FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hu, Y Wu, G Rusch, M Lukes, L Buetow, KH Zhang, JH Hunter, KW AF Hu, Ying Wu, Gang Rusch, Michael Lukes, Luanne Buetow, Kenneth H. Zhang, Jinghui Hunter, Kent W. TI Integrated cross-species transcriptional network analysis of metastatic susceptibility SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene expression; mouse models ID BREAST-CANCER METASTASIS; TRANSGENIC MOUSE MODEL; GENE-EXPRESSION; SPINDLE CHECKPOINT; MAMMARY-TUMORS; C-MYC; PROGNOSIS; PROGRESSION; SIGNATURE; SURVIVAL AB Metastatic disease is the proximal cause of mortality for most cancers and remains a significant problem for the clinical management of neoplastic disease. Recent advances in global transcriptional analysis have enabled better prediction of individuals likely to progress to metastatic disease. However, minimal overlap between predictive signatures has precluded easy identification of key biological processes contributing to the prometastatic transcriptional state. To overcome this limitation, we have applied network analysis to two independent human breast cancer datasets and three different mouse populations developed for quantitative analysis of metastasis. Analysis of these datasets revealed that the gene membership of the networks is highly conserved within and between species, and that these networks predicted distant metastasis free survival. Furthermore these results suggest that susceptibility to metastatic disease is cell-autonomous in estrogen receptor-positive tumors and associated with the mitotic spindle checkpoint. In contrast, nontumor genetics and pathway activities-associated stromal biology are significant modifiers of the rate of metastatic spread of estrogen receptor-negative tumors. These results suggest that the application of network analysis across species may provide a robust method to identify key biological programs associated with human cancer progression. C1 [Lukes, Luanne; Hunter, Kent W.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hu, Ying; Buetow, Kenneth H.] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Wu, Gang; Rusch, Michael; Zhang, Jinghui] St Jude Childrens Hosp, Memphis, TN USA. RP Hunter, KW (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Drs. Lalage Wakefield, Glenn Merlino, and Thomas Geiger for critical reading of this manuscript. Analyses of the Netherlands Cancer Institute dataset, Brd4 cell lines, and AKR and DBA F1 tumors were performed using BRB-ArrayTools developed by Dr. Richard Simon and BRB-ArrayTools Development Team. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 43 TC 20 Z9 20 U1 1 U2 3 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 FEB 21 PY 2012 VL 109 IS 8 BP 3184 EP 3189 DI 10.1073/pnas.1117872109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100098 PM 22308418 ER PT J AU Chesebro, B Klingeborn, M Race, B AF Chesebro, Bruce Klingeborn, Mikael Race, Brent TI Reply to Karapetyan: Viral synthesis and assembly is unlikely to occur under cell-free PMCA conditions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Chesebro, Bruce; Klingeborn, Mikael; Race, Brent] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM bchesebro@niaid.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 1 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 FEB 21 PY 2012 VL 109 IS 8 BP E462 EP E462 DI 10.1073/pnas.1120371109 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100002 ER PT J AU Kearney, MF Spindler, J Wiegand, A Shao, W Anderson, EM Maldarelli, F Ruscetti, FW Mellors, JW Hughes, SH Le Grice, SFJ Coffin, JM AF Kearney, Mary F. Spindler, Jonathan Wiegand, Ann Shao, Wei Anderson, Elizabeth M. Maldarelli, Frank Ruscetti, Francis W. Mellors, John W. Hughes, Steve H. Le Grice, Stuart F. J. Coffin, John M. TI Multiple Sources of Contamination in Samples from Patients Reported to Have XMRV Infection SO PLOS ONE LA English DT Article ID CHRONIC-FATIGUE-SYNDROME; VIRUS-RELATED VIRUS; PROSTATE-CANCER; RETROVIRUS XMRV; MOUSE DNA; SEQUENCES; CELLS AB Xenotropic murine leukemia virus (MLV)-related retrovirus (XMRV) was reported to be associated with prostate cancer by Urisman, et al. in 2006 and chronic fatigue syndrome (CFS) by Lombardi, et al. in 2009. To investigate this association, we independently evaluated plasma samples from 4 patients with CFS reported by Lombardi, et al. to have XMRV infection and from 5 healthy controls reported to be XMRV uninfected. We also analyzed viral sequences obtained from supernatants of cell cultures found to contain XMRV after coculture with 9 clinical samples from 8 patients. A qPCR assay capable of distinguishing XMRV from endogenous MLVs showed that the viral sequences detected in the CFS patient plasma behaved like endogenous MLVs and not XMRV. Single-genome sequences (N = 89) from CFS patient plasma were indistinguishable from endogenous MLVs found in the mouse genome that are distinct from XMRV. By contrast, XMRV sequences were detected by qPCR in 2 of the 5 plasma samples from healthy controls (sequencing of the qPCR product confirmed XMRV not MLV). Single-genome sequences (N = 234) from the 9 culture supernatants reportedly positive for XMRV were indistinguishable from XMRV sequences obtained from 22Rv1 and XMRV-contaminated 293T cell-lines. These results indicate that MLV DNA detected in the plasma samples from CFS patients evaluated in this study was from contaminating mouse genomic DNA and that XMRV detected in plasma samples from healthy controls and in cultures of patient samples was due to cross-contamination with XMRV (virus or nucleic acid). C1 [Kearney, Mary F.; Spindler, Jonathan; Wiegand, Ann; Anderson, Elizabeth M.; Maldarelli, Frank; Hughes, Steve H.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Shao, Wei] SAIC, Adv Biomed Comp Ctr, Frederick, MD USA. [Ruscetti, Francis W.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA. [Mellors, John W.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Kearney, MF (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM kearneym@mail.nih.gov FU FM Kirby Foundation; National Cancer Institute; National Cancer Institute (SAIC) [25XS119] FX Dr. Coffin was a Research Professor of the American Cancer Society, with support from the FM Kirby Foundation. Funding for this research was provided by the Intramural Research Program of the National Cancer Institute. Dr. Mellors was supported by a contract from the National Cancer Institute (SAIC contract 25XS119). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 15 Z9 15 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2012 VL 7 IS 2 AR e30889 DI 10.1371/journal.pone.0030889 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926YY UT WOS:000302871500020 PM 22363509 ER PT J AU Pegoraro, G Voss, TC Martin, SE Tuzmen, P Guha, R Misteli, T AF Pegoraro, Gianluca Voss, Ty C. Martin, Scott E. Tuzmen, Pinar Guha, Rajarshi Misteli, Tom TI Identification of Mammalian Protein Quality Control Factors by High-Throughput Cellular Imaging SO PLOS ONE LA English DT Article ID 20S PROTEASOME; ENDOPLASMIC-RETICULUM; IN-VIVO; DEGRADATION; UBIQUITIN; CELLS; TRANSLATION; EXPRESSION; MATURATION; TOXICITY AB Protein Quality Control (PQC) pathways are essential to maintain the equilibrium between protein folding and the clearance of misfolded proteins. In order to discover novel human PQC factors, we developed a high-content, high-throughput cell-based assay to assess PQC activity. The assay is based on a fluorescently tagged, temperature sensitive PQC substrate and measures its degradation relative to a temperature insensitive internal control. In a targeted screen of 1591 siRNA genes involved in the Ubiquitin-Proteasome System (UPS) we identified 25 of the 33 genes encoding for 26S proteasome subunits and discovered several novel PQC factors. An unbiased genome-wide siRNA screen revealed the protein translation machinery, and in particular the EIF3 translation initiation complex, as a novel key modulator of misfolded protein stability. These results represent a comprehensive unbiased survey of human PQC components and establish an experimental tool for the discovery of genes that are required for the degradation of misfolded proteins under conditions of proteotoxic stress. C1 [Pegoraro, Gianluca; Voss, Ty C.] NCI, NCI High Throughput Imaging Facil, NIH, Bethesda, MD 20892 USA. [Martin, Scott E.; Tuzmen, Pinar; Guha, Rajarshi] NIH, Ctr Translat Therapeut, Rockville, MD USA. RP Pegoraro, G (reprint author), NCI, NCI High Throughput Imaging Facil, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Pegoraro, Gianluca/0000-0003-2843-9464 FU NIH; NCI; Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 7 Z9 7 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2012 VL 7 IS 2 AR e31684 DI 10.1371/journal.pone.0031684 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926YY UT WOS:000302871500075 PM 22363705 ER PT J AU Sharma, YV Cojocaru, RI Ritter, LM Khattree, N Brooks, M Scott, A Swaroop, A Goldberg, AFX AF Sharma, Yagya V. Cojocaru, Radu I. Ritter, Linda M. Khattree, Nidhi Brooks, Matthew Scott, Alison Swaroop, Anand Goldberg, Andrew F. X. TI Protective Gene Expression Changes Elicited by an Inherited Defect in Photoreceptor Structure SO PLOS ONE LA English DT Article ID RDS MUTANT MICE; INDUCED RETINAL DEGENERATION; NRL(-/-) MOUSE RETINA; CELL-DEATH; MESSENGER-RNA; ALTERED EXPRESSION; OUTER SEGMENTS; FACTOR MEF2C; SLOW RDS; LIGHT AB Inherited defects in retinal photoreceptor structure impair visual transduction, disrupt relationship with the retinal pigment epithelium (RPE), and compromise cell viability. A variety of progressive retinal degenerative diseases can result, and knowledge of disease etiology remains incomplete. To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. Both the array and qPCR data revealed that gene expression changes were generally modest and dispersed amongst a variety of known functional networks. Although genes showing major (> 5-fold) differential expression were identified in a few instances, nearly all displayed transient temporal profiles, returning to WT levels by postnatal day (P) 21. These observations suggest that major defects in photoreceptor cell structure may induce early homeostatic responses, which function in a protective manner to promote cell viability. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and retina. Egr1 upregulation was associated with microglial activation and migration into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors may represent a protective immune mechanism which contributes to the characteristically slow retinal degeneration of the rds mouse model. C1 [Sharma, Yagya V.; Ritter, Linda M.; Khattree, Nidhi; Goldberg, Andrew F. X.] Oakland Univ, Eye Res Inst, Rochester, MI 48309 USA. [Brooks, Matthew; Scott, Alison; Swaroop, Anand] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Cojocaru, Radu I.; Brooks, Matthew; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Sharma, YV (reprint author), Oakland Univ, Eye Res Inst, Rochester, MI 48309 USA. EM goldberg@oakland.edu OI Scott, Alison/0000-0001-6969-4707; Swaroop, Anand/0000-0002-1975-1141 FU E. Matilda Zeigler Foundation; National Institutes of Health [EY013246, RR017890]; Foundation Fighting Blindness and intramural funds of the National Eye Institute FX This work was supported by the E. Matilda Zeigler Foundation and the National Institutes of Health [EY013246 and RR017890] to AFXG, and by The Foundation Fighting Blindness and intramural funds of the National Eye Institute to AS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 7 Z9 7 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2012 VL 7 IS 2 AR e31371 DI 10.1371/journal.pone.0031371 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926YY UT WOS:000302871500037 PM 22363631 ER PT J AU Zhang, G Schetter, A He, PJ Funamizu, N Gaedcke, J Ghadimi, BM Ried, T Hassan, R Yfantis, HG Lee, DH Lacy, C Maitra, A Hanna, N Alexander, HR Hussain, SP AF Zhang, Geng Schetter, Aaron He, Peijun Funamizu, Naotake Gaedcke, Jochen Ghadimi, B. Michael Ried, Thomas Hassan, Raffit Yfantis, Harris G. Lee, Dong H. Lacy, Curtis Maitra, Anirban Hanna, Nader Alexander, H. Richard Hussain, S. Perwez TI DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma SO PLOS ONE LA English DT Article ID COPY-NUMBER; CANCER; EXPRESSION; GEMCITABINE; CARCINOMA; MARKERS; GENES AB Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N=27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T: N ratio similar to 0.1, P < 0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = -0.35, P=0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P=0.035) and validation cohort (P=0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio=0.43, 95%CI=0.24-0.76, P=0.004) and multivariate analyses (hazard ratio=0.51, 95%CI=0.27-0.94, P=0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments. C1 [Zhang, Geng; Schetter, Aaron; He, Peijun; Funamizu, Naotake; Lacy, Curtis; Hussain, S. Perwez] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gaedcke, Jochen; Ghadimi, B. Michael] Univ Med, Dept Gen & Visceral Surg, Gottingen, Germany. [Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Hassan, Raffit] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Yfantis, Harris G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Maitra, Anirban] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Dept Surg, Div Surg Oncol, Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Zhang, G (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU National Cancer Institute, Center for Cancer Research, National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 27 Z9 29 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2012 VL 7 IS 2 AR e31507 DI 10.1371/journal.pone.0031507 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926YY UT WOS:000302871500049 PM 22363658 ER PT J AU Korn, EL Freidlin, B Abrams, JS Halabi, S AF Korn, Edward L. Freidlin, Boris Abrams, Jeffrey S. Halabi, Susan TI Design Issues in Randomized Phase II/III Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID II CLINICAL-TRIALS; INTERIM; CANCER; AGENTS; SELECTION AB Phase II trials are used to show sufficient preliminary activity of a new treatment (in single-arm designs or randomized screening designs) or to select among treatments with demonstrated activity (in randomized selection designs). The treatments prioritized in a phase II trial are then tested definitively against a control treatment in a randomized phase III trial. Randomized phase II/III trials use an adaptive trial design that combines these two types of trials in one, with potential gains in time and reduced numbers of patients required to be treated. Two key considerations in designing a phase II/III trial are whether to suspend accrual while the phase II data mature and the choice of phase II target treatment effect. We discuss these phase II/III design parameters, give examples of phase II/III trials, and provide recommendations concerning efficient phase II/III trial designs. J Clin Oncol 30: 667-671. (C) 2012 by American Society of Clinical Oncology C1 [Korn, Edward L.] NCI, Biometr Res Branch, Bethesda, MD 20852 USA. [Halabi, Susan] Duke Univ, Med Ctr, Durham, NC USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, EPN 8129, Bethesda, MD 20852 USA. EM korne@ctep.nci.nih.gov NR 23 TC 18 Z9 18 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2012 VL 30 IS 6 BP 667 EP 671 DI 10.1200/JCO.2011.38.5732 PG 5 WC Oncology SC Oncology GA 923MQ UT WOS:000302623800026 PM 22271475 ER PT J AU Noureldin, RA Liu, ST Nacif, MS Judge, DP Halushka, MK Abraham, TP Ho, C Bluemke, DA AF Noureldin, Radwa A. Liu, Songtao Nacif, Marcelo S. Judge, Daniel P. Halushka, Marc K. Abraham, Theodore P. Ho, Carolyn Bluemke, David A. TI The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic resonance SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Review ID LATE GADOLINIUM ENHANCEMENT; LEFT-VENTRICULAR HYPERTROPHY; DELAYED CONTRAST ENHANCEMENT; ANDERSON-FABRY-DISEASE; SUDDEN CARDIAC DEATH; MYOCARDIAL FIBROSIS; DIASTOLIC FUNCTION; MICROVASCULAR DYSFUNCTION; CLINICAL-FEATURES; GENE-MUTATIONS AB Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the heart. HCM is characterized by a wide range of clinical expression, ranging from asymptomatic mutation carriers to sudden cardiac death as the first manifestation of the disease. Over 1000 mutations have been identified, classically in genes encoding sarcomeric proteins. Noninvasive imaging is central to the diagnosis of HCM and cardiovascular magnetic resonance (CMR) is increasingly used to characterize morphologic, functional and tissue abnormalities associated with HCM. The purpose of this review is to provide an overview of the clinical, pathological and imaging features relevant to understanding the diagnosis of HCM. The early and overt phenotypic expression of disease that may be identified by CMR is reviewed. Diastolic dysfunction may be an early marker of the disease, present in mutation carriers prior to the development of left ventricular hypertrophy (LVH). Late gadolinium enhancement by CMR is present in approximately 60% of HCM patients with LVH and may provide novel information regarding risk stratification in HCM. It is likely that integrating genetic advances with enhanced phenotypic characterization of HCM with novel CMR techniques will importantly improve our understanding of this complex disease. C1 [Noureldin, Radwa A.; Liu, Songtao; Nacif, Marcelo S.; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Liu, Songtao; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Mol Biomed Imaging Lab, Bethesda, MD USA. [Judge, Daniel P.; Abraham, Theodore P.] Johns Hopkins Univ, Div Cardiol, Dept Med, Baltimore, MD USA. [Halushka, Marc K.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Ho, Carolyn] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Ho, Carolyn/0000-0002-7334-7924; Halushka, Marc/0000-0002-7112-7389; Bluemke, David/0000-0002-8323-8086 FU Radiology and Imaging Sciences Department, Clinical Center; National Institute of Biomedical Imaging and Bioengineering, NIH; Radiology & Imaging Sciences Department, National Institutes of Health Clinical Center. Bethesda, USA FX Dr. Radwa A. Noureldin is a fellow in the Imaging Sciences Training Program supported in part by the Radiology and Imaging Sciences Department, Clinical Center and Intramural Research Program at the National Institute of Biomedical Imaging and Bioengineering, NIH.; Funding sources Radiology & Imaging Sciences Department, National Institutes of Health Clinical Center. Bethesda, MD. 20892. USA NR 121 TC 42 Z9 46 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD FEB 20 PY 2012 VL 14 AR 17 DI 10.1186/1532-429X-14-17 PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 916HI UT WOS:000302091400001 PM 22348519 ER PT J AU Alexandre, KB Gray, ES Mufhandu, H McMahon, JB Chakauya, E O'Keefe, BR Chikwamba, R Morris, L AF Alexandre, Kabamba B. Gray, Elin S. Mufhandu, Hazel McMahon, James B. Chakauya, Ereck O'Keefe, Barry R. Chikwamba, Rachel Morris, Lynn TI The lectins griffithsin, cyanovirin-N and scytovirin inhibit HIV-1 binding to the DC-SIGN receptor and transfer to CD4(+) cells SO VIROLOGY LA English DT Article DE Griffithsin; Cyanovirin-N; Scytovirin; Mannose-rich glycans; HIV-1 gp120; DC-SIGN receptor ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYANOBACTERIUM SCYTONEMA-VARIUM; ENVELOPE GLYCOPROTEIN GP120; DENDRITIC CELLS; SUBTYPE-C; NEUTRALIZING ANTIBODIES; INACTIVATING PROTEIN; CARBOHYDRATE-BINDING; VAGINAL TRANSMISSION; SEXUAL TRANSMISSION AB It is generally believed that during the sexual transmission of HIV-1, the glycan-specific DC-SIGN receptor binds the virus and mediates its transfer to CD4(+) cells. The lectins griffithsin (GRFT), cyanovirin-N (CV-N) and scytovirin (SVN) inhibit HIV-1 infection by binding to mannose-rich glycans on gp120. We measured the ability of these lectins to inhibit both the HIV-1 binding to DC-SIGN and the DC-SIGN-mediated HIV-1 infection of CD4(+) cells. While GRFT, CV-N and SVN were moderately inhibitory to DC-SIGN binding, they potently inhibited DC-SIGN-transfer of HIV-1. The introduction of the 234 glycosylation site abolished HIV-1 sensitivity to lectin inhibition of binding to DC-SIGN and virus transfer to susceptible cells. However, the addition of the 295 glycosylation site increased the inhibition of transfer. Our data suggest that GRFT. CV-N and SVN can block two important stages of the sexual transmission of HIV-1, DC-SIGN binding and transfer, supporting their further development as microbicides. (C) 2011 Elsevier Inc. All rights reserved. C1 [Alexandre, Kabamba B.; Gray, Elin S.; Morris, Lynn] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa. [Mufhandu, Hazel; Chakauya, Ereck; Chikwamba, Rachel] CSIR, Pretoria, South Africa. [McMahon, James B.; O'Keefe, Barry R.] NCI Frederick, Mol Targets Lab, Ctr Canc Res, Frederick, MD USA. RP Morris, L (reprint author), Natl Inst Communicable Dis, Private Bag X4, ZA-2131 Johannesburg, South Africa. EM lynnm@nicd.ac.za FU NEPAD Agency/SANBio; South African AIDS Vaccine Initiative (SAAVI); Columbia University; Fogarty International Center, NIH [D43TW00231]; NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Nono Mkhize and Dr. Penny Moore for helpful suggestions and Mary Phoswa for technical assistance. This work was funded by BioFISA program of NEPAD Agency/SANBio under the microbicide project, the South African AIDS Vaccine Initiative (SAAVI) and a training fellowship to KBA from Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International Center, NIH (AITRP grant # D43TW00231). This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (B. O. & J. M.). NR 70 TC 20 Z9 20 U1 2 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2012 VL 423 IS 2 BP 175 EP 186 DI 10.1016/j.virol.2011.12.001 PG 12 WC Virology SC Virology GA 885TI UT WOS:000299803300008 PM 22209231 ER PT J AU Hasebe, R Raymond, GJ Horiuchi, M Caughey, B AF Hasebe, Rie Raymond, Gregory J. Horiuchi, Motohiro Caughey, Byron TI Reaction of complement factors varies with prion strains in vitro and in vivo SO VIROLOGY LA English DT Article DE Prion; Scrapie; Complement factors; Strain difference ID TRANSMISSIBLE MINK ENCEPHALOPATHY; DEPENDENT DIFFERENCES; SCRAPIE PATHOGENESIS; CLASSICAL PATHWAY; GENE-EXPRESSION; CELL-CULTURE; B-CELLS; PROTEIN; C1Q; ACTIVATION AB Roles of complement factors in prion infection of the central nervous system remain unclear. In this study, we assessed the strain-dependent reactivity of complement factors in prion infections of Neuro2a (N2a) cells and mouse brains. N2a cells persistently infected with either Chandler or 22L scrapie strains were cultured in the presence of normal mouse serum (NMS), followed by staining with phosphatidylserine binding protein and early apoptosis marker Annexin V. The proportion of Annexin V positive cells was increased both in Chandler- and 22L-infected cells. Preincubation of NMS with anti-C1q, C3 and/or C9 antibodies reduced Annexin V positive cells in Chandler-infected cells, while only anti-C3 antibodies were effective on 22L-infected cells. The immunohistochemistry showed that deposition of C1q and C3 was different between Chandler- and 22L-infected mouse brains. These results indicate that the reactivity of complement factors differs between prion strains both in vitro and in vivo. (C) 2011 Elsevier Inc. All rights reserved. C1 [Hasebe, Rie; Horiuchi, Motohiro] Hokkaido Univ, Grad Sch Vet Med, Lab Vet Hyg, Kita Ku, Sapporo, Hokkaido 0600818, Japan. [Hasebe, Rie; Raymond, Gregory J.; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Hasebe, R (reprint author), Hokkaido Univ, Grad Sch Vet Med, Lab Vet Hyg, Kita Ku, Nishi 9,Kita 18, Sapporo, Hokkaido 0600818, Japan. EM r-hasebe@vetmed.hokudai.ac.jp FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [ZIA AI000580-20, ZIA ZI000580-21]; Ministry of Education, Culture, Sports, Science and Technology [23780303]; Ministry of Health, Labour and Welfare of Japan [H23-Nanchi-Ippan-013] FX The authors greatly appreciate Dr. David Dorward in Microscopy Unit, Dr. Dan Long, Ms. Rebecca Rosenke and Ms. Lori Lubke in Histology Section, Rocky Mountain Laboratories, NIH/NIAID for technical support. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (project no. ZIA AI000580-20 & ZIA ZI000580-21). This work was also supported by Grand-in-Aid for Young Scientist (B) from the Ministry of Education, Culture, Sports, Science and Technology (grant no. 23780303) and by a grant for Research on Measures for Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan (grant no. H23-Nanchi-Ippan-013). NR 49 TC 7 Z9 7 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2012 VL 423 IS 2 BP 205 EP 213 DI 10.1016/j.virol.2011.11.017 PG 9 WC Virology SC Virology GA 885TI UT WOS:000299803300011 PM 22222213 ER PT J AU Ventetuolo, CE Barr, RG Bluemke, DA Jain, A Delaney, JAC Hundley, WG Lima, JAC Kawut, SM AF Ventetuolo, Corey E. Barr, R. Graham Bluemke, David A. Jain, Aditya Delaney, Joseph A. C. Hundley, W. Gregory Lima, Joao A. C. Kawut, Steven M. TI Selective Serotonin Reuptake Inhibitor Use Is Associated with Right Ventricular Structure and Function: The MESA-Right Ventricle Study SO PLOS ONE LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; SMOOTH-MUSCLE HYPERPLASIA; HEART-FAILURE; CARDIAC-HYPERTROPHY; PLASMA SEROTONIN; MYOCARDIAL-INFARCTION; MAJOR DEPRESSION; TRANSPORTER; ATHEROSCLEROSIS; GENDER AB Purpose: Serotonin and the serotonin transporter have been implicated in the development of pulmonary hypertension (PH). Selective serotonin reuptake inhibitors (SSRIs) may have a role in PH treatment, but the effects of SSRI use on right ventricular (RV) structure and function are unknown. We hypothesized that SSRI use would be associated with RV morphology in a large cohort without cardiovascular disease (N = 4114). Methods: SSRI use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were assessed via cardiac magnetic resonance imaging. The cross-sectional relationship between SSRI use and each RV measure was assessed using multivariable linear regression; analyses for RV mass and end-diastolic volume (RVEDV) were stratified by sex. Results: After adjustment for multiple covariates including depression and left ventricular measures, SSRI use was associated with larger RV stroke volume (RVSV) (2.75 mL, 95% confidence interval [CI] 0.48-5.02 mL, p = 0.02). Among men only, SSRI use was associated with greater RV mass (1.08 g, 95% CI 0.19-1.97 g, p = 0.02) and larger RVEDV (7.71 mL, 95% 3.02-12.40 mL, p = 0.001). SSRI use may have been associated with larger RVEDV among women and larger RV end-systolic volume in both sexes. Conclusions: SSRI use was associated with higher RVSV in cardiovascular disease-free individuals and, among men, greater RV mass and larger RVEDV. The effects of SSRI use in patients with (or at risk for) RV dysfunction and the role of sex in modifying this relationship warrant further study. C1 [Ventetuolo, Corey E.] Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. [Barr, R. Graham] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. [Jain, Aditya; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Delaney, Joseph A. C.] Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Kawut, Steven M.] Univ Penn, Dept Med, Penn Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Ventetuolo, CE (reprint author), Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. EM kawut@upenn.edu OI Ventetuolo, Corey /0000-0002-4223-4775; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [R01-HL086719, R01-HL074406, RO1-HL074338, R01-HL077612, N01-HC95159, N01-HC95160, N01-HC95161, N01-HC95162, N01-HC95163, N01-HC95164, N01-HC95165, N01-HC95166, N01-HC95167, N01-HC95168, N01-HC95169] FX This work was supported by the National Institutes of Health grants R01-HL086719, R01-HL074406, RO1-HL074338, R01-HL077612, N01-HC95159 through HC95169. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 4 Z9 4 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 17 PY 2012 VL 7 IS 2 AR e30480 DI 10.1371/journal.pone.0030480 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926TC UT WOS:000302853600033 PM 22363441 ER PT J AU West, XZ Meller, N Malinin, NL Deshmukh, L Meller, J Mahabeleshwar, GH Weber, ME Kerr, BA Vinogradova, O Byzova, TV AF West, Xiaoxia Z. Meller, Nahum Malinin, Nikolay L. Deshmukh, Lalit Meller, Julia Mahabeleshwar, Ganapati H. Weber, Malory E. Kerr, Bethany A. Vinogradova, Olga Byzova, Tatiana V. TI Integrin beta(3) Crosstalk with VEGFR Accommodating Tyrosine Phosphorylation as a Regulatory Switch SO PLOS ONE LA English DT Article ID PATHOLOGICAL ANGIOGENESIS; DEPENDENT ACTIVATION; CYTOPLASMIC DOMAIN; NMR-SPECTROSCOPY; BINDING; PROTEIN; ALPHA(IIB)BETA(3); RECEPTOR-2; MODULATION; MECHANISMS AB Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between beta(3) integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of beta(3) and VEGFR2. Specifically, the membrane-proximal motif around (YLSI)-Y-801 in VEGFR2 mediates its binding to non-phosphorylated beta 3CT, accommodating an alpha-helical turn in integrin bound conformation. We also show that Y-747 phosphorylation of beta(3) enhances the above interaction. To demonstrate the importance of beta(3) phosphorylation in endothelial cell functions, we synthesized beta 3CT-mimicking Y-747 phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y-747 but not F-747 significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y-747 peptide exhibits inhibitory effect only in WT but not in beta(3) integrin knock-out or beta(3) integrin knock-in cells expressing beta(3) with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2. C1 [West, Xiaoxia Z.; Meller, Nahum; Malinin, Nikolay L.; Meller, Julia; Mahabeleshwar, Ganapati H.; Weber, Malory E.; Kerr, Bethany A.; Byzova, Tatiana V.] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44106 USA. [Deshmukh, Lalit; Vinogradova, Olga] Univ Connecticut, Dept Pharmaceut Sci, Sch Pharm, Storrs, CT USA. [Deshmukh, Lalit] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Mahabeleshwar, Ganapati H.] Case Western Reserve Univ, Sch Med, Univ Hosp Harrington McLaughlin Heart & Vasc Inst, Cleveland, OH USA. [Mahabeleshwar, Ganapati H.] Case Western Reserve Univ, Sch Med, Case Cardiovasc Res Inst, Cleveland, OH USA. RP West, XZ (reprint author), Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44106 USA. EM olga.vinogradova@uconn.edu; byzovat@ccf.org RI Kerr, Bethany/D-1644-2012; Malinin, Nikolay/J-4271-2012; Deshmukh, Lalit/C-5073-2015; OI Kerr, Bethany/0000-0002-2995-7549; Vinogradova, Olga/0000-0001-5101-7361; Malinin, Nikolay/0000-0002-2654-1783 FU National Institute of Health (NIH); American Heart Association FX This work was supported in parts by National Institute of Health (NIH) grants to TVB and American Heart Association and NIH grants to OV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 40 TC 15 Z9 15 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 17 PY 2012 VL 7 IS 2 AR e31071 DI 10.1371/journal.pone.0031071 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926TC UT WOS:000302853600105 PM 22363548 ER PT J AU Aschebrook-Kilfoy, B Heltshe, SL Nuckols, JR Sabra, MM Shuldiner, AR Mitchell, BD Airola, M Holford, TR Zhang, YW Ward, MH AF Aschebrook-Kilfoy, Briseis Heltshe, Sonya L. Nuckols, John R. Sabra, Mona M. Shuldiner, Alan R. Mitchell, Braxton D. Airola, Matt Holford, Theodore R. Zhang, Yawei Ward, Mary H. TI Modeled nitrate levels in well water supplies and prevalence of abnormal thyroid conditions among the Old Order Amish in Pennsylvania SO ENVIRONMENTAL HEALTH LA English DT Article DE Nitrate; Thyroid Conditions; TSH; Old Order Amish; Water pollution; Drinking water ID NUTRITION EXAMINATION SURVEY; CONTERMINOUS UNITED-STATES; SODIUM-IODIDE SYMPORTER; DIETARY NITRATE; NATIONAL-HEALTH; DRINKING-WATER; PERCHLORATE; THIOCYANATE; CONTAMINATION; CONSUMPTION AB Background: Nitrate is a widespread contaminant of drinking water supplies, especially in agricultural areas. Nitrate intake from drinking water and dietary sources can interfere with the uptake of iodide by the thyroid, thus potentially impacting thyroid function. Methods: We assessed the relation of estimated nitrate levels in well water supplies with thyroid health in a cohort of 2,543 Old Order Amish residing in Lancaster, Chester, and Lebanon counties in Pennsylvania for whom thyroid stimulating hormone (TSH) levels were measured during 1995-2008. Nitrate measurement data (1976-2006) for 3,613 wells in the study area were obtained from the U. S. Geological Survey and we used these data to estimate concentrations at study participants' residences using a standard linear mixed effects model that included hydrogeological covariates and kriging of the wells' residuals. Nitrate levels estimated by the model ranged from 0.35 mg/L to 16.4 mg/L N-NO3-, with a median value of 6.5 mg/L, which was used as the cutpoint to define high and low nitrate exposure. In a validation analysis of the model, we calculated that the sensitivity of the model was 67% and the specificity was 93%. TSH levels were used to define the following outcomes: clinical hyperthyroidism (n = 10), clinical hypothyroidism (n = 56), subclinical hyperthyroidism (n = 25), and subclinical hypothyroidism (n = 228). Results: In women, high nitrate exposure was significantly associated with subclinical hypothyroidism (OR = 1.60; 95% CI: 1.11-2.32). Nitrate was not associated with subclinical thyroid disease in men or with clinical thyroid disease in men or women. Conclusions: Although these data do not provide strong support for an association between nitrate in drinking water and thyroid health, our results do suggest that further exploration of this hypothesis is warranted using studies that incorporate individual measures of both dietary and drinking water nitrate intake. C1 [Aschebrook-Kilfoy, Briseis; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Aschebrook-Kilfoy, Briseis; Holford, Theodore R.; Zhang, Yawei] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. [Heltshe, Sonya L.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Nuckols, John R.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Sabra, Mona M.] Mem Sloan Kettering Canc Ctr, Dept Med, Endocrine Serv, New York, NY 10021 USA. [Shuldiner, Alan R.; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Aschebrook-Kilfoy, Briseis] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Airola, Matt] Westat Corp, Rockville, MD USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. EM wardm@mail.nih.gov OI Mitchell, Braxton/0000-0003-4920-4744 FU American Federation of Aging Research (F.S.C.); NIH [R01 DK54261, TU2CA105666]; American Diabetes Association; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC); University of Maryland General Clinical Research Center [M01 RR 16500]; General Clinical Research Centers Program; National Center for Research Resources (NCRR); NIH/National Cancer Institute; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488] FX We gratefully acknowledge our Amish liaisons and field workers and the extraordinary cooperation and support of the Amish community, without whom these studies would not be possible. The study was supported by research grants from the American Federation of Aging Research (F.S.C.), NIH R01 DK54261 (A. R. S.) the American Diabetes Association (A. R. S.), the Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC), and the University of Maryland General Clinical Research Center, Grant M01 RR 16500, the General Clinical Research Centers Program, National Center for Research Resources (NCRR), NIH. This research was supported in part by the Intramural Research Program of the NIH/National Cancer Institute, including an interagency personnel agreement between NCI and Colorado State University. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center (grant P30 DK072488). Briseis Aschebrook-Kilfoy was supported by NIH training grant TU2CA105666. NR 36 TC 4 Z9 4 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD FEB 17 PY 2012 VL 11 AR 6 DI 10.1186/1476-069X-11-6 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 909PE UT WOS:000301575900001 PM 22339761 ER PT J AU Mousley, CJ Yuan, PH Gaur, NA Trettin, KD Nile, AH Deminoff, SJ Dewar, BJ Wolpert, M Macdonald, JM Herman, PK Hinnebusch, AG Bankaitis, VA AF Mousley, Carl J. Yuan, Peihua Gaur, Naseem A. Trettin, Kyle D. Nile, Aaron H. Deminoff, Stephen J. Dewar, Brian J. Wolpert, Max Macdonald, Jeffrey M. Herman, Paul K. Hinnebusch, Alan G. Bankaitis, Vytas A. TI A Sterol-Binding Protein Integrates Endosomal Lipid Metabolism with TOR Signaling and Nitrogen Sensing SO CELL LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; GOLGI-APPARATUS; COMPLEX; TRANSPORT; PATHWAY; GCN4; TRANSCRIPTION; TRAFFICKING; TRANSLATION; HOMEOSTASIS AB Kes1, and other oxysterol-binding protein superfamily members, are involved in membrane and lipid trafficking through trans-Golgi network (TGN) and endosomal systems. We demonstrate that Kes1 represents a sterol-regulated antagonist of TGN/endosomal phosphatidylinositol-4-phosphate signaling. This regulation modulates TOR activation by amino acids and dampens gene expression driven by Gcn4, the primary transcriptional activator of the general amino acid control regulon. Kes1-mediated repression of Gcn4 transcription factor activity is characterized by nonproductive Gcn4 binding to its target sequences, involves TGN/endosome-derived sphingolipid signaling, and requires activity of the cyclin-dependent kinase 8 (CDK8) module of the enigmatic "large Mediator'' complex. These data describe a pathway by which Kes1 integrates lipid metabolism with TORC1 signaling and nitrogen sensing. C1 [Mousley, Carl J.; Yuan, Peihua; Trettin, Kyle D.; Nile, Aaron H.; Wolpert, Max; Bankaitis, Vytas A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. [Gaur, Naseem A.; Hinnebusch, Alan G.] Eugene Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Deminoff, Stephen J.; Herman, Paul K.] Ohio State Univ, Dept Mol Genet & Microbiol, Columbus, OH 43210 USA. [Dewar, Brian J.; Macdonald, Jeffrey M.] Univ N Carolina, Dept Biomed Engn, Sch Med, Chapel Hill, NC 27599 USA. RP Mousley, CJ (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. EM mousley@email.unc.edu; vytas@med.unc.edu RI Yuan, Peihua/G-9088-2013; OI Yuan, Peihua/0000-0002-4633-0692; Gaur, Naseem/0000-0002-1224-8789 FU NIH [GM44530, GM65227]; NIEHS [T32EX007126, GM075941]; UNC FX This paper is dedicated to the memories of Christian Raetz and Eugene Kennedy. The work was supported by NIH grant GM44530 to V.A.B.; N.G. and A.G.H. were supported by the Intramural Research Program of the NIH; S.J.D. and P.K.H. by NIH grant GM65227 awarded to P.K.H.; and B.J.D. and J.M.M. by NIEHS T32EX007126 and GM075941. K.D.T. acknowledges support from the UNC William W. and Ida W. Taylor Honors Mentored Research Fellows Program. We thank Doug Cyr, Scott Moye Rowley, Chris Burd, and Dan Klionsky for strains and plasmids, Colin Stirling for CPY antibody, Chris Stefan, Scott Emr, and Maria Cardenas for discussions, and Lora Yanagisawa, Victoria Hewitt, and Robert Sons for comments on the manuscript. We acknowledge the UNC Lineberger Comprehensive Cancer Center Genome Analysis and Nucleic Acids Core facilities. NR 38 TC 43 Z9 44 U1 4 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 17 PY 2012 VL 148 IS 4 BP 702 EP 715 DI 10.1016/j.cell.2011.12.026 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 897DH UT WOS:000300622400012 PM 22341443 ER PT J AU Bedrood, S Li, YY Isas, JM Hegde, BG Baxa, U Haworth, IS Langen, R AF Bedrood, Sahar Li, Yiyu Isas, J. Mario Hegde, Balachandra G. Baxa, Ulrich Haworth, Ian S. Langen, Ralf TI Fibril Structure of Human Islet Amyloid Polypeptide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOLID-STATE NMR; EXPERIMENTAL CONSTRAINTS; INSULIN-SECRETION; HUMAN AMYLIN; PEPTIDE; PROTEIN; MODEL; MICE; CONFORMATION; AGGREGATION AB Misfolding and amyloid fibril formation by human islet amyloid polypeptide (hIAPP) are thought to be important in the pathogenesis of type 2 diabetes, but the structures of the misfolded forms remain poorly understood. Here we developed an approach that combines site-directed spin labeling with continuous wave and pulsed EPR to investigate local secondary structure and to determine the relative orientation of the secondary structure elements with respect to each other. These data indicated that individual hIAPP molecules take up a hairpin fold within the fibril. This fold contains two beta-strands that are much farther apart than expected from previous models. Atomistic structural models were obtained using computational refinement with EPR data as constraints. The resulting family of structures exhibited a left-handed helical twist, in agreement with the twisted morphology observed by electron microscopy. The fibril protofilaments contain stacked hIAPP monomers that form opposing beta-sheets that twist around each other. The two beta-strands of the monomer adopt out-of-plane positions and are staggered by about three peptide layers (similar to 15 angstrom). These results provide a mechanism for hIAPP fibril formation and could explain the remarkable stability of the fibrils. Thus, the structural model serves as a starting point for understanding and preventing hIAPP misfolding. C1 [Langen, Ralf] Univ So Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Li, Yiyu; Haworth, Ian S.] Univ So Calif, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA. [Baxa, Ulrich] NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Langen, R (reprint author), Univ So Calif, Zilkha Neurogenet Inst, 1501 San Pablo St, Los Angeles, CA 90033 USA. EM langen@usc.edu FU National Institutes of Health [AG027936]; University of Southern California Center for High-performance Computing and Communications FX This work was supported, in whole or in part, by National Institutes of Health Grant AG027936 (to R. L.).; Computation for the work described in this study was supported by the University of Southern California Center for High-performance Computing and Communications. NR 34 TC 56 Z9 56 U1 7 U2 38 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 FEB 17 PY 2012 VL 287 IS 8 BP 5235 EP 5241 DI 10.1074/jbc.M111.327817 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897HE UT WOS:000300638000006 PM 22187437 ER PT J AU Tran, DT Zhang, LP Zhang, Y Tian, E Earl, LA Ten Hagen, KG AF Tran, Duy T. Zhang, Liping Zhang, Ying Tian, E. Earl, Lesley A. Ten Hagen, Kelly G. TI Multiple Members of the UDP-GalNAc: Polypeptide N-Acetylgalactosaminyltransferase Family Are Essential for Viability in Drosophila SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID O-GLYCOSYLATION; TRANSGENIC RNAI; CELL-ADHESION; GERM-LINE; PROTEIN; EXPRESSION; MELANOGASTER; MUTATIONS; SECRETION; GLYCANS AB Mucin-type O-glycosylation represents a major form of post-translational modification that is conserved across most eukaryotic species. This type of glycosylation is initiated by a family of enzymes (GalNAc-Ts in mammals and PGANTs in Drosophila) whose members are expressed in distinct spatial and temporal patterns during development. Previous work from our group demonstrated that one member of this family is essential for viability and another member modulates extracellular matrix composition and integrin-mediated cell adhesion during development. To investigate whether other members of this family are essential, we employed RNA interference (RNAi) to each gene in vivo. Using this approach, we identified 4 additional pgant genes that are required for viability. Ubiquitous RNAi to pgant4, pgant5, pgant7, or the putative glycosyltransferase CG30463 resulted in lethality. Tissue-specific RNAi was also used to define the specific organ systems and tissues in which each essential family member is required. Interestingly, each essential pgant had a unique complement of tissues in which it was required. Additionally, certain tissues (mesoderm, digestive system, and tracheal system) required more than one pgant, suggesting unique functions for specific enzymes in these tissues. Expanding upon our RNAi results, we found that conventional mutations in pgant5 resulted in lethality and specific defects in specialized cells of the digestive tract, resulting in loss of proper digestive system acidification. In summary, our results highlight essential roles for O-glycosylation and specific members of the pgant family in many aspects of development and organogenesis. C1 [Tran, Duy T.; Zhang, Liping; Tian, E.; Earl, Lesley A.; Ten Hagen, Kelly G.] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD 20892 USA. [Zhang, Ying] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA. RP Ten Hagen, KG (reprint author), Bldg 30,Rm 426,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM Kelly.Tenhagen@nih.gov FU National Institutes of Health of the NIDCR FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIDCR. NR 48 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 17 PY 2012 VL 287 IS 8 BP 5243 EP 5252 DI 10.1074/jbc.M111.306159 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897HE UT WOS:000300638000007 PM 22157008 ER PT J AU Kedar, VP Zucconi, BE Wilson, GM Blackshear, PJ AF Kedar, Vishram P. Zucconi, Beth E. Wilson, Gerald M. Blackshear, Perry J. TI Direct Binding of Specific AUF1 Isoforms to Tandem Zinc Finger Domains of Tristetraprolin (TTP) Family Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA DEADENYLATION; RICH ELEMENT; POLY(A) TAIL; POLY(A)-BINDING PROTEIN; DEFICIENCY SYNDROME; TNF-ALPHA; TURNOVER; STABILITY; YEAST; DECAY AB Tristetraprolin (TTP) is the prototype of a family of CCCH tandem zinc finger proteins that can bind to AU-rich elements in mRNAs and promote their decay. TTP binds to mRNA through its central tandem zinc finger domain; it then promotes mRNA deadenylation, considered to be the rate-limiting step in eukaryotic mRNA decay. We found that TTP and its related family members could bind to certain isoforms of another AU-rich element-binding protein, HNRNPD/AUF1, as well as a related protein, laAUF1. The interaction domain within AUF1p45 appeared to be a C-terminal "GY" region, and the interaction domain within TTP was the tandem zinc finger domain. Surprisingly, binding of AUF1p45 to TTP occurred even with TTP mutants that lacked RNA binding activity. In cell extracts, binding of AUF1p45 to TTP potentiated TTP binding to ARE-containing RNA probes, as determined by RNA gel shift assays; AUF1p45 did not bind to the RNA probes under these conditions. Using purified, recombinant proteins and a synthetic RNA target in FRET assays, we demonstrated that AUF1p45, but not AUF1p37, increased TTP binding affinity for RNA similar to 5-fold. These data suggest that certain isoforms of AUF1 can serve as "co-activators" of TTP family protein binding to RNA. The results raise interesting questions about the ability of AUF1 isoforms to regulate the mRNA binding and decay-promoting activities of TTP and its family members as well as the ability of AUF1 proteins to serve as possible physical links between TTP and other mRNA decay proteins and structures. C1 [Kedar, Vishram P.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Zucconi, Beth E.; Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), F1-13 NIEHS,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU National Institutes of Health (NIEHS); American Heart Association [11PRE6900008]; National Institutes of Health [T32 GM066706]; [R01 CA102428] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program (NIEHS) and by Grant R01 CA102428 (to G. M. W.).; Supported by American Heart Association Grant 11PRE6900008 and National Institutes of Health Grant T32 GM066706. NR 52 TC 22 Z9 22 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 FEB 17 PY 2012 VL 287 IS 8 BP 5459 EP 5471 DI 10.1074/jbc.M111.312652 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897HE UT WOS:000300638000026 PM 22203679 ER PT J AU Feng, Y Mckee, K Tran, K O'Dell, S Schmidt, SD Phogat, A Forsell, MN Hedestam, GBK Mascola, JR Wyatt, RT AF Feng, Yu Mckee, Krisha Tran, Karen O'Dell, Sijy Schmidt, Stephen D. Phogat, Adhuna Forsell, Mattias N. Hedestam, Gunilla B. Karlsson Mascola, John R. Wyatt, Richard T. TI Biochemically Defined HIV-1 Envelope Glycoprotein Variant Immunogens Display Differential Binding and Neutralizing Specificities to the CD4-binding Site SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; B-CELL RESPONSES; SUBTYPE-C; ANTIBODY-SPECIFICITIES; MONOCLONAL-ANTIBODIES; OLIGOMERIC STRUCTURE; GP120 GLYCOPROTEINS; IMMUNE-RESPONSES; CD4 BINDING; T4 MOLECULE AB HIV-1 gp120 binds the primary receptor CD4. Recently, a plethora of broadly neutralizing antibodies to the gp120 CD4-binding site (CD4bs) validated this region as a target for immunogen design. Here, we asked if modified HIV-1 envelope glycoproteins (Env) designed to increase CD4 recognition might improve recognition by CD4bs neutralizing antibodies and more efficiently elicit such reactivities. We also asked if CD4bs stabilization, coupled with altering the Env format (monomer to trimer or cross-clade), might better elicit neutralizing antibodies by focusing the immune response on the functionally conserved CD4bs. We produced monomeric and trimeric Envs stabilized by mutations within the gp120 CD4bs cavity (pocket-filling; PF2) or by appending heterologous trimerization motifs to soluble Env ectodomains (gp120/gp140). Recombinant glycoproteins were purified to relative homogeneity, and ligand binding properties were analyzed by ELISA, surface plasmon resonance, and isothermal titration microcalorimetry. In some formats, the PF2 substitutions increased CD4 affinity, and importantly, PF2-containing proteins were better recognized by the broadly neutralizing CD4bs mAbs, VRC01 and VRC-PG04. Based on this analysis, we immunized selected Env variants into rabbits using heterologous or homologous regimens. Analysis of the sera revealed that homologous inoculation of the PF2-containing, variable region-deleted YU2 gp120 trimers (Delta V123/PF2-GCN4) more rapidly elicited CD4bs-directed neutralizing antibodies compared with other regimens, whereas homologous trimers elicited increased neutralization potency, mapping predominantly to the gp120 third major variable region (V3). These results suggest that some engineered Env proteins may more efficiently direct responses toward the conserved CD4bs and be valuable to elicit antibodies of greater neutralizing capacity. C1 [Feng, Yu; Tran, Karen; Wyatt, Richard T.] Scripps Res Inst, Dept Immunol & Microbial Sci, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Mckee, Krisha; O'Dell, Sijy; Schmidt, Stephen D.; Phogat, Adhuna; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. [Forsell, Mattias N.] Karolinska Inst, Dept Med, Translat Immunol Unit, SE-17177 Stockholm, Sweden. RP Wyatt, RT (reprint author), 10550 N Torrey Pines Rd, La Jolla, CA USA. EM wyatt@scripps.edu RI Feng, Yu/A-3396-2012; Schmidt, Stephen/B-5398-2012 FU National Institutes of Health NIAID; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation; Swedish Research Council FX This work was supported, in whole or in part, by National Institutes of Health NIAID intramural research program. This work was also supported by the International AIDS Vaccine Initiative, the Bill and Melinda Gates Foundation, and the Swedish Research Council. NR 70 TC 39 Z9 39 U1 0 U2 7 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 FEB 17 PY 2012 VL 287 IS 8 BP 5673 EP 5686 DI 10.1074/jbc.M111.317776 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897HE UT WOS:000300638000044 PM 22167180 ER PT J AU Wu, YN Wang, S Farooq, SM Castelvetere, MP Hou, YN Gao, JL Navarro, JV Oupicky, D Sun, F Li, CY AF Wu, Yanning Wang, Shuo Farooq, Shukkur M. Castelvetere, Marcello P. Hou, Yuning Gao, Ji-Liang Navarro, Javier V. Oupicky, David Sun, Fei Li, Chunying TI A Chemokine Receptor CXCR2 Macromolecular Complex Regulates Neutrophil Functions in Inflammatory Diseases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; PHOSPHOLIPASE-C-BETA; HUMAN INTERLEUKIN-8 RECEPTOR; CYSTIC-FIBROSIS; EXPERIMENTAL COLITIS; TRANSEPITHELIAL MIGRATION; SIGNAL-TRANSDUCTION; PLASMA-MEMBRANE; PDZ DOMAINS; PROTEIN AB Inflammation plays an important role in a wide range of human diseases such as ischemia-reperfusion injury, arteriosclerosis, cystic fibrosis, inflammatory bowel disease, etc. Neutrophilic accumulation in the inflamed tissues is an essential component of normal host defense against infection, but uncontrolled neutrophilic infiltration can cause progressive damage to the tissue epithelium. The CXC chemokine receptor CXCR2 and its specific ligands have been reported to play critical roles in the pathophysiology of various inflammatory diseases. However, it is unclear how CXCR2 is coupled specifically to its downstream signaling molecules and modulates cellular functions of neutrophils. Here we show that the PDZ scaffold protein NHERF1 couples CXCR2 to its downstream effector phospholipase C( PLC)beta 2, forming a macromolecular complex, through a PDZ-based interaction. We assembled a macromolecular complex of CXCR2.NHERF1.PLC-beta 2 in vitro, and we also detected such a complex in neutrophils by co-immunoprecipitation. We further observed that the CXCR2-containing macromolecular complex is critical for the CXCR2-mediated intracellular calcium mobilization and the resultant migration and infiltration of neutrophils, as disrupting the complex with a cell permeant CXCR2-specific peptide (containing the PDZ motif) inhibited intracellular calcium mobilization, chemotaxis, and transepithelial migration of neutrophils. Taken together, our data demonstrate a critical role of the PDZ-dependent CXCR2 macromolecular signaling complex in regulating neutrophil functions and suggest that targeting the CXCR2 multiprotein complex may represent a novel therapeutic strategy for certain inflammatory diseases. C1 [Wu, Yanning; Wang, Shuo; Farooq, Shukkur M.; Castelvetere, Marcello P.; Hou, Yuning; Li, Chunying] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. [Li, Chunying] Wayne State Univ, Sch Med, Cardiovasc Res Inst, Detroit, MI 48201 USA. [Li, Chunying] Wayne State Univ, Sch Med, Barbara Ann Karmanos Canc Inst, Detroit, MI 48201 USA. [Sun, Fei] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. [Oupicky, David] Wayne State Univ, Sch Med, Dept Pharmaceut Sci, Detroit, MI 48201 USA. [Gao, Ji-Liang] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Navarro, Javier V.] Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX 77555 USA. RP Li, CY (reprint author), Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, 540 E Canfield,5312 Scott Hall, Detroit, MI 48201 USA. EM cl@med.wayne.edu OI Oupicky, David/0000-0003-4710-861X FU American Heart Association [0765185B]; Elsa U. Pardee Foundation; Wayne State University; Cardiovascular Research Institute Isis Initiative; National Institutes of Health [HL096800] FX This work was supported by American Heart Association (Greater SE Affiliate) Beginning Grant-in-aid 0765185B (to C. L.), an Elsa U. Pardee Foundation research grant (to C. L.), Wayne State University intramural startup fund and a Cardiovascular Research Institute Isis Initiative award (to C. L.), and National Institutes of Health Grant HL096800 (to F. S.). NR 63 TC 29 Z9 29 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 FEB 17 PY 2012 VL 287 IS 8 BP 5744 EP 5755 DI 10.1074/jbc.M111.315762 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897HE UT WOS:000300638000050 PM 22203670 ER PT J AU Lee, HH Nemecek, D Schindler, C Smith, WJ Ghirlando, R Steven, AC Bonifacino, JS Hurley, JH AF Lee, Hyung Ho Nemecek, Daniel Schindler, Christina Smith, William J. Ghirlando, Rodolfo Steven, Alasdair C. Bonifacino, Juan S. Hurley, James H. TI Assembly and Architecture of Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; ANALYTICAL ULTRACENTRIFUGATION; ELECTRON-MICROSCOPY; PROTEIN COMPLEX; MOUSE MODEL; DYSBINDIN; GENE; ADAPTER; SCHIZOPHRENIA; EXPRESSION AB BLOC-1 (biogenesis of lysosome-related organelles complex-1) is critical for melanosome biogenesis and has also been implicated in neurological function and disease. We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, similar to 300 angstrom long and similar to 30 angstrom in diameter. The individual domains are flexibly connected such that the linear chain undergoes bending by as much as 45 degrees. Two stable subcomplexes were defined, pallidin-Cappuccino-BLOS1 and dysbindin-Snapin-BLOS2. Both subcomplexes are 1:1:1 heterotrimers that form extended structures as indicated by their hydrodynamic properties. The two subcomplexes appear to constitute flexible units within the larger BLOC-1 chain, an arrangement conducive to simultaneous interactions with multiple BLOC-1 partners in the course of tubular endosome biogenesis and sorting. C1 [Steven, Alasdair C.] NIAMS, NIH, Bethesda, MD 20892 USA. [Lee, Hyung Ho] Kookmin Univ, Dept Bio & Nano Chem, Seoul 136702, South Korea. [Lee, Hyung Ho] Kookmin Univ, Dept Integrat Biomed Sci & Engn, Seoul 136702, South Korea. [Lee, Hyung Ho; Ghirlando, Rodolfo; Hurley, James H.] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. [Schindler, Christina; Smith, William J.; Bonifacino, Juan S.] Eunice Kennedy Shriver NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMS, NIH, Bldg 50,Rm 1517, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov; juan@helix.nih.gov; hurley@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU National Institutes of Health of NIDDK; NICHD; NIAMS; Deutsche Forschungsgemeinschaft FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Programs of NIDDK (to J. H. H.), NICHD (to J. S. B.), and NIAMS (to A. C. S.). This work was also supported by a fellowship from the Deutsche Forschungsgemeinschaft (to C. S.). NR 42 TC 23 Z9 31 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 FEB 17 PY 2012 VL 287 IS 8 BP 5882 EP 5890 DI 10.1074/jbc.M111.325746 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897HE UT WOS:000300638000062 PM 22203680 ER PT J AU Chun, JH Pike, VW AF Chun, Joong-Hyun Pike, Victor W. TI Regiospecific Syntheses of Functionalized Diaryliodonium Tosylates via [Hydroxy(tosyloxy)iodo]arenes Generated in Situ from (Diacetoxyiodo)arenes SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ONE-POT SYNTHESIS; ARYL IODIDES; ARYLBORONIC ACIDS; FACILE SYNTHESIS; KOSERS REAGENT; 1ST SYNTHESIS; IODINE; DERIVATIVES; F-18; REACTIVITIES AB Ready access to F-18-labeled aryl synthons is required for preparing novel radiotracers for molecular imaging with positron emission tomography. Diaryliodonium salts react with cyclotron-produced no-carrier-added [F-18]fluoride ion to produce [F-18]aryl fluorides. We aimed to prepare functionalized diaryliodonium salts to serve as potential precursors for producing useful F-18-labeled aryl synthons, such as F-18-labeled halomethylbenzenes, benzaldehydes, and benzoic acid esters. Such salts were designed to have one functionalized aryl ring, one relatively electron-rich ring, such as 4-methoxyphenyl or 2-thienyl, and a nonfluorine containing weakly nucleophilic anion. Generation of a [hydroxy(tosyloxy)iodo]arene from a functionalized (diacetoxyiodo)arene in situ followed by treatment with an electron-rich arene, such as anisole or thiophene, or with a functionalized arylstannane gave expedient regiospecific access to a wide range of functionally diverse diaryliodonium tosylates in moderate to high yields (44-98%), The described methodology broadens the scope for producing new functionalized diaryliodonium salts for diverse applications. C1 [Chun, Joong-Hyun; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Room B3 C346A,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU National Insitutes of Health (NIMH) FX This research was supported by the Intramural Research Program of the National Insitutes of Health (NIMH). NR 43 TC 17 Z9 17 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD FEB 17 PY 2012 VL 77 IS 4 BP 1931 EP 1938 DI 10.1021/jo202517v PG 8 WC Chemistry, Organic SC Chemistry GA 893FC UT WOS:000300340000031 PM 22276914 ER PT J AU Oliveira, GD Lieberman, J Barillas-Mury, C AF Oliveira, Giselle de Almeida Lieberman, Joshua Barillas-Mury, Carolina TI Epithelial Nitration by a Peroxidase/NOX5 System Mediates Mosquito Antiplasmodial Immunity SO SCIENCE LA English DT Article ID ANOPHELES-GAMBIAE; MIDGUT CELLS; PLASMODIUM; COMPLEMENT; INVASION; DISEASE AB Plasmodium ookinetes traverse midgut epithelial cells before they encounter the complement system in the mosquito hemolymph. We identified a heme peroxidase (HPX2) and NADPH oxidase 5 (NOX5) as critical mediators of midgut epithelial nitration and antiplasmodial immunity that enhance nitric oxide toxicity in Anopheles gambiae. We show that the two immune mechanisms that target ookinetes-epithelial nitration and thioester-containing protein 1 (TEP1)-mediated lysis-work sequentially, and we propose that epithelial nitration works as an opsonization-like system that promotes activation of the mosquito complement cascade. C1 [Oliveira, Giselle de Almeida; Lieberman, Joshua; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. RP Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Rockville, MD 20892 USA. EM cbarillas@niaid.nih.gov OI Oliveira, Giselle/0000-0002-5898-7843 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. We thank A. Laughinghouse and K. Lee for insectary support; J. Ribeiro and J. Valenzuela for their comments and insight; and L. Garver and B. Marshall for editorial assistance. NR 17 TC 60 Z9 60 U1 1 U2 14 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 FEB 17 PY 2012 VL 335 IS 6070 BP 856 EP 859 DI 10.1126/science.1209678 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 893LC UT WOS:000300356400044 ER PT J AU Wang, QS Zhou, H Gao, HM Chen, SH Chu, CH Wilson, B Hong, JS AF Wang, Qingshan Zhou, Hui Gao, Huiming Chen, Shih-Heng Chu, Chun-Hsien Wilson, Belinda Hong, Jau-Shyong TI Naloxone inhibits immune cell function by suppressing superoxide production through a direct interaction with gp91(phox) subunit of NADPH oxidase SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Neuroinflammation; Microglia; NADPH oxidase; Opioid receptor; Binding ID DOPAMINERGIC-NEURONS; INFLAMMATORY DAMAGE; OPIOID ANALGESIA; MICROGLIA; MORPHINE; BINDING; DEXTROMETHORPHAN; DEGENERATION; INVOLVEMENT; ACTIVATION AB Background: Both (-) and (+)-naloxone attenuate inflammation-mediated neurodegeneration by inhibition of microglial activation through superoxide reduction in an opioid receptor-independent manner. Multiple lines of evidence have documented a pivotal role of overactivated NADPH oxidase (NOX2) in inflammation-mediated neurodegeneration. We hypothesized that NOX2 might be a novel action site of naloxone to mediate its anti-inflammatory actions. Methods: Inhibition of NOX-2-derived superoxide by (-) and (+)-naloxone was measured in lipopolysaccharide (LPS)-treated midbrain neuron-glia cultures and phorbol myristate acetate (PMA)-stimulated neutrophil membranes by measuring the superoxide dismutase (SOD)-inhibitable reduction of tetrazolium salt (WST-1) or ferricytochrome c. Further, various ligand (H-3-naloxone) binding assays were performed in wild type and gp91(phox-/-) neutrophils and transfected COS-7 and HEK293 cells. The translocation of cytosolic subunit p47(phox) to plasma membrane was assessed by western blot. Results: Both (-) and (+)-naloxone equally inhibited LPS- and PMA-induced superoxide production with an IC50 of 1.96 and 2.52 mu M, respectively. Competitive binding of H-3-naloxone with cold (-) and (+)-naloxone in microglia showed equal potency with an IC50 of 2.73 and 1.57 mu M, respectively. H-3-Naloxone binding was elevated in COS-7 and HEK293 cells transfected with gp91(phox); in contrast, reduced H-3-naloxone binding was found in neutrophils deficient in gp91(phox) or in the presence of a NOX2 inhibitor. The specificity and an increase in binding capacity of H-3-naloxone were further demonstrated by 1) an immunoprecipitation study using gp91(phox) antibody, and 2) activation of NOX2 by PMA. Finally, western blot studies showed that naloxone suppressed translocation of the cytosolic subunit p47(phox) to the membrane, leading to NOX2 inactivation. Conclusions: Strong evidence is provided indicating that NOX2 is a non-opioid novel binding site for naloxone, which is critical in mediating its inhibitory effect on microglia overactivation and superoxide production. C1 [Wang, Qingshan; Zhou, Hui; Gao, Huiming; Chen, Shih-Heng; Chu, Chun-Hsien; Wilson, Belinda; Hong, Jau-Shyong] Natl Inst Environm Hlth Sci, Neuropharmacol Sect, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Hong, JS (reprint author), Natl Inst Environm Hlth Sci, Neuropharmacol Sect, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. EM hong3@niehs.nih.gov FU National Institutes of Health/National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences. We thank Dr. Saurabh Chatterjee and Baozhong Zhao at the National Institute of Environmental Health Sciences and Esteban Oyarzabal at University of North Carolina, Chapel Hill, for their helpful suggestions in editing this article. NR 45 TC 30 Z9 31 U1 3 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD FEB 16 PY 2012 VL 9 AR 32 DI 10.1186/1742-2094-9-32 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 917IL UT WOS:000302167000001 PM 22340895 ER PT J AU Jonsson, H Helgadottir, GP Aspelund, T Sverrisdottir, JE Eiriksdottir, G Sigurdsson, S Eliasson, GJ Jonsson, A Ingvarsson, T Harris, TB Launer, L Gudnason, V AF Jonsson, Helgi Helgadottir, Gudrun P. Aspelund, Thor Sverrisdottir, Johanna E. Eiriksdottir, Gudny Sigurdsson, Sigurdur Eliasson, Gudmundur J. Jonsson, Asbjorn Ingvarsson, Thorvaldur Harris, Tamara B. Launer, Lenore Gudnason, Vilmundur TI The use of digital photographs for the diagnosis of hand osteoarthritis: the AGES-Reykjavik study SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE Hand ostearthritis; Generalized osteoarthritis; Epidemiology; Imaging; Photography ID RADIOGRAPHIC OSTEOARTHRITIS; OSTEO-ARTHROSIS; ASSOCIATION; PREVALENCE; RELIABILITY; POPULATION; DISABILITY; CRITERIA; PATTERN; IMPACT AB Background: The objective of the study was to standardize a method using digital photographs to diagnose and grade hand osteoarthritis (HOA), to compare it with radiographs and clinical examination with regard to prevalence and relation to symptoms, and finally to construct a simple shortened version suitable for use in very large studies, where a global estimate may be preferable. Methods: High quality photographs with standard distance and hand positioning were analysed for the presence of HOA and subsequently compared with standard radiographs and clinical examination in 381 random participants in the AGES-Reykjavik Study, a large population study. The mean age of the participants was 76 years. Results: Using the photographic method, the most commonly affected joints were the second DIP joints followed by the third DIP joints and second and third PIP joints. Both interobserver (ICC = 0.83) and intraobserver reading agreements (ICC = 0.89) were acceptable. On comparison with radiography and clinical examination, aggregate scores were significantly correlated (R-s 0.35-0.69), more so in females (R-s 0.53-0.72) than males. Hand pain in males showed very little association with HOA findings by the three methods but all methods showed a comparable moderate association with hand pain in females. The performance of photography in predicting pain on most days for at least a month in females was comparable to that of radiography and clinical examination (AUC 0.63 p = 0.004). Analysis of intermittent pain yielded similar results for in the DIP and PIP joints (OR 3.2-3.3, p < 0.01), but for the CMC1 joints, both radiography (OR 9.0, p < 0.0001), and clinical examination (OR 9.8, p < 0.0001), had higher predictive odds ratios for pain than photography (OR 3.6, p < 0.0001)., A shortened, rapidly performed form of reading photographs also showed a high degree of correlation with the other methods (R-s 0.56-0.82). Conclusion: High quality hand photographs can be used to diagnose and grade hand osteoarthritis. The method has the advantage of being inexpensive and easy to perform. By using a slightly simplified method of reading, it appears to be highly suitable for use in large studies. C1 [Jonsson, Helgi; Jonsson, Asbjorn] Univ Iceland, Landspitalinn Univ Hosp, IS-108 Reykjavik, Iceland. [Helgadottir, Gudrun P.] Univ Iceland, IS-108 Reykjavik, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Iceland Heart Assoc, IS-108 Reykjavik, Iceland. [Sverrisdottir, Johanna E.; Eiriksdottir, Gudny; Sigurdsson, Sigurdur] Iceland Heart Assoc, Kopavogur, Iceland. [Eliasson, Gudmundur J.] Roentgen Domus Med, Reykjavik, Iceland. [Ingvarsson, Thorvaldur] Akureyri Cent Hosp, Akureyri, Iceland. [Harris, Tamara B.; Launer, Lenore] NIA, Bethesda, MD 20892 USA. RP Jonsson, H (reprint author), Univ Iceland, Landspitalinn Univ Hosp, IS-108 Reykjavik, Iceland. EM helgi@hi.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH [N01-AG-12100]; Icelandic Heart Association; Althingi (the Icelandic Parliament); Icelandic Osteoarthritis Fund; University of Iceland Research FX Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), the Icelandic Osteoarthritis Fund and the University of Iceland Research Fund. The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. NR 34 TC 7 Z9 7 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD FEB 16 PY 2012 VL 13 AR 20 DI 10.1186/1471-2474-13-20 PG 13 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 903VS UT WOS:000301150500001 PM 22340303 ER PT J AU Silbergleit, R Durkalski, V Lowenstein, D Conwit, R Pancioli, A Palesch, Y Barsan, W AF Silbergleit, Robert Durkalski, Valerie Lowenstein, Daniel Conwit, Robin Pancioli, Arthur Palesch, Yuko Barsan, William CA NETT Investigators TI Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DIAZEPAM; MIDAZOLAM; LORAZEPAM; SEIZURES; CHILDREN AB BACKGROUND Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route. METHODS This double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points. RESULTS At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscularmidazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups. CONCLUSIONS For subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials. gov number, NCT00809146.) C1 [Silbergleit, Robert; Barsan, William] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48105 USA. [Durkalski, Valerie; Palesch, Yuko] Med Univ S Carolina, Dept Med, Div Biostat & Epidemiol, Charleston, SC USA. [Lowenstein, Daniel] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Conwit, Robin] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Pancioli, Arthur] Univ Cincinnati, Dept Emergency Med, Cincinnati, OH USA. RP Silbergleit, R (reprint author), Univ Michigan, Dept Emergency Med, Suite 3100,24 Frank Lloyd Wright Dr, Ann Arbor, MI 48105 USA. EM robert.silbergleit@umich.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [U01NS056975, U01NS059041]; National Institutes of Health Office; Biomedical Advanced Research and Development Authority of the Assistant Secretary for Preparedness and Response FX Supported by awards from the National Institute of Neurological Disorders and Stroke (NINDS) (U01NS056975 and U01NS059041); the National Institutes of Health Office of the Director CounterACT Program; and the Biomedical Advanced Research and Development Authority of the Assistant Secretary for Preparedness and Response. NR 11 TC 185 Z9 189 U1 4 U2 12 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 FEB 16 PY 2012 VL 366 IS 7 BP 591 EP 600 DI 10.1056/NEJMoa1107494 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 892IL UT WOS:000300279800004 PM 22335736 ER PT J AU Kawashima, S Ueki, Y Kato, T Matsukawa, N Mima, T Hallett, M Ito, K Ojika, K AF Kawashima, Shoji Ueki, Yoshino Kato, Takashi Matsukawa, Noriyuki Mima, Tatsuya Hallett, Mark Ito, Kengo Ojika, Kosei TI Changes in Striatal Dopamine Release Associated with Human Motor-Skill Acquisition SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; LONG-TERM POTENTIATION; BASAL GANGLIA; SYNAPTIC PLASTICITY; PARKINSONS-DISEASE; PREFRONTAL CORTEX; HAND MOVEMENT; HUMAN-BRAIN; MEMORY; CONSOLIDATION AB The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using C-11-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The C-11-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that C-11-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition. C1 [Kawashima, Shoji; Ueki, Yoshino; Matsukawa, Noriyuki; Ojika, Kosei] Nagoya City Univ, Dept Neurol & Neurosci, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi, Japan. [Kato, Takashi; Ito, Kengo] Natl Ctr Geriatr & Gerontol, Dept Brain Sci & Mol Imaging, Res Inst, Obu, Aichi, Japan. [Mima, Tatsuya] Kyoto Univ, Human Brain Res Ctr, Grad Sch Med, Sakyo Ku, Kyoto, Japan. [Hallett, Mark] NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. RP Kawashima, S (reprint author), Nagoya City Univ, Dept Neurol & Neurosci, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi, Japan. EM yueki@med.nagoya-cu.ac.jp OI Mima, Tatsuya/0000-0001-7787-4855 NR 67 TC 8 Z9 8 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 FEB 15 PY 2012 VL 7 IS 2 AR e31728 DI 10.1371/journal.pone.0031728 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925DP UT WOS:000302741300091 PM 22355391 ER PT J AU Matsuki, T Zaka, M Guerreiro, R van der Brug, MP Cooper, JA Cookson, MR Hardy, JA Howell, BW AF Matsuki, Tohru Zaka, Mariam Guerreiro, Rita van der Brug, Marcel P. Cooper, Jonathan A. Cookson, Mark R. Hardy, John A. Howell, Brian W. TI Identification of Stk25 as a Genetic Modifier of Tau Phosphorylation in Dab1-Mutant Mice SO PLOS ONE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; APOE RECEPTOR 2; ALZHEIMERS-DISEASE; NEURONAL POLARIZATION; BRAIN-DEVELOPMENT; CORTICAL-NEURONS; RNA INTERFERENCE; TRANSGENIC MICE; REELIN PATHWAY; VLDL RECEPTOR AB Hyperphosphorylation of the microtubule binding protein Tau is a feature of a number of neurodegenerative diseases, including Alzheimer's disease. Tau is hyperphosphorylated in the hippocampus of dab1-null mice in a strain-dependent manner; however, it has not been clear if the Tau phosphorylation phenotype is a secondary effect of the morbidity of these mutants. The dab1 gene encodes a docking protein that is required for normal brain lamination and dendritogenesis as part of the Reelin signaling pathway. We show that dab1 gene inactivation after brain development leads to Tau hyperphosphorylation in anatomically normal mice. Genomic regions that regulate the phospho Tau phenotype in dab1 mutants have previously been identified. Using a microarray gene expression comparison between dab1-mutants from the high-phospho Tau expressing and low-phospho Tau expressing strains, we identified Stk25 as a differentially expressed modifier of dab1-mutant phenotypes. Stk25 knockdown reduces Tau phosphorylation in embryonic neurons. Furthermore, Stk25 regulates neuronal polarization and Golgi morphology in an antagonistic manner to Dab1. This work provides insights into the complex regulation of neuronal behavior during brain development and provides insights into the molecular cascades that regulate Tau phosphorylation. C1 [Matsuki, Tohru; Howell, Brian W.] SUNY Upstate Med Univ, Syracuse, NY USA. [Zaka, Mariam] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Guerreiro, Rita; van der Brug, Marcel P.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Cooper, Jonathan A.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA. RP Matsuki, T (reprint author), SUNY Upstate Med Univ, Syracuse, NY USA. EM howellb@upstate.edu RI Hardy, John/C-2451-2009; Guerreiro, Rita/A-1327-2011; OI Howell, Brian/0000-0002-0204-0773 FU National Institute of Neurological Disorders and Stroke intramural; State University of New York, Upstate Medical University; National Institutes of Health [CA41072]; National Institute on Aging FX This work was supported by National Institute of Neurological Disorders and Stroke intramural and State University of New York, Upstate Medical University startup funds for BWH, National Institutes of Health grant CA41072 to JAC, and National Institute on Aging intramural funds for MRC. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 50 TC 10 Z9 10 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 FEB 15 PY 2012 VL 7 IS 2 AR e31152 DI 10.1371/journal.pone.0031152 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925DP UT WOS:000302741300040 PM 22355340 ER PT J AU Schomacker, H Hebner, RM Boonyaratanakornkit, J Surman, S Amaro-Carambot, E Collins, PL Schmidt, AC AF Schomacker, Henrick Hebner, Rebecca M. Boonyaratanakornkit, Jim Surman, Sonja Amaro-Carambot, Emerito Collins, Peter L. Schmidt, Alexander C. TI The C Proteins of Human Parainfluenza Virus Type 1 Block IFN Signaling by Binding and Retaining Stat1 in Perinuclear Aggregates at the Late Endosome SO PLOS ONE LA English DT Article ID SENDAI-VIRUS; V-PROTEIN; VACCINE CANDIDATES; ALPHA-INTERFERON; RNA-SYNTHESIS; NUCLEAR ACCUMULATION; MANNOSE 6-PHOSPHATE; NONHUMAN-PRIMATES; GAMMA-INTERFERON; PREVENTING STAT1 AB Interferons (IFNs) play a crucial role in the antiviral immune response. Whereas the C proteins of wild-type human parainfluenza virus type 1 (WT HPIV1) inhibit both IFN-beta induction and signaling, a HPIV1 mutant encoding a single amino acid substitution (F170S) in the C proteins is unable to block either host response. Here, signaling downstream of the type 1 IFN receptor was examined in Vero cells to define at what stage WT HPIV1 can block, and F170S HPIV1 fails to block, IFN signaling. WT HPIV1 inhibited phosphorylation of both Stat1 and Stat2, and this inhibition was only slightly reduced for F170S HPIV1. Degradation of Stat1 or Stat2 was not observed. The HPIV1 C proteins were found to accumulate in the perinuclear space, often forming large granules, and co-localized with Stat1 and the cation-independent mannose 6-phosphate receptor (M6PR) that is a marker for late endosomes. Upon stimulation with IFN-beta, both the WT and F170S C proteins remained in the perinuclear space, but only the WT C proteins prevented Stat1 translocation to the nucleus. In addition, WT HPIV1 C proteins, but not F170S C proteins, co-immunoprecipitated both phosphorylated and unphosphorylated Stat1. Our findings suggest that the WT HPIV1 C proteins form a stable complex with Stat1 in perinuclear granules that co-localize with M6PR, and that this direct interaction between the WT HPIV1 C proteins and Stat1 is the basis for the ability of HPIV1 to inhibit IFN signaling. The F170S mutation in HPIV1 C did not prevent perinuclear co-localization with Stat1, but apparently weakened this interaction such that, upon IFN stimulation, Stat1 was translocated to the nucleus to induce an antiviral response. C1 [Schomacker, Henrick; Hebner, Rebecca M.; Boonyaratanakornkit, Jim; Surman, Sonja; Amaro-Carambot, Emerito; Collins, Peter L.; Schmidt, Alexander C.] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Schomacker, H (reprint author), NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM schmidta@niaid.nih.gov OI Tripp, Ralph/0000-0002-2924-9956 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; NIH; MedImmune, LLC FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. This research was also supported in part by a cooperative research and development agreement (CRADA) between NIH and MedImmune, LLC, for the development of HPIV, RSV and HPMV vaccines. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 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 FEB 15 PY 2012 VL 7 IS 2 AR e28382 DI 10.1371/journal.pone.0028382 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925DP UT WOS:000302741300001 PM 22355301 ER PT J AU Jin, SM Youle, RJ AF Jin, Seok Min Youle, Richard J. TI PINK1-and Parkin-mediated mitophagy at a glance SO JOURNAL OF CELL SCIENCE LA English DT Editorial Material ID MITOCHONDRIAL-DNA DELETIONS; SUBSTANTIA-NIGRA NEURONS; PROTEIN-DEGRADATION; PINK1/PARKIN-MEDIATED MITOPHAGY; RETICULOCYTE MATURATION; OXIDATIVE STRESS; KINASE PINK1; DISEASE; AUTOPHAGY; MUTATIONS C1 [Jin, Seok Min; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Ctr Dr,10-5D37, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov NR 60 TC 123 Z9 128 U1 4 U2 19 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 FEB 15 PY 2012 VL 125 IS 4 BP 795 EP 799 DI 10.1242/jcs.093849 PG 5 WC Cell Biology SC Cell Biology GA 925NF UT WOS:000302767200001 PM 22448035 ER PT J AU Wurster, AL Precht, P Becker, KG Wood, WH Zhang, YQ Wang, Z Pazin, MJ AF Wurster, Andrea L. Precht, Patricia Becker, Kevin G. Wood, William H., III Zhang, Yongqing Wang, Zhong Pazin, Michael J. TI IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme SO BMC IMMUNOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; HELPER-CELL DIFFERENTIATION; DISEASE SUSCEPTIBILITY LOCI; EMBRYONIC STEM-CELLS; GENE-EXPRESSION; T-CELLS; THYMOCYTE DEVELOPMENT; FACTOR GATA-3; CYCLE CONTROL; CHIP-SEQ AB Background: SWI/SNF chromatin remodeling enzymes play a critical role in the development of T helper lymphocytes, including Th2 cells, and directly program chromatin structure at Th2 cytokine genes. Different versions of SWI/SNF complexes, including BAF and PBAF, have been described based on unique subunit composition. However, the relative role of BAF and PBAF in Th cell function and cytokine expression has not been reported. Results: Here we examine the role of the PBAF SWI/SNF complex in Th cell development and gene expression using mice deficient for a PBAF-specific component, BAF180. We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus. Conclusions: These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription. C1 [Becker, Kevin G.; Wood, William H., III; Zhang, Yongqing] NIA, Gene Express & Genom Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wang, Zhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Wurster, Andrea L.; Precht, Patricia; Pazin, Michael J.] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Pazin, MJ (reprint author), NHGRI, NIH, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM pazinm@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656; Pazin, Michael/0000-0002-7561-3640 FU NIH, National Institute on Aging [1 Z01 AG000524] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, 1 Z01 AG000524. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 6 Z9 7 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD FEB 15 PY 2012 VL 13 AR 9 DI 10.1186/1471-2172-13-9 PG 19 WC Immunology SC Immunology GA 919JX UT WOS:000302322300001 PM 22336179 ER PT J AU Li, J Lu, ZY AF Li, Jiao Lu, Zhiyong TI Automatic identification and normalization of dosage forms in drug monographs SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article ID MEDICATION INFORMATION AB Background: Each day, millions of health consumers seek drug-related information on the Web. Despite some efforts in linking related resources, drug information is largely scattered in a wide variety of websites of different quality and credibility. Methods: As a step toward providing users with integrated access to multiple trustworthy drug resources, we aim to develop a method capable of identifying drug's dosage form information in addition to drug name recognition. We developed rules and patterns for identifying dosage forms from different sections of full-text drug monographs, and subsequently normalized them to standardized RxNorm dosage forms. Results: Our method represents a significant improvement compared with a baseline lookup approach, achieving overall macro-averaged Precision of 80%, Recall of 98%, and F-Measure of 85%. Conclusions: We successfully developed an automatic approach for drug dosage form identification, which is critical for building links between different drug-related resources. C1 [Li, Jiao; Lu, Zhiyong] Natl Lib Med, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov FU National Institutes of Health, National Library of Medicine FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 23 TC 0 Z9 0 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD FEB 15 PY 2012 VL 12 AR 9 DI 10.1186/1472-6947-12-9 PG 9 WC Medical Informatics SC Medical Informatics GA 914GJ UT WOS:000301937200002 PM 22336431 ER PT J AU von Eyss, B Maaskola, J Memczak, S Mollmann, K Schuetz, A Loddenkemper, C Tanh, MD Otto, A Muegge, K Heinemann, U Rajewsky, N Ziebold, U AF von Eyss, Bjoern Maaskola, Jonas Memczak, Sebastian Moellmann, Katharina Schuetz, Anja Loddenkemper, Christoph Tanh, Mai-Dinh Otto, Albrecht Muegge, Kathrin Heinemann, Udo Rajewsky, Nikolaus Ziebold, Ulrike TI The SNF2-like helicase HELLS mediates E2F3-dependent transcription and cellular transformation SO EMBO JOURNAL LA English DT Article DE cell-cycle re-entry; E2F3; HELLS; H3K27me3; prostate tumour ID CYCLE PROGRESSION; DNA METHYLATION; BLADDER-CANCER; E2F FAMILY; IN-VIVO; LSH; PROLIFERATION; GENE; AMPLIFICATION; ACTIVATION AB for their dependence on the Retinoblastoma protein and their role in cellular proliferation. E2F3 is uniquely amplified in specific human tumours where its expression is inversely correlated with the survival of patients. Here, E2F3B interaction partners were identified by mass spectrometric analysis. We show that the SNF2-like helicase HELLS interacts with E2F3A in vivo and cooperates with its oncogenic functions. Depletion of HELLS severely perturbs the induction of E2F-target genes, hinders cell-cycle re-entry and growth. Using chromatin immmunoprecipitation coupled to sequencing, we identified genome-wide targets of HELLS and E2F3A/B. HELLS binds promoters of active genes, including the trithorax-related MLL1, and co-regulates E2F3-dependent genes. Strikingly, just as E2F3, HELLS is overexpressed in human tumours including prostate cancer, indicating that either factor may contribute to the malignant progression of tumours. Our work reveals that HELLS is important for E2F3 in tumour cell proliferation. The EMBO Journal (2012) 31, 972-985. doi: 10.1038/emboj.2011.451; Published online 13 December 2011 C1 [Maaskola, Jonas; Rajewsky, Nikolaus; Ziebold, Ulrike] Max Delbruck Ctr Mol Med MDC, Berlin Inst Med Syst Biol, Lab Syst Biol Gene Regulatory Elements, D-13125 Berlin, Germany. [Schuetz, Anja; Heinemann, Udo] Max Delbruck Ctr Mol Med MDC, Prot Sample Prod Facil, D-13125 Berlin, Germany. [Loddenkemper, Christoph] Charite Campus Benjamin Franklin, Res Ctr ImmunoSci, Berlin, Germany. [Muegge, Kathrin] NCI, Lab Canc Prevent, SAIC Frederick, Frederick, MD 21701 USA. RP Ziebold, U (reprint author), Max Delbruck Ctr Mol Med MDC, Berlin Inst Med Syst Biol, Lab Syst Biol Gene Regulatory Elements, Robert Roessle Str 10, D-13125 Berlin, Germany. EM uziebold@mdc-berlin.de RI Ziebold, Ulrike/N-4487-2013; Heinemann, Udo/S-3379-2016; OI Heinemann, Udo/0000-0002-8191-3850; von Eyss, Bjoern/0000-0002-4731-6841 FU Helmholtz Association of German Research Centres; KKP-Charite [C/09/04]; Marie Curie Excellence [FP6-2658 ES-TRAP] FX We thank our colleagues from the Hagemeier, Helin, JA Lees, Nevins, Eilers and Gaubatz laboratories for reagents. Our special thanks go to Svetlana Lebedeva and Wei Chen. The Protein Sample Production Facility at the MDC is funded by the Helmholtz Association of German Research Centres. We thank J Tischer and T Dornblut for excellent technical assistance. This projected was supported by a KKP-Charite grant (C/09/04). UZ was funded by a Marie Curie Excellence Grant (FP6-2658 ES-TRAP). NR 48 TC 17 Z9 17 U1 0 U2 7 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 FEB 15 PY 2012 VL 31 IS 4 BP 972 EP 985 DI 10.1038/emboj.2011.451 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 900FN UT WOS:000300872100018 PM 22157815 ER PT J AU Finkel, J Guptill, V Khaibullina, A Spornick, N Vasconcelos, O Liewehr, DJ Steinberg, SM Quezado, ZMN AF Finkel, Julia Guptill, Virginia Khaibullina, Alfia Spornick, Nicholas Vasconcelos, Olavo Liewehr, David J. Steinberg, Seth M. Quezado, Zenaide M. N. TI The three isoforms of nitric oxide synthase distinctively affect mouse nocifensive behavior SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Nociception; Pain; Vocalization; Nitric oxide; Mouse ID CURRENT VOCALIZATION THRESHOLD; INDUCED THERMAL HYPERALGESIA; PERIPHERAL-NERVE INJURY; FACTOR-KAPPA-B; NEUROPATHIC PAIN; PHARMACOLOGICAL INHIBITION; NOCICEPTION ASSAY; GENETIC KNOCKOUT; SEX-DIFFERENCES; DEFICIENT MICE AB Nitric oxide synthases (NOSs) have been shown to modulate thermal hyperalgesia and mechanical hypersensitivity in inflammatory and neuropathic pain. However, little is known about the effect of NOSs on baseline function of sensory nerve fibers. Using genetic deficiency and pharmacologic inhibition of NOSs, we examined the impact of the three isoforms NOS1, NOS2, and NOS3 on baseline nocifensive behavior by measuring current vocalization threshold in response to electrical stimulation at 5, 250, 2000 Hz that preferentially stimulate C, A delta, and A beta fibers. In response to 5, 250 and 2000 Hz, NOS1-deficient animals had significantly higher current vocalization thresholds compared with wild-type. Genetic deficiency of NOS2 was associated with higher current vocalization thresholds in response to 5 Hz (C-fiber) stimulation. In contrast, NOS3-deficient animals had an overall weak trend toward lower current vocalization thresholds at 5 Hz and significantly lower current vocalization threshold compared with wild-type animals at 250 and 2000 Hz. Therefore, NOSs distinctively affect baseline mouse current vocalization threshold and appear to play a role on nocifensive response to electrical stimulation of sensory nerve fibers. (c) 2011 Elsevier Inc. All rights reserved. C1 [Quezado, Zenaide M. N.] George Washington Univ, Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Div Anesthesiol & Pain Med,Sch Med & Hlth Sci, Washington, DC 20010 USA. [Guptill, Virginia; Quezado, Zenaide M. N.] NIH, Dept Perioperat Med, Ctr Clin, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Vasconcelos, Olavo] Hunter Holmes McGuire Vet Adm Med Ctr, Electromyog Lab, Richmond, VA USA. RP Quezado, ZMN (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Div Anesthesiol & Pain Med,Sch Med & Hlth Sci, 111 Michigan Ave, Washington, DC 20010 USA. EM zquezado@childrensnational.org RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU National Institutes of Health Clinical Center, National Institutes of Health; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC FX This research was supported by the Intramural Research Program of the National Institutes of Health Clinical Center, National Institutes of Health and by The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC. NR 39 TC 6 Z9 7 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD FEB 15 PY 2012 VL 26 IS 2 BP 81 EP 88 DI 10.1016/j.niox.2011.12.004 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 911EL UT WOS:000301700000001 PM 22202903 ER PT J AU Namanja, HA Emmert, D Davis, DA Campos, C Miller, DS Hrycyna, CA Chmielewski, J AF Namanja, Hilda A. Emmert, Dana Davis, David A. Campos, Christopher Miller, David S. Hrycyna, Christine A. Chmielewski, Jean TI Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-Glycoprotein at the Blood-Brain Barrier with Prodrug Abacavir Dimers SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MULTIDRUG-RESISTANCE; PROTEASE INHIBITORS; ANTIRETROVIRAL THERAPY; GENETIC-ANALYSIS; DRUG-BINDING; TRANSPORTER; EFFLUX; LYMPHOCYTES; DELIVERY AB Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and antiviral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two functions: inhibit P-gp efflux at the BBB and revert to monomeric therapeutic within cellular reducing environments. The prodrug dimers are potent P-gp inhibitors in cell culture and in a brain capillary model of the BBB. Significantly, these agents demonstrate anti-HIV activity in two T-cell-based HIV assays, a result that is linked to cellular reversion of the prodrug to abacavir. This strategy represents a platform technology that may be applied to other therapies with limited brain penetration due to P-glycoprotein. C1 [Namanja, Hilda A.; Emmert, Dana; Hrycyna, Christine A.; Chmielewski, Jean] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Davis, David A.] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Campos, Christopher; Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Hrycyna, CA (reprint author), Purdue Univ, Dept Chem, 560 Oval Dr, W Lafayette, IN 47907 USA. EM chml@purdue.edu FU National Institutes of Health; Purdue Research Foundation FX We acknowledge the National Institutes of Health and the Purdue Research Foundation for support of this work. We dedicate this work to Professor Ronald Breslow on the occasion of his 80th birthday. NR 44 TC 23 Z9 23 U1 2 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 15 PY 2012 VL 134 IS 6 BP 2976 EP 2980 DI 10.1021/ja206867t PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 903ZD UT WOS:000301161500034 PM 21866921 ER PT J AU Wu, CWW Gu, H Zou, QH Lu, HB Stein, EA Yang, YH AF Wu, Changwei W. Gu, Hong Zou, Qihong Lu, Hanbing Stein, Elliot A. Yang, Yihong TI TE-dependent spatial and spectral specificity of functional connectivity SO NEUROIMAGE LA English DT Article; Proceedings Paper CT 19th ISMRM Scientific Meeting CY 2011 CL Montreal, CANADA SP ISMRM DE fMRI; Spontaneous fluctuations; Functional connectivity; Echo time; Frequency ID RESTING-STATE FMRI; LOW-FREQUENCY FLUCTUATIONS; MONKEY VISUAL-CORTEX; MAGNETIC-RESONANCE; HUMAN BRAIN; PHYSIOLOGICAL NOISE; MULTIPLE-SCLEROSIS; DEFAULT NETWORK; SIGNAL CHANGES; BOLD SIGNAL AB Previous studies suggest that spontaneous fluctuations in the resting-state fMRI (RS-fMRI) signal may reflect fluctuations in transverse relaxation time (T-2(*)) rather than spin density (S-0). However, such S-0 and T-2(*) features have not been well characterized. In this study, spatial and spectral characteristics of functional connectivity on sensorimotor, default-mode, dorsal attention, and primary visual systems were examined using a multiple gradient-echo sequence at 3 T. In the spatial domain, we found broad, local correlations at short echo times (TE <= 14 ms) due to dominant S-0 contribution, whereas long-range connections mediated by T-2(*) became explicit at TEs longer than 22 ms. In the frequency domain, compared with the flat spectrum of S-0, spectral power of the T-2(*)-weighted signal elevated significantly with increasing TE, particularly in the frequency ranges of 0.008-0.023 Hz and 0.037-0.043 Hz. Using the S-0 spectrum as a reference, we propose two indices to measure spectral signal change (SSC) and spectral contrast-to-noise ratio (SCNR), respectively, for quantifying the RS-fMRI signal. These indices demonstrated TE dependency of connectivity-related fluctuation strength, resembling functional contrasts in activation-based fMRI. These findings further confirm that large-scale functional circuit connectivity based on BOLD contrast may be constrained within specific frequency ranges in every brain network, and the spectral features of S-0 and T-2(*) could be valuable for interpreting and quantifying RS-fMRI data. Published by Elsevier Inc. C1 [Wu, Changwei W.; Gu, Hong; Lu, Hanbing; Stein, Elliot A.; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Wu, Changwei W.] Natl Cent Univ, Inst Biomed Engn, Tao Yuan, Taiwan. [Zou, Qihong] Peking Univ, MRI Res Ctr, Beijing 100871, Peoples R China. [Zou, Qihong] Peking Univ, Beijing City Key Lab Med Phys & Engn, Beijing 100871, Peoples R China. RP Yang, YH (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM YihongYang@intra.nida.nih.gov FU Intramural NIH HHS [ZIA DA000469-08, ZIA DA000469-07, Z99 DA999999] NR 56 TC 4 Z9 4 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3075 EP 3084 DI 10.1016/j.neuroimage.2011.11.030 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100001 PM 22119650 ER PT J AU Shrestha, S Hirvonen, J Hines, CS Henter, ID Svenningsson, P Pike, VW Innis, RB AF Shrestha, Saurav Hirvonen, Jussi Hines, Christina S. Henter, Ioline D. Svenningsson, Per Pike, Victor W. Innis, Robert B. TI Serotonin-1A receptors in major depression quantified using PET: Controversies, confounds, and recommendations SO NEUROIMAGE LA English DT Review DE Major depressive disorder (MDD); Neuroimaging; Permeability-glycoprotein (P-gp); Positron emission tomography (PET); Radioligand; Serotonin-1A (5-HT1A) receptors ID POSITRON-EMISSION-TOMOGRAPHY; 5-HT1A RECEPTOR; P-GLYCOPROTEIN; IN-VIVO; HUMAN BRAIN; RADIOACTIVE METABOLITES; REFERENCE REGION; RODENT BRAIN; HUMAN PLASMA; 1A BINDING AB The serotonin-1A (5-HT1A) receptor is of particular interest in human positron emission tomography (PET) studies of major depressive disorder (MDD). Of the eight studies investigating this issue in the brains of patients with MDD, four reported decreased 5-HT1A receptor density, two reported no change, and two reported increased 5-HT1A receptor density. While clinical heterogeneity may have contributed to these differing results, methodological factors by themselves could also explain the discrepancies. This review highlights several of these factors, including the use of the cerebellum as a reference region and the imprecision of measuring the concentration of parent radioligand in arterial plasma, the method otherwise considered to be the 'gold standard'. Other potential confounds also exist that could restrict or unexpectedly affect the interpretation of results. For example, the radioligand may be a substrate for an efflux transporter - like P-gp - at the blood-brain barrier; furthermore, the binding of the radioligand to the receptor in various stages of cellular trafficking is unknown. Efflux transport and cellular trafficking may also be differentially expressed in patients compared to healthy subjects. We believe that, taken together, the existing disparate findings do not reliably answer the question of whether 5-HT1A receptors are altered in MDD or in subgroups of patients with MDD. In addition, useful meta-analysis is precluded because only one of the imaging centers acquired all the data necessary to address these methodological concerns. We recommend that in the future, individual centers acquire more thorough data capable of addressing methodological concerns, and that multiple centers collaborate to meaningfully pool their data for meta-analysis. Published by Elsevier Inc. C1 [Shrestha, Saurav; Hirvonen, Jussi; Hines, Christina S.; Henter, Ioline D.; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Shrestha, Saurav; Svenningsson, Per] Karolinska Univ Hosp L8 01, Ctr Mol Med, S-17176 Stockholm, Sweden. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr,MSC 1026,Bldg 10,Room B1D43, Bethesda, MD 20892 USA. EM saurav.shrestha@nih.gov; jussi.hirvonen@utu.fi; christina.hines@nih.gov; ioline.henter@nih.gov; per.svenningsson@ki.se; pikev@mail.nih.gov; robert.innis@nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). The authors thank Ramin Parsey (Columbia University) for providing graphs of [carbonyl- 11C]WAY-100635 (Fig. 3A) and Jeih-San Liow (NIMH) for providing graphs of [11C]RWAY (Fig. 3B). NR 51 TC 35 Z9 35 U1 0 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3243 EP 3251 DI 10.1016/j.neuroimage.2011.11.029 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100020 PM 22155042 ER PT J AU Amiez, C Hadj-Bouziane, F Petrides, M AF Amiez, C. Hadj-Bouziane, F. Petrides, M. TI Response selection versus feedback analysis in conditional visuo-motor learning SO NEUROIMAGE LA English DT Article DE Conditional visuo-motor associations; Premotor cortex; Striatum; fMRI; Human ID DORSAL PREMOTOR CORTEX; POSITRON-EMISSION-TOMOGRAPHY; BASAL GANGLIA; NEURONAL-ACTIVITY; PREFRONTAL CORTEX; FRONTAL-CORTEX; CAUDATE-NUCLEUS; FUNCTIONAL-ORGANIZATION; PRE-SUPPLEMENTARY; PARIETAL CORTEX AB Conditional associative sensori-motor learning (i.e. the acquisition of specific arbitrary sensori-motor mappings) involves several processes that depend upon the integrity of the fronto-striatal system. The specific role of the different components of the fronto-striatal system in this type of learning is still unclear and was examined in the present functional Magnetic Resonance Imaging (fMRI) study in humans. The subjects had to learn by trial and error arbitrary associations between visual stimuli and motor responses in an experimental paradigm designed to dissociate between the neuronal substrates specifically involved in the selection of the appropriate response and in the analysis of the feedback obtained during the learning and post-learning periods. First, the results demonstrate that the dorsal premotor (PMd) cortex is the critical structure for the acquisition and execution of arbitrary mappings of visual stimuli to motor responses. Second, they reveal an important shift in activation from the cognitive fronto-striatal network (involving the caudate nucleus, the dorsolateral prefrontal cortex, and the PMd) to the motor fronto-striatal network (involving the putamen and the PMd) as we move from initial learning of sensori-motor relations to the post-learning selection of the responses. Finally, they show that feedback processing, but not response selection, increased activity in the anterior cingulate and orbitofrontal cortical regions, demonstrating the selective involvement of these limbic frontal regions in the processing of the consequences of a given action. Altogether our data suggest that, in conditional visuo-motor learning, the associations are critically regulated by the dorsal premotor cortex and the striatum, with additional brain areas contributing to specific aspects of the learning and performance of such associations. (C) 2011 Elsevier Inc. All rights reserved. C1 [Amiez, C.; Petrides, M.] McGill Univ, Montreal Neurol Inst, Neuropsychol Cognit Neurosci Unit, Montreal, PQ H3A 2B4, Canada. [Hadj-Bouziane, F.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Amiez, C (reprint author), INSERM, U846, Stem Cell & Brain Res Inst, 18 Ave Doyen Lepine, F-69675 Bron, France. EM celine.amiez@inserm.fr RI Hadj-Bouziane, Fadila/A-1180-2013; amiez, celine/H-3079-2014 FU Canadian Institutes of Health Research (CIHR) [FRN 37753]; Neurodis Foundation; NIMH IRP; Fyssen FX This research was supported by Canadian Institutes of Health Research (CIHR) grant FRN 37753 to Michael Petrides. C. Amiez was supported by a CIHR fellowship and the Neurodis Foundation. F. Hadj-Bouziane was supported by the NIMH IRP, the Fyssen, and the Neurodis Foundation. NR 68 TC 18 Z9 18 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3723 EP 3735 DI 10.1016/j.neuroimage.2011.10.058 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100067 PM 22040737 ER PT J AU Hagberg, GE Bianciardi, M Brainovich, V Cassara, AM Maraviglia, B AF Hagberg, Gisela E. Bianciardi, Marta Brainovich, Valentina Cassara, Antonino Mario Maraviglia, Bruno TI Phase stability in fMRI time series: Effect of noise regression, off-resonance correction and spatial filtering techniques SO NEUROIMAGE LA English DT Article DE Gradient echo EPI; Time series; Phase; Physiological noise; Retrospective correction ID MAGNETIC-RESONANCE; PHYSIOLOGICAL NOISE; NEURONAL-ACTIVITY; ECHO-PLANAR; RETROSPECTIVE ESTIMATION; MRI DETECTION; HUMAN BRAIN; 1.5 T; FIELD; CURRENTS AB Although the majority of fMRI studies exploit magnitude changes only, there is an increasing interest regarding the potential additive information conveyed by the phase signal. This integrated part of the complex number furnished by the MR scanners can also be used for exploring direct detection of neuronal activity and for thermography. Few studies have explicitly addressed the issue of the available signal stability in the context of phase time-series, and therefore we explored the spatial pattern of frequency specific phase fluctuations, and evaluated the effect of physiological noise components (heart beat and respiration) on the phase signal. Three categories of retrospective noise reduction techniques were explored and the temporal signal stability was evaluated in terms of a physiologic noise model, for seven fMRI measurement protocols in eight healthy subjects at 3 T. for segmented CSF, gray and white matter voxels. We confirmed that for most processing methods, an efficient use of the phase information is hampered by the fact that noise from physiological and instrumental sources contributes significantly more to the phase than to the magnitude instability. Noise regression based on the phase evolution of the central k-space point, RETROICOR, or an ortho-normalized combination of these were able to reduce their impact, but without bringing phase stability down to levels expected from the magnitude signal. Similar results were obtained after targeted removal of scan-to-scan variations in the bulk magnetic field by the dynamic off-resonance in k-space (DORK) method and by the temporal off-resonance alignment of single-echo time series technique (TOAST). We found that spatial high-pass filtering was necessary, and in vivo a Gaussian filter width of 20 mm was sufficient to suppress physiological noise and bring the phase fluctuations to magnitude levels. Stronger filters brought the fluctuations down to levels dictated by thermal noise contributions, and for 62.5 mm(3) voxels the phase stability was as low as 5 mrad (0.27 degrees). In conditions of low SNRo and high temporal sampling rate (short TR); we achieved an upper bound for the phase instabilities at 0.0017 ppm, which is close to the dHb contribution to the GM/WM phase contrast. (C) 2011 Elsevier Inc. All rights reserved. C1 [Hagberg, Gisela E.; Bianciardi, Marta; Brainovich, Valentina; Cassara, Antonino Mario; Maraviglia, Bruno] IRRCS, Santa Lucia Sci Fdn, I-0179 Rome, Italy. [Bianciardi, Marta] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Cassara, Antonino Mario; Maraviglia, Bruno] Museo Storico Fis & Ctr Studi & Ric E Fermi, I-00184 Rome, Italy. [Cassara, Antonino Mario; Maraviglia, Bruno] Univ Roma La Sapienza, Dipartimento Fis, Grp GI, I-00185 Rome, Italy. RP Hagberg, GE (reprint author), Neuroimaging Lab, Via Ardeatina 306, I-00179 Rome, Italy. EM g.hagberg@hsantalucia.it; bianciardim@mail.nih.gov; v.brainovich@usl9.toscana.it; antonio.cassara@roma1.infn.it; bruno.maraviglia@roma1.infn.it RI Hagberg, Gisela/A-2134-2010; OI Hagberg, Gisela/0000-0003-2176-7086; Maraviglia, Bruno/0000-0003-2354-8039; Cassara, Antonino Mario/0000-0003-3375-7440 NR 53 TC 11 Z9 11 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3748 EP 3761 DI 10.1016/j.neuroimage.2011.10.095 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100069 PM 22079450 ER PT J AU Sigurdsson, S Aspelund, T Forsberg, L Fredriksson, J Kjartansson, O Oskarsdottir, B Jonsson, PV Eiriksdottir, G Harris, TB Zijdenbos, A van Buchem, MA Launer, LJ Gudnason, V AF Sigurdsson, Sigurdur Aspelund, Thor Forsberg, Lars Fredriksson, Jesper Kjartansson, Olafur Oskarsdottir, Bryndis Jonsson, Palmi V. Eiriksdottir, Gudny Harris, Tamara B. Zijdenbos, Alex van Buchem, Mark A. Launer, Lenore J. Gudnason, Vilmundur TI Brain tissue volumes in the general population of the elderly The AGES-Reykjavik Study SO NEUROIMAGE LA English DT Article DE Brain volume; White matter hyperintensities; Atrophy; Magnetic resonance imaging; Population based; AGES-Reykjavik study ID WHITE-MATTER LESIONS; OLDER-ADULTS; RISK-FACTORS; GRAY-MATTER; MRI; MORPHOLOGY; ATROPHY; GENDER; IMAGES AB Imaging studies have reported conflicting findings on how brain structure differs with age and sex. This may be explained by discrepancies and limitations in study population and study design. We report a study on brain tissue volumes in one of the largest cohorts of individuals studied to date of subjects with high mean age (mean +/- standard deviation (SD) 76 +/- 6 years). These analyses are based on magnetic resonance imaging (MRI) scans acquired at baseline on 4303 non-demented elderly, and 367 who had a second MRI, on average 2.5 +/- 0.2 years later. Tissue segmentation was performed with an automatic image analysis pipeline. Total brain parenchymal (TBP) volume decreased with increasing age while there was an increase in white matter hyperintensities (WMH) in both sexes. A reduction in both normal white matter (NWM)- and gray matter (GM) volume contributed to the brain shrinkage. After adjusting for intra-cranial volume, women had larger brain volumes compared to men (3.32%, p<0.001) for TBP volume in the cross-sectional analysis. The longitudinal analysis showed a significant age-sex interaction in TBP volume with a greater rate of annual change in men (-0.70%, 95%CI: -0.78% to -0.63%) than women (-0.55%, 95%CI: -0.61% to -0.49%). The annual change in the cross-sectional data was approximately 40% less than the annual change in the longitudinal data and did not show significant age-sex interaction. The findings indicate that the cross-sectional data underestimate the rate of change in tissue volumes with age as the longitudinal data show greater rate of change in tissue volumes with age for all tissues. (C) 2011 Elsevier Inc. All rights reserved. C1 [Sigurdsson, Sigurdur; Aspelund, Thor; Forsberg, Lars; Kjartansson, Olafur; Oskarsdottir, Bryndis; Jonsson, Palmi V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Aspelund, Thor; Jonsson, Palmi V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Fredriksson, Jesper] Raforninn Inc, Reykjavik, Iceland. [Zijdenbos, Alex] Biospective Inc, Montreal, PQ, Canada. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Sigurdsson, S (reprint author), Iceland Heart Assoc, IS-201 Kopavogur, Iceland. EM sigurdur@hjarta.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH [N01-AG-1-2100]; NIA; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. NR 45 TC 32 Z9 32 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3862 EP 3870 DI 10.1016/j.neuroimage.2011.11.024 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100079 PM 22119006 ER PT J AU Alexander-Bloch, A Lambiotte, R Roberts, B Giedd, J Gogtay, N Bullmore, ET AF Alexander-Bloch, Aaron Lambiotte, Renaud Roberts, Ben Giedd, Jay Gogtay, Nitin Bullmore, Edward T. TI The discovery of population differences in network community structure: New methods and applications to brain functional networks in schizophrenia SO NEUROIMAGE LA English DT Article DE Brain networks; Modularity; Community structure; Graph theory; Schizophrenia; Resting-state fMRI ID COMMON STEREOTACTIC SPACE; MODULAR ORGANIZATION; MRI; OPTIMIZATION; REGISTRATION; CLUSTERINGS; ACTIVATION; SOFTWARE; CHILDREN; INSULA AB The modular organization of the brain network can vary in two fundamental ways. The amount of inter-versus intra-modular connections between network nodes can be altered, or the community structure itself can be perturbed, in terms of which nodes belong to which modules (or communities). Alterations have previously been reported in modularity, which is a function of the proportion of intra-modular edges over all modules in the network. For example, we have reported that modularity is decreased in functional brain networks in schizophrenia: There are proportionally more inter-modular edges and fewer intra-modular edges. However, despite numerous and increasing studies of brain modular organization, it is not known how to test for differences in the community structure, i.e., the assignment of regional nodes to specific modules. Here, we introduce a method based on the normalized mutual information between pairs of modular networks to show that the community structure of the brain network is significantly altered in schizophrenia, using resting-state fMRI in 19 participants with childhood-onset schizophrenia and 20 healthy participants. We also develop tools to show which specific nodes (or brain regions) have significantly different modular communities between groups, a subset that includes right insular and perisylvian cortical regions. The methods that we propose are broadly applicable to other experimental contexts, both in neuroimaging and other areas of network science. Published by Elsevier Inc. C1 [Alexander-Bloch, Aaron; Bullmore, Edward T.] Univ Cambridge, Dept Psychiat, Behav & Clin Neurosci Inst, Cambridge, England. [Alexander-Bloch, Aaron; Giedd, Jay; Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Alexander-Bloch, Aaron] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lambiotte, Renaud] Univ Namur, Dept Math, Namur, Belgium. [Roberts, Ben] Univ Cambridge, Stat Lab, Cambridge CB2 1SB, England. RP Alexander-Bloch, A (reprint author), Herchel Smith Bldg Brain & Mind Sci,Cambridge Bio, Cambridge CB2 0SZ, England. EM aalexanderbloch@gmail.com; etb23@cam.ac.uk RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; Bullmore, Edward/C-1706-2012; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Bullmore, Edward/0000-0002-8955-8283; Alexander-Bloch, Aaron/0000-0001-6554-1893; Lambiotte, Renaud/0000-0002-0583-4595 FU National Institutes of Health (NIH); Medical Research Council; Wellcome Trust; NIH-Oxford-Cambridge FX This research was funded by the Intramural Research Program of the National Institutes of Health (NIH). The Behavioural and Clinical Neurosciences Institute is supported by the Medical Research Council and the Wellcome Trust. Aaron Alexander-Bloch is supported by the NIH-Oxford-Cambridge Scholarship program and the NIH MD/PhD Partnership program. NR 62 TC 56 Z9 57 U1 2 U2 27 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3889 EP 3900 DI 10.1016/j.neuroimage.2011.11.035 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100082 PM 22119652 ER PT J AU Lee, J Shmueli, K Kang, BT Yao, B Fukunaga, M van Gelderen, P Palumbo, S Bosetti, F Silva, AC Duyn, JH AF Lee, Jongho Shmueli, Karin Kang, Byeong-Teck Yao, Bing Fukunaga, Masaki van Gelderen, Peter Palumbo, Sara Bosetti, Francesca Silva, Afonso C. Duyn, Jeff H. TI The contribution of myelin to magnetic susceptibility-weighted contrasts in high-field MRI of the brain SO NEUROIMAGE LA English DT Article DE T-2* decay; R-2* relaxation; Phase image; Resonance frequency image; Demyelination; Cuprizone; Formalin fixation ID CUPRIZONE-INDUCED DEMYELINATION; CENTRAL-NERVOUS-SYSTEM; GRADIENT-ECHO MRI; WHITE-MATTER; CORPUS-CALLOSUM; DIFFUSION PROPERTIES; PHASE-CONTRAST; FIBER ORIENTATION; WATER RELAXATION; CEREBRAL-CORTEX AB T-2*-weighted gradient-echo MRI images at high field (>= 7 T) have shown rich image contrast within and between brain regions. The source for these contrast variations has been primarily attributed to tissue magnetic susceptibility differences. In this study, the contribution of myelin to both T-2* and frequency contrasts is investigated using a mouse model of demyelination based on a cuprizone diet. The demyelinated brains showed significantly increased T-2* in white matter and a substantial reduction in gray-white matter frequency contrast, suggesting that myelin is a primary source for these contrasts. Comparison of in-vivo and in-vitro data showed that, although tissue T-2* values were reduced by formalin fixation, gray-white matter frequency contrast was relatively unaffected and fixation had a negligible effect on cuprizone-induced changes in T-2* and frequency contrasts. Published by Elsevier Inc. C1 [Lee, Jongho; Shmueli, Karin; Yao, Bing; van Gelderen, Peter; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Lee, Jongho] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Kang, Byeong-Teck; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Kang, Byeong-Teck] Chungbuk Natl Univ, Coll Vet Med, Dept Vet Internal Med, Cheongju, Chungbuk, South Korea. [Fukunaga, Masaki] Osaka Univ, WPI Immunol Frontier Res Ctr, Osaka, Japan. [Palumbo, Sara; Bosetti, Francesca] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), 3 W Gates Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM jonghoyi@upenn.edu RI Fukunaga, Masaki/F-6441-2013; palumbo, sara/B-1603-2013; Shmueli, Karin/B-9432-2017 OI Fukunaga, Masaki/0000-0003-1010-2644; palumbo, sara/0000-0002-3809-6058; FU NIH, NINDS FX This research was supported (in part) by the Intramural Research Program of the NIH, NINDS. NR 73 TC 66 Z9 66 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3967 EP 3975 DI 10.1016/j.neuroimage.2011.10.076 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100089 PM 22056461 ER PT J AU Lee, SH Kravitz, DJ Baker, CI AF Lee, Sue-Hyun Kravitz, Dwight J. Baker, Chris I. TI Disentangling visual imagery and perception of real-world objects SO NEUROIMAGE LA English DT Article DE Object recognition; fMRI; Human; Mental imagery; Vision; Top-down ID POSITRON-EMISSION-TOMOGRAPHY; MENTAL-IMAGERY; CONNECTIONIST NEUROPSYCHOLOGY; RETINOTOPIC CORTEX; CORTICAL REGIONS; NEURAL SYSTEMS; BRAIN; RECOGNITION; ACTIVATION; AREAS AB During mental imagery, visual representations can be evoked in the absence of "bottom-up" sensory input. Prior studies have reported similar neural substrates for imagery and perception, but studies of brain-damaged patients have revealed a double dissociation with some patients showing preserved imagery in spite of impaired perception and others vice versa. Here, we used fMRI and multi-voxel pattern analysis to investigate the specificity, distribution, and similarity of information for individual seen and imagined objects to try and resolve this apparent contradiction. In an event-related design, participants either viewed or imagined individual named object images on which they had been trained prior to the scan. We found that the identity of both seen and imagined objects could be decoded from the pattern of activity throughout the ventral visual processing stream. Further, there was enough correspondence between imagery and perception to allow discrimination of individual imagined objects based on the response during perception. However, the distribution of object information across visual areas was strikingly different during imagery and perception. While there was an obvious posterior-anterior gradient along the ventral visual stream for seen objects, there was an opposite gradient for imagined objects. Moreover, the structure of representations (i.e. the pattern of similarity between responses to all objects) was more similar during imagery than perception in all regions along the visual stream. These results suggest that while imagery and perception have similar neural substrates, they involve different network dynamics, resolving the tension between previous imaging and neuropsychological studies. Published by Elsevier Inc. C1 [Lee, Sue-Hyun; Kravitz, Dwight J.; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Lee, SH (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM sue-hyun.lee@nih.gov RI Kravitz, Dwight/B-8430-2012; Lee, Sue Hyun/F-5490-2015; OI Baker, Chris/0000-0001-6861-8964 FU NIMH FX This work was supported by the NIMH Intramural Research Program. Thanks to V. Elkis, S. Truong and J. Arizpe for help with data collection, Z. Saad for help with data analysis and A. Martin, M. Behrmann, A. Harel and members of the Laboratory of Brain and Cognition, NIMH for helpful comments and discussion. NR 51 TC 33 Z9 34 U1 1 U2 28 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 4064 EP 4073 DI 10.1016/j.neuroimage.2011.10.055 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100097 PM 22040738 ER PT J AU Enose-Akahata, Y Matsuura, E Tanaka, Y Oh, U Jacobson, S AF Enose-Akahata, Yoshimi Matsuura, Eiji Tanaka, Yuetsu Oh, Unsong Jacobson, Steven TI Minocycline modulates antigen-specific CTL activity through inactivation of mononuclear phagocytes in patients with HTLV-I associated neurologic disease SO RETROVIROLOGY LA English DT Article DE HTLV-I; HAM/TSP; monocyte; CTL; minocycline ID VIRUS TYPE-I; T-CELL LEUKEMIA; TROPICAL SPASTIC PARAPARESIS; SPINAL-CORD LESIONS; DENDRITIC CELLS; PERIPHERAL-BLOOD; SPONTANEOUS PROLIFERATION; PROVIRAL LOAD; INFECTION; TAX AB Background: The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases. Results: Phenotypic analysis of CD14(+) monocytes in HAM/TSP patients demonstrated high expression of CX(3)CR1 and HLA-DR in CD14(low)CD16(+) monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-alpha and IL-1 beta in cultured CD14(+) cells of HAM/TSP patients. CD14(+) cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4(+) T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-alpha expression in CD14(+) cells and IL-1 beta release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-gamma expression in CD8(+) T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-gamma expression in CD8(+) T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14(+) cells. Conclusion: These results demonstrate that minocycline directly inhibits the activated MPs and that the downregulation of MP function can modulate CD8(+) T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP. C1 [Enose-Akahata, Yoshimi; Matsuura, Eiji; Oh, Unsong; Jacobson, Steven] NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. [Matsuura, Eiji] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Neurol & Geriatr, Kagoshima 8908544, Japan. [Tanaka, Yuetsu] Univ Ryukyus, Grad Sch, Dept Immunol, Okinawa 9030215, Japan. [Tanaka, Yuetsu] Univ Ryukyus, Fac Med, Okinawa 9030215, Japan. [Oh, Unsong] Virginia Commonwealth Univ, Dept Neurol, Sch Med, Richmond, VA 23298 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. EM JacobsonS@ninds.nih.gov RI MATSUURA, EIJI/E-1231-2013 OI MATSUURA, EIJI/0000-0001-8215-8853 FU NINDS, NIH FX This research was supported by the Intramural Research Program of the NINDS, NIH. NR 55 TC 8 Z9 8 U1 0 U2 2 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 FEB 15 PY 2012 VL 9 AR 16 DI 10.1186/1742-4690-9-16 PG 14 WC Virology SC Virology GA 911MP UT WOS:000301721500001 PM 22335964 ER PT J AU Reiss, TF Moss, J Osborne, M Curtis, JR Hill, NS AF Reiss, Theodore F. Moss, Joel Osborne, Molly Curtis, J. Randall Hill, Nicholas S. TI Collaborative Science and the American Thoracic Society Cooperation in Harmony with Conflict of Interest SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material C1 [Reiss, Theodore F.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Moss, Joel] NHLBI, NIH, Bethesda, MD 20892 USA. [Osborne, Molly] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Curtis, J. Randall] Univ Washington, Amer Thorac Soc, Seattle, WA 98195 USA. [Hill, Nicholas S.] Tufts Med Ctr, Amer Thorac Soc, Boston, MA USA. RP Reiss, TF (reprint author), Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. FU Intramural NIH HHS NR 12 TC 1 Z9 1 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2012 VL 185 IS 4 BP 347 EP 349 DI 10.1164/rccm.201110-1824ED PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 897EY UT WOS:000300629900002 PM 22336672 ER PT J AU Davies, MA Fox, PS Papadopoulos, NE Bedikian, AY Hwu, WJ Lazar, AJ Prieto, VG Culotta, KS Madden, TL Xu, QY Huang, S Deng, WL Ng, CS Gupta, S Liu, WB Dancey, JE Wright, JJ Bassett, RL Hwu, P Kim, KB AF Davies, Michael A. Fox, Patricia S. Papadopoulos, Nicholas E. Bedikian, Agop Y. Hwu, Wen-Jen Lazar, Alexander J. Prieto, Victor G. Culotta, Kirk S. Madden, Timothy L. Xu, Quanyun Huang, Sha Deng, Wanleng Ng, Chaan S. Gupta, Sanjay Liu, Wenbin Dancey, Janet E. Wright, John J. Bassett, Roland L. Hwu, Patrick Kim, Kevin B. TI Phase I Study of the Combination of Sorafenib and Temsirolimus in Patients with Metastatic Melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID MULTIKINASE INHIBITOR SORAFENIB; REFRACTORY SOLID TUMORS; TISSUE MICROARRAYS; RAF KINASE; CELL-DEATH; CANCER; BRAF; TARGET; MTOR; AKT AB Purpose: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma. Patients and Methods: Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins. Results: A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hyper-triglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK. Conclusions: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK. Clin Cancer Res; 18(4); 1120-28. (C)2012 AACR. C1 [Kim, Kevin B.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Unit 430, Houston, TX 77030 USA. [Davies, Michael A.; Deng, Wanleng] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Fox, Patricia S.; Liu, Wenbin; Bassett, Roland L.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Lazar, Alexander J.; Prieto, Victor G.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Culotta, Kirk S.; Madden, Timothy L.; Xu, Quanyun; Huang, Sha] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Ng, Chaan S.; Gupta, Sanjay] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Dancey, Janet E.] Ontario Inst Canc Res, Toronto, ON, Canada. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Kim, KB (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Unit 430, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM kkim@mdanderson.org RI Lazar, Alexander/A-3416-2008 OI Lazar, Alexander/0000-0002-6395-4499 FU NCI [UO1 CA062461, N01 CM 17003]; NIH through the MD Anderson Cancer Center [CA016672]; P50 SPORE Career Development Grant; ASCO Young Investigator Award; MD Anderson Cancer Center [NIH-NCI-CA-16672] FX This work was supported in part by NCI grants UO1 CA062461 and N01 CM 17003, the NIH through the MD Anderson Cancer Center support grant CA016672, the P50 SPORE Career Development Grant (K.B. Kim), the ASCO Young Investigator Award (M.A. Davies), and the MD Anderson Cancer Center Physician-Scientist Program (M.A. Davies, A.J. Lazar). The MDACC RPPA Core Facility is supported by M. D. Anderson Cancer Center Core Grant NIH-NCI-CA-16672. NR 40 TC 26 Z9 26 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2012 VL 18 IS 4 BP 1120 EP 1128 DI 10.1158/1078-0432.CCR-11-2436 PG 9 WC Oncology SC Oncology GA 897EO UT WOS:000300628100022 PM 22223528 ER PT J AU Kobayashi, H Choyke, PL AF Kobayashi, Hisataka Choyke, Peter L. TI Response to Comment on "Rapid Cancer Detection by Topically Spraying a gamma-Glutamyltranspeptidase-Activated Fluorescent Probe" SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Letter AB It takes considerable time and effort to create a successful imaging agent for clinical translation. In general, there are two approaches to developing new agents-bottom-up and top-down-which we compare here. C1 [Kobayashi, Hisataka; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov NR 4 TC 0 Z9 0 U1 6 U2 18 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 15 PY 2012 VL 4 IS 121 AR 121lr1 DI 10.1126/scitranslmed.3003757 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 898HR UT WOS:000300732600006 ER PT J AU Wang, Y Shi, M Chung, KA Zabetian, CP Leverenz, JB Berg, D Srulijes, K Trojanowski, JQ Lee, VMY Siderowf, AD Hurtig, H Litvan, I Schiess, MC Peskind, ER Masuda, M Hasegawa, M Lin, XM Pan, C Galasko, D Goldstein, DS Jensen, PH Yang, H Cain, KC Zhang, J AF Wang, Yu Shi, Min Chung, Kathryn A. Zabetian, Cyrus P. Leverenz, James B. Berg, Daniela Srulijes, Karin Trojanowski, John Q. Lee, Virginia M. -Y. Siderowf, Andrew D. Hurtig, Howard Litvan, Irene Schiess, Mya C. Peskind, Elaine R. Masuda, Masami Hasegawa, Masato Lin, Xiangmin Pan, Catherine Galasko, Douglas Goldstein, David S. Jensen, Poul Henning Yang, Hui Cain, Kevin C. Zhang, Jing TI Phosphorylated alpha-Synuclein in Parkinson's Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; MULTIPLE-SYSTEM ATROPHY; HUMAN CEREBROSPINAL-FLUID; RICHARDSONS-SYNDROME; CONSENSUS STATEMENT; ALZHEIMERS-DISEASE; PSP-PARKINSONISM; LEWY BODIES; DIAGNOSIS; NEURODEGENERATION AB Phosphorylated alpha-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson's disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129 together with total alpha-synuclein in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of similar to 600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total alpha-synuclein concentrations in CSF, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether the concentration of PS-129 in CSF will be useful for diagnosing PD and for monitoring PD severity and progression. C1 [Wang, Yu; Shi, Min; Lin, Xiangmin; Pan, Catherine; Yang, Hui; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Wang, Yu] Huazhong Univ Sci & Technol, Dept Neurosurg, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China. [Chung, Kathryn A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Zabetian, Cyrus P.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. [Zabetian, Cyrus P.; Leverenz, James B.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98104 USA. [Leverenz, James B.; Peskind, Elaine R.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98105 USA. [Leverenz, James B.; Peskind, Elaine R.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Berg, Daniela; Srulijes, Karin] Univ Tubingen, Dept Neurodegenerat, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany. [Berg, Daniela; Srulijes, Karin] Univ Tubingen, German Ctr Neurodegenerat Dis, D-72076 Tubingen, Germany. [Trojanowski, John Q.; Lee, Virginia M. -Y.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Inst Aging,Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Siderowf, Andrew D.; Hurtig, Howard] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19107 USA. [Litvan, Irene] Univ Louisville, Sch Med, Div Movement Disorders, Louisville, KY 40202 USA. [Schiess, Mya C.] Univ Texas Hlth Sci Ctr, Dept Neurol, Houston, TX 77030 USA. [Masuda, Masami; Hasegawa, Masato] Tokyo Metropolitan Inst Med Sci, Dept Neuropathol & Cell Biol, Setagaya Ku, Tokyo 1568585, Japan. [Goldstein, David S.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Community Networks Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Jensen, Poul Henning] Aarhus Univ, Dept Med Chem, DK-8000 Aarhus C, Denmark. [Cain, Kevin C.] Univ Washington, Dept Biostat, Seattle, WA 98105 USA. RP Zhang, J (reprint author), Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. EM zhangj@uw.edu RI Shi, Min/G-6165-2012; OI Shi, Min/0000-0002-6901-2558; , xiangmin/0000-0001-9128-689X FU NIH [AG025327, AG033398, ES004696-5897, ES007033-6364, NS057567, NS060252, NS062684, NS065070, NS053488]; Lundbeck Foundation; European Community [241791]; Avid Radiopharmaceuticals FX Funding: The investigation was supported by the NIH (grants AG025327, AG033398, ES004696-5897, ES007033-6364, NS057567, and NS060252 to J.Z.; NS062684 to J.Z., C. P.Z., and J.B.L.; NS065070 to C. P.Z.; and NS053488 to J.Q.T., V.M.-Y.L., and A. D. S.), the Lundbeck Foundation, and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 241791 (to P.H.J.).; Competing interests: A. D. S. serves as a consultant for Teva Neuroscience and has grant support from Avid Radiopharmaceuticals not related to this investigation. J.B.L. serves as a consultant for Bayer, Novartis, and Teva Neuroscience. The other authors declare that they have no competing interests. NR 32 TC 30 Z9 30 U1 2 U2 19 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 15 PY 2012 VL 4 IS 121 AR 121ra20 DI 10.1126/scitranslmed.3002566 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 898HR UT WOS:000300732600004 PM 22344688 ER PT J AU Vazquez, E Sethi, AA Freeman, L Zalos, G Chaudhry, H Haser, E Aicher, BO Aponte, A Gucek, M Kato, GJ Waclawiw, MA Remaley, AT Cannon, RO AF Vazquez, Edward Sethi, Amar A. Freeman, Lita Zalos, Gloria Chaudhry, Hira Haser, Erin Aicher, Brittany O. Aponte, Angel Gucek, Marjan Kato, Gregory J. Waclawiw, Myron A. Remaley, Alan T. Cannon, Richard O., III TI High-Density Lipoprotein Cholesterol Efflux, Nitration of Apolipoprotein A-I, and Endothelial Function in Obese Women SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; BODY-MASS; HDL; OXIDATION; CELLS; FRAMINGHAM; TRANSPORT; IMPACT AB Subjects at risk of atherosclerosis might have dysfunctional high-density lipoprotein (HDL) despite normal cholesterol content in the plasma. We considered whether the efflux of excess cellular cholesterol to HDL from obese subjects is associated with impaired arterial endothelial function, a biomarker of cardiovascular risk. A total of 54 overweight (body mass index [BMI] 25 to 29.9 kg/m(2)) or obese (BMI >= 30 kg/m(2)) women, aged 46 +/- 11 years, were enrolled in a worksite wellness program. The HDL cholesterol averaged 57 +/- 17 mg/dl and was inversely associated with the BMI (r = -0.419, p = 0.002). Endothelial function was assessed using brachial artery flow-mediated dilation. Cholesterol efflux from H-3-cholesterol labeled baby hamster kidney cells transfected with the adenosine triphosphate-binding cassette transporter 1 showed 8.2% to 22.5% cholesterol efflux within 18 hours when incubated with 1% serum and was positively correlated with brachial artery flow.. mediated dilation (p < 0.05), especially in the 34 subjects with BMI >= 30 kg/m(2) (r = 0.482, p = 0.004). This relation was independent of age, HDL or low-density lipoprotein cholesterol concentrations in plasma, blood pressure, or insulin resistance on stepwise multiple regression analysis (beta = 0.31, R-2 = 0.21, p = 0.007). Nitration of apolipoprotein A-I tyrosine residues (using sandwich enzyme-linked immunosorbent assay) was significantly greater in women with a BMI >= 30 kg/m(2) and the lowest cholesterol efflux than in women with a BMI of 25 to 29.9 kg/m(2) and the greatest cholesterol efflux (p = 0.01). In conclusion, we have shown that decreased cholesterol efflux by way of the adenosine triphosphate-binding cassette transporter 1 is associated with increased nitration of apolipoprotein A-I in HDL and is an independent predictor of impaired endothelial function in women with a BMI of >= 30 kg/m(2). This finding suggests that the functional measures of HDL might be better markers for cardiovascular risk than the HDL cholesterol levels in this population. Published by Elsevier Inc. (Am J Cardiol 2012;109:527-532) C1 [Cannon, Richard O., III] NHLBI, Cardiovasc Pulm Branch, Prote Core Facil, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Vazquez, Edward] Mt Sinai Sch Med, New York, NY 10029 USA. [Vazquez, Edward] NIH, Clin Res Training Program, Ctr Clin, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Cardiovasc Pulm Branch, Prote Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. EM cannonr@nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU National Heart, Lung, and Blood Institute; Clinical Center, National Institutes of Health, Bethesda, Maryland FX This research was funded by the intramural research programs of the National Heart, Lung, and Blood Institute and the Clinical Center, National Institutes of Health, Bethesda, Maryland. NR 27 TC 8 Z9 9 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2012 VL 109 IS 4 BP 527 EP 532 DI 10.1016/j.amjcard.2011.10.008 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 896SO UT WOS:000300591900015 PM 22105786 ER PT J AU Rienstra, M Sun, JX Magnani, JW Sinner, MF Lubitz, SA Sullivan, LM Ellinor, PT Benjamin, EJ AF Rienstra, Michiel Sun, Jenny X. Magnani, Jared W. Sinner, Moritz F. Lubitz, Steven A. Sullivan, Lisa M. Ellinor, Patrick T. Benjamin, Emelia J. TI White Blood Cell Count and Risk of Incident Atrial Fibrillation (From the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; CARDIOTHORACIC SURGERY; LEUKOCYTE COUNT; STATIN THERAPY; MORTALITY; INFLAMMATION; ASSOCIATION; PREDICTOR; COHORT AB Several studies have reported that inflammatory markers are associated with atrial fibrillation (AF). The white blood cell (WBC) count is a widely available and broadly used marker of systemic inflammation. We sought to investigate the association between an increased WBC count and incident AF and whether this association is mediated by smoking, myocardial infarction, and heart failure. We examined the participants in the Framingham Heart Study original cohort. Cox proportional hazard regression analysis was used to examine the relation between the WBC count and incident AF during a 5-year follow-up period. We adjusted for standard AF risk factors, smoking, previous myocardial infarction, and interim myocardial infarction and heart failure before the incident AF. Our sample consisted of 936 participants (mean age 76 +/- 6 years and 61% women). The median WBC count was 6.4 x 10(9)/L (25th to 75th percentile 5.6 x 10(9)/L to 7.8 x 10(9)/L). During a median 5-year follow-up period, 82 participants (9%) developed new-onset AF. After adjusting for standard risk factors for AF, an increased WBC count was significantly associated with incident AF, with a hazard ratio per SD (0.26 x 10(9)/L) increase of 2.22 (95% confidence interval 1.10 to 4.48; p = 0.03). We found no substantive differences adjusting for smoking, previous myocardial infarction, interim myocardial infarction, or heart failure. In conclusion, in our community-based sample, an increased WBC count was associated with incident AF during 5 years of follow-up. Our findings provide additional evidence for the relation between systemic inflammation and AF. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:533-537) C1 [Rienstra, Michiel; Magnani, Jared W.; Sinner, Moritz F.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rienstra, Michiel; Magnani, Jared W.; Sinner, Moritz F.; Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Rienstra, Michiel; Sinner, Moritz F.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Sun, Jenny X.; Sullivan, Lisa M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Sinner, Moritz F.] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. RP Benjamin, EJ (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM emelia@bu.edu OI Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-25195]; Boston University School of Medicine, Boston, Massachusetts; Netherlands Organization for Scientific Research, The Hague, The Netherlands [825.09.020]; American Heart Association (Dallas, Texas) [09FTF2190028]; German Heart Foundation (Frankfurt, Germany); National Institutes of Health, Bethesda, Maryland [1R01 HL092577, 1RC1HL101056, 1R01HL102214, R01AG028321, 6R01-NS 17950, 5R21DA027021, 5RO1HL104156, 1K24HL105780]; Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation Initiative (Boston University, Boston, Massachusetts) FX The Framingham Heart Study is supported by grant N01-HC-25195 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland and by Boston University School of Medicine, Boston, Massachusetts. Dr. Rienstra is supported by Rubicon grant 825.09.020 from The Netherlands Organization for Scientific Research, The Hague, The Netherlands; Dr. Magnani is supported by American Heart Association Award 09FTF2190028 (Dallas, Texas). Dr. Sinner is supported by the German Heart Foundation (Frankfurt, Germany). This work was supported by grant 1R01 HL092577 from the National Institutes of Health, Bethesda, Maryland to Drs. Benjamin and Ellinor, grants 1RC1HL101056, 1R01HL102214, and R01AG028321 and support via grant 6R01-NS 17950 to Dr. Benjamin, and grants 5R21DA027021, 5RO1HL104156, 1K24HL105780 to Dr. Ellinor. This study was partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation Initiative (Boston University, Boston, Massachusetts). NR 32 TC 27 Z9 30 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2012 VL 109 IS 4 BP 533 EP 537 DI 10.1016/j.amjcard.2011.09.049 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 896SO UT WOS:000300591900016 PM 22100030 ER PT J AU Singh, NS Paul, RK Sichler, M Moaddel, R Bernier, M Wainer, IW AF Singh, Nagendra S. Paul, Rajib K. Sichler, Megan Moaddel, Ruin Bernier, Michel Wainer, Irving W. TI Capillary electrophoresis-laser-induced fluorescence (CE-LIF) assay for measurement of intracellular D-serine and serine racemase activity SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE D-Ser; L-Ser; Glycine; Enantioselective resolution; Serine racemase monomer; Serine racemase dimer ID PERFORMANCE LIQUID-CHROMATOGRAPHY; AMINO-ACID OXIDASE; RAT-BRAIN; ORTHO-PHTHALDIALDEHYDE; DERIVATIZATION AB An enantioselective capillary electrophoresis-laser-induced fluorescence (CE-LIF) method for the analysis of D-serine (D-Ser) in cellular matrices has been developed. The assay involves derivatization with FITC followed by CE-LIF using 0.5 mM hydroxyl propyl-beta-cyclodextrin in borate buffer [80 mM, pH 9.3]. The method was able to resolve D-Set and L-Ser with an enantioselectivity (alpha) of 1.03 and a resolution (R-s) of 1.37. Linearity was established from 0.25 to 100.00 mu M. The assay was also able to enantioselectively resolve 6 additional amino acid racemates. The method was applied to the determination of intracellular D-Set concentrations in PC-12, C6, 1312N1, and HepG2 cell lines. This method was used to determine the concentration-dependent increases in D-Ser and associated EC50 values produced by L-Ser and the concentration-dependent decreases in D-Ser and associated IC50 values produced by glycine, a competitive inhibitor of serine racemase (SR). Western blot analysis determined that the PC-12 and C6 cell lines contained monomeric and dimeric forms of SR while the 1321N1 and HepG2 cells contained only the monomeric form. Although the SR dimer has been identified as the active form of the enzyme, all four of the tested cell lines expressed enzymatically active SR. Published by Elsevier Inc. C1 [Wainer, Irving W.] NIA, Bioanalyt & Drug Discovery Unit, Clin Invest Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Bioanalyt & Drug Discovery Unit, Clin Invest Lab, NIH,Biomed Res Ctr, 251 Bayview Blvd,Room 08B133, Baltimore, MD 21224 USA. EM WainerIr@grc.nia.nih.gov RI Singh, Nagendra/K-8966-2015; OI Bernier, Michel/0000-0002-5948-368X FU National Institute on Aging/NIH FX This work was supported by funding from the Intramural Research Program of the National Institute on Aging/NIH. NR 20 TC 16 Z9 16 U1 5 U2 34 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 15 PY 2012 VL 421 IS 2 BP 460 EP 466 DI 10.1016/j.ab.2011.10.003 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 895WW UT WOS:000300528400015 PM 22037294 ER PT J AU Taher, L Narlikar, L Ovcharenko, I AF Taher, Leila Narlikar, Leelavati Ovcharenko, Ivan TI CLARE: Cracking the LAnguage of Regulatory Elements SO BIOINFORMATICS LA English DT Article ID HEART ENHANCERS; DATABASE; IDENTIFICATION; GENOMES; UPDATE; SITES; TOOLS AB CLARE is a computational method designed to reveal sequence encryption of tissue- specific regulatory elements. Starting with a set of regulatory elements known to be active in a particular tissue/process, it learns the sequence code of the input set and builds a predictive model from features specific to those elements. The resulting model can then be applied to user-supplied genomic regions to identify novel candidate regulatory elements. CLARE's model also provides a detailed analysis of transcription factors that most likely bind to the elements, making it an invaluable tool for understanding mechanisms of tissue- specific gene regulation. C1 [Taher, Leila; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Narlikar, Leelavati] CSIR, Chem Engn & Proc Dev Div, Natl Chem Lab, Pune 411008, Maharashtra, India. RP Taher, L (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM taherl@ncbi.nlm.nih.gov; ovcharen@nih.gov FU National Institutes of Health, National Library of Medicine FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 16 TC 4 Z9 4 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2012 VL 28 IS 4 BP 581 EP 583 DI 10.1093/bioinformatics/btr704 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 895IT UT WOS:000300490500018 PM 22199387 ER PT J AU Huang, WC Li, LP Myers, JR Marth, GT AF Huang, Weichun Li, Leping Myers, Jason R. Marth, Gabor T. TI ART: a next-generation sequencing read simulator SO BIOINFORMATICS LA English DT Article AB ART is a set of simulation tools that generate synthetic next-generation sequencing reads. This functionality is essential for testing and benchmarking tools for next- generation sequencing data analysis including read alignment, de novo assembly and genetic variation discovery. ART generates simulated sequencing reads by emulating the sequencing process with built-in, technology-specific read error models and base quality value profiles parameterized empirically in large sequencing datasets. We currently support all three major commercial next- generation sequencing platforms: Roche's 454, Illumina's Solexa and Applied Biosystems' SOLiD. ART also allows the flexibility to use customized read error model parameters and quality profiles. C1 [Huang, Weichun; Li, Leping; Myers, Jason R.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Marth, Gabor T.] Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA. RP Huang, WC (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. EM weichun.huang@nih.gov; gabor.marth@bc.edu FU National Institutes of Health; National Institute of Environmental Health Sciences [ES101765]; National Human Genome Research Institute, National Institutes of Health [HG003698, HG004719] FX Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences (ES101765); National Human Genome Research Institute, National Institutes of Health (HG003698 and HG004719 to G. T. M.) in part. NR 7 TC 179 Z9 183 U1 1 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2012 VL 28 IS 4 BP 593 EP 594 DI 10.1093/bioinformatics/btr708 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 895IT UT WOS:000300490500023 PM 22199392 ER PT J AU Kim, S Kwon, D Shin, SY Wilbur, WJ AF Kim, Sun Kwon, Dongseop Shin, Soo-Yong Wilbur, W. John TI PIE the search: searching PubMed literature for protein interaction information SO BIOINFORMATICS LA English DT Article AB Motivation: Finding protein-protein interaction (PPI) information from literature is challenging but an important issue. However, keyword search in PubMed (R) is often time consuming because it requires a series of actions that refine keywords and browse search results until it reaches a goal. Due to the rapid growth of biomedical literature, it has become more difficult for biologists and curators to locate PPI information quickly. Therefore, a tool for prioritizing PPI informative articles can be a useful assistant for finding this PPI-relevant information. Results: PIE (Protein Interaction information Extraction) the search is a web service implementing a competition-winning approach utilizing word and syntactic analyses by machine learning techniques. For easy user access, PIE the search provides a PubMed-like search environment, but the output is the list of articles prioritized by PPI confidence scores. By obtaining PPI-related articles at high rank, researchers can more easily find the up-to-date PPI information, which cannot be found in manually curated PPI databases. C1 [Kim, Sun; Wilbur, W. John] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Kwon, Dongseop] Myongji Univ, Dept Comp Engn, Gyeonggi Do 449728, South Korea. [Shin, Soo-Yong] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Clin Epidemiol & Biostat, Seoul 135798, South Korea. RP Kim, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM sun.kim@nih.gov RI Shin, Soo-Yong/K-3156-2012 FU National Institutes of Health, National Library of Medicine; National Research Foundation of Korea (NRF) [NRF-2011-0002437] FX Intramural Research Program of the National Institutes of Health, National Library of Medicine (to S.K. and W.J.W.); Basic Science Research Program through the National Research Foundation of Korea (NRF) (NRF-2011-0002437) (to D.K.). NR 7 TC 15 Z9 16 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2012 VL 28 IS 4 BP 597 EP 598 DI 10.1093/bioinformatics/btr702 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 895IT UT WOS:000300490500025 PM 22199390 ER PT J AU Teer, JK Green, ED Mullikin, JC Biesecker, LG AF Teer, Jamie K. Green, Eric D. Mullikin, James C. Biesecker, Leslie G. TI VarSifter: Visualizing and analyzing exome-scale sequence variation data on a desktop computer SO BIOINFORMATICS LA English DT Article ID GENOMES AB VarSifter is a graphical software tool for desktop computers that allows investigators of varying computational skills to easily and quickly sort, filter, and sift through sequence variation data. A variety of filters and a custom query framework allow filtering based on any combination of sample and annotation information. By simplifying visualization and analyses of exome-scale sequence variation data, this program will help bring the power and promise of massively-parallel DNA sequencing to a broader group of researchers. C1 [Teer, Jamie K.; Green, Eric D.; Mullikin, James C.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Mullikin, JC (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM mullikin@mail.nih.gov FU National Human Genome Research Institute FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute. Associate Editor: Jonathan Wren NR 13 TC 51 Z9 51 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2012 VL 28 IS 4 BP 599 EP 600 DI 10.1093/bioinformatics/btr711 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 895IT UT WOS:000300490500026 PM 22210868 ER PT J AU Chen, HS Portier, K Ghosh, K Naishadham, D Kim, HJ Zhu, L Pickle, LW Krapcho, M Scoppa, S Jemal, A Feuer, EJ AF Chen, Huann-Sheng Portier, Kenneth Ghosh, Kaushik Naishadham, Deepa Kim, Hyune-Ju Zhu, Li Pickle, Linda W. Krapcho, Martin Scoppa, Steve Jemal, Ahmedin Feuer, Eric J. TI Predicting US- and state-level cancer counts for the current calendar year SO CANCER LA English DT Article DE cancer mortality; cancer surveillance; Surveillance; Epidemiology; and End Results; temporal projection; projection methods ID EMPIRICAL MODE DECOMPOSITION; MORTALITY; RATES AB BACKGROUND: A study was undertaken to evaluate the temporal projection methods that are applied by the American Cancer Society to predict 4-year-ahead projections. METHODS: Cancer mortality data recorded in each year from 1969 through 2007 for the United States overall and for each state from the National Center for Health Statistics was obtained. Based on the mortality data through 2000, 2001, 2002, and 2003, Projections were made 4 years ahead to estimate the expected number of cancer deaths in 2004, 2005, 2006, 2007, respectively, in the United States and in each state, using 5 projection methods. These predictive estimates were compared to the observed number of deaths that occurred for all cancers combined and 47 cancer sites at the national level, and 21 cancer sites at the state level. RESULTS: Among the models that were compared, the joinpoint regression model with modified Bayesian information criterion selection produced estimates that are closest to the actual number of deaths. Overall, results show the 4-year-ahead projection has larger error than 3-year-ahead projection of death counts when the same method is used. However, 4-year-ahead projection from the new method performed better than the 3-year-ahead projection from the current state-space method. CONCLUSIONS: The Joinpoint method with modified Bayesian information criterion model has the smallest error of all the models considered for 4-year-ahead projection of cancer deaths to the current year for the United States overall and for each state. This method will be used by the American Cancer Society to project the number of cancer deaths starting in 2012. Cancer 2012;118:1091-9. (C) 2012 American Cancer Society. C1 [Chen, Huann-Sheng; Zhu, Li; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Portier, Kenneth; Naishadham, Deepa; Jemal, Ahmedin] Amer Canc Soc, Atlanta, GA 30329 USA. [Ghosh, Kaushik] Univ Nevada, Las Vegas, NV 89154 USA. [Kim, Hyune-Ju] Syracuse Univ, Syracuse, NY USA. [Pickle, Linda W.] StatNet Consulting LLC, Gaithersburg, MD USA. [Krapcho, Martin; Scoppa, Steve] Informat Management Serv Inc, Silver Spring, MD USA. RP Chen, HS (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. EM Huann-Sheng.Chen@nih.gov RI Chen, Huann-Sheng/D-6328-2013 OI Chen, Huann-Sheng/0000-0002-5905-8050 FU National Institutes of Health (NIH) [HHSN261201000671P, HHSN261201000509, HHSN261201100094P] FX Dr Ghosh's work is supported by National Institutes of Health (NIH) contract HHSN261201000671P. Dr Kim's work is supported by NIH contract HHSN261201000509. Dr Pickle's work is supported by NIH contract HHSN261201100094P. The other authors made no disclosure. NR 17 TC 23 Z9 24 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2012 VL 118 IS 4 BP 1091 EP 1099 DI 10.1002/cncr.27404 PG 9 WC Oncology SC Oncology GA 886EF UT WOS:000299834300028 PM 22228565 ER PT J AU Zhu, L Pickle, LW Ghosh, K Naishadham, D Portier, K Chen, HS Kim, HJ Zou, ZH Cucinelli, J Kohler, B Edwards, BK King, J Feuer, EJ Jemal, A AF Zhu, Li Pickle, Linda W. Ghosh, Kaushik Naishadham, Deepa Portier, Kenneth Chen, Huann-Sheng Kim, Hyune-Ju Zou, Zhaohui Cucinelli, James Kohler, Betsy Edwards, Brenda K. King, Jessica Feuer, Eric J. Jemal, Ahmedin TI Predicting US- and state-level cancer counts for the current calendar year SO CANCER LA English DT Article DE cancer incidence; cancer surveillance; Surveillance; Epidemiology; and End Results (SEER); National Program of Cancer Registries (NPCR); spatiotemporal; projection methods ID UNITED-STATES; RATES; MORTALITY; IMPACT AB BACKGROUND. The current study was undertaken to evaluate the spatiotemporal projection models applied by the American Cancer Society to predict the number of new cancer cases. METHODS. Adaptations of a model that has been used since 2007 were evaluated. Modeling is conducted in 3 steps. In step I, ecologic predictors of spatiotemporal variation are used to estimate age-specific incidence counts for every county in the country, providing an estimate even in those areas that are missing data for specific years. Step II adjusts the step I estimates for reporting delays. In step III, the delay-adjusted predictions are projected 4 years ahead to the current calendar year. Adaptations of the original model include updating covariates and evaluating alternative projection methods. Residual analysis and evaluation of 5 temporal projection methods were conducted. RESULTS. The differences between the spatiotemporal model-estimated case counts and the observed case counts for 2007 were < 1%. After delays in reporting of cases were considered, the difference was 2.5% for women and 3.3% for men. Residual analysis indicated no significant pattern that suggested the need for additional covariates. The vector autoregressive model was identified as the best temporal projection method. CONCLUSIONS. The current spatiotemporal prediction model is adequate to provide reasonable estimates of case counts. To project the estimated case counts ahead 4 years, the vector autoregressive model is recommended to be the best temporal projection method for producing estimates closest to the observed case counts. Cancer 2012;118:1100-9. (C) 2012 American Cancer Society. C1 [Zhu, Li; Chen, Huann-Sheng; Edwards, Brenda K.; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Pickle, Linda W.] StatNet Consulting LLC, Gaithersburg, MD USA. [Ghosh, Kaushik] Univ Nevada, Dept Math Sci, Las Vegas, NV 89154 USA. [Portier, Kenneth] Amer Canc Soc, Stat & Evaluat Ctr, Atlanta, GA 30329 USA. [Kim, Hyune-Ju] Syracuse Univ, Dept Math, Syracuse, NY 13244 USA. [Zou, Zhaohui; Cucinelli, James] Informat Management Serv Inc, Silver Spring, MD USA. [Kohler, Betsy] N Amer Assoc Cent Canc Registries, Springfield, IL USA. [King, Jessica] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. RP Zhu, L (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. EM li.zhu@nih.gov RI Chen, Huann-Sheng/D-6328-2013 OI Chen, Huann-Sheng/0000-0002-5905-8050 FU National Institutes of Health (NIH) [HHSN261201100094P, HHSN261201000671P, HHSN261201000509P] FX Dr. Pickle's work is supported by National Institutes of Health (NIH) contract HHSN261201100094P. Dr. Ghosh's work is supported by NIH contract HHSN261201000671P. Dr. Kim's work is partially supported by NIH contract HHSN261201000509P. NR 28 TC 23 Z9 24 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2012 VL 118 IS 4 BP 1100 EP 1109 DI 10.1002/cncr.27405 PG 10 WC Oncology SC Oncology GA 886EF UT WOS:000299834300029 PM 22228583 ER PT J AU Aris, SM Pommier, Y AF Aris, Sheena M. Pommier, Yves TI Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor AZD7762 SO CANCER RESEARCH LA English DT Article ID S-PHASE CHECKPOINT; DNA-DAMAGE; KINASE INHIBITOR; PROTEIN-KINASE; STRAND BREAKS; CHK2 KINASE; MAMMALIAN-CELLS; CANCER-CELLS; SINGLE-CELL; REPLICATION AB Novel topoisomerase I (Top1) inhibitors are in clinical development to circumvent the drawbacks of camptothecins (CPT). Here, we report molecular investigations into LMP-400, an indenoisoquinoline Top1 inhibitor in phase 1 clinical trial, by itself and in combination with the cell-cycle checkpoint inhibitor AZD7762. We examined drug effects on DNA replication and killing of cancer cells and found that LMP-400 showed synergistic antiproliferative activity when combined with AZD7762 in human colon carcinoma cells. Inhibition of S-phase progression and bromodeoxyuridine incorporation were similarly induced by LMP-400 and CPT and were abrogated by AZD7762. Replication studied by single DNA molecule analyses and immunofluorescence microscopy (molecular combing) showed rapid inhibition of fork progression in response to LMP-400 treatment with subsequent recapitulation after AZD7762 addition. AZD7762 inhibited both the activation/autophosphosphorylation of Chk1 and Chk2 at nanomolar concentrations in LMP-400-treated cells. This potent dual inhibition of Chk1 and Chk2 by AZD7762 was below the drug concentrations required to abrogate cell-cycle inhibition and produce synergism with LMP-400. Also, the synergism was independent of Chk2 both in Chk2-complemented cells and Chk2 knockout cells, suggesting additional mechanisms for cell-cycle abrogation by AZD7762. Together, our findings show a rationale for combining cell-cycle checkpoint inhibitors with the novel non-CPT indenoisoquinoline Top1 inhibitors. Cancer Res; 72(4); 979-89. (C) 2011 AACR. C1 [Aris, Sheena M.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NIH, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research; National Cancer Institute; CRADA; Astra Zeneca FX This work was supported by the Center for Cancer Research and the Intramural Program of the National Cancer Institute, and by a CRADA with Astra Zeneca. NR 50 TC 18 Z9 18 U1 0 U2 2 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 FEB 15 PY 2012 VL 72 IS 4 BP 979 EP 989 DI 10.1158/0008-5472.CAN-11-2579 PG 11 WC Oncology SC Oncology GA 897ET UT WOS:000300629100017 PM 22189968 ER PT J AU Ren, L Hong, SH Chen, QR Briggs, J Cassavaugh, J Srinivasan, S Lizardo, MM Mendoza, A Xia, AY Avadhani, N Khan, J Khanna, C AF Ren, Ling Hong, Sung-Hyeok Chen, Qing-Rong Briggs, Joseph Cassavaugh, Jessica Srinivasan, Satish Lizardo, Michael M. Mendoza, Arnulfo Xia, Ashley Y. Avadhani, Narayan Khan, Javed Khanna, Chand TI Dysregulation of Ezrin Phosphorylation Prevents Metastasis and Alters Cellular Metabolism in Osteosarcoma SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER METASTASIS; TUMOR-GROWTH; MODELING METASTASIS; MURINE OSTEOSARCOMA; ERM PROTEINS; EXPRESSION; INEFFICIENCY; MEMBRANE; ACTIN; CELLS AB Ezrin links the plasma membrane to the actin cytoskeleton where it plays a pivotal role in the metastatic progression of several human cancers; however, the precise mechanistic basis for its role remains unknown. Here, we define transitions between active (phosphorylated open) and inactive (dephosphorylated closed) forms of Ezrin that occur during metastatic progression in osteosarcoma. In our evaluation of these conformations we expressed C-terminal mutant forms of Ezrin that are open (phosphomimetic T567D) or closed (phosphodeficient T567A) and compared their biologic characteristics to full-length wild-type Ezrin in osteosarcoma cells. Unexpectedly, cells expressing open, active Ezrin could form neither primary orthotopic tumors nor lung metastases. In contrast, cells expressing closed, inactive Ezrin were also deficient in metastasis but were unaffected in their capacity for primary tumor growth. By imaging single metastatic cells in the lung, we found that cells expressing either open or closed Ezrin displayed increased levels of apoptosis early after their arrival in the lung. Gene expression analysis suggested dysregulation of genes that are functionally linked to carbohydrate and amino acid metabolism. In particular, cells expressing closed, inactive Ezrin exhibited reduced lactate production and basal or ATP-dependent oxygen consumption. Collectively, our results suggest that dynamic regulation of Ezrin phosphorylation at amino acid T567 that controls structural transitions of this protein plays a pivotal role in tumor progression and metastasis, possibly in part by altering cellular metabolism. Cancer Res; 72(4); 1001-12. (C) 2011 AACR. C1 [Ren, Ling; Hong, Sung-Hyeok; Briggs, Joseph; Cassavaugh, Jessica; Lizardo, Michael M.; Mendoza, Arnulfo; Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, Qing-Rong; Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Xia, Ashley Y.] NIAID, Off Biomed Informat, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Srinivasan, Satish; Avadhani, Narayan] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. RP Khanna, C (reprint author), NCI, Tumor & Metastasis Biol Sect, Ctr Canc Res, Convent Dr,Rm 2144, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU NIH [RO1 CA-22762] FX This research was supported by the NIH Intramural Research Program and NIH grant RO1 CA-22762. NR 45 TC 22 Z9 27 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 FEB 15 PY 2012 VL 72 IS 4 BP 1001 EP 1012 DI 10.1158/0008-5472.CAN-11-0210 PG 12 WC Oncology SC Oncology GA 897ET UT WOS:000300629100019 PM 22147261 ER PT J AU Dupont, C Harvey, AJ Armant, DR Zelinski, MB Brenner, CA AF Dupont, Catherine Harvey, Alexandra J. Armant, D. Randall Zelinski, Mary B. Brenner, Carol A. TI Expression profiles of cohesins, shugoshins and spindle assembly checkpoint genes in rhesus macaque oocytes predict their susceptibility for aneuploidy during embryonic development SO CELL CYCLE LA English DT Article DE aneuploidy; chromosomal abnormalities; cohesin; oocytes; spindle assembly checkpoint; shugoshins ID SISTER-CHROMATID COHESION; HUMAN PREIMPLANTATION EMBRYOS; IN-VITRO FERTILIZATION; MATERNAL AGE; CELL-CYCLE; CHROMOSOMAL-ABNORMALITIES; RECURRENT MISCARRIAGE; MAMMALIAN OOCYTES; MOUSE OOCYTE; MITOSIS AB High frequencies of chromosomal anomalies are reported in human and non-human primate in vitro-produced preimplantation embryos. It is unclear why certain embryos develop aneuploidies while others remain euploid. A differential susceptibility to aneuploidy is most likely a consequence of events that occur before oocyte collection. One hypothesis is that the relative transcript levels of cohesins, shugoshins and spindle assembly checkpoint genes are correlated with the occurrence of chromosomal anomalies. Transcript levels of these genes were quantified in individual oocytes that were either mature (group 1, low aneuploidy rate) or immature (group 2, high aneuploidy rate) at retrieval, utilizing TaqMan-based real-time PCR. The transcript level in each oocyte was categorized as absent, below the median or above the median in order to conduct comparisons. Statistically significant differences were observed between group 1 and group 2 for SGOL1 and BUB1. There were more oocytes with SGOL1 expression levels above the median in group 1, while oocytes lacking BUB1 were only observed in group 1. These findings suggest that higher SGOL1 levels in group 1 oocytes could better protect against a premature separation of sister chromatids than in embryos derived from group 2 oocytes. The absence of BUB1 transcripts in group 1 was frequently associated with reduced expression of either mitotic cohesins or shugoshins. We hypothesize that ablation of BUB1 could induce mitotic arrest in oocytes that fail to express a complete complement of cohesins and shugoshins, thereby reducing the number of developing aneuploid preimplantation embryos. C1 [Dupont, Catherine; Harvey, Alexandra J.; Brenner, Carol A.] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. [Dupont, Catherine; Harvey, Alexandra J.; Armant, D. Randall; Brenner, Carol A.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Zelinski, Mary B.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Reprod Sci, Beaverton, OR USA. RP Brenner, CA (reprint author), Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. EM cbrenner@uno.edu OI Armant, D. Randall/0000-0001-5904-9325; HARVEY, ALEXANDRA/0000-0001-6696-0950 FU National Institutes of Health [HD045966, RR015395, HD046553]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS; Oregon National Primate Research Center [RR00163] FX Supported by National Institutes of Health grants HD045966, RR015395 and HD046553; by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS; and by the Oregon National Primate Research Center, RR00163. NR 62 TC 5 Z9 5 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB 15 PY 2012 VL 11 IS 4 BP 740 EP 748 DI 10.4161/cc.11.4.19207 PG 9 WC Cell Biology SC Cell Biology GA 897CY UT WOS:000300621400024 PM 22327397 ER PT J AU Sitaraman, R Leppla, SH AF Sitaraman, Ramakrishnan Leppla, Stephen H. TI Methylation-dependent DNA restriction in Bacillus anthracis SO GENE LA English DT Article DE Restriction; Methylation; Bacillus anthracis; Transformation; Plasmids ID ESCHERICHIA-COLI; 6-METHYLADENINE RESIDUES; ADENINE METHYLATION; SUBTILIS MARBURG; PLASMID DNA; TRANSFORMATION; MUTANTS; THURINGIENSIS; REPLICATION; MUTAGENESIS AB Bacillus anthracis, the causative agent of anthrax, is poorly transformed with DNA that is methylated on adenine or cytosine. Here we characterize three genetic loci encoding type IV methylation-dependent restriction enzymes that target DNA containing C5-methylcytosine (m5C). Strains in which these genes were inactivated, either singly or collectively, showed increased transformation by methylated DNA. Additionally, a triple mutant with an similar to 30-kb genomic deletion could be transformed by DNA obtained from Dam(+)Dcm(+) E. coli, although at a low frequency of similar to-10(-3) transformants/10(6) cfu. This strain of B. anthracis can potentially serve as a preferred host for shuttle vectors that express recombinant proteins, including proteins to be used in vaccines. The gene(s) responsible for the restriction of m6A-containing DNA in B. anthracis remain unidentified, and we suggest that poor transformation by such DNA could in part be a consequence of the inefficient replication of hemimethylated DNA in B. anthracis. Published by Elsevier By. C1 [Sitaraman, Ramakrishnan; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, Lab Bacterial Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM minraj@gmail.com; sleppla@niaid.nih.gov OI Sitaraman, Ramakrishnan/0000-0002-4577-4224 FU NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. Dr. Andrei P. Pomerantsev's detailed technical advice on the genetic manipulation of B. anthracis and his generosity in sharing the pCrePA plasmid is deeply appreciated. We thank Dr. Timothy D. Read for sharing the then unpublished sequence information on the putative mrr gene, Andrew McKenzie for analysis of RE expression data derived from online databases, and Mini Varughese for assistance in preparing the manuscript. The pHY304 plasmid was a kind gift of Dr. Craig E. Rubens. REBASE is maintained by New England Biolabs. E. coil strain GM33 was obtained from the Coli Genetic Stock Center, Yale University, New Haven, CT, U.S.A. NR 29 TC 6 Z9 6 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 15 PY 2012 VL 494 IS 1 BP 44 EP 50 DI 10.1016/j.gene.2011.11.061 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 896CK UT WOS:000300542800006 PM 22178763 ER PT J AU Yanpallewar, SU Barrick, CA Palko, ME Fulgenzi, G Tessarollo, L AF Yanpallewar, Sudhirkumar U. Barrick, Colleen A. Palko, Mary Ellen Fulgenzi, Gianluca Tessarollo, Lino TI Tamalin Is a Critical Mediator of Electroconvulsive Shock-Induced Adult Neuroplasticity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CHRONIC ANTIDEPRESSANT TREATMENT; EMBRYONIC STEM-CELLS; GRANULE CELLS; SCAFFOLD PROTEIN; RAT HIPPOCAMPUS; DENTATE GYRUS; BASAL DENDRITES; TYROSINE KINASE; GENE-EXPRESSION; NEUROGENESIS AB The molecular mechanisms underlying the effects of electroconvulsive shock (ECS) therapy, a fast-acting and very effective antidepressant therapy, are poorly understood. Changes related to neuroplasticity, including enhanced adult hippocampal neurogenesis and neuronal arborization, are believed to play an important role in mediating the effects of ECS. Here we show a dynamic upregulation of the scaffold protein tamalin, selectively in the hippocampus of animals subjected to ECS. Interestingly, this gene upregulation is functionally significant because tamalin deletion in mice abrogated ECS-induced neurogenesis in the adult mouse hippocampus. Furthermore, loss of tamalin blunts mossy fiber sprouting and dendritic arborization caused by ECS. These data suggest an essential role for tamalin in ECS-induced adult neuroplasticity and provide new insight into the pathways that are involved in mediating ECS effects. C1 [Yanpallewar, Sudhirkumar U.; Barrick, Colleen A.; Palko, Mary Ellen; Fulgenzi, Gianluca; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Tessarollo, L (reprint author), NCI, Neural Dev Sect, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560,Room 32-31D, Frederick, MD 21702 USA. EM tessarol@mail.nih.gov OI Fulgenzi, Gianluca/0000-0003-2646-7728 FU National Cancer Institute, Center for Cancer Research, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. We thank Eileen Southon and Susan Reid for technical help in generating the tamalin mutant mouse model, Jodi Becker for technical help, and Dr. Mehdii Tufti for the homer1a construct. NR 40 TC 8 Z9 8 U1 0 U2 0 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 FEB 15 PY 2012 VL 32 IS 7 BP 2252 EP 2262 DI 10.1523/JNEUROSCI.5493-11.2012 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 895ZO UT WOS:000300535400004 PM 22396401 ER PT J AU Amenta, AR Creely, HE Mercado, MLT Hagiwara, H McKechnie, BA Lechner, BE Rossi, SG Wang, Q Owens, RT Marrero, E Mei, L Hoch, W Young, MF McQuillan, DJ Rotundo, RL Fallon, JR AF Amenta, Alison R. Creely, Hilliary E. Mercado, Mary Lynn T. Hagiwara, Hiroki McKechnie, Beth A. Lechner, Beatrice E. Rossi, Susana G. Wang, Qiang Owens, Rick T. Marrero, Emilio Mei, Lin Hoch, Werner Young, Marian F. McQuillan, David J. Rotundo, Richard L. Fallon, Justin R. TI Biglycan Is an Extracellular MuSK Binding Protein Important for Synapse Stability SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TORPEDO ELECTRIC ORGAN; NEUROMUSCULAR-JUNCTION; ACETYLCHOLINE-RECEPTORS; SKELETAL-MUSCLE; IN-VIVO; SARCOGLYCAN COMPLEX; REGENERATING MUSCLE; MUSCULAR-DYSTROPHY; BASAL LAMINA; AGRIN AB The receptor tyrosine kinase MuSK is indispensable for nerve-muscle synapse formation and maintenance. MuSK is necessary for prepatterning of the endplate zone anlage and as a signaling receptor for agrin-mediated postsynaptic differentiation. MuSK-associated proteins such as Dok7, LRP4, and Wnt11r are involved in these early events in neuromuscular junction formation. However, the mechanisms regulating synapse stability are poorly understood. Here we examine a novel role for the extracellular matrix protein biglycan in synapse stability. Synaptic development in fetal and early postnatal biglycan null (bgn(-/o)) muscle is indistinguishable from wild-type controls. However, by 5 weeks afterbirth, nerve-muscle synapses in bgn(-/o) mice are abnormal as judged by the presence of perijunctional folds, increased segmentation, and focal misalignment of acetylcholinesterase and AChRs. These observations indicate that previously occupied presynaptic and postsynaptic territory has been vacated. Biglycan binds MuSK and the levels of this receptor tyrosine kinase are selectively reduced at bgn(-/o) synapses. In bgn(-/o) myotubes, the initial stages of agrin-induced MuSK phosphorylation and AChR clustering are normal, but the AChR clusters are unstable. This stability defect can be substantially rescued by the addition of purified biglycan. Together, these results indicate that biglycan is an extracellular ligand for MuSK that is important for synapse stability. C1 [Amenta, Alison R.; Creely, Hilliary E.; Mercado, Mary Lynn T.; Hagiwara, Hiroki; McKechnie, Beth A.; Lechner, Beatrice E.; Fallon, Justin R.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Creely, Hilliary E.] Brown Univ, Grad Program Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Rossi, Susana G.; Marrero, Emilio; Rotundo, Richard L.] Univ Miami, Dept Cell Biol & Anat, Miami, FL 33136 USA. [Wang, Qiang; Mei, Lin] Med Coll Georgia, Inst Mol Med & Genet, Augusta, GA 30912 USA. [Owens, Rick T.; McQuillan, David J.] LifeCell Corp, Branchburg, NJ 08876 USA. [Hoch, Werner] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Young, Marian F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Fallon, JR (reprint author), Brown Univ, Dept Neurosci, Box G-L, Providence, RI 02912 USA. EM Justin_Fallon@Brown.edu RI Mei, Lin/G-8755-2012 FU National Institutes of Health [HD23924, RR15578, AR42826, R44 NS045432, AG05917, T32GM007601]; Division of Intramural Research, National Institute of Dental and Craniofacial Research of the Intramural Research Program, NIH, Department of Health and Human Services; Muscular Dystrophy Association; Fulbright FX This work was funded by grants from the National Institutes of Health (HD23924 and RR15578 to J.R.F.; AR42826 and R44 NS045432 to D.J.M.; AG05917 to R.L.R.; T32GM007601 to H.E.C.), the Division of Intramural Research, National Institute of Dental and Craniofacial Research of the Intramural Research Program, NIH, Department of Health and Human Services (to M.F.Y.), and the Muscular Dystrophy Association (to R.L.R.). B.E.L. was a fellow of the Pediatric Scientist Development Program, HD00850. H.E.C. was supported In part by a Fulbright Fellowship. We gratefully acknowledge generous gifts of reagents from D. Glass, S. Burden, S. Froehner, and A. Ross. We thank R. Balice-Gordon and C. Cisterni for advice on whole mount preparations, and R. Creton and S. Kunz for their advice on confocal microscopy. The expert technical assistance of Carol Ayala for the electron microscopy is gratefully acknowledged. NR 64 TC 28 Z9 29 U1 2 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 15 PY 2012 VL 32 IS 7 BP 2324 EP 2334 DI 10.1523/JNEUROSCI.4610-11.2012 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 895ZO UT WOS:000300535400010 PM 22396407 ER PT J AU Zaghloul, KA Weidemann, CT Lega, BC Jaggi, JL Baltuch, GH Kahana, MJ AF Zaghloul, Kareem A. Weidemann, Christoph T. Lega, Bradley C. Jaggi, Jurg L. Baltuch, Gordon H. Kahana, Michael J. TI Neuronal Activity in the Human Subthalamic Nucleus Encodes Decision Conflict during Action Selection SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BASAL GANGLIA; NEURAL BASIS; MULTIPLE ALTERNATIVES; BILATERAL STIMULATION; PERCEPTUAL DECISION; FUNCTIONAL-ANATOMY; CORTEX; NEUROBIOLOGY; BRAIN; PARKINSONISM AB The subthalamic nucleus (STN), which receives excitatory inputs from the cortex and has direct connections with the inhibitory pathways of the basal ganglia, is well positioned to efficiently mediate action selection. Here, we use microelectrode recordings captured during deep brain stimulation surgery as participants engage in a decision task to examine the role of the human STN in action selection. We demonstrate that spiking activity in the STN increases when participants engage in a decision and that the level of spiking activity increases with the degree of decision conflict. These data implicate the STN as an important mediator of action selection during decision processes. C1 [Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Weidemann, Christoph T.] Swansea Univ, Dept Psychol, Swansea SA2 8PP, W Glam, Wales. [Lega, Bradley C.; Jaggi, Jurg L.; Baltuch, Gordon H.] Hosp Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Kahana, Michael J.] Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA. RP Zaghloul, KA (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3020,10 Ctr Dr, Bethesda, MD 20892 USA. EM kareem.zaghloul@nih.gov RI Weidemann, Christoph/E-8857-2011; OI Weidemann, Christoph T./0000-0002-4280-2744 FU NIH [K99NS067241-01, MH55687]; Dana Foundation FX This work was supported in part by NIH Grants K99NS067241-01 and MH55687 and by the Dana Foundation. We thank M. Kerr, K. McGill, and the staff of the Pennsylvania Neurological Institute for their invaluable help in coordinating patient recruitment for this study and for conducting preoperative and postoperative testing. We also thank J. Kable and J. Jacobs for insightful comments on this manuscript. NR 34 TC 44 Z9 44 U1 1 U2 10 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 FEB 15 PY 2012 VL 32 IS 7 BP 2453 EP 2460 DI 10.1523/JNEUROSCI.5815-11.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 895ZO UT WOS:000300535400022 PM 22396419 ER PT J AU Fanning, AS Van Itallie, CM Anderson, JM AF Fanning, Alan S. Van Itallie, Christina M. Anderson, James M. TI Zonula occludens-1 and-2 regulate apical cell structure and the zonula adherens cytoskeleton in polarized epithelia SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TIGHT JUNCTION PROTEIN; APKC KINASE-ACTIVITY; PDZ-DOMAIN PROTEINS; BELT-LIKE ADHERENS; MYOSIN-II MOTOR; ACTIN CYTOSKELETON; BARRIER FUNCTION; ELECTRON-MICROSCOPY; DIRECT BINDING; E-CADHERIN AB The structure and function of both adherens (AJ) and tight (TJ) junctions are dependent on the cortical actin cytoskeleton. The zonula occludens (ZO)-1 and -2 proteins have context-dependent interactions with both junction types and bind directly to F-actin and other cytoskeletal proteins, suggesting ZO-1 and -2 might regulate cytoskeletal activity at cell junctions. To address this hypothesis, we generated stable Madin-Darby canine kidney cell lines depleted of both ZO-1 and -2. Both paracellular permeability and the localization of TJ proteins are disrupted in ZO-1/-2-depleted cells. In addition, immunocytochemistry and electron microscopy revealed a significant expansion of the perijunctional actomyosin ring associated with the AJ. These structural changes are accompanied by a recruitment of 1-phosphomyosin light chain and Rho kinase 1, contraction of the actomyosin ring, and expansion of the apical domain. Despite these changes in the apical cytoskeleton, there are no detectable changes in cell polarity, localization of AJ proteins, or the organization of the basal and lateral actin cytoskeleton. We conclude that ZO proteins are required not only for TJ assembly but also for regulating the organization and functional activity of the apical cytoskeleton, particularly the perijunctional actomyosin ring, and we speculate that these activities are relevant both to cellular organization and epithelial morphogenesis. C1 [Fanning, Alan S.] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Fanning, Alan S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Van Itallie, Christina M.; Anderson, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Fanning, AS (reprint author), Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. EM alan_fanning@med.unc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK061397]; Division of Intramural Research, National Heart, Lung, and Blood Institute; Office of the Director, National Institutes of Health FX The authors thank Mark Peifer, Alpha Yap, Keith Burridge, Laurel Rodgers, and members of our laboratories for many thoughtful conversations and/or comments on the manuscript. We also thank Jennifer Holmes and Tanner Beam for technical support; Sandra Citi, Klaus Ebnet, George Ojakian, and Bruce Stevenson for sharing antibodies; and Michael Chua and Neal Kramarcy of the Michael Hooker Microcopy Facility for advice on confocal imaging. We are especially grateful to Erika Wittchen and the Burridge Lab for reagents and advice pertaining to Rho-GTPase assays, to Katy Liu for assistance with 3D culture, and to Victoria Madden and Steven Ray of the Microscopy Services Laboratory at the University of North Carolina, Chapel Hill, for EM. This project was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK061397) to A. S. F. and by intramural funding from the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Office of the Director, National Institutes of Health (C.M.V.I. and J.M.A.). NR 72 TC 67 Z9 69 U1 1 U2 9 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB 15 PY 2012 VL 23 IS 4 BP 577 EP 590 DI 10.1091/mbc.E11-09-0791 PG 14 WC Cell Biology SC Cell Biology GA 897CP UT WOS:000300619500007 PM 22190737 ER PT J AU McCracken, ST Kaiser, M Boshoff, HI Boyd, PDW Copp, BR AF McCracken, Stephen T. Kaiser, Marcel Boshoff, Helena I. Boyd, Peter D. W. Copp, Brent R. TI Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photo-dimers SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Malaria; Tuberculosis; Natural product; Pyran-2-one; Photochemical dimerisation ID POLYGALA-SABULOSA POLYGALACEAE; MYCOBACTERIUM-TUBERCULOSIS; INHIBITORY-ACTIVITY; ALPINIA-SPECIOSA; DIHYDROSTYRYL-2-PYRONES; STYRYL-2-PYRONES; CONSTITUENTS; BIOSYNTHESIS; METABOLITES; DERIVATIVES AB Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of Mycobacterium tuberculosis and a range of tropical diseases including Plasmodium falciparum and Leishmania donovani. In an effort to expand the structure-activity relationship of this compound class towards infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesized. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense and Trypanosoma cruzi. Of the styryl-pyranones, natural product 3 and non-natural styrene and naphthalene substituted examples 13, 18, 21, 22 and 23 exhibited antimalarial activity (IC50 < 10 mu M) with selectivity indices (SI) > 10. Delta(7) Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers 5 and 34 exhibited moderate IC(50)s of 2.3 to 17 mu M towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers 31 and 33 were identified as being moderately active towards P. falciparum (IC50 1.5 and 1.7 mu M) with good selectivity (SI similar to 80). The 4-tert-butyl aniba-dimer A analogue 33 also exhibited activity towards L. donovani (IC50 4.5 mu M), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis. (C) 2011 Elsevier Ltd. All rights reserved. C1 [McCracken, Stephen T.; Boyd, Peter D. W.; Copp, Brent R.] Univ Auckland, Sch Chem Sci, Auckland 1142, New Zealand. [Kaiser, Marcel] Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland. [Kaiser, Marcel] Univ Basel, CH-4003 Basel, Switzerland. [Boshoff, Helena I.] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. RP Copp, BR (reprint author), Univ Auckland, Sch Chem Sci, Private Bag 92019, Auckland 1142, New Zealand. EM b.copp@auckland.ac.nz RI Copp, Brent/D-3706-2009; OI Copp, Brent/0000-0001-5492-5269; Kaiser, Marcel/0000-0003-1785-7302 FU University of Auckland; Auckland Medical Research Foundation; NIH, NIAID; Tertiary Education Commission of New Zealand FX We thank the University of Auckland and Auckland Medical Research Foundation for funding. This research was supported in part by the Intramural Research Program of the NIH, NIAID. We also thank M. Cal, S. Sax, and C. Stalder (Swiss TPH) for assistance with parasitic assays, Dr M. Schmitz for assistance with NMR data acquisition, and Ms. R. Imatdieva for MS data. STM wishes to acknowledge the Tertiary Education Commission of New Zealand for a scholarship. NR 30 TC 17 Z9 17 U1 1 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD FEB 15 PY 2012 VL 20 IS 4 BP 1482 EP 1493 DI 10.1016/j.bmc.2011.12.053 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 893XO UT WOS:000300391200014 PM 22285027 ER PT J AU Baird, DD Steiner, AZ AF Baird, Donna D. Steiner, Anne Z. TI Anti-Mullerian Hormone: A Potential New Tool in Epidemiologic Studies of Female Fecundability SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE anti-Mullerian hormone; epidemiology; fertility; research design ID SELF-REPORTED TIME; ANTIMULLERIAN HORMONE; MENSTRUAL-CYCLE; INTRAUTERINE-DEVICE; DELAYED CONCEPTION; TUBAL INFERTILITY; PROLONGED TIME; SERUM-LEVELS; PREGNANCY; FERTILITY AB The objective of the present commentary is to suggest that epidemiologists explore the use of anti-Mullerian hormone (AMH) as a new measurement tool in fecundability studies. The authors briefly summarize the advantages and limitations of the 3 current approaches to studies of fecundability. All 3 approaches involve the collection of time-to-pregnancy or attempt-time data, and most are limited to participants who plan their pregnancies. AMH is produced by ovarian follicles during their early growth stages and is measured clinically to assess ovarian reserve (the number of remaining oocytes). Unlike time to pregnancy, serum AMH level can be assessed regardless of pregnancy-attempt status. Measurements are not significantly affected by phase of the menstrual cycle, oral contraceptive use, or early pregnancy. The authors suggest that AMH measurement can be a valuable addition to traditionally designed fecundability studies. In addition, this hormone should be investigated as an independent measure of fecundability in studies that focus on exposures hypothesized to target the ovary. C1 [Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Steiner, Anne Z.] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, NIH, A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural NIH HHS NR 53 TC 15 Z9 16 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2012 VL 175 IS 4 BP 245 EP 249 DI 10.1093/aje/kwr439 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 888ZC UT WOS:000300042200001 PM 22247047 ER PT J AU Carroll, RJ Midthune, D Subar, AF Shumakovich, M Freedman, LS Thompson, FE Kipnis, V AF Carroll, Raymond J. Midthune, Douglas Subar, Amy F. Shumakovich, Marina Freedman, Laurence S. Thompson, Frances E. Kipnis, Victor TI Taking Advantage of the Strengths of 2 Different Dietary Assessment Instruments to Improve Intake Estimates for Nutritional Epidemiology SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE combining dietary instruments; data collection; dietary assessment; energy adjustment; epidemiologic methods; measurement error; nutrient density; nutrient intake ID FOOD FREQUENCY QUESTIONNAIRES; MEASUREMENT ERROR; 24-HOUR RECALL; BREAST-CANCER; PRACTICAL METHOD; COHORT; RECORD; BIOMARKERS; ACCURACY; FAT AB With the advent of Internet-based 24-hour recall (24HR) instruments, it is now possible to envision their use in cohort studies investigating the relation between nutrition and disease. Understanding that all dietary assessment instruments are subject to measurement errors and correcting for them under the assumption that the 24HR is unbiased for usual intake, here the authors simultaneously address precision, power, and sample size under the following 3 conditions: 1) 1-12 24HRs; 2) a single calibrated food frequency questionnaire (FFQ); and 3) a combination of 24HR and FFQ data. Using data from the Eating at America's Table Study (1997-1998), the authors found that 4-6 administrations of the 24HR is optimal for most nutrients and food groups and that combined use of multiple 24HR and FFQ data sometimes provides data superior to use of either method alone, especially for foods that are not regularly consumed. For all food groups but the most rarely consumed, use of 2-4 recalls alone, with or without additional FFQ data, was superior to use of FFQ data alone. Thus, if self-administered automated 24HRs are to be used in cohort studies, 4-6 administrations of the 24HR should be considered along with administration of an FFQ. C1 [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, Coll Sci, College Stn, TX 77843 USA. [Freedman, Laurence S.] Gertner Inst Epidemiol, Tel Hashomer, Israel. [Midthune, Douglas; Shumakovich, Marina; Kipnis, Victor] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Subar, Amy F.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Thompson, Frances E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Carroll, RJ (reprint author), Texas A&M Univ, Dept Stat, Coll Sci, Blocker Bldg,Room 447, College Stn, TX 77843 USA. EM carroll@stat.tamu.edu FU National Cancer Institute [R37-CA057030]; King Abdullah University of Science and Technology [KUS-CI-016-04]; National Institutes of Health [HHSN261200633000] FX Dr. Raymond J. Carroll's research was supported by a grant (R37-CA057030) from the National Cancer Institute. Dr. Carroll was also supported by Award KUS-CI-016-04 from the King Abdullah University of Science and Technology. Dr. Laurence S. Freedman was supported by the National Institutes of Health (under contract HHSN261200633000). NR 31 TC 44 Z9 45 U1 2 U2 23 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2012 VL 175 IS 4 BP 340 EP 347 DI 10.1093/aje/kwr317 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 888ZC UT WOS:000300042200012 PM 22273536 ER PT J AU Grimsley-Myers, CM Sipe, CW Wu, DK Lu, XW AF Grimsley-Myers, Cynthia M. Sipe, Conor W. Wu, Doris K. Lu, Xiaowei TI Redundant functions of Rac GTPases in inner ear morphogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Rac GTPase; Otic epithelium; Semicircular canal; Cochlea; Spiral ganglion; Convergent extension ID PLANAR CELL POLARITY; NULL MUTANT MICE; BETA-CATENIN; RHO-GTPASES; ADHERENS JUNCTIONS; SENSORY EPITHELIA; SONIC HEDGEHOG; GENE; PROLIFERATION; EXPRESSION AB Development of the mammalian inner ear requires coordination of cell proliferation, cell fate determination and morphogenetic movements. While significant progress has been made in identifying developmental signals required for inner ear formation, less is known about how distinct signals are coordinated by their downstream mediators. Members of the Rac family of small GTPases are known regulators of cytoskeletal remodeling and numerous other cellular processes. However, the function of Rac GTPases in otic development is largely unexplored. Here, we show that Rac1 and Rac3 redundantly regulate many aspects of inner ear morphogenesis. While no morphological defects were observed in Rac3(-/-) mice, Rac1(CKO); Rac3(-/-) double mutants displayed enhanced vestibular and cochlear malformations compared to Rac1(CKO) single mutants. Moreover, in Rac1(CKO); Rac3(-/-) mutants, we observed compromised E-cadherin-mediated cell adhesion, reduced cell proliferation and increased cell death in the early developing otocyst, leading to a decreased size and malformation of the membranous labyrinth. Finally, cochlear extension was severely disrupted in Rac1(CKO); Rac3(-/-) mutants, accompanied by a loss of epithelial cohesion and formation of ectopic sensory patches underneath the cochlear duct. The compartmentalized expression of otic patterning genes within the Rac1(CKO); Rac3(-/-) mutant otocyst was largely normal, however, indicating that Rac proteins regulate inner ear morphogenesis without affecting cell fate specification. Taken together, our results reveal an essential role for Rac GTPases in coordinating cell adhesion, cell proliferation, cell death and cell movements during otic development. (C) 2011 Elsevier Inc. All rights reserved. C1 [Grimsley-Myers, Cynthia M.; Sipe, Conor W.; Lu, Xiaowei] Univ Virginia, Dept Cell Biol, Charlottesville, VA 22908 USA. [Wu, Doris K.] Natl Inst Deafness & Commun Disorders, Lab Mol Biol, Rockville, MD 20850 USA. RP Lu, XW (reprint author), Univ Virginia, Dept Cell Biol, Box 800732,1300 Jefferson Pk Ave, Charlottesville, VA 22908 USA. EM xl6f@virginia.edu FU NIH [R01 DC009238]; Jeffress Research Grant; Hartwell Foundation; NIH for Cell and Molecular Biology at the University of Virginia [T32 GM008136] FX We thank Drs. Noelle Dwyer, Jason Kinchen and Jing Yu for helpful comments on the manuscript, Wenxia Li for technical support, Dr. Noelle Dwyer for antibodies, Drs. Jing Yu and Nora Heisterkamp for mice, Dr. Ping-Xian Xu for in situ probes, and Dr. Bernd Fritzsch and members of the Lu laboratory for helpful discussions. This study was supported by the NIH grant R01 DC009238 and a Jeffress Research Grant (to X.L.). C.G-M. was supported by a fellowship from the Hartwell Foundation. C.W.S. was supported by NIH training grant T32 GM008136 for Cell and Molecular Biology at the University of Virginia. The authors declare no conflicts of interest. NR 74 TC 3 Z9 3 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2012 VL 362 IS 2 BP 172 EP 186 DI 10.1016/j.ydbio.2011.12.008 PG 15 WC Developmental Biology SC Developmental Biology GA 890IE UT WOS:000300137500006 PM 22182523 ER PT J AU Saravanamuthu, SS Le, TT Gao, CY Cojocaru, RI Pandiyan, P Liu, CQ Zhang, J Zelenka, PS Brown, NL AF Saravanamuthu, Senthil S. Le, Tien T. Gao, Chun Y. Cojocaru, Radu I. Pandiyan, Pushpa Liu, Chunqiao Zhang, Jun Zelenka, Peggy S. Brown, Nadean L. TI Conditional ablation of the Notch2 receptor in the ocular lens SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Notch2; Lens fiber cell differentiation; Lens development; Jag1; p21Cip1 ID FIBER CELL-DIFFERENTIATION; GENE-EXPRESSION; GROWTH-FACTOR; EYE LENS; PATHWAY; FOXE3; PROLIFERATION; DEGRADATION; P57(KIP2); PROTEIN AB Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation. (C) 2011 Elsevier Inc. All rights reserved. C1 [Le, Tien T.; Brown, Nadean L.] Cincinnati Childrens Hosp Res Fdn, Div Dev Biol, Cincinnati, OH 45229 USA. [Saravanamuthu, Senthil S.; Gao, Chun Y.; Zelenka, Peggy S.] NEI, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. [Cojocaru, Radu I.; Liu, Chunqiao] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Pandiyan, Pushpa] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zhang, Jun] NEI, Histopathol Core Facil, NIH, Bethesda, MD 20892 USA. RP Brown, NL (reprint author), Cincinnati Childrens Hosp Res Fdn, Div Dev Biol, ML 7007,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM Nadean.Brown@cchmc.org RI Liu, Chunqiao/O-3391-2013 OI Liu, Chunqiao/0000-0002-0299-7401 FU National Eye Institute [Z01-EY000238]; NIH R01 [EY18097] FX The authors thank Tom Gridley for Notch2CKO/CKO mice; Ruth Ashery-Padan and Joram Piatigorsky for Le-Cre transgenic mice; Richard Lang for Cryb antibody; Peter Carlsson for Foxe3 antibody; Eric VVawrousek for Crya antibody, Barbara Norman for technical expertise; and Richard Lang and Tiffany Cook for valuable discussion. This work was supported by the National Eye Institute Intramural Research Program Z01-EY000238 to PSZ and NIH R01 grant EY18097 to NLB. NR 56 TC 11 Z9 11 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2012 VL 362 IS 2 BP 219 EP 229 DI 10.1016/j.ydbio.2011.11.011 PG 11 WC Developmental Biology SC Developmental Biology GA 890IE UT WOS:000300137500009 PM 22173065 ER PT J AU Engels, EA Pfeiffer, RM Kasiske, BL AF Engels, Eric A. Pfeiffer, Ruth M. Kasiske, Bertram L. TI Cancer Risk After Organ Transplantation Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Engels, Eric A.; Pfeiffer, Ruth M.] NCI, Rockville, MD USA. [Kasiske, Bertram L.] Sci Registry Transplant Recipients, Minneapolis, MN USA. RP Engels, EA (reprint author), NCI, Rockville, MD USA. EM engelse@exchange.nih.gov NR 1 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 FEB 15 PY 2012 VL 307 IS 7 BP 663 EP 664 DI 10.1001/jama.2012.141 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 892HY UT WOS:000300278500013 ER PT J AU Gillison, ML Broutian, T Pickard, RKL Tong, ZY Xiao, WH Kahle, L Graubard, BI Chaturvedi, AK AF Gillison, Maura L. Broutian, Tatevik Pickard, Robert K. L. Tong, Zhen-you Xiao, Weihong Kahle, Lisa Graubard, Barry I. Chaturvedi, Anil K. TI Prevalence of Oral HPV Infection in the United States, 2009-2010 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPES; NUTRITION EXAMINATION SURVEY; SQUAMOUS-CELL CARCINOMAS; NECK CANCERS; INTRAEPITHELIAL NEOPLASIA; OROPHARYNGEAL CANCER; NATIONAL-HEALTH; COSTA-RICA; RISK; HEAD AB Context Human papillomavirus (HPV) infection is the principal cause of a distinct form of oropharyngeal squamous cell carcinoma that is increasing in incidence among men in the United States. However, little is known about the epidemiology of oral HPV infection. Objective To determine the prevalence of oral HPV infection in the United States. Design, Setting, and Participants A cross-sectional study was conducted as part of the National Health and Nutrition Examination Survey (NHANES) 2009-2010, a statistically representative sample of the civilian noninstitutionalized US population. Men and women aged 14 to 69 years examined at mobile examination centers were eligible. Participants (N=5579) provided a 30-second oral rinse and gargle with mouthwash. For detection of HPV types, DNA purified from oral exfoliated cells was evaluated by polymerase chain reaction and type-specific hybridization. Demographic and behavioral data were obtained by standardized interview. Statistical analyses used NHANES sample weights to provide weighted prevalence estimates for the US population. Main Outcome Measures Prevalence of oral HPV infection. Results The prevalence of oral HPV infection among men and women aged 14 to 69 years was 6.9% (95% CI, 5.7%-8.3%) and of HPV type 16 was 1.0% (95% CI, 0.7%-1.3%). Oral HPV infection followed a bimodal pattern with respect to age, with peak prevalence among individuals aged 30 to 34 years (7.3%; 95% CI, 4.6%-11.4%) and 60 to 64 years (11.4%; 95% CI, 8.5%-15.1%). Men had a significantly higher prevalence than women for any oral HPV infection (10.1% [95% CI, 8.3%-12.3%] vs 3.6% [95% CI, 2.6%-5.0%], P < .001; unadjusted prevalence ratio [PR], 2.80 [95% CI, 2.02-3.88]). Infection was less common among those without vs those with a history of any type of sexual contact (0.9% [95% CI, 0.4%-1.8%] vs 7.5% [95% CI, 6.1%-9.1%], P < .001; PR, 8.69 [95% CI, 3.91-19.31]) and increased with number of sexual partners (P < .001 for trend) and cigarettes smoked per day (P < .001 for trend). Associations with age, sex, number of sexual partners, and current number of cigarettes smoked per day were independently associated with oral HPV infection in multivariable models. Conclusion Among men and women aged 14 to 69 years in the United States, the overall prevalence of oral HPV infection was 6.9%, and the prevalence was higher among men than among women. JAMA. 2012;307(7):693-703 Published online January 26, 2012. doi:10.1001/jama.2012.101 C1 [Gillison, Maura L.; Broutian, Tatevik; Pickard, Robert K. L.; Tong, Zhen-you; Xiao, Weihong] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Kahle, Lisa] Informat Management Serv Inc, Silver Spring, MD USA. [Graubard, Barry I.; Chaturvedi, Anil K.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Gillison, ML (reprint author), Ohio State Univ, Ctr Comprehens Canc, 420 W 12th Ave, Columbus, OH 43210 USA. EM maura.gillison@osumc.edu RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Merck; Ohio State University Comprehensive Cancer Center; John and Nina Cassils; National Cancer Institute FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Gillison is the principal investigator of the unrestricted grant from Merck in support of this study and has been a consultant to Merck and GlaxoSmithKline. No other disclosures were reported.; This study was supported by the Ohio State University Comprehensive Cancer Center, Merck, John and Nina Cassils, and the Intramural Research Program of the National Cancer Institute. NR 39 TC 330 Z9 335 U1 0 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 15 PY 2012 VL 307 IS 7 BP 693 EP 703 DI 10.1001/jama.2012.101 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 892HY UT WOS:000300278500026 PM 22282321 ER PT J AU Shirota, Y Shirota, H Klinman, DM AF Shirota, Yuko Shirota, Hidekazu Klinman, Dennis M. TI Intratumoral Injection of CpG Oligonucleotides Induces the Differentiation and Reduces the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CONTAINING OLIGODEOXYNUCLEOTIDES; THERAPEUTIC APPLICATIONS; ESTABLISHED TUMORS; ANTITUMOR IMMUNITY; TLR9 AGONISTS; BACTERIAL-DNA; T-CELLS; CANCER; PF-3512676; CARCINOMA AB Immunostimulatory CpG oligonucleotides (ODN) activate cells that express TLR9 and have been shown to improve the host's response to tumor Ags. Unfortunately, the immunosuppressive microenvironment that surrounds many cancers inhibits Ag-specific cellular responses and thus interferes with CpG-mediated immunotherapy. Myeloid-derived suppressor cells (MDSC) represent an important constituent of this immunosuppressive milieu. Large numbers of MDSC are present in and near tumor sites where they inhibit the activity of Ag-specific T and NK cells. Current studies indicate that the delivery of CpG ODN directly into the tumor bed reduces the immunosuppressive activity of monocytic (CD11b(+), Ly6G(-), Ly6C(high)) MDSC. Monocytic MDSC express TLR9 and respond to CpG stimulation by 1) losing their ability to suppress T cell function, 2) producing Th1 cytokines, and 3) differentiating into macrophages with tumoricidal capability. These findings provide insight into a novel mechanism by which CpG ODN contribute to tumor regression, and they support intratumoral injection as the optimal route for their delivery. The Journal of Immunology, 2012, 188: 1592-1599. C1 [Shirota, Yuko; Shirota, Hidekazu; Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Shirota, Hidekazu] NCI, Basic Sci Program, Sci Applicat Int Corp Frederick, Frederick, MD 21703 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, Bldg 567,Room 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU National Cancer Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. NR 40 TC 80 Z9 81 U1 0 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2012 VL 188 IS 4 BP 1592 EP 1599 DI 10.4049/jimmunol.1101304 PG 8 WC Immunology SC Immunology GA 890IT UT WOS:000300139000004 PM 22231700 ER PT J AU Longo, DM Louie, B Putta, S Evensen, E Ptacek, J Cordeiro, J Wang, E Pos, Z Hawtin, RE Marincola, FM Cesano, A AF Longo, Diane M. Louie, Brent Putta, Santosh Evensen, Erik Ptacek, Jason Cordeiro, James Wang, Ena Pos, Zoltan Hawtin, Rachael E. Marincola, Francesco M. Cesano, Alessandra TI Single-Cell Network Profiling of Peripheral Blood Mononuclear Cells from Healthy Donors Reveals Age- and Race-Associated Differences in Immune Signaling Pathway Activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8 T-CELLS; CLONAL EXPANSION; FLOW-CYTOMETRY; DIFFERENTIATION; AUTOIMMUNITY; SURVIVAL; RECEPTOR; DISEASE; SYSTEM AB A greater understanding of the function of the human immune system at the single-cell level in healthy individuals is critical for discerning aberrant cellular behavior that occurs in settings such as autoimmunity, immunosenescence, and cancer. To achieve this goal, a systems-level approach capable of capturing the response of the interdependent immune cell types to external stimuli is required. In this study, an extensive characterization of signaling responses in multiple immune cell subpopulations within PBMCs from a cohort of 60 healthy donors was performed using single-cell network profiling (SCNP). SCNP is a multiparametric flow cytometry-based approach that enables the simultaneous measurement of basal and evoked signaling in multiple cell subsets within heterogeneous populations. In addition to establishing the interindividual degree of variation within a broad panel of immune signaling responses, the possible association of any observed variation with demographic variables including age and race was investigated. Using half of the donors as a training set, multiple age- and race-associated variations in signaling responses in discrete cell subsets were identified, and several were subsequently confirmed in the remaining samples (test set). Such associations may provide insight into age-related immune alterations associated with high infection rates and diminished protection following vaccination and into the basis for ethnic differences in autoimmune disease incidence and treatment response. SCNP allowed for the generation of a functional map of healthy immune cell signaling responses that can provide clinically relevant information regarding both the mechanisms underlying immune pathological conditions and the selection and effect of therapeutics. The Journal of Immunology, 2012, 188: 1717-1725. C1 [Longo, Diane M.; Louie, Brent; Putta, Santosh; Evensen, Erik; Ptacek, Jason; Cordeiro, James; Hawtin, Rachael E.; Cesano, Alessandra] Nodality, San Francisco, CA 94080 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Pos, Zoltan] Semmelweis Univ, Dept Genet Cell & Immunobiol, H-1089 Budapest, Hungary. RP Longo, DM (reprint author), Nodality, 170 Harbor Way,Suite 200, San Francisco, CA 94080 USA. EM diane.longo@nodality.com RI Pos, Zoltan/C-3623-2014 OI Pos, Zoltan/0000-0002-2574-7616 FU Intramural NIH HHS [Z01 CL002118-02] NR 32 TC 22 Z9 23 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2012 VL 188 IS 4 BP 1717 EP 1725 DI 10.4049/jimmunol.1102514 PG 9 WC Immunology SC Immunology GA 890IT UT WOS:000300139000017 PM 22246624 ER PT J AU Zhou, R Horai, R Silver, PB Mattapallil, MJ Zarate-Blades, CR Chong, WP Chen, J Rigden, RC Villasmil, R Caspi, RR AF Zhou, Ru Horai, Reiko Silver, Phyllis B. Mattapallil, Mary J. Zarate-Blades, Carlos R. Chong, Wai Po Chen, Jun Rigden, Rachael C. Villasmil, Rafael Caspi, Rachel R. TI The Living Eye "Disarms" Uncommitted Autoreactive T Cells by Converting Them to Foxp3(+) Regulatory Cells following Local Antigen Recognition SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; RETINOIC ACID; IMMUNE PRIVILEGE; AQUEOUS-HUMOR; PIGMENT-EPITHELIUM; TGF-BETA; AUTOIMMUNE-DISEASE; PROLIFERATION; MECHANISMS; UVEITIS AB Immune privilege is used by the eye, brain, reproductive organs, and gut to preserve structural and functional integrity in the face of inflammation. The eye is arguably the most vulnerable and, therefore, also the most "privileged" of tissues; paradoxically, it remains subject to destructive autoimmunity. It has been proposed, although never proven in vivo, that the eye can induce T regulatory cells (Tregs) locally. Using Foxp3-GFP reporter mice expressing a retina-specific TCR, we now show that uncommitted T cells rapidly convert in the living eye to Foxp3(+) Tregs in a process involving retinal Ag recognition, de novo Foxp3 induction, and proliferation. This takes place within the ocular tissue and is supported by retinoic acid, which is normally present in the eye because of its function in the chemistry of vision. Nonconverted T cells showed evidence of priming but appeared restricted from expressing effector function in the eye. Pre-existing ocular inflammation impeded conversion of uncommitted T cells into Tregs. Importantly, retina-specific T cells primed in vivo before introduction into the eye were resistant to Treg conversion in the ocular environment and, instead, caused severe uveitis. Thus, uncommitted T cells can be disarmed, but immune privilege is unable to protect from uveitogenic T cells that have acquired effector function prior to entering the eye. These findings shed new light on the phenomenon of immune privilege and on its role, as well as its limitations, in actively controlling immune responses in the tissue. The Journal of Immunology, 2012, 188: 1742-1750. C1 [Zhou, Ru; Horai, Reiko; Silver, Phyllis B.; Mattapallil, Mary J.; Zarate-Blades, Carlos R.; Chong, Wai Po; Chen, Jun; Rigden, Rachael C.; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Villasmil, Rafael] NEI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N222,10 Ctr Dr,MSC 1857, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov RI Zarate-Blades, Carlos/C-9663-2015; OI Zarate-Blades, Carlos/0000-0002-7728-7869; Caspi, Rachel/0000-0002-7140-7671 FU National Institutes of Health/National Eye Institute [EY000184] FX This work was supported by National Institutes of Health/National Eye Institute intramural funding, Project EY000184. NR 47 TC 31 Z9 32 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2012 VL 188 IS 4 BP 1742 EP 1750 DI 10.4049/jimmunol.1102415 PG 9 WC Immunology SC Immunology GA 890IT UT WOS:000300139000020 PM 22238462 ER PT J AU Spolski, R Wang, L Wan, CK Bonville, CA Domachowske, JB Kim, HP Yu, ZX Leonard, WJ AF Spolski, Rosanne Wang, Lu Wan, Chi-Keung Bonville, Cynthia A. Domachowske, Joseph B. Kim, Hyoung-Pyo Yu, Zuxi Leonard, Warren J. TI IL-21 Promotes the Pathologic Immune Response to Pneumovirus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; CONTROL PULMONARY INFLAMMATION; SYNCYTIAL VIRUS-INFECTION; CD4(+) T-CELLS; PNEUMONIA VIRUS; NEUTROPHIL RECRUITMENT; IN-VIVO; MICE; INTERLEUKIN-21; ACTIVATION AB IL-21 is a cytokine with pleiotropic actions, promoting terminal differentiation of B cells, increased Ig production, and the development of Th17 and T follicular helper cells. IL-21 is also implicated in the development of autoimmune disease and has antitumor activity. In this study, we investigated the role of IL-21 in host defense to pneumonia virus of mice (PVM), which initiates an infection in mice resembling that of respiratory, syncytial virus disease in humans. We found that PVM-infected mice expressed IL-21 in lung CD4(+) T cells. Following infection, Il21r(-/-) mice exhibited less lung infiltration by neutrophils than did wild-type (WT) mice and correspondingly had lower levels of the chemokine CXCL1 in bronchoalveolar lavage fluid and lung parenchyma. CD8(+), CD4(+), and gamma delta T cell numbers were also lower in the lungs of PVM-infected Il21r(-/-) mice than in infected WT mice, with normal Th17 cytokines but diminished IL-6 production in PVM-infected Il21r(-/-) mice. Strikingly, Il21r(-/-) mice had enhanced survival following PVM infection, and moreover, treatment of WT mice with soluble IL-21R-Fc fusion protein enhanced their survival. These data reveal that IL-21 promotes the pathogenic inflammatory effect of PVM and indicate that manipulating IL-21 signaling may represent an immunomodulatory strategy for controlling PVM and potentially other respiratory virus infections. The Journal of Immunology, 2012, 188: 1924-1932. C1 [Spolski, Rosanne; Wang, Lu; Wan, Chi-Keung; Kim, Hyoung-Pyo; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Bonville, Cynthia A.; Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. [Kim, Hyoung-Pyo] Yonsei Univ, Coll Med, Dept Environm Med Biol, Inst Trop Med,Brain Korea Project Med Sci 21, Seoul 120752, South Korea. [Yu, Zuxi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute; Children's Miracle Network of New York FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute (to R.S., L.W., C.-K.W., H.-P.K., Z.Y., and W.J.L.) and the Children's Miracle Network of New York (to C.A.B. and J.B.D.). NR 42 TC 22 Z9 25 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2012 VL 188 IS 4 BP 1924 EP 1932 DI 10.4049/jimmunol.1100767 PG 9 WC Immunology SC Immunology GA 890IT UT WOS:000300139000039 PM 22238461 ER PT J AU Minisman, G Bhanushali, M Conwit, R Wolfe, GI Aban, I Kaminski, HJ Cutter, G AF Minisman, Greg Bhanushali, Minal Conwit, Robin Wolfe, Gil I. Aban, Inmaculada Kaminski, Henry J. Cutter, Gary TI Implementing clinical trials on an international platform: Challenges and perspectives SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Review DE Clinical research; Multinational clinical trials; International clinical trials; Thymectomy; Myasthenia gravis; Phase 3 clinical trials ID MULTICENTER; EXPERIENCE; HEALTH AB The importance of conducting medical research on a global or international platform cannot be overemphasized in current times. Sponsors are encouraging international clinical trials for a number of reasons. Globally, clinical trials are under increasing pressure to meet patient recruitment goals quickly and efficiently, at times with very limited resources. Conducting clinical trials in multiple countries increases access to potentially eligible study subjects. It is reasonable to believe that international trials will be completed more quickly and efficiently, leading to more rapid advancement in science and conservation of research-specific resources. Rapid advancement in science can reduce the burden of disease, promote health, and extend longevity for all people. In addition, generalizability, one of the major goals of translational medicine, will increase when recruiting patients from multiple countries and multiple ethnicities. Further, improvement of global health may be possible when certain types of clinical trials are conducted in countries that would not otherwise have access to an innovative drug or intervention. Published by Elsevier B.V. C1 [Minisman, Greg; Aban, Inmaculada; Cutter, Gary] Univ Alabama, Sch Publ Hlth, Dept Biostat, Sect Res Methods & Clin Trials, Birmingham, AL 35294 USA. [Bhanushali, Minal; Conwit, Robin] NINDS, Rockville, MD 20890 USA. [Bhanushali, Minal; Conwit, Robin] NIH, Rockville, MD 20890 USA. [Wolfe, Gil I.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Kaminski, Henry J.] George Washington Univ, Dept Neurol, Washington, DC 20037 USA. RP Bhanushali, M (reprint author), 6001 Execut Blvd,Suite 2-216, Rockville, MD 20890 USA. EM bhanushalimj@mail.nih.gov FU National Institute of Neurological Disorders and Stroke [U01 N5042685-06] FX The clinical trial MGTX referenced in the manuscript is supported by a grant from the National Institute of Neurological Disorders and Stroke (U01 N5042685-06 - Thymectomy i n Non-thymomatous MG patients on prednisone). NR 12 TC 6 Z9 6 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD FEB 15 PY 2012 VL 313 IS 1-2 BP 1 EP 6 DI 10.1016/j.jns.2011.10.004 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 888BM UT WOS:000299978800001 PM 22047648 ER PT J AU Raben, N Wong, A Ralston, E Myerowitz, R AF Raben, Nina Wong, Amanda Ralston, Evelyn Myerowitz, Rachel TI Autophagy and mitochondria in Pompe disease: Nothing is so new as what has long been forgotten SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE autophagy; muscle; mitochondria; lysosome; glycogen storage ID ENZYME REPLACEMENT THERAPY; ACID MALTASE DEFICIENCY; SINGLE MUSCLE-FIBERS; SKELETAL-MUSCLE; MOUSE MODEL; GLYCOGEN; STORAGE; MICE; INFANTILE; CELLS AB Macroautophagy (often referred to as autophagy) is an evolutionarily conserved intracellular system by which macromolecules and organelles are delivered to lysosomes for degradation and recycling. Autophagy is robustly induced in response to starvation in order to generate nutrients and energy through the lysosomal degradation of cytoplasmic components. Constitutive, basal autophagy serves as a quality control mechanism for the elimination of aggregated proteins and worn-out or damaged organelles, such as mitochondria. Research during the last decade has made it clear that malfunctioning or failure of this system is associated with a wide range of human pathologies and age-related diseases. Our recent data provide strong evidence for the role of autophagy in the pathogenesis of Pompe disease, a lysosomal glycogen storage disease caused by deficiency of acid alpha-glucosidase (GAA). Large pools of autophagic debris in skeletal muscle cells can be seen in both our GAA knockout model and patients with Pompe disease. In this review, we will focus on these recent data, and comment on the not so recent observations pointing to the involvement of autophagy in skeletal muscle damage in Pompe disease. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Raben, Nina] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Ralston, Evelyn] NIAMS, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. [Myerowitz, Rachel] NIDDK, NIH, Bethesda, MD 20892 USA. RP Raben, N (reprint author), NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr,Bld 50-1345 NIAMS, Bethesda, MD 20892 USA. EM rabenn@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health; NIH; Genzyme Corporation FX The research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health. Amanda Wong was supported in part by a Cooperative Research and Development Agreement (CRADA) between the NIH and Genzyme Corporation. NR 53 TC 40 Z9 41 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4868 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD FEB 15 PY 2012 VL 160C IS 1 SI SI BP 13 EP 21 DI 10.1002/ajmg.c.31317 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 879ZG UT WOS:000299372700003 PM 22253254 ER PT J AU Zeng, XL Thumati, NR Fleisig, HB Hukezalie, KR Savage, SA Giri, N Alter, BP Wong, JMY AF Zeng, Xi-Lei Thumati, Naresh R. Fleisig, Helen B. Hukezalie, Kyle R. Savage, Sharon A. Giri, Neelam Alter, Blanche P. Wong, Judy M. Y. TI The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita SO HUMAN MOLECULAR GENETICS LA English DT Article ID HOYERAAL-HREIDARSSON-SYNDROME; PLURIPOTENT STEM-CELLS; H/ACA SMALL NUCLEOLAR; RNA; MUTATIONS; GENE; DKC1; COMPONENT; DISEASE; FAMILY AB X-linked dyskeratosis congenita (X-DC) is caused by mutations in the housekeeping nucleolar protein dyskerin. Amino acid changes associated with X-DC are remarkably heterogeneous. Peripheral mononuclear blood cells and fibroblasts isolated from X-DC patients harbor lower steady-state telomerase RNA (TER) levels and shorter telomeres than healthy age-matched controls. Previously, we showed that retroviral expression of recombinant TER, together with expression of recombinant telomerase reverse transcriptase, restored telomere maintenance and proliferative capacity in X-DC patient cells. Using rare X-DC isoforms (Delta L37 and A386T dyskerin), we showed that telomere maintenance defects observed in X-DC are solely due to decreased steady-state levels of TER. Disease-associated reductions in steady-state TER levels cause deficiencies in telomere maintenance. Here, we confirm these findings in other primary X-DC patient cell lines coding for the most common (A353V dyskerin) and more clinically severe (K314R and A353V dyskerin) X-DC isoforms. Using cell lines derived from these patients, we also examined the steady-state levels of other hinge-ACA motif RNAs and did not find differences in their in vivo accumulations. We show, for the first time, that purified telomerase holoenzyme complexes from different X-DC cells have normal catalytic activity. Our data confirm that dyskerin promotes TER stability in vivo, endorsing the development of TER supplementation strategies for the treatment of X-DC. C1 [Zeng, Xi-Lei; Thumati, Naresh R.; Fleisig, Helen B.; Hukezalie, Kyle R.; Wong, Judy M. Y.] Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada. [Hukezalie, Kyle R.; Wong, Judy M. Y.] Univ British Columbia, Grad Program Genet, Vancouver, BC V5Z 1M9, Canada. [Savage, Sharon A.; Giri, Neelam; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Wong, JMY (reprint author), 2146 East Mall, Vancouver, BC, Canada. EM judy.wong@ubc.ca RI Savage, Sharon/B-9747-2015; OI Savage, Sharon/0000-0001-6006-0740; Wong, Judy/0000-0001-5572-4143 FU Lisa Leathwood, Westat, Inc (NIH) [N02-CP-11019, N02-CP-65504, N02-CP-65501]; Canadian Institutes of Health Research [MOP-81094]; Michael Smith Foundation for Health Research; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX We thank Kathleen Collins for sharing reagents and cell lines. We also thank Lisa Leathwood, Westat, Inc (NIH contracts N02-CP-11019, N02-CP-65504 and N02-CP-65501) for excellent study management. Rafael Zhao provide technical help with data analysis and we thanked him for this contribution.; This work was supported by the Canadian Institutes of Health Research operating grant (MOP-81094) and the Michael Smith Foundation for Health Research. J.M.Y.W. is a Tier 2 Canada Research Chair and a Michael Smith Foundation for Health Research Scholar. This work was also supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 46 TC 8 Z9 9 U1 0 U2 1 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 FEB 15 PY 2012 VL 21 IS 4 BP 721 EP 729 DI 10.1093/hmg/ddr504 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 885QA UT WOS:000299792800001 PM 22058290 ER PT J AU Perez, SVD Kim, R Li, ZW Marquez, VE Patel, S Plath, K Clark, AT AF Perez, Silvia V. Diaz Kim, Rachel Li, Ziwei Marquez, Victor E. Patel, Sanjeet Plath, Kathrin Clark, Amander T. TI Derivation of new human embryonic stem cell lines reveals rapid epigenetic progression in vitro that can be prevented by chemical modification of chromatin SO HUMAN MOLECULAR GENETICS LA English DT Article ID HUMAN SOMATIC-CELLS; X-CHROMOSOME INACTIVATION; HUMAN FIBROBLASTS; DEFINED FACTORS; HUMAN ES; GENE; PLURIPOTENCY; CULTURE; RNA; METHYLATION AB Human embryonic stem cells (hESCs) are pluripotent cell types derived from the inner cell mass of human blastocysts. Recent data indicate that the majority of established female XX hESC lines have undergone X chromosome inactivation (XCI) prior to differentiation, and XCI of hESCs can be either XIST-dependent (class II) or XIST-independent (class III). XCI of female hESCs precludes the use of XX hESCs as a cell-based model for examining mechanisms of XCI, and will be a challenge for studying X-linked diseases unless strategies are developed to reactivate the inactive X. In order to recover nuclei with two active X chromosomes (class I), we developed a reprogramming strategy by supplementing hESC media with the small molecules sodium butyrate and 3-deazaneplanocin A (DZNep). Our data demonstrate that successful reprogramming can occur from the XIST-dependent class II nuclear state but not class III nuclear state. To determine whether these small molecules prevent XCI, we derived six new hESC lines under normoxic conditions (UCLA1-UCLA6). We show that class I nuclei are present within the first 20 passages of hESC derivation prior to cryopreservation, and that supplementation with either sodium butyrate or DZNep preserve class I nuclei in the self-renewing state. Together, our data demonstrate that self-renewal and survival of class I nuclei are compatible with normoxic hESC derivation, and that chemical supplementation after derivation provides a strategy to prevent epigenetic progression and retain nuclei with two active X chromosomes in the self-renewing state. C1 [Perez, Silvia V. Diaz; Li, Ziwei; Clark, Amander T.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA USA. [Perez, Silvia V. Diaz; Li, Ziwei; Clark, Amander T.] Univ Calif Los Angeles, Coll Letters & Sci, Los Angeles, CA USA. [Kim, Rachel; Plath, Kathrin; Clark, Amander T.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Plath, Kathrin; Clark, Amander T.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. [Patel, Sanjeet; Plath, Kathrin] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90024 USA. [Kim, Rachel; Patel, Sanjeet; Plath, Kathrin; Clark, Amander T.] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA. [Marquez, Victor E.] NCI, Frederick, MA USA. RP Clark, AT (reprint author), 621 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM clarka@ucla.edu OI Plath, Kathrin/0000-0001-7796-3372 FU NIH/NIGMS [P01 P01GM081621]; UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (UCLA-BSCRC); CIRM; UCLA-BSCRC; NIH FX This work was supported by P01 funds from the NIH/NIGMS (P01 P01GM081621), and funds from the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (UCLA-BSCRC). The derivation and characterization of hESC lines UCLA1-6 was supported exclusively by a New Cell Line Award from CIRM and the UCLA-BSCRC (A. T. C.), and not funding from the NIH. NR 47 TC 18 Z9 18 U1 1 U2 7 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 FEB 15 PY 2012 VL 21 IS 4 BP 751 EP 764 DI 10.1093/hmg/ddr506 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 885QA UT WOS:000299792800003 ER PT J AU Costanzi, S Vilar, S AF Costanzi, Stefano Vilar, Santiago TI In Silico screening for agonists and blockers of the beta(2) adrenergic receptor: Implications of inactive and activated state structures SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE G protein-coupled receptors; ss 2 adrenergic receptor; agonists; blockers; virtual screening ID PROTEIN-COUPLED RECEPTORS; STRUCTURE-BASED DISCOVERY; DRUG-LIKE MOLECULES; BETA(2)-ADRENERGIC RECEPTOR; BETA-2-ADRENERGIC RECEPTOR; 7-TRANSMEMBRANE RECEPTORS; ACCURATE PREDICTION; HOMOLOGY MODELS; LIGAND; BINDING AB Ten crystal structures of the beta 2 adrenergic receptor have been published, reflecting different signaling states. Here, through controlled-docking experiments, we examined the implications of using inactive or activated structures on the in silico screening for agonists and blockers of the receptor. Specifically, we targeted the crystal structures solved in complex with carazolol (2RH1), the neutral antagonist alprenalol, the irreversible agonist FAUC50 (3PDS), and the full agonist BI-167017 (3P0G). Our results indicate that activated structures favor agonists over blockers, whereas inactive structures favor blockers over agonists. This tendency is more marked for activated than for inactive structures. Additionally, agonists tend to receive more favorable docking scores when docked at activated rather than inactive structures, while blockers do the opposite. Hence, the difference between the docking scores attained with an activated and an inactive structure is an excellent means for the classification of ligands into agonists and blockers as we determined through receiver operating characteristic curves and linear discriminant analysis. With respect to virtual screening, all structures prioritized well agonists and blockers over nonbinders. However, inactive structures worked better for blockers and activated structures worked better for agonists, respectively. Notably, the combination of individual docking experiments through receptor ensemble docking resulted in an excellent performance in the retrieval of both agonists and blockers. Finally, we demonstrated that the induced-fit docking of agonists is a viable way of modifying an inactive crystal structure and bias it toward the in silico recognition of agonists rather than blockers. (C) 2011 Wiley Periodicals, Inc. J Comput Chem, 2011 C1 [Costanzi, Stefano; Vilar, Santiago] NIDDKD, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. RP Costanzi, S (reprint author), NIDDKD, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. EM stefanoc@mail.nih.gov RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU NIH, NIDDK FX Grant sponsor: This research was supported by the intramural research program of the NIH, NIDDK. NR 52 TC 15 Z9 15 U1 0 U2 2 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 FEB 15 PY 2012 VL 33 IS 5 BP 561 EP 572 DI 10.1002/jcc.22893 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 880NZ UT WOS:000299415400010 PM 22170280 ER PT J AU Baldwin, MKL Kaskan, PM Zhang, B Chino, YM Kaas, JH AF Baldwin, Mary K. L. Kaskan, Peter M. Zhang, Bin Chino, Yuzo M. Kaas, Jon H. TI Cortical and subcortical connections of V1 and V2 in early postnatal macaque monkeys SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE V1; V2; pulvinar; lateral geniculate nucleus; macaque monkey ID PRIMARY VISUAL-CORTEX; CYTOCHROME-OXIDASE STRIPES; LATERAL GENICULATE-NUCLEUS; CLASSICAL RECEPTIVE-FIELD; CAT STRIATE CORTEX; AREA V2; INTRINSIC CONNECTIONS; RHESUS-MONKEY; THIN STRIPES; HORIZONTAL CONNECTIONS AB Connections of primary (V1) and secondary (V2) visual areas were revealed in macaque monkeys ranging in age from 2 to 16 weeks by injecting small amounts of cholera toxin subunit B (CTB). Cortex was flattened and cut parallel to the surface to reveal injection sites, patterns of labeled cells, and patterns of cytochrome oxidase (CO) staining. Projections from the lateral geniculate nucleus and pulvinar to V1 were present at 4 weeks of age, as were pulvinar projections to thin and thick CO stripes in V2. Injections into V1 in 4- and 8-week-old monkeys labeled neurons in V2, V3, middle temporal area (MT), and dorsolateral area (DL)/V4. Within V1 and V2, labeled neurons were densely distributed around the injection sites, but formed patches at distances away from injection sites. Injections into V2 labeled neurons in V1, V3, DL/V4, and MT of monkeys 2-, 4-, and 8-weeks of age. Injections in thin stripes of V2 preferentially labeled neurons in other V2 thin stripes and neurons in the CO blob regions of V1. A likely thick stripe injection in V2 at 4 weeks of age labeled neurons around blobs. Most labeled neurons in V1 were in superficial cortical layers after V2 injections, and in deep layers of other areas. Although these features of adult V1 and V2 connectivity were in place as early as 2 postnatal weeks, labeled cells in V1 and V2 became more restricted to preferred CO compartments after 2 weeks of age. J. Comp. Neurol., 2012;520:544569. (C) 2011 Wiley Periodicals, Inc. C1 [Baldwin, Mary K. L.; Kaas, Jon H.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37203 USA. [Kaskan, Peter M.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Zhang, Bin] Nova SE Univ, Dept Optometry, Ft Lauderdale, FL 33314 USA. [Chino, Yuzo M.] Univ Houston, Coll Optometry, Houston, TX 77204 USA. RP Kaas, JH (reprint author), Vanderbilt Univ, Dept Psychol, 301 Wilson Hall,111 21st Ave S, Nashville, TN 37203 USA. EM jon.kaas@vanderbilt.edu FU National Eye Institute [RO1-EY-008128, RO1 EY-02686, T32-EY-007135]; CORE [P30 EY-007751, P30 EY-008126] FX Grant sponsor: the National Eye Institute; Grant numbers: RO1-EY-008128 (to Y.M.C), RO1 EY-02686 (to J.H.K), T32-EY-007135 (to P.M.K), and CORE grants P30 EY-007751, and P30 EY-008126. NR 128 TC 18 Z9 18 U1 2 U2 14 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 FEB 15 PY 2012 VL 520 IS 3 BP 544 EP 569 DI 10.1002/cne.22732 PG 26 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 862BG UT WOS:000298064200005 PM 21800316 ER PT J AU Snyder, JS Clifford, MA Jeurling, SI Cameron, HA AF Snyder, Jason S. Clifford, Meredith A. Jeurling, Sarah I. Cameron, Heather A. TI Complementary activation of hippocampal-cortical subregions and immature neurons following chronic training in single and multiple context versions of the water maze SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Adult neurogenesis; Hippocampus; Neocortex; Spatial learning; Memory; Immediate-early gene ID REMOTE SPATIAL MEMORY; RAT DENTATE GYRUS; LONG-TERM-MEMORY; ANTERIOR CINGULATE CORTEX; GENERATED GRANULE CELLS; ADULT NEUROGENESIS; FOS EXPRESSION; C-FOS; GENE-EXPRESSION; FEAR MEMORY AB Neurobiological studies of memory typically involve single learning sessions that last minutes or days. In natural settings, however, animals are constantly learning. Here we investigated how several weeks of spatial water maze training influences subsequent activation of neocortical and hippocampal subregions, including adult-born neurons. Mice were either trained in a single context or in a variant of the task in which the spatial cues and platform location changed every 3 days, requiring constant new learning. On the final day, half of the mice in each training group were tested in a novel context and the other half were tested in their previous, familiar context. Two hours later mice were perfused to measure subregion-specific expression of the immediate-early gene zif268, a marker of neuronal activation. None of the training paradigms affected the magnitude of adult neurogenesis. However, different neuronal populations were activated depending on prior training history, final context novelty, or a combination of these 2 factors. The anterior cingulate cortex was more activated by novel context exposure, regardless of the type of prior training. The suprapyramidal blade of the dentate gyrus and region CA3 showed greater activation in mice trained in multiple contexts, primarily after exposure to a familiar context. In immature granule neurons, multiple context training enhanced activation regardless of final context novelty. CA1 showed no significant changes in zif268 expression across any training condition. In naive control mice, training on the final day increased zif268 expression in CA3. CA1 and the anterior cingulate cortex, but not the dentate gyrus, relative to mice that remained in their cages (transport controls). Unexpectedly, immature granule cells showed a decrease in zif268 expression in naive learners relative to transport controls. These findings suggest novel and complementary roles for hippocampal, neocortical, and immature neuronal populations in learning and memory. Published by Elsevier B.V. C1 [Snyder, Jason S.; Clifford, Meredith A.; Jeurling, Sarah I.; Cameron, Heather A.] NIMH, Unit Neuroplast, NIH, Bethesda, MD 20892 USA. RP Snyder, JS (reprint author), NIMH, Unit Neuroplast, NIH, Bldg 35-3C911,MSC3718, Bethesda, MD 20892 USA. EM snyderjason@mail.nih.gov RI Cameron, Heather/E-6221-2011; OI Cameron, Heather/0000-0002-3245-5777; Snyder, Jason/0000-0002-5509-0272 FU National Institutes of Health, National Institute of Mental Health [1ZIAMH002784] FX This research was supported by the Intramural Program of the National Institutes of Health, National Institute of Mental Health, 1ZIAMH002784. The authors would like to thank Laura Grigereit for assistance with histology and image acquisition. NR 63 TC 14 Z9 14 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD FEB 14 PY 2012 VL 227 IS 2 SI SI BP 330 EP 339 DI 10.1016/j.bbr.2011.06.025 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 907FU UT WOS:000301404000004 PM 21736899 ER PT J AU Klaus, F Hauser, T Lindholm, AK Cameron, HA Slomianka, L Lipp, HP Amrein, I AF Klaus, Fabienne Hauser, Thomas Lindholm, Anna K. Cameron, Heather A. Slomianka, Lutz Lipp, Hans-Peter Amrein, Irmgard TI Different regulation of adult hippocampal neurogenesis in Western house mice (Mus musculus domesticus) and C57BL/6 mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Exercise; Motivation; Context; Strain; Comparative; Optical fractionator ID DENTATE GYRUS; CELL-PROLIFERATION; VOLUNTARY EXERCISE; RAT HIPPOCAMPUS; GENETIC INFLUENCE; MOUSE; STRESS; PERFORMANCE; NEURONS; DOUBLECORTIN AB Adult hippocampal neurogenesis (AHN) of laboratory rodents is enhanced by physical exercise in a running wheel. However, little is known about modulation of AHN in wild-living rodent species. The finding that AHN cannot be modulated by voluntary exercise in wild wood mice suggests that AHN may be regulated differently under natural conditions than in laboratory adapted animals. In order to minimize genetic influences, we aimed to investigate the genetically closest wild-living relatives of laboratory mice. Here, C57BL/6 mice and F1 offspring of wild house mice (Mus musculus domesticus) were tested in two different running paradigms: voluntary running and running-for-food - a condition in which mice had to run for their daily allowance of food. In house mice, we found a non-significant trend towards increased numbers of proliferating cells and doublecortin-positive immature neurons in both voluntary runners and runners-for-food. Voluntary running in C57BL/6 mice resulted in a 30% increase in cell proliferation and a pronounced 70% increase in doublecortin-positive cells. C57BL/6 runners-for-food ran as much as voluntary runners, but they showed no enhancement of cell proliferation, a small increase in the number of doublecortin-positive cells and more pyknotic cells compared to controls. Taken together, these findings suggest that motivational aspects of running are critical determinants of the increased cell proliferation in C57BL/6 mice. In contrast, running has smaller and context-independent effects in house mice. The findings imply a difference in the regulation of AHN in C57BL/6 mice and their wild-derived conspecifics. (C) 2011 Elsevier B.V. All rights reserved. C1 [Klaus, Fabienne; Hauser, Thomas; Slomianka, Lutz; Lipp, Hans-Peter; Amrein, Irmgard] Univ Zurich, Inst Anat, CH-8057 Zurich, Switzerland. [Lindholm, Anna K.] Univ Zurich, Inst Evolutionary Biol & Environm Studies, CH-8057 Zurich, Switzerland. [Cameron, Heather A.] NIH, Bethesda, MD 20892 USA. RP Amrein, I (reprint author), Univ Zurich, Inst Anat, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM i.amrein@anatom.uzh.ch RI Lindholm, Anna/E-5207-2012; Slomianka, Lutz/I-3889-2012; Cameron, Heather/E-6221-2011 OI Lindholm, Anna/0000-0001-8460-9769; Cameron, Heather/0000-0002-3245-5777 FU Barbara Konig; NCCR 'Neural Plasticity and Repair'; Swiss National Science Foundation [3100A0_122589/1]; National Institutes of Health, National Institute of Mental Health [1ZIAMH002784] FX We gratefully acknowledge the technical laboratory assistance of Sarah Notzli and the support for the wild mouse experiment by Barbara Konig. This work was supported by the NCCR 'Neural Plasticity and Repair' (F.K.) and the Swiss National Science Foundation (3100A0_122589/1) (H-P.L. and I.A.) and the Intramural Program of the National Institutes of Health, National Institute of Mental Health, 1ZIAMH002784 (H.A.C.). NR 62 TC 12 Z9 12 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD FEB 14 PY 2012 VL 227 IS 2 SI SI BP 340 EP 347 DI 10.1016/j.bbr.2011.07.026 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 907FU UT WOS:000301404000005 PM 21803074 ER PT J AU Snyder, JS Cameron, HA AF Snyder, Jason S. Cameron, Heather A. TI Could adult hippocampal neurogenesis be relevant for human behavior? SO BEHAVIOURAL BRAIN RESEARCH LA English DT Review DE Adult neurogenesis; Dentate gyrus; CA3; Circuits; Human; Rodent ID GENERATED GRANULE CELLS; RAT DENTATE GYRUS; ENHANCED SYNAPTIC PLASTICITY; LONG-TERM POTENTIATION; AGE-RELATED DECLINE; PATTERN SEPARATION; OLD-AGE; AXONAL PROJECTIONS; MEMORY FORMATION; PYRAMIDAL CELLS AB Although the function of adult neurogenesis is still unclear, tools for directly studying the behavioral role of new hippocampal neurons now exist in rodents. Since similar studies are impossible to do in humans, it is important to assess whether the role of new neurons in rodents is likely to be similar to that in humans. One feature of adult neurogenesis that varies tremendously across species is the number of neurons that are generated, so a key question is whether there are enough neurons generated in humans to impact function. In this review we examine neuroanatomy and circuit function in the hippocampus to ask how many granule neurons are needed to impact hippocampal function and then discuss what is known about numbers of new neurons produced in adult rats and humans. We conclude that relatively small numbers of neurons could affect hippocampal circuits and that the magnitude of adult neurogenesis in adult rats and humans is probably larger than generally believed. Published by Elsevier B.V. C1 [Snyder, Jason S.; Cameron, Heather A.] NIMH, Unit Neuroplast, NIH, Bethesda, MD 20892 USA. RP Snyder, JS (reprint author), NIMH, Unit Neuroplast, NIH, Bldg 35-3C911,MSC3718, Bethesda, MD 20892 USA. EM snyderjason@mail.nih.gov RI Cameron, Heather/E-6221-2011; OI Cameron, Heather/0000-0002-3245-5777; Snyder, Jason/0000-0002-5509-0272 FU Intramural NIH HHS [ZIA MH002784-09] NR 121 TC 31 Z9 33 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD FEB 14 PY 2012 VL 227 IS 2 SI SI BP 384 EP 390 DI 10.1016/j.bbr.2011.06.024 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 907FU UT WOS:000301404000012 PM 21736900 ER PT J AU Agrawal, A DeSoto, J Fullagar, JL Maddali, K Rostami, S Richman, DD Pommier, Y Cohen, SM AF Agrawal, Arpita DeSoto, Jamie Fullagar, Jessica L. Maddali, Kasthuraiah Rostami, Shahrzad Richman, Douglas D. Pommier, Yves Cohen, Seth M. TI Probing chelation motifs in HIV integrase inhibitors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STRAND TRANSFER; IN-VITRO; RALTEGRAVIR; POTENT; RESISTANCE; AIDS; ELVITEGRAVIR; INFECTION; DISCOVERY; INTASOME AB A series of HIV integrase (HIV-1 IN) inhibitors were synthesized to evaluate the role of the metal-binding group (MBG) in this class of metalloenzyme inhibitors. A total of 21 different raltegravirchelator derivative (RCD) compounds were prepared that differed only in the nature of the MBG. These IN strand-transfer inhibitors (INSTIs) were evaluated in vitro in cell-free enzyme activity assays, and the in vitro results were further validated in cell culture experiments. All of the active compounds showed selective inhibition of the strand-transfer reaction over 3'-processing, suggesting a common mode of action with raltegravir. The results of the in vitro activity suggest that the nature of the MBG donor atoms, the overall MBG structure, and the specific arrangement of the MBG donor atom triad are essential for obtaining maximal HIV-1 IN inhibition. At least two compounds (RCD-4, RCD-5) containing a hydroxypyrone MBG were found to display superior strand-transfer inhibition when compared to an abbreviated analogue of raltegravir (RCD-1). By isolating and examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may provide access to a unique class of HIV-1 IN inhibitors, and may help overcome rising raltegravir resistance. C1 [Agrawal, Arpita; DeSoto, Jamie; Fullagar, Jessica L.; Cohen, Seth M.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Maddali, Kasthuraiah; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rostami, Shahrzad; Richman, Douglas D.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Rostami, Shahrzad; Richman, Douglas D.] Vet Affairs San Diego Healthcare Syst, Dept Med, La Jolla, CA 92161 USA. RP Cohen, SM (reprint author), Univ Calif San Diego, Dept Chem & Biochem, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM scohen@ucsd.edu FU National Institutes of Health [R01GM098435, AI69432, AI043638, MH62512, MH083552, AI077304, AI36214, AI047745, AI74621, AI080353]; University of California at San Diego Center for AIDS Research (CFAR); National Cancer Research, Center for Cancer Research; James B. Pendleton Charitable Trust; Intramural AIDS Targeted Program FX This work was supported by National Institutes of Health Grant R01GM098435 (to S. M. C.), a developmental grant from the University of California at San Diego Center for AIDS Research (CFAR) (S. M. C.), the intramural program of the National Cancer Research, Center for Cancer Research, and an Intramural AIDS Targeted Program (K. M. and Y.P.). The authors thank the University of California at San Diego CFAR Translational Virology Core that is supported by National Institutes of Health Grants AI69432, AI043638, MH62512, MH083552, AI077304, AI36214, AI047745, AI74621, and AI080353 and the James B. Pendleton Charitable Trust. NR 32 TC 23 Z9 23 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2012 VL 109 IS 7 BP 2251 EP 2256 DI 10.1073/pnas.1112389109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200025 PM 22308350 ER PT J AU Gowher, H Brick, K Camerini-Otero, RD Felsenfeld, G AF Gowher, Humaira Brick, Kevin Camerini-Otero, R. Daniel Felsenfeld, Gary TI Vezf1 protein binding sites genome-wide are associated with pausing of elongating RNA polymerase II SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION ELONGATION; ENHANCER BLOCKING; GENE-REGULATION; IN-VIVO; COMPLEX; MRG15; METHYLATION; MECHANISMS; SEQUENCES; PROMOTER AB The protein Vezf1 plays multiple roles important for embryonic development. In Vezf1(-/-) mouse embryonic stem (mES) cells, our earlier data showed widespread changes in gene-expression profiles, including decreased expression of the full-length active isoform of Dnmt3b methyltransferase and concomitant genome-wide reduction in DNA methylation. Here we show that in HeLaS3 cells there is a strong genome-wide correlation between Vezf1 binding and peaks of elongating Ser2-P RNA polymerase (Pol) II, reflecting Vezf1-dependent slowing of elongation. In WT mES cells, the elongating form of RNA pol II accumulates near Vezf1 binding sites within the dnmt3b gene and at several other Vezf1 sites, and this accumulation is significantly reduced at these sites in Vezf1(-/-) mES cells. Depending upon genomic location, Vezf1-mediated Pol II pausing can have different regulatory roles in transcription and splicing. We find examples of genes in which Vezf1 binding sites are located near cassette exons, and in which loss of Vezf1 leads to a change in the relative abundance of alternatively spliced messages. We further show that Vezf1 interacts with Mrg15/Mrgbp, a protein that recognizes H3K36 trimethylation, consistent with the role of histone modifications at alternatively spliced sites. C1 [Gowher, Humaira; Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Brick, Kevin; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov OI Brick, Kevin/0000-0002-9596-6400 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank the members of our laboratory for their advice and help; Dr. Nick Proudfoot for providing pMLPIII-MAZ constructs for in-vitro transcription assays; and Dr. Ann Dean for providing antibodies. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 42 TC 11 Z9 11 U1 2 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2012 VL 109 IS 7 BP 2370 EP 2375 DI 10.1073/pnas.1121538109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200046 PM 22308494 ER PT J AU Tang, GH Wang, Y Park, S Bajpayee, NS Vi, D Nagaoka, Y Birnbaumer, L Jiang, MS AF Tang, Guanghua Wang, Ying Park, Sangeun Bajpayee, Neil S. Vi, Diana Nagaoka, Yoshiko Birnbaumer, Lutz Jiang, Meisheng TI G(o)2 G protein mediates galanin inhibitory effects on insulin release from pancreatic beta cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glycemia; GTP-binding protein-coupled receptor; heterotrimeric; signal transduction; Alzheimer's disease ID SENSITIVE K+ CHANNELS; MICE LACKING; MOLECULAR CHARACTERIZATION; PRESYNAPTIC INHIBITION; ADENYLATE-CYCLASE; ISLET FUNCTION; GAMMA SUBUNIT; CLONED HUMAN; SECRETION; RECEPTOR AB The neuropeptide galanin regulates numerous physiological activities in the body, including feeding and metabolism, learning and memory, nociception and spinal reflexes, and anxiety and related behaviors. Modulation of blood glucose levels by suppressing insulin release was the first reported activity for galanin. This inhibition was mediated by one or more pertussis toxin-sensitive G proteins of the G(i/o) subfamily. However, the molecular identities of the specific G protein(s) and intracellular effectors have not been fully revealed. Recently, we demonstrated that mice lacking G(o)2, but not other members of the Gi/o protein family, secrete more insulin than controls upon glucose challenge, indicating that G(o)2 is a major transducer for the inhibitory regulation of insulin secretion. In this study, we investigated galanin signaling mechanisms in beta cells using cell biological and electrophysiological approaches. We found that islets lacking G(o)2, but not other Gi/o proteins, lose the inhibitory effect of galanin on insulin release. Potentiation of ATP-sensitive potassium (K-ATP) and inhibition of calcium currents by galanin were disrupted by anti-G(o)2 alpha antibodies. Galanin actions on K-ATP and calcium currents were completely lost in G(o)2(-/-) beta cells. Furthermore, the hyperglycemic effect of galanin is also blunted in G(o)2(-/-) mice. Our results demonstrate that G(o)2 mediates the inhibition of insulin release by galanin by regulating both K-ATP and Ca2+ channels in mice. Our findings provide insight into galanin's action in glucose homeostasis. The results may also be relevant to the understanding of galanin signaling in other biological systems, especially the central nervous system. C1 [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Tang, Guanghua; Wang, Ying; Park, Sangeun; Bajpayee, Neil S.; Vi, Diana; Nagaoka, Yoshiko; Jiang, Meisheng] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Birnbaumer, L (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov; jm@ucla.edu FU National Institutes of Health [DK069771, DK19318, Z01-ES101643] FX This work is supported by National Institutes of Health Grants DK069771 (to M.J.) and DK19318 (to L. B.) and in part by Intramural Research Program of the NIH Project Z01-ES101643 (to L. B.). NR 53 TC 26 Z9 26 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2012 VL 109 IS 7 BP 2636 EP 2641 DI 10.1073/pnas.1200100109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200092 PM 22308501 ER PT J AU Paytubi, S McMahon, SA Graham, S Liu, HT Botting, CH Makarova, KS Koonin, EV Naismith, JH White, MF AF Paytubi, Sonia McMahon, Stephen A. Graham, Shirley Liu, Huanting Botting, Catherine H. Makarova, Kira S. Koonin, Eugene V. Naismith, James H. White, Malcolm F. TI Displacement of the canonical single-stranded DNA-binding protein in the Thermoproteales SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Archaea; molecular evolution; replication protein A ID CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; SULFOLOBUS-SOLFATARICUS; STRUCTURE PREDICTION; NUCLEIC-ACIDS; A RPA; SSB; IDENTIFICATION; DEINOCOCCUS; DOMAIN AB ssDNA-binding proteins (SSBs) based on the oligonucleotide-binding fold are considered ubiquitous in nature and play a central role in many DNA transactions including replication, recombination, and repair. We demonstrate that the Thermoproteales, a clade of hyperthermophilic Crenarchaea, lack a canonical SSB. Instead, they encode a distinct ssDNA-binding protein that we term "ThermoDBP," exemplified by the protein Ttx1576 from Thermoproteus tenax. ThermoDBP binds specifically to ssDNA with low sequence specificity. The crystal structure of Ttx1576 reveals a unique fold and a mechanism for ssDNA binding, consisting of an extended cleft lined with hydrophobic phenylalanine residues and flanked by basic amino acids. Two ssDNA-binding domains are linked by a coiled-coil leucine zipper. ThermoDBP appears to have displaced the canonical SSB during the diversification of the Thermoproteales, a highly unusual example of the loss of a "ubiquitous" protein during evolution. C1 [Paytubi, Sonia; McMahon, Stephen A.; Graham, Shirley; Liu, Huanting; Botting, Catherine H.; Naismith, James H.; White, Malcolm F.] Univ St Andrews, St Andrews KY16 9ST, Fife, Scotland. [Makarova, Kira S.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Naismith, JH (reprint author), Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland. EM naismith@st-and.ac.uk; mfw2@st-and.ac.uk RI Naismith, James/H-3408-2012; White, Malcolm/A-6055-2010 OI Naismith, James/0000-0001-6744-5061; White, Malcolm/0000-0003-1543-9342 FU Wellcome Trust; Biotechnology and Biological Sciences Research Council [BB/S/B14450]; US Department of Health and Human Services FX We thank Richard Hutton for helpful discussions, Bettina Siebers for the T. tenax biomass and genome sequence, and the University of St Andrews Mass Spectrometry and Proteomics Facility, which is funded by grants from the Wellcome Trust. This work was funded by Biotechnology and Biological Sciences Research Council Grant BB/S/B14450. K. S. M. and E. V. K. are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine, National Institutes of Health). NR 53 TC 15 Z9 15 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 FEB 14 PY 2012 VL 109 IS 7 BP E398 EP E405 DI 10.1073/pnas.1113277108 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200005 PM 22106294 ER PT J AU Chaudhary, A Hilton, MB Seaman, S Haines, DC Stevenson, S Lemotte, PK Tschantz, WR Zhang, XYM Saha, S Fleming, T St Croix, B AF Chaudhary, Amit Hilton, Mary Beth Seaman, Steven Haines, Diana C. Stevenson, Susan Lemotte, Peter K. Tschantz, William R. Zhang, Xiaoyan M. Saha, Saurabh Fleming, Tony St. Croix, Brad TI TEM8/ANTXR1 Blockade Inhibits Pathological Angiogenesis and Potentiates Tumoricidal Responses against Multiple Cancer Types SO CANCER CELL LA English DT Article ID ENDOTHELIAL MARKER 8; CAPILLARY MORPHOGENESIS PROTEIN-2; GROWTH-FACTOR VEGF; TUMOR ANGIOGENESIS; ANTHRAX TOXIN; LIVER-REGENERATION; ACTIN CYTOSKELETON; RECEPTOR; CELLS; GENES AB Current antiangiogenic agents used to treat cancer only partially inhibit neovascularization and cause normal tissue toxicities, fueling the need to identify therapeutic agents that are more selective for pathological angiogenesis. Tumor endothelial marker 8 (TEM8), also known as anthrax toxin receptor 1 (ANTXR1), is a highly conserved cell-surface protein overexpressed on tumor-infiltrating vasculature. Here we show that genetic disruption of Tem8 results in impaired growth of human tumor xenografts of diverse origin including melanoma, breast, colon, and lung cancer. Furthermore, antibodies developed against the TEM8 extracellular domain blocked anthrax intoxication, inhibited tumor-induced angiogenesis, displayed broad antitumor activity, and augmented the activity of clinically approved anticancer agents without added toxicity. Thus, TEM8 targeting may allow selective inhibition of pathological angiogenesis. C1 [Chaudhary, Amit; Hilton, Mary Beth; Seaman, Steven; St. Croix, Brad] NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Hilton, Mary Beth] NCI, Basic Res Program, SAIC, NIH, Frederick, MD 21702 USA. [Haines, Diana C.] NCI, Vet Pathol Sect, Pathol Histotechnol Lab, SAIC,NIH, Frederick, MD 21702 USA. [Stevenson, Susan; Lemotte, Peter K.; Tschantz, William R.; Zhang, Xiaoyan M.; Saha, Saurabh; Fleming, Tony] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. RP St Croix, B (reprint author), NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. EM stcroix@ncifcrf.gov RI Seaman, Steven/A-2755-2013 OI Seaman, Steven/0000-0003-3349-3334 FU Novartis Institutes for BioMedical Research; NCI, NIH, Department of Health and Social Services (DHSS); NCI [HHSN261200800001E] FX We thank Drs. Bert Vogelstein, Terry Van Dyke, Lino Tessarollo, and Isaiah J. Fidler for helpful suggestions. We thank Rou-Fun Kwong for help with the initial selection and characterization of anti-TEM8 antibodies. We thank Dr. Stephen H. Leppla, National Institute of Allergy and Infectious Diseases, NIH, for the CHO, CHO/TEM8, and CHO/CMG2 cells, recombinant PA, and lethal factor, and Dr. Arthur E. Frankel for the AF334 hybridoma. This work was supported in part by a Cooperative Research and Development Agreement between the Novartis Institutes for BioMedical Research and the intramural research program of the NCI, NIH, Department of Health and Social Services (DHSS), and with federal funds from the NCI under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the DHSS nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 41 TC 35 Z9 37 U1 1 U2 19 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 FEB 14 PY 2012 VL 21 IS 2 BP 212 EP 226 DI 10.1016/j.ccr.2012.01.004 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 895DI UT WOS:000300476000012 PM 22340594 ER PT J AU Afonso, PV Parent, CA AF Afonso, Philippe V. Parent, Carole A. TI Neutrophils under Tension SO DEVELOPMENTAL CELL LA English DT Editorial Material ID EUKARYOTIC CHEMOTAXIS; LEADING-EDGE; MOTILITY; POLARITY; SIGNALS AB An article by Houk et al. (2012) in Cell provides insight into the mechanisms confining membrane protrusions to the front of migrating neutrophils. The authors rule out a role for diffusion of inhibitory signals and show that membrane tension is necessary and sufficient to restrict signals that lead to protrusions. C1 [Afonso, Philippe V.; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov RI Afonso, Philippe/D-2234-2014 OI Afonso, Philippe/0000-0002-4828-3797 FU Intramural NIH HHS [Z99 CA999999] NR 10 TC 0 Z9 0 U1 0 U2 0 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 FEB 14 PY 2012 VL 22 IS 2 BP 236 EP 238 DI 10.1016/j.devcel.2012.01.017 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 895CH UT WOS:000300473300002 PM 22340489 ER PT J AU Lazarou, M Jin, SM Kane, LA Youle, RJ AF Lazarou, Michael Jin, Seok Min Kane, Lesley A. Youle, Richard J. TI Role of PINK1 Binding to the TOM Complex and Alternate Intracellular Membranes in Recruitment and Activation of the E3 Ligase Parkin SO DEVELOPMENTAL CELL LA English DT Article ID OUTER MITOCHONDRIAL-MEMBRANE; RECESSIVE PARKINSONISM; PROTEIN-DEGRADATION; IMPORT RECEPTORS; MITOPHAGY; TRANSLOCATION; DISEASE; MUTATIONS; DYSFUNCTION; MUTANTS AB Mutations in the mitochondria! kinase PINK1 and the cytosolic E3 ligase Parkin can cause Parkinson's disease. Damaged mitochondria accumulate PINK1 on the outer membrane where, dependent on kinase activity, it recruits and activates Parkin to induce mitophagy, potentially maintaining organelle fidelity. How PINK1 recruits Parkin is unknown. We show that endogenous PINK1 forms a 700 kDa complex with the translocase of the outer membrane (TOM) selectively on depolarized mitochondria whereas PINK1 ectopically targeted to the outer membrane retains association with TOM on polarized mitochondria. Inducibly targeting PINK1 to peroxisomes or lysosomes, which lack a TOM complex, recruits Parkin and activates ubiquitin ligase activity on the respective organelles. Once there, Parkin induces organelle selective autophagy of peroxisomes but not lysosomes. We propose that the association of PINK1 with the TOM complex allows rapid reimport of PINK1 to rescue repolarized mitochondria from mitophagy, and discount mitochondrial-specific factors for Parkin translocation and activation. C1 [Lazarou, Michael; Jin, Seok Min; Kane, Lesley A.; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov OI Lazarou, Michael/0000-0003-2150-5545 FU National Institute of Neurological Disorders and Stroke FX We thank Drs. Koji Yamano and Derek Narendra for valuable suggestions, Dr. Mike Ryan for kindly providing the Tom22 antibody, Dr. Bart De Strooper for kindly sharing the PARL-/- MEFs, and Dr. Chunxin Wang for the PINK1-V5/His HeLa cells. This work is supported by the National Institute of Neurological Disorders and Stroke intramural program. NR 55 TC 162 Z9 167 U1 1 U2 34 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 FEB 14 PY 2012 VL 22 IS 2 BP 320 EP 333 DI 10.1016/j.devcel.2011.12.014 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 895CH UT WOS:000300473300012 PM 22280891 ER PT J AU Avvakumov, GV Walker, JR Xue, S Allali-Hassani, A Asinas, A Nair, UB Fang, XY Zuo, XB Wane, YX Wilkinson, KD Dhe-Paganon, S AF Avvakumov, George V. Walker, John R. Xue, Sheng Allali-Hassani, Abdellah Asinas, Abdalin Nair, Usha B. Fang, Xianyang Zuo, Xiaobing Wane, Yun-Xing Wilkinson, Keith D. Dhe-Paganon, Sirano TI Two ZnF-UBP Domains in Isopeptidase T (USP5) SO BIOCHEMISTRY LA English DT Article ID SMALL-ANGLE SCATTERING; UBIQUITIN-LIKE PROTEINS; RAY SOLUTION SCATTERING; BIOLOGICAL MACROMOLECULES; RECOGNITION; RESOLUTION; ENZYMES; SYSTEM; CHAINS AB Human ubiquitin-specific cysteine protease 5 (USP5, also known as ISOT and isopeptidase T), an 835-residue multidomain enzyme, recycles ubiquitin by hydrolyzing isopeptide bonds in a variety of unanchored polyubiquitin substrates. Activation of the enzyme's hydrolytic activity toward ubiquitin-AMC (7-amino-4-methylcoumarin), a fluorogenic substrate, by the addition of free, unanchored monoubiquitin suggested an allosteric mechanism of activation by the ZnF-UBP domain (residues 163-291), which binds the substrate's unanchored diglycine carboxyl tail. By determining the structure of full-length USP5, we discovered the existence of a cryptic ZnF-UBP domain (residues 1-156), which was tightly bound to the catalytic core and was indispensable for catalytic activity. In contrast, the previously characterized ZnF-UBP domain did not contribute directly to the active site; a paucity of interactions suggested flexibility between these two domains consistent with an ability by the enzyme to hydrolyze a variety of different polyubiquitin chain linkages. Deletion of the known ZnF-UBP domain did not significantly affect rate of hydrolysis of ubiquitin-AMC and suggested that it is likely associated mainly with substrate targeting and specificity. Together, our findings show that USP5 uses multiple ZnF-UBP domains for substrate targeting and core catalytic function. C1 [Avvakumov, George V.; Walker, John R.; Xue, Sheng; Allali-Hassani, Abdellah; Asinas, Abdalin; Nair, Usha B.; Dhe-Paganon, Sirano] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. [Avvakumov, George V.; Xue, Sheng; Asinas, Abdalin; Nair, Usha B.; Dhe-Paganon, Sirano] Univ Toronto, Dept Physiol, Toronto, ON M5G 1L7, Canada. [Fang, Xianyang; Wane, Yun-Xing] NCI, Struct Biophys Lab, Protein Nucl Acid Interact Sect, Frederick, MD 21702 USA. [Zuo, Xiaobing] Argonne Natl Lab, Xray Sci Div, Argonne, IL 60439 USA. [Wilkinson, Keith D.] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. RP Dhe-Paganon, S (reprint author), Univ Toronto, Struct Genom Consortium, 101 Coll St, Toronto, ON M5G 1L7, Canada. EM dhepaganon@utoronto.ca RI Zuo, Xiaobing/F-1469-2010; OI Zuo, Xiaobing/0000-0002-0134-4804 FU Canadian Institutes for Health Research; Canadian Foundation for Innovation; Genome Canada through the Ontario Genomics Institute; GlaxoSmithKline; Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; Merck Co.; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust; National Cancer Institute, National Institutes of Health, Department of the Human Health Service, USA; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357, 22978] FX The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. Y.-X. Wang. and X. Fang are supported by the Intramural Research funds of the National Cancer Institute, National Institutes of Health, Department of the Human Health Service, USA.; Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract DE-AC02-06CH11357 and under the Partner User Proposal PUP No. 22978. We thank Drs. S. Seifert and R. E. Winans (BESSRC, sector 12-ID) at Argonne National Laboratory for their support for synchrotron experiments. NR 32 TC 20 Z9 20 U1 4 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 14 PY 2012 VL 51 IS 6 BP 1188 EP 1198 DI 10.1021/bi200854q PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 890GK UT WOS:000300132900014 PM 22283393 ER PT J AU Naranjo-Suarez, S Carlson, BA Tsuji, PA Yoo, MH Gladyshev, VN Hatfield, DL AF Naranjo-Suarez, Salvador Carlson, Bradley A. Tsuji, Petra A. Yoo, Min-Hyuk Gladyshev, Vadim N. Hatfield, Dolph L. TI HIF-Independent Regulation of Thioredoxin Reductase 1 Contributes to the High Levels of Reactive Oxygen Species Induced by Hypoxia SO PLOS ONE LA English DT Article ID MITOCHONDRIAL RESPIRATORY-CHAIN; INDUCIBLE FACTOR; GENE-EXPRESSION; COMPLEX-III; ACTIVATION; TRANSCRIPTION; ANGIOGENESIS; ALPHA; ROS; FACTOR-1-ALPHA AB Cellular adaptation to hypoxic conditions mainly involves transcriptional changes in which hypoxia inducible factors (HIFs) play a critical role. Under hypoxic conditions, HIF protein is stabilized due to inhibition of the activity of prolyl hydroxylases (EGLNs). Because the reaction carried out by these enzymes uses oxygen as a co-substrate it is generally accepted that the hypoxic inhibition of EGLNs is due to the reduction in oxygen levels. However, several studies have reported that hypoxic generation of mitochondrial reactive oxygen species (ROS) is required for HIF stabilization. Here, we show that hypoxia downregulates thioredoxin reductase 1 (TR1) mRNA and protein levels. This hypoxic TR1 regulation is HIF independent, as HIF stabilization by EGLNs inhibitors does not affect TR1 expression and HIF deficiency does not block TR1 hypoxic-regulation, and it has an effect on TR1 function, as hypoxic conditions also reduce TR1 activity. We found that, when cultured under hypoxic conditions, TR1 deficient cells showed a larger accumulation of ROS compared to control cells, whereas TR1 over-expression was able to block the hypoxic generation of ROS. Furthermore, the changes in ROS levels observed in TR1 deficient or TR1 over-expressing cells did not affect HIF stabilization or function. These results indicate that hypoxic TR1 down-regulation is important in maintaining high levels of ROS under hypoxic conditions and that HIF stabilization and activity do not require hypoxic generation of ROS. C1 [Naranjo-Suarez, Salvador; Carlson, Bradley A.; Tsuji, Petra A.; Yoo, Min-Hyuk; Hatfield, Dolph L.] Natl Canc Inst, Lab Canc Prevent, Mol Biol Selenium Sect, Bethesda, MD 20892 USA. [Tsuji, Petra A.] Johns Hopkins Med Inst, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21205 USA. [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD USA. [Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA USA. RP Naranjo-Suarez, S (reprint author), Natl Canc Inst, Lab Canc Prevent, Mol Biol Selenium Sect, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; NIH FX This work was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to DLH) and NIH grants (to VNG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 9 Z9 10 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 13 PY 2012 VL 7 IS 2 AR e30470 DI 10.1371/journal.pone.0030470 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925BB UT WOS:000302733900009 PM 22348009 ER PT J AU Zheng, ZL Chinnasamy, N Morgan, RA AF Zheng, Zhili Chinnasamy, Nachimuthu Morgan, Richard A. TI Protein L: a novel reagent for the detection of Chimeric Antigen Receptor (CAR) expression by flow cytometry SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID CHAIN VARIABLE DOMAIN; LYMPHOCYTES; SPECIFICITY; THERAPY AB Background: There has been significant progress in the last two decades on the design of chimeric antigen receptors (CAR) for adoptive immunotherapy targeting tumor-associated antigens. Structurally CARs consist of a single chain antibody fragment directed against a tumor-associated antigen fused to an extracellular spacer and transmembrane domain followed by T cell cytoplasmic signaling moieties. Currently several clinical trials are underway using gene modified peripheral blood lymphocytes (PBL) with CARs directed against a variety of tumor associated antigens. Despite the improvements in the design of CARs and expansion of the number of target antigens, there is no universal flow cytometric method available to detect the expression of CARs on the surface of transduced lymphocytes. Methods: Currently anti-fragment antigen binding (Fab) conjugates are most widely used to determine the expression of CARs on gene-modified lymphocytes by flow cytometry. The limitations of these reagents are that many of them are not commercially available, generally they are polyclonal antibodies and often the results are inconsistent. In an effort to develop a simple universal flow cytometric method to detect the expression of CARs, we employed protein L to determine the expression of CARs on transduced lymphocytes. Protein L is an immunoglobulin (Ig)-binding protein that binds to the variable light chains (kappa chain) of Ig without interfering with antigen binding site. Protein L binds to most classes of Ig and also binds to single-chain antibody fragments (scFv) and Fab fragments. Results: We used CARs derived from both human and murine antibodies to validate this novel protein L based flow cytometric method and the results correlated well with other established methods. Activated human PBLs were transduced with retroviral vectors expressing two human antibody based CARs (anti-EGFRvIII, and anti-VEGFR2), two murine antibody derived CARs (anti-CSPG4, and anti-CD19), and two humanized mouse antibody based CARs (anti-ERBB2, and anti-PSCA). Transduced cells were stained first with biotin labeled protein L followed by phycoerythrin (PE)-conjugated streptavidin (SA) and analyzed by flow cytometry. For comparison, cells were stained in parallel with biotin conjugated goat-anti-mouse Fab or CAR specific fusion proteins. Using protein L, all CAR transduced lymphocytes exhibited specific staining pattern ranging from 40 to 80% of positive cells (compared to untransduced cells) and staining was comparable to the pattern observed with anti-Fab antibodies. Conclusion: Our data demonstrate the feasibility of employing Protein L as a general reagent for the detection of CAR expression on transduced lymphocytes by flow cytometry. C1 [Zheng, Zhili; Chinnasamy, Nachimuthu; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov NR 11 TC 20 Z9 21 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 13 PY 2012 VL 10 AR 29 DI 10.1186/1479-5876-10-29 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 917ZK UT WOS:000302218100001 PM 22330761 ER PT J AU Makarova, KS Koonin, EV Kelman, Z AF Makarova, Kira S. Koonin, Eugene V. Kelman, Zvi TI The CMG (CDC45/RecJ, MCM, GINS) complex is a conserved component of the DNA replication system in all archaea and eukaryotes SO BIOLOGY DIRECT LA English DT Article ID STRUCTURE PREDICTION; PROTEINS; HELICASE; DATABASE; GENOMES; INITIATION; MECHANISM; EVOLUTION; DOMAIN; SERVER AB Background: In eukaryotes, the CMG (CDC45, MCM, GINS) complex containing the replicative helicase MCM is a key player in DNA replication. Archaeal homologs of the eukaryotic MCM and GINS proteins have been identified but until recently no homolog of the CDC45 protein was known. Two recent developments, namely the discovery of archaeal (G) under bar INS (a) under bar ssociated (n) under bar uclease (GAN) that belongs to the RecJ family of the DHH hydrolase superfamily and the demonstration of homology between the DHH domains of CDC45 and RecJ, show that at least some Archaea possess a full complement of homologs of the CMG complex subunits. Here we present the results of in-depth phylogenomic analysis of RecJ homologs in archaea. Results: We confirm and extend the recent hypothesis that CDC45 is the eukaryotic ortholog of the bacterial and archaeal RecJ family nucleases. At least one RecJ homolog was identified in all sequenced archaeal genomes, with the single exception of Caldivirga maquilingensis. These proteins include previously unnoticed remote RecJ homologs with inactivated DHH domain in Thermoproteales. Combined with phylogenetic tree reconstruction of diverse eukaryotic, archaeal and bacterial DHH subfamilies, this analysis yields a complex scenario of RecJ family evolution in Archaea which includes independent inactivation of the nuclease domain in Crenarchaeota and Halobacteria, and loss of this domain in Methanococcales. Conclusions: The archaeal complex of a CDC45/RecJ homolog, MCM and GINS is homologous and most likely functionally analogous to the eukaryotic CMG complex, and appears to be a key component of the DNA replication machinery in all Archaea. It is inferred that the last common archaeo-eukaryotic ancestor encoded a CMG complex that contained an active nuclease of the RecJ family. The inactivated RecJ homologs in several archaeal lineages most likely are dedicated structural components of replication complexes. Reviewers: This article was reviewed by Prof. Patrick Forterre, Dr. Stephen John Aves (nominated by Dr. Purificacion Lopez-Garcia) and Prof. Martijn Huynen. For the full reviews, see the Reviewers' Comments section. C1 [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MD 20894 USA. [Kelman, Zvi] Univ Maryland, NIST, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. RP Makarova, KS (reprint author), NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MD 20894 USA. EM makarova@ncbi.nlm.nih.gov FU NSF [MCB-0815646]; US Department of Health and Human Services (National Library of Medicine) FX This work was supported in part by NSF grant MCB-0815646 (to ZK). KSM and EVK are supported by the intramural funds of the US Department of Health and Human Services (National Library of Medicine). The identification of specific commercial software products in this paper is for the purpose of specifying a protocol, and does not imply a recommendation or endorsement by the National Institute of Standards and Technology. NR 38 TC 45 Z9 47 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD FEB 13 PY 2012 VL 7 AR 7 DI 10.1186/1745-6150-7-7 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 913FE UT WOS:000301860100001 PM 22329974 ER PT J AU McDonald, CJ McDonald, MH AF McDonald, Clement J. McDonald, Michael H. TI Electronic Medical Records and Preserving Primary Care Physicians' Time SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID QUALITY C1 [McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20892 USA. [McDonald, Michael H.] Univ Wisconsin, Sch Med, Dept Surg, Madison, WI 53706 USA. RP McDonald, MH (reprint author), 3209 Dryden Dr, Madison, WI 53704 USA. EM mmcdona1@wisc.edu FU Intramural NIH HHS NR 10 TC 10 Z9 10 U1 1 U2 2 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 FEB 13 PY 2012 VL 172 IS 3 BP 285 EP 287 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 891NL UT WOS:000300223800026 PM 22332168 ER PT J AU Baumann, M Giunta, C Krabichler, B Ruschendorf, F Zoppi, N Colombi, M Bittner, RE Quijano-Roy, S Muntoni, F Cirak, S Schreiber, G Zou, YQ Hu, Y Romero, NB Carlier, RY Amberger, A Deutschmann, A Straub, V Rohrbach, M Steinmann, B Rostasy, K Karall, D Bonnemann, CG Zschocke, J Fauth, C AF Baumann, Matthias Giunta, Cecilia Krabichler, Birgit Rueschendorf, Franz Zoppi, Nicoletta Colombi, Marina Bittner, Reginald E. Quijano-Roy, Susana Muntoni, Francesco Cirak, Sebahattin Schreiber, Gudrun Zou, Yaqun Hu, Ying Romero, Norma Beatriz Carlier, Robert Yves Amberger, Albert Deutschmann, Andrea Straub, Volker Rohrbach, Marianne Steinmann, Beat Rostasy, Kevin Karall, Daniela Boennemann, Carsten G. Zschocke, Johannes Fauth, Christine TI Mutations in FKBP14 Cause a Variant of Ehlers-Danlos Syndrome with Progressive Kyphoscoliosis, Myopathy, and Hearing Loss SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CONGENITAL MUSCULAR-DYSTROPHY; THUMB-CLUBFOOT SYNDROME; SYNDROME TYPE-VI; SYNDROME EDS; OSTEOGENESIS IMPERFECTA; EXTRACELLULAR-MATRIX; LINKAGE ANALYSIS; BRUCK SYNDROME; CROSS-LINKS; MUSCLE AB We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPlases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment. C1 [Baumann, Matthias; Rostasy, Kevin; Karall, Daniela] Innsbruck Med Univ, Dept Paediat Neonatol Paediat Neurol & Inherited, A-6020 Innsbruck, Austria. [Baumann, Matthias; Rohrbach, Marianne; Steinmann, Beat] Univ Childrens Hosp, Div Metab, Connect Tissue Unit, CH-8032 Zurich, Switzerland. [Giunta, Cecilia; Rohrbach, Marianne; Steinmann, Beat] Univ Childrens Hosp, CRC, CH-8032 Zurich, Switzerland. [Krabichler, Birgit; Amberger, Albert; Deutschmann, Andrea; Karall, Daniela; Zschocke, Johannes; Fauth, Christine] Innsbruck Med Univ, Div Human Genet, A-6020 Innsbruck, Austria. [Rueschendorf, Franz] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Zoppi, Nicoletta; Colombi, Marina] Univ Brescia, Dept Biomed Sci & Biotechnol, Div Biol & Genet, I-25123 Brescia, Italy. [Bittner, Reginald E.] Med Univ Vienna, Ctr Anat & Cell Biol, Dept Neuromuscular Res, A-1090 Vienna, Austria. [Quijano-Roy, Susana] UVSQ, Ctr Natl Reference Malad Neuromusculaires Garches, Serv Pediat, Hop Univ Raymond Poincare,APHP, F-92380 Garches, France. [Muntoni, Francesco; Cirak, Sebahattin] Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England. [Schreiber, Gudrun] Klinikum Kassel, Dept Neuropaediat, D-34125 Kassel, Germany. [Zou, Yaqun; Hu, Ying; Boennemann, Carsten G.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Romero, Norma Beatriz] Grp Hosp Univ Pitie Salpetriere, Inst Myol, Unite Morphol Neuromusculaire, F-75013 Paris, France. [Carlier, Robert Yves] Univ Paris Ile De France, Hop Raymond Poincare, AP HP, Dept Radiol, F-92380 Garches, France. [Straub, Volker] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. RP Baumann, M (reprint author), Innsbruck Med Univ, Dept Paediat Neonatol Paediat Neurol & Inherited, A-6020 Innsbruck, Austria. EM matthias.baumann@uki.at; christine.fauth@i-med.ac.at OI Rohrbach, Marianne/0000-0002-4013-6012; Colombi, Marina/0000-0002-3105-5990; Giunta, Cecilia/0000-0002-9313-8257 FU Gottfried und Julia Bangerter-Rhyner Stiftung; Muscular Dystrophy Campaign Centre; Great Ormond Street Hospital Children's Charity FX We express our gratitude to all families who participated in this study. We thank Marius Kraenzlin for urinary pyridinoline analysis, Ingrid Hausser-Siller and Patricie Paesold-Burda for helpful discussions, Angelika Schwarze for skilful technical assistance, Rudolf Funke for providing photographs of individual P6, Beril Talim, Haluk Topaloglu, and Julia Wanschitz for providing muscle biopsy data, and Dan Lipsker for skin examination results in individual P4. This work was supported by a grant from the Gottfried und Julia Bangerter-Rhyner Stiftung to C.G. and M.R. The support of the Muscular Dystrophy Campaign Centre grant to the Dubowitz Neuromuscular Centre is gratefully acknowledged. F.M. is supported by the Great Ormond Street Hospital Children's Charity. NR 50 TC 42 Z9 43 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 10 PY 2012 VL 90 IS 2 BP 201 EP 216 DI 10.1016/j.ajhg.2011.12.004 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 898KV UT WOS:000300742200002 PM 22265013 ER PT J AU Forsberg, LA Rasi, C Razzaghian, HR Pakalapati, G Waite, L Thilbeault, KS Ronowicz, A Wineinger, NE Tiwari, HK Boomsma, D Westerman, MP Harris, JR Lyle, R Essand, M Eriksson, F Assimes, TL Iribarren, C Strachan, E O'Hanlon, TP Rider, LG Miller, FW Giedraitis, V Lannfelt, L Ingelsson, M Piotrowski, A Pedersen, NL Absher, D Dumanski, JP AF Forsberg, Lars A. Rasi, Chiara Razzaghian, Hamid R. Pakalapati, Geeta Waite, Lindsay Thilbeault, Krista Stanton Ronowicz, Anna Wineinger, Nathan E. Tiwari, Hemant K. Boomsma, Dorret Westerman, Maxwell P. Harris, Jennifer R. Lyle, Robert Essand, Magnus Eriksson, Fredrik Assimes, Themistocles L. Iribarren, Carlos Strachan, Eric O'Hanlon, Terrance P. Rider, Lisa G. Miller, Frederick W. Giedraitis, Vilmantas Lannfelt, Lars Ingelsson, Martin Piotrowski, Arkadiusz Pedersen, Nancy L. Absher, Devin Dumanski, Jan P. TI Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COPY-NUMBER-VARIATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; CORONARY-ARTERY-DISEASE; MYELODYSPLASTIC SYNDROMES; MONOZYGOTIC TWINS; MITOCHONDRIAL-DNA; HUMAN TISSUES; MOSAICISM; REARRANGEMENTS; ANEUPLOIDIES AB Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects >= 60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were 55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence. C1 [Forsberg, Lars A.; Rasi, Chiara; Razzaghian, Hamid R.; Pakalapati, Geeta; Essand, Magnus; Eriksson, Fredrik; Dumanski, Jan P.] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75185 Uppsala, Sweden. [Waite, Lindsay; Thilbeault, Krista Stanton; Absher, Devin] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Ronowicz, Anna; Piotrowski, Arkadiusz] Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80416 Gdansk, Poland. [Wineinger, Nathan E.; Tiwari, Hemant K.] Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. [Boomsma, Dorret] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Westerman, Maxwell P.] Mt Sinai Hosp, Med Ctr, Chicago, IL 60608 USA. [Harris, Jennifer R.] Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, N-0403 Oslo, Norway. [Lyle, Robert] Oslo Univ Hosp, Dept Med Genet, N-0407 Oslo, Norway. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Iribarren, Carlos] Kaiser Fdn Res Inst, Oakland, CA 94612 USA. [Strachan, Eric] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [Strachan, Eric] Univ Washington, Twin Registry, Seattle, WA 98104 USA. [O'Hanlon, Terrance P.; Rider, Lisa G.; Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Giedraitis, Vilmantas; Lannfelt, Lars; Ingelsson, Martin] Uppsala Univ, Dept Publ Hlth & Caring Sci, Div Mol Geriatr, S-75185 Uppsala, Sweden. [Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. RP Dumanski, JP (reprint author), Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75185 Uppsala, Sweden. EM jan.dumanski@igp.uu.se RI Piotrowski, Arkadiusz/A-5484-2010; OI Piotrowski, Arkadiusz/0000-0002-0823-0607; Eriksson, Fredrik/0000-0001-9548-3276; Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Ellison Medical Foundation; Swedish Cancer Society; Swedish Research Council [80576801, 70374401]; Science for Life Laboratory-Uppsala; Foundation for Polish Science [FOCUS 4/2008, FOCUS 4/08/2009]; Uppsala University, Uppsala University Hospital FX We thank Lars Feuk, Brigitte Schlegelberger, Jacek Witkowski, Greg Cooper, Richard Rosenquist Brandell, Eva Hellstrom-Lindberg, Chris Gunther, and Eva Tiensuu Janson for critical review of the manuscript and Larry Mansouri and Juan R. Gonzalez for methodological advice. This study was sponsored by grants from the Ellison Medical Foundation (J.P.D. and D.A.) and from the Swedish Cancer Society, the Swedish Research Council, and the Science for Life Laboratory-Uppsala (J.P.D.). A.P. acknowledges FOCUS 4/2008 and FOCUS 4/08/2009 grants from the Foundation for Polish Science. Genotyping was performed in part by the SNP&SEQ Technology Platform, which is supported by Uppsala University, Uppsala University Hospital, the Science for Life Laboratory-Uppsala, and the Swedish Research Council (contracts 80576801 and 70374401). NR 43 TC 74 Z9 74 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 10 PY 2012 VL 90 IS 2 BP 217 EP 228 DI 10.1016/j.ajhg.2011.12.009 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 898KV UT WOS:000300742200003 PM 22305530 ER PT J AU Numata, S Ye, TZ Hyde, TM Guitart-Navarro, X Tao, R Wininger, M Colantuoni, C Weinberger, DR Kleinman, JE Lipska, BK AF Numata, Shusuke Ye, Tianzhang Hyde, Thomas M. Guitart-Navarro, Xavier Tao, Ran Wininger, Michael Colantuoni, Carlo Weinberger, Daniel R. Kleinman, Joel E. Lipska, Barbara K. TI DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HUMAN BRAIN; MONOZYGOTIC TWINS; CPG ISLAND; EPIGENETIC DIFFERENCES; BIPOLAR DISORDER; GENE-EXPRESSION; SCHIZOPHRENIA; GENOME; HYPERMETHYLATION; AGE AB The human prefrontal cortex (PFC), a mastermind of the brain, is one of the last brain regions to mature. To investigate the role of epigenetics in the development of PFC, we examined DNA methylation in similar to 14,500 genes at similar to 27,000 CpG loci focused on 5' promoter regions in 108 subjects range in age from fetal to elderly. DNA methylation in the PFC shows unique temporal patterns across life. The fastest changes occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. At the genome level, the transition from fetal to postnatal life is typified by a reversal of direction, from demethylation prenatally to increased methylation postnatally. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes, including genes involved in brain development and in de novo DNA methylation. Our results indicate that promoter DNA methylation in the human PFC is a highly dynamic process modified by genetic variance and regulating gene transcription. Additional discovery is made possible with a stand-alone application, BrainCloudMethyl. C1 [Numata, Shusuke; Ye, Tianzhang; Hyde, Thomas M.; Tao, Ran; Wininger, Michael; Colantuoni, Carlo; Weinberger, Daniel R.; Kleinman, Joel E.; Lipska, Barbara K.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Ye, Tianzhang; Hyde, Thomas M.; Colantuoni, Carlo; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Guitart-Navarro, Xavier] NIDA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Colantuoni, Carlo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. EM lipskab@mail.nih.gov RI Tao, Ran/C-2662-2013; Tao, Ran/L-3460-2014; Lipska, Barbara/E-4569-2017 FU National Institute of Mental Health at the National Institutes of Health FX We thank Liqin Wang and Vesna Imamovic for their technical expertise; Mary Herman for her contribution to the Clinical Brain Disorders Branch/National Institute of Mental Health brain collection; Abdel Elkahloun at National Human Genome Research Institute Microarray Core Facility for scanning data; and Ronald Zielke, Robert Johnson, and Robert Vigorito at the NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland School of Medicine, for their collection of brains. We also thank the families of the deceased for the donations of brain tissue and their time and effort devoted to the consent process and interviews. This research was supported by the Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health. NR 52 TC 160 Z9 162 U1 3 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 10 PY 2012 VL 90 IS 2 BP 260 EP 272 DI 10.1016/j.ajhg.2011.12.020 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 898KV UT WOS:000300742200006 PM 22305529 ER PT J AU Johnston, JJ Gropman, AL Sapp, JC Teer, JK Martin, JM Liu, CF Yuan, X Ye, ZH Cheng, LZ Brodsky, RA Biesecker, LG AF Johnston, Jennifer J. Gropman, Andrea L. Sapp, Julie C. Teer, Jamie K. Martin, Jodie M. Liu, Cyndi F. Yuan, Xuan Ye, Zhaohui Cheng, Linzhao Brodsky, Robert A. Biesecker, Leslie G. TI The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MENTAL-RETARDATION; STEM-CELLS; A GENE; GLYCOSYLPHOSPHATIDYLINOSITOL; PROTEINS; INACTIVATION; DEFICIENCY; ANEMIA; EXONS; PNH AB Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PICA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PICA mutation, c.1234C>T, which predicts p.Arg412*. This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412* PICA has residual function. Transfection of a mutant p.Arg412* PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412*) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family. C1 [Johnston, Jennifer J.; Sapp, Julie C.; Teer, Jamie K.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Gropman, Andrea L.; Martin, Jodie M.] Childrens Natl Med Ctr, Div Neurol, Washington, DC 20010 USA. [Liu, Cyndi F.; Yuan, Xuan; Ye, Zhaohui; Cheng, Linzhao; Brodsky, Robert A.] Johns Hopkins Univ, Dept Internal Med, Div Hematol, Baltimore, MD USA. [Biesecker, Leslie G.] NHGRI, NIH, Intramural Sequencing Ctr, Rockville, MD USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov OI Ye, Zhaohui/0000-0001-5272-9168 FU National Human Genome Research Institute, National Institutes of Health FX The authors thank M. Abubakar, G. Bowles-Johnson, S. Covington, C. Gomez, A. Hutchins, F. Porter, M. Raygada, O. Rennert, and other clinicians at Georgetown University Hospital, Children's National Medical Center, and Johns Hopkins University for clinical investigations of this family. J. Hanover assisted with attempts to revive the frozen fibroblasts of patient IV-4. Julia Fekecs assisted with graphics. Most importantly, we gratefully acknowledge the family and dedicate this work to the memory of Walker P. Carter, Jr and Michael H. Carter III. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 24 TC 54 Z9 55 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 10 PY 2012 VL 90 IS 2 BP 295 EP 300 DI 10.1016/j.ajhg.2011.11.031 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 898KV UT WOS:000300742200010 PM 22305531 ER PT J AU Knight, M Berg, C Brocklehurst, P Kramer, M Lewis, G Oats, J Roberts, CL Spong, C Sullivan, E van Roosmalen, J Zwart, J AF Knight, Marian Berg, Cynthia Brocklehurst, Peter Kramer, Michael Lewis, Gwyneth Oats, Jeremy Roberts, Christine L. Spong, Catherine Sullivan, Elizabeth van Roosmalen, Jos Zwart, Joost TI Amniotic fluid embolism incidence, risk factors and outcomes: a review and recommendations SO BMC PREGNANCY AND CHILDBIRTH LA English DT Review ID SEVERE MATERNAL MORBIDITY; POPULATION-BASED COHORT; NETHERLANDS; PREGNANCY; DELIVERY AB Background: Amniotic fluid embolism (AFE) is a rare but severe complication of pregnancy. A recent systematic review highlighted apparent differences in the incidence, with studies estimating the incidence of AFE to be more than three times higher in North America than Europe. The aim of this study was to examine population-based regional or national data from five high-resource countries in order to investigate incidence, risk factors and outcomes of AFE and to investigate whether any variation identified could be ascribed to methodological differences between the studies. Methods: We reviewed available data sources on the incidence of AFE in Australia, Canada, the Netherlands, the United Kingdom and the USA. Where information was available, the risk factors and outcomes of AFE were examined. Results: The reported incidence of AFE ranged from 1.9 cases per 100 000 maternities (UK) to 6.1 per 100 000 maternities (Australia). There was a clear distinction between rates estimated using different methodologies. The lowest estimated incidence rates were obtained through validated case identification (range 1.9-2.5 cases per 100 000 maternities); rates obtained from retrospective analysis of population discharge databases were significantly higher (range 5.5-6.1 per 100 000 admissions with delivery diagnosis). Older maternal age and induction of labour were consistently associated with AFE. Conclusions: Recommendation 1: Comparisons of AFE incidence estimates should be restricted to studies using similar methodology. The recommended approaches would be either population-based database studies using additional criteria to exclude false positive cases, or tailored data collection using existing specific population-based systems. Recommendation 2: Comparisons of AFE incidence between and within countries would be facilitated by development of an agreed case definition and an agreed set of criteria to minimise inclusion of false positive cases for database studies. Recommendation 3: Groups conducting detailed population-based studies on AFE should develop an agreed strategy to allow combined analysis of data obtained using consistent methodologies in order to identify potentially modifiable risk factors. Recommendation 4: Future specific studies on AFE should aim to collect information on management and longer-term outcomes for both mothers and infants in order to guide best practice, counselling and service planning. C1 [Knight, Marian; Brocklehurst, Peter; Lewis, Gwyneth] Univ Oxford, Natl Perinatal Epidemiol Unit, Oxford, England. [Berg, Cynthia] Ctr Dis Control & Prevent CDC, Div Reprod Hlth, Atlanta, GA USA. [Kramer, Michael] McGill Univ, Dept Pediat, Fac Med, Montreal, PQ H3A 2T5, Canada. [Kramer, Michael] McGill Univ, Dept Epidemiol & Biostat, Fac Med, Montreal, PQ, Canada. [Oats, Jeremy] Consultat Council Obstet & Paediat Mortal & Morbi, Melbourne, Vic, Australia. [Roberts, Christine L.] Univ Sydney, Royal N Shore Hosp, Kolling Inst Med Res, Sydney, NSW 2006, Australia. [Spong, Catherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Rockville, MD USA. [Sullivan, Elizabeth] Univ New S Wales, Perinatal & Reprod Epidemiol Res Unit, Sch Womens & Childrens Hlth, Sydney, NSW, Australia. [van Roosmalen, Jos; Zwart, Joost] Leiden Univ, Med Ctr, Dept Obstet, Leiden, Netherlands. RP Knight, M (reprint author), Univ Oxford, Natl Perinatal Epidemiol Unit, Oxford, England. EM marian.knight@npeu.ox.ac.uk RI Knight, Marian/B-6225-2009; OI Knight, Marian/0000-0002-1984-4575; Sullivan, Elizabeth/0000-0002-8718-2753 FU National Perinatal Epidemiology Unit, University of Oxford; National Institute for Health Research National Coordinating Centre for Research Capacity Development; National Institute for Health Research (NIHR) [RP-PG-0608-10038]; NHMRC; McKern Travelling Research Scholarship FX We would like to acknowledge the assistance of Ms Kate Fitzpatrick, National Perinatal Epidemiology Unit, University of Oxford in preparing UK figures. The workshop was funded by the National Perinatal Epidemiology Unit, University of Oxford.; MK was supported by a personal fellowship from the National Institute for Health Research National Coordinating Centre for Research Capacity Development and this paper presents independent research commissioned by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Programme Grant RP-PG-0608-10038). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.; CR was supported by a NHMRC Senior Research Fellowship and a McKern Travelling Research Scholarship. NR 19 TC 30 Z9 32 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD FEB 10 PY 2012 VL 12 AR 7 DI 10.1186/1471-2393-12-7 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 908LP UT WOS:000301492200001 PM 22325370 ER PT J AU Basselin, M Ramadan, E Rapoport, SI AF Basselin, Mireille Ramadan, Epolia Rapoport, Stanley I. TI Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans SO BRAIN RESEARCH BULLETIN LA English DT Review DE Arachidonic acid; Bipolar disorder; Brain imaging; Docosahexaenoic acid; Mood stabilizers; Neuroinflammation ID CYTOSOLIC PHOSPHOLIPASE A(2); POSITRON-EMISSION-TOMOGRAPHY; RAT FRONTAL-CORTEX; CEREBRAL GLUCOSE-UTILIZATION; POLYUNSATURATED FATTY-ACIDS; MILD COGNITIVE IMPAIRMENT; DNA-BINDING ACTIVITY; NICOTINIC ACETYLCHOLINE-RECEPTORS; POSTMORTEM ORBITOFRONTAL CORTEX; TRANSPORTER KNOCKOUT MICE AB The polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), important second messengers in brain, are released from membrane phospholipid following receptor-mediated activation of specific phospholipase A(2) (PLA(2)) enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that their incorporation rates equal their rates of metabolic consumption by brain. Thus, quantitative imaging of unesterified plasma AA or DHA incorporation into brain can be used as a biomarker of brain PUFA metabolism and neurotransmission. We have employed our method to image and quantify effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M-1,M-3,M-5, serotonergic 5-HT2A/2C, dopaminergic D-2-like (D-2, D-3, D-4) or glutamatergic N-methyl-D-aspartic acid (NMDA) receptors, and effects of inhibition of acetylcholinesterase, of selective serotonin and dopamine reuptake transporter inhibitors, of neuroinflammation (HIV-1 and lipopolysaccharide) and excitotoxicity, and in genetically modified rodents. The method has been extended for the use with positron emission tomography (PET), and can be employed to determine how human brain AA/DHA signaling and consumption are influenced by diet, aging, disease and genetics. Published by Elsevier Inc. C1 [Basselin, Mireille; Ramadan, Epolia; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Ramadan, E (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM ramadanir@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 276 TC 16 Z9 17 U1 4 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 EI 1873-2747 J9 BRAIN RES BULL JI Brain Res. Bull. PD FEB 10 PY 2012 VL 87 IS 2-3 BP 154 EP 171 DI 10.1016/j.brainresbull.2011.12.001 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 909FP UT WOS:000301548300003 PM 22178644 ER PT J AU Venkatesan, M Amaratunga, C Campino, S Auburn, S Koch, O Lim, P Uk, S Socheat, D Kwiatkowski, DP Fairhurst, RM Plowe, CV AF Venkatesan, Meera Amaratunga, Chanaki Campino, Susana Auburn, Sarah Koch, Oliver Lim, Pharath Uk, Sambunny Socheat, Duong Kwiatkowski, Dominic P. Fairhurst, Rick M. Plowe, Christopher V. TI Using CF11 cellulose columns to inexpensively and effectively remove human DNA from Plasmodium falciparum-infected whole blood samples SO MALARIA JOURNAL LA English DT Article DE CF11; Cellulose powder; Leukocyte depletion; Plasmodium falciparum; Malaria; Next-generation sequencing ID HYBRID SELECTION; RESISTANCE AB Background: Genome and transcriptome studies of Plasmodium nucleic acids obtained from parasitized whole blood are greatly improved by depletion of human DNA or enrichment of parasite DNA prior to next-generation sequencing and microarray hybridization. The most effective method currently used is a two-step procedure to deplete leukocytes: centrifugation using density gradient media followed by filtration through expensive, commercially available columns. This method is not easily implemented in field studies that collect hundreds of samples and simultaneously process samples for multiple laboratory analyses. Inexpensive syringes, hand-packed with CF11 cellulose powder, were recently shown to improve ex vivo cultivation of Plasmodium vivax obtained from parasitized whole blood. This study was undertaken to determine whether CF11 columns could be adapted to isolate Plasmodium falciparum DNA from parasitized whole blood and achieve current quantity and purity requirements for Illumina sequencing. Methods: The CF11 procedure was compared with the current two-step standard of leukocyte depletion using parasitized red blood cells cultured in vitro and parasitized blood obtained ex vivo from Cambodian patients with malaria. Procedural variations in centrifugation and column size were tested, along with a range of blood volumes and parasite densities. Results: CF11 filtration reliably produces 500 nanograms of DNA with less than 50% human DNA contamination, which is comparable to that obtained by the two-step method and falls within the current quality control requirements for Illumina sequencing. In addition, a centrifuge-free version of the CF11 filtration method to isolate P. falciparum DNA at remote and minimally equipped field sites in malaria-endemic areas was validated. Conclusions: CF11 filtration is a cost-effective, scalable, one-step approach to remove human DNA from P. falciparum-infected whole blood samples. C1 [Venkatesan, Meera; Plowe, Christopher V.] Univ Maryland, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21201 USA. [Venkatesan, Meera; Plowe, Christopher V.] Univ Maryland, Sch Med, WorldWide Antimalarial Resistance Network Mol Mod, Baltimore, MD 21201 USA. [Amaratunga, Chanaki; Lim, Pharath; Fairhurst, Rick M.] NIAID, NIH, Bethesda, MD 20892 USA. [Campino, Susana; Auburn, Sarah; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Cambridge, England. [Auburn, Sarah] Charles Darwin Univ, Menzies Sch Hlth Res, Global Hlth Div, Darwin, NT 0909, Australia. [Koch, Oliver; Kwiatkowski, Dominic P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Lim, Pharath; Uk, Sambunny; Socheat, Duong] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Plowe, Christopher V.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21201 USA. EM cplowe@medicine.umaryland.edu RI Koch, Oliver/A-9480-2016; OI Auburn, Sarah/0000-0002-4638-536X; Kwiatkowski, Dominic/0000-0002-5023-0176 FU WorldWide Antimalarial Resistance Network; National Institute of Allergy and Infectious Diseases of the US National Institutes of Health; Howard Hughes Medical Institute; Wellcome Trust [098051] FX The authors thank the patients from the study populations in Pursat and Ratanakiri, Cambodia, as well as the site staff members who collected and processed blood samples. The authors are grateful to Suon Seila and Sreng Sokunthea at the National Malaria Centre in Phnom Penh for their managerial and technical assistance in Pursat, Cambodia. The authors also thank Matthew Adams and Malathi Vadla at the University of Maryland, and Daniel Alcock and Eleanor Drury at the Wellcome Trust Sanger Institute, for their technical assistance in conducting laboratory experiments. This research was supported by the WorldWide Antimalarial Resistance Network, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health, the Howard Hughes Medical Institute, and the Wellcome Trust [098051]. NR 13 TC 25 Z9 25 U1 0 U2 5 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 FEB 10 PY 2012 VL 11 AR 41 DI 10.1186/1475-2875-11-41 PG 7 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 909XK UT WOS:000301600200001 PM 22321373 ER PT J AU Johnson, B Zhang, K Gay, M Neuberger, T Horovitz, S Hallett, M Sebastianelli, W Slobounov, S AF Johnson, Brian Zhang, Kai Gay, Michael Neuberger, Thomas Horovitz, Silvina Hallett, Mark Sebastianelli, Wayne Slobounov, Semyon TI Metabolic alterations in corpus callosum may compromise brain functional connectivity in MTBI patients: An H-1-MRS study SO NEUROSCIENCE LETTERS LA English DT Article DE MTBI; Subacute; H-1-MRS; Functional connectivity ID MAGNETIC-RESONANCE-SPECTROSCOPY; DEFAULT MODE NETWORK; STRUCTURAL CONNECTIVITY; AXONAL INJURY; MILD; PERFORMANCE; CONCUSSION; RECOVERY; DEFICITS AB After clinical resolution of signs and symptoms of mild traumatic brain injury (MTBI) it is still not clear if there are residual abnormalities of structural or functional brain networks. We have previously documented disrupted interhemispheric functional connectivity in 'asymptomatic' concussed individuals during the sub-acute phase of injury. Testing of 15 normal volunteers (NV) and 15 subacute MTBI subjects was performed within 24 h of clinical symptoms resolution and medical clearance for the first stage of aerobic activity. In this MRS study we report: (a) both in the genu and splenium of the corpus callosum NAA/Cho and NAA/Cr ratios were significantly (p < 0.05) lower in MTBI subjects shortly after the injury compared to NVs, and (b) the metabolic ratio NAA/Cho in the splenium significantly correlated with the magnitude of inter-hippocampal functional connectivity in normal volunteers, but not in MTBI. This novel finding supports our hypothesis that the functional disruption of interhemispheric brain networks in MTBI subjects results from compromised metabolic integrity of the corpus callosum and that this persists despite apparent clinical return to baseline. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Johnson, Brian; Zhang, Kai; Gay, Michael; Slobounov, Semyon] Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. [Johnson, Brian; Neuberger, Thomas] Penn State Univ, Dept Bioengn, University Pk, PA 16802 USA. [Sebastianelli, Wayne; Slobounov, Semyon] Penn State Univ, HMC, Dept Orthoped & Med Rehabil, University Pk, PA 16802 USA. [Horovitz, Silvina; Hallett, Mark; Slobounov, Semyon] NINDS, NIH, Bethesda, MD 20892 USA. RP Slobounov, S (reprint author), Penn State Univ, Dept Kinesiol, 19 Recreat Bldg, University Pk, PA 16802 USA. EM sms18@psu.edu FU National Institutes of Health [RO1 NS056227-01A2] FX This work was supported by National Institutes of Health Grant RO1 NS056227-01A2 'Identification of Athletes at Risk for Traumatic Brain Injury'. NR 33 TC 17 Z9 17 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 10 PY 2012 VL 509 IS 1 BP 5 EP 8 DI 10.1016/j.neulet.2011.11.013 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 903DV UT WOS:000301097100002 PM 22108503 ER PT J AU Finkel, T AF Finkel, Toren TI Signal Transduction by Mitochondrial Oxidants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID HEMATOPOIETIC STEM-CELLS; HYPOXIA-INDUCIBLE FACTOR; OXIDATIVE STRESS; INFLAMMASOME ACTIVATION; RESPIRATORY-CHAIN; ROS PRODUCTION; DJ-1; METABOLISM; AUTOPHAGY; KINASE AB The production of mitochondrial reactive oxygen species occurs as a consequence of aerobic metabolism. Mitochondrial oxidants are increasingly viewed less as byproducts of metabolism and more as important signaling molecules. Here, I review several notable examples, including the cellular response to hypoxia, aspects of innate immunity, the regulation of autophagy, and stem cell self-renewal capacity, where evidence suggests an important regulatory role for mitochondrial oxidants. C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU National Institutes of Health; Ellison Medical Foundation FX This work was supported, in whole or in part, by National Institutes of Health intramural funds. This work was also supported by the Ellison Medical Foundation. This is the sixth article in the Thematic Minireview Series on Redox Sensing and Regulation. NR 55 TC 111 Z9 114 U1 4 U2 26 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 10 PY 2012 VL 287 IS 7 BP 4434 EP 4440 DI 10.1074/jbc.R111.271999 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500007 PM 21832045 ER PT J AU Seabold, GK Wang, PY Petralia, RS Chang, K Zhou, A McDermott, MI Wang, YX Milgram, SL Wenthold, RJ AF Seabold, Gail K. Wang, Philip Y. Petralia, Ronald S. Chang, Kai Zhou, Arthur McDermott, Mark I. Wang, Ya-Xian Milgram, Sharon L. Wenthold, Robert J. TI Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ER RETENTION SIGNAL; AUTISM SPECTRUM DISORDERS; NMDA RECEPTOR; MENTAL-RETARDATION; CELL-SURFACE; DENDRITIC SPINES; PLASMA-MEMBRANE; TRANSMEMBRANE PROTEINS; EXPRESSION; FAMILY AB Synaptic adhesion-like molecules (SALMs) are a family of cell adhesion molecules involved in neurite outgrowth and synapse formation. Of the five family members, only SALM1, -2, and -3 contain a cytoplasmic C-terminal PDZ-binding motif. We have found that SALM1 is unique among the SALMs because deletion of its PDZ-binding motif (SALM1 Delta PDZ) blocks its surface expression in heterologous cells. When expressed in hippocampal neurons, SALM1 Delta PDZ had decreased surface expression in dendrites and the cell soma but not in axons, suggesting that the PDZ-binding domain may influence cellular trafficking of SALMs to specific neuronal locations. Endoglycosidase H digestion assays indicated that SALM1 Delta PDZ is retained in the endoplasmic reticulum (ER) in heterologous cells. However, when the entire C-terminal tail of SALM1 was deleted, SALM1 was detected on the cell surface. Using serial deletions, we identified a region of SALM1 that contains a putative dileucine ER retention motif, which is not present in the other SALMs. Mutation of this DXXXLL motif allowed SALM1 to leave the ER and enhanced its surface expression in heterologous cells and neurons. An increase in the number of protrusions at the dendrites and cell body was observed when this SALM1 mutant was expressed in hippocampal neurons. With electron microscopy, these protrusions appeared to be irregular, enlarged spines and filopodia. Thus, enrichment of SALM1 on the cell surface affects dendritic arborization, and intracellular motifs regulate its dendritic versus axonal localization. C1 [Seabold, Gail K.; Wang, Philip Y.; Petralia, Ronald S.; Chang, Kai; Zhou, Arthur; Wang, Ya-Xian; Wenthold, Robert J.] NIDCD, Neurochem Lab, Bethesda, MD 20892 USA. [Seabold, Gail K.; McDermott, Mark I.; Milgram, Sharon L.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Seabold, GK (reprint author), NIDCD, NIH, 50 S Dr,Bldg 50,Rm 4144, Bethesda, MD 20892 USA. EM Gail.Seabold@nih.gov FU National Institutes of Health, NIDCD FX This work was supported, in whole or in part, by the National Institutes of Health, NIDCD, Intramural Research Program. NR 73 TC 6 Z9 7 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 10 PY 2012 VL 287 IS 7 BP 4470 EP 4484 DI 10.1074/jbc.M111.279661 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500011 PM 22174418 ER PT J AU Tribouillard-Tanvier, D Carroll, JA Moore, RA Striebel, JF Chesebro, B AF Tribouillard-Tanvier, Deborah Carroll, James A. Moore, Roger A. Striebel, James F. Chesebro, Bruce TI Role of Cyclophilin A from Brains of Prion-infected Mice in Stimulation of Cytokine Release by Microglia and Astroglia in Vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; SPONGIFORM ENCEPHALOPATHIES; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; CREUTZFELDT-JAKOB; MASS-SPECTROMETRY; OXIDATIVE STRESS; PROTEIN; SCRAPIE; DISEASE AB Prion diseases or transmissible spongiform encephalopathy diseases are typically characterized by deposition of abnormally folded partially protease-resistant host-derived prion protein (PrPres), which is associated with activated glia and increased release of cytokines. This neuroinflammatory response may play a role in transmissible spongiform encephalopathy pathogenesis. We previously reported that brain homogenates from prion-infected mice induced cytokine protein release in primary astroglial and microglial cell cultures. Here we measured cytokine release by cultured glial cells to determine what factors in infected brain contributed to activation of microglia and astroglia. In assays analyzing IL-12p40 and CCL2 (MCP-1), glial cells were not stimulated in vitro by either PrPres purified from infected mouse brains or prion protein amyloid fibrils produced in vitro. However, significant glial stimulation was induced by clarified scrapie brain homogenates lacking PrPres. This stimulation was greatly reduced both by antibody to cyclophilin A (CyPA), a known mediator of inflammation in peripheral tissues, and by cyclosporine A, a CyPA inhibitor. In biochemical studies, purified truncated CyPA fragments stimulated a pattern of cytokine release by microglia and astroglia similar to that induced by scrapie-infected brain homogenates, whereas purified full-length CyPA was a poor stimulator. This requirement for CyPA truncation was not reported in previous studies of stimulation of peripheral macrophages, endothelial cell cardiomyocytes, and vascular smooth muscle cells. Therefore, truncated CyPA detected in brain following prion infection may have an important role in the activation of brain-derived primary astroglia and microglia in prion disease and perhaps other neurodegenerative or neuroinflammatory diseases. C1 [Tribouillard-Tanvier, Deborah; Carroll, James A.; Moore, Roger A.; Striebel, James F.; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bchesebro@nih.gov FU National Institutes of Health through the Division of Intramural Research, NIAID FX This work was supported, in whole or in part, by the National Institutes of Health through the Division of Intramural Research, NIAID. NR 55 TC 14 Z9 15 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 FEB 10 PY 2012 VL 287 IS 7 BP 4628 EP 4639 DI 10.1074/jbc.M111.269480 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500025 PM 22179611 ER PT J AU Yuan, XJ Protchenko, O Philpott, CC Hamza, I AF Yuan, Xiaojing Protchenko, Olga Philpott, Caroline C. Hamza, Iqbal TI Topologically Conserved Residues Direct Heme Transport in HRG-1-related Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; IRON UPTAKE; FERRIC REDUCTASE; YEAST; GENES; TRANSCRIPTION; BIOSYNTHESIS; HOMEOSTASIS; ACTIVATION; MECHANISM AB Caenorhabditis elegans and human HRG-1-related proteins are conserved, membrane-bound permeases that bind and translocate heme in metazoan cells via a currently uncharacterized mechanism. Here, we show that cellular import of heme by HRG-1-related proteins from worms and humans requires strategically located amino acids that are topologically conserved across species. We exploit a heme synthesis-defective Saccharomyces cerevisiae mutant to model the heme auxotrophy of C. elegans and demonstrate that, under heme-deplete conditions, the endosomal CeHRG-1 requires both a specific histidine in the predicted second transmembrane domain (TMD2) and the FARKY motif in the C terminus tail for heme transport. By contrast, the plasma membrane CeHRG-4 transports heme by utilizing a histidine in the exoplasmic (E2) loop and the FARKY motif. Optimal activity under heme-limiting conditions, however, requires histidine in the E2 loop of CeHRG-1 and tyrosine in TMD2 of CeHRG-4. An analogous system exists in humans, because mutation of the synonymous histidine in TMD2 of hHRG-1 eliminates heme transport activity, implying an evolutionary conserved heme transport mechanism that predates vertebrate origins. Our results support a model in which heme is translocated across membranes facilitated by conserved amino acids positioned on the exoplasmic, cytoplasmic, and transmembrane regions of HRG-1-related proteins. These findings may provide a framework for understanding the structural basis of heme transport in eukaryotes and human parasites, which rely on host heme for survival. C1 [Yuan, Xiaojing; Hamza, Iqbal] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Yuan, Xiaojing; Hamza, Iqbal] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Protchenko, Olga; Philpott, Caroline C.] NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Hamza, I (reprint author), Univ Maryland, Dept Anim & Avian Sci, 2413 Anim & Avian Sci,Bldg 142, College Pk, MD 20742 USA. EM hamza@umd.edu FU National Institutes of Health [R01DK74797, R01DK85035] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01DK74797 and R01DK85035 (to I. H.). NR 45 TC 25 Z9 27 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 10 PY 2012 VL 287 IS 7 BP 4914 EP 4924 DI 10.1074/jbc.M111.326785 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500052 PM 22174408 ER PT J AU Ohana, E Shcheynikov, N Park, M Muallem, S AF Ohana, Ehud Shcheynikov, Nikolay Park, Meeyoung Muallem, Shmuel TI Solute Carrier Family 26 Member a2 (Slc26a2) Protein Functions as an Electroneutral SO42-/OH-/Cl- Exchanger Regulated by Extracellular Cl- SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DYSPLASIA SULFATE TRANSPORTER; MULTIPLE EPIPHYSEAL DYSPLASIA; CYSTIC-FIBROSIS; DTDST GENE; CHONDRODYSPLASIA PHENOTYPE; CHLORIDE CHANNEL; PANCREATIC-DUCT; HCO3-SECRETION; MALE-FERTILITY; FINE-STRUCTURE AB Slc26a2 is a ubiquitously expressed SO42- transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO42- and the ion gradients that mediate SO42- uptake are poorly understood. We report here that Slc26a2 functions as an SO42-/2OH(-), SO42-/2Cl(-), andSO(4)(2-)/OH-/Cl- exchanger, depending on the Cl- and OH- gradients. At inward Cl- and outward pH gradients (high Cl-o(-) and low pH(o)) Slc26a2 functions primarily as an SO4o2-/2OH(i)(-) exchanger. At low Cl-o(-) and high pH(o) Slc26a2 functions increasingly as an SO4o2-/2Cl(i)(-) exchanger. The reverse is observed for SO4i2-/2OH(o)(-) and SO4i2-/2Cl(o)(-) exchange. Slc26a2 also exchanges Cl- for I-, Br-, and NO3- and Cl-o(-) competes with SO42- on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO4i2-/2OH(o)(-) exchange. Slc26a2 can transport oxalate in exchange for OH- and/or Cl- with properties similar to SO42- transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence (367)GFXXP(371) between TMD7 and TMD8 close to the conserved Glu(417) in the permeation pathway. Mutation of Glu(417) eliminated transport by Slc26a2, whereas mutation of Phe(368) increased the affinity for SO4o2- 8-fold while reducing the affinity for Cl-o(-) 2 fold, but without affecting regulation by Cl-o(-). These findings clarify the mechanism of net SO42- transport and describe a novel regulation of Slc26a2 by an extracellular anion binding site and should help in further understanding aberrant SLC26A2 function in diastrophic dysplasia. C1 [Ohana, Ehud; Shcheynikov, Nikolay; Park, Meeyoung; Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Muallem, S (reprint author), NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Room 1N-113, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov FU National Institutes of Health from NIDCR [Z1A-DE000735]; Machiah Foundation [2008-0702]; foundation of the Jewish Community Federation of San Francisco; Peninsula, Marin, and Sonoma Counties FX This work was supported, in whole or in part, by National Institutes of Health Grant Z1A-DE000735 from NIDCR.; Supported by a Machiah Fellowship (Grant 2008-0702) awarded through the Machiah Foundation, a supporting foundation of the Jewish Community Federation of San Francisco, the Peninsula, Marin, and Sonoma Counties. NR 57 TC 18 Z9 19 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 10 PY 2012 VL 287 IS 7 BP 5122 EP 5132 DI 10.1074/jbc.M111.297192 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500070 PM 22190686 ER PT J AU Lifson, AR Krantz, EM Grambsch, PL Macalino, GE Crum-Cianflone, NF Ganesan, A Okulicz, JF Eaton, A Powers, JH Eberly, LE Agan, BK AF Lifson, Alan R. Krantz, Elizabeth M. Grambsch, Patricia L. Macalino, Grace E. Crum-Cianflone, Nancy F. Ganesan, Anuradha Okulicz, Jason F. Eaton, Anne Powers, John H. Eberly, Lynn E. Agan, Brian K. CA Infect Dis Clinical Res Program TI Clinical, demographic and laboratory parameters at HAART initiation associated with decreased post-HAART survival in a US military prospective HIV cohort SO AIDS RESEARCH AND THERAPY LA English DT Article DE Highly active antiretroviral therapy; mortality; CD4+lymphocyte count ID STARTING ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; COLLABORATIVE ANALYSIS; INFECTED INDIVIDUALS; CELL COUNT; MORTALITY; AIDS; DETERMINANTS; PROGNOSIS AB Background: Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality. Methods: We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel. Results: Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with <= 50 CD4+ cells/mm(3) before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with >= 500 CD4+ cells/mm(3)). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those >= 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), <= 50 CD4+ cells/mm(3) (vs. CD4+ >= 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log(10) increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant. Conclusions: Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival. C1 [Lifson, Alan R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Krantz, Elizabeth M.; Grambsch, Patricia L.; Eaton, Anne; Eberly, Lynn E.] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Lifson, Alan R.; Krantz, Elizabeth M.; Grambsch, Patricia L.; Macalino, Grace E.; Crum-Cianflone, Nancy F.; Ganesan, Anuradha; Okulicz, Jason F.; Eberly, Lynn E.; Agan, Brian K.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Crum-Cianflone, Nancy F.] USN, San Diego Med Ctr, San Diego, CA 92152 USA. [Ganesan, Anuradha] Natl Naval Med Ctr, Bethesda, MD USA. [Okulicz, Jason F.] San Antonio Mil Med Ctr, Infect Dis Serv, San Antonio, TX USA. [Powers, John H.] NIAID, NIH, Bethesda, MD 20892 USA. RP Lifson, AR (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. EM lifso001@umn.edu; bagan@idcrp.org OI Polis, Michael/0000-0002-9151-2268; Agan, Brian/0000-0002-5114-1669; Eberly, Lynn/0000-0003-4763-330X FU U.S. Government; Infectious Disease Clinical Research Program [IDCRP-000-14]; Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Y1-AI-5072] FX Additional members of the Infectious Disease Clinical Research Program HIV/ STI Working Group include Susan Banks, Mary Bavaro, Helen Chun, Cathy Decker, Connor Eggleston, Susan Fraser, Joshua Hartzell, Gunther Hsue, Arthur Johnson, Mark Kortepeter, Tahaniyat Lalani, Michael Landrum, Michelle Linfesty, Scott Merritt, Robert O'Connell, Sheila Peel, Michael Polis, Roseanne Ressnerk, Edmund Tramont, Tyler Warkentien, Paige Waterman, Amy Weintrob, Timothy Whitman, Glenn Wortmann, and Michael Zapor. The content and views expressed in this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the NIH or the Department of Health and Human Services, the DoD or the Departments of the Army, Navy, Air Force, Department of Defense, nor the U. S. Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Support for this work (IDCRP-000-14) was provided by the Infectious Disease Clinical Research Program, a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072. NR 25 TC 4 Z9 4 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD FEB 10 PY 2012 VL 9 AR 4 DI 10.1186/1742-6405-9-4 PG 7 WC Infectious Diseases SC Infectious Diseases GA 072RD UT WOS:000313689000001 PM 22339893 ER PT J AU Adesunloye, B Huang, X Ning, YMM Madan, RA Gulley, JL Beatson, M Kluetz, PG Adelberg, D Arlen, PM Parnes, HL Mulquin, M Steinberg, SM Wright, JJ Trepel, JB Dawson, NA Chen, C Apolo, AB Figg, WD Dahut, WL AF Adesunloye, Bamidele Huang, Xuan Ning, Yangmin M. Madan, Ravi A. Gulley, James L. Beatson, Melony Kluetz, Paul Gustav Adelberg, David Arlen, Philip M. Parnes, Howard L. Mulquin, Marcia Steinberg, Seth M. Wright, John Joseph Trepel, Jane B. Dawson, Nancy Ann Chen, Clara Apolo, Andrea Borghese Figg, William Douglas Dahut, William L. TI Phase II trial of bevacizumab and lenalidomide with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, US FDA, Silver Spring, MD USA. NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 207 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400208 PM 28143000 ER PT J AU Adesunloye, B Stein, WD Wilkerson, J Huang, X Karzai, FH Madan, RA Apolo, AB Figg, WD Dahut, WL Fojo, T AF Adesunloye, Bamidele Stein, Wilfred Donald Wilkerson, Julia Huang, Xuan Karzai, Fatima H. Madan, Ravi A. Apolo, Andrea Borghese Figg, William Douglas Dahut, William L. Fojo, Tito TI Tumor regression and growth rates determined in two intramural NCI prostate cancer trials: The growth rate constant as an indicator of therapeutic efficacy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Jerusalem, Israel. NCI, NIH, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 133 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400134 PM 28143234 ER PT J AU Apolo, AB Bochner, B Steinberg, SM Bajorin, DF Kelly, WK Quinn, DI Vogelzang, NJ Sridhar, SS AF Apolo, Andrea Borghese Bochner, Bernard Steinberg, Seth M. Bajorin, Dean F. Kelly, William Kevin Quinn, David I. Vogelzang, Nicholas J. Sridhar, Srikala S. TI Examining the management of muscle-invasive bladder cancer (MIBC) by medical oncologists (MO) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Southern Calif Norris Comprehens Canc Ctr, Los Angeles, CA USA. US Oncol Res LLC, McKesson Specialty Hlth, The Woodlands, TX USA. Comprehens Canc Ctr Nevada, Las Vegas, NV USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 298 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400297 PM 28143161 ER PT J AU Choueiri, TK Vaishampayan, UN Rosenberg, JE Logan, T Harzstark, AL Rini, BI Srinivas, S Adams, LM Sherman, LJ Ottesen, LH McDermott, DF Bottaro, DP Linehan, WM Srinivasan, R AF Choueiri, Toni K. Vaishampayan, Ulka N. Rosenberg, Jonathan E. Logan, Theodore Harzstark, Andrea Lynne Rini, Brian I. Srinivas, Sandy Adams, Laurel M. Sherman, Laurie Jill Ottesen, Lone Harild McDermott, David F. Bottaro, Donald P. Linehan, W. Marston Srinivasan, Ramaprasad TI A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Stanford Med Ctr, Stanford, CA USA. GlaxoSmithKline, Res Triangle Pk, NC USA. GlaxoSmithKline, Philadelphia, PA USA. GlaxoSmithKline Oncol R&D, Uxbridge, Middx, England. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 355 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400354 ER PT J AU Hattangadi, JA Chen, MH Sun, L D'Amico, AV AF Hattangadi, Jona Ashok Chen, Ming-Hui Sun, Leon D'Amico, Anthony Victor TI Early detection of high-grade prostate cancer using digital rectal examination in men with a normal PSA and risk of death. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Univ Connecticut, Storrs, CT USA. NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 147 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400148 PM 28143304 ER PT J AU Karzai, FH Apolo, AB Adelberg, DE Madan, RA Gulley, JL Arlen, PM Parnes, HL Pierpoint, A Kohler, DR Price, DK Steinberg, SM Trepel, JB Figg, WD Dahut, WL AF Karzai, Fatima H. Apolo, Andrea Borghese Adelberg, David E. Madan, Ravi Amrit Gulley, James L. Arlen, Philip M. Parnes, Howard L. Pierpoint, Ann Kohler, David R. Price, Douglas K. Steinberg, Seth M. Trepel, Jane B. Figg, William Douglas Dahut, William L. TI A phase I study of TRC105 (anti-CD105 [endoglin] antibody) in metastatic castration-resistant prostate cancer (mCRPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 117 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400118 PM 28143022 ER PT J AU Klein, EA Thompson, I Tangen, CM Lucia, MS Goodman, P Minasian, LM Ford, LG Parnes, HL Gaziano, JM Karp, DD Lieber, MM Walther, PJ Parsons, JK Chin, J Darke, AK Lippman, SM Goodman, GE Meyskens, FL Baker, LH AF Klein, Eric A. Thompson, Ian Tangen, Catherine M. Lucia, M. Scott Goodman, Phyllis Minasian, Lori M. Ford, Leslie G. Parnes, Howard L. Gaziano, J. Michael Karp, Daniel D. Lieber, Michael M. Walther, Philip John Parsons, J. Kellogg Chin, Joseph Darke, Amy K. Lippman, Scott Michael Goodman, Gary E. Meyskens, Frank L. Baker, Laurence H. TI Vitamin E and the risk of prostate cancer: Updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Colorado, Sch Med, Aurora, CO USA. SWOG Stat Ctr, Seattle, WA USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Mayo Clin, Rochester, MN USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. London Hlth Sci Ctr, London, ON, Canada. Swedish Canc Inst, Seattle, WA USA. Chao Family Comprehens Canc Ctr, Orange, CA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 7 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400009 PM 28143337 ER PT J AU Pisle, ST Pressler, HM Troutman, SM Eisner, JR Rafferty, SW Schotzinger, RJ Moore, WR Figg, WD AF Pisle, Stephen Todd Pressler, Heather M. Troutman, Sarah M. Eisner, Joel Robert Rafferty, Stephen W. Schotzinger, Robert J. Moore, William R. Figg, William Douglas TI Activity of VT-464, a selective CYP17 lyase inhibitor, in the LNCaP prostate cancer xenograft model SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 SAIC Frederick, Clin Pharmacol Program, Bethesda, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Viamet Pharmaceut Inc, Morrisville, NC USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 64 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400066 PM 28142955 ER PT J AU Reece, KM Troutman, SM Pressler, HM Pisle, ST Figg, WD AF Reece, Kelie M. Troutman, Sarah M. Pressler, Heather M. Pisle, Stephen T. Figg, William Douglas TI Androgen receptor and HIF-1 alpha interaction in prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI Frederick, Clin Pharmacol Program, SAIC Frederick, Frederick, MD USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 197 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400198 PM 28143193 ER PT J AU Sheets, NC Goldin, G Meyer, AM Wu, Y Chang, Y Sturmer, T Holmes, JA Reeve, BB Godley, PA Carpenter, WR Chen, RC AF Sheets, Nathan Christopher Goldin, Gregg Meyer, Anne-Marie Wu, Yang Chang, YunKyung Sturmer, Til Holmes, Jordan A. Reeve, Bryce B. Godley, Paul Alphonso Carpenter, William Ruffin Chen, Ronald C. TI Comparative effectiveness of intensity modulated radiation therapy (IMRT), proton therapy (PT), and conformal radiation therapy (CRT) in the treatment of localized prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ North Carolina Hosp, Chapel Hill, NC USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Bethesda, MD 20892 USA. RI Carpenter, William/E-5125-2013 NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 3 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400005 PM 28143332 ER PT J AU Shuch, B Ricketts, C Sourbier, C Tsutsumi, S Zhang, XY Belldegrun, AS Wood, CG Linehan, WM Neckers, L AF Shuch, Brian Ricketts, Christopher Sourbier, Carole Tsutsumi, Shinji Zhang, Xiu-ying Belldegrun, Arie S. Wood, Christopher G. Linehan, W. Marston Neckers, Len TI Metabolic evaluation of sporadic papillary kidney cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Calif Los Angeles, Los Angeles Sch Med, Los Angeles, CA USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 377 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400376 PM 28143218 ER PT J AU Sigurdardottir, L Valdimarsdottir, UA Mucci, L Fall, K Rider, JR Schernhammer, ES Czeisler, CA Launer, L Harris, TB Stampfer, MJ Gudnason, V Lockley, SW AF Sigurdardottir, Lara Valdimarsdottir, Unnur Anna Mucci, Lorelei Fall, Katja Rider, Jennifer R. Schernhammer, Eva S. Czeisler, Charles A. Launer, Lenore Harris, Tamara B. Stampfer, Meir J. Gudnason, Vilmundur Lockley, Steven W. TI Insomnia among elderly men and risk of prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Iceland, Ctr Publ Hlth Sci, Reykjavik, Iceland. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Orebro Univ Hosp, Clin Epidemiol Unit, Orebro, Sweden. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. NIA, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Iceland Heart Assoc, Kopavogur, Iceland. RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 78 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400080 PM 28142941 ER PT J AU Sissung, T Kirkland, CT Reece, KM Arnold, JT Figg, WD AF Sissung, Tristan Kirkland, C. Tyler Reece, Kelie M. Arnold, Julia T. Figg, William Douglas TI Effect of thalidomide on the TGF beta-1-mediated synthesis of testosterone from DHEA in prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 141 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400142 PM 28143326 ER PT J AU Srinivasan, R Bottaro, DP Choueiri, TK Vaishampayan, UN Rosenberg, JE Logan, T Harzstark, AL Rini, BI Srinivas, S Adams, LM Laubscher, K Ottesen, LH McDermott, DF Linehan, WM AF Srinivasan, Ramaprasad Bottaro, Donald P. Choueiri, Toni K. Vaishampayan, Ulka N. Rosenberg, Jonathan E. Logan, Theodore Harzstark, Andrea Lynne Rini, Brian I. Srinivas, Sandy Adams, Laurel M. Laubscher, Kevin Ottesen, Lone Harild McDermott, David F. Linehan, W. Marston TI Correlation of germline MET mutation with response to the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Results from a multicenter phase II study (MET111644). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Stanford Med Ctr, Stanford, CA USA. GlaxoSmithKline, Res Triangle Pk, NC USA. GlaxoSmithKline Oncol R&D, Uxbridge, Middx, England. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 372 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400371 PM 28143239 ER PT J AU Stein, MN DiPaola, RS Mayer, TM Jeyamohan, C Metzger, D Anand, M Ivy, SP AF Stein, Mark N. DiPaola, Robert S. Mayer, Tina M. Jeyamohan, Chandrika Metzger, Dorinda Anand, Monica Ivy, S. Percy CA Prostate Canc Clinical Trials Cons TI A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Canc Inst New Jersey, New Brunswick, NJ USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 219 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400220 PM 28142966 ER PT J AU Torfadottir, JE Valdimarsdottir, UA Mucci, L Stampfer, MJ Kasperzyk, J Fall, K Tryggvadottir, L Aspelund, T Olafsson, O Harris, TB Jonsson, E Tulinus, H Adami, HO Gudnason, V Steingrimsdottir, L AF Torfadottir, Johanna Eyrun Valdimarsdottir, Unnur Anna Mucci, Lorelei Stampfer, Meir J. Kasperzyk, Julie Fall, Katja Tryggvadottir, Laufey Aspelund, Thor Olafsson, Orn Harris, Tamara B. Jonsson, Eirikur Tulinus, Hrafn Adami, Hans-Olov Gudnason, Vilmundur Steingrimsdottir, Laufey TI Rye bread consumption in early life and reduced risk of advanced prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Iceland, Ctr Publ Hlth Sci, Reykjavik, Iceland. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Orebro Univ Hosp, Clin Epidemiol Unit, Orebro, Sweden. Iceland Canc Registry, Reykjavik, Iceland. Iceland Heart Assoc, Kopavogur, Iceland. NIA, Bethesda, MD 20892 USA. Landspitali Unvers Hosp, Reykjavik, Iceland. Univ Iceland, Fac Food Sci & Nutr, Unit Nutr Res, Reykjavik, Iceland. RI Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008 OI Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 79 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400081 PM 28142940 ER PT J AU Troutman, SM Sissung, TM Cropp, CD Venzon, DJ Spencer, SD Price, DK Figg, WD AF Troutman, Sarah M. Sissung, Tristan M. Cropp, Cheryl D. Venzon, David J. Spencer, Shawn D. Price, Douglas K. Figg, William Douglas TI Association between variants on 8q24 and prostate cancer: A review and meta-analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NHGRI, Baltimore, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 28 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400030 PM 28142910 ER PT J AU Ruan, XY Kocher, JPA Pommier, Y Liu, HF Reinhold, WC AF Ruan, Xiaoyang Kocher, Jean-Pierre A. Pommier, Yves Liu, Hongfang Reinhold, William C. TI Mass Homozygotes Accumulation in the NCI-60 Cancer Cell Lines As Compared to HapMap Trios, and Relation to Fragile Site Location SO PLOS ONE LA English DT Article ID MAINTAINS GENOMIC STABILITY; HOMOLOGOUS RECOMBINATION; MITOTIC RECOMBINATION; SUBSTRATE LENGTH; OVARIAN-CANCER; HETEROZYGOSITY; TUMOR; COMMON; EXPRESSION; IDENTIFICATION AB Runs of homozygosity (ROH) represents extended length of homozygotes on a long genomic distance. In oncology, it is known as loss of heterozygosity (LOH) if identified exclusively in cancer cell rather than in matched control cell. Studies have identified several genomic regions which show consistent ROH in different kinds of carcinoma. To query whether this consistency can be observed on broader spectrum, both in more cancer types and in wider genomic regions, we investigated ROH patterns in the National Cancer Institute 60 cancer cell line panel (NCI-60) and HapMap Caucasian healthy trio families. Using results from Affymetrix 500 K SNP arrays, we report a genome wide significant association of ROH regions between the NCI-60 and HapMap samples, with much a higher level of ROH (11 fold) in the cancer cell lines. Analysis shows that more severe ROH found in cancer cells appears to be the extension of existing ROH in healthy state. In the HapMap trios, the adult subgroup had a slightly but significantly higher level (1.02 fold) of ROH than did the young subgroup. For several ROH regions we observed the co-occurrence of fragile sites (FRAs). However, FRA on the genome wide level does not show a clear relationship with ROH regions. C1 [Ruan, Xiaoyang; Kocher, Jean-Pierre A.; Liu, Hongfang] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Ruan, Xiaoyang; Pommier, Yves; Liu, Hongfang; Reinhold, William C.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Ruan, XY (reprint author), Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. EM liu.hongfang@mayo.edu; wcr@mail.nih.gov FU National Institutes of Health, Center for Cancer Research, National Cancer Institute; National Science Foundation [ABI: 0845523]; National Institute of Health [R01LM009959A1] FX This study was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute, and also by National Science Foundation ABI: 0845523 and National Institute of Health R01LM009959A1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 9 Z9 9 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 9 PY 2012 VL 7 IS 2 AR e31628 DI 10.1371/journal.pone.0031628 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 924ZQ UT WOS:000302730200028 PM 22347499 ER PT J AU Yi, L Chandrasekaran, P Venkatesan, S AF Yi, Ling Chandrasekaran, Prabha Venkatesan, Sundararajan TI TLR Signaling Paralyzes Monocyte Chemotaxis through Synergized Effects of p38 MAPK and Global Rap-1 Activation SO PLOS ONE LA English DT Article ID TOLL-LIKE RECEPTOR-2; CHEMOKINE RECEPTORS; NEUTROPHIL CHEMOTAXIS; DENDRITIC CELLS; BACTERIAL LIPOPOLYSACCHARIDE; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; TYROSINE PHOSPHORYLATION; VASCULAR ENDOTHELIUM; LYMPHOCYTE ARREST AB Toll-like receptors (TLRs) that recognize pathogen associated molecular patterns and chemoattractant receptors (CKRs) that orchestrate leukocyte migration to infected tissue are two arms of host innate immunity. Although TLR signaling induces synthesis and secretion of proinflammatory cytokines and chemokines, which recruit leukocytes, many studies have reported the paradoxical observation that TLR stimulation inhibits leukocyte chemotaxis in vitro and impairs their recruitment to tissues during sepsis. There is consensus that physical loss of chemokine receptor (CKR) at the RNA or protein level or receptor usage switching are the mechanisms underlying this effect. We show here that a brief (<15 min) stimulation with LPS (lipopolysaccharide) at similar to 0.2 ng/ml inhibited chemotactic response from CCR2, CXCR4 and FPR receptors in monocytes without downmodulation of receptors. A 3 min LPS pre-treatment abolished the polarized accumulation of F-actin, integrins and PIP3 (phosphatidylinositol-3,4,5-trisphosphate) in response to chemokines in monocytes, but not in polymorphonuclear neutrophils (PMNs). If chemoattractants were added before or simultaneously with LPS, chemotactic polarization was preserved. LPS did not alter the initial G-protein signaling, or endocytosis kinetics of agonist-occupied chemoattractant receptors (CKRs). The chemotaxis arrest did not result from downmodulation of receptors or from inordinate increase in adhesion. LPS induced rapid p38 MAPK activation, global redistribution of activated Rap1 (Ras-proximate-1 or Ras-related protein 1) GTPase and Rap1GEF (guanylate exchange factor) Epac1 (exchange proteins activated by cyclic AMP) and disruption of intracellular gradient. Co-inhibition of p38 MAPK and Rap1 GTPase reversed the LPS induced breakdown of chemotaxis suggesting that LPS effect requires the combined function of p38 MAPK and Rap1 GTPase. C1 [Yi, Ling] NIAID, Mol Cell Biol Unit, Lab Mol Immunol, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Yi, L (reprint author), NIAID, Mol Cell Biol Unit, Lab Mol Immunol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sv1s@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS FX This research was funded entirely by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 14 Z9 14 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 9 PY 2012 VL 7 IS 2 AR e30404 DI 10.1371/journal.pone.0030404 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 924ZQ UT WOS:000302730200002 PM 22347375 ER PT J AU Sridhara, V Bai, DL Chi, A Shabanowitz, J Hunt, DF Bryant, SH Geer, LY AF Sridhara, Viswanadham Bai, Dina L. Chi, An Shabanowitz, Jeffrey Hunt, Donald F. Bryant, Stephen H. Geer, Lewis Y. TI Increasing peptide identifications and decreasing search times for ETD spectra by pre-processing and calculation of parent precursor charge SO PROTEOME SCIENCE LA English DT Article ID ELECTRON-TRANSFER DISSOCIATION; TANDEM MASS-SPECTRA; PROTEIN IDENTIFICATION; STATE DETERMINATION; ACTIVATION METHOD; SEQUENCE-ANALYSIS; SPECTROMETRY; DATABASE AB Background: Electron Transfer Dissociation [ETD] can dissociate multiply charged precursor polypeptides, providing extensive peptide backbone cleavage. ETD spectra contain charge reduced precursor peaks, usually of high intensity, and whose pattern is dependent on its parent precursor charge. These charge reduced precursor peaks and associated neutral loss peaks should be removed before these spectra are searched for peptide identifications. ETD spectra can also contain ion-types other than c and z. Modifying search strategies to accommodate these ion-types may aid in increased peptide identifications. Additionally, if the precursor mass is measured using a lower resolution instrument such as a linear ion trap, the charge of the precursor is often not known, reducing sensitivity and increasing search times. We implemented algorithms to remove these precursor peaks, accommodate new ion-types in noise filtering routine in OMSSA and to estimate any unknown precursor charge, using Linear Discriminant Analysis [LDA]. Results: Spectral pre-processing to remove precursor peaks and their associated neutral losses prior to protein sequence library searches resulted in a 9.8% increase in peptide identifications at a 1% False Discovery Rate [FDR] compared to previous OMSSA filter. Modifications to the OMSSA noise filter to accommodate various ion-types resulted in a further 4.2% increase in peptide identifications at 1% FDR. Moreover, ETD spectra when searched with charge states obtained from the precursor charge determination algorithm is shown to be up to 3.5 times faster than the general range search method, with a minor 3.8% increase in sensitivity. Conclusion: Overall, there is an 18.8% increase in peptide identifications at 1% FDR by incorporating the new precursor filter, noise filter and by using the charge determination algorithm, when compared to previous versions of OMSSA. C1 [Sridhara, Viswanadham; Bryant, Stephen H.; Geer, Lewis Y.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Bai, Dina L.; Shabanowitz, Jeffrey; Hunt, Donald F.] Univ Virginia, Dept Chem, Charlottesville, VA USA. [Chi, An] Merck Res Labs, Boston, MA USA. [Hunt, Donald F.] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. RP Geer, LY (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM lewis.geer@nih.gov RI Hunt, Donald/I-6936-2012; Geer, Lewis/H-2714-2014 OI Hunt, Donald/0000-0003-2815-6368; FU NIH, National Library of Medicine; NIH [GM 037537] FX This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine and by NIH GM 037537 to DFH. NR 25 TC 3 Z9 3 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-5956 J9 PROTEOME SCI JI Proteome Sci. PD FEB 9 PY 2012 VL 10 AR 8 DI 10.1186/1477-5956-10-8 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 918JK UT WOS:000302245400001 PM 22321509 ER PT J AU Tatari-Calderone, Z Stojakovic, M Dewan, R Le Bouder, G Jankovic, D Vukmanovic, S AF Tatari-Calderone, Zohreh Stojakovic, Milica Dewan, Ramita Le Bouder, Gama Jankovic, Dragana Vukmanovic, Stanislav TI Age-related accumulation of T cells with markers of relatively stronger autoreactivity leads to functional erosion of T cells SO BMC IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MAJOR HISTOCOMPATIBILITY COMPLEX; SYSTEMIC-LUPUS-ERYTHEMATOSUS; AGING IMMUNE-SYSTEM; MULTIPLE-SCLEROSIS; HOMEOSTATIC PROLIFERATION; SIGNAL-TRANSDUCTION; IN-VIVO; INTERLEUKIN-10-DEFICIENT MICE AB Background: Thymic involution is a prominent characteristic of an aging immune system. When thymic function is reduced/absent, the peripheral T cell pool is subject to the laws of peripheral T cell homeostasis that favor survival/ expansion of T cell receptors with relatively higher functional avidity for self-peptide/MHC complexes. Due to difficulties in assessing the TCR avidity in polyclonal population of T cells, it is currently not known whether high avidity T cells preferentially survive in aging individuals, and what impact this might have on the function of the immune system and development of autoimmune diseases. Results: The phenotype of T cells from aged mice (18-24 months) indicating functional TCR avidity (CD3 and CD5 expression) correlates with the level of preserved thymic function. In mice with moderate thymic output (> 30% of peripheral CD62L(hi) T cells), T cells displayed CD3(low)CD5(hi) phenotype characteristic for high functional avidity. In old mice with drastically low numbers of CD62L(hi) T cells reduced CD5 levels were found. After adult thymectomy, T cells of young mice developed CD3(low)CD5(hi) phenotype, followed by a CD3(low)CD5(low) phenotype. Spleens of old mice with the CD3(low)/CD5(hi) T cell phenotype displayed increased levels of IL-10 mRNA, and their T cells could be induced to secrete IL-10 in vitro. In contrast, downmodulation of CD5 was accompanied with reduced IL-10 expression and impaired anti-CD3 induced proliferation. Irrespective of the CD3/CD5 phenotype, reduced severity of experimental allergic myelitis occurred in old mice. In MTB TCR beta transgenic mice that display globally elevated TCR avidity for self peptide/MHC, identical change patterns occurred, only at an accelerated pace. Conclusions: These findings suggest that age-associated dysfunctions of the immune system could in part be due to functional erosion of T cells devised to protect the hosts from the prolonged exposure to T cells with high-avidity for self. C1 [Tatari-Calderone, Zohreh; Stojakovic, Milica; Dewan, Ramita; Le Bouder, Gama; Vukmanovic, Stanislav] Childrens Natl Med Ctr, Childrens Res Inst, Ctr Canc & Immunol Res, Washington, DC 20010 USA. [Stojakovic, Milica; Vukmanovic, Stanislav] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Vukmanovic, S (reprint author), Childrens Natl Med Ctr, Childrens Res Inst, Ctr Canc & Immunol Res, Washington, DC 20010 USA. EM svukmano@cnmc.org FU National Institutes of Health; National Heart, Lung, and Blood Institute [1U54 HL090503]; National Institute for Allergy and Infectious Diseases [1R01 AI48837, 1R01 AI41573] FX This work was supported in part by a grants from the National Institutes of Health; National Heart, Lung, and Blood Institute 1U54 HL090503 (ZT-C), and by 1R01 AI48837 and 1R01 AI41573 from the National Institute for Allergy and Infectious Diseases (SV). NR 74 TC 6 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD FEB 9 PY 2012 VL 13 AR 8 DI 10.1186/1471-2172-13-8 PG 11 WC Immunology SC Immunology GA 907UX UT WOS:000301445600001 PM 22321827 ER PT J AU O'Donghaile, D Childs, RW Leitman, SF AF O'Donghaile, Diarmaid Childs, Richard W. Leitman, Susan F. TI Blood consult: granulocyte transfusions to treat invasive aspergillosis in a patient with severe aplastic anemia awaiting mismatched hematopoietic progenitor cell transplantation SO BLOOD LA English DT Editorial Material ID RECIPIENTS; THERAPY; DONORS C1 [O'Donghaile, Diarmaid; Leitman, Susan F.] NHLBI, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Leitman, SF (reprint author), NHLBI, Dept Transfus Med, Ctr Clin, NIH, Bldg 10,Rm 1C-711, Bethesda, MD 20892 USA. EM sleitman@nih.gov NR 10 TC 8 Z9 8 U1 0 U2 0 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 FEB 9 PY 2012 VL 119 IS 6 BP 1353 EP 1355 DI 10.1182/blood-2011-10-345751 PG 3 WC Hematology SC Hematology GA 894IR UT WOS:000300420900010 PM 22110248 ER PT J AU Zhao, L Melenhorst, JJ Alemu, L Kirby, M Anderson, S Kench, M Hoogstraten-Miller, S Brinster, L Kamikubo, Y Gilliland, DG Liu, PP AF Zhao, Ling Melenhorst, Jan J. Alemu, Lemlem Kirby, Martha Anderson, Stacie Kench, Maggie Hoogstraten-Miller, Shelley Brinster, Lauren Kamikubo, Yasuhiko Gilliland, D. Gary Liu, P. Paul TI KIT with D816 mutations cooperates with CBFB-MYH11 for leukemogenesis in mice SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CORE-BINDING-FACTOR; RECEPTOR TYROSINE KINASE; STEM-CELL FACTOR; GASTROINTESTINAL STROMAL TUMORS; PROTOONCOGENE C-KIT; SIGNALING PATHWAY; PROGNOSTIC IMPACT; INHIBITOR PKC412; LUNG-CANCER AB KIT mutations are the most common secondary mutations in inv(16) acute myeloid leukemia (AML) patients and are associated with poor prognosis. It is therefore important to verify that KIT mutations cooperate with CBFB-MYH11, the fusion gene generated by inv(16), for leukemogenesis. Here, we transduced wildtype and conditional Cbfb-MYH11 knockin (KI) mouse bone marrow (BM) cells with KIT D816V/Y mutations. KIT transduction caused massive BM Lin(-) cell death and fewer colonies in culture that were less severe in the KI cells. D816Y KIT but not wild-type KIT enhanced proliferation in Lin(-) cells and led to more mixed lineage colonies from transduced KI BM cells. Importantly, 60% and 80% of mice transplanted with KIBM cells expressing D816V or D816Y KIT, respectively, died from leukemia within 9 months, whereas no control mice died. Results from limiting dilution transplantations indicate higher frequencies of leukemia-initiating cells in the leukemia expressing mutated KIT. Signaling pathway analysis revealed that p44/42 MAPK and Stat3, but not AKT and Stat5, were strongly phosphorylated in the leukemia cells. Finally, leukemia cells carrying KIT D816 mutations were sensitive to the kinase inhibitor PKC412. Our data provide clear evidence for cooperation between mutated KIT and CBFB-MYH11 during leukemogenesis. (Blood. 2012;119(6):1511-1521) C1 [Zhao, Ling; Alemu, Lemlem; Kamikubo, Yasuhiko; Liu, P. Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Melenhorst, Jan J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hoogstraten-Miller, Shelley] NHGRI, Off Lab Anim Med, NIH, Bethesda, MD 20892 USA. [Brinster, Lauren] NIH, Diagnost & Res Serv Branch, Off Director, Bethesda, MD 20892 USA. [Gilliland, D. Gary] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Liu, PP (reprint author), 49 Convent Dr,49-3A26, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural Research Program, National Human Genome Research Institute, National Institutes of Health. NR 50 TC 17 Z9 17 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 9 PY 2012 VL 119 IS 6 BP 1511 EP 1521 DI 10.1182/blood-2011-02-338210 PG 11 WC Hematology SC Hematology GA 894IR UT WOS:000300420900027 PM 22160378 ER PT J AU Sun, K Alvarez, M Ames, E Barao, I Chen, MY Longo, DL Redelman, D Murphy, WJ AF Sun, Kai Alvarez, Maite Ames, Erik Barao, Isabel Chen, Mingyi Longo, Dan L. Redelman, Doug Murphy, William J. TI Mouse NK cell-mediated rejection of bone marrow allografts exhibits patterns consistent with Ly49 subset licensing SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; MHC CLASS-I; EXPRESSING INHIBITORY KIR; SELF-TOLERANCE; GRAFT-REJECTION; T-CELLS; RECEPTORS; TRANSPLANTATION; MOLECULES; EDUCATION AB Natural killer (NK) cells can mediate the rejection of bone marrow allografts and exist as subsets based on expression of inhibitory/activating receptors that can bind MHC. In vitro data have shown that NK subsets bearing Ly49 receptors for self-MHC class I have intrinsically higher effector function, supporting the hypothesis that NK cells undergo a host MHC-dependent functional education. These subsets also play a role in bone marrow cell (BMC) allograft rejection. Thus far, little in vivo evidence for this preferential licensing across mouse strains with different MHC haplotypes has been shown. We assessed the intrinsic response potential of the different Ly49(+) subsets in BMC rejection by using beta 2-microglobulin deficient (beta 2m(-/-)) mice as donors. Using congenic and allogeneic mice as recipients and depleting the different Ly49 subsets, we found that NK subsets bearing Ly49s, which bind "self-MHC" were found to be the dominant subset responsible for beta 2m(-/-) BMC rejection. This provides in vivo evidence for host MHC class I-dependent functional education. Interestingly, all H2(d) strain mice regardless of background were able to resist significantly greater amounts of beta 2m(-/-), but not wild-type BMC than H2(b) mice, providing evidence that the rheostat hypothesis regarding Ly49 affinities for MHC and NK-cell function impacts BMC rejection capability. (Blood. 2012;119(6):1590-1598) C1 [Sun, Kai; Alvarez, Maite; Ames, Erik; Murphy, William J.] Univ Calif Davis, Dept Dermatol, Sch Med, Sacramento, CA 95817 USA. [Barao, Isabel] Univ Nevada, Dept Microbiol & Immunol, Reno, NV 89557 USA. [Chen, Mingyi] Univ Calif Davis, Dept Pathol & Lab Med, Sacramento, CA 95817 USA. [Longo, Dan L.] NIA, Dept Immunol, NIH, Baltimore, MD 21224 USA. [Redelman, Doug] Univ Nevada, Dept Physiol & Cell Biol, Reno, NV 89557 USA. [Murphy, William J.] Univ Calif Davis, Dept Internal Med, Sch Med, Sacramento, CA 95817 USA. RP Murphy, WJ (reprint author), Univ Calif Davis, Dept Dermatol, Sch Med, CTSC IRC Suite 1630,2921 Stockton Blvd, Sacramento, CA 95817 USA. EM wmjmurphy@ucdavis.edu FU National Institutes of Health [R01-HL089905] FX This work was supported by the National Institutes of Health (grant R01-HL089905). NR 47 TC 17 Z9 19 U1 0 U2 0 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 FEB 9 PY 2012 VL 119 IS 6 BP 1590 EP 1598 DI 10.1182/blood-2011-08-374314 PG 9 WC Hematology SC Hematology GA 894IR UT WOS:000300420900036 PM 22184406 ER PT J AU Connelly, L Jang, H Arce, FT Capone, R Kotler, SA Ramachandran, S Kagan, BL Nussinov, R Lal, R AF Connelly, Laura Jang, Hyunbum Arce, Fernando Teran Capone, Ricardo Kotler, Samuel A. Ramachandran, Srinivasan Kagan, Bruce L. Nussinov, Ruth Lal, Ratnesh TI Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-D-Enantiomer of Alzheimer's beta-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID CELL PLASMA-MEMBRANE; MOLECULAR-DYNAMICS; BILAYER-MEMBRANES; BINDING-SITES; DISEASE; PROTEIN; FIBRILS; CONFORMATION; HYPOTHESIS; PRECURSOR AB Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of beta-amyloid (A beta) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves A beta peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the A beta peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the A beta peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of A beta-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length A beta(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-A beta isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-A beta(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of A beta ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through A beta interaction with membrane receptors. C1 [Jang, Hyunbum; Nussinov, Ruth] NCI, Ctr Canc Res, Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Connelly, Laura; Arce, Fernando Teran; Capone, Ricardo; Kotler, Samuel A.; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Connelly, Laura; Arce, Fernando Teran; Capone, Ricardo; Kotler, Samuel A.; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Dept Mech & Aerosp Engn, La Jolla, CA 92093 USA. [Connelly, Laura; Arce, Fernando Teran; Capone, Ricardo; Kotler, Samuel A.; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Mat Sci Program, La Jolla, CA 92093 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, Dept Psychiat, David Geffen Sch Med, Semel Inst Neurosci Human Behav, Los Angeles, CA 90024 USA. [Nussinov, Ruth] Tel Aviv Univ, Dept Human Mol Genet & Biochem, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Ctr Canc Res, Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov; rlal@ucsd.edu RI Capone, Ricardo/D-1943-2010; Ramachandran, Srinivasan/G-5300-2010 OI Capone, Ricardo/0000-0002-7327-9837; Ramachandran, Srinivasan/0000-0002-4912-0279 FU National Institutes of Health (National Institute on Aging) [AG028709]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the National Institutes of Health (National Institute on Aging AG028709 to RL.). This project has been funded in whole or partially with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. This research was supported (partially) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. All simulations had been performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 55 TC 46 Z9 46 U1 2 U2 40 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD FEB 9 PY 2012 VL 116 IS 5 BP 1728 EP 1735 DI 10.1021/jp2108126 PG 8 WC Chemistry, Physical SC Chemistry GA 888DY UT WOS:000299985200029 PM 22217000 ER PT J AU Gregoriou, GG Gotts, SJ Desimone, R AF Gregoriou, Georgia G. Gotts, Stephen J. Desimone, Robert TI Cell-Type-Specific Synchronization of Neural Activity in FEF with V4 during Attention SO NEURON LA English DT Article ID FRONTAL EYE FIELD; SACCADE TARGET SELECTION; HUMAN CORTICOSPINAL SYSTEM; COVERT SPATIAL ATTENTION; MACAQUE AREA V4; VISUAL-ATTENTION; SUPERIOR COLLICULUS; NEURONAL SYNCHRONIZATION; PREFRONTAL CORTEX; MOTOR CORTEX AB Shifts of gaze and shifts of attention are closely linked and it is debated whether they result from the same neural mechanisms. Both processes involve the frontal eye fields (FEF), an area which is also a source of top-down feedback to area V4 during covert attention. To test the relative contributions of oculomotor and attention-related FEF signals to such feedback, we recorded simultaneously from both areas in a covert attention task and in a saccade task. In the attention task, only visual and visuomovement FEF neurons showed enhanced responses, whereas movement cells were unchanged. Importantly, visual, but not movement or visuomovement cells, showed enhanced gamma frequency synchronization with activity in V4 during attention. Within FEF, beta synchronization was increased for movement cells during attention but was suppressed in the saccade task. These findings support the idea that the attentional modulation of visual processing is not mediated by movement neurons. C1 [Gregoriou, Georgia G.] Univ Crete, Dept Basic Sci, Fac Med, Iraklion 71003, Crete, Greece. [Gregoriou, Georgia G.] Fdn Res & Technol, Inst Appl & Computat Math, Iraklion 70013, Crete, Greece. [Gotts, Stephen J.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Desimone, Robert] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. RP Gregoriou, GG (reprint author), Univ Crete, Dept Basic Sci, Fac Med, Iraklion 71003, Crete, Greece. EM gregoriou@med.uoc.gr RI Gotts, Stephen/J-4842-2012; Gregoriou, Georgia/F-7759-2011 OI Gregoriou, Georgia/0000-0002-4002-6657 FU European Community [PIRG05-GA-2009-246761]; General Secretariat for Research and Technology [9FR27]; University of Crete [3004]; National Institutes of Health (USA) [MH64445]; National Institute of Mental Health, Division of Intramural Research; [5R01EY017921] FX We thank Grant Pielli, Donovan Stock and Courtney Alfes for help with the animal training and Steve Stefanou and George Spiropoulos for help with preliminary analysis. The authors were supported by a 5R01EY017921 Grant to R.D., by the European Community's Seventh Framework Programme (Grant PIRG05-GA-2009-246761), the General Secretariat for Research and Technology (Grant 9FR27), and the Special Account of Research Funds, University of Crete (Grant 3004) to G.G.G. S.J.G. was supported initially by MH64445 from the National Institutes of Health (USA) and later by the National Institute of Mental Health, Division of Intramural Research. NR 75 TC 68 Z9 68 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 9 PY 2012 VL 73 IS 3 BP 581 EP 594 DI 10.1016/j.neuron.2011.12.019 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 890JJ UT WOS:000300140600017 PM 22325208 ER PT J AU Jayasooriya, S Hislop, A Peng, YC Croom-carter, D Jankey, Y Bell, A Dong, T Rowland-Jones, S Rickinson, A Walther, M Whittle, H AF Jayasooriya, Shamanthi Hislop, Andrew Peng, Yanchun Croom-carter, Debbie Jankey, Ya Bell, Andrew Dong, Tao Rowland-Jones, Sarah Rickinson, Alan Walther, Michael Whittle, Hilton TI Revisiting the Effect of Acute P. falciparum Malaria on Epstein-Barr Virus: Host Balance in the Setting of Reduced Malaria Endemicity SO PLOS ONE LA English DT Article ID T-CELL IMMUNITY; B-CELL; BURKITTS-LYMPHOMA; GAMBIAN CHILDREN; AFRICAN CHILDREN; IN-VIVO; DIFFERENTIATION; REACTIVATION; PARASITEMIA; PREVALENCE AB Burkitt's lymphoma (BL), an EBV-associated tumour, occurs at high incidence in populations where malaria is holoendemic. Previous studies in one such population suggested that acute P. falciparum infection impairs EBV-specific T-cell surveillance, allowing expansion of EBV infected B-cells from which BL derives. We re-examined the situation in the same area, The Gambia, after a reduction in malaria endemicity. Cellular immune responses to EBV were measured in children with uncomplicated malaria before (day 0) and after treatment (day 28), comparing EBV genome loads in blood and EBV-specific CD8(+) T-cell numbers (assayed by MHC Class I tetramers and IFN gamma ELISPOTS) with those seen in age-and sex-matched healthy controls. No significant changes were seen in EBV genome loads, percentage of EBV-specific CD8(+) T-cells and IFN gamma producing T-cells in acute versus convalescent samples, nor any difference versus controls. Regression assays performed also no longer detected any impairment of EBV-specific T-cell surveillance. Acute uncomplicated malaria infection no longer alters EBV-specific immune responses in children in The Gambia. Given the recent decline in malaria incidence in that country, we hypothesise that gross disturbance of the EBV-host balance may be a specific effect of acute malaria only in children with a history of chronic/recurrent malaria challenge. C1 [Jayasooriya, Shamanthi; Jankey, Ya; Walther, Michael; Whittle, Hilton] MRC Labs, Fajara, Gambia. [Jayasooriya, Shamanthi; Hislop, Andrew; Croom-carter, Debbie; Bell, Andrew; Rickinson, Alan] Univ Birmingham, Sch Canc Studies, Birmingham, W Midlands, England. [Peng, Yanchun; Dong, Tao; Rowland-Jones, Sarah] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [Walther, Michael] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Whittle, Hilton] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England. RP Jayasooriya, S (reprint author), MRC Labs, Fajara, Gambia. EM hcwhittle@yahoo.co.uk OI Bell, Andrew/0000-0001-9520-4417 FU Medical Research Council (MRC), Gambia; MRC FX This work was funded by the Medical Research Council (MRC), Gambia and Dr S Jayasooriya was a recipient of an MRC studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 8 PY 2012 VL 7 IS 2 AR e31142 DI 10.1371/journal.pone.0031142 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 924ZP UT WOS:000302730100046 PM 22347443 ER PT J AU Sokolov, MV Panyutin, IV Neumann, RD AF Sokolov, Mykyta V. Panyutin, Irina V. Neumann, Ronald D. TI Unraveling the Global microRNAome Responses to Ionizing Radiation in Human Embryonic Stem Cells SO PLOS ONE LA English DT Article ID HUMAN GASTRIC-CANCER; MIRNA MICROARRAY ANALYSIS; HUMAN FIBROBLASTS; INTEGRATIVE ANALYSIS; ENDOTHELIAL-CELLS; GENE-EXPRESSION; DOWN-REGULATION; CYCLE ARREST; LUNG-CANCER; DNA-REPAIR AB MicroRNAs (miRNA) comprise a group of short ribonucleic acid molecules implicated in regulation of key biological processes and functions at the post-transcriptional level. Ionizing radiation (IR) causes DNA damage and generally triggers cellular stress response. However, the role of miRNAs in IR-induced response in human embryonic stem cells (hESC) has not been defined yet. Here, by using system biology approaches, we show for the first time, that miRNAome undergoes global alterations in hESC (H1 and H9 lines) after IR. Interrogation of expression levels of 1,090 miRNA species in irradiated hESC showed statistically significant changes in 54 genes following 1 Gy of X-ray exposures; global miRNAome alterations were found to be highly temporally and cell line - dependent in hESC. Time-course studies showed that the 16 hr miRNAome radiation response of hESC is much more robust compared to 2 hr-response signature (only eight genes), and may be involved in regulating the cell cycle. Quantitative real-time PCR performed on some miRNA species confirms the robustness of our miRNA microarray platform. Positive regulation of differentiation-, cell cycle-, ion transport-and endomembrane system-related processes were predicted to be negatively affected by miRNAome changes in irradiated hESC. Our findings reveal a fundamental role of miRNAome in modulating the radiation response, and identify novel molecular targets of radiation in hESC. C1 [Sokolov, Mykyta V.; Panyutin, Irina V.; Neumann, Ronald D.] NIH, Ctr Clin, Div Nucl Med, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Sokolov, MV (reprint author), NIH, Ctr Clin, Div Nucl Med, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. EM sokolovm@mail.nih.gov FU National Institutes of Health, Clinical Center FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, Clinical Center. No additional external funding 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 75 TC 19 Z9 19 U1 3 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 FEB 8 PY 2012 VL 7 IS 2 AR e31028 DI 10.1371/journal.pone.0031028 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 924ZP UT WOS:000302730100033 PM 22347422 ER PT J AU Wei, DT Ren, CC Chen, XY Zhao, H AF Wei, Dingtai Ren, Chuancheng Chen, Xiaoyuan Zhao, Heng TI The Chronic Protective Effects of Limb Remote Preconditioning and the Underlying Mechanisms Involved in Inflammatory Factors in Rat Stroke SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; CEREBRAL-ISCHEMIA; FOCAL ISCHEMIA; MILD HYPOTHERMIA; BRAIN; TIM-3; REPERFUSION; EXPRESSION; DAMAGE; CARDIOPROTECTION AB We recently demonstrated that limb remote preconditioning (LRP) protects against focal ischemia measured 2 days post-stroke. Here, we studied whether LRP provides long-term protection and improves neurological function. We also investigated whether LRP transmits its protective signaling via the afferent nerve pathways from the preconditioned limb to the ischemic brain and whether inflammatory factors are involved in LRP, including the novel galectin-9/Tim-3 inflammatory cell signaling pathway, which induces cell death in lymphocytes. LRP in the left hind femoral artery was performed immediately before stroke. LRP reduced brain injury size both at 2 days and 60 days post-stroke and improved behavioral outcomes for up to 2 months. The sensory nerve inhibitors capsaicin and hexamethonium, a ganglion blocker, abolished the protective effects of LRP. In addition, LRP inhibited edema formation and blood-brain barrier (BBB) permeability measured 2 days post-stroke. Western blot and immunostaining analysis showed that LRP inhibited protein expression of both galectin-9 and T-cell immunoglobulin domain and mucin domain 3 (Tim-3), which were increased after stroke. In addition, LRP decreased iNOS and nitrotyrosine protein expression after stroke. In conclusion, LRP executes long-term protective effects against stroke and may block brain injury by inhibiting activities of the galectin-9/Tim-3 pathway, iNOS, and nitrotyrosine. C1 [Wei, Dingtai; Ren, Chuancheng; Zhao, Heng] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Wei, Dingtai; Ren, Chuancheng; Zhao, Heng] Stanford Univ, Stroke Ctr, Stanford, CA 94305 USA. [Wei, Dingtai] Tianjin Med Univ, Dept Radiol, Gen Hosp, Tianjin, Peoples R China. [Wei, Dingtai] Fujian Med Univ, Dept Radiol, Ningde Hosp, Fuzhou, Fujian, Peoples R China. [Ren, Chuancheng] Fudan Univ, Shanghai Hosp 5, Shanghai 200433, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD USA. RP Wei, DT (reprint author), Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. EM hzhao@stanford.edu FU NINDS [1R21NS057750-01A2, 1R01NS 064136-01] FX This study was supported by NINDS grants 1R21NS057750-01A2 (HZ) and 1R01NS 064136-01 (HZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 28 Z9 31 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 8 PY 2012 VL 7 IS 2 AR e30892 DI 10.1371/journal.pone.0030892 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 924ZP UT WOS:000302730100029 PM 22347410 ER PT J AU Singh, N Sun, HM Chaudhury, S AbdulHameed, MDM Wallqvist, A Tawa, G AF Singh, Narender Sun, Hongmao Chaudhury, Sidhartha AbdulHameed, Mohamed Diwan M. Wallqvist, Anders Tawa, Gregory TI A physicochemical descriptor-based scoring scheme for effective and rapid filtering of kinase-like chemical space SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID DRUG-LIKE PROPERTIES; COMBINATORIAL LIBRARY DESIGN; MOLECULAR-PROPERTIES; TARGETED LIBRARY; SELECTION CRITERIA; PROTEIN-KINASES; IN-VITRO; DISCOVERY; PREDICTION; INHIBITORS AB Background: The current chemical space of known small molecules is estimated to exceed 10(60) structures. Though the largest physical compound repositories contain only a few tens of millions of unique compounds, virtual screening of databases of this size is still difficult. In recent years, the application of physicochemical descriptor-based profiling, such as Lipinski's rule-of-five for drug-likeness and Oprea's criteria of lead-likeness, as early stage filters in drug discovery has gained widespread acceptance. In the current study, we outline a kinase-likeness scoring function based on known kinase inhibitors. Results: The method employs a collection of 22,615 known kinase inhibitors from the ChEMBL database. A kinase-likeness score is computed using statistical analysis of nine key physicochemical descriptors for these inhibitors. Based on this score, the kinase-likeness of four publicly and commercially available databases, i.e., National Cancer Institute database (NCI), the Natural Products database (NPD), the National Institute of Health's Molecular Libraries Small Molecule Repository (MLSMR), and the World Drug Index (WDI) database, is analyzed. Three of these databases, i.e., NCI, NPD, and MLSMR are frequently used in the virtual screening of kinase inhibitors, while the fourth WDI database is for comparison since it covers a wide range of known chemical space. Based on the kinase-likeness score, a kinase-focused library is also developed and tested against three different kinase targets selected from three different branches of the human kinome tree. Conclusions: Our proposed methodology is one of the first that explores how the narrow chemical space of kinase inhibitors and its relevant physicochemical information can be utilized to build kinase-focused libraries and prioritize pre-existing compound databases for screening. We have shown that focused libraries generated by filtering compounds using the kinase-likeness score have, on average, better docking scores than an equivalent number of randomly selected compounds. Beyond library design, our findings also impact the broader efforts to identify kinase inhibitors by screening pre-existing compound libraries. Currently, the NCI library is the most commonly used database for screening kinase inhibitors. Our research suggests that other libraries, such as MLSMR, are more kinase-like and should be given priority in kinase screenings. C1 [Singh, Narender; Chaudhury, Sidhartha; AbdulHameed, Mohamed Diwan M.; Wallqvist, Anders; Tawa, Gregory] USA, DoD Biotechnol High Performance Comp Software App, Telemed & Adv Technol Res Ctr, Med Res & Mat Command, Ft Detrick, MD 21702 USA. [Sun, Hongmao] NIH Chem Genom Ctr, Rockville, MD 20850 USA. RP Tawa, G (reprint author), USA, DoD Biotechnol High Performance Comp Software App, Telemed & Adv Technol Res Ctr, Med Res & Mat Command, Ft Detrick, MD 21702 USA. EM gtawa@bioanalysis.org RI AbdulHameed, Mohamed Diwan M/O-3088-2015; OI AbdulHameed, Mohamed Diwan M/0000-0003-1483-4084; wallqvist, anders/0000-0002-9775-7469 FU U.S. Department of Defense Threat Reduction Agency [TMTI0004_09_BH_T] FX Funding of this research was provided by the U.S. Department of Defense Threat Reduction Agency Grant TMTI0004_09_BH_T. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or of the U.S. Department of Defense. NR 66 TC 3 Z9 3 U1 0 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD FEB 8 PY 2012 VL 4 AR 4 DI 10.1186/1758-2946-4-4 PG 12 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 917EE UT WOS:000302154500001 PM 22316383 ER PT J AU Myers, MG Heymsfield, SB Haft, C Kahn, BB Laughlin, M Leibel, RL Tschop, MH Yanovski, JA AF Myers, Martin G., Jr. Heymsfield, Steven B. Haft, Carol Kahn, Barbara B. Laughlin, Maren Leibel, Rudolph L. Tschoep, Matthias H. Yanovski, Jack A. TI Challenges and Opportunities of Defining Clinical Leptin Resistance SO CELL METABOLISM LA English DT Review ID INSULIN-RESISTANCE; IN-VIVO; RECOMBINANT LEPTIN; ENERGY-BALANCE; MESSENGER-RNA; OBESITY; RECEPTOR; MICE; BRAIN; DEFICIENCY AB The widespread use of the inadequately defined term "leptin resistance" led the National Institutes of Health to convene a workshop aimed at developing a quantitative definition of this term that would facilitate mechanistic research into leptin's actions in human health and disease. Although leptin-responsive conditions are recognized, the field is limited by a lack of robust, easily quantifiable behavioral or metabolic biomarkers of the hormone's action. Further advances require biomarkers that can be used to identify patients who may benefit from leptin therapy and that are useful for understanding the determinants of clinical leptin responsiveness. C1 [Myers, Martin G., Jr.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48105 USA. [Myers, Martin G., Jr.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48105 USA. [Heymsfield, Steven B.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Haft, Carol; Laughlin, Maren] NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. [Kahn, Barbara B.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Leibel, Rudolph L.] Columbia Univ, Dept Pediat & Med, New York, NY 10032 USA. [Tschoep, Matthias H.] Univ Cincinnati, Dept Med, Cincinnati, OH 45229 USA. [Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. RP Myers, MG (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48105 USA. EM mgmyers@umich.edu; steven.heymsfield@pbrc.edu RI Tschoep, Matthias/I-5443-2014; OI Yanovski, Jack/0000-0001-8542-1637; Tschoep, Matthias/0000-0002-4744-371X FU National Institute of Diabetes and Digestive and Kidney Diseases FX This conference was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. NR 67 TC 66 Z9 66 U1 0 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD FEB 8 PY 2012 VL 15 IS 2 BP 150 EP 156 DI 10.1016/j.cmet.2012.01.002 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 895FM UT WOS:000300481600006 PM 22326217 ER PT J AU Clarke, MA Rodriguez, AC Gage, JC Herrero, R Hildesheim, A Wacholder, S Burk, R Schiffman, M AF Clarke, Megan A. Cecilia Rodriguez, Ana Gage, Julia C. Herrero, Rolando Hildesheim, Allan Wacholder, Sholom Burk, Robert Schiffman, Mark TI A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection SO BMC INFECTIOUS DISEASES LA English DT Article DE HPV; Vaginal pH; Cervical neoplasia; Aging; Chlamydia ID CHLAMYDIA-TRACHOMATIS; CERVICAL NEOPLASIA; BACTERIAL VAGINOSIS; COSTA-RICA; WOMEN; CANCER; CLASSIFICATION; GUANACASTE; RISK AB Background: Vaginal pH is related to genital tract inflammation and changes in the bacterial flora, both suggested cofactors for persistence of human papillomavirus (HPV) infection. To evaluate the relationship between vaginal pH and HPV, we analyzed data from our large population-based study in Guanacaste, Costa Rica. We examined vaginal pH and the risk of HPV infection, cytological abnormalities, and C. trachomatis infection. Methods: Our study included 9,165 women aged 18-97 at enrollment with a total of 28,915 visits (mean length of follow-up = 3.4 years). Generalized estimating equations were used to evaluate the relationship between vaginal pH and HPV infection (both overall and single versus multiple types) and low-grade squamous intraepithelial lesions (LSIL), the cytomorphic manifestation of HPV infection. The relationship between enrollment vaginal pH and C. trachomatis infection was assessed by logistic regression. Results were stratified by age at visit. Results: Detection of HPV was positively associated with vaginal pH, mainly in women < 35 years (p-trend = 0.009 and 0.007 for women aged < 25 and 25-34 years, respectively). Elevated vaginal pH was associated with 30% greater risk of infection with multiple HPV types and with LSIL, predominantly in women younger than 35 and 65+ years of age. Detection of C. trachomatis DNA was associated with increased vaginal pH in women < 25 years (OR 2.2 95% CI 1.0-5.0). Conclusions: Our findings suggest a possible association of the cervical microenvironment as a modifier of HPV natural history in the development of cervical precancer and cancer. Future research should include studies of vaginal pH in a more complex assessment of hormonal changes and the cervicovaginal microbiome as they relate to the natural history of cervical neoplasia. C1 [Clarke, Megan A.; Gage, Julia C.; Hildesheim, Allan; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Bethesda, MD 20892 USA. [Cecilia Rodriguez, Ana; Herrero, Rolando] Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Burk, Robert] Albert Einstein Coll Med, Dept Pediat Microbiol & Immunol, Bronx, NY 10467 USA. [Clarke, Megan A.] NCI, Clin Genet Branch, DCEG, Rockville, MD 20852 USA. RP Clarke, MA (reprint author), NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Bethesda, MD 20892 USA. EM clarkma2@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU National Institutes of Health [N01-CP-21081, N01-CP-33061, N01-CP-40542, N01-CP-50535, N01-CP-81023]; National Cancer Institute, National Institutes of Health, Department of Health and Human Services; [CA78527] FX National Institutes of Health contracts (N01-CP-21081, N01-CP-33061, N01-CP-40542, N01-CP-50535, N01-CP-81023) and grant (CA78527 to R.D.B.). The Guanacaste cohort (design and conduct of the study, sample collection, cytology, data management, analysis and interpretation of the data) was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. HPV testing was supported by Dr. Burk's grant support. NR 31 TC 24 Z9 31 U1 3 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD FEB 8 PY 2012 VL 12 AR 33 DI 10.1186/1471-2334-12-33 PG 9 WC Infectious Diseases SC Infectious Diseases GA 902TI UT WOS:000301063500001 PM 22316377 ER PT J AU Berzofsky, JA AF Berzofsky, Jay A. TI Improving Immunotherapy: Revisiting the Immunologist's Little Secret SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID DENDRITIC CELLS C1 NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM berzofsj@mail.nih.gov NR 13 TC 0 Z9 0 U1 0 U2 3 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 FEB 8 PY 2012 VL 4 IS 120 AR 120fs4 DI 10.1126/scitranslmed.3003658 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 891NJ UT WOS:000300223600001 PM 22323826 ER PT J AU Pierson, TC Kuhn, RJ AF Pierson, Theodore C. Kuhn, Richard J. TI Capturing a Virus while It Catches Its Breath SO STRUCTURE LA English DT Editorial Material ID DENGUE-VIRUS; ENVELOPE PROTEIN; ANTIBODY; EPITOPES; SURFACE; VACCINE C1 [Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. [Kuhn, Richard J.] Purdue Univ, Markey Ctr Struct Biol, Dept Biol Sci, W Lafayette, IN 47907 USA. RP Pierson, TC (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bldg 10, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov; kuhnr@purdue.edu FU Intramural NIH HHS [ZIA AI000957-08]; NIAID NIH HHS [P01 AI055672] NR 11 TC 7 Z9 7 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD FEB 8 PY 2012 VL 20 IS 2 BP 200 EP 202 DI 10.1016/j.str.2012.01.014 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 893WI UT WOS:000300388000003 PM 22325768 ER PT J AU Henderson, R Sali, A Baker, ML Carragher, B Devkota, B Downing, KH Egelman, EH Feng, ZK Frank, J Grigorieff, N Jiang, W Ludtke, SJ Medalia, O Penczek, PA Rosenthal, PB Rossmann, MG Schmid, MF Schroder, GF Steven, AC Stokes, DL Westbrook, JD Wriggers, W Yang, HW Young, J Berman, HM Chiu, W Kleywegt, GJ Lawson, CL AF Henderson, Richard Sali, Andrej Baker, Matthew L. Carragher, Bridget Devkota, Batsal Downing, Kenneth H. Egelman, Edward H. Feng, Zukang Frank, Joachim Grigorieff, Nikolaus Jiang, Wen Ludtke, Steven J. Medalia, Ohad Penczek, Pawel A. Rosenthal, Peter B. Rossmann, Michael G. Schmid, Michael F. Schroeder, Gunnar F. Steven, Alasdair C. Stokes, David L. Westbrook, John D. Wriggers, Willy Yang, Huanwang Young, Jasmine Berman, Helen M. Chiu, Wah Kleywegt, Gerard J. Lawson, Catherine L. TI Outcome of the First Electron Microscopy Validation Task Force Meeting SO STRUCTURE LA English DT News Item ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; HERPES-SIMPLEX-VIRUS; ESCHERICHIA-COLI RIBOSOME; RESOLUTION DENSITY MAPS; GROUP-II CHAPERONIN; SINGLE-PARTICLE; CRYO-EM; CRYOELECTRON MICROSCOPY; MACROMOLECULAR ASSEMBLIES; 3-DIMENSIONAL STRUCTURE C1 [Devkota, Batsal; Feng, Zukang; Westbrook, John D.; Yang, Huanwang; Young, Jasmine; Berman, Helen M.; Lawson, Catherine L.] Rutgers State Univ, Dept Chem & Chem Biol & Res Collaboratory Struct, Piscataway, NJ 08854 USA. [Henderson, Richard] MRC Lab Mol Biol, Cambridge CB2 0QH, England. [Sali, Andrej] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Dept Pharmaceut Chem, Calif Inst Quantitat Biosci, San Francisco, CA 94158 USA. [Baker, Matthew L.; Ludtke, Steven J.; Schmid, Michael F.; Chiu, Wah] Baylor Coll Med, Natl Ctr Macromol Imaging, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Carragher, Bridget] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Downing, Kenneth H.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Life Sci Div, Berkeley, CA 94720 USA. [Egelman, Edward H.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22904 USA. [Frank, Joachim] Columbia Univ, Howard Hughes Med Inst, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Frank, Joachim] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Grigorieff, Nikolaus] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Grigorieff, Nikolaus] Brandeis Univ, Howard Hughes Med Inst, Waltham, MA 02454 USA. [Jiang, Wen] Purdue Univ, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. [Jiang, Wen; Rossmann, Michael G.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Medalia, Ohad] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel. [Medalia, Ohad] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, IL-84105 Beer Sheva, Israel. [Penczek, Pawel A.] Univ Texas Houston, Houston Med Sch, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Rosenthal, Peter B.] MRC Natl Inst Med Res, Div Phys Biochem, London NW7 1AA, England. [Schroeder, Gunnar F.] Forschungszentrum Julich, Inst Complex Syst ICS 6, D-52425 Julich, Germany. [Steven, Alasdair C.] NIAMSD, Lab Struct Biol Res, NIH, Bethesda, MD 20892 USA. [Stokes, David L.] NYU, Skirball Inst Biomol Med, Sch Med, New York, NY 10012 USA. [Wriggers, Willy] DE Shaw Res, New York, NY 10036 USA. [Kleywegt, Gerard J.] EMBL EBI, Prot Data Bank Europe, Cambridge CB10 1SD, England. RP Lawson, CL (reprint author), Rutgers State Univ, Dept Chem & Chem Biol & Res Collaboratory Struct, 610 Taylor Rd, Piscataway, NJ 08854 USA. EM cathy.lawson@rutgers.edu RI Schroder, Gunnar/H-5261-2013; OI Schroder, Gunnar/0000-0003-1803-5431; Westbrook, John/0000-0002-6686-5475; Carragher, Bridget/0000-0002-0624-5020; Egelman, Edward/0000-0003-4844-5212; Kleywegt, Gerard J./0000-0002-4670-0331 FU Biotechnology and Biological Sciences Research Council [BB/G022577/1]; Medical Research Council [MC_U105184322, MC_U117581334]; NCRR NIH HHS [P41 RR002250, P41RR002250]; NIGMS NIH HHS [R01 GM060635, R01 GM079429, R01GM079429]; Wellcome Trust [088944] NR 115 TC 139 Z9 139 U1 2 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD FEB 8 PY 2012 VL 20 IS 2 BP 205 EP 214 DI 10.1016/j.str.2011.12.014 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 893WI UT WOS:000300388000005 PM 22325770 ER PT J AU Geisler, IM Schneider, JP AF Geisler, Iris M. Schneider, Joel P. TI Evolution-Based Design of an Injectable Hydrogel SO ADVANCED FUNCTIONAL MATERIALS LA English DT Article DE self-assembly; peptides; hydrogels; injectable materials; encapsulation ID SELF-ASSEMBLING PEPTIDE; MESENCHYMAL STEM-CELLS; BIOMEDICAL APPLICATIONS; SMALL MOLECULES; DRUG-DELIVERY; IN-VITRO; SCAFFOLDS; RELEASE; BEHAVIOR; PHOTOPOLYMERIZATION AB A new class of simple, linear, amphiphilic peptides are developed that have the ability to undergo triggered self-assembly into self-supporting hydrogels. Under non-gelling aqueous conditions, these peptides exist in a random coil conformation and peptide solutions have the viscosity of water. On the addition of a buffered saline solution, the peptides assemble into a beta-sheet rich network of fibrils, ultimately leading to hydrogelation. A family of nine peptides is prepared to study the influence of peptide length and amino acid composition on the rate of self-assembly and hydrogel material properties. The amino acid composition is modulated by varying residue hydrophobicity and hydrophilicity on the two opposing faces of the amphiphile. The conformation of peptides in their soluble and gel state is studied by circular dichroism (CD), while the resultant material properties of their gels is investigated using oscillatory sheer rheology. One weight percent gels formed under physiological conditions have storage modulus (G') values that vary from approximate to 20 to approximate to 800 Pa, with sequence length and hydrophobic character playing a dominant roll in defining hydrogel rigidity. Based on the structural and functional data provided by the nine-peptide family members, an optimal sequence, namely LK13, is evolved. LK13 (LKLKLKLKLKLKL-NH2) undergoes triggered self-assembly, affording the most rigid gel of those studied (G'=797 +/- 105). It displays shear thin-recovery behavior, allowing its delivery by syringe and is cytocompatibile as assessed with murine C3H10t1/2 mesenchymal stem cells. C1 [Geisler, Iris M.; Schneider, Joel P.] NCI, NIH, Frederick, MD 21702 USA. RP Geisler, IM (reprint author), NCI, NIH, Frederick, MD 21702 USA. EM Joel.Schneider@nih.gov RI Schneider, Joel/N-2610-2014 FU National Cancer Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. The authors would like to acknowledge Katelyn Nagy and Kunio Nagashima for their work with TEM imaging. NR 65 TC 30 Z9 30 U1 8 U2 94 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1616-301X J9 ADV FUNCT MATER JI Adv. Funct. Mater. PD FEB 8 PY 2012 VL 22 IS 3 BP 529 EP 537 DI 10.1002/adfm.201102330 PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 884UL UT WOS:000299734200007 ER PT J AU Heuett, WJ Miller, BV Racette, SB Holloszy, JO Chow, CC Periwal, V AF Heuett, William J. Miller, Bernard V., III Racette, Susan B. Holloszy, John O. Chow, Carson C. Periwal, Vipul TI Bayesian Functional Integral Method for Inferring Continuous Data from Discrete Measurements SO BIOPHYSICAL JOURNAL LA English DT Article ID OBESE AFRICAN-AMERICANS; C-PEPTIDE; GLUCOSE-TOLERANCE; INSULIN-SECRETION; EXTRACTION; DIET AB Inference of the insulin secretion rate (ISR) from C-peptide measurements as a quantification of pancreatic beta-cell function is clinically important in diseases related to reduced insulin sensitivity and insulin action. ISR derived from C-peptide concentration is an example of nonparametric Bayesian model selection where a proposed ISR time-course is considered to be a "model". An inferred value of inaccessible continuous variables from discrete observable data is often problematic in biology and medicine, because it is a priori unclear how robust the inference is to the deletion of data points, and a closely related question, how much smoothness or continuity the data actually support. Predictions weighted by the posterior distribution can be cast as functional integrals as used in statistical field theory. Functional integrals are generally difficult to evaluate, especially for nonanalytic constraints such as positivity of the estimated parameters. We propose a computationally tractable method that uses the exact solution of an associated likelihood function as a prior probability distribution for a Markov-chain Monte Carlo evaluation of the posterior for the full model. As a concrete application of our method, we calculate the ISR from actual clinical C-peptide measurements in human subjects with varying degrees of insulin sensitivity. Our method demonstrates the feasibility of functional integral Bayesian model selection as a practical method for such data-driven inference, allowing the data to determine the smoothing timescale and the width of the prior probability distribution on the space of models. In particular, our model comparison method determines the discrete time-step for interpolation of the unobservable continuous variable that is supported by the data. Attempts to go to finer discrete time-steps lead to less likely models. C1 [Heuett, William J.] Marymount Univ, Dept Math, Arlington, VA 22207 USA. [Heuett, William J.; Chow, Carson C.; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. [Miller, Bernard V., III] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Racette, Susan B.] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, St Louis, MO USA. [Holloszy, John O.] Washington Univ, Sch Med, Dept Med, Div Geriatr & Nutr Sci, St Louis, MO 63110 USA. RP Heuett, WJ (reprint author), Marymount Univ, Dept Math, Arlington, VA 22207 USA. EM wheuett@marymount.edu; vipulp@mail.nih.gov RI Chow, Carson/A-7970-2009; Periwal, Vipul/I-1728-2012; OI Racette, Susan/0000-0002-6932-1887 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland FX This work was supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. NR 17 TC 3 Z9 3 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 8 PY 2012 VL 102 IS 3 BP 399 EP 406 DI 10.1016/j.bpj.2011.12.046 PG 8 WC Biophysics SC Biophysics GA 890CK UT WOS:000300122500004 PM 22325261 ER PT J AU Koch, D Rosoff, WJ Jiang, JJ Geller, HM Urbach, JS AF Koch, Daniel Rosoff, William J. Jiang, Jiji Geller, Herbert M. Urbach, Jeffrey S. TI Strength in the Periphery: Growth Cone Biomechanics and Substrate Rigidity Response in Peripheral and Central Nervous System Neurons SO BIOPHYSICAL JOURNAL LA English DT Article ID HIPPOCAMPAL-NEURONS; NEURITE ELONGATION; FORCE MICROSCOPY; FOCAL ADHESIONS; POINT CONTACTS; CYTOSKELETAL DYNAMICS; MECHANICAL TENSION; AXONAL ELONGATION; TRACTION FORCE; OUTGROWTH AB There is now considerable evidence of the importance of mechanical cues in neuronal development and regeneration. Motivated by the difference in the mechanical properties of the tissue environment between the peripheral (PNS) and central (CNS) nervous systems, we compare substrate-stiffness-dependent outgrowth and traction forces from PNS (dorsal root ganglion (DRG)) and CNS (hippocampal) neurons. We show that neurites from DRG neurons display maximal outgrowth on substrates with a Young's modulus of similar to 1000 Pa, whereas hippocampal neurite outgrowth is independent of substrate stiffness. Using traction force microscopy, we also find a substantial difference in growth cone traction force generation, with DRG growth cones exerting severalfold larger forces compared with hippocampal growth cones. The traction forces generated by DRG and hippocampal growth cones both increase with increasing stiffness, and DRG growth cones growing on substrates with a Young's modulus of 1000 Pa strengthen considerably after 18-30 h. Finally, we find that retrograde actin flow is almost three times faster in hippocampal growth cones than in DRG. Moreover, the density of paxillin puncta is significantly lower in hippocampal growth cones, suggesting that stronger substrate coupling of the DRG cytoskeleton is responsible for the remarkable difference in traction force generation. These findings reveal a differential adaptation of cytoskeletal dynamics to substrate stiffness in growth cones of different neuronal types, and highlight the potential importance of the mechanical properties of the cellular environment for neuronal navigation during embryonic development and nerve regeneration. C1 [Koch, Daniel; Rosoff, William J.; Jiang, Jiji; Urbach, Jeffrey S.] Georgetown Univ, Dept Phys, Washington, DC 20057 USA. [Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Urbach, JS (reprint author), Georgetown Univ, Dept Phys, Washington, DC 20057 USA. EM urbach@physics.georgetown.edu OI Urbach, Jeffrey/0000-0002-1593-520X; Geller, Herbert/0000-0002-7048-6144 FU National Institute of Neurological Disorders and Stroke [1R01NS064250-01]; National Heart, Lung, and Blood Institute FX This work was supported by National Institute of Neurological Disorders and Stroke grant 1R01NS064250-01 (J.S.U.) and the National Heart, Lung, and Blood Institute Intramural Research Program (H.M.G.). NR 51 TC 77 Z9 79 U1 3 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 8 PY 2012 VL 102 IS 3 BP 452 EP 460 DI 10.1016/j.bpj.2011.12.025 PG 9 WC Biophysics SC Biophysics GA 890CK UT WOS:000300122500010 PM 22325267 ER PT J AU Pfefferkorn, CM Heinrich, F Sodt, AJ Maltsev, AS Pastor, RW Lee, JC AF Pfefferkorn, Candace M. Heinrich, Frank Sodt, Alexander J. Maltsev, Alexander S. Pastor, Richard W. Lee, Jennifer C. TI Depth of alpha-Synuclein in a Bilayer Determined by Fluorescence, Neutron Reflectometry, and Computation SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; SOLUTION NMR-SPECTROSCOPY; PULSED ESR MEASUREMENTS; PARKINSONS-DISEASE; TRYPTOPHAN FLUORESCENCE; SECONDARY STRUCTURE; IN-VITRO; VESICLE PERMEABILIZATION; PHOSPHOLIPID-BINDING; MEMBRANE INTERACTION AB alpha-Synuclein (alpha-syn) membrane interactions are implicated in the pathogenesis of Parkinson's disease. Fluorescence and neutron reflectometry (NR) measurements reveal that alpha-syn penetrates similar to 9-14 angstrom into the outer leaflet of the bilayer, with a substantial portion of the membrane-bound polypeptide extending into the aqueous solvent. For the first time, to our knowledge, we used NR to obtain direct quantitative evidence of alpha-syn-induced membrane thinning. To examine the effect of specific residues on membrane penetration depths, we used a series of W4-containing N-terminal peptides. We identified that the first 15 residues (P15) nearly recapitulate the features of the full-length protein (i.e., partition constants, molecular Mobility, and insertion of the W4 side chain into the bilayer), and found that as few as the first four N-terminal residues are sufficient for vesicle binding. Although at least one imperfect amphipathic repeat sequence (KAKEGV) is required for alpha-helical formation, secondary structural formation has little effect on membrane affinity. To develop an N-terminal alpha-syn model for bilayer interactions, we performed molecular-dynamics simulations of the P15 peptide submerged in a bilayer. The simulation results are highly consistent with experimental data indicating a broad low-energy region (8.5-14.5 angstrom) for W4 insertion. C1 [Pfefferkorn, Candace M.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Sodt, Alexander J.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Maltsev, Alexander S.] NIDDK, Lab Chem Phys, NIH, Bethesda, MD USA. [Heinrich, Frank] Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA. [Heinrich, Frank] Natl Inst Stand & Technol, Ctr Neutron Res, Gaithersburg, MD 20899 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI Maltsev, Alexander/A-8175-2012; Heinrich, Frank/A-5339-2010; Lee, Jennifer/E-9658-2015 OI Heinrich, Frank/0000-0002-8579-553X; Lee, Jennifer/0000-0003-0506-8349 FU NHLBI; NIDDK, National Institutes of Health FX This work was supported by the Intramural Research Program of the NHLBI and NIDDK, National Institutes of Health. Research was performed in part at the NIST for Nanoscale Science and Technology. NR 88 TC 33 Z9 33 U1 2 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 8 PY 2012 VL 102 IS 3 BP 613 EP 621 DI 10.1016/j.bpj.2011.12.051 PG 9 WC Biophysics SC Biophysics GA 890CK UT WOS:000300122500028 PM 22325285 ER PT J AU Colloca, L Finniss, D AF Colloca, Luana Finniss, Damien TI Nocebo Effects, Patient-Clinician Communication, and Therapeutic Outcomes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Colloca, Luana] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Colloca, Luana] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Finniss, Damien] Univ Sydney, Royal N Shore Hosp, Pain Management & Res Inst, St Leonards, NSW 2065, Australia. RP Colloca, L (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM luana.colloca@nih.gov OI Colloca, Luana/0000-0002-6503-4709 FU Intramural NIH HHS NR 8 TC 89 Z9 90 U1 1 U2 30 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 FEB 8 PY 2012 VL 307 IS 6 BP 567 EP 568 DI 10.1001/jama.2012.115 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 888GT UT WOS:000299992500018 PM 22318275 ER PT J AU Girgis, HZ Ovcharenko, I AF Girgis, Hani Z. Ovcharenko, Ivan TI Predicting tissue specific cis-regulatory modules in the human genome using pairs of co-occurring motifs SO BMC BIOINFORMATICS LA English DT Article ID DE-NOVO DISCOVERY; TRANSCRIPTION FACTORS; GENE-EXPRESSION; HEART ENHANCERS; BINDING-SITES; IDENTIFICATION; LIVER; SEQUENCES; CLUSTERS; DNA AB Background: Researchers seeking to unlock the genetic basis of human physiology and diseases have been studying gene transcription regulation. The temporal and spatial patterns of gene expression are controlled by mainly non-coding elements known as cis-regulatory modules (CRMs) and epigenetic factors. CRMs modulating related genes share the regulatory signature which consists of transcription factor (TF) binding sites (TFBSs). Identifying such CRMs is a challenging problem due to the prohibitive number of sequence sets that need to be analyzed. Results: We formulated the challenge as a supervised classification problem even though experimentally validated CRMs were not required. Our efforts resulted in a software system named CrmMiner. The system mines for CRMs in the vicinity of related genes. CrmMiner requires two sets of sequences: a mixed set and a control set. Sequences in the vicinity of the related genes comprise the mixed set, whereas the control set includes random genomic sequences. CrmMiner assumes that a large percentage of the mixed set is made of background sequences that do not include CRMs. The system identifies pairs of closely located motifs representing vertebrate TFBSs that are enriched in the training mixed set consisting of 50% of the gene loci. In addition, CrmMiner selects a group of the enriched pairs to represent the tissue-specific regulatory signature. The mixed and the control sets are searched for candidate sequences that include any of the selected pairs. Next, an optimal Bayesian classifier is used to distinguish candidates found in the mixed set from their control counterparts. Our study proposes 62 tissue-specific regulatory signatures and putative CRMs for different human tissues and cell types. These signatures consist of assortments of ubiquitously expressed TFs and tissue-specific TFs. Under controlled settings, CrmMiner identified known CRMs in noisy sets up to 1: 25 signal-to-noise ratio. CrmMiner was 21-75% more precise than a related CRM predictor. The sensitivity of the system to locate known human heart enhancers reached up to 83%. CrmMiner precision reached 82% while mining for CRMs specific to the human CD4(+) T cells. On several data sets, the system achieved 99% specificity. Conclusion: These results suggest that CrmMiner predictions are accurate and likely to be tissue-specific CRMs. We expect that the predicted tissue-specific CRMs and the regulatory signatures broaden our knowledge of gene transcription regulation. C1 [Girgis, Hani Z.; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20896 USA. RP Ovcharenko, I (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, 9600 Rockville Pike, Bethesda, MD 20896 USA. EM ovcharen@nih.gov FU National Institutes of Health, National Library of Medicine FX The authors would like to thank Sharon Milgram and David Landsman for helpful discussions. We also thank the anonymous reviewers whose comments have improved this manuscript. HZG thanks Virginia LoCastro for her invaluable comments on the writing of the manuscript. HZG would like to thank Loren Hansen, Ben Busby, and Jeff Skinner for several discussions. The authors thank Charles Vinson for suggesting that the regulatory signatures consist of ubiquitously expressed and tissue-specific transcription factors. IO thanks Leila Taher for providing the gene expression data. HZG is grateful to Verma Walker and the NIH Fellows Editorial Board for their help with editing. This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 55 TC 5 Z9 5 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 7 PY 2012 VL 13 AR 25 DI 10.1186/1471-2105-13-25 PG 17 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 946JO UT WOS:000304348000001 PM 22313678 ER PT J AU Zwart, SR Jessup, JM Ji, JP Smith, SM AF Zwart, Sara R. Jessup, J. Milburn Ji, Jiuping Smith, Scott M. TI Saturation Diving Alters Folate Status and Biomarkers of DNA Damage and Repair SO PLOS ONE LA English DT Article ID RED-CELL MASS; NUTRITIONAL-STATUS; BODY IRON; BED REST; CANCER; DIVE; HUMANS; NEOCYTOLYSIS; GAMMA-H2AX; DISEASE AB Exposure to oxygen-rich environments can lead to oxidative damage, increased body iron stores, and changes in status of some vitamins, including folate. Assessing the type of oxidative damage in these environments and determining its relationships with changes in folate status are important for defining nutrient requirements and designing countermeasures to mitigate these effects. Responses of humans to oxidative stressors were examined in participants undergoing a saturation dive in an environment with increased partial pressure of oxygen, a NASA Extreme Environment Mission Operations mission. Six participants completed a 13-d saturation dive in a habitat 19 m below the ocean surface near Key Largo, FL. Fasting blood samples were collected before, twice during, and twice after the dive and analyzed for biochemical markers of iron status, oxidative damage, and vitamin status. Body iron stores and ferritin increased during the dive (P < 0.001), with a concomitant decrease in RBC folate (P < 0.001) and superoxide dismutase activity (P < 0.001). Folate status was correlated with serum ferritin (Pearson r = -0.34, P < 0.05). Peripheral blood mononuclear cell poly(ADP-ribose) increased during the dive and the increase was significant by the end of the dive (P < 0.001); gamma-H2AX did not change during the mission. Together, the data provide evidence that when body iron stores were elevated in a hyperoxic environment, a DNA damage repair response occurred in peripheral blood mononuclear cells, but double-stranded DNA damage did not. In addition, folate status decreases quickly in this environment, and this study provides evidence that folate requirements may be greater when body iron stores and DNA damage repair responses are elevated. C1 [Zwart, Sara R.] Univ Space Res Assoc, Houston, TX USA. [Jessup, J. Milburn; Ji, Jiuping] Natl Canc Inst, Bethesda, MD USA. [Smith, Scott M.] NASA, Lyndon B Johnson Space Ctr, Houston, TX 77058 USA. RP Zwart, SR (reprint author), Univ Space Res Assoc, Houston, TX USA. EM sara.zwart-1@nasa.gov FU NASA FX This study was supported by the NASA Human Research Program Human Health and Countermeasures Element. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 8 Z9 9 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 FEB 7 PY 2012 VL 7 IS 2 AR e31058 DI 10.1371/journal.pone.0031058 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 917MF UT WOS:000302180600027 PM 22347427 ER PT J AU Berezhkovskii, AM Barzykin, AV AF Berezhkovskii, Alexander M. Barzykin, Alexander V. TI Search for a small hole in a cavity wall by intermittent bulk and surface diffusion SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ESCAPE AB We study the search of a small round hole in the wall of a spherical cavity by a diffusing particle, which can reversibly bind to the cavity wall and diffuse on the surface being in the bound state. There are two channels for the particle first passage to the hole, through the bulk, and through the surface. We propose a coarse-grained model of the search process and use it to derive simple approximate formulas for the mean time required for the particle to reach the hole for the first time and for the probability of the first passage to the hole through the bulk channel. This is done for two distributions of the particle starting point: (1) Uniform distribution over the cavity volume and (2) uniform distribution over the cavity wall. We check the accuracy of the approximate formulas by comparing their predictions with the corresponding quantities found by solving the mixed bulk-surface diffusion problem numerically by the finite difference method. The comparison shows excellent agreement between the analytical and numerical results. (C) 2012 American Institute of Physics. [doi:10.1063/1.3682243] C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Barzykin, Alexander V.] Royal Bank Scotland, London EC2M 4AA, England. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@mail.nih.gov FU National Institutes of Health (NIH), the Center for Information Technology FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), the Center for Information Technology. NR 15 TC 11 Z9 11 U1 0 U2 4 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD FEB 7 PY 2012 VL 136 IS 5 AR 054115 DI 10.1063/1.3682243 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 896EC UT WOS:000300547200015 PM 22320733 ER PT J AU Pinsky, PF AF Pinsky, Paul F. TI Comparative Effectiveness of Digital Versus Film-Screen Mammography SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), NCI, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 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 FEB 7 PY 2012 VL 156 IS 3 BP 250 EP 250 DI 10.7326/0003-4819-156-3-201202070-00023 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 887XD UT WOS:000299964200017 PM 22312151 ER PT J AU Putney, JW AF Putney, James W. TI Calcium Signaling: Deciphering the Calcium-NFAT Pathway SO CURRENT BIOLOGY LA English DT Editorial Material ID GENE-REGULATION; CHANNELS AB Rapid cellular calcium oscillations activate gene expression hours later. How this temporal response amplification is achieved has until now been largely a mystery. An elegant combination of experimental strategies and a model that encompasses non-linear inputs and outputs now sheds new light on this long-standing problem. C1 NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov NR 13 TC 4 Z9 5 U1 0 U2 7 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 FEB 7 PY 2012 VL 22 IS 3 BP R87 EP R89 DI 10.1016/j.cub.2011.12.030 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 889JO UT WOS:000300070200008 PM 22321308 ER PT J AU Agniswamy, J Sayer, JM Weber, IT Louis, JM AF Agniswamy, Johnson Sayer, Jane M. Weber, Irene T. Louis, John M. TI Terminal Interface Conformations Modulate Dimer Stability Prior to Amino Terminal Autoprocessing of HIV-1 Protease SO BIOCHEMISTRY LA English DT Article ID RESOLUTION CRYSTAL-STRUCTURES; POL POLYPROTEIN PRECURSOR; VIRUS TYPE-1 GAG; REVERSE-TRANSCRIPTASE; TRANSFRAME PROTEIN; INHIBITION; MECHANISM; ENZYMES; RESIDUES; CLEAVAGE AB The HIV-1 protease (PR) mediates its own release (autoprocessing) from the polyprotein precursor, Gag-Pol, flanked by the transframe region (TFR) and reverse transcriptase at its N- and C-termini, respectively. Autoprocessing at the N-terminus of PR mediates stable dimer formation essential for catalytic activity, leading to the formation of infectious virus. An antiparallel beta-sheet interface formed by the four N- and C-terminal residues of each subunit is important for dimer stability. Here, we present the first high-resolution crystal structures of model protease precursor-clinical inhibitor (PI darunavir or saquinavir) complexes, revealing varying conformations of the N-terminal flanking (S-4FNF-1) and interface residues (P(1)QIT(4)). A 180 degrees rotation of the T-4-L-5 peptide bond is accompanied by a new Q(2)-L-5 hydrogen bond and complete disengagement of PQIT from the beta-sheet dimer interface, which may be a feature for intramolecular autoprocessing. This result is consistent with drastically lower thermal stability by 14-20 degrees C of PI complexes of precursors and the mature PR lacking its PQIT residues (by 18.3 degrees C). Similar to the TFR-PR precursor, this deletion also results in a darunavir dissociation constant (2 x 10(4))-fold higher and a markedly increased dimer dissociation constant relative to the mature PR The terminal beta-sheet perturbations of the dimeric structure likely account for the drastically poorer inhibition of autoprocessing of TFR-PR relative to the mature PR, even though significant differences in active site-PI interactions in these structures were not observed. The novel conformations of the dimer interface may be exploited to target selectively the protease precursor prior to its N-terminal cleavage. C1 [Sayer, Jane M.; Louis, John M.] NIDDK, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Agniswamy, Johnson; Weber, Irene T.] Georgia State Univ, Dept Biol, Mol Basis Dis Program, Atlanta, GA 30303 USA. RP Louis, JM (reprint author), NIDDK, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM johnl@intra.niddk.nih.gov FU NIDDK, National Institutes of Health; Office of the Director, NIH; NIH [GM062920] FX This research was supported by the Intramural Research Program of the NIDDK, National Institutes of Health and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH, and grant GM062920 from the NIH. NR 38 TC 16 Z9 16 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 7 PY 2012 VL 51 IS 5 BP 1041 EP 1050 DI 10.1021/bi201809s PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 886NE UT WOS:000299860300012 PM 22242794 ER PT J AU Lee, HM Roth, BL AF Lee, Hyeong-Min Roth, Bryan L. TI Hallucinogen actions on human brain revealed SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PREFRONTAL CORTEX; 5-HT2A RECEPTORS; APICAL DENDRITES; PYRAMIDAL CELLS; MECHANISM; AGONIST C1 [Roth, Bryan L.] Univ N Carolina, Sch Med, Program Neurosci, Dept Pharmacol, Chapel Hill, NC 27514 USA. Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27514 USA. Univ N Carolina, NIMH, Psychoact Drug Screening Program, Sch Med, Chapel Hill, NC 27514 USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Program Neurosci, Dept Pharmacol, Chapel Hill, NC 27514 USA. EM bryan_roth@med.unc.edu RI Lee, HM/D-2777-2011; Roth, Bryan/F-3928-2010 FU NIDA NIH HHS [R01 DA017204]; NIMH NIH HHS [R01 MH061887] NR 14 TC 8 Z9 8 U1 3 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 FEB 7 PY 2012 VL 109 IS 6 BP 1820 EP 1821 DI 10.1073/pnas.1121358109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 887KC UT WOS:000299925000017 PM 22308478 ER PT J AU Boura, E Hurley, JH AF Boura, Evzen Hurley, James H. TI Structural basis for membrane targeting by the MVB12-associated beta-prism domain of the human ESCRT-I MVB12 subunit SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV; protein structure; protein-membrane interactions; X-ray crystallography; subcellular localization ID MULTIVESICULAR BODY; PHOSPHATIDYLINOSITOL 3-PHOSPHATE; SORTING MACHINERY; PROTEIN; COMPLEX; TSG101; CYTOKINESIS; TRAFFICKING; BINDING; YEAST AB MVB12-associated beta-prism (MABP) domains are predicted to occur in a diverse set of membrane-associated bacterial and eukaryotic proteins, but their existence, structure, and biochemical properties have not been characterized experimentally. Here, we find that the MABP domains of the MVB12A and B subunits of ESCRT-I are functional modules that bind in vitro to liposomes containing acidic lipids depending on negative charge density. The MABP domain is capable of autonomously localizing to subcellular puncta and to the plasma membrane. The 1.3-angstrom atomic resolution crystal structure of the MVB12B MABP domain reveals a beta-prism fold, a hydrophobic membrane-anchoring loop, and an electropositive phosphoinositide-binding patch. The basic patch is open, which explains how it senses negative charge density but lacks stereo-selectivity. These observations show how ESCRT-I could act as a coincidence detector for acidic phospholipids and protein ligands, enabling it to function both in protein transport at endosomes and in cytokinesis and viral budding at the plasma membrane. C1 [Boura, Evzen; 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 hurley@helix.nih.gov RI Boura, Evzen/I-2626-2012; Boura, Evzen/G-5275-2014 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Office of the Director, National Institutes of Health; Intramural AIDS Research Fellowship FX We thank W. Sundquist, J. Bonifacino, and Y. Ye for reagents and B. Beach and L. Saidi for excellent technical assistance. Crystallographic data were collected at Southeast Regional Collaborative Access Team 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. This work was supported by the Intramural Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (J.H.H.), the Intramural AIDS Targeted Anti-viral Program of the Office of the Director, National Institutes of Health (J.H.H.), and an Intramural AIDS Research Fellowship (to E.B.). NR 44 TC 18 Z9 18 U1 1 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 FEB 7 PY 2012 VL 109 IS 6 BP 1901 EP 1906 DI 10.1073/pnas.1117597109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 887KC UT WOS:000299925000028 PM 22232651 ER PT J AU Reiner, RC King, AA Emch, M Yunus, M Faruque, ASG Pascual, M AF Reiner, Robert C., Jr. King, Aaron A. Emch, Michael Yunus, Mohammad Faruque, A. S. G. Pascual, Mercedes TI Highly localized sensitivity to climate forcing drives endemic cholera in a megacity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE risk propagation; cholera and flooding; disease forecasting; inhomogeneous Markov chain; spatiotemporal dynamics of urban cholera ID INFECTIOUS-DISEASE; VIBRIO-CHOLERAE; BANGLADESH; DYNAMICS; EPIDEMIC; MODEL; MEASLES; FLOODS; DHAKA; HAITI AB The population dynamics of endemic cholera in urban environments-in particular interannual variation in the size and distribution of seasonal outbreaks-remain poorly understood and highly unpredictable. In part, this situation is due to the considerable demographic, socioeconomic, and environmental heterogeneity of large and growing urban centers. Despite this heterogeneity, the influence of climate variability on the population dynamics of infectious diseases is considered a large-scale, regional, phenomenon, and as such has been previously addressed for cholera only with temporal models that do not incorporate spatial structure. Here we show that a probabilistic spatial model can explain cholera dynamics in the megacity of Dhaka, Bangladesh, and afford a basis for cholera forecasts at lead times of 11 mo. Critically, we find that the action of climate variability (El Nino southern oscillation and flooding) is quite localized: There is a climate-sensitive urban core that acts to propagate risk to the rest of the city. The modeling framework presented here should be applicable to cholera in other cities, as well as to other infectious diseases in urban settings and other biological systems with spatiotemporal interactions. C1 [Reiner, Robert C., Jr.; King, Aaron A.; Pascual, Mercedes] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [King, Aaron A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Emch, Michael] Univ N Carolina, Dept Geog, Chapel Hill, NC 27599 USA. [Yunus, Mohammad; Faruque, A. S. G.] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Pascual, Mercedes] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Reiner, RC (reprint author), Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. EM rcreiner@ucdavis.edu RI King, Aaron/B-8092-2012 OI King, Aaron/0000-0001-6159-3207 FU National Oceanic and Atmospheric Administration [F020704]; Government of the People's Republic of Bangladesh; Canadian International Development Agency; Swedish International Development Cooperative Agency; Department for International Development, United Kingdom; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank Benjamin A. Cash for his input on climate data, and Andrea Rinaldi and two anonymous referees for helpful comments. This research was supported by the National Oceanic and Atmospheric Administration's Program on Oceans and Health (Grant # F020704). The cholera case data used in this paper were collected with the support of ICDDR,B and its donors who provide unrestricted support to ICDDR, B for its operation and research. Current donors providing unrestricted support include the Government of the People's Republic of Bangladesh, the Canadian International Development Agency, the Swedish International Development Cooperative Agency, and the Department for International Development, United Kingdom. We gratefully acknowledge these donors for their support and commitment to ICDDR,B's research efforts. M. P. is an investigator of the Howard Hughes Medical Institute. A. A. K. acknowledges the support of the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 31 TC 31 Z9 31 U1 6 U2 41 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 FEB 7 PY 2012 VL 109 IS 6 BP 2033 EP 2036 DI 10.1073/pnas.1108438109 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 887KC UT WOS:000299925000050 PM 22308325 ER PT J AU Beltran, WA Cideciyan, AV Lewin, AS Iwabe, S Khanna, H Sumaroka, A Chiodo, VA Fajardo, DS Roman, AJ Deng, WT Swider, M Aleman, TS Boye, SL Genini, S Swaroop, A Hauswirth, WW Jacobson, SG Aguirre, GD AF Beltran, William A. Cideciyan, Artur V. Lewin, Alfred S. Iwabe, Simone Khanna, Hemant Sumaroka, Alexander Chiodo, Vince A. Fajardo, Diego S. Roman, Alejandro J. Deng, Wen-Tao Swider, Malgorzata Aleman, Tomas S. Boye, Sanford L. Genini, Sem Swaroop, Anand Hauswirth, William W. Jacobson, Samuel G. Aguirre, Gustavo D. TI Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE retina; retinal degeneration ID RPGR EXON ORF15; LEBER CONGENITAL AMAUROSIS; GTPASE REGULATOR RPGR; MOUSE MODEL; DISEASE EXPRESSION; CONE VISION; RETINAL DEGENERATION; CHILDHOOD BLINDNESS; MUTATION ANALYSIS; CANINE MODEL AB Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment. C1 [Beltran, William A.; Iwabe, Simone; Genini, Sem; Aguirre, Gustavo D.] Univ Penn, Sch Vet Med, Sect Ophthalmol, Philadelphia, PA 19104 USA. [Cideciyan, Artur V.; Sumaroka, Alexander; Roman, Alejandro J.; Swider, Malgorzata; Aleman, Tomas S.; Jacobson, Samuel G.] Univ Penn, Perelman Sch Med, Dept Ophthalmol, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Lewin, Alfred S.; Fajardo, Diego S.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Khanna, Hemant; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Khanna, Hemant] Univ Massachusetts, Sch Med, Dept Ophthalmol, Worcester, MA 01605 USA. [Chiodo, Vince A.; Deng, Wen-Tao; Boye, Sanford L.; Hauswirth, William W.] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Beltran, WA (reprint author), Univ Penn, Sch Vet Med, Sect Ophthalmol, Philadelphia, PA 19104 USA. EM wbeltran@vet.upenn.edu; gda@vet.upenn.edu OI Lewin, Alfred/0000-0002-4192-9727; Swaroop, Anand/0000-0002-1975-1141 FU National Institutes of Health [EY-06855, EY-17549, EY-007961, EY-021721, P30 EY-001583, 2PNEY018241]; Foundation Fighting Blindness; Fight for Sight Nowak; Midwest Eye Banks and Transplantation Center; Macula Vision Research Foundation; Van Sloun Fund for Canine Genetic Research; Hope for Vision FX We thank Svetlana Savina for help with immunohistochemistry, Karla Carlisle and the Retinal Disease Studies Facility staff for animal care, Lydia Melnyk for research coordination, Dr. Muayyad al-Ubaidi for the human IRBP promoter plasmid, and Dr. Cheryl Craft for the human cone arrestin antibody. This work was supported by National Institutes of Health Grants EY-06855, EY-17549, EY-007961, EY-021721, P30 EY-001583, and 2PNEY018241, the Foundation Fighting Blindness, a Fight for Sight Nowak family grant, the Midwest Eye Banks and Transplantation Center, the Macula Vision Research Foundation, the Van Sloun Fund for Canine Genetic Research, and Hope for Vision. NR 59 TC 96 Z9 97 U1 2 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 FEB 7 PY 2012 VL 109 IS 6 BP 2132 EP 2137 DI 10.1073/pnas.1118847109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 887KC UT WOS:000299925000067 PM 22308428 ER PT J AU Sabatino, M Ren, JQ David-Ocampo, V England, L McGann, M Tran, M Kuznetsov, SA Khuu, H Balakumaran, A Klein, HG Robey, PG Stroncek, DF AF Sabatino, Marianna Ren, Jiaqiang David-Ocampo, Virginia England, Lee McGann, Michael Tran, Minh Kuznetsov, Sergei A. Khuu, Hanh Balakumaran, Arun Klein, Harvey G. Robey, Pamela G. Stroncek, David F. TI The establishment of a bank of stored clinical bone marrow stromal cell products SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID MESENCHYMAL STEM-CELLS; VERSUS-HOST-DISEASE; AMYOTROPHIC-LATERAL-SCLEROSIS; FETAL CALF SERUM; IN-VITRO; THERAPY; TRANSPLANTATION; MICROENVIRONMENT; PROLIFERATION; EFFICACY AB Background: Bone marrow stromal cells (BMSCs) are being used to treat a variety of conditions. For many applications a supply of cryopreserved products that can be used for acute therapy is needed. The establishment of a bank of BMSC products from healthy third party donors is described. Methods: The recruitment of healthy subjects willing to donate marrow for BMSC production and the Good Manufacturing Practices (GMP) used for assessing potential donors, collecting marrow, culturing BMSCs and BMSC cryopreservation are described. Results: Seventeen subjects were enrolled in our marrow collection protocol for BMSC production. Six of the 17 subjects were found to be ineligible during the donor screening process and one became ill and their donation was cancelled. Approximately 12 ml of marrow was aspirated from one posterior iliac crest of 10 donors; one donor donated twice. The BMSCs were initially cultured in T-75 flasks and then expanded for three passages in multilayer cell factories. The final BMSC product was packaged into units of 100 x 10(6) viable cells, cryopreserved and stored in a vapor phase liquid nitrogen tank under continuous monitoring. BMSC products meeting all lot release criteria were obtained from 8 of the 11 marrow collections. The rate of growth of the primary cultures was similar for all products except those generated from the two oldest donors. One lot did not meet the criteria for final release; its CD34 antigen expression was greater than the cut off set at 5%. The mean number of BMSC units obtained from each donor was 17 and ranged from 3 to 40. Conclusions: The production of large numbers of BMSCs from bone marrow aspirates of healthy donors is feasible, but is limited by the high number of donors that did not meet eligibility criteria and products that did not meet lot release criteria. C1 [Sabatino, Marianna; Ren, Jiaqiang; David-Ocampo, Virginia; England, Lee; McGann, Michael; Tran, Minh; Khuu, Hanh; Klein, Harvey G.; Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Kuznetsov, Sergei A.; Balakumaran, Arun; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Bone Marrow Stromal Cell Transplant Center, NIH; DTM, Clinical Center, NIH FX We thank the entire staff of the Cell Processing Section of the DTM, Clinical Center for their help with this work and the Bone Marrow Stromal Cell Transplant Center, NIH and DTM, Clinical Center, NIH for their financial support. NR 33 TC 16 Z9 16 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 6 PY 2012 VL 10 AR 23 DI 10.1186/1479-5876-10-23 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 917ZF UT WOS:000302217500002 PM 22309358 ER PT J AU Hoffman, SA Aravind, L Velmurugan, S AF Hoffman, Seth A. Aravind, Lakshminarayanan Velmurugan, Soundarapandian TI Female Anopheles gambiae antennae: increased transcript accumulation of the mosquito-specific odorant-binding-protein OBP2 SO PARASITES & VECTORS LA English DT Article DE Anopheles gambiae; Odorant; Binding; Protein; Antennae ID GENE-EXPRESSION; PHEROMONE; SEQUENCE; PATTERN; PCR AB Background: New interventions are required to optimally and sustainably control the Anopheles sp. mosquitoes that transmit malaria and filariasis. The mosquito olfactory system is important in host seeking (transmission) and mate finding (reproduction). Understanding olfactory function could lead to development of control strategies based on repelling parasite-carrying mosquitoes or attracting them into a fatal trap. Findings: Our initial focus is on odorant binding proteins with differential transcript accumulation between female and male mosquitoes. We report that the odorant binding protein, OBP2 (AGAP003306), had increased expression in the antennae of female vs. male Anopheles gambiae sensu stricto (G3 strain). The increased expression in antennae of females of this gene by quantitative RT-PCR was 4.2 to 32.3 fold in three independent biological replicates and two technical replicate experiments using A. gambiae from two different laboratories. OBP2 is a member of the vast OBP superfamily of insect odorant binding proteins and belongs to the predominantly dipteran clade that includes the Culex oviposition kairomone-binding OBP1. Phylogenetic analysis indicates that its orthologs are present across culicid mosquitoes and are likely to play a conserved role in recognizing a molecule that might be critical for female behavior. Conclusions: OBP2 has increased mRNA transcript accumulation in the antennae of female as compared to male A. gambiae. This molecule and related molecules may play an important role in female mosquito feeding and breeding behavior. This finding may be a step toward providing a foundation for understanding mosquito olfactory requirements and developing control strategies based on reducing mosquito feeding and breeding success. C1 [Hoffman, Seth A.; Velmurugan, Soundarapandian] Sanaria Inc, Rockville, MD 20850 USA. [Hoffman, Seth A.; Aravind, Lakshminarayanan] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Hoffman, Seth A.] Cornell Univ, Ithaca, NY 14850 USA. RP Velmurugan, S (reprint author), Sanaria Inc, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM svelmurugan@sanaria.com NR 29 TC 4 Z9 6 U1 0 U2 8 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 FEB 6 PY 2012 VL 5 AR 27 DI 10.1186/1756-3305-5-27 PG 6 WC Parasitology SC Parasitology GA 910SP UT WOS:000301662500002 PM 22309624 ER PT J AU Srivastava, R Xi, ZX Gardner, EL AF Srivastava, Ratika Xi, Zheng-Xiong Gardner, Eliot L. TI Cocaine-taking and cocaine-seeking behaviors in rats remain stable after systemic administration of GYKI 52466: A non-competitive AMPA receptor antagonist SO NEUROSCIENCE LETTERS LA English DT Article DE GYKI 52466; AMPA receptor antagonist; Cocaine; Self-administration; Reinstatement ID GLUTAMATE TRANSMISSION; INDUCED REINSTATEMENT; ADDICTION; DOPAMINE; RELAPSE; NEUROBIOLOGY; STIMULATION; INVOLVEMENT; MECHANISM AB Given the posited role of enhanced AMPA-mediated synaptic transmission in relapse to drug seeking, we investigated whether systemic administration of the AMPA receptor antagonist GYKI 52466 inhibits cocaine-taking and cocaine-seeking behavior in rats. Rats were trained to self-administer cocaine until stable self-administration was achieved. Effects of GYKI 52466 (1, 3, or 10 mg/kg, i.v.) on cocaine self-administration were assessed. Animals were allowed to re-establish stable cocaine self-administration and were then behaviorally extinguished from drug taking. The effects of GYKI 52466 (3, 10 mg/kg, i.v.) on cocaine-induced reinstatement of drug-seeking behavior were assessed. We found that GYKI 52466 failed to inhibit cocaine-taking and cocaine-seeking in both the self-administration and reinstatement paradigms. We suggest that although AMPA receptors may be involved in cocaine reward and addiction, the AMPA receptor antagonist GYKI 52466 has low therapeutic potential for cocaine addiction treatment. Published by Elsevier Ireland Ltd. C1 [Srivastava, Ratika; Xi, Zheng-Xiong; Gardner, Eliot L.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. EM ratika.srivastava@nih.gov; zxi@mail.nih.gov FU National institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services FX This research was supported entirely by the Intramural Research Program of the National institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 26 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 6 PY 2012 VL 508 IS 2 BP 106 EP 109 DI 10.1016/j.neulet.2011.12.028 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 900VD UT WOS:000300918700009 PM 22206835 ER PT J AU Song, MO Lee, CH Yang, HO Freedman, JH AF Song, Min Ok Lee, Chang-Ho Yang, Hyun Ok Freedman, Jonathan H. TI Endosulfan upregulates AP-1 binding and ARE-mediated transcription via ERK1/2 and p38 activation in HepG2 cells SO TOXICOLOGY LA English DT Article DE Endosulfan; AP-1; ARE; ERK; p38; HepG2 ID DRUG-METABOLIZING-ENZYMES; HUMAN HACAT KERATINOCYTES; MAP KINASE PATHWAYS; GENE-EXPRESSION; C-JUN; LIPID-PEROXIDATION; PROTEIN-KINASES; REACTIVE OXYGEN; IN-VITRO; ORGANOCHLORINE INSECTICIDES AB Endosulfan is an organochlorine insecticide and has been implicated in neurotoxicity, hepatotoxicity, immunosuppression and teratogenicity. However, the molecular mechanism of endosulfan toxicity is not yet clear. Recent studies demonstrated that oxidative stress induced by endosulfan is involved in its toxicity and accumulating evidence suggests that endosulfan can modulate the activities of stress-responsive signal transduction pathways including extracellular signal regulated kinases (ERK) 1/2. However, none of the previous studies investigated the ability of endosulfan to modulate activating protein-1 (AP-1) binding and antioxidant response element (ARE)-mediated transcription as an underlying mechanism of endosulfan toxicity. In this report, we show that treatment of HepG2 cells with endosulfan significantly increased oxidative stress-responsive transcription via AP-1 activation. In addition, endosulfan-induced transcription was enhanced in cells depleted of glutathione by buthionine sulfoximine (BSO) treatment. Exposure to endosulfan resulted in a significant increase in the activities of MAPKs, ERK1/2 and p38. Endosulfan-induced increases in enzymatic activities of these MAPKs were consistent with MAPK phosphorylation. Endosulfan exposure also caused an increase in c-Jun phosphorylation. These results suggest a model for endosulfan toxicity in which endosulfan increases ERK1/2 and p38 activities and these activated MAPKs then increase c-Jun phosphorylation. Phosphorylated c-Jun, in turn, increases AP-1 activity, which results in activation of ARE-mediated transcription. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Song, Min Ok; Yang, Hyun Ok] Korea Inst Sci & Technol, Kangnung, Gangwon Do, South Korea. [Song, Min Ok; Freedman, Jonathan H.] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Lee, Chang-Ho] Kangnung Wonju Natl Univ, Coll Nat Sci, Dept Biol, Gangwon Do 210702, South Korea. RP Song, MO (reprint author), Korea Inst Sci & Technol, 679 Saimdang Ro, Kangnung, Gangwon Do, South Korea. EM songmo@kist.re.kr FU NIH; NIEHS [Z01ES102045] FX This work was supported (in part) by the Intramural Research Program of the NIH and NIEHS (Z01ES102045). NR 68 TC 13 Z9 15 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 6 PY 2012 VL 292 IS 1 BP 23 EP 32 DI 10.1016/j.tox.2011.11.013 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 895XY UT WOS:000300531200003 PM 22146149 ER PT J AU Zhu, FQ Hummer, G AF Zhu, Fangqiang Hummer, Gerhard TI Convergence and error estimation in free energy calculations using the weighted histogram analysis method SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE free energy; potential of mean force; weighted histogram analysis method; statistical error; systematic error; optimization algorithm; convergence rate; block average; molecular dynamics; Monte Carlo ID MONTE-CARLO INTEGRATION; REPLICA EXCHANGE; MEAN FORCE; SIMULATIONS; SURFACES; CHANNEL; PROTEIN; PATHS AB The weighted histogram analysis method (WHAM) has become the standard technique for the analysis of umbrella sampling simulations. In this article, we address the challenges (1) of obtaining fast and accurate solutions of the coupled nonlinear WHAM equations, (2) of quantifying the statistical errors of the resulting free energies, (3) of diagnosing possible systematic errors, and (4) of optimally allocating of the computational resources. Traditionally, the WHAM equations are solved by a fixed-point direct iteration method, despite poor convergence and possible numerical inaccuracies in the solutions. Here, we instead solve the mathematically equivalent problem of maximizing a target likelihood function, by using superlinear numerical optimization algorithms with a significantly faster convergence rate. To estimate the statistical errors in one-dimensional free energy profiles obtained from WHAM, we note that for densely spaced umbrella windows with harmonic biasing potentials, the WHAM free energy profile can be approximated by a coarse-grained free energy obtained by integrating the mean restraining forces. The statistical errors of the coarse-grained free energies can be estimated straightforwardly and then used for the WHAM results. A generalization to multidimensional WHAM is described. We also propose two simple statistical criteria to test the consistency between the histograms of adjacent umbrella windows, which help identify inadequate sampling and hysteresis in the degrees of freedom orthogonal to the reaction coordinate. Together, the estimates of the statistical errors and the diagnostics of inconsistencies in the potentials of mean force provide a basis for the efficient allocation of computational resources in free energy simulations. (c) 2011 Wiley Periodicals, Inc. J Comput Chem, 2012 C1 [Zhu, Fangqiang; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, FQ (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM zhuf@niddk.nih.gov; hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU NIDDK, NIH FX Contract/grant sponsors: Intramural Research Programs of the NIDDK, NIH. NR 25 TC 70 Z9 71 U1 5 U2 48 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD FEB 5 PY 2012 VL 33 IS 4 BP 453 EP 465 DI 10.1002/jcc.21989 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 874KG UT WOS:000298955100011 PM 22109354 ER PT J AU Muzzio, M Huang, ZH Hu, SC Johnson, WD McCormick, DL Kapetanovic, IM AF Muzzio, Miguel Huang, Zhihua Hu, Shu-Chieh Johnson, William D. McCormick, David L. Kapetanovic, Izet M. TI Determination of resveratrol and its sulfate and glucuronide metabolites in plasma by LC-MS/MS and their pharmacokinetics in dogs SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Resveratrol; Metabolites; Dog; Plasma; Pharmacokinetics ID PERFORMANCE LIQUID-CHROMATOGRAPHY; CANCER CHEMOPREVENTIVE AGENT; TRANS-RESVERATROL; LOW BIOAVAILABILITY; HEALTHY-VOLUNTEERS; RAT; HPLC; IDENTIFICATION; ABSORPTION; MECHANISMS AB An analytical approach for the determination of trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) and its glucuronide and sulfate conjugates in dog plasma by LC-MS/MS (without enzymatic hydrolysis of the conjugates) was validated to support pre-clinical toxicological and pharmacological studies.The approach required two independent sample extractions and consequent instrument runs. Samples for resveratrol determination were prepared by protein precipitation with acetonitrile: acetonitrile-methanol was used instead for resveratrol metabolites. Chromatographic separation was performed using a C18 column (30 mm x 2.0 mm) at a flow rate of 0.25 mL/min. For resveratrol the mobile phase consisted of A: 5 mM ammonium acetate in water-isopropanol (98:2, v/v) and B: methanol-isopropanol (98:2, v/v) and for metabolites the mobile phase was modified as follows: A: 0.1% (v/v) formic acid in water and B: 0.1% (v/v) formic acid in acetonitrile. Total run time was 12 min for each run with retention times of about 4-5 min for all analytes. A turbo ion spray source was used operating in negative mode for resveratrol and resveratrol sulfate and in positive mode for resveratrol glucuronide. Calibration curves were linear from 5 to 1000 ng/mL for resveratrol and its glucuronide, and 10-2000 ng/mL for resveratrol sulfate. Linearity was assessed using the internal standard method for resveratrol and the external standard method for the metabolites. Method accuracy was 90-112% of the true value for all analytes with precision of 9% RSD or less for all validation experiments. The validated method was applied to a preclinical toxicology study in dogs after oral administration (200-1200 mg/kg) of the agent. Peak plasma resveratrol concentration (C-max) for most animals was observed within 1-5 h of dosing, with group mean values in the 1.7-9.9 mu g/mL (7.5-43 mu M) range. Area under the plasma concentration-time curve (AUC) mean values for resveratrol ranged from 3.6 to 44 mu g/ml. for all study groups and were generally proportional to the dose, with no consistent statistically significant changes observed for gender or number of doses. Mean molecular-weight adjusted ratios of resveratrol metabolites to resveratrol for AUC ranged from 1 to 9 for resveratrol glucuronide and from 2 to 11 for resveratrol sulfate. (C) 2011 Elsevier B.V. All rights reserved. C1 [Muzzio, Miguel; Huang, Zhihua; Hu, Shu-Chieh; Johnson, William D.; McCormick, David L.] IIT, Life Sci Grp, Res Inst, Chicago, IL 60616 USA. [Kapetanovic, Izet M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Muzzio, M (reprint author), IIT, Life Sci Grp, Res Inst, Chicago, IL 60616 USA. EM mmuzzio@iitri.org FU Division of Cancer Prevention, National Cancer Institute [N01-CN-43304, HHSN261200433004C] FX This research was supported by contract N01-CN-43304 (HHSN261200433004C) from the Division of Cancer Prevention, National Cancer Institute. The authors thank Heidi Kreuzer for assistance with the manuscript. NR 34 TC 26 Z9 26 U1 2 U2 40 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD FEB 5 PY 2012 VL 59 BP 201 EP 208 DI 10.1016/j.jpba.2011.10.023 PG 8 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 857KD UT WOS:000297716500029 PM 22079044 ER PT J AU Kang, H Davis-Dusenbery, BN Nguyen, PH Lal, A Lieberman, J Van Aelst, L Lagna, G Hata, A AF Kang, Hara Davis-Dusenbery, Brandi N. Nguyen, Peter H. Lal, Ashish Lieberman, Judy Van Aelst, Linda Lagna, Giorgio Hata, Akiko TI Bone Morphogenetic Protein 4 Promotes Vascular Smooth Muscle Contractility by Activating MicroRNA-21 (miR-21), which Down-regulates Expression of Family of Dedicator of Cytokinesis (DOCK) Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR GENE; CANCER CELLS; TARGETS; GROWTH; PROLIFERATION; INVASION; IDENTIFICATION; RECOGNITION; METASTASIS; MATURATION AB The bone morphogenetic protein 4 (BMP4) signaling pathway plays a critical role in the promotion and maintenance of the contractile phenotype in vascular smooth muscle cell (vSMC). Misexpression or inactivating mutations of the BMP receptor gene can lead to dedifferentiation of vSMC characterized by increased migration and proliferation that is linked to vascular proliferative disorders. Previously we demonstrated that vSMCs increase microRNA-21 (miR-21) biogenesis upon BMP4 treatment, which induces contractile gene expression by targeting programmed cell death 4 (PDCD4). To identify novel targets of miR-21 that are critical for induction of the contractile phenotype by BMP4, biotinylated miR-21 was expressed in vSMCs followed by an affinity purification of mRNAs associated with miR-21. Nearly all members of the dedicator of cytokinesis (DOCK) 180-related protein superfamily were identified as targets of miR-21. Down-regulation of DOCK4, -5, and -7 by miR-21 inhibited cell migration and promoted cytoskeletal organization by modulating an activity of small GTPase. Thus, this study uncovers a regulatory mechanism of the vSMC phenotype by the BMP4-miR-21 axis through DOCK family proteins. C1 [Kang, Hara; Lagna, Giorgio; Hata, Akiko] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. [Kang, Hara; Davis-Dusenbery, Brandi N.; Nguyen, Peter H.; Lagna, Giorgio; Hata, Akiko] Tufts Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. [Lal, Ashish; Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Lal, Ashish; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20889 USA. [Van Aelst, Linda] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Hata, Akiko] Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. RP Hata, A (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, 555 Mission Bay Blvd, San Francisco, CA 94158 USA. EM akiko.hata@ucsf.edu RI Davis-Dusenbery, Brandi/N-2798-2013; Lieberman, Judy/A-2717-2015 OI Davis-Dusenbery, Brandi/0000-0001-7811-8613; FU National Institutes of Health [HD042149, HL093154, HL082854]; American Heart Association [0940095N]; LeDucq Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants HD042149, HL093154, and HL082854 (to A. H.). This work was also supported by American Heart Association Grant 0940095N and a LeDucq Foundation transatlantic network grant (to A. H.). NR 50 TC 47 Z9 51 U1 1 U2 8 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 FEB 3 PY 2012 VL 287 IS 6 BP 3976 EP 3986 DI 10.1074/jbc.M111.303156 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 894EX UT WOS:000300410900032 PM 22158624 ER PT J AU Chung, SM Miller, JT Johnson, BC Hughes, SH Le Grice, SFJ AF Chung, Suhman Miller, Jennifer T. Johnson, Barry C. Hughes, Stephen H. Le Grice, Stuart F. J. TI Mutagenesis of Human Immunodeficiency Virus Reverse Transcriptase p51 Subunit Defines Residues Contributing to Vinylogous Urea Inhibition of Ribonuclease H Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV RNASE-H; WILD-TYPE; POSITIONAL ADAPTABILITY; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; DRUG-RESISTANCE; DNA-POLYMERASE; NUCLEIC-ACID; TYPE-1; DESIGN AB The vinylogous urea, NSC727447, was proposed to allosterically inhibit ribonucleaseH(RNase H) activity of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) by interacting with the thumb subdomain of its non-catalytic p51 subunit. Proximity of the p51 thumb to the p66 RNase H domain implied that inhibitor binding altered active site geometry, whereas protein footprinting suggested a contribution from alpha-helix I residues Cys-280 and Lys-281. To more thoroughly characterize the vinylogous urea binding site, horizontal alanine scanning mutagenesis between p51 residues Lys-275 and Thr-286 (comprising alpha-helix I and portions of the neighboring alpha H/alpha I and alpha I/alpha J connecting loops) was combined with a limited vertical scan of Cys-280. A contribution from Cys-280 was strengthened by our observation that all substitutions at this position rendered selectively mutated, reconstituted p66/p51 heterodimers similar to 45-fold less sensitive to inhibition. An similar to 19-fold reduced IC50 for p51 mutant T286A coupled with a 2-8-fold increased IC50 when intervening residues were substituted supports our original proposal of p51 alpha-helix I as the vinylogous urea binding site. In contrast to these allosteric inhibitors, mutant enzymes retained equivalent sensitivity to the natural product alpha-hydroxytropolone inhibitor manicol, which x-ray crystallography has demonstrated functions by chelating divalent metal at the p66 RNase H active site. Finally, reduced DNA strand-transfer activity together with increased vinylogous urea sensitivity of p66/p51 heterodimers containing short p51 C-terminal deletions suggests an additional role for the p51 C terminus in nucleic acid binding that is compromised by inhibitor binding. C1 [Chung, Suhman; Miller, Jennifer T.; Johnson, Barry C.; Hughes, Stephen H.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), Bldg 535,Rm 312,1050 Boyles St, Frederick, MD 21702 USA. EM legrices@mail.nih.gov FU National Institutes of Health, NCI, Center for Cancer Research FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, NCI, Center for Cancer Research. NR 44 TC 11 Z9 11 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 3 PY 2012 VL 287 IS 6 BP 4066 EP 4075 DI 10.1074/jbc.M111.314781 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 894EX UT WOS:000300410900040 PM 22105069 ER PT J AU Kimura, T Yeliseev, AA Vukoti, K Rhodes, SD Cheng, KJ Rice, KC Gawrisch, K AF Kimura, Tomohiro Yeliseev, Alexei A. Vukoti, Krishna Rhodes, Steven D. Cheng, Kejun Rice, Kenner C. Gawrisch, Klaus TI Recombinant Cannabinoid Type 2 Receptor in Liposome Model Activates G Protein in Response to Anionic Lipid Constituents SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FUNCTIONAL RECONSTITUTION; CB2 RECEPTORS; MEMBRANE-PROTEINS; CRYSTAL-STRUCTURE; COUPLED RECEPTOR; PHASE-TRANSITION; OCTYL GLUCOSIDE; NEURONAL CELLS; BINDING-SITE; IMMUNE CELLS AB Human cannabinoid type 2 (CB2) receptor expressed in Escherichia coli was purified and successfully reconstituted in the functional form into lipid bilayers composed of POPC, 1-palmitoyl- 2-oleoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl- sn-glycero-3-phospho-L-serine (POPS), and cholesteryl hemisuccinate (CHS). Reconstitution was performed by detergent removal from the protein/lipid/detergent mixed micelles either on an adsorbent column, or by rapid dilution to below the critical micelle concentration of detergent followed by removal of detergent monomers on a concentrator. Proteoliposomes prepared at a protein/phospholipid/CHS molar ratio of 1/620 - 650/210-220 are free of detergent as shown by H-1 NMR, have a homogeneous protein/lipid ratio shown by isopycnic gradient ultracentrifugation, and are small in size with a mean diameter of 150-200 nm as measured by dynamic light scattering. Functional integrity of the reconstituted receptor was confirmed by quantitative binding of H-2-labeled agonist CP-55,940-d(6) measured by H-2 magic angle spinning NMR, as well as by activation of G protein. The efficiency of G protein activation by agonist-bound CB2 receptor was affected by negative electric surface potentials of proteoliposomes controlled by the content of anionic CHS or POPS. The activation was highest at an anionic lipid content of about 50 mol %. There was no correlation between the efficiency of G protein activation and an increase of hydrocarbon chain order induced by CHS or cholesterol. The results suggest the importance of anionic lipids in regulating signal transduction by CB2 receptor and other class A GPCR. The successful reconstitution of milligram quantities of pure, functional CB2 receptor enables a wide variety of structural studies. C1 [Kimura, Tomohiro; Yeliseev, Alexei A.; Vukoti, Krishna; Rhodes, Steven D.; Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20852 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, NIH, Bethesda, MD 20852 USA. RP Yeliseev, AA (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20852 USA. EM yeliseeva@mail.nih.gov; gawrisch@helix.nih.gov FU National Institutes of Health from the of the NIAAA; NIDA FX This work was supported, in whole or in part, by a National Institutes of Health grant from the Intramural Research Programs of the NIAAA and NIDA. NR 79 TC 17 Z9 17 U1 0 U2 15 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 FEB 3 PY 2012 VL 287 IS 6 BP 4076 EP 4087 DI 10.1074/jbc.M111.268425 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 894EX UT WOS:000300410900041 PM 22134924 ER PT J AU Zhuang, XL Northup, JK Ray, K AF Zhuang, Xiaolei Northup, John K. Ray, Kausik TI Large Putative PEST-like Sequence Motif at the Carboxyl Tail of Human Calcium Receptor Directs Lysosomal Degradation and Regulates Cell Surface Receptor Level SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; AUTOSOMAL-DOMINANT HYPOCALCEMIA; SENSING RECEPTOR; HYPOCALCIURIC HYPERCALCEMIA; SIGNAL-TRANSDUCTION; COUPLED RECEPTORS; CYTOPLASMIC TAIL; UBIQUITINATION; EXPRESSION; PHOSPHORYLATION AB A deletion between amino acid residues Ser(895) and Val(1075) in the carboxyl terminus of the human calcium receptor (hCaR), which causes autosomal dominant hypocalcemia, showed enhanced signaling activity and increased cell surface expression in HEK293 cells (Lienhardt, A., Garabedian, M. G., Bai, M., Sinding, C., Zhang, Z., Lagarde, J. P., Boulesteix, J., Rigaud, M., Brown, E. M., and Kottler, M. L. (2000) J. Clin. Endocrinol. Metab. 85, 1695-1702). To identify the underlying mechanism(s) for these increases, we investigated the effects of carboxyl tail truncation and deletion in hCaR mutants using a combination of biochemical and cell imaging approaches to define motifs that participate in regulating cell surface numbers of this G protein-coupled receptor. Our data indicate a rapid constitutive receptor internalization of the cell surface hCaR, accumulating in early (Rab7 positive) and late endosomal (LAMP1 positive) sorting compartments, before targeting to lysosomes for degradation. Recycling of hCaR back to the cell surface was also evident. Truncation and deletion mapping defined a 51-amino acid sequence between residues 920 and 970 that is required for targeting to lysosomes and degradation but not for internalization or recycling of the receptor. No singular sequence motif was identified, instead the required sequence elements seem to distribute throughout this entire interval. This interval includes a high proportion of acidic and hydroxylated amino acid residues, suggesting a similarity to PEST-like degradation motif (PEST find score of +10) and several glutamine repeats. The results define a novel large PEST-like sequence that participates in the sorting of internalized hCaR routed to the lysosomal/degradation pathway that regulates cell surface receptor numbers. C1 [Zhuang, Xiaolei; Northup, John K.; Ray, Kausik] NIDCD, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Northup, JK (reprint author), Lab Cellular Biol, 5 Res Court,Rm 2A11, Rockville, MD 20850 USA. EM northupJK@nidcd.nih.gov; rayk@nidcd.nih.gov FU National Institutes of Health of the NIDCD, National Institues of Health FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIDCD, National Institues of Health. NR 38 TC 8 Z9 9 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 3 PY 2012 VL 287 IS 6 BP 4165 EP 4176 DI 10.1074/jbc.M111.271528 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 894EX UT WOS:000300410900050 PM 22158862 ER PT J AU Miller, TW Wang, EA Gould, S Stein, EV Kaur, S Lim, L Amarnath, S Fowler, DH Roberts, DD AF Miller, Thomas W. Wang, Evelyn A. Gould, Serge Stein, Erica V. Kaur, Sukhbir Lim, Langston Amarnath, Shoba Fowler, Daniel H. Roberts, David D. TI Hydrogen Sulfide Is an Endogenous Potentiator of T Cell Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; CYSTATHIONINE-GAMMA-LYASE; ANIMATION-LIKE STATE; ULCERATIVE-COLITIS; ACTIN POLYMERIZATION; MYOCARDIAL-ISCHEMIA; COLONIC SULFIDE; MICE; RAT; LYMPHOCYTE AB H2S is an endogenous signaling molecule that may act via protein sulfhydrylation to regulate various physiological functions. H2S is also a byproduct of dietary sulfate metabolism by gut bacteria. Inflammatory bowel diseases such as ulcerative colitis are associated with an increase in the colonization of the intestine by sulfate reducing bacteria along with an increase in H2S production. Consistent with its increased production, H2S is implicated as a mediator of ulcerative colitis both in its genesis or maintenance. As T cells are well established mediators of inflammatory bowel disease, we investigated the effect of H2S exposure on T cell activation. Using primary mouse T lymphocytes (CD3+), OT-II CD4+ T cells, and the human Jurkat T cell line, we show that physiological levels of H2S potentiate TCR-induced activation. Nanomolar levels of H2S (50-500 nM) enhance T cell activation assessed by CD69 expression, interleukin-2 expression, and CD25 levels. Exposure of T cells to H2S dose-dependently enhances TCR-stimulated proliferation with a maximum at 300 nM (30% increase, p < 0.01). Furthermore, activation increases the capacity of T cells to make H2S via increased expression of cystathionine gamma-lyase and cystathionine beta-synthase. Disrupting this response by silencing these H2S producing enzymes impairs T cell activation, and proliferation and can be rescued by the addition of 300 nM H2S. Thus, H2S represents a novel autocrine immunomodulatory molecule in T cells. C1 [Miller, Thomas W.; Wang, Evelyn A.; Gould, Serge; Stein, Erica V.; Kaur, Sukhbir; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lim, Langston] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Amarnath, Shoba; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10,Rm 2A33,10 Ctr Dr,MSC1500, 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; Stein, Erica/0000-0001-8778-8846 FU National Institutes of Health of the National Cancer Institute, Center for Cancer Research [1ZIA SC 009174] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the National Cancer Institute, Center for Cancer Research (Grant 1ZIA SC 009174). NR 67 TC 33 Z9 35 U1 2 U2 22 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 FEB 3 PY 2012 VL 287 IS 6 BP 4211 EP 4221 DI 10.1074/jbc.M111.307819 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 894EX UT WOS:000300410900054 PM 22167178 ER PT J AU Zhou, Q Liu, L Xu, F Li, H Sergeev, Y Dong, FT Jiang, RX MacDonald, I Sui, RF AF Zhou, Qi Liu, Liang Xu, Fei Li, Hui Sergeev, Yuri Dong, Fangtian Jiang, Ruxin MacDonald, Ian Sui, Ruifang TI Genetic and phenotypic characteristics of three Mainland Chinese families with choroideremia SO MOLECULAR VISION LA English DT Article ID RAB ESCORT PROTEIN-1; REP-1 GENE; MUTATIONS; CONFORMATION; OPTIMIZATION; CHM AB Purpose: To describe the phenotype and genotype of three Mainland Chinese families affected by choroideremia (CHM). Methods: Complete ophthalmic examinations were conducted in three unrelated Chinese families with CHM. Peripheral blood samples were collected from the families for genetic and immunoblot analysis. All exons and flanking intronic regions of the gene encoding Rab escort protein-1 (Rep-1) were amplified with PCR and screened for mutations with Sanger sequencing. The three-dimensional structure of mutated Rep-1 was modeled using sequence homology with rat proteins to analyze the effect of the mutation detected in one family. Results: All affected males had characteristic signs and symptoms of CHM; however, central visual acuity impairment occurred earlier than expected. All female carriers older than 45 years had pigmentary changes, and one female carrier was symptomatic with vision loss. Three different mutations in Rep-1, c. 1801-1G>A, c.1130T>A, and c.612delAG, were detected in the three families. Conclusions: In Mainland Chinese families, the central visual acuity of male patients with CHM can be affected at an early age (second decade), whereas female CHM carriers may manifest signs and symptoms at a later age (>= 45 years). One previously reported and two novel Rep-1 mutations were detected in three Chinese patients with CHM. C1 [Zhou, Qi; Liu, Liang; Xu, Fei; Li, Hui; Dong, Fangtian; Jiang, Ruxin; Sui, Ruifang] Beijing Union Med Coll Hosp, Peking Union Med Coll, Dept Ophthalmol, Beijing 100730, Peoples R China. [Zhou, Qi; Liu, Liang; Xu, Fei; Li, Hui; Dong, Fangtian; Jiang, Ruxin; Sui, Ruifang] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Sergeev, Yuri] NEI, NIH, Baltimore, MD USA. [MacDonald, Ian] Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2M7, Canada. RP Sui, RF (reprint author), Beijing Union Med Coll Hosp, Peking Union Med Coll, Dept Ophthalmol, 1 Shuai Fu Yuan, Beijing 100730, Peoples R China. EM hrfsui@yahoo.com OI MacDonald, Ian/0000-0001-7472-8385 FU Ministry of Science and Technology of the People's Republic of China [2010DFB33430]; Ministry of Human Resources and Social Security of the People's Republic of China; Foundation Fighting Blindness, USA [CD-CL-0808-0470-PUMCH] FX We thank the patients and their families for taking part in this research. We are grateful for financial support from the Ministry of Science and Technology of the People's Republic of China (Grant No.: 2010DFB33430), the Ministry of Human Resources and Social Security of the People's Republic of China and the Foundation Fighting Blindness, USA (Grant No.: CD-CL-0808-0470-PUMCH). NR 19 TC 4 Z9 5 U1 0 U2 0 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 FEB 3 PY 2012 VL 18 IS 34 BP 309 EP 316 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 905AW UT WOS:000301244500001 PM 22355242 ER PT J AU Park, SJ Ahmad, F Philp, A Baar, K Williams, T Luo, HB Ke, HM Rehmann, H Taussig, R Brown, AL Kim, MK Beaven, MA Burgin, AB Manganiello, V Chung, JH AF Park, Sung-Jun Ahmad, Faiyaz Philp, Andrew Baar, Keith Williams, Tishan Luo, Haibin Ke, Hengming Rehmann, Holger Taussig, Ronald Brown, Alexandra L. Kim, Myung K. Beaven, Michael A. Burgin, Alex B. Manganiello, Vincent Chung, Jay H. TI Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases SO CELL LA English DT Article ID ACTIVATED PROTEIN-KINASE; SMALL-MOLECULE ACTIVATORS; LIFE-SPAN; PHOSPHOLIPASE-C; CYCLIC-AMP; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL-FUNCTION; CALORIE RESTRICTION; SIGNALING PATHWAY; CARDIAC MYOCYTES AB Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca2+ levels and activates the CamKK beta-AMPK pathway via phospholipase C and the ryanodine receptor Ca2+-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging. C1 [Park, Sung-Jun; Brown, Alexandra L.; Kim, Myung K.; Chung, Jay H.] NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Ahmad, Faiyaz; Manganiello, Vincent] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Philp, Andrew; Baar, Keith] Univ Calif Davis, Funct Mol Biol Lab, Davis, CA 95616 USA. [Williams, Tishan; Ke, Hengming] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Luo, Haibin] Sun Yat Sen Univ, Sch Pharmaceut Sci, Struct Biol Lab, Guangzhou 510006, Guangdong, Peoples R China. [Rehmann, Holger] Univ Med Ctr, Dept Mol Canc Res, Ctr Biomed Genet, NL-3584 CG Utrecht, Netherlands. [Rehmann, Holger] Univ Med Ctr, Canc Genom Ctr, NL-3584 CG Utrecht, Netherlands. [Taussig, Ronald] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Burgin, Alex B.] Emerald BioStruct, Bainbridge Isl, WA 98110 USA. RP Chung, JH (reprint author), NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM chungj@nhlbi.nih.gov FU National Heart Lung and Blood Institute, National Institutes of Health; Netherlands Organization for Scientific Research (NWO) FX This work was supported by the Intramural Research Program, National Heart Lung and Blood Institute, National Institutes of Health. We thank Andrew Marks for the Ryr2 phosphoantibody; Dr. Yan Tang for sharing data regarding inhibition of PDE3 by resveratrol; Marije Rensen-De Leeuw and Yan Tang for technical assistance; Shutong Yang and Dalton Saunders for animal management; and Alexandra Brown for manuscript review and comments. H.R. is supported by the Netherlands Organization for Scientific Research (NWO). NR 67 TC 527 Z9 546 U1 19 U2 188 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 3 PY 2012 VL 148 IS 3 BP 421 EP 433 DI 10.1016/j.cell.2012.01.017 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 891NX UT WOS:000300225000012 PM 22304913 ER PT J AU Volkow, ND Baler, RD AF Volkow, Nora D. Baler, Ruben D. TI To Stop or Not to Stop? SO SCIENCE LA English DT Editorial Material ID RECEPTOR AVAILABILITY; ORBITOFRONTAL CORTEX; DOPAMINE-D-2 RECEPTORS; HUMAN BRAIN; METABOLISM; TEMPERAMENT; INVOLVEMENT; ADDICTION; ABUSERS C1 [Volkow, Nora D.; Baler, Ruben D.] NIDA, Rockville, MD 20857 USA. RP Volkow, ND (reprint author), NIDA, 6001 Execut Blvd, Rockville, MD 20857 USA. EM nvolkow@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 17 TC 14 Z9 15 U1 2 U2 19 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 FEB 3 PY 2012 VL 335 IS 6068 BP 546 EP 548 DI 10.1126/science.1218170 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 885HI UT WOS:000299769200031 PM 22301310 ER PT J AU Sethi, AJ Wikramanayake, RM Angerer, RC Range, RC Angerer, LM AF Sethi, Aditya J. Wikramanayake, Radhika M. Angerer, Robert C. Range, Ryan C. Angerer, Lynne M. TI Sequential Signaling Crosstalk Regulates Endomesoderm Segregation in Sea Urchin Embryos SO SCIENCE LA English DT Article ID NUCLEAR BETA-CATENIN; GENE NETWORK; VEGETAL PLATE; SPECIFICATION; ENDODERM; NOTCH; INDUCTION; CELLS; MESENDODERM; ACTIVATION AB The segregation of embryonic endomesoderm into separate endoderm and mesoderm fates is not well understood in deuterostomes. Using sea urchin embryos, we showed that Notch signaling initiates segregation of the endomesoderm precursor field by inhibiting expression of a key endoderm transcription factor in presumptive mesoderm. The regulatory circuit activated by this transcription factor subsequently maintains transcription of a canonical Wnt (cWnt) ligand only in endoderm precursors. This cWnt ligand reinforces the endoderm state, amplifying the distinction between emerging endoderm and mesoderm. Before gastrulation, Notch-dependent nuclear export of an essential beta-catenin transcriptional coactivator from mesoderm renders it refractory to cWnt signals, insulating it against an endoderm fate. Thus, we report that endomesoderm segregation is a progressive process, requiring a succession of regulatory interactions between cWnt and Notch signaling. C1 [Sethi, Aditya J.; Angerer, Robert C.; Range, Ryan C.; Angerer, Lynne M.] NIDCR, NIH, Bethesda, MD 20892 USA. [Wikramanayake, Radhika M.] Univ Oxford, Dept Publ Hlth, Oxford, England. RP Angerer, LM (reprint author), NIDCR, NIH, Bethesda, MD 20892 USA. EM langerer@mail.nih.gov FU National Institute of Dental and Craniofacial Research, NIH FX The authors thank D. Adams and R. Benabentos for their comments. Funding was provided by the Intramural Program at the National Institute of Dental and Craniofacial Research, NIH. NR 31 TC 21 Z9 21 U1 1 U2 14 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 FEB 3 PY 2012 VL 335 IS 6068 BP 590 EP 593 DI 10.1126/science.1212867 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 885HI UT WOS:000299769200045 PM 22301319 ER PT J AU Arizpe, J Kravitz, DJ Yovel, G Baker, CI AF Arizpe, Joseph Kravitz, Dwight J. Yovel, Galit Baker, Chris I. TI Start Position Strongly Influences Fixation Patterns during Face Processing: Difficulties with Eye Movements as a Measure of Information Use SO PLOS ONE LA English DT Article ID PERCEPTION; GAZE; RECOGNITION; AUTISM; REPRESENTATIONS; FAMILIARITY; ASYMMETRIES; INVERSION; REVEAL; SPAN AB Fixation patterns are thought to reflect cognitive processing and, thus, index the most informative stimulus features for task performance. During face recognition, initial fixations to the center of the nose have been taken to indicate this location is optimal for information extraction. However, the use of fixations as a marker for information use rests on the assumption that fixation patterns are predominantly determined by stimulus and task, despite the fact that fixations are also influenced by visuo-motor factors. Here, we tested the effect of starting position on fixation patterns during a face recognition task with upright and inverted faces. While we observed differences in fixations between upright and inverted faces, likely reflecting differences in cognitive processing, there was also a strong effect of start position. Over the first five saccades, fixation patterns across start positions were only coarsely similar, with most fixations around the eyes. Importantly, however, the precise fixation pattern was highly dependent on start position with a strong tendency toward facial features furthest from the start position. For example, the often-reported tendency toward the left over right eye was reversed for the left starting position. Further, delayed initial saccades for central versus peripheral start positions suggest greater information processing prior to the initial saccade, highlighting the experimental bias introduced by the commonly used center start position. Finally, the precise effect of face inversion on fixation patterns was also dependent on start position. These results demonstrate the importance of a non-stimulus, non-task factor in determining fixation patterns. The patterns observed likely reflect a complex combination of visuo-motor effects and simple sampling strategies as well as cognitive factors. These different factors are very difficult to tease apart and therefore great caution must be applied when interpreting absolute fixation locations as indicative of information use, particularly at a fine spatial scale. C1 [Arizpe, Joseph; Kravitz, Dwight J.; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Arizpe, Joseph] UCL, Inst Cognit Neurosci, Visual Cognit Grp, London, England. [Yovel, Galit] Tel Aviv Univ, Dept Psychol, IL-69978 Tel Aviv, Israel. RP Arizpe, J (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM arizpej@mail.nih.gov; bakerchris@mail.nih.gov RI Kravitz, Dwight/B-8430-2012; Arizpe, Joseph/N-1399-2014; OI Arizpe, Joseph/0000-0001-8958-7757; Baker, Chris/0000-0001-6861-8964 FU National Institutes of Mental Health; United States-Israel Binational Science Foundation FX This work was supported by the Intramural Program of the National Institutes of Mental Health and by the United States-Israel Binational Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 29 Z9 29 U1 3 U2 20 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 FEB 2 PY 2012 VL 7 IS 2 AR e31106 DI 10.1371/journal.pone.0031106 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 914UV UT WOS:000301979000019 PM 22319606 ER PT J AU Riviere, I Dunbar, CE Sadelain, M AF Riviere, Isabelle Dunbar, Cynthia E. Sadelain, Michel TI Hematopoietic stem cell engineering at a crossroads SO BLOOD LA English DT Review ID ZINC-FINGER NUCLEASES; INTEGRATION SITE SELECTION; RETROVIRAL VECTOR DESIGN; BLOOD CD34(+) CELLS; FOAMY VIRUS VECTORS; SEVERE COMBINED IMMUNODEFICIENCY; X-LINKED ADRENOLEUKODYSTROPHY; CHRONIC GRANULOMATOUS-DISEASE; ECTOPIC HOXB4 EXPRESSION; GENOME-WIDE ANALYSIS AB The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead. (Blood. 2012; 119(5):1107-1116) C1 [Riviere, Isabelle; Sadelain, Michel] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Sadelain, M (reprint author), Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, Mol Pharmacol & Chem Program, Box 182,1275 York Ave, New York, NY 10065 USA. EM m-sadelain@ski.mskcc.org FU National Institutes of Health [HL053750, CA59350, CA08748]; Experimental Therapeutics Center at Memorial Sloan-Kettering Cancer Center; Niarchos Foundation; Leonardo Giambrone Foundation; Cooley's Anemia Foundation; NYSTEM FX I.R. and M. S. were supported by the National Institutes of Health (grants HL053750, CA59350, and CA08748), the Experimental Therapeutics Center at Memorial Sloan-Kettering Cancer Center, the Niarchos Foundation, the Leonardo Giambrone Foundation, the Cooley's Anemia Foundation, and NYSTEM. NR 141 TC 29 Z9 29 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 FEB 2 PY 2012 VL 119 IS 5 BP 1107 EP 1116 DI 10.1182/blood-2011-09-349993 PG 10 WC Hematology SC Hematology GA 894AW UT WOS:000300400300009 PM 22096239 ER PT J AU Lavelle, D Vaitkus, K Ling, YH Ruiz, MA Mahfouz, R Ng, KP Negrotto, S Smith, N Terse, P Engelke, KJ Covey, J Chan, KK DeSimone, J Saunthararajah, Y AF Lavelle, Donald Vaitkus, Kestis Ling, Yonghua Ruiz, Maria A. Mahfouz, Reda Ng, Kwok Peng Negrotto, Soledad Smith, Nicola Terse, Pramod Engelke, Kory J. Covey, Joseph Chan, Kenneth K. DeSimone, Joseph Saunthararajah, Yogen TI Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; SINGLE-NUCLEOTIDE POLYMORPHISM; SICKLE-CELL-DISEASE; GAMMA-GLOBIN GENE; CYTOSINE-ARABINOSIDE; CYTIDINE DEAMINASE; FETAL-HEMOGLOBIN; DIFFERENTIATION TREATMENT; CLINICAL-PHARMACOLOGY; DNA METHYLTRANSFERASE AB The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2 mu M administered 2x/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the gamma-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy. (Blood. 2012;119(5):1240-1247) C1 [Lavelle, Donald; Vaitkus, Kestis; Ruiz, Maria A.; DeSimone, Joseph; Saunthararajah, Yogen] Univ Illinois, Dept Med, Chicago, IL USA. [Lavelle, Donald; Vaitkus, Kestis; DeSimone, Joseph] Jesse Brown VA Med Ctr, Chicago, IL USA. [Ling, Yonghua; Chan, Kenneth K.] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Mahfouz, Reda; Ng, Kwok Peng; Negrotto, Soledad; Saunthararajah, Yogen] Cleveland Clin, Cleveland, OH 44106 USA. [Smith, Nicola; Terse, Pramod; Covey, Joseph] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Engelke, Kory J.] Avanza Labs, Gaithersburg, MD USA. RP Saunthararajah, Y (reprint author), Taussig Canc Inst, 9500 Euclid Ave R40, Cleveland, OH 44195 USA. EM saunthy@ccf.org RI Mahfouz, Reda/G-2307-2011 OI Mahfouz, Reda/0000-0003-4250-9422 FU National Heart, Lung, and Blood Institute [U54HL090513]; National Institute of Diabetes and Digestive and Kidney Diseases [PR081404]; National Cancer Institute under the NIH-RAID [N01-CM-52205, N01-CM-42204] FX This work was supported by the National Heart, Lung, and Blood Institute (U54HL090513), the National Institute of Diabetes and Digestive and Kidney Diseases, Congressionally Directed Medical Research Programs (PR081404), and the National Cancer Institute (contracts N01-CM-52205 and N01-CM-42204 under the NIH-RAID Pilot Program). NR 50 TC 28 Z9 28 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 2 PY 2012 VL 119 IS 5 BP 1240 EP 1247 DI 10.1182/blood-2011-08-371690 PG 8 WC Hematology SC Hematology GA 894AW UT WOS:000300400300024 PM 22160381 ER PT J AU He, S Wang, JN Kato, K Xie, F Varambally, S Mineishi, S Kuick, R Mochizuki, K Liu, YNA Nieves, E Mani, RS Chinnaiyan, AM Marquez, VE Zhang, Y AF He, Shan Wang, Jina Kato, Koji Xie, Fang Varambally, Sooryanarayana Mineishi, Shin Kuick, Rork Mochizuki, Kazuhiro Liu, Yongnian Nieves, Evelyn Mani, Ram-Shankar Chinnaiyan, Arul M. Marquez, Victor E. Zhang, Yi TI Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells SO BLOOD LA English DT Article ID S-ADENOSYLHOMOCYSTEINE HYDROLASE; BONE-MARROW-TRANSPLANTATION; IN-VIVO; PHARMACOLOGICAL DISRUPTION; CHROMATIN MODIFICATIONS; TRANSCRIPTION FACTOR; LYSINE METHYLATION; HYDROXAMIC ACID; CANCER-CELLS; LEUKEMIA AB Histone methylation is thought to be important for regulating Ag-driven T-cell responses. However, little is known about the effect of modulating histone methylation on inflammatory T-cell responses. We demonstrate that in vivo administration of the histone methylation inhibitor 3-deazaneplanocin A (DZNep) arrests ongoing GVHD in mice after allogeneic BM transplantation. DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury. This effect was associated with the ability of DZNep to selectively reduce trimethylation of histone H3 lysine 27, deplete the histone methyltransferase Ezh2 specific to trimethylation of histone H3 lysine 27, and activate proapoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not affect the survival of alloantigen-unresponsive T cells in vivo and naive T cells stimulated by IL-2 or IL-7 in vitro. Importantly, inhibition of histone methylation by DZNep treatment in vivo preserved the antileukemia activity of donor T cells and did not impair the recovery of hematopoiesis and lymphocytes, leading to significantly improved survival of recipients after allogeneic BM transplantation. Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat ongoing GVHD and other T cell-mediated inflammatory disorders in a broad context. (Blood. 2012;119(5): 1274-1282) C1 [Zhang, Yi] Univ Michigan, Dept Internal Med, Ctr Canc 6219, Ann Arbor, MI 48109 USA. [Wang, Jina] Fudan Univ, Dept Urol, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Varambally, Sooryanarayana; Mani, Ram-Shankar; Chinnaiyan, Arul M.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Kuick, Rork] Univ Michigan, Comprehens Canc Ctr Biostat Core, Ann Arbor, MI 48109 USA. [Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Zhang, Y (reprint author), Univ Michigan, Dept Internal Med, Ctr Canc 6219, 1500 E Med Dr, Ann Arbor, MI 48109 USA. EM yizha@med.umich.edu RI He, Shan/C-4989-2015 FU Damon Runyon-Rachleff Innovation Award; American Cancer Society; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by a Damon Runyon-Rachleff Innovation Award (Y.Z.) and the American Cancer Society (Y.Z.), and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 49 TC 29 Z9 30 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 2 PY 2012 VL 119 IS 5 BP 1274 EP 1282 DI 10.1182/blood-2011-06364422 PG 9 WC Hematology SC Hematology GA 894AW UT WOS:000300400300028 PM 22117046 ER PT J AU Kazenwadel, J Secker, GA Liu, YJJ Rosenfeld, JA Wildin, RS Cuellar-Rodriguez, J Hsu, AP Dyack, S Fernandez, CV Chong, CE Babic, M Bardy, PG Shimamura, A Zhang, MY Walsh, T Holland, SM Hickstein, DD Horwitz, MS Hahn, CN Scott, HS Harvey, NL AF Kazenwadel, Jan Secker, Genevieve A. Liu, Yajuan J. Rosenfeld, Jill A. Wildin, Robert S. Cuellar-Rodriguez, Jennifer Hsu, Amy P. Dyack, Sarah Fernandez, Conrad V. Chong, Chan-Eng Babic, Milena Bardy, Peter G. Shimamura, Akiko Zhang, Michael Y. Walsh, Tom Holland, Steven M. Hickstein, Dennis D. Horwitz, Marshall S. Hahn, Christopher N. Scott, Hamish S. Harvey, Natasha L. TI Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TRANSCRIPTION FACTOR; SPORADIC MONOCYTOPENIA; HEMATOPOIETIC DEFECT; AUTOSOMAL-DOMINANT; ENDOTHELIAL-CELLS; EMBERGER SYNDROME; BINDING; GENE; EXPRESSION AB Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), "MonoMAC" syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development. (Blood. 2012;119(5): 1283-1291) C1 [Kazenwadel, Jan; Secker, Genevieve A.; Bardy, Peter G.; Harvey, Natasha L.] SA Pathol, Div Haematol, Ctr Canc Biol, Adelaide, SA 5000, Australia. [Liu, Yajuan J.; Horwitz, Marshall S.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Rosenfeld, Jill A.] PerkinElmer, Signature Genom, Spokane, WA USA. [Wildin, Robert S.] St Lukes Childrens Hosp, Pediat Genet & State Idaho Genet Program, Dept Hlth & Welf, Boise, ID USA. [Cuellar-Rodriguez, Jennifer; Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dyack, Sarah] IWK Hlth Ctr, Dept Pediat, Maritime Med Genet Serv, Halifax, NS, Canada. [Dyack, Sarah; Fernandez, Conrad V.] Dalhousie Univ, Halifax, NS, Canada. [Fernandez, Conrad V.] IWK Hlth Ctr, Dept Bioeth, Halifax, NS, Canada. [Chong, Chan-Eng; Babic, Milena; Hahn, Christopher N.; Scott, Hamish S.] SA Pathol, Dept Mol Pathol, Ctr Canc Biol, Adelaide, SA 5000, Australia. [Chong, Chan-Eng; Hahn, Christopher N.; Scott, Hamish S.; Harvey, Natasha L.] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Shimamura, Akiko; Zhang, Michael Y.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Shimamura, Akiko] Seattle Childrens Hosp, Seattle, WA USA. [Zhang, Michael Y.; Walsh, Tom] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Zhang, Michael Y.; Walsh, Tom] Univ Washington, Dept Med, Seattle, WA USA. [Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Scott, Hamish S.] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA, Australia. RP Harvey, NL (reprint author), SA Pathol, Div Haematol, Ctr Canc Biol, POB 14, Adelaide, SA 5000, Australia. EM hamish.scott@health.sa.gov.au; natasha.harvey@health.sa.gov.au RI Scott, Hamish/B-2122-2009; Kazenwadel, Janette/E-6620-2012; OI Scott, Hamish/0000-0002-5813-631X; Kazenwadel, Janette/0000-0001-6216-3444; Walsh, Tom/0000-0002-8875-0310 FU National Health and Medical Research Council of Australia [1002317, 626959, 461204]; Cancer Council of South Australia; MedVet Pty Ltd; National Institutes of Health [R01DK058161, T32GM007266] FX This work was supported by the National Health and Medical Research Council of Australia (project grant 1002317, H.S.S.; project grant 626959, N.L.H.; and fellowship 461204, H.S.S.), the Cancer Council of South Australia (H.S.S. and N.L.H.), MedVet Pty Ltd (H.S.S. and N.L.H.), and National Institutes of Health (grants R01DK058161 and T32GM007266, M.S.H.). NR 49 TC 78 Z9 79 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 FEB 2 PY 2012 VL 119 IS 5 BP 1283 EP 1291 DI 10.1182/blood-2011-08-374363 PG 9 WC Hematology SC Hematology GA 894AW UT WOS:000300400300029 PM 22147895 ER PT J AU Barouch, DH Liu, JY Li, HL Maxfield, LF Abbink, P Lynch, DM Iampietro, MJ SanMiguel, A Seaman, MS Ferrari, G Forthal, DN Ourmanov, I Hirsch, VM Carville, A Mansfield, KG Stablein, D Pau, MG Schuitemaker, H Sadoff, JC Billings, EA Rao, M Robb, ML Kim, JH Marovich, MA Goudsmit, J Michael, NL AF Barouch, Dan H. Liu, Jinyan Li, Hualin Maxfield, Lori F. Abbink, Peter Lynch, Diana M. Iampietro, M. Justin SanMiguel, Adam Seaman, Michael S. Ferrari, Guido Forthal, Donald N. Ourmanov, Ilnour Hirsch, Vanessa M. Carville, Angela Mansfield, Keith G. Stablein, Donald Pau, Maria G. Schuitemaker, Hanneke Sadoff, Jerald C. Billings, Erik A. Rao, Mangala Robb, Merlin L. Kim, Jerome H. Marovich, Mary A. Goudsmit, Jaap Michael, Nelson L. TI Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys SO NATURE LA English DT Article ID CELLULAR IMMUNE-RESPONSES; LOW-DOSE CHALLENGE; IMMUNODEFICIENCY VIRUS SIVMAC239; PATHOGENIC SIV; INFECTION; HIV-1; REPLICATION; ANTIBODIES; MACAQUES; VECTORS AB Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges(1-3). Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection(4,5) against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys. C1 [Barouch, Dan H.; Liu, Jinyan; Li, Hualin; Maxfield, Lori F.; Abbink, Peter; Lynch, Diana M.; Iampietro, M. Justin; SanMiguel, Adam; Seaman, Michael S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. [Barouch, Dan H.] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Ferrari, Guido] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Forthal, Donald N.] Univ Calif Irvine, Sch Med, Irvine, CA 92717 USA. [Ourmanov, Ilnour; Hirsch, Vanessa M.] NIAID, Bethesda, MA 20892 USA. [Carville, Angela; Mansfield, Keith G.] New England Primate Res Ctr, Southborough, MA 01772 USA. [Stablein, Donald] EMMES Corp, Rockville, MD 20850 USA. [Pau, Maria G.; Schuitemaker, Hanneke; Sadoff, Jerald C.; Goudsmit, Jaap] Crucell Holland BV, NL-2301 CA Leiden, Netherlands. [Billings, Erik A.; Rao, Mangala; Robb, Merlin L.; Kim, Jerome H.; Marovich, Mary A.; Michael, Nelson L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. RP Barouch, DH (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu RI Ferrari, Guido/A-6088-2015 FU US Military Research and Material Command; US Military HIV Research Program [W81XWH-07-2-0067]; Ragon Institute of MGH, MIT and Harvard; National Institutes of Health [AI066924, AI078526, AI084794, AI095985, AI060354, AI002642, RR000168]; Bill and Melinda Gates Foundation FX We thank M. Pensiero, A. Fauci, E. Borducchi, S. Clark, R. Hamel, S. King, P. Kozlowski, A. La Porte, G. Landucci, A. Oza, J. Perry, L. Peter, A. Riggs, G. Shaw, N. Simmons, K. Smith, K. Stanley, F. Stephens, Y.-H. Sun, G. Weverling and E. Zablowsky for advice, assistance and reagents. We thank L. Picker, G. Silvestri and B. Walker for critically reviewing this manuscript. The SIVMAC239 peptide pools were obtained from the NIH AIDS Research and Reference Reagent Program. We acknowledge support from the US Military Research and Material Command and the US Military HIV Research Program (W81XWH-07-2-0067); the Ragon Institute of MGH, MIT and Harvard; the National Institutes of Health (AI066924, AI078526, AI084794, AI095985, AI060354, AI002642, RR000168); and the Bill and Melinda Gates Foundation. The opinions in this manuscript are those of the authors and do not reflect the views of the US Department of Defense. NR 30 TC 257 Z9 262 U1 4 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 2 PY 2012 VL 482 IS 7383 BP 89 EP U115 DI 10.1038/nature10766 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 884RN UT WOS:000299726000041 PM 22217938 ER PT J AU Fauci, AS Morens, DM AF Fauci, Anthony S. Morens, David M. TI 200 NEJM ANNIVERSARY ARTICLE The Perpetual Challenge of Infectious Diseases SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID ANTIBIOTIC-RESISTANCE; POLIO ERADICATION; UNITED-STATES; TRANSMISSION; EMERGENCE; VIRUS; MICROBIOTA; IDENTIFICATION; 21ST-CENTURY; PLAGUES AB Among the many challenges to health, infectious diseases stand out for their ability to have a profound impact on the human species. Great pandemics and local epidemics alike have influenced the course of wars, determined the fates of nations and empires, and affected the progress of civilization, making infections compelling actors in the drama of human history.(1-11) For 200 years, the Journal has captured the backdrop to this human drama in thousands of articles about infectious diseases and about biomedical research and public health efforts to understand, treat, control, and prevent them. C1 [Fauci, Anthony S.; Morens, David M.] NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, Bldg 31,Rm 7A-03, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 75 TC 121 Z9 129 U1 7 U2 41 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 FEB 2 PY 2012 VL 366 IS 5 BP 454 EP 461 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 884QX UT WOS:000299724400010 PM 22296079 ER PT J AU Kelada, SNP Aylor, DL Peck, BCE Ryan, JF Tavarez, U Buus, RJ Miller, DR Chesler, EJ Threadgill, DW Churchill, GA de Villena, FPM Collins, FS AF Kelada, Samir N. P. Aylor, David L. Peck, Bailey C. E. Ryan, Joseph F. Tavarez, Urraca Buus, Ryan J. Miller, Darla R. Chesler, Elissa J. Threadgill, David W. Churchill, Gary A. de Villena, Fernando Pardo-Manuel Collins, Francis S. TI Genetic Analysis of Hematological Parameters in Incipient Lines of the Collaborative Cross SO G3-GENES GENOMES GENETICS LA English DT Article DE Mouse Genetic Resource; Mouse Collaborative Cross hematology hemoglobin beta mean red cell volume; QTL mouse genetics complex traits shared ancestry ID QUANTITATIVE TRAIT LOCI; GENOME-WIDE ASSOCIATION; MOUSE HEMOGLOBINS; ERYTHROID TRAITS; PLATELET COUNT; COMPLEX TRAITS; GLOBIN GENES; BETA-GLOBIN; MICE; POPULATION AB Hematological parameters, including red and white blood cell counts and hemoglobin concentration, are widely used clinical indicators of health and disease. These traits are tightly regulated in healthy individuals and are under genetic control. Mutations in key genes that affect hematological parameters have important phenotypic consequences, including multiple variants that affect susceptibility to malarial disease. However, most variation in hematological traits is continuous and is presumably influenced by multiple loci and variants with small phenotypic effects. We used a newly developed mouse resource population, the Collaborative Cross (CC), to identify genetic determinants of hematological parameters. We surveyed the eight founder strains of the CC and performed a mapping study using 131 incipient lines of the CC. Genome scans identified quantitative trait loci for several hematological parameters, including mean red cell volume (Chr 7 and Chr 14), white blood cell count (Chr 18), percent neutrophils/lymphocytes (Chr 11), and monocyte number (Chr 1). We used evolutionary principles and unique bioinformatics resources to reduce the size of candidate intervals and to view functional variation in the context of phylogeny. Many quantitative trait loci regions could be narrowed sufficiently to identify a small number of promising candidate genes. This approach not only expands our knowledge about hematological traits but also demonstrates the unique ability of the CC to elucidate the genetic architecture of complex traits. C1 [Kelada, Samir N. P.; Peck, Bailey C. E.; Ryan, Joseph F.; Tavarez, Urraca; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Aylor, David L.; Buus, Ryan J.; Miller, Darla R.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Miller, Darla R.; Chesler, Elissa J.] Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. [Chesler, Elissa J.; Churchill, Gary A.; de Villena, Fernando Pardo-Manuel] Jackson Lab, Bar Harbor, ME 04609 USA. [Threadgill, David W.] N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA. RP Collins, FS (reprint author), NHGRI, Genome Technol Branch, NIH, Bldg 1,Room 126, Bethesda, MD 20892 USA. EM collinslab@mail.nih.gov RI Threadgill, David/N-4425-2013 OI Threadgill, David/0000-0003-3538-1635 FU National Human Genome Research Institute, National Institutes of Health (NIH); U.S. Department of Energy, Office of Biological and Environmental Research; NIH [U01CA134240, U01CA105417, F32GM090667]; National Institutes of General Medical Sciences Centers of Excellence in Systems Biology program [GM-076468] FX This work was supported in part by the intramural program of the National Human Genome Research Institute, National Institutes of Health (NIH), the U.S. Department of Energy, Office of Biological and Environmental Research, and by NIH grants U01CA134240, U01CA105417, F32GM090667, and National Institutes of General Medical Sciences Centers of Excellence in Systems Biology program grant GM-076468. NR 57 TC 36 Z9 36 U1 3 U2 12 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD FEB 1 PY 2012 VL 2 IS 2 BP 157 EP 165 DI 10.1534/g3.111.001776 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 055JE UT WOS:000312411000003 PM 22384394 ER PT J AU Reitzel, AM Ryan, JF Tarrant, AM AF Reitzel, Adam M. Ryan, Joseph F. Tarrant, Ann M. TI Establishing a model organism: A report from the first annual Nematostella meeting SO BIOESSAYS LA English DT Article ID SEA-ANEMONE; GENE-EXPRESSION; VECTENSIS; CNIDARIA; ORIGINS; ANTHOZOA; STARLET; PROTEIN; HOX C1 [Reitzel, Adam M.; Tarrant, Ann M.] Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA USA. [Ryan, Joseph F.] Natl Human Genome Res Inst, National Institutes Health, Genome Technol Branch, Bethesda, MD USA. RP Reitzel, AM (reprint author), Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA USA. EM areitzel@whoi.edu OI Tarrant, Ann/0000-0002-1909-7899 NR 25 TC 5 Z9 5 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD FEB PY 2012 VL 34 IS 2 BP 158 EP 161 DI 10.1002/bies.201100145 PG 4 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 874UL UT WOS:000298983500030 PM 22102371 ER PT J AU Walling, A Weeks, J Kahn, K Tisnado, D Keating, N Dy, S Hopkins, J Arora, N Pantoja, P Malin, J AF Walling, Anne Weeks, Jane Kahn, Katherine Tisnado, Diana Keating, Nancy Dy, Sydney Hopkins, Johns Arora, Neeraj Pantoja, Philip Malin, Jennifer TI Unmet Need for Symptom Management in a Newly Diagnosed Population of Lung and Colorectal Cancer Patients SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract CT Annual Assembly of the American-Academy-of-Hospice-and-Palliative-Medicine and the Hospice-and-Palliative-Nurses-Associations CY MAR 07-10, 2012 CL Denver, CO SP Amer Acad Hospice & Palliative Med, Hospice & Palliative Nurses Assoc C1 [Walling, Anne] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Weeks, Jane] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tisnado, Diana] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Keating, Nancy] Harvard Univ, Sch Med, Boston, MA USA. [Dy, Sydney; Hopkins, Johns; Arora, Neeraj] NCI, Bethesda, MD 20892 USA. [Pantoja, Philip] US Dept Vet Affairs, North Hills, CA USA. [Malin, Jennifer] VA Greater Los Angeles, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD FEB PY 2012 VL 43 IS 2 BP 377 EP 378 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 889DY UT WOS:000300054900091 ER PT J AU Schaub, NP Alimchandani, M Quezado, M Kalina, PM Eberhardt, JS Alexander, HR Bartlett, DL Libutti, SK Pingpank, JF Royal, RE Hughes, MS Rudloff, U Kammula, US Phan, GQ Stojadinovic, A Avital, I AF Schaub, N. P. Alimchandani, M. Quezado, M. Kalina, P. M. Eberhardt, J. S. Alexander, H. R. Bartlett, D. L. Libutti, S. K. Pingpank, J. F. Royal, R. E. Hughes, M. S. Rudloff, U. Kammula, U. S. Phan, G. Q. Stojadinovic, A. Avital, I. TI Bayesian Belief Network Model for Peritoneal Mesothelioma after Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Accurately Predicts Survival SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 65th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 21-24, 2012 CL Orlando, FL SP Soc Surg Oncol (SSO) C1 [Schaub, N. P.; Alimchandani, M.; Quezado, M.; Alexander, H. R.; Bartlett, D. L.; Libutti, S. K.; Pingpank, J. F.; Royal, R. E.; Hughes, M. S.; Rudloff, U.; Kammula, U. S.; Phan, G. Q.; Stojadinovic, A.; Avital, I.] NIH, Rockville, MD USA. [Kalina, P. M.; Eberhardt, J. S.] DecisionQ Corp, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2012 VL 19 SU 1 BP S8 EP S8 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 025PE UT WOS:000310202700008 ER PT J AU Weisbrod, A Kitano, M Patterson, E Gesuwan, K Linehan, M Kebebew, E AF Weisbrod, A. Kitano, M. Patterson, E. Gesuwan, K. Linehan, M. Kebebew, E. TI Clinical Utility of 18F-FDOPA in Von Hippel-Lindau Syndrome SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 65th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 21-24, 2012 CL Orlando, FL SP Soc Surg Oncol (SSO) C1 [Weisbrod, A.; Kitano, M.; Patterson, E.; Gesuwan, K.; Linehan, M.; Kebebew, E.] NCI, Endocrine Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2012 VL 19 SU 1 BP S111 EP S111 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 025PE UT WOS:000310202700317 ER PT J AU Weisbrod, A Liewehr, D Steinberg, S Patterson, E Linehan, M Nilubol, N Kebebew, E AF Weisbrod, A. Liewehr, D. Steinberg, S. Patterson, E. Linehan, M. Nilubol, N. Kebebew, E. TI Association of Type-O Blood with Pancreatic Neuroendocrine Tumors in Von Hippel-Lindau Syndrome SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 65th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 21-24, 2012 CL Orlando, FL SP Soc Surg Oncol (SSO) C1 [Weisbrod, A.; Liewehr, D.; Steinberg, S.; Patterson, E.; Linehan, M.; Nilubol, N.; Kebebew, E.] NCI, Endocrine Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2012 VL 19 SU 1 BP S38 EP S38 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 025PE UT WOS:000310202700097 ER PT J AU Hammachi, F Morrison, GM Sharov, AA Livigni, A Narayan, S Papapetrou, EP O'Malley, J Kaji, K Ko, MSH Ptashne, M Brickman, JM AF Hammachi, Fella Morrison, Gillian M. Sharov, Alexei A. Livigni, Alessandra Narayan, Santosh Papapetrou, Eirini P. O'Malley, James Kaji, Keisuke Ko, Minoru S. H. Ptashne, Mark Brickman, Joshua M. TI Transcriptional Activation by Oct4 Is Sufficient for the Maintenance and Induction of Pluripotency SO CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; SELF-RENEWAL; DEVELOPMENTAL REGULATORS; MOUSE EMBRYOS; TARGET GENES; POU DOMAIN; ES CELLS; DIFFERENTIATION; NETWORK; EXPRESSION AB Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing the coding sequence of Oct4 or Xlpou91 (the Xenopus homolog of Oct4) fused to activating regions, but not those fused to repressing regions, behave as Oct4, suppressing differentiation and promoting maintenance of undifferentiated phenotypes in vivo and in vitro. An Oct4 activation domain fusion supported embryonic stem cell self-renewal in vitro at lower concentrations than that required for Oct4 while alleviating the ordinary requirement for the cytokine LIF. At still lower levels of the fusion, LIF dependence was restored. We conclude that the necessary and sufficient function of Oct4 in promoting pluripotency is to activate specific target genes. C1 [Hammachi, Fella; Morrison, Gillian M.; Livigni, Alessandra; O'Malley, James; Kaji, Keisuke; Brickman, Joshua M.] Univ Edinburgh, Sch Biol Sci, Inst Stem Cell Res, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland. [Sharov, Alexei A.; Ko, Minoru S. H.] NIA, Genet Lab, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. [Narayan, Santosh; Ptashne, Mark] Mem Sloan Kettering Canc Ctr, Mol Biol Program, New York, NY 10065 USA. [Papapetrou, Eirini P.] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Brickman, Joshua M.] Univ Copenhagen, Danish Stem Cell Ctr DanStem, DK-2200 Copenhagen N, Denmark. RP Brickman, JM (reprint author), Univ Edinburgh, Sch Biol Sci, Inst Stem Cell Res, MRC Ctr Regenerat Med, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland. EM m-ptashne@mskcc.org; joshua.brickman@sund.ku.dk RI Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Brickman, Joshua/0000-0003-1580-7491 FU BBSRC [BB/C506605]; Scottish Funding Council; Medical Research Council [MRC G0701428]; Intramural Research Program of the NIH; National Institute on Aging [Z01AG AG000656, Z01AG000662]; New York Stem Cell Science (NYSTEM) Program [C026407]; Algerian Government FX We would like to thank Hitoshi Niwa and Austin Smith for provision of materials; Laxmi M. S. Tirunagari for technical assistance; Michel Sadelain for advice; and Alfonso Martinez Arias, Sally Lowell, Val Wilson, and the entire Brickman and Ptashne labs for critical reading of this manuscript. This work was supported by the BBSRC (BB/C506605), Scottish Funding Council, the Medical Research Council (MRC G0701428) (to J.M.B.), the Intramural Research Program of the NIH, the National Institute on Aging (Z01AG AG000656, Z01AG000662) (to M. S. H. K.), and the New York Stem Cell Science (NYSTEM) Program (C026407) (to M. P.). F. H. was supported by a scholarship from the Algerian Government. J.M.B. is an MRC Senior Non-Clinical Research Fellow. NR 57 TC 29 Z9 29 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REPORTS JI Cell Reports PD FEB PY 2012 VL 1 IS 2 BP 99 EP 109 DI 10.1016/j.celrep.2011.12.002 PG 11 WC Cell Biology SC Cell Biology GA 019AV UT WOS:000309710200003 PM 22832160 ER PT J AU Cembrowski, MS Logan, SM Tian, M Jia, L Li, W Kath, WL Riecke, H Singer, JH AF Cembrowski, Mark S. Logan, Stephen M. Tian, Miao Jia, Li Li, Wei Kath, William L. Riecke, Hermann Singer, Joshua H. TI The Mechanisms of Repetitive Spike Generation in an Axonless Retinal Interneuron SO CELL REPORTS LA English DT Article ID AII AMACRINE CELLS; NEUROTRANSMITTER RELEASE ENHANCER; BULLFROG SYMPATHETIC NEURONS; MAMMALIAN RETINA; MOUSE RETINA; ELECTRICAL SYNAPSES; POTASSIUM CURRENTS; GANGLION-CELLS; RABBIT RETINA; SIGNALS AB Several types of retinal interneurons exhibit spikes but lack axons. One such neuron is the AII amacrine cell, in which spikes recorded at the soma exhibit small amplitudes (<10 mV) and broad time courses (>5 ms). Here, we used electrophysiological recordings and computational analysis to examine the mechanisms underlying this atypical spiking. We found that somatic spikes likely represent large, brief action potential-like events initiated in a single, electrotonically distal dendritic compartment. In this same compartment, spiking undergoes slow modulation, likely by an M-type K conductance. The structural correlate of this compartment is a thin neurite that extends from the primary dendritic tree: local application of TTX to this neurite, or excision of it, eliminates spiking. Thus, the physiology of the axonless AII is much more complex than would be anticipated from morphological descriptions and somatic recordings; in particular, the AII possesses a single dendritic structure that controls its firing pattern. C1 [Cembrowski, Mark S.; Kath, William L.; Riecke, Hermann] Northwestern Univ, Dept Engn Sci & Appl Math, Evanston, IL 60208 USA. [Kath, William L.] Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA. [Logan, Stephen M.; Tian, Miao; Singer, Joshua H.] Northwestern Univ, Dept Ophthalmol, Chicago, IL 60611 USA. [Singer, Joshua H.] Northwestern Univ, Dept Physiol, Chicago, IL 60611 USA. [Jia, Li; Li, Wei] NEI, Dept Unit Retinal Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Cembrowski, MS (reprint author), Northwestern Univ, Dept Engn Sci & Appl Math, Evanston, IL 60208 USA. EM cembrowski@u.northwestern.edu RI Riecke, Hermann/B-7388-2009; Kath, William/B-6771-2009 FU NIH-CRCNS [EY021372]; NSF; Research to Prevent Blindness (RPB); NEI intramural research program; [EY017836] FX This work was supported by EY017836 to J.H.S., NIH-CRCNS EY021372 to J.H.S., W. L. K., and H. R., a NSF Graduate Research Fellowship to M. S. C., an unrestricted grant from Research to Prevent Blindness (RPB) to the Department of Ophthalmology at Northwestern, and the NEI intramural research program to W. L. J.H.S. is a RPB Special Scholar for Retinitis Pigmentosa. We are very grateful to Dr. D. Paul for supplying the Cx36 knock-out mice. We thank Dr. T. Jarsky for many helpful discussions, Dr. J. Demb for comments on drafts of the manuscript, and V. J. Dudley for technical assistance. NR 43 TC 18 Z9 18 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REPORTS JI Cell Reports PD FEB PY 2012 VL 1 IS 2 BP 155 EP 166 DI 10.1016/j.celrep.2011.12.006 PG 12 WC Cell Biology SC Cell Biology GA 019AV UT WOS:000309710200008 PM 22832164 ER PT J AU Mitchell, GF Verwoert, GC Tarasov, KV Isaacs, A Smith, AV Yasmin Rietzschel, ER Tanaka, T Liu, YM Parsa, A Najjar, SS O'Shaughnessy, KM Sigurdsson, S De Buyzere, ML Larson, MG Sie, MPS Andrews, JS Post, WS Mattace-Raso, FUS McEniery, CM Eiriksdottir, G Segers, P Vasan, RS van Rijn, MJE Howard, TD McArdle, PF Dehghan, A Jewell, ES Newhouse, SJ Bekaert, S Hamburg, NM Newman, AB Hofman, A Scuteri, A De Bacquer, D Ikram, MA Psaty, BM Fuchsberger, C Olden, M Wain, LV Elliott, P Smith, NL Felix, JF Erdmann, J Vita, JA Sutton-Tyrrell, K Sijbrands, EJG Sanna, S Launer, LJ De Meyer, T Johnson, AD Schut, AFC Herrington, DM Rivadeneira, F Uda, M Wilkinson, IB Aspelund, T Gillebert, TC Van Bortel, L Benjamin, EJ Oostra, BA Ding, JZ Gibson, Q Uitterlinden, AG Abecasis, GR Cockcroft, JR Gudnason, V De Backer, GG Ferrucci, L Harris, TB Shuldiner, AR van Duijn, CM Levy, D Lakatta, EG Witteman, JCM AF Mitchell, Gary F. Verwoert, Germaine C. Tarasov, Kirill V. Isaacs, Aaron Smith, Albert V. Yasmin Rietzschel, Ernst R. Tanaka, Toshiko Liu, Yongmei Parsa, Afshin Najjar, Samer S. O'Shaughnessy, Kevin M. Sigurdsson, Sigurdur De Buyzere, Marc L. Larson, Martin G. Sie, Mark P. S. Andrews, Jeanette S. Post, Wendy S. Mattace-Raso, Francesco U. S. McEniery, Carmel M. Eiriksdottir, Gudny Segers, Patrick Vasan, Ramachandran S. van Rijn, Marie Josee E. Howard, Timothy D. McArdle, Patrick F. Dehghan, Abbas Jewell, Elizabeth S. Newhouse, Stephen J. Bekaert, Sofie Hamburg, Naomi M. Newman, Anne B. Hofman, Albert Scuteri, Angelo De Bacquer, Dirk Ikram, Mohammad Arfan Psaty, Bruce M. Fuchsberger, Christian Olden, Matthias Wain, Louise V. Elliott, Paul Smith, Nicholas L. Felix, Janine F. Erdmann, Jeanette Vita, Joseph A. Sutton-Tyrrell, Kim Sijbrands, Eric J. G. Sanna, Serena Launer, Lenore J. De Meyer, Tim Johnson, Andrew D. Schut, Anna F. C. Herrington, David M. Rivadeneira, Fernando Uda, Manuela Wilkinson, Ian B. Aspelund, Thor Gillebert, Thierry C. Van Bortel, Luc Benjamin, Emelia J. Oostra, Ben A. Ding, Jingzhong Gibson, Quince Uitterlinden, Andre G. Abecasis, Goncalo R. Cockcroft, John R. Gudnason, Vilmundur De Backer, Guy G. Ferrucci, Luigi Harris, Tamara B. Shuldiner, Alan R. van Duijn, Cornelia M. Levy, Daniel Lakatta, Edward G. Witteman, Jacqueline C. M. CA AortaGen Consortium TI Common Genetic Variation in the 3 '-BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk The AortaGen Consortium SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE aorta; arterial stiffness; pulse wave velocity; genetics; cardiovascular disease ID GENOME-WIDE ASSOCIATION; ARTERIAL STIFFNESS; AORTIC STIFFNESS; HYPERTENSIVE PATIENTS; T-CELL; INDEPENDENT PREDICTOR; PROTEIN EXPRESSION; BLOOD-PRESSURE; RECEPTOR; PROMOTER AB Background-Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. Methods and Results-We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, beta=-0.075 +/- 0.012 SD/allele, P=2.8x10(-10); replication beta=-0.086 +/- 0.020 SD/allele, P=1.4x10(-6)). Combined results for rs7152623 from 11 cohorts gave beta=-0.076 +/- 0.010 SD/allele, P=3.1x10(-15). The association persisted when adjusted for mean arterial pressure (beta=-0.060 +/- 0.009 SD/allele, P=1.0x10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, beta =-0.081 +/- 0.014 SD/allele, P=2.3x10(-9)) and older (9 cohorts, n=12 026, beta=-0.061 +/- 0.014 SD/allele, P=-9.4x10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004). Conclusions-Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events. (Circ Cardiovasc Genet. 2012;5:81-90.) C1 [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA 02062 USA. [Verwoert, Germaine C.; Dehghan, Abbas; Ikram, Mohammad Arfan; Felix, Janine F.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Verwoert, Germaine C.; Mattace-Raso, Francesco U. S.; Sijbrands, Eric J. G.; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Isaacs, Aaron; Sie, Mark P. S.; van Rijn, Marie Josee E.; Schut, Anna F. C.; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Genet Epidemiol Unit, Rotterdam, Netherlands. [Tarasov, Kirill V.; Najjar, Samer S.; Scuteri, Angelo; Lakatta, Edward G.] Natl Inst Aging, Intramural Res Program, NIH, Lab Cardiovasc Sci, Baltimore, MD USA. [Tarasov, Kirill V.] Natl Inst Aging, Intramural Res Program, NIH, Genet Lab, Baltimore, MD USA. [Tanaka, Toshiko; Ferrucci, Luigi] Natl Inst Aging, Intramural Res Program, NIH, Clin Res Branch, Baltimore, MD USA. [Launer, Lenore J.; Harris, Tamara B.] Natl Inst Aging, Intramural Res Program, NIH, Lab Epidemiol Demog & Biometry, Baltimore, MD USA. [Isaacs, Aaron; Oostra, Ben A.; van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Smith, Albert V.; Eiriksdottir, Gudny; Sanna, Serena; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Yasmin; O'Shaughnessy, Kevin M.] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Rietzschel, Ernst R.; De Buyzere, Marc L.; Gillebert, Thierry C.] Ghent Univ Hosp, Dept Cardiol, Ghent, Belgium. [Rietzschel, Ernst R.] Univ Ghent, Dept Internal Med, Ghent, Belgium. [De Bacquer, Dirk; De Backer, Guy G.] Univ Ghent, Dept Publ Hlth, Ghent, Belgium. [Segers, Patrick] Univ Ghent, BioMMeda Biofluid Tissue & Solid Mech Med Applica, Inst Biomed Technol, Ghent, Belgium. [De Meyer, Tim] Univ Ghent, Fac Biosci Engn, Dept Mol Biotechnol, Ghent, Belgium. [Bekaert, Sofie] Univ Ghent, Clin Res Ctr, Ghent, Belgium. [Van Bortel, Luc] Univ Ghent, Heymans Inst Pharm, Ghent, Belgium. [Liu, Yongmei] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Andrews, Jeanette S.] Wake Forest Univ, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Herrington, David M.] Wake Forest Univ, Dept Cardiol, Winston Salem, NC 27109 USA. [Ding, Jingzhong] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Parsa, Afshin; McArdle, Patrick F.; Gibson, Quince; Shuldiner, Alan R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Najjar, Samer S.] Washington Hosp Ctr, Div Cardiol, Washington, DC 20010 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Vasan, Ramachandran S.; Olden, Matthias; Johnson, Andrew D.; Benjamin, Emelia J.; Levy, Daniel] NIILBIs Framingham Study, Framingham, MA USA. [Post, Wendy S.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Vasan, Ramachandran S.; Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Dept Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Howard, Timothy D.] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Jewell, Elizabeth S.; Fuchsberger, Christian; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Newman, Anne B.; Sutton-Tyrrell, Kim] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Psaty, Bruce M.; Smith, Nicholas L.] Univ Washington, Cardiovasc Hlth Study, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Smith, Nicholas L.] Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept VA Off Res & Dev, Seattle, WA USA. [Olden, Matthias] Univ Med Ctr Regensburg, Dept Epidemiol & Prevent Med, Dept Internal Med 2, Regensburg, Germany. [Wain, Louise V.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC HPA Ctr Environm & Hlth, London, England. [Felix, Janine F.] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Sigurdsson, Sigurdur; Uda, Manuela] Cittadella Univ Monseratto, Ist Neurogenet & Neurofarmacol, Consiglio Nazl Ric, Cagliari, Italy. [Cockcroft, John R.] Cardiff Univ, Wales Heart Res Inst, Dept Cariol, Cardiff, Wales. [Shuldiner, Alan R.] VA Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Johnson, Andrew D.; Levy, Daniel] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Johnson, Andrew D.; Levy, Daniel] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edgewater Dr,Suite 201A, Norwood, MA 02062 USA. EM GaryFMitchell@mindspring.com RI De Meyer, Tim/D-3892-2011; Johnson, Andrew/G-6520-2013; Aspelund, Thor/C-5983-2008; Newman, Anne/C-6408-2013; Gudnason, Vilmundur/K-6885-2015; Mattace- Raso, Francesco/L-2541-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; Newhouse, Stephen/C-9330-2011; OI De Meyer, Tim/0000-0003-2994-9693; Aspelund, Thor/0000-0002-7998-5433; Newman, Anne/0000-0002-0106-1150; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Newhouse, Stephen/0000-0002-1843-9842; Felix, Janine/0000-0002-9801-5774; Fuchsberger, Christian/0000-0002-5918-8947; Ikram, Mohammad Arfan/0000-0003-0372-8585; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Gillebert, Thierry/0000-0002-3832-919X; Wain, Louise/0000-0003-4951-1867 FU National Institutes of Health; National Institute on Aging Intramural Research Program; Hjartavernd (Icelandic Heart Association); Althingi (Icelandic Parliament); NIH, National Institute on Aging; Netherlands Organization for Scientific Research; Erasmus Medical Center; Centre for Medical Systems Biology (CMSB); Netherlands Kidney Foundation; National Heart, Lung, and Blood Institute's Framingham Heart Study; Affymetrix, Inc; National Heart, Lung, and Blood Institute; National Institutes on Aging; Donald W. Reynolds Foundation; NIH National Institute on Aging; National Center for Research Resources; National Institute of Diabetes, Digestive, and Kidney Disease; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging; Netherlands Organization for Scientific Research (Vici grant); National Institute on Aging; National Human Genome Research Institute; British Heart Foundation; Cambridge BioMedical Research Centre Award; Addenbrooke's Charitable Trust; Fonds voor Wetenschappelijk Onderzoek-Vlaanderen FWO FX The Age, Gene/Environment Susceptibility Reykjavik Study is funded by the National Institutes of Health, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Baltimore Longitudinal Study of Aging (BLSA) is supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The ERF study was supported by grants from the Netherlands Organization for Scientific Research, Erasmus Medical Center and the Centre for Medical Systems Biology (CMSB) and the Netherlands Kidney Foundation. The Framingham Heart Study was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study and its contract with Affymetrix, Inc for genotyping services. Additional support was provided by the National Heart, Lung, and Blood Institute, the National Institutes on Aging, and a grant from the Donald W. Reynolds Foundation. The Amish studies are supported by grants and contracts from the NIH National Institute on Aging, National Heart, Lung, and Blood Institute, National Center for Research Resources, and the National Institute of Diabetes, Digestive, and Kidney Disease. The Dynamics of Health, Aging and Body Composition (Health ABC) Study was supported by contracts from the National Institutes on Aging. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research and Research Institute for Diseases in the Elderly. This study was supported by the Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging and the Netherlands Organization for Scientific Research (Vici grant). The SardiNIA team is supported by contracts from the National Institute on Aging and, in part, by the Intramural Research Program of the NIH, National Institute on Aging and by research grants from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The Anglo-Cardiff Study was supported by grants and fellowships from the British Heart Foundation, the Cambridge BioMedical Research Centre Award, and the Addenbrooke's Charitable Trust. The Asklepios Study is supported by a Fonds voor Wetenschappelijk Onderzoek-Vlaanderen FWO research grant. A full list of funding sources appears in the online-only Data Supplement Note. NR 45 TC 31 Z9 33 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2012 VL 5 IS 1 BP 81 EP 90 DI 10.1161/CIRCGENETICS.111.959817 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 021KQ UT WOS:000309884100015 PM 22068335 ER PT J AU Murabito, JM White, CC Kavousi, M Sun, YV Feitosa, MF Nambi, V Lamina, C Schillert, A Coassin, S Bis, JC Broer, L Crawford, DC Franceschini, N Frikke-Schmidt, R Haun, M Holewijn, S Huffman, JE Hwang, SJ Kiechl, S Kollerits, B Montasser, ME Nolte, IM Rudock, ME Senft, A Teumer, A van der Harst, P Vitart, V Waite, LL Wood, AR Wassel, CL Absher, DM Allison, MA Amin, N Arnold, A Asselbergs, FW Aulchenko, Y Bandinelli, S Barbalic, M Boban, M Brown-Gentry, K Couper, DJ Criqui, MH Dehghan, A den Heijer, M Dieplinger, B Ding, JZ Dorr, M Espinola-Klein, C Felix, SB Ferrucci, L Folsom, AR Fraedrich, G Gibson, Q Goodloe, R Gunjaca, G Haltmayer, M Heiss, G Hofman, A Kieback, A Kiemeney, LA Kolcic, I Kullo, IJ Kritchevsky, SB Lackner, KJ Li, XH Lieb, WG Lohman, K Meisinger, C Melzer, D Mohler, ER Mudnic, I Mueller, T Navis, G Oberhollenzer, F Olin, JW O'Connell, J O'Donnell, CJ Palmas, W Penninx, BW Petersmann, A Polasek, O Psaty, BM Rantner, B Rice, K Rivadeneira, F Rotter, JI Seldenrijk, A Stadler, M Summerer, M Tanaka, T Tybjaerg-Hansen, A Uitterlinden, AG van Gilst, WH Vermeulen, SH Wild, SH Wild, PS Willeit, J Zeller, T Zemunik, T Zgaga, L Assimes, TL Blankenberg, S Boerwinkle, E Campbell, H Cooke, JP de Graaf, J Herrington, D Kardia, SLR Mitchell, BD Murray, A Munzel, T Newman, AB Oostra, BA Rudan, I Shuldiner, AR Snieder, H van Duijn, CM Volker, U Wright, AF Wichmann, HE Wilson, JF Witteman, JCM Liu, YM Hayward, C Borecki, IB Ziegler, A North, KE Cupples, LA Kronenberg, F AF Murabito, Joanne M. White, Charles C. Kavousi, Maryam Sun, Yan V. Feitosa, Mary F. Nambi, Vijay Lamina, Claudia Schillert, Arne Coassin, Stefan Bis, Joshua C. Broer, Linda Crawford, Dana C. Franceschini, Nora Frikke-Schmidt, Ruth Haun, Margot Holewijn, Suzanne Huffman, Jennifer E. Hwang, Shih-Jen Kiechl, Stefan Kollerits, Barbara Montasser, May E. Nolte, Ilja M. Rudock, Megan E. Senft, Andrea Teumer, Alexander van der Harst, Pim Vitart, Veronique Waite, Lindsay L. Wood, Andrew R. Wassel, Christina L. Absher, Devin M. Allison, Matthew A. Amin, Najaf Arnold, Alice Asselbergs, Folkert W. Aulchenko, Yurii Bandinelli, Stefania Barbalic, Maja Boban, Mladen Brown-Gentry, Kristin Couper, David J. Criqui, Michael H. Dehghan, Abbas den Heijer, Martin Dieplinger, Benjamin Ding, Jingzhong Doerr, Marcus Espinola-Klein, Christine Felix, Stephan B. Ferrucci, Luigi Folsom, Aaron R. Fraedrich, Gustav Gibson, Quince Goodloe, Robert Gunjaca, Grgo Haltmayer, Meinhard Heiss, Gerardo Hofman, Albert Kieback, Arne Kiemeney, Lambertus A. Kolcic, Ivana Kullo, Iftikhar J. Kritchevsky, Stephen B. Lackner, Karl J. Li, Xiaohui Lieb, Wolfgang Lohman, Kurt Meisinger, Christa Melzer, David Mohler, Emile R., III Mudnic, Ivana Mueller, Thomas Navis, Gerjan Oberhollenzer, Friedrich Olin, Jeffrey W. O'Connell, Jeff O'Donnell, Christopher J. Palmas, Walter Penninx, Brenda W. Petersmann, Astrid Polasek, Ozren Psaty, Bruce M. Rantner, Barbara Rice, Ken Rivadeneira, Fernando Rotter, Jerome I. Seldenrijk, Adrie Stadler, Marietta Summerer, Monika Tanaka, Toshiko Tybjaerg-Hansen, Anne Uitterlinden, Andre G. van Gilst, Wiek H. Vermeulen, Sita H. Wild, Sarah H. Wild, Philipp S. Willeit, Johann Zeller, Tanja Zemunik, Tatijana Zgaga, Lina Assimes, Themistocles L. Blankenberg, Stefan Boerwinkle, Eric Campbell, Harry Cooke, John P. de Graaf, Jacqueline Herrington, David Kardia, Sharon L. R. Mitchell, Braxton D. Murray, Anna Muenzel, Thomas Newman, Anne B. Oostra, Ben A. Rudan, Igor Shuldiner, Alan R. Snieder, Harold van Duijn, Cornelia M. Voelker, Uwe Wright, Alan F. Wichmann, H. -Erich Wilson, James F. Witteman, Jacqueline C. M. Liu, Yongmei Hayward, Caroline Borecki, Ingrid B. Ziegler, Andreas North, Kari E. Cupples, L. Adrienne Kronenberg, Florian TI Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease ID CORONARY-ARTERY-DISEASE; ABDOMINAL AORTIC-ANEURYSM; CARDIOVASCULAR RISK-FACTORS; SEQUENCE VARIANT; MYOCARDIAL-INFARCTION; SUSCEPTIBILITY LOCI; ATHEROSCLEROSIS; GENE; POPULATION; MORTALITY AB Background-Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. Methods and Results-Continuous ABI and PAD (ABI <= 0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the <= 2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (approximate to 60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (beta=-0.006, P=2.46x10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65x10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6x10(-5)), CYBA (rs3794624, P=6.3x10(-5)), and rs1122608 (LDLR, P=0.0026). Conclusions-Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI. (Circ Cardiovasc Genet. 2012;5:100-112.) C1 [Murabito, Joanne M.; Hwang, Shih-Jen; O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA 01701 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [White, Charles C.; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Kavousi, Maryam; Broer, Linda; Amin, Najaf; Aulchenko, Yurii; Dehghan, Abbas; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Kavousi, Maryam; Broer, Linda; Dehghan, Abbas; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] NGI Sponsored Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [Kavousi, Maryam; Broer, Linda; Dehghan, Abbas; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Ctr Med Syst Biol, Rotterdam, Netherlands. [Sun, Yan V.] Emory Univ, Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Nambi, Vijay] Baylor Coll Med, Dept Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Lamina, Claudia; Coassin, Stefan; Haun, Margot; Kollerits, Barbara; Rantner, Barbara; Summerer, Monika; Kronenberg, Florian] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Innsbruck, Austria. [Ziegler, Andreas] Univ Klinikum Schleswig Holstein, Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Franceschini, Nora; Heiss, Gerardo; North, Kari E.] Univ N Carolina, Dept Epidemiol, Univ N Carolina Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Holewijn, Suzanne; de Graaf, Jacqueline] Radboud Univ Nijmegen, Med Ctr, Dept Gen Internal Med, NL-6525 ED Nijmegen, Netherlands. [Huffman, Jennifer E.; Vitart, Veronique; Wright, Alan F.; Hayward, Caroline] Western Gen Hosp, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Kiechl, Stefan; Willeit, Johann] Innsbruck Med Univ, Dept Neurol, Innsbruck, Austria. [Montasser, May E.; Gibson, Quince; O'Connell, Jeff; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Nolte, Ilja M.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Gen Epidemiol & Bioinformat, Groningen, Netherlands. [Rudock, Megan E.; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Teumer, Alexander; Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [van der Harst, Pim; van Gilst, Wiek H.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Waite, Lindsay L.; Absher, Devin M.] Hudson Alpha Inst Biotechnol, Huntsville, AL USA. [Wassel, Christina L.; Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Arnold, Alice; Rice, Ken] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol Heart & Lungs, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. Azienda Sanitaria Firenze, Geriatr Rehabil Unit, Florence, Italy. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Gunjaca, Grgo; Mudnic, Ivana] Univ Split, Dept Pharmacol, Split, Croatia. [Couper, David J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol & Epidemiol, NL-6525 ED Nijmegen, Netherlands. [Dieplinger, Benjamin; Haltmayer, Meinhard] Konventhosp Barmherzige Brueder Linz, Dept Lab Med, Linz, Austria. [Ding, Jingzhong; Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Doerr, Marcus; Felix, Stephan B.; Kieback, Arne] Univ Med, Dept Internal Med Cardiol Angiol & Pneumol & Inte, Greifswald, Germany. [Espinola-Klein, Christine; Lackner, Karl J.; Wild, Philipp S.] Johannes Gutenberg Univ Mainz, Univ Med Ctr Mainz, Dept Med 2, D-6500 Mainz, Germany. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Fraedrich, Gustav; Rantner, Barbara] Innsbruck Med Univ, Dept Vasc Surg, Innsbruck, Austria. [Kiemeney, Lambertus A.; Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6525 ED Nijmegen, Netherlands. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Sch Med, Dept Publ Hlth, Split, Croatia. [Kullo, Iftikhar J.] Mayo Clin, Gonda Vasc Ctr, Rochester, MN USA. [Li, Xiaohui] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Lieb, Wolfgang] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Lohman, Kurt] Wake Forest Univ, Sch Med, Dept Biostat, Winston Salem, NC 27109 USA. [Meisinger, Christa] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Melzer, David] Univ Exeter, Peninsula Coll Med & Dent, Dept Epidemiol & Publ Hlth, Exeter EX4 4QJ, Devon, England. [Mohler, Emile R., III] Univ Penn, Perelman Sch Med, Div Cardiovasc, Vasc Med Sect, Philadelphia, PA 19104 USA. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Oberhollenzer, Friedrich] Bruneck Hosp, Dept Internal Med, Brunico, Italy. [Olin, Jeffrey W.] Mt Sinai Med Ctr, New York, NY 10029 USA. [O'Donnell, Christopher J.] NHLBI, Bethesda, MD 20892 USA. [Palmas, Walter] Columbia Univ, Dept Med, New York, NY USA. [Penninx, Brenda W.; Seldenrijk, Adrie] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, EMGO Inst, Amsterdam, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Petersmann, Astrid] Univ Med, Inst Clin Chem & Lab Med, Greifswald, Germany. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Rotter, Jerome I.] Univ Calif Los Angeles, Los Angeles, CA USA. Hietzing Hosp, Med Dept Metab Dis & Nephrol 3, Vienna, Austria. [Wild, Sarah H.; Zgaga, Lina; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Wild, Philipp S.] Johannes Gutenberg Univ Mainz, Univ Med Ctr Mainz, Ctr Thrombosis & Hemostasis, D-6500 Mainz, Germany. [Blankenberg, Stefan] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. Univ Split, Dept Biol, Split, Croatia. [Zgaga, Lina; Rudan, Igor] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia. [Assimes, Themistocles L.; Cooke, John P.] Stanford Univ, Med Ctr, Sch Med, Dept Med, Stanford, CA 94305 USA. [Herrington, David] Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. [Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Shuldiner, Alan R.] VA Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Wichmann, H. -Erich] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [North, Kari E.] Univ N Carolina, Sch Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA. RP Murabito, JM (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01701 USA. EM murabito@bu.edu; Florian.Kronenberg@i-med.ac.at RI Rivadeneira, Fernando/O-5385-2015; Vermeulen, H.H.M./L-4716-2015; Rudan, Igor/I-1467-2012; Hayward, Caroline/M-8818-2016; Boban, Mladen/E-2777-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Mudnic, Ivana/E-4793-2017; Lieb, Wolfgang/C-1990-2012; Rice, Kenneth/A-4150-2013; Meisinger, Christine/B-5358-2014; Crawford, Dana/C-1054-2012; Kronenberg, Florian/B-1736-2008; Graaf, J./H-8038-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Newman, Anne/C-6408-2013; Aulchenko, Yurii/M-8270-2013; Kiemeney, Lambertus/D-3357-2009 OI Melzer, David/0000-0002-0170-3838; Allison, Matthew/0000-0003-0777-8272; Mitchell, Braxton/0000-0003-4920-4744; Dehghan, Abbas/0000-0001-6403-016X; Kritchevsky, Stephen/0000-0003-3336-6781; Ziegler, Andreas/0000-0002-8386-5397; Cooke, John/0000-0003-0033-9138; Meisinger, Christa/0000-0002-9026-6544; Rivadeneira, Fernando/0000-0001-9435-9441; Rudan, Igor/0000-0001-6993-6884; Hayward, Caroline/0000-0002-9405-9550; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Mudnic, Ivana/0000-0003-4169-2886; Murabito, Joanne/0000-0002-0192-7516; Cupples, L. Adrienne/0000-0003-0273-7965; Zgaga, Lina/0000-0003-4089-9703; Murray, Anna/0000-0002-2351-2522; Rice, Kenneth/0000-0001-5779-4495; Kronenberg, Florian/0000-0003-2229-1120; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Newman, Anne/0000-0002-0106-1150; Aulchenko, Yurii/0000-0002-7899-1575; Kiemeney, Lambertus/0000-0002-2368-1326 FU University of Maryland General Clinical Research Center [M01 RR 16500]; Mid-Atlantic Nutrition Obesity Research Center [P30 DK072488]; General Clinical Research Centers Program, National Center for Research Resources (NCRR); Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC); NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C]; National Human Genome Research Institute [U01HG004402]; NIH [HHSN268200625226C, UL1RR025005, 5R01HL087660]; NINDS; NIA [AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NHLBI, NIDDK [R01HL08770003I, R01DK06833603, R01DK07568101]; National Heart, Lung and Blood Institute [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Rheinland-Pfalz (Stiftung Rheinland Pfalz fur Innovation) [AZ 961-386261/733]; Johannes Gutenberg-University of Mainz; Boehringer Ingelheim; PHILIPS Medical Systems; National Genome Network "NGFNplus" [A3 01GS0833, 01GS0831]; Federal Ministry of Education and Research, Germany; National Institutes of Health [HHSN268200782096C]; Italian Ministry of Health [ICS110.1/RF97.71]; MedStar Health Research Institute; Austrian Genome Research Programme GEN-AU; Austrian Heart Fund; Austrian National Bank [13662]; Helmholtz Zentrum Munchen; German National Genome Research Net NGFN2 and NGFNplus [01GS0823]; ZonMW [10-000-1002]; GGZ Buitenamstel-Geestgronden; Rivierduinen; University Medical Center Groningen; GGZ 25 Lentis; GGZ Friesland; GGZ Drenthe; Genetic Association Information Network (GAIN) of the Foundation for the US NIH; GAIN; NIMH [MH081802]; RUNMC; Netherlands Heart Foundation [2003B057]; Stichting Nationale Computerfaciliteiten (National Computing Facilities Foundation, NCF); Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organization for Scientific Research, NWO); Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Netherlands Organization for Scientific Research (NOW) [918-76-619]; Erasmus University Rotterdam (EUR) fellowship; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Medical Research Council UK; Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302]; European Union [LSHG-CT-2006-018947, 037631]; EUROSPAN (European Special Populations Research Network); European Commission [018947, LSHG-CT-2006-01947]; Netherlands Organisation for Scientific Research, Erasmus MC; Centre for Medical Systems Biology (CMSB); Netherlands Brain Foundation (HersenStichting Nederland); Chief Scientist Office of Scottish Government; Royal Society; Pustertaler Verein zur Pravention von Herz- und Hirngefaesserkrankungen; Gesundheitsbezirk Bruneck; Assessorat fuer Gesundheit; Province of Bolzano, Italy; Danish Medical Research Council (Copenhagen); Research Fund at Rigshospitalet, Copenhagen University Hospital (Copenhagen); Chief Physician Johan Boserup; Lise Boserup's Fund (Copenhagen); Ingeborg and Leo Dannin's Grant (Copenhagen); Henry Hansen's and Wife's Grant (Copenhagen); Centers for Disease Control and Prevention; Dutch Kidney Foundation E033; EU [LSHM CT 2006 037697]; NWO VENI [916.76.170]; General Clinical Research Center, Stanford University School of Medicine [RO1 HL-75774, 1K12 HL087746, 1P50HL083800, M01 RR 00070]; Stanford Cardiovascular Institute; Upper Austrian Government; [R01 088119]; [R01 AR046838]; [U01 HL72515]; [R01 AG18728]; [AG000219]; [HL08770002]; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156]; [HHSN268201100011C]; [HHSN268201100012C]; [R01HL087641]; [R01HL59367]; [R01HL086694]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133]; [HL080295]; [HL075366]; [HL087652]; [HL105756] FX The Amish Study was supported by grants R01 088119, R01 AR046838, U01 HL72515, and R01 AG18728, the University of Maryland General Clinical Research Center, Grant M01 RR 16500, Mid-Atlantic Nutrition Obesity Research Center Grant P30 DK072488, General Clinical Research Centers Program, National Center for Research Resources (NCRR), and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC). Dr. Montasser was supported by AG000219. ARIC is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C and infrastructure support UL1RR025005. CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and NHLBI grants HL080295, HL075366, HL087652, HL105756, with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491. The Family Heart Study GWAS was funded by grant HL08770002, and the work was supported by NHLBI contract numbers R01HL08770003I, and R01DK06833603 and R01DK07568101 from NIDDK. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (Contract No. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. "Genetic Epidemiology Network of Arteriopathy (GENOA) study is supported by the NIH, grant number 5R01HL087660." The Gutenberg Heart Study is funded through Rheinland-Pfalz ("Stiftung Rheinland Pfalz fur Innovation," contract number AZ 961-386261/733), the research programs " Wissen schafft Zukunft" and "Schwerpunkt Vaskulare Pravention" of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Heart Study. This research also was supported by the National Genome Network "NGFNplus" (contract number project A3 01GS0833 and 01GS0831), by the Federal Ministry of Education and Research, Germany. Health ABC was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The GWAS was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The InCHIANTI study baseline (1998-2000) was supported as a " targeted project"(ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the NIA (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by NIA (Contracts: N.1-AG-1-1 and N.; 1-AG-1-2111; the InCHIANTI Follow-ups 2 and 3 studies (2004-2010) were funded by NIA (Contract: N01-AG-5-0002), supported in part by the NIA Intramural research program. A portion of the support was through a R and D contract with MedStar Health Research Institute. KORA F3 and KORA F4 were partially funded by the "Genomics of Lipid-associated Disorders-GOLD" of the "Austrian Genome Research Programme GEN-AU" and by the Austrian Heart Fund to F. Kronenberg and by the Austrian National Bank (Project-Nr. 13662) to Barbara Kollerits. The MONICA/KORA Augsburg cohort study was financed by the Helmholtz Zentrum Munchen and the German National Genome Research Net NGFN2 and NGFNplus (H.-E. Wichmann 01GS0823). NESDA was supported by the Geestkracht program of ZonMW [grant 10-000-1002]; matching funds from universities and mental health care institutes involved in NESDA (GGZ Buitenamstel-Geestgronden, Rivierduinen, University Medical Center Groningen, GGZ 25 Lentis, GGZ Friesland, GGZ Drenthe). Genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US NIH, and analysis was supported by grants from GAIN and the NIMH (MH081802). NBS support was obtained from RUNMC. The measurement of ABI was supported by Grant 2003B057 of the Netherlands Heart Foundation. This work was sponsored by the Stichting Nationale Computerfaciliteiten (National Computing Facilities Foundation, NCF) for the use of supercomputer facilities, with financial support from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organization for Scientific Research, NWO). The Rotterdam GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. Dr Jacqueline Witteman is supported by Netherlands Organization for Scientific Research (NOW) grant (vici, 918-76-619). Abbas Dehghan is supported by Erasmus University Rotterdam (EUR) fellowship. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. SHIP is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. CROATIA Studies (Croatia-Vis, Croatia-Korcula, and Croatia-Split) were supported by grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302), and CROATIA-Vis by the European Union framework program 6 European Special Populations Research Network (EUROSPAN) project (contract LSHG-CT-2006-018947). The genotyping for the ERF study was supported by EUROSPAN (European Special Populations Research Network) and the European Commission FP6 STRP grant (018947; LSHG-CT-2006-01947).; The ERF study was further supported by grants from the Netherlands Organisation for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the Netherlands Brain Foundation (HersenStichting Nederland). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. The Bruneck Study was supported by the Pustertaler Verein zur Pravention von Herz- und Hirngefaesserkrankungen, Gesundheitsbezirk Bruneck, and the Assessorat fuer Gesundheit, Province of Bolzano, Italy. The Copenhagen City Heart Study was supported by a Specific Targeted Research Project grant from the European Union, Sixth Framework Programme Priority (FP-2005-LIFESCIHEALTH-6) contract 037631, the Danish Medical Research Council (Copenhagen), the Research Fund at Rigshospitalet, Copenhagen University Hospital (Copenhagen), Chief Physician Johan Boserup and Lise Boserup's Fund (Copenhagen), Ingeborg and Leo Dannin's Grant (Copenhagen), and Henry Hansen's and Wife's Grant (Copenhagen). Genotyping was supported by a grant from the Austrian Heart Fund. National Health and Nutrition Examination Surveys (NHANES) are supported by the Centers for Disease Control and Prevention. The Vanderbilt University Center for Human Genetics Research, Computational Genomics Core, provided computational or analytical support for this work. MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. "Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278." The PREVEND study is supported by the Dutch Kidney Foundation (Grant E033), EU project grant GENECURE (FP-6 LSHM CT 2006 037697), and NWO VENI (grant number 916.76.170). The CAVASIC study was partially funded by the "Genomics of Lipid-associated Disorders-GOLD" of the "Austrian Genome Research Programme GEN-AU" and by the Austrian Heart Fund and the Austrian National Bank (Project-Nr. 13662). GenePAD was supported by grants RO1 HL-75774, 1K12 HL087746, 1P50HL083800, as well as grant M01 RR 00070 (General Clinical Research Center, Stanford University School of Medicine) and the Stanford Cardiovascular Institute. The LIPAD project was supported in part by a grant from the Upper Austrian Government. Genotyping was supported by a grant from the Austrian Heart Fund. NR 57 TC 50 Z9 52 U1 2 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2012 VL 5 IS 1 BP 100 EP 112 DI 10.1161/CIRCGENETICS.111.961292 PG 13 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 021KQ UT WOS:000309884100017 PM 22199011 ER PT J AU Thanassoulis, G Peloso, GM Pencina, MJ Hoffmann, U Fox, CS Cupples, LA Levy, D D'Agostino, RB Hwang, SJ O'Donnell, CJ AF Thanassoulis, George Peloso, Gina M. Pencina, Michael J. Hoffmann, Udo Fox, Caroline S. Cupples, L. Adrienne Levy, Daniel D'Agostino, Ralph B., Sr. Hwang, Shih-Jen O'Donnell, Christopher J. TI A Genetic Risk Score Is Associated With Incident Cardiovascular Disease and Coronary Artery Calcium The Framingham Heart Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE genetics; single nucleotide polymorphisms; cardiovascular disease; coronary heart disease; risk prediction; reclassification ID GENOME-WIDE ASSOCIATION; SINGLE NUCLEOTIDE POLYMORPHISMS; MIDDLE-AGED ADULTS; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS RISK; COMPUTED-TOMOGRAPHY; CHROMOSOME 9P21.3; AMERICAN-COLLEGE; COMPLEX DISEASES; TASK-FORCE AB Background-Limited data exist regarding the use of a genetic risk score (GRS) for predicting risk of incident cardiovascular disease (CVD) in US-based samples. Methods and Results-By using findings from recent genome-wide association studies, we constructed GRSs composed of 13 genetic variants associated with myocardial infarction or other manifestations of coronary heart disease (CHD) and 102 genetic variants associated with CHD or its major risk factors. We also updated the 13 single-nucleotide polymorphism (SNP) GRSs with 16 SNPs recently discovered by genome-wide association studies. We estimated the association, discrimination, and risk reclassification of each GRS for incident cardiovascular events and prevalent coronary artery calcium (CAC). In analyses adjusted for age, sex, CVD risk factors, and parental history of CVD, the 13 SNP GRSs were significantly associated with incident hard CHD (hazard ratio, 1.07; 95% CI, 1.00-1.15; P=0.04), CVD (hazard ratio per allele, 1.05; 95% CI, 1.01-1.09; P=0.03), and high CAC (defined as >75th age-and sex-specific percentile; odds ratio per allele, 1.18; 95% CI, 1.11-1.26; P=3.4 x 10(-7)). The GRS did not improve discrimination for incident CHD or CVD but led to modest improvements in risk reclassification. However, significant improvements in discrimination and risk reclassification were observed for the prediction of high CAC. The addition of 16 newly discovered SNPs to the 13 SNP GRSs did not significantly modify these results. Conclusions-A GRS composed of 13 SNPs associated with coronary disease is an independent predictor of cardiovascular events and of high CAC, modestly improves risk reclassification for incident CHD, and significantly improves discrimination for high CAC. The addition of recently discovered SNPs did not significantly improve the performance of this GRS. (Circ Cardiovasc Genet. 2012; 5:113-121.) C1 [Thanassoulis, George; Peloso, Gina M.; Pencina, Michael J.; Fox, Caroline S.; Cupples, L. Adrienne; Levy, Daniel; D'Agostino, Ralph B., Sr.; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, NIH, Framingham Heart Study, Framingham, MA 01702 USA. [Thanassoulis, George] McGill Univ, Ctr Hlth, Div Cardiol & Clin Epidemiol, Montreal, PQ, Canada. [Thanassoulis, George] Boston Univ, Sch Med, Boston, MA 02118 USA. [Pencina, Michael J.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Fox, Caroline S.; Levy, Daniel; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Div Intramural Res, Bethesda, MD 20892 USA. [Hoffmann, Udo; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hoffmann, Udo; Fox, Caroline S.; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP O'Donnell, CJ (reprint author), NHLBI, NIH, Framingham Heart Study, 73 Mt Wayte Ave 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov OI Cupples, L. Adrienne/0000-0003-0273-7965 FU National Heart, Lung, and Blood Institute of National Institutes of Health; Boston University School of Medicine; National Heart, Lung, and Blood Institute [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Canadian Institute of Health Research; Fonds de Recherche en Sante du Quebec FX From the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195). Part of this work was also supported by the National Heart, Lung, and Blood Institute's contract with Affymetrix, Inc, for genotyping services (contract N02-HL-6-4278). Analyses are based in part on the efforts and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. Dr Thanassoulis is supported by a Research Fellowship from the Canadian Institute of Health Research and the Fonds de Recherche en Sante du Quebec. NR 55 TC 87 Z9 91 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2012 VL 5 IS 1 BP 113 EP 121 DI 10.1161/CIRCGENETICS.111.961342 PG 9 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 021KQ UT WOS:000309884100018 PM 22235037 ER PT J AU Cizza, G Rother, KI AF Cizza, G. Rother, K. I. TI Beyond fast food and slow motion: Weighty contributors to the obesity epidemic SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Review DE Cortisol; endocrinology; environment; individualized medicine; leptin; prevention; stress ID SHORT-SLEEP DURATION; BODY-MASS INDEX; BARIATRIC SURGERY; ALZHEIMERS-DISEASE; METABOLIC SYNDROME; PUTATIVE CONTRIBUTORS; NECK CIRCUMFERENCE; UNITED-STATES; RISK; STRESS AB Decreased physical activity and marketing-driven increased consumption of "junk" food, dubbed "The Big Two", are generally regarded as the most important contributors to the obesity epidemic. However, the full picture contains many more pieces of the puzzle. We address several additional issues and review current clinical developments in obesity research. In spite of dramatic advancements in our understanding of the adipose organ and its endocrine and immune products, the ultimate causes of the obesity epidemic remain elusive. Treatment is plagued by poor adherence to life style modifications, and available pharmacological options are marginally effective, often also associated with major side effects. Surgical treatments, albeit effective in decreasing body weight, are invasive and expensive. Thus, our approaches to finding the causes, improving the existing treatments, and inventing novel therapies must be manifold. (J. Endocrinol. Invest. 35: 236-242, 2012) (C) 2012, Editrice Kurtis C1 [Cizza, G.] NIDDK, Sect Neuroendocrinol Obes, Ctr Clin, NIH,DHHS, Bethesda, MD USA. [Rother, K. I.] NIDDK, Sect Pediat Diabet & Metab, Ctr Clin, NIH,DHHS, Bethesda, MD USA. RP Cizza, G (reprint author), CRC, Bldg 10,Rm 6-3940, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov FU Intramural NIH HHS [Z99 DK999999, ZIA DK075052-01, ZIA DK047049-04, ZIA DK075053-01] NR 95 TC 6 Z9 7 U1 1 U2 20 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD FEB PY 2012 VL 35 IS 2 BP 236 EP 242 DI 10.3275/8182 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 955RU UT WOS:000305039400020 PM 22183119 ER PT J AU Briassoulis, G Horvath, A Christoforou, P Lodish, M Xekouki, P Quezado, M Patronas, N Keil, MF Stratakis, CA AF Briassoulis, George Horvath, Anelia Christoforou, Paola Lodish, Maya Xekouki, Paraskevi Quezado, Martha Patronas, Nicholas Keil, Meg F. Stratakis, Constantine A. TI Lack of mutations in the gene coding for the hGR (NR3C1) in a pediatric patient with ACTH-secreting pituitary adenoma, absence of stigmata of Cushing's syndrome and unusual histologic features SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE cortisol resistance; Cushing's disease; pituitary tumors ID HUMAN GLUCOCORTICOID-RECEPTOR; PRIMARY CORTISOL RESISTANCE; LIGAND-BINDING DOMAIN; POINT MUTATION; DISEASE; POLYMORPHISMS; EXPRESSION; ISOFORMS; COMPLEX; TUMORS AB Background: Rare cases of human glucocorticoid receptor (hGR alpha) (NR3C1) gene mutations have been described in the gemline or somatic state in Cushing's disease (CD). Aim: We describe a pediatric patient with CD with clinical evidence of partial glucocorticoid resistance (GR) due to the relative absence of stigmata of Cushing's syndrome (CS). Case description: A 14-year-old boy with slow growth and hypertension, but no other signs of CS was admitted for CD evaluation. Urinary free cortisol levels (UFC) were consistently 2-3-fold the upper normal range. Pituitary magnetic resonance imaging (MRI) revealed a 3x4 mm hypoenhancing lesion in the right side of the pituitary gland anteriorly (microadenoma). A graded dexamethasone suppression test indicated that the patient had partial GR. Histology confirmed an adrenocorticotrophin (ACTH)-producing pituitary adenoma. We hypothesized that a NR3C1 mutation was present. Sequencing of the entire coding region of the gene produced normal results in both peripheral and tumor DNA. Conclusion: We present the case of a pediatric patient with an ACTH-producing tumor but little evidence of CS. No mutations in the coding sequence of NR3C1 were detected. We conclude that low level somatic mosaicism for NR3C1 mutations or a mutation in another molecule participating in hGR alpha-signaling may account for this case. C1 [Briassoulis, George; Horvath, Anelia; Christoforou, Paola; Lodish, Maya; Xekouki, Paraskevi; Keil, Meg F.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Briassoulis, George; Lodish, Maya; Keil, Meg F.; Stratakis, Constantine A.] NIH, Interinst Training Program, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Patronas, Nicholas] NIH, Dept Diagnost Radiol, Clin Res Ctr, Bethesda, MD 20892 USA. [Briassoulis, George] Univ Hosp, Pediat Intens Care Unit, Iraklion 71110, Crete, Greece. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 10,CRC,Room 1-3330,10 Ctr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Crete, Heraklion, Crete, Greece FX This study was supported by the Intramural Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and in part by a sabbatical to Dr. G. Briassoulis by the University of Crete, Heraklion, Crete, Greece. NR 32 TC 1 Z9 1 U1 1 U2 5 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD FEB PY 2012 VL 25 IS 1-2 BP 213 EP 219 DI 10.1515/JPEM.2011.371 PG 7 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 964PG UT WOS:000305708000037 PM 22570980 ER PT J AU Lodish, MB Mastroyannis, SA Sinaii, N Boikos, SA Stratakis, CA AF Lodish, Maya B. Mastroyannis, Spyridon A. Sinaii, Ninet Boikos, Sosipatros A. Stratakis, Constantine A. TI Known VDR polymorphisms are not associated with bone mineral density measures in pediatric Cushing disease SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE Cushing syndrome; genetics; glucocorticoids; osteoporosis; pediatrics ID SURGICAL CURE AB Decreased bone mineral density (BMD) has been documented in adults with Cushing disease (CD), and allelic variants of the vitamin D receptor (VDR) gene have been associated with osteopenia. Genetic factors play an important role in bone accrual and its response to various diseases; among them, the most studied are the allelic variants of the VDR gene. There is debate as to whether described variants in the VDR gene have an effect on BMD. In the current study, we sought to analyze whether BMD differences in patients with CD were associated with the Taq1 and Apa1 VDR allelotypes. The data showed lack of association between BMD and these widely studied VDR polymorphisms, suggesting that the effect of endogenous hypercortisolism on bone in the context of CD does not depend on VDR genotypes. C1 [Lodish, Maya B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,CRC, Bethesda, MD 20892 USA. [Lodish, Maya B.; Stratakis, Constantine A.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIH, Pediat Endocrinol Interinst Training Program, Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. RP Lodish, MB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,CRC, Room 1-3330,Bldg 10,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development FX This study was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development. NR 6 TC 0 Z9 0 U1 0 U2 1 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD FEB PY 2012 VL 25 IS 1-2 BP 221 EP 223 DI 10.1515/jpem-2011-0364 PG 3 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 964PG UT WOS:000305708000038 PM 22570981 ER PT J AU Pincus, HA Spaeth-Rublee, B AF Pincus, Harold Alan Spaeth-Rublee, Brigitta TI Quality of mental healthcare SO NEUROPSYCHIATRY LA English DT Editorial Material ID PERFORMANCE; ILLNESS C1 [Pincus, Harold Alan] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Pincus, Harold Alan] New York Presbyterian Hosp, New York, NY USA. [Pincus, Harold Alan] Columbias Irving Inst Clin & Translat Res, New York, NY USA. [Pincus, Harold Alan] RAND Corp, Santa Monica, CA 90406 USA. [Pincus, Harold Alan] Univ Pittsburgh, RAND, Hlth Inst, Pittsburgh, PA 15260 USA. [Pincus, Harold Alan] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Pincus, Harold Alan] Robert Wood Johnson Fdn, Natl Programs, Princeton, NJ USA. [Pincus, Harold Alan] Amer Psychiat Assoc, Res Off, Washington, DC 20005 USA. [Pincus, Harold Alan] NIMH, Bethesda, MD 20892 USA. [Spaeth-Rublee, Brigitta] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. RP Pincus, HA (reprint author), New York State Psychiat Inst & Hosp, Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA. EM pincush@pi.cpmc.columbia.edu NR 15 TC 1 Z9 1 U1 1 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1758-2008 J9 NEUROPSYCHIATRY-LOND JI Neuropsychiatry PD FEB PY 2012 VL 2 IS 1 BP 13 EP 17 DI 10.2217/NPY.12.5 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 961DL UT WOS:000305444000007 ER PT J AU Elmore, SA AF Elmore, Susan A. TI Enhanced Histopathology of the Immune System: A Review and Update SO TOXICOLOGIC PATHOLOGY LA English DT Review DE enhanced histopathology; lymphoid organs; immune system; immunomodulation; immunotoxicity; terminology ID RISK-ASSESSMENT; PATHOLOGY CONSIDERATIONS; EXTENDED HISTOPATHOLOGY; LYMPHOID-TISSUE; BONE-MARROW; IMMUNOTOXICITY; HISTOLOGY; VALIDATION; GUIDELINES; TOXICOLOGY AB Enhanced histopathology (EH) of the immune system is a tool that the pathologist can use to assist in the detection of lymphoid organ lesions when evaluating a suspected immunomodulatory test article within a subchronic study or as a component of a more comprehensive, tiered approach to immunotoxicity testing. There are three primary points to consider when performing EH: (1) each lymphoid organ has separate compartments that support specific immune functions; (2) these compartments should be evaluated individually; and (3) semiquantitative descriptive rather than interpretive terminology should be used to characterize any changes. Enhanced histopathology is a screening tool that should be used in conjunction with study data including clinical signs, gross changes, body weight, spleen and thymus weights, other organ or tissue changes, and clinical pathology. Points to consider include appropriate tissue collection, sectioning, and staining; lesion grading; and diligent comparison with concurrent controls. The value of EH of lymphoid organs is to aid in the identification of target cell type, changes in cell production and cell death, changes in cellular trafficking and recirculation, and determination of mechanism of action. C1 Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Elmore, SA (reprint author), Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Natl Toxicol Program, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). This article may be the work product of an employee or group of employees of the NIEHS, NIH, however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the United States government. NR 29 TC 10 Z9 10 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2012 VL 40 IS 2 BP 148 EP 156 DI 10.1177/0192623311427571 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 961JL UT WOS:000305460600003 PM 22089843 ER PT J AU DeWitt, JC Peden-Adams, MM Keller, JM Germolec, DR AF DeWitt, Jamie C. Peden-Adams, Margie M. Keller, Jennifer M. Germolec, Dori R. TI Immunotoxicity of Perfluorinated Compounds: Recent Developments SO TOXICOLOGIC PATHOLOGY LA English DT Article DE perfluorinated compounds; immunotoxicity; inflammation; perfluorooctane sulfonate; perfluorooctanoic acid; peroxisome proliferator activated receptor alpha ID PERFLUOROOCTANE SULFONATE PFOS; ACTIVATED RECEPTOR-ALPHA; SHORT-TERM EXPOSURE; FEMALE B6C3F1 MICE; NF-KAPPA-B; PEROXISOME-PROLIFERATOR; HUMORAL IMMUNITY; MARINE MAMMALS; UNITED-STATES; FLUORINATED HYDROCARBONS AB Perfluorinated compounds (PFCs) are environmentally widespread, persistent, and bioaccumulative chemicals with multiple toxicities reported in experimental models and wildlife, including immunomodulation. The two most commonly detected compounds, which also generally occur in the highest concentrations in environmentally exposed organisms, are perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). PFOA and PFOS have been reported to alter inflammatory responses, production of cytokines, and adaptive and innate immune responses in rodent models, avian models, reptilian models, and mammalian and nonmammalian wildlife. Mounting evidence suggests that immune effects in laboratory animal models occur at serum concentrations below, within the reported range, or just above those reported for highly exposed humans and wildlife. Thus, the risk of immune effects for humans and wildlife exposed to PFCs cannot be discounted, especially when bioaccumulation and exposure to multiple PFCs are considered. This review contains brief descriptions of current and recently published work exploring immunomodulation by PFOA, PFOS, and other PFCs in rodent models, alternative laboratory models, and wildlife. C1 [DeWitt, Jamie C.] E Carolina Univ, Dept Pharmacol & Toxicol, Brody Sch Med, Greenville, NC 27834 USA. [Peden-Adams, Margie M.] Univ Nevada, Harry Reid Ctr Environm Studies, Las Vegas, NV 89154 USA. [Keller, Jennifer M.] Natl Inst Stand & Technol, Hollings Marine Lab, Charleston, SC USA. [Germolec, Dori R.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. RP DeWitt, JC (reprint author), E Carolina Univ, Dept Pharmacol & Toxicol, Brody Sch Med, 6S-10 Brody Bldg,600 Moye Blvd, Greenville, NC 27834 USA. EM dewittj@ecu.edu OI DeWitt, Jamie/0000-0002-0440-4059 FU National Institute of Environmental Health Sciences, National Institutes of Health FX The author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the U.S. government. NR 101 TC 87 Z9 88 U1 7 U2 78 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2012 VL 40 IS 2 BP 300 EP 311 DI 10.1177/0192623311428473 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA 961JL UT WOS:000305460600020 PM 22109712 ER PT J AU Boorman, G Crabbs, TA Kolenda-Roberts, H Latimer, K Miller, AD Muravnick, KB Nyska, A Ochoa, R Pardo, ID Ramot, Y Rao, DB Schuh, J Suttie, A Travlos, GS Ward, JM Wolf, JC Elmore, SA AF Boorman, Gary Crabbs, Torrie A. Kolenda-Roberts, Holly Latimer, Ken Miller, Andrew D. Muravnick, Kathleen B. Nyska, Abraham Ochoa, Ricardo Pardo, Ingrid D. Ramot, Yuval Rao, Deepa B. Schuh, JoAnn Suttie, Andrew Travlos, Greg S. Ward, Jerrold M. Wolf, Jeffrey C. Elmore, Susan A. TI Proceedings of the 2011 National Toxicology Program Satellite Symposium SO TOXICOLOGIC PATHOLOGY LA English DT Article DE NTP Satellite Symposium; ameloblastoma; gas gland hyperplasia; stomach cystic hyperplasia; sodium dichromate dihydrate; olfactory neuroblastoma; cynomolgus monkey; adnexal degeneration; parakeratotic hyperkeratosis; oligodendroglioma; microglioma; microcytic hypochromic anemia; microcytosis; spherocytosis; poikilocytosis; green tea; Ginkgo biloba; corneal dystrophy; Dutch belted rabbit valvulitis; valvulopathy; post-transplant lymphoproliferative disease ID RESPIRATORY-TRACT LESIONS; GREEN TEA EXTRACTS; OLFACTORY NEUROBLASTOMA; RAT ERYTHROCYTES; NEURO-BLASTOMA; TOXICITY; DRUG; 1-NITROSOPIPERAZINE; CARCINOGENICITY; SPHEROCYTOSIS AB The 2011 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held in Denver, Colorado in advance of the Society of Toxicologic Pathology's 30th Annual Meeting. The goal of the NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting or discussion. Some lesions and topics covered during the symposium include: proliferative lesions from various fish species including ameloblastoma, gas gland hyperplasia, nodular regenerative hepatocellular hyperplasia, and malignant granulosa cell tumor; spontaneous cystic hyperplasia in the stomach of CD1 mice and histiocytic aggregates in the duodenal villous tips of treated mice; an olfactory neuroblastoma in a cynomolgus monkey; various rodent skin lesions, including follicular parakeratotic hyperkeratosis, adnexal degeneration, and epithelial intracytoplasmic accumulations; oligodendroglioma and microgliomas in rats; a diagnostically challenging microcytic, hypochromic, responsive anemia in rats; a review of microcytes and microcytosis; nasal lesions associated with green tea extract and Ginkgo biloba in rats; corneal dystrophy in Dutch belted rabbits; valvulopathy in rats; and lymphoproliferative disease in a cynomolgus monkey. C1 [Elmore, Susan A.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Boorman, Gary; Latimer, Ken; Suttie, Andrew] Covance Labs Inc, Chantilly, VA USA. [Crabbs, Torrie A.; Kolenda-Roberts, Holly] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Miller, Andrew D.] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. [Muravnick, Kathleen B.] Tufts Cummings Sch Vet Med, North Grafton, MA USA. [Nyska, Abraham] Timrat, Toxicol Pathol, Tel Aviv, Israel. [Nyska, Abraham] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Ochoa, Ricardo] Preclin Safety Inc, Niantic, CT USA. [Pardo, Ingrid D.] Pfizer Inc, Groton, CT 06340 USA. [Ramot, Yuval] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Rao, Deepa B.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Schuh, JoAnn] JCL Schuh PLLC, Bainbridge Isl, WA USA. [Schuh, JoAnn] Biol Test Ctr, Irvine, CA USA. [Ward, Jerrold M.] NIAID, NIH, Bethesda, MD USA. [Wolf, Jeffrey C.] Expt Pathol Labs Inc, Sterling, VA USA. RP Elmore, SA (reprint author), Natl Inst Environm Hlth Sci, Natl Toxicol Program, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX The authors wish to thank Eli Ney of the NIEHS for her unique and creative cover artwork for the Symposium handouts as well as for her technical expertise in formatting the speaker's PowerPoint presentations. Thanks also to both Eli Ney and Beth Mahler of EPL for their assistance with manuscript image preparation and to David Sabio of EPL for assistance during the Symposium. Appreciation also goes to Sue Pitsch, Krystle Correll, Tierre Miller, and Maureen Kettering of Association Innovation and Management, Inc. for their valuable help with annual advertising and meeting facilities. Also integral to the success of this meeting was the security provided by William Stoeffler of the Stoeffler Group, LLC. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). This article may be the work product of an employee or group of employees of the NIEHS, NIH; however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH, or the United States government. NR 54 TC 4 Z9 4 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2012 VL 40 IS 2 BP 321 EP 344 DI 10.1177/0192623311427713 PG 24 WC Pathology; Toxicology SC Pathology; Toxicology GA 961JL UT WOS:000305460600023 PM 22089839 ER PT J AU Gillet, JP Gottesman, MM AF Gillet, Jean-Pierre Gottesman, Michael M. TI Overcoming multidrug resistance in cancer: 35 years after the discovery of ABCB1 SO DRUG RESISTANCE UPDATES LA English DT Editorial Material C1 [Gillet, Jean-Pierre; Gottesman, Michael M.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Gillet, JP (reprint author), NCI, Cell Biol Lab, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM gilletjp@mail.nih.gov; gottesmanm@mail.nih.gov RI gillet, jean-pierre/A-3714-2012 NR 0 TC 20 Z9 20 U1 1 U2 13 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2012 VL 15 IS 1-2 SI SI BP 2 EP 4 DI 10.1016/j.drup.2012.03.001 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951MX UT WOS:000304725800002 PM 22465109 ER PT J AU Amiri-Kordestani, L Basseville, A Kurdziel, K Fojo, AT Bates, SE AF Amiri-Kordestani, Laleh Basseville, Agnes Kurdziel, Karen Fojo, Antonio Tito Bates, Susan E. TI Targeting MDR in breast and lung cancer: Discriminating its potential importance from the failure of drug resistance reversal studies SO DRUG RESISTANCE UPDATES LA English DT Review DE MDR-1/Pgp; Tc-99m-sestamibi; 18F fluoropaclitaxel; Breast cancer; Lung cancer; Drug penetration ID PHASE-II TRIAL; PREDICTING CHEMOTHERAPY RESPONSE; SINGLE NUCLEOTIDE POLYMORPHISMS; CISPLATIN-BASED CHEMOTHERAPY; PLATINUM-BASED CHEMOTHERAPY; P-GLYCOPROTEIN EXPRESSION; PREGNANE-X-RECEPTOR; BLOOD-BRAIN-BARRIER; MULTIDRUG-RESISTANCE; NEOADJUVANT CHEMOTHERAPY AB This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies. Published by Elsevier Ltd. C1 [Amiri-Kordestani, Laleh; Basseville, Agnes; Fojo, Antonio Tito; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kurdziel, Karen] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov FU Intramural NIH HHS [ZIA BC010620-06, Z01 BC010620-04, Z01 BC010620-05, ZIA BC010620-07] NR 148 TC 61 Z9 67 U1 0 U2 23 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 EI 1532-2084 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2012 VL 15 IS 1-2 SI SI BP 50 EP 61 DI 10.1016/j.drup.2012.02.002 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951MX UT WOS:000304725800006 PM 22464282 ER PT J AU Shaffer, BC Gillet, JP Patel, C Baer, MR Bates, SE Gottesman, MM AF Shaffer, Brian C. Gillet, Jean-Pierre Patel, Chirayu Baer, Maria R. Bates, Susan E. Gottesman, Michael M. TI Drug resistance: Still a daunting challenge to the successful treatment of AML SO DRUG RESISTANCE UPDATES LA English DT Review DE Acute myeloid leukemia; Multidrug resistance; ABC transporters; Cancer stem cells; Gene signatures ID ACUTE-MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; HEMATOPOIETIC STEM-CELLS; BINDING CASSETTE TRANSPORTERS; P-GLYCOPROTEIN EXPRESSION; SOUTHWEST-ONCOLOGY-GROUP; MULTIDRUG-RESISTANCE; DE-NOVO; MDR1 GENE; GROUP-B AB Resistance to chemotherapy remains a challenging issue for patients and their physicians. P-glycoprotein (Pgp, MDR1, ABCB1), as well as a family of structurally and functionally related proteins, are plasma membrane transporters able to efflux a variety of substrates from the cell cytoplasm, including chemotherapeutic agents. The discovery of ABCB1 made available a potential target for pharmacologic down-regulation of efflux-mediated chemotherapy resistance. In patients with acute myeloid leukemia (AML), a neoplasm characterized by proliferation of poorly differentiated myeloid progenitor cells, leukemic cells often express ABCB1 at high levels, which may lead to the development of resistance to chemotherapy. Thus, AML seemed to be a likely cancer for which the addition of drug efflux inhibitors to the chemotherapeutic regimen would improve outcomes in patients. Despite this rational hypothesis, the majority of clinical trials evaluating this strategy have failed to reach a positive endpoint, most recently the Eastern Cooperative Oncology Group E3999 trial. Here we review data suggesting the importance of ABCB1 in AML, address the failure of clinical trials to support a therapeutic strategy aimed at modulating ABCB1-mediated resistance, and consider the type of research that should be conducted in this field going forward. Published by Elsevier Ltd. C1 [Gillet, Jean-Pierre; Patel, Chirayu; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shaffer, Brian C.; Bates, Susan E.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Baer, Maria R.] Univ Maryland, Dept Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI gillet, jean-pierre/A-3714-2012 FU National Institutes of Health, the National Cancer Institute FX This research was funded in part by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. NR 88 TC 75 Z9 78 U1 2 U2 17 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2012 VL 15 IS 1-2 SI SI BP 62 EP 69 DI 10.1016/j.drup.2012.02.001 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951MX UT WOS:000304725800007 PM 22409994 ER PT J AU Shukla, S Chen, ZS Ambudkar, SV AF Shukla, Suneet Chen, Zhe-Sheng Ambudkar, Suresh V. TI Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance SO DRUG RESISTANCE UPDATES LA English DT Review DE ABC transporter; ABCG2; Cancer chemotherapy; Multidrug resistance; P-glycoprotein; Tyrosine kinase inhibitor ID GROWTH-FACTOR RECEPTOR; CHRONIC MYELOID-LEUKEMIA; REVERSES MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN ABCB1; ORGANIC CATION TRANSPORTER-1; CHRONIC MYELOGENOUS LEUKEMIA; HIGH-AFFINITY INTERACTION; HEMATOPOIETIC STEM-CELLS; SUBFAMILY-B MEMBER-1; HUMAN TUMOR-CELLS AB Tyrosine kinases (TKs) are involved in key signaling events/pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Deregulated activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to inhibit specific kinases whose constitutive activity results in specific cancer types. These TKIs have been found to demonstrate effective anticancer activity and some of them have been approved by the Food and Drug Administration for clinical use or are in clinical trials. However, these targeted therapeutic agents are also transported by ATP-binding cassette (ABC) transporters, resulting in altered pharmacokinetics or development of resistance to these drugs in cancer patients. This review covers the recent findings on the interactions of clinically important TKIs with ABC drug transporters. Future research efforts in the development of novel TKIs with specific targets, seeking improved activity, should consider these underlying causes of resistance to TKIs in cancer cells. Published by Elsevier Ltd. C1 [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Zhe-Sheng] St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Allied Hlth Profess, Queens, NY 11439 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH; NIH [1R15CA143701]; St.John's University [579-1110] FX We thank Mr. George Leiman (NCI, NIH) and Miss Janice Shen (Brooklyn College of The City University of New York/SUNY Downstate College of Medicine) for editorial assistance. This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH and by the NIH grant (no. 1R15CA143701) and St.John's University Seed grant (no. 579-1110) to ZS Chen. NR 142 TC 55 Z9 59 U1 0 U2 19 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2012 VL 15 IS 1-2 SI SI BP 70 EP 80 DI 10.1016/j.drup.2012.01.005 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951MX UT WOS:000304725800008 PM 22325423 ER PT J AU Lavi, O Gottesman, MM Levy, D AF Lavi, Orit Gottesman, Michael M. Levy, Doron TI The dynamics of drug resistance: A mathematical perspective SO DRUG RESISTANCE UPDATES LA English DT Review DE Drug-dependent/independent resistance; Drug scheduling and sequencing; Evolution of resistance; Mathematical modeling; Multidrug resistance ID NORTON-SIMON HYPOTHESIS; PRIMARY BREAST-CANCER; P-GLYCOPROTEIN PUMP; MULTIDRUG-RESISTANCE; TUMOR-GROWTH; COMBINATION CHEMOTHERAPY; COMPUTER-SIMULATION; ANTICANCER THERAPY; STEM-CELLS; DOSE-DENSE AB Resistance to chemotherapy is a key impediment to successful cancer treatment that has been intensively studied for the last three decades. Several central mechanisms have been identified as contributing to the resistance. In the case of multidrug resistance (MDR), the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Mathematical models of drug resistance have dealt with many of the known aspects of this field, such as pharmacologic sanctuary and location/diffusion resistance, intrinsic resistance, induced resistance and acquired resistance. In addition, there are mathematical models that take into account the kinetic/phase resistance, and models that investigate intracellular mechanisms based on specific biological functions (such as ABC transporters, apoptosis and repair mechanisms). This review covers aspects of MDR that have been mathematically studied, and explains how, from a methodological perspective, mathematics can be used to study drug resistance. We discuss quantitative approaches of mathematical analysis, and demonstrate how mathematics can be used in combination with other experimental and clinical tools. We emphasize the potential benefits of integrating analytical and mathematical methods into future clinical and experimental studies of drug resistance. Published by Elsevier Ltd. C1 [Lavi, Orit; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Levy, Doron] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Levy, Doron] Univ Maryland, Ctr Sci Computat & Math Modeling CSCAMM, College Pk, MD 20742 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov; dlevy@math.umd.edu FU National Institutes of Health, National Cancer Institute; NSF/NIGMS [DMS-0758374]; National Cancer Institute [R01CA130817] FX We would like to thank George Leiman for editorial assistance. The work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The work of DL was supported in part by the joint NSF/NIGMS program under grant number DMS-0758374 and by grant number R01CA130817 from the National Cancer Institute. NR 77 TC 18 Z9 19 U1 3 U2 40 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 EI 1532-2084 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2012 VL 15 IS 1-2 SI SI BP 90 EP 97 DI 10.1016/j.drup.2012.01.003 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951MX UT WOS:000304725800010 PM 22387162 ER PT J AU Pluchino, KM Hall, MD Goldsborough, AS Callaghan, R Gottesman, MM AF Pluchino, Kristen M. Hall, Matthew D. Goldsborough, Andrew S. Callaghan, Richard Gottesman, Michael M. TI Collateral sensitivity as a strategy against cancer multidrug resistance SO DRUG RESISTANCE UPDATES LA English DT Review DE Multidrug resistance; Collateral sensitivity; P-glycoprotein; MDR1-selective; Verapamil; MRP1 ID MAGNETIC-RESONANCE SPECTROSCOPY; ISATIN-BETA-THIOSEMICARBAZONES; DESMOSDUMOTIN-B ANALOGS; P-GLYCOPROTEIN; CELL-LINES; IRON CHELATORS; IN-VITRO; VERAPAMIL HYPERSENSITIVITY; SELECTIVE ACTIVITY; ANTITUMOR-ACTIVITY AB While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS. Published by Elsevier Ltd. C1 [Pluchino, Kristen M.; Hall, Matthew D.; Goldsborough, Andrew S.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Pluchino, Kristen M.; Callaghan, Richard] Univ Oxford, Nuffield Dept Clin Lab Sci, Oxford, England. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM gottesmm@mail.nih.gov RI Callaghan, Richard/B-7032-2012 OI Callaghan, Richard/0000-0001-6136-3532 FU National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. We thank George Leiman for editorial assistance. NR 71 TC 94 Z9 99 U1 3 U2 23 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2012 VL 15 IS 1-2 SI SI BP 98 EP 105 DI 10.1016/j.drup.2012.03.002 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951MX UT WOS:000304725800011 PM 22483810 ER PT J AU Zhang, YJ Pastan, I AF Zhang, Yujian Pastan, Ira TI Modulating Mesothelin Shedding to Improve Therapy SO ONCOTARGET LA English DT Editorial Material ID CANCER; ACTIVATION C1 [Zhang, Yujian; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zhang, YJ (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM Zhang@otsuka-us.com NR 8 TC 4 Z9 4 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB PY 2012 VL 3 IS 2 BP 114 EP 115 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 940SX UT WOS:000303914500002 ER PT J AU Zheng, YM Chang, SH Boopathi, E Burkett, S John, M Malkowicz, SB Chacko, S AF Zheng, Yongmu Chang, Shaohua Boopathi, Ettickan Burkett, Sandra John, Mary Malkowicz, S. Bruce Chacko, Samuel TI Generation of a human urinary bladder smooth muscle cell line SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE Human smooth muscle; Myosin isoform; Contractility; Stable phenotype ID DEPENDENT PROTEIN-KINASE; HEAVY-CHAIN GENE; OUTLET OBSTRUCTION; HUMAN-CHROMOSOMES; IN-VITRO; EXPRESSION; PHENOTYPE; CALDESMON AB We report a cell line (hBSM) established from human urinary bladder wall smooth muscle that maintains most of the phenotypic characteristics of smooth muscle cells. Cells were dissociated from the muscular layer with collagenase (1 mg/ml) and collected and grown in M199 supplemented with 10% fetal calf serum and 1% antibiotic-antimycotic. Primary cultures were grown for 2 d and small colonies were isolated by placing glass rings around the colonies. These colonies were picked up with a fine-tipped Pasteur pipette and subcultured. This procedure was repeated several times until a culture with a uniform stable morphology was obtained. hBSM cells are elongated with tapered ends, and in high density cultures, they form swirls of cells arranged in parallel. These cells have a doubling time of approximately 72 h. Western blotting and immunofluorescence microscopy revealed stable expression of smooth muscle-specific proteins, including myosin isoforms (N-terminal isoforms SM-A/B and C-terminal isoforms SM1/2), SM22, alpha-smoothmuscle actin, h-caldesmon, Ca2+-dependent myosin light chain kinase, and protein kinase G. These cells contract upon exposure to 10 mu M bethanechol and this contraction is reversible by washing away the drug. Karyotyping showed tetraploidy with a modal chromosome number of 87, with multiple rearrangements. To our knowledge, the hBSM cell line is the first human cell line established from bladder wall smooth muscle that expresses both N- and C-terminal smooth muscle myosin isoforms. This cell line will provide a valuable tool for studying transcriptional regulation of smooth muscle myosin isoforms and effects of drugs on cellular function. C1 [Chacko, Samuel] Univ Penn, Glenolden Res Lab, Glenolden, PA 19036 USA. [Zheng, Yongmu; Chang, Shaohua; Boopathi, Ettickan; John, Mary; Malkowicz, S. Bruce; Chacko, Samuel] Univ Penn, Div Urol, Philadelphia, PA 19104 USA. [Chacko, Samuel] Univ Penn, Dept Pathobiol, Philadelphia, PA 19104 USA. [Burkett, Sandra] NCI, Cytogenet Core Facil, Frederick, MD 21701 USA. RP Chacko, S (reprint author), Univ Penn, Glenolden Res Lab, 500 S Ridgeway Ave, Glenolden, PA 19036 USA. EM samuel.chacko@uphs.upenn.edu OI Ettickan, Boopathi/0000-0001-9431-7719 FU NIH [RO1 DK069898, P50 DK052620] FX This study was supported by NIH grants RO1 DK069898 and P50 DK052620. We thank Ms. Jocelyn McCabe for her help with preparing the manuscript and Dr. Sunish Mohanan for his help with microscopy and imaging. We also thank Mr. Brian Haldman (Dr. Chris Cremo's laboratory, Department of Biochemistry, University of Nevada School of Medicine, Reno, Nevada) for the generous gift of purified gizzard myosin. NR 29 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD FEB PY 2012 VL 48 IS 2 BP 84 EP 96 DI 10.1007/s11626-011-9473-9 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 934WU UT WOS:000303478300003 ER PT J AU Weyemi, U Parekh, PR Redon, CE Bonner, WM AF Weyemi, Urbain Parekh, Palak R. Redon, Christophe E. Bonner, William M. TI SOD2 deficiency promotes aging phenotypes in mouse skin SO AGING-US LA English DT Article DE SOD2; free radicals; senescence; skin aging ID MN-SUPEROXIDE-DISMUTASE; LIFE-SPAN; DNA-DAMAGE; OVEREXPRESSION; SENESCENCE; REDUCTION; MUTATIONS; CANCER C1 [Weyemi, Urbain; Parekh, Palak R.; Redon, Christophe E.; Bonner, William M.] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Bonner, WM (reprint author), NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. EM bonnerw@mail.nih.gov RI Parekh, Palak/B-7042-2015; Weyemi, Urbain/E-2083-2016 OI Parekh, Palak/0000-0001-9201-5194; NR 17 TC 8 Z9 8 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD FEB PY 2012 VL 4 IS 2 BP 116 EP 118 PG 3 WC Cell Biology SC Cell Biology GA 931SS UT WOS:000303240200006 PM 22328603 ER PT J AU Fonte, JS Robles, JF Chen, CC Reynolds, J Whatley, M Ling, A Mercado-Asis, LB Adams, KT Martucci, V Fojo, T Pacak, K AF Fonte, Jay S. Robles, Jeremyjones F. Chen, Clara C. Reynolds, James Whatley, Millie Ling, Alexander Mercado-Asis, Leilani B. Adams, Karen T. Martucci, Victoria Fojo, Tito Pacak, Karel TI False-negative I-123-MIBG SPECT is most commonly found in SDHB-related pheochromocytoma or paraganglioma with high frequency to develop metastatic disease SO ENDOCRINE-RELATED CANCER LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MIBG SCINTIGRAPHY; MALIGNANT PHEOCHROMOCYTOMAS; METAIODOBENZYLGUANIDINE; DIAGNOSIS; LOCALIZATION; PET; MUTATIONS; THERAPY; CATECHOLAMINES AB The purpose of this study was to present the characteristics and outcome of patients with proven pheochromocytoma or paraganglioma who had false-negative iodine-123 metaiodobenzylguanidine single photon emission computed tomography (I-123-MIBG SPECT). Twenty-one patients with false-negative I-123-MIBG SPECT (7 males, 14 females), aged 13-55 years (mean: 41.40 years), were included. We classified them as nonmetastatic or metastatic according to the stage of the disease at the time of false-negative I-123-MIBG SPECT study, the location and size of the tumor, plasma and urinary catecholamine and metanephrine levels, genetic mutations, and outcome in terms of occurrence and progression of metastases and death. Thirteen patients were evaluated for metastatic tumors, while the remaining eight were seen for nonmetastatic disease. All primary tumors and multiple metastatic foci did not show avid I-123-MIBG uptake regardless of the tumor diameter. The majority of patients had extraadrenal tumors with hypersecretion of normetanephrine or norepinephrine. SDHB mutations were present in 52% (n=11) of cases, RET mutation in 4% (n=1), and the rest were apparently sporadic. Twenty-four percent (n=5) had metastatic disease on initial presentation. Fourteen patients were followed for 3-7 years. Of them, 71% (n=10) had metastatic disease and the majority had SDHB mutations. Nine are still alive, while five (four with SDHB) died due to metastatic disease. We concluded that false-negative I-123-MIBG SPECT is frequently related to metastatic tumors and usually due to SDHB mutations with unfavorable prognosis. We therefore recommend that patients with false-negative I-123-MIBG SPECT be tested for SDHB mutations and undergo more regular and close follow-up. Endocrine-Related Cancer (2012) 19 83-93 C1 [Fonte, Jay S.; Robles, Jeremyjones F.; Adams, Karen T.; Martucci, Victoria; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.; Reynolds, James; Whatley, Millie] NIH, Div Nucl Med, Radiol & Imaging Sci Dept, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Fonte, Jay S.; Robles, Jeremyjones F.; Mercado-Asis, Leilani B.] Univ Santo Tomas Hosp, Sect Endocrinol & Metab, Dept Med, Manila 1008, Philippines. [Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU National Institute of Child Health and Human Development/National Institutes of Health; Section of Endocrinology and Metabolism, Department of Medicine, University of Santo Tomas Hospital, Manila, Philippines; Thomasian Endocrine Progress Inc. FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development/National Institutes of Health.; J S Fonte, MD and J F Robles, MD acknowledge the staff of the Section of Endocrinology and Metabolism, Department of Medicine, University of Santo Tomas Hospital, Manila, Philippines; and Thomasian Endocrine Progress Inc. for their invaluable support during their training at the National Institutes of Health. NR 43 TC 31 Z9 31 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2012 VL 19 IS 1 BP 83 EP 93 DI 10.1530/ERC-11-0243 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 930NW UT WOS:000303147100014 PM 22167067 ER PT J AU Albo, ME Litman, HJ Lemack, GE Richter, HE Chai, TC Kenton, K Kraus, SR Sirls, LT Zyczynski, H Norton, P Gormley, EA Kusek, JW Brubaker, LB AF Albo, M. E. Litman, H. J. Lemack, G. E. Richter, H. E. Chai, T. C. Kenton, K. Kraus, S. R. Sirls, L. T. Zyczynski, H. Norton, P. Gormley, E. A. Kusek, J. W. Brubaker, L. B. CA Urinary Incontinence Treatment Net TI Twenty-four month outcomes of randomized equivalence trial of retropubic and transobturator midurethral slings (TOMUS) SO EUROPEAN UROLOGY SUPPLEMENTS LA English DT Meeting Abstract C1 [Albo, M. E.] Univ Calif San Diego, Dept Urol, San Diego, CA 92103 USA. [Litman, H. J.] New England Res Inst, Boston, MA USA. [Lemack, G. E.] SW Texas State Univ, Dept Urol, Dallas, TX USA. [Richter, H. E.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Chai, T. C.] Univ Maryland, Dept Urol, Baltimore, MD 21201 USA. [Kenton, K.; Brubaker, L. B.] Loyola Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Kraus, S. R.] Univ Texas San Antonio, Dept Urol, San Antonio, TX USA. [Sirls, L. T.] William Beaumont Hosp, Dept Urol, Detroit, MI USA. [Zyczynski, H.] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA 15213 USA. [Norton, P.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Gormley, E. A.] Dartmouth Hitchcock Med Ctr, Dept Urol, Dartmouth, NS, Canada. [Kusek, J. W.] NIDDK, NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9056 J9 EUR UROL SUPPL JI Eur. Urol. Suppl. PD FEB PY 2012 VL 11 IS 1 BP E171 EP U579 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 928RP UT WOS:000303001300221 ER PT J AU Tatokoro, M Koga, F Yoshida, S Fukushima, H Kawakami, S Fujii, Y Neckers, L Kihara, K AF Tatokoro, M. Koga, F. Yoshida, S. Fukushima, H. Kawakami, S. Fujii, Y. Neckers, L. Kihara, K. TI Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder cancer stem cells SO EUROPEAN UROLOGY SUPPLEMENTS LA English DT Meeting Abstract C1 [Tatokoro, M.; Koga, F.; Yoshida, S.; Fukushima, H.; Kawakami, S.; Fujii, Y.; Kihara, K.] Tokyo Med & Dent Univ, Grad Sch, Dept Urol, Tokyo, Japan. [Neckers, L.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9056 J9 EUR UROL SUPPL JI Eur. Urol. Suppl. PD FEB PY 2012 VL 11 IS 1 BP E670 EP U432 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 928RP UT WOS:000303001301210 ER PT J AU Tasso, R Ilengo, C Quarto, R Cancedda, R Caspi, RR Pennesi, G AF Tasso, Roberta Ilengo, Cristina Quarto, Rodolfo Cancedda, Ranieri Caspi, Rachel R. Pennesi, Giuseppina TI Mesenchymal Stem Cells Induce Functionally Active T-Regulatory Lymphocytes in a Paracrine Fashion and Ameliorate Experimental Autoimmune Uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID GROWTH-FACTOR-BETA; BONE-MARROW; STROMAL CELLS; IMMUNE-RESPONSE; MICE; UVEORETINITIS; DISEASE; ANTIGEN; IRBP; DIFFERENTIATION AB PURPOSE. Mesenchymal stem/progenitor cells (MSCs) have regenerative and immunomodulatory properties, exerted by cell-cell contact and in a paracrine fashion. Part of their immunosuppressive activity has been ascribed to their ability to promote the induction of CD4(+)CD25(+)FoxP3(+) T lymphocytes with regulatory functions (Treg). Here the authors studied the effect of MSCs on the induction of Treg and on the development of autoimmunity, and they examined the possibility that MSC-mediated Treg induction could be attributed to the secretion of soluble factors. METHODS. The authors induced experimental autoimmune uveitis (EAU) in mice by immunization with the 1-20 peptide of the intraphotoreceptor binding protein. At the same time, some of the animals were treated intraperitoneally with syngeneic MSCs. The authors checked T-cell responses and in vitro Treg conversion by cell proliferation and blocking assays, in cell-cell contact and transwell settings. TGF beta and TGF beta receptor gene expression analyses were performed by real-time PCR. RESULTS. The authors found that a single intraperitoneal injection of MSCs was able to significantly attenuate EAU and that a significantly higher percentage of adaptive Treg was present in MSC-treated mice than in MSC-untreated animals. In vitro blocking of antigen presentation by major histocompatibility complex class II precluded priming and clonal expansion of antigen-specific Treg, whereas blockade of TGF beta impaired the expression of FoxP3, preventing the conversion of CD4(+) T cells into functionally active Treg. CONCLUSIONS. The authors demonstrated that MSCs can inhibit EAU and that their immunomodulatory function is due at least in part to the induction of antigen-specific Treg in a paracrine fashion by secreting TGF beta. (Invest Ophthalmol Vis Sci. 2012; 53: 786-793) DOI: 10.1167/iovs.11-8211 C1 [Tasso, Roberta] Univ Genoa, DOBIG, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. [Tasso, Roberta; Cancedda, Ranieri; Pennesi, Giuseppina] AOU San Martino IST, Natl Inst Canc Res, Genoa, Italy. [Ilengo, Cristina; Quarto, Rodolfo] Adv Biotechnol Ctr, Stem Cell Lab, Genoa, Italy. [Caspi, Rachel R.] NEI, Immunol Lab, Natl Inst Hlth, Bethesda, MD USA. RP Tasso, R (reprint author), Univ Genoa, DOBIG, Dept Oncol Biol & Genet, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. EM roberta.tasso@istge.it RI Tasso, Roberta/J-7237-2016; OI Tasso, Roberta/0000-0003-0956-7006; Caspi, Rachel/0000-0002-7140-7671; Quarto, Rodolfo/0000-0002-1146-894X FU Italian Ministry of University and Research; National Eye Institute/National Institutes of Health FX Supported by grants from the Italian Ministry of University and Research. RRC is supported by National Eye Institute/National Institutes of Health intramural funding. NR 43 TC 35 Z9 38 U1 0 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2012 VL 53 IS 2 BP 786 EP 793 DI 10.1167/iovs.11-8211 PG 8 WC Ophthalmology SC Ophthalmology GA 925VA UT WOS:000302788600033 PM 22232435 ER PT J AU Tu, ZD Li, Y Smith, D Doller, C Sugita, S Chan, CC Qian, SG Fung, J Caspi, RR Lu, LN Lin, F AF Tu, Zhidan Li, Yan Smith, Dawn Doller, Catherine Sugita, Sunao Chan, Chi-Chao Qian, Shiguang Fung, John Caspi, Rachel R. Lu, Lina Lin, Feng TI Myeloid Suppressor Cells Induced by Retinal Pigment Epithelial Cells Inhibit Autoreactive T-Cell Responses That Lead to Experimental Autoimmune Uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID TUMOR PROGRESSION; IMMUNE-SYSTEM; INTERLEUKIN-6; ACCUMULATION; LYMPHOCYTES; EXPRESSION; SECRETION; BETA; MICE AB PURPOSE. To test whether retinal pigment epithelial (RPE) cells are able to induce myeloid-derived suppressor cell (MDSC) differentiation from bone marrow (BM) progenitors. METHODS. BM cells were cocultured with or without RPE cells in the presence of GM-CSF and IL-4. Numbers of resultant MDSCs were assessed by flow cytometry after 6 days of incubation. The ability of the RPE cell-induced MDSCs to inhibit T cells was evaluated by a CFSE-based T-cell proliferation assay. To explore the mechanism by which RPE cells induce MDSC differentiation, PD-L1-deficient RPE cells and blocking antibodies against TGF-beta, CTLA-2 alpha, and IL-6 were used. RPE cell-induced MDSCs were adoptively transferred into mice immunized with interphotoreceptor retinoid-binding protein in complete Freund's adjuvant to test their efficacy in suppressing autoreactive T-cell responses in experimental autoimmune uveitis (EAU). RESULTS. RPE cells induced the differentiation of MDSCs. These RPE cell-induced MDSCs significantly inhibited T-cell proliferation in a dose-dependent manner. PD-L1-deficient RPE cells induced MDSC differentiation as efficiently as wild-type RPE cells, and neutralizing TGF-beta or CTLA-2 alpha did not alter the numbers of induced MDSCs. However, blocking IL-6 reduced the efficacy of RPE cell-induced MDSC differentiation. Finally, adoptive transfer of RPE cell-induced MDSCs suppressed IRBP-specific T-cell responses that led to EAU. CONCLUSIONS. RPE cells induce the differentiation of MDSCs from bone marrow progenitors. Both cell surface molecules and soluble factors are important in inducing MDSC differentiation. PD-L1, TGF-beta, and CTLA-2 alpha were not measurably involved in RPE cell-induced MDSC differentiation, whereas IL-6 was important in the process. The induction of MDSCs could be another mechanism by which RPE cells control immune reactions in the retina, and RPE cell-induced MDSCs should be further investigated as a potential approach to therapy for autoimmune posterior uveitis. (Invest Ophthalmol Vis Sci. 2012;53:959-966) DOI:10.1167/iovs.11-8377 C1 [Lin, Feng] Case Western Reserve Univ, Sch Med, Inst Pathol, Dept Pathol, Cleveland, OH 44106 USA. [Smith, Dawn; Doller, Catherine] Case Western Reserve Univ, Dept Ophthalmol, Cleveland, OH 44106 USA. [Sugita, Sunao] Tokyo Med & Dent Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Tokyo, Japan. [Chan, Chi-Chao; Caspi, Rachel R.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Qian, Shiguang; Fung, John; Lu, Lina] Cleveland Clin, Dept Surg, Cleveland, OH 44106 USA. RP Lin, F (reprint author), Case Western Reserve Univ, Sch Med, Inst Pathol, Dept Pathol, 2085 Adelbert Rd, Cleveland, OH 44106 USA. EM feng.lin@case.edu RI Fung, John/A-2679-2012; li, yan/B-8629-2015; OI Caspi, Rachel/0000-0002-7140-7671 FU National Institutes of Health [EY020956, NS052471, EY11373] FX Supported by National Institutes of Health Grants EY020956 (FL), NS052471 (FL), and EY11373 for the Core Facilities. NR 32 TC 18 Z9 18 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2012 VL 53 IS 2 BP 959 EP 966 DI 10.1167/iovs.11-8377 PG 8 WC Ophthalmology SC Ophthalmology GA 925VA UT WOS:000302788600059 PM 22247470 ER PT J AU Osborne, TS Khanna, C AF Osborne, T. S. Khanna, C. TI A Review of the Association between Osteosarcoma Metastasis and Protein Translation SO JOURNAL OF COMPARATIVE PATHOLOGY LA English DT Article DE dog; metastasis; osteosarcoma; protein translation ID INITIATION-FACTOR 4E; HIGH-GRADE OSTEOSARCOMA; CAP-BINDING PROTEIN; RAT EMBRYO FIBROBLASTS; MESSENGER-RNA; OSTEOGENIC-SARCOMA; PROTOONCOGENE EIF4E; BREAST CARCINOMAS; TUMOR-METASTASIS; ANTISENSE RNA AB The malignant transformation of mesenchymal cells within the bone leads to the development of osteosarcoma (OS), but the genetic underpinnings of these events are not understood. From a clinical perspective, primary tumour management can be achieved successfully in most patients. However, the development of metastasis to the lungs represents the most common cause of death in OS patients. A clearer understanding of metastasis biology is required to improve cancer mortality and improve outcomes. Modelling the genetics, biology and therapy of OS can be accomplished through research involving a number of species. Most notable is the naturally occurring form of OS that develops in dogs. Through a cross-species and comparative approach important questions can be asked within specific and suitable models to advance our understanding of this disease and its common metastatic outcome. A comparative perspective on the problem of OS metastasis that utilizes a cross-species approach may offer unique opportunities to assist in this prioritization and generate new hypotheses related to this important clinical problem. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Osborne, T. S.; Khanna, C.] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Khanna, C (reprint author), NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 92 TC 39 Z9 41 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9975 J9 J COMP PATHOL JI J. Comp. Pathol. PD FEB-APR PY 2012 VL 146 IS 2-3 BP 132 EP 142 DI 10.1016/j.jcpa.2011.12.007 PG 11 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 928HG UT WOS:000302973200006 PM 22297074 ER PT J AU Zatzick, D AF Zatzick, Douglas TI TOWARD THE ESTIMATION OF POPULATION IMPACT IN EARLY POSTTRAUMATIC STRESS DISORDER INTERVENTION TRIALS SO DEPRESSION AND ANXIETY LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; INJURED TRAUMA SURVIVORS; PUBLIC-HEALTH IMPACT; PREVENTIVE INTERVENTIONS; PTSD; CARE; EPIDEMIOLOGY; VETERANS; BARRIERS C1 [Zatzick, Douglas] NIMH, Serv Nonspecialty Settings NIMH SRNS Study Sect, Bethesda, MD 20892 USA. [Zatzick, Douglas] Univ Washington, Harborview Level Trauma Ctr 1, Psychiat Consultat Liaison Serv, Seattle, WA 98104 USA. RP Zatzick, D (reprint author), Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Harborview Injury Prevent & Res Ctr, 325 9th Ave,Box 359911, Seattle, WA 98104 USA. EM dzatzick@u.washington.edu FU National Institute of Mental Health [R01/MH073613, K24/MH086814] FX This work was supported by National Institute of Mental Health Grants R01/MH073613 and K24/MH086814. NR 39 TC 4 Z9 4 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD FEB PY 2012 VL 29 IS 2 BP 79 EP 84 DI 10.1002/da.21912 PG 6 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 923KO UT WOS:000302618400001 PM 22495939 ER PT J AU Gorlas, A Koonin, EV Bienvenu, N Prieur, D Geslin, C AF Gorlas, Aurore Koonin, Eugene V. Bienvenu, Nadege Prieur, Daniel Geslin, Claire TI TPV1, the first virus isolated from the hyperthermophilic genus Thermococcus SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID SEA HYDROTHERMAL VENT; THERMOPHILIC ARCHAEON SULFOLOBUS; COMPLETE GENOME SEQUENCE; GENETIC ELEMENTS; EVOLUTIONARY HISTORY; PYROCOCCUS-ABYSSI; HYPERSALINE LAKE; SP. NOV.; DNA; PLASMIDS AB We describe a novel virus, TPV1 (Thermococcus prieurii virus 1), which was discovered in a hyperthermophilic euryarchaeote isolated from a deep-sea hydrothermal chimney sample collected at a depth of 2700 m at the East Pacific Rise. TPV1 is the first virus isolated and characterized from the hyperthermophilic euryarchaeal genus Thermococcus. TPV1 particles have a lemon-shaped morphology (140 nm x 80 nm) similar to the structures previously reported for Fuselloviruses and for the unclassified virus-like particle PAV1 (Pyrococcus abyssi virus 1). The infection with TPV1 does not cause host lysis and viral replication can be induced by UV irradiation. TPV1 contains a double-stranded circular DNA of 21.5 kb, which is also present in high copy number in a free form in the host cell. The TPV1 genome encompasses 28 predicted genes; the protein sequences encoded in 16 of these genes show no significant similarity to proteins in public databases. Proteins predicted to be involved in genome replication were identified as well as transcriptional regulators. TPV1 encodes also a predicted integrase of the tyrosine recombinase family. The only two genes that are homologous between TPV1 and PAV1 are TPV1-22 and TPV1-23, which encode proteins containing a concanavalin A-like lectin/glucanase domain that might be involved in virus-host recognition. C1 [Gorlas, Aurore; Bienvenu, Nadege; Prieur, Daniel; Geslin, Claire] CNRS, UBO IUEM, UMR 6197, LMEE, F-29280 Plouzane, France. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Geslin, C (reprint author), CNRS, UBO IUEM, UMR 6197, LMEE, Pl Nicolas Copernic,Technopole Brest Iroise, F-29280 Plouzane, France. EM claire.geslin@univ-brest.fr FU MENRT; CNRS 'PID Origines des Planetes et de la Vie'; Foundation for Research on Biodiversity (FRB); ANR Deep Oases FX We thank the captain and crew of the NO L'Atalante, the pilots and support crew of the submersible Nautile, the chief scientist D. Jollivet, and M. Gaillard for helping us to collect deep-sea hydrothermal vent samples during the BioSpeedo oceanographic cruise. We thank G. Sinquin for assistance in electron microscopy and Natalya Yutin for help with phylogenetic analysis. Reviewers are also greatly acknowledged. This work was financially supported by a MENRT grant for A. Gorlas; CNRS 'PID Origines des Planetes et de la Vie' programs (2007-2009); The Foundation for Research on Biodiversity (FRB) (2009) and the ANR Deep Oases. NR 67 TC 35 Z9 35 U1 0 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD FEB PY 2012 VL 14 IS 2 BP 503 EP 516 DI 10.1111/j.1462-2920.2011.02662.x PG 14 WC Microbiology SC Microbiology GA 922HZ UT WOS:000302539300017 PM 22151304 ER PT J AU Li, WH Niu, G Lang, LX Guo, N Ma, Y Kiesewetter, DO Backer, JM Shen, BZ Chen, XY AF Li, Weihua Niu, Gang Lang, Lixin Guo, Ning Ma, Ying Kiesewetter, Dale O. Backer, Joseph M. Shen, Baozhong Chen, Xiaoyuan TI PET imaging of EGF receptors using [F-18]FBEM-EGF in a head and neck squamous cell carcinoma model SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE PET; [F-18]FBEM-cEGF; HNSCC; EGFR ID EPIDERMAL-GROWTH-FACTOR; HER-KINASE AXIS; MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; PLUS CETUXIMAB; IN-VIVO; TUMORS; CU-64-DOTA-CETUXIMAB; LOCALIZATION; XENOGRAFTS AB Purpose To prepare and evaluate a new radiotracer for molecular imaging of cell surface receptors for epidermal growth factor (EGF). Methods Cys-tagged EGF (cEGF) was labeled with F-18 by coupling the free thiol group of the Cys tag with N-[2-(4-[F-18]fluorobenzamido) ethyl] maleimide ([F-18]FBEM) to form [F-18]FBEM-cEGF. Cell uptake, internalization and efflux of [F-18]FBEM-cEGF were tested in human head and neck squamous carcinoma UM-SCC1 cells. In vivo tumor targeting and pharmacokinetics of the radiotracers were evaluated in UM-SCC1 tumor-bearing athymic nude mice by static and dynamic microPET imaging. Ex vivo biodistribution assays were performed to confirm the noninvasive imaging results. Results The radiolabeling yield for [F-18]FBEM-cEGF was over 60%, based on starting [F-18]FBEM. [F-18]FBEM-cEGF exhibited rapid blood clearance through both hepatobiliary and renal excretion. UM-SCC1 tumors were clearly visualized and showed modest tracer uptake of 2.60 +/- 0.59 %ID/g at 30 min after injection. Significantly higher tumor uptake of [F-18]FBEM-cEGF (5.99 +/- 1.61% ID/g at 30 min after injection, p<0.01) and tumor/nontumor ratio were achieved by coinjection of 50 mu g of unlabeled EGF. Decreased liver uptake of [F-18]FBEM-cEGF was observed when unlabeled EGF was coadministered. Conclusion With optimized liver blocking, [F-18]FBEM-cEGF has the potential to be used in a noninvasive and quantitative manner for detection of malignant lesions and evaluation of EGFR activity. C1 [Li, Weihua; Shen, Baozhong] Harbin Med Coll, Dept Med Imaging & Nucl Med, Affiliated Hosp 4, Harbin 150001, Peoples R China. [Li, Weihua; Niu, Gang; Lang, Lixin; Guo, Ning; Ma, Ying; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Backer, Joseph M.] SibTech Inc, Brookfield, CT 06804 USA. RP Shen, BZ (reprint author), Harbin Med Coll, Dept Med Imaging & Nucl Med, Affiliated Hosp 4, 37 Yinhang St, Harbin 150001, Peoples R China. EM shenbzh@vip.sina.com; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009] FX This project was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) and the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). We thank Dr. Henry S. Eden for proof-reading the manuscript. NR 38 TC 16 Z9 16 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD FEB PY 2012 VL 39 IS 2 BP 300 EP 308 DI 10.1007/s00259-011-1969-8 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 918YC UT WOS:000302286600013 PM 22109665 ER PT J AU Shannon, E Sandoval, F Greig, N Stagg, P AF Shannon, E. Sandoval, F. Greig, N. Stagg, P. TI Lenalidomide alone or lenalidomide plus dexamethasone significantly inhibit IgG and IgM in vitro ... A possible explanation for their mechanism of action in treating multiple myeloma SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE Thalidomide; Lenalidomide; Dexamethasone; IgM; IgG ID ERYTHEMA-NODOSUM LEPROSUM; NK-CELL-FUNCTION; IMMUNOGLOBULIN-SYNTHESIS; THALIDOMIDE; IL-2; CORTICOSTEROIDS; DIFFERENTIATION; INTERLEUKIN-6; LYMPHOCYTES; POKEWEED AB Lenalidomide (len) is an analog of thalidomide (thal), and both are used in the treatment of a diverse group of medical conditions. A common finding in this group is the detection of immunoglobulin in skin lesions, or high levels of immunoglobulin or myeloma protein in serum and urine. While their mechanism(s) of action is not known, the drugs are noted for their ability to modulate monocyte, lymphocyte, and natural killer cell functions: suppression of immunoglobulin synthesis could offer an explanation for their effectiveness in treating multiple myeloma (MM). Our objective was to determine if, on an equimolar basis, that, len or dexamethasone (dex) could affect pokeweed (PWM)-induced synthesis of IgG, IgM and IL-2. When peripheral blood mononuclear cells were stimulated with PWM, len surpassed thal in suppressing IgM and IgG, and enhancing IL-2. Dex enhanced IgG, and suppressed IL-2. When the stimulated cells were treated with len (an effective promoter of IL-2 and suppressor of IgM and IgG) plus dex (an effective suppressor of IL-2 and enhancer of IgG), the net result was suppression of IgM and IgG. The synthesis of IgM and IgG by putative PWM-stimulated B cell blasts is significantly blocked by len. This suggest that the B-lymphocyte is a targeted cell for len, and that suppression of the synthesis of IgG and IgM could provide an explanation for the mechanism by which len effectively treats MM. Published by Elsevier B.V. C1 [Shannon, E.] Louisiana State Univ, US Dept Hlth & Human Serv, Hlth Resources & Serv Adm, Natl Hansens Dis Programs,Lab Res Branch,SVM, Baton Rouge, LA 70803 USA. [Greig, N.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Stagg, P.] Med Oncol LLC, Baton Rouge, LA USA. RP Shannon, E (reprint author), Louisiana State Univ, US Dept Hlth & Human Serv, Hlth Resources & Serv Adm, Natl Hansens Dis Programs,Lab Res Branch,SVM, Skip Bertman Dr, Baton Rouge, LA 70803 USA. EM eshannon@hrsa.gov FU National Institute on Aging, NIH FX We wish to thank Mr. jay Thomas and the blood donors at the Blood Bank of Our Lady of the Lake Hospital in Baton Rouge, LA; Ms. Aileen Brassard and the blood donors attending the Oncology Clinic in Baton Rouge La. A special thanks to Dr. W. Krotoski for the helpful suggestions. NG is supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 30 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD FEB PY 2012 VL 12 IS 2 BP 441 EP 446 DI 10.1016/j.intimp.2011.12.023 PG 6 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 924BG UT WOS:000302665000016 PM 22245427 ER PT J AU Sinicrope, FA Foster, NR Yoon, HH Smyrk, TC Kim, GP Allegra, CJ Yothers, G Nikcevich, DA Sargent, DJ AF Sinicrope, Frank A. Foster, Nathan R. Yoon, Harry H. Smyrk, Thomas C. Kim, George P. Allegra, Carmen J. Yothers, Greg Nikcevich, Daniel A. Sargent, Daniel J. TI Association of Obesity With DNA Mismatch Repair Status and Clinical Outcome in Patients With Stage II or III Colon Carcinoma Participating in NCCTG and NSABP Adjuvant Chemotherapy Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS INDEX; COLORECTAL-CANCER RISK; MICROSATELLITE-INSTABILITY STATUS; ISLAND METHYLATOR PHENOTYPE; CIGARETTE-SMOKING; PHYSICAL-ACTIVITY; RECTAL-CANCER; LIFE-STYLE; FLUOROURACIL; THERAPY AB Purpose Although the importance of obesity in colon cancer risk and outcome is recognized, the association of body mass index (BMI) with DNA mismatch repair (MMR) status is unknown. Patients and Methods BMI (kg/m(2)) was determined in patients with TNM stage II or III colon carcinomas (n = 2,693) who participated in randomized trials of adjuvant chemotherapy. The association of BMI with MMR status and survival was analyzed by logistic regression and Cox models, respectively. Results Overall, 427 (16%) tumors showed deficient MMR (dMMR), and 630 patients (23%) were obese (BMI >= 30 kg/m(2)). Obesity was significantly associated with younger age (P = .021), distal tumor site (P = .012), and a lower rate of dMMR tumors (10% v 17%; P < .001) compared with normal weight. Obesity remained associated with lower rates of dMMR (odds ratio, 0.57; 95% CI, 0.41 to 0.79; P < .001) after adjusting for tumor site, stage, sex, and age. Among obese patients, rates of dMMR were lower in men compared with women (8% v 13%; P < .041). Obesity was associated with higher recurrence rates (P = .0034) and independently predicted worse disease-free survival (DFS; hazard ratio [HR], 1.37; 95% CI, 1.14 to 1.64; P = .0010) and overall survival (OS), whereas dMMR predicted better DFS (HR, 0.59; 95% CI, 0.47 to 0.74; P < .001) and OS. The favorable prognosis of dMMR was maintained in obese patients. Conclusion Colon cancers from obese patients are less likely to show dMMR, suggesting obesity-related differences in the pathogenesis of colon cancer. Although obesity was independently associated with adverse outcome, the favorable prognostic impact of dMMR was maintained among obese patients. J Clin Oncol 30: 406-412. (C) 2011 by American Society of Clinical Oncology C1 [Sinicrope, Frank A.; Foster, Nathan R.; Yoon, Harry H.; Smyrk, Thomas C.; Nikcevich, Daniel A.; Sargent, Daniel J.] Mayo Clin, N Cent Canc Treatment Grp, Rochester, MN 55905 USA. [Nikcevich, Daniel A.] Essentia Hlth, Duluth Community Clin Oncol Program, Duluth, MN USA. [Kim, George P.] Mayo Clin, Jacksonville, FL 32224 USA. [Allegra, Carmen J.] Univ Florida, Gainesville, FL USA. [Yothers, Greg] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Allegra, Carmen J.; Yothers, Greg] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP Sinicrope, FA (reprint author), Mayo Clin, N Cent Canc Treatment Grp, 200 1st St SW, Rochester, MN 55905 USA. EM Sinicrope.frank@mayo.edu OI Sargent, Daniel/0000-0002-2684-4741; Yothers, Greg/0000-0002-7965-7333 FU National Cancer Institute, National Institutes of Health [K05CA-142885] FX Supported, in part, by Grant No. K05CA-142885 (Senior Scientist Award to F. A. S.) from the National Cancer Institute, National Institutes of Health. NR 59 TC 21 Z9 21 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2012 VL 30 IS 4 BP 406 EP 412 DI 10.1200/JCO.2011.39.2563 PG 7 WC Oncology SC Oncology GA 923LN UT WOS:000302620900020 PM 22203756 ER PT J AU Schulz, SC Nelson, KJ AF Schulz, S. Charles Nelson, Katharine J. TI THIS ISSUE: Borderline Personality Disorder SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Schulz, S. Charles] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Schulz, S. Charles] NCI, Bethesda, MD 20892 USA. [Schulz, S. Charles] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Schulz, S. Charles] Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. [Schulz, S. Charles] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Nelson, Katharine J.] Univ Minnesota, Dept Psychiat, Borderline Personal Program, Minneapolis, MN 55455 USA. RP Schulz, SC (reprint author), Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD FEB PY 2012 VL 42 IS 2 BP 43 EP 44 DI 10.3928/00485713-20120124-02 PG 2 WC Psychiatry SC Psychiatry GA 923KM UT WOS:000302618200002 ER PT J AU Kanchanawong, P Waterman, CM AF Kanchanawong, Pakorn Waterman, Clare M. TI Advances in light-based imaging of three-dimensional cellular ultrastructure SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID STRUCTURED-ILLUMINATION MICROSCOPY; OPTICAL RECONSTRUCTION MICROSCOPY; SINGLE-MOLECULE LOCALIZATION; FLUORESCENCE MICROSCOPY; STIMULATED-EMISSION; LIVING CELLS; SUBDIFFRACTION-RESOLUTION; PLANE ILLUMINATION; DIFFRACTION-LIMIT; SCALE RESOLUTION AB Visualization methods are key to gaining insights into cellular structure and function. Since diffraction has long confined optical microscopes to a resolution no better than hundreds of nanometers, the observation of ultrastructural features has traditionally been the domain of electron microscopes (EM). In the past decade, however, advances in super-resolution fluorescence microscopy have considerably expanded the capability of light-based imaging techniques. Advantages of fluorescent labeling such as high sensitivity, specificity, and multichannel capability, can now be exploited to dissect ultrastructural features of cells. With recent methods capable of imaging specific proteins with a resolution on the order of a few tens of nanometers in 3-dimensions, this has made it possible to elucidate the molecular organization of many complex cellular structures. C1 [Kanchanawong, Pakorn; Waterman, Clare M.] NHLBI, Bethesda, MD 20892 USA. RP Kanchanawong, P (reprint author), Natl Univ Singapore, Mechanobiol Inst, Singapore 117548, Singapore. EM biekp@nus.edu.sg; watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU Division of Intramural Research, National Heart Lung and Blood Institute FX PK and CMW would like to acknowledge funding from the Division of Intramural Research, National Heart Lung and Blood Institute. NR 71 TC 16 Z9 17 U1 1 U2 20 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD FEB PY 2012 VL 24 IS 1 BP 125 EP 133 DI 10.1016/j.ceb.2011.11.010 PG 9 WC Cell Biology SC Cell Biology GA 917VO UT WOS:000302206900017 PM 22209239 ER PT J AU Liu, EY Buyske, S Aragaki, AK Peters, U Boerwinkle, E Carlson, C Carty, C Crawford, DC Haessler, J Hindorff, LA Le Marchand, L Manolio, TA Matise, T Wang, W Kooperberg, C North, KE Li, Y AF Liu, Eric Yi Buyske, Steven Aragaki, Aaron K. Peters, Ulrike Boerwinkle, Eric Carlson, Chris Carty, Cara Crawford, Dana C. Haessler, Jeff Hindorff, Lucia A. Le Marchand, Loic Manolio, Teri A. Matise, Tara Wang, Wei Kooperberg, Charles North, Kari E. Li, Yun TI Genotype Imputation of Metabochip SNPs Using a Study-Specific Reference Panel of similar to 4,000 Haplotypes in African Americans From the Women's Health Initiative SO GENETIC EPIDEMIOLOGY LA English DT Article DE genotype imputation; Metabochip; internal reference; African Americans; rare variants ID GENOME-WIDE ASSOCIATION; MISSING HERITABILITY; MULTIPLE POPULATIONS; COMPLEX TRAITS; MAP; GENERALIZABILITY; CHALLENGES; GENETICS; DISEASES; DESIGN AB Genetic imputation has become standard practice in modern genetic studies. However, several important issues have not been adequately addressed including the utility of study-specific reference, performance in admixed populations, and quality for less common (minor allele frequency [MAF] 0.005-0.05) and rare (MAF < 0.005) variants. These issues only recently became addressable with genome-wide association studies (GWAS) follow-up studies using dense genotyping or sequencing in large samples of non-European individuals. In this work, we constructed a study-specific reference panel of 3,924 haplotypes using African Americans in the Women's Health Initiative (WHI) genotyped on both the Metabochip and the Affymetrix 6.0 GWAS platform. We used this reference panel to impute into 6,459 WHI SNP Health Association Resource (SHARe) study subjects with only GWAS genotypes. Our analysis confirmed the imputation quality metric Rsq (estimated r(2), specific to each SNP) as an effective post-imputation filter. We recommend different Rsq thresholds for different MAF categories such that the average (across SNPs) Rsq is above the desired dosage r2 (squared Pearson correlation between imputed and experimental genotypes). With a desired dosage r(2) of 80%, 99.9% (97.5%, 83.6%, 52.0%, 20.5%) of SNPs with MAF > 0.05 (0.03-0.05, 0.01-0.03, 0.005-0.01, and 0.001-0.005) passed the post-imputation filter. The average dosage r(2) for these SNPs is 94.7%, 92.1%, 89.0%, 83.1%, and 79.7%, respectively. These results suggest that for African Americans imputation of Metabochip SNPs from GWAS data, including low frequency SNPs with MAF 0.005-0.05, is feasible and worthwhile for power increase in downstream association analysis provided a sizable reference panel is available. Genet. Epidemiol. 36: 107-117, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Li, Yun] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Liu, Eric Yi; Wang, Wei] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [Buyske, Steven; Matise, Tara] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Aragaki, Aaron K.; Peters, Ulrike; Carlson, Chris; Carty, Cara; Haessler, Jeff; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Hindorff, Lucia A.; Manolio, Teri A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Li, Yun] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Li, Y (reprint author), Univ N Carolina, Dept Genet, Campus Box 7264, Chapel Hill, NC 27599 USA. EM yunli@med.unc.edu RI Carty, Cara/B-8683-2013; Liu, Eric Yi/B-6221-2016; OI Buyske, Steven/0000-0001-8539-5416 FU National Human Genome Research Institute (NHGRI); National Heart, Lung, and Blood Institute; NIH; U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; [5 UC2 HL102924-02]; [3-R01-CA082659-11S1]; [R01HG006292]; [U01HG004803 (CALiCo)]; [U01HG004798 (EAGLE)]; [U01HG004802 (MEC)]; [U01HG004790 (WHI)]; [U01HG004801] FX We thank the WHI SHARe and PAGE consortia for generating the data. We also thank Dr. Karen Mohlke and other members of the CLHNS study for allowing us to use their data. Y.L. is partially supported by 5 UC2 HL102924-02 (awarded to K.E.N.), 3-R01-CA082659-11S1, and R01HG006292 (awarded to Y.L.). The PAGE program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org.; The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI.investigators.shortlist.pdf. NR 40 TC 29 Z9 29 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 BP 107 EP 117 DI 10.1002/gepi.21603 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900004 PM 22851474 ER PT J AU Pendergrass, SA Torstenson, ES Ambite, JL Avery, CL Cai, CX Fesinmeyer, MD Haiman, C Heiss, G Hindorff, LA Hsu, CN Kooperberg, C Le Marchand, L Lin, Y Matise, TC Monroe, K North, KE Wilkens, LR Buyske, S Crawford, DC Ritchie, MD AF Pendergrass, Sarah A. Torstenson, Eric S. Ambite, Jose-Luis Avery, Christy L. Cai, Congxing Fesinmeyer, Megan D. Haiman, Chris Heiss, Gerardo Hindorff, Lucia A. Hsu, Chu-Nan Kooperberg, Charles Le Marchand, Loic Lin, Yi Matise, Tara C. Monroe, Kristine North, Kari E. Wilkens, Lynne R. Buyske, Steve Crawford, Dana C. Ritchie, Marylyn D. TI A Phenome-wide Exploration of Novel Genotype-Phenotype Associations and Pleiotropy using Metabo Chip in the PAGE Study SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Pendergrass, Sarah A.; Crawford, Dana C.; Ritchie, Marylyn D.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Ambite, Jose-Luis; Cai, Congxing; Hsu, Chu-Nan] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Fesinmeyer, Megan D.; Kooperberg, Charles; Lin, Yi] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Haiman, Chris; Monroe, Kristine] Univ So Calif, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Hindorff, Lucia A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Le Marchand, Loic; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Buyske, Steve] Rutgers State Univ, Dept Genet, Dept Stat, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 20 BP 123 EP 124 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900025 ER PT J AU Ahn, K Gao, J Lee, Y Rapoport, JL Yao, Y AF Ahn, Kwangmi Gao, James Lee, Yohan Rapoport, Judith L. Yao, Yin TI A Novel Statistical Method For Testing The Association Of Rare Variants In A Case-Parent Trio Design SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Ahn, Kwangmi; Gao, James; Lee, Yohan; Rapoport, Judith L.; Yao, Yin] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 32 BP 127 EP 127 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900037 ER PT J AU Suktitipat, B Mathias, RA Vaidya, D Yanek, LR Young, JH Becker, LC Becker, DM Wilson, AF Fallin, MD AF Suktitipat, Bhoom Mathias, Rasika A. Vaidya, Dhananjay Yanek, Lisa R. Young, J. Hunter Becker, Lewis C. Becker, Diane M. Wilson, Alexander F. Fallin, M. Danielle TI The Robustness of Generalized Estimating Equations for Association Tests in Extended Family Data SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Suktitipat, Bhoom; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Mathias, Rasika A.; Vaidya, Dhananjay; Yanek, Lisa R.; Young, J. Hunter; Becker, Lewis C.; Becker, Diane M.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Fallin, M. Danielle] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 35 BP 127 EP 128 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900040 ER PT J AU Liang, XY Pfeiffer, RM Wheeler, W Maeder, D Burdette, L Meredith, Y Chanock, S Margaret, TA Goldstein, AM Yang, XHR AF Liang, Xueying Pfeiffer, Ruth M. Wheeler, William Maeder, Dennis Burdette, Laurie Meredith, Yeager Chanock, Stephen Margaret, Tucker A. Goldstein, Alisa M. Yang, Xiaohong R. TI Association Of Genetic Variants With The Risk Of Dysplastic Nevi In Melanoma-Prone Families With And Without CDKN2A/CDK4 Mutations SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Liang, Xueying] US FDA, Div Epidemiol, CDRH, Rockville, MD 20857 USA. [Pfeiffer, Ruth M.; Margaret, Tucker A.; Goldstein, Alisa M.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wheeler, William] Informat Management Serv Inc, Washington, DC USA. [Maeder, Dennis; Burdette, Laurie; Meredith, Yeager; Chanock, Stephen] SAIC Frederick Inc, Core Genotyping Facil, Frederick, MD USA. RI Bianchi Scarra, Giovanna/G-8933-2014 OI Bianchi Scarra, Giovanna/0000-0002-6127-1192 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 36 BP 128 EP 128 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900041 ER PT J AU Li, Q Bailey-Wilson, JE AF Li, Qing Bailey-Wilson, Joan E. TI Evaluation Of Methods To Detect GXG Interaction In Case-Parent Trio Data SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Li, Qing; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 39 BP 129 EP 129 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900044 ER PT J AU Simpson, CL Green, T Doan, B Amos, CI Pinney, SM Kupert, E de Andrade, M Yang, P Schwartz, AG Fain, PR Gazdar, A Minna, J Wiest, JS Rothschild, H Mandal, D You, M Coons, TA Gaba, C Anderson, MW Bailey-Wilson, JE AF Simpson, Claire L. Green, Tiffany Doan, Betty Amos, Christopher I. Pinney, Susan M. Kupert, Elena de Andrade, Mariza Yang, Ping Schwartz, Ann G. Fain, Pam R. Gazdar, Adi Minna, John Wiest, Jonathan S. Rothschild, Henry Mandal, Diptasri You, Ming Coons, Teresa A. Gaba, Colette Anderson, Marshall W. Bailey-Wilson, Joan E. TI Covariate-Based Linkage Analysis Of Lung Cancer Risk Reveals Novel Loci On 9p21 And 20q12 SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Simpson, Claire L.; Green, Tiffany; Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD USA. [Doan, Betty] Johns Hopkins Sch Med, Baltimore, MD USA. [Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Pinney, Susan M.; Kupert, Elena; Anderson, Marshall W.] Univ Cincinnati, Cincinnati, OH USA. [de Andrade, Mariza; Yang, Ping] Mayo Clin, Dept Hlth Sci, Rochester, MN USA. [Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Fain, Pam R.] Univ Colorado, Denver, CO 80202 USA. [Gazdar, Adi; Minna, John] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Wiest, Jonathan S.] NCI, NIH, Bethesda, MD 20892 USA. [Rothschild, Henry; Mandal, Diptasri] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [You, Ming] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Coons, Teresa A.] Saccomanno Res Inst, Grand Junction, CO USA. [Coons, Teresa A.] John McConnell Math & Sci Ctr Western Colorado, Grand Junction, CO USA. [Gaba, Colette] Med Coll Ohio, Toledo, OH 43699 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 47 BP 131 EP 131 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900054 ER PT J AU Marenne, G Chanock, SJ Perez-Jurado, L Rothman, N Rodriguez, B Kogevinas, M Garcia-Closas, M Silverman, DT Real, FX Malats, N Genin, E AF Marenne, Gaelle Chanock, Stephen J. Perez-Jurado, Luis Rothman, Nathaniel Rodriguez, Benjamin Kogevinas, Manolis Garcia-Closas, Montserrat Silverman, Debra T. Real, Francisco X. Malats, Nuria Genin, Emmanuelle TI Copy Number Variant Detection Using SNP-Chips: Impact Of Calling Performances On Association Tests SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Marenne, Gaelle] CNIO, INSERM, U946, Madrid, Spain. [Chanock, Stephen J.; Rothman, Nathaniel; Garcia-Closas, Montserrat; Silverman, Debra T.] NCI, Bethesda, MD 20892 USA. [Perez-Jurado, Luis; Rodriguez, Benjamin] Univ Pompeu Fabra, Barcelona, Spain. [Kogevinas, Manolis] Inst Municipal Invest Med, Barcelona, Spain. RI Genin, Emmanuelle/C-4974-2013; Perez Jurado, Luis Alberto/M-7706-2015; Kogevinas, Manolis/C-3918-2017 OI Genin, Emmanuelle/0000-0003-4117-2813; NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 54 BP 133 EP 133 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900059 ER PT J AU Yang, XHR Zhao, SH Pfeiffer, RM Tucker, MA Goldstein, AM AF Yang, Xiaohong R. Zhao, Sihui Pfeiffer, Ruth M. Tucker, Margaret A. Goldstein, Alisa M. TI Characterization Of Germ-Line Copy Number Variations In Melanoma-Prone Families With And Without CDKN2A/CDK4 Mutations SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Yang, Xiaohong R.; Pfeiffer, Ruth M.; Tucker, Margaret A.; Goldstein, Alisa M.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 57 BP 134 EP 134 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900062 ER PT J AU Timofeeva, MN Brennan, P Landi, MT Rafnar, T Houlston, R Hung, RJ Amos, CI AF Timofeeva, Maria N. Brennan, Paul Landi, Maria T. Rafnar, Thorunn Houlston, Richard Hung, Rayjean Amos, Christopher I. CA Area 1 Transdisciplinary Res Canc TI Meta-analysis of Genome-Wide Associations Studies of Lung Cancer SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Timofeeva, Maria N.; Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Landi, Maria T.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rafnar, Thorunn] deCODE Genet, Reykjavik, Iceland. [Houlston, Richard] Inst Canc Res, London, England. [Hung, Rayjean] Samuel Lunenfeld Res Inst, Toronto, ON, Canada. [Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. RI Hung, Rayjean/A-7439-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 102 BP 146 EP 147 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900107 ER PT J AU Brossard, M Corda, E Iles, MM Barrett, JH Goldstein, AM Kanetsky, P Gillanders, EM Bakker, B Gruis, N Newton-Bishop, JA Bishop, DT Geno, MEL Demenais, F AF Brossard, Myriam Corda, Eve Iles, Mark M. Barrett, Jenny H. Goldstein, Alisa M. Kanetsky, Peter Gillanders, Elizabeth M. Bakker, Bert Gruis, Nelleke Newton-Bishop, Julia A. Bishop, D. Timothy Geno, M. E. L. Demenais, Florence TI To What Extent Genotype Imputations Are Able To Identify Causal Variants In Genome-Wide Association Studies? SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Brossard, Myriam; Corda, Eve; Demenais, Florence] Fdn Jean Dausset CEPH, INSERM, U946, Paris, France. [Iles, Mark M.; Barrett, Jenny H.; Newton-Bishop, Julia A.; Bishop, D. Timothy] Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds, W Yorkshire, England. [Goldstein, Alisa M.] NCI, Genet Epidemiol Br, DCEG, NIH, Bethesda, MD 20892 USA. [Kanetsky, Peter] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gillanders, Elizabeth M.] NHGRI, Inherited Dis Res Br, NIH, Baltimore, MD USA. [Bakker, Bert] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Gruis, Nelleke] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Geno, M. E. L.] Melanoma Genet Consortium, Leeds, W Yorkshire, England. RI Bakker, Egbert/D-3525-2009; Demenais, Florence/G-3298-2013 OI Bakker, Egbert/0000-0002-2843-7357; Demenais, Florence/0000-0001-8361-0936 NR 0 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 103 BP 147 EP 147 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900108 ER PT J AU Heid, IM Winkler, TW Randall, JC Behrens, G Kutalik, Z Berndt, SI Jackson, AU Kilpelainen, TO Monda, KL Qi, L Workalemahu, T Czajkowski, J Day, F Esko, T Feitosa, MF Magi, R Mathieson, I Steinthorsdottir, V Thorleifsson, G Borecki, IB Loos, RJF North, KE Lindgren, CM AF Heid, I. M. Winkler, T. W. Randall, J. C. Behrens, G. Kutalik, Z. Berndt, S. I. Jackson, A. U. Kilpelainen, T. O. Monda, K. L. Qi, L. Workalemahu, T. Czajkowski, J. Day, F. Esko, T. Feitosa, M. F. Magi, R. Mathieson, I. Steinthorsdottir, V. Thorleifsson, G. Borecki, I. B. Loos, R. J. F. North, K. E. Lindgren, C. M. TI To Stratify Or Not To Stratify: What Can Be Learned From Power Considerations And A Practical Genome-Wide Search On Sex-Difference In The GIANT Consortium SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Heid, I. M.; Winkler, T. W.; Behrens, G.] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Randall, J. C.; Magi, R.; Mathieson, I.; Lindgren, C. M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Kutalik, Z.] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Berndt, S. I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Jackson, A. U.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Kilpelainen, T. O.; Day, F.; Loos, R. J. F.] Addenbrookes Hosp, Med Res Council MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Monda, K. L.; North, K. E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Qi, L.; Workalemahu, T.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Czajkowski, J.; Feitosa, M. F.; Borecki, I. B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63108 USA. [Esko, T.] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Steinthorsdottir, V.; Thorleifsson, G.] Decode Genet, Reykjavik, Iceland. RI Feitosa, Mary/K-8044-2012 OI Feitosa, Mary/0000-0002-0933-2410 NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 105 BP 147 EP 148 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900110 ER PT J AU Cropp, CD Kim, Y Molloy, AM Mills, JL Kirke, PN Scott, JM Brody, LC Wilson, AF Bailey-Wilson, JE AF Cropp, Cheryl D. Kim, Yoonhee Molloy, Anne M. Mills, James L. Kirke, Peader N. Scott, John M. Brody, Lawrence C. Wilson, Alexander F. Bailey-Wilson, Joan E. TI Novel Functional Variants For Serum Uric Acid And Total Serum Bilirubin Levels In An Irish Population SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Cropp, Cheryl D.; Kim, Yoonhee; Wilson, Alexander F.; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Bethesda, MD USA. [Molloy, Anne M.; Scott, John M.] Trinity Coll Dublin, Sch Immunol & Biochem, Dublin, Ireland. [Mills, James L.] NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Kirke, Peader N.] Hlth Res Board Ireland, Child Hlth Epidemiol Unit, Dublin, Ireland. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 147 BP 160 EP 161 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900152 ER PT J AU Chen, HS Zhang, SP Pfeiffer, R AF Chen, Huann-Sheng Zhang, Shunpu Pfeiffer, Ruth TI A Sequential Combined P-Value Test For Multiple Hypothesis Testing And Its Application In Significance Analysis In Genomic Studies SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Chen, Huann-Sheng] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Zhang, Shunpu] Univ Nebraska, Dept Stat, Lincoln, NE 68583 USA. [Pfeiffer, Ruth] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Chen, Huann-Sheng/D-6328-2013 OI Chen, Huann-Sheng/0000-0002-5905-8050 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 176 BP 168 EP 169 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900181 ER PT J AU Zhu, ZZ Hou, LF Bollati, V Tarantini, L Marinelli, B Cantone, L Yang, AS Vokonas, P Lissowska, J Fustinoni, S Pesatori, AC Bonzini, M Apostoli, P Costa, G Bertazzi, PA Chow, WH Schwartz, J Baccarelli, A AF Zhu, Zhong-Zheng Hou, Lifang Bollati, Valentina Tarantini, Letizia Marinelli, Barbara Cantone, Laura Yang, Allen S. Vokonas, Pantel Lissowska, Jolanta Fustinoni, Silvia Pesatori, Angela C. Bonzini, Matteo Apostoli, Pietro Costa, Giovanni Bertazzi, Pier Alberto Chow, Wong-Ho Schwartz, Joel Baccarelli, Andrea TI Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Blood; DNA methylation; epigenetics; meta-analysis; repetitive elements ID SQUAMOUS-CELL CARCINOMA; LINE-1 HYPOMETHYLATION; MICROSATELLITE INSTABILITY; NECK-CANCER; LIFE-STYLE; ALU; EXPOSURE; ALCOHOL; DISEASE; GENOME AB Background Estimates of global DNA methylation from repetitive DNA elements, such as Alu and LINE-1, have been increasingly used in epidemiological investigations because of their relative low-cost, high-throughput and quantitative results. Nevertheless, determinants of these methylation measures in healthy individuals are still largely unknown. The aim of this study was to examine whether age, gender, smoking habits, alcohol drinking and body mass index (BMI) are associated with Alu or LINE-1 methylation levels in blood leucocyte DNA of healthy individuals. Methods Individual data from five studies including a total of 1465 healthy subjects were combined. DNA methylation was quantified by PCR-pyrosequencing. Results Age [beta = -0.011% of 5-methyl-cytosine (% 5mC)/year, 95% confidence interval (CI) -0.020 to -0.001% 5mC/year] and alcohol drinking (beta = -0.214, 95% CI -0.415 to -0.013) were inversely associated with Alu methylation. Compared with females, males had lower Alu methylation (beta = -0.385, 95% CI -0.665 to -0.104) and higher LINE-1 methylation (-0.796, 95% CI 0.261 to 1.330). No associations were found with smoking or BMI. Percent neutrophils and lymphocytes in blood counts exhibited a positive (beta=0.036, 95% CI 0.010 to 0.061) and negative (beta = -0.038, 95% CI -0.065 to -0.012) association with LINE-1 methylation, respectively. Conclusions Global methylation measures in blood DNA vary in relation with certain host and lifestyle characteristics, including age, gender, alcohol drinking and white blood cell counts. These findings need to be considered in designing epidemiological investigations aimed at identifying associations between DNA methylation and health outcomes. C1 [Zhu, Zhong-Zheng; Bollati, Valentina; Tarantini, Letizia; Marinelli, Barbara; Cantone, Laura; Fustinoni, Silvia; Pesatori, Angela C.; Costa, Giovanni; Bertazzi, Pier Alberto; Baccarelli, Andrea] Univ Milan, Ctr Mol & Genet Epidemiol, Dept Environm & Occupat Hlth, I-20122 Milan, Italy. [Zhu, Zhong-Zheng; Bollati, Valentina; Tarantini, Letizia; Marinelli, Barbara; Cantone, Laura; Fustinoni, Silvia; Pesatori, Angela C.; Costa, Giovanni; Bertazzi, Pier Alberto; Baccarelli, Andrea] IRCCS Maggiore Policlin Hosp, Mangiagalli & Regina Elena Fdn, Milan, Italy. [Zhu, Zhong-Zheng] 113 Hosp Peoples Liberat Army, Dept Oncol, Ningbo, Zhejiang, Peoples R China. [Hou, Lifang] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Hou, Lifang] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Yang, Allen S.] Univ So Calif, Div Hematol, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Vokonas, Pantel] Boston Univ, Sch Med, VA Boston Healthcare Syst, Dept Med, Boston, MA 02118 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Bonzini, Matteo] Univ Insubria, Dept Clin & Biol Sci, Varese, Italy. [Apostoli, Pietro] Univ Brescia, Dept Expt & Appl Med Occupat Med & Ind Hyg, Brescia, Italy. [Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Schwartz, Joel; Baccarelli, Andrea] Harvard Univ, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Dept Environm Hlth, Boston, MA 02115 USA. RP Baccarelli, A (reprint author), Univ Milan, Ctr Mol & Genet Epidemiol, Dept Environm & Occupat Hlth, Via San Barnaba 8, I-20122 Milan, Italy. EM andrea.baccarelli@unimi.it RI Fustinoni, Silvia/I-8773-2012; Bonzini, Matteo/K-7540-2016; bertazzi, pietro alberto/D-5039-2017; OI Fustinoni, Silvia/0000-0002-0287-7338; Bonzini, Matteo/0000-0002-6405-7554; bertazzi, pietro alberto/0000-0003-3475-2449; Baccarelli, Andrea/0000-0002-3436-0640; Lissowska, Jolanta/0000-0003-2695-5799; pesatori, angela/0000-0002-0261-3252; Cantone, Laura/0000-0003-3660-129X; Bollati, Valentina/0000-0002-0370-9598 FU National Institute of Environmental Health Sciences [ES015172-01]; Environmental Protection Agency [R83241601, R827353]; Cooperative Studies Program/Epidemiology Research and Information Center of the U. S. Department of Veterans Affairs; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC); Intramural Research Program (Division of Cancer Epidemiology and Genetics, NCI) of the National Institutes of Health; Diane Belfer Program for Human Microbial Diversity; National Institutes of Health [R01GM63270]; Italian Association for Cancer Research (AIRC) [(2008-10) [6016]]; Cariplo Foundation [2007-5469]; Italian Ministry of Scientific Research (MIUR) [PRIN-20072S2HT8]; Milan University FX Study 1: National Institute of Environmental Health Sciences [ES015172-01] and Environmental Protection Agency [R83241601, R827353]. The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U. S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Study 2: Intramural Research Program (Division of Cancer Epidemiology and Genetics, NCI) of the National Institutes of Health, Diane Belfer Program for Human Microbial Diversity and the National Institutes of Health [R01GM63270]. Study 3: Italian Association for Cancer Research (AIRC) (2008-10) [6016]. Study 4: Cariplo Foundation [2007-5469] and Italian Ministry of Scientific Research (MIUR) [PRIN-20072S2HT8]. Study 5: Milan University intramural funding. NR 62 TC 101 Z9 104 U1 2 U2 23 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2012 VL 41 IS 1 BP 126 EP 139 DI 10.1093/ije/dyq154 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 915LH UT WOS:000302026800017 PM 20846947 ER PT J AU Sofat, R Casas, JP Webster, AR Bird, AC Mann, SS Yates, JRW Moore, AT Sepp, T Cipriani, V Bunce, C Khan, JC Shahid, H Swaroop, A Abecasis, G Branham, KEH Zareparsi, S Bergen, AA Klaver, CCW Baas, DC Zhang, K Chen, YH Gibbs, D Weber, BHF Keilhauer, CN Fritsche, LG Lotery, A Cree, AJ Griffiths, HL Bhattacharya, SS Chen, LL Jenkins, SA Peto, T Lathrop, M Leveillard, T Gorin, MB Weeks, DE Ortube, MC Ferrell, RE Jakobsdottir, J Conley, YP Rahu, M Seland, JH Soubrane, G Topouzis, F Vioque, J Tomazzoli, L Young, I Whittaker, J Chakravarthy, U de Jong, PTVM Smeeth, L Fletcher, A Hingorani, AD AF Sofat, Reecha Casas, Juan P. Webster, Andrew R. Bird, Alan C. Mann, Samantha S. Yates, John R. W. Moore, Anthony T. Sepp, Tiina Cipriani, Valentina Bunce, Catey Khan, Jane C. Shahid, Humma Swaroop, Anand Abecasis, Goncalo Branham, Kari E. H. Zareparsi, Sepideh Bergen, Arthur A. Klaver, Caroline C. W. Baas, Dominique C. Zhang, Kang Chen, Yuhong Gibbs, Daniel Weber, Bernhard H. F. Keilhauer, Claudia N. Fritsche, Lars G. Lotery, Andrew Cree, Angela J. Griffiths, Helen L. Bhattacharya, Shomi S. Chen, Li L. Jenkins, Sharon A. Peto, Tunde Lathrop, Mark Leveillard, Thierry Gorin, Michael B. Weeks, Daniel E. Ortube, Maria Carolina Ferrell, Robert E. Jakobsdottir, Johanna Conley, Yvette P. Rahu, Mati Seland, Johan H. Soubrane, Gisele Topouzis, Fotis Vioque, Jesus Tomazzoli, Laura Young, Ian Whittaker, John Chakravarthy, Usha de Jong, Paulus T. V. M. Smeeth, Liam Fletcher, Astrid Hingorani, Aroon D. TI Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis ID FACTOR HY402H POLYMORPHISM; C-REACTIVE PROTEIN; JAPANESE POPULATION; Y402H VARIANT; HEMICENTIN-1 GENES; CIGARETTE-SMOKING; CHROMOSOME 10Q26; NO ASSOCIATION; RISK-FACTORS; CFH GENE AB Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry. Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association. C1 [Casas, Juan P.; Hingorani, Aroon D.] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London WC1E 6BT, England. [Sofat, Reecha; Hingorani, Aroon D.] UCL, Dept Med, Ctr Clin Pharmacol, London WC1E 6BT, England. [Casas, Juan P.; Whittaker, John; Smeeth, Liam; Fletcher, Astrid] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [Webster, Andrew R.; Bird, Alan C.; Mann, Samantha S.; Yates, John R. W.; Moore, Anthony T.; Sepp, Tiina; Cipriani, Valentina; Bunce, Catey; Bhattacharya, Shomi S.; Chen, Li L.; Jenkins, Sharon A.; Peto, Tunde] UCL, Inst Ophthalmol, London WC1E 6BT, England. [Webster, Andrew R.; Bird, Alan C.; Mann, Samantha S.; Yates, John R. W.; Moore, Anthony T.; Cipriani, Valentina; Bunce, Catey; Bhattacharya, Shomi S.; Chen, Li L.; Jenkins, Sharon A.; Peto, Tunde] Moorfields Eye Hosp, London, England. [Yates, John R. W.; Khan, Jane C.; Shahid, Humma] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Swaroop, Anand; Branham, Kari E. H.; Zareparsi, Sepideh] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. [Swaroop, Anand] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Zhang, Kang; Chen, Yuhong] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA. [Zhang, Kang; Chen, Yuhong] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Zhang, Kang; Chen, Yuhong; Gibbs, Daniel] Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, Moran Eye Ctr, Salt Lake City, UT USA. [Weber, Bernhard H. F.; Fritsche, Lars G.] Univ Regensburg, Inst Human Genet, D-8400 Regensburg, Germany. [Keilhauer, Claudia N.] Univ Wurzburg, Hosp Eye, Wurzburg, Germany. [Lotery, Andrew; Cree, Angela J.; Griffiths, Helen L.] Univ Southampton, Southampton Gen Hosp, Div Clin Neurosci, Southampton SO9 5NH, Hants, England. [Lathrop, Mark] Ctr Natl Genotypage, F-91057 Evry, France. [Lathrop, Mark] Fdn Jean Dausset Ceph, F-75010 Paris, France. [Leveillard, Thierry] UPMC Univ Paris 06, CNRS, INSERM, U968,UMR S 968,Inst Vis,UMR 7210, F-75012 Paris, France. [Gorin, Michael B.; Ortube, Maria Carolina] Univ Calif Los Angeles, Jules Stein Eye Inst, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Weeks, Daniel E.; Ferrell, Robert E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Weeks, Daniel E.; Ferrell, Robert E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Jakobsdottir, Johanna] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. [Seland, Johan H.] Univ Bergen, Stavanger Univ Hosp, Stavanger, Norway. [Soubrane, Gisele] Univ Paris, Serv Ophtalmol, Paris, France. [Topouzis, Fotis] Aristotle Univ Thessaloniki, AHEPA Hosp, Dept Ophthalmol A, GR-54006 Thessaloniki, Greece. [Vioque, Jesus] Univ Miguel Hernandez, Elche, Spain. [Vioque, Jesus] Dpto Salud Publ, Alacant 03550, Spain. [Tomazzoli, Laura] Univ Verona, Osped Borgo Trento, Sez Oftalmol, Dipartimento Sci Neurol & Vis, I-37124 Verona, Italy. [Young, Ian] Royal Victoria Hosp, Ctr Publ Hlth, Belfast BT12 6BJ, Antrim, North Ireland. [Whittaker, John] GlaxoSmithKline Inc, Med Res Ctr, Stat Platforms & Technol, Stevenage SG1 2NY, Herts, England. [Chakravarthy, Usha] Queens Univ Belfast, Inst Clin Sci, Ctr Vis & Vasc Sci, Belfast BT7 1NN, Antrim, North Ireland. RP Hingorani, AD (reprint author), UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, 1-19 Torrington Pl, London WC1E 6BT, England. EM a.hingorani@ucl.ac.uk RI Cipriani, Valentina/A-8549-2012; Bergen, Arthur/J-3637-2013; vioque, jesus/A-1066-2008; Klaver, Caroline/A-2013-2016; Rahu, Mati/A-9981-2008; OI Cipriani, Valentina/0000-0002-0839-9955; Young, Ian/0000-0003-3890-3152; Swaroop, Anand/0000-0002-1975-1141; Bunce, Catey/0000-0002-0935-3713; Vioque, Jesus/0000-0002-2284-148X; Weeks, Daniel/0000-0001-9410-7228; Abecasis, Goncalo/0000-0003-1509-1825 FU Medical Research Council [G0601354, G0000682]; British Heart Foundation [FS/07/011, FS 05/125]; Guide Dogs for the Blind Association; UK Department of Health's NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital; UCL Institute of Ophthalmology; Fight for Sight UK; German Research Foundation [WE1259/18-1, WE1259/19-1]; Ruth and Milton Steinbach Foundation, New York; Alcon Research Institute, Fort Worth; Medical Research Council, UK [G0000067]; NIH [EY-016862, R01 EY9859]; Macula Vision Research Foundation; Harold Falls Professorship; ANVVB; Netherlands Macula Fund; LSBS; Research for Prevent Blindness, New York; American Health Assistance Foundation; University of California, Los Angeles; Macular Vision Research Foundation; British Council for Prevention of Blindness; Macular Disease Society; Estonian Ministry of Education and Science [01921112s02, SF0940026s07]; Alcon; [EUQLK6-CT-1999-02094] FX This work was supported by a Medical Research Council Biomarkers Award G0601354. R.S. was supported by a British Heart Foundation (Schillingford) Clinical Training Fellowship (FS/07/011). A.D.H. was supported by British Heart Foundation Senior Fellowship (FS 05/125). V.C. is funded by a grant from the Guide Dogs for the Blind Association. A.M., A.W. and J.Y. receive funding from the UK Department of Health's NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The views expressed in the publication are those of the authors and not necessarily those of the Department of Health. The Moorfields Study in addition was funded by the Medical Research Council (Award number G0000682), the Mercer Fund (Fight for Sight UK). L.S. holds a Wellcome Trust Senior Research Fellowship. EUREYE was funded by EUQLK6-CT-1999-02094. B.H.F.W. is supported by grants from the German Research Foundation (WE1259/18-1, WE1259/19-1), the Ruth and Milton Steinbach Foundation, New York and the Alcon Research Institute, Fort Worth. Cambridge AMD Study was funded by Grant G0000067 from the Medical Research Council, UK. AS and GA received funding from the NIH EY-016862, AS received funding from Macula Vision Research Foundation and the Harold Falls Professorship. A.A.B. is supported by the ANVVB, the Netherlands Macula Fund and the LSBS. The Pittsburgh Study was funded by the National Institutes of Health grant NIH R01 EY9859, Research for Prevent Blindness, New York, and the American Health Assistance Foundation and the Harold and Pauline Price Endowed Professorship (to Professor Gorin) at University of California, Los Angeles. Andrew Lotery is funded by the Macular Vision Research Foundation, The British Council for Prevention of Blindness and the Macular Disease Society. Mati Rahu is funded by the Estonian Ministry of Education and Science (target funding 01921112s02 and SF0940026s07). A.D.H. has provided non-remunerated advice to GlaxoSmithKline and London Genetics and has received honoraria for speaking at educational meetings on cardiovascular risk which have been donated in whole or part to charity. J.W. is 90% employed at GlaxoSmithKline whilst retaining a 10% appointment at the London School of Hygiene and Tropical Medicine. P.T.V.M. de.J. and B.H.F.W. have unrestricted research awards from Alcon. NR 58 TC 37 Z9 37 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2012 VL 41 IS 1 BP 250 EP 262 DI 10.1093/ije/dyr204 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 915LH UT WOS:000302026800030 PM 22253316 ER PT J AU Metzger, MB Hristova, VA Weissman, AM AF Metzger, Meredith B. Hristova, Ventzislava A. Weissman, Allan M. TI HECT and RING finger families of E3 ubiquitin ligases at a glance SO JOURNAL OF CELL SCIENCE LA English DT Article ID RETICULUM-ASSOCIATED DEGRADATION; TUMOR-SUPPRESSOR PROTEIN; PEROXISOMAL IMPORT RECEPTOR; MOTILITY FACTOR-RECEPTOR; HEAT-SHOCK PROTEINS; X-LINKED INHIBITOR; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; CONJUGATING ENZYME; U-BOX AB This article is part of a Minifocus on Ubiquitin. For further reading, please see related articles: 'Ubiquitin and SUMO in DNA repair at a glance' by Helle D. Ulrich (J. Cell Sci. 125, 249-254), 'Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control' by Annamaria Mocciaro and Michael Rape (J. Cell Sci. 125, 255-263), 'The role of ubiquitylation in receptor endocytosis and endosomal sorting' by Kaisa Haglund and Ivan Dikic (J. Cell Sci. 125, 265-275), 'Cellular functions of the DUBs' by Michael J. Clague et al. (J. Cell Sci. 125, 277-286), 'Non-canonical ubiquitin-based signals for proteasomal degradation' by Yelena Kravtsova-Ivantsiv and Aaron Ciechanover (J. Cell Sci. 125, 539-548) and 'No one can whistle a symphony alone how different ubiquitin linkages cooperate to orchestrate NF-kappa B activity' by Anna C. Schmukle and Henning Walczak (J. Cell Sci. 125, 549-559). C1 [Metzger, Meredith B.; Hristova, Ventzislava A.; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, 1050 Boyles St, Frederick, MD 21702 USA. EM amw@nih.gov FU National Institutes of Health, National Cancer Institute; Center for Cancer Research FX Research in the authors' laboratory is supported by the National Institutes of Health, National Cancer Institute and the Center for Cancer Research. NR 145 TC 163 Z9 168 U1 7 U2 48 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 FEB 1 PY 2012 VL 125 IS 3 BP 531 EP 537 DI 10.1242/jcs.091777 PG 7 WC Cell Biology SC Cell Biology GA 920HY UT WOS:000302396100001 PM 22389392 ER PT J AU Anselmo, J Medeiros, S Carneiro, V Greene, E Levy, I Nesterova, M Lyssikatos, C Horvath, A Carney, JA Stratakis, CA AF Anselmo, Joao Medeiros, Sandra Carneiro, Victor Greene, Elizabeth Levy, Isaac Nesterova, Maria Lyssikatos, Charalampos Horvath, Anelia Carney, J. Aidan Stratakis, Constantine A. TI A Large Family with Carney Complex Caused by the S147G PRKAR1A Mutation Shows a Unique Spectrum of Disease Including Adrenocortical Cancer SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PROTEIN-KINASE-A; REGULATORY SUBUNIT; SIGNALING PATHWAYS; GENE; TUMORS; CARCINOMA; FEATURES; KINDREDS; CATENIN; UPDATE AB Context: Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, wedescribe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-alpha (RI alpha) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC. Objective: We studied the genotype-phenotype correlation in CNC. Design and Setting: We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center. Patients: Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations. Results: Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RI alpha defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RI alpha and increased protein kinase A activity in vitro. Conclusions: In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD. (J Clin Endocrinol Metab 97:351-359, 2012) C1 [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC,E Labs, Sect Endocrinol & Genet,Program Dev Endocrinol &, Bethesda, MD 20892 USA. [Anselmo, Joao] Hosp Div Espirito Santo, Serv Endocrinol & Nutr, P-9500 Sao Miguel, Azores, Portugal. [Medeiros, Sandra] Hosp Div Espirito Santo, Serv Dermatol, P-9500 Sao Miguel, Azores, Portugal. [Carneiro, Victor] Hosp Div Espirito Santo, Serv Anat Patol, P-9500 Sao Miguel, Azores, Portugal. [Carney, J. Aidan] Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC,E Labs, Sect Endocrinol & Genet,Program Dev Endocrinol &, Bldg 10,Room 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, intramural National Institutes of Health [Z01-HD-000642-04] FX This work was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, intramural National Institutes of Health Project Z01-HD-000642-04 (to C.A.S.). NR 26 TC 18 Z9 19 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP 351 EP 359 DI 10.1210/jc.2011-2244 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800027 PM 22112814 ER PT J AU Krakoff, J AF Krakoff, Jonathan TI The Platform for Adipose Tissue Expansion during Positive Energy Balance SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID GENE-EXPRESSION; WEIGHT; OBESITY; MACROPHAGES; ACTIVATION; RECEPTOR C1 NIDDK, NIH, ENDO, Obes & Diabet Clin Res Sect, Phoenix, AZ 85016 USA. RP Krakoff, J (reprint author), NIDDK, NIH, ENDO, Obes & Diabet Clin Res Sect, 4212 N 16th St, Phoenix, AZ 85016 USA. EM jkrakoff@mail.nih.gov FU Intramural NIH HHS NR 19 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP 377 EP 379 DI 10.1210/jc.2011-3320 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800030 PM 22312090 ER PT J AU Malozowski, S AF Malozowski, Saul TI Reports of Increased Mortality and GH: Will This Affect Current Clinical Practice? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID GROWTH-HORMONE TREATMENT; LONG-TERM C1 NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. RP Malozowski, S (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, 6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 12 TC 9 Z9 9 U1 1 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP 380 EP 383 DI 10.1210/jc.2011-3363 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800031 PM 22312091 ER PT J AU Simonds, WF AF Simonds, William F. TI A New Look at Vitamin D Metabolism and "Idiopathic" Hypercalcemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID INFANTILE HYPERCALCEMIA; CYP24A1; MUTATIONS; MICE C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Room 8C-101,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. EM wfs@helix.nih.gov FU Intramural NIH HHS NR 10 TC 2 Z9 2 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP 384 EP 386 DI 10.1210/jc.2011-3405 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800032 PM 22312092 ER PT J AU Winer, KK Zhang, B Shrader, JA Peterson, D Smith, M Albert, PS Cutler, GB AF Winer, Karen K. Zhang, Bo Shrader, Joseph A. Peterson, Donna Smith, Michaele Albert, Paul S. Cutler, Gordon B., Jr. TI Synthetic Human Parathyroid Hormone 1-34 Replacement Therapy: A Randomized Crossover Trial Comparing Pump Versus Injections in the Treatment of Chronic Hypoparathyroidism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FATIGUE SYMPTOM INVENTORY; LONG-TERM TREATMENT; VITAMIN-D; HYPOCALCEMIC HYPERCALCIURIA; DIHYDROTACHYSTEROL THERAPY; CANCER-PATIENTS; HUMAN PTH(1-34); CALCIUM; CALCITRIOL; PARATHYROID-HORMONE-1-34 AB Context: Vitamin D therapy for hypoparathyroidism does not restore PTH-dependent renal calcium reabsorption, which can lead to renal damage. An alternative approach, PTH 1-34 administered twice daily, provides acceptable long-term treatment but is associated with nonphysiological serum calcium fluctuation. Objective: Our objective was to compare continuous PTH 1-34 delivery, by insulin pump, with twice-daily delivery. Research Design and Methods: In a 6-month, open-label, randomized, crossover trial, PTH 1-34 was delivered by pump or twice-daily sc injection. After each 3-month study period, serum and 24-h urine mineral levels and bone turnover markers were measured daily for 3 d, and 24-h biochemical profiles were determined for serum minerals and 1,25-dihydroxyvitamin D3 and for urine minerals and cAMP. Study Participants and Setting: Eight patients with postsurgical hypoparathyroidism (mean +/- SD age 46 +/- 5.6 yr) participated at a tertiary care referral center. Results: Pump vs. twice-daily delivery of PTH 1-34 produced less fluctuation in serum calcium, a more than 50% reduction in urine calcium (P = 0.002), and a 65% reduction in the PTH dose to maintain eucalcemia (P < 0.001). Pump delivery also produced higher serum magnesium level (P = 0.02), normal urine magnesium, and reduced need for magnesium supplements. Finally, pump delivery normalized bone turnover markers and significantly lowered urinary cross-linked N-telopeptide of type 1 collagen and pyridinium crosslinks compared with twice-daily injections (P < 0.05). Conclusion: Pump delivery of PTH 1-34 provides the closest approach to date to physiological replacement therapy for hypoparathyroidism. (J Clin Endocrinol Metab 97:391-399, 2012) C1 [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Winer, KK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM winerk@mail.nih.gov FU Pharmaceutical Development Service (PDS); Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We acknowledge the support from George Grimes, Judith Starling, and the staff of the Pharmaceutical Development Service (PDS), who purchased and prepared the PTH1-34. We gratefully recognize the clinical excellence of the five NW staff and Clinical Fellows and the support of Diane McClusky, R.N., M.J. Grove, R.N., and Kieu-Phuong Vu.; The omnipod pump devices were generously provided by Insulet Corp., which had no involvement in study design or implementation. This study was funded in part by the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 36 TC 52 Z9 58 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP 391 EP 399 DI 10.1210/jc.2011-1908 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800034 PM 22090268 ER PT J AU de Bruin, C Hofland, LJ Nieman, LK van Koetsveld, PM Waaijers, AM Sprij-Mooij, DM van Essen, M Lamberts, SWJ de Herder, WW Feelders, RA AF de Bruin, C. Hofland, L. J. Nieman, L. K. van Koetsveld, P. M. Waaijers, A. M. Sprij-Mooij, D. M. van Essen, M. Lamberts, S. W. J. de Herder, W. W. Feelders, R. A. TI Mifepristone Effects on Tumor Somatostatin Receptor Expression in Two Patients with Cushing's Syndrome due to Ectopic Adrenocorticotropin Secretion SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CELL LUNG-CANCER; IN-VITRO; DIFFERENTIAL-DIAGNOSIS; CORTICOTROPH ADENOMAS; PITUITARY-ADENOMAS; ANALOG SOM230; LOCALIZATION; SCINTIGRAPHY; DOPAMINE; GLUCOCORTICOIDS AB Context: Two patients presented with Cushing's syndrome due to ectopic ACTH secretion. Initial localization studies included computed tomography, magnetic resonance imaging, and octreoscans (In-111-pentreotide scintigraphy), which were negative in both patients. They were treated with the glucocorticoid receptor antagonist mifepristone, with improvement in their clinical symptoms. Follow-up octreoscans after, respectively, 6 and 12 months showed the unequivocal presence of a bronchial carcinoid in both patients. Objective: The objective of the study was to correlate in vivo and in vitro findings in patients with ectopic ACTH-producing syndrome. Methods: We determined the expression of somatostatin and dopamine receptors by immunohistochemistry (patients 1 and 2), quantitative PCR, and in vitro culturing of tumor cells (patient 1 only). In Vitro Results: Both tumors were strongly positive for somatostatin receptor type 2 (sst2) on immunohistochemistry, whereas one of the tumors (patient 1) was also dopamine receptor subtype 2 (D2) positive on both immunohistochemistry and quantitative PCR. Octreotide (a sst2 preferring analog) and cabergoline (D2 agonist) both decreased the ACTH levels in the cultured tumor cells of patient 1. Conclusion: We describe two patients with ACTH-producing bronchial carcinoids, in whom a direct down-regulatory effect of glucocorticoid levels on tumoral sst2 receptor expression is suggested by a remarkable change in octreoscan status after successful mifepristone therapy. Further studies will have to demonstrate whether glucocorticoid lowering or antagonizing therapy may be used to improve the diagnostic accuracy of somatostatin receptor scintigraphy in patients with ectopic ACTH production of unknown primary origin. (J Clin Endocrinol Metab 97:455-462, 2012) C1 [de Bruin, C.; Hofland, L. J.; van Koetsveld, P. M.; Waaijers, A. M.; Sprij-Mooij, D. M.; Lamberts, S. W. J.; de Herder, W. W.; Feelders, R. A.] Erasmus MC, Div Endocrinol, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands. [van Essen, M.] Erasmus MC, Dept Nucl Med, NL-3015 CE Rotterdam, Netherlands. [Nieman, L. K.] NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP de Bruin, C (reprint author), Erasmus MC, Div Endocrinol, Dept Internal Med, Gravendijkwal 230, NL-3015 CE Rotterdam, Netherlands. EM christiaandb@hotmail.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported in part by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 31 TC 24 Z9 24 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP 455 EP 462 DI 10.1210/jc.2011-1264 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800041 PM 22090282 ER PT J AU Lungu, AO Zadeh, ES Goodling, A Cochran, E Gorden, P AF Lungu, Andreea O. Zadeh, Elika Safar Goodling, Anne Cochran, Elaine Gorden, Phillip TI Insulin Resistance Is a Sufficient Basis for Hyperandrogenism in Lipodystrophic Women with Polycystic Ovarian Syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HYPOTHALAMIC AMENORRHEA; CLINICAL-IMPLICATIONS; ACANTHOSIS NIGRICANS; LEPTIN REPLACEMENT; HYPERINSULINEMIA; PATHOGENESIS; INDUCTION; THERAPY; DISEASE; GROWTH AB Context: The lipodystrophies (LD) are characterized by metabolic abnormalities (insulin resistance, hypertriglyceridemia, and diabetes) and a polycystic ovarian syndrome (PCOS) phenotype. Therapeutic administration of leptin improves insulin sensitivity and the metabolic features. Objective: The objective of the study was to investigate whether the PCOS features are corrected by increasing insulin sensitivity as a function of leptin treatment. Design: This was a prospective, open-label trial using leptin replacement in various forms of lipodystrophy. Setting: The study was performed at the Clinical Center at the National Institutes of Health. Patients or Other Participants: Twenty-three female patients with LD were enrolled in a leptin replacement trial from 2000 to the present. Different parameters were assessed at baseline and after 1 yr of therapy. Intervention(s): Patients were treated with leptin for at least 1 yr. Main Outcome Measure(s): We evaluated free testosterone, SHBG, and IGF-I at baseline and after 1 yr of leptin. Results: Testosterone levels decreased from 3.05 +/- 0.6 ng/ml at baseline to 1.7 +/- 0.3 ng/ml (P +/- 0.02). SHBG increased from 14.5 +/- 2 to 25 +/- 3.5 nmol/liter after 1 yr of leptin therapy. There were no significant changes in the levels of gonadotropins and ovarian size as a result of leptin replacement therapy. IGF-I increased significantly after leptin therapy from 150 +/- 14 to 195 +/- 17. There was a significant decrease in triglycerides and glycosylated hemoglobin in the context of reduced insulin requirements. Conclusions: In the present study, we show that LD may be a model for the common forms of PCOS and that the endocrine features are corrected by leptin therapy, which reduces insulin resistance. (J Clin Endocrinol Metab 97: 563-567, 2012) C1 [Lungu, Andreea O.; Zadeh, Elika Safar; Goodling, Anne; Cochran, Elaine; Gorden, Phillip] NIDDK, Diabet Endocrine & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), 10 Ctr Dr,MSC 1612,Room CRC 6-5940, Bethesda, MD 20892 USA. EM phillipg@intra.niddk.nih.gov NR 25 TC 20 Z9 22 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP 563 EP 567 DI 10.1210/jc.2011-1896 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800053 PM 22090274 ER PT J AU Lodish, M Dagalakis, U Chen, CC Sinaii, N Whitcomb, P Aikin, A Dombi, E Marcus, L Widemann, B Fox, E Chuk, M Balis, F Wells, S Stratakis, CA AF Lodish, Maya Dagalakis, Urania Chen, Clara C. Sinaii, Ninet Whitcomb, Patricia Aikin, Alberta Dombi, Eva Marcus, Leigh Widemann, Brigitte Fox, Elizabeth Chuk, Meredith Balis, Frank Wells, Samuel, Jr. Stratakis, Constantine A. TI In-111-Octreotide Scintigraphy for Identification of Metastatic Medullary Thyroid Carcinoma in Children and Adolescents SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SOMATOSTATIN RECEPTOR SCINTIGRAPHY; OCTREOTIDE SCINTIGRAPHY; CANCER; GUIDELINES; MANAGEMENT; DIAGNOSIS; THERAPY AB Context: Most medullary thyroid cancers (MTC) express somatostatin receptors; therefore, In-111-octreotide somatostatin receptor scintigraphy (SRS) may be useful in detecting sites of metastases in children with MTC. Objective: The aim of the study was to evaluate tumor metastases in children and adolescents with MTC using SRS in comparison to conventional imaging. Design and Setting: A case series was conducted as part of baseline evaluation for cancer treatment protocol at the National Institutes of Health Clinical Center. Patients: Eleven patients with a median age of 15 (range, 9-17) yr participated in the study, 10 with histologically proven, metastatic MTC due to the M918T mutation of the RET protooncogene, and one with a known RET polymorphism. Intervention: After receiving 0.086 mCi/kg (111)Indium-pentreotide, patients were examined with a single photon emission computed tomography scan 4 and 24 h after injection. Baseline conventional imaging, including computed tomography (neck, chest, abdomen, +/- pelvis, adrenals), magnetic resonance imaging (neck), and bone scan, was performed on all patients. Main Outcome Measures: SRS results were compared with conventional imaging. Results: Five of the 11 patients had abnormal findings on SRS. Of the 53 total target lesions present in the patients, only 24.5% were accurately identified through SRS. Conclusions: SRS appears to be less sensitive than conventional imaging at detecting the full extent of metastatic disease in children and adolescents with hereditary MTC. SRS incompletely identified sites of tumor and failed to visualize small sites of tumor or liver and lung metastases, and it has a limited role in the evaluation of metastatic disease in pediatric MTC patients. (J Clin Endocrinol Metab 97: E207-E212, 2012) C1 [Lodish, Maya; Dagalakis, Urania; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.] Natl Inst Hlth Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. [Sinaii, Ninet] Natl Inst Hlth Clin Ctr, Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. [Whitcomb, Patricia; Aikin, Alberta; Dombi, Eva; Marcus, Leigh; Widemann, Brigitte] NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Fox, Elizabeth; Balis, Frank] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Chuk, Meredith] Childrens Hosp Pittsburgh, Div Pediat Hematol Oncol, Pittsburgh, PA 15224 USA. [Wells, Samuel, Jr.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Lodish, M (reprint author), NICHHD, NIH, Program Dev Endocrinol & Genet, Bldg 10-CRC,Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health & Human Development FX This work was supported by the Intramural programs of the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. NR 23 TC 9 Z9 9 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2012 VL 97 IS 2 BP E207 EP E212 DI 10.1210/jc.2011-2766 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904VP UT WOS:000301226800006 PM 22162469 ER PT J AU McBain, CJ AF McBain, Chris J. TI Cortical inhibitory neuron basket cells: from circuit function to disruption SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID DIVERSITY C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Porter Neurosci Bldg,Rm 3C903, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov NR 9 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2012 VL 590 IS 4 BP 667 EP 667 DI 10.1113/jphysiol.2012.227967 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 897VB UT WOS:000300685900004 PM 22344982 ER PT J AU Rio, CACD McBain, CJ Pelkey, KA AF Rio, Christian A. Cea-del McBain, Chris J. Pelkey, Kenneth A. TI An update on cholinergic regulation of cholecystokinin-expressing basket cells SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Review ID NICOTINIC ACETYLCHOLINE-RECEPTORS; HIPPOCAMPAL CA1 INTERNEURONS; ASYNCHRONOUS GABA RELEASE; PERISOMATIC INHIBITION; TRANSMITTER RELEASE; SYNAPTIC POTENTIALS; CA2+ CHANNELS; MODULATION; ACTIVATION; DIVERSITY AB Information processing and transfer within cortical circuits requires precise spatiotemporal coordination of excitatory principal cell activity by a relatively small population of inhibitory interneurons that exhibit remarkable anatomical, molecular and electrophysiological diversity. One subtype of interneuron, the cholecystokinin-expressing basket cell (CCKBC), is particularly well suited to integrate and impart emotional features of an animal's physiological state to principal cell entrainment through the inhibitory network as CCKBCs are highly susceptible to neuromodulation by local and subcortically generated signals commonly associated with mood such as cannabinoids, serotonin and acetylcholine. Here we briefly review recent studies that have elucidated the cellular mechanisms underlying cholinergic regulation of CCKBCs. C1 [McBain, Chris J.; Pelkey, Kenneth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [Rio, Christian A. Cea-del] Childrens Natl Med Ctr, Neurosci Res Ctr, Washington, DC 20010 USA. RP McBain, CJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov FU NICHD FX This work was supported by an NICHD intramural award to C.J.M. NR 57 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2012 VL 590 IS 4 BP 695 EP 702 DI 10.1113/jphysiol.2011.225342 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 897VB UT WOS:000300685900007 ER PT J AU Jamal, M Rath, BH Tsang, PS Camphausen, K Tofilon, PJ AF Jamal, Muhammad Rath, Barbara H. Tsang, Patricia S. Camphausen, Kevin Tofilon, Philip J. TI The Brain Microenvironment Preferentially Enhances the Radioresistance of CD133(+) Glioblastoma Stem-like Cells SO NEOPLASIA LA English DT Article ID HISTONE H2AX PHOSPHORYLATION; TUMOR-INITIATING CELLS; STRAND BREAK REPAIR; DNA-DAMAGE; CANCER; LINES; RADIOTHERAPY; GAMMA-H2AX; PROFILES; SURVIVAL AB Brain tumor xenografts initiated from glioblastoma (GBM) CD133(+) tumor stem-like cells (TSCs) are composed of TSC and non-TSC subpopulations, simulating the phenotypic heterogeneity of GBMs in situ. Given that the discrepancies between the radiosensitivity of GBM cells in vitro and the treatment response of patients suggest a role for the microenvironment in GBM radioresistance, we compared the response of TSCs and non-TSCs irradiated under in vitro and orthotopic conditions. As a measure of radioresponse determined at the individual cell level, gamma.H2AX and 53BP1 foci were quantified in CD133(+) cells and their differentiated (CD133(-)) progeny. Under in vitro conditions, no difference was detected between CD133(+) and CD133(-) cells in foci induction or dispersal after irradiation. However, irradiation of orthotopic xenografts initiated from TSCs resulted in the induction of fewer gamma H2AX and 53BP1 foci in CD133(+) cells compared to their CD133(-) counterparts within the same tumor. Xenograft irradiation resulted in a tumor growth delay of approximately 7 days with a corresponding increase in the percentage of CD133(+) cells at 7 days after radiation, which persisted to the onset of neurologic symptoms. These results suggest that, although the radioresponse of TSCs and non-TSCs does not differ under in vitro growth conditions, CD133(+) cells are relatively radioresistant under intracerebral growth conditions. Whereas these findings are consistent with the suspected role for TSCs as a determinant of GBM radioresistance, these data also illustrate the dependence of the cellular radioresistance on the brain microenvironment. C1 [Jamal, Muhammad; Rath, Barbara H.; Tsang, Patricia S.; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), NCI, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM tofilonp@mail.nih.gov NR 28 TC 51 Z9 56 U1 0 U2 4 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD FEB PY 2012 VL 14 IS 2 BP 150 EP 158 DI 10.1593/neo.111794 PG 9 WC Oncology SC Oncology GA 922HP UT WOS:000302538300007 PM 22431923 ER PT J AU Janakiram, NB Mohammed, A Qian, L Choi, CI Steele, VE Rao, CV AF Janakiram, Naveena B. Mohammed, Altaf Qian, Li Choi, Chang-In Steele, Vernon E. Rao, Chinthalapally V. TI Chemopreventive Effects of RXR-Selective Rexinoid Bexarotene on Intestinal Neoplasia of ApcMin/+ Mice SO NEOPLASIA LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; RETINOID-X-RECEPTOR; HUMAN COLON-CANCER; CYCLOOXYGENASE-2 INHIBITOR; COLORECTAL-CANCER; CELL-LINE; MIN MICE; ACID; SUPPRESSION; LGD1069 AB Retinoid X receptor (RXR) has been implicated in several neoplastic diseases. Previously, we have shown that RXR-alpha is downregulated in human and rodent colonic tumors, suggesting a potential target for colon cancer prevention (http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key-statistics). Experiments were designed to assess the chemopreventive efficacy of the selective RXR agonist bexarotene for the suppression of intestinal tumorigenesis in Apc(Min/+) mice. Before the efficacy studies, we determined that the maximal tolerated dose in C57BL/6J mice was less than 400 ppm. For the efficacy study, 6-week-old male and female C57BL/6J-Apc(Min/+) mice (nine mice per group) were fed diets containing 0, 30, and 60 ppm of bexarotene or 200 ppm of bexarotene for 80 days before intestinal tumors were evaluated. Dietary administration of 30 and 60 ppm of bexarotene suppressed the intestinal polyp formation by 38% (P < .015) and 60% (P <. 0001) in males, respectively, and by 8.5% and 37% (P < .007) in females, respectively. Also, significant inhibition (50%-100%) of colonic tumor formation was observed in both male and female mice with bexarotene treatment. Administration of 200 ppm of bexarotene showed significant suppression of tumor formation (66%, P < .0001); however, it had significant toxicity. Intestinal tumors of bexarotene-fed mice showed significantly reduced expression of proliferating cell nuclear antigen (60%, P < .0001), cyclin D1, and cyclooxygenase 2 and increased RXR-alpha messenger RNA and uptake of oleate (34%, P < .01). Also, bexarotene-fed mice showed dose-dependent suppression of serum triglycerides (25%-72%, P < .0001) and inflammatory cytokines. C1 [Janakiram, Naveena B.; Mohammed, Altaf; Qian, Li; Choi, Chang-In; Rao, Chinthalapally V.] Univ Oklahoma, Ctr Chemoprevent & Canc Drug Dev, Hlth Sci Ctr,Dept Med, Hem Onc Sect,PC Stephenson Oklahoma Canc Ctr, Oklahoma City, OK 73104 USA. [Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Ctr Chemoprevent & Canc Drug Dev, Hlth Sci Ctr,Dept Med, Hem Onc Sect,PC Stephenson Oklahoma Canc Ctr, 975 NE 10th St,BRC 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU Public Health Service/National Institutes of Health, National Cancer Institute [NO1-CN 53300, R01CA-109247] FX This work was supported by Public Health Service/National Institutes of Health, National Cancer Institute (NO1-CN 53300 and R01CA-109247). NR 37 TC 24 Z9 24 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1476-5586 J9 NEOPLASIA JI Neoplasia PD FEB PY 2012 VL 14 IS 2 BP 159 EP 168 DI 10.1593/neo.111440 PG 10 WC Oncology SC Oncology GA 922HP UT WOS:000302538300008 PM 22431924 ER PT J AU Hauger, RL Olivares-Reyes, JA Dautzenberg, FM Lohr, JB Braun, S Oakley, RH AF Hauger, Richard L. Alberto Olivares-Reyes, J. Dautzenberg, Frank M. Lohr, James B. Braun, Sandra Oakley, Robert H. TI Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy SO NEUROPHARMACOLOGY LA English DT Review DE beta arrestin; Biased agonist; CRF receptor; GRK ID CORTICOTROPIN-RELEASING-FACTOR; POSTTRAUMATIC-STRESS-DISORDER; PROTEIN-COUPLED RECEPTOR; MECHANISM REGULATING STRESS; CRF RECEPTOR; GENE-EXPRESSION; HOMOLOGOUS DESENSITIZATION; POTENTIAL MECHANISM; DEPRESSIVE BEHAVIOR; NEUROTROPHIC FACTOR AB The reasons for differences in vulnerability or resilience to the development of posttraumatic stress disorder (PTSD) are unclear. Here we review key genetic diatheses and molecular targets especially signaling pathways that mediate responses to trauma and severe stress and their potential contribution to the etiology of PTSD. Sensitization of glucocorticoid receptor (GR) signaling and dysregulation of GR modulators FKBP5, STAT5B, Bcl-2, and Bax have been implicated in PTSD pathophysiology. Furthermore, Akt, NF kappa B, MKP-1, and p11, which are G protein-coupled receptor (GPCR) pathway molecules, can promote or prevent sustained high anxiety- and depressive-like behavior following severe stress. Agonist-induced activation of the corticotropin releasing factor CRF1 receptor is crucial for survival in the context of serious danger or trauma, but persistent CRF1 receptor hypersignaling when a threatening or traumatic situation is no longer present is maladaptive. CRF1 receptor single nucleotide polymorphisms (SNPs) can confer susceptibility or resilience to childhood trauma while a SNP for the PAC1 receptor, another class B1 GPCR, has been linked genetically to PTSD. GRK3 phosphorylation of the CRF1 receptor protein and subsequent binding of beta arrestin2 rapidly terminate Gs-coupled CRF1 receptor signaling by homologous desensitization. A deficient GRK-beta arrestin2 mechanism would result in excessive CRF1 receptor signaling thereby contributing to PTSD and co-morbid posttraumatic depression. Clinical trials are needed to assess if small molecule CRF1 receptor antagonists are effective prophylactic agents when administered immediately after trauma. beta arrestin2-biased agonists for CRF receptors and possibly other GPCRs implicated in PTSD, however, may prove to be novel pharmacotherapy with greater selectivity and therapeutic efficacy. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Hauger, Richard L.; Lohr, James B.; Braun, Sandra] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Hauger, Richard L.; Lohr, James B.] VA Healthcare Syst, Ctr Excellence Stress & Mental Hlth, San Diego, CA 92161 USA. [Alberto Olivares-Reyes, J.] Natl Polytech Inst CINVESTAV IPN, Ctr Res & Adv Studies, Dept Biochem, Mexico City 07360, DF, Mexico. [Dautzenberg, Frank M.] Nycomed GmbH, D-78467 Constance, Germany. [Oakley, Robert H.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Hauger, RL (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM rhauger@ucsd.edu FU Department of Veterans Affairs (DVA); VA Center of Excellence for Stress and Mental Health (CESAMH); Mental Illness Research, Education and Clinical Center (MIRECC) of VISN22; NIH/NIA [AG018386]; NIH/NIMH [MH074697]; NIH, National Institute of Environmental Health Sciences; CINVESTAV-IPN, a UC MEXUS-CONACYT; Fundacion Miguel Aleman FX The authors declare no conflict of interest. Dr. Hauger was supported by a Merit Review grant from the Department of Veterans Affairs (DVA); the VA Center of Excellence for Stress and Mental Health (CESAMH) and Mental Illness Research, Education and Clinical Center (MIRECC) of VISN22; and NIH/NIA (AG018386) and NIH/NIMH (MH074697) RO1 grants. Dr. Oakley received support from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Dr. Lohr was supported by the VA Center of Excellence for Stress and Mental Health (CESAMH). Dr. Olivares-Reyes was supported by CINVESTAV-IPN, a UC MEXUS-CONACYT grant for collaborative projects, and a Grant for Research on Health from Fundacion Miguel Aleman 2010. NR 84 TC 21 Z9 24 U1 6 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2012 VL 62 IS 2 BP 705 EP 714 DI 10.1016/j.neuropharm.2011.11.007 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 909FZ UT WOS:000301549300018 PM 22122881 ER PT J AU Ossola, B Schendzielorz, N Chen, SH Bird, GS Tuominen, RK Mannisto, PT Hong, JS AF Ossola, Bernardino Schendzielorz, Nadia Chen, Shih-Heng Bird, Gary S. Tuominen, Raimo K. Mannisto, Pekka T. Hong, Jau-Shyong TI Amantadine protects dopamine neurons by a dual action: Reducing activation of microglia and inducing expression of GNDF in astroglia (vol 61, pg 574, 2011) SO NEUROPHARMACOLOGY LA English DT Correction C1 [Ossola, Bernardino; Schendzielorz, Nadia; Chen, Shih-Heng; Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Bird, Gary S.] NIEHS, Lab Signal Transduct, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Ossola, Bernardino; Schendzielorz, Nadia; Tuominen, Raimo K.; Mannisto, Pekka T.] Univ Helsinki, Fac Pharm, Div Pharmacol & Toxicol, FIN-00014 Helsinki, Finland. RP Hong, JS (reprint author), NIEHS, Toxicol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Bernardino.ossola@helsinki.fi; Nadia.Schendzielorz@helsinki.f; Chens3@niehs.nih.gov; bird@niehs.nih.gov; raimo.tuominen@helsinki.fi; pekka.mannisto@helsinki.fi; hong3@niehs.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2012 VL 62 IS 2 BP 1162 EP 1162 DI 10.1016/j.neuropharm.2011.09.020 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 909FZ UT WOS:000301549300068 ER PT J AU Nair, A Chen, AP Pothuri, B AF Nair, Abhilasha Chen, Alice P. Pothuri, Bhavana TI The Maze of PARP Inhibitors in Ovarian Cancer SO ONCOLOGY-NEW YORK LA English DT Review ID POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; NEGATIVE BREAST-CANCER; BRCA2 MUTATIONS; CARCINOMA; RESISTANCE; RADIOSENSITIZATION; FEATURES; TUMORS; CELLS; CHEMOTHERAPY C1 [Nair, Abhilasha; Chen, Alice P.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Pothuri, Bhavana] NYU Langone Med Ctr, Dept Obstet & Gynecol, NYU Womens Canc Program, New York, NY USA. RP Nair, A (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 56 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD FEB PY 2012 VL 26 IS 2 BP 136 EP + PG 4 WC Oncology SC Oncology GA 896UO UT WOS:000300597100002 PM 22489346 ER PT J AU Berg, CD AF Berg, Christine D. TI Formidable Challenges Ahead for Lung Cancer Screening SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID RISK PREDICTION; NODULES C1 NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Berg, CD (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RI Berg , Christine/K-1047-2014 NR 12 TC 2 Z9 2 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD FEB PY 2012 VL 26 IS 2 BP 182 EP + PG 2 WC Oncology SC Oncology GA 896UO UT WOS:000300597100010 PM 22489354 ER PT J AU Uhlenhaut, C Cohen, JI Pavletic, S Illei, G Gea-Banacloche, JC Abu-Asab, M Krogmann, T Gubareva, L McClenahan, S Krause, PR AF Uhlenhaut, C. Cohen, J. I. Pavletic, S. Illei, G. Gea-Banacloche, J. C. Abu-Asab, M. Krogmann, T. Gubareva, L. McClenahan, S. Krause, P. R. TI Use of a novel virus detection assay to identify coronavirus HKU1 in the lungs of a hematopoietic stem cell transplant recipient with fatal pneumonia SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE viral infections; generic virus detection; virus discovery; immunocompromised; coronavirus; HKU1 ID COMMUNITY-ACQUIRED PNEUMONIA; INFLUENZA-A VIRUS; INFECTION; CHILDREN; OLD AB A 38-year-old female patient with systemic lupus erythematosus presented with pulmonary infiltrates and hypoxemia for several months following immunodepleting autologous hematopoietic stem cell transplantation. She was treated for influenza, which was isolated repeatedly from oropharynx and bronchoalveolar lavage (BAL) fluids, and later empirically for lupus pneumonitis, but died 6 months after transplant. Autopsy findings failed to show influenza in the lungs or lupus pneumonitis. A novel generic polymerase chain reaction (PCR)-based assay using degenerate primers identified human coronavirus (CoV) HKU1 RNA in BAL fluid at autopsy. CoVwas confirmed by virus-specific PCRs of lung tissue at autopsy. Electron microscopy showed viral particles consistent with CoV HKU1 in lung tissue both at autopsy and from aprevious biopsy. Although human CoV HKU1 infection is not usually severe, in highly immunocompromised patients, it can be associated with fatal pneumonia. C1 [Uhlenhaut, C.; McClenahan, S.; Krause, P. R.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. [Cohen, J. I.; Krogmann, T.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Pavletic, S.; Gea-Banacloche, J. C.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Illei, G.] NIAMSD, Mol Physiol & Therapeut Branch, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Illei, G.] NIAMSD, Off Clin Director, Bethesda, MD 20892 USA. [Abu-Asab, M.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Gubareva, L.] Ctr Dis Control & Prevent, Virus Surveillance & Diag Branch, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Krause, PR (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. EM philip.krause@fda.hhs.gov OI Krause, Philip/0000-0002-1045-7536; Abu-Asab, Mones/0000-0002-4047-1232 FU Center for Biologics Evaluation and Research; National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Cancer Institute, and the Centers for Disease Control and Prevention FX This work was supported by the intramural research programs of the Center for Biologics Evaluation and Research, the National Institute of Allergy and Infectious Diseases, the National Institute of Dental and Craniofacial Research, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Cancer Institute, and the Centers for Disease Control and Prevention. NR 21 TC 5 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-2273 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD FEB PY 2012 VL 14 IS 1 BP 79 EP 85 DI 10.1111/j.1399-3062.2011.00657.x PG 7 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA 895MW UT WOS:000300501300012 PM 21749586 ER PT J AU Nasseri-Moghaddam, S Dawsey, SM AF Nasseri-Moghaddam, Siavosh Dawsey, Sanford M. TI "Prognostic Factors for Esophageal Squamous Cell Carcinoma - A Population-Based Study in Golestan Province, Iran, a High Incidence Area" SO ARCHIVES OF IRANIAN MEDICINE LA English DT Editorial Material AB In a recently published article in PLOS ONE, follow-up data from a large case-control study of esophageal squamous cell carcinoma (ESCC) patients in Golestan Province, Iran (a high incidence area for this disease) has been used by Aghcheli et al. to assess patient survival and its contributing factors. The authors have reported on 426 (out of an original 449) patients with ESCC who were diagnosed between 2002 and 2007, and followed through June 2008. They found a median survival of seven months and a five-year survival of 3.3%. Patients with "potentially curative treatment" had better overall survival. The investigators also calculated the hazard ratio (HR) and 95% confidence intervals (95% CI) for factors they considered to be important for survival. Survival was similar in both sexes, but those who lived in urban areas (HR195% CI: 0.70/0.54-0.90) and those who were of non-Turkmen ethnicity (HR195% Cl: 0.76/0.61-0.96) had a better survival rate. In addition, a higher stage of disease at diagnosis was related to worse prognosis, but this effect was lost when "potentially curative treatment" was included in the model. Unfortunately, staging information was available in fewer than 30% of the cases. Higher age was associated with poorer prognosis in an initial multivariate analysis, but when "potentially curative treatment" was included in the model, the association was no longer significant. Those who chewed "nass" (a mixture of tobacco, lime, and ash) had a borderline significant worse prognosis in the final multivariate model, which included "potentially curative treatment" [HR: 1.38 (0.99-1.92)]. The authors concluded that ESCC has a very poor prognosis in Golestan Province, and that age, residence (urban vs. rural), ethnicity, stage at diagnosis, type of treatment received by the patient, and nass chewing were factors that affected the outcome. Considering those who received "potentially curative treatment" had a five-year survival of about 25%, aggressive treatment was proposed when possible. C1 [Nasseri-Moghaddam, Siavosh] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran, Iran. [Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Nasseri-Moghaddam, S (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran, Iran. NR 5 TC 0 Z9 0 U1 0 U2 0 PU ACAD MEDICAL SCIENCES I R IRAN PI TEHRAN PA PO BOX 19395-5655, TEHRAN, 00000, IRAN SN 1029-2977 J9 ARCH IRAN MED JI Arch. Iran. Med. PD FEB PY 2012 VL 15 IS 2 BP 118 EP 119 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 913UB UT WOS:000301901800015 ER PT J AU Wurster, AL Pazin, MJ AF Wurster, Andrea L. Pazin, Michael J. TI ATP-dependent chromatin remodeling in T cells SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Review DE chromatin remodeling; gene regulation; T-Lymphocytes; distal regulatory elements; cytokine transcription; SWI/SNF; enhancers ID CD4 GENE-EXPRESSION; GM-CSF PROMOTER; THYMOCYTE DEVELOPMENT; GLUCOCORTICOID-RECEPTOR; FUNCTIONAL DIFFERENCES; LYMPHOCYTE DEVELOPMENT; HISTONE ACETYLATION; MI-2/NURD COMPLEX; SWI/SNF COMPLEX; BAF COMPLEX AB One of the best studied systems for mammalian chromatin remodeling is transcriptional regulation during T cell development. The variety of these studies have led to important findings in T cell gene regulation and cell fate determination. Importantly, these findings have also advanced our knowledge of the function of remodeling enzymes in mammalian gene regulation. First we briefly present biochemical and cell-free analysis of 3 types of ATP dependent remodeling enzymes (SWI/SNF, Mi2, and ISWI) to construct an intellectual framework to understand how these enzymes might be working. Second, we compare and contrast the function of these enzymes during early (thymic) and late (peripheral) T cell development. Finally, we examine some of the gaps in our present understanding. C1 [Wurster, Andrea L.; Pazin, Michael J.] NIA, Intramural Res Program, Lab Mol Biol & Immunol, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Pazin, MJ (reprint author), NHGRI, NIH, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM pazinm@mail.nih.gov OI Pazin, Michael/0000-0002-7561-3640 FU NIH, National Institute on Aging [1 Z01 AG000524] FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging, 1 Z01 AG000524. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 125 TC 2 Z9 2 U1 0 U2 3 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2012 VL 90 IS 1 BP 1 EP 13 DI 10.1139/O11-042 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 918DH UT WOS:000302229000001 PM 21999456 ER PT J AU Wurster, AL Precht, P Pazin, MJ AF Wurster, Andrea L. Precht, Patricia Pazin, Michael J. TI ATP-dependent remodeling enzymes and T helper cell differentiation SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Meeting Abstract C1 [Wurster, Andrea L.; Precht, Patricia; Pazin, Michael J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2012 VL 90 IS 1 BP 109 EP 109 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 918DH UT WOS:000302229000010 ER PT J AU Cusano, NE Kiel, DP Demissie, S Karasik, D Cupples, LA Corella, D Gao, Q Richardson, K Yiannakouris, N Ordovas, JM AF Cusano, Natalie E. Kiel, Douglas P. Demissie, Serkalem Karasik, David Cupples, L. Adrienne Corella, Dolores Gao, Qiong Richardson, Kris Yiannakouris, Nikos Ordovas, Jose M. TI A Polymorphism in a Gene Encoding Perilipin 4 Is Associated with Height but not with Bone Measures in Individuals from the Framingham Osteoporosis Study SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE Perilipin 1; Perilipin 4; Bone mineral density; Bone geometry; Framingham Osteoporosis Study ID GENOME-WIDE ASSOCIATION; MINERAL DENSITY; ADIPOSE-TISSUE; ELDERLY-MEN; OLD-AGE; WOMEN; MASS; OBESITY; DIETARY; GEOMETRY AB There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development. C1 [Cusano, Natalie E.] Columbia Univ, Div Endocrinol, Dept Med, Coll Phys & Surg, New York, NY 10032 USA. [Cusano, Natalie E.; Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Kiel, Douglas P.; Karasik, David] Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Kiel, Douglas P.; Karasik, David] Harvard Univ, Sch Med, Boston, MA USA. [Demissie, Serkalem; Cupples, L. Adrienne; Gao, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Demissie, Serkalem; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Corella, Dolores; Richardson, Kris; Yiannakouris, Nikos; Ordovas, Jose M.] Tufts Univ, Jean Mayer US Dept Agr Human Nutr, Res Ctr Aging, Boston, MA 02111 USA. [Corella, Dolores] Univ Valencia, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Valencia, Spain. [Ordovas, Jose M.] CNIC, Dept Epidemiol & Populat Genet, Madrid, Spain. RP Cusano, NE (reprint author), Columbia Univ, Div Endocrinol, Dept Med, Coll Phys & Surg, 630 W 168th St,PH 8 W-864, New York, NY 10032 USA. EM nc2433@columbia.edu OI Kiel, Douglas/0000-0001-8474-0310; Karasik, David/0000-0002-8826-0530 FU Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health; Boston University School of Medicine; National Heart, Lung, and Blood Institute's [N01-HC-25195]; National Institute of Arthritis, Musculoskeletal and Skin Diseases; National Institute on Aging [R01 AR/AG 41398, R01 AR050066]; NIH [HL54776, DK075030]; US Department of Agriculture Research Service [53-K06-5-10, 58-1950-9-001] FX This work is from the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The Framingham Heart Study core examinations were supported by the National Heart, Lung, and Blood Institute's (contract N01-HC-25195). Measurements of phenotypes were funded by the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute on Aging (grants R01 AR/AG 41398 and R01 AR050066). Genetic analyses were supported by NIH grants HL54776 and DK075030 and by the US Department of Agriculture Research Service (contracts 53-K06-5-10 and 58-1950-9-001). We gratefully acknowledge the Framingham Study members who participated in this study as well as the study coordinators, who contributed to the success of this work. NR 44 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD FEB PY 2012 VL 90 IS 2 BP 96 EP 107 DI 10.1007/s00223-011-9552-7 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 912JY UT WOS:000301795500004 PM 22210160 ER PT J AU Datta, SR Patterson, GH AF Datta, Sandeep Robert Patterson, George H. TI Optical highlighter molecules in neurobiology SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID PHOTOCONVERTIBLE FLUORESCENT PROTEIN; DENDRITIC SPINES; IN-VIVO; HIPPOCAMPAL-NEURONS; SYNAPTIC PLASTICITY; SINGLE-CELL; TRANSPORT; ZEBRAFISH; NUCLEUS; ACTIN AB The development of advanced optical methods has played a key role in propelling progress in neurobiology. Genetically-encoded fluorescent molecules found in nature have enabled labeling of individual neurons to study their physiology and anatomy. Here we discuss the recent use of both native and synthetic optical highlighter proteins to address key problems in neurobiology, including questions relevant to synaptic function, neuroanatomy, and the organization of neural circuits. C1 [Datta, Sandeep Robert] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Biophoton Sect, Bethesda, MD 20892 USA. RP Datta, SR (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Room 336,Warren Alpert Bldg,220 Longwood Ave, Boston, MA 02115 USA. EM srdatta@hms.harvard.edu; pattersg@mail.nih.gov FU National Institutes of Health; National Institute of Biomedical Imaging and Bioengineering; National Institutes of Deafness and Communication Disorders [RO1DC011558]; NIH Office of the Director's New Innovator Program [DP2OD007109]; McKnight Foundation; Searle Foundation; Biomedical Sciences from the Burroughs Wellcome Foundation FX This work was funded in part by the Intramural Research Program of the National Institutes of Health including the National Institute of Biomedical Imaging and Bioengineering (GHP), and by grants from the National Institutes of Deafness and Communication Disorders (RO1DC011558), the NIH Office of the Director's New Innovator Program (DP2OD007109), the McKnight Foundation, the Searle Foundation and from a Career Award in Biomedical Sciences from the Burroughs Wellcome Foundation (SRD). NR 77 TC 1 Z9 1 U1 1 U2 15 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 2012 VL 22 IS 1 BP 111 EP 120 DI 10.1016/j.conb.2011.11.007 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 913JS UT WOS:000301874400015 PM 22129781 ER PT J AU Briggman, KL Bock, DD AF Briggman, Kevin L. Bock, Davi D. TI Volume electron microscopy for neuronal circuit reconstruction SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID IN-VIVO; SECTION; ULTRASTRUCTURE; FLUORESCENCE; TOMOGRAPHY; MOSAICKING; CELLS AB The last decade has seen a rapid increase in the number of tools to acquire volume electron microscopy (EM) data. Several new scanning EM (SEM) imaging methods have emerged, and classical transmission EM (TEM) methods are being scaled up and automated. Here we summarize the new methods for acquiring large EM volumes, and discuss the tradeoffs in terms of resolution, acquisition speed, and reliability. We then assess each method's applicability to the problem of reconstructing anatomical connectivity between neurons, considering both the current capabilities and future prospects of the method. Finally, we argue that neuronal 'wiring diagrams' are likely necessary, but not sufficient, to understand the operation of most neuronal circuits: volume EM imaging will likely find its best application in combination with other methods in neuroscience, such as molecular biology, optogenetics, and physiology. C1 [Briggman, Kevin L.] NINDS, Circuit Dynam & Connect Unit, NIH, Bethesda, MD 20892 USA. [Bock, Davi D.] Howard Hughes Med Inst, Ashburn, VA USA. RP Briggman, KL (reprint author), NINDS, Circuit Dynam & Connect Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM briggmankl@mail.nih.gov; bockd@janelia.hhmi.org FU Howard Hughes Medical Institute NR 42 TC 76 Z9 76 U1 3 U2 32 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 2012 VL 22 IS 1 BP 154 EP 161 DI 10.1016/j.conb.2011.10.022 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 913JS UT WOS:000301874400020 PM 22119321 ER PT J AU Tolar, J Becker, PS Clapp, DW Hanenberg, H de Heredia, CD Kiem, HP Navarro, S Qasba, P Rio, P Schmidt, M Sevilla, J Verhoeyen, E Thrasher, AJ Bueren, J AF Tolar, Jakub Becker, Pamela S. Clapp, D. Wade Hanenberg, Helmut Diaz de Heredia, Cristina Kiem, Hans-Peter Navarro, Susana Qasba, Pankaj Rio, Paula Schmidt, Manfred Sevilla, Julian Verhoeyen, Els Thrasher, Adrian J. Bueren, Juan TI Gene Therapy for Fanconi Anemia: One Step Closer to the Clinic SO HUMAN GENE THERAPY LA English DT Editorial Material ID CELL TRANSPLANTATION; SOMATIC MOSAICISM; REVERSE MOSAICISM; ENGRAFTMENT; MOBILIZATION; COLLECTION; MOUSE; MODEL; MICE C1 [Tolar, Jakub] Univ Minnesota, Sch Med, Dept Pediat Blood & Marrow Transplantat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Becker, Pamela S.] Univ Washington, Sch Med, Seattle, WA 98109 USA. [Clapp, D. Wade; Hanenberg, Helmut] Indiana Univ Sch Med, Riley Hosp Children, Cincinnati, OH 45202 USA. [Hanenberg, Helmut] Univ Dusseldorf, Dept Otorhinolaryngol, Sch Med, D-40225 Dusseldorf, Germany. [Diaz de Heredia, Cristina] Hosp Val dHebron, Dept Hematol & Oncol, Barcelona 08035, Spain. [Kiem, Hans-Peter] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Navarro, Susana; Rio, Paula; Bueren, Juan] Ctr Invest Energet Medioambientales & Technol CIE, Hematopoiesis & Gene Therapy Div, Madrid 28040, Spain. [Navarro, Susana; Rio, Paula; Bueren, Juan] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28040, Spain. [Qasba, Pankaj] NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. [Schmidt, Manfred] German Canc Res Ctr, Dept Translat Oncol, D-69120 Heidelberg, Germany. [Schmidt, Manfred] Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Sevilla, Julian] Hosp Infantil Univ Nino Jesus, Inst Invest Sanitaria Princesa, Madrid 28009, Spain. [Verhoeyen, Els] Univ Lyon 1, INSERM, EVIR, Human Virol Dept,Ecole Normal Super Lyon,U758, F-69007 Lyon, France. [Thrasher, Adrian J.] UCL Inst Child Hlth, Ctr Immunodeficiency, Mol Immunol Unit, London WC1N 1EH, England. [Thrasher, Adrian J.] Great Ormond St Hosp NHS Trust, Dept Immunol, London WC1N 3JH, England. RP Tolar, J (reprint author), Univ Minnesota, Sch Med, Dept Pediat Blood & Marrow Transplantat, Div Blood & Marrow Transplantat, 420 Delaware St SE,MMC 366, Minneapolis, MN 55455 USA. EM tolar003@umn.edu RI Navarro, Susana/L-9300-2014; Bueren, Juan/L-6112-2014; Diaz de Heredia, Cristina/G-4016-2016; Verhoeyen, Els/H-6360-2016; Rio, Paula/G-8681-2015 OI Navarro, Susana/0000-0002-0764-5384; Bueren, Juan/0000-0002-3228-7013; Sevilla, Julian/0000-0002-6852-1860; Tolar, Jakub/0000-0002-0957-4380; Diaz de Heredia, Cristina/0000-0001-8086-296X; Rio, Paula/0000-0002-5424-5543 FU NCI NIH HHS [R01 CA155294]; NHLBI NIH HHS [R01HL84645]; Wellcome Trust [090233] NR 31 TC 18 Z9 18 U1 0 U2 8 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD FEB PY 2012 VL 23 IS 2 BP 141 EP 144 DI 10.1089/hum.2011.237 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 895UN UT WOS:000300522200002 PM 22248350 ER PT J AU Wei, ZS Yao, JH Wang, SJ Liu, JM Summers, RM AF Wei, Zhuoshi Yao, Jianhua Wang, Shijun Liu, Jiamin Summers, Ronald M. TI Automated teniae coli detection and identification on computed tomographic colonography SO MEDICAL PHYSICS LA English DT Article DE CT colonography; teniae coli; Gabor filter banks ID AIDED POLYP DETECTION; CT COLONOGRAPHY; VIRTUAL COLONOSCOPY; ILEOCECAL VALVE; FALSE POSITIVES; COLONIC POLYPS; SUPINE; PRONE; REGISTRATION; FEASIBILITY AB Purpose: Computed tomographic colonography (CTC) is a minimally invasive technique for colonic polyps and cancer screening. Teniae coli are three bands of longitudinal smooth muscle on the colon surface. Teniae coli are important anatomically meaningful landmarks on human colon. In this paper, the authors propose an automatic teniae coli detection method for CT colonography. Methods: The original CTC slices are first segmented and reconstructed to a 3D colon surface. Then, the 3D colon surface is unfolded using a reversible projection technique. After that the unfolded colon is projected to a 2D height map. The teniae coli are detected using the height map and then reversely projected back to the 3D colon. Since teniae are located at the junctions where the haustral folds meet, the authors apply 2D Gabor filter banks to extract features of haustral folds. The maximum response of the filter banks is then selected as the feature image. The fold centers are then identified based on local maxima and thresholding on the feature image. Connecting the fold centers yields a path of the folds. Teniae coli are extracted as lines running between the fold paths. The authors used the spatial relationship between ileocecal valve (ICV) and teniae mesocolica (TM) to identify the TM, then the teniae omentalis (TO) and the teniae libera (TL) can be identified subsequently. Results: The authors tested the proposed method on 47 cases of 37 patients, 10 of the patients with both supine and prone CT scans. The proposed method yielded performance with an average normalized root mean square error (RMSE) (+/- standard deviation [95% confidence interval]) of 4.87% (+/- 2.93%, [4.05% 5.69%]). Conclusions: The proposed fully-automated teniae coli detection and identification method is accurate and promising for future clinical applications. (C) 2012 American Association of Physicists in Medicine. [DOI: 10.1118/1.3679013] C1 [Wei, Zhuoshi; Yao, Jianhua; Wang, Shijun; Liu, Jiamin; Summers, Ronald M.] NCI, Ctr Clin, Imaging Biomarkers & Comp Aided Diag Lab, NIH, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NCI, Ctr Clin, Imaging Biomarkers & Comp Aided Diag Lab, NIH, Bethesda, MD 20892 USA. EM rms@nih.gov FU NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. The authors thank Dr. Perry Pickhardt, Dr. J. Richard Choi, and Dr. William Schindler for providing CT colonography data. NR 36 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD FEB PY 2012 VL 39 IS 2 BP 964 EP 975 DI 10.1118/1.3679013 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 891KN UT WOS:000300215800041 PM 22320805 ER PT J AU Kalish, H Phillips, TM AF Kalish, Heather Phillips, Terry M. TI Assessment of chemokine profiles in human skin biopsies by an immunoaffinity capillary electrophoresis chip SO METHODS LA English DT Article DE Atopic dermatitis; Biopsy; Chemokines; Chip-based CE; Immunoaffinity ID ATOPIC-DERMATITIS; MICROCHIP; CE; BIOMARKERS; INFLAMMATION; ATTRACTION; DEVICE; FLUIDS AB Atopic dermatitis is a skin condition resulting in a skin rash from exposure to environmental factors. Skin biopsies taken from patients suffering from atopic dermatitis were micro-dissected and analyzed using a microchip-based immunoaffinity CE system for the presence of CXCL1, CXCL5 and CXCL8 and CCL1, CCL3 and CCL5 chemokines. Disposable immunoaffinity disks with immobilized antibodies were used to capture the CXC and CC chemokines from the homogenized skin samples. The captured analytes were then labeled with AlexaFluor 633, eluted from the disk and separated by CE. The labeled chemokines were identified and quantified by laser induced fluorescence. The total analysis time was less than 40 min, including the biopsy microdissection, pre-analysis preparation of the sample and the ICE-CHIP analysis, which took less than 10 min with inter- and intra-assay CV's below 6.4%. Microchip-based immunoaffinity CE could distinguish between normal skin biopsies and those with inflammation. Patients with neutrophil cellular infiltrates by histopathology showed increased concentrations of CXCL1, CXCL5 and CXCL8 while increases of CCL1, CCL3 and CCL5 corresponded to the patient group demonstrating monocytic and T-lymphocyte infiltration by histopathology. This system demonstrates the ability to identify and quantify immunochemical analytes in frozen sections taken from clinical histopathology samples. Published by Elsevier Inc. C1 [Kalish, Heather; Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Micro Analyt Immunochem Unit, NIH, Bethesda, MD 20817 USA. RP Kalish, H (reprint author), Natl Inst Biomed Imaging & Bioengn, Micro Analyt Immunochem Unit, NIH, Bldg 13,Room 3E41,13 Ctr Dr, Bethesda, MD 20817 USA. EM KalishH@mail.nih.gov FU National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Program of the National Institutes of Health, Bethesda, MD, USA. The authors have declared no conflict of interest. NR 41 TC 12 Z9 12 U1 2 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD FEB PY 2012 VL 56 IS 2 BP 198 EP 203 DI 10.1016/j.ymeth.2011.12.003 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 916LN UT WOS:000302105400013 PM 22197729 ER PT J AU Li, ZJ Huang, H Chen, P He, M Li, YY Arnovitz, S Jiang, X He, CJ Hyjek, E Zhang, J Zhang, ZY Elkahloun, A Cao, DL Shen, C Wunderlich, M Wang, YG Neilly, MB Jin, J Wei, MJ Lu, J Valk, PJM Delwel, R Lowenberg, B Le Beau, MM Vardiman, J Mulloy, JC Zeleznik-Le, NJ Liu, PP Zhang, JW Chen, JJ AF Li, Zejuan Huang, Hao Chen, Ping He, Miao Li, Yuanyuan Arnovitz, Stephen Jiang, Xi He, Chunjiang Hyjek, Elizabeth Zhang, Jun Zhang, Zhiyu Elkahloun, Abdel Cao, Donglin Shen, Chen Wunderlich, Mark Wang, Yungui Neilly, Mary Beth Jin, Jie Wei, Minjie Lu, Jun Valk, Peter J. M. Delwel, Ruud Lowenberg, Bob Le Beau, Michelle M. Vardiman, James Mulloy, James C. Zeleznik-Le, Nancy J. Liu, Paul P. Zhang, Jiwang Chen, Jianjun TI miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia SO NATURE COMMUNICATIONS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION PROFILE; MESSENGER-RNA; HISTONE MODIFICATIONS; MICRORNAS; CELLS; HOXA9; MEIS1; STEM AB HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL -rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL -rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought. C1 [Li, Zejuan; Huang, Hao; Chen, Ping; He, Miao; Li, Yuanyuan; Arnovitz, Stephen; Jiang, Xi; He, Chunjiang; Cao, Donglin; Shen, Chen; Neilly, Mary Beth; Le Beau, Michelle M.; Chen, Jianjun] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Hyjek, Elizabeth; Vardiman, James] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Zhang, Jun; Zhang, Jiwang] Loyola Univ, Inst Oncol, Cardinal Bernardin Canc Ctr, Med Ctr, Maywood, IL 60153 USA. [Zhang, Zhiyu] Univ Chicago, Tang Ctr Herbal Med Res, Chicago, IL 60637 USA. [Elkahloun, Abdel; Liu, Paul P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Wunderlich, Mark; Mulloy, James C.] Univ Cincinnati, Div Expt Hematol & Canc Biol, Cincinnati Childrens Hosp, Med Ctr,Coll Med, Cincinnati, OH 45229 USA. [He, Miao; Wei, Minjie] China Med Univ, Dept Pharmacol, Shenyang 110001, Liaoning, Peoples R China. [Cao, Donglin] Guangdong 2 Prov People s Hosp, Dept Lab Med, Guangzhou 510317, Guangdong, Peoples R China. [Wang, Yungui; Jin, Jie] Zhejiang Univ, Inst Hematol, Affiliated Hosp 1, Coll Med, Hangzhou 310058, Zhejiang, Peoples R China. [Lu, Jun] Yale Univ, Dept Genet, Yale Stem Cell Ctr, New Haven, CT 06520 USA. [Valk, Peter J. M.; Delwel, Ruud; Lowenberg, Bob] Erasmus Univ, Dept Hematol, Med Ctr, NL-3000 CA Rotterdam, Netherlands. [Zeleznik-Le, Nancy J.] Loyola Univ, Med Ctr, Dept Med, Maywood, IL 60153 USA. RP Chen, JJ (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM jchen@medicine.bsd.uchicago.edu OI He, Chunjiang/0000-0002-4868-331X FU National Institutes of Health (NIH) [R01, CA127277, R01 CA118319, R01 HL95896, HL087188]; American Cancer Society (ACS); LLS Special Fellowship; Gabrielle's Angel Fondation for Cancer Research; Leukemia and Lymphoma Society (LLS); Fidelity Foundation; National Human Genome Research Institute, NIH; [P01 CA40046]; [P30 CA014599] FX We thank Dr. Janet D. Rowley and Colles Price for their constructive suggestions and comments, and Drs Gang Huang, Long Zhang and Roger Luo for their technical support on isolation and retroviral transduction of mouse foetal liver cells, mouse tail vein injection and general mouse BM transplantation assays. 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.), LLS Special Fellowship (Z.L.), Gabrielle's Angel Fondation for Cancer Research (J.C.; Z.L.; H. H.), Leukemia and Lymphoma Society (LLS) Translational Research Grant (J.C.), Fidelity Foundation (J.C.), NIH R01 CA118319 Sub-Award (J.C. M. and J.C.), R01 HL95896 (J.Z.), HL087188 (N.J. Z.-L.), Intramural Research Program of 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). J.C.M. is a Leukemia and Lymphoma Society (LLS) Scholar. NR 60 TC 42 Z9 47 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2012 VL 3 AR 688 DI 10.1038/ncomms1681 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 915XE UT WOS:000302060100029 PM 22353710 ER PT J AU Midega, JT Smith, DL Olotu, A Mwangangi, JM Nzovu, JG Wambua, J Nyangweso, G Mbogo, CM Christophides, GK Marsh, K Bejon, P AF Midega, Janet T. Smith, Dave L. Olotu, Ally Mwangangi, Joseph M. Nzovu, Joseph G. Wambua, Juliana Nyangweso, George Mbogo, Charles M. Christophides, George K. Marsh, Kevin Bejon, Philip TI Wind direction and proximity to larval sites determines malaria risk in Kilifi District in Kenya SO NATURE COMMUNICATIONS LA English DT Article ID ENTOMOLOGICAL INOCULATION RATE; ANOPHELES-GAMBIAE; TRANSMISSION; MOSQUITOS; CHILDREN; COAST; VILLAGE; AREA; EPIDEMIOLOGY; PHILIPPINES AB Studies of the fine-scale spatial epidemiology of malaria consistently identify malaria hotspots, comprising clusters of homesteads at high transmission intensity. These hotspots sustain transmission, and may be targeted by malaria-control programmes. Here we describe the spatial relationship between the location of Anopheles larval sites and human malaria infection in a cohort study of 642 children, aged 1-10-years-old. Our data suggest that proximity to larval sites predict human malaria infection, when homesteads are upwind of larval sites, but not when homesteads are downwind of larval sites. We conclude that following oviposition, female Anophelines fly upwind in search for human hosts and, thus, malaria transmission may be disrupted by targeting vector larval sites in close proximity, and downwind to malaria hotspots. C1 [Midega, Janet T.; Olotu, Ally; Mwangangi, Joseph M.; Nzovu, Joseph G.; Wambua, Juliana; Nyangweso, George; Mbogo, Charles M.; Marsh, Kevin; Bejon, Philip] Ctr Geog Med Res Coast, KEMRI Wellcome Trust Collaborat Res Programme, Kilifi 80108, Kenya. [Midega, Janet T.; Christophides, George K.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England. [Smith, Dave L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Smith, Dave L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Marsh, Kevin; Bejon, Philip] Univ Oxford, Churchill Hosp, Ctr Clin Vaccinol & Trop Med, Oxford OX3 7LJ, England. RP Midega, JT (reprint author), Ctr Geog Med Res Coast, KEMRI Wellcome Trust Collaborat Res Programme, POB 230, Kilifi 80108, Kenya. EM tjmidega@yahoo.com RI Smith, David/L-8850-2013; OI Smith, David/0000-0003-4367-3849; Christophides, George/0000-0002-3323-1687 FU EU at Imperial College, London; MRC (UK); Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank the Meteorological Office, UK for providing the wind-speed data from Mombasa airport and Moses C. Kiti for the Kilifi wind-speed data. We thank David Benz for making available the MODIS data with Fourier transformations (Spatial Ecology and Epidemiology group, Department of Zoology, University of Oxford). J.M. is funded by the EU FP7 project funds at Imperial College, London. P. B. is funded by the MRC (UK). D. L. S. is funded by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. This paper is published with the permission of the Director of KEMRI. NR 42 TC 27 Z9 27 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2012 VL 3 AR 674 DI 10.1038/ncomms1672 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 915XE UT WOS:000302060100015 PM 22334077 ER PT J AU Fang, H Clark, DJ Hayes, JJ AF Fang, He Clark, David J. Hayes, Jeffrey J. TI DNA and nucleosomes direct distinct folding of a linker histone H1 C-terminal domain SO NUCLEIC ACIDS RESEARCH LA English DT Article ID INTRINSIC PROTEIN DISORDER; AMINO-ACID-COMPOSITION; SECONDARY STRUCTURE; IN-VIVO; CHROMATIN; BINDING; LOCALIZATION; SPERM; H-1; CONDENSATION AB We previously documented condensation of the H1 CTD consistent with adoption of a defined structure upon nucleosome binding using a bulk FRET assay, supporting proposals that the CTD behaves as an intrinsically disordered domain. In the present study, by determining the distances between two different pairs of sites in the C-terminal domain of full length H1 by FRET, we confirm that nucleosome binding directs folding of the disordered H1 C-terminal domain and provide additional distance constraints for the condensed state. In contrast to nucleosomes, FRET observed upon H1 binding to naked DNA fragments includes both intra- and inter-molecular resonance energy transfer. By eliminating inter-molecular transfer, we find that CTD condensation induced upon H1-binding naked DNA is distinct from that induced by nucleosomes. Moreover, analysis of fluorescence quenching indicates that H1 residues at either end of the CTD experience distinct environments when bound to nucleosomes, and suggest that the penultimate residue in the CTD (K195) is juxtaposed between the two linker DNA helices, proposed to form a stem structure in the H1-bound nucleosome. C1 [Fang, He; Hayes, Jeffrey J.] Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14625 USA. [Clark, David J.] NICHHD, Sect Chromatin & Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Hayes, JJ (reprint author), Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14625 USA. EM jeffrey_hayes@urmc.rochester.edu RI fang, he/H-3172-2016 FU National Institutes of Health [GM52426]; National Institutes of Health (National Institute of Child Health and Human Development) FX National Institutes of Health grant [Grant GM52426] (to J.J.H.); the Intramural Research Program of the National Institutes of Health (National Institute of Child Health and Human Development). Funding for open access charge: National Institutes of Health. NR 39 TC 30 Z9 31 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2012 VL 40 IS 4 BP 1475 EP 1484 DI 10.1093/nar/gkr866 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902UY UT WOS:000301069400014 PM 22021384 ER PT J AU Ramamoorthy, M Tadokoro, T Rybanska, I Ghosh, AK Wersto, R May, A Kulikowicz, T Sykora, P Croteau, DL Bohr, VA AF Ramamoorthy, Mahesh Tadokoro, Takashi Rybanska, Ivana Ghosh, Avik K. Wersto, Robert May, Alfred Kulikowicz, Tomasz Sykora, Peter Croteau, Deborah L. Bohr, Vilhelm A. TI RECQL5 cooperates with Topoisomerase II alpha in DNA decatenation and cell cycle progression SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SISTER-CHROMATID EXCHANGE; RNA-POLYMERASE-II; BLOOM-SYNDROME PROTEIN; ESCHERICHIA-COLI RECQ; HUMAN RECQ5-BETA; CHROMOSOME SEGREGATION; SYNDROME HELICASE; BREAST-CANCER; S-PHASE; REPLICATION AB DNA decatenation mediated by Topoisomerase II is required to separate the interlinked sister chromatids post-replication. SGS1, a yeast homolog of the human RecQ family of helicases interacts with Topoisomerase II and plays a role in chromosome segregation, but this functional interaction has yet to be identified in higher organisms. Here, we report a physical and functional interaction of Topoisomerase II alpha with RECQL5, one of five mammalian RecQ helicases, during DNA replication. Direct interaction of RECQL5 with Topoisomerase II alpha stimulates the decatenation activity of Topoisomerase II alpha. Consistent with these observations, RECQL5 co-localizes with Topoisomerase II alpha during S-phase of the cell cycle. Moreover, cells with stable depletions of RECQL5 display a slow proliferation rate, a G2/M cell cycle arrest and late S-phase cycling defects. Metaphase spreads generated from RECQL5-depleted cells exhibit undercondensed and entangled chromosomes. Further, RECQL5-depleted cells activate a G2/M checkpoint and undergo apoptosis. These phenotypes are similar to those observed when Topoisomerase II catalytic activity is inhibited. These results reveal an important role for RECQL5 in the maintenance of genomic stability and a new insight into the decatenation process. C1 [Ramamoorthy, Mahesh; Tadokoro, Takashi; Rybanska, Ivana; Ghosh, Avik K.; May, Alfred; Kulikowicz, Tomasz; Sykora, Peter; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Wersto, Robert] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Ramamoorthy, Mahesh/0000-0002-2359-5647 FU National Institutes of Health of the National Institute on Aging [Z01-AG000726-18]; National Institutes of Health FX This work was supported by the National Institutes of Health Intramural Program of the National Institute on Aging (Z01-AG000726-18). Funding for open access charge: National Institutes of Health. NR 62 TC 19 Z9 23 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2012 VL 40 IS 4 BP 1621 EP 1635 DI 10.1093/nar/gkr844 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902UY UT WOS:000301069400025 PM 22013166 ER PT J AU Scott, AL Ghedin, E Nutman, TB McReynolds, LA Poole, CB Slatko, BE Foster, JM AF Scott, A. L. Ghedin, E. Nutman, T. B. McReynolds, L. A. Poole, C. B. Slatko, B. E. Foster, J. M. TI Filarial and Wolbachia genomics SO PARASITE IMMUNOLOGY LA English DT Review DE Brugia; filarial; genome; Nematode; noncoding RNA; proteomics; transcriptomics; Wolbachia ID PARASITE BRUGIA-MALAYI; CAENORHABDITIS-ELEGANS; C-ELEGANS; LYMPHATIC FILARIASIS; DRAFT GENOME; ENDOSYMBIONT; GENE; EVOLUTION; TARGET; BIOSYNTHESIS AB Filarial nematode parasites, the causative agents for a spectrum of acute and chronic diseases including lymphatic filariasis and river blindness, threaten the well-being and livelihood of hundreds of millions of people in the developing regions of the world. The 2007 publication on a draft assembly of the 95-Mb genome of the human filarial parasite Brugia malayi representing the first helminth parasite genome to be sequenced has been followed in rapid succession by projects that have resulted in the genome sequencing of six additional filarial species, seven nonfilarial nematode parasites of animals and nearly 30 plant parasitic and free-living species. Parallel to the genomic sequencing, transcriptomic and proteomic projects have facilitated genome annotation, expanded our understanding of stage-associated gene expression and provided a first look at the role of epigenetic regulation of filarial genomes through microRNAs. The expansion in filarial genomics will also provide a significant enrichment in our knowledge of the diversity and variability in the genomes of the endosymbiotic bacterium Wolbachia leading to a better understanding of the genetic principles that govern filarialWolbachia mutualism. The goal here is to provide an overview of the trends and advances in filarial and Wolbachia genomics. C1 [Scott, A. L.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Ghedin, E.] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Dept Computat & Syst Biol, Pittsburgh, PA USA. [Nutman, T. B.] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [McReynolds, L. A.; Poole, C. B.; Slatko, B. E.; Foster, J. M.] New England Biolabs Inc, Ipswich, MA USA. RP Scott, AL (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, 615 North Wolfe, Baltimore, MD 21205 USA. EM ascott@jhsph.edu FU Filarial Genome Project; filarial research community FX We thank our colleagues of the Filarial Genome Project and the filarial research community for their continued support and encouragement. We thank Shelly Michalski (University of Wisconsin, Oshkosh) and Bruce Christensen (University of Wisconsin, Madison) for their input on B. malayi transcriptomics. NR 57 TC 11 Z9 12 U1 2 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0141-9838 EI 1365-3024 J9 PARASITE IMMUNOL JI Parasite Immunol. PD FEB-MAR PY 2012 VL 34 IS 2-3 SI SI BP 121 EP 129 DI 10.1111/j.1365-3024.2011.01344.x PG 9 WC Immunology; Parasitology SC Immunology; Parasitology GA 895OA UT WOS:000300504500009 PM 22098559 ER PT J AU Sullivan, K Froshaug, D Furst, D Nash, R Mayes, M Crofford, L McSweeney, P Goldmuntz, E Keyes-Elstein, L Khanna, D AF Sullivan, K. Froshaug, D. Furst, D. Nash, R. Mayes, M. Crofford, L. McSweeney, P. Goldmuntz, E. Keyes-Elstein, L. Khanna, D. TI ORGAN FUNCTION AND QUALITY OF LIFE CORRELATES AT RANDOMIZATION ON THE SCOT (SCLERODERMA: CYCLOPHOSPHAMIDE OR TRANSPLANTION) TRIAL SO RHEUMATOLOGY LA English DT Meeting Abstract CT 2nd Systemic Sclerosis World Congress CY FEB 02-04, 2012 CL Madrid, SPAIN C1 [Sullivan, K.] Duke Univ, Durham, NC 27706 USA. [Froshaug, D.; Keyes-Elstein, L.] Rho Fed Syst, Chapel Hill, NC USA. [Furst, D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Nash, R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Mayes, M.] Univ Texas Houston, Houston, TX USA. [Crofford, L.] Univ Kentucky, Lexington, KY USA. [McSweeney, P.] Rocky Mt Canc Ctr, Denver, CO USA. [Goldmuntz, E.] NIH, Bethesda, MD 20892 USA. [Khanna, D.] Univ Michigan, Ann Arbor, MI 48109 USA. RI Crofford, Leslie/J-8010-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD FEB PY 2012 VL 51 SU 2 BP 1 EP 1 PG 1 WC Rheumatology SC Rheumatology GA 914TC UT WOS:000301974300003 ER PT J AU Dunsmoor, JE Martin, A LaBar, KS AF Dunsmoor, Joseph E. Martin, Alex LaBar, Kevin S. TI Role of conceptual knowledge in learning and retention of conditioned fear SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Emotional arousal; Generalization; Fear conditioning; Associative learning; Phobia; Posttraumatic stress disorder ID POSTTRAUMATIC-STRESS-DISORDER; STIMULUS-GENERALIZATION; COGNITIVE NEUROSCIENCE; EMOTIONAL MEMORY; AROUSAL; HUMANS; REPRESENTATION; METAANALYSIS; HIPPOCAMPUS; ACQUISITION AB Associating sensory cues with aversive outcomes is a relatively basic process shared across species. Yet higher-order cognitive processes likely contribute to associative fear learning in many circumstances, especially in humans. Here we ask whether fears can be acquired based on conceptual knowledge of object categories, and whether such concept-based fear conditioning leads to enhanced memory representations for conditioned objects. Participants were presented with a heterogeneous collection of images of animals and tools. Objects from one category were reinforced by an electrical shock, whereas the other category was never reinforced. Results confirmed concept-based fear learning through subjective report of shock expectancy, heightened skin conductance responses, and enhanced 24 h recognition memory for items from the conditioned category. These results provide novel evidence that conditioned fear can generalize through knowledge of object concepts, and sheds light on the persistent nature of fear memories and category-based fear responses symptomatic of some anxiety disorders. (C) 2011 Elsevier B.V. All rights reserved. C1 [Dunsmoor, Joseph E.; LaBar, Kevin S.] Duke Univ, Ctr Cognit Neurosci, Dept Psychol & Neurosci, Durham, NC 27708 USA. [Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP LaBar, KS (reprint author), Duke Univ, Ctr Cognit Neurosci, Dept Psychol & Neurosci, Durham, NC 27708 USA. EM klabar@duke.edu RI martin, alex/B-6176-2009 FU NSF [0745919]; NIH [R01 DA027802, F31 MH090682] FX We thank Vishnu Murty for helpful comments and Philip Kragel for assistance with coding the presentation graphics program. This work was supported by NSF grant 0745919 and NIH grants R01 DA027802 and F31 MH090682. NR 48 TC 30 Z9 30 U1 4 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD FEB PY 2012 VL 89 IS 2 BP 300 EP 305 DI 10.1016/j.biopsycho.2011.11.002 PG 6 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 909JI UT WOS:000301560400004 PM 22118937 ER PT J AU Kim, SH Cornwell, B Kim, SE AF Kim, Sang Hee Cornwell, Brian Kim, Sang Eun TI Individual differences in emotion regulation and hemispheric metabolic asymmetry SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Frontal asymmetry; Positron emission tomography; Reappraisal; Prefrontal; Caudate; Anterior cingulate ID FRONTAL EEG ASYMMETRY; BRAIN ELECTRICAL ASYMMETRY; NEGATIVE EMOTION; NEUROTICISM; EXTROVERSION; REAPPRAISAL; PERSONALITY; DEPRESSION; PREDICTS; AMYGDALA AB Recent studies of emotion regulation have reported that frequent use of reappraisal is associated with greater experience of positive emotions and increased sense of well-being, which, in turn, have been observed in individuals with greater left-sided prefrontal cortical activity. We hypothesized that frequent use of reappraisal would be correlated with greater left-sided biases of metabolic activity in prefrontal regions as well as in subcortical structures to which the former are interconnected. Twenty male volunteers were scanned at rest with 18 F-fluorodeoxyglucose positron emission tomography. Self-reported emotion regulation style and an emotional regulation task were administered outside the scanner. Results revealed that frequent reappraisers showed greater left-sided biases of metabolic activity in the dorsolateral prefrontal and caudate regions. Regulation successes in increasing emotions were associated with left-sided metabolic asymmetry in the anterior cingulate. Findings suggest that asymmetric metabolism in prefrontal and subcortical regions are associated with emotion regulation style and also with regulation success. (C) 2011 Elsevier B.V. All rights reserved. C1 [Kim, Sang Hee] Korea Univ, Dept Brain & Cognit Engn, Sci Lib 604B, Seoul 136713, South Korea. [Cornwell, Brian] NIMH, NIH, Bethesda, MD 20892 USA. [Kim, Sang Eun] Seoul Natl Univ, Coll Med, Dept Nucl Med, Bundang Hosp, Seoul, South Korea. RP Kim, SH (reprint author), Korea Univ, Dept Brain & Cognit Engn, Sci Lib 604B, Anam Dong 5Ga, Seoul 136713, South Korea. EM sangheekim.ku@gmail.com; kse@snu.ac.kr RI Kim, Sang Eun/J-5401-2012 FU Ministry of Education, Science and Technology, the Republic of Korea; National Research Foundation of Korea (NRF) [2009-0083265, 2010-0005689, R31-10008] FX This work was supported by grants from National Nuclear R&D Program (2009-0083265), Basic Science Research Program (2010-0005689) and World Class University program (R31-10008) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, the Republic of Korea. NR 41 TC 8 Z9 8 U1 4 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD FEB PY 2012 VL 89 IS 2 BP 382 EP 386 DI 10.1016/j.biopsycho.2011.11.013 PG 5 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 909JI UT WOS:000301560400013 PM 22172658 ER PT J AU Bjork, JM Chen, G Hommer, DW AF Bjork, James M. Chen, Gang Hommer, Daniel W. TI Psychopathic tendencies and mesolimbic recruitment by cues for instrumental and passively obtained rewards SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Reward; Psychopathy; Incentive motivation; fMRI; Instrumental behavior ID ORBITOFRONTAL CORTEX DYSFUNCTION; RESPONSE REVERSAL; NUCLEUS-ACCUMBENS; DECISION-MAKING; SELF-REPORT; SYSTEMS; PERSONALITY; ACTIVATION; HYPERSENSITIVITY; ANTICIPATION AB Psychopathy is a constellation of self-serving attitudes and antisocial behaviors with little regard to cost to self and others. Might this symptomatology arise in part from an exaggerated response of brain motivational circuitry to prospective rewards? We examined whether psychopathic tendencies are associated with increased recruitment of incentive neurocircuitry during anticipation of instrumental and conditioned rewards. Healthy controls completed the Psychopathic Personality Inventory (PPI), then were presented with response-contingent and passively delivered rewards during functional MRI. PPI scores correlated negatively with reaction time to incentivized targets, but not with reaction time to non-incentivized targets. PPI scores also correlated positively with recruitment of ventral striatum and anterior cingulate cortex during instrumental reward anticipation. PPI scores also correlated with middle frontal cortex recruitment during anticipation of passively received rewards. These data indicate that in psychiatrically healthy controls, individuals with greater endorsement of psychopathic tendencies show more robust neurophysiological and behavioral signatures of incentive motivation. Published by Elsevier B.V.. C1 [Bjork, James M.] NIDA, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. [Chen, Gang] NIMH, NIH, Bethesda, MD 20892 USA. [Hommer, Daniel W.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Bjork, JM (reprint author), NIDA, Div Clin Neurosci & Behav Res, NIH, 6001 Execut Blvd,Room 3172, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU National Institute on Alcohol Abuse and Alcoholism FX This research was sponsored by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism. NR 44 TC 29 Z9 29 U1 2 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD FEB PY 2012 VL 89 IS 2 BP 408 EP 415 DI 10.1016/j.biopsycho.2011.12.003 PG 8 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 909JI UT WOS:000301560400016 PM 22178441 ER PT J AU Schindler, CW Goldberg, SR AF Schindler, Charles W. Goldberg, Steven R. TI Accelerating cocaine metabolism as an approach to the treatment of cocaine abuse and toxicity SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID MUTANT BACTERIAL COCAINE; HUMAN BUTYRYLCHOLINESTERASE; CATALYTIC ANTIBODIES; HUMAN-PLASMA; CARDIOVASCULAR-RESPONSES; PRETREATMENT DRUGS; RHESUS-MONKEYS; HALF-LIFE; IN-VITRO; RATS AB One pharmacokinetic approach to the treatment of cocaine abuse and toxicity involves the development of compounds that can be safely administered to humans and that accelerate the metabolism of cocaine to inactive components. Catalytic antibodies have been developed and shown to accelerate cocaine metabolism, but their catalytic efficiency for cocaine is relatively low. Mutations of human butyrylcholinesterase and a bacterial cocaine esterase found in the soil of coca plants have also been developed. These compounds accelerate cocaine metabolism and antagonize the behavioral and toxic effects of cocaine in animal models. Of these two approaches, the human butyrylcholinesterase mutants show the most immediate promise as they would not be expected to evoke an immune response in humans. C1 [Schindler, Charles W.; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, DHHS,NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, DHHS,NIH,Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM cschindl@helix.nih.gov FU NIH, NIDA FX Preparation of this review was supported by the Intramural Research Program of the NIH, NIDA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 92 TC 8 Z9 8 U1 2 U2 10 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD FEB PY 2012 VL 4 IS 2 BP 163 EP 175 DI 10.4155/FMC.11.181 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 911YA UT WOS:000301759400010 PM 22300096 ER PT J AU Gorelick, DA AF Gorelick, David A. TI Pharmacokinetic strategies for treatment of drug overdose and addiction SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID BACTERIAL COCAINE ESTERASE; SINGLE-CHAIN ANTIBODY; HUMAN BUTYRYLCHOLINESTERASE; MONOCLONAL-ANTIBODY; SMOKING-CESSATION; THERAPEUTIC VACCINE; NICOTINE ADDICTION; ABUSE; METHAMPHETAMINE; RATS AB The pharmacokinetic treatment strategy targets the drug molecule itself, aiming to reduce drug concentration at the site of action, thereby minimizing any pharmacodynamic effect. This approach might be useful in the treatment of acute drug toxicity/overdose and in the long-term treatment of addiction. Phase Ila controlled clinical trials with anticocaine and antinicotine vaccines have shown good tolerability and some efficacy, but Phase Ilb and III trials have been disappointing because of the failure to generate adequate antibody titers in most participants. Monoclonal antibodies against cocaine, methamphetamine and phencyclidine have shown promise in animal studies, as has enhancing cocaine metabolism with genetic variants of human butyrylcholinesterase, with a bacterial esterase, and with catalytic monoclonal antibodies. Pharmacokinetic treatments offer potential advantages in terms of patient adherence, absence of medication interactions and benefit for patients who cannot take standard medications. C1 NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorelick, DA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU US NIH, National Institute on Drug Abuse FX D Gorelick is supported by the Intramural Research Program, US NIH, National Institute on Drug Abuse. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 82 TC 14 Z9 14 U1 0 U2 10 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD FEB PY 2012 VL 4 IS 2 BP 227 EP 243 DI 10.4155/FMC.11.190 PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 911YA UT WOS:000301759400014 PM 22300100 ER PT J AU Chopra, A Shan, L Eckelman, WC Leung, K Latterner, M Bryant, SH Menkens, A AF Chopra, Arvind Shan, Liang Eckelman, W. C. Leung, Kam Latterner, Martin Bryant, Stephen H. Menkens, Anne TI Molecular Imaging and Contrast Agent Database (MICAD): Evolution and Progress SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Molecular imaging probes; Contrast agents; Database; Positron emission tomography (PET); Single-photon emission computed tomography (SPECT); Magnetic resonance imaging (MRI); X-ray/computed tomography (X-ray/CT); Optical imaging (OI); Ultrasound imaging ID DRUG DEVELOPMENT; NIH ROADMAP; RECEPTORS AB The purpose of writing this review is to showcase the Molecular Imaging and Contrast Agent Database (MICAD; www.micad.nlm.nih.gov) to students, researchers, and clinical investigators interested in the different aspects of molecular imaging. This database provides freely accessible, current, online scientific information regarding molecular imaging (MI) probes and contrast agents (CA) used for positron emission tomography, single-photon emission computed tomography, magnetic resonance imaging, X-ray/computed tomography, optical imaging and ultrasound imaging. Detailed information on >1,000 agents in MICAD is provided in a chapter format and can be accessed through PubMed. Lists containing >4,250 unique MI probes and CAs published in peer-reviewed journals and agents approved by the United States Food and Drug Administration as well as a comma separated values file summarizing all chapters in the database can be downloaded from the MICAD homepage. Users can search for agents in MICAD on the basis of imaging modality, source of signal/contrast, agent or target category, preclinical or clinical studies, and text words. Chapters in MICAD describe the chemical characteristics (structures linked to PubChem), the in vitro and in vivo activities, and other relevant information regarding an imaging agent. All references in the chapters have links to PubMed. A Supplemental Information Section in each chapter is available to share unpublished information regarding an agent. A Guest Author Program is available to facilitate rapid expansion of the database. Members of the imaging community registered with MICAD periodically receive an e-mail announcement (eAnnouncement) that lists new chapters uploaded to the database. Users of MICAD are encouraged to provide feedback, comments, or suggestions for further improvement of the database by writing to the editors at micad@nlm.nih.gov. C1 [Chopra, Arvind; Shan, Liang; Eckelman, W. C.; Leung, Kam; Latterner, Martin; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Menkens, Anne] NCI, NIH, Bethesda, MD 20894 USA. RP Chopra, A (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM chopraa@mail.nih.gov FU National Institutes of Health FX We thank Jeremiah McAdams for his assistance with the writing of this review. Funding for the Molecular Imaging and Contrast Agent Database is provided by the Intramural Research Program of the National Institutes of Health. NR 27 TC 15 Z9 15 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2012 VL 14 IS 1 BP 4 EP 13 DI 10.1007/s11307-011-0521-3 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 909SE UT WOS:000301583900002 PM 21989943 ER PT J AU Wang, H Chen, XY AF Wang, Hui Chen, Xiaoyuan TI Visualization of Copper Metabolism by (CuCl2)-Cu-64-PET SO MOLECULAR IMAGING AND BIOLOGY LA English DT Editorial Material ID WILSONS-DISEASE; RADIOACTIVE COPPER; TRANSPORT; STRESS; TARGET; CELLS C1 [Wang, Hui; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [ZIA EB000073-01] NR 20 TC 7 Z9 7 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2012 VL 14 IS 1 BP 14 EP 16 DI 10.1007/s11307-011-0483-5 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 909SE UT WOS:000301583900003 PM 21384206 ER PT J AU Chin, FT Shen, B Liu, SL Berganos, RA Chang, E Mittra, E Chen, XY Gambhir, SS AF Chin, Frederick T. Shen, Bin Liu, Shuanglong Berganos, Rhona A. Chang, Edwin Mittra, Erik Chen, Xiaoyuan Gambhir, Sanjiv S. TI First Experience with Clinical-Grade [F-18]FPP(RGD)(2): An Automated Multi-step Radiosynthesis for Clinical PET Studies SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Oncology; Peptides; Radiopharmaceuticals; [F-18]FPP(RGD)(2); Automated radiosynthesis; Clinical PET; Tumor angiogenesis; Integrins ID INTEGRIN ALPHA(V)BETA(3) EXPRESSION; RGD PEPTIDES; ALPHA-V-BETA-3 INTEGRIN; CANCER-PATIENTS AB Purpose: A reliable and routine process to introduce a new F-18-labeled dimeric RGD-peptide tracer ([F-18]FPP(RGD)(2)) for noninvasive imaging of alpha(v)beta(3) expression in tumors needed to be developed so the tracer could be evaluated for the first time in man. Clinical-grade [F-18]FPP (RGD)(2) was screened in mouse prior to our first pilot study in human. Procedures: [F-18]FPP(RGD)(2) was synthesized by coupling 4-nitrophenyl-2-[F-18]Fluoropropionate ([F-18] NPE) with the dimeric RGD-peptide (PEG3-c(RGDyK)(2)). Imaging studies with [F-18]FPP(RGD)(2) in normal mice and a healthy human volunteer were carried out using small animal and clinical PET scanners, respectively. Results: Through optimization of each radiosynthetic step, [F-18]FPP(RGD)(2) was obtained with RCYs of 16.9 +/- 2.7% (n=8, EOB) and specific radioactivity of 114 +/- 72 GBq/mu mol (3.08 +/- 1.95 Ci/mu mol; n=8, EOB) after 170 min of radiosynthesis. In our mouse studies, high radioactivity uptake was only observed in the kidneys and bladder with the clinical-grade tracer. Favorable [F-18]FPP (RGD)(2) biodistribution in human studies, with low background signal in the head, neck, and thorax, showed the potential applications of this RGD-peptide tracer for detecting and monitoring tumor growth and metastasis. Conclusions: A reliable, routine, and automated radiosynthesis of clinical-grade [F-18]FPP(RGD)(2) was established. PET imaging in a healthy human volunteer illustrates that [F-18]FPP(RGD)(2) possesses desirable pharmacokinetic properties for clinical noninvasive imaging of alpha(v)beta(3) expression. Further imaging studies using [F-18]FPP(RGD)(2) in patient volunteers are now under active investigation. C1 [Chin, Frederick T.; Shen, Bin; Liu, Shuanglong; Berganos, Rhona A.; Chang, Edwin; Gambhir, Sanjiv S.] Stanford Univ, Sch Med, Bio X Program, Dept Radiol,MIPS, Stanford, CA 94305 USA. [Chin, Frederick T.; Shen, Bin; Liu, Shuanglong; Berganos, Rhona A.; Chang, Edwin; Gambhir, Sanjiv S.] Stanford Univ, Sch Med, Bio X Program, Dept Bioengn,MIPS, Stanford, CA 94305 USA. [Mittra, Erik; Gambhir, Sanjiv S.] Mol Imaging Program, Dept Radiol, Div Nucl Med, Stanford, CA 94305 USA. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chin, FT (reprint author), Stanford Univ, Sch Med, Bio X Program, Dept Radiol,MIPS, Stanford, CA 94305 USA. EM chinf@stanford.edu RI Shen, Bin/F-8111-2014 FU NCI ICMIC [P50 CA114747]; Doris Duke foundation FX This research was financially supported by an NCI ICMIC P50 CA114747 Grant (SSG) and the Doris Duke foundation (SSG). We are also grateful to GE Medical Systems and Dr. David Dick for their technical support. NR 19 TC 44 Z9 47 U1 1 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2012 VL 14 IS 1 BP 88 EP 95 DI 10.1007/s11307-011-0477-3 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 909SE UT WOS:000301583900012 PM 21400112 ER PT J AU Chen, K Sun, XL Niu, G Ma, Y Yap, LP Hui, XL Wu, KC Fan, DM Conti, PS Chen, XY AF Chen, Kai Sun, Xilin Niu, Gang Ma, Ying Yap, Li-Peng Hui, Xiaoli Wu, Kaichun Fan, Daiming Conti, Peter S. Chen, Xiaoyuan TI Evaluation of Cu-64 Labeled GX1: A Phage Display Peptide Probe for PET Imaging of Tumor Vasculature SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Cu-64-Labeled GX1 peptide; PET imaging; Tumor vasculature; Phage display ID POSITRON-EMISSION-TOMOGRAPHY; INTEGRIN ALPHA(V)BETA(3) EXPRESSION; TARGET-SPECIFIC DELIVERY; CYCLIC RGD PEPTIDE; COPPER-64 RADIOPHARMACEUTICALS; GASTRIC-CANCER; ANGIOGENIC SWITCH; MICROPET; TUMORIGENESIS; RADIONUCLIDES AB Purpose: Molecular imaging using positron emission tomography (PET) radiotracers targeted to tumor vasculature offers a noninvasive method for early detection of tumor angiogenesis and efficient monitoring of response to anti-tumor vasculature therapy. The previous in vitro results demonstrated that the GX1 peptide, identified by phage display technology, is a tumor vasculature endotheliumspecific ligand. In this study, we evaluated a Cu-64-labeled GX1 peptide as a potential radiotracer for microPET imaging of tumor vasculature in a U87MG tumor xenografted mouse model. Methods: Macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N, N', N '', N'''-tetraacetic acid (DOTA)-conjugated GX1 peptide was synthesized and radiolabeled with Cu-64 (t(1/2) = 12.7 h) in ammonium acetate buffer. The Cu-64-labeled GX1 peptide was then subjected to in vitro tumor cell uptake study, small animal PET and direct tissue sampling biodistribution studies in a U87MG tumor xenografted mouse model. Results: The in vitro experiment demonstrated that Cu-64-DOTA-GX1 is stable in PBS with more than 91% of Cu-64-DOTA-GX1 peptide remaining intact after 24 h of incubation. Cellular uptake and retention studies revealed Cu-64-DOTA-GX1 binds to U87MG glioma cells and has good tumor cell retention. For small animal PET imaging studies, the U87MG tumors were all clearly visible with high contrast to contralateral background at all measured time points after injection of Cu-64-DOTA-GX1 while high accumulation in liver and kidneys were also observed at early time points. The U87MG tumor uptake was determined to be the highest (7.97 +/- 0.75% ID/g) at 24 h pi. The blocking experiment was achieved by co-injection of Cu-64-DOTA-GX1 with non-radiolabeled GX1 peptide (20 mg/kg) at 24 h pi, suggesting Cu-64-DOTA-GX1 is a target-specific tracer. Furthermore, the biodistribution results were consistent with the quantification of microPET imaging, demonstrating the highest ratio (16.09 +/- 1.21) of tumor/muscle uptake of Cu-64-DOTA-GX1 at 24 h pi for non-blocking group and significant decreased ratio (6.57 +/- 0.58) for blocking group. Finally, metabolic studies suggested that (64)CuDOTA-GX1 is stable inmouse blood and urine in vivo at early time point while the metal transchelation may also occur in mouse liver and kidneys. Conclusion: Our studies demonstrate that Cu-64-DOTA-GX1 is a promising radiotracer for imaging tumor vasculature. C1 [Chen, Kai; Yap, Li-Peng; Conti, Peter S.] Univ So Calif, Keck Sch Med, Dept Radiol, Mol Imaging Ctr, Los Angeles, CA 90033 USA. [Chen, Kai; Sun, Xilin; Niu, Gang; Ma, Ying; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Hui, Xiaoli; Wu, Kaichun; Fan, Daiming] Fourth Mil Med Univ, Xijing Hosp, Inst Digest Dis, Xian 710032, Shanxi, Peoples R China. [Hui, Xiaoli; Wu, Kaichun; Fan, Daiming] Fourth Mil Med Univ, Xijing Hosp, State Key Lab Canc Biol, Xian 710032, Shanxi, Peoples R China. RP Chen, K (reprint author), Univ So Calif, Keck Sch Med, Dept Radiol, Mol Imaging Ctr, 2250 Alcazar St,CSC 103, Los Angeles, CA 90033 USA. EM chenkai@usc.edu; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health; USC Department of Radiology; Provost's Biomedical Imaging Science Initiative FX This study was supported in part by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health, the USC Department of Radiology, and the Provost's Biomedical Imaging Science Initiative. NR 39 TC 18 Z9 19 U1 0 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2012 VL 14 IS 1 BP 96 EP 105 DI 10.1007/s11307-011-0479-1 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 909SE UT WOS:000301583900013 PM 21360213 ER PT J AU Weiss, ID Jacobson, O Kiesewetter, DO Jacobus, JP Szajek, LP Chen, XY Farber, JM AF Weiss, Ido D. Jacobson, Orit Kiesewetter, Dale O. Jacobus, John P. Szajek, Lawrence P. Chen, Xiaoyuan Farber, Joshua M. TI Positron Emission Tomography Imaging of Tumors Expressing the Human Chemokine Receptor CXCR4 in Mice with the Use of Cu-64-AMD3100 SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE CXCR4; AMD3100; PET; Tumor; Imaging ID CANCER METASTASIS; FACTOR-I; CELLS; MICROENVIRONMENT; REPLICATION; XENOGRAFTS; INHIBITION; ANTAGONIST; SYSTEM; GROWTH AB Purpose: Expression of CXCR4 in cancers has been correlated with poor prognosis and increased metastasis. Quantifying CXCR4 expression non-invasively might aid in prognostication and monitoring therapy. We evaluated a radiolabeled antagonist of CXCR4, Cu-64-AMD3100, as a positron-emitting imaging agent. Procedures: CXCR4-transfected or non-transfected cell lines were injected into mice to form xenografts. Accumulation of Cu-64-AMD3100 in tumors was analyzed by small-animal PET and biodistribution assays. Results: Cu-64-AMD3100 accumulated in CXCR4-expressing, but not CXCR4-negative, tumors. For CXCR4-expressing tumors, tumor-to-blood and tumor-to-muscle ratios were 23-41 and 50-59, respectively, depending on tumor type. Excess of unlabeled Cu-AMD3100 or AMD3100 significantly reduced Cu-64-AMD3100 accumulation in CXCR4-expressing tumors. Human-absorbed dose calculations predicted a dose limit of 444 MBq. Conclusions: CXCR4 can be imaged in tumors using Cu-64-AMD3100. Dosimetry studies suggest that imaging in humans is feasible. We conclude that Cu-64-AMD3100 should be investigated as a potential agent for imaging and quantifying CXCR4 in tumors. C1 [Weiss, Ido D.; Farber, Joshua M.] NIAID, Lab Mol Immunol, Bethesda, MD 20892 USA. [Jacobson, Orit; Kiesewetter, Dale O.; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. [Jacobus, John P.] NIH, Radiat Safety Operat Branch, Bethesda, MD 20892 USA. [Szajek, Lawrence P.] NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Farber, JM (reprint author), NIAID, Lab Mol Immunol, 10 Ctr Dr,Room 11N111, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institute of Biomedical Imaging and Bioengineering FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Biomedical Imaging and Bioengineering. We wish to thank Dr. David McDermott from NIAID, NIH, for providing reagents and advice. NR 38 TC 16 Z9 17 U1 2 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2012 VL 14 IS 1 BP 106 EP 114 DI 10.1007/s11307-010-0466-y PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 909SE UT WOS:000301583900014 PM 21347799 ER PT J AU Farkas, S Nagy, K Palkovits, M Kovacs, GG Jia, ZS Donohue, S Pike, V Halldin, C Mathe, D Harkany, T Gulyas, B Csiba, L AF Farkas, Szabolcs Nagy, Katalin Palkovits, Miklos Kovacs, Gabor G. Jia, Zhisheng Donohue, Sean Pike, Vic Halldin, Christer Mathe, Domokos Harkany, Tibor Gulyas, Balazs Csiba, Laszlo TI [I-125]SD-7015 reveals fine modalities of CB1 cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer's disease SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE Alzheimer's disease; Braak classification; Endocannabinoid system; Molecular imaging; Biomarker; Human brain autoradiography; CB1R; [I-125]SD7015 ID POSITRON-EMISSION-TOMOGRAPHY; MESSENGER-RNA EXPRESSION; HUMAN BRAIN; BASAL GANGLIA; ENDOGENOUS CANNABINOIDS; PARKINSONS-DISEASE; PET RADIOLIGAND; AGED RATS; BINDING; ENDOCANNABINOIDS AB The cannabinoid type-1 receptor (CB1R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB(1)Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB, R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB1R radioligand to investigate regional variations in CB1R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer's disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB(1)Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB1R autoradiography with [I-125]SD-7015 as radioligand. Regional concentration of [I-125]SD-7015, corresponding to, and thereby representing, regional CB1R densities, were expressed in fM/g_tissue. The results show that CB1B density inversely correlates with Braak tau pathology with the following tendency: controls 100 m. No clustering was detected among clinically apparent infections. Conclusions/Significance: Seroprevalence of previously circulating DENV serotypes can be a predictor of transmission risk for a different invading serotype and, thus, identify targets for strategically placed surveillance and intervention. Seroprevalence of a specific serotype is also important, but does not preclude other contributing factors, such as mosquito density, in determining where transmission of that virus will occur. Regardless of the epidemiological context or virus serotype, human movement appears to be an important factor in defining the spatial dimensions of DENV transmission and, thus, should be considered in the design and evaluation of surveillance and intervention strategies. C1 [Liebman, Kelly A.; Stoddard, Steven T.; Morrison, Amy C.; Minnick, Sharon; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Stoddard, Steven T.; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Morrison, Amy C.; Rocha, Claudio; Russell, Kevin L.; Olson, James G.; Blair, Patrick J.; Kochel, Tadeusz] USN, Med Res Ctr Detachment, Washington, DC USA. [Sihuincha, Moises] Hosp Apoyo Iquitos, Region Loreto, Peru. [Watts, Douglas M.] Univ Texas El Paso, El Paso, TX 79968 USA. RP Liebman, KA (reprint author), Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. EM kaliebman@ucdavis.edu RI Valle, Ruben/A-7512-2013 FU National Institute of Allergy and Infectious Disease; Military Infectious Disease Research Program [S0025_02_LI]; Loreto Regional Health Department FX This research was supported by a grant from the National Institute of Allergy and Infectious Disease and the Military Infectious Disease Research Program grant number S0025_02_LI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank the residents of Iquitos, Peru, for allowing us to undertake this study in and around their homes. We greatly appreciate support of the Loreto Regional Health Department, including Drs. Carlos Calampa, Jorge Reyes, Ruben Naupay, Carlos Vidal, Hugo Rodriguez, and Martin Casapia, who all facilitated our work in Iquitos. Karla Block supervised the phlebotomy team and provided logistical support for the project. We thank Renan Ricarte Ruiz Chavez for processing blood samples and keeping the phlebotomy team happy and Leslye Angulo for tracking down student participants. Serological Surveys were carried out by Joel Cahuachi Tuesta, Jacqueline Cardenas Perez, Junnelhy Mireya Flores Lopez, Juan Flores Michi, Marcelina Flores Michi, Elga Lopez Guerrero, Xiomara Mafaldo Garcia, Nora Marin Moreno, Maria Juana Martinez Salas, Orfelinda Morales Tejada, Geraldine Ocmin Galan, Zenith Maria Pezo Villacorta, Zoila Martha Reategui Chota, Luis Riveros Lopez, Rubiela Nerza Rubio Briceno, Rosana Magaly Soltero Jimenez, Zenith Tamani Guerrero, Moises Tanchiva Tuanama, Sarita Del Pilar Tuesta Davila. Angelica Espinoza, Roxana Caceda, and Roger Castio for carrying out the serological testing, Carolina Guevara for supervision of the NMRCD virology laboratory, and Juan Perez for data management. Dr. Truman Sharp, Ms. Lucy Rubio, and Ms. Roxana Lescano of the U.S. Naval Medical Research Center in Lima, Peru, were instrumental in facilitating these studies. We also thank Brett Forshey, William K. Reisen, and David Smith for their comments on earlier drafts. NR 51 TC 27 Z9 27 U1 1 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2012 VL 6 IS 2 AR e1472 DI 10.1371/journal.pntd.0001472 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 901FX UT WOS:000300949200005 PM 22363822 ER PT J AU Steel, C Varma, S Nutman, TB AF Steel, Cathy Varma, Sudhir Nutman, Thomas B. TI Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HUMAN LYMPHATIC FILARIASIS; HUMAN DENDRITIC CELLS; CD4(+) T-CELLS; WUCHERERIA-BANCROFTI; CLINICAL MANIFESTATIONS; NONENDEMIC POPULATIONS; IMMUNE RESPONSIVENESS; ONCHOCERCA-VOLVULUS; CYTOKINE RESPONSES; PARASITE ANTIGENS AB Background: Human filarial infection is characterized by downregulated parasite-antigen specific T cell responses but distinct differences exist between patients with longstanding infection (endemics) and those who acquired infection through temporary residency or visits to filarial-endemic regions (expatriates). Methods and Findings: To characterize mechanisms underlying differences in T cells, analysis of global gene expression using human spotted microarrays was conducted on CD4(+) and CD8(+) T cells from microfilaremic Loa loa-infected endemic and expatriate patients. Assessment of unstimulated cells showed overexpression of genes linked to inflammation and caspase-associated cell death, particularly in endemics, and enrichment of the Th1/Th2 canonical pathway in endemic CD4+ cells. However, pathways within CD8(+) unstimulated cells were most significantly enriched in both patient groups. Antigen (Ag)-driven gene expression was assessed to microfilarial Ag (MfAg) and to the nonparasite Ag streptolysin O (SLO). For MfAg-driven cells, the number of genes differing significantly from unstimulated cells was greater in endemics compared to expatriates (p < 0.0001). Functional analysis showed a differential increase in genes associated with NFkB (both groups) and caspase activation (endemics). While the expatriate response to MfAg was primarily a CD4(+) pro-inflammatory one, the endemic response included CD4(+) and CD8(+) cells and was linked to insulin signaling, histone complexes, and ubiquitination. Unlike the enrichment of canonical pathways in CD8(+) unstimulated cells, both groups showed pathway enrichment in CD4(+) cells to MfAg. Contrasting with the divergent responses to MfAg seen between endemics and expatriates, the CD4(+) response to SLO was similar; however, CD8(+) cells differed strongly in the nature and numbers (156 [endemics] vs 36 [expatriates]) of genes with differential expression. Conclusions: These data suggest several important pathways are responsible for the different outcomes seen among filarial-infected patients with varying levels of chronicity and imply an important role for CD8(+) cells in some of the global changes seen with lifelong exposure. C1 [Steel, Cathy; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir] NIAID, Bioinformat & Computat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Steel, C (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM csteel@niaid.nih.gov RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU National Institutes of Health/National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 3 Z9 3 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2012 VL 6 IS 2 AR e1527 DI 10.1371/journal.pntd.0001527 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 901FX UT WOS:000300949200039 PM 22389737 ER PT J AU Pilotto, A Sancarlo, D Aucella, F Fontana, A Addante, F Copetti, M Panza, F Strippoli, GFM Ferrucci, L AF Pilotto, Alberto Sancarlo, Daniele Aucella, Filippo Fontana, Andrea Addante, Filomena Copetti, Massimiliano Panza, Francesco Strippoli, Giovanni F. M. Ferrucci, Luigi TI Addition of the Multidimensional Prognostic Index to the Estimated Glomerular Filtration Rate Improves Prediction of Long-Term All-Cause Mortality in Older Patients with Chronic Kidney Disease SO REJUVENATION RESEARCH LA English DT Article ID COMPREHENSIVE GERIATRIC ASSESSMENT; ACUTE-CARE HOSPITALS; ELDERLY-PATIENTS; RENAL-DISEASE; SURVIVAL; PREVALENCE; VALIDATION; EQUATIONS; DIALYSIS; PEOPLE AB Current prognostic scores of chronic kidney disease (CKD) are not accurate in older patients. The aim of this study was to evaluate the prognostic accuracy of the Multidimensional Prognostic Index (MPI) in comparison with and in addition to the estimated glomerular filtration rate (eGFR) to predict long-term all-cause mortality in hospitalized older patients with CKD. In a prospective cohort study with a mean follow-up of 2 years, we calculated eGFR according to the Modification of Diet in Renal Disease study and collected information on functional, cognitive, nutritional, co-morbidities, drug use, and co-habitation status to calculate the MPI on 1,198 patients aged >= 65 years with a diagnosis of CKD from an hospital-based sample. The all-cause mortality incidence rate for 100 person-years was 18.3 (men 22.7 vs. women 15.3, p < 0.0001). Adding the MPI to the eGFR model significantly improved all-cause mortality prediction accuracy: The C-index increased from 0.579 to 0.648 (p < 0.0001), with correct reclassification of 25.9% of patients (Net Reclassification Improvement [NRI], 0.259, p < 0.0001; Integrated Discrimination Improvement [IDI], 3.8%, p < 0.0001). The correct reclassification was higher in patients who did not die (259/741 patients, reclassification rate = 34.9%) than in patients who died (62/457 patients, reclassification rate = 13.6%). Conversely, adding the eGFR to the MPI model seems to improve prediction accuracy less consistently. In fact, the C-index increased, but not significantly (from 0.639 to 0.648, p = 0.444), with correct reclassification of 5.8% of patients (NRI, 0.058, p = 0.012; IDI, 0.009, p = 0.001), suggesting a small, although significant improvement. Adding MPI information to the eGFR markedly improved the prediction of 2-year all-cause mortality in older patients with CKD. A multidimensional evaluation for all-cause mortality risk prediction should be considered in older patients with CKD. C1 [Pilotto, Alberto] S Antonio Hosp, Geriatr Unit, Azienda ULSS Padova 16, I-35127 Padua, Italy. [Pilotto, Alberto; Sancarlo, Daniele; Addante, Filomena; Panza, Francesco] IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Gerontol Geriatr Res Lab, Foggia, Italy. [Aucella, Filippo] IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Nephrol Unit, Foggia, Italy. [Aucella, Filippo] IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Dialysis Ctr, Foggia, Italy. [Strippoli, Giovanni F. M.] Consorzio Mario Negri Sud, Dept Clin Pharmacol & Epidemiol, Chieti, Italy. Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Strippoli, Giovanni F. M.] Diaverum Med Sci Off, Lund, Sweden. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Pilotto, A (reprint author), S Antonio Hosp, Geriatr Unit, Azienda ULSS Padova 16, Via Facciolati 71, I-35127 Padua, Italy. EM alberto.pilotto@sanita.padova.it RI Fontana, Andrea/J-8584-2016; Copetti, Massimiliano/K-3186-2016; Sancarlo, Daniele/C-1056-2017; OI Fontana, Andrea/0000-0002-6660-5315; Copetti, Massimiliano/0000-0002-7960-5947; Sancarlo, Daniele/0000-0001-9541-6364; Strippoli, Giovanni/0000-0002-6936-0616; Panza, Francesco/0000-0002-7220-0656 FU Ministry of Health, Italy; IRCCS; National Institute of Aging, Baltimore, Maryland FX All authors had full access to all data and had final responsibility for the decision to submit for publication. Study design, data analysis, and writing: A. Pilotto, F. Aucella, G. Strippoli, and L. Ferrucci; data collection, analysis, and writing: D. Sancarlo, F. Addante, M. Copetti, A. Fontana, and F. Panza. This work was supported by Ministry of Health, Italy, IRCCS Research Program 2009-2011, and by the Intramural Research Program of the National Institute of Aging, Baltimore, Maryland. NR 33 TC 16 Z9 16 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 J9 REJUV RES JI Rejuv. Res. PD FEB PY 2012 VL 15 IS 1 BP 82 EP 88 DI 10.1089/rej.2011.1210 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 897FA UT WOS:000300630200009 PM 22352434 ER PT J AU Boggs, DL Kelly, DL McMahon, RP Gold, JM Gorelick, DA Linthicum, J Conley, RR Liu, F Waltz, J Huestis, MA Buchanan, RW AF Boggs, Douglas L. Kelly, Deanna L. McMahon, Robert P. Gold, James M. Gorelick, David A. Linthicum, Jared Conley, Robert R. Liu, Fang Waltz, James Huestis, Marilyn A. Buchanan, Robert W. TI Rimonabant for neurocognition in schizophrenia: A 16-week double blind randomized placebo controlled trial SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Rimonabant; Cognition; Schizophrenia; CB1 receptor antagonist; Probabilistic learning ID CB1 ANTAGONIST RIMONABANT; NEUROPSYCHOLOGICAL STATUS; REPEATABLE BATTERY; RECEPTOR ANTAGONIST; HEALTHY-VOLUNTEERS; SPATIAL MEMORY; SCREENING-TEST; ACTIVATION; EXPRESSION; VALIDITY AB Objective: To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia. Methods: Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study. Results: In comparison to rimonabant (20 mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects. Conclusions: Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback. (C) 2011 Elsevier B.V. All rights reserved. C1 [Kelly, Deanna L.; McMahon, Robert P.; Gold, James M.; Linthicum, Jared; Liu, Fang; Waltz, James; Buchanan, Robert W.] Univ Maryland, Maryland Psychiat Res Ctr, Sch Med, Catonsville, MD 21228 USA. [Boggs, Douglas L.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Gorelick, David A.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Conley, Robert R.] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Buchanan, RW (reprint author), Univ Maryland, Maryland Psychiat Res Ctr, Sch Med, Box 21247, Catonsville, MD 21228 USA. EM rwbuchan@mprc.umaryland.edu RI McMahon, Robert/C-5462-2009 FU National Institutes of Mental Health (NIMH) [R34 MH 077839, P30 068580]; National Institute on Drug Abuse (NIDA); NIDA Residential Research Support Services [N01 DA-5-9909] FX This study was supported by the National Institutes of Mental Health (NIMH) grants R34 MH 077839 (PI: Robert W. Buchanan) and P30 068580 (P.I.: Robert W. Buchanan), the Intramural Research Program, National Institute on Drug Abuse (NIDA), and the National Institute on Drug Abuse (NIDA) and NIDA Residential Research Support Services Contract N01 DA-5-9909 (P.I.: Deanna Kelly). NR 26 TC 17 Z9 18 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB PY 2012 VL 134 IS 2-3 BP 207 EP 210 DI 10.1016/j.schres.2011.11.009 PG 4 WC Psychiatry SC Psychiatry GA 900FE UT WOS:000300871200015 PM 22137462 ER PT J AU Sredni, B Longo, DL AF Sredni, Benjamin Longo, Dan L. TI Cancer immunotherapy: Are we there yet? SO SEMINARS IN CANCER BIOLOGY LA English DT Editorial Material C1 [Sredni, Benjamin; Longo, Dan L.] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie Inst AIDS & Immunol Res, IL-52900 Ramat Gan, Israel. [Longo, Dan L.] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Sredni, B (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie Inst AIDS & Immunol Res, IL-52900 Ramat Gan, Israel. EM srednib@gmail.com; longod@grc.nia.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2012 VL 22 IS 1 BP 1 EP 2 DI 10.1016/j.semcancer.2012.01.001 PG 2 WC Oncology SC Oncology GA 911CN UT WOS:000301695000001 PM 22240249 ER PT J AU Biragyn, A Longo, DL AF Biragyn, Arya Longo, Dan L. TI Neoplastic "Black Ops": Cancer's subversive tactics in overcoming host defenses SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE Cancer escape; Regulatory T cells; Tregs; Tumor-evoked regulatory B cells tBregs; Cancer immunotherapy ID REGULATORY T-CELLS; MYELOID SUPPRESSOR-CELLS; GROWTH-FACTOR-BETA; IMMUNOLOGICAL SELF-TOLERANCE; GALACTOSIDE-BINDING PROTEIN; LARGE ESTABLISHED MELANOMA; MAMMARY-CARCINOMA 4T1; TUMOR-BEARING MICE; B-CELLS; BREAST-CANCER AB Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross-talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack. Published by Elsevier Ltd. C1 [Biragyn, Arya; Longo, Dan L.] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Biragyn, A (reprint author), NIA, Lab Mol Biol & Immunol, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov FU National Institute on Aging, NIH FX We are grateful to Ana Lustig (NIA/NIH) for helpful comments and suggestions. This research was supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 171 TC 11 Z9 11 U1 1 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2012 VL 22 IS 1 BP 50 EP 59 DI 10.1016/j.semcancer.2012.01.005 PG 10 WC Oncology SC Oncology GA 911CN UT WOS:000301695000007 PM 22257681 ER PT J AU Singh, R Singh, S Briles, DE Taub, DD Hollingshead, SK Lillard, JW AF Singh, Rajesh Singh, Shailesh Briles, David E. Taub, Dennis D. Hollingshead, Susan K. Lillard, James W., Jr. TI CCL5-independent helper T lymphocyte responses to immuno-dominant pneumococcal surface protein A epitopes SO VACCINE LA English DT Article DE T helper cytokine; Streptococcus pneumoniae; HTL epitope ID STREPTOCOCCUS-PNEUMONIAE; B-CELLS; IMMUNE-RESPONSE; NASOPHARYNGEAL CARRIAGE; DISEASE PROGRESSION; CHEMOKINE RECEPTORS; MICE; INFECTION; RANTES; EXPRESSION AB Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Several antigens, in addition to the polysaccharide capsule, have been implicated in both the virulence and protective immunity against Streptococcus pneumoniae; one of the best-studied S. pneumoniae antigens is pneumococcal surface protein A (PspA). Recently, it was shown that genetic polymorphisms could diminish CCL5 expression, which results in increased susceptibility to and progression of infectious diseases. We previously showed CCL5 blockade reduced PspA-specific humoral and cellular pneumococcal immunity, during S. pneumoniae strain EF3030-induced carriage, by diminishing IFN-gamma and enhancing IL-10 secretion by effector T cells. We also identified immuno-dominant helper T lymphocyte (HTL) epitopes in PspA peptide 19-23 (PspA(199-246)), which caused comparatively more cytokine secretion and proliferation responses by splenic and cervical lymph node (CLN) CD4(+) T cells from mice previously challenged with S. pneumoniae strain EF3030. In this study, we sought to determine if PspA(199-246)-specific CDA(+) T cells responses were resistant to the effect of CCL5 deficiency. In short, T cell responses against these NIL epitopes were resistant to CCL5 inhibition, than compared to cells from control or naive mice, and unaffected by reduced co-stimulatory molecule expression caused by CCL5 blockade. CCL5 deficiency also corresponded with a higher number of IL-10(+) CD11b(+) CD11c(Lo) and CD11b(+) CD11c(Hi) cells and lower IFN-gamma expression by similar cells, than compared to controls. These data confirm CCL5 is an essential factor for optimal pneumococcal adaptive immunity and show CD4(+) T cell responses to PspA(199-246) are largely resistant to CCL5 deficiency. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Singh, Rajesh; Singh, Shailesh; Lillard, James W., Jr.] Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. [Briles, David E.; Hollingshead, Susan K.] Univ Alabama, Med Sch Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Taub, Dennis D.] NIA, Baltimore, MD 21224 USA. RP Lillard, JW (reprint author), Morehouse Sch Med, Dept Microbiol Biochem & Immunol, 720 Westview Dr SE, Atlanta, GA 30310 USA. EM jlillard@msm.edu FU National Institute of Health [AI021548, AI057808, RR03034]; Research Centers in Minority Institutions Program (RCMI); Flow Cytometry and Cell Sorting Core at Morehouse School of Medicine FX The content of this manuscript benefited from many fruitful conversations with members of the Morehouse School of Medicine and the University of Alabama at Birmingham. This study was supported by National Institute of Health grants (AI021548, AI057808, and RR03034) and also supported by the Research Centers in Minority Institutions Program (RCMI) funded Flow Cytometry and Cell Sorting Core at Morehouse School of Medicine. NR 48 TC 1 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 1 PY 2012 VL 30 IS 6 BP 1181 EP 1190 DI 10.1016/j.vaccine.2011.12.020 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 901JO UT WOS:000300963400028 PM 22178100 ER PT J AU Hughes, SO Cross, MB Hennessy, E Tovar, A Economos, CD Power, TG AF Hughes, Sheryl O. Cross, Matthew B. Hennessy, Erin Tovar, Alison Economos, Christina D. Power, Thomas G. TI Caregiver's Feeding Styles Questionnaire. Establishing cutoff points SO APPETITE LA English DT Article DE Parent feeding; Feeding styles; Minorities; Cutoff points ID WEIGHT STATUS; CES-D; CONSUMPTION; PRESCHOOL; FAMILIES; CHILDREN; OBESITY AB Researchers use the Caregiver's Feeding Styles Questionnaire (CFSQ) to categorize parent feeding into authoritative, authoritarian, indulgent, and uninvolved styles. The CFSQ assesses self-reported feeding and classifies parents using median splits which are used in a substantial body of parenting literature and allow for direct comparison across studies on dimensions of demandingness and responsiveness. No national norms currently exist for the CFSQ. This paper establishes and recommends cutoff points most relevant for low-income, minority US samples that researchers and clinicians can use to assign parents to feeding styles. Median scores for five studies are examined and the average across these studies reported. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Hughes, Sheryl O.; Cross, Matthew B.] Baylor Coll Med, Dept Pediat, USDA ARS Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Hennessy, Erin] NCI, Bethesda, MD 20892 USA. [Tovar, Alison; Economos, Christina D.] Tufts Univ, John Hancock Res Ctr Phys Act Nutr & Obes Prevent, Gerald J & Dorothy R Friedman Sch Nutr Sci & Poli, Boston, MA 02111 USA. [Power, Thomas G.] Washington State Univ, Dept Human Dev, Pullman, WA 99164 USA. RP Hughes, SO (reprint author), Baylor Coll Med, Dept Pediat, USDA ARS Childrens Nutr Res Ctr, 1100 Bates St, Houston, TX 77030 USA. EM shughes@bcm.edu OI Cross, Matthew B./0000-0002-9495-0976 FU United States Department of Agriculture [2006-55215-16695]; NIH [R01HD057841-04, 3R01HD057841-03S]; USDA/ARS [58-6250-0-008] FX This research was supported by funds from the United States Department of Agriculture, Grant No. 2006-55215-16695, NIH R01HD057841-04, and postdoctoral research funds provided by NIH supplement 3R01HD057841-03S. This work is a publication of the United States Department of Agriculture (USDA/ARS) Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, and has been funded in part with federal funds from the USDA/ARS under Cooperative Agreement No. 58-6250-0-008. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement from the US government. NR 21 TC 15 Z9 15 U1 5 U2 15 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 J9 APPETITE JI Appetite PD FEB PY 2012 VL 58 IS 1 BP 393 EP 395 DI 10.1016/j.appet.2011.11.011 PG 3 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA 900BT UT WOS:000300862300054 PM 22119478 ER PT J AU Buchold, GM AF Buchold, Gregory M. TI Meiotic Genetics Moves Forward with SPATA22 (repro42) SO BIOLOGY OF REPRODUCTION LA English DT Editorial Material ID INDUCED MUTANT MOUSE; STRAND-BREAK FORMATION; SYNAPTONEMAL COMPLEX; TARGETED DISRUPTION; CHROMOSOME SYNAPSIS; MALE MEIOSIS; DEFECTIVE SPERMATOGENESIS; TRANSCRIPTION FACTOR; MALE-FERTILITY; DNA-REPAIR C1 NIEHS, Gamete Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Buchold, GM (reprint author), NIEHS, Gamete Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. EM greg.buchold@nih.gov NR 50 TC 1 Z9 1 U1 2 U2 11 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD FEB PY 2012 VL 86 IS 2 AR 42 DI 10.1095/biolreprod.111.097436 PG 4 WC Reproductive Biology SC Reproductive Biology GA 906JN UT WOS:000301341500001 PM 22088917 ER PT J AU Buch, ER Shanechi, AM Fourkas, AD Weber, C Birbaumer, N Cohen, LG AF Buch, Ethan R. Shanechi, Amirali Modir Fourkas, Alissa D. Weber, Cornelia Birbaumer, Niels Cohen, Leonardo G. TI Parietofrontal integrity determines neural modulation associated with grasping imagery after stroke SO BRAIN LA English DT Article DE motor learning; skill; stroke; rehabilitation; brain-computer interface; imagery ID BRAIN-COMPUTER-INTERFACE; INDUCED MOVEMENT THERAPY; PRIMARY MOTOR CORTEX; VENTRAL PREMOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; SUBCORTICAL STROKE; FUNCTIONAL REORGANIZATION; NEUROLOGICAL PRINCIPLES; NETWORK REORGANIZATION; STRUCTURAL PLASTICITY AB Chronic stroke patients with heterogeneous lesions, but no direct damage to the primary sensorimotor cortex, are capable of longitudinally acquiring the ability to modulate sensorimotor rhythms using grasping imagery of the affected hand. Volitional modulation of neural activity can be used to drive grasping functions of the paralyzed hand through a brain-computer interface. The neural substrates underlying this skill are not known. Here, we investigated the impact of individual patient's lesion pathology on functional and structural network integrity related to this volitional skill. Magnetoencephalography data acquired throughout training was used to derive functional networks. Structural network models and local estimates of extralesional white matter microstructure were constructed using T-1-weighted and diffusion-weighted magnetic resonance imaging data. We employed a graph theoretical approach to characterize emergent properties of distributed interactions between nodal brain regions of these networks. We report that interindividual variability in patients' lesions led to differential impairment of functional and structural network characteristics related to successful post-training sensorimotor rhythm modulation skill. Patients displaying greater magnetoencephalography global cost-efficiency, a measure of information integration within the distributed functional network, achieved greater levels of skill. Analysis of lesion damage to structural network connectivity revealed that the impact on nodal betweenness centrality of the ipsilesional primary motor cortex, a measure that characterizes the importance of a brain region for integrating visuomotor information between frontal and parietal cortical regions and related thalamic nuclei, correlated with skill. Edge betweenness centrality, an analogous measure, which assesses the role of specific white matter fibre pathways in network integration, showed a similar relationship between skill and a portion of the ipsilesional superior longitudinal fascicle connecting premotor and posterior parietal visuomotor regions known to be crucially involved in normal grasping behaviour. Finally, estimated white matter microstructure integrity in regions of the contralesional superior longitudinal fascicle adjacent to primary sensorimotor and posterior parietal cortex, as well as grey matter volume co-localized to these specific regions, positively correlated with sensorimotor rhythm modulation leading to successful brain-computer interface control. Thus, volitional modulation of ipsilesional neural activity leading to control of paralyzed hand grasping function through a brain-computer interface after longitudinal training relies on structural and functional connectivity in both ipsilesional and contralesional parietofrontal pathways involved in visuomotor information processing. Extant integrity of this structural network may serve as a future predictor of response to longitudinal therapeutic interventions geared towards training sensorimotor rhythms in the lesioned brain, secondarily improving grasping function through brain-computer interface applications. C1 [Buch, Ethan R.; Shanechi, Amirali Modir; Fourkas, Alissa D.; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Buch, Ethan R.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Shanechi, Amirali Modir] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Weber, Cornelia; Birbaumer, Niels] Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. [Birbaumer, Niels] Osped San Camillo, IRCCS, Venice, Italy. RP Buch, ER (reprint author), Bldg 10,Room 7D54,MSC 1428,10 Ctr Dr, Bethesda, MD 20892 USA. EM buche@ninds.nih.gov; cohenl@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX Intramural Research Program National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 123 TC 48 Z9 50 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2012 VL 135 BP 596 EP 614 DI 10.1093/brain/awr331 PN 2 PG 19 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 895GZ UT WOS:000300485600031 PM 22232595 ER PT J AU Keyes, KM Eaton, NR Krueger, RF McLaughlin, KA Wall, MM Grant, BF Hasin, DS AF Keyes, Katherine M. Eaton, Nicholas R. Krueger, Robert F. McLaughlin, Katie A. Wall, Melanie M. Grant, Bridget F. Hasin, Deborah S. TI Childhood maltreatment and the structure of common psychiatric disorders SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID ALCOHOL-USE-DISORDER; NATIONAL COMORBIDITY SURVEY; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE DISORDERS; MENTAL-HEALTH SURVEYS; SEXUAL-ABUSE; PHYSICAL ABUSE; DRUG-USE AB Background Previous research suggests that various types of childhood maltreatment frequently co-occur and confer risk for multiple psychiatric diagnoses. This non-specific pattern of risk may mean that childhood maltreatment increases vulnerability to numerous specific psychiatric disorders through diverse, specific mechanisms or that childhood maltreatment engenders a generalised liability to dimensions of psychopathology. Although these competing explanations have different implications for intervention, they have never been evaluated empirically. Aims We used a latent variable approach to estimate the associations of childhood maltreatment with underlying dimensions of internalising and externalising psychopathology and with specific disorders after accounting for the latent dimensions. We also examined gender differences in these associations. Method Data were drawn from a nationally representative survey of 34 653 US adults. Lifetime DSM-IV psychiatric disorders were assessed using the AUDADIS-IV. Physical, sexual and emotional abuse and neglect were assessed using validated measures. Analyses controlled for other childhood adversities and sociodemographics. Results The effects were fully mediated through the latent liability dimensions, with an impact on underlying liability levels to internalising and externalising psychopathology rather than specific psychiatric disorders. Important gender differences emerged with physical abuse associated only with externalising liability in men, and only with internalising liability in women. Neglect was not significantly associated with latent liability levels. Conclusions The association between childhood maltreatment and common psychiatric disorders operates through latent liabilities to experience internalising and externalising psychopathology, indicating that the prevention of maltreatment may have a wide range of benefits in reducing the prevalence of many common mental disorders. Different forms of abuse have gender-specific consequences for the expression of internalising and externalising psychopathology, suggesting gender-specific aetiological pathways between maltreatment and psychopathology. C1 [Keyes, Katherine M.; Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, Coll Phys & Surg, New York, NY 10032 USA. [Keyes, Katherine M.; Hasin, Deborah S.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Eaton, Nicholas R.; Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [McLaughlin, Katie A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Gen Pediat, Boston, MA USA. [Wall, Melanie M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Keyes, KM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, Coll Phys & Surg, 1051 Riverside Dr 123, New York, NY 10032 USA. EM kmk2104@columbia.edu OI McLaughlin, Katie/0000-0002-1362-2410 FU National Institute on Alcoholism and Alcohol Abuse [K05 AA014223, U01 AA018111]; National Institute of Drug Abuse [F31-DA026689]; Robert Wood Johnson Foundation [053572]; National Institute of Mental Health [K01 MH092526]; New York State Psychiatric Institute FX This research was supported in part by grants from the National Institute on Alcoholism and Alcohol Abuse (K05 AA014223 to D.S.H; U01 AA018111 to D.S.H), a fellowship from the National Institute of Drug Abuse (F31-DA026689 to K.M.K), the Robert Wood Johnson Foundation (Grant Number 053572 to K.A.M.), the National Institute of Mental Health (K01 MH092526 to K.A.M.) and support from New York State Psychiatric Institute. NR 75 TC 77 Z9 77 U1 6 U2 142 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD FEB PY 2012 VL 200 IS 2 BP 107 EP 115 DI 10.1192/bjp.bp.111.093062 PG 9 WC Psychiatry SC Psychiatry GA 906BD UT WOS:000301319000005 PM 22157798 ER PT J AU Joseph, J Purucker, M Eskandanian, K Batshaw, M Tuchman, M AF Joseph, Jill Purucker, Mary Eskandanian, Kolaleh Batshaw, Mark Tuchman, Mendel TI The Clinical and Translational Science Institute at Children's National: Improving Health through Pediatric Research SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article C1 [Joseph, Jill; Eskandanian, Kolaleh; Batshaw, Mark; Tuchman, Mendel] George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Washington, DC 20052 USA. [Purucker, Mary] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Tuchman, M (reprint author), George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Washington, DC 20052 USA. EM mtuchman@cnmc.org FU NIH National Center for Research Resources [UL1RR031988] FX This work was supported by Award Number UL1RR031988 from the NIH National Center for Research Resources. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Special thanks to Brian Jacobs, MD for his work on Children's IQ Network (R). CTS NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2012 VL 5 IS 1 BP 5 EP 7 DI 10.1111/j.1752-8062.2011.00368.x PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 900FU UT WOS:000300872800003 PM 22376250 ER PT J AU Glasgow, RE Chambers, D AF Glasgow, Russell E. Chambers, David TI Developing Robust, Sustainable, Implementation Systems Using Rigorous, Rapid and Relevant Science SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE implementation; dissemination; research methods; translation; comparative effectiveness research ID PHYSICAL-ACTIVITY INTERVENTIONS; RANDOMIZED CONTROLLED-TRIALS; PRACTICAL CLINICAL-TRIALS; EXTERNAL VALIDITY; PRIMARY-CARE; HEALTH; TRANSLATION; RECOMMENDATIONS; EFFICACY; QUALITY AB Background: Current approaches to medical science generally have not resulted in rapid, robust integration into feasible, sustainable real world healthcare programs and policies. Implementation science risks falling short of expectations if it aligns with historical norms. Fundamentally different scientific approaches are needed to accelerate such integration. Methods: We propose that the key goal of implementation science should be to study the development, spread and sustainability of broadly applicable and practical programs, treatments, guidelines, and policies that are contextually relevant and robust across diverse settings, delivery staff, and subgroups. We recommend key conceptual and methodological characteristics needed to accomplish these goals. Results: The methods to produce such advances should be rapid, rigorous, transparent, and contextually relevant. We recommend approaches that incorporate a systems perspective, investigate generalizability, are transparent, and employ practical measures and participatory approaches. Conclusions: To produce different outcomes, we need to think and act differently. Implications of such an implementation science approach include fundamental changes that should be relevant to Clinical Translational Science Award investigators, comparative effectiveness researchers, those interested in pragmatic trials, grant funders, and community partners. Clin Trans Sci 2012; Volume 5: 48-55 C1 [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Chambers, David] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM glasgowre@mail.nih.gov NR 43 TC 63 Z9 63 U1 2 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2012 VL 5 IS 1 BP 48 EP 55 DI 10.1111/j.1752-8062.2011.00383.x PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 900FU UT WOS:000300872800010 PM 22376257 ER PT J AU Rosenblum, D AF Rosenblum, Daniel TI Access to Core Facilities and Other Research Resources Provided by the Clinical and Translational Science Awards SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE clinical trials; translational research; biostatistics; phase I; phase II; tests; core services; regulatory knowledge; novel methodologies; research navigation; research resources AB Principal investigators who received Clinical and Translational Science Awards created academic homes for biomedical research. They developed program-supported websites to offer coordinated access to a range of core facilities and other research resources. Visitors to the 60 websites will find at least 170 generic services, which this review has categorized in the following seven areas: (1) core facilities, (2) biomedical informatics, (3) funding, (4) regulatory knowledge and support, (5) biostatistics, epidemiology, research design, and ethics, (6) participant and clinical interaction resources, and (7) community engagement. In addition, many websites facilitate access to resources with search engines, navigators, studios, project development teams, collaboration tools, communication systems, and teaching tools. Each of these websites may be accessed from a single site, . The ability to access the research resources from 60 of the nation's academic health centers presents a novel opportunity for investigators engaged in clinical and translational research. Clin Trans Sci 2012; Volume 5: 78-82 C1 NIH, Div Clin Res Resources, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Rosenblum, D (reprint author), NIH, Div Clin Res Resources, Natl Ctr Res Resources, Bldg 10, Bethesda, MD 20892 USA. EM rosenblumd@mail.NIH.gov NR 4 TC 3 Z9 3 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2012 VL 5 IS 1 BP 78 EP 82 DI 10.1111/j.1752-8062.2011.00385.x PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 900FU UT WOS:000300872800015 PM 22376262 ER PT J AU Hazard, M Steele, S Wang, DW Pearson, T Scheideler, M Dewhurst, S AF Hazard, Mike Steele, Scott Wang, Dongwen Pearson, Thomas Scheideler, Mark Dewhurst, Steve TI CTSA-IP:A Solution to Identifying and Aggregating Intellectual Property across the NIH Clinical Translational Science Award (CTSA) Consortium of Biomedical Research Institutes (vol 4, pg 328, 2011) SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Correction C1 [Hazard, Mike; Wang, Dongwen] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14627 USA. [Steele, Scott] Univ Rochester, Med Ctr, Key Funct Clin & Translat Sci Inst, Off Res Alliances & Public Private Partnership, Rochester, NY 14642 USA. [Pearson, Thomas] Univ Rochester, Sch Med & Dent, Dept Community & Prevent Med, Rochester, NY USA. [Scheideler, Mark] NINDS, Off Translat Res, NIH, Bethesda, MD 20892 USA. [Dewhurst, Steve] Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY USA. RP Hazard, M (reprint author), Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14627 USA. NR 1 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2012 VL 5 IS 1 BP 112 EP 112 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 900FU UT WOS:000300872800022 ER PT J AU Bornstein, MH Suwalsky, JTD Breakstone, DA AF Bornstein, Marc H. Suwalsky, Joan T. D. Breakstone, Dana A. TI Emotional relationships between mothers and infants: Knowns, unknowns, and unknown unknowns SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID AUTISM SPECTRUM DISORDERS; AVAILABILITY SCALES; CHILD DYADS; ATTACHMENT REPRESENTATIONS; MATERNAL SENSITIVITY; YOUNG-CHILDREN; DOWN-SYNDROME; 3 COUNTRIES; STILL-FACE; 2 REGIONS AB An overview of the literature pertaining to the construct of emotional availability is presented, illustrated by a sampling of relevant studies. Methodological, statistical, and conceptual problems in the existing corpus of research are discussed, and suggestions for improving future investigations of this important construct are offered. C1 [Bornstein, Marc H.; Suwalsky, Joan T. D.; Breakstone, Dana A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM marc_h_bornstein@nih.gov FU Intramural NIH HHS [ZIA HD001119-24] NR 117 TC 9 Z9 9 U1 4 U2 20 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD FEB PY 2012 VL 24 IS 1 BP 113 EP 123 DI 10.1017/S0954579411000708 PG 11 WC Psychology, Developmental SC Psychology GA 892EX UT WOS:000300270600010 PM 22292998 ER PT J AU Spinelli, S Schwandt, ML Lindell, SG Heilig, M Suomi, SJ Higley, JD Goldman, D Barr, CS AF Spinelli, Simona Schwandt, Melanie L. Lindell, Stephen G. Heilig, Markus Suomi, Stephen J. Higley, J. Dee Goldman, David Barr, Christina S. TI The serotonin transporter gene linked polymorphic region is associated with the behavioral response to repeated stress exposure in infant rhesus macaques SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID CSF MONOAMINE METABOLITE; PROMOTER POLYMORPHISM; HARM AVOIDANCE; SEPARATION PARADIGM; SOCIAL SEPARATION; REGULATORY REGION; MAJOR DEPRESSION; USE DISORDERS; MONKEYS; VULNERABILITY AB The short allele of the serotonin transporter linked polymorphic legion (5-HTTLPR) moderates the effects of stress on vulnerability to mood and anxiety disorders. The mechanism by which this occurs may relate to differential sensitivity to stressful life events. Here we explored whether 5-HTTLPR and sex affected behavioral responses to repeated maternal separation in infant rhesus macaques. Behaviors were collected during the acute (Day I) and the chronic (Days 2-4) phases of the separation, and the effects of duration of separation (acute vs. chronic), genotype (long/long vs. short allele), and sex (male vs. female) on behavioral responses were analyzed across four successive separations. Males increased their levels of locomotion with repeated maternal separation, whereas females exhibited an increase in frequency of self-directed behavior, a measure of "depression-like" behavior. The short-allele predicted increased environmental exploration, particularly during the chronic phase of social separation, indicative of higher arousal. In addition, the short-allele carriers were more likely to increase their levels of self-directed behavior during The chronic phase of separation, as a function of repeated exposures. These findings suggest that the short allele may increase reactivity to repeated, chronic stressors, leaving them more vulnerable to affective psychopathology, with females particularly vulnerable. C1 [Suomi, Stephen J.] NICHHD, Bethesda, MD 20892 USA. [Higley, J. Dee] Brigham Young Univ, Provo, UT 84602 USA. RP Spinelli, S (reprint author), Univ Zurich Hosp, Preclin Lab Translat Res Affect Disorders, Clin Affect Disorders & Gen Psychiat, August Forel Str 7, CH-8008 Zurich, Switzerland. EM spinellisimona@gmail.com RI Goldman, David/F-9772-2010; Schwandt, Melanie/L-9866-2016; OI Goldman, David/0000-0002-1724-5405; Heilig, Markus/0000-0003-2706-2482 FU Intramural NIH HHS [Z01 AA000301-09, ZIA AA000311-01] NR 59 TC 15 Z9 15 U1 1 U2 14 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD FEB PY 2012 VL 24 IS 1 BP 157 EP 165 DI 10.1017/S0954579411000745 PG 9 WC Psychology, Developmental SC Psychology GA 892EX UT WOS:000300270600015 PM 22293001 ER PT J AU Groninger, H AF Groninger, Hunter TI A Gravely Ill Patient Faces The Grim Results Of Outliving Her Eligibility For Hospice Benefits SO HEALTH AFFAIRS LA English DT Editorial Material C1 NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Groninger, H (reprint author), NIH, Pain & Palliat Care Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov NR 0 TC 3 Z9 3 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD FEB PY 2012 VL 31 IS 2 BP 452 EP 455 DI 10.1377/HLTHAFF.2011.0473 PG 4 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 894GE UT WOS:000300414300026 PM 22323175 ER PT J AU Arbes, SJ Calatroni, A Mitchell, HE Gergen, PJ AF Arbes, S. J., Jr. Calatroni, A. Mitchell, H. E. Gergen, P. J. TI Age-Dependent Interaction Between Atopy and Eosinophils in Asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Arbes, S. J., Jr.; Calatroni, A.; Mitchell, H. E.] Rho Inc, Chapel Hill, NC USA. [Gergen, P. J.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB153 EP AB153 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400576 ER PT J AU Bai, Y Chan, EC Kirshenbaum, AS Fischer, ER Simakova, O Maric, I Metcalfe, DD Wilson, TM AF Bai, Y. Chan, E. C. Kirshenbaum, A. S. Fischer, E. R. Simakova, O. Maric, I. Metcalfe, D. D. Wilson, T. M. TI Effects of the KIT K509I Extracellular Activating Mutation on Human Mast Cell Homeostasis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Bai, Y.; Chan, E. C.; Kirshenbaum, A. S.; Metcalfe, D. D.; Wilson, T. M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Fischer, E. R.] NIAID, Res Technol Sect, Rocky Mt Labs, NIH, Bethesda, MD 20892 USA. [Simakova, O.; Maric, I.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB121 EP AB121 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400461 ER PT J AU Glesner, J Wuenschmann, S Koid, A Mueller, GA Pedersen, LC Chapman, MD Pomes, A AF Glesner, J. Wuenschmann, S. Koid, A. Mueller, G. A. Pedersen, L. C. Chapman, M. D. Pomes, A. TI Monoclonal Antibodies for Defining Conformational Epitopes in Ara h 2 and Ara h 6 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Glesner, J.; Wuenschmann, S.; Koid, A.; Chapman, M. D.; Pomes, A.] INDOOR Biotechnol Inc, Charlottesville, VA USA. [Mueller, G. A.; Pedersen, L. C.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB233 EP AB233 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133401046 ER PT J AU Jones, SM Burks, AW Wood, RA Fleischer, DM Sicherer, SH Lindblad, RW Stablein, D Henning, AK Vickery, BP Liu, AH Scurlock, AM Shreffler, WG Plaut, M Sampson, HA AF Jones, S. M. Burks, A. W. Wood, R. A. Fleischer, D. M. Sicherer, S. H. Lindblad, R. W. Stablein, D. Henning, A. K. Vickery, B. P. Liu, A. H. Scurlock, A. M. Shreffler, W. G. Plaut, M. Sampson, H. A. TI A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Egg Oral Immunotherapy in Children: An Analysis of Clinical Tolerance SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Jones, S. M.; Scurlock, A. M.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Jones, S. M.; Scurlock, A. M.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Burks, A. W.; Vickery, B. P.] Duke Univ, Med Ctr, Durham, NC USA. [Wood, R. A.] Johns Hopkins Univ, Med Ctr, Baltimore, MD 21218 USA. [Fleischer, D. M.; Liu, A. H.] Natl Jewish Hlth, Denver, CO USA. [Sicherer, S. H.; Sampson, H. A.] Mt Sinai Sch Med, New York, NY USA. [Lindblad, R. W.; Stablein, D.; Henning, A. K.] EMMES Corp, Rockville, MD USA. [Shreffler, W. G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Plaut, M.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB65 EP AB65 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400246 ER PT J AU Khoury, P Holland, N Heller, T Kleiner, DE Klion, AD AF Khoury, P. Holland, N. Heller, T. Kleiner, D. E. Klion, A. D. TI Eosinophilic Liver Involvement In Hypereosinophilic Syndrome: Clinico-pathologic Findings In Eight Patients SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Khoury, P.; Holland, N.; Heller, T.; Kleiner, D. E.; Klion, A. D.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB98 EP AB98 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400370 ER PT J AU Klion, AD Roufosse, FE Kahn, J Gleich, GJ Schwartz, LB Singh, A Rosenwasser, LJ Denburg, J Ring, J Rothenberg, ME Sheikh, J Haig, AE Mallett, S Templeton, D Ortega, H AF Klion, A. D. Roufosse, F. E. Kahn, J. Gleich, G. J. Schwartz, L. B. Singh, A. Rosenwasser, L. J. Denburg, J. Ring, J. Rothenberg, M. E. Sheikh, J. Haig, A. E. Mallett, S. Templeton, D. Ortega, H. TI Long-term Safety And Efficacy Of Mepolizumab For The Treatment Of Hypereosinophilic Syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Klion, A. D.] NIAID, NIH, Bethesda, MD 20892 USA. [Roufosse, F. E.] Univ Libre Bruxelles, Brussels, Belgium. [Kahn, J.] Hop Foch, Suresnes, France. [Gleich, G. J.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Schwartz, L. B.] Virginia Commonwealth Univ, Richmond, VA USA. [Singh, A.] Royal N Shore Hosp, Sydney, NSW, Australia. [Rosenwasser, L. J.] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Denburg, J.] Canc Care Nova Scotia, Halifax, NS, Canada. [Ring, J.] Tech Univ Munich, Munich, Germany. [Rothenberg, M. E.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Sheikh, J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Haig, A. E.] GlaxoSmithKline Inc, King Of Prussia, PA USA. [Templeton, D.; Ortega, H.] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB203 EP AB203 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400765 ER PT J AU Komarow, HD Meyer, J Gorbach, AM Liu, W Medic, N Young, M Nelson, C Arceo, S Desai, A Metcalfe, DD AF Komarow, H. D. Meyer, J. Gorbach, A. M. Liu, W. Medic, N. Young, M. Nelson, C. Arceo, S. Desai, A. Metcalfe, D. D. TI Real-time Imaging Assessment of Blood Flow, Temperature and Skin Color on Patients with Cold-induced Urticaria: Correlation with Histamine and Tryptase Release SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Komarow, H. D.; Medic, N.; Nelson, C.; Arceo, S.; Desai, A.; Metcalfe, D. D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Meyer, J.; Gorbach, A. M.; Liu, W.] Natl Inst Biomed Imaging & Bioengn, Infrared Imaging & Thermometry Unit, NIH, Bethesda, MD USA. [Young, M.] NCI Frederick, Clin Res Directorate, CMRP, SAIC Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB141 EP AB141 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400533 ER PT J AU Lichtenberger, FJ Medic, N Desai, A Bandara, G Metcalfe, DD AF Lichtenberger, F. J. Medic, N. Desai, A. Bandara, G. Metcalfe, D. D. TI Abnormal Mast Cell Migration in the Wv/+ Piebald Mouse SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Lichtenberger, F. J.; Medic, N.; Desai, A.; Bandara, G.; Metcalfe, D. D.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB121 EP AB121 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400459 ER PT J AU Visness, CM Jaffee, KF Calatroni, A Wood, RA Gergen, PJ Gern, JE AF Visness, C. M. Jaffee, K. F. Calatroni, A. Wood, R. A. Gergen, P. J. Gern, J. E. TI Novel Analysis Methods for Longitudinal Cytokine Response Data in a Birth Cohort Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Visness, C. M.; Jaffee, K. F.; Calatroni, A.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Wood, R. A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Gergen, P. J.] NIH, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Gern, J. E.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB199 EP AB199 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400750 ER PT J AU Weir, C Yeatts, K Vizuete, W London, S Salo, PM Jaramillo, R Zeldin, D AF Weir, C. Yeatts, K. Vizuete, W. London, S. Salo, P. M. Jaramillo, R. Zeldin, D. TI 1. Ambient Air Pollution and Allergic Sensitization: Results from the National Health and Examination Survey (NHANES) 2005-2006 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Weir, C.; Yeatts, K.; Vizuete, W.] Univ N Carolina, Chapel Hill, NC USA. [London, S.; Salo, P. M.] NIEHS, Res Triangle Pk, NC 27709 USA. [Jaramillo, R.] SRA Int Inc, Durham, NC USA. [Zeldin, D.] NIEHS, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB19 EP AB19 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400073 ER PT J AU Wildfire, J Arbes, S Gergen, P AF Wildfire, J. Arbes, S. Gergen, P. TI Changes in Prevalence with Different Definitions of a ''Positive'' Skin Test SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Wildfire, J.; Arbes, S.] Rho Inc, Chapel Hill, NC USA. [Gergen, P.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB5 EP AB5 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400021 ER PT J AU Zoerner, AA Batkai, S Suchy, MT Gutzki, FM Engeli, S Jordan, J Tsikas, D AF Zoerner, Alexander A. Batkai, Sandor Suchy, Maria-Theresia Gutzki, Frank-Mathias Engeli, Stefan Jordan, Jens Tsikas, Dimitrios TI Simultaneous UPLC-MS/MS quantification of the endocannabinoids 2-arachidonoyl glycerol (2AG), 1-arachidonoyl glycerol (1AG), and anandamide in human plasma: Minimization of matrix-effects, 2AG/1AG isomerization and degradation by toluene solvent extraction SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE AEA; 2AG; Clinical studies; Endocannabinoids; Isomerisation; Matrix-effects; Plasma; Quantification; Tandem mass spectrometry ID TANDEM MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; BIOLOGICAL SAMPLES; MONITORING PHOSPHOLIPIDS; CANNABINOID RECEPTOR; N-ACYLETHANOLAMINES; QUANTITATIVE METHOD; BRAIN-TISSUE; PURIFICATION; ACID AB Analysis of the endocannabinoid (EC) system's key molecules 2-arachidonoyl glycerol (2AG) and arachidonoyl ethanolamide (anandamide. AEA) is challenging due to several peculiarities. 2AG isomerizes spontaneously to its biologically inactive analogue 1-arachidonoyl glycerol (1AG) by acyl migration and it is only chromatographically distinguishable from 1AG. Matrix-effects caused primarily by co-extracted phospholipids may further compromise analysis. In addition, 2AG and 1AG are unstable under certain conditions like solvent evaporation or reconstitution of dried extracts. We examined effects of different organic solvents and their mixtures, such as toluene, ethyl acetate, and chloroform-methanol, on 2AG/1AG isomerisation, 2AG/1AG stability, and matrix-effects in the UPLC-MS/MS analysis of 2AG and AEA in human plasma. Toluene prevented, both, 2AG isomerisation to 1AG and degradation of 2AG/1AG during evaporation. Toluene extracts contain only 2% of matrix-effect-causing plasma phospholipids compared to extracts from the traditionally used solvent mixture chloroform-methanol. Toluene and all other tested organic solvents provide comparable 2AG and AEA extraction yields (60-80%). Based on these favourable toluene properties, we developed and validated a UPLC-MS/MS method with positive electrospray ionization (ESI+) that allows for simultaneous accurate and precise measurement of 2AG and AEA in human plasma. The UPLC-MS/MS method was cross-validated with a previously described fully-validated GC-MS/MS method for AEA in human plasma. A close correlation (r(2) = 0.821) was observed between the results obtained from UPLC-MS/MS (y) and GC-MS/MS (x) methods (y = 0.01 + 0.85x). The UPLC-MS/MS method is suitable for routine measurement of 2AG and AEA in human plasma samples (1 mL) in clinical settings as shown by quality control plasma samples processed over a period of 100 days. The UPLC-MS/MS method was further extended to human urine. In urine, AEA was not detectable and 2AG was detected in only 3 out of 19 samples from healthy subjects at 160,180 and 212 pM corresponding to 12.3, 14.5 and 9.9 pmol/mmol creatinine, respectively. (C) 2011 Elsevier B.V. All rights reserved. C1 [Zoerner, Alexander A.; Batkai, Sandor; Suchy, Maria-Theresia; Gutzki, Frank-Mathias; Engeli, Stefan; Jordan, Jens; Tsikas, Dimitrios] Hannover Med Sch, Inst Clin Pharmacol, D-30625 Hannover, Germany. [Batkai, Sandor] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Zoerner, AA (reprint author), Hannover Med Sch, Inst Clin Pharmacol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM zoerner.alexander@mh-hannover.de RI Batkai, Sandor/H-7983-2014 NR 34 TC 33 Z9 33 U1 2 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD FEB 1 PY 2012 VL 883 SI SI BP 161 EP 171 DI 10.1016/j.jchromb.2011.06.025 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 900AL UT WOS:000300858900019 PM 21752730 ER PT J AU Bull, S Farsides, B Ayele, FT AF Bull, Susan Farsides, Bobbie Ayele, Fasil Tekola TI TAILORING INFORMATION PROVISION AND CONSENT PROCESSES TO RESEARCH CONTEXTS: THE VALUE OF RAPID ASSESSMENTS SO JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS LA English DT Article DE consent; research ethics; empirical research; Africa; The Gambia; Ethiopia ID RANDOMIZED CONTROLLED-TRIAL; OBTAINING INFORMED-CONSENT; VACCINE TRIAL; DEVELOPING-COUNTRIES; PARENTAL CONSENT; HEALTH RESEARCH; RESEARCH PARTICIPATION; BIOMEDICAL-RESEARCH; SOUTHERN ETHIOPIA; CLINICAL-TRIALS AB GUIDANCE REQUIRES THAT CONSENT processes for research be appropriately tailored to their cultural context. This paper discusses the use of rapid assessments to identify cultural and ethical issues arising when explaining research in studies in The Gambia and Ethiopia. The assessments provided insights into appropriate ways of providing information to minimize the risk of stigmatizing vulnerable research populations; research participants' views about the most important information to provide about research and their understandings of research; and perceived constraints upon reaching voluntary decisions about participation. These insights demonstrate that rapid assessments are a relatively quick and inexpensive intervention that can provide valuable information to assist in the tailoring of information provision and consent processes to research context while maintaining and enhancing participants' fundamental protections. C1 [Bull, Susan] Univ Oxford, Ethox Ctr, Div Publ Hlth, Oxford OX3 7LF, England. [Bull, Susan] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7LF, England. [Farsides, Bobbie] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Ayele, Fasil Tekola] NIH, Ctr Res Genom & Global Hlth, Bethesda, MD USA. RP Bull, S (reprint author), Univ Oxford, Ethox Ctr, Div Publ Hlth, Old Rd Campus, Oxford OX3 7LF, England. EM susan.bull@ethox.ox.ac.uk OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Wellcome Trust, UK [068909, 079791, 087285] FX We are indebted to Philip Hill and Dolly Jackson-Sillah for facilitating this research in The Gambia. In Ethiopia we are indebted to Meskele Ashine of the MFTPA for his support in logistics and Ashenafi Debebe for conducting the interviews with the community in Wolaitigna. The research was funded by the Wellcome Trust, UK, with grants 068909, 079791 and 087285. The funding body had no direct role in the study design; the collection, analysis, and interpretation of data; or the writing or submission of this paper for publication. NR 71 TC 15 Z9 15 U1 1 U2 3 PU UNIV CALIFORNIA PRESS PI BERKELEY PA C/O JOURNALS & DIGITAL PUBLISHING DIVISION, 2000 CENTER ST, STE 303, BERKELEY, CA 94704-1223 USA SN 1556-2646 J9 J EMPIR RES HUM RES JI J. Empir. Res. Hum. Res. Ethics PD FEB PY 2012 VL 7 IS 1 BP 37 EP 52 DI 10.1525/jer.2012.7.1.37 PG 16 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA 904OY UT WOS:000301209000005 PM 22378133 ER PT J AU McQuiston, TJ Williamson, PR AF McQuiston, Travis J. Williamson, Peter R. TI Paradoxical roles of alveolar macrophages in the host response to Cryptococcus neoformans SO JOURNAL OF INFECTION AND CHEMOTHERAPY LA English DT Review DE Cryptococcus; Cryptococcosis; Macrophage; Lung disease ID ALLERGIC BRONCHOPULMONARY-MYCOSIS; PULMONARY INFECTION; T-CELLS; MYCOBACTERIUM-TUBERCULOSIS; INTRACELLULAR PARASITISM; CAPSULAR POLYSACCHARIDE; ACTIVATED MACROPHAGES; SUPEROXIDE DISMUTASES; CONFERS RESISTANCE; SEROLOGIC EVIDENCE AB Cryptococcus neoformans (Cn) is a fungal pathogen that is a serious health threat to immunocompromised individuals. Upon environmental exposure, infectious fungal propagules are inhaled into the host's lungs. The anticryptococcal actions of alveolar macrophages (AM), the predominant host phagocyte of the innate immune system in the lungs, are fundamental in determining whether containment and clearance of the pathogen occurs by the development of an adapted immune response or whether infection is established and progresses to disease. However, the fungus is also capable of surviving the antimicrobial actions of AM and exploits these host phagocytes to establish infection and exacerbate disease. In addition, there is evidence suggesting that cryptococcosis may occur following reactivation of latent cryptococcal infection. Currently, the role of AM and the fungal factors contributing to latent cryptococcosis are unknown. This review examines the AM-Cn interaction and how it affects the development of pulmonary disease with a focus on host and pathogen factors enabling latency to occur. C1 [McQuiston, Travis J.; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Williamson, PR (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 10,Rm 11N234 MSC 1888, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU NIH, NIAID FX This work was supported by the Intramural Research Program of the NIH, NIAID. We would like also to acknowledge manuscript editorial review by J. Abbott. NR 86 TC 13 Z9 13 U1 2 U2 7 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 1341-321X J9 J INFECT CHEMOTHER JI J. Infect. Chemother. PD FEB PY 2012 VL 18 IS 1 BP 1 EP 9 DI 10.1007/s10156-011-0306-2 PG 9 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 893FZ UT WOS:000300342900001 PM 22045161 ER PT J AU Kar, G Keskin, O Nussinov, R Gursoy, A AF Kar, Gozde Keskin, Ozlem Nussinov, Ruth Gursoy, Attila TI Human Proteome-scale Structural Modeling of E2-E3 Interactions Exploiting Interface Motifs SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE ubiquitination; E2; E3; proteomics; protein-protein interactions; protein-protein interfaces; degradation; proteome-scale structural maps ID UBIQUITIN-CONJUGATING ENZYMES; POLYUBIQUITIN CHAIN; DRUG DISCOVERY; HECT-DOMAIN; HOT-SPOTS; SUBCELLULAR-LOCALIZATION; PROTEASOME SYSTEM; QUALITY-CONTROL; LIGASE COMPLEX; E2 AB Ubiquitination is crucial for many cellular processes such as protein degradation, DNA repair, transcription regulation, and cell signaling. Ubiquitin attachment takes place via a sequential enzymatic cascade involving ubiquitin activation (by El enzymes), ubiquitin conjugation (by E2 enzymes), and ubiquitin substrate tagging (by E3 enzymes). E3 ligases mediate ubiquitin transfer from E2s to substrates and as such confer substrate specificity. Although E3s can interact and function with numerous E2s, it is still unclear how they choose which E2 to use. Identifying all E2 partners of an E3 is essential for inferring the principles guiding E2 selection by an E3. Here we model the interactions of E3 and E2 proteins in a large, proteome-scale strategy based on interface structural motifs, which allows elucidation of (1) which E3s interact with which E2s in the human ubiquitination pathway and (2) how they interact with each other. Interface analysis of E2-E3 complexes reveals that loop L1 of E2s is critical for binding; the residue in the sixth position in loop L1 is widely utilized as an interface hot spot and appears indispensible for E2 interactions. Other loop L1 residues also confer specificity on the E2-E3 interactions: HECT E3s are in contact with the residue in the second position in loop L1 of E2s, but this is not the case for the RING finger type E3s. Our modeled E2-E3 complexes illuminate how slight sequence variations in E2 residues may contribute to specificity in E3 binding. These findings may be important for discovering drug candidates targeting E3s, which have been implicated in many diseases. C1 [Kar, Gozde; Keskin, Ozlem; Gursoy, Attila] Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. [Kar, Gozde; Keskin, Ozlem; Gursoy, Attila] Koc Univ, Coll Engn, TR-34450 Istanbul, Turkey. [Nussinov, Ruth] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Keskin, O (reprint author), Koc Univ, Ctr Computat Biol & Bioinformat, Rumelifeneri Yolu, TR-34450 Istanbul, Turkey. EM agursoy@ku.edu.tr RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU TUBITAK [109T343, 109E207]; Turkish Academy of Sciences (TUBA); National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This work has been supported by TUBITAK (Research Grant Numbers: 109T343 and 109E207). O.K. acknowledges Turkish Academy of Sciences (TUBA). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 84 TC 29 Z9 29 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2012 VL 11 IS 2 BP 1196 EP 1207 DI 10.1021/pr2009143 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 894WN UT WOS:000300458300058 PM 22149024 ER PT J AU Kinsinger, CR Apffel, J Baker, M Bian, XP Borchers, CH Bradshaw, R Brusniak, MY Chan, DW Deutsch, EW Domon, B Gorman, J Grimm, R Hancock, W Hermjakob, H Horn, D Hunter, C Kolar, P Kraus, HJ Langen, H Linding, R Moritz, RL Omenn, GS Orlando, R Pandey, A Ping, PP Rahbar, A Rivers, R Seymour, SL Simpson, RJ Slotta, D Smith, RD Stein, SE Tabb, DL Tagle, D Yates, JR Rodriguez, H AF Kinsinger, Christopher R. Apffel, James Baker, Mark Bian, Xiaopeng Borchers, Christoph H. Bradshaw, Ralph Brusniak, Mi-Youn Chan, Daniel W. Deutsch, Eric W. Domon, Bruno Gorman, Jeff Grimm, Rudolf Hancock, William Hermjakob, Henning Horn, David Hunter, Christie Kolar, Patrik Kraus, Hans-Joachim Langen, Hanno Linding, Rune Moritz, Robert L. Omenn, Gilbert S. Orlando, Ron Pandey, Akhilesh Ping, Peipei Rahbar, Amir Rivers, Robert Seymour, Sean L. Simpson, Richard J. Slotta, Douglas Smith, Richard D. Stein, Stephen E. Tabb, David L. Tagle, Danilo Yates, John R., III Rodriguez, Henry TI Recommendations for Mass Spectrometry Data Quality Metrics for Open Access Data (Corollary to the Amsterdam Principles) SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE selected reaction monitoring; bioinformatics; data quality; metrics; open access; Amsterdam Principles; standards ID PROTEIN IDENTIFICATION DATA; SHOTGUN PROTEOMICS; PEPTIDE IDENTIFICATION; CLINICAL PROTEOMICS; MINIMUM INFORMATION; STATISTICAL-MODEL; GUIDELINES; RESOURCE; SPECTRA; REPRODUCIBILITY AB Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the U.S. National Cancer Institute (NCI) convened the "International Workshop on Proteomic Data Quality Metrics" in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, funding agencies, and data repositories. Attendees discussed and agreed up on two primary needs for the wide use of quality metrics: (1) an evolving list of comprehensive quality metrics and (2) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in the Journal of Proteome Research, Molecular and Cellular Proteomics, Proteomics, and Proteomics Clinical Applications as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals. C1 [Kinsinger, Christopher R.] NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. Agilent Res Labs, Santa Clara, CA 95051 USA. Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. NCI, Ctr Bioinformat & Informat Technol, NIH, Bethesda, MD 20892 USA. Univ Victoria, Genome BC Prote Ctr, Victoria, BC V8Z 7X8, Canada. Univ Calif San Francisco, Mass Spectrometry Facil, San Francisco, CA 94143 USA. Inst Syst Biol, Seattle, WA 98103 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA. Inst Syst Biol, Seattle, WA 98109 USA. CRP Sante, Luxembourg Clin Prote Ctr, L-1445 Strassen, Luxembourg. Queensland Inst Med Res, Prot Discovery Ctr, Herston, Qld 4029, Australia. Agilent Technol, Santa Clara, CA 95051 USA. Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. European Bioinformat Inst, Prote Serv, Cambridge CB10 1SD, England. Thermo Fisher Sci, Prote Software Strateg Mkt, San Jose, CA 95134 USA. AB SCIEX, Foster City, CA 94404 USA. Commiss European Communities, Directorate Gen Res, B-1049 Brussels, Belgium. Wiley VCH, D-69469 Weinheim, Germany. Hoffmann La Roche AG, Exploratory Biomarkers, CH-4070 Basel, Switzerland. Tech Univ Denmark DTU, Cellular Signal Integrat Grp C SIG, Ctr Biol Sequence Anal CBS, Dept Syst Biol, DK-2800 Lyngby, Denmark. Inst Syst Biol, Cellular & Mol Log Unit, Seattle, WA 98103 USA. Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21231 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NCI, Small Business Dev Ctr, NIH, Bethesda, MD 20892 USA. La Trobe Univ, La Trobe Inst Mol Sci, Bundoora, Vic 3086, Australia. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. Pacific NW Natl Lab, Richland, WA 99352 USA. NIST, Chem Reference Data Grp, Gaithersburg, MD 20899 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA 92037 USA. RP Kinsinger, CR (reprint author), NCI, Off Canc Clin Prote Res, NIH, 31 Ctr Dr,MSC 2580, Bethesda, MD 20892 USA. EM kinsingc@mail.nih.gov RI Pandey, Akhilesh/B-4127-2009; Smith, Richard/J-3664-2012; OI Pandey, Akhilesh/0000-0001-9943-6127; Smith, Richard/0000-0002-2381-2349; Ping, Peipei/0000-0003-3583-3881; Omenn, Gilbert S./0000-0002-8976-6074; Hermjakob, Henning/0000-0001-8479-0262; Baker, Mark/0000-0001-5858-4035 FU Intramural NIH HHS [Z99 CA999999]; NHGRI NIH HHS [RC2 HG005805]; NIGMS NIH HHS [P50 GM076547] NR 51 TC 5 Z9 5 U1 4 U2 40 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2012 VL 11 IS 2 BP 1412 EP 1419 DI 10.1021/pr201071t PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 894WN UT WOS:000300458300077 PM 22053864 ER PT J AU Shardell, M D'Adamo, C Alley, DE Miller, RR Hicks, GE Milaneschi, Y Semba, RD Cherubini, A Bandinelli, S Ferrucci, L AF Shardell, Michelle D'Adamo, Christopher Alley, Dawn E. Miller, Ram R. Hicks, Gregory E. Milaneschi, Yuri Semba, Richard D. Cherubini, Antonio Bandinelli, Stefania Ferrucci, Luigi TI Serum 25-Hydroxyvitamin D, Transitions Between Frailty States, and Mortality in Older Adults: The Invecchiare in Chianti Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the Gerontological-Society-of-America CY NOV 19-20, 2009 CL Atlanta, GA SP Gerontol Soc Amer DE frailty; mortality; vitamin D ID VITAMIN-D DEFICIENCY; MARGINAL STRUCTURAL MODELS; RANDOMIZED CONTROLLED-TRIALS; D SUPPLEMENTATION; PHYSICAL PERFORMANCE; DEPRESSIVE SYMPTOMS; MUSCLE STRENGTH; ALL-CAUSE; WOMEN; MEN AB OBJECTIVES: To assess whether serum 25-hydroxyvitamin D (25(OH)D) concentrations relate to transitions between the states of robustness, prefrailty, and frailty and to mortality in older adults. DESIGN: The Invecchiare in Chianti (InCHIANTI) Study, a prospective cohort study. SETTING: Tuscany, Italy. PARTICIPANTS: Adults aged 65 and older (N = 1,155). MEASUREMENTS: Serum 25(OH)D concentrations measured at baseline; frailty state (robust, prefrail, frail) assessed at baseline and 3 and 6 years after enrollment; and vital status determined 3 and 6 years after enrollment. RESULTS: The median (interquartile range) 25(OH)D concentration was 16.0 ng/mL (10.4-25.6 ng/mL; multiply by 2.496 to convert to nmol/L). Prefrail participants with 25(OH) D levels less than 20 ng/mL were 8.9% (95% confidence interval (CI) = 2.5-15.2%) more likely to die, 3.0% (95% CI = -5.6-14.6%) more likely to become frail, and 7.7% (95% CI = -3.5-18.7%) less likely to become robust than prefrail participants with 25(OH) D levels of 20 ng/mL or more. In prefrail participants, each 5-ng/mL decrement of continuous 25(OH)D was associated with 1.46 times higher odds of dying (95% CI = 1.18 -2.07) and 1.13 higher odds of incident frailty (95% CI = 0.90-1.39) than with recovery of robustness. Transi-tions from robustness or frailty were not associated with 25(OH)D levels. CONCLUSION: Results provide evidence that prefrailty is an "at risk" state from which older adults with high 25 (OH)D levels are more likely to recover than to decline, but high 25(OH)D levels were not associated with recovery from frailty. Thus, 25(OH)D levels should be investigated as a potential therapy to treat prefrailty and prevent further decline. J Am Geriatr Soc 60: 256-264, 2012. C1 [Shardell, Michelle; Alley, Dawn E.; Miller, Ram R.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [D'Adamo, Christopher] Univ Maryland, Sch Med, Dept Family & Community Med, Baltimore, MD 21201 USA. [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Newark, DE USA. [Milaneschi, Yuri; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Cherubini, Antonio] Univ Perugia, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. [Bandinelli, Stefania] Tuscany Reg Hlth Agcy, Florence, Italy. RP Shardell, M (reprint author), 660 W Redwood St, Baltimore, MD 21201 USA. EM mshardel@epi.umaryland.edu OI Cherubini, Antonio/0000-0003-0261-9897 FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL094507]; NIA NIH HHS [K23 AG027746-01A2, K23 AG027746, K23AG027746, K25 AG034216, K25 AG034216-01A2, R01 AG027012, T32 AG000262, T32 AG00262]; NICHD NIH HHS [K12 HD043489, K12 HD043489-01, K12 HD055931, K12HD04389, K12HD055931, R21 HD057274, R21 HD057274-01A1, R21HD057274] NR 49 TC 22 Z9 23 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2012 VL 60 IS 2 BP 256 EP 264 DI 10.1111/j.1532-5415.2011.03830.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 897ST UT WOS:000300677400009 PM 22283177 ER PT J AU Pietrzak, RH Goldstein, RB Southwick, SM Grant, BF AF Pietrzak, Robert H. Goldstein, Rise B. Southwick, Steven M. Grant, Bridget F. TI Physical Health Conditions Associated with Posttraumatic Stress Disorder in US Older Adults: Results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE posttraumatic stress disorder; medical; comorbidity; epidemiology; older adults ID PSYCHIATRIC DIAGNOSTIC MODULES; GENERAL-POPULATION SAMPLE; IV AUDADIS-IV; PRIMARY-CARE; HEART-DISEASE; RISK-FACTORS; PTSD; COMORBIDITY; RELIABILITY; PREVALENCE AB OBJECTIVES: To present findings on past-year medical conditions associated with lifetime trauma exposure and full and partial posttraumatic stress disorder (PTSD) in a nationally representative sample of U. S. older adults. DESIGN: Face-to-face diagnostic interviews. SETTING: Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. PARTICIPANTS: Nine thousand four hundred sixty-three adults aged 60 and older. MEASUREMENTS: Logistic regression analyses adjusting for sociodemographic characteristics and psychiatric comorbidity were used to evaluate associations between PTSD status and past-year medical disorders; linear regression models evaluated associations with past-month physical functioning. RESULTS: After adjustment for sociodemographic characteristics and comorbid lifetime mood, anxiety, substance use, attention-deficit/hyperactivity, and personality disorders, respondents with lifetime PTSD were more likely than respondents who reported experiencing one or more traumatic life events but who did not meet lifetime criteria for full or partial PTSD (trauma controls) to report being diagnosed with hypertension, angina pectoris, tachycardia, other heart disease, stomach ulcer, gastritis, and arthritis (odds ratios (ORs) = 1.3-1.8) by a healthcare professional; they also scored lower on a measure of physical functioning than controls and respondents with partial PTSD. Respondents with lifetime partial PTSD were more likely than controls to report past-year diagnoses of gastritis (OR = 1.7), angina pectoris (OR = 1.5), and arthritis (OR = 1.4) and reported worse physical functioning. Number of lifetime traumatic event types was associated with most of the medical conditions assessed; adjustment for these events reduced the magnitudes of and rendered nonsignificant most associations between PTSD status and medical conditions. CONCLUSION: Older adults with lifetime PTSD have high rates of several physical health conditions, many of which are chronic disorders of aging, and poorer physical functioning. Older adults with lifetime partial PTSD have higher rates of gastritis, angina pectoris, and arthritis and poorer physical functioning. J Am Geriatr Soc 60: 296-303, 2012. C1 [Pietrzak, Robert H.] Yale Univ, Sch Med, Natl Ctr Posttraumat Stress Disorder, VA Connecticut Healthcare Syst,Dept Psychiat, West Haven, CT 06516 USA. [Pietrzak, Robert H.; Goldstein, Rise B.; Southwick, Steven M.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Pietrzak, RH (reprint author), Yale Univ, Sch Med, Natl Ctr Posttraumat Stress Disorder, VA Connecticut Healthcare Syst,Dept Psychiat, 950 Campbell Ave 151-E, West Haven, CT 06516 USA. EM robert.pietrzak@yale.edu OI Goldstein, Rise/0000-0002-9603-9473 FU CogState, Inc.; NIAAA; National Institute on Drug Abuse; National Institutes of Health, NIAAA; National Center for Posttraumatic Stress Disorder FX Dr. Pietrzak receives partial salary support from CogState, Inc. for work that bears no relationship to the present study.; The NESARC is funded by the 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. Preparation of this manuscript was supported in part by the National Center for Posttraumatic Stress Disorder and a private donation. Dr. Goldstein takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 30 TC 43 Z9 43 U1 1 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2012 VL 60 IS 2 BP 296 EP 303 DI 10.1111/j.1532-5415.2011.03788.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 897ST UT WOS:000300677400015 PM 22283516 ER PT J AU Altmann, SE Smith, AL Dyall, J Johnson, RF Dodd, LE Jahrling, PB Paragas, J Blaney, JE AF Altmann, Sharon E. Smith, Alvin L. Dyall, Julie Johnson, Reed F. Dodd, Lori E. Jahrling, Peter B. Paragas, Jason Blaney, Joseph E. TI Inhibition of cowpox virus and monkeypox virus infection by mitoxantrone SO ANTIVIRAL RESEARCH LA English DT Article DE Poxvirus; Mitoxantrone; Cowpox; Monkeypox; Synergy ID ANTINEOPLASTIC AGENT MITOXANTRONE; SELECTIVE IMMUNOMODULATION; COMPOUND ST-246; ANIMAL-MODELS; VACCINIA; REPLICATION; MICE; IDENTIFICATION; CIDOFOVIR; EFFICACY AB Mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. To determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. Mitoxantrone demonstrated an EC50 of 0.25 mu M against cowpox and 0.8 mu M against monkeypox. Intraperitoneal treatment of cowpox virus-challenged C57Bl/6 mice with 0.5 mg/kg mitoxantrone resulted in 25% survival and a significant increase in survival time. In an effort to improve its efficacy, mitoxantrone was tested for synergistic activity with cidofovir. In vitro tests demonstrated significant synergy between the two drugs against cowpox; however, no synergistic effect on animal survival or median time-to-death was seen in intranasally-infected BALB/c mice. Significantly fewer animals survived when treated with a combination of 0.5 mg/kg mitoxantrone and 100 mg/kg cidofovir than with 100 mg/kg cidofovir alone. This is, to our knowledge, the first report of limited anti-orthopoxvirus activity by mitoxantrone in an animal model. Published by Elsevier B.V. C1 [Altmann, Sharon E.; Smith, Alvin L.; Johnson, Reed F.; Jahrling, Peter B.; Blaney, Joseph E.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. [Dyall, Julie; Jahrling, Peter B.; Paragas, Jason] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD 21702 USA. [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Altmann, SE (reprint author), 8200 Res Plaza,Rm 3A109, Frederick, MD 21702 USA. EM altmannse@niaid.nih.gov FU University of Florida; NIAID Division of Intramural Research FX The authors thank Grant McFadden (University of Florida) for the gift of the cowpox and cowpox-GFP viruses, Xiao Liu (NIAID) for assistance with statistics, and Russ Byrum, Isis Alexander, Bernardo Rosa, and Nicholas Oberlander for technical assistance. This work was supported, in part, by the NIAID Division of Intramural Research. NR 26 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 2012 VL 93 IS 2 BP 305 EP 308 DI 10.1016/j.antiviral.2011.12.001 PG 4 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 900CF UT WOS:000300863500014 PM 22182595 ER PT J AU Smyth, JT Putney, JW AF Smyth, Jeremy T. Putney, James W. TI Regulation of store-operated calcium entry during cell division SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE calcium entry; cell division; Orai; protein phosphorylation; store-operated channel; stromal-interacting molecule protein (STIM protein) ID PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; CA2+ INFLUX; I-CRAC; CHANNEL FUNCTION; MICE LACKING; T-CELL; STIM1; ORAI1; ACTIVATION AB Store-operate Ca2+ channels gate Ca2+ entry into the cytoplasm in response to the depletion of Ca2+ from endoplasmic reticulum Ca2+ stores. The major molecular components of store-operated Ca2+ entry are STIM (stromal-interacting molecule) 1 (and in some instances STIM2) that serves as the endoplasmic reticulum Ca2+ sensor, and Orai (Orai1, Orai2 and Orai3) which function as pore-forming subunits of the store-operated channel. It has been known for some time that store-operated Ca2+ entry is shut down during cell division. Recent work has revealed complex mechanisms regulating the functions and locations of both STIM1 and Orai1 in dividing cells. C1 [Putney, James W.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Smyth, Jeremy T.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences FX Work from our laboratories cited in the present paper was supported by the Intramural Program, National Institutes of Health, National Institute of Environmental Health Sciences. NR 45 TC 11 Z9 11 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD FEB PY 2012 VL 40 BP 119 EP 123 DI 10.1042/BST20110612 PN 1 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 890HV UT WOS:000300136600021 PM 22260676 ER PT J AU Tsaneva-Atanasova, K Caunt, CJ Armstrong, SP Perrett, RM McArdle, CA AF Tsaneva-Atanasova, Krasimira Caunt, Christopher J. Armstrong, Stephen P. Perrett, Rebecca M. McArdle, Craig A. TI Decoding neurohormone pulse frequency by convergent signalling modules SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE extracellular-signal-regulated kinase (ERK); frequency decoding; gonadotropin-releasing hormone (GnRH); mathematical model; nuclear factor of activated T-cells (NFAT) ID GONADOTROPIN-RELEASING-HORMONE; PROTEIN-COUPLED RECEPTORS; GENE-EXPRESSION; SUBUNIT GENES; TRANSCRIPTION; ACTIVATION; KINASE; NFAT; BETA; ERK AB GnRH (gonadotropin-releasing hormone) mediates control of reproduction. It is secreted in pulses and acts via intracellular effectors to activate gene expression. Submaximal GnRH pulse frequency can elicit maximal responses, yielding bell-shaped frequency-response curves characteristic of genuine frequency decoders. GnRH frequency decoding is therapeutically important (pulsatile GnRH can drive ovulation in assisted reproduction, whereas sustained activation can treat breast and prostate cancers), but the mechanisms are unknown. In the present paper, we review recent work in this area, placing emphasis on the regulation of transcription, and showing how mathematical modelling of GnRH effects on two effectors [ERK (extracellular-signal-regulated kinase) and NFAT (nuclear factor of activated T-cells)] reveals the potential for genuine frequency decoding as an emergent feature of the GnRH signalling network, rather than an intrinsic feature of a given protein or pathway within it. C1 [Perrett, Rebecca M.; McArdle, Craig A.] Univ Bristol, Sch Clin Sci, Labs Integrat Neurosci & Endocrinol, Bristol BS1 3NY, Avon, England. [Tsaneva-Atanasova, Krasimira] Univ Bristol, Dept Engn Math, Bristol Ctr Appl Nonlinear Math, Bristol BS8 1TR, Avon, England. [Caunt, Christopher J.] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. [Armstrong, Stephen P.] NIDDK, Steroid Hormones Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP McArdle, CA (reprint author), Univ Bristol, Sch Clin Sci, Labs Integrat Neurosci & Endocrinol, Whitson St, Bristol BS1 3NY, Avon, England. EM craig.mcardle@bristol.ac.uk RI Tsaneva-Atanasova, Krasimira/A-7153-2011; OI McArdle, Craig/0000-0003-4836-5351; Tsaneva-Atanasova, Krasimira/0000-0002-6294-7051 FU Wellcome Trust [084588]; Medical Research Council [93447]; Biotechnology and Biological Sciences Research Council; University of Bristol Laboratories for Integrative Neuroscience and Endocrinology FX This work was funded by Project Grants from the Wellcome Trust [grant number 084588] and Medical Research Council [grant number 93447], as well as a Biotechnology and Biological Sciences Research Council Doctoral Training Award to the University of Bristol Laboratories for Integrative Neuroscience and Endocrinology. NR 39 TC 3 Z9 3 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD FEB PY 2012 VL 40 BP 273 EP 278 DI 10.1042/BST20110645 PN 1 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 890HV UT WOS:000300136600049 PM 22260704 ER PT J AU Zierhut, H Linet, MS Robison, LL Severson, RK Spector, L AF Zierhut, Heather Linet, Martha S. Robison, Leslie L. Severson, Richard K. Spector, Logan TI Family history of cancer and non-malignant diseases and risk of childhood acute lymphoblastic leukemia: A Children's Oncology Group Study SO CANCER EPIDEMIOLOGY LA English DT Article DE Pediatric; Cancer; Acute lymphoblastic leukemia; Case-control study; Autoimmune; Allergies; Family history ID RHEUMATOID-ARTHRITIS PATIENTS; UNITED-STATES; CONGENITAL-ABNORMALITIES; BIRTH CHARACTERISTICS; AUTOIMMUNE-DISEASES; POPULATION; SIBLINGS; VALIDITY; METAANALYSIS; ASSOCIATION AB Background: Studies of family history of cancer and non-malignant diseases in childhood acute lymphoblastic leukemia (ALL) show inconsistent findings. Most studies show no increased risk with family history of cancer. Non-malignant diseases such as allergic diseases, autoimmune diseases, birth defects and thyroid diseases have been reported to be associated with ALL. Methods: We conducted a case-control study of family history of cancer and selected non-malignant conditions (allergic diseases, autoimmune diseases, birth defects, and thyroid diseases). ALL cases were obtained from Children's Cancer Group institutions from January 1989 to June 1993. Controls were recruited via random digit dialing. Family history for first degree relatives and grandparents of ALL cases and controls was collected by structured telephone questionnaires. Conditional logistical regression was used to calculate odds ratios adjusting for potential confounders. Results: We found a borderline association of ALL and having a family member with a history of cancer in cases (n = 1842) compared to controls (n = 1986) (OR = 0.98, 95%CI = 0.93, 1.00) and an inverse association for esophageal cancer based on small numbers. Family history of food and drug allergies demonstrated a modestly reduced risk (OR = 0.83, 95%CI = 0.73, 0.95) as did family history of rheumatoid arthritis (OR = 0.79, 95%CI = 0.65, 0.96). There were no associations with family history of any autoimmune diseases, immunodeficiencies, birth defects, thyroid diseases and risk of childhood ALL. Conclusions: These results show no association of overall family history of cancer with childhood ALL, while providing additional evidence for an inverse association with family history of allergic disease. Two potentially new associations of ALL with family history of esophageal cancer and rheumatoid arthritis require confirmation in other studies and validation with medical records. (C) 2011 Published by Elsevier Ltd. C1 [Zierhut, Heather; Spector, Logan] Univ Minnesota Twin Cities, Minneapolis, MN 55455 USA. [Linet, Martha S.] NCI, Bethesda, MD 20892 USA. [Robison, Leslie L.] St Jude Childrens Hosp, St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Severson, Richard K.] Wayne State Univ, Detroit, MI 48201 USA. RP Spector, L (reprint author), Univ Minnesota Twin Cities, 420 Delaware St SE,MMC 715,Room 1-187,Moos Tower,, Minneapolis, MN 55455 USA. EM zier0034@umn.edu; linetm@mail.nih.gov; Les.robison@stjude.org; rseverson@med.wayne.edu; spector@umn.edu OI Zierhut, Heather/0000-0003-1941-664X FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services [CA 13539, U10 CA98543]; Children's Cancer Research Fund, Minneapolis, MN FX Supported in part by Grant CA 13539 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Chair's Grant U10 CA98543, and the Children's Cancer Research Fund, Minneapolis, MN. NR 46 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD FEB PY 2012 VL 36 IS 1 BP 45 EP 51 DI 10.1016/j.canep.2011.06.004 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 900ZY UT WOS:000300932600018 PM 22018949 ER PT J AU Zhang, JH Seigneur, EM Pandey, M Loshakov, A Dagur, PK Connelly, PS Koo, L Panicker, LM Simonds, WF AF Zhang, J-H Seigneur, E. M. Pandey, M. Loshakov, A. Dagur, P. K. Connelly, P. S. Koo, L. Panicker, L. M. Simonds, W. F. TI The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome SO CELL DEATH & DISEASE LA English DT Article DE PAF1 complex; HRPT2; apoptosis; eIF4E; 4E-BP; s6k ID FAMILIAL ISOLATED HYPERPARATHYROIDISM; RNA-POLYMERASE-II; HUMAN PAF COMPLEX; HEREDITARY HYPERPARATHYROIDISM; BINDING PROTEIN; GROWTH-FACTORS; HRPT2 GENE; MEN1 GENE; PARAFIBROMIN; MUTATIONS AB Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome associated with a high risk of parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. The molecular pathways that distinguish malignant from benign parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye phenotype of lobe, encoding the fly homolog of Akt1s1/PRAS40. We report now an interaction between hyx and Tor, a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein (EIF4EBP), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to parathyroid malignant transformation. Cell Death and Disease (2012) 3, 266; doi: 10.1038/cddis.2012.6; published online 2 February 2012 C1 [Zhang, J-H; Seigneur, E. M.; Pandey, M.; Loshakov, A.; Panicker, L. M.; Simonds, W. F.] NIDDK, Metab Dis Branch, NIAID, NIH, Bethesda, MD 20892 USA. [Dagur, P. K.] NIAID, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Connelly, P. S.] NHLBI, Electron Microscopy Core Facil, NIAID, NIH, Bethesda, MD 20892 USA. [Koo, L.] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIDDK, Metab Dis Branch, NIAID, NIH, Bldg 10,Room 8C-101,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. EM wfs@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases FX We are grateful to Sunita Agarwal and Stephen Marx for encouragement and helpful discussions. This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases. NR 40 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD FEB PY 2012 VL 3 AR e266 DI 10.1038/cddis.2012.6 PG 11 WC Cell Biology SC Cell Biology GA 899BG UT WOS:000300786500004 PM 22297294 ER PT J AU Goldstein, DS Holmes, C Sewell, L Park, MY Sharabi, Y AF Goldstein, David S. Holmes, Courtney Sewell, LaToya Park, Mee Yeong Sharabi, Yehonatan TI Sympathetic noradrenergic before striatal dopaminergic denervation: relevance to Braak staging of synucleinopathy SO CLINICAL AUTONOMIC RESEARCH LA English DT Article DE Parkinson; Synuclein; Braak; Sympathetic nervous system; Norepinephrine ID PARKINSON-DISEASE; ORTHOSTATIC HYPOTENSION; AUTONOMIC FAILURE; LEWY BODIES; DISORDERS; DEMENTIA AB Braak's staging concept of Lewy body disease pathogenesis is based on a spatiotemporal sequence of alpha-synuclein deposition, with autonomic nervous system involvement before synucleinopathy in substantia nigra neurons. A patient with primary chronic autonomic failure underwent biennial brain 6-[F-18]DOPA and myocardial 6-[F-18] dopamine scanning over 4 years. Low myocardial radioactivity indicated cardiac noradrenergic denervation that persisted. Striatal 6-[F-18]DOPA-derived radioactivity initially was normal, 2 years later was decreased subtly, and by 4 years was clearly decreased, accompanied by dementia and parkinsonism. In this case, neuroimaging evidence of cardiac noradrenergic denervation and subsequent progressive striatal dopaminergic denervation fit with Braak staging. C1 [Goldstein, David S.; Holmes, Courtney; Sewell, LaToya; Park, Mee Yeong; Sharabi, Yehonatan] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, 10 Ctr Dr MSC 1620,Bldg 10,Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU NIH, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. Ms. Tereza Jenkins (Clinical Neurocardiology Section) coordinated patient travel. Sandra Pechnik, RN (Clinical Neurocardiology Section) assisted with clinical procedures and scheduling. NR 17 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD FEB PY 2012 VL 22 IS 1 BP 57 EP 61 DI 10.1007/s10286-011-0136-4 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 899XE UT WOS:000300849200007 PM 21796351 ER PT J AU Nakayama, S Ikenaga, T Kawakami, K Ono, F Hatta, K AF Nakayama, Sohei Ikenaga, Takanori Kawakami, Koichi Ono, Fumihito Hatta, Kohei TI Transgenic line with gal4 insertion useful to study morphogenesis of craniofacial perichondrium, vascular endothelium-associated cells, floor plate, and dorsal midline radial glia during zebrafish development SO DEVELOPMENT GROWTH & DIFFERENTIATION LA English DT Article DE cartilage; commissural axons; infrared laser-evoked gene operator; KikGR; Rohon-Beard cells ID ROHON-BEARD NEURONS; CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; SPINAL-CORD; IN-VIVO; TRANSCRIPTIONAL ACTIVATOR; FLUORESCENT PROTEIN; LARVAL ZEBRAFISH; GENE INDUCTION; DANIO-RERIO AB Zebrafish is a good model for studying vertebrate development because of the availability of powerful genetic tools. We are interested in the study of the craniofacial skeletal structure of the zebrafish. For this purpose, we performed a gene trap screen and identified a Gal4 gene trap line, SAGFF(LF)134A. We then analyzed the expression pattern of SAGFF(LF)134A;Tg(UAS:GFP) and found that green fluorescent protein (GFP) was expressed not only in craniofacial skeletal elements but also in the vascular system, as well as in the nervous system. In craniofacial skeletal elements, strong GFP expression was detected not only in chondrocytes but also in the perichondrium. In the vascular system, GFP was expressed in endothelium-associated cells. In the spinal cord, strong GFP expression was found in the floor plate, and later in the dorsal radial glia located on the midline. Taking advantage of this transgenic line, which drives Gal4 expression in specific tissues, we crossed SAGFF(LF)134A with several UAS reporter lines. In particular, time-lapse imaging of photoconverted floor-plate cells of SAGFF(LF)134A;Tg(UAS:KikGR) revealed that the floor-plate cells changed their shape within 36 h from cuboidal/trapezoidal to wine glass shaped. Moreover, we identified a novel mode of association between axons and glia. The putative paths for the commissural axons, including pax8-positive CoBL interneurons, were identified as small openings in the basal endfoot of each floor plate. Our results indicate that the transgenic line would be useful for studying the morphogenesis of less-well-characterized tissues of interest, including the perichondrium, dorsal midline radial glia, late-stage floor plate, and vascular endothelium-associated cells. C1 [Nakayama, Sohei; Ikenaga, Takanori; Hatta, Kohei] Univ Hyogo, Grad Sch Life Sci, Kamigori, Hyogo 6781297, Japan. [Kawakami, Koichi] Grad Univ Adv Studies SOKENDAI, Natl Inst Genet, Div Mol & Dev Biol, Dept Genet, Mishima, Shizuoka 4118540, Japan. [Ono, Fumihito] NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Hatta, K (reprint author), Univ Hyogo, Grad Sch Life Sci, 3-2-1 Koto, Kamigori, Hyogo 6781297, Japan. EM khatta@sci.u-hyogo.ac.jp OI Ikenaga, Takanori/0000-0002-7321-9703 FU National Institute of Child Health and Human Development (NICHD); JSPS; Ministry of Education, Culture, Sports, Science, and Technology of Japan; University of Hyogo FX We thank Dr A. Kawahara (RIKEN QBiC), Dr R. N. Kelsh (University of Bath), Dr C. B. Chien (University of Utah), Dr H. Takeda (The University of Tokyo), and Zebrafish National BioResource Project for their kind gifts of Tg (flk1:mRFP), Tg(-4.9sox10:EGFP), Tg(isl2b:EGFP)zc7, Tol-056 enhancer trap line, and AB line, respectively. The Zn8 antibody developed by Dr B. Trevarrow was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development (NICHD) and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242. This work was supported by a JSPS Research Fellowship to S.N.; by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and by a Grant-in-Aid for Special Education and Research from the University of Hyogo to K.H. NR 53 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0012-1592 J9 DEV GROWTH DIFFER JI Dev. Growth Diff. PD FEB PY 2012 VL 54 IS 2 BP 202 EP 215 DI 10.1111/j.1440-169X.2011.01322.x PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 898UD UT WOS:000300766600006 PM 22348745 ER PT J AU Cockburn, JJB Sanchez, MEN Goncalvez, AP Zaitseva, E Stura, EA Kikuti, CM Duquerroy, S Dussart, P Chernomordik, LV Lai, CJ Rey, FA AF Cockburn, Joseph J. B. Sanchez, M. Erika Navarro Goncalvez, Ana P. Zaitseva, Elena Stura, Enrico A. Kikuti, Carlos M. Duquerroy, Stephane Dussart, Philippe Chernomordik, Leonid V. Lai, Ching-Juh Rey, Felix A. TI Structural insights into the neutralization mechanism of a higher primate antibody against dengue virus SO EMBO JOURNAL LA English DT Article DE antibody; dengue; structure ID WEST-NILE-VIRUS; ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; MEMBRANE-FUSION; DOMAIN-III; SURFACE EPITOPES; FAB FRAGMENTS; PROTEIN; INFECTION AB The four serotypes of dengue virus (DENV-1 to -4) cause the most important emerging viral disease. Protein E, the principal viral envelope glycoprotein, mediates fusion of the viral and endosomal membranes during virus entry and is the target of neutralizing antibodies. However, the epitopes of strongly neutralizing human antibodies have not been described despite their importance to vaccine development. The chimpanzee Mab 5H2 potently neutralizes DENV-4 by binding to domain I of E. The crystal structure of Fab 5H2 bound to E from DENV-4 shows that antibody binding prevents formation of the fusogenic hairpin conformation of E, which together with in-vitro assays, demonstrates that 5H2 neutralizes by blocking membrane fusion in the endosome. Furthermore, we show that human sera from patients recovering from DENV-4 infection contain antibodies that bind to the 5H2 epitope region on domain I. This study, thus, provides new information and tools for effective vaccine design to prevent dengue disease. The EMBO Journal (2012) 31, 767-779. doi: 10.1038/emboj.2011.439; Published online 2 December 2011 C1 [Cockburn, Joseph J. B.; Sanchez, M. Erika Navarro; Kikuti, Carlos M.; Duquerroy, Stephane; Rey, Felix A.] Inst Pasteur, Dept Virol, Unite Virol Struct, Paris, France. [Cockburn, Joseph J. B.; Sanchez, M. Erika Navarro; Kikuti, Carlos M.; Duquerroy, Stephane; Rey, Felix A.] CNRS, URA3015, Paris, France. [Goncalvez, Ana P.; Lai, Ching-Juh] NIAID, Mol Viral Biol Sect, Infect Dis Lab, NIH, Bethesda, MA USA. [Zaitseva, Elena; Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MA USA. [Stura, Enrico A.] CEA, IBiTec S, Serv Ingn Mol Prot, Lab Toxinol Mol & Biotechnol, Gif Sur Yvette, France. [Dussart, Philippe] Inst Pasteur, Ctr Natl Reference Arbovirus & Virus Influenza, Cayenne, French Guiana. RP Cockburn, JJB (reprint author), Canc Res UK, Cell Motil Lab, London Res Inst, 44 Lincolns Inn Fields, London WC2A 3LY, England. EM joseph.cockburn@cancer.org.uk; rey@pasteur.fr RI STURA, Enrico/A-2793-2010; Rey, Felix/B-6497-2012; OI STURA, Enrico/0000-0001-6718-2118; Rey, Felix/0000-0002-9953-7988 FU PDVI; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; EMBO [ALTF-194-2005]; Marie Curie Intra-European Fellowship [EIF-25456-DENLIG]; Merck-Serono; ANR FX We thank Scott Halstead and Susie Kliks for their important support through the PDVI; Ahmed Haouz and Patrick Weber from the Protein Crystallization platform at the Pasteur Institute, Paris, and the staff of the PX1 beamline at the Swiss Light Source for beamline support; Clemens Vonhrein, Oliver Smart and Gerard Bricogne (Global phasing limited) for assistance in data processing and structure refinement; Dr S-T Yang (National Institutes of Health) for advice on liposome-based assays; Dr W Gillette and his colleagues at the Protein Expression Laboratory, SAIC-Frederick/NCI (Frederick, MD) for assistance in the production of recombinant Fab 5H2. This work was supported by a PDVI grant to FAR, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases to CJL, the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a National Institutes of Health Intramural Biodefense Research grant (both to LVC). JJBC was supported by an EMBO long-term fellowship (ALTF-194-2005) and a Marie Curie Intra-European Fellowship (EIF-25456-DENLIG). FAR also acknowledges support from Merck-Serono and from the ANR grant 'DENTRY'. NR 56 TC 31 Z9 31 U1 3 U2 7 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 FEB 1 PY 2012 VL 31 IS 3 BP 767 EP 779 DI 10.1038/emboj.2011.439 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 900FJ UT WOS:000300871700023 PM 22139356 ER PT J AU Sable, CA Aliyu, ZY Dham, N Nouraie, M Sachdev, V Sidenko, S Miasnikova, GY Polyakova, LA Sergueeva, AI Okhotin, DJ Bushuev, V Remaley, AT Niu, XM Castro, OL Gladwin, MT Kato, GJ Prchal, JT Gordeuk, VR AF Sable, Craig A. Aliyu, Zakari Y. Dham, Niti Nouraie, Mehdi Sachdev, Vandana Sidenko, Stanislav Miasnikova, Galina Y. Polyakova, Lydia A. Sergueeva, Adelina I. Okhotin, Daniel J. Bushuev, Vladimir Remaley, Alan T. Niu, Xiaomei Castro, Oswaldo L. Gladwin, Mark T. Kato, Gregory J. Prchal, Josef T. Gordeuk, Victor R. TI Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia) SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE pulmonary hypertension; tricuspid regurgitation velocity; ferritin; VHL; hypoxia inducible factor ID SICKLE-CELL-DISEASE; HUMAN CARDIOPULMONARY PHYSIOLOGY; SOCIETY-OF-ECHOCARDIOGRAPHY; TASK-FORCE; OXYGEN HOMEOSTASIS; INDUCIBLE FACTOR-1; RISK-FACTOR; HYPERTENSION; CHILDREN; MICE AB Background Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. The objectives of this study were to provide a comprehensive echocardiographic assessment of cardiovascular physiology and to identify clinical, hematologic and cardiovascular risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia. Design and Methods This cross-sectional observational study of 120 adult and pediatric VHLR200W homozygotes and 31 controls at outpatient facilities in Chuvashia, Russian Federation included echocardiography assessment of pulmonary artery pressure (tricuspid regurgitation velocity), cardiac volume, and systolic and diastolic function, as well as hematologic and clinical parameters. We determined the prevalence and risk factors for elevation of tricuspid regurgitation velocity in this population and its relationship to phlebotomy. Results The age-adjusted mean +/- SE tricuspid regurgitation velocity was higher in VHLR200W homozygotes than controls with normal VHL alleles (2.5+/-0.03 vs. 2.3+/-0.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.8+/-0.05 vs. 4.5+/-0.09 cm, P=0.005) and left atrial diameter (3.4+/-0.04 vs. 3.2+/-0.08 cm, P=0.011) were also greater in the VHLR200W homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHLR200W homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29; P=0.009). Conclusions Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic pressure, even after adjustment for echocardiography estimates of blood volume. Lower ferritin concentration, which is associated with phlebotomy, independently predicts higher tricuspid regurgitation velocity (www.clinicaltrials.gov identifier NCT00495638). C1 [Sable, Craig A.; Dham, Niti] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA. [Aliyu, Zakari Y.; Nouraie, Mehdi; Niu, Xiaomei; Castro, Oswaldo L.] Howard Univ, Dept Med, Washington, DC 20059 USA. [Aliyu, Zakari Y.; Nouraie, Mehdi; Niu, Xiaomei; Castro, Oswaldo L.] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Aliyu, Zakari Y.] Taraba State Specialist Hosp, Jalingo, Nigeria. [Sachdev, Vandana; Sidenko, Stanislav; Remaley, Alan T.; Kato, Gregory J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Sergueeva, Adelina I.] Cheboksary Childrens Hosp, Cheboksary, Russia. [Miasnikova, Galina Y.; Polyakova, Lydia A.] Chuvash Republ Clin Hosp 2, Cheboksary, Russia. [Okhotin, Daniel J.] Russian Res Serv, Vancouver, WA USA. [Bushuev, Vladimir] Chuvash Republ Cardiac Ctr, Cheboksary, Russia. [Gladwin, Mark T.] Univ Pittsburgh, Pittsburgh, PA USA. [Prchal, Josef T.] Univ Utah, Salt Lake City, UT USA. [Gordeuk, Victor R.] Univ Illinois, Chicago, IL USA. RP Sable, CA (reprint author), 111 Michigan Ave NW, Washington, DC 20010 USA. EM csable@cnmc.org RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU NHLBI [2 R25 HL003679-08, 1 R01 HL079912-02]; Howard University GCRC from NCRR, NIH, Bethesda, MD, USA [2MOI RR10284-10]; National Institutes of Health FX supported in part by grants ns. 2 R25 HL003679-08 and 1 R01 HL079912-02 from NHLBI, by Howard University GCRC grant n. 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, USA, and by the intramural research program of the National Institutes of Health. NR 46 TC 9 Z9 9 U1 0 U2 4 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD FEB PY 2012 VL 97 IS 2 BP 193 EP 200 DI 10.3324/haematol.2011.051839 PG 8 WC Hematology SC Hematology GA 898UB UT WOS:000300766300012 PM 21993671 ER PT J AU Carvajal-Cuenca, A Sua, LF Silva, NM Pittaluga, S Royo, C Song, JY Sargent, RL Espinet, B Climent, F Jacobs, SA Delabie, J Naresh, KN Bagg, A Brousset, P Warnke, RA Serrano, S Harris, NL Swerdlow, SH Jaffe, ES Campo, E AF Carvajal-Cuenca, Alejandra Sua, Luz F. Silva, Nhora M. Pittaluga, Stefania Royo, Cristina Song, Joo Y. Sargent, Rachel L. Espinet, Blanca Climent, Fina Jacobs, Samuel A. Delabie, Jan Naresh, Kikkeri N. Bagg, Adam Brousset, Pierre Warnke, Roger A. Serrano, Sergi Harris, Nancy Lee Swerdlow, Steven H. Jaffe, Elaine S. Campo, Elias TI In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE in situ mantle cell lymphoma; in situ involvement by mantle cell-lymphoma-like cells; indolent behavior ID FOLLICULAR LYMPHOMA; HEALTHY-INDIVIDUALS; NUCLEAR EXPRESSION; INVOLVEMENT; PATTERN; FEATURES; DISEASE; GENES; STAGE; ZONE AB Background Cyclin D1-positive B cells are occasionally found in the mantle zones of reactive lymphoid follicles, a condition that has been called "in situ mantle cell lymphoma". The clinical significance of this lesion remains uncertain. Design and Methods The clinical and pathological characteristics, including SOX11 expression, of 23 cases initially diagnosed as in situ mantle cell lymphoma were studied. Results Seventeen of the 23 cases fulfilled the criteria for in situ mantle cell lymphoma. In most cases, the lesions were incidental findings in reactive lymph nodes. The t(11; 14) was detected in all eight cases examined. SOX11 was positive in seven of 16 cases (44%). Five cases were associated with other small B-cell lymphomas. In two cases, both SOX11-positive, the in situ mantle cell lymphoma lesions were discovered after the diagnosis of overt lymphoma; one 4 years earlier, and one 3 years later. Twelve of the remaining 15 patients had a follow-up of at least 1 year (median 2 years; range, 1-19.5), of whom 11 showed no evidence of progression, including seven who were not treated. Only one of 12 patients with an in situ mantle cell lymphoma lesion and no diagnosis of mantle cell lymphoma at the time developed an overt lymphoma, 4 years later; this case was also SOX11-positive. The six remaining cases were diagnosed as mantle cell lymphoma with a mantle zone pattern. Five were SOX11-positive and four of them were associated with lymphoma without a mantle zone pattern. Conclusions In situ mantle cell lymphoma lesions are usually an incidental finding with a very indolent behavior. These cases must be distinguished from mantle cell lymphoma with a mantle zone pattern and overt mantle cell lymphoma because they may not require therapeutic intervention. C1 [Campo, Elias] Univ Barcelona, Hosp Clin, IDIBAPS, Dept Anat Pathol, E-08036 Barcelona, Spain. [Pittaluga, Stefania; Song, Joo Y.; Jaffe, Elaine S.] NCI, Bethesda, MD 20892 USA. [Sargent, Rachel L.; Jacobs, Samuel A.; Swerdlow, Steven H.] Univ Pittsburgh, Pittsburgh, PA USA. [Espinet, Blanca; Serrano, Sergi] Autonomous Univ Barcelona, Hosp Mar, Barcelona, Spain. [Climent, Fina] Bellvitge Univ Hosp, Barcelona, Spain. [Delabie, Jan] Oslo Univ Hosp, Oslo, Norway. [Naresh, Kikkeri N.] Hammersmith Hosp, London, England. [Bagg, Adam] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Brousset, Pierre] Univ Toulouse, CHU Purpan, Toulouse, France. [Warnke, Roger A.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Harris, Nancy Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Campo, E (reprint author), Univ Barcelona, Hosp Clin, IDIBAPS, Dept Anat Pathol, Villarroel 170, E-08036 Barcelona, Spain. EM ecampo@clinic.ub.es RI Royo, Cristina/H-3193-2015; Song, Joo/E-5356-2016; OI Royo, Cristina/0000-0002-1214-4656; Song, Joo/0000-0003-3497-2513; Delabie, Jan/0000-0001-5023-0689; Sua, Luz F/0000-0001-9574-2370; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU European Regional Development Fund; Comision Interministerial de Ciencia y Tecnologia (CICYT) [SAF08-03630]; Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD06/0020/0039]; Instituto de Salud Carlos III (ISCIII); Spanish Ministry of Science and Innovation; Generalitat de Catalunya [2009SGR992]; University of Costa Rica (UCR); Centro de Desarrollo Estrategico e Informacion en Salud y Seguridad Social (CENDEISSS) of Costa Rica FX this work was supported by grants from the European Regional Development Fund; the Comision Interministerial de Ciencia y Tecnologia (CICYT) SAF08-03630; RD06/0020/0039 from Red Tematica de Investigacion Cooperativa en Cancer (RTICC); Instituto de Salud Carlos III (ISCIII); Spanish Ministry of Science and Innovation, and the Generalitat de Catalunya 2009SGR992. AC-C has received a fellowship from the University of Costa Rica (UCR) and the Centro de Desarrollo Estrategico e Informacion en Salud y Seguridad Social (CENDEISSS) of Costa Rica. NR 33 TC 39 Z9 45 U1 1 U2 3 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD FEB PY 2012 VL 97 IS 2 BP 270 EP 278 DI 10.3324/haematol.2011.052621 PG 9 WC Hematology SC Hematology GA 898UB UT WOS:000300766300024 PM 22058203 ER PT J AU Murnane, KS Kimmel, HL Rice, KC Howell, LL AF Murnane, K. S. Kimmel, H. L. Rice, K. C. Howell, L. L. TI The neuropharmacology of prolactin secretion elicited by 3,4-methylenedioxymethamphetamine ("ecstasy"): A concurrent microdialysis and plasma analysis study SO HORMONES AND BEHAVIOR LA English DT Article DE MDMA; Serotonin; Prolactin; Fluoxetine; M100907; Rhesus ID RHESUS-MONKEYS; META-CHLOROPHENYLPIPERAZINE; RECEPTOR ANTAGONISTS; SQUIRREL-MONKEYS; MDMA; SEROTONIN; COCAINE; RELEASE; RATS; NEUROENDOCRINE AB 3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug "ecstasy". Racemic MDMA (S,R(+/-)-MDMA) and its stereoisomers elicit complex spectrums of psychobiological. neurochemical, and hormonal effects. In this regard, recent findings demonstrated that S,R(+/-)-MDMA and its stereoisomer R(-)-MDMA elicit increases in striatal extracellular serotonin levels and plasma levels of the hormone prolactin in rhesus monkeys. In the present mechanistic study, we evaluated the role of the serotonin transporter and the 5-HT2A receptor in S,R(+/-)-MDMA- and R(-)-MDMA-elicited prolactin secretion in rhesus monkeys through concurrent microdialysis and plasma analysis determinations and drug interaction experiments. Concurrent neurochemical and hormone determinations showed a strong positive temporal correlation between serotonin release and prolactin secretion. Consistent with their distinct mechanisms of action and previous studies showing that the serotonin transporter inhibitor fluoxetine attenuates the behavioral and neurochemical effects of S,R(+/-)-MDMA, pretreatment with fluoxetine attenuated serotonin release elicited by either S,R(+/-)-MDMA or R(-)-MDMA. As hypothesized, at a dose that had no significant effects on circulating prolactin levels when administered alone, fluoxetine also attenuated prolactin secretion elicited by S,R(+/-)-MDMA. In contrast, combined pretreatment with both fluoxetine and the selective 5-HT2A receptor antagonist M100907 was required to attenuate prolactin secretion elicited by R(-)-MDMA, suggesting that this stereoisomer of S,R(+/-)-MDMA elicits prolactin secretion through both serotonin release and direct agonism of 5-HT2A receptors. Accordingly, these findings inform our understanding of the neuropharmacology of both S,R(+/-)-MDMA and R(-)MDMA and the regulation of prolactin secretion. (C) 2011 Elsevier Inc. All rights reserved. C1 [Murnane, K. S.; Kimmel, H. L.; Howell, L. L.] Emory Univ, Yerkes Natl Primate Res Ctr, Div Neuropharmacol & Neurol Dis, Atlanta, GA 30322 USA. [Kimmel, H. L.; Howell, L. L.] Emory Univ, Dept Pharmacol, Atlanta, GA 30322 USA. [Rice, K. C.] Natl Inst Drug Abuse, Chem Biol Res Branch, NIH, Bethesda, MD USA. [Rice, K. C.] NIAAA, NIH, Bethesda, MD USA. [Howell, L. L.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. RP Howell, LL (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Div Neuropharmacol & Neurol Dis, 954 Gatewood Rd, Atlanta, GA 30322 USA. EM leonard@rmy.emory.edu RI Kimmel, Heather/A-6617-2008; Kimmel, Heather/E-9135-2014 OI Kimmel, Heather/0000-0001-8278-0095; Kimmel, Heather/0000-0001-8278-0095 FU National Institutes of Health [DA000517, DA010344]; Yerkes Base Grant [RR00165]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX The authors would like to thank Jodi Godfrey, Juliet Brown, and Lisa Neidert for their expert technical assistance on this project. Furthermore, we would like to thank the Yerkes National Primate Research Center's Biomarkers Core Laboratory for the care and speed with which they carried out the prolactin assays. Finally, we would like to thank the animal care staff at the Yerkes center for their fine animal husbandry services. These studies were funded by the National Institutes of Health [DA000517 and DA010344 (LLH)] and by the Yerkes Base Grant [RR00165 (KSM; HLK; LLH)]. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. NR 45 TC 7 Z9 7 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X J9 HORM BEHAV JI Horm. Behav. PD FEB PY 2012 VL 61 IS 2 BP 181 EP 190 DI 10.1016/j.yhbeh.2011.10.012 PG 10 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA 899LJ UT WOS:000300817100004 PM 22197270 ER PT J AU Taal, HR Verwoert, GC Demirkan, A Janssens, ACJW Rice, K Ehret, G Smith, AV Verhaaren, BFJ Witteman, JCM Hofman, A Vernooij, MW Uitterlinden, AG Rivadeneira, F Ikram, MA Levy, D van der Heijden, AJ Jaddoe, VWV van Duijn, CM AF Taal, Hendrik R. Verwoert, Germaine C. Demirkan, Ayse Janssens, A. Cecile J. W. Rice, Kenneth Ehret, Georg Smith, Albert V. Verhaaren, Ben F. J. Witteman, Jacqueline C. M. Hofman, Albert Vernooij, Meike W. Uitterlinden, Andre G. Rivadeneira, Fernando Ikram, M. Arfan Levy, Daniel van der Heijden, Albert J. Jaddoe, Vincent W. V. van Duijn, Cornelia M. CA Cohort Heart Aging Res Genome Epid TI Genome-Wide Profiling of Blood Pressure in Adults and Children SO HYPERTENSION LA English DT Article DE genome-wide association; genome-wide profiling; genetic risk scores; blood pressure; hypertension ID COMPLEX DISEASE; HYPERTENSION; ASSOCIATION; POPULATION; PREDICTION; CHILDHOOD; BURDEN; HEART; SCAN; RISK AB Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolicblood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n = 29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n = 2072) and a child population (n = 1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained <= 1.2% (P = 9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P = 0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P = 8.9*10(-10)] and 1.4% [P = 3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life. (Hypertension. 2012; 59: 241-247.). Online Data Supplement C1 [Taal, Hendrik R.; Hofman, Albert; Jaddoe, Vincent W. V.] Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands. [Taal, Hendrik R.; Verwoert, Germaine C.; Demirkan, Ayse; Janssens, A. Cecile J. W.; Verhaaren, Ben F. J.; Witteman, Jacqueline C. M.; Hofman, Albert; Vernooij, Meike W.; Uitterlinden, Andre G.; Rivadeneira, Fernando; Ikram, M. Arfan; Jaddoe, Vincent W. V.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Taal, Hendrik R.; van der Heijden, Albert J.; Jaddoe, Vincent W. V.] Erasmus MC, Dept Paediat, Rotterdam, Netherlands. [Verwoert, Germaine C.; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Verhaaren, Ben F. J.; Vernooij, Meike W.; Ikram, M. Arfan] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Smith, Albert V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Levy, Daniel] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Washington, DC USA. [Ehret, Georg] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Ehret, Georg] Univ Hosp Geneva, Dept Cardiol, Geneva, Switzerland. [Ehret, Georg] Univ Lausanne, Inst Social & Prevent Med, Lausanne, Switzerland. RP Jaddoe, VWV (reprint author), Erasmus MC, Generat R Study Grp Ae 006, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM v.jaddoe@erasmusmc.nl RI EHRET, Georg/A-9532-2009; Rivadeneira, Fernando/O-5385-2015; Vernooij, Meike/E-4061-2016; Smith, Albert/K-5150-2015; OI EHRET, Georg/0000-0002-5730-0675; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Janssens, A Cecile/0000-0002-6153-4976; Ikram, Mohammad Arfan/0000-0003-0372-8585 FU Netherlands Organization for Scientific Research (Netherlands Organisation for Scientific Research) [175.010.2005.011, 911.03.012]; Research Institute for Diseases in the Elderly [014.93.015, RIDE2]; Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research [050-060-810]; Netherlands Heart Foundation [2009B102]; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Dutch Kidney Foundation [C08.2251]; Cohort for Heart and Aging Research in Genome Epidemiology consortium FX This Rotterdam Study III support for genotyping was provided by The Netherlands Organization for Scientific Research (Netherlands Organisation for Scientific Research Groot, 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (014.93.015; RIDE2). This study was supported by The Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research project No. 050-060-810. This study was further financially supported by The Netherlands Heart Foundation grant 2009B102 (to B.F.J.V. and M.A.I.). The first phase of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; and The Netherlands Organization for Health Research and Development (ZonMw). Additional support was provided by a grant from the Dutch Kidney Foundation (C08.2251; RT). The funding sources of other cohorts in the Cohort for Heart and Aging Research in Genome Epidemiology consortium are described in the online Data Supplement (please see http://hyper.ahajournals.org). NR 24 TC 19 Z9 19 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2012 VL 59 IS 2 BP 241 EP + DI 10.1161/HYPERTENSIONAHA.111.179481 PG 20 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 879FT UT WOS:000299315800027 PM 22203742 ER PT J AU Lee, J Romero, R Dong, Z Lee, DC Dong, Y Mittal, P Chaiworapongsa, T Hassan, SS Kim, CJ AF Lee, JoonHo Romero, Roberto Dong, Zhong Lee, Deug-Chan Dong, Yi Mittal, Pooja Chaiworapongsa, Tinnakorn Hassan, Sonia S. Kim, Chong Jai TI Glycogen Phosphorylase Isoenzyme BB Plasma Concentration Is Elevated in Pregnancy and Preterm Preeclampsia SO HYPERTENSION LA English DT Article DE small-for-gestational-age neonate; labor; hypoxia; placenta ID ANTI-ANGIOGENIC FACTORS; FOR-GESTATIONAL-AGE; FETAL-GROWTH; MATERNAL PLASMA; HUMAN PLACENTA; HYPERTENSION; ECLAMPSIA; TERM; RISK; RESTRICTION AB Glycogen phosphorylase is a key enzyme in glycogenolysis. Released with myocardial ischemia, blood concentration of glycogen phosphorylase isoenzyme BB (GPBB) is a marker of acute coronary syndromes. Pregnancy imposes metabolic stress, and preeclampsia is associated with cardiac complications. However, plasma GPBB concentration during pregnancy is unknown. This study was conducted to determine maternal plasma GPBB concentration in normal pregnancy and in preeclampsia. Plasma samples from 6 groups (n = 396) were studied: nonpregnant and pregnant women with normal term delivery, term and preterm preeclampsia, and term and preterm small-for-gestational-age neonates. GPBB concentration was measured with a specific immunoassay. Placental tissues (n = 45) obtained from pregnant women with preterm and term preeclampsia, spontaneous preterm delivery, and normal term delivery were analyzed for potential GPBB expression by immunoblotting. Median plasma GPBB concentration was higher in pregnant women than in nonpregnant women (38.7 versus 9.2 ng/mL; P < 0.001), which remained significant after adjusting for age, race, and parity. Maternal plasma GPBB concentrations did not change throughout gestation. Cases of preterm (but not term) preeclampsia had higher median plasma GPBB concentrations than gestational age-matched normal pregnancy cases (72.6 versus 26.0 ng/mL; P = 0.001). Small-for-gestational-age neonates did not affect plasma GPBB concentration. GPBB was detected in the placenta and was less abundant in preterm preeclampsia than in preterm delivery cases (P < 0.01). There is physiological elevation of plasma GPBB concentration during pregnancy; an increase in maternal plasma GPBB is a novel phenotype of preterm preeclampsia. It is strongly suggested that these changes are attributed to GPBB of placental origin. (Hypertension. 2012; 59: 274-282.). Online Data Supplement C1 [Kim, Chong Jai] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. [Romero, Roberto] Univ Ulsan, Coll Med, Ctr Mol Med & Genet, Seoul 138736, South Korea. [Romero, Roberto; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Univ Ulsan, Coll Med, Dept Obstet & Gynecol, Seoul 138736, South Korea. [Lee, JoonHo; Romero, Roberto; Lee, Deug-Chan; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Kim, Chong Jai] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kim, CJ (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, 88,Olympic Ro 43 Gil, Seoul 138736, South Korea. EM prbchiefstaff@med.wayne.edu; ckim@amc.seoul.kr FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services FX This work was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services. NR 49 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2012 VL 59 IS 2 BP 274 EP + DI 10.1161/HYPERTENSIONAHA.111.177444 PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 879FT UT WOS:000299315800031 PM 22215716 ER PT J AU Jennings, BL Anderson, LJ Estes, AM Yaghini, FA Fang, XR Porter, J Gonzalez, FJ Campbell, WB Malik, KU AF Jennings, Brett L. Anderson, Larry J. Estes, Anne M. Yaghini, Fariborz A. Fang, Xiao R. Porter, Jason Gonzalez, Frank J. Campbell, William B. Malik, Kafait U. TI Cytochrome P450 1B1 Contributes to Renal Dysfunction and Damage Caused by Angiotensin II in Mice SO HYPERTENSION LA English DT Article DE angiotensin II; CYP1B1; Cyp1b1(-/-) mice; renal function; oxidative stress ID SMOOTH-MUSCLE-CELLS; SPONTANEOUSLY HYPERTENSIVE-RATS; VASCULAR SUPEROXIDE-PRODUCTION; BLOOD-PRESSURE REGULATION; ACTIVATED PROTEIN-KINASE; ARACHIDONIC-ACID; OXIDATIVE STRESS; 20-HYDROXYEICOSATETRAENOIC ACID; NADPH OXIDASE; ENDOTHELIAL DYSFUNCTION AB Cytochrome P450 1B1 contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the kidney, as well as in salt and water homeostasis, and blood pressure regulation, we determined the contribution of cytochrome P450 1B1 to renal dysfunction and injury associated with angiotensin II-induced hypertension in male Cyp1b1(+/+) and Cyp1b1(-/-) mice. Angiotensin II infusion (700 ng/kg per minute) given by miniosmotic pumps for 13 and 28 days increased systolic blood pressure in Cyp1b1(+/+) mice; this increase was significantly reduced in Cyp1b1(-/-) mice. Angiotensin II increased renal Cyp1b1 activity, vascular resistance, and reactivity to vasoconstrictor agents and caused endothelial dysfunction in Cyp1b1(+/+) but not Cyp1b1(-/-) mice. Angiotensin II increased water consumption and urine output, decreased urine osmolality, increased urinary Na+ and K+ excretion, and caused proteinuria and albuminuria in Cyp1b1(+/+) mice that was diminished in Cyp1b1(-/-) mice. Infusion of angiotensin II for 28 but not 13 days caused renal fibrosis, tubular damage, and inflammation in Cyp1b1(+/+) mice, which was minimized in Cyp1b1(-/-) mice. Angiotensin II increased levels of 12- and 20-hydroxyeicosatetraenoic acids; reactive oxygen species; and activity of NADPH oxidase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src in the kidneys of Cyp1b1(+/+) but not Cyp1b1(-/-) mice. These data suggest that increased thirst, renal dysfunction, and injury and inflammation associated with angiotensin II-induced hypertension in mice depend on cytochrome P450 1B1 activity, thus indicating that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension. (Hypertension. 2012; 59: 348-354.). Online Data Supplement C1 [Jennings, Brett L.; Anderson, Larry J.; Estes, Anne M.; Yaghini, Fariborz A.; Fang, Xiao R.; Porter, Jason; Malik, Kafait U.] Univ Tennessee, Hlth Sci Ctr, Dept Pharmacol, Coll Med, Memphis, TN 38163 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. [Campbell, William B.] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. RP Malik, KU (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Pharmacol, Coll Med, 874 Union Ave, Memphis, TN 38163 USA. EM kmalik@uthsc.edu FU National Institutes of Health National Heart, Lung, and Blood Institute [R01-HL-19134-36, R01-HL-103673]; Neuroscience Institute, University of Tennessee Health Science Center; American Society of Pharmacology and Experimental Therapeutics FX This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute, grants R01-HL-19134-36 (to K.U.M) and R01-HL-103673 (to W.B.C). B.L.J. was partly supported by a fellowship from the Neuroscience Institute, University of Tennessee Health Science Center. L.J.A. was supported by a summer student fellowship from the American Society of Pharmacology and Experimental Therapeutics, and J.P. was a summer medical student fellow of the American Heart Association. NR 59 TC 22 Z9 23 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2012 VL 59 IS 2 BP 348 EP + DI 10.1161/HYPERTENSIONAHA.111.183301 PG 27 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 879FT UT WOS:000299315800040 PM 22184325 ER PT J AU Lai, EY Solis, G Luo, ZM Carlstrom, M Sandberg, K Holland, S Wellstein, A Welch, WJ Wilcox, CS AF Lai, En Yin Solis, Glenn Luo, Zaiming Carlstrom, Mattias Sandberg, Kathryn Holland, Steven Wellstein, Anton Welch, William J. Wilcox, Christopher S. TI p47(phox) Is Required for Afferent Arteriolar Contractile Responses to Angiotensin II and Perfusion Pressure in Mice SO HYPERTENSION LA English DT Article DE NADPH oxidase; hypertension; oxidative stress; reactive oxygen species ID SMOOTH-MUSCLE-CELLS; RENAL BLOOD-FLOW; NADPH OXIDASE ACTIVITY; OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE; INFUSED RATS; HYPERTENSION; AUTOREGULATION; ACTIVATION; KIDNEY AB Myogenic and angiotensin contractions of afferent arterioles generate reactive oxygen species. Resistance vessels express neutrophil oxidase-2 and -4. Angiotensin II activates p47(phox)/neutrophil oxidase-2, whereas it downregulates NOX-4. Therefore, we tested the hypothesis that p47(phox) enhances afferent arteriolar angiotensin contractions. Angiotensin II infusion in p47(phox) +/+ but not -/- mice increased renal cortical NADPH oxidase activity (7+/-1-12+/-1 [P<0.01] versus 5+/-1-7+/-1 10(3) . RLU . min(-1) . mu g protein(-1) [P value not significant]), mean arterial pressure (77+/-2-91+/-2 [P<0.005] versus 74+/-2-77+/-1 mm Hg [P value not significant]), and renal vascular resistance (7.5+/-0.4 -10.1+/-0.7 [P<0.01] versus 7.9+/-0.4-8.3+/-0.4 mm Hg/mL . min(-1) . gram kidney weight(-1) [P value not significant]). Afferent arterioles from p47(phox) -/- mice had a lesser myogenic response (3.1+/-0.4 versus 1.4+/-0.2 dynes . cm(-1) . mm Hg-1; P<0.02) and a lesser (P<0.05) contraction to 10(-6) M angiotensin II (diameter change +/+ : 9.3+/-0.2-3.4+/-0.6 . m versus -/- : 9.9+/-0.6 -7.5+/-0.4 mu m). Angiotensin and increased perfusion pressure generated significantly (P<0.05) more reactive oxygen species in p47(phox) +/+ than -/- arterioles. Angiotensin II infusion increased the maximum responsiveness of afferent arterioles from p47(phox) +/+ mice to 10(-6) M angiotensin II yet decreased the response in p47(phox) -/- mice. The angiotensin infusion increased the sensitivity to angiotensin II only in p47(phox) +/+ mice. We conclude that p47(phox) is required to enhance renal NADPH oxidase activity and basal afferent arteriolar myogenic and angiotensin II contractions and to switch afferent arteriolar tachyphylaxis to sensitization to angiotensin during a prolonged angiotensin infusion. These effects likely contribute to hypertension and renal vasoconstriction during infusion of angiotensin II. (Hypertension. 2012;59[part 2]:415-420.). Online Data Supplement C1 [Lai, En Yin; Solis, Glenn; Luo, Zaiming; Carlstrom, Mattias; Sandberg, Kathryn; Welch, William J.; Wilcox, Christopher S.] Georgetown Univ, Med Ctr, Div Nephrol & Hypertens, Washington, DC 20007 USA. [Lai, En Yin; Solis, Glenn; Luo, Zaiming; Carlstrom, Mattias; Sandberg, Kathryn; Welch, William J.; Wilcox, Christopher S.] Georgetown Univ, Med Ctr, Hypertens Kidney & Vasc Res Ctr, Washington, DC 20007 USA. [Wellstein, Anton] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. [Holland, Steven] NIAID, Bethesda, MD 20892 USA. RP Wilcox, CS (reprint author), Georgetown Univ, Med Ctr, Div Nephrol & Hypertens, 3800 Reservoir Rd,NW,PHC Bldg,F6003, Washington, DC 20007 USA. EM wilcoxch@georgetown.edu OI Wellstein, Anton/0000-0002-0570-4950 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-036079, DK-049870]; National Heart, Lung, and Blood Institute [HL-68686]; George E. Schreiner Chair of Nephrology FX This study was supported by research grants to C.S.W. and W.J.W. from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-036079 and DK-049870); and to C.S.W., W.J.W., A.W., and K.S. from the National Heart, Lung, and Blood Institute (HL-68686); and by funds from the George E. Schreiner Chair of Nephrology. NR 41 TC 23 Z9 23 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2012 VL 59 IS 2 BP 415 EP + DI 10.1161/HYPERTENSIONAHA.111.184291 PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 879FT UT WOS:000299315800051 PM 22184329 ER PT J AU Xu, X Veenstra, TD AF Xu, Xia Veenstra, Timothy D. TI Factors That Contribute to Assay Variation in Quantitative Analysis of Sex Steroid Hormones Using Liquid and Gas Chromatography-Mass Spectrometry SO JOURNAL OF CHEMICAL EDUCATION LA English DT Article DE Graduate Education/Research; Second-Year Undergraduate; Upper-Division Undergraduate; Analytical Chemistry; Biochemistry; Textbooks/Reference Books; Gas Chromatography; HPLC; Hormones; Mass Spectrometry ID ESTROGENS; CANCER; URINE; MEN AB The list of physiological events in which sex steroids play a role continues to increase. To decipher the roles that sex steroids play in any condition requires high quality cohorts of samples and assays that provide highly accurate quantitative measures. Liquid and gas chromatography coupled with mass spectrometry (LC-MS and GC-MS) have dramatically increased the capability to quantitatively measure sex steroids in complex biologic samples. Although it is important to optimize and calibrate the LC-MS and GC-MS steps, other areas such as sample preparation, molecular derivatization, and data analysis need to be carefully considered to minimize assay variation. The specific steps necessary for an effective quantitative assay are highly dependent on the type of sex steroid(s) being measured and the analytical steps described in this article will not be pertinent to every analyte. In this article, however, many of the steps necessary to develop an effective assay for sex steroids will be reviewed with a focus on areas that contribute to variation within the final quantitative results. The development of robust quantitative assays with high precision, accuracy, and reproducibility will continue to contribute to our understanding of the specific roles sex steroids play in diseases such as cancer. C1 [Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the United States Government. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. NR 15 TC 1 Z9 1 U1 2 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-9584 J9 J CHEM EDUC JI J. Chem. Educ. PD FEB PY 2012 VL 89 IS 2 BP 230 EP 233 DI 10.1021/ed1009442 PG 4 WC Chemistry, Multidisciplinary; Education, Scientific Disciplines SC Chemistry; Education & Educational Research GA 902ZB UT WOS:000301081600011 ER PT J AU Blanco, C Vesga-Lopez, O Stewart, JW Liu, SM Grant, BF Hasin, DS AF Blanco, Carlos Vesga-Lopez, Oriana Stewart, Jonathan W. Liu, Shang-Min Grant, Bridget F. Hasin, Deborah S. TI Epidemiology of Major Depression With Atypical Features: Results From the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; COMPREHENSIVE DEVELOPMENTAL MODEL; PSYCHIATRIC DIAGNOSTIC MODULES; AGE-OF-ONSET; USE-DISORDER; BIPOLAR-II; PERSONALITY-DISORDERS; DRUG MODULES; COMORBIDITY SURVEY AB Objective: To examine prevalence, correlates, comorbidity and treatment-seeking among individuals with a lifetime major depressive episode (MDE) with and without atypical features. Method: Data were derived from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, a large cross-sectional survey of a representative sample (N = 43,093) of the US population that assessed psychiatric disorders using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IVVersion (AUDADIS-IV). Comparison groups were defined based on the presence or absence of hypersomnia or hyperphagia in individuals who met criteria for lifetime DSM-IV MDE. Results: The presence of atypical features during an MDE was associated with greater rates of lifetime psychiatric comorbidity, including alcohol abuse, drug dependence, dysthymia, social anxiety disorder, specific phobia, and any personality disorder (all P values < .05), except antisocial personality disorder, than MDE without atypical features. Compared with the latter group, MDE with atypical features was associated with female gender, younger age at onset, more MDEs, greater episode severity and disability, higher rates of family history of depression, bipolar I disorder, suicide attempts, and larger mental health treatment-seeking rates (all P values < .05). Conclusions: Our data provide further evidence for the clinical significance and validity of this depressive specifier. Based on the presence of any of the 2 reversed vegetative symptoms during an MDE, most of the commonly cited validators of atypical depression were confirmed in our study. Major depressive episode with atypical features may be more common, severe, and impairing than previously documented. J Clin Psychiatry 2012;73(2):224-232 (C) Copyright 2011 Physicians Postgraduate Press, Inc. C1 [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Blanco, Carlos; Stewart, Jonathan W.; Liu, Shang-Min; Hasin, Deborah S.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Vesga-Lopez, Oriana] Harvard Univ, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Room 3077,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov RI Blanco, Carlos/I-4906-2013 OI Blanco, Carlos/0000-0001-6187-3057 FU Eli Lilly; National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Program; NIAAA; National Institutes of Health (NIH) [DA019606, DA020783, DA023200, DA023973, MH076051, MH082773, R01AA08159, K05AA00161]; American Foundation for Suicide Prevention; New York State Psychiatric Institute FX Dr Stewart has received financial support for his participation in a Continuing Medical Education course funded by Eli Lilly (course content was not screened by Eli Lilly). Drs Blanco, Vesga-Lopez, Grant, and Hasin and Ms Liu report no financial or other conflicts of interest related to the subject of this article.; The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health (NIH). This study is supported by NIH grants DA019606, DA020783, DA023200, DA023973, MH076051, and MH082773 (Dr Blanco); R01AA08159 and K05AA00161 (Dr Hasin); the American Foundation for Suicide Prevention (Dr Blanco); and the New York State Psychiatric Institute (Drs Blanco, Hasin, and Stewart). NR 57 TC 25 Z9 27 U1 1 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2012 VL 73 IS 2 BP 224 EP 232 DI 10.4088/JCP.10m06227 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 900TZ UT WOS:000300915100012 PM 21939615 ER PT J AU Han, P Lee, M Reeve, B Mariotto, A Wang, ZQ Hays, R Yabroff, R Topor, M Feuer, E AF Han, Paul Lee, Minjung Reeve, Bryce Mariotto, Angela Wang, Zhuoqiao Hays, Ron Yabroff, Robin Topor, Marie Feuer, Eric TI Development of a Prognostic Model for 6-month Mortality in Older Adults With Declining Health SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract CT Annual Assembly of the American-Academy-of-Hospice-and-Palliative-Medicine and the Hospice-and-Palliative-Nurses-Associations CY MAR 07-10, 2012 CL Denver, CO SP Amer Acad Hospice & Palliative Med, Hospice & Palliative Nurses Assoc C1 [Han, Paul] Maine Med Ctr, Res Inst, Portland, ME 04102 USA. [Lee, Minjung; Mariotto, Angela] NCI, Rockville, MD USA. [Reeve, Bryce] Univ N Carolina, Chapel Hill, NC USA. [Wang, Zhuoqiao; Topor, Marie] Informat Management Serv Inc, Silver Spring, MD USA. [Hays, Ron] Univ Calif Los Angeles, Los Angeles, CA USA. [Yabroff, Robin; Feuer, Eric] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD FEB PY 2012 VL 43 IS 2 BP 346 EP 347 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 889DY UT WOS:000300054900040 ER PT J AU Campbell, K Foster-Schubert, K Alfano, C Duggan, C Irwin, M McTiernan, A AF Campbell, Kristin Foster-Schubert, Karen Alfano, Catherine Duggan, Catherine Irwin, Melinda McTiernan, Anne TI Injuries in Sedentary Individuals Enrolled in a 12-Month, Randomized, Controlled, Exercise Trial SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE musculoskeletal; physical activity; bodily pain; overweight ID TIME PHYSICAL-ACTIVITY; QUALITY-OF-LIFE; MUSCULOSKELETAL INJURIES; ACTIVITY LEVEL; ACTIVE ADULTS; UNITED-STATES; RISK-FACTORS; US ADULTS; HEALTH; WOMEN AB Background: The risk of musculoskeletal injury with the introduction of moderate-to-vigorous exercise in sedentary adults is not well established. The purpose of this report is to examine the effect of a 12-month exercise intervention on musculoskeletal injury and bodily pain in predominately overweight, sedentary men (n = 102) and women (n = 100), ages 40 to 75 years. Methods: Participants were randomized to a moderate-to-vigorous aerobic exercise intervention (EX) (6 d/wk, 60 min/d, 60% to 85% max. heart rate) or usual lifestyle control (CON). Participants completed a self-report of musculoskeletal injury and body pain at baseline and 12-months. Results: The number of individuals reporting an injury (CON; 28% vs. EX; 28%, P = .95) did not differ by group. The most commonly injured site was lower leg/ankle&ot. The most common causes of injury were sports/physical activity, home maintenance, or "other." In the control group, bodily pain increased over the 12 months compared with the exercise group (CON -7.9, EX -1.4, P = .05). Baseline demographics and volume of exercise were not associated with injury risk. Conclusions: Previously sedentary men and women randomized to a 12-month aerobic exercise intervention with a goal of 360 min/wk reported the same number of injuries as those in the control group and less bodily pain. C1 [Campbell, Kristin] Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada. [Foster-Schubert, Karen] Univ Washington, Dept Med, Seattle, WA USA. [Alfano, Catherine] NCI, Off Canc Survivors, Bethesda, MD 20892 USA. [Duggan, Catherine; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth, Seattle, WA 98104 USA. [Irwin, Melinda] Yale Univ, Sch Publ Hlth, New Haven, CT USA. RP Campbell, K (reprint author), Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada. RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU Canadian Institutes of Health Research; NCI NIH HHS [R01 CA 77572-01, R01 CA077572] NR 29 TC 4 Z9 4 U1 0 U2 2 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD FEB PY 2012 VL 9 IS 2 BP 198 EP 207 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 901IO UT WOS:000300960800005 PM 22368219 ER PT J AU Muller, WG Heymann, JB Nagashima, K Guttmann, P Werner, S Rehbein, S Schneider, G McNally, JG AF Mueller, Waltraud G. Heymann, J. Bernard Nagashima, Kunio Guttmann, Peter Werner, Stephan Rehbein, Stefan Schneider, Gerd McNally, James G. TI Towards an atlas of mammalian cell ultrastructure by cryo soft X-ray tomography SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Soft X-ray tomography; Mammalian cells; Ultrastructure ID ELECTRON-MICROSCOPY; SPATIAL-RESOLUTION; BSOFT AB We provide a catalog of 3D cryo soft X-ray tomography (cryo-SXT) images obtained from similar to 6 to 12 mu m thick mouse adenocarcinoma cells. Included are multiple representative images of nuclei, nucleoli, nuclear membrane, nuclear membrane channels, mitochondria, lysosomes, endoplasmic reticulum, filaments and plasma membrane, plus three structures not previously described by cryo-SXT, namely Golgi, microvilli and nuclear-membrane blebs. Sections from the 3D cryo-SXT tomograms for all the preceding structures closely resemble those seen by thin-section transmission electron microscopy (TEM). Some structures such as nuclear-membrane channels and nuclear-membrane blebs are more easily detected by cryo-SXT than TEM most likely due to their better contrast and cellular preservation in cryo-SXT combined with the ability to rapidly locate these structures within a full 3D image. We identify and discuss two current limitations in cryo-SXT: variability in image quality and difficulties in detecting weaker contrast structures such as chromatin and various nuclear bodies. Progress on these points is likely to come from the solution of several technical problems in image acquisition, plus the implementation of advanced cryo soft X-ray microscopy approaches such as phase contrast or optical sectioning. Published by Elsevier Inc. C1 [Mueller, Waltraud G.; McNally, James G.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Heymann, J. Bernard] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Nagashima, Kunio] NCI, Electron Microscopy Lab, SAIC Frederick Inc, NIH, Frederick, MD 21702 USA. [Guttmann, Peter; Werner, Stephan; Rehbein, Stefan; Schneider, Gerd] Helmholtz Zentrum Berlin Mat & Energie GmbH, Inst Soft Matter & Funct Mat, Electron Storage Ring BESSY 2, D-12489 Berlin, Germany. RP McNally, JG (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, 41 Lib Dr, Bethesda, MD 20892 USA. EM mcnallyj@exchange.nih.gov RI Guttmann, Peter/H-9869-2015; OI Guttmann, Peter/0000-0002-0534-238X; Heymann, Bernard/0000-0002-8872-5326 FU Human Frontier Science Program [RGP0053/2005-C]; German Federal Ministry of Education and Research [05KS4BY1/7]; National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Cancer Institute, Center for Cancer Research [HHSN26120080001E] FX We thank Michael Kruhlak and Richard Leapman for advice and comments on the manuscript. This work was funded in part by the Human Frontier Science Program Research Grant Ref. RGP0053/2005-C, the German Federal Ministry of Education and Research under contract number 05KS4BY1/7, the intramural program of the National Institutes of Health, including the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Cancer Institute, Center for Cancer Research, including Science Applications International Corporations Frederick contract number HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government, NR 21 TC 27 Z9 28 U1 2 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD FEB PY 2012 VL 177 IS 2 BP 179 EP 192 DI 10.1016/j.jsb.2011.11.025 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 898PX UT WOS:000300755400002 PM 22155291 ER PT J AU Baker, SG AF Baker, Stuart G. TI Gene Signatures Revisited SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID EXPRESSION SIGNATURE; CANCER PROGRESSION; PREDICTION; DESIGN; TUMORS C1 NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, EPN 3118,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 19 TC 4 Z9 4 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB PY 2012 VL 104 IS 4 BP 262 EP 263 DI 10.1093/jnci/djr557 PG 2 WC Oncology SC Oncology GA 898FY UT WOS:000300725100003 PM 22262869 ER PT J AU Weissfeld, JL Schoen, RE Pinsky, PF Bresalier, RS Doria-Rose, VP Laiyemo, AO Church, T Yokochi, LA Yurgalevitch, S Rathmell, J Andriole, GL Buys, S Crawford, ED Fouad, M Isaacs, C Lamerato, L Reding, D Prorok, PC Berg, CD AF Weissfeld, Joel L. Schoen, Robert E. Pinsky, Paul F. Bresalier, Robert S. Doria-Rose, V. Paul Laiyemo, Adeyinka O. Church, Timothy Yokochi, Lance A. Yurgalevitch, Susan Rathmell, Joshua Andriole, Gerald L. Buys, Saundra Crawford, E. David Fouad, Mona Isaacs, Claudine Lamerato, Lois Reding, Douglas Prorok, Philip C. Berg, Christine D. CA PLCO Project Team TI Flexible Sigmoidoscopy in the Randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial: Added Yield from a Second Screening Examination SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SERVICES TASK-FORCE; BASE-LINE FINDINGS; NEGATIVE COLONOSCOPY; MEDICARE POPULATION; COST-EFFECTIVENESS; ADENOMA DETECTION; DETECTION RATES; RISK; SURVEILLANCE; NEOPLASIA AB Background Among randomized trials evaluating flexible sigmoidoscopy (FSG) for its effect on colorectal cancer mortality, only the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial screened its participants more than one time. We report outcomes from the PLCO screening FSG program and evaluate the increased yield produced by a second FSG. Methods Participants were screened by 60-cm FSG in 10 regional screening centers at study entry and 3 or 5 years later, depending on the time of random assignment. Results from subsequent diagnostic intervention were tracked and recorded in a standardized fashion, and outcomes were compared according to sex and age. The protocol discouraged repeat FSG in persons with colorectal cancer or adenoma diagnosed after the initial FSG. Results Of 77 447 enrollees, 67 073 (86.6%) had at least one FSG and 39 443 (50.9%) had two FSGs. Diagnostic intervention occurred in 74.9% after a positive first FSG and in 78.7% after a positive repeat FSG. The second FSG increased the screening yield by 32%: Colorectal cancer or advanced adenoma was detected in 37.8 per 1000 persons after first screening and in 49.8 per 1000 persons after all screenings. The second FSG increased the yield of cancer or advanced adenoma by 26% in women and by 34% in men. Of 223 subjects who received a diagnosis of colorectal carcinoma within 1 year of a positive FSG, 64.6% had stage I and 17.5% had stage II disease. Conclusions Repeat FSG increased the detection of colorectal cancer or advanced adenoma in women by one-fourth and in men by one-third. Screen-detected carcinomas were early stage (stage I or II) in greater than 80% of screened persons. Colorectal cancer mortality data from the PLCO, as the definitive endpoint, will follow in later publications. C1 [Weissfeld, Joel L.; Schoen, Robert E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Pinsky, Paul F.; Doria-Rose, V. Paul; Laiyemo, Adeyinka O.; Prorok, Philip C.; Berg, Christine D.] NCI, Canc Prevent Div, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bresalier, Robert S.; Lamerato, Lois] Henry Ford Hosp, Detroit, MI 48202 USA. [Bresalier, Robert S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Church, Timothy] Univ Minnesota, Minneapolis, MN USA. [Yokochi, Lance A.] Pacific Hlth Res Inst & Educ, Honolulu, HI USA. [Andriole, Gerald L.] Washington Univ, Sch Med, St Louis, MI USA. [Buys, Saundra] Univ Utah, Salt Lake City, UT USA. [Crawford, E. David] Univ Colorado, Denver, CO 80202 USA. [Fouad, Mona] Univ Alabama, Birmingham, AL USA. [Isaacs, Claudine] Lombardi Comprehens Canc Ctr, Washington, DC USA. [Reding, Douglas] Marshfield Clin Res Fdn, Marshfield, WI USA. [Yurgalevitch, Susan] Westat Corp, Rockville, MD USA. [Rathmell, Joshua] Informat Management Serv Inc, Rockville, MD USA. RP Weissfeld, JL (reprint author), UPMC Canc Pavil POB 2,4th Floor,5150 Ctr Ave, Pittsburgh, PA 15232 USA. EM jwepid@pitt.edu RI Berg , Christine/K-1047-2014; OI Doria-Rose, Vincent/0000-0002-8802-5143; Church, Timothy R./0000-0003-3292-5035 FU Division of Cancer Prevention, National Cancer Institute, NIH, DHHS [N01-CN-25404, N01-CN-25476, N01-CN-25511, N01-CN-25512, N01-CN-25513, N01-CN-25514, N01-CN-25515, N01-CN-25516, N01-CN-25518, N01-CN-25522, N01-CN-25524, N01-CN-75022] FX This work was supported by individual contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS, to each of the 10 screening centers and to the coordinating center (N01-CN-25404 to University of California Los Angeles Immunogenetics Ctr., N01-CN-25476 to Westat, Inc, N01-CN-25511 to University of Pittsburgh Cancer Institute, N01-CN-25512 to Henry Ford Health System, N01-CN-25513 to University of Minnesota School of Public Health, N01-CN-25514 to University of Colorado, N01-CN-25515 to Pacific Health Research & Education Institute, N01-CN-25516 to Washington University, N01-CN-25518 to Marshfield Clinic Research Foundation, N01-CN-25522 to Georgetown University Medical Center, N01-CN-25524 to University of Utah, and N01-CN-75022 to University of Alabama at Birmingham). NR 49 TC 12 Z9 13 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB PY 2012 VL 104 IS 4 BP 280 EP 289 DI 10.1093/jnci/djr549 PG 10 WC Oncology SC Oncology GA 898FY UT WOS:000300725100009 PM 22298838 ER PT J AU Fuhrman, BJ Schairer, C Gail, MH Boyd-Morin, J Xu, X Sue, LY Buys, SS Isaacs, C Keefer, LK Veenstra, TD Berg, CD Hoover, RN Ziegler, RG AF Fuhrman, Barbara J. Schairer, Catherine Gail, Mitchell H. Boyd-Morin, Jennifer Xu, Xia Sue, Laura Y. Buys, Saundra S. Isaacs, Claudine Keefer, Larry K. Veenstra, Timothy D. Berg, Christine D. Hoover, Robert N. Ziegler, Regina G. TI Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TANDEM MASS-SPECTROMETRY; POSSIBLE MECHANISM; SEX-HORMONES; 2-HYDROXYESTRONE; PROSTATE; COHORT; RATIO; REPRODUCIBILITY; PREMENOPAUSAL; COLLECTION AB Background Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites. Methods We conducted a prospective case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55-74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided. Results Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol. Conclusions More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer. C1 [Fuhrman, Barbara J.] NCI, Hormonal & Reprod Epidemiol Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet,NIH, Bethesda, MD 20892 USA. [Boyd-Morin, Jennifer] Informat Management Serv Inc, Silver Spring, MD USA. [Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Buys, Saundra S.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Isaacs, Claudine] Georgetown Univ, Lombardi Canc Ctr, Dept Med & Oncol, Washington, DC USA. [Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Berg, Christine D.] NCI, Early Detect Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Fuhrman, BJ (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet,NIH, 6120 Execut Blvd,Rm 5100, Bethesda, MD 20892 USA. EM fuhrmanb@mail.nih.gov RI Berg , Christine/K-1047-2014; Keefer, Larry/N-3247-2014; OI Keefer, Larry/0000-0001-7489-9555; Fuhrman, Barbara/0000-0002-1777-9888 FU Division of Cancer Epidemiology and Genetics; Center for Cancer Research of the National Cancer Institute (NCI), National Institutes of Health (NIH); Division of Cancer Prevention of the NCI, NIH; NCI, NIH, DHHS [HHSN261200800001E] FX This work was supported by the Intramural Research Programs of the Division of Cancer Epidemiology and Genetics and the Center for Cancer Research of the National Cancer Institute (NCI), National Institutes of Health (NIH); the Division of Cancer Prevention of the NCI, NIH; and contract HHSN261200800001E to SAIC, Inc, from NCI, NIH, DHHS. NR 45 TC 69 Z9 69 U1 0 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB PY 2012 VL 104 IS 4 BP 326 EP 339 DI 10.1093/jnci/djr531 PG 14 WC Oncology SC Oncology GA 898FY UT WOS:000300725100013 PM 22232133 ER PT J AU Roy, S Carass, A Bazin, PL Resnick, S Prince, JL AF Roy, Snehashis Carass, Aaron Bazin, Pierre-Louis Resnick, Susan Prince, Jerry L. TI Consistent segmentation using a Rician classifier SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Medical image segmentation; Tissue classification; Rician distribution; Biomedical imaging ID MAGNETIC-RESONANCE IMAGES; BRAIN MR-IMAGES; VOLUME TISSUE CLASSIFICATION; FUZZY C-MEANS; EM ALGORITHM; INHOMOGENEITY CORRECTION; MAXIMUM-LIKELIHOOD; MODEL; RECONSTRUCTION; OPTIMIZATION AB Several popular classification algorithms used to segment magnetic resonance brain images assume that the image intensities, or log-transformed intensities, satisfy a finite Gaussian mixture model. In these methods, the parameters of the mixture model are estimated and the posterior probabilities for each tissue class are used directly as soft segmentations or combined to form a hard segmentation. It is suggested and shown in this paper that a Rician mixture model fits the observed data better than a Gaussian model. Accordingly, a Rician mixture model is formulated and used within an expectation maximization (EM) framework to yield a new tissue classification algorithm called Rician Classifier using EM (RiCE). It is shown using both simulated and real data that RiCE yields comparable or better performance to that of algorithms based on the finite Gaussian mixture model. As well, we show that RiCE yields more consistent segmentation results when used on images of the same individual acquired with different T1-weighted pulse sequences. Therefore, RiCE has the potential to stabilize segmentation results in brain studies involving heterogeneous acquisition sources as is typically found in both multi-center and longitudinal studies. (C) 2011 Elsevier B.V. All rights reserved. C1 [Roy, Snehashis; Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Commun Lab, Baltimore, MD 21218 USA. [Bazin, Pierre-Louis] Max Planck Inst Human Cognit & Brain Sci, Neurophys Dept, Leipzig, Germany. [Resnick, Susan] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Roy, S (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Commun Lab, Baltimore, MD 21218 USA. EM sroy13@jhu.edu; aaron_carass@jhu.edu; bazin@cbs.mpg.de; resnicks@grc.nia.nih.gov; prince@jhu.edu RI Prince, Jerry/A-3281-2010; OI Prince, Jerry/0000-0002-6553-0876; Bazin, Pierre-Louis/0000-0002-0141-5510; Roy, Snehashis/0000-0002-7997-3993; Carass, Aaron/0000-0003-4939-5085 FU NIH, National Institute on Aging; NIH/NINDS [5R01NS037747] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. We are grateful to all the participants of the Baltimore Longitudinal Study on Aging (BLSA), as well as the neuroimaging staff for their dedication to these studies. This work was also supported by the NIH/NINDS under Grant 5R01NS037747. NR 71 TC 9 Z9 10 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD FEB PY 2012 VL 16 IS 2 BP 524 EP 535 DI 10.1016/j.media.2011.12.001 PG 12 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 898PN UT WOS:000300754400013 PM 22204754 ER PT J AU Hannoush, H Introne, WJ Chen, MY Lee, SJ O'Brien, K Suwannarat, P Kayser, MA Gahl, WA Sachdev, V AF Hannoush, Hwaida Introne, Wendy J. Chen, Marcus Y. Lee, Sook-Jin O'Brien, Kevin Suwannarat, Pim Kayser, Michael A. Gahl, William A. Sachdev, Vandana TI Aortic stenosis and vascular calcifications in alkaptonuria SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Alkaptonuria; Aortic stenosis; Cardiovascular; Calcification ID CORONARY-ARTERY CALCIUM; VALVE STENOSIS; OCHRONOSIS; ATHEROSCLEROSIS; RECOMMENDATIONS; QUANTIFICATION; NITISINONE AB Alkaptonuria is a rare metabolic disorder of tyrosine catabolism in which homogentisic acid (HGA) accumulates and is deposited throughout the spine, large joints, cardiovascular system, and various tissues throughout the body. In the cardiovascular system, pigment deposition has been described in the heart valves, endocardium, pericardium, aortic intima and coronary arteries. The prevalence of cardiovascular disease in patients with alkaptonuria varies in previous reports. We present a series of 76 consecutive adult patients with alkaptonuria who underwent transthoracic echocardiography between 2000 and 2009. A subgroup of 40 patients enrolled in a treatment study underwent non-contrast CT scans and these were assessed for vascular calcifications. Six of the 76 patients had aortic valve replacement. In the remaining 70 patients, 12 patients had aortic sclerosis and 7 patients had aortic stenosis. Unlike degenerative aortic valve disease, we found no correlation with standard cardiac risk factors. There was a modest association between the severity of aortic valve disease and joint involvement, however, we saw no correlation with urine HGA levels. Vascular calcifications were seen in the coronaries, cardiac valves, aortic root, descending aorta and iliac arteries. These findings suggest an important role for echocardiographic screening of alkaptonuria patients to detect valvular heart disease and cardiac CT to detect coronary artery calcifications. Published by Elsevier Inc. C1 [Hannoush, Hwaida; Chen, Marcus Y.; Lee, Sook-Jin; Sachdev, Vandana] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Introne, Wendy J.; O'Brien, Kevin; Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [O'Brien, Kevin] NIH, Off Rare Dis Res, Off Director, Bethesda, MD 20892 USA. [Suwannarat, Pim; Kayser, Michael A.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sachdev, V (reprint author), CRC, 10 Ctr Dr,5NE Room 1436, Bethesda, MD 20892 USA. EM sachdevv@nhlbi.nih.gov FU National Human Genome Research Institute; National Heart Lung and Blood Institute, NIH, DHHS FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute and the National Heart Lung and Blood Institute, NIH, DHHS. NR 23 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP 198 EP 202 DI 10.1016/j.ymgme.2011.10.017 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300006 PM 22100375 ER PT J AU Mudd, SH Wagner, C Luka, Z Stabler, SP Allen, RH Schroer, R Wood, T Wang, J Wong, LJ AF Mudd, S. Harvey Wagner, Conrad Luka, Zigmund Stabler, Sally P. Allen, Robert H. Schroer, Richard Wood, Timothy Wang, Jing Wong, Lee-Jun TI Two patients with hepatic mtDNA depletion syndromes and marked elevations of S-adenosylmethionine and methionine SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Mitochondria; Depletion; Methionine; S-adenosylmethionine; MPV17; DGUOK ID MITOCHONDRIAL-DNA DEPLETION; GLYCINE N-METHYLTRANSFERASE; ADENOSYL-L-METHIONINE; IMPAIRED HOMOCYSTEINE TRANSSULFURATION; COMPARATIVE GENOMIC HYBRIDIZATION; DEOXYGUANOSINE KINASE-DEFICIENCY; CHROMATOGRAPHY-MASS-SPECTROMETRY; SERUM CYSTATHIONINE LEVELS; FOLATE BINDING-PROTEIN; AMINO-ACID PATTERNS AB This paper reports studies of two patients proven by a variety of studies to have mitochondrial depletion syndromes due to mutations in either their MPV17 or DCUOK genes. Each was initially investigated metabolically because of plasma methionine concentrations as high as 15-21-fold above the upper limit of the reference range, then found also to have plasma levels of S-adenosylmethionine (AdoMet) 4.4-8.6-fold above the upper limit of the reference range. Assays of S-adenosylhomocysteine, total homocysteine, cystathionine, sarcosine, and other relevant metabolites and studies of their gene encoding glycine N-methyltransferase produced evidence suggesting they had none of the known causes of elevated methionine with or without elevated AdoMet Patient 1 grew slowly and intermittently, but was cognitively normal. At age 7 years he was found to have hepatocellular carcinoma, underwent a liver transplant and died of progressive liver and renal failure at age almost 9 years. Patient 2 had a clinical course typical of DGUOK deficiency and died at age 8 1/2 months. Although each patient had liver abnormalities, evidence is presented that such abnormalities are very unlikely to explain their elevations of AdoMet or the extent of their hypermethioninemias. A working hypothesis is presented suggesting that with mitochondrial depletion the normal usage of AdoMet by mitochondria is impaired, AdoMet accumulates in the cytoplasm of affected cells poor in glycine N-methyltransferase activity, the accumulated AdoMet causes methionine to accumulate by inhibiting activity of methionine adenosyltransferase H. and that both AdoMet and methionine consequently leak abnormally into the plasma. (C) 2011 Elsevier Inc. All rights reserved. C1 [Mudd, S. Harvey] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. [Wagner, Conrad; Luka, Zigmund] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. [Stabler, Sally P.; Allen, Robert H.] Univ Colorado, Sch Med, Div Hematol, Aurora, CO USA. [Schroer, Richard; Wood, Timothy] Greenwood Genet Ctr, Greenwood, SC 29646 USA. [Wang, Jing; Wong, Lee-Jun] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Mudd, SH (reprint author), NIMH, Mol Biol Lab, Bldg 10,Room 2646,10 Ctr Dr, Bethesda, MD 20892 USA. EM muddh@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999]; NIDDK NIH HHS [R01 DK015289] NR 73 TC 5 Z9 5 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP 228 EP 236 DI 10.1016/j.ymgme.2011.11.006 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300010 PM 22137549 ER PT J AU Beattie, L Yang, S Golas, G Peterson, J Pierson, T Adams, D Tifft, C AF Beattie, Lindsay Yang, Sandra Golas, Gretchen Peterson, Jessica Pierson, Tyler Adams, David Tifft, Cynthia TI Chitotriosidase as a Measure of Disease Burden in Patients with GM1 and GM2 Gangliosidosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 8th Anuual Research Meeting of the WORLD Symposium on Lysosomal Disease Networks CY FEB 07-10, 2012 CL San Diego, CA C1 [Beattie, Lindsay; Yang, Sandra; Golas, Gretchen; Peterson, Jessica; Adams, David; Tifft, Cynthia] NHGRI, NIH, Bethesda, MD 20892 USA. [Pierson, Tyler] NINDS, NIH, Bethesda, MD 20892 USA. [Peterson, Jessica] Des Moines Univ, Des Moines, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP S20 EP S20 DI 10.1016/j.ymgme.2011.11.027 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300038 ER PT J AU Patterson, M Porter, F Brown, T Vaurio, R AF Patterson, Marc Porter, Forbes Brown, Tanya Vaurio, Rebecca TI Longitudinal Study of Cognition in Patients with Niemann-Pick Disease, Type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 8th Anuual Research Meeting of the WORLD Symposium on Lysosomal Disease Networks CY FEB 07-10, 2012 CL San Diego, CA C1 [Patterson, Marc; Brown, Tanya] Mayo Clin, Rochester, MN USA. [Porter, Forbes] NIH, Bethesda, MD 20892 USA. [Vaurio, Rebecca] Kennedy Krieger Inst, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP S50 EP S51 DI 10.1016/j.ymgme.2011.11.128 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300139 ER PT J AU Tayebi, N Saranjam, H Chopra, S Levy, H Stubblefield, BK Cohen, IJ Bads, H Sidransky, E AF Tayebi, Nahid Saranjam, Hamid Chopra, Sameer Levy, Harvey Stubblefield, Barbara K. Cohen, Ian J. Bads, Hagit Sidransky, Ellen TI A Germline Mutation in Two Families with Gaucher Disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 8th Anuual Research Meeting of the WORLD Symposium on Lysosomal Disease Networks CY FEB 07-10, 2012 CL San Diego, CA C1 [Saranjam, Hamid; Stubblefield, Barbara K.; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Chopra, Sameer] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Levy, Harvey] Harvard Univ, Brigham & Womens Hosp, Div Genet, Childrens Hosp Boston,Sch Med, Boston, MA 02115 USA. [Cohen, Ian J.; Bads, Hagit] Rabin Med Ctr, Rapheal Recanti Genet Inst, Schneider Gaucher Clin, Petah Tiqwa, Israel. [Cohen, Ian J.; Bads, Hagit] Tel Aviv Univ, Sackler Fac Med, Ramat Aviv, Israel. RI Cohen, Ian/H-3358-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP S60 EP S60 DI 10.1016/j.ymgme.2011.11.159 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300170 ER PT J AU Velayati, A Tuzmen, P Guha, R Martin, S Goldin, E Sidransky, E AF Velayati, Arash Tuzmen, Pinar Guha, Rajarshi Martin, Scott Goldin, Ehud Sidransky, Ellen TI Genome-Wide RNAi Screen For Lysosomal Storage Disorders SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 8th Anuual Research Meeting of the WORLD Symposium on Lysosomal Disease Networks CY FEB 07-10, 2012 CL San Diego, CA C1 [Velayati, Arash; Goldin, Ehud; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Tuzmen, Pinar; Guha, Rajarshi; Martin, Scott] NHGRI, RNAi Screening Core Facil, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP S63 EP S63 DI 10.1016/j.ymgme.2011.11.168 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300179 ER PT J AU Westbroek, W Gustafson, AM Marugan, J Xiao, JB Zheng, W Velayati, A Goldin, E Sidransky, E AF Westbroek, Wendy Gustafson, Ann Marie Marugan, Juan Xiao, Jingbo Zheng, Wei Velayati, Arash Goldin, Ehud Sidransky, Ellen TI Cell-Based Evaluation of Small Molecules for Treatment of Pompe Disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 8th Anuual Research Meeting of the WORLD Symposium on Lysosomal Disease Networks CY FEB 07-10, 2012 CL San Diego, CA C1 [Marugan, Juan; Xiao, Jingbo; Zheng, Wei] NHGRI, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP S65 EP S65 DI 10.1016/j.ymgme.2011.11.175 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300186 ER PT J AU Sandrini, M Fertonani, A Cohen, LG Miniussi, C AF Sandrini, Marco Fertonani, Anna Cohen, Leonardo G. Miniussi, Carlo TI Double dissociation of working memory load effects induced by bilateral parietal modulation SO NEUROPSYCHOLOGIA LA English DT Article DE Transcranial direct current stimulation; Parietal lobe; Working memory; n-Back task; Familiarity ID DIRECT-CURRENT STIMULATION; TRANSCRANIAL MAGNETIC STIMULATION; DORSOLATERAL PREFRONTAL CORTEX; SHORT-TERM-MEMORY; POSTERIOR PARIETAL; BRAIN ACTIVATION; DECISION-MAKING; FUNCTIONAL MRI; TEMPORAL DYNAMICS; NEURONAL-ACTIVITY AB Transcranial magnetic stimulation and neuroimaging data have revealed bilateral posterior parietal cortex (PPC) involvement during verbal n-back working memory (WM). In this task as n (i.e., WM load) increases, subjects show poorer behavioral performance as well as greater activation of this brain area. Moreover, there is evidence that a brief period of practice or even increased familiarity with the task can improve WM performance and lead to activation changes in the PPC. The aim of this study was to investigate, using transcranial direct current stimulation (tDCS), the effects on WM load performance induced by different PPC modulation after increased familiarity with the task. After a short practice, we tested verbal WM using an n-back task (1-back vs. 2-back) before and after the application of bilateral tDCS over PPCs (left anodal-right cathodal, left cathodal-right anodal or sham). ANOVA showed a significant interaction between tDCS and task. In the 1-back task, left anodal-right cathodal modulation abolished improvement in reaction times observed in the other two modulation conditions. Conversely, in the 2-back task the same effect was observed after left cathodal-right anodal modulation relative to the other two modulation conditions. This double dissociation demonstrates either a differential engagement of each PPC or changes in the interhemispheric balance of activity across this brain region. Neuroimaging studies show parametric activation of the PPC as difficulty increases, but activation does not switch sides. Thus, our observed effects cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we suggest that these findings reflect the use of different processing strategies to perform these two tasks. In conclusion, after increased familiarity with the task, different tDCS modulations lead to changes in a task-related region depending on differences in processing strategies in 1-back vs. 2-back. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Sandrini, Marco; Cohen, Leonardo G.] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Sandrini, Marco] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Fertonani, Anna; Miniussi, Carlo] IRCCS Ctr San Giovanni Dio Fatebenefratelli, Cognit Neurosci Sect, Brescia, Italy. [Miniussi, Carlo] Univ Brescia, Dept Biomed Sci & Biotechnol, Natl Inst Neurosci, Brescia, Italy. RP Sandrini, M (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 10,Room 7D52, Bethesda, MD 20892 USA. EM marco.sandrini@nih.gov RI Westwood, Sam/P-7000-2015; Fertonani, Anna/A-7094-2012; Miniussi, Carlo/E-7602-2010; Sandrini, Marco/J-2276-2014 OI Fertonani, Anna/0000-0001-6507-499X; Miniussi, Carlo/0000-0002-5436-4745; Sandrini, Marco/0000-0002-1664-5722 FU NIH-Regione Lombardia (Italy) [3472] FX This work was supported by a NIH-Regione Lombardia (Italy) research career transition award (Regional provision n. 3472, 8th April 2008) to MS. NR 92 TC 23 Z9 23 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD FEB PY 2012 VL 50 IS 3 BP 396 EP 402 DI 10.1016/j.neuropsychologia.2011.12.011 PG 7 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 899LE UT WOS:000300816600006 PM 22223077 ER PT J AU Kaplan, R Doeller, CF Barnes, GR Litvak, V Duzel, E Bandettini, PA Burgess, N AF Kaplan, Raphael Doeller, Christian F. Barnes, Gareth R. Litvak, Vladimir Duezel, Emrah Bandettini, Peter A. Burgess, Neil TI Movement-Related Theta Rhythm in Humans: Coordinating Self-Directed Hippocampal Learning SO PLOS BIOLOGY LA English DT Article ID MEDIAL PREFRONTAL CORTEX; HUMAN SPATIAL NAVIGATION; WORKING-MEMORY TASK; BRAIN OSCILLATIONS; GAMMA OSCILLATIONS; DECLARATIVE MEMORY; VIRTUAL NAVIGATION; INTRACRANIAL EEG; EPISODIC MEMORY; SYNCHRONIZATION AB The hippocampus is crucial for episodic or declarative memory and the theta rhythm has been implicated in mnemonic processing, but the functional contribution of theta to memory remains the subject of intense speculation. Recent evidence suggests that the hippocampus might function as a network hub for volitional learning. In contrast to human experiments, electrophysiological recordings in the hippocampus of behaving rodents are dominated by theta oscillations reflecting volitional movement, which has been linked to spatial exploration and encoding. This literature makes the surprising cross-species prediction that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. We examined the links between theta, spatial exploration, and memory encoding by designing an interactive human spatial navigation paradigm combined with multimodal neuroimaging. We used both non-invasive whole-head Magnetoencephalography (MEG) to look at theta oscillations and Functional Magnetic Resonance Imaging (fMRI) to look at brain regions associated with volitional movement and learning. We found that theta power increases during the self-initiation of virtual movement, additionally correlating with subsequent memory performance and environmental familiarity. Performance-related hippocampal theta increases were observed during a static pre-navigation retrieval phase, where planning for subsequent navigation occurred. Furthermore, periods of the task showing movement-related theta increases showed decreased fMRI activity in the parahippocampus and increased activity in the hippocampus and other brain regions that strikingly overlap with the previously observed volitional learning network (the reverse pattern was seen for stationary periods). These fMRI changes also correlated with participant's performance. Our findings suggest that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. These findings directly extend the role of the hippocampus in spatial exploration in rodents to human memory and self-directed learning. C1 [Kaplan, Raphael] NIMH, UCL Joint Grad Partnership Program Neurosci, Bethesda, MD 20892 USA. [Kaplan, Raphael; Doeller, Christian F.; Duezel, Emrah; Burgess, Neil] UCL, UCL Inst Cognit Neurosci, London, England. [Kaplan, Raphael; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Kaplan, Raphael; Doeller, Christian F.; Barnes, Gareth R.; Litvak, Vladimir; Burgess, Neil] UCL, UCL Inst Neurol, London, England. [Doeller, Christian F.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. [Barnes, Gareth R.; Litvak, Vladimir] UCL, Wellcome Trust Ctr Neuroimaging, London, England. [Duezel, Emrah] Otto Von Guericke Univ, Inst Cognit Neurol & Dementia Res, Magdeburg, Germany. [Duezel, Emrah] German Ctr Neurodegenerat Dis DZNE, Magdeberg, Germany. RP Kaplan, R (reprint author), NIMH, UCL Joint Grad Partnership Program Neurosci, Bethesda, MD 20892 USA. EM raphael.kaplan@nih.gov; n.burgess@ucl.ac.uk RI Litvak, Vladimir/C-1533-2008; Burgess, Neil/B-2420-2009; Doeller, Christian/E-6376-2012; OI Burgess, Neil/0000-0003-0646-6584; Kaplan, Raphael/0000-0002-5023-1566 FU Medical Research Council; Wellcome Trust; National Institute of Mental Health; National Institutes of Health; European Research Council FX The research was supported by Medical Research Council and Wellcome Trust grants to NB, the National Institute of Mental Health Intramural Research Program, the National Institutes of Health Graduate Partnership Program (RK), a European Research Council grant to CD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 41 Z9 42 U1 2 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD FEB PY 2012 VL 10 IS 2 AR e1001267 DI 10.1371/journal.pbio.1001267 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 901GL UT WOS:000300951500012 PM 22389627 ER PT J AU Chen, HY Hayashi, G Lai, OY Dilthey, A Kuebler, PJ Wong, TV Martin, MP Vina, MAF McVean, G Wabl, M Leslie, KS Maurer, T Martin, JN Deeks, SG Carrington, M Bowcock, AM Nixon, DF Liao, W AF Chen, Haoyan Hayashi, Genki Lai, Olivia Y. Dilthey, Alexander Kuebler, Peter J. Wong, Tami V. Martin, Maureen P. Vina, Marcelo A. Fernandez McVean, Gil Wabl, Matthias Leslie, Kieron S. Maurer, Toby Martin, Jeffrey N. Deeks, Steven G. Carrington, Mary Bowcock, Anne M. Nixon, Douglas F. Liao, Wilson TI Psoriasis Patients Are Enriched for Genetic Variants That Protect against HIV-1 Disease SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HLA-C ALLELES; EXPOSED UNINFECTED INDIVIDUALS; LONG-TERM NONPROGRESSORS; CLASS-I MOLECULES; SUSCEPTIBILITY LOCI; HAPLOTYPE ANALYSIS; CELL-ACTIVATION; PEPTIDE CARGO; ARTHRITIS AB An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis. C1 [Chen, Haoyan; Hayashi, Genki; Lai, Olivia Y.; Wong, Tami V.; Leslie, Kieron S.; Maurer, Toby; Liao, Wilson] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Dilthey, Alexander; McVean, Gil] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Kuebler, Peter J.; Nixon, Douglas F.] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. [Martin, Maureen P.; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD 21701 USA. [Vina, Marcelo A. Fernandez] Stanford Univ, Dept Pathol, Palo Alto, CA 94304 USA. [Wabl, Matthias] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, HIV AIDS Program, San Francisco, CA USA. [Bowcock, Anne M.] Washington Univ, Sch Med, Dept Genet, Div Human Genet, St Louis, MO 63110 USA. RP Chen, HY (reprint author), Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. EM liaowi@derm.ucsf.edu OI Nixon, Douglas/0000-0002-2801-1786; McVean, Gil/0000-0002-5012-4162; Bowcock, Anne/0000-0001-8691-9090 FU National Institutes of Health [HHSN261200800001E, R01AI041570, AR050266, 5K08AR057763-02]; Foundation for the National Institutes of Health; National Psoriasis Foundation; Genetic Association Information Network (GAIN); Wellcome Trust [076113, 085475]; Centers for AIDS Research at UCSF [PO AI27763]; CFAR Network of Integrated Systems [R24 AI067039]; UCSF CTSI [UL1 RR024131]; NIAID [RO1 AI087145, K24AI069994, AI 76174]; amfAR; Ragon Institute; Peter and Shelagh Godsoe Family Foundation through the AIDS Research Institute at UCSF; National Cancer Institute; Center for Cancer Research FX Funding for the Collaborative Association Study of Psoriasis was provided by the National Institutes of Health, the Foundation for the National Institutes of Health, and the National Psoriasis Foundation. Support for genotyping of samples was provided through the Genetic Association Information Network (GAIN). Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. This work was supported in part by the Centers for AIDS Research at UCSF (PO AI27763), CFAR Network of Integrated Systems (R24 AI067039), the UCSF CTSI (UL1 RR024131), NIAID (RO1 AI087145, K24AI069994, AI 76174), amfAR, and the Ragon Institute. This research was made possible in part through support from The Peter and Shelagh Godsoe Family Foundation through the AIDS Research Institute at UCSF. 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 U. S. Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has also been funded in part with federal funds from the National Institutes of Health under awards R01AI041570 (MW), AR050266 (AMB), and 5K08AR057763-02 (WL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 19 Z9 19 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2012 VL 8 IS 2 AR e1002514 DI 10.1371/journal.pgen.1002514 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 898GA UT WOS:000300725500032 PM 22577363 ER PT J AU Demirkan, A van Duijn, CM Ugocsai, P Isaacs, A Pramstaller, PP Liebisch, G Wilson, JF Johansson, A Rudan, I Aulchenko, YS Kirichenko, AV Janssens, ACJW Jansen, RC Gnewuch, C Domingues, FS Pattaro, C Wild, SH Jonasson, I Polasek, O Zorkoltseva, IV Hofman, A Karssen, LC Struchalin, M Floyd, J Igl, W Biloglav, Z Broer, L Pfeufer, A Pichler, I Campbell, S Zaboli, G Kolcic, I Rivadeneira, F Huffman, J Hastie, ND Uitterlinden, A Franke, L Franklin, CS Vitart, V Nelson, CP Preuss, M Bis, JC O'Donnell, CJ Franceschini, N Witteman, JCM Axenovich, T Oostra, BA Meitinger, T Hicks, AA Hayward, C Wright, AF Gyllensten, U Campbell, H Schmitz, G AF Demirkan, Ayse van Duijn, Cornelia M. Ugocsai, Peter Isaacs, Aaron Pramstaller, Peter P. Liebisch, Gerhard Wilson, James F. Johansson, Asa Rudan, Igor Aulchenko, Yurii S. Kirichenko, Anatoly V. Janssens, A. Cecile J. W. Jansen, Ritsert C. Gnewuch, Carsten Domingues, Francisco S. Pattaro, Cristian Wild, Sarah H. Jonasson, Inger Polasek, Ozren Zorkoltseva, Irina V. Hofman, Albert Karssen, Lennart C. Struchalin, Maksim Floyd, James Igl, Wilmar Biloglav, Zrinka Broer, Linda Pfeufer, Arne Pichler, Irene Campbell, Susan Zaboli, Ghazal Kolcic, Ivana Rivadeneira, Fernando Huffman, Jennifer Hastie, Nicholas D. Uitterlinden, Andre Franke, Lude Franklin, Christopher S. Vitart, Veronique Nelson, Christopher P. Preuss, Michael Bis, Joshua C. O'Donnell, Christopher J. Franceschini, Nora Witteman, Jacqueline C. M. Axenovich, Tatiana Oostra, Ben A. Meitinger, Thomas Hicks, Andrew A. Hayward, Caroline Wright, Alan F. Gyllensten, Ulf Campbell, Harry Schmitz, Gerd CA DIAGRAM Consortium CARDIoGRAM Consortium CHARGE Consortium EUROSPAN Consortium TI Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations SO PLOS GENETICS LA English DT Article ID TANDEM MASS-SPECTROMETRY; HIGH-THROUGHPUT QUANTIFICATION; FATTY-ACIDS; SUSCEPTIBILITY LOCI; MEMBRANE-LIPIDS; HUMAN PLATELETS; LYSOPHOSPHATIDYLCHOLINE; DISEASE; PHOSPHATIDYLCHOLINE; ATHEROSCLEROSIS AB Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88 x 10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10 x 10(-57)). After a correction for multiple comparisons (P-value, 2.2 x 10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits. C1 [Demirkan, Ayse; van Duijn, Cornelia M.; Isaacs, Aaron; Aulchenko, Yurii S.; Karssen, Lennart C.; Struchalin, Maksim; Broer, Linda] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Demirkan, Ayse; van Duijn, Cornelia M.; Isaacs, Aaron; Aulchenko, Yurii S.; Karssen, Lennart C.; Struchalin, Maksim; Broer, Linda] Erasmus Univ, Dept Clin Genet, Med Ctr, Genet Epidemiol Unit, NL-3000 DR Rotterdam, Netherlands. [van Duijn, Cornelia M.; Isaacs, Aaron; Oostra, Ben A.] Ctr Med Sytems Biol, Leiden, Netherlands. [van Duijn, Cornelia M.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre; Witteman, Jacqueline C. M.] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Ugocsai, Peter; Liebisch, Gerhard; Gnewuch, Carsten; Schmitz, Gerd] Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany. [Pramstaller, Peter P.; Domingues, Francisco S.; Pattaro, Cristian; Pfeufer, Arne; Pichler, Irene; Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Wilson, James F.; Rudan, Igor; Wild, Sarah H.; Campbell, Susan; Vitart, Veronique; Campbell, Harry] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Johansson, Asa; Jonasson, Inger; Igl, Wilmar; Zaboli, Ghazal; Gyllensten, Ulf] Uppsala Univ, Dept Genet & Pathol, Rudbeck Lab, Uppsala, Sweden. [Rudan, Igor] Univ Hosp Sestre Milosrdnice, Inst Clin Med Res, Zagreb, Croatia. [Rudan, Igor; Jonasson, Inger; Polasek, Ozren; Kolcic, Ivana] Univ Split, Fac Med, Croatian Ctr Global Hlth, Split, Croatia. [Kirichenko, Anatoly V.; Zorkoltseva, Irina V.; Axenovich, Tatiana] Russian Acad Sci, Inst Cytol & Genet, Siberian Div, Novosibirsk 630090, Russia. [Jansen, Ritsert C.] Univ Groningen, Groningen Bioinformat Ctr, Groningen Biomol Sci & Biotechnol Inst, Groningen, Netherlands. [Floyd, James; Franklin, Christopher S.] Wellcome Trust Sanger Inst, Hinxton, England. [Biloglav, Zrinka] Univ Zagreb, Fac Med, Andrija Stampar Sch Publ Hlth, Zagreb 41000, Croatia. [Rivadeneira, Fernando; Uitterlinden, Andre] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Huffman, Jennifer; Hastie, Nicholas D.; Vitart, Veronique; Hayward, Caroline; Wright, Alan F.] Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland. [Franke, Lude] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Nelson, Christopher P.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Preuss, Michael] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. [Preuss, Michael] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Bis, Joshua C.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Dept Med, Cardiol Div,Massachusetts Gen Hosp, Boston, MA USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Meitinger, Thomas] Munich Heart Alliance, Munich, Germany. RP Demirkan, A (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. EM a.isaacs@erasmusmc.nl RI Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Hayward, Caroline/M-8818-2016; Franke, Lude/P-7036-2016; Kolcic, Ivana/E-2713-2017; Hicks, Andrew/E-9518-2017; Liebisch, Gerhard/G-6130-2010; Willenborg, Christina/D-2668-2012; Rudan, Igor/I-1467-2012; Boehm, Bernhard/F-8750-2015; Gudnason, Vilmundur/K-6885-2015; Jansen, Ritsert/C-1160-2013; Elliott, Amanda/G-5120-2012; Pfeufer, Arne/B-6634-2013; Aulchenko, Yurii/M-8270-2013; Pramstaller, Peter/C-2357-2008; Johansson, Asa/G-5270-2011 OI Karssen, Lennart C./0000-0002-1959-342X; Kleber, Marcus/0000-0003-0663-7275; Pichler, Irene/0000-0001-8251-0757; Janssens, A Cecile/0000-0002-6153-4976; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Hide, Winston/0000-0002-8621-3271; Zeggini, Eleftheria/0000-0003-4238-659X; Jorgensen, Torben/0000-0001-9453-2830; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Hayward, Caroline/0000-0002-9405-9550; Franke, Lude/0000-0002-5159-8802; Kolcic, Ivana/0000-0001-7918-6052; Hicks, Andrew/0000-0001-6320-0411; Liebisch, Gerhard/0000-0003-4886-0811; Willenborg, Christina/0000-0001-5217-6882; Rudan, Igor/0000-0001-6993-6884; Gudnason, Vilmundur/0000-0001-5696-0084; Jansen, Ritsert/0000-0003-2977-9110; Aulchenko, Yurii/0000-0002-7899-1575; Johansson, Asa/0000-0002-2915-4498 FU European Commission [018947 (LSHG-CT-2006-01947), 2007-202272]; Netherlands Organisation for Scientific Research [NWO-RFBR 047.017.043]; Russian Foundation for Basic Research [NWO-RFBR 047.017.043]; Netherlands Organisation for Scientific Research (Pionier) [047.016.009, 047.017.043]; Centre for Medical Systems Biology (CMSB; National Genomics Initiative); Erasmus MC; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; South Tyrolean Sparkasse Foundation; Swedish Natural Sciences Research Council; Swedish Medical Research Council; European Commission through EUROSPAN; Foundation for Strategic Research (SSF); Linneaus Centre for Bioinformatics (LCB); Scottish Executive Health Department; Royal Society; Wellcome Trust Clinical Research Facility in Edinburgh; Medical Research Council UK; Ministry of Science, Education, and Sport of the Republic of Croatia [108-1080315-0302] FX EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947). High-throughput genome-wide association analysis of the data was supported by a joint grant from the Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Lipidomic analysis was supported by the European Commission FP7 grant LipidomicNet (2007-202272). The ERF study was supported by grants from the Netherlands Organisation for Scientific Research (Pionier, 047.016.009, 047.017.043), Erasmus MC, and the Centre for Medical Systems Biology (CMSB; National Genomics Initiative). In South Tyrol, the MICROS study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, and the South Tyrolean Sparkasse Foundation. The Northern Swedish Population Health Study (NSPHS) was supported by grants from the Swedish Natural Sciences Research Council, Swedish Medical Research Council, the European Commission through EUROSPAN, the Foundation for Strategic Research (SSF), and the Linneaus Centre for Bioinformatics (LCB). The ORCADES study was supported by the Scottish Executive Health Department, the Royal Society, and the Wellcome Trust Clinical Research Facility in Edinburgh. The CROATIA_Vis study in the Croatian island of Vis was supported through grants from the Medical Research Council UK and Ministry of Science, Education, and Sport of the Republic of Croatia (number 108-1080315-0302). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 63 Z9 63 U1 2 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2012 VL 8 IS 2 AR e1002490 DI 10.1371/journal.pgen.1002490 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 898GA UT WOS:000300725500014 PM 22359512 ER PT J AU Findley, K Sun, S Fraser, JA Hsueh, YP Averette, AF Li, WJ Dietrich, FS Heitman, J AF Findley, Keisha Sun, Sheng Fraser, James A. Hsueh, Yen-Ping Averette, Anna Floyd Li, Wenjun Dietrich, Fred S. Heitman, Joseph TI Discovery of a Modified Tetrapolar Sexual Cycle in Cryptococcus amylolentus and the Evolution of MAT in the Cryptococcus Species Complex SO PLOS GENETICS LA English DT Article ID UNIPARENTAL MITOCHONDRIAL INHERITANCE; MICROBIAL PATHOGENS; NEOFORMANS; FUNGI; FILOBASIDIELLA; GENETICS; GENES; LOCUS; YEAST; REPRODUCTION AB Sexual reproduction in fungi is governed by a specialized genomic region called the mating-type locus (MAT). The human fungal pathogenic and basidiomycetous yeast Cryptococcus neoformans has evolved a bipolar mating system (a, alpha) in which the MAT locus is unusually large (> 100 kb) and encodes >20 genes including homeodomain (HD) and pheromone/receptor (P/R) genes. To understand how this unique bipolar mating system evolved, we investigated MAT in the closely related species Tsuchiyaea wingfieldii and Cryptococcus amylolentus and discovered two physically unlinked loci encoding the HD and P/R genes. Interestingly, the HD (B) locus sex-specific region is restricted (similar to 2 kb) and encodes two linked and divergently oriented homeodomain genes in contrast to the solo HD genes (SXI1 alpha, SXI2a) of C. neoformans and Cryptococcus gattii. The P/R (A) locus contains the pheromone and pheromone receptor genes but has expanded considerably compared to other outgroup species (Cryptococcus heveanensis) and is linked to many of the genes also found in the MAT locus of the pathogenic Cryptococcus species. Our discovery of a heterothallic sexual cycle for C. amylolentus allowed us to establish the biological roles of the sex-determining regions. Matings between two strains of opposite mating-types (A1B1xA2B2) produced dikaryotic hyphae with fused clamp connections, basidia, and basidiospores. Genotyping progeny using markers linked and unlinked to MAT revealed that meiosis and uniparental mitochondrial inheritance occur during the sexual cycle of C. amylolentus. The sexual cycle is tetrapolar and produces fertile progeny of four mating-types (A1B1, A1B2, A2B1, and A2B2), but a high proportion of progeny are infertile, and fertility is biased towards one parental mating-type (A1B1). Our studies reveal insights into the plasticity and transitions in both mechanisms of sex determination (bipolar versus tetrapolar) and sexual reproduction (outcrossing versus inbreeding) with implications for similar evolutionary transitions and processes in fungi, plants, and animals. C1 [Findley, Keisha] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Findley, Keisha; Sun, Sheng; Averette, Anna Floyd; Li, Wenjun; Dietrich, Fred S.; Heitman, Joseph] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC USA. [Fraser, James A.] Univ Queensland, Sch Mol & Microbial Sci, Brisbane, Qld, Australia. [Hsueh, Yen-Ping] CALTECH, Div Biol, Pasadena, CA 91125 USA. RP Findley, K (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM heitm001@duke.edu RI Fraser, James/B-4918-2012 OI Fraser, James/0000-0001-5724-5285 FU NIAID R37 [AI39115-14, R01, AI50113-08]; NIH [5R01-AI063443-04 S1, 1-P30] FX This work was supported by NIAID R37 grant AI39115-14 and R01 grant AI50113-08 to JH and an NIH Minority Supplement 5R01-AI063443-04 S1 Sub # 1-P30 that supported KF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 17 Z9 17 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2012 VL 8 IS 2 AR e1002528 DI 10.1371/journal.pgen.1002528 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 898GA UT WOS:000300725500044 PM 22359516 ER PT J AU Fukuda, T Pratto, F Schimenti, JC Turner, JMA Camerini-Otero, RD Hoog, C AF Fukuda, Tomoyuki Pratto, Florencia Schimenti, John C. Turner, James M. A. Camerini-Otero, R. Daniel Hoog, Christer TI Phosphorylation of Chromosome Core Components May Serve as Axis Marks for the Status of Chromosomal Events during Mammalian Meiosis SO PLOS GENETICS LA English DT Article ID SISTER-CHROMATID COHESION; SYNAPTONEMAL COMPLEX; MEIOTIC CHROMOSOMES; DNA RECOMBINATION; PROMOTES SYNAPSIS; MOLECULAR-BIOLOGY; MALE-FERTILITY; BODY FORMATION; MOUSE; MICE AB Meiotic recombination and chromosome synapsis between homologous chromosomes are essential for proper chromosome segregation at the first meiotic division. While recombination and synapsis, as well as checkpoints that monitor these two events, take place in the context of a prophase I-specific axial chromosome structure, it remains unclear how chromosome axis components contribute to these processes. We show here that many protein components of the meiotic chromosome axis, including SYCP2, SYCP3, HORMAD1, HORMAD2, SMC3, STAG3, and REC8, become post-translationally modified by phosphorylation during the prophase I stage. We found that HORMAD1 and SMC3 are phosphorylated at a consensus site for the ATM/ATR checkpoint kinase and that the phosphorylated forms of HORMAD1 and SMC3 localize preferentially to unsynapsed chromosomal regions where synapsis has not yet occurred, but not to synapsed or desynapsed regions. We investigated the genetic requirements for the phosphorylation events and revealed that the phosphorylation levels of HORMAD1, HORMAD2, and SMC3 are dramatically reduced in the absence of initiation of meiotic recombination, whereas BRCA1 and SYCP3 are required for normal levels of phosphorylation of HORMAD1 and HORMAD2, but not of SMC3. Interestingly, reduced HORMAD1 and HORMAD2 phosphorylation is associated with impaired targeting of the MSUC (meiotic silencing of unsynapsed chromatin) machinery to unsynapsed chromosomes, suggesting that these post-translational events contribute to the regulation of the synapsis surveillance system. We propose that modifications of chromosome axis components serve as signals that facilitate chromosomal events including recombination, checkpoint control, transcription, and synapsis regulation. C1 [Fukuda, Tomoyuki; Hoog, Christer] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Pratto, Florencia; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD USA. [Schimenti, John C.] Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14853 USA. [Turner, James M. A.] Natl Inst Med Res, MRC, Div Stem Cell Biol & Dev Genet, London NW7 1AA, England. RP Fukuda, T (reprint author), Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. EM tomoyuki.fukuda@ki.se; christer.hoog@ki.se FU Swedish Cancer Society; Swedish Research Council; Torsten och Ragnar Soderbergs Stiftelser; Karolinska Institutet; NIDDK (NIH); Uehara Memorial Foundation; Japan Society for the Promotion of Science FX This work was supported by grants from the Swedish Cancer Society (http://www.cancerfonden.se), the Swedish Research Council (http://www.vr.se), Torsten och Ragnar Soderbergs Stiftelser (http://www.soderbergsstiftelser.se), and Karolinska Institutet (http://www.ki.se). RDC-O was supported by the NIDDK (NIH) Intramural Research Program (http://www2.niddk.nih.gov). TF was supported by postdoctoral fellowships from the Uehara Memorial Foundation (http://www.ueharazaidan.com) and the Japan Society for the Promotion of Science (http://www.jsps.go.jp). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 21 Z9 33 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2012 VL 8 IS 2 AR e1002485 DI 10.1371/journal.pgen.1002485 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 898GA UT WOS:000300725500012 PM 22346761 ER PT J AU Long, JR Cai, QY Sung, H Shi, JJ Zhang, B Choi, JY Wen, WQ Delahanty, RJ Lu, W Gao, YT Shen, HB Park, SK Chen, KX Shen, CY Ren, ZF Haiman, CA Matsuo, K Kim, MK Khoo, US Iwasaki, M Zheng, Y Xiang, YB Gu, K Rothman, N Wang, WJ Hu, ZB Liu, Y Yoo, KY Noh, DY Han, BG Lee, MH Zheng, H Zhang, LN Wu, PE Shieh, YL Chan, SY Wang, SM Xie, XM Kim, SW Henderson, BE Le Marchand, L Ito, H Kasuga, Y Ahn, SH Kang, HS Chan, KYK Iwata, H Tsugane, S Li, C Shu, XO Kang, DH Zheng, W AF Long, Jirong Cai, Qiuyin Sung, Hyuna Shi, Jiajun Zhang, Ben Choi, Ji-Yeob Wen, Wanqing Delahanty, Ryan J. Lu, Wei Gao, Yu-Tang Shen, Hongbing Park, Sue K. Chen, Kexin Shen, Chen-Yang Ren, Zefang Haiman, Christopher A. Matsuo, Keitaro Kim, Mi Kyung Khoo, Ui Soon Iwasaki, Motoki Zheng, Ying Xiang, Yong-Bing Gu, Kai Rothman, Nathaniel Wang, Wenjing Hu, Zhibin Liu, Yao Yoo, Keun-Young Noh, Dong-Young Han, Bok-Ghee Lee, Min Hyuk Zheng, Hong Zhang, Lina Wu, Pei-Ei Shieh, Ya-Lan Chan, Sum Yin Wang, Shenming Xie, Xiaoming Kim, Sung-Won Henderson, Brian E. Le Marchand, Loic Ito, Hidemi Kasuga, Yoshio Ahn, Sei-Hyun Kang, Han Sung Chan, Kelvin Y. K. Iwata, Hiroji Tsugane, Shoichiro Li, Chun Shu, Xiao-Ou Kang, Dae-Hee Zheng, Wei TI Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer SO PLOS GENETICS LA English DT Article ID CHINESE WOMEN; GENETIC-VARIANTS; CONFER SUSCEPTIBILITY; COMMON VARIANTS; RISK; GROWTH; STRATIFICATION; ALLELES; ALPHA; BARX2 AB Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-beta activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8x10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9x10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6x10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively. C1 [Long, Jirong; Cai, Qiuyin; Shi, Jiajun; Zhang, Ben; Wen, Wanqing; Delahanty, Ryan J.; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Sung, Hyuna; Choi, Ji-Yeob; Park, Sue K.; Kang, Dae-Hee] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Lu, Wei; Zheng, Ying; Gu, Kai; Wang, Wenjing] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Shen, Hongbing; Hu, Zhibin; Liu, Yao] Nanjing Med Univ, Dept Epidemiol & Biostat, Nanjing, Jiangsu, Peoples R China. [Park, Sue K.; Yoo, Keun-Young; Kang, Dae-Hee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Park, Sue K.; Noh, Dong-Young; Kim, Sung-Won; Kang, Dae-Hee] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea. [Chen, Kexin; Zheng, Hong; Zhang, Lina] Tianjin Med Univ, Canc Inst & Hosp, Dept Epidemiol & Biostat, Tianjin, Peoples R China. [Shen, Chen-Yang; Wu, Pei-Ei; Shieh, Ya-Lan] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Taichung, Taiwan. [Ren, Zefang] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou 510275, Guangdong, Peoples R China. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Matsuo, Keitaro; Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Kim, Mi Kyung; Ahn, Sei-Hyun; Kang, Han Sung] Natl Canc Ctr, Breast Canc Ctr, Canc Epidemiol Div, Goyang, South Korea. [Kim, Mi Kyung; Ahn, Sei-Hyun; Kang, Han Sung] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Surg, Ulsan 680749, South Korea. [Khoo, Ui Soon; Chan, Kelvin Y. K.] Univ Hong Kong, Li Ka Shing Fac Med, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Iwasaki, Motoki; Tsugane, Shoichiro] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Epidemiol & Prevent Div, Tokyo 104, Japan. [Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Noh, Dong-Young; Kim, Sung-Won] Seoul Natl Univ, Coll Med, Dept Surg, Seoul, South Korea. [Han, Bok-Ghee] Korea Natl Inst Hlth, Ctr Genome Sci, Seoul, South Korea. [Lee, Min Hyuk] Soonchunhyang Univ Hosp, Dept Surg, Puchon, South Korea. [Chan, Sum Yin] Queen Mary Hosp, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. [Wang, Shenming] Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou 510275, Guangdong, Peoples R China. [Xie, Xiaoming] Sun Yat Sen Univ, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Canc Res Ctr, Honolulu, HI 96822 USA. [Kasuga, Yoshio] Nagano Matsushiro Gen Hosp, Dept Surg, Nagano, Japan. [Chan, Kelvin Y. K.] Univ Hong Kong, Li Ka Shing Fac Med, Dept Obstet & Gynecol, Hong Kong, Hong Kong, Peoples R China. [Iwata, Hiroji] Aichi Canc Ctr Cent Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Li, Chun] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. RP Long, JR (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. EM wei.zheng@vanderbilt.edu RI Yoo, Keun-Young/J-5548-2012; Park, Sue Kyung/J-2757-2012; Li, Chun/B-8388-2012; Khoo, Ui Soon/C-1345-2014; Tsugane, Shocichiro/A-2424-2015; Shen, CY/F-6271-2010; Noh, Dong-Young/G-5531-2011; Choi, Ji-Yeob/J-2796-2012; Kang, Dae Hee/E-8631-2012; Kim, Sung-Won/J-5409-2012 OI Khoo, Ui Soon/0000-0003-2200-7505; Matsuo, Keitaro/0000-0003-1761-6314; FU U.S. National Institutes of Health [R01CA124558, R01CA148667, R01CA64277, R37CA070867]; Ingram Professorship and Research Reward [R01CA118229, R01CA092585]; Department of Defense (DOD) [BC011118, R01CA122756, BC050791, R01 CA137013]; Vanderbilt-Ingram Cancer Center [P30 CA68485]; BRL (Basic Research Laboratory) through the National Research Foundation of Korea; Ministry of Education, Science and Technology [2011-0001564]; Ministry for Health, Welfare, and Family Affairs, Republic of Korea [1020350]; Shanghai Breast Cancer Study [R01CA64277]; Shanghai Women's Health Study [R37CA070867]; Shanghai Breast Cancer Survival Study [R01CA118229]; Shanghai Endometrial Cancer Study [R01CA092585]; Seoul Breast Cancer Study (Ministry of Health & Welfare, Republic of Korea) [0620410-1]; Nanjing Study (Jiangsu, China) [09KJA330001]; Tianjin Study (National Natural Science Foundation of China) [30771844]; Taiwan Biobank Study [DOH97-01]; Hong Kong Study (Research Grant Council, Hong Kong SAR, China) [HKU 7520/05M, 76730M]; Guangzhou Breast Cancer Study (National Natural Science Foundation of China) [81072383]; Multiethnic Cohort Study [CA63464, CA54281, CA132839]; Nagano Breast Cancer Study (Ministry of Health, Labor, and Welfare of Japan, Ministry of Education, Culture, Sports, Science, and Technology of Japan) [17015049, 221S0001]; Aichi Cancer Center (Ministry of Education, Culture, Sports, Science, and Technology of Japan, Ministry of Health, Labor, and Welfare of Japan) [17015052, H20-002] FX This research was supported in part by U.S. National Institutes of Health grants R01CA124558, R01CA148667, R01CA64277, and R37CA070867, as well as Ingram Professorship and Research Reward funds to W Zheng; R01CA118229, R01CA092585, and Department of Defense (DOD) Idea Award BC011118 to X-O Shu; R01CA122756 and DOD Idea Award BC050791 to Q Cai; R01 CA137013 to J Long. Sample preparation and genotyping assays at Vanderbilt were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by Vanderbilt-Ingram Cancer Center (P30 CA68485). The SeBCS was supported by BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0001564). The KOHBRA/KOGES was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare, and Family Affairs, Republic of Korea (#1020350). Participating studies (Principal Investigator, grant support) in the consortium are as follows: the Shanghai Breast Cancer Study (W Zheng, R01CA64277), the Shanghai Women's Health Study (W Zheng, R37CA070867), the Shanghai Breast Cancer Survival Study (X-O Shu, R01CA118229), the Shanghai Endometrial Cancer Study (X-O Shu, R01CA092585, contributing only controls to the consortium), the Seoul Breast Cancer Study (D-H Kang, the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea, 0620410-1), the Nanjing Study (H Shen, 09KJA330001, Jiangsu, China), the Tianjin Study (K Chen, the National Natural Science Foundation of China Grant No. 30771844), the Taiwan Biobank Study (C-Y Shen, DOH97-01), the Hong Kong Study (US Khoo, Research Grant Council, Hong Kong SAR, China, HKU 7520/05M and 76730M), the Guangzhou Breast Cancer Study (Z Ren, the National Natural Science Foundation of China Grant No. 81072383), the Multiethnic Cohort Study (BE Henderson, CA63464; LN Kolonel, CA54281; and CA Haiman, CA132839), the Nagano Breast Cancer Study (S Tsugane, Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare of Japan, and for Scientific Research on Priority Areas, 17015049, and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan), and the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (K Tajima, Grants-in-Aid for Scientific Research on Priority Areas, 17015052, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; H Tanaka, Grants-in-Aid for the Third Term Comprehensive Ten- Year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare of Japan, H20-002). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 69 Z9 70 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2012 VL 8 IS 2 AR e1002532 DI 10.1371/journal.pgen.1002532 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 898GA UT WOS:000300725500045 PM 22383897 ER PT J AU Daar, IO AF Daar, Ira O. TI Non-SH2/PDZ reverse signaling by ephrins SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Ephrin; Eph; Cell adhesion; Reverse signaling; Cell movement ID PLANAR CELL POLARITY; RECEPTOR TYROSINE KINASE; CRANIAL NEURAL CREST; EPH-RECEPTOR; VASCULAR MORPHOGENESIS; TRANSMEMBRANE LIGANDS; CYTOPLASMIC DOMAIN; TISSUE BOUNDARIES; EYE FIELD; PHOSPHORYLATION AB Great strides have been made regarding our understanding of the processes and signaling events influenced by Eph/ephrin signaling that play a role in cell adhesion and cell movement. However, the precise mechanisms by which these signaling events regulate cell and tissue architecture still need further resolution. The Eph/ephrin signaling pathways and the ability to regulate cell-cell adhesion and motility constitutes an impressive system for regulating tissue separation and morphogenesis (Pasquale, 2005, 2008 [1,2]). Moreover, the de-regulation of this signaling system is linked to the promotion of aggressive and metastatic tumors in humans [2]. In the following section, we discuss some of the interesting mechanisms by which ephrins can signal through their own intracellular domains (reverse signaling) either independent of forward signaling or in addition to forward signaling through a cognate receptor. In this review we discuss how ephrins (Eph ligands) "reverse signal" through their intracellular domains to affect cell adhesion and movement, but the focus is on modes of action that are independent of SH2 and PDZ interactions. Published by Elsevier Ltd. C1 NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Daar, IO (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM daar@ncifcrf.gov OI Daar, Ira/0000-0003-2657-526X FU NIH, National Cancer Institute FX I wish to apologize to all of my colleagues whose work was not cited in this review. Many have contributed greatly to our understanding of the role of the Eph-ephrin system in biology, but space considerations prevented the inclusion of their work. Research in the Daar laboratory on the described topics was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 94 TC 24 Z9 24 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD FEB PY 2012 VL 23 IS 1 BP 65 EP 74 DI 10.1016/j.semcdb.2011.10.012 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 899DV UT WOS:000300796300009 PM 22040914 ER PT J AU Molloy, MJ Bouladoux, N Belkaid, Y AF Molloy, Michael J. Bouladoux, Nicolas Belkaid, Yasmine TI Intestinal microbiota: Shaping local and systemic immune responses SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Commensals; Flora; Regulation; Immunity; Bacteria ID REGULATORY T-CELLS; SEGMENTED FILAMENTOUS BACTERIA; INFLAMMATORY-BOWEL-DISEASE; ORAL TOLERANCE INDUCTION; GERM-FREE MICE; LIPOPOLYSACCHARIDE LPS REGULATION; CENTRAL-NERVOUS-SYSTEM; DENDRITIC CELLS; RETINOIC ACID; IN-VITRO AB Recent studies have highlighted the fundamental role of commensal microbes in the maintenance of host homeostasis. For instance, commensals can play a major role in the control of host defense, metabolism and tissue development. Over the past few years, abundant experimental data also support their central role in the induction and control of both innate and adaptive responses. It is now clearly established that commensals are not equal in their capacity to trigger control regulatory or effector responses, however, the molecular basis of these differences has only recently begun to be explored. This review will discuss recent findings evaluating how commensals shape both effector and regulatory responses at steady state and during infections and the consequence of this effect on local and systemic protective and inflammatory responses. Published by Elsevier Ltd. C1 [Molloy, Michael J.; Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-243, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX We would like to apologize to the authors we did not cite because of space constrains. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 140 TC 52 Z9 52 U1 3 U2 24 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD FEB PY 2012 VL 24 IS 1 BP 58 EP 66 DI 10.1016/j.smim.2011.11.008 PG 9 WC Immunology SC Immunology GA 901KA UT WOS:000300964600009 PM 22178452 ER PT J AU Li, XR Kumar, A Zhang, F Lee, C Tang, ZS AF Li, Xuri Kumar, Anil Zhang, Fan Lee, Chunsik Tang, Zhongshu TI Complicated life, complicated VEGF-B SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; HYPOXIC PULMONARY-HYPERTENSION; TRANSGENIC MICE; IN-VIVO; DEFICIENT MICE; MYOCARDIAL HYPERTROPHY; PARKINSONS-DISEASE; LYMPHATIC VESSELS; FAMILY-MEMBERS; KNOCKOUT MICE AB No other member of the VEGF (vascular endothelial growth factor) family has been as mysterious as VEGF-B. Notwithstanding its name, VEGF-B can hardly be regarded as a growth factor because growth occurs fairly normally in Vegf-b deficient mice. Moreover, VEGF-B is barely angiogenic under most conditions, although it was expected to be an angiogenic factor for a long time. Under certain conditions, VEGF-B has been shown to be involved in blood vessel growth. Under other conditions, however, VEGF-B can act to inhibit tumor growth and angiogenesis. Given these contradictory findings, the biological function of VEGF-B appears enigmatic. In this review, we summarize recent advances in VEGF-B biology and discuss its multifaceted roles, the underlying mechanisms, and the potential therapeutic implications. C1 [Li, Xuri; Kumar, Anil; Zhang, Fan; Lee, Chunsik; Tang, Zhongshu] NEI, NIH, Rockville, MD 20852 USA. RP Li, XR (reprint author), NEI, NIH, Rockville, MD 20852 USA. EM lixur@nei.nih.gov RI Kumar, Anil/K-8504-2012 FU National Eye Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Eye Institute, part of the National Institutes of Health. The authors have no conflicting financial interests. NR 70 TC 16 Z9 19 U1 5 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD FEB PY 2012 VL 18 IS 2 BP 119 EP 127 DI 10.1016/j.molmed.2011.11.006 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 902IO UT WOS:000301032000007 PM 22178229 ER PT J AU Ponnoth, DS Nayeem, MA Kunduri, SS Tilley, SL Zeldin, DC Ledent, C Mustafa, SJ AF Ponnoth, Dovenia S. Nayeem, Mohammed A. Kunduri, Swati S. Tilley, Stephen L. Zeldin, Darryl C. Ledent, Catherine Mustafa, S. Jamal TI Role of omega-hydroxylase in adenosine-mediated aortic response through MAP kinase using A(2A)-receptor knockout mice SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE adenosine receptors; relaxation; contraction; cytochrome p4504a; extracellular signal-regulated kinase-1/2 kinases ID SMOOTH-MUSCLE-CELLS; ACTIVATED PROTEIN-KINASES; BOVINE CORONARY-ARTERIES; 20-HYDROXYEICOSATETRAENOIC ACID; RESISTANCE ARTERIES; ARACHIDONIC-ACID; CYP EPOXYGENASES; A(3) RECEPTORS; A(1) RECEPTOR; VASCULAR-TONE AB Ponnoth DS, Nayeem MA, Kunduri SS, Tilley SL, Zeldin DC, Ledent C, Mustafa SJ. Role of omega-hydroxylase in adenosine-mediated aortic response through MAP kinase using A(2A) receptor knockout mice. Am J Physiol Regul Integr Comp Physiol 302: R400-R408, 2012. First published December 7, 2011; doi:10.1152/ajpregu.00481.2011.-Previously, we have shown that A(2A) adenosine receptor (A(2A)AR) knockout mice (KO) have increased contraction to adenosine. The signaling mechanism(s) for A(2A)AR is still not fully understood. In this study, we hypothesize that, in the absence of A(2A)AR, omega-hydroxylase (Cyp4a) induces vasoconstriction through mitogen-activated protein kinase (MAPK) via upregulation of adenosine A(1) receptor (A(1)AR) and protein kinase C (PKC). Organ bath and Western blot experiments were done using isolated aorta from A(2A)KO and corresponding wild-type (WT) mice. Isolated aortic rings from WT and A(2A)KO mice were precontracted with submaximal dose of phenylephrine (10(-6) M), and concentration responses for selective A(1)AR, A(2A)AR agonists, angiotensin II and cytochrome P-450-epoxygenase, 20-hydroxyeicosatrienoic acid (20-HETE) PKC, PKC-alpha, and ERK1/2 inhibitors were obtained. 2-p-(2-Carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680, A(2A)AR agonist) induced concentration-dependent relaxation in WT, which was blocked by methylsulfonyl-propargyloxyphenylhexanamide (cytochrome P-450-epoxygenase inhibitor; 10(-5) M) and also with removal of endothelium. A(1) agonist, 2-chloro-N-6-cyclopentyladenosine (CCPA) produced higher contraction in A(2A)KO aorta than WT (49.2 +/- 8.5 vs. 27 +/- 5.9% at 10(-6) M, P < 0.05). 20-HETE produced higher contraction in A(2A)KO than WT (50.6 +/- 8.8 vs. 21.1 +/- 3.3% at 10(-7) M, P < 0.05). Contraction to CCPA in WT and A(2A)KO aorta was inhibited by PD-98059 (p42/p44 MAPK inhibitor; 10(-6) M), chelerythrine chloride (nonselective PKC blocker; 10(-6) M), Go-6976 (selective PKC-alpha inhibitor; 10(-7) M), and HET0016 (20-HETE inhibitor; 10(-5) M). Also, contraction to 20-HETE in WT and A(2A)KO aorta was inhibited by PD-98059 and Go-6976. Western blot analysis indicated the upregulation of A(1)AR, Cyp4a, PKC-alpha, and phosphorylated-ERK1/2 in A(2A)KO compared with WT (P < 0.05), while expression of Cyp2c29 was significantly higher in WT. CCPA (10(-6) M) increased the protein expression of PKC-alpha and phosphorylated-ERK1/2, while HET0016 significantly reduced the CCPA-induced increase in expression of these proteins. These data suggest that, in the absence of A(2A)AR, Cyp4a induces vasoconstriction through MAPK via upregulation of A(1)AR and PKC-alpha. C1 [Mustafa, S. Jamal] W Virginia Univ, Sch Med, Dept Physiol & Pharmacol, Ctr Cardiovasc & Resp Sci, Morgantown, WV 26506 USA. [Tilley, Stephen L.] Univ N Carolina, Div Pulm & Crit Care Med, Dept Med, Chapel Hill, NC USA. [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC USA. [Ledent, Catherine] Univ Libre Bruxelles, Brussels, Belgium. RP Mustafa, SJ (reprint author), W Virginia Univ, Sch Med, Dept Physiol & Pharmacol, Ctr Cardiovasc & Resp Sci, Morgantown, WV 26506 USA. EM sjmustafa@hsc.wvu.edu RI Nayeem, Mohammed/A-3949-2017 OI Nayeem, Mohammed/0000-0002-7827-4760 FU National Heart, Lung, and Blood Institute [HL-027339, HL-094447, HL-071802]; National Institute of Environmental Health Sciences [Z01 ES025034] FX This work was supported by National Heart, Lung, and Blood Institute Grants HL-027339, HL-094447 (S. J. Mustafa), and HL-071802 (S. L. Tilley), and National Institute of Environmental Health Sciences Z01 ES025034 (D. C. Zeldin). NR 46 TC 11 Z9 11 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD FEB PY 2012 VL 302 IS 4 BP R400 EP R408 DI 10.1152/ajpregu.00481.2011 PG 9 WC Physiology SC Physiology GA 898JH UT WOS:000300738200002 PM 22160543 ER PT J AU Chiu, R Li, W Herber, RP Marshall, SJ Young, M Ho, SP AF Chiu, R. Li, W. Herber, R. P. Marshall, S. J. Young, M. Ho, S. P. TI Effects of biglycan on physico-chemical properties of ligament-mineralized tissue attachment sites SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE Cementum; Soft-hard tissue interfaces; Tissue mechanics; Bone-tooth biomechanics; Bone-PDL-cementum complex; Proteoglycans; Structure; Mechanical properties ID LEUCINE-RICH PROTEOGLYCANS; EHLERS-DANLOS-SYNDROME; DEFICIENT MICE; TARGETED DISRUPTION; COLLAGEN FIBRILS; ENAMEL FORMATION; DECORIN; BONE; FIBROMODULIN; EXPRESSION AB Matrix proteoglycans define matrix structure, mineralization, and resulting biomechanics of tissues and their attachment sites. Objective: We therefore investigated physical and (bio)chemical differences in enamel and periodontal tissues/attachment sites from mice that lack a specific nanoscale small leucine-rich proteoglycan (SLRPs) named biglycan (BGN). Design: Experimental groups consisted of N = 4, biglycan knockout (BGNKO) and N = 5 wildtype (WT) 8-week-old, male C3H mice. Morphology, histochemical and mechanical analyses were performed through micro X-ray computed tomography (Micro XCT (TM)), immunohistochemistry, and microindentation. Unless mentioned otherwise, all differences between BGNKO and WT were demonstrated to be statistically significant through Student's t-tests with a 95% confidence interval (P <= 0.05). Results: Histomorphometry performed by using Micro XCT (TM) images indicated significantly higher BGNKO-enamel (0.46 +/- 0.03 mm(3)) and BGNKO-root (1.81 +/- 0.10 mm(3)) volumes compared to WT-enamel (0.37 +/- 0.02 mm(3)) and WT-root (1.65 +/- 0.07 mm(3)). BGNKO tooth size was relatively larger than WT mice, with no significant difference between skull sizes. Immunohistochemistry indicated BGN expression in the periodontal ligament (PDL), alveolar bone (AB), at the bone-PDL and cementum-PDL attachment sites in WT mice. Deeper AB resorption pits within interdental region of BGNKO specimens compared to WT resulting in significant differences in PDL-space of BGNKO (93 +/- 13 mu m) and WT (74 +/- 11 mu m) were observed. Microhardness of BGNKO-enamel (2.46 +/- 0.60 GPa) and BGNKO-AB (0.52 +/- 0.10 GPa) was significantly lower than WT-enamel (2.67 +/- 0.60 GPa) and WT-AB (0.54 +/- 0.10 GPa). Conclusion: Results indicate that BGNKO-mice exhibit significant differences in tissue properties compared to WT-mice. (C) 2011 Published by Elsevier Ltd. C1 [Chiu, R.; Marshall, S. J.; Ho, S. P.] Univ Calif San Francisco, Dept Prevent & Restorat Dent Sci, Div Biomat & Bioengn, San Francisco, CA 94143 USA. [Li, W.] Univ Calif San Francisco, Dept Orofacial Sci, Div Pediat Dent, San Francisco, CA 94143 USA. [Herber, R. P.] Univ Calif San Francisco, Dept Orofacial Sci, Div Orthodont, San Francisco, CA 94143 USA. [Young, M.] NIDCR, NIH, Bethesda, MD USA. RP Ho, SP (reprint author), Univ Calif San Francisco, Dept Prevent & Restorat Dent Sci, Div Biomat & Bioengn, D 2252,707 Parnassus Ave, San Francisco, CA 94143 USA. EM sunita.ho@ucsf.edu OI Ho, Sunita/0000-0001-9999-8226 FU NIH/NIDCR [R00DE018212]; NIH/NCRR [S10 RR026645]; Department of Preventive and Restorative Dental Sciences, UCSF; Department of Orofacial Sciences, UCSF FX Support was provided by NIH/NIDCR R00DE018212 (SPH) and NIH/NCRR S10 RR026645 (SPH), and Departments of Preventive and Restorative Dental Sciences and Orofacial Sciences, UCSF. NR 44 TC 7 Z9 7 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD FEB PY 2012 VL 57 IS 2 BP 177 EP 187 DI 10.1016/j.archoralbio.2011.08.011 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 899FN UT WOS:000300801900009 PM 21963335 ER PT J AU Moeller, TA Shukla, SJ Xia, MH AF Moeller, Timothy A. Shukla, Sunita J. Xia, Menghang TI Assessment of Compound Hepatotoxicity Using Human Plateable Cryopreserved Hepatocytes in a 1536-Well-Plate Format SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID THROUGHPUT SCREENING ASSAYS; DRUG-DRUG INTERACTIONS; HEPATOMA-CELL LINES; IN-VITRO MODELS; CYTOCHROME-P450 EXPRESSION; PHARMACEUTICAL RESEARCH; LIVER-TRANSPLANTATION; MALACHITE GREEN; TOXICITY; CYTOTOXICITY AB Hepatotoxicity is a major concern for both drug development and toxicological evaluation of environmental chemicals. The assessment of compound-induced hepatotoxicity has traditionally relied on in vivo testing; however, it is being replaced by human in vitro models due to an emphasis on the reduction of animal testing and species-specific differences. Since most cell lines and hybridomas lack the full complement of enzymes at physiological levels found in the liver, primary hepatocytes are the gold standard to study liver toxicities in vitro due to the retention of most of their in vivo activities. Here, we optimized a cell viability assay using plateable cryopreserved human hepatocytes in a 1536-well-plate format. The assay was validated by deriving inhibitory concentration at 50% values for 12 known compounds, including tamoxifen, staurosporine, and phenylmercuric acetate, with regard to hepatotoxicity and general cytotoxicity using multiple hepatocyte donors. The assay performed well, and the cytotoxicity of these compounds was confirmed in comparison to HepG2 cells. This is the first study to report the reliability of using plateable cryopreserved human hepatocytes for cytotoxicity studies in a 1536-well-plate format. These results suggest that plateable cryopreserved human hepatocytes can be scaled up for screening a large compound library and may be amenable to other hepatocytic assays such as metabolic or drug safety studies. C1 [Shukla, Sunita J.; Xia, Menghang] NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. [Moeller, Timothy A.] Celsis Vitro Technol, Baltimore, MD USA. RP Xia, MH (reprint author), NIH, NIH Chem Genom Ctr, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU Intramural Research Programs of the National Toxicology Program; National Institute of Environmental Health Sciences [Y2-ES-7020-01]; National Human Genome Research Institute, National Institutes of Health; NIH Roadmap for Medical Research FX We thank Srilatha Sakamuru and Jinghuan Zhao for technical support. This research was supported by the Intramural Research Programs of the National Toxicology Program, National Institute of Environmental Health Sciences Interagency Agreement Y2-ES-7020-01, and the National Human Genome Research Institute, National Institutes of Health, and the NIH Roadmap for Medical Research Molecular Libraries Program. NR 63 TC 7 Z9 7 U1 0 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD FEB PY 2012 VL 10 IS 1 BP 78 EP 87 DI 10.1089/adt.2010.0365 PG 10 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 896TX UT WOS:000300595400007 PM 22053711 ER PT J AU Nybo, K Gottesman, S AF Nybo, Kristie Gottesman, Susan TI In Search of an Explanation SO BIOTECHNIQUES LA English DT Editorial Material C1 [Gottesman, Susan] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Gottesman, Susan] NCI, Biochem Genet Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 2012 VL 52 IS 2 BP 71 EP 71 DI 10.2144/000113805 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 895CE UT WOS:000300473000002 PM 22313403 ER PT J AU Pavletic, SZ AF Pavletic, S. Z. TI Response as an end point in treatment trials for acute GVHD SO BONE MARROW TRANSPLANTATION LA English DT Editorial Material ID VERSUS-HOST-DISEASE; HEMATOPOIETIC-CELL TRANSPLANTATION; MARROW-TRANSPLANTATION; CLINICAL-TRIALS; THERAPY; ETANERCEPT; SURVIVAL; REGIMENS; INDEX C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Pavletic, SZ (reprint author), NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov NR 22 TC 2 Z9 2 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2012 VL 47 IS 2 BP 161 EP 163 DI 10.1038/bmt.2011.59 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 894GM UT WOS:000300415100001 PM 22314205 ER PT J AU Luger, SM Ringden, O Zhang, MJ Perez, WS Bishop, MR Bornhauser, M Bredeson, CN Cairo, MS Copelan, EA Gale, RP Giralt, SA Gulbas, Z Gupta, V Hale, GA Lazarus, HM Lewis, VA Lill, MC McCarthy, PL Weisdorf, DJ Pulsipher, MA AF Luger, S. M. Ringden, O. Zhang, M-J Perez, W. S. Bishop, M. R. Bornhauser, M. Bredeson, C. N. Cairo, M. S. Copelan, E. A. Gale, R. P. Giralt, S. A. Gulbas, Z. Gupta, V. Hale, G. A. Lazarus, H. M. Lewis, V. A. Lill, M. C. McCarthy, P. L. Weisdorf, D. J. Pulsipher, M. A. TI Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS SO BONE MARROW TRANSPLANTATION LA English DT Article DE allogeneic transplant; reduced intensity; AML ID HEMATOPOIETIC-CELL TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; BONE-MARROW-TRANSPLANTATION; TOTAL-BODY IRRADIATION; GRAFT-VERSUS-LEUKEMIA; CONDITIONING REGIMEN; MYELODYSPLASTIC SYNDROME; UNRELATED DONORS; OLDER PATIENTS AB Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning. Bone Marrow Transplantation (2012) 47, 203-211; doi:10.1038/bmt.2011.69; published online 28 March 2011 C1 [Weisdorf, D. J.] Univ Minnesota, Med Ctr, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Luger, S. M.] Hosp Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Ringden, O.] Karolinska Univ Hosp, Huddinge, Sweden. [Zhang, M-J; Perez, W. S.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Bishop, M. R.] NCI, Bethesda, MD 20892 USA. [Bornhauser, M.] Univ Klinikum Carl Gustav Carus, Dresden, Germany. [Bredeson, C. N.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Milwaukee, WI 53226 USA. [Cairo, M. S.] Morgan Stanley Childrens Hosp New York, New York, NY USA. [Copelan, E. A.] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. [Gale, R. P.] Celgene Corp, Summit, NJ USA. [Giralt, S. A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gulbas, Z.] Osmangazi Univ, Sch Med, Eskisehir, Turkey. [Gupta, V.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Hale, G. A.] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Lazarus, H. M.] Univ Hosp Case Med Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. [Lewis, V. A.] Alberta Childrens Prov Gen Hosp, Calgary, AB, Canada. [Lill, M. C.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [McCarthy, P. L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Pulsipher, M. A.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Med Ctr, Masonic Canc Ctr, 420 Delaware St SE,MMC 480, Minneapolis, MN 55455 USA. EM weisd001@umn.edu FU Public Health Service from National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI) [5U01HL069294]; National Institute of Allergy and Infectious Diseases [5U01HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc.; Astellas Pharma US Inc.; Baxter International Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc.; Biovitrum AB; Blood Center of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma Inc.; Dynal Biotech, an Invitrogen Company; Eisai Inc.; Enzon Pharmaceuticals Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell Ltd; GE Healthcare; Genentech Inc.; Genzyme Corporation; Histogenetics Inc.; HKS Medical Information Systems; Hospira Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co. Ltd; Leukemia & Lymphoma Society; Merck Company; Medical College of Wisconsin; MGI Pharma Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals Inc.; Miller Pharmacal Group; Milliman USA Inc.; Miltenyi Biotec Inc.; NMDP; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc.; Otsuka America Pharmaceutical Inc.; Pall Life Sciences; Pfizer Inc.; Saladax Biomedical Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; StemCyte Inc.; StemSoft Software Inc.; Sysmex America Inc.; Teva Pharmaceutical Industries; Therakos Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals Inc.; ViraCor Laboratories; ViroPharma Inc.; Wellpoint Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases; a grant/cooperative agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc.; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc.; Baxter International Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc.; Biovitrum AB; Blood Center of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma Inc.; Dynal Biotech, an Invitrogen Company; Eisai Inc.; Enzon Pharmaceuticals Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell Ltd; GE Healthcare; Genentech Inc.; Genzyme Corporation; Histogenetics Inc.; HKS Medical Information Systems; Hospira Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co. Ltd; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals Inc.; Miller Pharmacal Group; Milliman USA Inc.; Miltenyi Biotec Inc.; NMDP; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc.; Otsuka America Pharmaceutical Inc.; Pall Life Sciences; Pfizer Inc.; Saladax Biomedical Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; StemCyte Inc.; StemSoft Software Inc.; Sysmex America Inc.; Teva Pharmaceutical Industries; Therakos Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals Inc.; ViraCor Laboratories; ViroPharma Inc.; and Wellpoint Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense or any other agency of the US Government. We thank Karen Ballen, Willem Bujan, Steven Goldstein, Roger Herzig, Osman Ilhan, Luis Isola, Jane Liesveld, Gustavo Milone, David Rizzieri, James Russell, Mitchell Sabloff, Stella Santarone, Gary Schiller, Robert Soiffer, Edmund Waller, Roy Weiner and Peter Wiernik for helpful comments and insights. NR 26 TC 113 Z9 113 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2012 VL 47 IS 2 BP 203 EP 211 DI 10.1038/bmt.2011.69 PG 9 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 894GM UT WOS:000300415100007 PM 21441963 ER PT J AU Glaser, RL Dimitrakakis, C Messenger, AG AF Glaser, R. L. Dimitrakakis, C. Messenger, A. G. TI Improvement in scalp hair growth in androgen-deficient women treated with testosterone: a questionnaire study SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; 5-ALPHA-REDUCTASE ACTIVITY; INSULIN-RESISTANCE; COMMON BALDNESS; ALOPECIA; FINASTERIDE; PREVALENCE; HYPERANDROGENISM; FEMALES; HORMONE AB Background Androgens are thought to have an adverse effect on female scalp hair growth. However, our clinical experience of androgen replacement therapy in women with androgen deficiency, in which hair loss was seldom reported, led us to question this concept. Objectives To evaluate the effect of subcutaneous testosterone therapy on scalp hair growth in female patients. Methods A total of 285 women, treated for a minimum of 1 year with subcutaneous testosterone implants for symptoms of androgen deficiency, were asked to complete a survey that included questions on scalp and facial hair. Age, body mass index (BMI) and serum testosterone levels were examined. Results Out of the 285 patients, 76 (27%) reported hair thinning prior to treatment; 48 of these patients (63%) reported hair regrowth on testosterone therapy (responders). Nonresponders (i.e. no reported hair regrowth on therapy) had significantly higher BMIs than responders (P = 0.05). Baseline serum testosterone levels were significantly lower in women reporting hair loss prior to therapy than in those who did not (P = 0.0001). There was no significant difference in serum testosterone levels, measured 4 weeks after testosterone implantation, between responders and nonresponders. No patient in this cohort reported scalp hair loss on testosterone therapy. A total of 262 women (92%) reported some increase in facial hair growth. Conclusions Subcutaneous testosterone therapy was found to have a beneficial effect on scalp hair growth in female patients treated for symptoms of androgen deficiency. We propose this is due to an anabolic effect of testosterone on hair growth. The fact that no subject complained of hair loss as a result of treatment casts doubt on the presumed role of testosterone in driving female scalp hair loss. These results need to be confirmed by formal measurements of hair growth. C1 [Glaser, R. L.] Millennium Wellness Ctr, Dayton, OH 45458 USA. [Glaser, R. L.] Wright State Univ, Dept Surg, Boonshoft Sch Med, Dayton, OH 45435 USA. [Dimitrakakis, C.] NICHD, NIH, Bethesda, MD 20892 USA. [Dimitrakakis, C.] Univ Athens, Sch Med, Dept Ob Gyn 1, Athens 11528, Greece. [Messenger, A. G.] Royal Hallamshire Hosp, Dept Dermatol, Sheffield S10 2JF, S Yorkshire, England. RP Glaser, RL (reprint author), Millennium Wellness Ctr, 228 E Spring Valley Rd, Dayton, OH 45458 USA. EM rglaser@woh.rr.com NR 23 TC 5 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD FEB PY 2012 VL 166 IS 2 BP 274 EP 278 DI 10.1111/j.1365-2133.2011.10655.x PG 5 WC Dermatology SC Dermatology GA 897YN UT WOS:000300699200008 PM 21967243 ER PT J AU Flores-Santana, W Moody, T Chen, WB Gorczynski, MJ Shoman, ME Velazquez, C Thetford, A Mitchell, JB Cherukuri, MK King, SB Wink, DA AF Flores-Santana, Wilmarie Moody, Terry Chen, Weibin Gorczynski, Michael J. Shoman, Mai E. Velazquez, Carlos Thetford, Angela Mitchell, James B. Cherukuri, Murali K. King, S. Bruce Wink, David A. TI Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE NSAIDS; nitroxides; cancer; nitrosative stress; inflammation; antioxidants ID NITRIC-OXIDE RELEASE; BIOLOGICAL EVALUATION; CANCER PREVENTION; OXIDATIVE DAMAGE; SOD-MIMICS; INHIBITION; TEMPOL; NSAIDS; RAT; RADIOTHERAPY AB BACKGROUND AND PURPOSE Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox-active nitroxide group. TEMPO-aspirin (TEMPO-ASA) and TEMPO-indomethacin (TEMPO-IND) were synthesized and evaluated in the lung cancer cell line A549. EXPERIMENTAL APPROACHES We evaluated physico-chemical properties of TEMPO-ASA and TEMPO-IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase-like properties was assayed by measuring cytochrome c reduction and anti-inflammatory effects were assayed by measuring production of prostaglandin E-2 (PGE(2)) and leukotriene B-4 (LTB4). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo. KEY RESULTS MTD were: TEMPO (140 mg.kg(-1)), ASA (100 mg.kg(-1)), indomethacin (5 mg.kg(-1)), TEMPO-ASA (100 mg.kg(-1)) and TEMPO-IND (40 mg.kg(-1)). While TEMPO-ASA was as well tolerated as ASA, TEMPO-IND showed an eightfold improvement over indomethacin. TEMPO-IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO-ASA and TEMPO-IND inhibited production of PGE(2) and LTB4 in A549 cells with maximum effects at 100 mg.mL(-1) or 10 mg.mL(-1) respectively. CONCLUSIONS AND IMPLICATIONS The nitroxide-NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti-inflammatory effects, inhibiting cyclooxygenase and 5-lipoxygenase enzymes. These redox-modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID-associated toxicity. C1 [Flores-Santana, Wilmarie; Thetford, Angela; Mitchell, James B.; Cherukuri, Murali K.; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Moody, Terry] NCI, Off Director, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, Weibin; Gorczynski, Michael J.; Shoman, Mai E.; King, S. Bruce] Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA. [Velazquez, Carlos] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov FU NIH, National Cancer Institute FX This project has been funded through the Intramural Research Program of the NIH, National Cancer Institute. NR 43 TC 10 Z9 11 U1 2 U2 10 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 FEB PY 2012 VL 165 IS 4B BP 1058 EP 1067 DI 10.1111/j.1476-5381.2011.01527.x PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 881GC UT WOS:000299469600004 PM 21658022 ER PT J AU Schlom, J AF Schlom, Jeffrey TI Recent Advances in Therapeutic Cancer Vaccines SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article ID RESISTANT PROSTATE-CANCER; CELL LUNG-CANCER; COLONY-STIMULATING FACTOR; TUMOR MICROENVIRONMENT; FOLLICULAR LYMPHOMA; RECOMBINANT VACCINE; IMMUNE SUPPRESSION; CARCINOMA PATIENTS; SIPULEUCEL-T; IMMUNOTHERAPY C1 NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov NR 51 TC 7 Z9 7 U1 0 U2 8 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD FEB PY 2012 VL 27 IS 1 BP 2 EP 5 DI 10.1089/cbr.2012.1200 PG 4 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 896TV UT WOS:000300595200002 PM 22251077 ER PT J AU Hodge, JW Sharp, HJ Gameiro, SR AF Hodge, James W. Sharp, Hadley J. Gameiro, Sofia R. TI Abscopal Regression of Antigen Disparate Tumors by Antigen Cascade After Systemic Tumor Vaccination in Combination with Local Tumor Radiation SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE abscopal; radiation; vaccine; modulation; Fas; immunotherapy ID RECOMBINANT ANTICANCER VACCINES; T-CELL EPITOPE; IMMUNE-RESPONSES; COSTIMULATORY MOLECULES; IONIZING-RADIATION; ENDOTHELIAL-CELLS; DIVERSIFIED PRIME; PROSTATE-CANCER; RADIOTHERAPY; IRRADIATION AB Radiation is a primary modality in cancer treatment. Radiation can also reduce tumor growth outside the treatment field, often referred to as the abscopal effect. The mechanisms and therapeutic potential of the abscopal effect have not been fully elucidated. We evaluated the role of vaccination directed against a tumor-associated antigen (TAA) in the induction and amplification of radiation induced abscopal effects. Active-specific immunotherapy with a TAA-specific vaccine regimen was used to induce and potentiate T-cell responses against carcinoembryonic antigen (CEA) in combination with local irradiation of subcutaneous tumors. We examined the potential synergy of a poxvirus-based CEA vaccine regimen in CEA-transgenic (Tg) mice in combination with either external beam radiation or brachytherapy of local tumors. The induction of CD8(+) T cells specific for multiple TAAs not encoded by the vaccine was observed after the combination therapy. In two tumor models, the antigen cascade responses induced by vaccine and local irradiation mediated the regression of antigen negative metastases at distal subcutaneous or pulmonary sites. Clinically, local control of the primary tumor is necessary and can sometimes prevent metastases; however, irradiation generally fails to control preexisting metastases. These studies suggest that by coupling tumor irradiation with immunotherapy, the abscopal effect can transcend from anecdotal observation to a defined mechanism that can be exploited for the treatment of systemic disease. C1 [Hodge, James W.; Gameiro, Sofia R.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sharp, Hadley J.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B13, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH). NR 47 TC 37 Z9 38 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD FEB PY 2012 VL 27 IS 1 BP 12 EP 22 DI 10.1089/cbr.2012.1202 PG 11 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 896TV UT WOS:000300595200004 PM 22283603 ER PT J AU Gameiro, SR Caballero, JA Hodge, JW AF Gameiro, Sofia R. Caballero, Jorge A. Hodge, James W. TI Defining the Molecular Signature of Chemotherapy-Mediated Lung Tumor Phenotype Modulation and Increased Susceptibility to T-Cell Killing SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE chemoimmunotherapy; cisplatin; lung; T-cell response; vinorelbine ID NF-KAPPA-B; FACTOR PATHWAY INHIBITOR-2; COLON-CANCER-CELLS; CARCINOEMBRYONIC ANTIGEN; RECOMBINANT VACCINIA; PANCREATIC-CANCER; ICAM-1 EXPRESSION; SUPPRESSOR GENE; CEA VACCINE; CISPLATIN AB Chemotherapy with platinum doublets, including cisplatin plus vinorelbine, is standard of care for non small-cell lung cancer. Sublethal exposure to certain chemotherapeutic agents has been demonstrated to alter the phenotype or biology of human tumor cells, rendering them more susceptible to cytotoxic T lymphocyte (CTL)-mediated lysis. The effects of cisplatin/vinorelbine on tumor sensitivity to T-cell cytotoxicity and its molecular mechanisms, however, have not been fully elucidated. We examined the effect of this chemotherapy on growth, cell-surface phenotype, and CTL-mediated lysis of five distinct human lung carcinoma cell lines in vitro and examined the molecular mechanisms associated with enhanced CTL sensitivity. These studies demonstrate that sublethal exposure of human lung tumor cells to the platinum doublet modulates tumor cell phenotype and increases sensitivity to major histocompatibility complex restricted perforin/granzyme-mediated CTL killing. These studies also demonstrate that exposure to chemotherapy markedly decreased the protein secretion ratio of transforming growth factor-beta/interleukin (IL)-8. We examined the gene expression profile of two lung tumor cell lines to identify a shared gene signature in response to sublethal cisplatin/vinorelbine and found coordinate expression of only 16 transcripts, including those for cytokine/chemokine expression and apoptosis such as tumor necrosis factor-alpha, IL8, CXCL5, and B cell lymphoma-2 like genes (BCL-2). Overall, these results suggest that sublethal exposure to cisplatin/vinorelbine increases sensitivity to perforin/granzyme-mediated CTL killing by modulation of (a) tumor phenotype, (b) cytokine/chemokine milieu, and (c) the proapoptotic/antiapoptotic gene ratio. The data presented here propose a complex mechanism that is distinct from and complementary to that of immunogenic cell death. This molecular signature may be useful in predicting responses to immunotherapy as well as provide the rationale for the potential clinical benefit of the combined use of vaccine with cisplatin/vinorelbine regimens. C1 [Gameiro, Sofia R.; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Caballero, Jorge A.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B13, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We thank Dr. Jeffrey Schlom NCI, NIH, for his helpful suggestions in the review of this manuscript. The authors thank Marion Taylor for excellent technical assistance, and Debra Weingarten for her editorial assistance in the preparation of this manuscript. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 67 TC 13 Z9 13 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD FEB PY 2012 VL 27 IS 1 BP 23 EP 35 DI 10.1089/cbr.2012.1203 PG 13 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 896TV UT WOS:000300595200005 PM 22316209 ER PT J AU Shi, JX Chatterjee, N Rotunno, M Wang, YF Pesatori, AC Consonni, D Li, P Wheeler, W Broderick, P Henrion, M Eisen, T Wang, ZM Chen, W Dong, QO Albanes, D Thun, M Spitz, MR Bertazzi, PA Caporaso, NE Chanock, SJ Amos, CI Houlston, RS Landi, MT AF Shi, Jianxin Chatterjee, Nilanjan Rotunno, Melissa Wang, Yufei Pesatori, Angela C. Consonni, Dario Li, Peng Wheeler, William Broderick, Peter Henrion, Marc Eisen, Timothy Wang, Zhaoming Chen, Wei Dong, Qiong Albanes, Demetrius Thun, Michael Spitz, Margaret R. Bertazzi, Pier Alberto Caporaso, Neil E. Chanock, Stephen J. Amos, Christopher I. Houlston, Richard S. Landi, Maria Teresa TI Inherited Variation at Chromosome 12p13.33, Including RAD52, Influences the Risk of Squamous Cell Lung Carcinoma SO CANCER DISCOVERY LA English DT Article ID GENOME-WIDE ASSOCIATION; OBSTRUCTIVE PULMONARY-DISEASE; SUSCEPTIBILITY LOCUS; CANCER RISK; BREAST-CANCER; DNA-REPAIR; POPULATION; GENES; RECOMBINATION; INFLAMMATION AB Although lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies in Europeans have only robustly demonstrated 3 polymorphic variations that influence the risk of lung cancer. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a genome-wide association study of 5,355 European ever-smoker lung cancer patients and 4,344 smoking control subjects, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 single-nucleotide polymorphisms mapping to 917 genes in the HuGE-defined "inflammation" pathway. We identified a susceptibility locus for squamous cell lung carcinoma at 12p13.33 (RAD52, rs6489769) and replicated the association in 3 independent studies totaling 3,359 squamous cell lung carcinoma cases and 9,100 controls (OR = 1.20, P-combined = 2.3 x 10(-8)). SIGNIFICANCE: The combination of pathway-based approaches and information on disease-specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases. Cancer Discovery; 2(2); 131-9. (C) 2011 AACR. C1 [Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Chen, Wei; Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Dong, Qiong; Spitz, Margaret R.; Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Thun, Michael] Amer Canc Soc Epidemiol & Surveillance Res, Atlanta, GA USA. [Wang, Yufei; Broderick, Peter; Henrion, Marc; Houlston, Richard S.] Inst Canc Res, Div Epidemiol & Genet, Surrey, England. [Eisen, Timothy] Cambridge Biomed Ctr, Cambridge, England. [Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto] Univ Milan, Epidemiol Unit, IRCCS Fdn Ca Granda Osped Maggiore Policlin, Milan, Italy. [Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto] Univ Milan, Dept Occupat & Environm Hlth, Milan, Italy. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; bertazzi, pietro alberto/D-5039-2017; OI bertazzi, pietro alberto/0000-0003-3475-2449; Broderick, Peter/0000-0002-8348-5829; Henrion, Marc/0000-0003-1242-839X; pesatori, angela/0000-0002-0261-3252; Houlston, Richard/0000-0002-5268-0242 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; U.S. Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004]; NCI [NO1-CN-25514]; Georgetown University [NO1-CN-25522]; Pacific Health Research Institute [NO1-CN-25515]; Henry Ford Health System [NO1-CN-25512]; University of Minnesota [NO1-CN-25513]; Washington University [NO1-CN-25516]; University of Pittsburgh [NO1-CN-25511]; University of Utah [NO1-CN-25524]; Marshfield Clinic Research Foundation [NO1-CN-25518]; University of Alabama at Birmingham [NO1-CN-75022]; Westat, Inc. [NO1-CN-25476]; University of California, Los Angeles [NO1-CN-25404]; American Cancer Society; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01]; Johns Hopkins University [U01HG004438, HHSN268200782096C]; GENEVA Coordination Center [U01HG004446]; NIH [R01CA55769, R01 CAl27219, R01 CA133996, U19CAl21197, U19 CA14812701]; Cancer Research UK [C1298/A8780, C1298/A8362]; National Cancer Research Network; Helen Rollason Heal Cancer Charity; Sanofi-Aventis; NHS FX This study was supported by the Intramural Research Program of NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics.; ATBC was also supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI.; PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota, (NO1-CN-25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN-25524), the Marshfield Clinic Research Foundation (NO1-CN-25518), the University of Alabama at Birmingham (NO1-CN-75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN-25404).; The Cancer Prevention Study-II (CPS-II) Nutrition Cohort was supported by the American Cancer Society.; The NIH Genes, Environment and Health Initiative (GEI)partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C), and study coordination at the GENEVA Coordination Center (U01HG004446) for the EAGLE study and part of the PLCO. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics.; The "Texas" study was supported by NIH grants R01CA55769, R01 CAl27219, R01 CA133996, and U19CAl21197.; The UK1 and UK2 work was supported by Cancer Research UK (C1298/A8780 and C1298/A8362- Bobby Moore Fund for Cancer Research UK). Y. Wang was supported by an extramural NIH grant U19 CA14812701. We are also graceful to National Cancer Research Network, Helen Rollason Heal Cancer Charity, and Sanofi-Aventis and the NHS funding for the Royal Marsden Biomedical Research Centre. NR 34 TC 27 Z9 28 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD FEB PY 2012 VL 2 IS 2 BP 131 EP 139 DI 10.1158/2159-8290.CD-11-0246 PG 9 WC Oncology SC Oncology GA 896UV UT WOS:000300597800023 PM 22585858 ER PT J AU Aprelikova, O Green, JE AF Aprelikova, Olga Green, Jeffrey E. TI MicroRNA regulation in cancer-associated fibroblasts SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Review DE Cancer-associated fibroblasts; MicroRNA; Microenvironment; Tumor; CITIM 2011 ID BREAST-CANCER; TUMOR-STROMA; GENETIC ALTERATIONS; EPITHELIAL-CELLS; MYOFIBROBLASTS; MICROENVIRONMENT; TUMORIGENESIS; METASTASIS; CARCINOMA; DNA AB The microenvironment of cancer cells has proven to be a critical component of tumors that strongly influences cancer development and progression into invasive and metastatic disease. Compared to normal tissue, dramatic differences in gene expression occur in multiple cell types that constitute the tumor microenvironment including cancer-associated fibroblasts (CAFs) that are important stromal components of growing tumors. In this review, we present recent advances in understanding how microRNAs are deregulated in cancer-associated fibroblasts (CAFs) and how this affects tumor biology. The microRNA signature of CAFs is discussed with respect to their functional relevance to tumor cells as well as other cell types involved in tumor homeostasis. C1 [Aprelikova, Olga; Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Aprelikova, O (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Rm 4054,9000 Rockville Pike, Bethesda, MD 20892 USA. EM apreliko@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 59 TC 13 Z9 13 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD FEB PY 2012 VL 61 IS 2 BP 231 EP 237 DI 10.1007/s00262-011-1139-7 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA 897OR UT WOS:000300662200009 PM 22083346 ER PT J AU Hurwitz, AA Watkins, SK AF Hurwitz, Arthur A. Watkins, Stephanie K. TI Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Review DE Tumor microenvironment; T cell; Tolerance; Suppression; CITIM 2011 ID NF-KAPPA-B; PROSTATE-CANCER; CUTTING EDGE; MAST-CELLS; TOLERANCE; INFLAMMATION; ACTIVATION; GENERATION; MICE AB Immune suppression remains a consistent obstacle to successful anti-tumor immune responses. As tumors develop, they create a microenvironment that not only supports tumor growth and metastasis but also reduces potential adaptive immunity to tumor antigens. Among the many components of this tumor microenvironment is a population of dendritic cells which exert profound immune suppressive effects on T cells. In this review, we discuss our recent findings related to these tumor-associated dendritic cells and how targeting them may serve to generate more durable anti-tumor immune responses. C1 [Hurwitz, Arthur A.; Watkins, Stephanie K.] NCI, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Hurwitz, AA (reprint author), NCI, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, Canc & Inflammat Program, 211 Bldg 567,1050 Boyles St, Frederick, MD 21702 USA. EM hurwitza@mail.nih.gov FU NCI, NIH FX The work described in this review was supported in part by the intramural research programs of the NCI, NIH. The authors appreciate the critical review of Dr. Joost Oppenheim. NR 30 TC 39 Z9 46 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD FEB PY 2012 VL 61 IS 2 BP 289 EP 293 DI 10.1007/s00262-011-1181-5 PG 5 WC Oncology; Immunology SC Oncology; Immunology GA 897OR UT WOS:000300662200016 PM 22237887 ER PT J AU Mehta, N Wayne, AS Kim, YH Hale, GA Alvarado, CS Myskowski, P Jaffe, ES Busam, KJ Pulitzer, M Zwerner, J Horwitz, S AF Mehta, Neha Wayne, Alan S. Kim, Youn H. Hale, Gregory A. Alvarado, Carlos S. Myskowski, Patricia Jaffe, Elaine S. Busam, Klaus J. Pulitzer, Melissa Zwerner, Jeffrey Horwitz, Steven TI Bexarotene Is Active Against Subcutaneous Panniculitis-Like T-Cell Lymphoma in Adult and Pediatric Populations SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article DE Bexarotene; Cutaneous gamma/delta T-cell lymphoma; Subcutaneous panniculitis-like T-cell lymphoma ID CUTANEOUS LYMPHOMAS; DENILEUKIN DIFTITOX; PROGNOSTIC-FACTORS; CLASSIFICATION; THERAPY; INVOLVEMENT; TISSUE AB Subcutaneous panniculitis-like T-cell lymphoma (SPTL-AB) and cutaneous gamma/delta T-cell lymphoma (CGD-TCL) are rare cutaneous T-cell lymphomas for which no standard treatment exists. We report our experience with bexarotene, an oral retinoid, in 15 adults and children with these disorders. In this series, we found a 77% overall response rate of bexarotene with limited toxicity for these disorders. Introduction: Subcutaneous panniculitis-like T-cell lymphoma (SPTL-AB) and cutaneous gamma/delta T-cell lymphoma (CGD-TCL) are rare T-cell lymphomas with varying clinical courses. There is no standard treatment, although chemotherapy and hematopoietic stem cell transplantation are commonly used. We describe results using bexarotene for children and adults with these disorders. Methods: We identified 15 patients (12 adults, 3 children) who were treated with bexarotene between 2000 and 2010 from the Memorial Sloan-Kettering Cancer Center lymphoma database, the Stanford Cancer Center Registry, and the National Cancer Institute (NCI) pediatric lymphoma database. There were 8 females and 7 males, with a median age of 45 years (range, 3 years to 85 years). All patients had stage IV disease. Two of 15 and 4 of 15 patients had documented CGD-TCL and SPTL-AB, respectively; others were presumed to have SPTL-AB. Bexarotene was administered at flat doses corresponding to 91 to 339 mg/m(2)/d. Two of 15 patients received concurrent denileukin diftitox. Two children received bexarotene as maintenance therapy and were not evaluable for response. Results: Among those treated with bexarotene alone, the overall response rate (ORR) was 82% (6/11 complete response [CR], 3/11 partial response [PR]). One of the 2 patients treated with concomitant denileukin diftitox responded for an ORR of 10/13 (77%), including 54% CR and 23% PR. Median progression-free survival was 38.4 months; median duration of response was 26.3 months. Six patients developed hypothyroidism and 9 developed hyperlipidemia; one patient developed dose-limiting hypertriglyceridemia. One pediatric patient developed insulin-dependent diabetes mellitus. Conclusions: In this retrospective series, bexarotene showed a high response rate in SPTL-AB and CGD-TCL. It was generally well-tolerated with durable responses; therefore, bexarotene represents a promising therapy for children and adults with these disorders. C1 [Horwitz, Steven] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Mehta, Neha] New York PresbyterianWeil Cornell Med Ctr, Dept Med, New York, NY USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kim, Youn H.; Zwerner, Jeffrey] Stanford Univ, Med Ctr, Dept Dermatol, Stanford, CA 94305 USA. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, Dept Hematol Oncol, St Petersburg, FL 33701 USA. [Alvarado, Carlos S.] Emory Univ, Sch Med, Aflac Canc & Blood Disorders Ctr, Atlanta, GA USA. [Myskowski, Patricia] Mem Sloan Kettering Canc Ctr, Dept Dermatol, New York, NY 10021 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Busam, Klaus J.; Pulitzer, Melissa] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Horwitz, S (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM horwitzs@mskcc.org OI Jaffe, Elaine/0000-0003-4632-0301 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Jocelyn Maragulia for her assistance in the statistical analyses for this manuscript. NR 30 TC 33 Z9 34 U1 1 U2 6 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 EI 2152-2669 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD FEB PY 2012 VL 12 IS 1 BP 20 EP 25 DI 10.1016/j.clml.2011.06.016 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 895FO UT WOS:000300481800005 PM 22001256 ER PT J AU Balansky, R Ganchev, G Iltcheva, M Steele, VE De Flora, S AF Balansky, R. Ganchev, G. Iltcheva, M. Steele, V. E. De Flora, S. TI Transplacental Antioxidants Inhibit Lung Tumors in Mice Exposed to Cigarette Smoke After Birth: A Novel Preventative Strategy? SO CURRENT CANCER DRUG TARGETS LA English DT Review DE Antioxidants; ascorbic acid; cigarette smoke; emphysema; Lung cancer; N-acetyl-L-cysteine; pregnancy ID OXIDATIVE STRESS; N-ACETYLCYSTEINE; MOUSE LUNG; EPITHELIAL-CELLS; NEONATAL MICE; NEWBORN; LIVER; RAT; SUSCEPTIBILITY; PREVENTION AB Birth is characterized by an intense oxidative stress resulting in nucleotide alterations and gene overexpression in mouse lung. We showed that cigarette smoke (CS) is carcinogenic when exposure starts soon after birth and applied this bioassay to evaluate the efficacy of chemopreventive agents. The present study evaluated whether administration of the antioxidants N-acetyl-L-cysteine (NAC) and vitamin C or ascorbic acid (AsA) during pregnancy can protect strain H Swiss mice exposed to CS after birth. Exposure to CS, for 4 months, of newborns from untreated mice resulted in significant alterations at 8 months of life, including alveolar epithelial hyperplasia, emphysema, blood vessel proliferation, microadenomas, adenomas, and malignant tumors in lung, liver parenchymal degeneration and urinary bladder epithelium hyperplasia. Treatment throughout pregnancy with either NAC, a scavenger of reactive oxygen species, or AsA, an electron donor, did not affect fertility, parity, and body weight of newborns. Prenatal antioxidants significantly inhibited most lesions in adult mice exposed to CS since birth. For instance, the incidence of emphysema was reduced from 27.5% in CS-exposed mice that were untreated during pregnancy to 7.1% and 14.0% in those treated prenatally with NAC and AsA, respectively. Lung adenomas were reduced from 34.8% to 16.7% and 9.3%, respectively. Malignant lung tumors were reduced from 13.0% to 4.7% by prenatal AsA. Liver parenchymal degeneration was reduced from 58.0% to 14.3% by prenatal NAC. These data mechanistically support a "transplacental chemoprevention" strategy, aimed at protecting the newborn from oxidative stress and the adult from CS-related diseases appearing later in life. C1 [Balansky, R.; De Flora, S.] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Balansky, R.; Ganchev, G.; Iltcheva, M.] Natl Oncol Ctr, Sofia 1756, Bulgaria. [Steele, V. E.] NCI, Rockville, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it FU Bulgarian Ministry of Education, Youth and Science; U.S. National Cancer Institute [N01-CN-53301] FX This study was supported by the Bulgarian Ministry of Education, Youth and Science (National Science Fund) and by U.S. National Cancer Institute contract N01-CN-53301. NR 40 TC 10 Z9 10 U1 1 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD FEB PY 2012 VL 12 IS 2 BP 164 EP 169 PG 6 WC Oncology SC Oncology GA 897FT UT WOS:000300632700007 PM 22165969 ER PT J AU Hu, WF Gong, L Cao, Z Ma, H Ji, W Deng, M Liu, M Hu, XH Chen, P Yan, Q Chen, HG Liu, J Sun, S Zhang, L Liu, JP Wawrousek, E Li, DWC AF Hu, W. -F. Gong, L. Cao, Z. Ma, H. Ji, W. Deng, M. Liu, M. Hu, X. -H. Chen, P. Yan, Q. Chen, H. -G. Liu, J. Sun, S. Zhang, L. Liu, J. -P. Wawrousek, E. Li, D. W. -C. TI alpha A- and alpha B-Crystallins Interact with Caspase-3 and Bax to Guard Mouse Lens Development SO CURRENT MOLECULAR MEDICINE LA English DT Review DE alpha A-crystallin; alpha B-crystallin; apoptosis; Bax; caspase-3; cataract; lens differentition; lens epithelial cells ID HEAT-SHOCK-PROTEIN; EPITHELIAL-CELL APOPTOSIS; C-DEPENDENT ACTIVATION; CYTOCHROME-C; MOLECULAR CHAPERONE; NEGATIVE REGULATOR; INDUCED CATARACT; GENE-EXPRESSION; DEATH; HSP27 AB The small heat shock protein, alpha-crystallin, exists in two isoforms, alpha A and alpha B, and displays strong ability against stress-induced apoptosis. Regarding their functional mechanisms, we and others have demonstrated that they are able to regulate members in both caspase and Bcl-2 families. In addition, we have also shown that alpha A and alpha B may display differential anti-apoptotic mechanisms under certain stress conditions. While alpha A-crystallin regulates activation of the AKT signaling pathway, alpha B negatively regulates the MAPK pathway to suppress apoptosis induced by UV and oxidative stress. Although previous studies revealed that alpha A and alpha B could regulate members in both caspase and Bcl-2 families, the molecular mechanism, especially the in vivo regulation still waits to be elucidated. In the present communication, we present both in vitro and in vivo evidence to further demonstrate the regulation of caspase-3 and Bax by alpha A and alpha B. First, Surface Plasmon Resonance (SPR) and yeast two-hybrid selection analysis demonstrate that alpha A and alpha B directly bind to caspase-3 and Bax with differential affinities. Second, immunohistochemistry reveals that alpha A and alpha B regulate caspase-3 and Bax at different developmental stages of mouse embryo. Third, co-immunoprecipitation shows that alpha A and alpha B form in vivo interacting complexes with caspase-3 and Bax. Together, our results further confirm that alpha A and alpha B regulate caspase-3 and Bax in vitro and in vivo to regulate lens differentiation. C1 [Hu, W. -F.; Gong, L.; Cao, Z.; Ma, H.; Ji, W.; Deng, M.; Hu, X. -H.; Chen, P.; Yan, Q.; Chen, H. -G.; Liu, J.; Sun, S.; Zhang, L.; Liu, J. -P.; Li, D. W. -C.] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA. [Hu, W. -F.; Hu, X. -H.; Chen, P.; Liu, J.; Sun, S.; Zhang, L.; Li, D. W. -C.] Hunan Normal Univ, Coll Life Sci, Educ Minist China, Key Lab Prot Chem & Dev Biol, Changsha 410081, Hunan, Peoples R China. [Liu, M.] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan 430074, Hubei, Peoples R China. [Liu, M.] Huazhong Univ Sci & Technol, Ctr Human Genome Res, Wuhan 430074, Hubei, Peoples R China. [Wawrousek, E.] NEI, Mol & Dev Biol Lab, NIH, Rockville, MD 20892 USA. [Li, D. W. -C.] Univ Nebraska Med Ctr, Dept Ophthalmol & Visual Sci, Omaha, NE 68198 USA. RP Li, DWC (reprint author), Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA. EM dwli1688@hotmail.com RI cao, zhijun/F-4776-2012; Deng, Mi/K-8699-2012; Yan, Qin/F-5161-2012; Gong, Lili/F-8452-2014; Yan, Qin/K-3539-2013 OI Deng, Mi/0000-0003-4291-0144; Gong, Lili/0000-0002-6533-5333; Yan, Qin/0000-0002-6344-6398 FU National Institutes of Health [1R01 EY018380]; Lotus Scholar Program; University of Nebraska Medical Center; Chinese Scholarship Council; Education Ministry of Hunan Province Government FX This work is supported in part by the National Institutes of Health Grant 1R01 EY018380, and by the Lotus Scholar Program (DWL). LLG and MD are partially supported by the Graduate Fellowship from the University of Nebraska Medical Center. WKJ and PCC are partially supported by the Scholarship from Chinese Scholarship Council; LZ and PCC are also supported by a grant awarded by the Education Ministry of Hunan Province Government. NR 53 TC 29 Z9 30 U1 2 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD FEB PY 2012 VL 12 IS 2 BP 177 EP 187 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 897HJ UT WOS:000300638600007 PM 22280356 ER PT J AU Hu, JX Thor, D Zhou, YR Liu, T Wang, Y McMillin, SM Mistry, R Challiss, RAJ Costanzi, S Wess, J AF Hu, Jianxin Thor, Doreen Zhou, Yaru Liu, Tong Wang, Yan McMillin, Sara M. Mistry, Rajendra Challiss, R. A. John Costanzi, Stefano Wess, Juergen TI Structural aspects of M-3 muscarinic acetylcholine receptor dimer formation and activation SO FASEB JOURNAL LA English DT Article DE G-protein-coupled receptor; GPCR; disulfidescanning mutagenesis ID PROTEIN-COUPLED RECEPTOR; CROSS-LINKING STRATEGY; BETA(2)-ADRENERGIC RECEPTOR; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; DRUG DISCOVERY; GPCR; DIMERIZATION; AGONIST; INTERFACE AB To explore the structural mechanisms underlying the assembly and activation of family A GPCR dimers, we used the rat M-3 muscarinic acetylcholine receptor (M3R) as a model system. Studies with Cys-substituted mutant M3Rs expressed in COS-7 cells led to the identification of several mutant M3Rs that exclusively existed as cross-linked dimers under oxidizing conditions. The cross-linked residues were located at the bottom of transmembrane domain 5 (TM5) and within the N-terminal portion of the third intracellular loop (i3 loop). Studies with urea-stripped membranes demonstrated that M3R disulfide cross-linking did not require the presence of heterotrimeric G proteins. Molecular modeling studies indicated that the cross-linking data were in excellent agreement with the existence of a low-energy M3R dimer characterized by a TM5-TM5 interface. [S-35]GTP gamma S binding/G alpha(q/11) immunoprecipitation assays revealed that an M3R dimer that was cross-linked within the N-terminal portion of the i3 loop (264C) was functionally severely impaired (similar to 50% reduction in receptor-G-protein coupling, as compared to control M3R). These data support the novel concept that agonist-induced activation of M3R dimers requires a conformational change of the N-terminal segment of the i3 loop. Given the high degree of structural homology among family A GPCRs, these findings should be of broad significance.-Hu, J., Thor, D., Zhou, Y., Liu, T., Wang, Y., McMillin, S. M., Mistry, R., Challiss, R. A. J., Costanzi, S., Wess, J. Structural aspects of M-3 muscarinic acetylcholine receptor dimer formation and activation. FASEB J. 26, 604-616 (2012). www.fasebj.org C1 [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Costanzi, Stefano] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. [Zhou, Yaru] Hebei Med Univ, Dept Endocrinol, Hosp 3, Shijiazhuang, Peoples R China. [Mistry, Rajendra; Challiss, R. A. John] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-05,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU U.S. National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported by the Intramural Research Program of the U.S. National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The authors thank Ms. Vanivilasini Balachandran and Mr. Zifan Xiang (NIH, NIDDK) for excellent technical assistance. NR 38 TC 23 Z9 23 U1 1 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2012 VL 26 IS 2 BP 604 EP 616 DI 10.1096/fj.11-191510 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 895HA UT WOS:000300485700014 PM 22031716 ER PT J AU Purushotham, A Xu, Q Li, XL AF Purushotham, Aparna Xu, Qing Li, Xiaoling TI Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding SO FASEB JOURNAL LA English DT Article DE sirtuin; oxidative stress; GL/FFA cycle; phospholipid/lysolipid; testosterone ID ACTIVATED PROTEIN-KINASE; HEPATIC GENE-EXPRESSION; PANCREATIC BETA-CELLS; INSULIN-RESISTANCE; GLUCOSE-HOMEOSTASIS; MAMMALIAN SIRTUINS; CIRCADIAN CONTROL; LIPID-METABOLISM; SKELETAL-MUSCLE; DISEASE AB SIRT1 is a highly-conserved NAD(+)-dependent protein deacetylase that plays essential roles in the regulation of energy metabolism, genomic stability, and stress response. Although the functions of SIRT1 in many organs have been extensively studied in tissue-specific knockout mouse models, the systemic role of SIRT1 is still largely unknown as a result of severe developmental defects that result from whole-body knockout in mice. Here, we investigated the systemic functions of SIRT1 in metabolic homeostasis by utilizing a whole-body SIRT1 heterozygous mouse model. These mice are phenotypically normal under standard feeding conditions. However, when chronically challenged with a 40% fat diet, they become obese and insulin resistant, display increased serum cytokine levels, and develop hepatomegaly. Hepatic metabolomic analyses revealed that SIRT1 heterozygous mice have elevated gluconeogenesis and oxidative stress. Surprisingly, they are depleted of glycerolipid metabolites and free fatty acids, yet accumulate lysolipids. Moreover, high-fat feeding induces elevation of serum testosterone levels and enlargement of seminal vesicles in SIRT1 heterozygous males. Microarray analysis of liver mRNA indicates that they have altered expression of genes involved in steroid metabolism and glycerolipid metabolism. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of systemic energy and steroid hormone homeostasis.-Purushotham, A., Xu, Q., Li, X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. FASEB J. 26, 656-667 (2012). www.fasebj.org C1 [Purushotham, Aparna; Xu, Qing; Li, Xiaoling] Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC USA. RP Li, XL (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM lix3@niehs.nih.gov FU U.S. National Institutes of Health, NIEHS [Z01 ES102205] FX The authors thank Drs. Anton Jetten, Stephen Shears, John Cidlowski, and members of the X. L. laboratory for critical reading of the manuscript, and Dr. Michael W. McBurney (University of Ottawa, Ottawa, ON, Canada) for providing the SIRT1-null allele. The authors also thank the National Institute of Environmental Health Sciences (NIEHS) Laboratory of Experimental Pathology for histological staining and serum hormone ELISA; the NIEHS microarray facility for performing the microarray experiments, and Liwen Liu for analyzing the microarray data. This research was supported by the Intramural Research Program of the U.S. National Institutes of Health, NIEHS to X. L. (Z01 ES102205). NR 65 TC 20 Z9 22 U1 1 U2 13 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2012 VL 26 IS 2 BP 656 EP 667 DI 10.1096/fj.11-195172 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 895HA UT WOS:000300485700018 PM 22006157 ER PT J AU Muller, GA Hansen, U Xu, Z Griswold, B Talan, MI McDonnell, NB Briest, W AF Mueller, Gerd A. Hansen, Uwe Xu, Zhi Griswold, Benjamin Talan, Mark I. McDonnell, Nazli B. Briest, Wilfried TI Allele-specific siRNA knockdown as a personalized treatment strategy for vascular Ehlers-Danlos syndrome in human fibroblasts SO FASEB JOURNAL LA English DT Article DE extracellular matrix; collagen; RNA interference ID SYNDROME TYPE-IV; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; MARFAN-SYNDROME; RNAI; HAPLOINSUFFICIENCY; DISCRIMINATION; BIOGENESIS; DEATH; MODEL AB The vascular type of the Ehlers-Danlos syndrome (vEDS) is caused by dominant-negative mutations in the procollagen type III (COL3A1) gene. Patients with this autosomal dominant disorder have a shortened life expectancy due to complications from ruptured vessels or hollow organs. We tested the effectiveness of allele-specific RNA interference (RNAi) to reduce the mutated phenotype in fibroblasts. Small-interfering RNAs (siRNAs) discriminating between wild-type and mutant COL3A1 allele were identified by a luciferase reporter gene assay and in primary fibroblasts from a normal donor and a patient with vEDS. The best discriminative siRNA with the mutation at position 10 resulted in >90% silencing of the mutant allele without affecting the wild-type allele. Transmission and immunogold electron microscopy of extracted extracellular matrices from untreated fibroblasts of the patient with vEDS revealed structurally abnormal fibrils. After siRNA treatment, collagen fibrils became similar to fibrils from fibroblasts of normal and COL3A1 haploinsufficient donors. In addition, it was shown that expression of mutated COL3A1 activates the unfolded protein response and that reduction of the amount of mutated protein by siRNA reduces cellular stress. Taken together, the results provide evidence that allele-specific siRNAs are able to reduce negative effects of mutated COL3A1 proteins. Thus, the application of allele-specific RNAi may be a promising direction for future personalized therapies to reduce the severity of vEDS.-Muller, G. A., Hansen, U., Xu, Z., Griswold, B., Talan, M. I., McDonnell, N. B., Briest, W. Allele-specific siRNA knockdown as a personalized treatment strategy for vascular Ehlers-Danlos syndrome in human fibroblasts. FASEB J. 26, 668-677 (2012). www.fasebj.org C1 [Mueller, Gerd A.; Talan, Mark I.; Briest, Wilfried] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Xu, Zhi; Griswold, Benjamin; McDonnell, Nazli B.] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Hansen, Uwe] Univ Hosp Munster, Inst Physiol Chem & Pathobiochem, Munster, Germany. RP Briest, W (reprint author), Fritz Lipmann Inst, Leibniz Inst Age Res, Beutenbergstr 11, D-07745 Jena, Germany. EM wilfried.briest@arcor.de RI Xu, Zhi/I-2546-2012; OI Muller, Gerd A./0000-0002-4967-2487; Briest, Wilfried/0000-0003-4556-4849 FU U.S. National Institutes of Health, National Institute on Aging (NIA; Bethesda, MD, USA) FX The work was fully funded by the Intramural Research Program of the U.S. National Institutes of Health, National Institute on Aging (NIA; Bethesda, MD, USA). The authors are indebted to Shannon Marshall (NIA), Gerburg Hoelscher (University Hospital of Munster), and Barbara Schedding (University Hospital of Munster) for expert technical assistance. The authors owe special thanks to Kenneth R. Boheler (NIA) for helpful discussions. NR 37 TC 8 Z9 8 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2012 VL 26 IS 2 BP 668 EP 677 DI 10.1096/fj.11-182162 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 895HA UT WOS:000300485700019 PM 22038052 ER PT J AU Iraqi, FA Mahajne, M Salaymah, Y Sandovski, H Tayem, H Vered, K Balmer, L Hall, M Manship, G Morahan, G Pettit, K Scholten, J Tweedie, K Wallace, A Weerasekera, L Cleak, J Durrant, C Goodstadt, L Mott, R Yalcin, B Aylor, DL Baric, RS Bell, TA Bendt, KM Brennan, J Brooks, JD Buus, RJ Crowley, JJ Calaway, JD Calaway, ME Cholka, A Darr, DB Didion, JP Dorman, A Everett, ET Ferris, MT Mathes, WF Fu, CP Gooch, TJ Goodson, SG Gralinski, LE Hansen, SD Heise, MT Hoel, J Hua, KJ Kapita, MC Lee, S Lenarcic, AB Liu, EY Liu, HD McMillan, L Magnuson, TR Manly, KF Miller, DR O'Brien, DA Odet, F Pakatci, IK Pan, WQ de Villena, FPM Perou, CM Pomp, D Quackenbush, CR Robinson, NN Sharpless, NE Shaw, GD Spence, JS Sullivan, PF Sun, W Tarantino, LM Valdar, W Wang, J Wang, W Welsh, CE Whitmore, A Wiltshire, T Wright, FA Xie, YY Yun, ZN Zhabotynsky, V Zhang, ZJ Zou, F Powell, C Steigerwalt, J Threadgill, DW Chesler, EJ Churchill, GA Gatti, DM Korstanje, R Svenson, KL Collins, FS Crawford, N Hunter, K Kelada, SNP Peck, BCE Reilly, K Tavarez, U Bottomly, D Hitzeman, R McWeeney, SK Frelinger, J Krovi, H Phillippi, J Spritz, RA Aicher, L Katze, M Rosenzweig, E Shusterman, A Nashef, A Weiss, EI Houri-Haddad, Y Soller, M Williams, RW Schughart, K Yang, HN French, JE Benson, AK Kim, J Legge, R Low, SJ Ma, FR Martinez, I Walter, J Broman, KW Hallgrimsson, B Klein, O Weinstock, G Warren, WC Yang, YV Schwartz, D AF Iraqi, Fuad A. Mahajne, Mustafa Salaymah, Yasser Sandovski, Hani Tayem, Hanna Vered, Karin Balmer, Lois Hall, Michael Manship, Glynn Morahan, Grant Pettit, Ken Scholten, Jeremy Tweedie, Kathryn Wallace, Andrew Weerasekera, Lakshini Cleak, James Durrant, Caroline Goodstadt, Leo Mott, Richard Yalcin, Binnaz Aylor, David L. Baric, Ralph S. Bell, Timothy A. Bendt, Katharine M. Brennan, Jennifer Brooks, Jackie D. Buus, Ryan J. Crowley, James J. Calaway, John D. Calaway, Mark E. Cholka, Agnieszka Darr, David B. Didion, John P. Dorman, Amy Everett, Eric T. Ferris, Martin T. Mathes, Wendy Foulds Fu, Chen-Ping Gooch, Terry J. Goodson, Summer G. Gralinski, Lisa E. Hansen, Stephanie D. Heise, Mark T. Hoel, Jane Hua, Kunjie Kapita, Mayanga C. Lee, Seunggeun Lenarcic, Alan B. Liu, Eric Yi Liu, Hedi McMillan, Leonard Magnuson, Terry R. Manly, Kenneth F. Miller, Darla R. O'Brien, Deborah A. Odet, Fanny Pakatci, Isa Kemal Pan, Wenqi de Villena, Fernando Pardo-Manuel Perou, Charles M. Pomp, Daniel Quackenbush, Corey R. Robinson, Nashiya N. Sharpless, Norman E. Shaw, Ginger D. Spence, Jason S. Sullivan, Patrick F. Sun, Wei Tarantino, Lisa M. Valdar, William Wang, Jeremy Wang, Wei Welsh, Catherine E. Whitmore, Alan Wiltshire, Tim Wright, Fred A. Xie, Yuying Yun, Zaining Zhabotynsky, Vasyl Zhang, Zhaojun Zou, Fei Powell, Christine Steigerwalt, Jill Threadgill, David W. Chesler, Elissa J. Churchill, Gary A. Gatti, Daniel M. Korstanje, Ron Svenson, Karen L. Collins, Francis S. Crawford, Nigel Hunter, Kent Kelada, Samir N. P. Peck, Bailey C. E. Reilly, Karlyne Tavarez, Urraca Bottomly, Daniel Hitzeman, Robert McWeeney, Shannon K. Frelinger, Jeffrey Krovi, Harsha Phillippi, Jason Spritz, Richard A. Aicher, Lauri Katze, Michael Rosenzweig, Elizabeth Shusterman, Ariel Nashef, Aysar Weiss, Ervin I. Houri-Haddad, Yael Soller, Morris Williams, Robert W. Schughart, Klaus Yang, Hyuna French, John E. Benson, Andrew K. Kim, Jaehyoung Legge, Ryan Low, Soo Jen Ma, Fangrui Martinez, Ines Walter, Jens Broman, Karl W. Hallgrimsson, Benedikt Klein, Ophir Weinstock, George Warren, Wesley C. Yang, Yvana V. Schwartz, David CA Collaborative Cross Consortium TI The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population SO GENETICS LA English DT Article ID RECOMBINANT-INBRED LINES; QUANTITATIVE TRAIT LOCI; SYSTEMS GENETICS; COMPLEX TRAITS; SUBSPECIFIC ORIGIN; LABORATORY MOUSE; HOUSE MICE; RESOURCE; STRAINS; DISSECTION AB The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals. C1 [de Villena, Fernando Pardo-Manuel] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Balmer, Lois; Hall, Michael; Manship, Glynn; Morahan, Grant; Pettit, Ken; Scholten, Jeremy; Tweedie, Kathryn; Wallace, Andrew; Weerasekera, Lakshini] Univ Western Australia, Geniad Ltd, Nedlands, WA 6009, Australia. [Cleak, James; Durrant, Caroline; Goodstadt, Leo; Mott, Richard; Yalcin, Binnaz] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Iraqi, Fuad A.; Mahajne, Mustafa; Salaymah, Yasser; Sandovski, Hani; Tayem, Hanna; Vered, Karin] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Powell, Christine; Steigerwalt, Jill; Threadgill, David W.] N Carolina State Univ, Raleigh, NC 27695 USA. [Chesler, Elissa J.; Churchill, Gary A.; Gatti, Daniel M.; Korstanje, Ron; Svenson, Karen L.] Jackson Lab, Bar Harbor, ME 04607 USA. [Collins, Francis S.; Crawford, Nigel; Hunter, Kent; Kelada, Samir N. P.; Peck, Bailey C. E.; Reilly, Karlyne; Tavarez, Urraca] NIH, Bethesda, MD 20892 USA. [Bottomly, Daniel; Hitzeman, Robert; McWeeney, Shannon K.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Frelinger, Jeffrey; Krovi, Harsha; Phillippi, Jason] Univ Arizona, Tucson, AZ 85719 USA. [Spritz, Richard A.] Univ Colorado, Denver, CO 80202 USA. [Aicher, Lauri; Katze, Michael; Rosenzweig, Elizabeth] Univ Washington, Seattle, WA 98195 USA. [Shusterman, Ariel; Nashef, Aysar; Weiss, Ervin I.; Houri-Haddad, Yael] Hadassah Med Ctr, Fac Med Dent, IL-91120 Jerusalem, Israel. [Shusterman, Ariel; Nashef, Aysar; Weiss, Ervin I.; Houri-Haddad, Yael; Soller, Morris] Hebrew Univ Jerusalem, Jerusalem, Israel. [Williams, Robert W.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN 38163 USA. [Schughart, Klaus] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Schughart, Klaus] Univ Vet Med Hannover, Braunschweig, Germany. [Yang, Hyuna] Duke Univ, Durham, NC 27710 USA. [French, John E.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Benson, Andrew K.; Kim, Jaehyoung; Legge, Ryan; Low, Soo Jen; Ma, Fangrui; Martinez, Ines; Walter, Jens] Univ Nebraska, Lincoln, NE 68583 USA. [Broman, Karl W.] Univ Wisconsin, Madison, WI 53706 USA. [Hallgrimsson, Benedikt] Univ Calgary, Alberta Childrens Hosp Res Inst, Calgary, AB T2N 4N1, Canada. [Klein, Ophir] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Weinstock, George; Warren, Wesley C.] Washington Univ, Genome Inst, St Louis, MO 63108 USA. [Yang, Yvana V.; Schwartz, David] Univ Colorado, Sch Med, Denver, CO 80206 USA. RP de Villena, FPM (reprint author), Univ N Carolina, Dept Genet, 5046 Genet Med Bldg,Campus Box 7264, Chapel Hill, NC 27599 USA. EM fernando@med.unc.edu RI Hallgrimsson, Benedikt/A-9616-2008; Frelinger, Jeffrey/F-2448-2014; Liu, Eric Yi/B-6221-2016; Yalcin, Binnaz/P-5482-2016; Threadgill, David/N-4425-2013; OI Hallgrimsson, Benedikt/0000-0002-7192-9103; Frelinger, Jeffrey/0000-0002-2503-6267; Williams, Robert/0000-0001-8924-4447; Yalcin, Binnaz/0000-0002-1924-6807; Threadgill, David/0000-0003-3538-1635; Crowley, James/0000-0001-9051-1557; Zhabotynsky, Vasyl/0000-0003-1575-5732; Didion, John/0000-0002-8111-6261 FU National Institutes of Health [U01CA134240, P50MH090338, P50HG006582, U54AI081680]; Ellison Medical Foundation [AG-IA-0202-05]; National Science Foundation [IIS0448392, IIS0812464]; Australian Research Council [DP-110102067]; Wellcome Trust [085906/Z/08/Z, 083573/Z/07/Z, 090532/Z/09/Z]; University of North Carolina (UNC) School of Medicine; Lineberger Comprehensive Cancer Center at UNC; University Cancer Research Fund from the state of North Carolina; Tel-Aviv University FX This work is published under a consortium authorship (listed on opening page) that includes mouse breeders, tool developers, and users of the resources. We acknowledge the following members of the consortium who have made special significant contributions to generation of mice, genotyping, and analysis reported in this manuscript: Fuad A. Iraqi, Mustafa Mahajne, Yasser Salaymah, Hanna Tayem, Karin Vered, Hani Sandovski, Richard Mott, Caroline Durrant, David L. Aylor, Ryan J. Buus, John P. Didion, Chen-Ping Fu, Terry J. Gooch, Stephanie D. Hansen, Leonard McMillan, Kenneth F. Manly, Darla R. Miller, Fernando Pardo-Manuel de Villena, Ginger D. Shaw, Jason S. Spence, David W. Threadgill, Jeremy Wang, Catherine E. Welsh, Grant Morahan, Lois Balmer, Ken Pettit, and Michael Hall. This work was supported by grants from the National Institutes of Health U01CA134240, P50MH090338, P50HG006582, and U54AI081680; Ellison Medical Foundation grant AG-IA-0202-05, National Science Foundation grants IIS0448392, IIS0812464, the Australian Research Council grant DP-110102067, and the Wellcome Trust grants 085906/Z/08/Z, 083573/Z/07/Z, and 090532/Z/09/Z. Essential support was provided by the Dean of the University of North Carolina (UNC) School of Medicine, the Lineberger Comprehensive Cancer Center at UNC, and the University Cancer Research Fund from the state of North Carolina. We also thank Tel-Aviv University for their core funding and technical support. NR 59 TC 92 Z9 92 U1 6 U2 39 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2012 VL 190 IS 2 BP 389 EP U159 DI 10.1534/genetics.111.132639 PG 29 WC Genetics & Heredity SC Genetics & Heredity GA 897CW UT WOS:000300621200008 ER PT J AU Bateman, DA Wickner, RB AF Bateman, David A. Wickner, Reed B. TI [PSI+] Prion Transmission Barriers Protect Saccharomyces cerevisiae from Infection: Intraspecies 'Species Barriers' SO GENETICS LA English DT Article ID BETA-SHEET STRUCTURE; TERMINATION FACTOR ERF3; YEAST PRION; TRANSLATION TERMINATION; MOLECULAR-BASIS; MESSENGER-RNA; IN-VITRO; ENVIRONMENTAL-STRESS; STRAIN VARIATION; SUP35 PROTEIN AB [PSI+] is a prion of Sup35p, an essential translation termination and mRNA turnover factor. The existence of lethal [PSI+] variants, the absence of [PSI+] in wild strains, the mRNA turnover function of the Sup35p prion domain, and the stress reaction to prion infection suggest that [PSI+] is a disease. Nonetheless, others have proposed that [PSI+] and other yeast prions benefit their hosts. We find that wild Saccharomyces cerevisiae strains are polymorphic for the sequence of the prion domain and particularly in the adjacent M domain. Here we establish that these variations within the species produce barriers to prion transmission. The barriers are partially asymmetric in some cases, and evidence for variant specificity in barriers is presented. We propose that, as the PrP 129M/V polymorphism protects people from Creutzfeldt-Jakob disease, the Sup35p polymorphisms were selected to protect yeast cells from prion infection. In one prion incompatibility group, the barrier is due to N109S in the Sup35 prion domain and several changes in the middle (M) domain, with either the single N109S mutation or the group of M changes (without the N109S) producing a barrier. In another, the barrier is due to a large deletion in the repeat domain. All are outside the region previously believed to determine transmission compatibility. [SWI+], a prion of the chromatin remodeling factor Swi1p, was also proposed to benefit its host. We find that none of 70 wild strains carry this prion, suggesting that it is not beneficial. C1 [Bateman, David A.; Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Donna MacCallum for kindly sending strains J041047 and J940610 and Herman Edskes for several plasmids. We are grateful to Zhiqiang Du and Liming Li for kindly providing p416TEFSWI1NQ-YFP and strains 7D-694 and 7D-694SWI+. This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 76 TC 26 Z9 26 U1 1 U2 4 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 1943-2631 J9 GENETICS JI Genetics PD FEB PY 2012 VL 190 IS 2 BP 569 EP U463 DI 10.1534/genetics.111.136655 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA 897CW UT WOS:000300621200022 PM 22095075 ER PT J AU Scully, CG Lee, J Meyer, J Gorbach, AM Granquist-Fraser, D Mendelson, Y Chon, KH AF Scully, Christopher G. Lee, Jinseok Meyer, Joseph Gorbach, Alexander M. Granquist-Fraser, Domhnull Mendelson, Yitzhak Chon, Ki H. TI Physiological Parameter Monitoring from Optical Recordings With a Mobile Phone SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Breathing rate; heart rate variability (HRV); noninvasive monitoring; oxygen saturation; telemonitoring AB We show that a mobile phone can serve as an accurate monitor for several physiological variables, based on its ability to record and analyze the varying color signals of a fingertip placed in contact with its optical sensor. We confirm the accuracy of measurements of breathing rate, cardiac R-R intervals, and blood oxygen saturation, by comparisons to standard methods for making such measurements (respiration belts, ECGs, and pulse-oximeters, respectively). Measurement of respiratory rate uses a previously reported algorithm developed for use with a pulse-oximeter, based on amplitude and frequency modulation sequences within the light signal. We note that this technology can also be used with recently developed algorithms for detection of atrial fibrillation or blood loss. C1 [Scully, Christopher G.; Lee, Jinseok; Granquist-Fraser, Domhnull; Mendelson, Yitzhak; Chon, Ki H.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01607 USA. [Meyer, Joseph; Gorbach, Alexander M.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Chon, KH (reprint author), Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01607 USA. EM scullycg@wpi.edu; jinseok@wpi.edu; meyerjm@mail.nih.gov; gorbacha@mail.nih.gov; dgfraser@wpi.edu; ym@wpi.edu; kichon@wpi.edu FU Office of Naval Research work unit [N00014-08-1-0244]; National Institute of Biomedical Imaging and Bioengineering, National Institutes for Health, Bethesda, MD FX Manuscript received May 19, 2011; revised July 19, 2011; accepted July 21, 2011. Date of publication July 29, 2011; date of current version January 20, 2012. This work was supported by Office of Naval Research work unit N00014-08-1-0244. C. G. Scully, J. Meyer and A. M. Gorbach were supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes for Health, Bethesda, MD. Asterisk indicates corresponding author. NR 18 TC 116 Z9 120 U1 4 U2 37 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD FEB PY 2012 VL 59 IS 2 BP 303 EP 306 DI 10.1109/TBME.2011.2163157 PG 4 WC Engineering, Biomedical SC Engineering GA 895PF UT WOS:000300507800001 PM 21803676 ER PT J AU Liu, XF Abd-Elmoniem, KZ Stone, M Murano, EZ Zhuo, JC Gullapalli, RP Prince, JL AF Liu, Xiaofeng Abd-Elmoniem, Khaled Z. Stone, Maureen Murano, Emi Z. Zhuo, Jiachen Gullapalli, Rao P. Prince, Jerry L. TI Incompressible Deformation Estimation Algorithm (IDEA) From Tagged MR Images SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Divergence-free vector spline; HARP; incompressible motion; tagged MRI ID 3-DIMENSIONAL MYOCARDIAL STRAIN; LEFT-VENTRICULAR MOTION; THIN-PLATE SPLINES; NONRIGID REGISTRATION; TRACKING; RECONSTRUCTION; MODEL; DISPLACEMENT; RECOVERY; CONTRAST AB Measuring the 3D motion of muscular tissues, e. g., the heart or the tongue, using magnetic resonance (MR) tagging is typically carried out by interpolating the 2D motion information measured on orthogonal stacks of images. The incompressibility of muscle tissue is an important constraint on the reconstructed motion field and can significantly help to counter the sparsity and incompleteness of the available motion information. Previous methods utilizing this fact produced incompressible motions with limited accuracy. In this paper, we present an incompressible deformation estimation algorithm (IDEA) that reconstructs a dense representation of the 3D displacement field from tagged MR images and the estimated motion field is incompressible to high precision. At each imaged time frame, the tagged images are first processed to determine components of the displacement vector at each pixel relative to the reference time. IDEA then applies a smoothing, divergence-free, vector spline to interpolate velocity fields at intermediate discrete times such that the collection of velocity fields integrate over time to match the observed displacement components. Through this process, IDEA yields a dense estimate of a 3D displacement field that matches our observations and also corresponds to an incompressible motion. The method was validated with both numerical simulation and in vivo human experiments on the heart and the tongue. C1 [Liu, Xiaofeng] Gen Elect Global Res Ctr, Niskayuna, NY 12309 USA. [Abd-Elmoniem, Khaled Z.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Stone, Maureen] Univ Maryland, Sch Dent, Dept Neural & Pain Sci, Baltimore, MD 21201 USA. [Stone, Maureen] Univ Maryland, Sch Dent, Dept Orthodont, Baltimore, MD 21201 USA. [Murano, Emi Z.] Johns Hopkins Sch Med, Dept Otolaryngol, Baltimore, MD 21205 USA. [Murano, Emi Z.] Johns Hopkins Sch Med, Dept Head & Neck Surg, Baltimore, MD 21205 USA. [Zhuo, Jiachen; Gullapalli, Rao P.] Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA. [Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. RP Liu, XF (reprint author), Gen Elect Global Res Ctr, Niskayuna, NY 12309 USA. EM xiaofeng.liu@gmail.com; khaled@jhu.edu; maureenlstone@gmail.com; emurano1@jhmi.edu; jzhuo@umm.edu; rgullapalli@umm.edu; prince@jhu.edu RI Prince, Jerry/A-3281-2010; Abd-Elmoniem, Khaled/B-9289-2008 OI Prince, Jerry/0000-0002-6553-0876; Abd-Elmoniem, Khaled/0000-0002-1001-1702 FU National Institutes of Health/The National Heart, Lung, and Blood Institute (NIH/NHLBI) [R01HL47405]; NIH/National Cancer Institute (NIH/NCI) [R01CA133015]; NIH/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) [R00DC009279] FX Manuscript received June 20, 2011; revised August 07, 2011; accepted August 26, 2011. Date of publication September 19, 2011; date of current version February 03, 2012. This work was supported in part by the National Institutes of Health/The National Heart, Lung, and Blood Institute (NIH/NHLBI) under Grant R01HL47405, in part by the NIH/National Cancer Institute (NIH/NCI) under Grant R01CA133015, and in part by the NIH/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) under Grant R00DC009279. Asterisk indicates corresponding author. NR 67 TC 13 Z9 13 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD FEB PY 2012 VL 31 IS 2 BP 326 EP 340 DI 10.1109/TMI.2011.2168825 PG 15 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 891DU UT WOS:000300197500015 PM 21937342 ER PT J AU Hsu, LY Groves, DW Aletras, AH Kellman, P Arai, AE AF Hsu, Li-Yueh Groves, Daniel W. Aletras, Anthony H. Kellman, Peter Arai, Andrew E. TI A Quantitative Pixel-Wise Measurement of Myocardial Blood Flow by Contrast-Enhanced First-Pass CMR Perfusion Imaging Microsphere Validation in Dogs and Feasibility Study in Humans SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE cardiac magnetic resonance; gadolinium; myocardial ischemia; myocardial perfusion ID CORONARY-ARTERY-DISEASE; MAGNETIC-RESONANCE PERFUSION; MODEL-INDEPENDENT DECONVOLUTION; POSITRON-EMISSION-TOMOGRAPHY; MR PERFUSION; SPATIAL HETEROGENEITY; NONINVASIVE DETECTION; COMPUTED-TOMOGRAPHY; QUANTIFICATION; RESERVE AB OBJECTIVES The aim of this study was to evaluate fully quantitative myocardial blood flow (MBF) at a pixel level based on contrast-enhanced first-pass cardiac magnetic resonance (CMR) imaging in dogs and in patients. BACKGROUND Microspheres can quantify MBF in subgram regions of interest, but CMR perfusion imaging may be able to quantify MBF and differentiate blood flow at a much higher resolution. METHODS First-pass CMR perfusion imaging was performed in a dog model with local hyperemia induced by intracoronary adenosine. Fluorescent microspheres were the reference standard for MBF validation. CMR perfusion imaging was also performed on patients with significant coronary artery disease (CAD) by invasive coronary angiography. Myocardial time-signal intensity curves of the images were quantified on a pixel-by-pixel basis using a model-constrained deconvolution analysis. RESULTS Qualitatively, color CMR perfusion pixel maps were comparable to microsphere MBF bull's-eye plots in all animals. Pixel-wise CMR MBF estimates correlated well against subgram (0.49 +/- 0.14 g) microsphere measurements (r = 0.87 to 0.90) but showed minor underestimation of MBF. To reduce bias due to misregistration and minimize issues related to repeated measures, 1 hyperemic and 1 remote sector per animal were compared with the microsphere MBF, which improved the correlation (r = 0.97 to 0.98), and the bias was close to zero. Sector-wise and pixel-wise CMR MBF estimates also correlated well (r = 0.97). In patients, color CMR stress perfusion pixel maps showed regional blood flow decreases and transmural perfusion gradients in territories served by stenotic coronary arteries. MBF estimates in endocardial versus epicardial subsectors, and ischemic versus remote sectors, were all significantly different (p < 0.001 and p < 0.01, respectively). CONCLUSIONS Myocardial blood flow can be quantified at the pixel level (similar to 32 mu l of myocardium) on CMR perfusion images, and results compared well with microsphere measurements. High-resolution pixel-wise CMR perfusion maps can quantify transmural perfusion gradients in patients with CAD. (J Am Coll Cardiol Img 2012;5:154-66) (C) 2012 by the American College of Cardiology Foundation C1 [Hsu, Li-Yueh; Groves, Daniel W.; Aletras, Anthony H.; Kellman, Peter; Arai, Andrew E.] NHLBI, Adv Cardiovasc Imaging Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, NIH, US Dept HHS, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov OI Aletras, Anthony/0000-0002-3786-3817 FU National Heart, Lung, and Blood Institute (NHLBI) [1 Z01 HL004607-08 CE]; U.S. Government [HL-CR-05-004] FX Funded by the intramural program of the National Heart, Lung, and Blood Institute (NHLBI) (1 Z01 HL004607-08 CE). Supported in part by U.S. Government Cooperative Research and Development Award between NHLBI and Siemens Medical Solution (HL-CR-05-004). All authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 49 TC 47 Z9 48 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD FEB PY 2012 VL 5 IS 2 BP 154 EP 166 DI 10.1016/j.jcmg.2011.07.013 PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 896SL UT WOS:000300591600004 PM 22340821 ER PT J AU Eaton, NR Keyes, KM Krueger, RF Balsis, S Skodol, AE Markon, KE Grant, BF Hasin, DS AF Eaton, Nicholas R. Keyes, Katherine M. Krueger, Robert F. Balsis, Steve Skodol, Andrew E. Markon, Kristian E. Grant, Bridget F. Hasin, Deborah S. TI An Invariant Dimensional Liability Model of Gender Differences in Mental Disorder Prevalence: Evidence From a National Sample SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE comorbidity; gender differences; internalizing-externalizing; prevalence rates ID MAJOR DEPRESSIVE DISORDER; EPIDEMIOLOGIC SURVEY; UNITED-STATES; INTERNALIZING DISORDERS; SUBSTANCE DEPENDENCE; ANTISOCIAL-BEHAVIOR; 12-MONTH PREVALENCE; GENERAL-POPULATION; ALCOHOL DEPENDENCE; COMORBIDITY-SURVEY AB Epidemiological studies of categorical mental disorders consistently report that gender differences exist in many disorder prevalence rates and that disorders are often comorbid. Can a dimensional multivariate liability model be developed to clarify how gender impacts diverse, comorbid mental disorders? We pursued this possibility in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N = 43,093). Gender differences in prevalence were systematic such that women showed higher rates of mood and anxiety disorders, and men showed higher rates of antisocial personality and substance use disorders. We next investigated patterns of disorder comorbidity and found that a dimensional internalizing-externalizing liability model fit the data well, where internalizing is characterized by mood and anxiety disorders, and externalizing is characterized by antisocial personality and substance use disorders. This model was gender invariant, indicating that observed gender differences in prevalence rates originate from women and men's different average standings on latent internalizing and externalizing liability dimensions. As hypothesized, women showed a higher mean level of internalizing, while men showed a higher mean level of externalizing. We discuss implications of these findings for understanding gender differences in psychopathology and for classification and intervention. C1 [Eaton, Nicholas R.; Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Keyes, Katherine M.; Hasin, Deborah S.] Columbia Univ, Dept Epidemiol, New York, NY 10027 USA. [Keyes, Katherine M.; Hasin, Deborah S.] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. [Balsis, Steve] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Skodol, Andrew E.] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. [Skodol, Andrew E.] Univ Arizona, Dept Psychiat, Tucson, AZ 85721 USA. [Markon, Kristian E.] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Bethesda, MD USA. RP Eaton, NR (reprint author), Univ Minnesota, Dept Psychol, 75 E River Rd, Minneapolis, MN 55455 USA. EM nreaton@gmail.com FU Intramural NIH HHS; NIAAA NIH HHS [K05 AA014223, K05AA014223, U01 AA018111, U01 AA018111-02, U01AA018111]; NIDA NIH HHS [R01DA018652, F31 DA026689, F31DA026689, R01 DA018652] NR 44 TC 122 Z9 123 U1 9 U2 25 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD FEB PY 2012 VL 121 IS 1 BP 282 EP 288 DI 10.1037/a0024780 PG 7 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA 891DX UT WOS:000300198500030 PM 21842958 ER PT J AU Eisner, C Ow, H Yang, TX Jia, ZJ Dimitriadis, E Li, LL Wang, K Briggs, J Levine, M Schnermann, J Espey, MG AF Eisner, Christoph Ow, Hooisweng Yang, Tianxin Jia, Zhanjun Dimitriadis, Emilios Li, Lingli Wang, Kenneth Briggs, Josephine Levine, Mark Schnermann, Jurgen Espey, Michael Graham TI Measurement of plasma volume using fluorescent silica-based nanoparticles SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE dye tracer; albumin; dilution technique ID BLOOD-VOLUME; INDOCYANINE GREEN; GROWTH; MODEL; DYE AB Eisner C, Ow H, Yang T, Jia Z, Dimitriadis E, Li L, Wang K, Briggs J, Levine M, Schnermann J, Espey MG. Measurement of plasma volume using fluorescent silica-based nanoparticles. J Appl Physiol 112: 681-687, 2012. First published December 15, 2011; doi: 10.1152/japplphysiol.01068.2011.-Plasma volume (PV) is an important determinant of cardiovascular function and organ perfusion, and it is the target of infusion and diuretic therapies in daily clinical practice. Despite its fundamental importance PV is not commonly measured because available methods of tracer dilution are reliant on dye substances that suffer from numerous drawbacks including binding plasma proteins, spectral changes, and clearance kinetics that complicate analysis and interpretation. To address these issues, we have tested the utility of fluorescent nanoparticles comprised of a dye-rich silica core and polyethylene glycol-coated shell. Photophysical and visual analysis showed discrete size-gradated nanoparticle populations could be synthesized within a distribution tolerance of +/- 4 nm, which were optically unaffected in the presence of plasma/albumin. In normal mice, the cutoff for renal filtration of nanoparticles from blood into urine was <= 11 nm. A linear relationship between body weight and PV was readily determined in mice administered far red fluorescent nanoparticles sized either 20 or 30 nm. PV measurements using nanoparticles were correlated to values obtained with Evans blue dye. Induced expansion or contraction of PV was demonstrated with albumin or furosemide administration, respectively, in mice. Longitudinal experiments >30 min required matched untreated control mice to correct for nanoparticle loss (approximate to 30%) putatively to the reticuloendothelial/phagocyte system. Collectively, the findings support a nanotechnology-based solution to methodological problems in measure of PV, notably in clinical settings where information on hemodynamic changes may improve treatment of injury and disease. C1 [Eisner, Christoph; Li, Lingli; Levine, Mark; Schnermann, Jurgen; Espey, Michael Graham] NIDDK, NIH, Bethesda, MD 20892 USA. [Eisner, Christoph] Univ Med Mannheim, Dept Anesthesiol, Mannheim, Germany. [Ow, Hooisweng; Wang, Kenneth] Hybrid Silica Technol, Cambridge, MA USA. [Yang, Tianxin; Jia, Zhanjun] Univ Utah, Sch Med, Salt Lake City, UT USA. [Dimitriadis, Emilios] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Briggs, Josephine] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Espey, MG (reprint author), NIDDK, NIH, Bldg 10,Rm 4D57,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM sp@nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 23 TC 6 Z9 6 U1 0 U2 11 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB PY 2012 VL 112 IS 4 BP 681 EP 687 DI 10.1152/japplphysiol.01068.2011 PG 7 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 897CB UT WOS:000300617700018 PM 22174395 ER PT J AU Wang, Y Halper, M Wei, D Gu, HY Perl, Y Xu, JC Elhanan, G Chen, Y Spackman, KA Case, JT Hripcsak, G AF Wang, Yue Halper, Michael Wei, Duo Gu, Huanying Perl, Yehoshua Xu, Junchuan Elhanan, Gai Chen, Yan Spackman, Kent A. Case, James T. Hripcsak, George TI Auditing complex concepts of SNOMED using a refined hierarchical abstraction network SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE SNOMED; Terminology; Auditing; Quality assurance; Partitioning; Abstraction network; Taxonomy; Complex concept; Neighborhood auditing; Group auditing ID OBJECT-ORIENTED DATABASE; MEDICAL TERMINOLOGY; UMLS; REPRESENTATION; COMPLETENESS; CT AB Auditors of a large terminology, such as SNOMED CT, face a daunting challenge. To aid them in their efforts, it is essential to devise techniques that can automatically identify concepts warranting special attention. "Complex" concepts, which by their very nature are more difficult to model, fall neatly into this category. A special kind of grouping, called a partial-area, is utilized in the characterization of complex concepts. In particular, the complex concepts that are the focus of this work are those appearing in intersections of multiple partial-areas and are thus referred to as overlapping concepts. In a companion paper, an automatic methodology for identifying and partitioning the entire collection of overlapping concepts into disjoint, singly-rooted groups, that are more manageable to work with and comprehend, has been presented. The partitioning methodology formed the foundation for the development of an abstraction network for the overlapping concepts called a disjoint partial-area taxonomy. This new disjoint partial-area taxonomy offers a collection of semantically uniform partial-areas and is exploited herein as the basis for a novel auditing methodology. The review of the overlapping concepts is done in a top-down order within semantically uniform groups. These groups are themselves reviewed in a top-down order, which proceeds from the less complex to the more complex overlapping concepts. The results of applying the methodology to SNOMED's Specimen hierarchy are presented. Hypotheses regarding error ratios for overlapping concepts and between different kinds of overlapping concepts are formulated. Two phases of auditing the Specimen hierarchy for two releases of SNOMED are reported on. With the use of the double bootstrap and Fisher's exact test (two-tailed), the auditing of concepts and especially roots of overlapping partial-areas is shown to yield a statistically significant higher proportion of errors. (C) 2011 Elsevier Inc. All rights reserved. C1 [Halper, Michael] New Jersey Inst Technol, Dept Informat Technol, Newark, NJ 07102 USA. [Wang, Yue; Perl, Yehoshua; Xu, Junchuan; Elhanan, Gai] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Wei, Duo] Richard Stockton Coll New Jersey, Sch Business, Galloway, NJ 08205 USA. [Gu, Huanying] New York Inst Technol, Dept Comp Sci, New York, NY 10023 USA. [Elhanan, Gai] Halfpenny Technol Inc, Blue Bell, PA 19422 USA. [Chen, Yan] CUNY, BMCC, Comp Informat Syst Dept, New York, NY 10007 USA. [Spackman, Kent A.] IHTSDO, DK-2300 Copenhagen S, Denmark. [Case, James T.] NIH, Natl Lib Med, Bethesda, MD 20817 USA. [Hripcsak, George] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA. RP Halper, M (reprint author), New Jersey Inst Technol, Dept Informat Technol, Newark, NJ 07102 USA. EM mikehhalper@yahoo.com FU NLM [R-01-LM008912-01A1] FX This work was partially supported by the NLM under Grant R-01-LM008912-01A1. NR 43 TC 14 Z9 16 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2012 VL 45 IS 1 BP 1 EP 14 DI 10.1016/j.jbi.2011.08.016 PG 14 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 895EK UT WOS:000300478800001 PM 21907827 ER PT J AU Jing, X Kay, S Marley, T Hardiker, NR Cimino, JJ AF Jing, Xia Kay, Stephen Marley, Thomas Hardiker, Nicholas R. Cimino, James J. TI Incorporating personalized gene sequence variants, molecular genetics knowledge, and health knowledge into an EHR prototype based on the Continuity of Care Record standard SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Molecular Genetic Information; Sequence variants; Electronic health record; Personalized information; Standards; Information filters ID INFORMATION-SYSTEMS; CYSTIC-FIBROSIS; GENOMIC DATA AB Objectives: The current volume and complexity of genetic tests, and the molecular genetics knowledge and health knowledge related to interpretation of the results of those tests, are rapidly outstripping the ability of individual clinicians to recall, understand and convey to their patients information relevant to their care. The tailoring of molecular genetics knowledge and health knowledge in clinical settings is important both for the provision of personalized medicine and to reduce clinician information overload. In this paper we describe the incorporation, customization and demonstration of molecular genetic data (mainly sequence variants), molecular genetics knowledge and health knowledge into a standards-based electronic health record (EHR) prototype developed specifically for this study. Methods: We extended the CCR (Continuity of Care Record), an existing EHR standard for representing clinical data, to include molecular genetic data. An EHR prototype was built based on the extended CCR and designed to display relevant molecular genetics knowledge and health knowledge from an existing knowledge base for cystic fibrosis (OntoKBCF). We reconstructed test records from published case reports and represented them in the CCR schema. We then used the EHR to dynamically filter molecular genetics knowledge and health knowledge from OntoKBCF using molecular genetic data and clinical data from the test cases. Results: The molecular genetic data were successfully incorporated in the CCR by creating a category of laboratory results called "Molecular Genetics" and specifying a particular class of test ("Gene Mutation Test") in this category. Unlike other laboratory tests reported in the CCR, results of tests in this class required additional attributes ("Molecular Structure" and "Molecular Position") to support interpretation by clinicians. These results, along with clinical data (age, sex, ethnicity, diagnostic procedures, and therapies) were used by the EHR to filter and present molecular genetics knowledge and health knowledge from OntoKBCF. Conclusions: This research shows a feasible model for delivering patient sequence variants and presenting tailored molecular genetics knowledge and health knowledge via a standards-based EHR system prototype. EHR standards can be extended to include the necessary patient data (as we have demonstrated in the case of the CCR), while knowledge can be obtained from external knowledge bases that are created and maintained independently from the EHR. This approach can form the basis for a personalized medicine framework, a more comprehensive standards-based EHR system and a potential platform for advancing translational research by both disseminating results and providing opportunities for new insights into phenotype-genotype relationships. (C) 2011 Elsevier Inc. All rights reserved. C1 [Jing, Xia; Cimino, James J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. [Jing, Xia; Cimino, James J.] Natl Lib Med, Bethesda, MD USA. [Kay, Stephen] Univ Salford, Sch Hlth Sport & Rehabil Sci, Salford M5 4WT, Greater Manches, England. [Hardiker, Nicholas R.] Univ Salford, Sch Nursing & Midwifery, Salford M5 4WT, Greater Manches, England. RP Jing, X (reprint author), NIH, Lab Informat Dev, Ctr Clin, Bldg 10 CRC,Room 5-2740,10 Ctr Dr, Bethesda, MD 20892 USA. EM xia.jing@nih.gov RI Jing, Xia/F-4486-2012; OI Jing, Xia/0000-0002-1916-4588; Cimino, James/0000-0003-4101-1622 FU Overseas Research Students Awards Scheme (UK); University of Salford in the UK; National Library of Medicine; Clinical Center of the National Institutes of Health in the US FX This work had been supported by the Overseas Research Students Awards Scheme (UK), the University of Salford in the UK, and partly through intramural research funds from National Library of Medicine and the Clinical Center of the National Institutes of Health in the US. The authors thank Dr. Miao Sun for molecular genetics consulting and Dr. Yongsheng Gao for constructive discussions. NR 33 TC 14 Z9 14 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2012 VL 45 IS 1 BP 82 EP 92 DI 10.1016/j.jbi.2011.09.001 PG 11 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 895EK UT WOS:000300478800008 PM 21946299 ER PT J AU Bright, TJ Furuya, EY Kuperman, GJ Cimino, JJ Bakken, S AF Bright, Tiffani J. Furuya, E. Yoko Kuperman, Gilad J. Cimino, James J. Bakken, Suzanne TI Development and evaluation of an ontology for guiding appropriate antibiotic prescribing SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Ontology; Clinical decision support; Evaluation ID DECISION-SUPPORT-SYSTEM; BIOMEDICAL-ONTOLOGY; KNOWLEDGE; IMPACT; CONSUMPTION; ENVIRONMENT; PRINCIPLES; RESISTANCE; EVOLUTION; PROTEGE AB Objectives: To develop and apply formal ontology creation methods to the domain of antimicrobial prescribing and to formally evaluate the resulting ontology through intrinsic and extrinsic evaluation studies. Methods: We extended existing ontology development methods to create the ontology and implemented the ontology using Protege-OWL. Correctness of the ontology was assessed using a set of ontology design principles and domain expert review via the laddering technique. We created three artifacts to support the extrinsic evaluation (set of prescribing rules, alerts and an ontology-driven alert module, and a patient database) and evaluated the usefulness of the ontology for performing knowledge management tasks to maintain the ontology and for generating alerts to guide antibiotic prescribing. Results: The ontology includes 199 classes, 10 properties, and 1636 description logic restrictions. Twenty-three Semantic Web Rule Language rules were written to generate three prescribing alerts: (1) antibiotic-microorganism mismatch alert; (2) medication-allergy alert; and (3) non-recommended empiric antibiotic therapy alert. The evaluation studies confirmed the correctness of the ontology, usefulness of the ontology for representing and maintaining antimicrobial treatment knowledge rules, and usefulness of the ontology for generating alerts to provide feedback to clinicians during antibiotic prescribing. Conclusions: This study contributes to the understanding of ontology development and evaluation methods and addresses one knowledge gap related to using ontologies as a clinical decision support system component-a need for formal ontology evaluation methods to measure their quality from the perspective of their intrinsic characteristics and their usefulness for specific tasks. (C) 2011 Elsevier Inc. All rights reserved. C1 [Bright, Tiffani J.] Duke Univ, Med Ctr, Div Clin Informat, Durham, NC 27710 USA. [Furuya, E. Yoko] Columbia Univ, Dept Med, Div Infect Dis, New York, NY 10032 USA. [Kuperman, Gilad J.] NewYork Presbyterian Hosp, New York, NY 10065 USA. [Kuperman, Gilad J.; Bakken, Suzanne] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA. [Cimino, James J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bakken, Suzanne] Columbia Univ, Sch Nursing, New York, NY 10032 USA. RP Bright, TJ (reprint author), Duke Univ, Med Ctr, Div Clin Informat, 2200 W Main St,Suite 600, Durham, NC 27710 USA. EM tiffani.bright@gmail.com; eyf2002@columbia.edu; gkuperman@nyp.org; ciminoj@cc.nih.gov; sbh22@columbia.edu OI Cimino, James/0000-0003-4101-1622 FU National Institute of Nursing Research [T90 NR010824]; National Library of Medicine [T15 LM007079]; Health Resources and Services Administration [D11 HP07346] FX This work was performed as part of a PhD thesis at Columbia University and funded by the National Institute of Nursing Research through Grant T90 NR010824 and the National Library of Medicine Grant T15 LM007079. Bakken's contributions were funded through the Health Resources and Services Administration D11 HP07346. We thank Sarah Gilman for her effort and contribution as the Java programmer, Martini. O'Connor, and Jane Peace for feedback on the SWRL rules, Chintan Patel for contribution to the development of the ontology and SWRL rules, and Lindsay G. Cowell for assistance in implementing the BFO as the upper ontology. NR 51 TC 15 Z9 16 U1 0 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2012 VL 45 IS 1 BP 120 EP 128 DI 10.1016/j.jbi.2011.10.001 PG 9 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 895EK UT WOS:000300478800012 PM 22019377 ER PT J AU Wagner, KD Asarnow, JR Vitiello, B Clarke, G Keller, M Emslie, GJ Ryan, N Porta, G Iyengar, S Ritz, L Zelanzny, J Onorato, M Brent, D AF Wagner, Karen Dineen Asarnow, Joan Rosenbaum Vitiello, Benedetto Clarke, Gregory Keller, Martin Emslie, Graham J. Ryan, Neal Porta, Giovanna Iyengar, Satish Ritz, Louise Zelanzny, Jamie Onorato, Matthew Brent, David TI Out of the Black Box: Treatment of Resistant Depression in Adolescents and the Antidepressant Controversy SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; SUICIDAL EVENTS; TORDIA; TRIALS; SSRI; PREDICTORS; OUTCOMES AB Objective: The purpose of this article is to describe the effects of the pediatric antidepressant controversy on the Treatment of Serotonin-Selective Reuptake Inhibitor (SSRI) Resistant Depression in Adolescents (TORDIA) trial. Method: Adolescents, ages 12-18 years, with SSRI resistant depression were randomized to one of four treatments for a 12 week trial: Switch to different SSRI, switch to an alternate antidepressant (venlafaxine), switch to an alternate SSRI plus cognitive behavior therapy (CBT), or switch to venlafaxine plus CBT. Results: The health advisories and "black box'' warnings regarding suicidality and antidepressants in adolescents occurred during the course of the TORDIA trial. Revisions to the protocol, multiple-consent form changes, and re-consenting of patients were necessary. Recruitment of participants was adversely affected. Conclusion: Despite a cascade of unforeseen events that delayed the completion of the study, the TORDIA trial resulted in clinically important information about treatment-resistant depression in adolescents. C1 [Wagner, Karen Dineen] Univ Texas Med Branch, Div Child & Adolescent Psychiat, Galveston, TX 77555 USA. [Asarnow, Joan Rosenbaum] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Vitiello, Benedetto] NIMH, Child & Adolescent Treatment & Preventat Interven, Bethesda, MD 20892 USA. [Clarke, Gregory] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Keller, Martin] Brown Univ, Dept Psychiat, Providence, RI 02912 USA. [Emslie, Graham J.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Ryan, Neal; Porta, Giovanna; Zelanzny, Jamie; Brent, David] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Iyengar, Satish] Univ Pittsburgh, Dept Stat, Pittsburgh, PA USA. [Ritz, Louise] NIMH, Dept Res, Bethesda, MD 20892 USA. [Onorato, Matthew] Nationwide Childrens Hosp, Dept Psychiat, Columbus, OH USA. [Onorato, Matthew] Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. RP Wagner, KD (reprint author), Univ Texas Med Branch, Div Child & Adolescent Psychiat, Galveston, TX 77555 USA. EM kwagner@utmb.edu FU NIMH [MH61835, MH61856, MH61864, MH61869, MH61958, MH62014, MH66371]; Forest; GlaxoSmithKline; Lilly; Wyeth-Ayerst; Pfizer; Wyeth; National Institute of Mental Health; Guilford Press; Biobehavioral Diagnostics, Inc.; Eli Lilly; Forest Laboratories; Somerset FX This work was supported by NIMH grants MH61835 (Pittsburgh); MH61856 (Galveston); MH61864 (UCLA); MH61869 (Portland); MH61958 (Dallas); and MH62014 (Brown), and MH66371 (Pittsburgh). NIMH program staff participated in the design, implementation, analysis, and preparation of reports of the study. The opinions and assertions contained in this report are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Health and Human Services, the NIH, or the NIMH.; Dr. Karen Wagner (for the period 4/2008-4/2011) has received honoraria from American Psychiatric Association, American Institute of Biological Sciences, Physicians Postgraduate Press, CMP Medica, American Academy of Child and Adolescent Psychiatry, Madison Institute of Medicine, NIH, Mexican Psychiatric Association, Contemporary Forums, Doctors Hospital at Renaissance, UBM Medica, Quantia Communications, CME LLC, Nevada Psychiatric Association, Letters and Sciences, and American Society of Clinical Psychopharmacology. In the past, Dr. Wagner received research support and/or was a consultant to Forest, GlaxoSmithKline, Lilly, Wyeth-Ayerst, and Pfizer.; Dr. Martin Keller is or has been a consultant or received honoraria from Abbott, CENEREX, Cephalon, Cypress Bioscience, Cyberonics, Forest Laboratories, Medtronic, Organon, Novartis, Pfizer, Solvay, Wyeth, and Glaxo-Smith-Kline. He has received grants or research funding from Pfizer and Wyeth. He is or has been on an advisory board for Abbott Laboratories, CENEREX, Cyberonics, Cypress Bioscience, Forest Laboratories, Neuronetics, Novartis, Organon, Pfizer, and Glaxo-Smith-Kline.; Dr. David Brent receives research support from the National Institute of Mental Health. He receives royalties from Guilford Press and is UpToDate Psychiatry Editor.; Dr. Graham Emslie has received research support from the National Institute of Mental Health, Biobehavioral Diagnostics, Inc., Eli Lilly, Forest Laboratories, GlaxoSmithKline, and Somerset; he has been a consultant for Biobehavioral Diagnostics, Inc., Eli Lilly, Forest Laboratories, GlaxoSmithKline, INC Research Inc., Lundbeck Pfizer, Seaside, Shire Pharmaceuticals, Validus Pharmaceuticals, and Wyeth Pharmaceuticals; and has served on the Speakers Bureau for Forest Laboratories. NR 31 TC 8 Z9 8 U1 2 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB PY 2012 VL 22 IS 1 SI SI BP 5 EP 10 DI 10.1089/cap.2011.0045 PG 6 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 897FE UT WOS:000300630700003 PM 22251022 ER PT J AU Marks, MA Castle, PE Schiffman, M Gravitt, PE AF Marks, Morgan A. Castle, Philip E. Schiffman, Mark Gravitt, Patti E. TI Evaluation of Any or Type-Specific Persistence of High-Risk Human Papillomavirus for Detecting Cervical Precancer SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ASCUS-LSIL TRIAGE; CARCINOGENIC HUMAN-PAPILLOMAVIRUS; UNDETERMINED SIGNIFICANCE; LINEAR-ARRAY; YOUNG-WOMEN; CANCER; INFECTION; CYTOLOGY; LESIONS; COHORT AB High-risk human papillomavirus (HR-HPV) testing is increasingly important. We therefore examined the impact on accuracy of repeated versus one-time testing, type-specific versus pooled detection, and assay analytic sensitivity. By using a nested case-control design from the ASCUS-LSIL Triage Study, we selected women with incident cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2/3; n = 325) and a random sample of women with