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