Cartesian molecular dynamics simulations SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CONSTRAINTS; ALGORITHM; RATTLE; WATER; SHAKE AB An algorithm is presented to maintain rigid structures in Verlet based Cartesian molecular dynamics (MD) simulations. After each unconstrained MD step, the coordinates of selected particles are corrected to maintain rigid structures through an iterative procedure of rotation matrix computation. This algorithm, named as SHAPE and implemented in CHARMM program suite, avoids the calculations of Lagrange multipliers, so that the complexity of computation does not increase with the number of particles in a rigid structure. The implementation of this algorithm does not require significant modification of propagation integrator, and can be plugged into any Cartesian based MD integration scheme. A unique feature of the SHAPE method is that it is interchangeable with SHAKE for any object that can be constrained as a rigid structure using multiple SHAKE constraints. Unlike SHAKE, the SHAPE method can be applied to large linear (with three or more centers) and planar (with four or more centers) rigid bodies. Numerical tests with four model systems including two proteins demonstrate that the accuracy and reliability of the SHAPE method are comparable to the SHAKE method, but with much more applicability and efficiency. [http://dx.doi.org/10.1063/1.4756796] C1 [Tao, Peng; Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Tao, P (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Tao, Peng/H-4925-2014 OI Tao, Peng/0000-0002-2488-0239 FU Intramural Research Program of the NIH, NHLBI FX The research was supported by the Intramural Research Program of the NIH, NHLBI. Computational resources and services used in this work were provided by the LoBoS cluster of the National Institutes of Health. NR 19 TC 5 Z9 5 U1 0 U2 17 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 7 PY 2012 VL 137 IS 13 AR 134110 DI 10.1063/1.4756796 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 018LS UT WOS:000309662700013 PM 23039588 ER PT J AU Luo, SS Reed, M Mattingly, JC Koelle, K AF Luo, Shishi Reed, Michael Mattingly, Jonathan C. Koelle, Katia TI The impact of host immune status on the within-host and population dynamics of antigenic immune escape SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE viral evolution; intra-host dynamics; immune escape ID INFLUENZA-VIRUS INFECTION; EVOLUTIONARY DYNAMICS; PR8 STRAIN; VARIANTS; MODEL; MICE; HEMAGGLUTININ; INTERFERON; VOLUNTEERS; PATHOGENS AB Antigenically evolving pathogens such as influenza viruses are difficult to control owing to their ability to evade host immunity by producing immune escape variants. Experimental studies have repeatedly demonstrated that viral immune escape variants emerge more often from immunized hosts than from naive hosts. This empirical relationship between host immune status and within-host immune escape is not fully understood theoretically, nor has its impact on antigenic evolution at the population level been evaluated. Here, we show that this relationship can be understood as a trade-off between the probability that a new antigenic variant is produced and the level of viraemia it reaches within a host. Scaling up this intra-host level trade-off to a simple population level model, we obtain a distribution for variant persistence times that is consistent with influenza A/H3N2 antigenic variant data. At the within-host level, our results show that target cell limitation, or a functional equivalent, provides a parsimonious explanation for how host immune status drives the generation of immune escape mutants. At the population level, our analysis also offers an alternative explanation for the observed tempo of antigenic evolution, namely that the production rate of immune escape variants is driven by the accumulation of herd immunity. Overall, our results suggest that disease control strategies should be further assessed by considering the impact that increased immunity-through vaccination-has on the production of new antigenic variants. C1 [Luo, Shishi; Reed, Michael; Mattingly, Jonathan C.] Duke Univ, Dept Math, Durham, NC 27708 USA. [Koelle, Katia] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Luo, SS (reprint author), Duke Univ, Dept Math, Durham, NC 27708 USA. EM szl@math.duke.edu FU National Science Foundation [NSF-EF-1038593, NSF-0854879, NSF-EF-08-27416]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Center for Theoretical and Mathematical Sciences FX This work was funded by National Science Foundation grants NSF-EF-1038593 (M.R.), NSF-0854879 (J.C.M.) and NSF-EF-08-27416 (K.K.). K.K. was further supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. S.L. was supported by a fellowship from the Center for Theoretical and Mathematical Sciences. NR 34 TC 9 Z9 9 U1 0 U2 9 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD OCT 7 PY 2012 VL 9 IS 75 BP 2603 EP 2613 DI 10.1098/rsif.2012.0180 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998LK UT WOS:000308240400020 PM 22572027 ER PT J AU Butail, S Manoukis, N Diallo, M Ribeiro, JM Lehmann, T Paley, DA AF Butail, Sachit Manoukis, Nicholas Diallo, Moussa Ribeiro, Jose M. Lehmann, Tovi Paley, Derek A. TI Reconstructing the flight kinematics of swarming and mating in wild mosquitoes SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE target tracking; Anopheles gambiae; mosquito swarms; mating mosquitoes ID MULTIPLE HYPOTHESIS TRACKING; ANOPHELES-GAMBIAE; PERFORMANCE EVALUATION; REPRODUCTIVE ISOLATION; SAO-TOME; BEHAVIOR; ALGORITHM; SUCCESS; TARGETS; NUMBER AB We describe a novel tracking system for reconstructing three-dimensional tracks of individual mosquitoes in wild swarms and present the results of validating the system by filming swarms and mating events of the malaria mosquito Anopheles gambiae in Mali. The tracking system is designed to address noisy, low frame-rate (25 frames per second) video streams from a stereo camera system. Because flying A. gambiae move at 1-4 m s(-1), they appear as faded streaks in the images or sometimes do not appear at all. We provide an adaptive algorithm to search for missing streaks and a likelihood function that uses streak endpoints to extract velocity information. A modified multi-hypothesis tracker probabilistically addresses occlusions and a particle filter estimates the trajectories. The output of the tracking algorithm is a set of track segments with an average length of 0.6-1 s. The segments are verified and combined under human supervision to create individual tracks up to the duration of the video (90 s). We evaluate tracking performance using an established metric for multi-target tracking and validate the accuracy using independent stereo measurements of a single swarm. Three-dimensional reconstructions of A. gambiae swarming and mating events are presented. C1 [Butail, Sachit; Paley, Derek A.] Univ Maryland, Dept Aerosp Engn, College Pk, MD 20742 USA. [Manoukis, Nicholas] ARS, US Pacific Basin Agr Res Ctr, USDA, Hilo, HI 96720 USA. [Diallo, Moussa] Univ Bamako, Fac Med Pharm & Odontostomatol, Malaria Res & Training Ctr, Bamako, Mali. [Ribeiro, Jose M.; Lehmann, Tovi] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. RP Paley, DA (reprint author), Univ Maryland, Dept Aerosp Engn, College Pk, MD 20742 USA. EM dpaley@umd.edu RI Paley, Derek/B-4437-2013; OI Paley, Derek/0000-0002-3086-2395; Manoukis, Nicholas/0000-0001-5062-7256; Ribeiro, Jose/0000-0002-9107-0818 NR 42 TC 30 Z9 30 U1 0 U2 18 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD OCT 7 PY 2012 VL 9 IS 75 BP 2624 EP 2638 DI 10.1098/rsif.2012.0150 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998LK UT WOS:000308240400022 PM 22628212 ER PT J AU Yin, LH Shen, H Diaz-Ruiz, O Backman, CM Bae, E Yu, SJ Wang, Y AF Yin, Lian-Hu Shen, Hui Diaz-Ruiz, Oscar Baeckman, Cristina M. Bae, Eunkyung Yu, Seong-Jin Wang, Yun TI Early post-treatment with 9-cis retinoic acid reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson's disease SO BMC NEUROSCIENCE LA English DT Article ID BONE MORPHOGENETIC PROTEIN-7; FREELY-MOVING RATS; DOCOSAHEXAENOIC ACID; X-RECEPTOR; 9-CIS-RETINOIC ACID; INDUCED APOPTOSIS; NUCLEAR RECEPTOR; OXIDATIVE STRESS; BRAIN; PROTECTS AB Background: Retinoic acid (RA) is a biologically active derivative of vitamin A. Previous studies have demonstrated that RA has protective effects against damage caused by H2O2 or oxygen-glucose deprivation in mesangial and PC12 cells. Pretreatment with 9-cis-retinoic acid (9cRA) reduced infarction and TUNEL labeling in cerebral cortex as well as attenuated neurological deficits after distal middle cerebral artery occlusion in rats. The purpose of this study was to examine a protective role of 9cRA in dopaminergic (DA) neurons in a typical rodent model of Parkinson's disease (PD). Results: The protective role of 9cRA was first examined in rat primary ventromesencephalic culture. Treatment with 9cRA significantly reduced 6-hydroxydopamine (6-OHDA)-mediated cell death and TUNEL labeling in cultured dopaminergic neurons. The protective effect was also examined in adult male rats. Animals received unilateral 6-OHDA lesioning at the left medial forebrain bundle on day 0. Methamphetamine -induced rotational behavior was examined on days 6, 20 and 30 after lesioning. Animals were separated into 2 groups to balance rotational behavior and lesion extent on day 6 and were treated with either 9cRA or vehicle (i.c.v. on day 7 + intra-nasal from day 8 to day 14). Post-treatment with 9cRA significantly reduced methamphetamine -mediated ipislateral rotation at 20 and 30 days after lesioning. In vivo voltammetry was used to examine DA overflow in striatum. Treatment with 9cRA significantly increased KCl -evoked DA release in the lesioned striatum. 9cRA also increased tyrosine hydroxylase (+) cell number in the lesioned nigra as determined by unbiased stereology. Conclusion: Our data suggests that early post-treatment with 9cRA has a protective effect against neurodegeneration in nigrostriatal DA neurons in an animal model of PD. C1 [Yin, Lian-Hu; Shen, Hui; Bae, Eunkyung; Yu, Seong-Jin; Wang, Yun] NIDA, Neural Protect & Regenerat Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Diaz-Ruiz, Oscar; Baeckman, Cristina M.] NIDA, Integrat Neurosci Sect, IRP, Baltimore, MD USA. [Yin, Lian-Hu] Capital Med Univ, Luhe Teaching Hosp, Dept Neurosurg, Beijing, Peoples R China. RP Wang, Y (reprint author), NIDA, Neural Protect & Regenerat Sect, Intramural Res Program, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov RI backman, cristina/C-1276-2013 FU NIDA IRP FX This study was supported by NIDA IRP. NR 44 TC 12 Z9 12 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD OCT 6 PY 2012 VL 13 AR 120 DI 10.1186/1471-2202-13-120 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 056OE UT WOS:000312499200001 PM 23040108 ER PT J AU Lopera-Mesa, TM Mita-Mendoza, NK van de Hoef, DL Doumbia, S Konate, D Doumbouya, M Gu, WJ Traore, K Diakite, SAS Remaley, AT Anderson, JM Rodriguez, A Fay, MP Long, CA Diakite, M Fairhurst, RM AF Lopera-Mesa, Tatiana M. Mita-Mendoza, Neida K. van de Hoef, Diana L. Doumbia, Saibou Konate, Drissa Doumbouya, Mory Gu, Wenjuan Traore, Karim Diakite, Seidina A. S. Remaley, Alan T. Anderson, Jennifer M. Rodriguez, Ana Fay, Michael P. Long, Carole A. Diakite, Mahamadou Fairhurst, Rick M. TI Plasma Uric Acid Levels Correlate with Inflammation and Disease Severity in Malian Children with Plasmodium falciparum Malaria SO PLOS ONE LA English DT Article ID CEREBRAL MALARIA; DANGER SIGNAL; SERUM-LEVELS; CELLS; TRANSPORT; EXPRESSION; MORTALITY; MEDIATOR; IMMUNITY; FAILURE AB Background: Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of 'parasite-derived' UA stimulate immune cells to produce inflammatory cytokines in vitro. Methods and Findings: We measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNF alpha, IP-10, IFN gamma, GM-CSF, IL-1 beta) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09-1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97-1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNF alpha (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34-1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl). Conclusions: Elevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA and renal function may be involved. Defining pathogenic roles for parasite-derived UA precipitates, which we have not directly studied here, requires further investigation. C1 [Lopera-Mesa, Tatiana M.; Mita-Mendoza, Neida K.; Anderson, Jennifer M.; Long, Carole A.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Mita-Mendoza, Neida K.] Ctr Invest & Estudios Avanzados, Dept Biomed Mol, Mexico City, DF, Mexico. [van de Hoef, Diana L.; Rodriguez, Ana] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Doumbia, Saibou; Konate, Drissa; Doumbouya, Mory; Traore, Karim; Diakite, Seidina A. S.; Diakite, Mahamadou] Univ Bamako, Fac Med Pharm & Odontostomatol, Malaria Res & Training Ctr, Bamako, Mali. [Gu, Wenjuan] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Gu, Wenjuan; Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Rockville, MD USA. [Remaley, Alan T.] NIH, Dept Lab Med, NIH Clin Ctr, Bethesda, MD 20892 USA. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rfairhurst@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 14 Z9 14 U1 0 U2 4 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 OCT 5 PY 2012 VL 7 IS 10 AR e46424 DI 10.1371/journal.pone.0046424 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020QD UT WOS:000309827300027 PM 23071567 ER PT J AU Wang, H Jin, P Sabatino, M Ren, JQ Civini, S Bogin, V Ichim, TE Stroncek, DF AF Wang, Huan Jin, Ping Sabatino, Marianna Ren, Jiaqiang Civini, Sara Bogin, Vladimir Ichim, Thomas E. Stroncek, David F. TI Comparison of endometrial regenerative cells and bone marrow stromal cells SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Endometrial regenerative cells; Bone marrow stromal cells; Mesenchymal stromal cells; Mesenchymal stem cells; Regenerative medicine ID MESENCHYMAL STEM-CELLS; VERSUS-HOST-DISEASE; UMBILICAL-CORD BLOOD; ADIPOSE-TISSUE; DIFFERENTIATION; FIBROBLASTS; RESISTANT AB Background: Endometrial regenerative cells (ERC) and bone marrow stromal cells (BMSC) are being used in clinical trials. While they have been reported to have similar characteristics, they have not been directly compared. Methods: We compared micro RNA (miRNA) and gene expression profiles, soluble cytokine and growth factor levels and ability to inhibit ongoing mixed leukocyte reaction (MLR) of ERC and BMSC each derived from 6 healthy subjects. Results: ERC and BMSC miRNA and gene expression profiles were similar, but not identical; more differences were noted in the expression of genes than in miRNAs. Genes overexpressed in ERCs were more likely to be in immune and inflammation pathways and those overexpressed in BMSCs were more likely to be in stem cell and cancer signaling pathways. In addition, the levels of IL-8 and ICAM-1 were greater in ERC supernatants while the levels of HGF, VEGF, IL-6, CXCL12, TGFB1 and TGFB2 were greater in BMSC supernatants. Additionally, ERC demonstrated greater inhibition of the proliferation of mixed leukocyte cultures. Conclusions: These results suggest that the in vivo effects of ERC and BMSC may differ. Multiple properties of stromal cells are responsible for their in vivo effectiveness and ERC may be more effective for some of the clinical applications and BMSC for others. Studies in animal models or clinical trials will be required to more fully characterize the differences between ERC and BMSC. C1 [Wang, Huan; Jin, Ping; Sabatino, Marianna; Ren, Jiaqiang; Civini, Sara; Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Stroncek, David F.] NIH, Dept Transfus Med, Cell Proc Sect, Bethesda, MD 20892 USA. [Bogin, Vladimir; Ichim, Thomas E.] MediStem Inc, San Diego, CA USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural Research Program of the NIH, Clinical Center FX We thank that the NIH Bone Marrow Stromal Cell Transplant Center for providing the BMSC used in this study. This research was supported by the Intramural Research Program of the NIH, Clinical Center. NR 37 TC 20 Z9 22 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 5 PY 2012 VL 10 AR 207 DI 10.1186/1479-5876-10-207 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 044PN UT WOS:000311633600001 PM 23038994 ER PT J AU Klimov, AI Garten, R Russell, C Barr, IG Besselaar, TG Daniels, R Engelhardt, OG Grohmann, G Itamura, S Kelso, A McCauley, J Odagiri, T Smith, D Tashiro, M Xu, XY Webby, R Wang, DY Ye, ZP Shu, YL Zhang, WQ Cox, N AF Klimov, Alexander I. Garten, Rebecca Russell, Colin Barr, Ian G. Besselaar, Terry G. Daniels, Rod Engelhardt, Othmar G. Grohmann, Gary Itamura, Shigeyuki Kelso, Anne McCauley, John Odagiri, Takato Smith, Derek Tashiro, Masato Xu, Xiyan Webby, Richard Wang, Dayan Ye, Zhiping Shu Yuelong Zhang, Wenqing Cox, Nancy CA Writing Committee World Hlth Org C TI WHO recommendations for the viruses to be used in the 2012 Southern Hemisphere Influenza Vaccine: Epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from February to September 2011 SO VACCINE LA English DT Article DE Influenza; Vaccine; Human; Seasonal ID SUBSTITUTION AB In February and September each year the World Health Organisation (WHO) recommends influenza viruses to be included in influenza vaccines for the forthcoming winters in the Northern and Southern Hemispheres respectively. These recommendations are based on data collected by National Influenza Centres (NIC) through the Global Influenza Surveillance and Response System (GISRS) and a more detailed analysis of representative and potential antigenically variant influenza viruses from the WHO Collaborating Centres for Influenza (WHO CCs) and Essential Regulatory Laboratories (ERLs). This article provides a detailed summary of the antigenic and genetic properties of viruses and additional background data used by WHO experts during development of the recommendations for the 2012 Southern Hemisphere influenza vaccine composition. Published by Elsevier Ltd. C1 [Klimov, Alexander I.] Ctr Dis Control & Prevent, WHO Collaborating Ctr Surveillance Epidemiol & Co, Influenza Div, Atlanta, GA 30333 USA. [Barr, Ian G.; Kelso, Anne] WHO Collaborating Ctr Reference & Res Influenza, VIDRL, Melbourne, Australia. [Daniels, Rod; McCauley, John] Natl Inst Med Res, WHO Collaborating Ctr Reference & Res Influenza, London, England. [Itamura, Shigeyuki; Odagiri, Takato; Tashiro, Masato] NIID, WHO Collaborating Ctr Reference & Res Influenza, Tokyo, Japan. [Webby, Richard] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Wang, Dayan; Shu Yuelong] CNIC, WHO Collaborating Ctr Reference & Res Influenza, Beijing, Peoples R China. [Besselaar, Terry G.; Zhang, Wenqing] WHO Global Influenza Programme GIP, Geneva, Switzerland. [Engelhardt, Othmar G.] HPA, NIBSC, Potters Bar, Herts, England. [Ye, Zhiping] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Grohmann, Gary] TGA, Canberra, ACT, Australia. [Russell, Colin; Smith, Derek] Univ Cambridge, Cambridge CB2 1TN, England. [Russell, Colin; Smith, Derek] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Klimov, AI (reprint author), Ctr Dis Control & Prevent, WHO Collaborating Ctr Surveillance Epidemiol & Co, Influenza Div, 1600 Clifton Rd NE, Atlanta, GA 30333 USA. EM AKlimov@cdc.gov OI Russell, Colin/0000-0002-2113-162X FU Medical Research Council [MC_U117512708, MC_U117512723, MC_U117585868] NR 13 TC 33 Z9 34 U1 0 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 5 PY 2012 VL 30 IS 45 BP 6461 EP 6471 DI 10.1016/j.vaccine.2012.07.089 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 024NZ UT WOS:000310117200018 PM 22917957 ER PT J AU Kang, BT Leoni, RF Kim, DE Silva, AC AF Kang, Byeong-Teck Leoni, Renata F. Kim, Dong-Eog Silva, Afonso C. TI Phenylephrine-induced hypertension during transient middle cerebral artery occlusion alleviates ischemic brain injury in spontaneously hypertensive rats SO BRAIN RESEARCH LA English DT Article DE Arterial spin labeling; Cerebral blood flow; Hypertension; Ischemic stroke; Magnetic resonance imaging; Spontaneously hypertensive rat ID BLOOD-FLOW; FOCAL ISCHEMIA; CAROTID-ARTERY; STROKE TRIAL; EDEMA; AUTOREGULATION; TIME; QUANTIFICATION; HEMODILUTION; REPERFUSION AB Arterial hypertension is a major risk factor for ischemic stroke. However, the management of preexisting hypertension is still controversial in the treatment of acute stroke in hypertensive patients. The present study evaluates the influence of preserving hypertension during focal cerebral ischemia on stroke outcome in a rat model of chronic hypertension, the spontaneously hypertensive rats (SHR). Focal cerebral ischemia was induced by transient (1 h) occlusion of the middle cerebral artery, during which mean arterial blood pressure was maintained at normotension (110-120 mm Hg, group 1, n=6) or hypertension (160-170 mm Hg, group 2, n=6) using phenylephrine. T2-, diffusion- and perfusion-weighted MRI were performed serially at five different time points: before and during ischemia, and at 1, 4 and 7 days after ischemia. Lesion volume and brain edema were estimated from apparent diffusion coefficient maps and T2-weighted images. Regional cerebral blood flow (rCBF) was measured within and outside the perfusion deficient lesion and in the corresponding regions of the contralesional hemisphere. Neurological deficits were evaluated after reperfusion. Infarct volume, edema, and neurological deficits were significantly reduced in group 2 vs. group 1. In addition, higher values and rapid restoration of rCBF were observed in group 2, while rCBF in both hemispheres was significantly decreased in group 1. Maintaining preexisting hypertension alleviates ischemic brain injury in SHR by increasing collateral circulation to the ischemic region and allowing rapid restoration of rCBF. The data suggest that maintaining preexisting hypertension is a valuable approach to managing hypertensive patients suffering from acute ischemic stroke. Published by Elsevier B.V. C1 [Kang, Byeong-Teck; Leoni, Renata F.; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Kang, Byeong-Teck] Chungbuk Natl Univ, Lab Mol Imaging & Translat Res, Coll Vet Med, Cheongju, South Korea. [Leoni, Renata F.] Univ Sao Paulo, Dept Neurosci & Behav Sci, FMRP, BR-14049 Ribeirao Preto, Brazil. [Kim, Dong-Eog] Dongguk Univ, Mol Imaging & Neurovasc Res MINER Lab, Ilsan Hosp, Goyang, South Korea. RP Silva, AC (reprint author), Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,MSC 1065,Bldg 10,Room B1D106, Bethesda, MD 20892 USA. EM SilvaA@ninds.nih.gov OI Leoni, Renata/0000-0002-4568-0746 FU NIH, NINDS FX This research was supported by the Intramural Research Program of NIH, NINDS. NR 33 TC 6 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 5 PY 2012 VL 1477 BP 83 EP 91 DI 10.1016/j.brainres.2012.08.024 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 028HT UT WOS:000310414100009 PM 22954904 ER PT J AU Miyoshi, H Ajima, R Luo, CT Yamaguchi, TP Stappenbeck, TS AF Miyoshi, Hiroyuki Ajima, Rieko Luo, Christine T. Yamaguchi, Terry P. Stappenbeck, Thaddeus S. TI Wnt5a Potentiates TGF-beta Signaling to Promote Colonic Crypt Regeneration After Tissue Injury SO SCIENCE LA English DT Article ID CELL-CYCLE ARREST; STEM-CELLS; IN-VITRO; WNT/BETA-CATENIN; SMALL-INTESTINE; WOUND REPAIR; GENE; MOUSE; NICHE; EPITHELIUM AB Reestablishing homeostasis after tissue damage depends on the proper organization of stem cells and their progeny, though the repair mechanisms are unclear. The mammalian intestinal epithelium is well suited to approach this problem, as it is composed of well-delineated units called crypts of Lieberkuhn. We found that Wnt5a, a noncanonical Wnt ligand, was required for crypt regeneration after injury in mice. Unlike controls, Wnt5a-deficient mice maintained an expanded population of proliferative epithelial cells in the wound. We used an in vitro system to enrich for intestinal epithelial stem cells to discover that Wnt5a inhibited proliferation of these cells. Surprisingly, the effects of Wnt5a were mediated by activation of transforming growth factor-beta (TGF-beta) signaling. These findings suggest a Wnt5a-dependent mechanism for forming new crypt units to reestablish homeostasis. C1 [Ajima, Rieko; Yamaguchi, Terry P.; Stappenbeck, Thaddeus S.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Miyoshi, Hiroyuki; Luo, Christine T.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Yamaguchi, TP (reprint author), NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM stappenb@pathology.wustl.edu; yamagute@mail.nih.gov FU NIH [DK90251]; Pew Scholars Program in the Biomedical Sciences; Trans-National Institute of Diabetes and Digestive and Kidney Diseases Short-Term Training for Medical Students [5T35DK074375]; Washington Univ. Digestive Disease Research Core (NIH) [P30-DK52574]; NIH, National Cancer Institute, Center for Cancer Research FX We thank R. Kopan for comments on the manuscript, W. Pu for reagents, and R. Head and C. Storer for the microarray analysis. This work was funded by the NIH (grant DK90251); the Pew Scholars Program in the Biomedical Sciences; grant 5T35DK074375 (Trans-National Institute of Diabetes and Digestive and Kidney Diseases Short-Term Training for Medical Students); the Washington Univ. Digestive Disease Research Core (NIH grant P30-DK52574); and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Microarray data are available on Array Express (accession no. E-MTAB-1175). Materials transfer agreements will be required for the acquisition of the Wnt5af/f mice from the National Cancer Institute and the L-WRN cell line from the Washington Univ. Medical School. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. NR 37 TC 117 Z9 119 U1 1 U2 19 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 OCT 5 PY 2012 VL 338 IS 6103 BP 108 EP 113 DI 10.1126/science.1223821 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015PC UT WOS:000309457400064 PM 22956684 ER PT J AU Adalsteinsson, BT Gudnason, H Aspelund, T Harris, TB Launer, LJ Eiriksdottir, G Smith, AV Gudnason, V AF Adalsteinsson, Bjorn T. Gudnason, Haukur Aspelund, Thor Harris, Tamara B. Launer, Lenore J. Eiriksdottir, Gudny Smith, Albert V. Gudnason, Vilmundur TI Heterogeneity in White Blood Cells Has Potential to Confound DNA Methylation Measurements SO PLOS ONE LA English DT Article ID LEUKOCYTE COUNT; FACTOR-BETA; HUMAN GENES; PROFILES; PATTERNS; CANCER; ALPHA AB Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50-179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4-15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses. C1 [Adalsteinsson, Bjorn T.; Gudnason, Haukur; Aspelund, Thor; Eiriksdottir, Gudny; Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Adalsteinsson, Bjorn T.; Aspelund, Thor; Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Gudnason, V (reprint author), Iceland Heart Assoc, Kopavogur, Iceland. EM v.gudnason@hjarta.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845 FU Icelandic Heart Association; Icelandic Parliament; National Institutes of Health (NIH) [N01-AG-1-2100]; National Institute on Ageing (NIA); Icelandic Center for Research (RANNIS) [072012001] FX The Age, Gene/Environment Susceptibility (AGES)-Reykjavik and the Risk Evaluation For Infarct Estimates (REFINE)-Reykjavik studies were funded by the Icelandic Heart Association (www.hjarta.is) and the Icelandic Parliament (www.althingi.is). Additionally, AGES-Reykjavik has been funded by the National Institutes of Health (NIH), www.nih.gov, contract N01-AG-1-2100 and the National Institute on Ageing (NIA), www.nia.nih.gov, Intramural Research Program. REFINE-Reykjavik was also funded by the Icelandic Center for Research (RANNIS), www.rannis.is, contract 072012001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 71 Z9 72 U1 0 U2 4 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 OCT 5 PY 2012 VL 7 IS 10 AR e46705 DI 10.1371/journal.pone.0046705 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020QD UT WOS:000309827300052 PM 23071618 ER PT J AU Nikitovic, D Aggelidakis, J Young, MF Iozzo, RV Karamanos, NK Tzanakakis, GN AF Nikitovic, Dragana Aggelidakis, John Young, Marian F. Iozzo, Renato V. Karamanos, Nikos K. Tzanakakis, George N. TI The Biology of Small Leucine-rich Proteoglycans in Bone Pathophysiology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID GROWTH-FACTOR-BETA; MATRIX COMPONENT BIGLYCAN; CYCLIN-DEPENDENT KINASES; REPEAT PROTEIN FAMILY; EXTRACELLULAR-MATRIX; OSTEOBLAST DIFFERENTIATION; GENE-EXPRESSION; TOLL-LIKE; ECTOPIC OSSIFICATION; HISTOLOGICAL SUBTYPE AB The class of small leucine-rich proteoglycans (SLRPs) is a family of homologous proteoglycans harboring relatively small (36-42 kDa) protein cores compared with the larger cartilage and mesenchymal proteoglycans. SLRPs have been localized to most skeletal regions, with specific roles designated during all phases of bone formation, including periods relating to cell proliferation, organic matrix deposition, remodeling, and mineral deposition. This is mediated by key signaling pathways regulating the osteogenic program, including the activities of TGF-beta, bone morphogenetic protein, Wnt, and NF-kappa B, which influence both the number of available osteogenic precursors and their subsequent development, differentiation, and function. On the other hand, SLRP depletion is correlated with degenerative diseases such as osteoporosis and ectopic bone formation. This minireview will focus on the SLRP roles in bone physiology and pathology. C1 [Nikitovic, Dragana; Tzanakakis, George N.] Univ Crete, Sch Med, Dept Histol Embryol, Iraklion 71003, Greece. [Aggelidakis, John] Univ Hosp Herakl, Dept Orthoped, Iraklion 71003, Greece. [Young, Marian F.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Iozzo, Renato V.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Karamanos, Nikos K.] Univ Patras, Dept Chem, Biochem Lab, GR-26110 Patras, Greece. RP Tzanakakis, GN (reprint author), Univ Crete, Sch Med, Dept Histol Embryol, Iraklion 71003, Greece. EM tzanakak@med.uoc.gr RI Karamanos, Nikos/A-3616-2008; OI Karamanos, Nikos/0000-0003-3618-0288; Iozzo, Renato/0000-0002-5908-5112; Nikitovic, Dragana/0000-0003-3882-7399 FU National Institutes of Health [R01 CA39481, R01 CA47282]; NIDCR Division of Intramural Research; ELKE (Research Committee, University of Crete) [KA 3082] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA39481 and R01 CA47282 (to R. V. I.) and the NIDCR Division of Intramural Research (to M. F. Y.). This work was also supported by ELKE (Research Committee, University of Crete) Grant KA 3082 (to G. N. T.). NR 95 TC 38 Z9 39 U1 1 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 5 PY 2012 VL 287 IS 41 BP 33926 EP 33933 DI 10.1074/jbc.R112.379602 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 018IS UT WOS:000309654200001 PM 22879588 ER PT J AU Jana, M Mondal, S Gonzalez, FJ Pahan, K AF Jana, Malabendu Mondal, Susanta Gonzalez, Frank J. Pahan, Kalipada TI Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; HIGH-DENSITY-LIPOPROTEIN; CORONARY-HEART-DISEASE; PPAR-DELTA; ADOPTIVE TRANSFER; NITRIC-OXIDE; TRANSCRIPTIONAL REPRESSION; NEUTRAL SPHINGOMYELINASE AB An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-alpha (PPAR-alpha), we were unable to detect PPAR-alpha in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-alpha(-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-beta but not PPAR-gamma. Consistently, antisense knockdown of PPAR-beta, but not PPAR-gamma, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-beta(-/-) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-beta to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-beta to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-beta and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases. C1 [Jana, Malabendu; Mondal, Susanta; Pahan, Kalipada] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pahan, K (reprint author), Rush Univ, Med Ctr, Dept Neurol Sci, 1735 W Harrison St,Suite Cohn 320, Chicago, IL 60612 USA. EM Kalipada_Pahan@rush.edu FU National Institutes of Health [AT6681, NS64564, NS71479]; National Multiple Sclerosis Society [RG4170-A-1] FX This work was supported, in whole or in part, by National Institutes of Health Grants AT6681, NS64564, and NS71479 (to K. P.). This work was also supported by National Multiple Sclerosis Society Grant RG4170-A-1 (to M. J.). NR 49 TC 6 Z9 7 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 5 PY 2012 VL 287 IS 41 BP 34134 EP 34148 DI 10.1074/jbc.M112.398552 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 018IS UT WOS:000309654200019 PM 22879602 ER PT J AU Ligons, DL Tuncer, C Linowes, BA Akcay, IM Kurtulus, S Deniz, E Arslan, BA Cevik, SI Keller, HR Luckey, MA Feigenbaum, L Moroy, T Ersahin, T Atalay, R Erman, B Park, JH AF Ligons, Davinna L. Tuncer, Ceren Linowes, Brett A. Akcay, Izzet Mehmet Kurtulus, Sema Deniz, Emre Arslan, Belkis Atasever Cevik, Safak Isil Keller, Hilary R. Luckey, Megan A. Feigenbaum, Lionel Moeroey, Tarik Ersahin, Tulin Atalay, Rengul Erman, Batu Park, Jung-Hyun TI CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-CELL DEVELOPMENT; ZINC-FINGER PROTEIN; GA-BINDING-PROTEIN; IL-7 RECEPTOR; GENE-EXPRESSION; GLUCOCORTICOID-RECEPTOR; IL-7R-ALPHA EXPRESSION; THYMOCYTE DEVELOPMENT; ALPHA EXPRESSION; UP-REGULATION AB Interleukin-7 receptor alpha (IL-7R alpha) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7R alpha expression with diverse roles in T cell biology. Here we identify the transcriptional repressor, growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7R alpha up-regulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7R alpha up-regulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7R alpha transcription is up-regulated in the absence of Gfi1 and down-regulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8(+), and not CD4(+) T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo. C1 [Tuncer, Ceren; Akcay, Izzet Mehmet; Kurtulus, Sema; Deniz, Emre; Arslan, Belkis Atasever; Cevik, Safak Isil; Erman, Batu] Sabanci Univ, FENS, Biol Sci & Bioengn Program, TR-34956 Istanbul, Turkey. [Ligons, Davinna L.; Linowes, Brett A.; Keller, Hilary R.; Luckey, Megan A.; Park, Jung-Hyun] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] NCI, Sci Applicat Int Corp Frederick, Canc Res & Dev Ctr, Frederick, MD 21702 USA. [Moeroey, Tarik] Univ Montreal, Dept Microbiol & Immunol, Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Ersahin, Tulin; Atalay, Rengul] Bilkent Univ, Dept Mol Biol & Genet, TR-06800 Ankara, Turkey. [Erman, Batu] Sabanci Univ, Nanotechnol Res & Applicat Ctr, SUNUM, TR-34956 Istanbul, Turkey. RP Erman, B (reprint author), Sabanci Univ, FENS, Biol Sci & Bioengn Program, Univ Caddesi 27, TR-34956 Istanbul, Turkey. EM batu@sabanciuniv.edu; parkhy@mail.nih.gov RI CEVIK, ISIL/K-1320-2012; Atalay, Rengul/F-5780-2013; Ersahin, Tulin/M-5721-2013; Cetin-Atalay, Rengul/O-9826-2014; Davis, Megan/F-5339-2015 OI Atalay, Rengul/0000-0003-2408-6606; Ersahin, Tulin/0000-0002-7474-7890; Cetin-Atalay, Rengul/0000-0003-2408-6606; FU National Institutes of Health (NIH) grant from the Intramural Research Program, NCI, Center for Cancer Research; Scientific and Technological Research Council of Turkey; Turkish National Academy of Science; TUBITAK 1001 [109T315]; National Institutes of Health-FIRCA [1R03TW008208]; National Institutes of Health-GRIP [1R01TW007270] FX This work was supported, in whole or in part, by a National Institutes of Health (NIH) grant from the Intramural Research Program, NCI, Center for Cancer Research.; Supported by the Scientific and Technological Research Council of Turkey scholarships.; Supported by the Turkish National Academy of Science post-doctoral fellowship.; Supported by TUBITAK 1001 Grant 109T315, National Institutes of Health-FIRCA Grant 1R03TW008208, and National Institutes of Health-GRIP Grant 1R01TW007270. NR 60 TC 6 Z9 6 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 5 PY 2012 VL 287 IS 41 BP 34386 EP 34399 DI 10.1074/jbc.M112.378687 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 018IS UT WOS:000309654200041 PM 22865857 ER PT J AU Zhou, Q Lee, GS Brady, J Datta, S Katan, M Sheikh, A Martins, MS Bunney, TD Santich, BH Moir, S Kuhns, DB Priel, DAL Ombrello, A Stone, D Ombrello, MJ Khan, J Milner, JD Kastner, DL Aksentijevich, I AF Zhou, Qing Lee, Geun-Shik Brady, Jillian Datta, Shrimati Katan, Matilda Sheikh, Afzal Martins, Marta S. Bunney, Tom D. Santich, Brian H. Moir, Susan Kuhns, Douglas B. Priel, Debra A. Long Ombrello, Amanda Stone, Deborah Ombrello, Michael J. Khan, Javed Milner, Joshua D. Kastner, Daniel L. Aksentijevich, Ivona TI A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase C gamma 2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID B-CELL; ACTIVATION; AUTOIMMUNITY; TOLERANCE; SEQUENCE AB Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C>A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase C gamma 2 (PLC gamma 2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLC gamma 2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals' leukocytes showed clearly enhanced PLC gamma 2 activity, suggesting increased intracellular signaling in the PLC gamma 2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.Ser707Tyr substitution in PLC gamma 2 causes a distinct inflammatory phenotype that is not provoked by cold temperatures and that has different end-organ involvement and increased intracellular signaling at physiological temperatures. Our results highlight the utility of exome-sequencing technology in finding causal mutations in nuclear families with dominantly inherited traits otherwise intractable by linkage analysis. C1 [Zhou, Qing; Lee, Geun-Shik; Brady, Jillian; Sheikh, Afzal; Ombrello, Amanda; Stone, Deborah; Ombrello, Michael J.; Kastner, Daniel L.; Aksentijevich, Ivona] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Lee, Geun-Shik] Kangwon Natl Univ, Coll Vet Med, Chunchon 200701, Gangwon, South Korea. [Datta, Shrimati; Milner, Joshua D.] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. [Katan, Matilda; Martins, Marta S.; Bunney, Tom D.] UCL, Dept Struct & Mol Biol, London WC1E 6BT, England. [Santich, Brian H.; Moir, Susan] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Kuhns, Douglas B.; Priel, Debra A. Long] SAIC Frederick, Ft Detrick, MD 21702 USA. [Khan, Javed] NCI, Gaithersburg, MD 20877 USA. RP Aksentijevich, I (reprint author), NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. EM kastnerd@mail.nih.gov; aksentii@exchange.nih.gov RI Martins, Marta/A-9905-2013; Yu, Xiaomin/I-6407-2016 OI Martins, Marta/0000-0003-0429-9380; FU National Human Genome Research Institute; National Institute for Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD; Cancer Research, UK FX We would like to acknowledge Elaine Remmers and Jae Jin Chae for critical reading of the manuscript and Chyi-chia Lee for help with reviewing a histology slide. We would also like to acknowledge Nona Colbum, Maria Turner, Patrycja Hoffman, and Anne Jones for their help in caring for these affected individuals. This study has been supported by the National Human Genome Research Institute and the National Institute for Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD. Work in Matilda Katan's laboratory has been supported by Cancer Research, UK. NR 22 TC 80 Z9 84 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 5 PY 2012 VL 91 IS 4 BP 713 EP 720 DI 10.1016/j.ajhg.2012.08.006 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 017CU UT WOS:000309568500013 PM 23000145 ER PT J AU Franceschini, N van Rooij, FJA Prins, BP Feitosa, MF Karakas, M Eckfeldt, JH Folsom, AR Kopp, J Vaez, A Andrews, JS Baumert, J Boraska, V Broer, L Hayward, C Ngwa, JS Okada, Y Polasek, O Westra, HJ Wang, YA Del Greco, F Glazer, NL Kapur, K Id, P Lopez, LM Schillert, A Smith, AV Winkler, CA Zgaga, L Bandinelli, S Bergmann, S Boban, M Bochud, M Chen, YD Davies, G Dehghan, A Ding, JZ Doering, A Durda, JP Ferrucci, L Franco, OH Franke, L Gunjaca, G Hofman, A Hsu, FC Kolcic, I Kraja, A Kubo, M Lackner, KJ Launer, L Loehr, LR Li, G Meisinger, C Nakamura, Y Schwienbacher, C Starr, JM Takahashi, A Torlak, V Uitterlinden, AG Vitart, V Waldenberger, M Wild, PS Kirin, M Zeller, T Zemunik, T Zhang, QY Ziegler, A Blankenberg, S Boerwinkle, E Borecki, IB Campbell, H Deary, IJ Frayling, TM Gieger, C Harris, TB Hicks, AA Koenig, W O'Donnell, CJ Fox, CS Pramstaller, PP Psaty, BM Reiner, AP Rotter, JI Rudan, I Snieder, H Tanaka, T van Duijn, CM Vollenweider, P Waeber, G Wilson, JF Witteman, JCM Wolffenbuttel, BHR Wright, AF Wu, QY Liu, YM Jenny, NS North, KE Felix, JF Alizadeh, BZ Cupples, LA Perry, JRB Morris, AP AF Franceschini, Nora van Rooij, Frank J. A. Prins, Bram P. Feitosa, Mary F. Karakas, Mahir Eckfeldt, John H. Folsom, Aaron R. Kopp, Jeffrey Vaez, Ahmad Andrews, Jeanette S. Baumert, Jens Boraska, Vesna Broer, Linda Hayward, Caroline Ngwa, Julius S. Okada, Yukinori Polasek, Ozren Westra, Harm-Jan Wang, Ying A. Del Greco M, Fabiola Glazer, Nicole L. Kapur, Karen Kema, Id P. Lopez, Lorna M. Schillert, Arne Smith, Albert V. Winkler, Cheryl A. Zgaga, Lina Bandinelli, Stefania Bergmann, Sven Boban, Mladen Bochud, Murielle Chen, Y. D. Davies, Gail Dehghan, Abbas Ding, Jingzhong Doering, Angela Durda, J. Peter Ferrucci, Luigi Franco, Oscar H. Franke, Lude Gunjaca, Grog Hofman, Albert Hsu, Fang-Chi Kolcic, Ivana Kraja, Aldi Kubo, Michiaki Lackner, Karl J. Launer, Lenore Loehr, Laura R. Li, Guo Meisinger, Christa Nakamura, Yusuke Schwienbacher, Christine Starr, John M. Takahashi, Atsushi Torlak, Vesela Uitterlinden, Andre G. Vitart, Veronique Waldenberger, Melanie Wild, Philipp S. Kirin, Mirna Zeller, Tanja Zemunik, Tatijana Zhang, Qunyuan Ziegler, Andreas Blankenberg, Stefan Boerwinkle, Eric Borecki, Ingrid B. Campbell, Harry Deary, Ian J. Frayling, Timothy M. Gieger, Christian Harris, Tamara B. Hicks, Andrew A. Koenig, Wolfgang O'Donnell, Christopher J. Fox, Caroline S. Pramstaller, Peter P. Psaty, Bruce M. Reiner, Alex P. Rotter, Jerome I. Rudan, Igor Snieder, Harold Tanaka, Toshihiro van Duijn, Cornelia M. Vollenweider, Peter Waeber, Gerard Wilson, James F. Witteman, Jacqueline C. M. Wolffenbuttel, Bruce H. R. Wright, Alan F. Wu, Qingyu Liu, Yongmei Jenny, Nancy S. North, Karl E. Felix, Janine F. Alizadeh, Behrooz Z. Cupples, L. Adrienne Perry, John R. B. Morris, Andrew P. CA LifeLines Cohort Study TI Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BIOCHEMICAL TRAITS; SMOKING-BEHAVIOR; FC-RECEPTOR; ALBUMIN; DETERMINANTS; POPULATION; IDENTIFY; RISK; SNPS AB Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 x 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMDS-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease. C1 [Franceschini, Nora; Loehr, Laura R.; North, Karl E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [van Rooij, Frank J. A.; Broer, Linda; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.; Felix, Janine F.] Erasmus Univ, Med Ctr, ErasmusAGE, NL-3000 CA Rotterdam, Netherlands. [van Rooij, Frank J. A.; Broer, Linda; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.; Felix, Janine F.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [van Rooij, Frank J. A.; Broer, Linda; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.; Felix, Janine F.] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, NL-2300 RC Leiden, Netherlands. [Prins, Bram P.; Vaez, Ahmad; Snieder, Harold; Alizadeh, Behrooz Z.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Feitosa, Mary F.; Kraja, Aldi; Zhang, Qunyuan; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Karakas, Mahir; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Kopp, Jeffrey] NIDDK, NIH, Bethesda, MD 20892 USA. [Andrews, Jeanette S.; Hsu, Fang-Chi] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Baumert, Jens; Doering, Angela; Meisinger, Christa; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Boraska, Vesna; Zemunik, Tatijana] Univ Split, Sch Med, Dept Med Biol, Split 21000, Croatia. [Hayward, Caroline; Vitart, Veronique; Wright, Alan F.] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC,Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Ngwa, Julius S.; Wang, Ying A.; Cupples, L. Adrienne] Harvard Univ, Sch Publ Hlth, Boston Univ, Sch Publ Hlth,Dept Biostat, Boston, MA 02115 USA. [Okada, Yukinori; Takahashi, Atsushi] RIKEN, CGM, Lab Stat Anal, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Okada, Yukinori] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Bunkyo Ku, Tokyo 1130033, Japan. [Polasek, Ozren; Kolcic, Ivana] Univ Split, Sch Med, Dept Publ Hlth, Split 21000, Croatia. [Westra, Harm-Jan; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands. [Wang, Ying A.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Del Greco M, Fabiola; Schwienbacher, Christine; Hicks, Andrew A.; Pramstaller, Peter P.] Med Univ Lubeck, Affiliated Inst, Ctr Biomed, European Acad Bozen Bolzano EURAC, D-23562 Lubeck, Germany. [Glazer, Nicole L.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Kapur, Karen; Bergmann, Sven] Univ Lausanne, Univ Hosp Ctr, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Kema, Id P.] Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, NL-9700 RB Groningen, Netherlands. [Lopez, Lorna M.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Lopez, Lorna M.; Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9AD, Midlothian, Scotland. [Schillert, Arne; Ziegler, Andreas] Univ Hosp Schleswig Holstein, Inst Med Biometry & Stat, D-23538 Lubeck, Germany. [Smith, Albert V.] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Winkler, Cheryl A.] NCI, Mol Genet Epidemiol Sect, NIH, Frederick Natl Lab, Ft Detrick, MD 21702 USA. [Zgaga, Lina; Kirin, Mirna; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Queens Med Res Inst, Coll Med & Vet Med, Ctr Populat Hlth Sci, Edinburgh EH16 4TJ, Midlothian, Scotland. [Zgaga, Lina; Kirin, Mirna; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Queens Med Res Inst, Coll Med & Vet Med, Inst Genet & Mol Med, Edinburgh EH16 4TJ, Midlothian, Scotland. [Zgaga, Lina] Univ Zagreb, Sch Med, Dept Med Stat Epidemiol & Med Informat, Zagreb 10000, Croatia. [Bandinelli, Stefania; Gunjaca, Grog] Azienda Sanit Firenze, Geriatr Unit, I-50125 Florence, Italy. [Kapur, Karen; Bergmann, Sven] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Boban, Mladen] Univ Split, Sch Med, Dept Pharmacol, Split 21000, Croatia. [Bochud, Murielle] Univ Inst Social & Prevent Med, Community Prevent Unit, CH-1005 Lausanne, Switzerland. [Chen, Y. D.] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Los Angeles, CA 90048 USA. [Chen, Y. D.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. [Durda, J. Peter; Jenny, Nancy S.] Univ Vermont, Coll Med, Dept Pathol, Lab Clin Biochem Res, Burlington, VT 05405 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21225 USA. [Kubo, Michiaki] RIKEN, CGM, Lab Genotyping Dev, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Lackner, Karl J.] Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, D-55131 Mainz, Germany. [Launer, Lenore; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Li, Guo] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med,Minato Ku, Tokyo 1088639, Japan. [Schwienbacher, Christine] Univ Ferrara, Dept Expt & Diagnost Med, I-44121 Ferrara, Italy. [Starr, John M.] Univ Edinburgh, Dept Psychol, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Torlak, Vesela] Univ Hosp Split, Split 21000, Croatia. [Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Epidemiol Res Unit, D-85764 Neuherberg, Germany. [Wild, Philipp S.] Univ Med Ctr Mainz, Dept Med 2, D-55131 Mainz, Germany. [Zeller, Tanja; Blankenberg, Stefan] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, D-20246 Hamburg, Germany. [Boerwinkle, Eric] Univ Houston, Sch Publ Hlth, Div Epidemiol, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Frayling, Timothy M.; Perry, John R. B.] Univ Exeter, Peninsula Med Sch, Exeter EX2 5DW, Devon, England. [O'Donnell, Christopher J.; Fox, Caroline S.; Cupples, L. Adrienne] Natl Heart Lung & Blood Inst NHLBI Framingham Hea, Div Intramural Res, Framingham, MA 01702 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiol Div, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Reiner, Alex P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Tanaka, Toshihiro] RIKEN, Lab Cardiovasc Dis, CGM, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Vollenweider, Peter; Waeber, Gerard] Univ Lausanne Hosp, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9713 GZ Groningen, Netherlands. [Wu, Qingyu] Cleveland Clin, Mol Cardiol Nephrol & Hypertens Lerner Res Inst, Cleveland, OH 44195 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent Med, Winston Salem, NC 27157 USA. [Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM noraf@unc.edu; amorris@well.ox.ac.uk RI Hayward, Caroline/M-8818-2016; Franke, Lude/P-7036-2016; Boraska Perica, Vesna/D-8230-2017; Boban, Mladen/E-2777-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Wolffenbuttel, Bruce/A-8419-2011; Deary, Ian/C-6297-2009; Smith, Albert/K-5150-2015; Kubo, Michiaki/N-7947-2015; Bochud, Murielle/A-3981-2010; Colaus, PsyColaus/K-6607-2013; Waldenberger, Melanie/B-5355-2014; Meisinger, Christine/B-5358-2014; Pramstaller, Peter/C-2357-2008; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Tanaka, Toshihiro/J-9310-2014; Rudan, Igor/I-1467-2012; OI Hayward, Caroline/0000-0002-9405-9550; Franke, Lude/0000-0002-5159-8802; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Cupples, L. Adrienne/0000-0003-0273-7965; Felix, Janine/0000-0002-9801-5774; Wolffenbuttel, Bruce/0000-0001-9262-6921; Smith, Albert/0000-0003-1942-5845; Bochud, Murielle/0000-0002-5727-0218; Waldenberger, Melanie/0000-0003-0583-5093; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Tanaka, Toshihiro/0000-0001-6201-9784; Rudan, Igor/0000-0001-6993-6884; Zgaga, Lina/0000-0003-4089-9703; Gieger, Christian/0000-0001-6986-9554; Ziegler, Andreas/0000-0002-8386-5397; Meisinger, Christa/0000-0002-9026-6544; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Kopp, Jeffrey/0000-0001-9052-186X; Bergmann, Sven/0000-0002-6785-9034; Dehghan, Abbas/0000-0001-6403-016X FU Wellcome Trust [WT081682, WT064890, WT098017, WT090532]; AHA [0675001N, R01HL089651, U01HG004803] FX A.P.M acknowledges financial support from the Wellcome Trust, grant numbers WT081682, WT064890, WT098017, and WT090532. N.F. acknowledges financial support from AHA 0675001N, R01HL089651, and U01HG004803. NR 25 TC 40 Z9 40 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 5 PY 2012 VL 91 IS 4 BP 744 EP 753 DI 10.1016/j.ajhg.2012.08.021 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 017CU UT WOS:000309568500017 PM 23022100 ER PT J AU Salunke, S Giacoia, G Tuleu, C AF Salunke, Smita Giacoia, George Tuleu, Catherine CA European Paediat Formulation US PFI TI The STEP (Safety and Toxicity of Excipients for Paediatrics) database. Part 1-A need assessment study SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE STEP database; Excipients; Safety; Toxicity; Adverse effects; Paediatrics; EuPFI; US PFI AB Excipients that are commonly used in adult medicines have been associated with elevated toxicological risks and safety issues in children. However, the information available on their acceptability for paediatric age groups is sparse and distributed over various sources. Hence, European (Eu) and United States (US) Paediatric Formulation Initiatives (PFIs) are collaboratively creating a STEP database. Because the development of database is a costly and time consuming venture, it is important to capture the requirements from the potential users and identify at an early stage the content and features that will serve the specific needs so that they can incorporate into the databases as it is developed. Aim: To assess the need of STEP database, to determine the database content and structure that meets the needs of the potential users. Method: A global survey was conducted via EuPFI website and email invitations, targeting a representative cross section of industrial, regulatory, academic and clinical professionals, to capture the database requirements. Result: The survey revealed (1) the potential users of this database, (2) the excipients' toxicity and safety information needs, (3) the content and structure preferred for the database. Majority of respondents favoured the development of STEP database and reported that it would be a valuable resource. Conclusion and future work: The survey emphasized the need for STEP database and thus leads us to development of pilot database to assess the feasibility of developing such a database. (c) 2012 Elsevier B.V. All rights reserved. C1 [Salunke, Smita] UCL, Sch Pharm, Dept Pharmaceut, Ctr Paediat, London WC1N 1AX, England. [Giacoia, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, OPPB, NIH, Bethesda, MD 20892 USA. RP Salunke, S (reprint author), UCL, Sch Pharm, Dept Pharmaceut, Ctr Paediat, 29 39 Brunswick Sq, London WC1N 1AX, England. EM Smita.Salunke@pharmacy.ac.uk OI tuleu, catherine/0000-0001-8384-357X FU European Union Seventh Framework Programme FP7 [261060] FX The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no 261060. The authors would like to acknowledge the support of the Eu and US PFI members and Dr. Pertti Hakkinen for piloting the questionnaire. We would also like to acknowledge the assistance of Sara Kistler for advertising the survey and Patricia Fowler for support with this manuscript. NR 23 TC 24 Z9 24 U1 0 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD OCT 5 PY 2012 VL 435 IS 2 BP 101 EP 111 DI 10.1016/j.ijpharm.2012.05.004 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 993RH UT WOS:000307876800002 PM 22583848 ER PT J AU Ellis, RD Wu, YM Martin, LB Shaffer, D Miura, K Aebig, J Orcutt, A Rausch, K Zhu, DM Mogensen, A Fay, MP Narum, DL Long, C Miller, L Durbin, AP AF Ellis, Ruth D. Wu, Yimin Martin, Laura B. Shaffer, Donna Miura, Kazutoyo Aebig, Joan Orcutt, Andrew Rausch, Kelly Zhu, Daming Mogensen, Anders Fay, Michael P. Narum, David L. Long, Carole Miller, Louis Durbin, Anna P. TI Phase 1 Study in Malaria Naive Adults of BSAM2/Alhydrogel (R)+CPG 7909, a Blood Stage Vaccine against P. falciparum Malaria SO PLOS ONE LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; PLASMODIUM-FALCIPARUM; ANTIBODY TITER; TRIAL; PROTECTION; CHILDREN; IMMUNITY; IMMUNOGENICITY; RESPONSES; ADJUVANT AB A Phase 1 dose escalating study was conducted in malaria naive adults to assess the safety, reactogenicity, and immunogenicity of the blood stage malaria vaccine BSAM2/Alhydrogel (R)+ CPG 7909. BSAM2 is a combination of the FVO and 3D7 alleles of recombinant AMA1 and MSP1(42), with equal amounts by weight of each of the four proteins mixed, bound to Alhydrogel (R), and administered with the adjuvant CPG 7909. Thirty ( 30) volunteers were enrolled in two dose groups, with 15 volunteers receiving up to three doses of 40 mu g total protein at Days 0, 56, and 180, and 15 volunteers receiving up to three doses of 160 mu g protein on the same schedule. Most related adverse events were mild or moderate, but 4 volunteers experienced severe systemic reactions and two were withdrawn from vaccinations due to adverse events. Geometric mean antibody levels after two vaccinations with the high dose formulation were 136 mu g/ml for AMA1 and 78 mu g/ml for MSP1(42). Antibody responses were not significantly different in the high dose versus low dose groups and did not further increase after third vaccination. In vitro growth inhibition was demonstrated and was closely correlated with anti-AMA1 antibody responses. A Phase 1b trial in malaria-exposed adults is being conducted. C1 [Ellis, Ruth D.; Wu, Yimin; Martin, Laura B.; Aebig, Joan; Orcutt, Andrew; Rausch, Kelly; Zhu, Daming; Mogensen, Anders; Narum, David L.; Miller, Louis] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Shaffer, Donna; Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Miura, Kazutoyo; Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Rockville, MD USA. [Long, Carole] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Wu, YM (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. EM yiwu@niaid.nih.gov RI Martin, Laura/N-1789-2013 OI Martin, Laura/0000-0002-4431-4381 FU National Institutes of Health, National Institute of Allergy and Infectious Disease; PATH Malaria Vaccine Initiative (MVI); United States Agency for International Development (USAID) Malaria Vaccine Development Program FX This work was supported by the Intramural program of the National Institutes of Health, National Institute of Allergy and Infectious Disease. Support for the Growth Inhibition Assay (GIA) Reference Center was provided in part by the PATH Malaria Vaccine Initiative (MVI) and by the United States Agency for International Development (USAID) Malaria Vaccine Development Program through a 361 cooperative agreement between USAID and MVI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 19 Z9 20 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2012 VL 7 IS 10 AR e46094 DI 10.1371/journal.pone.0046094 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017HM UT WOS:000309580800008 PM 23056238 ER PT J AU Nguyen, R Dombi, E Widemann, BC Solomon, J Fuensterer, C Kluwe, L Friedman, JM Mautner, VF AF Nguyen, Rosa Dombi, Eva Widemann, Brigitte C. Solomon, Jeffrey Fuensterer, Carsten Kluwe, Lan Friedman, Jan M. Mautner, Victor-Felix TI Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1 SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE MRI scan; Neurofibroma; Plexiform; Neurofibromatosis 1; Tumour burden ID NERVE SHEATH TUMORS; TYPE-1; MRI AB Background: To examine the natural growth dynamics of internal plexiform neurofibromas (PNs) in patients with neurofibromatosis 1 (NF1). Methods: Two hundred and one NF1 patients underwent whole body MRI (WBMRI). Tumour burden was estimated volumetrically. Non-parametric Spearman's rho correlation coefficients were used to analyse the relationship of growth rate to tumour volume and age. Chi-squared and Mann-Whitney U tests were used for analysing the association of tumour occurrence with sex or age. Chi-squared tests were used to analyse the association of tumour growth with age group. Results: Seventy-one of 171 patients with serial WBMRI exams had internal PNs (median follow up 2.2 years [1.1 to 4.9 years]). Median whole body tumour volume was 86.4 mL [5.2 to 5878.5 mL]) with a median growth rate of 3.7%/year (-13.4 to 111%/year) that correlated with larger whole body tumour volume (P<0.001) and lower age (P=0.004). No new PNs developed in 273.0 patient-years among patients without tumours. Rate of new tumour development among patients with PNs was 0.6%/year (95% confidence interval 0.02 to 3.4%). Twenty-seven (13.5%) tumours increased significantly and were more frequent among children (P<0.001). Growth rate of tumours was inversely correlated with age (Spearman's rho=-0.330, P<0.001). Seventy-one (35.5%) tumours had smaller volumes on follow up (median -3.4%/year [-0.07% to -35.9%/year]). Conclusion: Children with NF1 and internal PNs are at risk for tumour growth. Most PNs grow slowly or not at all, and some decrease in size. New tumours are infrequent in NF1 patients with PNs and unlikely in patients without PNs. C1 [Nguyen, Rosa; Mautner, Victor-Felix] Univ Hosp Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [Nguyen, Rosa] Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA. [Dombi, Eva; Widemann, Brigitte C.; Solomon, Jeffrey] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Fuensterer, Carsten] MRI Inst Hamburg Othmarschen, Dept Radiol, Hamburg, Germany. [Kluwe, Lan] Univ Hosp Hamburg Eppendorf, Dept Maxillofacial Surg, Hamburg, Germany. [Friedman, Jan M.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. RP Nguyen, R (reprint author), Univ Hosp Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. EM rosi.nguyen@gmail.com OI Friedman, Jan/0000-0002-7482-9570 FU Deutsche Krebshilfe [106982] FX This work was supported by "Deutsche Krebshilfe" [106982 to RN]. NR 16 TC 17 Z9 17 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD OCT 4 PY 2012 VL 7 AR 75 DI 10.1186/1750-1172-7-75 PG 6 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 061OL UT WOS:000312857600001 PM 23035791 ER PT J AU Moktali, V Park, J Fedorova-Abrams, ND Park, B Choi, J Lee, YH Kang, S AF Moktali, Venkatesh Park, Jongsun Fedorova-Abrams, Natalie D. Park, Bongsoo Choi, Jaeyoung Lee, Yong-Hwan Kang, Seogchan TI Systematic and searchable classification of cytochrome P450 proteins encoded by fungal and oomycete genomes SO BMC GENOMICS LA English DT Article DE Cytochrome P450; Genome annotation; Clustering; Fungi; Evolution; Phylogenetics; Mycotoxin ID HORIZONTAL TRANSFER; PHANEROCHAETE-CHRYSOSPORIUM; ASPERGILLUS-FUMIGATUS; NECTRIA-HAEMATOCOCCA; PATHOGENICITY GENES; FUNCTIONAL-ANALYSIS; ACCESSION NUMBERS; P450 SUPERFAMILY; MULTIGENE FAMILY; CANDIDA-MALTOSA AB Background: Cytochrome P450 proteins (CYPs) play diverse and pivotal roles in fungal metabolism and adaptation to specific ecological niches. Fungal genomes encode extremely variable "CYPomes" ranging from one to more than 300 CYPs. Despite the rapid growth of sequenced fungal and oomycete genomes and the resulting influx of predicted CYPs, the vast majority of CYPs remain functionally uncharacterized. To facilitate the curation and functional and evolutionary studies of CYPs, we previously developed Fungal Cytochrome P450 Database (FCPD), which included CYPs from 70 fungal and oomycete species. Here we present a new version of FCPD (1.2) with more data and an improved classification scheme. Results: The new database contains 22,940 CYPs from 213 species divided into 2,579 clusters and 115 clans. By optimizing the clustering pipeline, we were able to uncover 36 novel clans and to assign 153 orphan CYP families to specific clans. To augment their functional annotation, CYP clusters were mapped to David Nelson's P450 databases, which archive a total of 12,500 manually curated CYPs. Additionally, over 150 clusters were functionally classified based on sequence similarity to experimentally characterized CYPs. Comparative analysis of fungal and oomycete CYPomes revealed cases of both extreme expansion and contraction. The most dramatic expansions in fungi were observed in clans CYP58 and CYP68 (Pezizomycotina), clans CYP5150 and CYP63 (Agaricomycotina), and family CYP509 (Mucoromycotina). Although much of the extraordinary diversity of the pan-fungal CYPome can be attributed to gene duplication and adaptive divergence, our analysis also suggests a few potential horizontal gene transfer events. Updated families and clans can be accessed through the new version of the FCPD database. Conclusions: FCPD version 1.2 provides a systematic and searchable catalogue of 9,550 fungal CYP sequences (292 families) encoded by 108 fungal species and 147 CYP sequences (9 families) encoded by five oomycete species. In comparison to the first version, it offers a more comprehensive clan classification, is fully compatible with Nelson's P450 databases, and has expanded functional categorization. These features will facilitate functional annotation and classification of CYPs encoded by newly sequenced fungal and oomycete genomes. Additionally, the classification system will aid in studying the roles of CYPs in the evolution of fungal adaptation to specific ecological niches. C1 [Moktali, Venkatesh; Park, Bongsoo; Kang, Seogchan] Penn State Univ, Integrat Biosci Program Bioinformat & Genom, University Pk, PA 16802 USA. [Kang, Seogchan] Penn State Univ, Dept Plant Pathol & Environm Microbiol, University Pk, PA 16802 USA. [Park, Jongsun; Choi, Jaeyoung; Lee, Yong-Hwan] Seoul Natl Univ, Fungal Bioinformat Lab, Seoul, South Korea. [Fedorova-Abrams, Natalie D.] SAIC Frederick, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Lee, Yong-Hwan] Seoul Natl Univ, Dept Agr Biotechnol, Seoul, South Korea. [Lee, Yong-Hwan] Seoul Natl Univ, Ctr Fungal Pathogenesis, Seoul, South Korea. RP Kang, S (reprint author), Penn State Univ, Integrat Biosci Program Bioinformat & Genom, University Pk, PA 16802 USA. EM sxk55@psu.edu RI Choi, Jaeyoung/H-8665-2013; Abrams, Natalie/F-4845-2011; OI Choi, Jaeyoung/0000-0003-2206-4593; Abrams, Natalie/0000-0001-9698-2819; Park, Jongsun/0000-0003-0786-4701; Kang, Seogchan/0000-0003-2291-5634 FU USDA Agriculture and Food Research Initiative Competitive Grants Program [2010-65110-20488]; National Research Foundation of Korea [2012-0001149, 2012-0000141]; Next-Generation Bio-Green 21 Program of Rural Development Administration in Korea [PJ00821201] FX This research has been supported by the USDA Agriculture and Food Research Initiative Competitive Grants Program (Grant no. 2010-65110-20488). The work in Lee's lab has been supported by the National Research Foundation of Korea (2012-0001149 and 2012-0000141) and the Next-Generation Bio-Green 21 Program of Rural Development Administration in Korea (PJ00821201). The authors would like to thank Douglas Whalen for lending his voice for the FCPD 1.2 video tutorials and for reviewing the paper and Jill Demers for reviewing the paper. NR 70 TC 31 Z9 31 U1 3 U2 38 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 OCT 4 PY 2012 VL 13 AR 525 DI 10.1186/1471-2164-13-525 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 051TL UT WOS:000312150200001 PM 23033934 ER PT J AU Yutin, N Koonin, EV AF Yutin, Natalya Koonin, Eugene V. TI Proteorhodopsin genes in giant viruses SO BIOLOGY DIRECT LA English DT Article ID MICROBIAL RHODOPSINS; PHOTOSYSTEM-I; PROTEINS; ARCHAEA; OCEAN; PHOTOTROPHY; EUKARYOTES; BACTERIA; GENOMES AB Viruses with large genomes encode numerous proteins that do not directly participate in virus biogenesis but rather modify key functional systems of infected cells. We report that a distinct group of giant viruses infecting unicellular eukaryotes that includes Organic Lake Phycodnaviruses and Phaeocystis globosa virus encode predicted proteorhodopsins that have not been previously detected in viruses. Search of metagenomic sequence data shows that putative viral proteorhodopsins are extremely abundant in marine environments. Phylogenetic analysis suggests that giant viruses acquired proteorhodopsins via horizontal gene transfer from proteorhodopsin-encoding protists although the actual donor(s) could not be presently identified. The pattern of conservation of the predicted functionally important amino acid residues suggests that viral proteorhodopsin homologs function as sensory rhodopsins. We hypothesize that viral rhodopsins modulate light-dependent signaling, in particular phototaxis, in infected protists. This article was reviewed by Igor B. Zhulin and Laksminarayan M. Iyer. For the full reviews, see the Reviewers' reports section. C1 [Yutin, Natalya; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services intramural funds FX The authors thank Oded Beja and Valerian Dolja for critical reading of the manuscript and useful suggestions. The authors' research is supported by the US Department of Health and Human Services intramural funds (to National Library of Medicine). NR 32 TC 21 Z9 21 U1 3 U2 33 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 OCT 4 PY 2012 VL 7 AR 34 DI 10.1186/1745-6150-7-34 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 042PI UT WOS:000311482900001 PM 23036091 ER PT J AU Schank, JR Ryabinin, AE Giardino, WJ Ciccocioppo, R Heilig, M AF Schank, Jesse R. Ryabinin, Andrey E. Giardino, William J. Ciccocioppo, Roberto Heilig, Markus TI Stress-Related Neuropeptides and Addictive Behaviors: Beyond the Usual Suspects SO NEURON LA English DT Review ID CORTICOTROPIN-RELEASING-FACTOR; VENTRAL TEGMENTAL AREA; COCAINE-SEEKING BEHAVIOR; DORSAL RAPHE NUCLEUS; NEUROKININ-1 RECEPTOR ANTAGONISM; CONDITIONED PLACE PREFERENCE; EDINGER-WESTPHAL NUCLEUS; ALCOHOL-PREFERRING RATS; ORPHANIN-FQ NOCICEPTIN; HYPOTHALAMIC HYPOCRETIN SYSTEM AB Addictive disorders are chronic, relapsing conditions that cause extensive disease burden. Genetic factors partly account for susceptibility to addiction, but environmental factors such as stressful experiences and prolonged exposure of the brain to addictive drugs promote its development. Progression to addiction involves neuroadaptations within neurocircuitry that mediates stress responses and is influenced by several peptidergic neuromodulators. While corticotrophin releasing factor is the prototypic member of this class, recent work has identified several additional stress-related neuropeptides that play an important role in regulation of drug intake and relapse, including the urocortins, nociceptin, substance P, and neuropeptide S. Here, we review this emerging literature, discussing to what extent the properties of these neuromodulators are shared or distinct and considering their potential as drug targets. C1 [Schank, Jesse R.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Ryabinin, Andrey E.; Giardino, William J.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Ciccocioppo, Roberto] Univ Camerino, Dept Expt Med & Publ Hlth, I-62032 Camerino, Italy. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 FU NIH [AA01760, AA016647, AA019793, AA021023, AA014351, AA017447] FX The authors thank Dr. Yavin Shaham for important comments on this manuscript and Mrs. Karen Smith for bibliographic assistance. The work was in part supported by NIH grants AA01760 (A.E.R.), AA016647 (A.E.R.), AA019793 (A.E.R.), AA021023 (W.J.G.), AA014351 (R.C.), and AA017447 (R.C.). NR 191 TC 37 Z9 37 U1 0 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD OCT 4 PY 2012 VL 76 IS 1 BP 192 EP 208 DI 10.1016/j.neuron.2012.09.026 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 020HG UT WOS:000309799000014 PM 23040815 ER PT J AU Ajiro, M Jia, R Zhang, LF Liu, XF Zheng, ZM AF Ajiro, Masahiko Jia, Rong Zhang, Lifang Liu, Xuefeng Zheng, Zhi-Ming TI Intron Definition and a Branch Site Adenosine at nt 385 Control RNA Splicing of HPV16 E6*I and E7 Expression SO PLOS ONE LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; PRE-MESSENGER-RNA; CERVICAL-CANCER; E6 ONCOPROTEIN; U2 SNRNP; MAMMALIAN INTRONS; BINDING-PROTEIN; POINT SEQUENCES; EXON SEQUENCES; IN-VITRO AB HPV16 E6 and E7, two viral oncogenes, are expressed from a single bicistronic pre-mRNA. In this report, we provide the evidence that the bicistronic pre-mRNA intron 1 contains three 5' splice sites (5' ss) and three 3' splice sites (3' ss) normally used in HPV16(+) cervical cancer and its derived cell lines. The choice of two novel alternative 5' ss (nt 221 5' ss and nt 191 5' ss) produces two novel isoforms of E6E7 mRNAs (E6*V and E6*VI). The nt 226 59 ss and nt 409 3' ss is preferentially selected over the other splice sites crossing over the intron to excise a minimal length of the intron in RNA splicing. We identified AACAAAC as the preferred branch point sequence (BPS) and an adenosine at nt 385 ( underlined) in the BPS as a branch site to dictate the selection of the nt 409 3' ss for E6*I splicing and E7 expression. Introduction of point mutations into the mapped BPS led to reduced U2 binding to the BPS and thereby inhibition of the second step of E6E7 splicing at the nt 409 3' ss. Importantly, the E6E7 bicistronic RNA with a mutant BPS and inefficient splicing makes little or no E7 and the resulted E6 with mutations of (91)QYNK(94) to (PSFW94)-P-91 displays attenuate activity on p53 degradation. Together, our data provide structural basis of the E6E7 intron 1 for better understanding of how viral E6 and E7 expression is regulated by alternative RNA splicing. This study elucidates for the first time a mapped branch point in HPV16 genome involved in viral oncogene expression. C1 [Ajiro, Masahiko; Jia, Rong; Zhang, Lifang; Liu, Xuefeng; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov FU NCI, Center for Cancer Research, NIH; JSPS, NIH FX The study was supported by the Intramural Research Program of the NCI, Center for Cancer Research, NIH and JSPS Research Fellowship for Japanese biomedical and behavioral researchers at NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 12 Z9 12 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2012 VL 7 IS 10 AR e46412 DI 10.1371/journal.pone.0046412 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017HM UT WOS:000309580800018 PM 23056301 ER PT J AU Raineri, M Gonzalez, B Goitia, B Garcia-Rill, E Krasnova, IN Cadet, JL Urbano, FJ Bisagno, V AF Raineri, Mariana Gonzalez, Betina Goitia, Belen Garcia-Rill, Edgar Krasnova, Irina N. Cadet, Jean Lud Urbano, Francisco J. Bisagno, Veronica TI Modafinil Abrogates Methamphetamine-Induced Neuroinflammation and Apoptotic Effects in the Mouse Striatum SO PLOS ONE LA English DT Article ID NIGROSTRIATAL DOPAMINE NEURONS; PROMOTING DRUG MODAFINIL; INDUCED NEUROTOXICITY; MICROGLIAL ACTIVATION; SUBSTITUTED AMPHETAMINES; TYROSINE-HYDROXYLASE; C57BL/6J MOUSE; BRAIN; DEATH; TRANSPORTERS AB Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wakepromoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4 x 5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2 x 90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum. C1 [Raineri, Mariana; Gonzalez, Betina; Bisagno, Veronica] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Invest Farmacol, Buenos Aires, DF, Argentina. [Goitia, Belen; Urbano, Francisco J.] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Fisiol Biol Mol & Neurociencias, Lab Fisiol & Biol Mol, Buenos Aires, DF, Argentina. [Krasnova, Irina N.; Cadet, Jean Lud] NIH NIDA Intramural Res Program, Mol Neuropsychiat Res Branch, Baltimore, MD USA. [Garcia-Rill, Edgar] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Ctr Translat Neurosci, Little Rock, AR 72205 USA. RP Bisagno, V (reprint author), Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Invest Farmacol, Buenos Aires, DF, Argentina. EM vbisagno@ffyb.uba.ar OI Garcia-Rill, Edgar/0000-0003-1367-3071 FU FONCYT-Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina) [BID 1728 OC.AR]; PICT; PIDRI-PRH; CONICET-PIP [2011-2013-11420100100072]; NIH [P20 GM103425-09] FX This work was supported by: FONCYT-Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina), BID 1728 OC.AR. PICT 2007-1009, PICT 2008-2019 and PIDRI-PRH 2007, CONICET-PIP 2011-2013-11420100100072, and by NIH P20 GM103425-09. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 14 Z9 14 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2012 VL 7 IS 10 AR e46599 DI 10.1371/journal.pone.0046599 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017HM UT WOS:000309580800031 PM 23056363 ER PT J AU Sunyer, R Jin, AJ Nossal, R Sackett, DL AF Sunyer, Raimon Jin, Albert J. Nossal, Ralph Sackett, Dan L. TI Fabrication of Hydrogels with Steep Stiffness Gradients for Studying Cell Mechanical Response SO PLOS ONE LA English DT Article ID ATOMIC-FORCE MICROSCOPY; SUBSTRATE STIFFNESS; RIGIDITY; MOVEMENT AB Many fundamental cell processes, such as angiogenesis, neurogenesis and cancer metastasis, are thought to be modulated by extracellular matrix stiffness. Thus, the availability of matrix substrates having well-defined stiffness profiles can be of great importance in biophysical studies of cell-substrate interaction. Here, we present a method to fabricate biocompatible hydrogels with a well defined and linear stiffness gradient. This method, involving the photopolymerization of films by progressively uncovering an acrylamide/bis-acrylamide solution initially covered with an opaque mask, can be easily implemented with common lab equipment. It produces linear stiffness gradients of at least 115 kPa/mm, extending from similar to 1 kPa to 240 kPa (in units of Young's modulus). Hydrogels with less steep gradients and narrower stiffness ranges can easily be produced. The hydrogels can be covalently functionalized with uniform coatings of proteins that promote cell adhesion. Cell spreading on these hydrogels linearly correlates with hydrogel stiffness, indicating that this technique effectively modifies the mechanical environment of living cells. This technique provides a simple approach that produces steeper gradients, wider rigidity ranges, and more accurate profiles than current methods. C1 [Sunyer, Raimon; Nossal, Ralph; Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Sunyer, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM raimon.sunyer@nih.gov RI Sunyer, Raimon/G-8605-2013; OI Jin, Albert/0000-0003-3826-1081; Sunyer, Raimon/0000-0003-0777-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; Agency of Research and Universities (Ministry of Economy and Knowledge, Catalan Government); Cofund program (Marie Curie Actions, Seventh Framework Programme of the European Union) FX This work was supported by funds from the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. R Sunyer was supported by a postdoctoral fellowship from the Agency of Research and Universities (Ministry of Economy and Knowledge, Catalan Government) and the Cofund program (Marie Curie Actions, Seventh Framework Programme of the European Union). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 42 Z9 42 U1 8 U2 57 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 OCT 4 PY 2012 VL 7 IS 10 AR e46107 DI 10.1371/journal.pone.0046107 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017HM UT WOS:000309580800010 PM 23056241 ER PT J AU Oh, J Segre, JA AF Oh, Julia Segre, Julia A. TI GENOMICS Resident risks SO NATURE LA English DT Editorial Material ID ASSOCIATION; INSIGHTS C1 [Oh, Julia; Segre, Julia A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Oh, J (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM julia.oh@nih.gov; jsegre@nhgri.nih.gov FU Intramural NIH HHS [ZIA HG000180-12] NR 7 TC 0 Z9 0 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 4 PY 2012 VL 490 IS 7418 BP 44 EP 46 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015LG UT WOS:000309446800027 PM 23038462 ER PT J AU Koboldt, DC Fulton, RS McLellan, MD Schmidt, H Kalicki-Veizer, J McMichael, JF Fulton, LL Dooling, DJ Ding, L Mardis, ER Wilson, RK Ally, A Balasundaram, M Butterfield, YSN Carlsen, R Carter, C Chu, A Chuah, E Chun, HJE Coope, RJN Dhalla, N Guin, R Hirst, C Hirst, M Holt, RA Lee, D Li, HYI Mayo, M Moore, RA Mungall, AJ Pleasance, E Robertson, AG Schein, JE Shafiei, A Sipahimalani, P Slobodan, JR Stoll, D Tam, A Thiessen, N Varhol, RJ Wye, N Zeng, T Zhao, YJ Birol, I Jones, SJM Marra, MA Cherniack, AD Saksena, G Onofrio, RC Pho, NH Carter, SL Schumacher, SE Tabak, B Hernandez, B Gentry, J Nguyen, H Crenshaw, A Ardlie, K Beroukhim, R Winckler, W Getz, G Gabriel, SB Meyerson, M Chin, L Park, PJ Kucherlapati, R Hoadley, KA Auman, JT Fan, C Turman, YJ Shi, Y Li, L Topal, MD He, XP Chao, HH Prat, A Silva, GO Iglesia, MD Zhao, W Usary, J Berg, JS Adams, M Booker, J Wu, JY Gulabani, A Bodenheimer, T Hoyle, AP Simons, JV Soloway, MG Mose, LE Jefferys, SR Balu, S Parker, JS Hayes, DN Perou, CM Malik, S Mahurkar, S Shen, H Weisenberger, DJ Triche, T Lai, PH Bootwalla, MS Maglinte, DT Berman, BP Van den Berg, DJ Baylin, SB Laird, PW Creighton, CJ Donehower, LA Getz, G Noble, M Voet, D Saksena, G Gehlenborg, N DiCara, D Zhang, JH Zhang, HL Wu, CJ Liu, SY Lawrence, MS Zou, LH Sivachenko, A Lin, P Stojanov, P Jing, R Cho, J Sinha, R Park, RW Nazaire, MD Robinson, J Thorvaldsdottir, H Mesirov, J Park, PJ Chin, L Reynolds, S Kreisberg, RB Bernard, B Bressler, R Erkkila, T Lin, J Thorsson, V Zhang, W Shmulevich, I Ciriello, G Weinhold, N Schultz, N Gao, JJ Cerami, E Gross, B Jacobsen, A Sinha, R Aksoy, BA Antipin, Y Reva, B Shen, RL Taylor, BS Ladanyi, M Sander, C Anur, P Spellman, PT Lu, YL Liu, WB Verhaak, RRG Mills, GB Akbani, R Zhang, NX Broom, BM Casasent, TD Wakefield, C Unruh, AK Baggerly, K Coombes, K Weinstein, JN Haussler, D Benz, CC Stuart, JM Benz, SC Zhu, JC Szeto, CC Scott, GK Yau, C Paul, EO Carlin, D Wong, C Sokolov, A Thusberg, J Mooney, S Ng, S Goldstein, TC Ellrott, K Grifford, M Wilks, C Ma, S Craft, B Yan, CH Hu, Y Meerzaman, D Gastier-Foster, JM Bowen, J Ramirez, NC Black, AD Pyatt, RE White, P Zmuda, EJ Frick, J Lichtenberg, T Brookens, R George, MM Gerken, MA Harper, HA Leraas, KM Wise, LJ Tabler, TR McAllister, C Barr, T Hart-Kothari, M Tarvin, K Saller, C Sandusky, G Mitchell, C Iacocca, MV Brown, J Rabeno, B Czerwinski, C Petrelli, N Dolzhansky, O Abramov, M Voronina, O Potapova, O Marks, JR Suchorska, WM Murawa, D Kycler, W Ibbs, M Korski, K Spychala, A Murawa, P Brzezinski, JJ Perz, H Lazniak, R Teresiak, M Tatka, H Leporowska, E Bogusz-Czerniewicz, M Malicki, J Mackiewicz, A Wiznerowicz, M Le, XV Kohl, B Tien, NV Thorp, R Bang, NV Sussman, H Phu, BD Hajek, R Hung, NP Tran, VTP Thang, HQ Khan, KZ Penny, R Mallery, D Curley, E Shelton, C Yena, P Ingle, JN Couch, FJ Lingle, WL King, TA Gonzalez-Angulo, AM Mills, GB Dyer, MD Liu, SY Meng, XL Patangan, M Waldman, F Stoppler, H Rathmell, WK Thorne, L Huang, M Boice, L Hill, A Morrison, C Gaudioso, C Bshara, W Daily, K Egea, SC Pegram, MD Gomez-Fernandez, C Dhir, R Bhargava, R Brufsky, A Shriver, CD Hooke, JA Campbell, JL Mural, RJ Hu, H Somiari, S Larson, C Deyarmin, B Kvecher, L Kovatich, AJ Ellis, MJ King, TA Hu, H Couch, FJ Mural, RJ Stricker, T White, K Olopade, O Ingle, JN Luo, CQ Chen, YQ Marks, JR Waldman, F Wiznerowicz, M Bose, R Chang, LW Beck, AH Gonzalez-Angulo, AM Pihl, T Jensen, M Sfeir, R Kahn, A Chu, A Kothiyal, P Wang, ZN Snyder, E Pontius, J Ayala, B Backus, M Walton, J Baboud, J Berton, D Nicholls, M Srinivasan, D Raman, R Girshik, S Kigonya, P Alonso, S Sanbhadti, R Barletta, S Pot, D Sheth, M Demchok, JA Shaw, KRM Yang, LM Eley, G Ferguson, ML Tarnuzzer, RW Zhang, JS Dillon, LAL Buetow, K Fielding, P Ozenberger, BA Guyer, MS Sofia, HJ Palchik, JD AF Koboldt, Daniel C. Fulton, Robert S. McLellan, Michael D. Schmidt, Heather Kalicki-Veizer, Joelle McMichael, Joshua F. Fulton, Lucinda L. Dooling, David J. Ding, Li Mardis, Elaine R. Wilson, Richard K. Ally, Adrian Balasundaram, Miruna Butterfield, Yaron S. N. Carlsen, Rebecca Carter, Candace Chu, Andy Chuah, Eric Chun, Hye-Jung E. Coope, Robin J. N. Dhalla, Noreen Guin, Ranabir Hirst, Carrie Hirst, Martin Holt, Robert A. Lee, Darlene Li, Haiyan I. Mayo, Michael Moore, Richard A. Mungall, Andrew J. Pleasance, Erin Robertson, A. Gordon Schein, Jacqueline E. Shafiei, Arash Sipahimalani, Payal Slobodan, Jared R. Stoll, Dominik Tam, Angela Thiessen, Nina Varhol, Richard J. Wye, Natasja Zeng, Thomas Zhao, Yongjun Birol, Inanc Jones, Steven J. M. Marra, Marco A. Cherniack, Andrew D. Saksena, Gordon Onofrio, Robert C. Pho, Nam H. Carter, Scott L. Schumacher, Steven E. Tabak, Barbara Hernandez, Bryan Gentry, Jeff Huy Nguyen Crenshaw, Andrew Ardlie, Kristin Beroukhim, Rameen Winckler, Wendy Getz, Gad Gabriel, Stacey B. Meyerson, Matthew Chin, Lynda Park, Peter J. Kucherlapati, Raju Hoadley, Katherine A. Auman, J. Todd Fan, Cheng Turman, Yidi J. Shi, Yan Li, Ling Topal, Michael D. He, Xiaping Chao, Hann-Hsiang Prat, Aleix Silva, Grace O. Iglesia, Michael D. Zhao, Wei Usary, Jerry Berg, Jonathan S. Adams, Michael Booker, Jessica Wu, Junyuan Gulabani, Anisha Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, Matthew G. Mose, Lisle E. Jefferys, Stuart R. Balu, Saianand Parker, Joel S. Hayes, D. Neil Perou, Charles M. Malik, Simeen Mahurkar, Swapna Shen, Hui Weisenberger, Daniel J. Triche, Timothy, Jr. Lai, Phillip H. Bootwalla, Moiz S. Maglinte, Dennis T. Berman, Benjamin P. Van den Berg, David J. Baylin, Stephen B. Laird, Peter W. Creighton, Chad J. Donehower, Lawrence A. Getz, Gad Noble, Michael Voet, Doug Saksena, Gordon Gehlenborg, Nils DiCara, Daniel Zhang, Juinhua Zhang, Hailei Wu, Chang-Jiun Liu, Spring Yingchun Lawrence, Michael S. Zou, Lihua Sivachenko, Andrey Lin, Pei Stojanov, Petar Jing, Rui Cho, Juok Sinha, Raktim Park, Richard W. Nazaire, Marc-Danie Robinson, Jim Thorvaldsdottir, Helga Mesirov, Jill Park, Peter J. Chin, Lynda Reynolds, Sheila Kreisberg, Richard B. Bernard, Brady Bressler, Ryan Erkkila, Timo Lin, Jake Thorsson, Vesteinn Zhang, Wei Shmulevich, Ilya Ciriello, Giovanni Weinhold, Nils Schultz, Nikolaus Gao, Jianjiong Cerami, Ethan Gross, Benjamin Jacobsen, Anders Sinha, Rileen Aksoy, B. Arman Antipin, Yevgeniy Reva, Boris Shen, Ronglai Taylor, Barry S. Ladanyi, Marc Sander, Chris Anur, Pavana Spellman, Paul T. Lu, Yiling Liu, Wenbin Verhaak, Roel R. G. Mills, Gordon B. Akbani, Rehan Zhang, Nianxiang Broom, Bradley M. Casasent, Tod D. Wakefield, Chris Unruh, Anna K. Baggerly, Keith Coombes, Kevin Weinstein, John N. Haussler, David Benz, Christopher C. Stuart, Joshua M. Benz, Stephen C. Zhu, Jingchun Szeto, Christopher C. Scott, Gary K. Yau, Christina Paul, Evan O. Carlin, Daniel Wong, Christopher Sokolov, Artem Thusberg, Janita Mooney, Sean Sam Ng Goldstein, Theodore C. Ellrott, Kyle Grifford, Mia Wilks, Christopher Ma, Singer Craft, Brian Yan, Chunhua Hu, Ying Meerzaman, Daoud Gastier-Foster, Julie M. Bowen, Jay Ramirez, Nilsa C. Black, Aaron D. Pyatt, Robert E. White, Peter Zmuda, Erik J. Frick, Jessica Lichtenberg, Taram. Brookens, Robin George, Myra M. Gerken, Mark A. Harper, Hollie A. Leraas, Kristen M. Wise, Lisa J. Tabler, Teresa R. McAllister, Cynthia Barr, Thomas Hart-Kothari, Melissa Tarvin, Katie Saller, Charles Sandusky, George Mitchell, Colleen Iacocca, Mary V. Brown, Jennifer Rabeno, Brenda Czerwinski, Christine Petrelli, Nicholas Dolzhansky, Oleg Abramov, Mikhail Voronina, Olga Potapova, Olga Marks, Jeffrey R. Suchorska, Wiktoria M. Murawa, Dawid Kycler, Witold Ibbs, Matthew Korski, Konstanty Spychala, Arkadiusz Murawa, Pawel Brzezinski, Jacek J. Perz, Hanna Lazniak, Radoslaw Teresiak, Marek Tatka, Honorata Leporowska, Ewa Bogusz-Czerniewicz, Marta Malicki, Julian Mackiewicz, Andrzej Wiznerowicz, Maciej Xuan Van Le Kohl, Bernard Nguyen Viet Tien Thorp, Richard Nguyen Van Bang Sussman, Howard Bui Duc Phu Hajek, Richard Nguyen Phi Hung Tran Viet The Phuong Huynh Quyet Thang Khan, Khurram Zaki Penny, Robert Mallery, David Curley, Erin Shelton, Candace Yena, Peggy Ingle, James N. Couch, Fergus J. Lingle, Wilma L. King, Tari A. Gonzalez-Angulo, Ana Maria Mills, Gordon B. Dyer, Mary D. Liu, Shuying Meng, Xiaolong Patangan, Modesto Waldman, Frederic Stoeppler, Hubert Rathmell, W. Kimryn Thorne, Leigh Huang, Mei Boice, Lori Hill, Ashley Morrison, Carl Gaudioso, Carmelo Bshara, Wiam Daily, Kelly Egea, Sophie C. Pegram, Mark D. Gomez-Fernandez, Carmen Dhir, Rajiv Bhargava, Rohit Brufsky, Adam Shriver, Craig D. Hooke, Jeffrey A. Campbell, Jamie Leigh Mural, Richard J. Hu, Hai Somiari, Stella Larson, Caroline Deyarmin, Brenda Kvecher, Leonid Kovatich, Albert J. Ellis, Matthew J. King, Tari A. Hu, Hai Couch, Fergus J. Mural, Richard J. Stricker, Thomas White, Kevin Olopade, Olufunmilayo Ingle, James N. Luo, Chunqing Chen, Yaqin Marks, Jeffrey R. Waldman, Frederic Wiznerowicz, Maciej Bose, Ron Chang, Li-Wei Beck, Andrew H. Gonzalez-Angulo, Ana Maria Pihl, Todd Jensen, Mark Sfeir, Robert Kahn, Ari Chu, Anna Kothiyal, Prachi Wang, Zhining Snyder, Eric Pontius, Joan Ayala, Brenda Backus, Mark Walton, Jessica Baboud, Julien Berton, Dominique Nicholls, Matthew Srinivasan, Deepak Raman, Rohini Girshik, Stanley Kigonya, Peter Alonso, Shelley Sanbhadti, Rashmi Barletta, Sean Pot, David Sheth, Margi Demchok, John A. Shaw, Kenna R. Mills Yang, Liming Eley, Greg Ferguson, Martin L. Tarnuzzer, Roy W. Zhang, Jiashan Dillon, Laura A. L. Buetow, Kenneth Fielding, Peter Ozenberger, Bradley A. Guyer, Mark S. Sofia, Heidi J. Palchik, Jacqueline D. CA Canc Genome Atlas Network TI Comprehensive molecular portraits of human breast tumours SO NATURE LA English DT Article ID BASAL-LIKE; MUTATIONAL EVOLUTION; HIGH-FREQUENCY; PIK3CA GENE; P53 STATUS; LUMINAL-B; CANCER; SUBTYPES; PATHWAYS; SUPPRESSOR AB We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer. C1 [Hoadley, Katherine A.; He, Xiaping; Chao, Hann-Hsiang; Prat, Aleix; Silva, Grace O.; Iglesia, Michael D.; Zhao, Wei; Berg, Jonathan S.; Adams, Michael; Weisenberger, Daniel J.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Koboldt, Daniel C.; Fulton, Robert S.; McLellan, Michael D.; Schmidt, Heather; Kalicki-Veizer, Joelle; McMichael, Joshua F.; Fulton, Lucinda L.; Dooling, David J.; Ding, Li; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Genome Inst, St Louis, MO 63108 USA. [Ding, Li; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Dept Genet, St Louis, MO 63110 USA. [Mardis, Elaine R.; Wilson, Richard K.; Ellis, Matthew J.; Bose, Ron] Washington Univ, Siteman Canc Ctr, St Louis, MO 63110 USA. [Ally, Adrian; Balasundaram, Miruna; Butterfield, Yaron S. N.; Carlsen, Rebecca; Carter, Candace; Chu, Andy; Chuah, Eric; Chun, Hye-Jung E.; Coope, Robin J. N.; Dhalla, Noreen; Guin, Ranabir; Hirst, Carrie; Hirst, Martin; Holt, Robert A.; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Pleasance, Erin; Robertson, A. Gordon; Schein, Jacqueline E.; Shafiei, Arash; Sipahimalani, Payal; Slobodan, Jared R.; Stoll, Dominik; Tam, Angela; Thiessen, Nina; Varhol, Richard J.; Wye, Natasja; Zeng, Thomas; Zhao, Yongjun; Birol, Inanc; Jones, Steven J. M.; Marra, Marco A.] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z, Canada. [Cherniack, Andrew D.; Saksena, Gordon; Onofrio, Robert C.; Pho, Nam H.; Carter, Scott L.; Schumacher, Steven E.; Tabak, Barbara; Hernandez, Bryan; Gentry, Jeff; Huy Nguyen; Crenshaw, Andrew; Ardlie, Kristin; Beroukhim, Rameen; Winckler, Wendy; Getz, Gad; Gabriel, Stacey B.; Meyerson, Matthew] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Schumacher, Steven E.; Tabak, Barbara; Beroukhim, Rameen; Nguyen Phi Hung] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Beroukhim, Rameen] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen; Meyerson, Matthew; Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beroukhim, Rameen; Meyerson, Matthew; Chin, Lynda] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Meyerson, Matthew; Beck, Andrew H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Chin, Lynda] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Park, Peter J.; Gehlenborg, Nils; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kucherlapati, Raju] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Hoadley, Katherine A.; Fan, Cheng; Turman, Yidi J.; Shi, Yan; Li, Ling; Topal, Michael D.; He, Xiaping; Chao, Hann-Hsiang; Prat, Aleix; Silva, Grace O.; Iglesia, Michael D.; Zhao, Wei; Usary, Jerry; Berg, Jonathan S.; Wu, Junyuan; Gulabani, Anisha; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Matthew G.; Mose, Lisle E.; Jefferys, Stuart R.; Balu, Saianand; Parker, Joel S.; Hayes, D. Neil; Perou, Charles M.; Malik, Simeen; Mahurkar, Swapna; Shen, Hui; Weisenberger, Daniel J.; Rathmell, W. Kimryn; Thorne, Leigh; Huang, Mei; Boice, Lori; Hill, Ashley] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Auman, J. Todd] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Auman, J. Todd] Univ N Carolina, Inst Pharmacogenet & Individualized Therapy, Chapel Hill, NC 27599 USA. [Topal, Michael D.; Booker, Jessica; Weisenberger, Daniel J.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Shen, Hui] Univ N Carolina, Div Med Oncol, Dept Internal Med, Chapel Hill, NC 27599 USA. [Triche, Timothy, Jr.; Lai, Phillip H.; Bootwalla, Moiz S.; Maglinte, Dennis T.; Berman, Benjamin P.; Van den Berg, David J.; Laird, Peter W.] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Div Canc Biol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Creighton, Chad J.; Donehower, Lawrence A.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Creighton, Chad J.; Donehower, Lawrence A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Donehower, Lawrence A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Donehower, Lawrence A.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Getz, Gad; Noble, Michael; Voet, Doug; Saksena, Gordon; Gehlenborg, Nils; DiCara, Daniel; Zhang, Hailei; Liu, Spring Yingchun; Lawrence, Michael S.; Zou, Lihua; Sivachenko, Andrey; Lin, Pei; Stojanov, Petar; Jing, Rui; Cho, Juok; Sinha, Raktim; Park, Richard W.; Nazaire, Marc-Danie; Robinson, Jim; Thorvaldsdottir, Helga; Mesirov, Jill; Chin, Lynda] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Zhang, Juinhua; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Inst Appl Canc Sci, Houston, TX 77054 USA. [Wu, Chang-Jiun] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77054 USA. [Park, Peter J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Reynolds, Sheila; Kreisberg, Richard B.; Bernard, Brady; Bressler, Ryan; Lin, Jake; Thorsson, Vesteinn; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Erkkila, Timo] Tampere Univ Technol, FIN-33101 Tampere, Finland. [Zhang, Wei] Univ Texas MD Anderson Canc Ctr, Canc Genom Core Lab, Houston, TX 77030 USA. [Ciriello, Giovanni; Weinhold, Nils; Schultz, Nikolaus; Gao, Jianjiong; Cerami, Ethan; Gross, Benjamin; Jacobsen, Anders; Sinha, Rileen; Aksoy, B. Arman; Antipin, Yevgeniy; Reva, Boris; Taylor, Barry S.; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Anur, Pavana; Spellman, Paul T.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Lu, Yiling; Mills, Gordon B.; Gonzalez-Angulo, Ana Maria] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Kleberg Ctr Mol Markers, Houston, TX 77030 USA. [Liu, Wenbin; Verhaak, Roel R. G.; Akbani, Rehan; Zhang, Nianxiang; Broom, Bradley M.; Casasent, Tod D.; Wakefield, Chris; Unruh, Anna K.; Baggerly, Keith; Coombes, Kevin; Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Haussler, David; Stuart, Joshua M.; Benz, Stephen C.; Zhu, Jingchun; Szeto, Christopher C.; Paul, Evan O.; Carlin, Daniel; Wong, Christopher; Sokolov, Artem; Sam Ng; Goldstein, Theodore C.; Ellrott, Kyle; Grifford, Mia; Wilks, Christopher; Ma, Singer; Craft, Brian] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Haussler, David; Stuart, Joshua M.; Benz, Stephen C.; Zhu, Jingchun; Szeto, Christopher C.; Paul, Evan O.; Carlin, Daniel; Wong, Christopher; Sokolov, Artem; Sam Ng; Goldstein, Theodore C.; Ellrott, Kyle; Grifford, Mia; Wilks, Christopher; Ma, Singer; Craft, Brian] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Haussler, David] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Benz, Christopher C.; Scott, Gary K.; Yau, Christina; Thusberg, Janita; Mooney, Sean] Buck Inst Res Aging, Novato, CA 94945 USA. [Yan, Chunhua; Hu, Ying; Meerzaman, Daoud; Buetow, Kenneth] NCI, Ctr Bioinformat & Informat Technol, Rockville, MD 20852 USA. [Gastier-Foster, Julie M.; Ramirez, Nilsa C.; Pyatt, Robert E.; White, Peter] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.; Bowen, Jay; Ramirez, Nilsa C.; Black, Aaron D.; Pyatt, Robert E.; White, Peter; Zmuda, Erik J.; Frick, Jessica; Lichtenberg, Taram.; Brookens, Robin; George, Myra M.; Gerken, Mark A.; Harper, Hollie A.; Leraas, Kristen M.; Wise, Lisa J.; Tabler, Teresa R.; McAllister, Cynthia; Barr, Thomas; Hart-Kothari, Melissa] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Tarvin, Katie] ABS Inc, Indianapolis, IN 46204 USA. [Saller, Charles] ABS Inc, Wilmington, DE 19801 USA. [Sandusky, George; Mitchell, Colleen] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Iacocca, Mary V.; Brown, Jennifer; Rabeno, Brenda; Czerwinski, Christine; Petrelli, Nicholas] Christiana Care, Helen F Graham Canc Ctr, Newark, DE 19713 USA. [Dolzhansky, Oleg] Moscow Hlth Dept, Moscow City Clin Oncol Dispensary 1, Moscow 105005, Russia. [Dolzhansky, Oleg] Moscow Hlth Dept, Cent IHC Lab, Moscow 105005, Russia. [Abramov, Mikhail] Russian Canc Res Ctr, Moscow 115478, Russia. [Voronina, Olga; Potapova, Olga] Cureline Inc, San Francisco, CA 94080 USA. [Marks, Jeffrey R.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Suchorska, Wiktoria M.; Murawa, Dawid; Kycler, Witold; Ibbs, Matthew; Korski, Konstanty; Spychala, Arkadiusz; Murawa, Pawel; Brzezinski, Jacek J.; Perz, Hanna; Lazniak, Radoslaw; Teresiak, Marek; Tatka, Honorata; Leporowska, Ewa; Bogusz-Czerniewicz, Marta; Malicki, Julian; Mackiewicz, Andrzej; Wiznerowicz, Maciej] Greater Poland Canc Ctr, PL-61866 Poznan, Poland. [Bogusz-Czerniewicz, Marta; Malicki, Julian; Mackiewicz, Andrzej] Poznan Univ Med Sci, PL-61701 Poznan, Poland. [Xuan Van Le; Kohl, Bernard] ILSBio LLC, Chestertown, MD 21620 USA. [Nguyen Viet Tien] Minist Hlth, Hanoi, Vietnam. [Thorp, Richard; Khan, Khurram Zaki] ILSBio LLC, Karachi, Pakistan. [Nguyen Van Bang; Bui Duc Phu] Hue Cent Hosp, Hue City, Vietnam. [Sussman, Howard] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Hajek, Richard] Univ Texas MD Anderson Canc Ctr, Ctr Minor Hlth Res, Houston, TX 77030 USA. [Nguyen Phi Hung] Natl Canc Inst, Hanoi, Vietnam. [Tran Viet The Phuong] Ho Chi Minh City Canc Ctr, Ho Chi Minh City, Vietnam. [Huynh Quyet Thang] Can Tho Canc Ctr, Can Tho, Vietnam. [Penny, Robert; Mallery, David; Curley, Erin; Shelton, Candace; Yena, Peggy] Int Genom Consortium, Phoenix, AZ 85004 USA. [Ingle, James N.; Couch, Fergus J.; Lingle, Wilma L.] Mayo Clin, Rochester, MN 55905 USA. [King, Tari A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10065 USA. [Mills, Gordon B.; Dyer, Mary D.; Liu, Shuying; Meng, Xiaolong; Patangan, Modesto] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Waldman, Frederic] Univ Calif San Francisco, San Francisco, CA 94143 USA. Canc Diagnost, San Juan Capistrano, CA 92675 USA. Quest Diagnost, Nichols Inst, San Juan Capistrano, CA 92675 USA. [Stoeppler, Hubert] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94115 USA. [Thorne, Leigh; Huang, Mei; Boice, Lori] UNC Lineberger Canc Ctr, Dept Pathol, UNC Tissue Procurement Facil, Chapel Hill, NC 27599 USA. [Morrison, Carl; Gaudioso, Carmelo; Bshara, Wiam] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [Daily, Kelly; Egea, Sophie C.; Pegram, Mark D.; Gomez-Fernandez, Carmen] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Pathol, Miami, FL 33136 USA. [Dhir, Rajiv] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Bhargava, Rohit; Brufsky, Adam] Univ Pittsburgh Med Ctr, Magee Womens Hosp, Pittsburgh, PA 15213 USA. [Shriver, Craig D.; Hooke, Jeffrey A.; Campbell, Jamie Leigh] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20899 USA. [Mural, Richard J.; Hu, Hai; Somiari, Stella; Larson, Caroline; Deyarmin, Brenda; Kvecher, Leonid; Luo, Chunqing; Chen, Yaqin] Windber Res Inst, Windber, PA 15963 USA. [Kovatich, Albert J.] MDR Global LLC, Windber, PA 15963 USA. [Ellis, Matthew J.; Bose, Ron] Washington Univ, Breast Canc Program, St Louis, MO 63110 USA. [Ellis, Matthew J.; Bose, Ron] Washington Univ, Dept Internal Med, Div Oncol, St Louis, MO 63110 USA. [Stricker, Thomas; White, Kevin] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Olopade, Olufunmilayo] Univ Chicago, Ctr Clin Canc Genet, Chicago, IL 60637 USA. [Chang, Li-Wei] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Pihl, Todd; Jensen, Mark; Sfeir, Robert; Kahn, Ari; Chu, Anna; Kothiyal, Prachi; Wang, Zhining; Snyder, Eric; Pontius, Joan; Ayala, Brenda; Backus, Mark; Walton, Jessica; Baboud, Julien; Berton, Dominique; Nicholls, Matthew; Srinivasan, Deepak; Raman, Rohini; Girshik, Stanley; Kigonya, Peter; Alonso, Shelley; Sanbhadti, Rashmi; Barletta, Sean; Pot, David] SRA Int, Fairfax, VA 22033 USA. [Sheth, Margi; Demchok, John A.; Shaw, Kenna R. Mills; Yang, Liming; Tarnuzzer, Roy W.; Zhang, Jiashan; Dillon, Laura A. L.; Fielding, Peter] NCI, Canc Genome Atlas Program Off, Ctr Canc Genom, Bethesda, MD 20892 USA. [Eley, Greg] Scimentis LLC, TCGA, Statham, GA 30666 USA. [Ferguson, Martin L.] MLF Consulting, Arlington, MA 02474 USA. [Ozenberger, Bradley A.; Guyer, Mark S.; Sofia, Heidi J.; Palchik, Jacqueline D.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Perou, CM (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. EM cperou@med.unc.edu RI Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; Holt, Robert/C-3303-2009; White, Peter/E-4301-2011; Prat, Aleix/P-8561-2014; Jacobsen, Anders/K-1081-2013; Schein, Jacquie/G-3674-2015; Gastier-Foster, Julie/E-3105-2011; Schumacher, Steven/E-9821-2013; Reva, Boris/B-6436-2014; Gao, Jianjiong/B-5673-2016; Hirst, Martin/B-7684-2016; Tang, Macy/B-9798-2014; Berman, Benjamin/D-5942-2014; Waha, Andreas/J-2950-2014; Laird, Peter/G-8683-2012 OI Sinha, Rileen/0000-0001-5497-5055; Casasent, Anna/0000-0002-7857-179X; Gehlenborg, Nils/0000-0003-0327-8297; Birol, Inanc/0000-0003-0950-7839; Schultz, Nikolaus/0000-0002-0131-4904; Ibbs, Matthew/0000-0003-2510-3447; Benz, Stephen/0000-0002-4067-0602; Triche, Tim/0000-0001-5665-946X; Hayes, D. Neil/0000-0001-6203-7771; Pot, David/0000-0002-1480-9826; White, Peter/0000-0002-5218-5903; Prat, Aleix/0000-0003-2377-540X; Jacobsen, Anders/0000-0001-6847-4980; Schumacher, Steven/0000-0002-6819-5647; Reva, Boris/0000-0002-8805-389X; Gao, Jianjiong/0000-0002-5739-1781; FU USA National Institutes of Health [U24CA143883, U24CA143858, U24CA143840, U24CA143799, U24CA143835, U24CA143845, U24CA143882, U24CA143867, U24CA143866, U24CA143848, U24CA144025, U54HG003079, P50CA116201, P50CA58223]; Susan G. Komen for the Cure; US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine; Breast Cancer Research Foundation FX We thank M. Sheth and S. Lucas for administrative coordination of TCGA activities, and C. Gunter for critical reading of the manuscript. This work was supported by the following grants from the USA National Institutes of Health: U24CA143883, U24CA143858, U24CA143840, U24CA143799, U24CA143835, U24CA143845, U24CA143882, U24CA143867, U24CA143866, U24CA143848, U24CA144025, U54HG003079, P50CA116201 and P50CA58223. Additional support was provided by the Susan G. Komen for the Cure, the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine, and the Breast Cancer Research Foundation. The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of Defense, or US Government. NR 56 TC 2909 Z9 2944 U1 102 U2 729 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 OCT 4 PY 2012 VL 490 IS 7418 BP 61 EP 70 DI 10.1038/nature11412 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015LG UT WOS:000309446800032 ER PT J AU von Moltke, J Trinidad, NJ Moayeri, M Kintzer, AF Wang, SB van Rooijen, N Brown, CR Krantz, BA Leppla, SH Gronert, K Vance, RE AF von Moltke, Jakob Trinidad, Norver J. Moayeri, Mahtab Kintzer, Alexander F. Wang, Samantha B. van Rooijen, Nico Brown, Charles R. Krantz, Bryan A. Leppla, Stephen H. Gronert, Karsten Vance, Russell E. TI Rapid induction of inflammatory lipid mediators by the inflammasome in vivo SO NATURE LA English DT Article ID CYTOSOLIC PHOSPHOLIPASE A(2); III SECRETION APPARATUS; CASPASE-1 ACTIVATION; IMMUNE RECOGNITION; NLRC4 INFLAMMASOME; MICE DEFICIENT; PYROPTOSIS; MECHANISM; INFECTION; FLAGELLIN AB Detection of microbial products by host inflammasomes is an important mechanism of innate immune surveillance. Inflammasomes activate the caspase-1 (CASP1) protease, which processes the cytokines interleukin (IL)-1 beta and IL-18, and initiates a lytic host cell death called pyroptosis(1). To identify novel CASP1 functions in vivo, we devised a strategy for cytosolic delivery of bacterial flagellin, a specific ligand for the NAIP5 (NLR family, apoptosis inhibitory protein 5)/NLRC4 (NLR family, CARD-domain-containing 4) inflammasome(2-4). Here we show that systemic inflammasome activation by flagellin leads to a loss of vascular fluid into the intestine and peritoneal cavity, resulting in rapid (less than 30 min) death in mice. This unexpected response depends on the inflammasome components NAIP5, NLRC4 and CASP1, but is independent of the production of IL-1 beta or IL-18. Instead, inflammasome activation results, within minutes, in an 'eicosanoid storm'-a pathological release of signalling lipids, including prostaglandins and leukotrienes, that rapidly initiate inflammation and vascular fluid loss. Mice deficient in cyclooxygenase-1, a critical enzyme in prostaglandin biosynthesis, are resistant to these rapid pathological effects of systemic inflammasome activation by either flagellin or anthrax lethal toxin. Inflammasome-dependent biosynthesis of eicosanoids is mediated by the activation of cytosolic phospholipase A(2) in resident peritoneal macrophages, which are specifically primed for the production of eicosanoids by high expression of eicosanoid biosynthetic enzymes. Our results therefore identify eicosanoids as a previously unrecognized cell-type-specific signalling output of the inflammasome with marked physiological consequences in vivo. C1 [von Moltke, Jakob; Trinidad, Norver J.; Vance, Russell E.] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Immunol & Pathogenesis, Berkeley, CA 94720 USA. [Kintzer, Alexander F.; Krantz, Bryan A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Wang, Samantha B.; Gronert, Karsten] Univ Calif Berkeley, Vis Sci Program, Berkeley, CA 94720 USA. [Moayeri, Mahtab; Leppla, Stephen H.] NIAID, Parasit Dis Lab, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. [van Rooijen, Nico] Vrije Univ Amsterdam, Fac Med, Dept Mol Cell Biol, NL-1081 BT Amsterdam, Netherlands. [Brown, Charles R.] Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA. RP Vance, RE (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, Div Immunol & Pathogenesis, 229 Stanley Hall, Berkeley, CA 94720 USA. EM kgronert@berkeley.edu; rvance@berkeley.edu OI Kintzer, Alexander/0000-0001-9630-7258; Krantz, Bryan/0000-0002-4911-5824 FU Burroughs Wellcome Fund; Cancer Research Institute; National Institutes of Health (NIH) [AI075039, AI080749, AI063302, EY016136, EY022208]; Cancer Research Coordinating Committee of the University of California FX We thank S. Mariathasan and V. Dixit for Nlrc4-/- mice; I. Bergin and S. Griffey for pathology reports; D. Crown for help with survival experiments; L. Lopez for support in our animal facility; D. Bautista and R. Nichols for help with calcium imaging; and M. Fontana and members of the Barton and Vance laboratories for discussions. Work in R.E.V.'s laboratory is supported by Investigator Awards from the Burroughs Wellcome Fund and the Cancer Research Institute and by National Institutes of Health (NIH) grants AI075039, AI080749 and AI063302. K.G.'s laboratory is supported by NIH grants EY016136 and EY022208. J.v.M. is supported by a grant from the Cancer Research Coordinating Committee of the University of California. NR 39 TC 122 Z9 124 U1 4 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 4 PY 2012 VL 490 IS 7418 BP 107 EP U126 DI 10.1038/nature11351 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015LG UT WOS:000309446800042 PM 22902502 ER PT J AU Schmitz, R Young, RM Ceribelli, M Jhavar, S Xiao, WM Zhang, MZ Wright, G Shaffer, AL Hodson, DJ Buras, E Liu, XL Powell, J Yang, YD Xu, WH Zhao, H Kohlhammer, H Rosenwald, A Kluin, P Muller-Hermelink, HK Ott, G Gascoyne, RD Connors, JM Rimsza, LM Campo, E Jaffe, ES Delabie, J Smeland, EB Ogwang, MD Reynolds, SJ Fisher, RI Braziel, RM Tubbs, RR Cook, JR Weisenburger, DD Chan, WC Pittaluga, S Wilson, W Waldmann, TA Rowe, M Mbulaiteye, SM Rickinson, AB Staudt, LM AF Schmitz, Roland Young, Ryan M. Ceribelli, Michele Jhavar, Sameer Xiao, Wenming Zhang, Meili Wright, George Shaffer, Arthur L. Hodson, Daniel J. Buras, Eric Liu, Xuelu Powell, John Yang, Yandan Xu, Weihong Zhao, Hong Kohlhammer, Holger Rosenwald, Andreas Kluin, Philip Mueller-Hermelink, Hans Konrad Ott, German Gascoyne, Randy D. Connors, Joseph M. Rimsza, Lisa M. Campo, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Ogwang, Martin D. Reynolds, Steven J. Fisher, Richard I. Braziel, Rita M. Tubbs, Raymond R. Cook, James R. Weisenburger, Dennis D. Chan, Wing C. Pittaluga, Stefania Wilson, Wyndham Waldmann, Thomas A. Rowe, Martin Mbulaiteye, Sam M. Rickinson, Alan B. Staudt, Louis M. TI Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics SO NATURE LA English DT Article ID B-CELL LYMPHOMA; PROTEINS; IMMUNOGLOBULIN; REGION AB Burkitt's lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies(1). The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways(2). BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein-Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL. C1 [Schmitz, Roland; Young, Ryan M.; Ceribelli, Michele; Jhavar, Sameer; Zhang, Meili; Shaffer, Arthur L.; Hodson, Daniel J.; Buras, Eric; Yang, Yandan; Xu, Weihong; Zhao, Hong; Kohlhammer, Holger; Wilson, Wyndham; Waldmann, Thomas A.; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Xiao, Wenming; Liu, Xuelu; Powell, John] NIH, Bioinformat & Mol Anal Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Wright, George] NCI, Biometr Res Branch, DCTD, NIH, Bethesda, MD 20892 USA. [Rosenwald, Andreas; Mueller-Hermelink, Hans Konrad] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. [Kluin, Philip] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, NL-9713 GZ Groningen, Netherlands. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, D-70376 Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Gascoyne, Randy D.; Connors, Joseph M.] British Columbia Canc Agcy, Vancouver, BC V5Z 1L3, Canada. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. [Campo, Elias] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain. [Jaffe, Elaine S.; Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Delabie, Jan] Univ Hosp, Rikshosp, Pathol Clin, N-0372 Oslo, Norway. [Smeland, Erlend B.] Univ Hosp, Rikshosp, Inst Canc Res, N-0310 Oslo, Norway. [Smeland, Erlend B.] Univ Oslo, Norwegian Radium Hosp, Fac Div, Ctr Canc Biomed, N-0310 Oslo, Norway. [Ogwang, Martin D.] St Marys Hosp Lacor, Gulu 256, Uganda. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Fisher, Richard I.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Tubbs, Raymond R.; Cook, James R.] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44195 USA. [Weisenburger, Dennis D.; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE 68198 USA. [Weisenburger, Dennis D.; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Microbiol, Omaha, NE 68198 USA. [Rowe, Martin; Rickinson, Alan B.] Univ Birmingham, Birmingham Canc Res UK Ctr, Sch Canc Sci, Birmingham B15 2TT, W Midlands, England. [Mbulaiteye, Sam M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Rockville, MD 20852 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov RI Rowe, Martin/B-2880-2009; OI Rowe, Martin/0000-0003-4139-7326; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU NIH, National Cancer Institute, Center for Cancer Research, an NCI SPECS grant [UO1-CA 114778]; Foundation for NIH; Cancer Research UK; Lymphoma/Leukemia Molecular Profiling Project (LLMPP); Dr Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe); NCI [N01-C0-12400] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, an NCI SPECS grant (UO1-CA 114778), by the Foundation for NIH, through a gift from the Richard A. Lauderbaugh Memorial Fund, and by Cancer Research UK. This study was conducted under the auspices of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). R.S. was supported by the Dr Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe). D.J.H. is a Kay Kendall Leukaemia Fund Intermediate research fellow. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). We thank K. Meyer for help with the GEO submission, T. Ellenberger for the TCF3 crystal structure coordinates, B. Tran (Center for Cancer Research Sequencing Facility) and K. Hartman for DNA sequencing and K. Rajewsky for discussions. The DLBCL data set is part of the Cancer Genomics Characterization Initiative (CGCI), supported by NCI contract N01-C0-12400 (http://cgap.nci.nih.gov/cgci.html/) and was obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap. We thank the participants in the EMBLEM Study (http://emblem.cancer.gov/) in Uganda, the EMBLEM Study staff for collecting and processing the samples and data, and the Government of Uganda for allowing the study to be done and samples to be exported for research. NR 21 TC 257 Z9 260 U1 12 U2 54 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 4 PY 2012 VL 490 IS 7418 BP 116 EP 120 DI 10.1038/nature11378 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015LG UT WOS:000309446800044 PM 22885699 ER PT J AU Throckmorton, DC Compton, WM Lurie, P AF Throckmorton, Douglas C. Compton, Wilson M. Lurie, Peter TI Management of Opioid Analgesic Overdose SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Throckmorton, Douglas C.; Lurie, Peter] Food & Drug Adm, Silver Spring, MD USA. [Compton, Wilson M.] Natl Inst Drug Abuse, Bethesda, MD USA. RP Throckmorton, DC (reprint author), Food & Drug Adm, Silver Spring, MD USA. EM douglas.throckmorton@fda.hhs.gov NR 3 TC 2 Z9 2 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 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 4 PY 2012 VL 367 IS 14 BP 1371 EP 1371 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 014WJ UT WOS:000309406100032 PM 23034041 ER PT J AU Tewari, S Spouge, JL AF Tewari, Susanta Spouge, John L. TI Coalescent: an open-source and scalable framework for exact calculations in coalescent theory SO BMC BIOINFORMATICS LA English DT Article DE Population genetics; Object oriented design; Framework; Java; Netbeans platform; Coalescent; Recursion; Exact calculation ID SEQUENCES; SAMPLE AB Background: Currently, there is no open-source, cross-platform and scalable framework for coalescent analysis in population genetics. There is no scalable GUI based user application either. Such a framework and application would not only drive the creation of more complex and realistic models but also make them truly accessible. Results: As a first attempt, we built a framework and user application for the domain of exact calculations in coalescent analysis. The framework provides an API with the concepts of model, data, statistic, phylogeny, gene tree and recursion. Infinite-alleles and infinite-sites models are considered. It defines pluggable computations such as counting and listing all the ancestral configurations and genealogies and computing the exact probability of data. It can visualize a gene tree, trace and visualize the internals of the recursion algorithm for further improvement and attach dynamically a number of output processors. The user application defines jobs in a plug-in like manner so that they can be activated, deactivated, installed or uninstalled on demand. Multiple jobs can be run and their inputs edited. Job inputs are persisted across restarts and running jobs can be cancelled where applicable. Conclusions: Coalescent theory plays an increasingly important role in analysing molecular population genetic data. Models involved are mathematically difficult and computationally challenging. An open-source, scalable framework that lets users immediately take advantage of the progress made by others will enable exploration of yet more difficult and realistic models. As models become more complex and mathematically less tractable, the need for an integrated computational approach is obvious. Object oriented designs, though has upfront costs, are practical now and can provide such an integrated approach. C1 [Tewari, Susanta; Spouge, John L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Tewari, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM tewaris@ncbi.nlm.nih.gov FU National Institutes of Health (NIH); Intramural Research Program of the NIH, National Library of Medicine FX This research was funded in part by National Institutes of Health (NIH); Intramural Research Program of the NIH, National Library of Medicine. NR 13 TC 1 Z9 1 U1 0 U2 7 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 OCT 3 PY 2012 VL 13 AR 257 DI 10.1186/1471-2105-13-257 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 091JM UT WOS:000315045600001 PM 23033878 ER PT J AU Novoa-Aponte, L Leon-Torres, A Patino-Ruiz, M Cuesta-Bernal, J Salazar, LM Landsman, D Marino-Ramirez, L Soto, CY AF Novoa-Aponte, Lorena Leon-Torres, Andres Patino-Ruiz, Miyer Cuesta-Bernal, Jenifer Salazar, Luz-Mary Landsman, David Marino-Ramirez, Leonardo Soto, Carlos-Yesid TI In silico identification and characterization of the ion transport specificity for P-type ATPases in the Mycobacterium tuberculosis complex SO BMC STRUCTURAL BIOLOGY LA English DT Article DE Tuberculosis; Mycobacterium tuberculosis complex; P-type ATPases; Ion transport; Conserved motifs ID GENE-EXPRESSION; MECHANISM; SUPERFAMILY; MACROPHAGES; EVOLUTION; VIRULENCE; FEATURES; BIOLOGY; ROLES AB Background: P-type ATPases hydrolyze ATP and release energy that is used in the transport of ions against electrochemical gradients across plasma membranes, making these proteins essential for cell viability. Currently, the distribution and function of these ion transporters in mycobacteria are poorly understood. Results: In this study, probabilistic profiles were constructed based on hidden Markov models to identify and classify P-type ATPases in the Mycobacterium tuberculosis complex (MTBC) according to the type of ion transported across the plasma membrane. Topology, hydrophobicity profiles and conserved motifs were analyzed to correlate amino acid sequences of P-type ATPases and ion transport specificity. Twelve candidate P-type ATPases annotated in the M. tuberculosis H37Rv proteome were identified in all members of the MTBC, and probabilistic profiles classified them into one of the following three groups: heavy metal cation transporters, alkaline and alkaline earth metal cation transporters, and the beta subunit of a prokaryotic potassium pump. Interestingly, counterparts of the non-catalytic beta subunits of Hydrogen/Potassium and Sodium/Potassium P-type ATPases were not found. Conclusions: The high content of heavy metal transporters found in the MTBC suggests that they could play an important role in the ability of M. tuberculosis to survive inside macrophages, where tubercle bacilli face high levels of toxic metals. Finally, the results obtained in this work provide a starting point for experimental studies that may elucidate the ion specificity of the MTBC P-type ATPases and their role in mycobacterial infections. C1 [Novoa-Aponte, Lorena; Leon-Torres, Andres; Patino-Ruiz, Miyer; Cuesta-Bernal, Jenifer; Salazar, Luz-Mary; Soto, Carlos-Yesid] Univ Nacl Colombia, Fac Sci, Dept Chem, Bogota, Colombia. [Landsman, David; Marino-Ramirez, Leonardo] NCBI, Computat Biol Branch, NLM, NIH, Bethesda, MD USA. [Marino-Ramirez, Leonardo] PanAmer Bioinformat Inst, Santa Marta, Magdalena, Colombia. RP Marino-Ramirez, L (reprint author), NCBI, Computat Biol Branch, NLM, NIH, Bethesda, MD USA. EM marino@ncbi.nlm.nih.gov RI Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Leon Torres, Andres Felipe/0000-0002-5014-9706; Novoa-Aponte, Lorena/0000-0003-3348-8383; Soto Ospina, Carlos Yesid/0000-0001-8694-7489; Landsman, David/0000-0002-9819-6675 FU Direccion de Investigacion Bogota (DIB)-Universidad Nacional de Colombia [12351, 12176, 11875, 11882]; Colciencias [13802]; National Institutes of Health; National Library of Medicine; National Center for Biotechnology Information FX This work was supported by the Direccion de Investigacion Bogota (DIB)-Universidad Nacional de Colombia, grants 12351, 12176, 11875, 11882 and Colciencias grant 13802. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine and National Center for Biotechnology Information. NR 38 TC 7 Z9 7 U1 0 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6807 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD OCT 3 PY 2012 VL 12 AR 25 DI 10.1186/1472-6807-12-25 PG 12 WC Biophysics SC Biophysics GA 089OD UT WOS:000314919000001 PM 23031689 ER PT J AU Galon, J Pages, F Marincola, FM Angell, HK Thurin, M Lugli, A Zlobec, I Berger, A Bifulco, C Botti, G Tatangelo, F Britten, CM Kreiter, S Chouchane, L Delrio, P Arndt, H Asslaber, M Maio, M Masucci, GV Mihm, M Vidal-Vanaclocha, F Allison, JP Gnjatic, S Hakansson, L Huber, C Singh-Jasuja, H Ottensmeier, C Zwierzina, H Laghi, L Grizzi, F Ohashi, PS Shaw, PA Clarke, BA Wouters, BG Kawakami, Y Hazama, S Okuno, K Wang, E O'Donnell-Tormey, J Lagorce, C Pawelec, G Nishimura, MI Hawkins, R Lapointe, R Lundqvist, A Khleif, SN Ogino, S Gibbs, P Waring, P Sato, N Torigoe, T Itoh, K Patel, PS Shukla, SN Palmqvist, R Nagtegaal, ID Wang, YL D'Arrigo, C Kopetz, S Sinicrope, FA Trinchieri, G Gajewski, TF Ascierto, PA Fox, BA AF Galon, Jerome Pages, Franck Marincola, Francesco M. Angell, Helen K. Thurin, Magdalena Lugli, Alessandro Zlobec, Inti Berger, Anne Bifulco, Carlo Botti, Gerardo Tatangelo, Fabiana Britten, Cedrik M. Kreiter, Sebastian Chouchane, Lotfi Delrio, Paolo Arndt, Hartmann Asslaber, Martin Maio, Michele Masucci, Giuseppe V. Mihm, Martin Vidal-Vanaclocha, Fernando Allison, James P. Gnjatic, Sacha Hakansson, Leif Huber, Christoph Singh-Jasuja, Harpreet Ottensmeier, Christian Zwierzina, Heinz Laghi, Luigi Grizzi, Fabio Ohashi, Pamela S. Shaw, Patricia A. Clarke, Blaise A. Wouters, Bradly G. Kawakami, Yutaka Hazama, Shoichi Okuno, Kiyotaka Wang, Ena O'Donnell-Tormey, Jill Lagorce, Christine Pawelec, Graham Nishimura, Michael I. Hawkins, Robert Lapointe, Rejean Lundqvist, Andreas Khleif, Samir N. Ogino, Shuji Gibbs, Peter Waring, Paul Sato, Noriyuki Torigoe, Toshihiko Itoh, Kyogo Patel, Prabhu S. Shukla, Shilin N. Palmqvist, Richard Nagtegaal, Iris D. Wang, Yili D'Arrigo, Corrado Kopetz, Scott Sinicrope, Frank A. Trinchieri, Giorgio Gajewski, Thomas F. Ascierto, Paolo A. Fox, Bernard A. TI Cancer classification using the Immunoscore: a worldwide task force SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; T-CELL SUBSETS; COLORECTAL-CANCER; BREAST-CANCER; IMMUNE CELLS; MICROSATELLITE INSTABILITY; IMMUNOTHERAPY BIOMARKERS; TUMOR-MARKERS; MELANOMA; CHEMOTHERAPY AB Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the ` Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). C1 [Galon, Jerome; Pages, Franck; Angell, Helen K.] INSERM, U872, Lab Integrat Canc Immunol, F-75006 Paris, France. [Galon, Jerome; Pages, Franck; Angell, Helen K.] Univ Paris 05, Paris, France. [Galon, Jerome; Pages, Franck; Angell, Helen K.] Univ Paris 06, Ctr Rech Cordeliers, Paris, France. [Galon, Jerome; Pages, Franck; Berger, Anne] HEGP, AP HP, Paris, France. [Galon, Jerome; Marincola, Francesco M.; Gajewski, Thomas F.; Fox, Bernard A.] Soc Immunotherapy Canc, Milwaukee, WI USA. [Marincola, Francesco M.; Wang, Ena] NIH, IDIS, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.; Wang, Ena; Trinchieri, Giorgio] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Rockville, MD USA. [Lugli, Alessandro; Zlobec, Inti] Univ Bern, Inst Pathol, CH-3010 Bern, Switzerland. [Bifulco, Carlo] Providence Portland Med Ctr, Dept Pathol, Portland, OR USA. [Botti, Gerardo; Tatangelo, Fabiana] Ist Nazl Studio & Cura Tumori Fdn G Pascale, Dept Pathol, Naples, Italy. [Britten, Cedrik M.; Kreiter, Sebastian; Huber, Christoph] Johannes Gutenberg Univ Mainz, TRON Translat Oncol, Univ Med Ctr, D-55122 Mainz, Germany. [Chouchane, Lotfi] Weill Cornell Med Coll, Doha, Qatar. [Delrio, Paolo] Ist Nazl Studio & Cura Tumori Fdn G Pascale, Colorectal Surg Dept, Naples, Italy. [Arndt, Hartmann] Univ Erlangen Nurnberg, Dept Pathol, D-91054 Erlangen, Germany. [Asslaber, Martin] Med Univ Graz, Inst Pathol, Graz, Austria. [Maio, Michele] Univ Hosp Siena, Div Med Oncol & Immunotherapy, Ist Toscano Tumori, Siena, Italy. [Masucci, Giuseppe V.] Karolinska Univ, Dept Oncol Pathol, Karolinska Inst, Stockholm, Sweden. [Mihm, Martin; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mihm, Martin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vidal-Vanaclocha, Fernando] CEU San Pablo Univ, Sch Med, Madrid, Spain. [Vidal-Vanaclocha, Fernando] HM Hosp Madrid Sci Fdn, Inst Appl Mol Med, Madrid, Spain. [Allison, James P.; Gnjatic, Sacha] Mem Sloan Kettering Canc Ctr, Ludwig Inst Canc Res, New York, NY 10021 USA. [Hakansson, Leif] Lund Univ, Lund, Sweden. [Singh-Jasuja, Harpreet] Immat Biotechnol GmbH, Tubingen, Germany. [Ottensmeier, Christian] Univ Southampton, Fac Med, Expt Canc Med Ctr, Southampton SO9 5NH, Hants, England. [Zwierzina, Heinz] Med Univ Innsbruck, Dept Haematol & Oncol, A-6020 Innsbruck, Austria. [Laghi, Luigi; Grizzi, Fabio] Humanitas Clin & Res Ctr, Milan, Italy. [Laghi, Luigi; Grizzi, Fabio] Humanitas Clin & Res Ctr, Dept Gastroenterol, Milan, Italy. [Ohashi, Pamela S.] Univ Hlth Network, Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON, Canada. [Ohashi, Pamela S.] Univ Hlth Network, Princess Margaret Hosp, Campbell Family Inst Canc Res, Toronto, ON, Canada. [Shaw, Patricia A.; Clarke, Blaise A.; Wouters, Bradly G.] Princess Margaret Canc Ctr, Ontario Canc Inst, Dept Lab Med, Toronto, ON, Canada. [Shaw, Patricia A.; Clarke, Blaise A.; Wouters, Bradly G.] Princess Margaret Canc Ctr, Ontario Canc Inst, Dept Pathobiol, Toronto, ON, Canada. [Shaw, Patricia A.; Clarke, Blaise A.; Wouters, Bradly G.] Princess Margaret Canc Ctr, Ontario Canc Inst, Dept Radiat Oncol, Toronto, ON, Canada. [Kawakami, Yutaka] Keio Univ, Sch Med, Div Cellular Signaling, Inst Adv Med Res, Tokyo, Japan. [Hazama, Shoichi] Yamaguchi Univ, Dept Digest Surg & Surg Oncol, Grad Sch Med, Yamaguchi, Japan. [Okuno, Kiyotaka] Kinki Univ, Sch Med, Dept Surg, Osaka 589, Japan. [O'Donnell-Tormey, Jill] Inst Canc Res, New York, NY USA. [Lagorce, Christine] Avicenne Hosp, AP HP, Dept Pathol, Bobigny, France. [Pawelec, Graham] Univ Tubingen, Med Res Ctr, Tubingen, Germany. [Nishimura, Michael I.] Loyola Univ, Med Ctr, Inst Oncol, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. [Hawkins, Robert] Univ Manchester, Sch Canc & Imaging Sci, Christie Hosp NHS Trust, Manchester, Lancs, England. [Lapointe, Rejean] Univ Montreal CRCHUM, Res Ctr, Univ Hosp, Montreal, PQ, Canada. [Lapointe, Rejean] Inst Canc Montreal, Montreal, PQ, Canada. [Lundqvist, Andreas] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Khleif, Samir N.] Georgia Hlth Sci Univ Canc Ctr, Augusta, GA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gibbs, Peter] Royal Melbourne Hosp, Dept Med Oncol, Melbourne, Vic, Australia. [Waring, Paul] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Sato, Noriyuki; Torigoe, Toshihiko] Sapporo Med Univ, Dept Pathol, Sch Med, Sapporo, Hokkaido, Japan. [Itoh, Kyogo] Kurume Univ, Sch Med, Dept Immunol & Immunotherapy, Kurume, Fukuoka 830, Japan. [Patel, Prabhu S.; Shukla, Shilin N.] Gujarat Canc Res Inst, Ahmadabad, Gujarat, India. [Palmqvist, Richard] Umea Univ, Dept Med Biosci, Umea, Sweden. [Nagtegaal, Iris D.] Radboud Univ Nijmegen, Dept Pathol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Wang, Yili] Xi An Jiao Tong Univ, Inst Canc Res, Ctr Translat Med, Xian 710049, Peoples R China. [D'Arrigo, Corrado] NHS, Dept Histopathol, Dorset Cty Hosp, DCHFT, Dorchester, England. [Kopetz, Scott] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Sinicrope, Frank A.] Mayo Clin, Rochester, MN 55905 USA. [Sinicrope, Frank A.] Mayo Coll Med, Rochester, MN 55905 USA. [Trinchieri, Giorgio] NCI, Canc Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Trinchieri, Giorgio] NIH, Trans NIH Ctr Human Immunol CHI, Frederick, MD USA. [Trinchieri, Giorgio] NCI, Canc Inflammat Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gajewski, Thomas F.] Univ Chicago, Chicago, IL 60637 USA. [Ascierto, Paolo A.] Ist Nazl Studio & Cura Tumori Fdn G Pascale, Med Oncol & Innovat Therapies Unit, Naples, Italy. [Ascierto, Paolo A.] Fdn Melanoma Onlus, Naples, Italy. [Fox, Bernard A.] Providence Portland Med Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Ctr, Lab Mol & Tumor Immunol, Portland, OR USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. RP Galon, J (reprint author), INSERM, U872, Lab Integrat Canc Immunol, F-75006 Paris, France. EM jerome.galon@crc.jussieu.fr RI Nagtegaal, Iris/A-2448-2014; Kawakami, Yutaka /E-7429-2013; Ottensmeier, Christian/E-8131-2012; OI Nagtegaal, Iris/0000-0003-0887-4127; Wouters, Bradly/0000-0002-8187-592X; Gibbs, Peter/0000-0003-1423-4484; Kawakami, Yutaka /0000-0003-4836-2855; Ottensmeier, Christian/0000-0003-3619-1657; Masucci, Giuseppe/0000-0002-9583-2306; Kopetz, Scott/0000-0001-9647-3416; coral, sandra/0000-0002-1308-3082; Pawelec, Graham/0000-0002-3600-0163; Lundqvist, Andreas/0000-0002-9709-2970 FU NCI NIH HHS [K05 CA142885] NR 39 TC 190 Z9 193 U1 13 U2 106 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 3 PY 2012 VL 10 AR 205 DI 10.1186/1479-5876-10-205 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 092FN UT WOS:000315104900001 PM 23034130 ER PT J AU Vukoti, K Kimura, T Macke, L Gawrisch, K Yeliseev, A AF Vukoti, Krishna Kimura, Tomohiro Macke, Laura Gawrisch, Klaus Yeliseev, Alexei TI Stabilization of Functional Recombinant Cannabinoid Receptor CB2 in Detergent Micelles and Lipid Bilayers SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED-RECEPTORS; ADENOSINE A(2A) RECEPTOR; ESCHERICHIA-COLI; LIGAND STABILIZATION; CRYSTAL-STRUCTURE; PICHIA-PASTORIS; DRUG DISCOVERY; EXPRESSION; PURIFICATION; ACTIVATION AB Elucidation of the molecular mechanisms of activation of G protein-coupled receptors (GPCRs) is among the most challenging tasks for modern membrane biology. For studies by high resolution analytical methods, these integral membrane receptors have to be expressed in large quantities, solubilized from cell membranes and purified in detergent micelles, which may result in a severe destabilization and a loss of function. Here, we report insights into differential effects of detergents, lipids and cannabinoid ligands on stability of the recombinant cannabinoid receptor CB2, and provide guidelines for preparation and handling of the fully functional receptor suitable for a wide array of downstream applications. While we previously described the expression in Escherichia coli, purification and liposome-reconstitution of multi-milligram quantities of CB2, here we report an efficient stabilization of the recombinant receptor in micelles - crucial for functional and structural characterization. The effects of detergents, lipids and specific ligands on structural stability of CB2 were assessed by studying activation of G proteins by the purified receptor reconstituted into liposomes. Functional structure of the ligand binding pocket of the receptor was confirmed by binding of H-2-labeled ligand measured by solid-state NMR. We demonstrate that a concerted action of an anionic cholesterol derivative, cholesteryl hemisuccinate (CHS) and high affinity cannabinoid ligands CP-55,940 or SR-144,528 are required for efficient stabilization of the functional fold of CB2 in dodecyl maltoside (DDM)/CHAPS detergent solutions. Similar to CHS, the negatively charged phospholipids with the serine headgroup (PS) exerted significant stabilizing effects in micelles while uncharged phospholipids were not effective. The purified CB2 reconstituted into lipid bilayers retained functionality for up to several weeks enabling high resolution structural studies of this GPCR at physiologically relevant conditions. C1 [Vukoti, Krishna; Kimura, Tomohiro; Macke, Laura; Gawrisch, Klaus; Yeliseev, Alexei] NIAAA, NIH, Bethesda, MD USA. RP Yeliseev, A (reprint author), NIAAA, NIH, Bethesda, MD USA. EM yeliseeva@mail.nih.gov FU intramural research program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH) FX This study was supported by the intramural research program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), to KG. KG participated in study design, data collection and analysis, decision to publish, and preparation of the manuscript. NR 48 TC 15 Z9 15 U1 1 U2 34 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 OCT 3 PY 2012 VL 7 IS 10 AR e46290 DI 10.1371/journal.pone.0046290 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015NU UT WOS:000309454000030 PM 23056277 ER PT J AU Janssen, MJ Leiva-Salcedo, E Buonanno, A AF Janssen, Megan J. Leiva-Salcedo, Elias Buonanno, Andres TI Neuregulin Directly Decreases Voltage-Gated Sodium Current in Hippocampal ErbB4-Expressing Interneurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; GAMMA OSCILLATIONS; PYRAMIDAL CELLS; MOUSE MODEL; NEURONS; SCHIZOPHRENIA; CHANNELS; ERBB4; SPIKING AB The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term potentiation at CA1 pyramidal neuron synapses in slices are mediated indirectly by dopamine. Here we studied whether NRG/ErbB signaling directly regulates interneuron intrinsic excitability by pharmacologically isolating ErbB4-expressing neurons in rat dissociated hippocampal cultures, which lack dopaminergic innervation. We found that NRG1 acutely attenuates ErbB4-expressing interneuron excitability by depolarizing the firing threshold; neurons treated with the pan-ErbB inhibitor PD158780 or negative for ErbB4 were unaffected. These effects of NRG1 are primarily attributable to decreased voltage-gated sodium channel activity, as current density was attenuated by similar to 60%. In stark contrast, NRG1 had minor effects on whole-cell potassium currents. Our data reveal the direct actions of NRG1 signaling in ErbB4-expressing interneurons, and offer novel insight into how NRG1/ErbB4 signaling can impact hippocampal activity. C1 [Buonanno, Andres] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Buonanno, A (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, Program Dev Neurosci, NIH, Bldg 35,Room 2C-1000,35 Lincoln Dr, Bethesda, MD 20892 USA. EM buonanno@mail.nih.gov FU NICHD FX M.J., E.L.-S., and A. B. were supported by the NICHD intramural research program. We thank Dr. Irina Karavanov for hippocampal cultures, and Drs. Stefano Vicini and Detlef Vullhorst for critical reading of the manuscript. NR 38 TC 10 Z9 10 U1 1 U2 12 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 OCT 3 PY 2012 VL 32 IS 40 BP 13889 EP 13895 DI 10.1523/JNEUROSCI.1420-12.2012 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 016GU UT WOS:000309506600023 PM 23035098 ER PT J AU Gahl, WA AF Gahl, William A. TI The Battlefield of Rare Diseases: Where Uncommon Insights Are Common SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Gahl, William A.] NIH, Human Genome Res Inst, Bethesda, MD 20892 USA. [Gahl, William A.] NIH, Undiag Dis Program, Bethesda, MD 20892 USA. RP Gahl, WA (reprint author), NIH, Human Genome Res Inst, Bethesda, MD 20892 USA. EM gahlw@helix.nih.gov FU Intramural NIH HHS [ZIA HG000215-10] NR 5 TC 3 Z9 3 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 3 PY 2012 VL 4 IS 154 AR 154ed7 DI 10.1126/scitranslmed.3004980 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 016NZ UT WOS:000309527300001 PM 23035044 ER PT J AU Kino, T AF Kino, Tomoshige TI Circadian Rhythms of Glucocorticoid Hormone Actions in Target Tissues: Potential Clinical Implications SO SCIENCE SIGNALING LA English DT Article ID STRESS SYSTEM; HISTONE ACETYLTRANSFERASE; PERIPHERAL CLOCK; RECEPTOR; DISORDERS; EXPRESSION; DEPRESSION; MECHANISM; DISEASES; COMPLEX AB Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations-including obesity, metabolic syndrome, and cardiovascular disease-by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov FU Intramural Research Program of NICHD, NIH; Athens University Medical School FX The studies presented were funded by the Intramural Research Program of NICHD, NIH, and the Athens University Medical School. NR 34 TC 12 Z9 13 U1 2 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD OCT 2 PY 2012 VL 5 IS 244 AR pt4 DI 10.1126/scisignal.2003333 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 022JI UT WOS:000309954100006 PM 23033538 ER PT J AU Kawut, SM Barr, RG Lima, JAC Praestgaard, A Johnson, WC Chahal, H Ogunyankin, KO Bristow, MR Kizer, JR Tandri, H Bluemke, DA AF Kawut, Steven M. Barr, R. Graham Lima, Joao A. C. Praestgaard, Amy Johnson, W. Craig Chahal, Harjit Ogunyankin, Kofo O. Bristow, Michael R. Kizer, Jorge R. Tandri, Harikrishna Bluemke, David A. TI Right Ventricular Structure Is Associated With the Risk of Heart Failure and Cardiovascular Death The Multi-Ethnic Study of Atherosclerosis (MESA)-Right Ventricle Study SO CIRCULATION LA English DT Article DE heart ventricles; hypertension, pulmonary; magnetic resonance imaging; pulmonary heart disease; survival ID PULMONARY ARTERIAL-HYPERTENSION; PROGNOSTIC VALUE; REFERENCE VALUES; SURVIVAL; DISEASE; MASS; SEX; VOLUMES; LUNG AB Background-Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline. Methods and Results-The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death ("death") until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4 +/- 10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55-4.10; P<0.001) and a doubling (or more) of risk with left ventricular mass at the mean value or lower (P for interaction=0.05). Conclusions-RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline. (Circulation. 2012;126:1681-1688.) C1 [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Kawut, Steven M.; Praestgaard, Amy] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.; Praestgaard, Amy] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Barr, R. Graham] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Lima, Joao A. C.; Chahal, Harjit; Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Johnson, W. Craig] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Ogunyankin, Kofo O.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Bristow, Michael R.] Univ Colorado, Dept Med, Denver, CO USA. [Kizer, Jorge R.] Weill Cornell Med Ctr, Dept Med, New York, NY USA. [Kizer, Jorge R.] Weill Cornell Med Ctr, Dept Publ Hlth, New York, NY USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. RP Kawut, SM (reprint author), 718 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kawut@upenn.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [R01-HL086719, R01-HL077612, K24-HL103844, N01-HC95159, N01-HC95160, N01-HC95161, N01-HC95162, N01-HC95163, N01-HC95164, N01-HC95165, N01-HC95166, N01-HC95167, N01-HC95168, N01-HC95169] FX This study was funded by National Institutes of Health R01-HL086719, R01-HL077612, K24-HL103844, and N01-HC95159 through N01-HC95169. NR 27 TC 62 Z9 64 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 2 PY 2012 VL 126 IS 14 BP 1681 EP + DI 10.1161/CIRCULATIONAHA.112.095216 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 016OM UT WOS:000309528600006 PM 22932258 ER PT J AU Ho, JE Liu, CY Lyass, A Courchesne, P Pencina, MJ Vasan, RS Larson, MG Levy, D AF Ho, Jennifer E. Liu, Chunyu Lyass, Asya Courchesne, Paul Pencina, Michael J. Vasan, Ramachandran S. Larson, Martin G. Levy, Daniel TI Galectin-3, a Marker of Cardiac Fibrosis, Predicts Incident Heart Failure in the Community SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE biomarker; epidemiology; heart failure; prognosis ID LEFT-VENTRICULAR HYPERTROPHY; SYSTOLIC DYSFUNCTION; NATRIURETIC PEPTIDE; SERUM GALECTIN-3; FRAMINGHAM; MORTALITY; SURVIVAL; MACROPHAGES; POPULATION; EXPRESSION AB Objectives The aim of this study was to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community. Background Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown. Methods Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years; 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression. Results Gal-3 was associated with increased left ventricular mass in age-adjusted and sex-adjusted analyses (p = 0.001); this association was attenuated in multivariate analyses (p = 0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up period of 11.2 years. Gal-3 was associated with risk for incident HF (hazard ratio [HR]: 1.28 per 1 SD increase in log Gal-3; 95% confidence interval [CI]: 1.14 to 1.43; p < 0.0001) and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR: 1.23; 95% CI: 1.04 to 1.47; p = 0.02). Gal-3 was also associated with risk for all-cause mortality (multivariable-adjusted HR: 1.15; 95% CI: 1.04 to 1.28; p = 0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the C-statistic and minor improvements in net reclassification improvement. Conclusions Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk for incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF. (J Am Coll Cardiol 2012;60:1249-56) (C) 2012 by the American College of Cardiology Foundation C1 [Ho, Jennifer E.; Liu, Chunyu; Lyass, Asya; Courchesne, Paul; Pencina, Michael J.; Vasan, Ramachandran S.; Larson, Martin G.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Ho, Jennifer E.; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Ho, Jennifer E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Lyass, Asya; Pencina, Michael J.; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association Clinical Research Program award FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Drs. Ho and Levy, contract N01-HC-25195). Dr. Ho is supported by an American Heart Association Clinical Research Program award. Galectin-3 assays were provided by BG Medicine (Waltham, Massachusetts). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 41 TC 165 Z9 172 U1 4 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 2 PY 2012 VL 60 IS 14 BP 1249 EP 1256 DI 10.1016/j.jacc.2012.04.053 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 016HM UT WOS:000309508400007 PM 22939561 ER PT J AU Blees, JS Bokesch, HR Rubsamen, D Schulz, K Milke, L Bajer, MM Gustafson, KR Henrich, CJ McMahon, JB Colburn, NH Schmid, T Brune, B AF Blees, Johanna S. Bokesch, Heidi R. Ruebsamen, Daniela Schulz, Kathrin Milke, Larissa Bajer, Magdalena M. Gustafson, Kirk R. Henrich, Curtis J. McMahon, James B. Colburn, Nancy H. Schmid, Tobias Bruene, Bernhard TI Erioflorin Stabilizes the Tumor Suppressor Pdcd4 by Inhibiting Its Interaction with the E3-ligase beta-TrCP1 SO PLOS ONE LA English DT Article ID NF-KAPPA-B; E3 UBIQUITIN LIGASE; BETA-TRCP; TRANSFORMATION SUPPRESSOR; SESQUITERPENE LACTONES; AP-1 TRANSACTIVATION; COLORECTAL-CANCER; EXPRESSION; PROTEIN; TRANSLATION AB Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70(S6K1)-dependent protein phosphorylation, beta-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase beta-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional beta-TrCP-targets (such as I kappa B alpha and beta-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1 alpha (a pVHL-target), implying selectivity for beta-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and I kappa B alpha-regulated alpha transcription factors, that is, AP-1 and NF-kappa B, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase beta-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition. C1 [Blees, Johanna S.; Ruebsamen, Daniela; Schulz, Kathrin; Milke, Larissa; Bajer, Magdalena M.; Schmid, Tobias; Bruene, Bernhard] Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, Frankfurt, Germany. [Bokesch, Heidi R.; Gustafson, Kirk R.; Henrich, Curtis J.; McMahon, James B.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Bokesch, Heidi R.; Henrich, Curtis J.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. RP Schmid, T (reprint author), Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, Frankfurt, Germany. EM T.Schmid@biochem.uni-frankfurt.de FU DFG [BR999, GRK1172]; LOEWE Schwerpunkt OSF [III L 4-518/55.004]; Hessian Ministry of Higher Education, Research and Arts; Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; NIH, Frederick National Laboratory for Cancer Research, National Cancer Institute, Center for Cancer Research; U.S. Government FX This work was supported by the DFG (BR999 and GRK1172) and the LOEWE Schwerpunkt OSF (III L 4-518/55.004 (2009)) funded by the Hessian Ministry of Higher Education, Research and Arts. This project was funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This research was also supported in part by the Intramural Research Program of NIH, Frederick National Laboratory for Cancer Research, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Two of the authors (HRB, CJH) are employed by SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, which is a U.S. Government contractor, thus funding comes from the U.S. Government. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 50 TC 16 Z9 17 U1 1 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 OCT 2 PY 2012 VL 7 IS 10 AR e46567 DI 10.1371/journal.pone.0046567 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015NG UT WOS:000309452600042 PM 23056346 ER PT J AU Covell, DG AF Covell, David G. TI Integrating Constitutive Gene Expression and Chemoactivity: Mining the NCI60 Anticancer Screen SO PLOS ONE LA English DT Article ID CYCLIN-DEPENDENT KINASES; CANCER-CELL LINES; OXIDATIVE STRESS; CONNECTIVITY MAP; DRUG DEVELOPMENT; SMALL MOLECULES; NORMAL-TISSUES; TUMOR; CAMPTOTHECIN; MECHANISM AB Studies into the genetic origins of tumor cell chemoactivity pose significant challenges to bioinformatic mining efforts. Connections between measures of gene expression and chemoactivity have the potential to identify clinical biomarkers of compound response, cellular pathways important to efficacy and potential toxicities; all vital to anticancer drug development. An investigation has been conducted that jointly explores tumor-cell constitutive NCI60 gene expression profiles and small-molecule NCI60 growth inhibition chemoactivity profiles, viewed from novel applications of self-organizing maps (SOMs) and pathway-centric analyses of gene expressions, to identify subsets of over- and under-expressed pathway genes that discriminate chemo-sensitive and chemo-insensitive tumor cell types. Linear Discriminant Analysis (LDA) is used to quantify the accuracy of discriminating genes to predict tumor cell chemoactivity. LDA results find 15% higher prediction accuracies, using similar to 30% fewer genes, for pathway-derived discriminating genes when compared to genes derived using conventional gene expression-chemoactivity correlations. The proposed pathway-centric data mining procedure was used to derive discriminating genes for ten well-known compounds. Discriminating genes were further evaluated using gene set enrichment analysis (GSEA) to reveal a cellular genetic landscape, comprised of small numbers of key over and under expressed on- and off-target pathway genes, as important for a compound's tumor cell chemoactivity. Literature-based validations are provided as support for chemo-important pathways derived from this procedure. Qualitatively similar results are found when using gene expression measurements derived from different microarray platforms. The data used in this analysis is available at http://pubchem.ncbi.nlm.nih.gov/ and http://www.ncbi.nlm.nih.gov/projects/geo (GPL96, GSE32474). C1 NIH, Dev Therapeut Program, Frederick Natl Lab, Frederick, MD USA. RP Covell, DG (reprint author), NIH, Dev Therapeut Program, Frederick Natl Lab, Frederick, MD USA. EM covelld@mail.nih.gov NR 78 TC 6 Z9 6 U1 0 U2 4 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 OCT 2 PY 2012 VL 7 IS 10 AR e44631 DI 10.1371/journal.pone.0044631 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 015NG UT WOS:000309452600006 PM 23056181 ER PT J AU Wood, LV AF Wood, Lauren V. TI Why I Voted "No" to Truvada PrEP SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID POPULATION PHARMACOKINETICS; HIV-INFECTION; TENOFOVIR C1 NCI, Bethesda, MD 20892 USA. RP Wood, LV (reprint author), NCI, Bldg 10,Room 6B04,10 Ctr Dr,MSC 1578, Bethesda, MD 20892 USA. EM woodl@mail.nih.gov NR 10 TC 6 Z9 6 U1 1 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 2 PY 2012 VL 157 IS 7 BP 519 EP 521 DI 10.7326/0003-4819-157-7-201210020-00511 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 016MQ UT WOS:000309523200007 PM 22821402 ER PT J AU Seol, Y Zhang, HL Pommier, Y Neuman, KC AF Seol, Yeonee Zhang, Hongliang Pommier, Yves Neuman, Keir C. TI A kinetic clutch governs religation by type IB topoisomerases and determines camptothecin sensitivity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer therapy; magnetic tweezers; single-molecule biophysics ID SINGLE-MOLECULE MEASUREMENTS; DNA SUPERCOIL RELAXATION; MAGNETIC TWEEZERS; LINKER DOMAIN; MECHANISM; INHIBITION; DYNAMICS; ROTATION; STRAND; PERSPECTIVE AB Type IB topoisomerases (Top1Bs) relax excessive DNA supercoiling associated with replication and transcription by catalyzing a transient nick in one strand to permit controlled rotation of the DNA about the intact strand. The natural compound camptothecin (CPT) and the cancer chemotherapeutics derived from it, irinotecan and topotecan, are highly specific inhibitors of human nuclear Top1B (nTop1). Previous work on vaccinia Top1B led to an elegant model that describes a straightforward dependence of rotation and religation on the torque caused by supercoiling. Here, we used a single-molecule DNA supercoil relaxation assay to measure the torque dependence of nTop1 and its inhibition by CPT. For comparison, we also examined mitochondrial Top1B and an N-terminal deletion mutant of nTop1. Despite substantial sequence homology in their core domains, nTop1 and mitochondrial Top1B exhibit dramatic differences in sensitivity to torque and CPT, with the N-terminal deletion mutant of nTop1 showing intermediate characteristics. In particular, nTop1 displays nearly torque-independent religation probability, distinguishing it from other Top1B enzymes studied to date. Kinetic modeling reveals a hitherto unobserved torque-independent transition linking the DNA rotation and religation phases of the enzymatic cycle. The parameters of this transition determine the torque sensitivity of religation and the efficiency of CPT binding. This "kinetic clutch" mechanism explains the molecular basis of CPT sensitivity and more generally provides a framework with which to interpret Top1B activity and inhibition. C1 [Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Seol, Yeonee; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov; neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Heart, Lung, and Blood Institute; National Cancer Institute, Center for Cancer Research, National Institutes of Health FX We thank Dr. Jon Silver, David Levens, and Laura Baranello for suggestions and advice and Hemai Parthasarathy, Tamara Litwin, and Dr. Richard Neuman for editing. This research was supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Center for Cancer Research, National Institutes of Health. NR 41 TC 21 Z9 21 U1 2 U2 11 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 OCT 2 PY 2012 VL 109 IS 40 BP 16125 EP 16130 DI 10.1073/pnas.1206480109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017SN UT WOS:000309611400041 PM 22991469 ER PT J AU Benson, MJ Aijo, T Chang, X Gagnon, J Pape, UJ Anantharaman, V Aravind, L Pursiheimo, JP Oberdoerffer, S Liu, XS Lahesmaa, R Lahdesmaki, H Rao, A AF Benson, Micah J. Aijo, Tarmo Chang, Xing Gagnon, John Pape, Utz J. Anantharaman, Vivek Aravind, L. Pursiheimo, Juha-Pekka Oberdoerffer, Shalini Liu, X. Shirley Lahesmaa, Riitta Lahdesmaki, Harri Rao, Anjana TI Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunoglobulin; mRNA splicing; transcriptional elongation; B cell maturation antigen ID B-CELL; POLY(A) SITE; MU-CHAIN; 3 ENDS; IMMUNOGLOBULIN; POLYADENYLATION; MEMBRANE; EXPRESSION; SEQUENCE; GENE AB B cells and plasma cells possess distinct RNA processing environments that respectively promote the expression of membrane-associated Ig by B cells versus the secretion of Ig by plasma cells. Through a combination of transcriptional profiling and screening using a lentiviral short-hairpin RNA interference library, we show that both the splicing factor hnRNPLL and the transcription elongation factor ELL2 modulate the ratio of secreted versus membrane-encoding Ighg2b transcripts in MPC11 plasmacytoma cell lines. hnRNPLL and ELL2 are both highly expressed in primary plasma cells relative to B cells, but hnRNPLL binds Ighg2b mRNA transcripts and promotes an increase in levels of the membrane-encoding Ighg2b isoform at the expense of the secreted Ighg2b isoform, whereas ELL2 counteracts this effect and drives Ig secretion by increasing the frequency of the secreted Ighg2b isoform. As in T cells, hnRNPLL also alters the splicing pattern of mRNA encoding the adhesion receptor CD44, promoting exon inclusion, and decreasing the overall level of CD44 expression. Further characterization of ELL2-dependent transcription by RNA-Seq revealed that similar to 12% of transcripts expressed by plasma cells were differentially processed because of the activities of ELL2, including B-cell maturation antigen BCMA, a receptor with a defined role in plasma cell survival. Taken together, our data identify hnRNPLL and ELL2 as regulators of pre-mRNA processing in plasma cells. C1 [Benson, Micah J.; Gagnon, John; Pape, Utz J.; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Benson, Micah J.; Gagnon, John; Pape, Utz J.; Rao, Anjana] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Benson, Micah J.; Gagnon, John; Pape, Utz J.; Rao, Anjana] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Aijo, Tarmo; Lahdesmaki, Harri] Aalto Univ, Sch Sci, Dept Informat & Comp Sci, FI-00076 Aalto, Finland. [Chang, Xing; Rao, Anjana] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. [Pape, Utz J.; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Pape, Utz J.; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Anantharaman, Vivek; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Pursiheimo, Juha-Pekka; Lahesmaa, Riitta; Lahdesmaki, Harri] Univ Turku, Turku Ctr Biotechnol, FI-20520 Turku, Finland. [Pursiheimo, Juha-Pekka; Lahesmaa, Riitta; Lahdesmaki, Harri] Abo Akad Univ, FI-20520 Turku, Finland. [Oberdoerffer, Shalini] NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Rao, Anjana] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92037 USA. [Rao, Anjana] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM arao@liai.org OI Gagnon, John/0000-0001-6208-5781; Anantharaman, Vivek/0000-0001-8395-0009; , chang xing/0000-0002-5072-9225 FU National Institutes of Health Grants [AI080875, AI40127, CA42471, HG4069]; Academy of Finland Grant [126063]; Centre of Excellence in Molecular Systems Immunology and Physiology Research [250114]; European Commission Seventh Framework Grant [EC-FP7-SYBILLA-201106]; Juvenile Diabetes Research Foundation; Sigrid Juselius Foundation; Biocenter Finland; Cancer Research Institute and Leukemia Lymphoma Society FX We thank the Finnish Microarray and Sequencing Center for the analysis of the samples. This study was supported in part by National Institutes of Health Grants AI080875, AI40127, and CA42471 (to A.R.), and HG4069 (to X.S.L); Academy of Finland Grant 126063 (to R.L.) and Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, Decision No. 250114 (to R.L. and H.L.); European Commission Seventh Framework Grant EC-FP7-SYBILLA-201106 (to R.L., TA, and H.L.); the Juvenile Diabetes Research Foundation (R.L.); the Sigrid Juselius Foundation (R.L., H.L., and A.R.); Biocenter Finland (R.L.); and postdoctoral fellowships from the Cancer Research Institute and Leukemia Lymphoma Society (to M.J.B.). NR 28 TC 13 Z9 13 U1 1 U2 7 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 OCT 2 PY 2012 VL 109 IS 40 BP 16252 EP 16257 DI 10.1073/pnas.1214414109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017SN UT WOS:000309611400063 PM 22991471 ER PT J AU Qiao, Y Zhu, LQ Sofi, H Lapinski, PE Horai, R Mueller, K Stritesky, GL He, X Teh, HS Wiest, DL Kappes, DJ King, PD Hogquist, KA Schwartzberg, PL Sant'Angelo, DB Chang, CH AF Qiao, Yu Zhu, Lingqiao Sofi, Hanief Lapinski, Philip E. Horai, Reiko Mueller, Kristen Stritesky, Gretta L. He, Xi Teh, Hung-Sia Wiest, David L. Kappes, Dietmar J. King, Philip D. Hogquist, Kristin A. Schwartzberg, Pamela L. Sant'Angelo, Derek B. Chang, Cheong-Hee TI Development of promyelocytic leukemia zinc finger-expressing innate CD4 T cells requires stronger T-cell receptor signals than conventional CD4 T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID THYMOCYTE-THYMOCYTE INTERACTION; TEC FAMILY KINASES; POSITIVE SELECTION; NEGATIVE SELECTION; LINEAGE COMMITMENT; ITK; MATURATION; DIFFERENTIATION; SURVIVAL; RASGRP1 AB MHC class II-expressing thymocytes and thymic epithelial cells can mediate CD4 T-cell selection resulting in functionally distinct thymocyte-selected CD4 (T-CD4) and epithelial-selected CD4 (E-CD4) T cells, respectively. However, little is known about how T-cell receptor (TCR) signaling influences the development of these two CD4 T-cell subsets. To study TCR signaling for T-CD4 T-cell development, we used a GFP reporter system of Nur77 in which GFP intensity directly correlates with TCR signaling strength. T-CD4 T cells expressed higher levels of GFP than E-CD4 T cells, suggesting that T-CD4 T cells received stronger TCR signaling than E-CD4 T cells during selection. Elimination of Ras GTPase-activating protein enhanced E-CD4 but decreased T-CD4 T-cell selection efficiency, suggesting a shift to negative selection. Conversely, the absence of IL-2-inducible T-cell kinase that causes poor E-CD4 T-cell selection due to insufficient TCR signaling improved T-CD4 T-cell generation, consistent with rescue from negative selection. Strong TCR signaling during T-CD4 T-cell development correlates with the expression of the transcription factor promyelocytic leukemia zinc finger protein. However, although modulation of the signaling strength affected the efficiency of T-CD4 T-cell development during positive and negative selection, the signaling strength is not as important for the effector function of T-CD4 T cells. These findings indicate that innate T-CD4 T cells, together with invariant natural killer T cells and gamma delta T cells, receive strong TCR signals during their development and that signaling requirements for the development and the effector functions are distinct. C1 [Qiao, Yu; Zhu, Lingqiao; Sofi, Hanief; Lapinski, Philip E.; King, Philip D.; Chang, Cheong-Hee] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Horai, Reiko; Mueller, Kristen; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Stritesky, Gretta L.; Hogquist, Kristin A.] Univ Minnesota, Dept Lab Med & Pathol, Ctr Immunol, Minneapolis, MN 55414 USA. [He, Xi; Wiest, David L.; Kappes, Dietmar J.] Fox Chase Canc Ctr, Inst Canc Res, Immune Cell Dev & Host Def Program, Philadelphia, PA 19111 USA. [Teh, Hung-Sia] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada. [Sant'Angelo, Derek B.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Child Hlth Inst New Jersey, New Brunswick, NJ 08901 USA. RP Chang, CH (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. EM heechang@umich.edu RI King, Phil/C-7104-2013; OI Wiest, David/0000-0002-0792-3188; Hogquist, Kristin/0000-0001-9963-5687 FU National Institutes of Health (NIH) Grants [T32 CA009138, CA153260, HL096498, AI083988, AI059739]; Robert Wood Johnson Foundation Grant [67038, AI073677]; National Human Genome Research Institute FX We thank Dr. Terry Geiger for critical reading of the manuscript. This research was supported in part by National Institutes of Health (NIH) Grants T32 CA009138 (to G.L.S.), CA153260 (to D.J.K.); HL096498 (to P.D.K); AI083988 and AI059739 and Robert Wood Johnson Foundation Grant 67038 to the Child Health Institute (to D.B.S.); AI073677 (to C.-H.C.); and by intramural funds from the National Human Genome Research Institute (to P.L.S.). CD1d tetramers were provided by the NIH tetramer facility. NR 40 TC 11 Z9 11 U1 0 U2 5 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 OCT 2 PY 2012 VL 109 IS 40 BP 16264 EP 16269 DI 10.1073/pnas.1207528109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017SN UT WOS:000309611400065 PM 22988097 ER PT J AU Walsh, ER Pisitkun, P Voynova, E Deane, JA Scott, BL Caspi, RR Bolland, S AF Walsh, Elizabeth R. Pisitkun, Prapaporn Voynova, Elisaveta Deane, Jonathan A. Scott, Bethany L. Caspi, Rachel R. Bolland, Silvia TI Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-cell-mediated autoimmunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE inflammation; SLE; T follicular helper cells ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TOLL-LIKE RECEPTORS; T-CELLS; MICE DEFICIENT; MURINE LUPUS; CD40 LIGAND; DISEASE; GENE; EXPRESSION; ALPHA AB Toll-like receptor 7 (Tlr7) has been linked to systemic lupus disease incidence in humans and mice, but how TLR7 potentiates autoimmunity is unclear. We used a Tlr7 transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined that Tlr7 exerts B-cell-intrinsic effects in promoting spontaneous germinal center (GC) and plasmablast B-cell development, and that these B-cell subsets are dependent on T-cell-derived signals through CD40L and SLAM-associated protein (SAP), but not IL-17. Antigen specificity also factored into TLR7-induced disease, as both a restricted T cell receptor (TCR) specificity and MHC haplotype H2(k/k) protected Tlr7tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop in Tlr7tgIgH(-/-) mice, suggesting either that spontaneous TLR7 activation does not occur in dendritic cells, or, if it does occur, cannot drive these events in the absence of B-cell aid. These data indicate that autoimmune disease in Tlr7tg mice is contingent upon B cells receiving stimulation both through innate pathways and T-cell-derived signals and suggest a codependent relationship between B cells and T cells in the development of autoimmunity. C1 [Walsh, Elizabeth R.; Pisitkun, Prapaporn; Voynova, Elisaveta; Scott, Bethany L.; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Deane, Jonathan A.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Bolland, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM SBolland@niaid.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Dr. Wenjie Zheng and Dr. Mary J. Mattapallil for technical help with experiments. We also thank Dr. Pam Schwartzberg for the gift of SAP-deficient mice. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 39 TC 35 Z9 37 U1 0 U2 8 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 OCT 2 PY 2012 VL 109 IS 40 BP 16276 EP 16281 DI 10.1073/pnas.1209372109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017SN UT WOS:000309611400067 PM 22988104 ER PT J AU Kelly, AC Shewmaker, FP Kryndushkin, D Wickner, RB AF Kelly, Amy C. Shewmaker, Frank P. Kryndushkin, Dmitry Wickner, Reed B. TI Sex, prions, and plasmids in yeast SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE two-micron DNA; population genetics ID BETA-SHEET STRUCTURE; TERMINATION FACTOR ERF3; 2-MU-M CIRCLE PLASMID; HET-S PRION; SACCHAROMYCES-CEREVISIAE; TRANSLATION TERMINATION; SPECIES BARRIERS; SELFISH DNA; HETEROKARYON INCOMPATIBILITY; ENVIRONMENTAL-STRESS AB Even deadly prions may be widespread in nature if they spread by infection faster than they kill off their hosts. The yeast prions [PSI+] and [URE3] (amyloids of Sup35p and Ure2p) were not found in 70 wild strains, while [PIN+] (amyloid of Rnq1p) was found in similar to 16% of the same population. Yeast prion infection occurs only by mating, balancing the detrimental effects of carrying the prion. We estimated the frequency of outcross mating as about 1% of mitotic doublings from the known detriment of carrying the 2-mu m DNA plasmid (similar to 1%) and its frequency in wild populations (38/70). We also estimated the fraction of total matings that are outcross matings (similar to 23- 46%) from the fraction of heterozygosity at the highly polymorphic RNQ1 locus (similar to 46%). These results show that the detriment of carrying even the mildest forms of [PSI+], [URE3], or [PIN+] is greater than 1%. We find that Rnq1p polymorphisms in wild strains include several premature stop codon alleles that cannot propagate [PIN+] from the reference allele and others with several small deletions and point mutations which show a small transmission barrier. Wild strains carrying [PIN+] are far more likely to be heterozygous at RNQ1 and other loci than are [pin-] strains, probably reflecting its being a sexually transmitted disease. Because sequence differences are known to block prion propagation or ameliorate its pathogenic effects, we hypothesize that polymorphism of RNQ1 was selected to protect cells from detrimental effects of the [PIN+] prion. C1 [Kelly, Amy C.; Wickner, Reed B.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Shewmaker, Frank P.; Kryndushkin, Dmitry] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Uniformed Services University of the Health Sciences (USUHS) FX This work was supported in part by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases and in part by the Uniformed Services University of the Health Sciences (USUHS). We thank the USUHS Biomedical Instrumentation Center facilities for providing assistance with microscopy. NR 67 TC 27 Z9 27 U1 0 U2 8 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 OCT 2 PY 2012 VL 109 IS 40 BP E2683 EP E2690 DI 10.1073/pnas.1213449109 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017SN UT WOS:000309611400009 PM 22949655 ER PT J AU Morton, LM AF Morton, Lindsay M. TI Smoking and lymphoma: a small part of a complex story SO LEUKEMIA & LYMPHOMA LA English DT Editorial Material ID NON-HODGKINS-LYMPHOMA; OCCUPATIONAL RISK-FACTORS; CIGARETTE-SMOKING; UNITED-STATES; TOBACCO USE; SUBTYPES; METAANALYSIS; LEUKEMIA; T(14/18); CANCER C1 [Morton, Lindsay M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Morton, LM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 7040,MSC 7238, Rockville, MD 20852 USA. EM mortonli@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 NR 22 TC 2 Z9 2 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD OCT PY 2012 VL 53 IS 10 BP 1853 EP 1854 DI 10.3109/10428194.2012.680454 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 204NE UT WOS:000323371200001 PM 22462617 ER PT J AU Austin, SK Dowd, KA Shrestha, B Nelson, CA Edeling, MA Johnson, S Pierson, TC Diamond, MS Fremont, DH AF Austin, S. Kyle Dowd, Kimberly A. Shrestha, Bimmi Nelson, Christopher A. Edeling, Melissa A. Johnson, Syd Pierson, Theodore C. Diamond, Michael S. Fremont, Daved H. TI Structural Basis of Differential Neutralization of DENV-1 Genotypes by an Antibody that Recognizes a Cryptic Epitope SO PLOS PATHOGENS LA English DT Article ID WEST-NILE-VIRUS; REACTIVE ANTIGENIC SITES; DENGUE-VIRUS; ENVELOPE PROTEIN; MONOCLONAL-ANTIBODY; DOMAIN-III; MEMBRANE-FUSION; MEDIATED NEUTRALIZATION; HEMORRHAGIC-FEVER; RHESUS-MONKEYS AB We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC' loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC' loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development. C1 [Austin, S. Kyle; Nelson, Christopher A.; Edeling, Melissa A.; Diamond, Michael S.; Fremont, Daved H.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Shrestha, Bimmi; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med Infect Dis, St Louis, MO USA. [Johnson, Syd] MacroGenics, Rockville, MD USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Fremont, Daved H.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Austin, SK (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. EM diamond@borcim.wustl.edu; fremont@wustl.edu FU Pediatric Dengue Vaccine Initiative, Burroughs Wellcome Fund; National Institute of Allergy and Infectious Diseases; NIH [R01-AI077955, U01-AI061373, U54 AI057160]; NIAID [HHSN272200700058C] FX This work was supported in part by the Pediatric Dengue Vaccine Initiative, Burroughs Wellcome Fund, the intramural program of the National Institute of Allergy and Infectious Diseases, and NIH grants R01-AI077955, U01-AI061373, and U54 AI057160 (Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research), and NIAID Contract No. HHSN272200700058C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 47 Z9 48 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2012 VL 8 IS 10 AR e1002930 DI 10.1371/journal.ppat.1002930 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 029XH UT WOS:000310530300007 PM 23055922 ER PT J AU Eksi, S Morahan, BJ Haile, Y Furuya, T Jiang, HY Ali, O Xu, HC Kiattibutr, K Suri, A Czesny, B Adeyemo, A Myers, TG Sattabongkot, J Su, XZ Williamson, KC AF Eksi, Saliha Morahan, Belinda J. Haile, Yoseph Furuya, Tetsuya Jiang, Hongying Ali, Omar Xu, Huichun Kiattibutr, Kirakorn Suri, Amreena Czesny, Beata Adeyemo, Adebowale Myers, Timothy G. Sattabongkot, Jetsumon Su, Xin-zhuan Williamson, Kim C. TI Plasmodium falciparum Gametocyte Development 1 (Pfgdv1) and Gametocytogenesis Early Gene Identification and Commitment to Sexual Development SO PLOS PATHOGENS LA English DT Article ID HUMAN MALARIA PARASITE; OOCYST PRODUCTION; RISK-FACTORS; EXPRESSION; CYTOADHERENCE; CHROMOSOME-9; TRANSMISSION; EVOLUTION; PROTEINS; DIFFERENTIATION AB Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut. Although essential for the spread of malaria through the population, little is known about the initiation of gametocytogenesis in vitro or in vivo. Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparum gametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation. Transcriptional analysis of Pfgdv1 negative and positive parasite lines identified a set of gametocytogenesis early genes (Pfge) that were significantly down-regulated (>10 fold) in the absence of Pfgdv1 and expression was restored after Pfgdv1 complementation. Progressive accumulation of Pfge transcripts during successive rounds of asexual replication in synchronized cultures suggests that gametocytes are induced continuously during asexual growth. Comparison of Pfge gene transcriptional profiles in patient samples divided the genes into two groups differing in their expression in mature circulating gametocytes and providing candidates to evaluate gametocyte induction and maturation separately in vivo. The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria. C1 [Eksi, Saliha; Morahan, Belinda J.; Haile, Yoseph; Ali, Omar; Suri, Amreena; Czesny, Beata; Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. [Morahan, Belinda J.; Furuya, Tetsuya; Jiang, Hongying; Su, Xin-zhuan; Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Xu, Huichun; Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, Inherited Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Kiattibutr, Kirakorn; Sattabongkot, Jetsumon] Armed Forces Res Inst Med Sci, Dept Entomol, US Army Med Component, Bangkok 10400, Thailand. [Myers, Timothy G.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Eksi, S (reprint author), Loyola Univ, Dept Biol, Chicago, IL 60626 USA. EM kwilli4@luc.edu RI Furuya, Tetsuya/H-2412-2013; Furuya, Tetsuya/J-5916-2013; OI Furuya, Tetsuya/0000-0003-3979-7072; Adeyemo, Adebowale/0000-0002-3105-3231; Su, Xinzhuan/0000-0003-3246-3248 FU Public Health Service grants, National Institute of Allergy and Infectious Diseases (NIAID) [AI40592, AI48826]; Division of Intramural Research, NIAID, National Institutes of Health FX This investigation received financial support from Public Health Service grants AI40592 and AI48826 from the National Institute of Allergy and Infectious Diseases (NIAID) and the Division of Intramural Research, NIAID, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 22 Z9 24 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2012 VL 8 IS 10 AR e1002964 DI 10.1371/journal.ppat.1002964 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 029XH UT WOS:000310530300027 PM 23093935 ER PT J AU Aan Het Rot, M Zarate, CA Charney, DS Mathew, SJ AF Aan Het Rot, Marije Zarate, Carlos A., Jr. Charney, Dennis S. Mathew, Sanjay J. TI Ketamine for Depression: Where Do We Go from Here? SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Antidepressant; bipolar disorder; glutamate; ketamine; major depressive disorder; treatment-resistant depression ID TREATMENT-RESISTANT DEPRESSION; D-ASPARTATE ANTAGONIST; RAPID ANTIDEPRESSANT RESPONSE; OPEN-LABEL TRIAL; ADD-ON TRIAL; MAJOR DEPRESSION; INTRAVENOUS KETAMINE; BIPOLAR DEPRESSION; ELECTROCONVULSIVE-THERAPY; DOUBLE-BLIND AB Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk-benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting. C1 [Aan Het Rot, Marije] Univ Groningen, Expt Psychopathol Program, Heymans Inst Psychol Res, Dept Psychol, NL-9712 TS Groningen, Netherlands. [Aan Het Rot, Marije] Univ Groningen, Sch Behav & Cognit Neurosci, NL-9712 TS Groningen, Netherlands. [Zarate, Carlos A., Jr.] NIH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY USA. [Mathew, Sanjay J.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Mathew, Sanjay J.] Michael E DeBakey VA Med Ctr, Houston, TX USA. RP Aan Het Rot, M (reprint author), Univ Groningen, Expt Psychopathol Program, Heymans Inst Psychol Res, Dept Psychol, Grote Kruisstr 2-1, NL-9712 TS Groningen, Netherlands. EM m.aan.het.rot@rug.nl OI aan het Rot, Marije/0000-0001-6761-7513 FU Netherlands Organization for Scientific Research; Department of Veterans Affairs; National Institute of Mental Health [R01MH81870, 5R01MH81870]; Banner Family Fund; Brain and Behavior Fund; Bristol-Myers Squibb; Bround Foundation; Evotec; Johnson Johnson; AstraZeneca; Cephalon, Inc.; Roche; Takeda FX Dr. aan het Rot is currently supported by a Veni grant from the Netherlands Organization for Scientific Research. Dr. Mathew is currently supported by the Department of Veterans Affairs and Grant No. R01MH81870 from National Institute of Mental Health.; Dr. aan het Rot reports no biomedical financial interests or potential conflicts of interest. Dr. Zarate is listed as a coinventor 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 U. S. government but will share a percentage of any royalties that may be received by the government. Dr. Mathew has, in the past 24 months, received research funding or salary support from the Banner Family Fund, Brain and Behavior Fund, Bristol-Myers Squibb, Bround Foundation, Department of Veterans Affairs, Evotec, Johnson & Johnson, and the National Institute of Mental Health (Grant No. 5R01MH81870) and has received consulting or lecture fees from AstraZeneca, Cephalon, Inc., Roche, and Takeda. He has received study drug from Sanofi-Aventis, the manufacturer of riluzole (Rilutek). In addition, Drs. Charney and Mathew have been named as inventors on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the U. S. Food and Drug Administration for this indication, Dr. Charney and the Mount Sinai School of Medicine could benefit financially. Dr. Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine is approved for this use. NR 60 TC 38 Z9 39 U1 3 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2012 VL 72 IS 7 BP 537 EP 547 DI 10.1016/j.biopsych.2012.05.003 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 004XE UT WOS:000308714000007 PM 22705040 ER PT J AU Leggio, L AF Leggio, L. TI Role of baclofen and modulation at GABA(B) receptor in treating addiction: a clinical prospective SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 25th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 13-17, 2012 CL Vienna, AUSTRIA SP European Coll Neuropsychopharmacol (ECNP) ID ALCOHOL-DEPENDENT PATIENTS; ABSTINENCE; SAFETY C1 [Leggio, L.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Leggio, L.] NIDA, Bethesda, MD USA. RI Leggio, Lorenzo/M-2972-2016 NR 3 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2012 VL 22 SU 2 BP S133 EP S134 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 130VQ UT WOS:000317948600059 ER PT J AU Rapoport, SI AF Rapoport, S. I. TI Arachidonic acid metabolism and neuroinflammation in bipolar disorder and its treatments SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 25th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 13-17, 2012 CL Vienna, AUSTRIA SP European Coll Neuropsychopharmacol (ECNP) C1 [Rapoport, S. I.] NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2012 VL 22 SU 2 BP S137 EP S137 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 130VQ UT WOS:000317948600067 ER PT J AU Clark, TT Nguyen, AB AF Clark, Trenette T. Nguyen, Anh B. TI Family Factors and Mediators of Substance Use Among African American Adolescents SO JOURNAL OF DRUG ISSUES LA English DT Article DE risk factor; protective factor; promotive factor; cultural factors; school factors; parental monitoring; family cohesion; acculturation; ethnic identity; racial socialization; classroom climate; achievement motivation ID DRUG-USE; ACADEMIC-ACHIEVEMENT; PROTECTIVE FACTORS; ETHNIC-IDENTITY; ABUSE PREVENTION; RACIAL IDENTITY; PEER INFLUENCES; DISCRIMINATION; RISK; SCHOOL AB This study uses a sample of 424 African American 8th- and 12th-grade students (mean age = 16.55; 65.1% girls) in the United States to examine how family protective factors explain cultural and school protective factors that prevent substance use. Questionnaires were administered between 2007 and 2009. Using structural equation modeling, results indicated that cultural and school factors partially mediated the relationship between family factors and lifetime substance use. School factors fully mediated the relationship between cultural factors and lifetime substance use. The findings suggest that parents promote cultural attributes, which in turn promotes school achievement, and in turn contributes to lower substance use. Limitations of the study, and implications for future research and prevention programs are discussed. C1 [Clark, Trenette T.] Univ N Carolina, Sch Social Work, Chapel Hill, NC 27599 USA. [Nguyen, Anh B.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. RP Clark, TT (reprint author), Univ N Carolina, Sch Social Work, 325 Pittsboro St,CB 3550, Chapel Hill, NC 27599 USA. EM ttclark@email.unc.edu NR 54 TC 1 Z9 1 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0426 J9 J DRUG ISSUES JI J. Drug Issues PD OCT PY 2012 VL 42 IS 4 BP 358 EP 372 DI 10.1177/0022042612461770 PG 15 WC Substance Abuse SC Substance Abuse GA 123MZ UT WOS:000317395500003 ER PT J AU Hall, AP Elcombe, CR Foster, JR Harada, T Kaufmann, W Knippel, A Kuttler, K Malarkey, DE Maronpot, RR Nishikawa, A Nolte, T Schulte, A Strauss, V York, MJ AF Hall, A. P. Elcombe, C. R. Foster, J. R. Harada, T. Kaufmann, W. Knippel, A. Kuettler, K. Malarkey, D. E. Maronpot, R. R. Nishikawa, A. Nolte, T. Schulte, A. Strauss, V. York, M. J. TI Liver Hypertrophy: A Review of Adaptive (Adverse and Non-adverse) Changes-Conclusions from the 3rd International ESTP Expert Workshop SO TOXICOLOGIC PATHOLOGY LA English DT Review DE liver; hypertrophy; adverse; non-adverse; AhR; CAR; PXR; PPAR alpha; weight; fasting; clinical pathology; omics ID PREGNANE-X-RECEPTOR; CONSTITUTIVE-ANDROSTANE RECEPTOR; GAMMA-GLUTAMYL-TRANSPEPTIDASE; MICROSOMAL-ENZYME INDUCTION; ARYL-HYDROCARBON RECEPTOR; PEROXISOME PROLIFERATOR WY-14,643; ALKALINE-PHOSPHATASE ACTIVITY; ANDROGEN CYPROTERONE-ACETATE; DRUG-METABOLIZING-ENZYMES; SPRAGUE-DAWLEY RATS AB Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPAR alpha. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach. C1 [Hall, A. P.; Foster, J. R.] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England. [Elcombe, C. R.] CXR Biosci, Dundee, Scotland. [Harada, T.] Inst Environm Toxicol, Ibaraki, Japan. [Kaufmann, W.; Knippel, A.] Merck KGaA, Nonclin Dev, Toxicology, Darmstadt, Germany. [Kuettler, K.; Strauss, V.] BASF SE, Dep GV TD, Ludwigshafen, Germany. [Malarkey, D. E.] NIEHS, Natl Toxicol Program, Pathol Grp, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Maronpot, R. R.] Maronpot Consulting LLC, Raleigh, NC USA. [Nishikawa, A.] Natl Inst Hlth Sci, Biol Safety Res Ctr, Tokyo, Japan. [Nolte, T.] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Schulte, A.] Bundesinst Risikobewertung, Berlin, Germany. RP Hall, AP (reprint author), AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England. EM peter.a.hall@astrazeneca.com FU ESTP FX The author(s) declared a potential conflict of interest with respect to the research, authorship, and/or publication of this article: Financial support for this workshop was provided by the ESTP. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH, or the United States government. NR 218 TC 43 Z9 43 U1 2 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD OCT PY 2012 VL 40 IS 7 BP 971 EP 994 DI 10.1177/0192623312448935 PG 24 WC Pathology; Toxicology SC Pathology; Toxicology GA 119DS UT WOS:000317078200001 PM 22723046 ER PT J AU Yoon, JH Srikantan, S Gorospe, M AF Yoon, Je-Hyun Srikantan, Subramanya Gorospe, Myriam TI MS2-TRAP (MS2-tagged RNA affinity purification): Tagging RNA to identify associated miRNAs SO METHODS LA English DT Article DE Post-transcriptional gene regulation; MicroRNA; RNA-binding protein; Ribonucleoprotein complex; Noncoding RNA ID POSTTRANSCRIPTIONAL GENE-REGULATION; BACTERIOPHAGE-MS2 COAT PROTEIN; MESSENGER-RNA; TRANSLATIONAL REPRESSION; RIBONUCLEOPROTEIN COMPLEXES; BINDING PROTEINS; MICRORNAS; YEAST; IDENTIFICATION; LOCALIZATION AB Cellular transcripts of all types, including coding messenger (m)RNAs and noncoding (nc)RNAs, are subject to extensive post-transcriptional regulation. Among the factors that elicit post-transcriptional control, microRNAs (miRNAs) have emerged as a major class of small regulatory RNAs. Since RNA-RNA interactions can be modeled computationally, several excellent programs have been developed to predict the interaction of miRNAs with target transcripts. However, many such predictions are not realized for different reasons, including absent or low-abundance expression of the miRNA in the cell, the existence of competing factors or conformational changes masking the microRNA site, and the possibility that target transcripts are not present in the prediction databases, as is the case for long ncRNAs. Here, we provide a systematic approach termed MS2-TRAP (tagged RNA affinity purification) for identifying miRNAs associated with a target transcript in the cellular context. We illustrate the use of this methodology by identifying microRNAs that associate with a long intergenic (Ii)ncRNA, based on the expression of the lincRNA tagged with MS2 RNA hairpins (lincRNA-p21-MS2) and the concomitant expression of a fusion protein recognizing the MS2 RNA hairpins, MS2-GST. After affinity pulldown of the ribonudeoprotein (RNP) complex comprising [MS2-GST/lincRNA-p21-MS2], the RNA in the pulldown material was isolated and reverse transcribed (RT). Subsequent assessment of the microRNAs present in the pulldown complex by using real-time quantitative (q)PCR analysis led to the identification of bona fide miRNAs that interact with and control the abundance of lincRNA-p21. We describe alternative designs and applications of this approach, and discuss its implications in deciphering post-transcriptional gene regulatory schemes. Published by Elsevier Inc. C1 [Yoon, Je-Hyun; Srikantan, Subramanya; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, LMBI, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM gorospem@grc.nia.nih.gov OI srikantan, subramanya/0000-0003-1810-6519 FU National Institute on Aging-Intramural Research Program, NIH FX This work was supported in its entirety by the National Institute on Aging-Intramural Research Program, NIH. NR 39 TC 31 Z9 31 U1 2 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD OCT PY 2012 VL 58 IS 2 BP 81 EP 87 DI 10.1016/j.ymeth.2012.07.004 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 107QH UT WOS:000316235300002 PM 22813890 ER PT J AU Gamrekelashvili, J Ormandy, LA Heimesaat, MM Kirschning, CJ Manns, MP Korangy, F Greten, TF AF Gamrekelashvili, Jaba Ormandy, Lars A. Heimesaat, Markus M. Kirschning, Carsten J. Manns, Michael P. Korangy, Firouzeh Greten, Tim F. TI Primary sterile necrotic cells fail to cross-prime CD8(+) T cells SO ONCOIMMUNOLOGY LA English DT Article DE tumor cells; sterile necrosis; death; cancer vaccine; cross-priming; CD8(+) T cells ID HEAT-SHOCK PROTEINS; DENDRITIC CELLS; IN-VIVO; DYING CELLS; IMMUNE-RESPONSES; APOPTOTIC CELLS; TUMOR-CELLS; RECEPTOR; MATURATION; DEATH AB Necrotic cells are known to activate the innate immune system and trigger inflammation by releasing damage associated molecular patterns (DAMPs). However, how necrotic cells influence the induction of antigen-specific CD8(+) T cell-mediated adaptive immune responses under sterile conditions, in the absence of pathogen associated molecular patterns (PAMPs), remains poorly understood. Here, we examined antigen-specific CD8(+) T-cell responses to primary sterile necrotic tumor cells both in vitro and in vivo. We found that primary necrotic cells alone fail to generate CD8(+) T cell-dependent immune responses toward cell-associated antigens. We show that necrotic cells trigger CD8(+) T-cell immunity only in the presence of PAMPs or analogs, such as p(dI-dC) and/or unmethylated CpG DNA. The electroporation of tumor cells with these PAMPs prior to necrosis induction triggered antigen-specific CD8(+) T-cell responses through a TLR9/MyD88-dependent pathway. In addition, we found that necrotic cells contain factors that can block the cross-priming of CD8(+) T cells even under non-sterile conditions and can serve as a possible mechanism of immunosuppression. These results suggest that antigen-specific CD8(+) T-cell responses to primary necrotic tumor cells can be induced in the presence of PAMPs and thus have a substantial impact on the development of antitumor vaccination strategies. C1 [Gamrekelashvili, Jaba; Korangy, Firouzeh; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Gamrekelashvili, Jaba; Ormandy, Lars A.; Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Ormandy, Lars A.] Univ Med Ctr, Dept Legal Med, Gottingen, Germany. [Heimesaat, Markus M.] Charite, Inst Mikrobiol & Hyg, Charite Campus Mitte, D-13353 Berlin, Germany. [Kirschning, Carsten J.] Univ Duisburg Essen, Inst Med Microbiol, Essen, Germany. RP Korangy, F (reprint author), NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EM firouzeh.korangy@nih.gov; tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU NIH, National Cancer Institute, Center for Cancer Research; Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer FX This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer to M.P.M. NR 56 TC 5 Z9 5 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 J9 ONCOIMMUNOLOGY JI OncoImmunology PD OCT PY 2012 VL 1 IS 7 BP 1017 EP 1026 DI 10.4161/onci.21098 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA 108GL UT WOS:000316279900003 ER PT J AU Madan, RA Heery, CR Gulley, JL AF Madan, Ravi A. Heery, Christopher R. Gulley, James L. TI Combination of vaccine and immune checkpoint inhibitor is safe with encouraging clinical activity SO ONCOIMMUNOLOGY LA English DT Editorial Material DE PROSTVAC; PSA-TRICOM; ipilimumab; vaccine; prostate cancer ID RESISTANT PROSTATE-CANCER; IMMUNOTHERAPY; ANTIGEN; TRIAL AB This commentary provides the authors' perspective on the article "Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial", which has recently been published in The Lancet Oncology. C1 [Madan, Ravi A.; Heery, Christopher R.; Gulley, James L.] NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 10 TC 9 Z9 9 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 J9 ONCOIMMUNOLOGY JI OncoImmunology PD OCT PY 2012 VL 1 IS 7 BP 1167 EP 1168 DI 10.4161/onci.20591 PG 2 WC Oncology; Immunology SC Oncology; Immunology GA 108GL UT WOS:000316279900020 ER PT J AU Reinboth, J Ascierto, ML Chen, NHG Zhang, Q Yu, YA Aguilar, RJ Carretero, R Worschech, A Zhao, YD Wang, EN Marincola, FM Szalay, AA AF Reinboth, Jennifer Ascierto, Maria L. Chen, Nanhai G. Zhang, Qian Yu, Yong A. Aguilar, Richard J. Carretero, Rafael Worschech, Andrea Zhao, Yingdong Wang, Ena Marincola, Francesco M. Szalay, Aladar A. TI Correlates Between Host and Viral Transcriptional Program Associated with Different Oncolytic Vaccinia Virus Isolates SO HUMAN GENE THERAPY METHODS LA English DT Article ID HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEINS; RNA-BINDING-PROTEINS; THYMIDINE KINASE; GENE-EXPRESSION; MESSENGER-RNA; IN-VITRO; HNRNP-L; RECURRENT MELANOMA; CANCER-THERAPY; POXVIRUS AB Vaccinia virus (VACV) has emerged as an attractive tool in oncolytic virotherapy. VACV replication efficiency plays a crucial role in the therapeutic outcome. However, little is known about the influence of host factors on viral replication efficiency and permissiveness of a host cell line to infection and oncolysis. In this study, replication of the attenuated VACV GLV-1h68 strain and three wild-type VACV isolates was determined in two autologous human melanoma cell lines (888-MEL and 1936-MEL). Host gene expression and viral gene expression in infected cells were evaluated via respective expression array platforms. Microarray analyses followed by sequential statistical approaches characterized human genes that change specifically due to virus infection. Viral gene transcription correlated with viral replication in a time-dependent manner. A set of human genes revealed strong correlations with the respective viral gene expression. Finally we identified a set of human genes with possible predictive value for viral replication in an independent dataset. The results demonstrate a probable correlation between viral replication, early gene expression, and the respective host response, and thus a possible involvement of human host factors in viral early replication. The characterization of human target genes that influence viral replication could help answer the question of host cell permissiveness to oncolytic virotherapy and provide important information for the development of novel recombinant vaccinia viruses with improved features to enhance replication rate and hence trigger therapeutic outcome. C1 [Reinboth, Jennifer; Chen, Nanhai G.; Zhang, Qian; Yu, Yong A.; Aguilar, Richard J.; Szalay, Aladar A.] Genelux Corp, San Diego Sci Ctr, San Diego, CA 92109 USA. [Reinboth, Jennifer; Ascierto, Maria L.; Carretero, Rafael; Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, CC & Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Reinboth, Jennifer; Szalay, Aladar A.] Univ Wurzburg, Dept Biochem, D-97074 Wurzburg, Germany. [Ascierto, Maria L.] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Ascierto, Maria L.] Univ Genoa, Ctr Excellence Biomed Res, I-16132 Genoa, Italy. [Chen, Nanhai G.; Zhang, Qian; Yu, Yong A.; Szalay, Aladar A.] Univ Calif San Diego, Rebecca & John Moores Comprehens Canc Ctr, Dept Radiat Oncol, La Jolla, CA 92093 USA. [Carretero, Rafael] Univ Granada, Dept Bioquim Biol Mol & Inmunol, E-18071 Granada, Spain. [Worschech, Andrea] Univ Wurzburg, Dept Internal Med 2, D-97080 Wurzburg, Germany. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Rockville, MD 20852 USA. [Szalay, Aladar A.] Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, D-97080 Wurzburg, Germany. [Szalay, Aladar A.] Univ Wurzburg, Inst Mol Infect Biol, D-97080 Wurzburg, Germany. RP Szalay, AA (reprint author), Genelux Corp, San Diego Sci Ctr, 3030 Bunker Hill St,Suite 310, San Diego, CA 92109 USA. EM aaszalay@genelux.com FU Genelux Corporation (R&D facility in San Diego, CA); Genelux Corporation FX The authors appreciate the excellent technical assistance of Mr. T. Trevino (Genelux Corporation), Mrs. H. Liu, Mrs. R. Shi, and Mr. J. Chen (all three from National Institutes of Health). We thank Genelux Corporation for provision of the customized vaccinia virus chips (by Affymetrix). Furthermore, this work was supported by a research grant from Genelux Corporation (R&D facility in San Diego, CA) awarded to the University of Wuerzburg, Germany.; N.G. Chen, Q. Zhang, Y.A. Yu, R.J. Aguilar, and A. A. Szalay are employees of Genelux Corporation and have personal financial interests in Genelux Corporation. J. Reinboth, special volunteer at NIH, is a graduate student in Dr. Szalay's laboratory in the Department of Biochemistry, University of Wurzburg, Germany, and is supported by a graduate stipend and foreign travel grant from Genelux Corporation. NR 60 TC 2 Z9 3 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1946-6536 J9 HUM GENE THER METHOD JI Hum. Gene Ther. Methods PD OCT PY 2012 VL 23 IS 5 BP 285 EP 296 DI 10.1089/hgtb.2012.057 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 105XZ UT WOS:000316107300001 PM 23131031 ER PT J AU Jarcho, JM Benson, BE Plate, RC Guyer, AE Detloff, AM Pine, DS Leibenluft, E Ernst, M AF Jarcho, Johanna M. Benson, Brenda E. Plate, Rista C. Guyer, Amanda E. Detloff, Allison M. Pine, Daniel S. Leibenluft, Ellen Ernst, Monique TI Developmental effects of decision-making on sensitivity to reward: An fMRI study SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Reward; Incentive; Brain; fMRI; Development; Adolescents; Decision-making ID INTRINSIC CONNECTIVITY NETWORKS; 16-AND 17-YEAR-OLD DRIVERS; EVENT-RELATED FMRI; PREFRONTAL CORTEX; RISK-TAKING; BEHAVIORAL-INHIBITION; EXECUTIVE CONTROL; ADOLESCENT BRAIN; PERSPECTIVE; ADULTS AB Studies comparing neural correlates of reward processing across development yield inconsistent findings. This challenges theories characterizing adolescents as globally hypo- or hypersensitive to rewards. Developmental differences in reward sensitivity may fluctuate based on reward magnitude, and on whether rewards require decision-making. We examined whether these factors modulate developmental differences in neural response during reward anticipation and/or receipt in 26 adolescents (14.05 +/- 2.37 yrs) and 26 adults (31.25 +/- 8.23 yrs). Brain activity was assessed with fMRI during reward anticipation, when subjects made responses with-vs.-without decision-making, to obtain large-vs.-small rewards, and during reward receipt. When reward-receipt required decision-making, neural activity did not differ by age. However, when reward receipt did not require decision-making, neural activity varied by development, reward magnitude, and stage of the reward task. During anticipation, adolescents, but not adults, exhibited greater activity in the insula, extending into putamen, and cingulate gyrus for large-vs.-small incentives. During feedback, adults, but not adolescents, exhibited greater activity in the precuneus for large-vs.-small incentives. These data indicate that age-related differences in reward sensitivity cannot be characterized by global hypo- or hyper-responsivity. Instead, neural responding in striatum, prefrontal cortex and precuneus is influenced by both situational demands and developmental factors. This suggests nuanced maturational effects in adolescent reward sensitivity. Published by Elsevier Ltd. C1 [Jarcho, Johanna M.; Benson, Brenda E.; Plate, Rista C.; Pine, Daniel S.; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Guyer, Amanda E.] Univ Calif Davis, Ctr Mind & Brain, Davis, CA USA. [Detloff, Allison M.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27706 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. RP Jarcho, JM (reprint author), NIMH, Sect Dev & Affect Neurosci, NIH, 9000 Rockville Pike,Bldg 15 K, Bethesda, MD 20892 USA. EM johanna.jarcho@nih.gov OI Jarcho, Johanna/0000-0001-9075-6968 FU Intramural Research Program of the National Institute of Health, National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institute of Health, National Institute of Mental Health. The authors would like to thank Nancy Adleman, Jennifer Britton, and Rick Reynolds for their invaluable advice on data analysis. NR 53 TC 20 Z9 20 U1 3 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD OCT PY 2012 VL 2 IS 4 BP 437 EP 447 DI 10.1016/j.dcn.2012.04.002 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 095ER UT WOS:000315318000006 PM 22591860 ER PT J AU Howden, R Kleeberger, SR AF Howden, Reuben Kleeberger, Steven R. TI Genetic and Environmental Influences on Gas Exchange SO COMPREHENSIVE PHYSIOLOGY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; TUMOR-NECROSIS-FACTOR; PARTICULATE AIR-POLLUTION; ACUTE LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR; HIGH-TRAIN LOW; BONE MORPHOGENETIC PROTEIN-4; NITRIC-OXIDE SYNTHASE AB Gas exchange is a critical process required for sufficient tissue perfusion. The environment, genetics, or a combination of the two can affect this process. Various strategies have evolved to overcome the specific gas exchange challenges in different environments and it is clear that some genes are pivotal to the development of gas exchanging organs (e.g. Bmp4). Lower partial pressure of oxygen (hypoxia), reducing the partial pressure gradient, makes gas exchange more challenging and therefore the height to which gas exchangers can travel above sea level is limited. However, some human populations (e.g. Tibetans) and other animals (e.g. Bar-headed goose) have adapted well to profoundly hypoxic conditions, suggesting genetic factors are important. Gas exchange can also be affected by air pollution, including particulate matter and ozone among others, and exposure can lead to cardiopulmonary responses depending on individual susceptibility or preexisting disease, both of which have genetic and environmental components. Diseases that affect gas exchange include, but are not limited to, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), and bronchopulmonary dysplasia. Moreover, different species successfully exchange gases in their specific environment, for example animals that fly or burrow. Under these conditions, common genetic mechanisms, and their interaction with environment, help to maintain, or are detrimental to, gas exchange. Published 2012. Compr Physiol 2:2595-2614, 2012. C1 [Howden, Reuben] Univ N Carolina, Charlotte, NC 28223 USA. [Kleeberger, Steven R.] NIEHS, Durham, NC USA. RP Howden, R (reprint author), Univ N Carolina, Charlotte, NC 28223 USA. EM rhowden@uncc.edu FU University of North Carolina at Charlotte; National Institute of Environmental Health Sciences Division of Intramural Research FX This work was supported by the University of North Carolina at Charlotte (Dr. Reuben Howden) and the National Institute of Environmental Health Sciences Division of Intramural Research (Dr. Steven R Kleeberger). NR 291 TC 1 Z9 1 U1 2 U2 19 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD OCT PY 2012 VL 2 IS 4 BP 2595 EP 2614 DI 10.1002/cphy.c110060 PG 20 WC Physiology SC Physiology GA 085ZN UT WOS:000314652900010 PM 23720259 ER PT J AU Gonzalez, FJ AF Gonzalez, Frank J. TI Nuclear Receptor Control of Enterohepatic Circulation SO COMPREHENSIVE PHYSIOLOGY LA English DT Article ID FARNESOID-X-RECEPTOR; BILE-ACID TRANSPORTER; SMALL HETERODIMER PARTNER; ORGANIC SOLUTE TRANSPORTER; FIBROBLAST-GROWTH-FACTOR; REV-ERB-ALPHA; TAUROCHOLATE COTRANSPORTING POLYPEPTIDE; FAMILIAL INTRAHEPATIC CHOLESTASIS; 7-ALPHA-HYDROXYLASE GENE CYP7A1; STEROL 27-HYDROXYLASE GENE AB Enterohepatic circulation is responsible for the capture of bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Bile acids are secreted from the liver in the form of mixed micelles that also contain phosphatidylcholines and cholesterol that facilitate the uptake of fats and vitamins from the diet due to the surfactant properties of bile acids and lipids. Bile acids are synthesized in the liver from cholesterol by a cascade of enzymes that carry out oxidation and conjugation reactions, and transported to the bile duct and gall bladder where they are stored before being released into the intestine. Bile flow from the gall bladder to the small intestine is triggered by food intake in accordance with its role in lipid and vitamin absorption from the diet. Bile acids are further metabolized by gut bacteria and are transported back to the circulation. Metabolites produced in the liver are termed primary bile acids or primary conjugated bile salts, while the metabolites generated by bacterial are called secondary bile acids. About 95% of bile acids are reabsorbed in the proximal and distal ileum into the hepatic portal vein and then into the liver sinusoids, where they are efficiently transported into the liver with little remaining in circulation. Each bile acid is reabsorbed about 20 times on average before being eliminated. Enterohepatic circulation is under tight regulation by nuclear receptor signaling, notably by the farnesoid X receptor (FXR). Published 2012. Compr Physiol 2:2811-2828, 2012. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov NR 166 TC 19 Z9 19 U1 0 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD OCT PY 2012 VL 2 IS 4 BP 2811 EP 2828 DI 10.1002/cphy.c120007 PG 18 WC Physiology SC Physiology GA 085ZN UT WOS:000314652900017 PM 23720266 ER PT J AU Core, LJ Waterfall, JJ Gilchrist, DA Fargo, DC Kwak, H Adelman, K Lis, JT AF Core, Leighton J. Waterfall, Joshua J. Gilchrist, Daniel A. Fargo, David C. Kwak, Hojoong Adelman, Karen Lis, John T. TI Defining the Status of RNA Polymerase at Promoters SO CELL REPORTS LA English DT Article ID HEAT-SHOCK; IN-VIVO; TRANSCRIPTION INITIATION; DROSOPHILA-MELANOGASTER; ACTIVE PROMOTERS; GENE-EXPRESSION; CORE PROMOTERS; HUMAN GENOME; POL-II; DIVERGENT TRANSCRIPTION AB Recent genome-wide studies in metazoans have shown that RNA polymerase II (Pol II) accumulates to high densities on many promoters at a rate-limited step in transcription. However, the status of this Pol II remains an area of debate. Here, we compare quantitative outputs of a global run-on sequencing assay and chromatin immunoprecipitation sequencing assays and demonstrate that the majority of the Pol II on Drosophila promoters is transcriptionally engaged; very little exists in a preinitiation or arrested complex. These promoter-proximal polymerases are inhibited from further elongation by detergent-sensitive factors, and knockdown of negative elongation factor, NELF, reduces their levels. These results not only solidify the notion that pausing occurs at most promoters, but demonstrate that it is the major rate-limiting step in early transcription at these promoters. Finally, the divergent elongation complexes seen at mammalian promoters are far less prevalent in Drosophila, and this specificity in orientation correlates with directional core promoter elements, which are abundant in Drosophila. C1 [Core, Leighton J.; Waterfall, Joshua J.; Kwak, Hojoong; Lis, John T.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Gilchrist, Daniel A.; Adelman, Karen] NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. [Fargo, David C.] NIEHS, Lab Integrated Bioinformat, NIH, Res Triangle Pk, NC 27709 USA. RP Lis, JT (reprint author), Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. EM jtl10@cornell.edu OI Gilchrist, Daniel/0000-0003-1668-2790 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101987]; NIH [GM25232, HG004845] FX We would like to thank Charles Danko and Andre Martins for help with R-programming, Peter Kharchenko for providing a Drosophila enhancer list, and Bing Ren for providing a human enhancer list from IMR90 cells. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101987) to K. A. and by NIH grants GM25232 and HG004845 to J.T.L. L.J.C., K.A., and J.T.L. conceived the study and designed the experiments. L.J.C. produced the GRO-seq data sets. K.A. and D.A.G. performed RNAi treatments and produced the ChIP data sets. L.J.C., D.A.G., J.J.W., K.A., D.C.F., and H.K. performed the data analysis. L.J.C., J.T.L., and K.A. wrote the paper. The authors declare that they filed a provisional patent (US 2010/0062946 A1) that describes the GRO-seq technology. NR 57 TC 81 Z9 84 U1 4 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT PY 2012 VL 2 IS 4 BP 1025 EP 1035 DI 10.1016/j.celrep.2012.08.034 PG 11 WC Cell Biology SC Cell Biology GA 083IA UT WOS:000314455600031 PM 23062713 ER PT J AU Gros, A Turcotte, S Wunderlich, JR Ahmadzadeh, M Dudley, ME Rosenberg, SA AF Gros, Alena Turcotte, Simon Wunderlich, John R. Ahmadzadeh, Mojgan Dudley, Mark E. Rosenberg, Steven A. TI Myeloid Cells Obtained from the Blood but Not from the Tumor Can Suppress T-cell Proliferation in Patients with Melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC MELANOMA; HEPATOCELLULAR-CARCINOMA; ACTIVATED GRANULOCYTES; IMMUNE SUPPRESSION; OVARIAN-CARCINOMA; PERIPHERAL-BLOOD; DENDRITIC CELLS; CANCER-PATIENTS; BEARING MICE; EOSINOPHILS AB Purpose: Myeloid-derived suppressor cells (MDSC) have emerged as an immune-regulatory cell type that is expanded in tumor-bearing mice, but less is known about their immune-suppressive role in patients with cancer. Experimental Design: To study the importance of MDSC in patients with melanoma, we characterized the frequency, phenotype, and suppressive function of blood myeloid-derived cells and tumor-infiltrating myeloid cells in 26 freshly resected melanomas. Results: Blood and tumor-infiltrating myeloid cells (Lin(-) CD11b(+)) could be phenotypically and morphologically classified into monocytes/macrophages, neutrophils, eosinophils, and immature myeloid cells according to marker expression (CD14(+), CD14(-) CD15(hi), CD14(-) CD15(int), and CD14(-) CD15(-), respectively). In contrast to the expansion of MDSC reported in tumor-bearing mice, we found no differences in the frequency and phenotype of myeloid subsets in the blood of patients with melanoma compared with healthy donors. Myeloid cells represented 12% of the live cells in the melanoma cell suspensions, and were phenotypically diverse with high tumor-to-tumor variability. Interestingly, a positive association was found between the percentage of Tregs and granulocytic cells (Lin CD11b(+) CD14(-) CD15(+)) infiltrating melanoma tumors. However, melanoma-infiltrating myeloid cells displayed impaired suppression of nonspecific T-cell proliferation compared with peripheral blood myeloid cells, in which monocytes and eosinophils were suppressive. Conclusions: Our findings provide a first characterization of the nature and suppressive function of the melanoma myeloid infiltrate and indicate that the suppressive function of MDSC in patients with melanoma seems far less than that based on murine tumor models. Clin Cancer Res; 18(19); 5212-23. (C)2012 AACR. C1 [Gros, Alena; Turcotte, Simon; Wunderlich, John R.; Dudley, Mark E.; Rosenberg, Steven A.] NCI, Bethesda, MD 20892 USA. [Ahmadzadeh, Mojgan] Stanford Univ, Stanford, CA 94305 USA. RP Rosenberg, SA (reprint author), NCI, Bldg 10 CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM SAR@nih.gov OI Gros, Alena/0000-0002-1207-1880 FU NIH; NCI FX This research was supported by the Intramural Research Program of the NIH and NCI. NR 53 TC 54 Z9 56 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2012 VL 18 IS 19 BP 5212 EP 5223 DI 10.1158/1078-0432.CCR-12-1108 PG 12 WC Oncology SC Oncology GA 048JF UT WOS:000311906600009 PM 22837179 ER PT J AU Sun, ZJ Zhang, L Hall, B Bian, YS Gutkind, JS Kulkarni, AB AF Sun, Zhi-Jun Zhang, Lu Hall, Bradford Bian, Yansong Gutkind, J. Silvio Kulkarni, Ashok B. TI Chemopreventive and Chemotherapeutic Actions of mTOR Inhibitor in Genetically Defined Head and Neck Squamous Cell Carcinoma Mouse Model SO CLINICAL CANCER RESEARCH LA English DT Article ID SURVIVIN EXPRESSION; MAMMALIAN TARGET; AKT/MAMMALIAN TARGET; SOMATIC ACQUISITION; CANCER; RAPAMYCIN; TGFBR1-ASTERISK-6A; ACTIVATION; THERAPY; PATHWAY AB Purpose: To assess the efficacy of rapamycin treatment in chemoprevention and chemotherapy of tumorigenesis in a genetically defined mouse model of head and neck squamous cell carcinoma (HNSCC). Experimental design: Knockdown of Tgfbr1 and/or Pten using siRNA-mediated RNA interference was carried out in human HNSCC cell lines to analyze molecular changes in the mTOR pathway. Tgfbr1(flox/flox); Pten(flox/flox); K14-CreER(tam) mice were treated with oral gavage of tamoxifen for the conditional deletion of Tgfbr1 and Pten in oral mucosa, resulting in HNSCC. Tgfbr1 and Pten conditonal deletion (2cKO) mice were treated with rapamycin before or after the onset of HNSCC, and the efficacy of this treatment was assessed by determining tumor burden, longevity, and molecular analysis of the mTOR pathway. Molecular changes observed in human HNSCC cell lines and 2cKO mice were compared to identify key alterations in the mTOR pathway. Results: Knockdown of Tgfbr1 and/or Pten in human HNSCC cell lines resulted in activation of mTOR activity complex 1 and increased levels of survivin. Furthermore, we observed similar changes in HNSCC of the 2cKO mouse. In the human HNSCC tissue array, a loss of Tgfbr1 expression correlated with increased survivin levels. Chemopreventive rapamycin treatment significantly delayed the onset of the HNSCC tumors and prolonged survival in 2cKO mice. In addition, we also found that rapamycin had a therapeutic effect on squamous cell carcinomas in these mice. In 2cKO HNSCC tongue tumors, rapamycin treatment induced apoptosis, inhibited cell proliferation and phosphorylation of Akt and S6, and decreased survivin expression. Conclusions: These findings indicate that tumorigenesis in 2cKO HNSCC is associated with activation of the Akt/mTOR/survivin pathway, and inhibition of this pathway by rapamycin treatment successfully ameliorates the onset and progression of tumorigenesis. Clin Cancer Res; 18(19); 5304-13. (C)2012 AACR. C1 [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Bian, Yansong] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Zhang, Lu] Wuhan Univ, State Key Lab Breeding Base Basic Sci Stomatol, Sch & Hosp Stomatol, Wuhan 430072, Peoples R China. [Zhang, Lu] Wuhan Univ, Key Lab Oral Biomed, Sch & Hosp Stomatol, Minist Educ, Wuhan 430072, Peoples R China. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Bldg 30,Room 130, Bethesda, MD 20892 USA. EM ak40m@nih.gov FU National Institute of Dental and Craniofacial Research, NIH [ZIA-DE-000698]; National Natural Science Foundation of China [81072203] FX Grant support was provided by the Intramural Research Programs of the National Institute of Dental and Craniofacial Research, NIH (A. B. Kulkarni, ZIA-DE-000698), National Natural Science Foundation of China (81072203). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U. S. C. section 1734 solely to indicate this fact. NR 31 TC 40 Z9 40 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2012 VL 18 IS 19 BP 5304 EP 5313 DI 10.1158/1078-0432.CCR-12-1371 PG 10 WC Oncology SC Oncology GA 048JF UT WOS:000311906600017 PM 22859719 ER PT J AU Hu, WS Hughes, SH AF Hu, Wei-Shau Hughes, Stephen H. TI HIV-1 Reverse Transcription SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; ROUS-SARCOMA-VIRUS; DIMERIZATION INITIATION SIGNAL; INFECTIOUS MOLECULAR CLONES; RETROVIRAL SHUTTLE VECTOR; DEPENDENT DNA POLYMERASE; SINGLE REPLICATION CYCLE; RIBONUCLEASE-H ACTIVITY; INTEGRATION IN-VIVO AB Reverse transcription and integration are the defining features of the Retroviridae; the common name "retrovirus" derives from the fact that these viruses use a virally encoded enzyme, reverse transcriptase (RT), to convert their RNA genomes into DNA. Reverse transcription is an essential step in retroviral replication. This article presents an overview of reverse transcription, briefly describes the structure and function of RT, provides an introduction to some of the cellular and viral factors that can affect reverse transcription, and discusses fidelity and recombination, two processes in which reverse transcription plays an important role. In keeping with the theme of the collection, the emphasis is on HIV-1 and HIV-1 RT. C1 [Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Hughes, Stephen H.] NCI, Vector Design & Replicat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, Vector Design & Replicat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 189 TC 23 Z9 24 U1 2 U2 21 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD OCT PY 2012 VL 2 IS 10 AR a006882 DI 10.1101/cshperspect.a006882 PG 22 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080YW UT WOS:000314281700012 ER PT J AU Harrison, SJ Bishton, M Bates, SE Grant, S Piekarz, RL Johnstone, RW Dai, Y Lee, B Araujo, ME Prince, HM AF Harrison, Simon J. Bishton, Mark Bates, Susan E. Grant, Steven Piekarz, Richard L. Johnstone, Ricky W. Dai, Yun Lee, Becki Araujo, Maria E. Prince, H. Miles TI A focus on the preclinical development and clinical status of the histone deacetylase inhibitor, romidepsin (depsipeptide, Istodax (R)) SO EPIGENOMICS LA English DT Article DE apoptosis; hematology; histone deacetylase inhibitor; malignancy; romidepsin ID T-CELL LYMPHOMA; ACUTE MYELOID-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; PHASE-II TRIAL; CHROMOBACTERIUM-VIOLACEUM NO-968; REFRACTORY MULTIPLE-MYELOMA; MALIGNANT B-CELLS; MYELODYSPLASTIC SYNDROMES; IN-VITRO; CHAPERONE FUNCTION AB Romidepsin (Istodax (R), depsipeptide, FR901228, FK228, NSC 630176) is a cyclic peptide, broad-spectrum, potent histone deacetylase inhibitor, with activity mainly against class I histone deacetylase enzymes. In this article, we give an overview of the putative modes of action, such as effects on gene expression, cell cycle regulation, apoptosis induction, DNA repair, protein acetylation and induction of autophagy. Romidepsin has mainly been developed as a therapy for hematologic malignancies and is approved by the US FDA for the treatment of cutaneous T-cell lymphomas. This report outlines the laboratory and clinical development of the compound as a single agent that has more recently been evaluated in combination with other anticancer therapeutics, such as proteasome inhibitors. C1 [Harrison, Simon J.; Bishton, Mark; Lee, Becki; Araujo, Maria E.; Prince, H. Miles] Peter MacCallum Canc Ctr, Haematol Serv, Melbourne, Vic, Australia. [Harrison, Simon J.; Bishton, Mark; Johnstone, Ricky W.; Prince, H. Miles] Peter MacCallum Canc Ctr, Canc Immunol Lab, Melbourne, Vic, Australia. [Harrison, Simon J.; Bates, Susan E.; Johnstone, Ricky W.; Prince, H. Miles] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia. [Grant, Steven; Dai, Yun] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Piekarz, Richard L.; Dai, Yun] NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Harrison, SJ (reprint author), Peter MacCallum Canc Ctr, Haematol Serv, Melbourne, Vic, Australia. EM simon.harrison@petermac.org OI Harrison, Simon/0000-0003-4555-6582 FU Celgene; NCI FX SJ Harrison and HM Prince have received grant funding and honoraria from Celgene. SE Bates recieves funding via Cooperative Research and Development Agreement between NCI and Celgene. 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 118 TC 16 Z9 16 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-1911 EI 1750-192X J9 EPIGENOMICS-UK JI Epigenomics PD OCT PY 2012 VL 4 IS 5 BP 571 EP 589 DI 10.2217/EPI.12.52 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 082NP UT WOS:000314399000015 PM 23130838 ER PT J AU Seaman, BJ Guardiani, EA Brewer, CC Zalewski, CK King, KA Rudy, S Van Waes, C Morgan, RA Dudley, ME Yang, JC Rosenberg, SA Kim, HJ AF Seaman, Bradley J. Guardiani, Elizabeth A. Brewer, Carmen C. Zalewski, Christopher K. King, Kelly A. Rudy, Susan Van Waes, Carter Morgan, Richard A. Dudley, Mark E. Yang, James C. Rosenberg, Steven A. Kim, H. Jeffrey TI Audiovestibular Dysfunction Associated with Adoptive Cell Immunotherapy for Melanoma SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE melanoma; melanocytes; stria vascularis; cochlea; vestibular organs; audiovestibular dysfunction; hearing loss; vestibular dysfunction; adoptive cell immunotherapy ID TUMOR-INFILTRATING LYMPHOCYTES; ANTIGEN; AUTOIMMUNITY; THERAPY AB Objective. To understand the audiologic and vestibular toxicities associated with adoptive cell immunotherapy (ACI) targeting pigment-pathway antigens on melanoma and to investigate the use of intratympanic steroid injections in the treatment of these toxicities. Study Design. Prospective nonrandomized study. Setting. Tertiary clinical research center. Methods. Thirty-two patients with progressive metastatic melanoma who failed conventional therapy underwent ACI with T cells genetically modified to target MART-1 (n = 18) or gp100 (n = 14). All patients received serial audiometric testing. Vestibular testing was performed on patients with vestibular complaints. Patients with significant deficits received intratympanic steroid injections. Results. Of 32 patients, 15 had no hearing change, 9 had mild hearing loss, and 8 had moderate hearing loss following treatment. Ten patients received intratympanic steroid injections for mild (n = 2) or moderate (n = 7) hearing loss or for significant imbalance (n = 1). Of those with mild hearing loss (n = 9), all but 1 recovered to pretreatment hearing levels. Four of 8 patients with moderate hearing loss recovered to baseline hearing levels, and 4 had partial recovery. All 7 patients with posttreatment vestibular complaints had demonstrable vestibular dysfunction. Three of these patients demonstrated recovery to normal vestibular function. The number of modified T cells infused for therapy correlated with the degree of audiovestibular deficit. Conclusion. Adoptive cell immunotherapy targeting pigment-pathway cell proteins, a novel therapy for melanoma, can induce hearing loss and vestibular dysfunction. The presumed mechanism of autoimmune attack on normal melanocytes in the cochlear stria vascularis and in the vestibular organs demonstrates the importance of melanocytes in normal inner ear function. C1 [Seaman, Bradley J.; Guardiani, Elizabeth A.; Kim, H. Jeffrey] Georgetown Univ, Med Ctr, Dept Otolaryngol Head & Neck Surg, Washington, DC 20007 USA. [Brewer, Carmen C.; Zalewski, Christopher K.; King, Kelly A.; Rudy, Susan; Van Waes, Carter; Kim, H. Jeffrey] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Morgan, Richard A.; Dudley, Mark E.; Yang, James C.; Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. RP Kim, HJ (reprint author), Georgetown Univ, Med Ctr, Dept Otolaryngol Head & Neck Surg, 3800 Reservoir Rd NW,1st Floor Gorman, Washington, DC 20007 USA. EM HK7@gunet.georgetown.edu FU National Cancer Institute; National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland FX The intramural research programs of the National Cancer Institute and the National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, supported this work. NR 13 TC 12 Z9 12 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD OCT PY 2012 VL 147 IS 4 BP 744 EP 749 DI 10.1177/0194599812448356 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 080ZL UT WOS:000314283700024 PM 22597578 ER PT J AU Shulman, ST Insel, TR AF Shulman, Stanford T. Insel, Thomas R. TI A Conversation with Thomas R. Insel, MD SO PEDIATRIC ANNALS LA English DT Editorial Material C1 [Insel, Thomas R.] NIMH, Bethesda, MD USA. [Insel, Thomas R.] Emory Univ, Atlanta, GA 30322 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0090-4481 EI 1938-2359 J9 PEDIATR ANN JI Pediatr. Annu. PD OCT PY 2012 VL 41 IS 10 BP 436 EP 436 DI 10.3928/00904481-20120924-17 PG 1 WC Pediatrics SC Pediatrics GA 082NS UT WOS:000314399300022 ER PT J AU Blanco, I de Serres, FJ Carcaba, V Lara, B Fernandez-Bustillo, E AF Blanco, Ignacio de Serres, Frederick J. Carcaba, Victoriano Lara, Beatriz Fernandez-Bustillo, Enrique TI Alpha-1 Antitrypsin Deficiency PI*Z and PI*S Gene Frequency Distribution Using on Maps of the World by an Inverse Distance Weighting (IDW) Multivariate Interpolation Method SO HEPATITIS MONTHLY LA English DT Article DE Alpha 1-Antitrypsin; Alpha 1-Antitrypsin Deficiency; Molecular Epidemiology ID ANCA-ASSOCIATED VASCULITIS; ALPHA(1)-ANTITRYPSIN DEFICIENCY; ESTIMATED NUMBERS; PREVALENCE; ANTITRYPSIN; COUNTRIES; ALLELES; DISEASE; HEALTH AB Background: Currently, there is a remarkable lack of genetic epidemiological studies on alpha 1-antitrypsin (AAT) deficiency in about half of the 193 countries of the World. This fact impedes the establishment of a true prevalence pattern of this deleterious hereditary disorder in extensive regions of human population. Objectives: The aim of the present study was to generate detailed maps of the frequency distribution of the two most frequent AAT deficiency alleles (i.e., PI*S and PI*Z) in all areas of the World. Materials and Methods: Available data provided by epidemiological studies performed in 94 of 193 countries worldwide was used to develop detailed maps of these two alleles, We employed an informatics mathematical approach, namely: the ArcMap [a component of ESRI's ArcGIS Geographical Information System (GIS), for Microsoft Windows], based on the inverse distance weighting (IDW) multivariate interpolation method, which creates new numerical points from known data, using a simple logarithm based in the distance existing between them. Results: In this method, PI*S and PI*Z frequencies were represented by colored scales, where qualitative colors were converted into quantitative data, providing information on their distribution in all parts of the world. This approach not only confirmed our previous data, but also provided digital images of the remaining regions of all continents. Conclusions: By using this approach, striking differences were found among regions, and unsuspected significant values of the PI*S and PI*Z alleles frequencies were obtained for several geographic regions where have not been studied yet. In fact, some of these regions might be considered as priority targets for further screening studies on AAT deficiency, in order to identify, and properly manage, individuals at risk for the diverse adverse health effects associated with AAT deficiency. Published by Kowsar Corp, 2012. cc 3.0. C1 [Blanco, Ignacio] Principal Asturias Biomed Res Off OIB FICYT, Oviedo, Spain. [Blanco, Ignacio] Alphal Antitrypsin Deficiency Spanish Registry, Barcelona, Spain. [de Serres, Frederick J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Carcaba, Victoriano] Valle Nalon Hosp, Dept Internal Med, Principado De Asturias, Spain. [Lara, Beatriz] Hosp Univ Vall dHebron, Inst Recerca Biomed Lleida IRB, Serv Pneumol,CIBERES Inst Salud Carlos 3, Hosp Univ Arnau Vilanova,Inst Recerca, Barcelona, Spain. [Fernandez-Bustillo, Enrique] Cent Univ Hosp Asturias, Biostat Unit, Principado De Asturias, Spain. RP Blanco, I (reprint author), Principal Asturias Biomed Res Off OIB FICYT, Oviedo, Spain. EM ignablanco@yahoo.com NR 19 TC 12 Z9 14 U1 1 U2 11 PU KOWSAR PUBL PI HOENSBROEK PA PATERSWEG 22,, HOENSBROEK, LIMBURG 6431 GC, NETHERLANDS SN 1735-143X J9 HEPAT MON JI Hepat. Mon. PD OCT PY 2012 VL 12 IS 10 AR e7434 DI 10.5812/hepatmon.7434 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 078RL UT WOS:000314117000012 PM 23166537 ER PT J AU Sochacki, KA Larson, BT Sengupta, DC Daniels, MP Shtengel, G Hess, HF Taraska, JW AF Sochacki, Kem A. Larson, Ben T. Sengupta, Deepali C. Daniels, Mathew P. Shtengel, Gleb Hess, Harald F. Taraska, Justin W. TI Imaging the post-fusion release and capture of a vesicle membrane protein SO NATURE COMMUNICATIONS LA English DT Article ID KISS-AND-RUN; CLATHRIN-MEDIATED ENDOCYTOSIS; FROG NEUROMUSCULAR JUNCTION; BOVINE CHROMAFFIN CELLS; SECRETORY GRANULES; SYNAPTIC VESICLES; PLASMA-MEMBRANE; PC12 CELLS; EXOCYTOSIS; FUSION AB The molecular mechanism responsible for capturing, sorting and retrieving vesicle membrane proteins following triggered exocytosis is not understood. Here we image the post-fusion release and then capture of a vesicle membrane protein, the vesicular acetylcholine transporter, from single vesicles in living neuroendocrine cells. We combine these measurements with super-resolution interferometric photo-activation localization microscopy and electron microscopy, and modelling to map the nanometer-scale topography and architecture of the structures responsible for the transporter's capture following exocytosis. We show that after exocytosis, the transporter rapidly diffuses into the plasma membrane, but most travels only a short distance before it is locally captured over a dense network of membrane-resident clathrin-coated structures. We propose that the extreme density of these structures acts as a short-range diffusion trap. They quickly sequester diffusing vesicle material and limit its spread across the membrane. This system could provide a means for clathrin-mediated endocytosis to quickly recycle vesicle proteins in highly excitable cells. C1 [Sochacki, Kem A.; Larson, Ben T.; Sengupta, Deepali C.; Taraska, Justin W.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Daniels, Mathew P.] NHLBI, Electron Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Shtengel, Gleb; Hess, Harald F.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. RP Taraska, JW (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM justin.taraska@nih.gov RI Taraska, Justin/H-8876-2016 OI Taraska, Justin/0000-0001-5355-9535 FU Intramural Research Program of the National Heart Lung and Blood Institute, National Institutes of Health; Howard Hughes Medical Institute FX We thank J. Silver (NHLBI), J. Hammer (NHLBI) and L.G. Wu (NINDS) for helpful reading and comments on the manuscript. We thank L. Greene (NHLBI) for advice and X. Zhao (NHLBI) for help with immunofluorescence staining. We thank G. Daniels (Leica Microsystems) for help with GSD super-resolution imaging. We also thank S. Esfahani (NHLBI) for technical advice and the 3D tilt series of the platinum replicas. We thank T. Towle and J.S. Yu for technical assistance. J.W. Taraska is supported by the Intramural Research Program of the National Heart Lung and Blood Institute, National Institutes of Health. G. Shtengel and H. Hess are supported by the Howard Hughes Medical Institute. NR 42 TC 21 Z9 21 U1 0 U2 41 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT PY 2012 VL 3 AR 1154 DI 10.1038/ncomms2158 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 070NE UT WOS:000313514100064 PM 23093191 ER PT J AU Vivar, C Potter, MC Choi, J Lee, JY Stringer, TP Callaway, EM Gage, FH Suh, H van Praag, H AF Vivar, Carmen Potter, Michelle C. Choi, Jiwon Lee, Ji-young Stringer, Thomas P. Callaway, Edward M. Gage, Fred H. Suh, Hoonkyo van Praag, Henriette TI Monosynaptic inputs to new neurons in the dentate gyrus SO NATURE COMMUNICATIONS LA English DT Article ID GENERATED GRANULE CELLS; ENHANCED SYNAPTIC PLASTICITY; SPATIAL-PATTERN SEPARATION; SOURCE DENSITY ANALYSIS; PERIRHINAL CORTEX; ADULT HIPPOCAMPUS; IN-VIVO; ENTORHINAL CORTEX; OLFACTORY-BULB; FASCIA DENTATA AB Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin. Here we combine rabies virus-mediated retrograde tracing with retroviral labelling of new granule cells (21, 30, 60, 90 days after injection) to selectively identify and quantify their monosynaptic inputs in vivo. Our results show that newborn granule cells receive afferents from intra-hippocampal cells (interneurons, mossy cells, area CA3 and transiently, mature granule cells) and septal cholinergic cells. Input from distal cortex (perirhinal (PRH) and lateral entorhinal cortex (LEC)) is sparse 21 days after injection and increases over time. Patch-clamp recordings support innervation by the LEC rather than from the medial entorhinal cortex. Mice with excitotoxic PRH/LEC lesions exhibit deficits in pattern separation but not in water maze learning. Thus, PRH/LEC input is an important functional component of new dentate gyrus neuron circuitry. C1 [Vivar, Carmen; Potter, Michelle C.; Stringer, Thomas P.; van Praag, Henriette] NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Choi, Jiwon; Callaway, Edward M.] Salk Inst Biol Studies, Syst Neurobiol Labs, La Jolla, CA 92037 USA. [Lee, Ji-young; Suh, Hoonkyo] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44195 USA. [Gage, Fred H.] Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA. RP Suh, H (reprint author), Cleveland Clin, Lerner Res Inst, Cleveland, OH 44195 USA. EM suhh2@ccf.org; vanpraagh@mail.nih.gov RI Callaway, Edward/D-4336-2011; van Praag, Henriette/F-3939-2015; OI Callaway, Edward/0000-0002-6366-5267; van Praag, Henriette/0000-0002-5727-434X; Suh, Hoonkyo/0000-0002-4227-2982 FU National Institute on Aging, Intramural Research Program FX This work was supported in part by the National Institute on Aging, Intramural Research Program. We are most grateful to Linda R. Kitabayashi for her expertise and help with preparation of the figures. We also thank Haleigh Golub, Neema Heivand, Nicholas Santistevan, Drs Lou Rezanka and Ian Wickersham for technical support. NR 60 TC 83 Z9 86 U1 0 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT PY 2012 VL 3 AR 1107 DI 10.1038/ncomms2101 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 070NE UT WOS:000313514100017 PM 23033083 ER PT J AU Yue, L Pawlowski, M Dellal, SS Xie, A Feng, F Otis, TS Bruzik, KS Qian, HH Pepperberg, DR AF Yue, Lan Pawlowski, Michal Dellal, Shlomo S. Xie, An Feng, Feng Otis, Thomas S. Bruzik, Karol S. Qian, Haohua Pepperberg, David R. TI Robust photoregulation of GABA(A) receptors by allosteric modulation with a propofol analogue SO NATURE COMMUNICATIONS LA English DT Article ID REFRACTORY STATUS EPILEPTICUS; AZOBENZENE PHOTOSWITCHES; GLUTAMATE-RECEPTOR; GANGLION-CELLS; ION CHANNELS; ACTIVATION; NEURONS; INHIBITION; SUBUNIT; BINDING AB Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photoregulation of GABA(A) receptors (GABA(A)Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABA(A)R allosteric modulator, which we have modified to contain photoisomerizable azobenzene. Using alpha(1)beta(2)gamma(2) GABA(A)Rs expressed in Xenopus laevis oocytes and native GABA(A)Rs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths similar to 440 nm), potentiates the gamma-aminobutyric acid-elicited response and, at higher concentrations, directly activates the receptors. cis-MPC088, generated from trans-MPC088 by ultraviolet light (similar to 365 nm), produces little, if any, receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with gamma-aminobutyric acid affords bidirectional photomodulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photocontrol of GABA(A)Rs by an allosteric ligand, and open new avenues for fundamental and clinically oriented research on GABA(A)Rs, a major class of neurotransmitter receptors in the central nervous system. C1 [Yue, Lan; Xie, An; Feng, Feng; Qian, Haohua; Pepperberg, David R.] Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA. [Yue, Lan; Pepperberg, David R.] Univ Illinois, Dept Bioengn, Chicago, IL 60607 USA. [Pawlowski, Michal; Bruzik, Karol S.] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Dellal, Shlomo S.] Univ Calif Los Angeles, Dept Neurobiol, Los Angeles, CA 90095 USA. [Xie, An] Univ Illinois, Dept Med, Chicago, IL 60612 USA. [Otis, Thomas S.] Univ Calif Los Angeles, Dept Neurobiol, Los Angeles, CA 90095 USA. [Qian, Haohua] NEI, NIH, Bethesda, MD 20892 USA. RP Pepperberg, DR (reprint author), Univ Illinois, Dept Ophthalmol & Visual Sci, 1855 W Taylor St, Chicago, IL 60612 USA. EM davipepp@uic.edu FU NIH [EY016094, EY001792, AA01973]; Rice Foundation (Skokie, IL); Hope for Vision (Washington, DC); Beckman Initiative for Macular Research (Los Angeles, CA); American Health Assistance Foundation (Clarksburg, MD); Research to Prevent Blindness (New York, NY); University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) [UL1RR029879] FX We thank Drs Robert F. Standaert, Helene A. Gussin and Deborah M. Little for helpful discussions; Dr Martin Wallner for providing cDNA for the alpha4, beta3, beta3(N265M) and delta GABAAR subunits; and Dr Matthew Shtrahman, Ms. Vivy Tran, Ms. Tara Nguyen and Dr Joyce Wondolowski for technical assistance. Supported by NIH grants EY016094, EY001792 and AA01973; the Daniel F. and Ada L. Rice Foundation (Skokie, IL); Hope for Vision (Washington, DC); the Beckman Initiative for Macular Research (Los Angeles, CA); the American Health Assistance Foundation (Clarksburg, MD); Research to Prevent Blindness (New York, NY); and by award UL1RR029879 from the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS). NR 59 TC 17 Z9 17 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT PY 2012 VL 3 AR 1095 DI 10.1038/ncomms2094 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 070NE UT WOS:000313514100005 PM 23033071 ER PT J AU Fried, M Muehlenbachs, A Duffy, PE AF Fried, Michal Muehlenbachs, Atis Duffy, Patrick E. TI Diagnosing malaria in pregnancy: an update SO EXPERT REVIEW OF ANTI-INFECTIVE THERAPY LA English DT Review DE diagnosis; PCR; placenta histology; Plasmodium falciparum; pregnancy malaria; RDT ID PLASMODIUM-FALCIPARUM MALARIA; POLYMERASE-CHAIN-REACTION; LOW-BIRTH-WEIGHT; HISTIDINE-RICH PROTEIN-2; MEDIATED ISOTHERMAL AMPLIFICATION; DESORPTION MASS-SPECTROMETRY; REAL-TIME PCR; PLACENTAL MALARIA; PERIPHERAL-BLOOD; CONTROLLED-TRIAL AB Expert Rev. Anti Infect. Ther. 10(10), 1177-1187 (2012) Pregnancy malaria (PM) due to Plasmodium falciparum is a major cause of morbidity and mortality for women and their offspring, but is difficult to recognize and diagnose. During PM, parasites typically sequester in the placenta, whereas peripheral blood smears often appear negative. In addition, many infected women remain asymptomatic, especially in areas of high transmission where systemic immunity is high, although sequelae including maternal anemia and intrauterine growth retardation develop insidiously and increase mortality. New rapid diagnostic tests (RDTs) have shown promise for malaria diagnosis in nonpregnant individuals, including a product recently approved by the US FDA for use in the USA. However, the sensitivity and specificity of RDTs for diagnosis of PM may be suboptimal. Here, we review the methods that are used to detect or diagnose PM, including blood smear microscopy, RDTs, PCR-based methods, and finally placental histology, which is often cited as the gold standard for use in research studies and clinical trials. C1 [Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20892 USA. [Fried, Michal; Duffy, Patrick E.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Muehlenbachs, Atis] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Muehlenbachs, Atis] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. RP Fried, M (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Rockville, MD 20892 USA. EM michal.fried@nih.gov FU US NIH [AI52059, 5U19AI065664]; Bill & Melinda Gates Foundation [47029]; NIAID-NIH FX This work was supported by grants from the US NIH grants AI52059, 5U19AI065664 and the Bill & Melinda Gates Foundation (47029) to PE Duffy. This work was supported in part by the Intramural Research Program of the NIAID-NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 85 TC 14 Z9 14 U1 1 U2 10 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-7210 J9 EXPERT REV ANTI-INFE JI Expert Rev. Anti-Infect. Ther. PD OCT PY 2012 VL 10 IS 10 BP 1177 EP 1187 DI 10.1586/ERI.12.98 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 066LR UT WOS:000313222800016 PM 23199403 ER PT J AU Duffy, PE Sahu, T Akue, A Milman, N Anderson, C AF Duffy, Patrick E. Sahu, Tejram Akue, Adovi Milman, Neta Anderson, Charles TI Pre-erythrocytic malaria vaccines: identifying the targets SO EXPERT REVIEW OF VACCINES LA English DT Review DE adjuvants; liver; Plasmodium falciparum; pre-erythrocytic malaria; rodent models; sporozoite; vaccine ID PLASMODIUM-FALCIPARUM SPOROZOITES; LIVER-STAGE ANTIGEN-1; CD8(+) T-LYMPHOCYTES; B SURFACE-ANTIGEN; CIRCUMSPOROZOITE PROTEIN VACCINE; APICAL MEMBRANE ANTIGEN-1; SINUSOIDAL CELL LAYER; NITRIC-OXIDE SYNTHASE; PHASE I/IIA SAFETY; RAT KUPFFER CELLS AB Pre-erythrocytic malaria vaccines target Plasmodium during its sporozoite and liver stages, and can prevent progression to blood-stage disease, which causes a million deaths each year. Whole organism sporozoite vaccines induce sterile immunity in animals and humans and guide subunit vaccine development. A recombinant protein-in-adjuvant pre-erythrocytic vaccine called RTS,S reduces clinical malaria without preventing infection in field studies and additional antigens may be required to achieve sterile immunity. Although few vaccine antigens have progressed to human testing, new insights into parasite biology, expression profiles and immunobiology have offered new targets for intervention. Future advances require human trials of additional antigens, as well as platforms to induce the durable antibody and cellular responses including CD8(+) T cells that contribute to sterile protection. C1 [Duffy, Patrick E.; Sahu, Tejram; Akue, Adovi; Anderson, Charles] NIAID, Lab Malaria Immunol & Vaccinol, Div Intramural Res, NIH, Rockville, MD 20892 USA. [Milman, Neta] Seattle BioMed, Malaria Program, Seattle, WA USA. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, Div Intramural Res, NIH, Rockville, MD 20892 USA. EM patrick.duffy@nih.gov OI Sahu, Tejram/0000-0002-0912-7660 FU Division of Intramural Research, NIAID, NIH; Malaria Vaccine Initiative at PATH FX PE Duffy is named as a co-inventor on patents for novel pre-erythrocytic malaria vaccine antigen candidates. The authors contributing to this review are supported by funds from Division of Intramural Research, NIAID, NIH, and by a grant from the Malaria Vaccine Initiative at PATH (to PE Duffy). 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 190 TC 29 Z9 30 U1 2 U2 22 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD OCT PY 2012 VL 11 IS 10 BP 1261 EP 1280 DI 10.1586/ERV.12.92 PG 20 WC Immunology SC Immunology GA 058GV UT WOS:000312623000018 PM 23176657 ER PT J AU Peach, ML Zakharov, AV Liu, RF Pugliese, A Tawa, G Wallqvist, A Nicklaus, MC AF Peach, Megan L. Zakharov, Alexey V. Liu, Ruifeng Pugliese, Angelo Tawa, Gregory Wallqvist, Anders Nicklaus, Marc C. TI Computational tools and resources for metabolism-related property predictions. I. Overview of publicly available (free and commercial) databases and software SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID SMALL-MOLECULE BINDING; COMPARATIVE TOXICOGENOMICS DATABASE; IN-SILICO; DRUG-METABOLISM; XENOBIOTIC METABOLISM; CYTOCHROME-P450 2D6; BIOLOGICAL-ACTIVITY; RS-PREDICTOR; P450 ENZYME; DISCOVERY AB Metabolism has been identified as a defining factor in drug development success or failure because of its impact on many aspects of drug pharmacology, including bioavailability, half-life and toxicity. In this article, we provide an outline and descriptions of the resources for metabolism-related property predictions that are currently either freely or commercially available to the public. These resources include databases with data on, and software for prediction of, several end points: metabolite formation, sites of metabolic transformation, binding to metabolizing enzymes and metabolic stability. We attempt to place each tool in historical context and describe, wherever possible, the data it was based on. For predictions of interactions with metabolizing enzymes, we show a typical set of results for a small test set of compounds. Our aim is to give a clear overview of the areas and aspects of metabolism prediction in which the currently available resources are useful and accurate, and the areas in which they are inadequate or missing entirely. C1 [Zakharov, Alexey V.; Pugliese, Angelo; Nicklaus, Marc C.] NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,DHHS,Frederich Natl Lab Canc Res,NIH, Frederick, MD 21702 USA. [Peach, Megan L.] SAIC Frederick Inc, CADD Grp, Biol Chem Lab, Frederick Natl Lab Canc Res,Basic Sci Program, Frederick, MD 21702 USA. [Liu, Ruifeng; Tawa, Gregory; Wallqvist, Anders] USA, Med Res & Mat Command, DoD Biotechnol HPC Software Applicat Inst, Frederick, MD 21702 USA. [Pugliese, Angelo] Comp Aided Drug Design Canc Res UK, Beatson Labs, Drug Discovery Programme, Glasgow G61 1BD, Lanark, Scotland. RP Nicklaus, MC (reprint author), NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,DHHS,Frederich Natl Lab Canc Res,NIH, Bldg 376,376 Boyles Str, Frederick, MD 21702 USA. EM mnl@helix.nih.gov RI pugliese, angelo/C-1729-2008; Nicklaus, Marc/N-4183-2014 FU NIH, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; US Department of Defense Threat Reduction Agency [TMTI0004_09_BH_T] FX This work was supported in part by the Intramural Research Program of NIH, Center for Cancer Research, in part with Federal finds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E, and in part by the US Department of Defense Threat Reduction Agency Grant TMTI0004_09_BH_T. 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 166 TC 10 Z9 10 U1 1 U2 31 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD OCT PY 2012 VL 4 IS 15 SI SI BP 1907 EP 1932 DI 10.4155/FMC.12.150 PG 26 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 055KI UT WOS:000312414500014 PM 23088273 ER PT J AU Zakharov, AV Peach, ML Sitzmann, M Filippov, IV McCartney, H Smith, LH Pugliese, A Nicklaus, MC AF Zakharov, Alexey V. Peach, Megan L. Sitzmann, Markus Filippov, Igor V. McCartney, Heather Smith, Layton H. Pugliese, Angelo Nicklaus, Marc C. TI Computational tools and resources for metabolism-related property predictions. 2. Application to prediction of half-life time in human liver microsomes SO FUTURE MEDICINAL CHEMISTRY LA English DT Article ID DRUG DISCOVERY; QSAR MODELS; QSPR MODELS; IN-VITRO; STABILITY; VALIDATION; TOXICITY; DATABASE; PASS; RAT AB Background: The most important factor affecting metabolic excretion of compounds from the body is their half-life time. This provides an indication of compound stability of, for example, drug molecules. We report on our efforts to develop QSAR models for metabolic stability of compounds, based on in vitro half-life assay data measured in human liver microsomes. Method: A variety of QSAR models generated using different statistical methods and descriptor sets implemented in both open-source and commercial programs (KNIME, GUSAR and StarDrop) were analyzed. The models obtained were compared using four different external validation sets from public and commercial data sources, including two smaller sets of in vivo half-life data in humans. Conclusion: In many cases, the accuracy of prediction achieved on one external test set did not correspond to the results achieved with another test set. The most predictive models were used for predicting the metabolic stability of compounds from the open NCI database, the results of which are publicly available on the NCI/CADD Group web server (http://cactus.nci.nih.gov). C1 [Zakharov, Alexey V.; Sitzmann, Markus; McCartney, Heather; Pugliese, Angelo; Nicklaus, Marc C.] NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,DHHS,Frederick Natl Lab Canc Res,NIH, Frederick, MD 21702 USA. [Peach, Megan L.; Filippov, Igor V.] SAIC Frederick SAIC Inc, CADD Grp, Biol Chem Lab, Frederick Natl Lab Canc Res,Basic Sci Program, Frederick, MD 21702 USA. [McCartney, Heather] Vanderbilt Univ, Interdisciplinary Grad Program, Nashville, TN 37240 USA. [Smith, Layton H.] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, Orlando, FL 32827 USA. [Pugliese, Angelo] Comp Aided Drug Design Canc Res UK, Beatson Labs, Drug Discovery Programme, Glasgow G61 1BD, Lanark, Scotland. RP Nicklaus, MC (reprint author), NCI, CADD Grp, Biol Chem Lab, Ctr Canc Res,DHHS,Frederick Natl Lab Canc Res,NIH, Bldg 376,376 Boyles Str, Frederick, MD 21702 USA. EM mnl@helix.nih.gov RI pugliese, angelo/C-1729-2008; Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU NIH [HG005033]; NIH, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by NIH grant HG005033 (L Smith), in part by the Intramural Research Program of NIH, Center for Cancer Research, and in part with Federal finds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. AV Zakharov is a member of the GUSAR Development Group, and co-holder of the Russian Patent No. 2006613591 of the GUSAR software, issued 16 October 2006 by the Russian State Patent Agency. 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 25 TC 10 Z9 10 U1 0 U2 16 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD OCT PY 2012 VL 4 IS 15 SI SI BP 1933 EP 1944 DI 10.4155/FMC.12.152 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 055KI UT WOS:000312414500015 PM 23088274 ER PT J AU Moeller, SJ Tomasi, D Honorio, J Volkow, ND Goldstein, RZ AF Moeller, S. J. Tomasi, D. Honorio, J. Volkow, N. D. Goldstein, R. Z. TI Dopaminergic involvement during mental fatigue in health and cocaine addiction SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE anterior cingulate cortex; color-word stroop; dopamine; executive function; fMRI; methylphenidate; midbrain; motivation; positron emission tomography; self-regulation ID ANTERIOR CINGULATE CORTEX; NUCLEUS-ACCUMBENS DOPAMINE; MEDIAL FRONTAL-CORTEX; DEPENDENT PATIENTS; COGNITIVE CONTROL; STROOP TASK; ORAL METHYLPHENIDATE; PREFRONTAL CORTICES; BRAIN ACTIVATION; DECISION-MAKING AB Dopamine modulates executive function, including sustaining cognitive control during mental fatigue. Using event-related functional magnetic resonance imaging (fMRI) during the color-word Stroop task, we aimed to model mental fatigue with repeated task exposures in 33 cocaine abusers and 20 healthy controls. During such mental fatigue (indicated by increased errors, and decreased post-error slowing and dorsal anterior cingulate response to error as a function of time-on-task), healthy individuals showed increased activity in the dopaminergic midbrain to error. Cocaine abusers, characterized by disrupted dopamine neurotransmission, showed an opposite pattern of response. This midbrain fMRI activity with repetition was further correlated with objective indices of endogenous motivation in all subjects: a state measure (task reaction time) and a trait measure (dopamine D2 receptor availability in caudate, as revealed by positron emission tomography data collected in a subset of this sample, which directly points to a contribution of dopamine to these results). In a second sample of 14 cocaine abusers and 15 controls, administration of an indirect dopamine agonist, methylphenidate, reversed these midbrain responses in both groups, possibly indicating normalization of response in cocaine abusers because of restoration of dopamine signaling but degradation of response in healthy controls owing to excessive dopamine signaling. Together, these multimodal imaging findings suggest a novel involvement of the dopaminergic midbrain in sustaining motivation during fatigue. This region might provide a useful target for strengthening self-control and/or endogenous motivation in addiction. Translational Psychiatry (2012) 2, e176; doi:10.1038/tp.2012.110; published online 23 October 2012 C1 [Moeller, S. J.; Honorio, J.; Goldstein, R. Z.] Brookhaven Natl Lab, Ctr Translat Neuroimaging, Dept Med Res, Upton, NY 11973 USA. [Tomasi, D.; Volkow, N. D.] NIAAA, Bethesda, MD 90034 USA. [Honorio, J.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Volkow, N. D.] NIDA, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, Ctr Translat Neuroimaging, Dept Med Res, POB 5000,30 Bell Ave, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Tomasi, Dardo/J-2127-2015; Moeller, Scott/L-5549-2016 OI Moeller, Scott/0000-0002-4449-0844 FU National Institute on Drug Abuse [1R01DA023579, 1F32DA030017-01]; NIH Intramural program; Brookhaven Science Associates, LLC [DE-AC02-98CHI-886]; US Department of Energy FX This study was supported by grants from the National Institute on Drug Abuse (to RZG: 1R01DA023579; to SJM: 1F32DA030017-01) and the NIH Intramural program. We gratefully acknowledge the contributions of Muhammad A Parvaz, Anna Konova, Nelly Alia-Klein, Thomas Maloney, Patricia A Woicik, Ruiliang Wang, Alex Panagopoulos, Dimitris Samaras, Frank Telang and Gene-Jack Wang. This manuscript has been authored by Brookhaven Science Associates, LLC under Contract No. DE-AC02-98CHI-886 with the US Department of Energy. The United States Government retains, and the publisher, by accepting the article for publication, acknowledges, a world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for the United States Government purposes. NR 96 TC 24 Z9 24 U1 0 U2 15 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 OCT PY 2012 VL 2 AR e176 DI 10.1038/tp.2012.110 PG 10 WC Psychiatry SC Psychiatry GA 062EB UT WOS:000312900800012 PM 23092980 ER PT J AU Hooten, NN Fitzpatrick, M Kompaniez, K Jacob, KD Moore, BR Nagle, J Barnes, J Lohani, A Evans, MK AF Hooten, Nicole Noren Fitzpatrick, Megan Kompaniez, Kari Jacob, Kimberly D. Moore, Brittany R. Nagle, Julia Barnes, Janice Lohani, Althaf Evans, Michele K. TI Coordination of DNA repair by NEIL1 and PARP-1: a possible link to aging SO AGING-US LA English DT Article DE PARP; base excision repair; DNA damage; oxidative stress; aging; glycosylase ID BASE-EXCISION-REPAIR; POLY(ADP-RIBOSE) POLYMERASE-ACTIVITY; GLYCOSYLASE NEIL1; MAMMALIAN-CELLS; OXIDIZED BASES; DAMAGE; CANCER; DISEASE; XRCC1; CENTENARIANS AB Oxidative DNA damage accumulates with age and is repaired primarily via the base excision repair (BER) pathway. This process is initiated by DNA glycosylases, which remove damaged bases in a substrate-specific manner. The DNA glycosylases human 8-oxoguanine-DNA glycosylase (OGG1) and NEIL1, a mammalian homolog of Escherichia coli endonuclease VIII, have overlapping yet distinct substrate specificity. Recently, we reported that OGG1 binds to the Poly(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein that poly(ADP-ribosyl)ates nuclear proteins in response to DNA damage and other cellular signals. Here, we show that NEIL1 and PARP-1 bind both in vitro and in vivo. PARP-1 binds to the C-terminal-100 amino acids of NEIL1 and NEIL1 binds to the BRCT domain of PARP-1. NEIL1 stimulates the poly(ADP-ribosyl)ation activity of PARP-1. Furthermore, NEIL-deficient fibroblasts have impaired poly(ADP-ribosyl) ation of cellular proteins after DNA damage, which can be rescued by NEIL1 expression. Additionally, PARP-1 inhibits NEIL1 incision activity in a concentration-dependent manner. Consistent with the idea of impaired DNA repair during aging, we observed differential binding of PARP-1 to recombinant NEIL1 in older mice compared to younger mice. These data further support the idea that dynamic interplay between different base excision repair proteins is important for efficient BER. C1 [Hooten, Nicole Noren; Fitzpatrick, Megan; Kompaniez, Kari; Jacob, Kimberly D.; Moore, Brittany R.; Nagle, Julia; Barnes, Janice; Lohani, Althaf; Evans, Michele K.] NIA, Lab Populat Sci, NIH, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIA, Lab Populat Sci, NIH, Baltimore, MD 21224 USA. EM me42v@nih.gov OI Noren Hooten, Nicole/0000-0002-1683-3838 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; Howard Hughes Medical Institute Program at Spelman College (HHMI) [52006134] FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. B.R.M was supported by the Howard Hughes Medical Institute Program at Spelman College (HHMI Grant # 52006134). The authors wish to thank Dr. R. Stephen Lloyd for the gift of the WT and NEIL1-/- MEFs, Dr. David Wilson, III for the NEIL1 cDNA, Dr. Rafael de Cabo and Dr. Evi Mercken for the young and old mouse livers and Dr. Sebastian Fugmann and Dr. Michael Seidman for comments on the manuscript. NR 53 TC 11 Z9 11 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD OCT PY 2012 VL 4 IS 10 BP 674 EP 685 PG 12 WC Cell Biology SC Cell Biology GA 048LB UT WOS:000311911800004 ER PT J AU Tominaga-Yamanaka, K Abdelmohsen, K Martindale, JL Yang, XL Taub, DD Gorospe, M AF Tominaga-Yamanaka, Kumiko Abdelmohsen, Kotb Martindale, Jennifer L. Yang, Xiaoling Taub, Dennis D. Gorospe, Myriam TI NF90 coordinately represses the senescence-associated secretory phenotype SO AGING-US LA English DT Article DE RNA-binding protein; ribonucleoprotein complex; mRNA translation; mRNA stability; post-transcriptional gene regulation; senescence ID RNA-BINDING PROTEINS; IL-2 MESSENGER-RNA; CELLULAR SENESCENCE; OXIDATIVE STRESS; EXPRESSION; PHOSPHORYLATION; FIBROBLASTS; NETWORKS; KINASE; HUR AB A hallmark trait of cellular senescence is the acquisition of a senescence-associated secretory phenotype (SASP). SASP factors include cytokines and their receptors (IL-6, IL-8, osteoprotegerin, GM-CSF), chemokines and their ligands (MCP-1, HCC4), and oncogenes (Gro1 and Gro2), many of them encoded by mRNAs whose stability and translation are tightly regulated. Using two models of human fibroblast senescence (WI-38 and IDH4 cells), we report the identification of RNA-binding protein NF90 as a post-transcriptional repressor of several SASP factors. In 'young', proliferating fibroblasts, NF90 was highly abundant, associated with numerous SASP mRNAs, and inhibited their expression. By contrast, senescent cells expressed low levels of NF90, thus allowing SASP factor expression to increase. NF90 elicited these effects mainly by repressing the translation of target SASP mRNAs, since silencing NF90 did not increase the steady-state levels of SASP mRNAs but elevated key SASP factors including MCP-1, GROa, IL-6, and IL-8. Our findings indicate that NF90 contributes to maintaining low levels of SASP factors in non-senescent cells, while NF90 reduction in senescent cells allows SASP factor expression to rise. C1 [Tominaga-Yamanaka, Kumiko; Abdelmohsen, Kotb; Martindale, Jennifer L.; Yang, Xiaoling; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Taub, Dennis D.] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging-Intramural Research Program, National Institutes of Health FX This work was supported in its entirety by the National Institute on Aging-Intramural Research Program, National Institutes of Health. NR 48 TC 15 Z9 15 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD OCT PY 2012 VL 4 IS 10 BP 695 EP 708 PG 14 WC Cell Biology SC Cell Biology GA 048LB UT WOS:000311911800006 PM 23117626 ER PT J AU Chatterjee, R Zhao, JF He, XM Shlyakhtenko, A Mann, I Waterfall, JJ Meltzer, P Sathyanarayana, BK FitzGerald, PC Vinson, C AF Chatterjee, Raghunath Zhao, Jianfei He, Ximiao Shlyakhtenko, Andrey Mann, Ishminder Waterfall, Joshua J. Meltzer, Paul Sathyanarayana, B. K. FitzGerald, Peter C. Vinson, Charles TI Overlapping ETS and CRE Motifs ((G)/(C)CGGAAGTGACGTCA) Preferentially Bound by GABP alpha and CREB Proteins SO G3-GENES GENOMES GENETICS LA English DT Article DE proximal promoters; transcription factor binding sites; co-localization; transcriptional start site; EMSA ID GENOME-WIDE ANALYSIS; FACTOR-BINDING SITES; RNA-POLYMERASE-II; CHIP-SEQ DATA; TRANSCRIPTION FACTORS; DNA-BINDING; DEPENDENT TRANSCRIPTION; PROXIMAL PROMOTERS; CPG METHYLATION; CORE PROMOTER AB Previously, we identified 8-bps long DNA sequences (8-mers) that localize in human proximal promoters and grouped them into known transcription factor binding sites (TFBS). We now examine split 8-mers consisting of two 4-mers separated by 1-bp to 30-bps (X-4-N1-30-X-4) to identify pairs of TFBS that localize in proximal promoters at a precise distance. These include two overlapping TFBS: the ETS double left right arrow ETS motif ((C)/(G)CCGGAAGCGGAA) and the ETS double left right arrow CRE motif ((C)/(G)CGGAAGTGACGTCAC). The nucleotides in bold are part of both TFBS. Molecular modeling shows that the ETS double left right arrow CRE motif can be bound simultaneously by both the ETS and the B-ZIP domains without protein-protein clashes. The electrophoretic mobility shift assay (EMSA) shows that the ETS protein GABP alpha and the B-ZIP protein CREB preferentially bind to the ETS double left right arrow CRE motif only when the two TFBS overlap precisely. In contrast, the ETS domain of ETV5 and CREB interfere with each other for binding the ETS double left right arrow CRE. The 11-mer (CGGAAGTGACG), the conserved part of the ETS double left right arrow CRE motif, occurs 226 times in the human genome and 83% are in known regulatory regions. In vivo GABP alpha and CREB ChIP-seq peaks identified the ETS double left right arrow CRE as the most enriched motif occurring in promoters of genes involved in mRNA processing, cellular catabolic processes, and stress response, suggesting that a specific class of genes is regulated by this composite motif. C1 [Chatterjee, Raghunath; Zhao, Jianfei; He, Ximiao; Shlyakhtenko, Andrey; Mann, Ishminder; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Waterfall, Joshua J.; Meltzer, Paul] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Sathyanarayana, B. K.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [FitzGerald, Peter C.] NCI, Genome Anal Unit, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), 9000 Rockville Pike,Bldg 37,Rm 3128, Bethesda, MD 20892 USA. EM Vinsonc@mail.nih.gov RI He, Ximiao/C-1292-2010 OI He, Ximiao/0000-0003-1253-5275 NR 55 TC 6 Z9 6 U1 0 U2 6 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD OCT 1 PY 2012 VL 2 IS 10 BP 1243 EP 1256 DI 10.1534/g3.112.004002 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 055ZN UT WOS:000312456700012 PM 23050235 ER PT J AU Hinnebusch, AG Lorsch, JR AF Hinnebusch, Alan G. Lorsch, Jon R. TI The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID START CODON SELECTION; GUANINE-NUCLEOTIDE EXCHANGE; 40S RIBOSOMAL-SUBUNIT; STRINGENT AUG SELECTION; TRANSFER-RNA BINDING; MESSENGER-RNA; IN-VIVO; CRYSTAL-STRUCTURE; PREINITIATION COMPLEX; MULTIFACTOR COMPLEX AB Translation initiation in eukaryotes is a highly regulated and complex stage of gene expression. It requires the action of at least 12 initiation factors, many of which are known to be the targets of regulatory pathways. Here we review our current understanding of the molecular mechanics of eukaryotic translation initiation, focusing on recent breakthroughs from in vitro and in vivo studies. We also identify important unanswered questions that will require new ideas and techniques to solve. C1 [Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Lorsch, Jon R.] Johns Hopkins Univ, Dept Biophys & Biophys Chem, Sch Med, Baltimore, MD 21205 USA. RP Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov; jlorsch@jhmi.edu OI Lorsch, Jon/0000-0002-4521-4999 NR 137 TC 15 Z9 17 U1 1 U2 37 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD OCT PY 2012 VL 4 IS 10 AR a011544 DI 10.1101/cshperspect.a011544 PG 25 WC Cell Biology SC Cell Biology GA 054MJ UT WOS:000312347600013 ER PT J AU Li, QS Zhang, YY Pene, V Cha, H Liang, TJ AF Li, Qisheng Zhang, Yong-Yuan Pene, Veronique Cha, Helen Liang, T. Jake TI Systems Biology of Host Dependencies in the Complete Life Cycle of Hepatitis C Virus SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Li, Qisheng; Zhang, Yong-Yuan; Pene, Veronique; Cha, Helen; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. RI Li, Qisheng/K-1909-2013 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 60 BP 222A EP 222A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601060 ER PT J AU Speliotes, EK Hernaez, R Feitosa, MF Palmer, ND Peyser, PA Harris, TB Wagenknecht, LE Liu, JK Kahali, B Carr, JJ Smith, AV Musani, SK Borecki, IB Bielak, LF Yerges-Armstrong, LM AF Speliotes, Elizabeth K. Hernaez, Ruben Feitosa, Mary F. Palmer, Nicholette D. Peyser, Patricia A. Harris, Tamara B. Wagenknecht, Lynne E. Liu, Jiankang Kahali, Bratati Carr, John J. Smith, Albert V. Musani, Solomon K. Borecki, Ingrid B. Bielak, Lawrence F. Yerges-Armstrong, Laura M. CA GOLD Consortium TI Genetic variants predispose to Nonalcoholic Fatty Liver Disease across ancestries SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Speliotes, Elizabeth K.; Peyser, Patricia A.; Kahali, Bratati; Bielak, Lawrence F.; GOLD Consortium] Univ Michigan, Ann Arbor, MI 48109 USA. [Hernaez, Ruben] Johns Hopkins Univ, Baltimore, MD USA. [Hernaez, Ruben] Washington Hosp Ctr, Washington, DC 20010 USA. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, St Louis, MO USA. [Palmer, Nicholette D.; Wagenknecht, Lynne E.; Carr, John J.] Wake Forest Sch Med, Winston Salem, NC USA. [Harris, Tamara B.] NIH, Bethesda, MD 20892 USA. [Liu, Jiankang; Musani, Solomon K.] Univ Mississippi, Jackson, MS 39216 USA. [Smith, Albert V.] Iceland Heart Assoc, Kopavogur, Iceland. [Yerges-Armstrong, Laura M.] Univ Maryland, Baltimore, MD 21201 USA. RI Hernaez, Ruben/C-4039-2014; Carr, John/A-1938-2012; Feitosa, Mary/K-8044-2012 OI Hernaez, Ruben/0000-0002-1518-4020; Carr, John/0000-0002-4398-8237; Feitosa, Mary/0000-0002-0933-2410 NR 0 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 100 BP 242A EP 242A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601100 ER PT J AU Anstee, QM Darlay, R Leathart, JB Clement, J Clement, K Aithal, GP Valenti, L Van Gaal, L Stickel, F Allison, ME Romero-Gomez, M Andrade, RJ Reeves, H Pihlajamaki, J Bedossa, P Kotronen, A Yki-Jarvinen, H Chalasani, NP Kleiner, DE Rotter, J Burt, AD Ratziu, V Cordell, HJ Daly, AK Day, CP AF Anstee, Quentin M. Darlay, Rebecca Leathart, Julian B. Clement, Joan Clement, Karine Aithal, Guruprasad P. Valenti, Luca Van Gaal, Luc Stickel, Felix Allison, Michael E. Romero-Gomez, Manuel Andrade, Raul J. Reeves, Helen Pihlajamaki, Jussi Bedossa, Pierre Kotronen, Anna Yki-Jarvinen, Hannele Chalasani, Naga P. Kleiner, David E. Rotter, Jerome Burt, Alastair D. Ratziu, Vlad Cordell, Heather J. Daly, Ann K. Day, Christopher P. TI Genome-Wide Association Analysis Confirms Importance of PNPLA3 and Identifies Novel Variants Associated With Histologically Progressive Steatohepatitis in NAFLD SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Anstee, Quentin M.; Leathart, Julian B.; Burt, Alastair D.; Daly, Ann K.; Day, Christopher P.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Darlay, Rebecca; Cordell, Heather J.] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Allison, Michael E.] Cambridge Univ Hosp NHS Fdn Trust, Cambridge, England. [Aithal, Guruprasad P.] Nottingham Univ Hosp NHS Trust, Nottingham Digest Dis Ctr, Biomed Res Unit, Natl Inst Hlth Res, Nottingham, England. [Ratziu, Vlad] Univ Paris 06, Paris, France. [Chalasani, Naga P.] Indiana Univ Sch Med, Indianapolis, IN USA. [Kleiner, David E.] NCI, Bethesda, MD 20892 USA. [Rotter, Jerome] Cedars Sinai Genet Inst, Los Angeles, CA USA. [Van Gaal, Luc] Univ Antwerp Hosp, Dept Endocrinol Diabetol & Metab, Edegem, Belgium. [Andrade, Raul J.] Hosp Univ Virgen de la Victoria, Fac Med, Malaga, Spain. [Clement, Joan; Clement, Karine] Hop La Pitie Salpetriere, Assistance Publ Hop Paris, ICAN Inst Cardiometab & Nutr, Paris, France. [Bedossa, Pierre] Beaujon Hosp, Assistance Publ Hop Paris, Dept Pathol, Paris, France. [Kotronen, Anna; Yki-Jarvinen, Hannele] Univ Helsinki, Helsinki, Finland. [Stickel, Felix] Univ Bern, Bern, Switzerland. [Pihlajamaki, Jussi] Univ Eastern Finland, Kuopio, Finland. [Romero-Gomez, Manuel] Univ Spain, Valme Univ Hosp, Seville, Spain. [Valenti, Luca] Univ Milan, Milan, Italy. [Reeves, Helen] Newcastle Univ, No Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RI Burt, Alastair/D-3634-2013; Romero Gomez, Manuel/L-8030-2014; Anstee, Quentin/L-2981-2013; Valenti, Luca/B-3695-2009 OI Burt, Alastair/0000-0002-3011-7774; Anstee, Quentin/0000-0002-9518-0088; Valenti, Luca/0000-0001-8909-0345 NR 0 TC 6 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 146 BP 265A EP 266A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601146 ER PT J AU Rotman, Y Fujita, K Koh, C Maeder, DL Kleiner, DE Zmuda, JM O'Brien, TR Sanyal, AJ Liang, TJ AF Rotman, Yaron Fujita, Koji Koh, Christopher Maeder, Dennis L. Kleiner, David E. Zmuda, Joseph M. O'Brien, Thomas R. Sanyal, Arun J. Liang, T. Jake TI Identification of HSD17B13 and RORA as Genes Involved in Pathogenesis of Nonalcoholic Fatty Liver Disease SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Rotman, Yaron; Fujita, Koji; Koh, Christopher; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Maeder, Dennis L.; O'Brien, Thomas R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Maeder, Dennis L.] SAIC Frederick, Bethesda, MD USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zmuda, Joseph M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Sanyal, Arun J.] Virginia Commonwealth Univ, Div Gastroenterol Hepatol & Nutr, Richmond, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 145 BP 265A EP 265A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601145 ER PT J AU Vickers, KC Levin, MG Seneshaw, M Min, H Tabet, F Fuchs, M Remaley, AT Sanyal, AJ AF Vickers, Kasey C. Levin, Michael G. Seneshaw, Mulugeta Min, Haeki Tabet, Fatiha Fuchs, Michael Remaley, Alan T. Sanyal, Arun J. TI Altered High-Density Lipoprotein Mediated Intercellular Transport of microRNAs in Nonalcoholic Steatohepatitis SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Vickers, Kasey C.; Levin, Michael G.; Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20892 USA. [Tabet, Fatiha] Heart Res Inst, Sydney, NSW, Australia. [Seneshaw, Mulugeta; Min, Haeki; Fuchs, Michael; Sanyal, Arun J.] Virginia Commonwealth Univ, Div Gastroenterol Hepatol & Nutr, Richmond, VA USA. 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 148 BP 266A EP 267A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601148 ER PT J AU Zhang, WC Tsuda, M Yang, GX Tsuneyama, K Ando, Y Kawata, K Park, O Leung, PS Coppel, RL Ansari, AA Ridgway, WM Gao, B Lian, ZX He, XS Gershwin, ME AF Zhang, Weici Tsuda, Masanobu Yang, Guo-Xiang Tsuneyama, Koichi Ando, Yugo Kawata, Kazuhito Park, Ogyi Leung, Patrick S. Coppel, Ross L. Ansari, Aftab A. Ridgway, William M. Gao, Bin Lian, Zhe-Xiong He, Xiao-Song Gershwin, M. Eric TI Dissecting the Role of Il-12 in Autoimmune Cholangitis of dnTGF beta RII Mice SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Zhang, Weici; Tsuda, Masanobu; Yang, Guo-Xiang; Tsuneyama, Koichi; Ando, Yugo; Kawata, Kazuhito; Leung, Patrick S.; Lian, Zhe-Xiong; He, Xiao-Song; Gershwin, M. Eric] Univ Calif Davis, Davis, CA 95616 USA. [Tsuda, Masanobu] Kansai Med Univ, Dept Emergency & Crit Care Med, Osaka, Japan. [Tsuneyama, Koichi] Toyama Univ, Dept Diagost Pathol, Grad Sch Med & Pharmaceut Sci Res, Toyama 930, Japan. [Park, Ogyi; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Coppel, Ross L.] Monash Univ, Dept Microbiol, Melbourne, Vic 3004, Australia. [Ansari, Aftab A.] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Ridgway, William M.] Univ Cincinnati, Coll Med, Div Immunol Allergy & Rheumatol, Cincinnati, OH USA. [Lian, Zhe-Xiong] Univ Sci & Technol China, Inst Immunol, Hefei 230026, Peoples R China. [Lian, Zhe-Xiong] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China. RI Coppel, Ross/A-6626-2008 OI Coppel, Ross/0000-0002-4476-9124 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 220 BP 302A EP 302A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601220 ER PT J AU Werner, JM Gara, N Abdalla, A Liang, TJ Ghany, MG Rehermann, B AF Werner, Jens M. Gara, Naveen Abdalla, Adil Liang, T. Jake Ghany, Marc G. Rehermann, Barbara TI Longevity of cellular and humoral immune responses to hepatitis B vaccination SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Werner, Jens M.; Gara, Naveen; Abdalla, Adil; Liang, T. Jake; Ghany, Marc G.; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 240 BP 313A EP 313A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601240 ER PT J AU Hernaez, R Hoofnagle, JH Rotman, Y AF Hernaez, Ruben Hoofnagle, Jay H. Rotman, Yaron TI Rheumatoid Factor in Chronic Hepatitis B Reflects Disease Activity and Stage SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Hernaez, Ruben] Johns Hopkins Sch Med, Baltimore, MD USA. [Hernaez, Ruben] Washington Hosp Ctr, Washington, DC 20010 USA. [Hoofnagle, Jay H.; Rotman, Yaron] NIDDKD, Liver Dis Branch, Bethesda, MD 20892 USA. RI Hernaez, Ruben/C-4039-2014 OI Hernaez, Ruben/0000-0002-1518-4020 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 342 BP 359A EP 359A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601341 ER PT J AU Wong, DK Ghany, MG Khalili, M Sterling, RK Lau, D Di Bisceglie, AM Terrault, N Lok, AS AF Wong, David K. Ghany, Marc G. Khalili, Mandana Sterling, Richard K. Lau, Daryl Di Bisceglie, Adrian M. Terrault, Norah Lok, Anna S. TI Hepatitis B in North America: Patients screened for the Hepatitis B Research Network (HBRN) Adult Cohort Study SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Wong, David K.] Univ Toronto, Toronto, ON, Canada. [Ghany, Marc G.] NIDDK, NIH, Bethesda, MD USA. [Khalili, Mandana] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Sterling, Richard K.] Virginia Commonwealth Univ, Richmond, VA USA. [Lau, Daryl] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Di Bisceglie, Adrian M.] St Louis Univ, St Louis, MO 63103 USA. [Terrault, Norah] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lok, Anna S.] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 347 BP 361A EP 361A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601346 ER PT J AU Yamashita, T Honda, M Nakamoto, Y Nio, K Hara, Y Zeng, SS Hayashi, T Yamashita, T Mizukoshi, E Wang, XW Kaneko, S AF Yamashita, Taro Honda, Masao Nakamoto, Yasunari Nio, Kouki Hara, Yasumasa Zeng, Sha Sha Hayashi, Takehiro Yamashita, Tatsuya Mizukoshi, Eishiro Wang, Xin W. Kaneko, Shuichi TI The Evolution of Diverse Cancer Stem Cells in Human Liver Cancer SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis (AASLD) C1 [Yamashita, Taro; Honda, Masao; Nakamoto, Yasunari; Nio, Kouki; Hara, Yasumasa; Zeng, Sha Sha; Hayashi, Takehiro; Yamashita, Tatsuya; Mizukoshi, Eishiro; Kaneko, Shuichi] Kanazawa Univ Hosp, Kanazawa, Ishikawa, Japan. [Wang, Xin W.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 515 BP 443A EP 443A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955601514 ER PT J AU Homolya, L Fu, D Gutkind, S Lippincott-Schwartz, J Arias, IM AF Homolya, Laszlo Fu, Dong Gutkind, Silvio Lippincott-Schwartz, Jennifer Arias, Irwin M. TI Hepatocyte polarization and canalicular network formation: the role of LKB1 SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis (AASLD) C1 [Fu, Dong; Gutkind, Silvio; Lippincott-Schwartz, Jennifer; Arias, Irwin M.] NICHD, Cell Biol & Metab Branch, NIH, DIR, Bethesda, MD USA. [Homolya, Laszlo] Semmelweis Univ, Inst Biophys, Budapest, Hungary. RI Homolya, Laszlo/N-1154-2016 NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 740 BP 545A EP 546A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602119 ER PT J AU Urban, TJ Shianna, K Barnhart, HX Chalasani, NP Fontana, RJ Serrano, J Stolz, A Goldstein, DB Watkins, PB AF Urban, Thomas J. Shianna, Kevin Barnhart, Huiman X. Chalasani, Naga P. Fontana, Robert J. Serrano, Jose Stolz, Andrew Goldstein, David B. Watkins, Paul B. TI Whole-exome sequencing identifies rare genetic variants that may contribute to isoniazid (INH)-induced liver injury SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Urban, Thomas J.; Shianna, Kevin; Goldstein, David B.] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC USA. [Barnhart, Huiman X.] Duke Clin Res Inst, Durham, NC USA. [Chalasani, Naga P.] Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN USA. [Fontana, Robert J.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Serrano, Jose] NIDDKD, Bethesda, MD 20892 USA. [Stolz, Andrew] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Watkins, Paul B.] Hamner Univ N Carolina, Inst Drug Safety Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 821 BP 593A EP 594A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602200 ER PT J AU Foureau, DM Walling, TL Kleiner, DE Ahrens, WA Jacobs, WC McKillop, LH Barnhart, HX Serrano, J Bonkovsky, HL AF Foureau, David M. Walling, Tracy L. Kleiner, David E. Ahrens, William A. Jacobs, W. Carl McKillop, Lain H. Barnhart, Huiman X. Serrano, Jose Bonkovsky, Herbert L. TI Profiles of Leukocytes Infiltrating Livers of Subjects with Drug-Induced Liver Injury (DILI) SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Foureau, David M.; Walling, Tracy L.; Ahrens, William A.; Jacobs, W. Carl; McKillop, Lain H.; Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Kleiner, David E.] NIH, Bethesda, MD 20892 USA. [Barnhart, Huiman X.] Duke Clin Res Inst, Durham, NC USA. [Serrano, Jose] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 827 BP 596A EP 597A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602206 ER PT J AU Hayashi, PH Barnhart, HX Fontana, RJ Chalasani, NP Davern, TJ Talwalkar, J Reddy, KR Stolz, A Hoofnagle, JH Rockey, DC AF Hayashi, Paul H. Barnhart, Huiman X. Fontana, Robert J. Chalasani, Naga P. Davern, Timothy J. Talwalkar, Jayant Reddy, K. Rajender Stolz, Andrew Hoofnagle, Jay H. Rockey, Don C. TI Reliability of the Drug Induced Liver Injury Network (DILIN) Expert Opinion Process in the Diagnosis of DILI SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Hayashi, Paul H.] Univ N Carolina, Chapel Hill, NC USA. [Barnhart, Huiman X.] Duke Univ, Durham, NC USA. [Fontana, Robert J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Chalasani, Naga P.] Indiana Univ, Indianapolis, IN 46204 USA. [Davern, Timothy J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Talwalkar, Jayant] Mayo Clin, Rochester, MN USA. [Reddy, K. Rajender] Univ Penn, Philadelphia, PA 19104 USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Branch, Bethesda, MD USA. [Rockey, Don C.] Univ Texas SW, Dallas, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 826 BP 596A EP 596A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602205 ER PT J AU Fontana, RJ Gu, JZ Barnhart, HX Hayashi, PH Reddy, KR Talwalkar, J Chalasani, NP Lee, WM Stolz, A Davern, TJ Watkins, P Serrano, J AF Fontana, Robert J. Gu, Jiezhun Barnhart, Huiman X. Hayashi, Paul H. Reddy, K. Rajender Talwalkar, Jayant Chalasani, Naga P. Lee, William M. Stolz, Andrew Davern, Timothy J. Watkins, Paul Serrano, Jose TI Subject race and liver biochemical profile are strongly associated with clinical outcomes and chronic liver injury: Results from the DILIN Prospective study SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Fontana, Robert J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Gu, Jiezhun; Barnhart, Huiman X.] Duke Clin Res Inst, Durham, NC USA. [Hayashi, Paul H.; Watkins, Paul] Univ N Carolina, Chapel Hill, NC USA. [Reddy, K. Rajender] Univ Penn, Philadelphia, PA 19104 USA. [Talwalkar, Jayant] Mayo Clin, Sch Med, Rochester, MN USA. [Chalasani, Naga P.] Indiana Univ, Indianapolis, IN 46204 USA. [Lee, William M.] Univ Texas SW, Dallas, TX USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Davern, Timothy J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Serrano, Jose] NIDDK, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 837 BP 601A EP 601A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602216 ER PT J AU Holczbauer, A Factor, VM Andersen, JB Kleiner, DE Raggi, C Marquardt, JU Kitade, M Seo, D Akita, H Durkin, M Thorgeirsson, SS AF Holczbauer, Agnes Factor, Valentina M. Andersen, Jesper B. Kleiner, David E. Raggi, Chiara Marquardt, Jens U. Kitade, Mitsuteru Seo, Deakwan Akita, Hirofumi Durkin, Marian Thorgeirsson, Snorri S. TI Modeling pathogenesis of liver cancer in lineage specific cell types SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Holczbauer, Agnes; Factor, Valentina M.; Andersen, Jesper B.; Raggi, Chiara; Marquardt, Jens U.; Kitade, Mitsuteru; Seo, Deakwan; Akita, Hirofumi; Durkin, Marian; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 840 BP 602A EP 602A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602219 ER PT J AU Han, S Hu, CL Moser, CD Shire, AM Chaiteerakij, R Miamen, AG Kim, TH Fang, Y Thorgeirsson, SS Fernandez-Zapico, ME Roberts, LR AF Han, Shaoshan Hu, Chunling Moser, Catherine D. Shire, Abdirashid M. Chaiteerakij, Roongruedee Miamen, Alexander G. Kim, Tae Hyo Fang, Yong Thorgeirsson, Snorri S. Fernandez-Zapico, Martin E. Roberts, Lewis R. TI Sulfatase 2 enhances hepatocellular carcinoma cell migration and invasion through activation of integrin alpha 3 beta 1 signaling SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Han, Shaoshan; Hu, Chunling; Moser, Catherine D.; Shire, Abdirashid M.; Chaiteerakij, Roongruedee; Miamen, Alexander G.; Kim, Tae Hyo; Fang, Yong; Roberts, Lewis R.] Mayo Clin, Coll Med, Ctr Basic Res Digest Dis, Rochester, MN USA. [Fernandez-Zapico, Martin E.] Mayo Clin, Schulze Ctr Novel Therapeut, Rochester, MN USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 865 BP 613A EP 613A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602244 ER PT J AU Staib, F Pelc, A Eftekhar-Afzali, S Krupp, M Thorgeirsson, SS Galle, PR Schilling, T Wang, XW Teufel, A Muller, M AF Staib, Frank Pelc, Agnes Eftekhar-Afzali, Shermineh Krupp, Markus Thorgeirsson, Snorri S. Galle, Peter R. Schilling, Tobias Wang, Xin W. Teufel, Andreas Mueller, Martina TI The p53 Family Gene Signature Predicts Prognosis in Hepatocellular Carcinoma SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Staib, Frank; Krupp, Markus; Galle, Peter R.; Teufel, Andreas] Johannes Gutenberg Univ Mainz, Dept Med 1, D-6500 Mainz, Germany. [Pelc, Agnes; Eftekhar-Afzali, Shermineh] Univ Heidelberg Hosp, Dept Internal Med Hepatol & Gastroenterol 4, Heidelberg, Germany. [Thorgeirsson, Snorri S.] NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schilling, Tobias] Univ Heidelberg Hosp, Dept Internal Med & Clin Chem 1, Heidelberg, Germany. [Wang, Xin W.] NCI, Lab Human Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mueller, Martina] Univ Hosp Regensburg, Dept Internal Med 1, Regensburg, Germany. [Teufel, Andreas] Johannes Gutenberg Univ Mainz, Univ Hosp, Core Facil Bioinformat, Mainz, Germany. 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 877 BP 618A EP 619A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602256 ER PT J AU Gara, N Abdalla, A Rivera, EM Zhao, XC Werner, JM Liang, TJ Hoofnagle, JH Rehermann, B Ghany, MG AF Gara, Naveen Abdalla, Adil Rivera, Elenita M. Zhao, Xiongce Werner, Jens M. Liang, T. Jake Hoofnagle, Jay H. Rehermann, Barbara Ghany, Marc G. TI Durability of Antibody Response Following Hepatitis B Vaccination in Healthcare Workers Vaccinated as Adults SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Gara, Naveen; Abdalla, Adil; Rivera, Elenita M.; Zhao, Xiongce; Werner, Jens M.; Liang, T. Jake; Hoofnagle, Jay H.; Rehermann, Barbara; Ghany, Marc G.] NIDDK, NIH, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 905 BP 630A EP 631A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602284 ER PT J AU Sarkar, S Rivera, EM Engle, RE Schechterly, CA Alter, HJ Bang, TJ Purcell, RH Hoofnagle, JH Ghany, MG AF Sarkar, Souvik Rivera, Elenita M. Engle, Ronald E. Schechterly, Cathy A. Alter, Harvey J. Bang, T. Jake Purcell, Robert H. Hoofnagle, Jay H. Ghany, Marc G. TI Acute Hepatitis E in the Workplace: An Epidemiologic Investigation SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Sarkar, Souvik; Rivera, Elenita M.; Bang, T. Jake; Ghany, Marc G.] NIDDK LDB Intramural, NIH, Bethesda, MD USA. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Hepatitis Virus Sect, NIH, Bethesda, MD 20892 USA. [Schechterly, Cathy A.; Alter, Harvey J.] NIH, DTM Infect Dis Sect, Bethesda, MD 20892 USA. [Hoofnagle, Jay H.] NIDDK, LDB, Extramural Branch, NIH, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 954 BP 654A EP 654A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602333 ER PT J AU Sarkar, S Weiss, A Liang, TJ Hoofnagle, JH Rotman, Y AF Sarkar, Souvik Weiss, Allison Liang, T. Jake Hoofnagle, Jay H. Rotman, Yaron TI Characteristics of Fatigue in patients with Chronic Liver Disease SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Sarkar, Souvik; Weiss, Allison; Liang, T. Jake; Hoofnagle, Jay H.; Rotman, Yaron] NIDDK, LDB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 981 BP 667A EP 668A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602360 ER PT J AU Noureddin, M Thomas, E Rotman, Y Liang, TJ AF Noureddin, Mazen Thomas, Emmanuel Rotman, Yaron Liang, T. Jake TI Hepatic expressions of interferons types I, II & III, interferon stimulated genes (ISGs) and IL28B genotypes and treatment response in hepatitis C SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Noureddin, Mazen; Thomas, Emmanuel; Rotman, Yaron; Liang, T. Jake] NIDDK, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 989 BP 671A EP 671A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602368 ER PT J AU Kohli, A Meissner, E Santich, B Barrett, L Funk, E Shaffer, A Burbelo, P Shiyakumar, B Polis, MA Masur, H Moir, S Kottilil, S AF Kohli, Anita Meissner, Eric Santich, Brian Barrett, Lisa Funk, Emily Shaffer, Ashton Burbelo, Peter Shiyakumar, Bhavana Polis, Michael A. Masur, Henry Moir, Susan Kottilil, Shyam TI Antibody response to core and B cell subpopulations distinguish treatment outcome in HIV/HCV patients treated with interferon and ribavirin SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Kohli, Anita; Meissner, Eric; Santich, Brian; Barrett, Lisa; Funk, Emily; Shaffer, Ashton; Shiyakumar, Bhavana; Moir, Susan; Kottilil, Shyam] NIH, LIR, Bethesda, MD 20892 USA. [Polis, Michael A.; Masur, Henry] NIH, CCMD, Bethesda, MD 20892 USA. [Burbelo, Peter] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1037 BP 693A EP 693A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602414 ER PT J AU Nakamura, I Yang, JD Mikhail, DS Lai, JP Roberts, LR AF Nakamura, Ikuo Yang, Ju Dong Mikhail, Dalia S. Lai, Jin-Ping Roberts, Lewis R. TI Brivanib attenuates hepatic fibrosis in vivo and stellate cell proliferation in vitro by inhibition of FGF and VEGF signaling SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Nakamura, Ikuo; Yang, Ju Dong; Mikhail, Dalia S.; Roberts, Lewis R.] Mayo Clin, Coll Med, Ctr Basic Res Digest Dis, Rochester, MN USA. [Lai, Jin-Ping] NCI, Pathol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1234 BP 779A EP 779A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602609 ER PT J AU Carpentier, A Li, QS Zhang, F Lee, SB Thorgeirsson, SS Liang, TJ AF Carpentier, Arnaud Li, Qisheng Zhang, Fang Lee, Seung Bum Thorgeirsson, Snorri S. Liang, T. Jake TI HCV infection of human stem cell-derived hepatocytes and potential strategy for treatment of viral liver diseases SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Carpentier, Arnaud; Li, Qisheng; Zhang, Fang; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Lee, Seung Bum; Thorgeirsson, Snorri S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Li, Qisheng/K-1909-2013 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1290 BP 803A EP 803A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602665 ER PT J AU Koh, C Zhao, XC Minniti, CP Conrey, AK Jackson, M Seamon, CA Kato, GJ Heller, T AF Koh, Christopher Zhao, Xiongce Minniti, Caterina P. Conrey, Anna K. Jackson, Mary Seamon, Catherine A. Kato, Gregory J. Heller, Theo TI Liver Stiffness Increases Acutely During Sickle Cell Vaso-Occlusive Crisis SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Koh, Christopher; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Minniti, Caterina P.; Conrey, Anna K.; Jackson, Mary; Seamon, Catherine A.; Kato, Gregory J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Off Director, NIH, Bethesda, MD USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1330 BP 820A EP 821A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955602703 ER PT J AU Brunt, EM Kleiner, DE Wilson, L Unalp, A Tonascia, J Neuschwander-Tetri, BA AF Brunt, Elizabeth M. Kleiner, David E. Wilson, Laura Unalp, Aynur Tonascia, James Neuschwander-Tetri, Brent A. TI Histologic Predictors of Improvement in Fibrosis in NASH: Results from the Clinical Research Network PIVENS Trial SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Brunt, Elizabeth M.] Washington Univ, Sch Med, St Louis, MO USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Laura; Unalp, Aynur; Tonascia, James] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, Med Ctr, St Louis, MO USA. NR 0 TC 1 Z9 1 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1480 BP 887A EP 887A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603079 ER PT J AU Longchamps, RJ Abey, S Martino, AC Del Valle-Pinero, AY Majors, B Henderson, WA AF Longchamps, Ryan J. Abey, Sarah Martino, Angela C. Del Valle-Pinero, Arseima Y. Majors, Benjamin Henderson, Wendy A. TI SPRED2, CD24, and MMP8 expression: Potential Markers for Fatty Liver Progression to Hepatocellular Carcinoma SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Longchamps, Ryan J.; Abey, Sarah; Martino, Angela C.; Del Valle-Pinero, Arseima Y.; Majors, Benjamin; Henderson, Wendy A.] NINR, NIH, DHHS, Bethesda, MD 20892 USA. 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1494 BP 892A EP 893A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603092 ER PT J AU Lavine, JE Yates, KP Brunt, EM Kleiner, DE Schwimmer, JB Murray, KF Molleston, JP Abrams, SH Rosenthal, P Loomba, R Unalp, A Tonascia, J AF Lavine, Joel E. Yates, Katherine P. Brunt, Elizabeth M. Kleiner, David E. Schwimmer, Jeffrey B. Murray, Karen F. Molleston, Jean P. Abrams, Stephanie H. Rosenthal, Philip Loomba, Rohit Unalp, Aynur Tonascia, James TI The natural history of nonalcoholic fatty liver disease in children and adolescents assessed in placebo recipients in the TONIC trial SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Lavine, Joel E.] Columbia Univ, New York, NY USA. [Yates, Katherine P.; Unalp, Aynur; Tonascia, James] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Brunt, Elizabeth M.] Washington Univ, St Louis, MO USA. [Kleiner, David E.] NCI, NIH, Bethesda, MD 20892 USA. [Schwimmer, Jeffrey B.; Loomba, Rohit] Univ Calif San Diego, San Diego, CA 92103 USA. [Murray, Karen F.] Univ Washington, Seattle, WA 98195 USA. [Molleston, Jean P.] Indiana Univ, Indianapolis, IN 46204 USA. [Abrams, Stephanie H.] Baylor Univ, Houston, TX 77030 USA. [Rosenthal, Philip] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1520 BP 905A EP 905A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603118 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, Constance E. Everhart, James E. TI Low Serum Alanine Aminotransferase (ALT) Activity Increases Mortality in the United States Population SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Ruhl, Constance E.] Social & Sci Syst Inc, Silver Spring, MD USA. [Everhart, James E.] NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1535 BP 911A EP 911A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603133 ER PT J AU Fontana, RJ Engle, RE Trivedi, S Scaglione, SJ Shaikh, OS Attar, N Lee, WM Araya, V Purcell, RH Battenhouse, H AF Fontana, Robert J. Engle, Ronald E. Trivedi, Sonal Scaglione, Steven J. Shaikh, Obaid S. Attar, Nahid Lee, William M. Araya, Victor Purcell, Robert H. Battenhouse, Holly TI The Role of Hepatitis E Virus infection in Adult American patients with Acute Liver Failure SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Fontana, Robert J.; Trivedi, Sonal; Scaglione, Steven J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Bethesda, MD 20892 USA. [Battenhouse, Holly] Med Univ S Carolina, Charleston, SC 29425 USA. [Shaikh, Obaid S.] Univ Pittsburgh, Pittsburgh, PA USA. [Attar, Nahid; Lee, William M.] Univ Texas SW, Dallas, TX USA. [Araya, Victor] Einstein Healthcare Network, Philadelphia, PA USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1642 BP 958A EP 959A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603239 ER PT J AU Bertola, A Gao, B AF Bertola, Adeline Gao, Bin TI E-selectin deficiency ameliorates alcohol-induced liver injury in mice SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Bertola, Adeline; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1687 BP 978A EP 978A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603283 ER PT J AU Marquardt, JU Becker, D Andersen, JB Seidel, D Eickmeier, I Ploch, P Gamstaetter, T Hansen, T Conner, EA Galle, PR Schott, E Thorgeirsson, SS Teufel, A AF Marquardt, Jens U. Becker, Diana Andersen, Jesper B. Seidel, Daniel Eickmeier, Ira Ploch, Philippe Gamstaetter, Thomas Hansen, Torsten Conner, Elizabeth A. Galle, Peter R. Schott, Eckart Thorgeirsson, Snorri S. Teufel, Andreas TI Comparative functional genomics define distinct molecular subtypes in autoimmune hepatitis SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Marquardt, Jens U.; Becker, Diana; Ploch, Philippe; Gamstaetter, Thomas; Galle, Peter R.; Teufel, Andreas] Johannes Gutenberg Univ Mainz, Dept Med, Mainz, Germany. [Marquardt, Jens U.; Andersen, Jesper B.; Conner, Elizabeth A.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, CCR, NIH, Bethesda, MD 20892 USA. [Seidel, Daniel; Eickmeier, Ira; Schott, Eckart] Charite, Dept Hepatol & Gastroenterol, CVK, D-13353 Berlin, Germany. [Hansen, Torsten] Johannes Gutenberg Univ Mainz, Inst Pathol, D-6500 Mainz, Germany. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1721 BP 993A EP 993A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603317 ER PT J AU Naggie, S Osinusi, A Himmel, T Lucas, J Thompson, JW Dubois, LG Moseley, MA Clark, PJ Kottilil, S Patel, K AF Naggie, Susanna Osinusi, Anu Himmel, Tiffany Lucas, Joseph Thompson, J. W. Dubois, Laura G. Moseley, Martin A. Clark, Paul J. Kottilil, Shyam Patel, Keyur TI Targeted proteomics signature identifies corticosteroid binding globulin peptides as highly predictive of treatment response in IL28B unfavorable genotype patients SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Naggie, Susanna; Clark, Paul J.; Patel, Keyur] Duke Clin Res Inst, Durham, NC USA. [Osinusi, Anu; Kottilil, Shyam] NIAID, Bethesda, MD 20892 USA. [Himmel, Tiffany; Lucas, Joseph; Thompson, J. W.; Dubois, Laura G.; Moseley, Martin A.] Duke Univ Med Ctr, Inst Genome Sci & Policy, Durham, NC USA. RI Clark, Paul/A-1480-2012 OI Clark, Paul/0000-0002-1821-4969 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1734 BP 999A EP 1000A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603330 ER PT J AU Gara, N Abdalla, AA Rivera, EM Zhao, XC Fryzek, N Noureddin, M Sarkar, S Heller, T Rotman, Y Doo, E Liang, TJ Hoofnagle, JH Ghany, MG AF Gara, Naveen Abdalla, Adil A. Rivera, Elenita M. Zhao, Xiongce Fryzek, Nancy Noureddin, Mazen Sarkar, Souvik Heller, Theo Rotman, Yaron Doo, Edward Liang, T. Jake Hoofnagle, Jay H. Ghany, Marc G. TI High Dose Ribavirin and Peginterferon for Chronic Hepatitis C Non-responders or Relapsers SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Gara, Naveen; Abdalla, Adil A.; Rivera, Elenita M.; Zhao, Xiongce; Fryzek, Nancy; Noureddin, Mazen; Sarkar, Souvik; Heller, Theo; Rotman, Yaron; Doo, Edward; Liang, T. Jake; Hoofnagle, Jay H.; Ghany, Marc G.] NIDDK, NIH, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1836 BP 1049A EP 1049A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603431 ER PT J AU Shukla, V Chen, J Yao, ZX Li, Y Chen, JS Katz, LH Majumdar, A Farci, P Mishra, L AF Shukla, Vivek Chen, Jian Yao, Zhixing Li, Ying Chen, Jiun-Sheng Katz, Lior H. Majumdar, Avijit Farci, Patrizia Mishra, Lopa TI TGF-beta signaling counteracts the effects of genotoxic metabolites and protects from genomic instability SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Shukla, Vivek; Chen, Jian; Yao, Zhixing; Li, Ying; Chen, Jiun-Sheng; Katz, Lior H.; Majumdar, Avijit; Mishra, Lopa] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Farci, Patrizia] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 1996 BP 1119A EP 1119A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603589 ER PT J AU Kleiner, DE Brunt, EM Lindor, KD Talwalkar, J AF Kleiner, David E. Brunt, Elizabeth M. Lindor, Keith D. Talwalkar, Jayant TI Standardized histological evaluation of Primary Sclerosing Cholangitis (PSC): Relationship of histological features to hallmark lesions of PSC SO HEPATOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 09-13, 2012 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Brunt, Elizabeth M.] Washington Univ, Sch Med, St Louis, MO USA. [Lindor, Keith D.] Arizona State Univ, Phoenix, AZ USA. [Talwalkar, Jayant] Mayo Clin, Rochester, MN 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2012 VL 56 SU 1 MA 2037 BP 1137A EP 1138A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 035OD UT WOS:000310955603630 ER PT J AU Iglesias-Bartolome, R Gutkind, JS AF Iglesias-Bartolome, Ramiro Gutkind, J. Silvio TI Exploiting the mTOR paradox for disease prevention SO ONCOTARGET LA English DT Editorial Material ID INDUCED MUCOSITIS; SENESCENCE C1 [Iglesias-Bartolome, Ramiro; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Iglesias-Bartolome, Ramiro/H-4460-2014 OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 FU Intramural NIH HHS NR 11 TC 26 Z9 26 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT PY 2012 VL 3 IS 10 BP 1061 EP 1063 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 055JC UT WOS:000312410800006 PM 23165441 ER PT J AU Dibrova, DV Chudetsky, MY Galperin, MY Koonin, EV Mulkidjanian, AY AF Dibrova, Daria V. Chudetsky, Michail Y. Galperin, Michael Y. Koonin, Eugene V. Mulkidjanian, Armen Y. TI The Role of Energy in the Emergence of Biology from Chemistry SO ORIGINS OF LIFE AND EVOLUTION OF BIOSPHERES LA English DT Article DE Bioenergetics; Cyclic nucleotides; ATP; Membrane potential; Evolution of membranes; Isoprenoid membranes ID ADENOSINE-TRIPHOSPHATE; LIPID BILAYERS; ZINC-SULFIDE; METAL-IONS; ORIGIN; LIFE; EVOLUTION; CELLS; BIOSYNTHESIS; PHOSPHATES AB Any scenario of the transition from chemistry to biology should include an "energy module" because life can exist only when supported by energy flow(s). We addressed the problem of primordial energetics by combining physico-chemical considerations with phylogenomic analysis. We propose that the first replicators could use abiotically formed, exceptionally photostable activated cyclic nucleotides both as building blocks and as the main energy source. Nucleoside triphosphates could replace cyclic nucleotides as the principal energy-rich compounds at the stage of the first cells, presumably because the metal chelates of nucleoside triphosphates penetrated membranes much better than the respective metal complexes of nucleoside monophosphates. The ability to exploit natural energy flows for biogenic production of energy-rich molecules could evolve only gradually, after the emergence of sophisticated enzymes and ion-tight membranes. We argue that, in the course of evolution, sodium-dependent membrane energetics preceded the proton-based energetics which evolved independently in bacteria and archaea. C1 [Dibrova, Daria V.; Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, Sch Bioengn & Bioinformat, Moscow 119992, Russia. [Chudetsky, Michail Y.] Russian Acad Sci, Inst Oil & Gas Problems, Moscow 119991, Russia. [Galperin, Michael Y.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119992, Russia. [Dibrova, Daria V.; Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. RP Mulkidjanian, AY (reprint author), Univ Osnabruck, Sch Phys, Barbarastr 7, D-49069 Osnabruck, Germany. EM amulkid@uos.de RI Galperin, Michael/B-5859-2013; Mulkidjanian, Armen/J-8086-2013 OI Galperin, Michael/0000-0002-2265-5572; Mulkidjanian, Armen/0000-0001-5844-3064 FU Deutsche Forschungsgemeinschaft [DFG-Mu-1285/1-10, DFG-436-RUS 113/963/0-1]; Russian Government [02.740.11.5228]; Volkswagen Foundation; Russian Foundation for Basic Research [RFBR 0-04-91331]; Deutscher Akademischer Austausch Dienst; National Library of Medicine at the National Institutes of Health FX Valuable discussions with participants of the meeting on the Open Questions on the Origin of Life at the University of Leicester are greatly appreciated. This study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG-Mu-1285/1-10, DFG-436-RUS 113/963/0-1), the Russian Government (No 02.740.11.5228) and the Volkswagen Foundation to A.Y.M., from the Russian Foundation for Basic Research to A.Y.M. (RFBR 0-04-91331), from the Deutscher Akademischer Austausch Dienst to D. V. D., and by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health (M.Y.G., E.V.K). NR 73 TC 8 Z9 9 U1 1 U2 36 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0169-6149 J9 ORIGINS LIFE EVOL B JI Orig. Life Evol. Biosph. PD OCT PY 2012 VL 42 IS 5 BP 459 EP 468 DI 10.1007/s11084-012-9308-z PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 052GS UT WOS:000312186300018 PM 23100130 ER PT J AU Mulkidjanian, AY Bychkov, AY Dibrova, DV Galperin, MY Koonin, EV AF Mulkidjanian, Armen Y. Bychkov, Andrew Yu. Dibrova, Daria V. Galperin, Michael Y. Koonin, Eugene V. TI Open Questions on the Origin of Life at Anoxic Geothermal Fields SO ORIGINS OF LIFE AND EVOLUTION OF BIOSPHERES LA English DT Article DE Geothermal separation; Hydrothermal alteration; Formamide; Borate; Zinc sulfide; K+/Na+ ratio ID RNA TERTIARY STRUCTURE; PREBIOTIC SYNTHESIS; COMMON ANCESTOR; ZINC-SULFIDE; METAL-IONS; EVOLUTION; EARTH; FORMAMIDE; SYSTEMS; PHOSPHORYLATION AB We have recently reconstructed the 'hatcheries' of the first cells by combining geochemical analysis with phylogenomic scrutiny of the inorganic ion requirements of universal components of modern cells (Mulkidjanian et al. Proc Natl Acad Sci U S A 109:E821-830, 2012). These ubiquitous, and by inference primordial, proteins and functional systems show affinity to and functional requirement for K+, Zn2+, Mn2+, and phosphate. Thus, protocells must have evolved in habitats with a high K+/Na+ ratio and relatively high concentrations of Zn, Mn and phosphorous compounds. Geochemical reconstruction shows that the ionic composition conducive to the origin of cells could not have existed in marine settings but is compatible with emissions of vapor-dominated zones of inland geothermal systems. Under an anoxic, CO2-dominated atmosphere, the ionic composition of pools of cool, condensed vapor at anoxic geothermal fields would resemble the internal milieu of modern cells. Such pools would be lined with porous silicate minerals mixed with metal sulfides and enriched in K+ ions and phosphorous compounds. Here we address some questions that have appeared in print after the publication of our anoxic geothermal field scenario. We argue that anoxic geothermal fields, which were identified as likely cradles of life by using a top-down approach and phylogenomics analysis, could provide geochemical conditions similar to those which were suggested as most conducive for the emergence of life by the chemists who pursuit the complementary bottom-up strategy. C1 [Mulkidjanian, Armen Y.; Dibrova, Daria V.] Univ Osnabruck, Sch Phys, D-49076 Osnabruck, Germany. [Bychkov, Andrew Yu.] Moscow MV Lomonosov State Univ, Sch Geol, Moscow 119992, Russia. [Galperin, Michael Y.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Mulkidjanian, Armen Y.; Dibrova, Daria V.] Moscow MV Lomonosov State Univ, Sch Bioengn & Bioinformat, Moscow 119992, Russia. [Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119992, Russia. RP Mulkidjanian, AY (reprint author), Univ Osnabruck, Sch Phys, Barbarastr 7, D-49076 Osnabruck, Germany. EM amulkid@uos.de RI Galperin, Michael/B-5859-2013; Mulkidjanian, Armen/J-8086-2013; Bychkov, Andrey/R-6693-2016 OI Galperin, Michael/0000-0002-2265-5572; Mulkidjanian, Armen/0000-0001-5844-3064; Bychkov, Andrey/0000-0003-2560-6423 FU Deutsche Forschungsgemeinschaft [DFG-Mu-1285/1-10, DFG-436-RUS 113/963/0-1]; Russian Government [02.740.11.5228]; Volkswagen Foundation; Russian Foundation for Basic Research [RFBR 0-04-91331, RFBR 10-05-00320]; Deutscher Akademischer Austausch Dienst; Intramural Research Program of the National Library of Medicine at the National Institutes of Health FX Valuable discussions with participants of the meeting on the Open Questions on the Origin of Life at the University of Leicester are greatly appreciated. This study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG-Mu-1285/1-10, DFG-436-RUS 113/963/0-1), the Russian Government (No 02.740.11.5228) and the Volkswagen Foundation to A.Y.M., from the Russian Foundation for Basic Research to A.Y.M. (RFBR 0-04-91331) and A.Y.B. (RFBR 10-05-00320), from the Deutscher Akademischer Austausch Dienst to D. V. D., and by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health (M.Y.G., E.V.K). NR 65 TC 10 Z9 15 U1 7 U2 39 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0169-6149 J9 ORIGINS LIFE EVOL B JI Orig. Life Evol. Biosph. PD OCT PY 2012 VL 42 IS 5 BP 507 EP 516 DI 10.1007/s11084-012-9315-0 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 052GS UT WOS:000312186300026 PM 23132762 ER PT J AU Borja-Aburto, VH Chowell, G Viboud, C Simonsen, L Miller, MA Grajales-Muniz, C Gonzalez-Bonilla, CR Diaz-Quinonez, JA Echevarria-Zuno, S AF Borja-Aburto, Victor H. Chowell, Gerardo Viboud, Cecile Simonsen, Lone Miller, Mark A. Grajales-Muniz, Concepcion Gonzalez-Bonilla, Cesar R. Diaz-Quinonez, Jose A. Echevarria-Zuno, Santiago TI Epidemiological Characterization of a Fourth Wave of Pandemic A/H1N1 Influenza in Mexico, Winter 2011-2012: Age Shift and Severity SO ARCHIVES OF MEDICAL RESEARCH LA English DT Article DE A/H1N1 influenza pandemic; Hospitalizations; Deaths; Age distribution; Transmissibility ID A H1N1 VIRUS; SEASONAL INFLUENZA; ANTIGENIC SIN; MORTALITY; TRANSMISSIBILITY; COPENHAGEN; PNEUMONIA; FEATURES; DEATHS AB Background and Aims. A substantial recrudescent wave of pandemic influenza A/H1N1 affected the Mexican population from December 1, 2011-March 20, 2012 following a 2-year period of sporadic transmission. Methods. We analyzed demographic and geographic data on all hospitalizations with severe acute respiratory infection (SARI) and laboratory-confirmed A/H1N1 influenza, and inpatient deaths, from a large prospective surveillance system maintained by a Mexican social security medical system during April 1, 2009-March 20, 2012. We also estimated the reproduction number (R) based on the growth rate of the daily case incidence by date of symptoms onset. Results. A total of 7569 SARI hospitalizations and 443 in-patient deaths (5.9%) were reported between December 1, 2011, and March 20, 2012 (1115 A/H1N1-positive inpatients and 154 A/H1N1-positive deaths). The proportion of laboratory-confirmed A/H1N1 hospitalizations and deaths was higher among subjects >= 60 years of age (chi(2) test, p <0.0001) and lower among younger age groups (chi(2) test, p <0.04) for the 2011-2012 pandemic wave compared to the earlier waves in 2009. The reproduction number of the winter 2011-2012 wave in central Mexico was estimated at 1.2-1.3, similar to that reported for the fall 2009 wave, but lower than that of spring 2009. Conclusions. We documented a substantial increase in the number of SARI hospitalizations during the period December 2011-March 2012 and an older age distribution of laboratory-confirmed A/H1N1 influenza hospitalizations and deaths relative to 2009 A/H1N1 pandemic patterns. The gradual change in the age distribution of A/H1N1 infections in the post-pandemic period is consistent with a build-up of immunity among younger populations. (C) 2012 IMSS. Published by Elsevier Inc. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. [Borja-Aburto, Victor H.; Grajales-Muniz, Concepcion; Gonzalez-Bonilla, Cesar R.; Diaz-Quinonez, Jose A.] Inst Mexicano Seguro Social, Coordinac Vigilancia Epidemiol & Apoyo Contingenc, Mexico City, DF, Mexico. [Chowell, Gerardo; Viboud, Cecile; Simonsen, Lone; Miller, Mark A.] NIH, Fogarty Int Ctr, Div Epidemiol & Populat Studies, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. [Echevarria-Zuno, Santiago] Inst Mexicano Seguro Social, Direcc Prestaciones Med, Mexico City, DF, Mexico. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Univ Ave, Tempe, AZ 85287 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Diaz-Quinonez, Jose Alberto/0000-0002-3503-7079; Gonzalez Bonilla, Cesar/0000-0002-2225-5069; Simonsen, Lone/0000-0003-1535-8526 FU International Influenza Unit, Office of Global Health Affairs, Department of Health and Human Services; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center FX This research was conducted in the context of the MISMS (Multinational Influenza Seasonal Mortality Study), an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). The MISMS study is funded by the International Influenza Unit, Office of Global Health Affairs, Department of Health and Human Services. LS acknowledges support from the RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center. NR 35 TC 19 Z9 19 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0188-4409 J9 ARCH MED RES JI Arch. Med. Res. PD OCT PY 2012 VL 43 IS 7 BP 563 EP 570 DI 10.1016/j.arcmed.2012.09.005 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 051IE UT WOS:000312119000009 PM 23079035 ER PT J AU Subbaramaiah, K Howe, LR Zhou, XK Yang, PY Hudis, CA Kopelovich, L Dannenberg, AJ AF Subbaramaiah, Kotha Howe, Louise R. Zhou, Xi Kathy Yang, Peiying Hudis, Clifford A. Kopelovich, Levy Dannenberg, Andrew J. TI Pioglitazone, a PPAR gamma Agonist, Suppresses CYP19 Transcription: Evidence for Involvement of 15-Hydroxyprostaglandin Dehydrogenase and BRCA1 SO CANCER PREVENTION RESEARCH LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; ELEVATED AROMATASE EXPRESSION; HUMAN BREAST ADIPOSE; PROSTAGLANDIN E-2; PROMOTER-II; GENE-EXPRESSION; ESTROGEN BIOSYNTHESIS; NUCLEAR RECEPTORS; CANCER CELLS; OBESITY AB Estrogen synthesis is catalyzed by cytochrome P450 aromatase, which is encoded by the CYP19 gene. In obese postmenopausal women, increased aromatase activity in white adipose tissue is believed to contribute to hormone-dependent breast cancer. Prostaglandin E-2 (PGE(2)) stimulates the cAMP -> protein kinase A (PKA) pathway leading to increased CYP19 transcription and elevated aromatase activity in inflamed white adipose tissue. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE(2). Here, we investigated the mechanism by which pioglitazone, a ligand of the nuclear receptor PPAR gamma suppressed aromatase expression. Treatment of human preadipocytes with pioglitazone suppressed Snail, a repressive transcription factor, resulting in elevated levels of 15-PGDH and reduced levels of PGE(2) in the culture medium. Pioglitazone also inhibited cAMP -> PKA signaling leading to reduced interaction between phosphorylated cAMP responsive element-binding protein, p300, and CYP19 I.3/II promoter. BRCA1, a repressor of CYP19 transcription, was induced by pioglitazone. Consistent with these in vitro findings, treatment of mice with pioglitazone activated PPAR gamma, induced 15-PGDH and BRCA1 while suppressing aromatase levels in the mammary gland. Collectively, these results indicate that the activation of PPAR gamma induces BRCA1 and suppresses the PGE(2)-> cAMP -> PKA axis leading to reduced levels of aromatase. PPAR gamma agonists may have a role in reducing the risk of hormone-dependent breast cancer in obese postmenopausal women. Cancer Prev Res; 5(10); 1183-94. (c) 2012 AACR. C1 [Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Yang, Peiying] Univ Texas MD Anderson Canc Ctr, Dept Gen Oncol, Houston, TX 77030 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Subbaramaiah, K (reprint author), Weill Cornell Canc Ctr, Dept Med, 525 E 68th St,Room F-203, New York, NY 10065 USA. EM ksubba@med.cornell.edu FU NCI [1R01CA154481, N01-CN-43302]; Breast Cancer Research Foundation; Botwinick-Wolfensohn Foundation FX This work was supported by NCI 1R01CA154481 and N01-CN-43302, the Breast Cancer Research Foundation, and the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick). NR 38 TC 14 Z9 14 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD OCT PY 2012 VL 5 IS 10 BP 1183 EP 1194 DI 10.1158/1940-6207.CAPR-12-0201 PG 12 WC Oncology SC Oncology GA 049VF UT WOS:000312010800004 PM 22787115 ER PT J AU Otto, M AF Otto, Michael TI Molecular insight into how MRSA is becoming increasingly dangerous SO VIRULENCE LA English DT Editorial Material C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural NIH HHS NR 0 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD OCT PY 2012 VL 3 IS 6 BP 521 EP 523 DI 10.1038/nm.2692 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 049RE UT WOS:000312000300010 PM 23076285 ER PT J AU Liu, CY Yang, Q Hwang, SJ Sun, FZ Johnson, AD Shirihai, OS Vasan, RS Levy, D Schwartz, F AF Liu, Chunyu Yang, Qiong Hwang, Shih-Jen Sun, Fengzhu Johnson, Andrew D. Shirihai, Orian S. Vasan, Ramachandran S. Levy, Daniel Schwartz, Faina TI Association of Genetic Variation in the Mitochondrial Genome With Blood Pressure and Metabolic Traits SO HYPERTENSION LA English DT Article DE Mitochondrial Genome; Association Study; genetics; hypertension; diabetes mellitus ID HAN CHINESE FAMILY; GENERAL-POPULATION; WIDE ASSOCIATION; ESSENTIAL-HYPERTENSION; DNA MUTATIONS; CENTRIC ARRAY; HEART; DISEASE; MTDNA; AGGREGATION AB Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA variation has become an additional target of investigation of the missing BP heritability. Analyses of common mitochondrial DNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of uncommon (frequency >5%) mitochon drial DNA variants with BP, we identified uncommon/rare variants through sequencing the entire mitochondrial genome in 32 unrelated individuals with extreme-high BP in the Framingham Heart Study and genotyped 40 mitochondrial single nucleotide polymorphisms in 7219 Framingham Heart Study participants. The nonsynonymous mitochondrial single nucleotide polymorphism 5913G>A (Asp4Asn) in the cytochrome c oxidase subunit 1 of respiratory complex IV demonstrated significant associations with BP and fasting blood glucose (FBG) levels. Individuals with the rare 5913A allele had, on average, 7-mm Hg higher systolic BP at baseline (P-empirical = 0.05) and 17-mg/dL higher mean FBG over 25 years of follow-up (P-empirical = 0.009). Significant associations with FBG levels were also detected for nonsynonymous mitochondrial single nucleotide polymorphism 3316G>A (Ala4Thr) in the NADH dehydrogenase subunit 1 of complex I. On average, individuals with rare allele 3316A had 17- and 25-mg/dL higher FBG at baseline (P-empirical = 0.01) and over 25 years of follow-up (P-empirical = 0.007). Our findings provide the first evidence of putative association of variants in the mitochondrial genome with systolic BP and FBG in the general population. Replication in independent samples, however, is needed to confirm these putative associations. (Hypertension. 2012; 60: 949-956.). Online Data Supplement C1 [Liu, Chunyu; Hwang, Shih-Jen; Johnson, Andrew D.; Vasan, Ramachandran S.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Liu, Chunyu; Hwang, Shih-Jen; Johnson, Andrew D.; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Sun, Fengzhu] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Shirihai, Orian S.; Vasan, Ramachandran S.; Levy, Daniel; Schwartz, Faina] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Liu, CY (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM chunyu.liu@nih.gov; fschw@bu.edu RI Sun, Fengzhu /G-4373-2010; Johnson, Andrew/G-6520-2013; Yang, Qiong/G-5438-2014; OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health [NO1-HC-25195]; Division of Intramural Research of the National Heart, Lung, and Blood Institute; National Institutes of Health/National Institute on Aging [RO1AG018412] FX The Framingham Heart Study is supported by National Institutes of Health contract NO1-HC-25195. The Center for Population Studies is supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (to D. L.), which funded the genotyping of 40 mitochondrial variants in 7219 Framingham participants. Mitochondrial sequencing and the genotyping of 10 mitochondrial variants in 1800 unrelated Framingham participants was supported by National Institutes of Health/National Institute on Aging grant RO1AG018412 (to F.S.). NR 66 TC 12 Z9 12 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2012 VL 60 IS 4 BP 949 EP + DI 10.1161/HYPERTENSIONAHA.112.196519 PG 27 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 006IF UT WOS:000308812000018 PM 22949535 ER PT J AU Arias-Loza, PA Kreissl, MC Kneitz, S Kaiser, FR Israel, I Hu, K Frantz, S Bayer, B Fritzemeier, KH Korach, KS Pelzer, T AF Arias-Loza, Paula-Anahi Kreissl, Michael C. Kneitz, Susanne Kaiser, Franz R. Israel, Ina Hu, Kai Frantz, Stefan Bayer, Barbara Fritzemeier, Karl-Heinz Korach, Kenneth S. Pelzer, Theo TI The Estrogen Receptor-alpha Is Required and Sufficient to Maintain Physiological Glucose Uptake in the Mouse Heart SO HYPERTENSION LA English DT Article DE estrogen receptors; cardiac metabolism; positron emission tomography; glucose transporter; hormones ID SPONTANEOUSLY HYPERTENSIVE-RATS; ADIPOSE-TISSUE; ER-BETA; CARDIAC-HYPERTROPHY; INSULIN-RESISTANCE; SKELETAL-MUSCLE; KNOCKOUT MICE; METABOLISM; ESTRADIOL; OVARIECTOMY AB Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate estrogen receptors (ERs) ER alpha and ER beta. Because female sex hormones enhance global glucose use and because myocardial function and mass are tightly linked to cardiac glucose metabolism, we tested the hypothesis that expression and activation of the ER alpha might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Cardiac glucose uptake quantified in vivo by F-18-fluorodeoxyglucose positron emission tomography was strongly impaired in ovariectomized compared with gonadal intact female C57BL/6JO mice. The selective ER alpha agonist 16 alpha-LE2 and the nonselective ER alpha and ER beta agonist 17 beta-estradiol completely restored cardiac glucose uptake in ovariectomized mice. Cardiac F-18-fluorodeoxyglucose uptake was strongly decreased in female ER alpha knockout mice compared with wild-type littermates. Analysis of cardiac mRNA accumulation by quantitative RT-PCR revealed an upregulation of genes involved in glycolisis and tricarboxylic acid cycle by ER alpha treatment. In conclusion, systemic activation of ER alpha is sufficient, and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardioprotective estrogen effects. (Hypertension. 2012; 60: 1070-1077.). Online Data Supplement C1 [Arias-Loza, Paula-Anahi; Hu, Kai; Frantz, Stefan; Bayer, Barbara; Pelzer, Theo] Univ Wurzburg, Dept Internal Med, D-97080 Wurzburg, Germany. [Kreissl, Michael C.; Kaiser, Franz R.; Israel, Ina] Univ Wurzburg, Dept Nucl Med, D-97080 Wurzburg, Germany. [Kneitz, Susanne] Univ Wurzburg, Dept Physiol Chem 1, Bioctr, D-97080 Wurzburg, Germany. [Fritzemeier, Karl-Heinz] Bayer HealthCare, Berlin, Germany. [Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Pelzer, T (reprint author), Univ Wurzburg, Dept Med Cardiol & Pneumol ZIM 1, Oberduerrbacher Str 6, D-97080 Wurzburg, Germany. EM pelzer_t@klinik.uni-wuerzburg.de RI Frantz, Stefan/G-1723-2012; OI Korach, Kenneth/0000-0002-7765-418X FU Interdisciplinary Center for Clinical Research "IZKF" Wuerzburg [Z-2/21]; comprehensive heart failure center Wuerzburg [CHFC D-5]; Division of Intramural Research (National Institute of Environmental Health Sciences/National Institutes of Health) [Z01ES70065]; Bayer-Schering Pharma AG Berlin; Bayer Pharma AG Berlin FX T.P. and M.C.K. received support from the Interdisciplinary Center for Clinical Research "IZKF" Wuerzburg (Z-2/21): and the comprehensive heart failure center Wuerzburg (CHFC D-5). The research of K. S. K. was supported by the Division of Intramural Research (National Institute of Environmental Health Sciences/National Institutes of Health; Z01ES70065). This research was supported in part by Bayer-Schering Pharma AG Berlin, which also provided the ER-alpha specific ligand 16 alpha-LE2.; T.P. has received financial support from the Bayer Pharma AG Berlin that relates to the evaluation of novel steroid hormone receptor ligands. NR 29 TC 9 Z9 9 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2012 VL 60 IS 4 BP 1070 EP + DI 10.1161/HYPERTENSIONAHA.111.190389 PG 15 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 006IF UT WOS:000308812000033 PM 22892812 ER PT J AU Simoes, EAF Babu, PG John, TJ Nirmala, S Solomon, S Lakshminarayana, CS Quinn, TC AF Simoes, Eric A. F. Babu, P. George John, T. Jacob Nirmala, S. Solomon, Suniti Lakshminarayana, C. S. Quinn, Thomas C. TI Evidence for HTLV-III infection in prostitutes in Tamil Nadu (India) (Reprinted from INDIAN JOURNAL OF MEDICAL RESEARCH, vol 85, pg 335-338, 1987) SO INDIAN JOURNAL OF MEDICAL RESEARCH LA English DT Reprint C1 Christian Med Coll & Hosp, ICMR Ctr Adv Res Virol, Vellore, Tamil Nadu, India. Madras Med Coll & Govt Gen Hosp, Inst Microbiol, Madras, Tamil Nadu, India. NIH, Bethesda, MD 20892 USA. RP John, TJ (reprint author), Christian Med Coll & Hosp, Dept Virol & Immunol, Vellore 632004, Tamil Nadu, India. NR 7 TC 0 Z9 0 U1 0 U2 2 PU INDIAN COUNCIL MEDICAL RES PI NEW DELHI PA PO BOX 4911 ANSARI NAGAR, NEW DELHI 110029, INDIA SN 0971-5916 J9 INDIAN J MED RES JI Indian J. Med. Res. PD OCT PY 2012 VL 136 IS 4 BP 335 EP 338 PG 4 WC Immunology; Medicine, General & Internal; Medicine, Research & Experimental SC Immunology; General & Internal Medicine; Research & Experimental Medicine GA 044DH UT WOS:000311599100027 ER PT J AU Proescholdt, MA Merrill, MJ Stoerr, EM Lohmeier, A Brawanski, A AF Proescholdt, Martin A. Merrill, Marsha J. Stoerr, Eva-Maria Lohmeier, Annette Brawanski, Alexander TI CAIX REGULATION OF EXTRACELLULAR PH AND INVASION IN GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Proescholdt, Martin A.; Stoerr, Eva-Maria; Lohmeier, Annette; Brawanski, Alexander] Univ Regensburg, Med Ctr, Regensburg, Germany. [Merrill, Marsha J.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 1 EP 1 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300002 ER PT J AU Merrill, MJ Sun, M Chen, M Edwards, NA Shively, SB Lonser, RR AF Merrill, Marsha J. Sun, Michael Chen, Masako Edwards, Nancy A. Shively, Sharon B. Lonser, Russell R. TI THE DEVELOPMENTAL LINEAGE MARKER PAX2 IS EXPRESSED IN CNS HEMANGIOBLASTOMAS IN VON HIPPEL-LINDAU DISEASE SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Merrill, Marsha J.; Sun, Michael; Chen, Masako; Edwards, Nancy A.; Shively, Sharon B.; Lonser, Russell R.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 11 EP 12 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300049 ER PT J AU Yang, CZ Iyer, R Yu, ACH Li, SQ Ikejiri, BL Zhuang, ZP Lonser, R AF Yang, Chunzhang Iyer, Rajiv Yu, Albert C. H. Li, Siqi Ikejiri, Barbara L. Zhuang, Zhengping Lonser, Russell TI beta-CATENIN SIGNALING INITIATES ASTROCYTE ACTIVATION AND CONTRIBUTES TO THE PATHOGENESIS OF GLIOMAS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Yang, Chunzhang; Iyer, Rajiv; Ikejiri, Barbara L.; Zhuang, Zhengping; Lonser, Russell] Natl Inst Neurol Disorder & Stroke, Bethesda, MD USA. [Yu, Albert C. H.; Li, Siqi] Peking Univ, Neurosci Res Inst, Beijing 100871, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 11 EP 11 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300047 ER PT J AU Edwards, NA Lonser, RR Merrill, MJ AF Edwards, Nancy A. Lonser, Russell R. Merrill, Marsha J. TI MAST CELLS ARE TUMOR-DERIVED IN VON HIPPEL-LINDAU DISEASE CNS HEMANGIOBLASTOMAS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Edwards, Nancy A.; Lonser, Russell R.; Merrill, Marsha J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 13 EP 13 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300054 ER PT J AU Chen, M Shen, J Edwards, NA Lonser, RR Merrill, MJ AF Chen, Masako Shen, John Edwards, Nancy A. Lonser, Russell R. Merrill, Marsha J. TI EXPRESSION OF beta-CATENIN IN BLOOD VESSELS OF CNS HEMANGIOBLASTOMAS IN VON HIPPEL-LINDAU DISEASE SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Chen, Masako; Shen, John; Edwards, Nancy A.; Lonser, Russell R.; Merrill, Marsha J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 16 EP 16 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300069 ER PT J AU Xie, Q Johnson, J Bradley, R Ascierto, ML Kang, L Koeman, J Marincola, FM Briggs, M Tanner, K Vande Woude, GF AF Xie, Qian Johnson, Jennifer Bradley, Robert Ascierto, Maria Libra Kang, Liang Koeman, Julie Marincola, Francesco M. Briggs, Michael Tanner, Kirk Vande Woude, George F. TI TARGETING THE MET SIGNALING PATHWAY IN GLIOBLASTOMA MULTIFORME: HEPATOCYTE GROWTH FACTOR-AUTOCRINE ACTIVATION INDICATES SENSITIVITY TO MET INHIBITORS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Xie, Qian; Johnson, Jennifer; Bradley, Robert; Kang, Liang; Koeman, Julie; Vande Woude, George F.] Van Andel Res Inst, Grand Rapids, MI USA. [Ascierto, Maria Libra; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Ascierto, Maria Libra; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Briggs, Michael] Woodland Pharmaceut, Shrewsbury, MA USA. [Tanner, Kirk] Vertex Pharmaceut Inc, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 25 EP 26 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300106 ER PT J AU Liu, YH Melin, B Wang, ZM Rajaraman, P Chanock, S Bondy, M AF Liu, Yanhong Melin, Beatrice Wang, Zhaoming Rajaraman, Preetha Chanock, Stephen Bondy, Melissa CA Gliogene Consortium TI INSIGHT IN GLIOMA SUSCEPTIBILITY THROUGH AN ANALYSIS OF 6p22.3, 12p13.33-12.1, 17q22-23.2 AND 18q23 SNP GENOTYPES IN FAMILIAL AND NON-FAMILIAL GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Liu, Yanhong; Bondy, Melissa; Gliogene Consortium] Baylor Coll Med, Houston, TX 77030 USA. [Melin, Beatrice] Umea Univ, Umea, Sweden. [Wang, Zhaoming; Rajaraman, Preetha; Chanock, Stephen] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 51 EP 52 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300213 ER PT J AU Peereboom, DM Seidman, AD Tabar, V Weil, RJ Thorsheim, HR Smith, QR Lockman, PR Steeg, PS AF Peereboom, David M. Seidman, Andrew D. Tabar, Viviane Weil, Robert J. Thorsheim, Helen R. Smith, Quentin R. Lockman, Paul R. Steeg, Patricia S. TI CAPECITABINE ENTRY INTO BRAIN METASTASES IN WOMEN WITH BREAST CANCER SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Peereboom, David M.; Weil, Robert J.] Cleveland Clin, Cleveland, OH 44106 USA. [Seidman, Andrew D.; Tabar, Viviane] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Thorsheim, Helen R.; Smith, Quentin R.; Lockman, Paul R.] Texas Tech Univ Hlth Sci Ctr, Amarillo, TX USA. [Steeg, Patricia S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 57 EP 57 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300230 ER PT J AU Sul, J Odia, Y Zhang, W Shih, J Butman, JA Hammoud, D Kreisl, TN Iwamoto, F Fine, HA AF Sul, Joohee Odia, Yazmin Zhang, Weiting Shih, Joanna Butman, John A. Hammoud, Dina Kreisl, Teri N. Iwamoto, Fabio Fine, Howard A. TI A PHASE II TRIAL OF INVESTIGATIONAL AGENT TANDUTINIB IN COMBINATION WITH BEVACIZUMAB FOR PATIENTS WITH RECURRENT GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Sul, Joohee; Odia, Yazmin; Zhang, Weiting; Shih, Joanna; Butman, John A.; Hammoud, Dina; Kreisl, Teri N.; Iwamoto, Fabio; Fine, Howard A.] NIH, Bethesda, MD 20892 USA. RI Hammoud, Dima/C-2286-2015 NR 0 TC 0 Z9 0 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 73 EP 73 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300292 ER PT J AU Curry, R Joyce, J Rosenblum, M Jaffe, E Matasar, M Lin, O Fisher, R Omuro, A AF Curry, Richard Joyce, Joanna Rosenblum, Marc Jaffe, Elaine Matasar, Matthew Lin, Oscar Fisher, Rebecca Omuro, Antonio TI HISTIOCYTIC SARCOMA OF THE CENTRAL NERVOUS SYSTEM: A CASE REPORT SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Curry, Richard; Joyce, Joanna; Rosenblum, Marc; Matasar, Matthew; Lin, Oscar; Omuro, Antonio] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Jaffe, Elaine] NIH, Bethesda, MD 20892 USA. [Fisher, Rebecca] St Lukes Roosevelt Hosp, New York, NY USA. OI Omuro, Antonio/0000-0003-4299-3664 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 77 EP 77 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300308 ER PT J AU Yin, C Iwamoto, FM Fraum, TJ Nayak, L AF Yin, Chao Iwamoto, Fabio M. Fraum, Tyler J. Nayak, Lakshmi TI PATTERNS OF TREATMENT AND SURVIVAL OF GBM PATIENTS WITH DIABETES MELLITUS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Yin, Chao; Fraum, Tyler J.] NIH, Bethesda, MD 20892 USA. [Iwamoto, Fabio M.] Columbia Univ, New York, NY USA. [Nayak, Lakshmi] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 77 EP 77 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300309 ER PT J AU Omuro, A Beal, K Ivy, P Gutin, P Wu, NA Kaley, T Karimi, S DeAngelis, L Pentsova, H Nolan, C Grommes, C Chan, T Mathew, R Droms, L Shimizu, F Tabar, V AF Omuro, Antonio Beal, Kathryn Ivy, Percy Gutin, Philip Wu, Nian Kaley, Thomas Karimi, Sasan DeAngelis, Lisa Pentsova, Helena Nolan, Craig Grommes, Christian Chan, Timothy Mathew, Raj Droms, Leif Shimizu, Fumiko Tabar, Viviane TI RO4929097 IN COMBINATION WITH RADIOTHERAPY AND TEMOZOLOMIDE FOR NEWLY DIAGNOSED MALIGNANT GLIOMA (MG): A PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) STUDY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Omuro, Antonio; Beal, Kathryn; Gutin, Philip; Wu, Nian; Kaley, Thomas; Karimi, Sasan; DeAngelis, Lisa; Pentsova, Helena; Nolan, Craig; Grommes, Christian; Chan, Timothy; Mathew, Raj; Droms, Leif; Shimizu, Fumiko; Tabar, Viviane] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, New York, NY USA. OI Kaley, Thomas/0000-0002-2540-8518; Omuro, Antonio/0000-0003-4299-3664 NR 0 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 80 EP 80 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300321 ER PT J AU Sloan, AE Nock, CJ Kerstetter, A Supko, J Ye, XB Barnholtz-Sloan, JS Miller, R Rich, J Takebe, N Prados, M Grossman, S AF Sloan, Andrew E. Nock, Charles J. Kerstetter, Amber Supko, Jeff Ye, Xiaobu Barnholtz-Sloan, Jill S. Miller, Robert Rich, Jeremy Takebe, Naoko Prados, Michael Grossman, Stuart TI TARGETING GLIOMA STEM CELLS (GSC): A BIOMARKER AND PHASE II STUDY OF GDC-0449 IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Sloan, Andrew E.; Nock, Charles J.; Kerstetter, Amber; Barnholtz-Sloan, Jill S.; Miller, Robert] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Sloan, Andrew E.; Nock, Charles J.; Barnholtz-Sloan, Jill S.; Rich, Jeremy] Case Comprehens Canc Ctr, Cleveland, OH USA. [Supko, Jeff] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ye, Xiaobu; Grossman, Stuart] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Rich, Jeremy] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Takebe, Naoko] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. [Prados, Michael] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 105 EP 105 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300418 ER PT J AU Odia, Y Orr, BA Eberhart, CG Rodriguez, F AF Odia, Yazmin Orr, Brent A. Eberhart, Charles G. Rodriguez, Fausto TI C-MYC/MYC IMMUNOREACTIVITY ASSOCIATES WITH YOUNGER AGE, ANAPLASTIC PHENOTYPE AND SECONDARY MALIGNANT GLIOMAS BASED ON IDH1(R132) MUTANT PROTEIN EXPRESSION SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Odia, Yazmin] NCI, NIH, Bethesda, MD 20892 USA. [Orr, Brent A.; Eberhart, Charles G.; Rodriguez, Fausto] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 106 EP 107 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300423 ER PT J AU Alimova, I Birks, DK Harris, P Venkataraman, S Marquez, VE Foreman, NK Vibhakar, R AF Alimova, Irina Birks, Diane K. Harris, Peter Venkataraman, Sujatha Marquez, Victor E. Foreman, Nicholas K. Vibhakar, Rajeev TI PHARMACOLOGIC INHIBITION OF EZH2 SUPPRESSES SELF-RENEWAL AND INDUCES RADIATION SENSITIVITY IN ATYPICAL RHABDOID TERATOID TUMOR CELLS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) CY NOV 15-18, 2012 CL Washington, DC SP Soc Neuro Oncol (SNO) C1 [Alimova, Irina; Birks, Diane K.; Harris, Peter; Venkataraman, Sujatha; Foreman, Nicholas K.; Vibhakar, Rajeev] Univ Colorado Denver, Aurora, CO USA. [Marquez, Victor E.] NCI, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2012 VL 14 SU 6 BP 116 EP 116 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 035TH UT WOS:000310971300460 ER EF