FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Yi, L Rosales, T Rose, JJ Chaudhury, B Knutson, JR Venkatesan, S AF Yi, Ling Rosales, Tilman Rose, Jeremy J. Chaudhury, Bhabhadeb Knutson, Jay R. Venkatesan, Sundararajan TI HIV-1 Nef Binds a Subpopulation of MHC-I throughout Its Trafficking Itinerary and Down-regulates MHC-I by Perturbing Both Anterograde and Retrograde Trafficking SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; VIRUS TYPE-1 NEF; CROSS-CORRELATION SPECTROSCOPY; LIVING CELLS; ANTIGEN PRESENTATION; ENDOCYTIC PATHWAY; PLASMA-MEMBRANE; CYTOPLASMIC TAIL; PHOTOBLEACHING RECOVERY; SERINE PHOSPHORYLATION AB The HIV protein Nef is thought to mediate immune evasion and promote viral persistence in part by down-regulating major histocompatibility complex class I protein (MHC-I or HLA-I) from the cell surface. Two different models have been proposed to explain this phenomenon as follows: 1) stimulation of MHC-I retrograde trafficking from and aberrant recycling to the plasma membrane, and 2) inhibition of anterograde trafficking of newly synthesized HLA-I from the endoplasmic reticulum to the plasma membrane. We show here that Nef simultaneously uses both mechanisms to down-regulate HLA-I in peripheral blood mononuclear cells or HeLa cells. Consistent with this, we found by using fluorescence correlation spectroscopy that a third of diffusing HLA-I at the endoplasmic reticulum, Golgi/trans-Golgi network, and the plasma membrane (PM) was associated with Nef. The binding of Nef was similarly avid for native HLA-I and recombinant HLA-I A2 at the PM. Nef binding to HLA-I at the PM was sensitive to specific inhibition of endocytosis. It was also attenuated by cyclodextrin disruption of PM lipid microdomain architecture, a change that also retarded lateral diffusion and induced large clusters of HLA-I. In all, our data support a model for Nef down-regulation of HLA-I that involves both major trafficking itineraries and persistent protein-protein interactions throughout the cell. C1 [Venkatesan, Sundararajan] NIAID, MCBU, LMI, NIH, Bethesda, MD 20892 USA. [Rosales, Tilman; Knutson, Jay R.] NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Venkatesan, S (reprint author), NIAID, MCBU, LMI, NIH, Bldg 10,Rm 6A05, Bethesda, MD 20892 USA. EM sv1s@nih.gov FU National Institutes of Health, Division of Intramural Research, NIAID FX This work was supported, in whole or in part, by National Institutes of Health grant from Division of Intramural Research, NIAID. NR 78 TC 19 Z9 21 U1 1 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 OCT 1 PY 2010 VL 285 IS 40 BP 30884 EP 30905 DI 10.1074/jbc.M110.135947 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 653YS UT WOS:000282135500055 PM 20622010 ER PT J AU Fitzkee, NC Bax, A AF Fitzkee, Nicholas C. Bax, Ad TI Facile measurement of H-1-N-15 residual dipolar couplings in larger perdeuterated proteins SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE ARTSY; Catalytic core domain; HIV integrase; Quantitative J correlation; TROSY; RDC ID HIV-1 INTEGRASE; PULSE SEQUENCES; BIOLOGICAL MACROMOLECULES; POLARIZATION TRANSFER; CRYSTAL-STRUCTURE; NMR-SPECTROSCOPY; CATALYTIC DOMAIN; LIQUID-CRYSTAL; ACTIVE-SITE; CORE DOMAIN AB We present a simple method, ARTSY, for extracting (1)J(NH) couplings and H-1-N-15 RDCs from an interleaved set of two-dimensional H-1-N-15 TROSY-HSQC spectra, based on the principle of quantitative J correlation. The primary advantage of the ARTSY method over other methods is the ability to measure couplings without scaling peak positions or altering the narrow line widths characteristic of TROSY spectra. Accuracy of the method is demonstrated for the model system GB3. Application to the catalytic core domain of HIV integrase, a 36 kDa homodimer with unfavorable spectral characteristics, demonstrates its practical utility. Precision of the RDC measurement is limited by the signal-to-noise ratio, S/N, achievable in the 2D TROSY-HSQC spectrum, and is approximately given by 30/(S/N) Hz. C1 [Fitzkee, Nicholas C.; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU NIDDK; NIH; Office of the Director, NIH FX We thank Alexander Maltsev for the sample of perdeuterated GB3 and for help in preparing the liquid crystalline solution for IN50-212 measurement, and Lishan Yao for the protonated GB3 mutant. This work was supported in part by the Intramural Research Program of the NIDDK, NIH, and by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 39 TC 37 Z9 37 U1 1 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD OCT PY 2010 VL 48 IS 2 BP 65 EP 70 DI 10.1007/s10858-010-9441-9 PG 6 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 659VW UT WOS:000282596100001 PM 20694505 ER PT J AU Ahmet, I Wan, RQ Mattson, MP Lakatta, EG Talan, MI AF Ahmet, Ismayil Wan, Ruiqian Mattson, Mark P. Lakatta, Edward G. Talan, Mark I. TI Chronic Alternate-Day Fasting Results in Reduced Diastolic Compliance and Diminished Systolic Reserve in Rats SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Diastolic dysfunction; heart failure; animal model; nutrition ID LEFT ATRIAL VOLUME; CALORIC RESTRICTION; MINERALOCORTICOID RECEPTOR; MYOCARDIAL-INFARCTION; DIETARY RESTRICTION; DISEASE; DYSFUNCTION; IMPROVES; RISK; METABOLISM AB Background: Based on animal experiments and limited data from the few human trials, alternate-day fasting (ADF) resulted in weight loss, prolonged life, reduced metabolic risk factors for diabetes and cardiovascular diseases, and reduced prevalence of age-related diseases. The present study is the first comprehensive examination of the long-term effects of ADF on general cardiovascular fitness in rats. Methods and Results: Four-month-old male Sprague-Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months with serial echocardiography. A comprehensive hemodynamic evaluation including a combined dobutamine volume stress test was performed at the end of the study, and hearts were harvested for histological assessment. The 6-month-long ADF diet resulted in a 9% reduction (P<.01) of cardiomyocyte diameter and 3-fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the ratio of early (E) and late atrial (A) waves, in Doppler-measured mitral flow was reduced (P<.01). Pressure-volume loop analyses revealed a "stiff" heart during diastole in ADF rats, whereas combined dobutamine and volume loading showed a significant reduction in left ventricular diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve. Conclusion: Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted. (J Cardiac Fail 2010:16:843-853) C1 [Ahmet, Ismayil; Lakatta, Edward G.; Talan, Mark I.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Wan, Ruiqian; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Talan, MI (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM talanm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging FX Fully funded by Intramural Research Program, National Institute on Aging. NR 33 TC 8 Z9 8 U1 1 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD OCT PY 2010 VL 16 IS 10 BP 843 EP 853 DI 10.1016/j.cardfail.2010.05.007 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 664XO UT WOS:000282997500007 PM 20932467 ER PT J AU Fu, D Wakabayashi, Y Ido, Y Lippincott-Schwartz, J Arias, IM AF Fu, Dong Wakabayashi, Yoshiyuki Ido, Yasuo Lippincott-Schwartz, Jennifer Arias, Irwin M. TI Regulation of bile canalicular network formation and maintenance by AMP-activated protein kinase and LKB1 SO JOURNAL OF CELL SCIENCE LA English DT Article DE AMPK; LKB1; Bile canaliculi; Polarity; Primary hepatocytes; Collagen sandwich culture; P-glycoprotein; Tight junction ID RAT HEPATOCYTES; CELL POLARITY; SANDWICH CONFIGURATION; LIVER-REGENERATION; EPITHELIAL-CELLS; TIGHT JUNCTIONS; MYOSIN-II; IN-VITRO; CULTURE; PHOSPHORYLATION AB AMP-activated protein kinase (AMPK), a cellular metabolic sensor, is essential in energy regulation and metabolism. Hepatocyte polarization during liver development and regeneration parallels increased metabolism. The current study investigates the effects of AMPK and its upstream activator LKB1 on polarity and bile canalicular network formation and maintenance in collagen sandwich cultures of rat hepatocytes. Immunostaining for the apical protein ABCB1 and the tight junction marker occludin demonstrated that canalicular network formation is sequential and is associated with activation of AMPK and LKB1. AMPK and LKB1 activators accelerated canalicular network formation. Inhibition of AMPK or LKB1 by dominant-negative AMPK or kinase-dead LKB1 constructs blocked canalicular network formation. AICAR and 2-deoxyglucose, which activate AMPK, circumvented the inhibitory effect of kinase-dead LKB1 on canalicular formation, indicating that AMPK directly affects canalicular network formation. After the canalicular network was formed, inhibition of AMPK and LKB1 by dominant-negative AMPK or kinase-dead LKB1 constructs resulted in loss of canalicular network, indicating that AMPK and LKB1 also participate in network maintenance. In addition, activation of AMPK and LKB1 prevented low-Ca2+-mediated disruption of the canalicular network and tight junctions. These studies reveal that AMPK and its upstream kinase, LKB1, regulate canalicular network formation and maintenance. C1 [Fu, Dong; Wakabayashi, Yoshiyuki; Lippincott-Schwartz, Jennifer; Arias, Irwin M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Ido, Yasuo] Boston Univ, Sch Med, Dept Med, Endocrinol Sect, Boston, MA 02118 USA. RP Arias, IM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM ariasi@mail.nih.gov RI Fu, Dong /J-1426-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health FX The authors appreciate the advice and suggestions of Lewis Cantley (Harvard Medical School, Boston, MA), Neil Ruderman (Boston University School of Medicine, Boston, MA) and Reuben Shaw (The Salk Institute for Biological Studies, La Jolla, CA). This project was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health. Deposited in PMC for release after 12 months. NR 49 TC 35 Z9 35 U1 2 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD OCT 1 PY 2010 VL 123 IS 19 BP 3294 EP 3302 DI 10.1242/jcs.068098 PG 9 WC Cell Biology SC Cell Biology GA 651ER UT WOS:000281908400010 PM 20826460 ER PT J AU Smyth, JT Hwang, SY Tomita, T DeHaven, WI Mercer, JC Putney, JW AF Smyth, Jeremy T. Hwang, Sung-Yong Tomita, Takuro DeHaven, Wayne I. Mercer, Jason C. Putney, James W. TI Activation and regulation of store-operated calcium entry SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Review DE store-operated Ca2+entry; CRAC; calcium influx; calcium channel; STIM1; STIM2; Orai1; Orai2; Orai3; TRPC ID CAPACITATIVE CA2+ ENTRY; LIGHT-CHAIN KINASE; FAST CA2+-DEPENDENT INACTIVATION; STROMAL INTERACTION MOLECULE-1; PLASMA MEMBRANE JUNCTIONS; CRAC CHANNEL ACTIVATION; EMBRYONIC KIDNEY-CELLS; PAROTID ACINAR-CELLS; ENDOPLASMIC-RETICULUM; TRPC CHANNELS AB Introduction I(CRAC) Orais STIM1 STIM2 STIM1, STIM2 and Ca2+ oscillations TRPCs and SOCE Conclusions The process of store-operated Ca2+ entry (SOCE), whereby Ca2+ influx across the plasma membrane is activated in response to depletion of intracellular Ca2+ stores in the endoplasmic reticulum (ER), has been under investigation for greater than 25 years; however, only in the past 5 years have we come to understand this mechanism at the molecular level. A surge of recent experimentation indicates that STIM molecules function as Ca2+ sensors within the ER that, upon Ca2+ store depletion, rearrange to sites very near to the plasma membrane. At these plasma membrane-ER junctions, STIM interacts with and activates SOCE channels of the Orai family. The molecular and biophysical data that have led to these findings are discussed in this review, as are several controversies within this rapidly expanding field. C1 [Smyth, Jeremy T.; Hwang, Sung-Yong; Tomita, Takuro; DeHaven, Wayne I.; Mercer, Jason C.; Putney, James W.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX Some of the research described in this review was supported by the Intramural Program of the NIH, National Institute of Environmental Health Sciences. NR 146 TC 114 Z9 117 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD OCT PY 2010 VL 14 IS 10 BP 2337 EP 2349 DI 10.1111/j.1582-4934.2010.01168.x PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 672OS UT WOS:000283596400001 PM 20807283 ER PT J AU Felici, A Giubellino, A Bottaro, DP AF Felici, Angelina Giubellino, Alessio Bottaro, Donald P. TI Gab1 Mediates Hepatocyte Growth Factor-Stimulated Mitogenicity and Morphogenesis in Multipotent Myeloid Cells SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE HGF; MET; GAB1; SHP-2; MYELOID CELLS ID TYROSINE-PHOSPHATASE SHP-2; ACTIVATED PROTEIN-KINASE; TRANSCRIPTION FACTOR GATA-2; PLECKSTRIN HOMOLOGY DOMAIN; HEMATOPOIETIC STEM-CELLS; SIGNAL-REGULATED KINASE; FACTOR RECEPTOR-BETA; GRB2 BINDING-SITE; C-MET; DOCKING PROTEIN AB Hepatocyte growth factor (HGF)-stimulated mitogenesis, motogenesis and morphogenesis in various cell types begins with activation of the Met receptor tyrosine kinase and the recruitment of intracellular adaptors and kinase substrates. The adapter protein Gab1 is a critical effector and substrate of activated Met, mediating morphogenesis, among other activities, in epithelial cells. To define its role downstream of Met in hematopoietic cells, Gab1 was expressed in the HGF-responsive, Gab1-negative murine myeloid cell line 32D. Interestingly, the adhesion and motility of Gab1-expressing cells were significantly greater than parental cells, independent of growth factor treatment. Downstream of activated Met, Gab1 expression was specifically associated with rapid Shp-2 recruitment and activation, increased mitogenic potency, suppression of GATA-1 expression and concomitant upregulation of GATA-2 transcription. In addition to enhanced proliferation, continuous culture of Gab1-expressing 32D cells in HGF resulted in cell attachment, filopodia extension and phenotypic changes suggestive of monocytic differentiation. Our results suggest that in myeloid cells, Gab1 is likely to enhance HGF mitogenicity by coupling Met to Shp-2 and GATA-2 expression, thereby potentially contributing to normal myeloid differentiation as well as oncogenic transformation. J. Cell. Biochem. 111: 310-321, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Felici, Angelina; Giubellino, Alessio; Bottaro, Donald P.] NCI, Urol Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, CCR, NIH, Bldg 10 CRC W Rm 2-5239,10 Ctr Dr MSC 1107, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010; OI Bottaro, Donald/0000-0002-5057-5334; Giubellino, Alessio/0000-0002-5352-0662 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD; NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD.; We thank Dr. M. Sachs for the pBat-Flag-Gab1, Dr. B. Neel for the pJ3Shp-2 Delta P and pJ3Shp-2CS expression vectors, Dr. G. Vande Woude for recombinant human HGF, Dr. M. Udey for helpful comments, Mr. N. Ellmore for technical assistance and Ms. V. Kapoor for FACS analysis. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 82 TC 10 Z9 11 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT 1 PY 2010 VL 111 IS 2 BP 310 EP 321 DI 10.1002/jcb.22695 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 658HZ UT WOS:000282482400007 PM 20506405 ER PT J AU Hartz, AMS Mahringer, A Miller, DS Bauer, B AF Hartz, Anika M. S. Mahringer, Anne Miller, David S. Bauer, Bjoern TI 17-beta-Estradiol: a powerful modulator of blood-brain barrier BCRP activity SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE BCRP; blood-brain barrier; estrogen; nongenomic regulation; transport ID CANCER-RESISTANCE-PROTEIN; PLACENTAL BEWO CELLS; NON-GENOMIC ACTIONS; P-GLYCOPROTEIN; MICROVESSEL ENDOTHELIUM; MULTIDRUG TRANSPORTER; HORMONAL-REGULATION; RESPONSE ELEMENT; UP-REGULATION; IN-VITRO AB The ATP-driven efflux transporter, breast cancer resistance protein (BCRP), handles many therapeutic drugs, including chemotherapeutics, limiting their ability to cross the blood-brain barrier. This study provides new insight into rapid, nongenomic regulation of BCRP transport activity at the blood-brain barrier. Using isolated brain capillaries from rats and mice as an ex vivo blood-brain barrier model, we show that BCRP protein is highly expressed in brain capillary membranes and functionally active in intact capillaries. We show that nanomolar concentrations of 17-beta-estradiol (E2) rapidly reduced BCRP transport activity in the brain capillaries. This E2-mediated effect occurred within minutes and did not involve transcription, translation, or proteasomal degradation, indicating a nongenomic mechanism. Removing E2 after 1 h fully reversed the loss of BCRP activity. Experiments using agonists and antagonists for estrogen receptor (ER)alpha and ER beta and brain capillaries from ER alpha and ER beta knockout mice demonstrated that E2 could signal through either receptor to reduce BCRP transport function. We speculate that this nongenomic E2-signaling pathway could potentially be used for targeting BCRP at the blood-brain barrier, in brain tumors, and in brain tumor stem cells to improve chemotherapy of the central nervous system. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1742-1755; doi:10.1038/jcbfm.2010.36; published online 10 March 2010 C1 [Bauer, Bjoern] Univ Minnesota, Dept Pharmaceut Sci, Coll Pharm, Duluth, MN 55812 USA. [Hartz, Anika M. S.] Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. [Mahringer, Anne] Univ Heidelberg, Inst Pharm & Mol Biotechnol, Div Pharmaceut Technol, Heidelberg, Germany. [Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Bauer, B (reprint author), Univ Minnesota, Dept Pharmaceut Sci, Coll Pharm, 1110 Kirby Dr,232 Life Sci, Duluth, MN 55812 USA. EM bjbauer@d.umn.edu FU NIH, National Institute of Environmental Health Sciences; Whiteside Institute for Clinical Research; UMN CoP; UMN FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (DSM), a research grant from the Whiteside Institute for Clinical Research (AMSH and BB), and UMN CoP startup funds (BB). NR 45 TC 37 Z9 40 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2010 VL 30 IS 10 BP 1742 EP 1755 DI 10.1038/jcbfm.2010.36 PG 14 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 657AK UT WOS:000282382200008 PM 20216549 ER PT J AU Revilla-Lopez, G Jimenez, AI Cativiela, C Nussinov, R Aleman, C Zanuy, D AF Revilla-Lopez, Guillermo Jimenez, Ana I. Cativiela, Carlos Nussinov, Ruth Aleman, Carlos Zanuy, David TI Conformational Profile of a Proline-Arginine Hybrid SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID MOLECULAR-DYNAMICS; SIDE-CHAIN; PEPTIDE CONFORMATION; MEDICINAL CHEMISTRY; FORCE-FIELD; ENERGY; PROTEINS; PREFERENCES; STABILITY; ANALOGS AB The intrinsic conformational preferences of a new nonproteinogenic amino acid have been explored by computational methods. This tailored molecule, named ((beta)Pro)Arg, is conceived as a replacement for arginine in bioactive peptides when the stabilization of folded turn-like conformations is required. The new residue features a proline skeleton that bears the guanidilated side chain of arginine at the C(beta) position of the five-membered pyrrolidine ring, in either a cis or a trans orientation with respect to the carboxylic acid. The conformational profiles of the N-acetyl-N '-methylamide derivatives of the cis and trans isomers of ((beta)Pro)Arg have been examined in the gas phase and in solution by B3LYP/6-3 I+G(d,p) calculations and molecular dynamics simulations. The main conformational features of both isomers represent a balance between geometric restrictions imposed by the five-membered pyrrolidine ring and the ability of the guanidilated side chain to interact with the backbone through hydrogen bonds. Thus, both cis- and trans-((beta)Pro)Arg exhibit a preference for the alpha(l), conformation as a consequence of the interactions established between the guanidinium moiety and the main-chain amide groups. C1 [Revilla-Lopez, Guillermo; Aleman, Carlos; Zanuy, David] Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, E-08028 Barcelona, Spain. [Jimenez, Ana I.; Cativiela, Carlos] Univ Zaragoza, CSIC, Inst Ciencia Mat Aragon, Dept Quim Organ, E-50009 Zaragoza, Spain. [Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. [Aleman, Carlos] Univ Politecn Cataluna, Ctr Res Nanoengn, E-08028 Barcelona, Spain. RP Aleman, C (reprint author), Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, Diagonal 647, E-08028 Barcelona, Spain. EM carlos.aleman@upc.edu; david.zanuy@upc.edu RI Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 FU Ministerio de Educacion y Ciencia [CTQ2007-62245]; Gobierno de Aragon; ICREA; National Cancer Institute; National Institutes of Health [HHSN261200-800001E]; Center for Cancer Research FX Gratitude is expressed to the Centre de Supercomputacio de Catalunya (CESCA). We also acknowledge the National Cancer Institute for partial allocation of computing time and staff support at the Advanced Biomedical Computing Center of the Frederick Cancer Research and Development Center. Classical calculations were partially carried out using the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). Financial support from the Ministerio de Educacion y Ciencia (Ramon y Cajal contract for D.Z., Project CTQ2007-62245), Gobierno de Aragon (research group E40), and Generalitat de Catalunya (research group 2009 SGR 925; XRQTC; ICREA Academia prize for excellence in research to C.A.) is gratefully acknowledged. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200-800001E. The content of this publication does not necessarily reflect the view of the 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 49 TC 2 Z9 2 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD OCT PY 2010 VL 50 IS 10 BP 1781 EP 1789 DI 10.1021/ci100135f PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 668PX UT WOS:000283283100003 PM 20886854 ER PT J AU Dong, Q Cheng, ZQ Chang, WH Blackman, BE Conte, FA Hu, JX Shoback, D Miller, WL AF Dong, Qing Cheng, Zhiqiang Chang, Wenhan Blackman, Brigitte E. Conte, Felix A. Hu, Jianxin Shoback, Dolores Miller, Walter L. TI Naturally-Occurring Mutation in the Calcium-Sensing Receptor Reveals the Significance of Extracellular Domain Loop III Region for Class C G-Protein-Coupled Receptor Function SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NEONATAL SEVERE HYPERPARATHYROIDISM; FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; METABOTROPIC GLUTAMATE-RECEPTOR; CELL-SURFACE EXPRESSION; HUMAN CA2+ RECEPTOR; SIGNAL-TRANSDUCTION; CA2+-SENSING RECEPTOR; SECONDARY HYPERPARATHYROIDISM; ENDOPLASMIC-RETICULUM; LINKED GLYCOSYLATION AB Context: Inactivating mutations of the calcium-sensing receptor (CaSR) cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Most mutations are clustered in the N-terminal and Cys-rich regions of the extracellular domain (ECD) and seven-transmembrane domain. Disease-causing mutations are uncommon in the C terminus of ECD. Objective: The aim of the study was to characterize the CaSR mutations causing neonatal severe hyperparathyroidism in a consanguineous family. Methods: Parathyroid glands from the index patient were stained for CaSR protein. The CaSR gene was sequenced, mutations were recreated in CaSR cDNA, and HEK293 cells were transfected with the CaSR mutant expression vector. Cellular CaSR targeting was detected by immunoblotting and immunocytochemistry; CaSR activity was assayed by inositol phosphate accumulation, MAPK activation, and single-cell microfluorimetry. Results: Immunocytochemistry showed reduced intracellular CaSR in patient parathyroids. An in-frame homozygous deletion/insertion mutation, c. 1031 > 1034 (delACAAinsT), replaced His344-Asn345 with a single Leu in CaSR loop III. The mutant reduced cell surface expression of CaSR in transfected HEK293 cells. Inositol phosphate accumulation, MAPK activation, and single-cell microfluorimetry revealed blunted signaling responses of the mutant receptor to changes in extracellular Ca2+ concentration. Conclusion: Deletion of His344-Asn345 in the ECD loop III region affects cell surface targeting of CaSR in transfected cells and in affected parathyroid glands. Absence of conserved Asn345 may interfere with CaSR folding or glycosylation, leading to poor protein targeting to the cell membrane. This loss-of-function mutant indicates that the ECD loop III is required for CaSR activity. (J Clin Endocrinol Metab 95: E245-E252, 2010) C1 [Dong, Qing; Conte, Felix A.; Miller, Walter L.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94121 USA. [Cheng, Zhiqiang; Chang, Wenhan; Shoback, Dolores] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Cheng, Zhiqiang; Chang, Wenhan; Shoback, Dolores] Univ Calif San Francisco, Dept Obstet & Gynecol, San Francisco, CA 94121 USA. [Blackman, Brigitte E.] Univ Calif San Francisco, Dept Reprod Sci, San Francisco, CA 94121 USA. [Cheng, Zhiqiang; Chang, Wenhan; Shoback, Dolores] Dept Vet Affairs Med Ctr, Endocrine Res Unit, San Francisco, CA 94121 USA. [Hu, Jianxin] NIDDKD, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Dong, Q (reprint author), Univ Calif San Francisco, Dept Pediat, S672D,513 Parnassus Ave, San Francisco, CA 94143 USA. EM dongq@peds.ucsf.edu RI Miller, Walter/J-3696-2012 FU National Institutes of Health (NIH) [K08 DK064626]; Veterans Affairs Merit Review; NIH/National Institute on Aging [R01AG21353-6]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR055588]; NIH [R01 DK37922] FX This work was supported by National Institutes of Health (NIH) Grant K08 DK064626 (to Q.D.); a Veterans Affairs Merit Review (to D.S.); NIH/National Institute on Aging Grant R01AG21353-6 and National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01AR055588 (to W.C. and D.S.); and NIH Grant R01 DK37922 (to W.L.M.). NR 40 TC 3 Z9 3 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 EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2010 VL 95 IS 10 BP E245 EP E252 DI 10.1210/jc.2010-0559 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 659NK UT WOS:000282573300054 PM 20631026 ER PT J AU Perl, S Kushner, JA Buchholz, BA Meeker, AK Stein, GM Hsieh, M Kirby, M Pechhold, S Liu, EH Harlan, DM Tisdale, JF AF Perl, S. Kushner, J. A. Buchholz, B. A. Meeker, A. K. Stein, G. M. Hsieh, M. Kirby, M. Pechhold, S. Liu, E. H. Harlan, D. M. Tisdale, J. F. TI Significant Human beta-Cell Turnover Is Limited to the First Three Decades of Life as Determined by in Vivo Thymidine Analog Incorporation and Radiocarbon Dating SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INSULIN REQUIREMENT; TRIMESTER AB Aims: Diabetes mellitus results from an absolute or relative deficiency of insulin-producing pancreatic beta-cells. The turnover rate of adult human beta-cells remains unknown. We employed two techniques to examine adult human islet beta-cell turnover and longevity in vivo. Methods: Subjects enrolled in National Institutes of Health clinical trials received thymidine analogs [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8 d to 4 yr prior to death. Archival autopsy samples from 10 patients (aged 17-74 yr) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin-staining cells. Human adult beta-cell longevity was determined by estimating the cells' genomic DNA integration of atmospheric (14)C. DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15-yr-old donor, and purified beta-cell DNA was obtained from two donors (ages 48 and 80 yr). 14C levels were then determined using accelerator mass spectrometry. Cellular "birth date" was determined by comparing the subject's DNA (14)C content relative to a well-established (14)C atmospheric prevalence curve. Results: In the two subjects less than 20 yr of age, 1-2% of the beta-cell nuclei costained for BrdU/IdU. No beta-cell nuclei costained in the eight patients more than 30 yr old. Consistent with the BrdU/IdU turnover data, beta-cell DNA (14)C content indicated that the "birth date" of cells occurred within the subject's first 30 yr of life. Conclusions: Under typical circumstances, human beta-cells and their cellular precursors are established by young adulthood. (J Clin Endocrinol Metab 95: E234-E239, 2010) C1 [Perl, S.; Pechhold, S.; Liu, E. H.; Harlan, D. M.] Natl Inst Diabet Digest & Kidney Dis NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Kushner, J. A.; Stein, G. M.] Univ Penn, Div Endocrinol & Diabet, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Buchholz, B. A.] Lawrence Livermore Natl Lab, Ctr Accelerator Mass Spectrometry, Livermore, CA 94550 USA. [Meeker, A. K.] Johns Hopkins Med Inst, Dept Pathol, Div Genitourinary Pathol, Baltimore, MD 21287 USA. [Kirby, M.] Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. [Perl, S.; Hsieh, M.; Kirby, M.; Tisdale, J. F.] NIDDK, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Perl, S.; Hsieh, M.; Kirby, M.; Tisdale, J. F.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Perl, S (reprint author), 10 Ctr Dr,Room 9N119, Bethesda, MD 20892 USA. EM perls@nhlbi.nih.gov RI Buchholz, Bruce/G-1356-2011 FU National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health (NIH); NIH/National Center for Research Resources [RR13461]; U.S. Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344] FX This work was supported in part by the intramural research program of the National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health (NIH) and NIH/National Center for Research Resources (RR13461). This work was performed in part under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under contract DE-AC52-07NA27344. NR 14 TC 101 Z9 101 U1 0 U2 8 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 OCT PY 2010 VL 95 IS 10 BP E234 EP E239 DI 10.1210/jc.2010-0932 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 659NK UT WOS:000282573300052 PM 20660050 ER PT J AU Wan, ZH Zhi, N Wong, SS Keyvanfar, K Liu, DL Raghavachari, N Munson, PJ Su, S Malide, D Kajigaya, S Young, NS AF Wan, Zhihong Zhi, Ning Wong, Susan Keyvanfar, Keyvan Liu, Delong Raghavachari, Nalini Munson, Peter J. Su, Su Malide, Daniela Kajigaya, Sachiko Young, Neal S. TI Human parvovirus B19 causes cell cycle arrest of human erythroid progenitors via deregulation of the E2F family of transcription factors SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DNA-DAMAGE RESPONSE; NONSTRUCTURAL PROTEIN; GENE-EXPRESSION; INFECTIOUS CLONE; P6 PROMOTER; NS1 PROTEIN; VIRUS; REPLICATION; APOPTOSIS; PHOSPHORYLATION AB Human parvovirus B19 (B19V) is the only human pathogenic parvovirus. It causes a wide spectrum of human diseases, including fifth disease (erythema infectiosum) in children and pure red cell aplasia in immunocompromised patients. B19V is highly erythrotropic and preferentially replicates in erythroid progenitor cells (EPCs). Current understanding of how B19V interacts with cellular factors to regulate disease progression is limited, due to a lack of permissive cell lines and animal models. Here, we employed a recently developed primary human CD36(+) EPC culture system that is highly permissive for B19V infection to identify cellular factors that lead to cell cycle arrest after B19V infection. We found that B19V exploited the E2F family of transcription factors by downregulating activating E2Fs (E2F1 to E2F3a) and upregulating repressive E2Fs (E2F4 to E2F8) in the primary CD36+ EPCs. B19V nonstructural protein 1 (NS1) was a key viral factor responsible for altering E2F1-E2F5 expression, but not E2F6-E2F8 expression. Interaction between NS1 and E2F4 or E2F5 enhanced the nuclear import of these repressive E2Fs and induced stable G(2) arrest. NS1-induced G(2) arrest was independent of p53 activation and increased viral replication. Downstream E2F4/E2F5 targets, which are potentially involved in the progression from G2 into M phase and erythroid differentiation, were identified by microarray analysis. These findings provide new insight into the molecular pathogenesis of B19V in highly permissive erythroid progenitors. C1 [Wan, Zhihong; Zhi, Ning; Wong, Susan; Keyvanfar, Keyvan; Su, Su; Kajigaya, Sachiko; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Liu, Delong; Munson, Peter J.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Raghavachari, Nalini] NHLBI, Gene Express Core Facil, NIH, Bethesda, MD 20892 USA. [Malide, Daniela] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Zhi, N (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10CRC,Rm 3E-5272,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhin@nhlbi.nih.gov FU NIH FX This work was supported by the NIH Intramural Research Program. We thank Dong Joo Kim for help in preparing the manuscript. NR 61 TC 35 Z9 37 U1 0 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2010 VL 120 IS 10 BP 3530 EP 3544 DI 10.1172/JCI41805 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 657DN UT WOS:000282393200016 PM 20890043 ER PT J AU Elrod, JW Wong, R Mishra, S Vagnozzi, RJ Sakthievel, B Goonasekera, SA Karch, J Gabel, S Farber, J Force, T Brown, JH Murphy, E Molkentin, JD AF Elrod, John W. Wong, Renee Mishra, Shikha Vagnozzi, Ronald J. Sakthievel, Bhuvana Goonasekera, Sanjeewa A. Karch, Jason Gabel, Scott Farber, John Force, Thomas Brown, Joan Heller Murphy, Elizabeth Molkentin, Jeffery D. TI Cyclophilin D controls mitochondrial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PERMEABILITY TRANSITION PORE; ACTIVATED RECEPTOR-ALPHA; FATTY-ACID OXIDATION; CELL-DEATH; RAT-HEART; CARDIAC DYSFUNCTION; RUTHENIUM RED; CYCLOSPORINE; MEMBRANE; CHANNEL AB Cyclophilin D (which is encoded by the Ppif gene) is a mitochondrial matrix peptidyl-prolyl isomerase known to modulate opening of the mitochondrial permeability transition pore (MPTP). Apart from regulating necrotic cell death, the physiologic function of the MPTP is largely unknown. Here we have shown that Ppif(-/-) mice exhibit substantially greater cardiac hypertrophy, fibrosis, and reduction in myocardial function in response to pressure overload stimulation than control mice. In addition, Ppif(-/-) mice showed greater hypertrophy and lung edema as well as reduced survival in response to sustained exercise stimulation. Cardiomyocyte-specific transgene expression of cyclophilin D in Ppif(-/-) mice rescued the enhanced hypertrophy, reduction in cardiac function, and rapid onset of heart failure following pressure overload stimulation. Mechanistically, the mal-adaptive phenotype phenotype in the hearts of Ppif(-/-) mice was associated with an alteration in MPTP-mediated Ca2+ efflux resulting in elevated levels of mitochondrial matrix Ca2+ and enhanced activation of Ca2+-dependent dehydrogenases. Elevated matrix Ca2+ led to increased glucose oxidation relative to fatty acids, thereby limiting the metabolic flexibility of the heart that is critically involved in compensation during stress. These findings suggest that the MPTP maintains homeostatic mitochondrial Ca2+ levels to match metabolism with alterations in myocardial workload, thereby suggesting a physiologic function for the MPTP. C1 [Elrod, John W.; Goonasekera, Sanjeewa A.; Karch, Jason; Molkentin, Jeffery D.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Howard Hughes Med Inst, Dept Pediat, Cincinnati, OH 45229 USA. [Wong, Renee; Gabel, Scott; Murphy, Elizabeth] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Mishra, Shikha; Brown, Joan Heller] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Vagnozzi, Ronald J.; Force, Thomas] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA. [Vagnozzi, Ronald J.; Force, Thomas] Thomas Jefferson Univ, Div Cardiol, Philadelphia, PA 19107 USA. [Sakthievel, Bhuvana; Farber, John] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA. RP Molkentin, JD (reprint author), Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Howard Hughes Med Inst, Dept Pediat, 240 Albert Sabin Way,MLC 7020, Cincinnati, OH 45229 USA. EM jeff.molkentin@cchmc.org OI Force, Thomas/0000-0002-0450-8659; Elrod, John/0000-0003-3925-2224 FU NIH [5F32HL092737, HL62927, HL81104, HL80101]; Fondation Leducq; Howard Hughes Medical Institute FX The authors greatly appreciate the technical expertise of Allen York and Michelle Sargent. This work was supported by grants from the NIH to J.W. Elrod (5F32HL092737), J.D. Molkentin (HL62927, HL81104), and to J.H. Brown (HL80101), as well as by an international grant in heart failure research from the Fondation Leducq and the Howard Hughes Medical Institute. NR 46 TC 155 Z9 159 U1 2 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2010 VL 120 IS 10 BP 3680 EP 3687 DI 10.1172/JCI43171 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 657DN UT WOS:000282393200030 PM 20890047 ER PT J AU Russell, M Silverman, A Fleg, JL Lee, ET Mete, M Weir, M Wilson, C Yeh, F Howard, BV Howard, WJ AF Russell, Marie Silverman, Angela Fleg, Jerome L. Lee, Elisa T. Mete, Mihriye Weir, Matthew Wilson, Charlton Yeh, Fawn Howard, Barbara V. Howard, Wm James TI Achieving lipid targets in adults with type 2 diabetes: The Stop Atherosclerosis in Native Diabetics Study SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE American Indians; Blood pressure; Cardiovascular disease; Carotid artery intima media thickness; Lipids ID CORONARY-HEART-DISEASE; BLOOD-PRESSURE; CONTROLLED-TRIAL; RISK-FACTORS; MELLITUS; CHOLESTEROL; PREVENTION; SANDS; ATORVASTATIN; GUIDELINES AB BACKGROUND: Although lipid management in diabetes is standard practice, goals often are neither met nor maintained. Strategies for achieving lower targets have not been explored. The Stop Atherosclerosis in Native Diabetics Study randomized patients with diabetes to standard versus aggressive lipid and blood pressure goals for 36 months. OBJECTIVE: To report strategies used to achieve and maintain lipid goals and to report adverse events (AEs). METHODS: Adults with type 2 diabetes and no history of cardiovascular disease (N = 499) were randomized to standard (low-density lipoprotein cholesterol [LDL-C] <= 100 mg/dL, non-high-density lipoprotein cholesterol [non-HDL-C] <= 130 mg/dL) or aggressive (LDL-C <= 70 mg/dL, non-HDL-C <= 100 mg/dL) targets. An algorithm was started with statin monotherapy, with intestinally acting agents added as required to reach LDL-C targets. Triglyceride [TG]-lowering agents were next used to reach non-HDL-C goals. Lipid management was performed by mid-level practitioners, with physician consultation, by the use of point-of-care lipid determinations. RESULTS: On average, both groups achieved the LDL-C and non-HDL-C goals within 12 months and maintained them throughout the study. At 36 months, mean (SD) LDL-C and non-HDL-C were 72 (24) and 102 (29) mg/dL in the aggressive group (AGG) and 104 (20) and 138 (26) mg/dL, respectively, in the standard group (STD); systolic blood pressure targets were 115 and 130 mmHg, respectively. A total of 68% of participants reached target LDL-C for greater than 50% of the visits and 46% for greater than 75% of visits. At 36 months, the AGG averaged 1.5 lipid lowering medications and the STD 1.2. Statins were used in 91% and 68% of the AGG and STD; ezetimibe by 31% and 10%; fibrates by 8% and 18%. No serious AEs were observed; AEs occurred in 18% of the AGG and 14% of the STD. CONCLUSION: Standard and aggressive lipid targets can be safely maintained in diabetic patients. Standardized algorithms, point-of-care lipid testing, and nonphysician providers facilitate care delivery. (C) 2010 National Lipid Association. All rights reserved. C1 [Howard, Wm James] Washington Hosp Ctr, Washington, DC 20010 USA. [Russell, Marie; Wilson, Charlton] Phoenix Indian Med Ctr, Phoenix, AZ USA. [Silverman, Angela; Mete, Mihriye; Howard, Barbara V.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Lee, Elisa T.; Yeh, Fawn] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Weir, Matthew] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Howard, WJ (reprint author), Washington Hosp Ctr, Rm 6A-126,110 Irving St NW, Washington, DC 20010 USA. EM wm.james.howard@medstar.net FU National Heart, Lung, and Blood Institute [U01-HL067031]; Merck/Schering Plough; Pfizer; Astra Zeneca; Merck; Schering Plough FX This work was supported by grant U01-HL067031 from the National Heart, Lung, and Blood Institute. Dr. B.V. Howard has served on the advisory boards of Merck/ Schering Plough and has received research support from Merck/Schering Plough. Dr. Wm. J. Howard has received research support as part of multicenter trials from Pfizer, Astra Zeneca, Merck, and Schering Plough; has served as a consultant for Merck, Schering Plough, and Pfizer; and has served on the speaker's bureau for Merck, Schering Plough, Pfizer, Astra Zeneca, Abbott, and Daiichi Sankyo. NR 18 TC 5 Z9 6 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD OCT PY 2010 VL 4 IS 5 BP 435 EP 443 DI 10.1016/j.jacl.2010.07.007 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 672ES UT WOS:000283566400021 PM 21076630 ER PT J AU Stevenson, LG Drake, SK Shea, YR Zelazny, AM Murray, PR AF Stevenson, Lindsay G. Drake, Steven K. Shea, Yvonne R. Zelazny, Adrian M. Murray, Patrick R. TI Evaluation of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Clinically Important Yeast Species SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID TRANSCRIBED SPACER REGIONS; RIBOSOMAL-RNA GENE; INVASIVE CANDIDIASIS; SEQUENCE-ANALYSIS; BACTERIA; MANAGEMENT; MYCOBACTERIA; INFECTIONS; CANDIDEMIA; SYSTEMS AB We evaluated the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for the rapid identification of yeast species. Using Bruker Daltonics MALDI BioTyper software, we created a spectral database library with m/z ratios of 2,000 to 20,000 Da for 109 type and reference strains of yeast (44 species in 8 genera). The database was tested for accuracy by use of 194 clinical isolates (23 species in 6 genera). A total of 192 (99.0%) of the clinical isolates were identified accurately by MALDI-TOF MS. The MALDI-TOF MS-based method was found to be reproducible and accurate, with low consumable costs and minimal preparation time. C1 [Stevenson, Lindsay G.; Drake, Steven K.; Shea, Yvonne R.; Zelazny, Adrian M.; Murray, Patrick R.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Murray, PR (reprint author), NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, 10 Ctr Dr,MSC 1508, Bethesda, MD 20892 USA. EM Pmurray@cc.nih.gov FU NIH Clinical Center; Department of Laboratory Medicine FX This research was supported by the Intramural Research Program of the NIH Clinical Center, Department of Laboratory Medicine. NR 29 TC 125 Z9 135 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2010 VL 48 IS 10 BP 3482 EP 3486 DI 10.1128/JCM.00687-09 PG 5 WC Microbiology SC Microbiology GA 659CN UT WOS:000282544700004 PM 20668126 ER PT J AU Keating, NL Landrum, MB Arora, NK Malin, JL Ganz, PA van Ryn, M Weeks, JC AF Keating, Nancy L. Landrum, Mary Beth Arora, Neeraj K. Malin, Jennifer L. Ganz, Patricia A. van Ryn, Michelle Weeks, Jane C. TI Cancer Patients' Roles in Treatment Decisions: Do Characteristics of the Decision Influence Roles? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; HEALTH OUTCOMES; OLDER WOMEN; PARTICIPATION; CARE; QUALITY; COMMUNICATION; PREFERENCES; INFORMATION; LIFE AB Purpose Patients with more active roles in decisions are more satisfied and may have better health outcomes. Younger and better educated patients have more active roles in decisions, but whether patients' roles in decisions differ by characteristics of the decision itself is unknown. Patients and Methods We surveyed a large, population-based cohort of patients with recently diagnosed lung or colorectal cancer about their roles in decisions regarding surgery, radiation therapy, and/or chemotherapy. We used multinomial logistic regression to assess whether characteristics of the decision, including evidence about the treatment's benefit, whether the decision was likely preference-sensitive (palliative therapy for metastatic cancer), and treatment modality, influenced patients' roles in that decision. Results Of 10,939 decisions made by 5,383 patients, 38.9% were patient controlled, 43.6% were shared, and 17.5% were physician controlled. When there was good evidence to support a treatment, shared control was greatest; when evidence was uncertain, patient control was greatest; and when there was no evidence for or evidence against a treatment, physician control was greatest (overall P < .001). Decisions about treatments for metastatic cancers tended to be more physician controlled than other decisions (P < .001). Conclusion Patients making decisions about treatments for which no evidence supports benefit and decisions about noncurative treatments reported more physician control, which suggests that patients may not want the responsibility of deciding on treatments that will not cure them. Better strategies for shared decision making may be needed when there is no evidence to support benefit of a treatment or when patients have terminal illnesses that cannot be cured. C1 [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Univ Calif Los Angeles, W Los Angeles Vet Affairs Hlth Care Ctr, Los Angeles, CA USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu FU National Cancer Institute (NCI) [U01 CA093344, U01 CA 093332, U01 CA093324, U01 CA093348, U01 CA093329, U01 CA01013, U01 CA093339]; Department of Veterans Affairs [CRS 02-164] FX Supported by Grants No. U01 CA093344 from the National Cancer Institute (NCI) to the Statistical Coordinating Center; U01 CA 093332 from the NCI-supported Primary Data Collection and Research Centers to DanaFarber Cancer Institute/Cancer Research Network; U01 CA093324 to Harvard Medical School/Northern California Cancer Center; U01 CA093348 to RAND/University of California, Los Angeles; U01 CA093329 to the University of Alabama at Birmingham; U01 CA01013 to the University of Iowa; U01 CA093339 to the University of North Carolina; and by Grant No. CRS 02-164 from the Department of Veterans Affairs to the Durham Veterans Affairs Medical Center CRS 02-164. NR 29 TC 52 Z9 52 U1 0 U2 3 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 OCT 1 PY 2010 VL 28 IS 28 BP 4364 EP 4370 DI 10.1200/JCO.2009.26.8870 PG 7 WC Oncology SC Oncology GA 655TP UT WOS:000282272700037 PM 20713872 ER PT J AU Johnson, FM Bekele, BN Feng, L Wistuba, I Tang, XM Tran, HT Erasmus, JJ Hwang, LL Takebe, N Blumenschein, GR Lippman, SM Stewart, DJ AF Johnson, Faye M. Bekele, B. Nebiyou Feng, Lei Wistuba, Ignacio Tang, Xi Ming Tran, Hai T. Erasmus, Jeremy J. Hwang, Li-Ling Takebe, Naoko Blumenschein, George R. Lippman, Scott M. Stewart, David J. TI Phase II Study of Dasatinib in Patients With Advanced Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SRC-FAMILY KINASES; INHIBITOR DASATINIB; SOLID TUMORS; RECEPTOR; EXPRESSION; ACTIVATION; ADENOCARCINOMA; CARCINOMA; INVASION; SURVIVAL AB Purpose Src family kinases (SFKs) promote cancer progression and are commonly expressed in non-small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib. Patients and Methods Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression. Results Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy. Conclusion Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC. C1 Univ Texas, Grad Sch Biomed Sci Houston, Houston, TX USA. NCI, Bethesda, MD 20892 USA. [Johnson, Faye M.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Unit 432, Houston, TX 77030 USA. RP Johnson, FM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Unit 432, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM fmjohns@mdanderson.org FU National Cancer Institute [N01 CM-62202] FX Supported by Grant No. N01 CM-62202 from the National Cancer Institute's Cancer Therapy Evaluation Program. Support for correlative laboratory work was provided by The University of Texas Lung Specialized Program of Research Excellence, Bristol-Myers Squibb, and the Commonwealth Foundation for Cancer Research. Dasatinib was provided by Bristol-Myers Squibb and the National Cancer Institute. NR 40 TC 80 Z9 86 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 OCT PY 2010 VL 28 IS 30 BP 4609 EP 4615 DI 10.1200/JCO.2010.30.5474 PG 7 WC Oncology SC Oncology GA 665SS UT WOS:000283056400029 PM 20855820 ER PT J AU Kelly, RJ Carter, C Giaccone, G AF Kelly, Ronan J. Carter, Corey Giaccone, Giuseppe TI Personalizing Therapy in an Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Resistant Non-Small-Cell Lung Cancer Using PF-00299804 and Trastuzumab SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-II TRIAL; DIMERIZATION INHIBITOR; OVEREXPRESSION; EXPRESSION; GEFITINIB; CARCINOMA; GEMCITABINE; PERTUZUMAB; MUTATIONS; CISPLATIN C1 [Kelly, Ronan J.; Giaccone, Giuseppe] NCI, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Carter, Corey] USN, Natl Med Ctr, Bethesda, MD 20084 USA. RP Kelly, RJ (reprint author), NCI, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 25 TC 31 Z9 32 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 1 PY 2010 VL 28 IS 28 BP E507 EP E510 DI 10.1200/JCO.2010.29.3126 PG 4 WC Oncology SC Oncology GA 655TP UT WOS:000282272700004 PM 20679607 ER PT J AU Zabor, EC Klebanoff, M Yu, K Zhang, J Nansel, T Andrews, W Schwebke, J Jeffcoat, M AF Zabor, Emily Craig Klebanoff, Mark Yu, Kai Zhang, Jun Nansel, Tonja Andrews, William Schwebke, Jane Jeffcoat, Marjorie TI Association between periodontal disease, bacterial vaginosis, and sexual risk behaviours SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE bacterial; bacterial infections; epidemiology; periodontal diseases; sexual behaviour; vaginosis ID LOW-BIRTH-WEIGHT; PRETERM BIRTH; ORAL SEX; PREGNANCY; DELIVERY; INFECTION; RESPONSES; OUTCOMES; THERAPY AB P>Background Both periodontal disease and bacterial vaginosis may cause adverse pregnancy outcomes. This study evaluated the association between periodontal disease and bacterial vaginosis. Materials and Methods Data from 3569 women enrolled in the Longitudinal Study of Vaginal Flora were used. Periodontal disease, defined as greater than three sites with >= 4 mm attachment loss, was assessed by specially calibrated hygienists at baseline. Positive bacterial vaginosis status was based on a Nugent Gram stain score >= 7. Pairs of independent variables were compared with Pearson's chi 2 and risk ratios were calculated through log-binomial regression. Results Twenty-eight per cent of women with bacterial vaginosis had periodontal disease compared with 22% without , corresponding to 1.29 (95% CI: 1.13, 1.47) times greater risk of periodontal disease among women with bacterial vaginosis. In adjusted analysis the risk ratio dropped to 1.23 (95% CI: 1.08, 1.40). Receptive oral sex with an uncircumcised partner was associated with 1.28 times (95% CI: 0.97, 1.69) the risk for periodontal disease compared with receptive oral sex with a circumcised partner, though the association is not statistically significant. Conclusions In this population, there is a small but significant association between periodontal disease and bacterial vaginosis and a possible trend between receptive oral sex with an uncircumcised partner and periodontal disease. C1 [Zabor, Emily Craig] Univ Minnesota, Div Biostat, Minneapolis, MN 55455 USA. [Klebanoff, Mark; Yu, Kai; Zhang, Jun; Nansel, Tonja] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Andrews, William; Schwebke, Jane] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Jeffcoat, Marjorie] Univ Penn, Sch Dent Med, Philadelphia, PA 19104 USA. RP Zabor, EC (reprint author), Univ Minnesota, Div Biostat, Mayo Bldg, Minneapolis, MN 55455 USA. EM zabor008@umn.edu OI Nansel, Tonja/0000-0002-8298-7595 FU NIH, NICHD [N01-HD-8-3293, Z01-HD002535-10] FX The Longitudinal Study of Vaginal Flora was supported by intramural funds (Z01-HD002535-10), and by contract (N01-HD-8-3293) from the NIH, NICHD. NR 30 TC 5 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD OCT PY 2010 VL 37 IS 10 BP 888 EP 893 DI 10.1111/j.1600-051X.2010.01593.x PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 647RM UT WOS:000281636300003 PM 20636412 ER PT J AU Prosser, LA Lee, SCK Barbe, MF VanSant, AF Lauer, RT AF Prosser, Laura A. Lee, Samuel C. K. Barbe, Mary F. VanSant, Ann F. Lauer, Richard T. TI Trunk and hip muscle activity in early walkers with and without cerebral palsy - A frequency analysis SO JOURNAL OF ELECTROMYOGRAPHY AND KINESIOLOGY LA English DT Article DE Cerebral palsy; Muscle; Trunk; Frequency; Gait ID BALANCE CONTROL; SURFACE EMG; CHILDREN; GAIT; WALKING; ACTIVATION; PATTERNS; ADOLESCENTS; RELIABILITY; STRATEGIES AB Poor control of postural muscles is a primary impairment in cerebral palsy (CP), yet core trunk and hip muscle activity has not been thoroughly investigated. Frequency analysis of electromyographic (EMG) signals provides insight about the intensity and pattern of muscle activation, correlates with functional measures in CP, and is sensitive to change after intervention. The objective of this study was to investigate differences in trunk and hip muscle activation frequency in children with CP compared to children with similar amounts of walking experience and typical development (TD). EMG data from 31 children (15 with CP, 16 with TD) were recorded from 16 trunk and hip muscles bilaterally. A time-frequency pattern was generated using the continuous wavelet transform and instantaneous mean frequency (IMNF) was calculated at each interval of the gait cycle. Functional principal component analysis (PCA) revealed that IMNF was significantly higher in the CP group throughout the gait cycle for all muscles. Additionally, stride-to-stride variability was higher in the CP group. This evidence demonstrated altered patterns of trunk and hip muscle activation in CP, including increased rates of motor unit firing, increased number of recruited motor units, and/or decreased synchrony of motor units. These altered muscle activation patterns likely contribute to muscle fatigue and decreased biomechanical efficiency in children with CP. Published by Elsevier Ltd. C1 [Prosser, Laura A.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Lee, Samuel C. K.] Shriners Hosp Children, Res Dept, Philadelphia, PA USA. [Lee, Samuel C. K.] Univ Delaware, Phys Therapy Dept, Newark, DE USA. [Barbe, Mary F.; VanSant, Ann F.; Lauer, Richard T.] Temple Univ, Dept Phys Therapy, Philadelphia, PA 19122 USA. [Barbe, Mary F.] Temple Univ, Dept Anat, Philadelphia, PA 19122 USA. [Barbe, Mary F.] Temple Univ, Dept Anat & Cell Biol, Philadelphia, PA 19122 USA. [Lauer, Richard T.] Temple Univ, Dept Elect & Comp Engn, Philadelphia, PA 19122 USA. RP Prosser, LA (reprint author), NIH, Dept Rehabil Med, Bldg 10 CRC,1-1469,10 Ctr Dr, Bethesda, MD 20892 USA. EM laura.prosser@nih.gov RI Prosser, Laura/C-1242-2009; Van Mulders, Benjamin/P-1241-2014 FU Section on Pediatrics; American Physical Therapy Association; NINDS [R03NS048875]; NICHD [R01HD043859]; NIH Clinical Center FX The authors thank Steve Capella and Jenny Lee for assistance with data collection, and Diana Deshefy, DPT, Samuel Pierce, PT, PhD and Erin Sheeder, DPT for assistance with participant recruitment. This work was funded by a Clinical Research Grant to Dr. Prosser from the Section on Pediatrics, American Physical Therapy Association, NINDS R03NS048875 to Dr. Lauer, and NICHD R01HD043859 to Dr. Lee. This research was also supported in part by the Intramural Research Program of the NIH Clinical Center. Portions of this work were presented at the 2009 Annual Meeting of the American Society of Biomechanics. NR 46 TC 12 Z9 14 U1 2 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1050-6411 J9 J ELECTROMYOGR KINES JI J. Electromyogr. Kinesiol. PD OCT PY 2010 VL 20 IS 5 BP 851 EP 859 DI 10.1016/j.jelekin.2010.04.005 PG 9 WC Neurosciences; Physiology; Rehabilitation; Sport Sciences SC Neurosciences & Neurology; Physiology; Rehabilitation; Sport Sciences GA 634JD UT WOS:000280576100010 PM 20472460 ER PT J AU Lu, SY Pike, VW AF Lu, Shuiyu Pike, Victor W. TI Synthesis of [F-18]xenon difluoride as a radiolabeling reagent from [F-18]fluoride ion in a micro-reactor and at production scale SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE [F-18]Xenon difluoride; [F-18]Fluoride ion; Labeling agent; Micro-reactor; Radiotracers ID POSITRON-EMISSION-TOMOGRAPHY; F-18 XENON DIFLUORIDE; DIVALENT XENON; FLUORINE-GAS; NO-CARRIER; PET; RADIOFLUORINATION; XEF2; ACETONITRILE; CHLOROFORM AB [F-18]Xenon difluoride ([F-18]XeF2), was produced by treating xenon difluoride with cyclotron-produced [F-18]fluoride ion to provide a potentially useful agent for labeling novel radiotracers with fluorine-18 (t(1/2) = 109.7 min) for imaging applications with positron emission tomography. Firstly, the effects of various reaction parameters, for example, vessel material, solvent, cation and base on this process were studied at room temperature. Glass vials facilitated the reaction more readily than polypropylene vials. The reaction was less efficient in acetonitrile than in dichloromethane. Cs+ or K+ with or without the cryptand. K 2.2.2, was acceptable as counter cation. The production of [F-18]XeF2 was retarded by K2CO3, suggesting that generation of hydrogen fluoride in the reaction milieu promoted the incorporation of fluorine-18 into xenon difluoride. Secondly, the effect of temperature was studied using a microfluidic platform in which [F-18]XeF2 was produced in acetonitrile at elevated temperature (>= 85 degrees C) over 94 s. These results enabled us to develop a method for obtaining [F-18]XeF2 on a production scale (up to 25 mCi) through reaction of [F-18]fluoride ion with xenon difluoride in acetonitrile at 90 degrees C for 10 min. [F-18]XeF2 was separated from the reaction mixture by distillation at 110 degrees C. Furthermore, [F-18]XeF2 was shown to be reactive towards substrates, such as 1-((trimethylsilyl)oxy)cyclohexene and fluorene. Published by Elsevier B.V. C1 [Lu, Shuiyu; Pike, Victor W.] NIMH, PET Radiopharmaceut Sci Sect, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Lu, SY (reprint author), NIMH, PET Radiopharmaceut Sci Sect, Mol Imaging Branch, NIH, 10 Ctr Dr,Room B3 C346, Bethesda, MD 20892 USA. EM Shuiyu.Lu@mail.nih.gov OI Lu, Shuiyu/0000-0003-0310-4318 FU National Institutes of Health (National Institute of Mental Health) [Z01-MH-002793] FX This research was supported by the Intramural Research Program (project # Z01-MH-002793) of the National Institutes of Health (National Institute of Mental Health). We are grateful to the NIH Clinical PET Department for the production of fluorine-18. We also thank Professor C. A. Ramsden (Keele University, UK) and Dr. F. I. Aigbirhio (Cambridge University, UK) for their comments on the draft manuscript. NR 57 TC 20 Z9 20 U1 2 U2 15 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD OCT PY 2010 VL 131 IS 10 BP 1032 EP 1038 DI 10.1016/j.jfluchem.2010.07.009 PG 7 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 671CK UT WOS:000283477300010 PM 20871806 ER PT J AU Okawa, H Pahlberg, J Rieke, F Birnbaumer, L Sampath, AP AF Okawa, Haruhisa Pahlberg, Johan Rieke, Fred Birnbaumer, Lutz Sampath, Alapakkam P. TI Coordinated control of sensitivity by two splice variants of G alpha(o) in retinal ON bipolar cells SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID AII AMACRINE CELLS; METABOTROPIC GLUTAMATE-RECEPTOR; MAMMALIAN RETINA; MOUSE RETINA; G-PROTEIN; LIGHT RESPONSE; ALPHA-SUBUNIT; DEPOLARIZING BIPOLAR; GAMMA-SUBUNITS; DENDRITIC TIPS AB The high sensitivity of scotopic vision depends on the efficient retinal processing of single photon responses generated by individual rod photoreceptors. At the first synapse in the mammalian retina, rod outputs are pooled by a rod "ON" bipolar cell, which uses a G-protein signaling cascade to enhance the fidelity of the single photon response under conditions where few rods absorb light. Here we show in mouse rod bipolar cells that both splice variants of the Go. subunit, G alpha(o1) and G alpha(o2), mediate light responses under the control of mGluR6 receptors, and their coordinated action is critical for maximizing sensitivity. We found that the light response of rod bipolar cells was primarily mediated by G alpha(o1), but the loss of G alpha(o2) caused a reduction in the light sensitivity. This reduced sensitivity was not attributable to the reduction in the total number of G(o) alpha subunits, or the altered balance of expression levels between the two splice variants. These results indicate that G alpha(o1) and G alpha(o2) both mediate a depolarizing light response in rod bipolar cells without occluding each other's actions, suggesting they might act independently on a common effector. Thus, G alpha(o2) plays a role in improving the sensitivity of rod bipolar cells through its action with G alpha(o1). The coordinated action of two splice variants of a single G. may represent a novel mechanism for the fine control of G-protein activity. C1 [Okawa, Haruhisa; Sampath, Alapakkam P.] Univ So Calif, Grad Program Neurosci, Los Angeles, CA 90089 USA. [Pahlberg, Johan; Sampath, Alapakkam P.] Univ So Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA. [Sampath, Alapakkam P.] Univ So Calif, Dept Physiol & Biophys, Los Angeles, CA 90089 USA. [Rieke, Fred] Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Rieke, Fred] Univ Washington, Sch Med, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Birnbaumer, Lutz] NIEHS, Res Triangle Pk, NC 27709 USA. RP Sampath, AP (reprint author), Univ So Calif, Grad Program Neurosci, Los Angeles, CA 90089 USA. EM asampath@usc.edu FU National Institutes of Health [EY17606, EY11850, Z01 ES101643]; Karl Kirchgessner Foundation; McKnight Endowment Fund for Neurosciences FX This work was supported by National Institutes of Health grants EY17606 (A.P. Sampath) and EY11850 (F. Rieke), the Intramural Research Program of the National Institutes of Health Z01 ES101643 (L. Birnbaumer), the Karl Kirchgessner Foundation (A.P. Sampath), and the McKnight Endowment Fund for Neurosciences (A.P. Sampath). NR 47 TC 19 Z9 19 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD OCT PY 2010 VL 136 IS 4 BP 443 EP 454 DI 10.1085/jgp.201010477 PG 12 WC Physiology SC Physiology GA 688EB UT WOS:000284831500005 PM 20837674 ER PT J AU Palmquist, AEL Koehly, LM Peterson, SK Shegog, M Vernon, SW Gritz, ER AF Palmquist, Aunchalee E. L. Koehly, Laura M. Peterson, Susan K. Shegog, Margarette Vernon, Sally W. Gritz, Ellen R. TI "The Cancer Bond": Exploring the Formation of Cancer Risk Perception in Families with Lynch Syndrome SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Risk perception; Family communication; Genetic testing; Lynch Syndrome; Genetic counseling ID NONPOLYPOSIS COLORECTAL-CANCER; HEREDITARY COLON-CANCER; GENETIC INFORMATION; COMMUNICATION; PREDISPOSITION; DISCLOSURE; MANAGEMENT; BELIEFS; MEMBERS AB This study explores the social context of hereditary cancer risk perception in three families, an African-American family, a Mexican-American family, and a Caucasian family, each with Lynch Syndrome documented by a mismatch repair gene mutation. Communication network assessments measured family communication about cancer experiences and genetic testing information among a total of 26 participants. Participant narratives were evaluated to gain insight into how family cancer experiences and genetic testing information have shaped perceptions of cancer risk. Analysis of communication networks indicated that some families discussed cancer experiences to a greater extent than genetic testing information, and vice-versa. Interviews elucidated that sharing both types of health information led participants to conceptualize linkages among a strong family history of cancer, genetic testing information, and cancer prevention strategies. Understanding how different types of family communication influence the formation of perceived hereditary disease risk may enhance efforts to tailor genetic counseling services for families. C1 [Palmquist, Aunchalee E. L.] Yale Univ, MacMillan Ctr, New Haven, CT 06520 USA. [Vernon, Sally W.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol & Behav Sci, Houston, TX USA. [Shegog, Margarette] Ohio State Univ, Sch Publ Hlth, Columbus, OH 43210 USA. [Peterson, Susan K.; Gritz, Ellen R.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Palmquist, Aunchalee E. L.; Koehly, Laura M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Palmquist, AEL (reprint author), Yale Univ, MacMillan Ctr, POB 208206, New Haven, CT 06520 USA. EM aunchalee.palmquist@yale.edu FU National Human Genome Research Institute, National Institutes of Health [2R01HG1200-6, Z01HG200335-01] FX This study was supported by the National Human Genome Research Institute, National Institutes of Health (2R01HG1200-6, PI: ERG). This research was also supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (Z01HG200335-01, PI: LMK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHGRI or NIH. This research was conducted as part of the first author's postdoctoral work in the Social and Behavioral Research Branch at the National Human Genome Research Institute. Dr. Palmquist is currently a postdoctoral associate and lecturer at The MacMillan Center, Yale University, New Haven, CT. We thank Sapna Kapoor and Linda Solomon for their assistance with data collection, Mary Fitzgerald and Heather Kitzman for their assistance in developing the interview guide, and ABT Associates for their assistance in transcribing the interviews. We extend our gratitude to our research participants for their generous contribution to this study. Finally, we would like to thank the anonymous reviewers for their invaluable suggestions regarding the revision of this paper. NR 37 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 J9 J GENET COUNS JI J. Genet. Couns. PD OCT PY 2010 VL 19 IS 5 BP 473 EP 486 DI 10.1007/s10897-010-9299-8 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 654RA UT WOS:000282184500005 PM 20401527 ER PT J AU Koppen, H Palm-Meinders, I Verschuren, M Launer, L van Buchem, M Ferrari, M Terwindt, G Kruit, M AF Koppen, H. Palm-Meinders, I. Verschuren, M. Launer, L. van Buchem, M. Ferrari, M. Terwindt, G. Kruit, M. TI Prevalence of diabetes, hypercholesterolemia and clinical stroke in migraine patients after 9 years follow-up: results of the population-based camera-2 study SO JOURNAL OF HEADACHE AND PAIN LA English DT Meeting Abstract C1 [Koppen, H.; Palm-Meinders, I.; van Buchem, M.; Ferrari, M.; Terwindt, G.; Kruit, M.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Koppen, H.] Haga Hosp, The Hague, Netherlands. [Verschuren, M.] RIVM, Ctr Prevent & Hlth Serv Res, Bilthoven, Netherlands. [Launer, L.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RI Kruit, Mark/K-2431-2012 OI Kruit, Mark/0000-0002-4319-834X NR 0 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1129-2369 EI 1129-2377 J9 J HEADACHE PAIN JI J. Headache Pain PD OCT PY 2010 VL 11 SU 1 MA 266 BP S60 EP S60 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V30BQ UT WOS:000208791900167 ER PT J AU Palm-Meinders, IH Koppen, H Moonen, JME Terwindt, GM Launer, LJ van Buchem, MA Ferrari, MD Kruit, MC AF Palm-Meinders, I. H. Koppen, H. Moonen, J. M. E. Terwindt, G. M. Launer, L. J. van Buchem, M. A. Ferrari, M. D. Kruit, M. C. TI Progression of infratentorial hyperintense lesions in migraine: the population-based camera-2 nine year follow-up MRI study SO JOURNAL OF HEADACHE AND PAIN LA English DT Meeting Abstract C1 [Palm-Meinders, I. H.; Koppen, H.; Moonen, J. M. E.; Terwindt, G. M.; van Buchem, M. A.; Ferrari, M. D.; Kruit, M. C.] Leiden Univ Med Ctr, Leiden, Netherlands. [Koppen, H.] Haga Hosp, The Hague, Netherlands. [Launer, L. J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RI Kruit, Mark/K-2431-2012 OI Kruit, Mark/0000-0002-4319-834X NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1129-2369 EI 1129-2377 J9 J HEADACHE PAIN JI J. Headache Pain PD OCT PY 2010 VL 11 SU 1 MA 240 BP S50 EP S50 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V30BQ UT WOS:000208791900142 ER PT J AU Palm-Meinders, IH Koppen, H Terwindt, GM Launer, LJ Konishi, J Bakkers, JTN Hofman, PAM Middelkoop, HAM van Buchem, MA Ferrari, MD Kruit, MC AF Palm-Meinders, I. H. Koppen, H. Terwindt, G. M. Launer, L. J. Konishi, J. Bakkers, J. T. N. Hofman, P. A. M. Middelkoop, H. A. M. van Buchem, M. A. Ferrari, M. D. Kruit, M. C. TI Progression and consequences of brain lesions in migraine: the population-based camera-2 nine year follow-up MRI study SO JOURNAL OF HEADACHE AND PAIN LA English DT Meeting Abstract C1 [Palm-Meinders, I. H.; Koppen, H.; Terwindt, G. M.; Konishi, J.; Middelkoop, H. A. M.; van Buchem, M. A.; Ferrari, M. D.; Kruit, M. C.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Koppen, H.] Haga Hosp, The Hague, Netherlands. [Launer, L. J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Bakkers, J. T. N.] Slingeland Ziekenhuis, Doetinchem, Netherlands. [Hofman, P. A. M.] Univ Limburg, Acad Hosp Maastricht, Maastricht, Netherlands. RI Kruit, Mark/K-2431-2012 OI Kruit, Mark/0000-0002-4319-834X NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1129-2369 EI 1129-2377 J9 J HEADACHE PAIN JI J. Headache Pain PD OCT PY 2010 VL 11 SU 1 MA 205 BP S42 EP S42 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V30BQ UT WOS:000208791900118 ER PT J AU Greten, TF Korangy, F AF Greten, Tim F. Korangy, Firouzeh TI Radiofrequency ablation for the treatment of HCC - Maybe much more than simple tumor destruction? SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material DE Immunotherapy; T cell; NK-cell ID PHOTODYNAMIC THERAPY; CELLS AB Background & Aims: Radiofrequency thermal ablation (RFA) is a minimally invasive technique used as standard local therapy of hepatocellular carcinoma and second-line treatment for metastatic liver tumors. Studies in preclinical models and in patients have shown that thermal destruction of tumor tissue can enhance anti-tumor cellular responses, but our knowledge of its impact on natural killer (NK) cells is still very limited. Methods: Thirty-seven patients undergoing RFA for hepatocellular carcinoma were studied for peripheral blood lymphocytes counts followed by phenotypic and functional characterization of NK-cell population. Results: Peripheral blood lymphocytes kinetics revealed an increased frequency and absolute number of NK-cells expressing higher levels of activatory along with reduced levels of inhibitory NK receptors, and increased functional NK-cell activity. A prevalent expansion of the CD3(-)CD56(dim) NK subset was observed compared to the CD3(-)CD56(bright) counterpart. Interferon-gamma production, anti-K562 cell-cytotoxicity, and antibody-dependent cell-cytotoxicity, appeared consistently increased in terms of both absolute activity and killing efficiency at 4 weeks after RFA, as compared to baseline. Interestingly, when recurrence-free survival was assessed in two groups of patients separated according to higher vs lower enhancement of cytotoxicity and/or interferon-gamma production, a significant difference was observed, thus suggesting a potential predictive role of NK functional assays on efficacy of RFA. Conclusions: RFA can lead to stimulation of NK-cells with a more differentiated and proactivatory phenotypic profile with general increase of functional activities. This observation may be relevant Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Greten, Tim F.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Korangy, Firouzeh] Hannover Med Sch, Dept Gastroenterol Hepatol & Endokrinol, D-3000 Hannover, Germany. RP Greten, TF (reprint author), NCI, Med Oncol Branch, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 7 TC 10 Z9 18 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD OCT PY 2010 VL 53 IS 4 BP 775 EP 776 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 660EM UT WOS:000282622800026 PM 20619917 ER PT J AU Rai, G Ray, S Milton, J Yang, J Ren, P Lempicki, R Mage, RG AF Rai, Geeta Ray, Satyajit Milton, Jacqueline Yang, Jun Ren, Ping Lempicki, Richard Mage, Rose G. TI Gene Expression Profiles in a Rabbit Model of Systemic Lupus Erythematosus Autoantibody Production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID OLIGONUCLEOTIDE ARRAYS; AUTOIMMUNE-DISEASE; CELL DEPLETION; SLE; INTERFERON; ANTIBODIES; PEPTIDE; BLOOD; SEQUENCE; DNA AB We previously reported the establishment of a rabbit (Oryctolagus cuniculus) model in which peptide immunization led to production of lupus-like autoantibodies including anti-Sm, -RNP, -SS-A, -SS-B, and -dsDNA characteristic of those produced in systemic lupus erythematosus (SLE) patients. Some neurologic symptoms in the form of seizures and nystagmus were observed. The animals used in the previous and in the current study were from a National Institute of Allergy and Infectious Diseases colony of rabbits that were pedigreed, Ig-allotype defined, but not inbred. Their genetic heterogeneity may correspond to that found among patients of a given ethnicity. We extended the information about this rabbit model by microarray-based expression profiling. We first demonstrated that human expression arrays could be used with rabbit RNA to yield information on molecular pathways. We then designed a study evaluating gene expression profiles in eight groups of control and treated rabbits (47 rabbits in total). Genes significantly upregulated in treated rabbits were associated with NK cytotoxicity, Ag presentation, leukocyte migration, cytokine activity, protein kinases, RNA spliceosomal ribonucleoproteins, intracellular signaling cascades, and glutamate receptor activity. These results link increased immune activation with upregulation of components associated with neurologic and anti-RNP responses, demonstrating the utility of the rabbit model to uncover biological pathways related to SLE-induced clinical symptoms, including neuropsychiatric lupus. Our finding of distinct gene expression patterns in rabbits that made anti-dsDNA compared with those that only made other anti-nuclear Abs should be further investigated in subsets of SLE patients with different autoantibody profiles. The Journal of Immunology, 2010, 185: 4446-4456. C1 [Rai, Geeta; Ray, Satyajit; Milton, Jacqueline; Mage, Rose G.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Yang, Jun; Ren, Ping; Lempicki, Richard] Natl Canc Inst Frederick, Sci Applicat Int Corp, Lab Bioinformat & Immunopathogenesis, Frederick, MD 21702 USA. RP Mage, RG (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM rmage@niaid.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the intramural research program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) and in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. NR 66 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2010 VL 185 IS 7 BP 4446 EP 4456 DI 10.4049/jimmunol.1001254 PG 11 WC Immunology SC Immunology GA 653BU UT WOS:000282059500073 PM 20817871 ER PT J AU Royal, RE Levy, C Turner, K Mathur, A Hughes, M Kammula, US Sherry, RM Topalian, SL Yang, JC Lowy, I Rosenberg, SA AF Royal, Richard E. Levy, Catherine Turner, Keli Mathur, Aarti Hughes, Marybeth Kammula, Udai S. Sherry, Richard M. Topalian, Suzanne L. Yang, James C. Lowy, Israel Rosenberg, Steven A. TI Phase 2 Trial of Single Agent Ipilimumab (Anti-CTLA-4) for Locally Advanced or Metastatic Pancreatic Adenocarcinoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE pancreatic cancer; immunotherapy; natural killer cells; ipilimumab; CTLA-4; gastrointestinal malignancies ID RANDOMIZED CONTROLLED-TRIAL; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; NATIONAL-CANCER-INSTITUTE; HIGH-DOSE INTERLEUKIN-2; CURATIVE RESECTION; III TRIAL; ADJUVANT CHEMOTHERAPY; PERIAMPULLARY REGION; COOPERATIVE GROUP; PROSTATE-CANCER AB New, effective therapies are needed for pancreatic ductal adenocarcinoma. Ipilimumab can mediate an immunologic tumor regression in other histologies. This phase II trial evaluated the efficacy of Ipilimumab for advanced pancreatic cancer. Subjects were adults with locally advanced or metastatic pancreas adenocarcinoma with measurable disease, good performance status, and minimal comorbidities. Ipilimumab was administered intra-venously (3.0 mg/kg every 3 wk; 4 doses/course) for a maximum of 2 courses. Response rate by response evaluation criteria in solid tumors criteria and toxicity were measured. Twenty-seven subjects were enrolled (metastatic disease: 20 and locally advanced: 7) with median age of 55 years (27 to 68 y) and good performance status (26 with Eastern Cooperative Oncology Group performance status = 0 to 1). Three subjects experienced >= grade 3 immune-mediated adverse events (colitis: 1, encephalitis: 1, hypohysitis: 1). There were no responders by response evaluation criteria in solid tumors criteria but a subject experienced a delayed response after initial progressive disease. In this subject, new metastases after 2 doses of Ipilimumab established progressive disease. But continued administration of the agent per protocol resulted in significant delayed regression of the primary lesion and 20 hepatic metastases. This was reflected in tumor markers normalization, and clinically significant improvement of performance status. Single agent Ipilimumab at 3.0 mg/kg/dose is ineffective for the treatment of advanced pancreas cancer. However, a significant delayed response in one subject of this trial suggests that immunotherapeutic approaches to pancreas cancer deserve further exploration. C1 [Royal, Richard E.; Levy, Catherine; Turner, Keli; Mathur, Aarti; Hughes, Marybeth; Kammula, Udai S.; Sherry, Richard M.; Topalian, Suzanne L.; Yang, James C.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Turner, Keli] NCI, Clin Res Training Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lowy, Israel] Medarex Inc, Princeton, NJ USA. RP Royal, RE (reprint author), 1515 Holcombe Blvd,Unit 444, Houston, TX 77098 USA. EM rroyal@mdanderson.org FU National Cancer Institute, National Institutes of Health FX Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 46 TC 184 Z9 187 U1 5 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 828 EP 833 DI 10.1097/CJI.0b013e3181eec14c PG 6 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800009 PM 20842054 ER PT J AU Goff, SL Smith, FO Klapper, JA Sherry, R Wunderlich, JR Steinberg, SM White, D Rosenberg, SA Dudley, ME Yang, JC AF Goff, Stephanie L. Smith, Franz O. Klapper, Jacob A. Sherry, Richard Wunderlich, John R. Steinberg, Seth M. White, Donald Rosenberg, Steven A. Dudley, Mark E. Yang, James C. TI Tumor Infiltrating Lymphocyte Therapy for Metastatic Melanoma: Analysis of Tumors Resected for TIL SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE metastatic melanoma; tumor-infiltrating lymphocytes; adoptive cell transfer ID ADOPTIVE CELL THERAPY; TCR; INTERLEUKIN-2 AB Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 49% to 72% of patients with many long-term durable responses. To undergo treatment a patient must have (1) a resectable tumor from which (2) TIL can be generated that (3) exhibit tumor-specific reactivity. From July 2002 to July 2007, 787 tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 patients (27%). Viable TILs were generated in 376 patients (94%), and active, specific TILs were identified in 269 patients (67%). Patient demographics and tumor characteristics were analyzed for possible prognostic factors for growth and activity. Gastrointestinal-derived TIL grew less frequently, whereas lymph node and lung-derived TIL exhibited specific activity more often. TIL that grew and exhibited specific reactivity were from tumors that were larger in diameter and digests that had a higher percentage of lymphocytes. Despite these considerations, active, specific TIL could be generated from almost any site of metastasis. As more centers begin exploring the use of adoptive transfer with TIL, this compendium may provide a framework for therapeutic decision making and future investigation. C1 [Goff, Stephanie L.; Smith, Franz O.; Klapper, Jacob A.; Sherry, Richard; Wunderlich, John R.; White, Donald; Rosenberg, Steven A.; Dudley, Mark E.; Yang, James C.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Goff, SL (reprint author), NCI, Surg Branch, NIH, CRC 3W-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM slgoffmd@gmail.com FU NIH Intramural Research FX Funded by NIH Intramural Research. NR 15 TC 43 Z9 46 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 840 EP 847 DI 10.1097/CJI.0b013e3181f05b91 PG 8 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800011 PM 20842052 ER PT J AU Abate-Daga, D Park, TS Palmer, DC Restifo, NP Rosenberg, SA Morgan, RA AF Abate-Daga, Daniel Park, Tristen S. Palmer, Douglas C. Restifo, Nicholas P. Rosenberg, Steven A. Morgan, Richard A. TI Development of a gamma-Retroviral Vector for the Expression of Artificial miRNAs in Human T Lymphocytes SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [Abate-Daga, Daniel; Park, Tristen S.; Palmer, Douglas C.; Restifo, Nicholas P.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 859 EP 859 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800014 ER PT J AU Bedognetti, D Uccellini, L Wang, E Dudley, ME Pos, Z Ascierto, ML De Giorgi, V Liu, H Chen, J Sertoli, MR Marincola, FM Rosenberg, SA AF Bedognetti, Davide Uccellini, Lorenzo Wang, Ena Dudley, Mark E. Pos, Zoltan Ascierto, Maria Libera De Giorgi, Valeria Liu, Hui Chen, Jingou Sertoli, Mario Roberto Marincola, Francesco M. Rosenberg, Steven A. TI Evaluation of CXCR3 and CCR5 Polymorphisms and Gene-Expression as Predictive Biomarkers of Clinical Response to Adoptive Therapy in Melanoma Patients SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [Bedognetti, Davide; Uccellini, Lorenzo; Wang, Ena; Pos, Zoltan; Ascierto, Maria Libera; De Giorgi, Valeria; Liu, Hui; Chen, Jingou; Marincola, Francesco M.] NIH, Dept Transfus Med, CC, Bethesda, MD USA. [Dudley, Mark E.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Bedognetti, Davide; Sertoli, Mario Roberto] Univ Genoa, Dept Oncol Biol Genet, Genoa, Italy. RI Bedognetti, Davide/A-9090-2012; Ascierto, Maria Libera/A-9239-2012 NR 0 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 860 EP 860 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800016 ER PT J AU Kerkar, SP Reger, R Muranski, P Yu, ZY Palmer, D Chinnasamy, D Klebanoff, CA Ji, Y Gattinoni, L Rosenberg, SA Trinchieri, G Restifo, NP AF Kerkar, Sid P. Reger, Robert Muranski, Pawel Yu, Zhiya Palmer, Douglas Chinnasamy, Dhanalakshmi Klebanoff, Christopher A. Ji, Yun Gattinoni, Luca Rosenberg, Steven A. Trinchieri, Giorgio Restifo, Nicholas P. TI Functional Reprogramming of the Tumor Stroma by IL-12 Engineered T Cells is Required for Anti-tumor Immunity SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [Kerkar, Sid P.; Reger, Robert; Muranski, Pawel; Yu, Zhiya; Palmer, Douglas; Chinnasamy, Dhanalakshmi; Klebanoff, Christopher A.; Ji, Yun; Gattinoni, Luca; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 861 EP 861 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800020 ER PT J AU Muranski, PJ Borman, Z Kerkar, S Ji, Y Gattinoni, L Reger, R Klebanoff, C Yu, ZY Ferreyra, G Kern, S Danner, RL Restifo, NP AF Muranski, Pawel J. Borman, Zachary Kerkar, Sid Ji, Yun Gattinoni, Luca Reger, Robert Klebanoff, Christopher Yu, Zhiya Ferreyra, Gabriela Kern, Steven Danner, Robert L. Restifo, Nicholas P. TI Adoptively Transferred Anti-Tumor Th17 Cells are Long-Lived and Evolve Into a Highly Active Memory Population with a Unique Molecular Signature SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [Muranski, Pawel J.; Borman, Zachary; Kerkar, Sid; Ji, Yun; Gattinoni, Luca; Reger, Robert; Klebanoff, Christopher; Yu, Zhiya; Restifo, Nicholas P.] NCI, Bethesda, MD 20892 USA. [Ferreyra, Gabriela; Kern, Steven; Danner, Robert L.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 862 EP 863 PG 2 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800024 ER PT J AU Park, TS Inozume, T Ahmadzadeh, M Hanada, KI Yang, J Rosenberg, SA Morgan, RA AF Park, Tristen S. Inozume, Takashi Ahmadzadeh, Mojgan Hanada, Ken-ichi Yang, James Rosenberg, Steven A. Morgan, Richard A. TI Artifical MicroRNA Targeting Programmed Death Receptor-1 to Enhance Adoptive Cell Transfer Therapy for Cancer SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [Park, Tristen S.; Inozume, Takashi; Ahmadzadeh, Mojgan; Hanada, Ken-ichi; Yang, James; Rosenberg, Steven A.; Morgan, Richard A.] NIH, Surg Branch, Bethesda, MD 20892 USA. RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 863 EP 863 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800025 ER PT J AU Ascierto, ML Kmieciak, M Idowu, M Grimes, M Dumur, C Wang, E Marincola, FM Bear, HD Manjili, MH AF Ascierto, Maria-Libera Kmieciak, Maciej Idowu, Michael Grimes, Margaret Dumur, Catherine Wang, Ena Marincola, Francesco M. Bear, Harry D. Manjili, Masoud H. TI Signatures of Immune Function Genes Associated with Recurrence-Free Survival in Breast Cancer Patients SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [Ascierto, Maria-Libera; Wang, Ena; Marincola, Francesco M.] NIH, Bethesda, MD 20892 USA. [Kmieciak, Maciej; Idowu, Michael; Grimes, Margaret; Dumur, Catherine; Bear, Harry D.; Manjili, Masoud H.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. RI Ascierto, Maria Libera/A-9239-2012 NR 0 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 881 EP 881 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800081 ER PT J AU De Giorgi, V Ascierto, ML Pos, Z Buonaguro, L Buonaguro, FM Wang, E Marincola, FM AF De Giorgi, Valeria Ascierto, Maria Libera Pos, Zoltan Buonaguro, Luigi Buonaguro, Franco M. Wang, Ena Marincola, Francesco M. TI Melanoma and IRFs: A New Classification of Melanoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [De Giorgi, Valeria; Ascierto, Maria Libera; Pos, Zoltan; Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Buonaguro, Luigi; Buonaguro, Franco M.] Fdn G Pascale, Lab Mol Biol & Viral Oncogenesis, Naples, Italy. [Buonaguro, Luigi; Buonaguro, Franco M.] Fdn G Pascale, AIDS Reference Ctr, Ist Nazl Tumori, Naples, Italy. RI Ascierto, Maria Libera/A-9239-2012; De Giorgi, Valeria/D-4582-2017 NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 885 EP 886 PG 2 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800095 ER PT J AU Ascierto, ML Worschech, A Castiello, L Wang, R Pos, Z Uccellini, L Bedognetti, D De Giorgi, V Thomas, J Yu, ZY Balachandran, S Rossano, F Restifo, N Szalay, A Ascierto, P Wang, E Marincola, FM AF Ascierto, Maria L. Worschech, Andrea Castiello, Luciano Wang, Richard Pos, Zoltan Uccellini, Lorenzo Bedognetti, Davide De Giorgi, Valeria Thomas, Jaime Yu, Zhiya Balachandran, Siddharth Rossano, Fabio Restifo, Nicholas Szalay, A. Ascierto, Paolo Wang, Ena Marincola, Francesco M. TI IKK Complex and NF-kappa B: Linkage Between Innate Immune Response and Oncolytic Based Viral Therapy SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract C1 [Ascierto, Maria L.; Castiello, Luciano; Wang, Richard; Pos, Zoltan; Uccellini, Lorenzo; Bedognetti, Davide; De Giorgi, Valeria; Thomas, Jaime; Wang, Ena; Marincola, Francesco M.] Natl Inst Hlth, Dept Transfus Med, Bethesda, MD USA. [Yu, Zhiya; Restifo, Nicholas] Natl Canc Inst, Bethesda, MD USA. [Worschech, Andrea; Szalay, A.] Genelux Corp, San Diego, CA USA. [Balachandran, Siddharth] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Rossano, Fabio; Ascierto, Paolo] Dept Gen Pathol, Naples, Italy. RI Restifo, Nicholas/A-5713-2008; Bedognetti, Davide/A-9090-2012; Ascierto, Maria Libera/A-9239-2012; Worschech, Andrea/I-3919-2012; De Giorgi, Valeria/D-4582-2017 OI Worschech, Andrea/0000-0002-4303-8653; NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2010 VL 33 IS 8 BP 891 EP 892 PG 2 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 653XQ UT WOS:000282131800114 ER PT J AU Gore, A Muralidhar, M Espey, MG Degenhardt, K Mantell, LL AF Gore, Ashwini Muralidhar, Maitreyi Espey, Michael Graham Degenhardt, Kurt Mantell, Lin L. TI Hyperoxia sensing: From molecular mechanisms to significance in disease SO JOURNAL OF IMMUNOTOXICOLOGY LA English DT Review DE Hyperoxia; inflammation; sensing; apoptosis; cell death; signaling; acute lung injury; ROS ID NF-KAPPA-B; ACUTE LUNG INJURY; GLYCATION END-PRODUCTS; TUMOR-NECROSIS-FACTOR; PULMONARY OXYGEN-TOXICITY; ACTIVATED PROTEIN-KINASE; RESPIRATORY-DISTRESS-SYNDROME; SIGNAL-TRANSDUCTION PATHWAYS; VASCULAR ENDOTHELIAL-CELLS; TRANSCRIPTION FACTOR NRF2 AB Oxygen therapy using mechanical ventilation with hyperoxia is necessary to treat patients with respiratory failure and distress. However, prolonged exposure to hyperoxia leads to the generation of excessive reactive oxygen species (ROS), causing cellular damage and multiple organ dysfunctions. As the lungs are directly exposed, hyperoxia can cause both acute and chronic inflammatory lung injury and compromise innate immunity. ROS may contribute to pulmonary oxygen toxicity by overwhelming redox homeostasis, altering signaling cascades that affect cell fate, ultimately leading to hyperoxia-induced acute lung injury (HALI). HALI is characterized by pronounced inflammatory responses with leukocyte infiltration, injury, and death of pulmonary cells, including epithelia, endothelia, and macrophages. Under hyperoxic conditions, ROS mediate both direct and indirect modulation of signaling molecules such as protein kinases, transcription factors, receptors, and pro-and anti-apoptotic factors. The focus of this review is to elaborate on hyperoxia-activated key sensing molecules and current understanding of their signaling mechanisms in HALI. A better understanding of the signaling pathways leading to HALI may provide valuable insights on its pathogenesis and may help in designing more effective therapeutic approaches. C1 [Gore, Ashwini; Muralidhar, Maitreyi; Degenhardt, Kurt; Mantell, Lin L.] St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Allied Hlth Profess, Queens, NY 11439 USA. [Espey, Michael Graham] NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD USA. [Mantell, Lin L.] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Ctr Lung & Heart Res, Manhasset, NY USA. [Mantell, Lin L.] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Ctr Inflammat & Immunol, Manhasset, NY USA. RP Mantell, LL (reprint author), St Johns Univ, Dept Pharmaceut Sci, Coll Pharm, 128-SB28 St Albert Hall,8000 Utopia Pkwy, Queens, NY 11439 USA. EM mantelll@stjohns.edu FU National Heart and Blood Institute [HL093708]; St. John's University; Feinstein Institute for Medical Research at the North Shore-Long Island Jewish Health System FX This work was supported by grants from the National Heart and Blood Institute (HL093708, LLM), St. John's University and the Feinstein Institute for Medical Research at the North Shore-Long Island Jewish Health System. The authors are alone responsible for the content and writing of the paper. NR 192 TC 43 Z9 56 U1 1 U2 9 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1547-691X J9 J IMMUNOTOXICOL JI J. Immunotoxicol. PD OCT-DEC PY 2010 VL 7 IS 4 BP 239 EP 254 DI 10.3109/1547691X.2010.492254 PG 16 WC Toxicology SC Toxicology GA 681LJ UT WOS:000284316600001 PM 20586583 ER PT J AU Guo, TL Germolec, DR Roesh, DM White, KL AF Guo, Tai L. Germolec, Dori R. Roesh, Denise M. White, Kimber L., Jr. TI Immunomodulation in female B6C3F1 mice following treatment with the HIV protease inhibitor saquinavir for 28 days by gavage SO JOURNAL OF IMMUNOTOXICOLOGY LA English DT Article DE Saquinavir; immunomodulation; antibody-forming cell response ID ANTIRETROVIRAL THERAPY; IN-VITRO; IMMUNE FUNCTION; TUMOR-CELLS; RITONAVIR; INFECTION; VIVO; COMBINATION; LYMPHOCYTES; FORMULATION AB Saquinavir (SQV) is a protease inhibitor that binds to the protease active site of the human immunodeficiency virus and prevents the cleavage of viral polyproteins resulting in the formation of non-infectious virus particles. The purpose of these studies was to determine the potential effects of SQV on the immune system in female B6C3F1 mice. SQV was administered by gavage twice daily for 28 days at total doses of 300, 600, and 1200 mg/kg/day. No significant differences were observed in body weight, or the weights of spleen, thymus, liver, kidneys, or lungs. Exposure to SQV produced no biologically meaningful changes in hematological parameters. However, a statistically significant increase in the number of T-cells (23%) was observed at the high dose level of SQV. The number of splenic immature T-cells (CD4(+)CD8(+) cells) also showed increases of 46% and 92% at the 600 and 1200 mg/kg dose levels, respectively. The immunoglobulin M antibody-forming cell (AFC) response was significantly increased by 41% when the data were expressed as AFC/10(6) spleen cells at the 1200 mg/kg dose level. Treatment with SQV had no effects on the mixed leukocyte response. Overall, the activities of natural killer cells and cytotoxic T-cells were not altered in SQV-treated animals when compared to vehicle controls. In addition, exposure to SQV did not affect host resistance in the B16F10 melanoma model. In conclusion, SQV produced an enhancement of the humoral immune response, possibly through modulating T-cell function in female B6C3F1 mice. C1 [Guo, Tai L.; Roesh, Denise M.; White, Kimber L., Jr.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Germolec, Dori R.] NIEHS, Res Triangle Pk, NC 27709 USA. RP White, KL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, POB 980613, Richmond, VA 23298 USA. EM klwhite@vcu.edu FU NIEHS [NO1-ES-05454] FX This study was supported by the NIEHS contract NO1-ES-05454. Dr. Kimber L. White, Jr. is the owner of a company, ImmunoTox (R), Inc., that conducts immunotoxicological studies under Good Laboratory Practices (GLP); however, none of the work presented here involved his company. NR 40 TC 1 Z9 1 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1547-691X J9 J IMMUNOTOXICOL JI J. Immunotoxicol. PD OCT-DEC PY 2010 VL 7 IS 4 BP 289 EP 297 DI 10.3109/1547691X.2010.495097 PG 9 WC Toxicology SC Toxicology GA 681LJ UT WOS:000284316600005 PM 20560775 ER PT J AU Smith, MJ Germolec, DR Luebke, RW Sheth, CM Auttachoat, W Guo, TL White, KL AF Smith, Matthew J. Germolec, Dori R. Luebke, Robert W. Sheth, Christopher M. Auttachoat, Wimolnut Guo, Tai L. White, Kimber L., Jr. TI Immunotoxicity of dibromoacetic acid administered via drinking water to female B6C3F1 mice SO JOURNAL OF IMMUNOTOXICOLOGY LA English DT Article DE Dibromoacetic acid; immunotoxicity; drinking water; disinfection by-products; haloacetic acids ID DISINFECTION BY-PRODUCTS; HOST-RESISTANCE; IMMUNE-RESPONSE; EXPOSURE; RATS; MODULATION; TOXICITY; CARCINOGENICITY; GENOTOXICITY; ANTIBODY AB Dibromoacetic acid (DBA) is a disinfection by-product commonly found in drinking water as a result of chlorination/ozonation processes. The Environmental Protection Agency estimates that more than 200 million people consume disinfected water in the United States. This study was conducted to evaluate the potential immunotoxicological effects of DBA exposure when administered for 28 days via drinking water to B6C3F1 mice, at concentrations of 125, 500, and 1000 mg/L. Multiple endpoints were evaluated to assess innate, humoral, and cell-mediated immune components, as well as host resistance. Standard toxicological parameters were unaffected, with the exception of a dose-responsive increase in liver weight and a decrease in thymus weight at the two highest exposure levels. Splenocyte differentials were affected, although the effects were not dose-responsive. Exposure to DBA did not significantly affect humoral immunity (immunoglobulin M [IgM] plaque assay and serum IgM anti-sheep erythrocyte titers) or cell-mediated immunity (mixed-leukocyte response). No effects were observed on innate immune function in either interferon-gamma-induced in vitro macrophage cytotoxic activity or basal natural killer (NK)-cell activity. Augmented NK-cell activity (following exposure to polyinosinic-polycytidylic acid) was decreased at the low dose, however the effect was not dose-responsive. Finally, DBA exposure had no effect on resistance to infection with either Streptococcus pneumoniae or Plasmodium yoelii, or challenge with B16F10 melanoma cells. With the exception of changes in thymus weight, these results indicate that DBA exposure resulted in no immunotoxic effects at concentrations much larger than those considered acceptable in human drinking water. C1 [Smith, Matthew J.; Sheth, Christopher M.; Auttachoat, Wimolnut; Guo, Tai L.; White, Kimber L., Jr.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Germolec, Dori R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Luebke, Robert W.] US EPA, Immunotoxicol Branch, Expt Toxicol Div, NHEERL, Res Triangle Pk, NC USA. RP White, KL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Med Coll Virginia Campus,Strauss Bldg,Room 2-011,, Richmond, VA 23298 USA. EM kwhite@vcu.edu FU NIEHS [ES 05454]; U.S. Environmental Protection Agency [DW75937992] FX This article may, in part, be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. This report has been reviewed by the U. S. Environmental Protection Agency's Office of Research and Development, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. This work was supported in part by NIEHS Contract ES 05454 and by the U.S. Environmental Protection Agency under interagency agreement DW75937992. NR 25 TC 3 Z9 3 U1 1 U2 8 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1547-691X J9 J IMMUNOTOXICOL JI J. Immunotoxicol. PD OCT-DEC PY 2010 VL 7 IS 4 BP 333 EP 343 DI 10.3109/1547691X.2010.519744 PG 11 WC Toxicology SC Toxicology GA 681LJ UT WOS:000284316600010 PM 20958156 ER PT J AU Kennedy, AD Wardenburg, JB Gardner, DJ Long, D Whitney, AR Braughton, KR Schneewind, O DeLeo, FR AF Kennedy, Adam D. Wardenburg, Juliane Bubeck Gardner, Donald J. Long, Daniel Whitney, Adeline R. Braughton, Kevin R. Schneewind, Olaf DeLeo, Frank R. TI Targeting of Alpha-Hemolysin by Active or Passive Immunization Decreases Severity of USA300 Skin Infection in a Mouse Model SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; PANTON-VALENTINE LEUKOCIDIN; SITE-DIRECTED MUTAGENESIS; MURINE MODEL; IN-VITRO; VIRULENCE DETERMINANT; HUMAN KERATINOCYTES; TOXIN GENE; PNEUMONIA; PATHOGENESIS AB Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are predominantly those affecting skin and soft tissues. Although progress has been made, our knowledge of the molecules that contribute to the pathogenesis of CA-MRSA skin infections is incomplete. We tested the hypothesis that alpha-hemolysin (Hla) contributes to the severity of USA300 skin infections in mice and determined whether vaccination against Hla reduces disease severity. Isogenic hla-negative (Delta hla) strains caused skin lesions in a mouse infection model that were significantly smaller than those caused by wild-type USA300 and Newman strains. Moreover, infection due to wild-type strains produced dermonecrotic skin lesions, whereas there was little or no dermonecrosis in mice infected with Delta hla strains. Passive immunization with Hla-specific antisera or active immunization with a nontoxigenic form of Hla significantly reduced the size of skin lesions caused by USA300 and prevented dermonecrosis. We conclude that Hla is a potential target for therapeutics or vaccines designed to moderate severe S. aureus skin infections. C1 [Kennedy, Adam D.; Whitney, Adeline R.; Braughton, Kevin R.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Gardner, Donald J.; Long, Daniel] NIAID, Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Wardenburg, Juliane Bubeck; Schneewind, Olaf] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health (NIH); Region V "Great Lakes" Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium (NIH) [1-U54-AI-057153] FX Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and Region V "Great Lakes" Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium (NIH Award 1-U54-AI-057153 to J.B.W. and O.S.). NR 38 TC 166 Z9 170 U1 2 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2010 VL 202 IS 7 BP 1050 EP 1058 DI 10.1086/656043 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 651FR UT WOS:000281912100009 PM 20726702 ER PT J AU Marshall, V Martro, E Labo, N Ray, A Wang, DA Mbisa, G Bagni, RK Volfovsky, N Casabona, J Whitby, D AF Marshall, Vickie Martro, Elisa Labo, Nazzarena Ray, Alex Wang, Dian Mbisa, Georginia Bagni, Rachel K. Volfovsky, Natalia Casabona, Jordi Whitby, Denise CA EURO-SHAKS Study Grp TI Kaposi Sarcoma (KS)-Associated Herpesvirus MicroRNA Sequence Analysis and KS Risk in a European AIDS-KS Case Control Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; SINGLE NUCLEOTIDE POLYMORPHISM; HUMAN-HERPESVIRUS-8 INFECTION; ENCODED MICRORNAS; UNITED-STATES; CANCER-RISK; IDENTIFICATION; RESPONSES; CELLS; IMMUNODEFICIENCY AB Background. We recently identified polymorphisms in Kaposi sarcoma-associated herpesvirus (KSHV)-encoded microRNA (miRNA) sequences from clinical subjects. Here, we examine whether any of these may contribute to KS risk in a European AIDS-KS case-control study. Methods. KSHV load in peripheral blood was determined by real-time quantitative polymerase chain reaction. Samples that had detectable viral loads were used to amplify the 2.8-kb miRNA encoding region plus a 646-bp fragment of the K12/T0.7 gene. Additionally, we characterized an 840-bp fragment of the K1 gene to determine KSHV subtypes. Results. KSHV DNA was detected in peripheral blood mononuclear cells of 49.6% of case patients and 6.8% of controls, and viral loads tended to be higher in case patients. Sequences from the miRNA-encoding regions were conserved overall, but distinct polymorphisms were detected, some of which occurred in primary miRNAs, pre-miRNAs, or mature miRNAs. Conclusions. Patients with KS were more likely to have detectable viral loads than were controls without disease. Despite high conservation in KSHV miRNA-encoded sequences, polymorphisms were observed, including some that have been reported elsewhere. Some polymorphisms could affect mature miRNA processing and appear to be associated with KS risk. C1 [Marshall, Vickie; Labo, Nazzarena; Ray, Alex; Wang, Dian; Mbisa, Georginia; Whitby, Denise] NCI, Viral Oncol Sect, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21702 USA. [Bagni, Rachel K.] NCI, Mol Detect Grp, Prot Express Lab, Adv Technol Program,SAIC Frederick, Frederick, MD 21702 USA. [Volfovsky, Natalia] NCI, Adv Biomed Comp Ctr, Informat Syst Program, SAIC Frederick, Frederick, MD 21702 USA. [Martro, Elisa] Hosp Badalona Germans Trias & Pujol, Microbiol Serv, Badalona, Spain. [Casabona, Jordi] Hosp Badalona Germans Trias & Pujol, Dept Salut, Ctr Estudis Epidemiol HIV SIDS Catalunya, Badalona, Spain. [Martro, Elisa] CIBER Epidemiol & Salud Publ, Madrid, Spain. RP Whitby, D (reprint author), NCI, Viral Oncol Sect, AIDS & Canc Virus Program, SAIC Frederick, POB B, Frederick, MD 21702 USA. EM whitbyd@mail.nih.gov RI Labo, Nazzarena/H-8655-2012; Gaya, Antonio/G-1726-2010; Martro, Elisa/K-9688-2015; OI Labo, Nazzarena/0000-0001-5953-4064; Gaya, Antonio/0000-0002-2200-5801; Martro, Elisa/0000-0002-2867-6649; Ocana, Inma/0000-0003-3699-0790; Casabona-Barbara, Jordi/0000-0003-4816-5536 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; DG XII of the European Commission (EURO-SHAKS) FX National Cancer Institute, National Institutes of Health (contract no. HHSN261200800001E), and DG XII of the European Commission (EURO-SHAKS). NR 29 TC 14 Z9 14 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2010 VL 202 IS 7 BP 1126 EP 1135 DI 10.1086/656045 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 651FR UT WOS:000281912100017 PM 20715927 ER PT J AU Kaler, SG Liew, CJ Donsante, A Hicks, JD Sato, S Greenfield, JC AF Kaler, Stephen G. Liew, Clarissa J. Donsante, Anthony Hicks, Julia D. Sato, Susumu Greenfield, Jacquelyn C. TI Molecular correlates of epilepsy in early diagnosed and treated Menkes disease SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID EARLY COPPER THERAPY; HIPPOCAMPAL-NEURONS; HORN SYNDROME; MUTATION; PLASMA AB Epilepsy is a major feature of Menkes disease, an X-linked recessive infantile neurodegenerative disorder caused by mutations in ATP7A, which produces a copper-transporting ATPase. Three prior surveys indicated clinical seizures and electroencephalographic (EEG) abnormalities in a combined 27 of 29 (93%) symptomatic Menkes disease patients diagnosed at 2 months of age or older. To assess the influence of earlier, presymptomatic diagnosis and treatment on seizure semiology and brain electrical activity, we evaluated 71 EEGs in 24 Menkes disease patients who were diagnosed and treated with copper injections in early infancy (a parts per thousand currency sign6 weeks of age), and whose ATP7A mutations we determined. Clinical seizures were observed in only 12.5% (3/24) of these patients, although 46% (11/24) had at least one abnormal EEG tracing, including 50% of patients with large deletions in ATP7A, 50% of those with small deletions, 60% of those with nonsense mutations, and 57% of those with canonical splice junction mutations. In contrast, five patients with mutations shown to retain partial function, either via some correct RNA splicing or residual copper transport capacity, had neither clinical seizures nor EEG abnormalities. Our findings suggest that early diagnosis and treatment improve brain electrical activity and decrease seizure occurrence in classical Menkes disease irrespective of the precise molecular defect. Subjects with ATP7A mutations that retain some function seem particularly well protected by early intervention against the possibility of epilepsy. C1 [Kaler, Stephen G.; Donsante, Anthony; Hicks, Julia D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bethesda, MD 20892 USA. [Liew, Clarissa J.; Sato, Susumu; Greenfield, Jacquelyn C.] NINDS, EEG Sect, NIH, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bldg 10,Room 10N-313,10 Ctr Dr,MSC 1853, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU NIH FX This study was supported by the NIH intramural research program. We thank the participating subjects and their parents, and gratefully acknowledge Maryellen Rechen and the nursing staffs of the Pediatric Inpatient, Day Hospital, and Outpatient units at the NIH Clinical Center for their expert patient care. NR 25 TC 25 Z9 27 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD OCT PY 2010 VL 33 IS 5 BP 583 EP 589 DI 10.1007/s10545-010-9118-2 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 655SP UT WOS:000282270100016 PM 20652413 ER PT J AU Quevedo-Diaz, MA Song, C Xiong, YB Chen, HY Wahl, LM Radulovic, S Medvedev, AE AF Quevedo-Diaz, Marco A. Song, Chang Xiong, Yanbao Chen, Haiyan Wahl, Larry M. Radulovic, Suzana Medvedev, Andrei E. TI Involvement of TLR2 and TLR4 in cell responses to Rickettsia akari SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE innate immunity; Toll-like receptors; signal transduction; cell activation; monocytes/ macrophages ID TOLL-LIKE RECEPTOR; NF-KAPPA-B; RESPIRATORY SYNCYTIAL VIRUS; PATTERN-RECOGNITION RECEPTOR; ENDOTOXIN TOLERANCE; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; CUTTING EDGE; ALVEOLAR MACROPHAGES; ENDOTHELIAL-CELLS AB A better understanding of the pathogenesis of rickettsial disease requires elucidation of mechanisms governing host defense during infection. TLRs are primary sensors of microbial pathogens that activate innate immune cells, as well as initiate and orchestrate adaptive immune responses. However, the role of TLRs in rickettsia recognition and cell activation remains poorly understood. In this study, we examined the involvement of TLR2 and TLR4 in recognition of Rickettsia akari, a causative agent of rickettsialpox. Transfection-based complementation of TLR2/4-negative HEK293T cells with human TLR2 or TLR4 coexpressed with CD14 and MD-2 enabled I kappa B-alpha degradation, NF-kappa B reporter activation, and IL-8 expression in response to heat-killed (HK) R. akari. The presence of the R753Q TLR2 or D299G TLR4 polymorphisms significantly impaired the capacities of the respective TLRs to signal HK R. akari-mediated NF-kappa B reporter activation in HEK293T transfectants. Blocking Ab against TLR2 or TLR4 markedly inhibited TNF-alpha release from human monocytes stimulated with HK R. akari, and TNF-alpha secretion elicited by infection with live R. akari was reduced significantly only upon blocking of TLR2 and TLR4. Live and HK R. akari exerted phosphorylation of IRAK1 and p38 MAPK in 293/TLR4/MD-2 or 293/TLR2 stable cell lines, whereas only live bacteria elicited responses in TLR2/4-negative HEK293T cells. These data demonstrate that HK R. akari triggers cell activation via TLR2 or TLR4 and suggest use of additional TLRs and/or NLRs by live R. akari. J. Leukoc. Biol. 88: 675-685; 2010. C1 [Quevedo-Diaz, Marco A.; Song, Chang; Xiong, Yanbao; Chen, Haiyan; Radulovic, Suzana; Medvedev, Andrei E.] Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. [Wahl, Larry M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Medvedev, AE (reprint author), Univ Maryland, Dept Microbiol & Immunol, Sch Med, 685 W Baltimore St,HSF I Bldg,Rm 380, Baltimore, MD 21201 USA. EM amedvedev@som.umaryland.edu FU NIH [R21 AI067468]; University of Maryland, Baltimore (UMB)-University of Maryland College Park (UMCP) Intramural NIH FX This work was supported by NIH grant R21 AI067468 and University of Maryland, Baltimore (UMB)-University of Maryland College Park (UMCP) Intramural NIH seed grant (to A. E. M.). We are thankful to Dr. Douglas T. Golenbock and Katherine Fitzgerald (University of Massachusetts School of Medicine) for providing us with expression vectors and cell lines. NR 73 TC 13 Z9 13 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2010 VL 88 IS 4 BP 675 EP 685 DI 10.1189/jlb.1009674 PG 11 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 692ZW UT WOS:000285195400009 PM 20616112 ER PT J AU Rodriguez, IR Larrayoz, IM AF Rodriguez, Ignacio R. Larrayoz, Ignacio M. TI Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration SO JOURNAL OF LIPID RESEARCH LA English DT Review DE 7-ketocholesterol; cytokines; oxysterols ID LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; OXYSTEROL-BINDING-PROTEIN; ENDOTHELIAL GROWTH-FACTOR; PIGMENT EPITHELIAL-CELLS; LIVER-X-RECEPTORS; HUMAN ATHEROSCLEROTIC LESIONS; SINGLET OXYGEN INTERMEDIACY; OXIDIZED LDL; STEROL 27-HYDROXYLASE AB This review will discuss the formation and potential implications of 7-ketocholesterol (7KCh) in the retina. 7KCh is a proinflammatory oxysterol known to be present in high amounts in oxidized LDL deposits associated with atheromatous plaques. 7KCh is generated in situ in these lipoprotein deposits where it can accumulate and reach very high concentrations. In normal primate retina, 7KCh has been found associated with lipoprotein deposits in the choriocapillaris, Bruch's membrane, and the retinal pigment epithelium (RPE). In photodamaged rats, 7KCh has been found in the neural retina in areas of high mitochondrial content, ganglion cells, photoreceptor inner segments and synapses, and the RPE. Intermediates found by LCMS indicate 7KCh is formed via a free radical-mediated mechanism catalyzed by iron. 7KCh seems to activate several kinase signaling pathways that work via nuclear factor kappa B and cause the induction of vascular endothelial growth factor, interleukin (IL)-6, and IL-8. There seems to be little evidence of 7KCh metabolism in the retina, although some form of efflux mechanism may be active. The chronic mode of formation and the potent inflammatory properties of 7KCh indicate it may be an "age-related" risk factor in aging diseases such as atherosclerosis, Alzheimer's, and age-related macular degeneration.-Rodriguez, I. R., and I. M. Larrayoz. Cholesterol oxidation in the retina: implications of 7-KCh formation in chronic inflammation and age-related macular degeneration. J. Lipid Res. 2010. 51:2847-2862. C1 [Rodriguez, Ignacio R.; Larrayoz, Ignacio M.] NEI, Mech Retinal Dis Sect, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, Mech Retinal Dis Sect, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov RI Larrayoz, Ignacio/I-5613-2012 OI Larrayoz, Ignacio/0000-0003-1629-152X NR 147 TC 56 Z9 56 U1 2 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2010 VL 51 IS 10 BP 2847 EP 2862 DI 10.1194/jlr.R004820 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 649GS UT WOS:000281756800001 PM 20567027 ER PT J AU Gao, F Kiesewetter, D Chang, L Rapoport, SI Igarashi, M AF Gao, Fei Kiesewetter, Dale Chang, Lisa Rapoport, Stanley I. Igarashi, Miki TI Quantifying conversion of linoleic to arachidonic and other n-6 polyunsaturated fatty acids in unanesthetized rats SO JOURNAL OF LIPID RESEARCH LA English DT Article DE liver; diet; modeling; kinetics ID LOW-DENSITY LIPOPROTEIN; DOCOSAHEXAENOIC ACID; BRAIN PHOSPHOLIPIDS; GENE-TRANSCRIPTION; HALF-LIVES; ADULT RATS; METABOLISM; ALPHA; DIET; BIOSYNTHESIS AB Isotope feeding studies report a wide range of conversion fractions of dietary shorter-chain polyunsaturated fatty acids (PUFAs) to long-chain PUFAs, which limits assessing nutritional requirements and organ effects of arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-3) acids. In this study, whole-body (largely liver) steady-state conversion coefficients and rates of circulating unesterified linoleic acid (LA, 18:2n-6) to esterified AA and other elongated n-6 PUFAs were quantified directly using operational equations, in unanesthetized adult rats on a high-DHA but AA-free diet, using 2 h of intravenous [U-(13)C] LA infusion. Unesterified LA was converted to esterified LA in plasma at a greater rate than to esterified gamma-linolenic (gamma-LNA, 18:3n-6), eicosatrienoic acid (ETA, 20:3n-6), or AA. The steady-state whole-body synthesis-secretion (conversion) coefficient k(i)(*) to AA equaled 5.4 x 10(-3) min(-1), while the conversion rate (coefficient x concentration) equaled 16.1 mu mol/day. This rate exceeds the reported brain AA consumption rate by 27-fold. As brain and heart cannot synthesize significant AA from circulating LA, liver synthesis is necessary to maintain their homeostatic AA concentrations in the absence of dietary AA. The heavy-isotope intravenous infusion method could be used to quantify steady-state liver synthesis-secretion of AA from LA under different conditions in rodents and in humans.-Gao, F., D. Kiesewetter, L. Chang, S. I. Rapoport, and M. Igarashi. Quantifying conversion of linoleic to arachidonic and other n-6 polyunsaturated fatty acids in unanesthetized rats. J Lipid Res. 2010. 51:2940-2946. C1 [Gao, Fei; Chang, Lisa; Rapoport, Stanley I.; Igarashi, Miki] Natl Inst Biomed Imaging & Bioengn, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Kiesewetter, Dale] Natl Inst Biomed Imaging & Bioengn, NIA, NIH, Bethesda, MD USA. [Kiesewetter, Dale] Natl Inst Biomed Imaging & Bioengn, Positron Emiss Tomog Radiochem Grp, NIH, Bethesda, MD USA. RP Gao, F (reprint author), Natl Inst Biomed Imaging & Bioengn, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM gaof@mail.nih.gov FU National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health FX This work was supported entirely by the Intramural Research Programs of the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The authors have no conflict of interest with regard to this work. NR 48 TC 9 Z9 9 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2010 VL 51 IS 10 BP 2940 EP 2946 DI 10.1194/jlr.M005595 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 649GS UT WOS:000281756800007 PM 20622136 ER PT J AU Bronte-Tinkew, J Scott, ME Lilja, E AF Bronte-Tinkew, Jacinta Scott, Mindy E. Lilja, Emily TI Single Custodial Fathers' Involvement and Parenting: Implications for Outcomes in Emerging Adulthood SO JOURNAL OF MARRIAGE AND FAMILY LA English DT Article DE adolescents; emerging adults; parental involvement; parenting styles; single-parent families ID ADOLESCENT RISK BEHAVIORS; FAMILY-STRUCTURE; LIFE-COURSE; YOUNG-ADULT; PATERNAL INVOLVEMENT; ACADEMIC-ACHIEVEMENT; INTACT FAMILIES; SELF-ESTEEM; CHILD; COHABITATION AB Using a sample of 3,977 youths from the National Longitudinal Survey of Youth (NLSY97), this study examines the unique characteristics of single-custodial-father families with adolescents and the effects of single fathers' involvement and parenting on outcomes in emerging adulthood. Findings suggest that single-custodial-father families are distinct from single-mother and 2-biological-parent families in terms of sociodemographic characteristics, parenting styles, and involvement. Parenting styles and involvement mediate the differences between single-father families and 2-parent families in terms of high school completion and disconnectedness and partially mediate differences for single-custodial-father families with a partner. Family and sociodemographic characteristics are also associated with being disconnected for adolescents residing with a cohabiting custodial father. C1 [Bronte-Tinkew, Jacinta] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. [Scott, Mindy E.; Lilja, Emily] Child Trends, Washington, DC 20008 USA. RP Bronte-Tinkew, J (reprint author), NIH, Ctr Sci Review, 6701 Rockledge Dr,Room 3164,MSC 7770, Bethesda, MD 20892 USA. EM jacinta.bronte-tinkew@nih.gov; mscott@childtrends.org; elilja@childtrends.org NR 62 TC 12 Z9 12 U1 1 U2 24 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-2445 J9 J MARRIAGE FAM JI J. Marriage Fam. PD OCT PY 2010 VL 72 IS 5 BP 1107 EP 1127 DI 10.1111/j.1741-3737.2010.00753.x PG 21 WC Family Studies; Sociology SC Family Studies; Sociology GA 656YD UT WOS:000282376100005 ER PT J AU Jahouh, F Saksena, R Aiello, D Napoli, A Sindona, G Kovac, P Banoub, JH AF Jahouh, Farid Saksena, Rina Aiello, Donatella Napoli, Anna Sindona, Giovanni Kovac, Pavol Banoub, Joseph H. TI Glycation sites in neoglycoglycoconjugates from the terminal monosaccharide antigen of the O-PS of Vibrio cholerae O1, serotype Ogawa, and BSA revealed by matrix-assisted laser desorption-ionization tandem mass spectrometry SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE MALDI-TOF/TOF-MS; MALDI-CID-TOF-TOF-MS/MS; neoglycoconjugate vaccine; hapten; BSA; protein carrier ID BOVINE SERUM-ALBUMIN; CONJUGATE VACCINES; LIPOPOLYSACCHARIDE; PROTEINS; INABA; POLYSACCHARIDE; NOMENCLATURE; SACCHARIDE; FRAGMENTS; CARRIER AB We present the MALDI-TOF/TOF-MS analyses of various hapten - bovine serum albumin (BSA) neoglycoconjugates obtained by squaric acid chemistry coupling of the spacer-equipped, terminal monosaccharide of the O-specific polysaccharide of Vibrio cholerae O1, serotype Ogawa, to BSA. These analyses allowed not only to calculate the molecular masses of the hapten-BSA neoglycoconjugates with different hapten-BSA ratios (4.3, 6.6 and 13.2) but, more importantly, also to localize the covalent linkages (conjugation sites) between the hapten and the carrier protein. Determination of the site of glycation was based on comparison of the MALDI-TOF/TOF-MS analysis of the peptides resulting from the digestion of BSA with similar data resulting from the digestion of BSA glycoconjugates, followed by sequencing by MALDI-TOF/TOF-MS/MS of the glycated peptides. The product-ion scans of the protonated molecules were carried out with a MALDI-TOF/TOF-MS/MS tandem mass spectrometer equipped with a high-collision energy cell. The high-energy collision-induced dissociation (CID) spectra afforded product ions formed by fragmentation of the carbohydrate hapten and amino acid sequences conjugated with fragments of the carbohydrate hapten. We were able to identify three conjugation sites on lysine residues (Lys235, Lys437 and Lys455). It was shown that these lysine residues are very reactive and bind lysine specific reagents. We presume that these Lys residues belong to those that are considered to be sterically more accessible on the surface of the tridimensional structure. The identification of the y-series product ions was very useful for the sequencing of various peptides. The series of a- and b-product ions confirmed the sequence of the conjugated peptides. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Banoub, Joseph H.] Dept Fisheries & Oceans Canada, Sci Branch, Special Projects, St John, NF A1C 5X1, Canada. [Jahouh, Farid; Banoub, Joseph H.] Mem Univ Newfoundland, Dept Chem, St John, NF A1B 3X7, Canada. [Saksena, Rina; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. [Aiello, Donatella; Napoli, Anna; Sindona, Giovanni] Univ Calabria, Dept Chem, Arcavacata Di Rende, CS, Italy. RP Banoub, JH (reprint author), Dept Fisheries & Oceans Canada, Sci Branch, Special Projects, St John, NF A1C 5X1, Canada. EM banoubjo@dfo-mpo.gc.ca RI NAPOLI, ANNA/B-5250-2011; OI NAPOLI, ANNA/0000-0002-7004-7643; sindona, giovanni/0000-0002-5623-5795 NR 34 TC 10 Z9 10 U1 2 U2 9 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD OCT PY 2010 VL 45 IS 10 BP 1148 EP 1159 DI 10.1002/jms.1796 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 672TQ UT WOS:000283610200008 PM 20860010 ER PT J AU Soto, E Romero, R Vaisbuch, E Erez, O Mazaki-Tovi, S Kusanovic, JP Dong, Z Chaiworapongsa, T Yeo, L Mittal, P Hassan, SS AF Soto, Eleazar Romero, Roberto Vaisbuch, Edi Erez, Offer Mazaki-Tovi, Shali Kusanovic, Juan Pedro Dong, Zhong Chaiworapongsa, Tinnakorn Yeo, Lami Mittal, Pooja Hassan, Sonia S. TI Fragment Bb: evidence for activation of the alternative pathway of the complement system in pregnant women with acute pyelonephritis SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Acute respiratory distress syndrome; asymptomatic bacteriuria; inflammation; innate immunity; pregnancy; Th1/Th2; urinary tract infection ID INFLAMMATORY RESPONSE SYNDROME; FACTOR-H POLYMORPHISM; INNATE IMMUNE-SYSTEM; MACULAR DEGENERATION; COMPLICATING PREGNANCY; ARTHRITIS; C5A; LEUKOCYTES; MONOCYTES; SEPSIS AB Objective. Pyelonephritis during pregnancy is associated with a more severe course than in the non-pregnant state. This has been attributed to an increased susceptibility of pregnant women to microbial products. The complement system is part of innate immunity and its alternative pathway is activated mainly by microorganisms. The purpose of this study was to determine if activation of the alternative pathway of the complement system (determined by maternal fragment Bb concentrations) occurs in pregnant women with acute pyelonephritis. Methods. This cross-sectional study included the following groups: (1) normal pregnant women (n = 62) and (2) pregnant women with pyelonephritis (n-38). Maternal plasma fragment Bb concentrations were determined by ELISA. Nonparametric statistics were used for analyses. Results. (1) Pregnant women with pyelonephritis had a higher median plasma concentration of fragment Bb than those with a normal pregnancy (1.3 mu g/ml, IQR: 1.1-1.9 vs. 0.8 mu g/ml, IQR: 0.7-0.9; p<50.001); (2) No significant differences were observed in the median maternal plasma concentration of fragment Bb between pregnant women with pyelonephritis who had a positive blood culture and those with a negative blood culture (1.4 mu g/ml, IQR: 1.1-3.5 vs. 1.3 mu g/ml, IQR: 1.1-1.9; p = 0.2). Conclusions. Pregnant women with acute pyelonephritis have evidence of activation of the alternative pathway of the complement system, regardless of the presence or absence of a positive blood culture. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Soto, Eleazar; Romero, Roberto; Vaisbuch, Edi; Erez, Offer; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Yeo, Lami; Mittal, Pooja; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Soto, Eleazar; Romero, Roberto; Vaisbuch, Edi; Erez, Offer; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Dong, Zhong; Chaiworapongsa, Tinnakorn; Yeo, Lami; Mittal, Pooja; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 69 TC 8 Z9 8 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD OCT PY 2010 VL 23 IS 10 BP 1085 EP 1090 DI 10.3109/14767051003649870 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 653HW UT WOS:000282081100002 PM 20218820 ER PT J AU Cruciani, L Romero, R Vaisbuch, E Kusanovic, JP Chaiworapongsa, T Mazaki-Tovi, S Dong, Z Kim, SK Ogge, G Yeo, L Mittal, P Hassan, SS AF Cruciani, Laura Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Mazaki-Tovi, Shali Dong, Zhong Kim, Sun Kwon Ogge, Giovanna Yeo, Lami Mittal, Pooja Hassan, Sonia S. TI Pentraxin 3 in maternal circulation: An association with preterm labor and preterm PROM, but not with intra-amniotic infection/inflammation SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Amniocentesis; cytokines; MIAC; microbial invasion of the amniotic cavity; pattern recognition receptors; preterm delivery; preterm prelabor rupture of membranes; PPROM; pregnancy ID C-REACTIVE PROTEIN; AMYLOID-P COMPONENT; TUMOR-NECROSIS-FACTOR; ACUTE-PHASE PROTEINS; RECOGNITION RECEPTOR PTX3; HUMORAL INNATE IMMUNITY; NORMAL HUMAN-PREGNANCY; LONG PENTRAXIN; DENDRITIC CELLS; METABOLIC CHARACTERISTICS AB Objective. Pentraxin 3 (PTX3) is an acute-phase protein that has an important role in the regulation of the innate immune response. The aim of this study was to determine if maternal plasma PTX3 concentration changes in the presence of intra-amniotic infection and/or inflammation (IAI) in women with preterm labor (PTL) and intact membranes, as well as those with preterm prelabor rupture of membranes (preterm PROM). Study design. This cross-sectional study included women in the following groups: (1) nonpregnant (n = 40); (2) uncomplicated pregnancies in the first (n 22), second (n 22) or third trimester (n 71, including 50 women at term not in labor); (3) uncomplicated pregnancies at term with spontaneous labor (n 49); (4) PTL and intact membranes who delivered at term (n 49); (5) PTL without IAI who delivered preterm (n 26); (6) PTL with IAI (n 65); (7) preterm PROM without IAI (n 25); and (8) preterm PROM with IAI (n 77). Maternal plasma PTX3 concentrations were determined by ELISA. Results. (1) Maternal plasma PTX3 concentrations increased with advancing gestational age (r = 0.62, p < 50.001); (2) women at term with spontaneous labor had a higher median plasma PTX3 concentration than those at term not in labor (8.29 ng/ml vs. 5.98 ng/ml, p = 0.013); (3) patients with an episode of PTL, regardless of the presence or absence of IAI and whether these patients delivered preterm or at term had a higher median plasma PTX3 concentration than normal pregnant women (p<0.001 for all comparisons); (4) similarly, patients with preterm PROM, with or without IAI had a higher median plasma PTX3 concentration than normal pregnant women (p<0.001 for both comparisons); and (5) among patients with PTL and those with preterm PROM, IAI was not associated with significant changes in the median maternal plasma PTX3 concentrations. Conclusions. The maternal plasma PTX3 concentration increases with advancing gestational age and is significantly elevated during labor at term and in the presence of spontaneous preterm labor or preterm PROM. These findings could not be explained by the presence of IAI, suggesting that the increased PTX3 concentration is part of the physiologic or pathologic activation of the pro-inflammatory response in the maternal circulation during the process of labor at term or preterm. C1 [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, Hutzel Womens Hosp, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Cruciani, Laura; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mazaki-Tovi, Shali; Dong, Zhong; Kim, Sun Kwon; Ogge, Giovanna; Yeo, Lami; Mittal, Pooja; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mazaki-Tovi, Shali; Yeo, Lami; Mittal, Pooja; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, Hutzel Womens Hosp, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 79 TC 12 Z9 12 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD OCT PY 2010 VL 23 IS 10 BP 1097 EP 1105 DI 10.3109/14767050903551509 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 653HW UT WOS:000282081100004 PM 20121391 ER PT J AU Mazaki-Tovi, S Vaisbuch, E Romero, R Kusanovic, JP Chaiworapongsa, T Kim, SK Nhan-Chang, CL Gomez, R Savasan, ZA Madan, I Yoon, BH Yeo, L Mittal, P Ogge, G Gonzalez, JM Hassan, SS AF Mazaki-Tovi, Shali Vaisbuch, Edi Romero, Roberto Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Kim, Sun Kwon Nhan-Chang, Chia-Ling Gomez, Ricardo Savasan, Zeynep Alpay Madan, Ichchha Yoon, Bo Hyun Yeo, Lami Mittal, Pooja Ogge, Giovanna Gonzalez, Juan M. Hassan, Sonia S. TI Maternal and neonatal circulating visfatin concentrations in patients with pre-eclampsia and a small-for-gestational age neonate SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Visfatin; adipokines; cytokine; pregnancy; foetal growth restriction; appropriate-for-gestational age; umbilical cord blood ID COLONY-ENHANCING FACTOR; SERUM ADIPONECTIN MULTIMERS; HUMAN FETAL MEMBRANES; INTRAUTERINE GROWTH RESTRICTION; FACTOR RECEPTOR-1 CONCENTRATION; TYPE-2 DIABETES-MELLITUS; NORMAL-PREGNANCY; SOLUBLE ENDOGLIN; PRETERM LABOR; BIRTH-WEIGHT AB Objective. Maternal circulating visfatin concentrations are higher in patients with a small-for-gestational-age (SGA) neonate than in those who delivered an appropriate-for-gestational age (AGA) neonate or in those with pre-eclampsia. It has been proposed that enhanced transfer of visfatin from the foetal to maternal circulation may account for the high concentrations of maternal visfatin observed in patients with an SGA neonate. The aims of this study were: (1) to determine whether cord blood visfatin concentrations differ between normal neonates, SGA neonates and newborns of pre-eclamptic mothers; and (2) to assess the relationship between maternal and foetal circulating visfatin concentrations in patients with an SGA neonate and those with pre-eclampsia. Study design. This cross-sectional study included 88 pregnant women and their neonates, as well as 22 preterm neonates in the following groups: (1) 44 normal pregnant women at term and their AGA neonates; (2) 22 normotensive pregnant women and their SGA neonates; (3) 22 women with pre-eclampsia and their neonates; and (4) 22 preterm neonates delivered following spontaneous preterm labour without funisitis or histologic chorioamnionitis, matched for gestational age with infants of pre-eclamptic mothers. Maternal plasma and cord blood visfatin concentrations were determined by ELISA. Nonparametric statistics were used for analyses. Results. (1) The median visfatin concentration was lower in umbilical cord blood than in maternal circulation, in normal pregnancy, SGA and pre-eclampsia groups (p<0.001 for all comparisons); (2) the median cord blood visfatin concentrations did not differ significantly between term AGA or SGA neonates, infants of mothers with pre-eclampsia and their gestational-age-matched preterm AGA neonates; (3) maternal and cord blood visfatin concentrations correlated only in the normal term group (r=0.48, p=0.04). Conclusion. Circulating visfatin concentrations are lower in the foetal than in the maternal circulation and did not significantly differ between the study groups. Thus, it is unlikely that the foetal circulation is the source of the high maternal visfatin concentrations reported in patients with an SGA neonate. C1 [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Kim, Sun Kwon; Nhan-Chang, Chia-Ling; Savasan, Zeynep Alpay; Madan, Ichchha; Yeo, Lami; Mittal, Pooja; Ogge, Giovanna; Gonzalez, Juan M.; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Kim, Sun Kwon; Nhan-Chang, Chia-Ling; Savasan, Zeynep Alpay; Madan, Ichchha; Yeo, Lami; Mittal, Pooja; Ogge, Giovanna; Gonzalez, Juan M.; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Bethesda, MD USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Nhan-Chang, Chia-Ling; Savasan, Zeynep Alpay; Madan, Ichchha; Yeo, Lami; Mittal, Pooja; Gonzalez, Juan M.; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Hutzel Womens Hosp, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Gomez, Ricardo] Pontificia Univ Catolica Chile, Sotero Rio Hosp, Dept Obstet & Gynecol, CEDIP Ctr Perinatal Diag & Res, Santiago, Chile. [Yoon, Bo Hyun] Seoul Natl Univ, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Box 4,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Ogge, Giovanna/G-6109-2011; Yoon, Bo Hyun/H-6344-2011; OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch, Division of Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported in part by the Perinatology Research Branch, Division of Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 108 TC 17 Z9 17 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD OCT PY 2010 VL 23 IS 10 BP 1119 EP 1128 DI 10.3109/14767050903572190 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 653HW UT WOS:000282081100007 PM 20121389 ER PT J AU Jones, NL Peiffer, AM Lambros, A Guthold, M Johnson, AD Tytell, M Ronca, AE Eldridge, JC AF Jones, Nancy L. Peiffer, Ann M. Lambros, Ann Guthold, Martin Johnson, A. Daniel Tytell, Michael Ronca, April E. Eldridge, J. Charles TI Developing a problem-based learning (PBL) curriculum for professionalism and scientific integrity training for biomedical graduate students SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID RESPONSIBLE CONDUCT; EDUCATION; ETHICS AB A multidisciplinary faculty committee designed a curriculum to shape biomedical graduate students into researchers with a high commitment to professionalism and social responsibility and to provide students with tools to navigate complex, rapidly evolving academic and societal environments with a strong ethical commitment. The curriculum used problem-based learning (PBL), because it is active and learner-centred and focuses on skill and process development. Two courses were developed: Scientific Professionalism: Scientific Integrity addressed discipline-specific and broad professional norms and obligations for the ethical practice of science and responsible conduct of research (RCR). Scientific Professionalism: Bioethics and Social Responsibility focused on current ethical and bioethical issues within the scientific profession, and implications of research for society. Each small-group session examined case scenarios that included: (1) learning objectives for professional norms and obligations; (2) key ethical issues and philosophies within each topic area; (3) one or more of the RCR instructional areas; and (4) at least one type of moral reflection. Cases emphasised professional standards, obligations and underlying philosophies for the ethical practice of science, competing interests of stakeholders and oversight of science (internal and external). To our knowledge, this is the first use of a longitudinal, multi-semester PBL course to teach scientific integrity and professionalism. Both faculty and students endorsed the active learning approach for these topics, in contrast to a compliance-based approach that emphasises learning rules and regulations. C1 [Jones, Nancy L.] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Winston Salem, NC 27106 USA. [Peiffer, Ann M.] Wake Forest Univ Hlth Sci, Dept Radiol, Winston Salem, NC USA. [Lambros, Ann] Wake Forest Univ Hlth Sci, Ctr Excellence Res Teaching & Learning, Winston Salem, NC USA. [Lambros, Ann] Wake Forest Univ Hlth Sci, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Guthold, Martin] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Biol, Winston Salem, NC 27109 USA. [Tytell, Michael] Wake Forest Univ Hlth Sci, Dept Neurobiol & Anat, Winston Salem, NC USA. [Ronca, April E.] Wake Forest Univ Hlth Sci, Dept Obstet & Gynecol, Winston Salem, NC USA. [Eldridge, J. Charles] Wake Forest Univ Hlth Sci, Dept Physiol & Pharmacol, Winston Salem, NC USA. RP Jones, NL (reprint author), NIAID, SPEB, OSPFM, NIH,DHHS, Bldg 31,7A46F,MSC 2520, Bethesda, MD 20892 USA. EM jonesna@niaid.nih.gov FU National Science Foundation [NSF 0530023] FX This project was supported by NSF 0530023 from the National Science Foundation (JCE, principal investigator). NR 29 TC 11 Z9 11 U1 4 U2 24 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD OCT PY 2010 VL 36 IS 10 BP 614 EP 619 DI 10.1136/jme.2009.035220 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 655VI UT WOS:000282282400008 PM 20797979 ER PT J AU Jones, NL Peiffer, AM Lambros, A Eldridge, JC AF Jones, Nancy L. Peiffer, Ann M. Lambros, Ann Eldridge, J. Charles TI Problem-based learning for professionalism and scientific integrity training of biomedical graduate students: process evaluation SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID RESPONSIBLE CONDUCT; ETHICS; PERCEPTIONS; INSTRUCTION; EDUCATION AB Objective We conducted a process evaluation to (a) assess the effectiveness of a new problem-based learning curriculum designed to teach professionalism and scientific integrity to biomedical graduate students and (b) modify the course to enhance its relevance and effectiveness. The content presented realistic cases and issues in the practice of science, to promote skill development and to acculturate students to professional norms of science. Method We used 5-step Likert-scaled questions, open-ended questions, and interviews of students and facilitators to assess curricular effectiveness. Results Both facilitators and students perceived course objectives were achieved. For example, respondents preferred active learning over lectures; both faculty and students perceived that the curriculum increased their understanding of norms, role obligations and responsibilities of professional scientists. They also reported an increased ability to identify ethical situations and felt that they had developed skills in moral reasoning and effective group work. Conclusions These data helped to improve course implementation and instructional material. For example, to correct a negative perception that this was an 'ethics' course, we redesigned case debriefing activities to reinforce learning objectives and important skills. We refined cases to be more engaging and relevant for students, and gave facilitators more specific training and resources for each case. The problem-based learning small group strategy can stimulate an environment whereby participants are more aware of ethical implications of science, and increase their socialisation and open communication about professional behaviour. C1 [Jones, Nancy L.] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Jones, Nancy L.] Trinity Int Univ, Dept Bioeth, Deerfield, IL USA. [Peiffer, Ann M.] Wake Forest Univ Hlth Sci, Dept Radiol, Winston Salem, NC USA. [Lambros, Ann] Wake Forest Univ Hlth Sci, Ctr Excellence Res Teaching & Learning Social Sci, Winston Salem, NC USA. [Eldridge, J. Charles] Wake Forest Univ Hlth Sci, Dept Physiol & Pharmacol, Winston Salem, NC USA. RP Jones, NL (reprint author), NIAID, SPEB, OSPFM, NIH,DHHS, Bldg 31,7A46F,MSC 2520, Bethesda, MD 20892 USA. EM jonesna@niaid.nih.gov FU National Science Foundation,Wilson Boulevard, Arlington, Virginia, USA; NSF [0530023] FX This project was supported by NSF 0530023 (JCE, principal investigator), The National Science Foundation, 4201 Wilson Boulevard, Arlington, Virginia 22230, USA NR 19 TC 7 Z9 8 U1 2 U2 14 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD OCT PY 2010 VL 36 IS 10 BP 620 EP 626 DI 10.1136/jme.2009.035238 PG 7 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 655VI UT WOS:000282282400009 PM 20663754 ER PT J AU Miller, FG Truog, RD AF Miller, Franklin G. Truog, Robert D. TI Decapitation and the definition of death SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID BRAIN-DEATH AB Although established in the law and current practice, the determination of death according to neurological criteria continues to be controversial. Some scholars have advocated return to the traditional circulatory and respiratory criteria for determining death because individuals diagnosed as 'brain dead' display an extensive range of integrated biological functioning with the aid of mechanical ventilation. Others have attempted to refute this stance by appealing to the analogy between decapitation and brain death. Since a decapitated animal is obviously dead, and 'brain death' represents physiological decapitation, brain dead individuals must be dead. In this article we refute this 'decapitation gambit.' We argue that decapitated animals are not necessarily dead, and that, moreover, the analogy between decapitation and the clinical syndrome of brain death is flawed. C1 [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Truog, Robert D.] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU Clinical Center, NIH FX This research was supported in part by the Intramural Research Program of the Clinical Center, NIH. NR 15 TC 8 Z9 8 U1 0 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD OCT PY 2010 VL 36 IS 10 BP 632 EP 634 DI 10.1136/jme.2009.035196 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 655VI UT WOS:000282282400011 PM 20650913 ER PT J AU Pangilinan, F Mitchell, A VanderMeer, J Molloy, AM Troendle, J Conley, M Kirke, PN Sutton, M Sequeira, JM Quadros, EV Scott, JM Mills, JL Brody, LC AF Pangilinan, F. Mitchell, A. VanderMeer, J. Molloy, A. M. Troendle, J. Conley, M. Kirke, P. N. Sutton, M. Sequeira, J. M. Quadros, E. V. Scott, J. M. Mills, J. L. Brody, L. C. TI Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID MATERNAL VITAMIN-B-12 STATUS; AMNIOTIC-FLUID; SPINA-BIFIDA; HOMOCYSTEINE REMETHYLATION; HAPLOTYPE RECONSTRUCTION; IRISH POPULATION; BIRTH-DEFECTS; GENETIC RISK; FOLATE; REDUCTASE AB Objective Women who have low cobalamin (vitamin B(12)) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCbIR) mediates uptake of cobalamin into cells. Inherited variants in the TCbIR gene as NTD risk factors were evaluated. Methods Case-control and family-based tests of association were used to screen common variation in TCbIR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings. Results 2 tightly linked variants associated with NTDs in a recessive model were found: TCbIR rs2336573 (G220R; p(corr)=0.0080, corrected for multiple hypothesis testing) and TCbIR rs9426 (p(corr)=0.0279). These variants were also associated with NTDs in a family-based test before multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R; RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). A copy number variant distal to TCbIR and two previously unreported exonic insertion-deletion polymorphisms were described. Conclusions TCbIR rs2336573 (G220R) and TCbIR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly 1000 controls, indicating that this NTD risk factor may be of low frequency and high penetrance. 9 other variants are in perfect linkage disequilibrium with the associated single nucleotide polymorphisms. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCbIR plays a role in NTD risk and that these variants may modulate cobalamin metabolism. C1 [Pangilinan, F.; Mitchell, A.; VanderMeer, J.; Brody, L. C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. [Molloy, A. M.] Trinity Coll Dublin, Dept Clin Med, Dublin, Ireland. [Troendle, J.; Conley, M.; Mills, J. L.] Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Kirke, P. N.; Sutton, M.] Hlth Res Board, Child Hlth Epidemiol Unit, Dublin, Ireland. [Sequeira, J. M.; Quadros, E. V.] SUNY Downstate Med Ctr, Dept Med, Brooklyn, NY USA. [Sequeira, J. M.; Quadros, E. V.] SUNY Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY USA. [Scott, J. M.] Trinity Coll Dublin, Dept Biochem, Dublin, Ireland. RP Brody, LC (reprint author), NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Room 5306,Bldg 50,50 S Dr,MSC 8004, Bethesda, MD 20892 USA. EM lbrody@helix.nih.gov OI Molloy, Anne/0000-0002-1688-9049 FU National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [DK064732]; Department of Health and Human Services; Health Research Board, Ireland FX The authors acknowledge the research support from the intramural research programmes of the National Human Genome Research Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Department of Health and Human Services and the Health Research Board, Ireland. EVQ and JMS are supported by the National Institutes of Health grant DK064732. NR 52 TC 20 Z9 20 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD OCT PY 2010 VL 47 IS 10 BP 677 EP 685 DI 10.1136/jmg.2009.073775 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 671TI UT WOS:000283533500005 PM 20577008 ER PT J AU Yao, K Crawford, JR Komaroff, AL Ablashi, DV Jacobson, S AF Yao, Karen Crawford, John R. Komaroff, Anthony L. Ablashi, Dharam V. Jacobson, Steven TI Review Part 2: Human Herpesvirus-6 in Central Nervous System Diseases SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HHV-6; central nervous system ID CHRONIC-FATIGUE-SYNDROME; STEM-CELL TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; MULTIPLE-SCLEROSIS PATIENTS; CONTROL BRAIN-TISSUE; SERUM HHV-6 DNA; CEREBROSPINAL-FLUID; HUMAN-HERPESVIRUS-6 INFECTION; LIMBIC ENCEPHALITIS; FATAL ENCEPHALITIS C1 [Yao, Karen; Jacobson, Steven] NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. [Crawford, John R.] Univ Calif San Diego, Dept Neurosci & Pediat, San Diego, CA 92103 USA. [Komaroff, Anthony L.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Komaroff, Anthony L.] Harvard Univ, Sch Med, Boston, MA USA. [Ablashi, Dharam V.] HHV 6 Fdn, Santa Barbara, CA USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Bldg 10,Room 5C-103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002817-18, Z01 NS003040-01, Z01 NS002817-19] NR 110 TC 39 Z9 40 U1 2 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD OCT PY 2010 VL 82 IS 10 BP 1669 EP 1678 DI 10.1002/jmv.21861 PG 10 WC Virology SC Virology GA 640VE UT WOS:000281081000007 PM 20827763 ER PT J AU Lynn, EG Stevens, MV Wong, RP Carabenciov, D Jacobson, J Murphy, E Sack, MN AF Lynn, Edward G. Stevens, Mark V. Wong, Renee P. Carabenciov, Darin Jacobson, Jeremy Murphy, Elizabeth Sack, Michael N. TI Transient upregulation of PGC-1 alpha diminishes cardiac ischemia tolerance via upregulation of ANT1 SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE PGC-1 alpha; Cardiac ischemia-reperfusion; ANTI ID THERMOGENIC COACTIVATOR PGC-1; MITOCHONDRIAL BIOGENESIS; SKELETAL-MUSCLE; GENE-EXPRESSION; MECHANISMS; CARDIOMYOPATHY; CARDIOPROTECTION; OVEREXPRESSION; PROTECTION; PROTEIN-3 AB Prolonged cardiac overexpression of the mitochondrial biogenesis regulatory transcriptional coactivator PGC-1 alpha disrupts cardiac contractile function and its genetic ablation limits cardiac capacity to enhance workload. In contrast, transient induction of PGC-1 alpha alleviates neuronal cell oxidative stress and enhances skeletal myotube anti-oxidant defenses. We explored whether transient upregulation of PGC-1 alpha in the heart protects against ischemia-reperfusion injury. The transient induction of PGC-1 alpha in the cardiac-restricted inducible PGC-1 alpha transgenic mouse, increased PGC-1 alpha protein levels 5-fold. Following 25 min of ischemia and 2 h of reperfusion on a Langendorff perfusion apparatus, contractile recovery and the rate pressure product was significantly blunted in mice overexpressing PGC-1 alpha vs. controls. Affymetrix gene array analysis showed a 3-fold PGC-1 alpha-mediated upregulation of adenine nucleotide translocase 1 (ANT1). As ANT1 upregulation induces cardiomyocyte cell death we investigated whether the induction of ANT1 by PGC-1 alpha contributes to this enhanced ischemia-stress susceptibility. Infection with adenovirus harboring PGC-1 alpha into cardiac-derived H9c2 cells significantly upregulates ANT1 without changing basal cell viability. In response to anoxia-reoxygenation injury cell death is significantly increased following PGC-1 alpha overexpression. This detrimental effect is abolished following siRNA knockdown of ANT1. Similarly, the attenuation of ANT-1 in the presence of PGC-1 alpha overexpression preserves the mitochondrial membrane potential in response to hydrogen-peroxide stress. Interestingly, the isolated knockdown of ANT1 also protects H9c2 cells from anoxia-reoxygenation injury. Taken together these data suggest that transient induction of PGC-1 alpha in the murine heart decreases ischemia-reperfusion contractile recovery and diminishes anoxia-reoxygenation tolerance in H9c2 cells. These adverse phenotypes appear to be mediated, in part, by PGC-1 alpha induced upregulation of ANT1. Published by Elsevier Ltd. C1 [Lynn, Edward G.; Stevens, Mark V.; Wong, Renee P.; Carabenciov, Darin; Jacobson, Jeremy; Murphy, Elizabeth; Sack, Michael N.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), NHLBI, Translat Med Branch, NIH, Bld 10-CRC,Room 5-3150,10 Ctr Dr, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov OI Lynn, Edward/0000-0002-8011-5558 FU NHLBI Division of Intramural Research FX We would like to thank the members of the NHLBI Genotyping Core, including Nalini Raghavachari and Xiuli Xu for their assistance with the gene array expression analysis. We would also like to thank Ann Williams from the NHLBI Flow Cytometry core for assistance. This work is funded by NHLBI Division of Intramural Research Funds. We thank Daniel P. Kelly and Maria L Valencik for the gift of the cardiac inducible PGC-1 alpha transgenic mouse. NR 34 TC 15 Z9 17 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD OCT PY 2010 VL 49 IS 4 BP 693 EP 698 DI 10.1016/j.yjmcc.2010.06.008 PG 6 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 650TR UT WOS:000281875900017 PM 20600099 ER PT J AU Pagan, I Firth, C Holmes, EC AF Pagan, Israel Firth, Cadhla Holmes, Edward C. TI Phylogenetic Analysis Reveals Rapid Evolutionary Dynamics in the Plant RNA Virus Genus Tobamovirus SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Article DE Tobamoviruses; Evolutionary dynamics; Virus-host codivergence ID TOBACCO-MOSAIC-VIRUS; SPONTANEOUS MUTATION; NICOTIANA-GLAUCA; POPULATION; RECOMBINATION; SUBSTITUTION; BOTTLENECKS; RESISTANCE; RATES; MODEL AB Early studies on the evolutionary dynamics of plant RNA viruses suggested that they may evolve more slowly than their animal counterparts, sometimes dramatically so. However, these estimates were often based on an assumption of virus host codivergence over time-scales of many millions of years that is difficult to verify. An important example are viruses of the genus Tobamovirus, where the assumption of host virus codivergence over 100 million years has led to rate estimates in the range of similar to 1 x 10-8 nucleotide substitutions per site, per year. Such a low evolutionary rate is in apparent contradiction with the ability of some tobamoviruses to quickly overcome inbred genetic resistance. To resolve how rapidly molecular evolution proceeds in the tobomaviruses, we estimated rates of nucleotide substitution, times to common ancestry, and the extent of congruence between virus and host phylogenies. Using Bayesian coalescent methods applied to time-stamped sequences, we estimated mean evolutionary rates at the nucleotide and amino acid levels of between 1 x 10(-5) and 1.3 x 10(-3) substitutions per site, per year, and hence similar to those seen in a broad range of animal and plant RNA viruses. Under these rates, a conservative estimate for the time of origin of the sampled tobamoviruses is within the last 100,000 years, and hence a far more recently than proposed assuming codivergence. This is supported by our cophylogeny analysis which revealed significantly discordant evolutionary histories between the tobamoviruses and the plant families they infect. C1 [Pagan, Israel; Firth, Cadhla; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pagan, I (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM jip3@psu.edu RI Pagan, Israel/H-1843-2015; OI Pagan, Israel/0000-0001-8876-1194; Holmes, Edward/0000-0001-9596-3552 FU Marie Curie Fellowship [PIOF-GA-2009-236470]; NSERC Canada; NIH [R01-GM080533] FX This work was supported by Marie Curie Fellowship PIOF-GA-2009-236470 to IF, NSERC Canada to CF, and NIH grant R01-GM080533 to ECH. We thank Dr. Andrew Kitchen for valuable comments, and all the authors who kindly provided collection information for their sequence data. NR 47 TC 20 Z9 21 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-2844 J9 J MOL EVOL JI J. Mol. Evol. PD OCT PY 2010 VL 71 IS 4 BP 298 EP 307 DI 10.1007/s00239-010-9385-4 PG 10 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 658FK UT WOS:000282475700005 PM 20838783 ER PT J AU Kane, LA Youle, RJ AF Kane, Lesley A. Youle, Richard J. TI Mitochondrial fission and fusion and their roles in the heart SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Review DE Mitochondria; Fission; Fusion; Heart ID DYNAMIN-RELATED GTPASE; DOMINANT OPTIC ATROPHY; INNER-MEMBRANE-FUSION; WD REPEAT PROTEIN; OUTER-MEMBRANE; SACCHAROMYCES-CEREVISIAE; GIANT MITOCHONDRIA; MAMMALIAN-CELLS; S-NITROSYLATION; SKELETAL-MUSCLE AB Mitochondria are dynamic organelles that usually exist in extensive and interconnected networks that undergo constant remodeling through fission and fusion. These processes are governed by distinct sets of proteins whose mechanism and regulation we are only beginning to fully understand. Early studies on mitochondrial dynamics were performed in yeast and simple mammalian cell culture models that allowed easy visualization of these intricate networks. Equipped with this core understanding, the field is now expanding into more complex systems. Cardiac cells are a particularly interesting example because they have unique energetic and spatial demands that make the study of their mitochondria both challenging and potentially very fruitful. This review will provide an overview of mitochondrial fission and fusion as well as recent developments in the understanding of these processes in the heart. C1 [Youle, Richard J.] NINDS, Surg Neurol Branch, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Kane, Lesley A.; Youle, Richard J.] NINDS, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Surg Neurol Branch, Porter Neurosci Res Ctr, Bldg 35,Room 2C-917,35 Convent Dr,MSC 3704, Bethesda, MD 20892 USA. EM youle@helix.nih.gov FU National Institutes of Health FX The authors' would like to thank Geoffrey Hesketh for the images used in Fig. 2. Work in the authors' laboratory is funded by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 95 TC 22 Z9 22 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 J9 J MOL MED JI J. Mol. Med. PD OCT PY 2010 VL 88 IS 10 BP 971 EP 979 DI 10.1007/s00109-010-0674-6 PG 9 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 652ZT UT WOS:000282052100003 PM 20835916 ER PT J AU Chen, J Aguilera, G AF Chen, J. Aguilera, G. TI Vasopressin Protects Hippocampal Neurones in Culture Against Nutrient Deprivation or Glutamate-Induced Apoptosis SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE vasopressin; V1 receptor; apoptosis; MAPK; ERK; PI3; Akt; hippocampus ID METHYL-D-ASPARTATE; EPIDERMAL GROWTH-FACTOR; MAP KINASE CASCADE; SIGNAL-TRANSDUCTION; RAT HIPPOCAMPUS; AMINO-ACIDS; CELL-LINE; RECEPTOR; BRAIN; PATHWAY AB Vasopressin (VP) secreted within the brain modulates neuronal function by acting as a neurotransmitter. Recent studies show that VP prevents serum deprivation-induced apoptosis in the neuronal cell line, H32. To determine whether VP is anti-apoptotic in hippocampal neurones, primary cultures of these neurones were used to examine the effect of VP on neuronal culture supplement (B27) deprivation-, or glutamate-induced apoptosis, and the signalling pathways mediating the effects. Removal of B27 supplement from the culture medium for 24 h or the addition of glutamate (3-10 mu m) decreased neuronal viability (P < 0.05) and increased Tdt-mediated dUTP nick-end labelling (TUNEL) staining and caspase-3 activity (P < 0.05), which is consistent with apoptotic cell death. VP (10 nm) reduced B27 deprivation- or glutamate-induced cell death (P < 0.05). These anti-apoptotic effects of VP were completely blocked by a V1 but not a V2 receptor antagonist, indicating that they are mediated via V1 VP receptors. The anti-apoptotic effect of VP in neurones involves activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and inositol trisphosphate/protein kinase B (Akt) signalling pathways. This was shown by the transient increases in phospho-ERK and phospho-Akt after incubation with VP revealed by western blot analyses, and the ability of specific inhibitors to reduce the inhibitory effect of VP on caspase-3 activity and TUNEL staining by 70% and 35%, respectively (P < 0.05). These studies demonstrate that VP has anti-apoptotic actions in hippocampal neurones, an effect that is mediated by the MAPK/ERK and phosphatidylinositol-3 kinase/Akt signalling pathways. The ability of VP to reduce nutrient deprivation or glutamate overstimulation-induced neuronal death suggests that VP acts as a neuroprotective agent within the brain. C1 [Chen, J.; Aguilera, G.] NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH,CRC, Room 1E-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM greti_aguilera@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This work was supported by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 64 TC 9 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD OCT PY 2010 VL 22 IS 10 BP 1072 EP 1081 DI 10.1111/j.1365-2826.2010.02054.x PG 10 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 650DH UT WOS:000281828400004 PM 20673301 ER PT J AU Benninger, DH Lomarev, M Lopez, G Wassermann, EM Li, XB Considine, E Hallett, M AF Benninger, David H. Lomarev, Mikhail Lopez, Grisel Wassermann, Eric M. Li, Xiaobai Considine, Elaine Hallett, Mark TI Transcranial direct current stimulation for the treatment of Parkinson's disease SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID HUMAN MOTOR CORTEX; NONINVASIVE CORTICAL STIMULATION; GLOBUS-PALLIDUS STIMULATION; DEEP BRAIN-STIMULATION; MAGNETIC STIMULATION; DC-STIMULATION; EXCITABILITY CHANGES; SUBTHALAMIC NUCLEUS; DOPAMINE RELEASE; MODULATION AB Background Progression of Parkinson's disease (PD) is characterised by motor deficits which eventually respond less to dopaminergic therapy and thus pose a therapeutic challenge. Deep brain stimulation has proven efficacy but carries risks and is not possible in all patients. Non-invasive brain stimulation has shown promising results and may provide a therapeutic alternative. Objective To investigate the efficacy of transcranial direct current stimulation (tDCS) in the treatment of PD. Design Randomised, double blind, sham controlled study. Setting Research institution. Methods The efficacy of anodal tDCS applied to the motor and prefrontal cortices was investigated in eight sessions over 2.5 weeks. Assessment over a 3 month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, Unified Parkinson's Disease Rating Scale (UPDRS), Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility. Results Twenty-five PD patients were investigated, 13 receiving tDCS and 12 sham stimulation. tDCS improved gait by some measures for a short time and improved bradykinesia in both the on and off states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well being, and self-assessed mobility did not differ between the tDCS and sham interventions. Conclusion tDCS of the motor and prefrontal cortices may have therapeutic potential in PD but better stimulation parameters need to be established to make the technique clinically viable. C1 [Benninger, David H.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lomarev, Mikhail] St Petersburg VM Bekhterev Psychoneurol Res Inst, St Petersburg, Russia. [Wassermann, Eric M.] NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. RP Benninger, DH (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 7D37 MSC1428,Ctr Dr, Bethesda, MD 20892 USA. EM benningerd@ninds.nih.gov RI Benninger, David/A-8157-2015 OI Benninger, David/0000-0002-1049-9533 FU NINDS, NIH; USAMRMC [W81XWH-06-1-0534]; National Institutes of Health FX This research was supported by the Intramural Research Program of the NINDS, NIH and in part by a grant from the USAMRMC (W81XWH-06-1-0534).; MH has received personal compensation or travel expenses for activities with Neurotoxin Institute, John Templeton Foundation, Parkinson's and Ageing Research Foundation, University of Pennsylvania, Thomas Jefferson University, Baylor College of Medicine, American Academy of Neurology, Medical University of South Carolina, Northshore-Long Island Jewish Hospital, American Clinical Neurophysiology Society, Columbia University, University of Alabama, Blackwell Publisher, Cambridge University Press, Springer Verlag, Taylor and Francis Group, Oxford University Press, John Wiley and Sons and Elsevier as an advisory board member, an editor, a writer or a speaker. MH has received licence fee payments from the National Institutes of Health for the H-coil, a type of coil for magnetic stimulation. MH and his wife held stock in Agilent Technologies, Amgen, Amylin Pharmaceuticals, Merck and Co, Monsanto Co New Del, Sanofi Aventis Adr, Coventry Health Care Inc, Sigma Aldrich Corp, Warner Chilcott Ltd, Pfizer Inc, Genentech, Inc, United Health Group, St Jude Medical and Eli Lilly and Company. NR 40 TC 88 Z9 92 U1 2 U2 26 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD OCT PY 2010 VL 81 IS 10 BP 1105 EP 1111 DI 10.1136/jnnp.2009.202556 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 654OD UT WOS:000282176900053 PM 20870863 ER PT J AU Akahata, Y Abrams, A Oh, U Maloney, E Jacobson, S AF Akahata, Yoshimi Abrams, Anna Oh, Unsong Maloney, Elizabeth Jacobson, Steven TI The use of a luciferase immunoprecipitation systems (LIPS) assay in the detection of anti-HTLV-I antibody responses in HAM/TSP, ATL, and asymptomatic HTLV-I carriers SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 10th International Symposium on NeuroVirology CY OCT 12-16, 2010 CL Milan, ITALY C1 [Akahata, Yoshimi; Abrams, Anna; Oh, Unsong; Jacobson, Steven] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Maloney, Elizabeth] US FDA, Div Epidemiol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2010 VL 16 SU 1 BP 3 EP 4 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 670GS UT WOS:000283409800008 ER PT J AU Boasso, A Royle, CM Doumazos, S Aquino, VN Biasin, M Piacentini, L Fuchs, D Lo Caputo, S Shearer, GM Clerici, M Graham, DR AF Boasso, Adriano Royle, Caroline M. Doumazos, Spyridon Aquino, Veronica N. Biasin, Mara Piacentini, Luca Fuchs, Dietmar Lo Caputo, Sergio Shearer, Gene M. Clerici, Mario Graham, David R. TI Chronic innate immune activation in the immunopathogenesis of HIV infection SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 10th International Symposium on NeuroVirology CY OCT 12-16, 2010 CL Milan, ITALY C1 [Boasso, Adriano; Royle, Caroline M.; Doumazos, Spyridon] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Med,Immunol Sect, Chelsea & Westminster Hosp,Div Infect Dis, London, England. [Aquino, Veronica N.; Graham, David R.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Retrovirus Lab, Baltimore, MD USA. [Biasin, Mara; Piacentini, Luca; Clerici, Mario] Univ Milan, Cattedra Immunol, Milan, Italy. [Fuchs, Dietmar] Innsbruck Med Univ, Bioctr, Div Biol Chem, Innsbruck, Austria. [Lo Caputo, Sergio] Osped SM Annunziata, Div Malattie Infett, Florence, Italy. [Shearer, Gene M.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Clerici, Mario] Fdn Don Gnocchi IRCCS, Milan, Italy. [Graham, David R.] Johns Hopkins Sch Med, Dept Med, Johns Hopkins Bayview Prote Ctr, Baltimore, MD USA. RI biasin, mara/G-7426-2012; Piacentini, Luca/K-8908-2016 OI Piacentini, Luca/0000-0003-1022-4481 NR 0 TC 0 Z9 0 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2010 VL 16 SU 1 BP 11 EP 12 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 670GS UT WOS:000283409800024 ER PT J AU Marshall, LJ Dunham, LD Major, EO AF Marshall, Leslie J. Dunham, Lisa D. Major, Eugene O. TI The Transcription Factor Spi-B Binds Unique Sequences Present in the Tandem Repeat Promoter/Enhancer of JC Virus and Supports Viral Activity SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 10th International Symposium on NeuroVirology CY OCT 12-16, 2010 CL Milan, ITALY C1 [Marshall, Leslie J.; Dunham, Lisa D.; Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2010 VL 16 SU 1 BP 54 EP 54 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 670GS UT WOS:000283409800117 ER PT J AU Oh, U McCormick, M Datta, D Turner, R Bobb, K Monie, D Sliskovic, DR Zhang, J Meshulam, J Jacobson, S AF Oh, Unsong McCormick, Matthew Datta, Dibyadeep Turner, Richard Bobb, Kathryn Monie, Dileep Sliskovic, D. Robert Zhang, Jie Meshulam, Jeffrey Jacobson, Steven TI NFkB activation promotes immune activation in HTLV-I-associated myelopathy/tropical spastic paraparesis SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 10th International Symposium on NeuroVirology CY OCT 12-16, 2010 CL Milan, ITALY C1 [Oh, Unsong; McCormick, Matthew; Datta, Dibyadeep; Turner, Richard; Jacobson, Steven] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Bobb, Kathryn; Monie, Dileep; Zhang, Jie; Meshulam, Jeffrey] Profectus Biosci Inc, Baltimore, MD USA. [Sliskovic, D. Robert] IDSC, Chelsea, MI USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2010 VL 16 SU 1 BP 63 EP 64 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 670GS UT WOS:000283409800139 ER PT J AU Wohler, JE Gaitan, MI Harberts, E Huebner, A Silva, AC Reich, DS AF Wohler, Jillian E. Gaitan, Maria I. Harberts, Erin Huebner, Alyssa Silva, Afonso C. Reich, Daniel S. TI Effects of HHV-6A Infection in the Common Marmoset SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 10th International Symposium on NeuroVirology CY OCT 12-16, 2010 CL Milan, ITALY C1 [Wohler, Jillian E.; Harberts, Erin; Huebner, Alyssa] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Gaitan, Maria I.; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RI Silva, Afonso/A-7129-2009; Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2010 VL 16 SU 1 BP 90 EP 91 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 670GS UT WOS:000283409800197 ER PT J AU Krebs-Smith, SM Guenther, PM Subar, AF Kirkpatrick, SI Dodd, KW AF Krebs-Smith, Susan M. Guenther, Patricia M. Subar, Amy F. Kirkpatrick, Sharon I. Dodd, Kevin W. TI Americans Do Not Meet Federal Dietary Recommendations SO JOURNAL OF NUTRITION LA English DT Article ID INTAKE DISTRIBUTIONS; FOOD GUIDANCE; POPULATION; NUTRIENTS; PATTERNS; SYSTEM AB A longstanding goal of dietary surveillance has been to estimate the proportion of the population with intakes above or below a target, such as a recommended level of intake. However, until now, statistical methods for assessing the alignment of food intakes with recommendations have been lacking. The purposes of this study were to demonstrate the National Cancer Institute's method of estimating the distribution of usual intake of foods and determine the proportion of the U.S. population who does not meet federal dietary recommendations. Data were obtained from the 2001-2004 NHANES for 16,338 persons, aged 2 y and older. Quantities of foods reported on 24-h recalls were translated into amounts of various food groups using the MyPyramid Equivalents Database. Usual dietary intake distributions were modeled, accounting for sequence effect; weekend/weekday effect, sex, age, poverty income ratio, and race/ethnicity. The majority of the population did not meet recommendations for all of the nutrient-rich food groups, except total grains and meat and beans. Concomitantly, overconsumption of energy from solid fats, added sugars, and alcoholic beverages ("empty calories") was ubiquitous. Over 80% of persons age >= 71 y and over 90% of all other sex-age groups had intakes of empty calories that exceeded the discretionary calorie allowances. In conclusion, nearly the entire U.S. population consumes a diet that is not on par with recommendations. These findings add another piece to the rather disturbing picture that is emerging of a nation's diet in crisis. J. Nutr. 140: 1832-1838, 2010. C1 [Krebs-Smith, Susan M.; Subar, Amy F.; Kirkpatrick, Sharon I.; Dodd, Kevin W.] NCI, Bethesda, MD 20892 USA. [Guenther, Patricia M.] USDA, Ctr Nutr Policy & Promot, Alexandria, VA 22302 USA. RP Krebs-Smith, SM (reprint author), NCI, Bethesda, MD 20892 USA. EM krebssms@mail.nih.gov OI Kirkpatrick, Sharon/0000-0001-9896-5975 NR 30 TC 250 Z9 251 U1 1 U2 18 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD OCT PY 2010 VL 140 IS 10 BP 1832 EP 1838 DI 10.3945/jn.110.124826 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 704WM UT WOS:000286086300019 PM 20702750 ER PT J AU Mehr, S Jones, KJ Singh-Grewal, D Aksentijevich, I Kakakios, A AF Mehr, Sam Jones, Kristi J. Singh-Grewal, Davinder Aksentijevich, Ivona Kakakios, Alyson TI Chronic urticaria of neonatal onset: A potential sign of autoinflammation SO JOURNAL OF PAEDIATRICS AND CHILD HEALTH LA English DT Article DE anakinra; chronic infantile neurological; cutaneous and articular syndrome; NOMID ID CIAS1 MUTATIONS; CRYOPYRINOPATHIES AB We present a 6 year old boy with chronic urticaria of neonatal onset associated in childhood with features of neurological and joint inflammation. Genetic analysis confirmed the diagnosis of neonatal onset multi-inflammatory disorder (NOMID). Daily subcutaneous anti-IL-1 receptor antagonist therapy resulted in a dramatic and sustained amelioration of systemic inflammation. NOMID must be considered in any child with chronic urticaria of neonatal/infantile onset, particularly if associated with joint and/or neurological inflammation. C1 [Mehr, Sam; Kakakios, Alyson] Childrens Hosp Westmead, Dept Allergy & Immunol, Sydney, NSW 2145, Australia. [Singh-Grewal, Davinder] Childrens Hosp Westmead, Dept Rheumatol, Sydney, NSW 2145, Australia. [Jones, Kristi J.] Childrens Hosp Westmead, Western Sydney Genet Program, Sydney, NSW 2145, Australia. [Mehr, Sam; Singh-Grewal, Davinder] Univ Sydney, Childrens Hosp Westmead, Sch Clin, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Aksentijevich, Ivona] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Genet & Genom Branch, Bethesda, MD USA. RP Kakakios, A (reprint author), Childrens Hosp Westmead, Dept Allergy Immunol & Infect Dis, Locked Bag 4001, Sydney, NSW 2145, Australia. EM alysonk@chw.edu.au FU Australian Allergy Foundation FX SM was partly supported by funds received from the Australian Allergy Foundation. NR 5 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1034-4810 J9 J PAEDIATR CHILD H JI J. Paediatr. Child Health PD OCT PY 2010 VL 46 IS 10 BP 608 EP 610 DI 10.1111/j.1440-1754.2009.01688.x PG 3 WC Pediatrics SC Pediatrics GA 667BR UT WOS:000283168100015 PM 20163528 ER PT J AU Raetz, EA Salzer, WL AF Raetz, Elizabeth A. Salzer, Wanda L. TI Tolerability and Efficacy of L-Asparaginase Therapy in Pediatric Patients With Acute Lymphoblastic Leukemia SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE L-asparaginase; pegaspargase; acute lymphoblastic leukemia; toxicity; hypersensitivity ID ACUTE LYMPHOCYTIC-LEUKEMIA; ESCHERICHIA-COLI-ASPARAGINASE; CHILDRENS ONCOLOGY GROUP; RECEIVING L-ASPARAGINASE; ERWINIA L-ASPARAGINASE; DOSE L-ASPARAGINASE; CANCER-STUDY-GROUP; PEG-ASPARAGINASE; SYNTHETASE EXPRESSION; E. COLI AB L-asparaginase (L-ASNase) has been an essential component of multiagent chemotherapy for acute lymphoblastic leukemia in childhood for over 3 decades. There are currently 2 Food and Drug Administration (FDA)-approved formulations of L-ASNase derived from Escherichia coli and 1 non-FDA approved formulation derived from Erwinia chrysanthemi. Modifications in L-ASNase have included pegylation, which decreases drug immunogenicity and increases the half-life, allowing less frequent administration. Although L-ASNase is well-tolerated in most patients and causes little myelosuppression, significant toxicities occur in up to 30% of patients. Hypersensitivity is the most common toxicity of L-ASNase therapy and limits the further use of the drug. Other significant toxicities relate to a reduction in protein synthesis and include pancreatitis, thrombosis, central nervous system complications, and liver dysfunction. The spectrum of common toxicities and the efficacy of different formulations of L-ASNase are presented in this review. C1 [Raetz, Elizabeth A.] NYU, Inst Canc, Dept Pediat, Div Pediat Hematol Oncol,Sch Med, New York, NY 10016 USA. [Salzer, Wanda L.] NCI, Bethesda, MD 20892 USA. RP Raetz, EA (reprint author), NYU, Inst Canc, Dept Pediat, Div Pediat Hematol Oncol,Sch Med, 160 E 32nd St,2nd Floor, New York, NY 10016 USA. EM elizabeth.raetz@nyumc.org NR 104 TC 37 Z9 39 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD OCT PY 2010 VL 32 IS 7 BP 554 EP 563 DI 10.1097/MPH.0b013e3181e6f003 PG 10 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 664TC UT WOS:000282984400007 PM 20724951 ER PT J AU Choi, MR Jiles, C Seibel, NL AF Choi, Mi Rim Jiles, Cynthia Seibel, Nita L. TI Aprepitant Use in Children, Adolescents, and Young Adults for the Control of Chemotherapy-Induced Nausea and Vomiting (CINV) SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE aprepitant; chemotherapy induced nausea and vomiting; antiemetics; pediatric ID RECEPTOR ANTAGONIST APREPITANT; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; RECEIVING CHEMOTHERAPY; CANCER-PATIENTS; DEXAMETHASONE; ANTIEMETICS; PROPHYLAXIS; PREVENTION; EFFICACY AB Background: One of the most common and distressing side effects for cancer patients is chemotherapy-induced nausea and vomiting (CINV). New antiemetics, such as the NK-1 receptor inhibitor aprepitant, have been reported to improve control of this side effect in adults. However, little is known about its effect in the pediatric oncology population, with only a few reported cases in the literature. Methods: This was a retrospective chart review on the use of aprepitant in the pediatric oncology population in our institution. Results: Thirty-two charts and a total of 146 cycles of chemotherapy were reviewed. Mean age was 10 years. Highly emetogenic chemotherapy was used in 23/32 patients and moderately emetogenic chemotherapy in 9/32. Antiemetic regimens consisted of aprepitant + 5-HT3 RA + dexamethasone (Regimen 1, 20/32 patients) or aprepitant + 5-HT3 RA (Regimen 2, in 12/32). Eight out of thirty-two patients were chemotherapy-naive and received aprepitant on their first cycle. In 24/32 patients, aprepitant was added later in their treatment, with 12/24 reporting resolution of CINV after its addition. Conclusions: Aprepitant when combined with standard antiemetics, was well tolerated in the pediatric oncology population studied. However, there is still a need to conduct prospective studies to determine the optimal efficacy of aprepitant in the pediatric oncology population. C1 [Choi, Mi Rim; Jiles, Cynthia; Seibel, Nita L.] Childrens Natl Med Ctr, Div Hematol & Oncol, Washington, DC 20010 USA. [Seibel, Nita L.] George Washington Univ, Sch Med & Publ Hlth, Washington, DC USA. RP Seibel, NL (reprint author), NCI, Canc Therapy Evaluat Program, 6130 Execut Blvd,Room 7025, Bethesda, MD 20892 USA. EM seibelnl@mail.nih.gov NR 22 TC 14 Z9 14 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD OCT PY 2010 VL 32 IS 7 BP E268 EP E271 DI 10.1097/MPH.0b013e3181e5e1af PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 664TC UT WOS:000282984400017 PM 20736848 ER PT J AU Bolton, JM Pagura, J Enns, MW Grant, B Sareen, J AF Bolton, James M. Pagura, Jina Enns, Murray W. Grant, Bridget Sareen, Jitender TI A population-based longitudinal study of risk factors for suicide attempts in major depressive disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Major depressive disorder; Suicide attempt; Epidemiology; Anxiety disorder; Personality disorder ID NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE-DISORDER; PSYCHIATRIC DIAGNOSTIC MODULES; POSTTRAUMATIC-STRESS-DISORDER; INTERVIEW SCHEDULE AUDADIS; 10-YEAR FOLLOW-UP; PERSONALITY-DISORDERS; ANXIETY DISORDERS; CLINICAL PREDICTORS; MENTAL-DISORDERS AB No longitudinal study has examined risk factors for future suicide attempts in major depressive disorder in a nationally representative sample. The objective of this study was to investigate baseline sociodemographic characteristics, comorbid mental disorders, specific depressive symptoms, and previous suicidal behavior as potential risk factors for suicide attempts at 3 years follow-up. Data came from the national epidemiologic survey on alcohol and related conditions (NESARC), a large nationally representative longitudinal survey of mental illness in adults (Wave 1 (2001-2002); Wave 2 (2004-2005) n = 34,653]. Logistic regression examined associations between risk factors present at Wave 1 and suicide attempts at Wave 2 (n = 169) among individuals with major depressive disorder at baseline assessment (n = 6004). Risk factors for incident suicide attempts at Wave 2 (n = 63) were identified among those with major depressive disorder at Wave 1 and no lifetime history of suicide attempts (n = 5170). Results revealed specific comorbid anxiety, personality, and substance use disorders to be associated with incident suicide attempts at Wave 2. Comorbid borderline personality disorder was strongly associated with suicide attempts in all models. Several comorbid disorders were strongly associated with suicide attempts at Wave 2 even after adjusting for previous suicidal behavior, notably posttraumatic stress disorder (adjusted odds ratio (AOR) = 2.20; 95% confidence interval (95% CI) 1.27-3.83) and dependent personality disorder (AOR = 4.43; 95% CI 1.93-10.18). These findings suggest that mental illness comorbidity confers an increased risk of future suicide attempts in major depressive disorder that is not solely accounted for by past suicidal behavior. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Bolton, James M.; Enns, Murray W.; Sareen, Jitender] Univ Manitoba, Dept Psychiat, Winnipeg, MB R3T 2N2, Canada. [Pagura, Jina] Univ Manitoba, Dept Clin Psychol, Winnipeg, MB, Canada. [Enns, Murray W.; Sareen, Jitender] Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3T 2N2, Canada. [Grant, Bridget] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIA, Bethesda, MD USA. RP Bolton, JM (reprint author), PZ430-771 Bannatyne Ave, Winnipeg, MB R3E 3N4, Canada. EM jbolton@hsc.mb.ca FU Manitoba Health Research Council; Canadian Institutes of Health Research (CIHR) [152348] FX Preparation of this article was supported by:; (1) Manitoba Health Research Council operating grant awarded to Dr. Bolton.; (2) Canadian Institutes of Health Research (CIHR) New Investigator Award (#152348) to Dr. Sareen. NR 58 TC 58 Z9 61 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD OCT PY 2010 VL 44 IS 13 BP 817 EP 826 DI 10.1016/j.jpsychires.2010.01.003 PG 10 WC Psychiatry SC Psychiatry GA 657FO UT WOS:000282398800003 PM 20122697 ER PT J AU Kenakin, T Agnati, LF Caron, M Fredholm, B Guidoli, D Kobilka, B Lefkowitz, RW Lohse, M Woods, A Fuxe, K AF Kenakin, Terry Agnati, Luigi F. Caron, Marc Fredholm, Bertil Guidoli, Diego Kobilka, Brian Lefkowitz, Robert W. Lohse, Martin Woods, Amina Fuxe, Kjell TI International Workshop at the Nobel Forum, Karolinska Institutet on G protein-coupled receptors: finding the words to describe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus be reached? SO JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION LA English DT Article ID LIGANDS; ACTIVATION; REVEALS AB A meeting was held May 1 9, 2010 at the Karolinski Institute on Nomenclature in Pharmacology. This meeting occurred in conjunction with the Symposium The Changing World of G Protein Coupled Receptors: From Monomers to Dimers and Receptor Mosaics (Higher-order Oligomers) held the previous day at the Royal Swedish Academy of Science. Two broad topics of nomenclature were discussed; ligand nomenclature and the definition of 'receptor-receptor' interactions. This paper summarizes discussions on these topics along with a consensus definition of the term 'receptor-receptor' interaction. C1 [Kenakin, Terry] GlaxoSmithKline Res & Dev Ltd, Res Triangle Pk, NC 27709 USA. [Agnati, Luigi F.] IRCCS, San Camillo, Lido Venezia, Italy. [Lefkowitz, Robert W.] Duke Univ, Howard Hughes Med Inst, Durham, NC USA. [Fredholm, Bertil; Fuxe, Kjell] Karolinska Inst, Stockholm, Sweden. [Guidoli, Diego] Univ Padua, Padua, Italy. [Kobilka, Brian] Stanford Univ, Stanford, CA 94305 USA. [Lohse, Martin] Univ Wurzburg, Wurzburg, GA USA. [Woods, Amina] NIDA IRP, Baltimore, MD USA. RP Kenakin, T (reprint author), GlaxoSmithKline Res & Dev Ltd, POB 13398, Res Triangle Pk, NC 27709 USA. EM terry.p.kenakin@gsk.com RI Lohse, Martin/A-7160-2012; OI Lohse, Martin/0000-0002-0599-3510; Fuxe, Kjell/0000-0001-8491-4288 NR 7 TC 16 Z9 16 U1 0 U2 8 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1079-9893 J9 J RECEPT SIG TRANSD JI J. Recept. Signal Transduct. PD OCT PY 2010 VL 30 IS 5 SI SI BP 284 EP 286 DI 10.3109/10799893.2010.512438 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 671CD UT WOS:000283476500003 PM 20858022 ER PT J AU Woods, AS AF Woods, Amina S. TI The dopamine D-4 receptor, the ultimate disordered protein SO JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION LA English DT Article DE Dopamine D4 Receptor; Disordered proteins; AKAP; Heteromers; Adenosine A2A Receptor ID ELECTROSTATIC INTERACTION; ADENOSINE A(2A); SH3 DOMAINS; HETEROMERIZATION; PREDICTION; COMPLEXITY; SEQUENCE; MOSAICS; NEURONS AB The human D4 dopamine receptor is a synaptic neurotransmitter receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its structure makes it a very unusual and interesting G protein-coupled receptor (GPCR) as it has several polymorphic variants of its gene in the region encoding the third intracellular loop (IL3). This region contains from two to seven or more similar 48 base pair repeats. These repeats cause this protein to have a very high disorder index and this, in turn, makes it very interactive with other proteins. Among GPCRs in general, the unusually proline-rich IL3 is unique to the D4 receptor (D4R). We believe that, as in the D2R, this region of the receptor plays a role in it's interaction with other receptors. C1 NIDA IRP, NIH, Struct Biol Unit, Cellular Neurobiol Branch, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), NIDA IRP, NIH, Struct Biol Unit, Cellular Neurobiol Branch, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU National Institute on Drug Abuse, NIH; Office of National Drug Control Policy (ONDCP) FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. The authors thank the Office of National Drug Control Policy (ONDCP) for instrumentation funding, with-out which this and other projects could not have been accomplished. NR 28 TC 12 Z9 14 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1079-9893 J9 J RECEPT SIG TRANSD JI J. Recept. Signal Transduct. PD OCT PY 2010 VL 30 IS 5 SI SI BP 331 EP 336 DI 10.3109/10799893.2010.513842 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 671CD UT WOS:000283476500008 PM 20836733 ER PT J AU Silverman, MN Sternberg, EM AF Silverman, Marni N. Sternberg, Esther M. TI Matching Therapy to Body Rhythms: An Endocrine Approach to Treating Rheumatoid Arthritis SO JOURNAL OF RHEUMATOLOGY LA English DT Editorial Material ID PREDNISONE; EFFICACY C1 [Silverman, Marni N.; Sternberg, Esther M.] NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Rockville, MD 20852 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, NIH, 5625 Fishers Lane,Room 4N-13,MSC 9401, Rockville, MD 20852 USA. EM sternbee@mail.nih.gov FU Intramural NIH HHS [ZIA MH002585-20] NR 8 TC 6 Z9 7 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD OCT PY 2010 VL 37 IS 10 BP 1981 EP 1982 DI 10.3899/jrheum.100688 PG 2 WC Rheumatology SC Rheumatology GA 663DY UT WOS:000282864400001 PM 20889607 ER PT J AU Strohsnitter, WC Noller, KL Troisi, R Robboy, SJ Hatch, EE Titus-Ernstoff, L Kaufman, RH Palmer, JR Anderson, D Hoover, RN AF Strohsnitter, William C. Noller, Kenneth L. Troisi, Rebecca Robboy, Stanley J. Hatch, Elizabeth E. Titus-Ernstoff, Linda Kaufman, Raymond H. Palmer, Julie R. Anderson, Diane Hoover, Robert N. TI Autoimmune Disease Incidence Among Women Prenatally Exposed to Diethylstilbestrol SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE DIETHYLSTILBESTROL; PRENATAL EXPOSURE; AUTOIMMUNE DISEASE; PROSPECTIVE STUDY ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; IN-UTERO; REVISED CRITERIA; RISK; PREGNANCY; CLASSIFICATION; EPIDEMIOLOGY; HEALTH; CANCER AB Objective. Animal studies have suggested that prenatal diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women. Methods. A group of women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON), and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were and who were not prenatally DES-exposed. Results. Overall, there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (RR 1.2; 95% CI 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR 4.9; 95% CI 1.1, 21.6) and an inverse association among women who were 45 years and older (RR 0.1; 95% CI 0.01, 0.7). Conclusion. Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study. (First Release July 15 2010; J Rheumatol 2010;37:2167-73; doi:10.3899/jrheum.091092) C1 [Strohsnitter, William C.] Tufts Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. [Palmer, Julie R.] Boston Univ, Sch Publ Hlth, Slone Epidemiol Ctr, Boston, MA USA. [Noller, Kenneth L.] Amer Board Obstet & Gynecol, Dallas, TX USA. [Troisi, Rebecca; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Robboy, Stanley J.] Duke Univ, Dept Pathol, Durham, NC 27706 USA. [Titus-Ernstoff, Linda] Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Lebanon, NH 03766 USA. [Kaufman, Raymond H.] Methodist Hosp, Houston, TX 77030 USA. [Anderson, Diane] Univ Chicago, Chicago, IL 60637 USA. RP Strohsnitter, WC (reprint author), Tufts Med Ctr, Dept Obstet & Gynecol, 800 Washington St, Boston, MA 02111 USA. EM wstrohsnitter@tuftsmedicalcenter.org OI Palmer, Julie/0000-0002-6534-335X; Hatch, Elizabeth/0000-0001-7901-3928 FU NIH [N01-CP-55507, N01-CP-55508, N01-CP-55509, N01-CP-55510, N01-CP-51010-66] FX Supported by NIH contracts N01-CP-55507, N01-CP-55508, N01-CP-55509, N01-CP-55510, and N01-CP-51010-66. NR 28 TC 7 Z9 7 U1 1 U2 3 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD OCT PY 2010 VL 37 IS 10 BP 2167 EP 2173 DI 10.3899/jrheum.091092 PG 7 WC Rheumatology SC Rheumatology GA 663DY UT WOS:000282864400029 PM 20634240 ER PT J AU Catherino, WH Malik, M Driggers, P Chappel, S Segars, J Davis, J AF Catherino, William H. Malik, Minnie Driggers, Paul Chappel, Scott Segars, James Davis, Joseph TI Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Selective progesterone receptor modulator; Apoptosis; Endometrium; Leiomyoma; Myometrium; Extracellular matrix ID UTERINE LEIOMYOMATA; PENICILLIUM-OBLATUM; MIFEPRISTONE; CDB-2914; FIBROIDS; WOMEN; ELUCIDATION; ASOPRISNIL; MANAGEMENT; CDB-4124 AB Uterine leiomyomas are highly prevalent and often symptomatic, but current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. The goal of these studies was to determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on leiomyoma cell proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947. In vitro progestational activity was assessed by alkaline phosphatase assay and ER-a expression. In vivo progestational activity was assayed by the McPhail assay. Proliferation and gene expression studies were performed in immortalized human leiomyoma and myometrial cells. Both CP8863 and CP8947 were highly selective for progesterone receptor (PR) but not for ER-alpha, AR, and GR. Both compounds induced alkaline phosphatase comparably to progesterone, while CP8947 induced ER-alpha in leiomyoma cells but not myometrial cells. CP8947 was progestational in rabbit endometrium Nanomolar CP8947 treatment inhibited human leiomyoma but not myometrial cell proliferation. Extracellular matrix components were decreased in leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations. CP8947 was a potent novel non-steroidal SPRM that was selective for PR, demonstrated progestational activity in enclometrium, inhibited leiomyoma cell proliferation and decreased ECM component production, without disrupting myometrial cell proliferation. Published by Elsevier Ltd. C1 [Catherino, William H.; Malik, Minnie; Segars, James] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Catherino, William H.; Driggers, Paul; Segars, James; Davis, Joseph] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Chappel, Scott] Tokai Pharmaceut Inc, Cambridge, MA USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM wcatherino@usuhs.mil OI Malik, Minnie/0000-0003-1129-6575 FU Tokai Pharmaceuticals, Inc.; PRAE, NICHD, NIH FX This work was supported by a research grant from Tokai Pharmaceuticals, Inc. and by the intramural research program of the PRAE, NICHD, NIH NR 42 TC 17 Z9 18 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD OCT PY 2010 VL 122 IS 4 BP 279 EP 286 DI 10.1016/j.jsbmb.2010.05.005 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 673TW UT WOS:000283687100020 PM 20493256 ER PT J AU Hopkins, R Esposito, D Gillette, W AF Hopkins, Ralph Esposito, Dominic Gillette, William TI Widening the bottleneck: Increasing success in protein expression and purification SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Protein purification; Baculovirus; High throughput ID ENABLING TECHNOLOGIES; STRUCTURAL GENOMICS; CLONING; DNA AB The number of variables at play in the expression and purification of a single protein dwarf those involved in sequencing a genome. Although certain trends are apparent, there is no one-size-fits-all approach to the process of purifying proteins. Thus, whereas numerous genome sequencing projects are providing an overwhelming number of interesting open reading frames for structural biologists to study, fully realizing the potential of this resource is still only a distant hope. We will discuss several current approaches to high throughput expression and purification as well as strategies that have served us well to quickly identify lead protein expression constructs in the context of a core service protein expression and purification laboratory. The use of the baculovirus expression vector system and implementation of a purification screening method will be emphasized. (C) 2010 Elsevier Inc. All rights reserved. C1 [Hopkins, Ralph; Esposito, Dominic; Gillette, William] NCI, Prot Express Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Gillette, W (reprint author), NCI, Prot Express Lab, SAIC Frederick Inc, Bldg 327,Room 6, Frederick, MD 21702 USA. EM gillettew@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 13 TC 5 Z9 5 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD OCT PY 2010 VL 172 IS 1 SI SI BP 14 EP 20 DI 10.1016/j.jsb.2010.07.005 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 650YA UT WOS:000281889200003 PM 20650317 ER PT J AU Merikangas, KR He, JP Burstein, M Swanson, SA Avenevoli, S Cui, LH Benjet, C Georgiades, K Swendsen, J AF Merikangas, Kathleen Ries He, Jian-ping Burstein, Marcy Swanson, Sonja A. Avenevoli, Shelli Cui, Lihong Benjet, Corina Georgiades, Katholiki Swendsen, Joel TI Lifetime Prevalence of Mental Disorders in U.S. Adolescents: Results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A) SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE epidemiology; adolescents; mental disorders; National Comorbidity Survey; correlates ID HIGH-SCHOOL-STUDENTS; III-R DISORDERS; PSYCHIATRIC-DISORDERS; RISK-FACTORS; CHILD; HEALTH; EPIDEMIOLOGY; RATES; PSYCHOPATHOLOGY; ANXIETY AB Objective: To present estimates of the lifetime prevalence of DSM-IV mental disorders with and without severe impairment, their comorbidity across broad classes of disorder, and their sociodemographic correlates. Method: The National Comorbidity Survey Adolescent Supplement NCS-A is a nationally representative face-to-face survey of 10,123 adolescents aged 13 to 18 years in the continental United States. DSM-IV mental disorders were assessed using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview. Results: Anxiety disorders were the most common condition (31.9%), followed by behavior disorders (19.1%), mood disorders (14.3%), and substance use disorders (11.4%), with approximately 40% of participants with one class of disorder also meeting criteria for another class of lifetime disorder. The overall prevalence of disorders with severe impairment and/or distress was 22.2% (11.2% with mood disorders, 8.3% with anxiety disorders, and 9.6% behavior disorders). The median age of onset for disorder classes was earliest for anxiety (6 years), followed by 11 years for behavior, 13 years for mood, and 15 years for substance use disorders. Conclusions: These findings provide the first prevalence data on a broad range of mental disorders in a nationally representative sample of U.S. adolescents. Approximately one in every four to five youth in the U.S. meets criteria for a mental disorder with severe impairment across their lifetime. The likelihood that common mental disorders in adults first emerge in childhood and adolescence highlights the need for a transition from the common focus on treatment of U.S. youth to that of prevention and early intervention. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(10):980-989. C1 [Merikangas, Kathleen Ries; He, Jian-ping; Burstein, Marcy; Swanson, Sonja A.; Cui, Lihong] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Avenevoli, Shelli] NIMH, Div Dev Translat Res, Bethesda, MD 20892 USA. [Georgiades, Katholiki] McMaster Univ, Hamilton, ON L8S 4L8, Canada. [Swendsen, Joel] CNRS, Natl Ctr Sci Res, Bordeaux, France. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bldg 35,Room 1A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov RI Benjet, Corina/D-7363-2012; OI Benjet, Corina/0000-0002-4569-6094 FU National Institute of Mental Health [U01-MH60220]; National Institute of Drug Abuse [R01 DA016558]; Robert Wood Johnson Foundation [044708]; John W. Alden Trust FX The National Comorbidity Survey Adolescent Supplement (NCS-A) and the larger program of related NCS surveys ore supported by the National Institute of Mental Health (U01-MH60220) and the National Institute of Drug Abuse (R01 DA016558) with supplemental support from Substance Abuse and Mental Health Services Administration, the Robert Wood Johnson Foundation (Grant 044708), and the John W. Alden Trust. The NCS-A was carried out in conjunction with the World Health Organization World Mental Health Survey Initiative.; This work was supported by the Intramural Research Program of the Notional Institute of Mental Health. The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or U.S. Government. NR 44 TC 974 Z9 984 U1 30 U2 180 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2010 VL 49 IS 10 BP 980 EP 989 DI 10.1016/j.jaac.2010.05.017 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 655ZQ UT WOS:000282295600002 PM 20855043 ER PT J AU Oji, V Tadini, G Akiyama, M Bardon, CB Bodemer, C Bourrat, E Coudiere, P DiGiovanna, JJ Elias, P Fischer, J Fleckman, P Gina, M Harper, J Hashimoto, T Hausser, I Hennies, HC Hohl, D Hovnanian, A Ishida-Yamamoto, A Jacyk, WK Leachman, S Leigh, I Mazereeuw-Hautier, J Milstone, L Morice-Picard, F Paller, AS Richard, G Schmuth, M Shimizu, H Sprecher, E Van Steensel, M Taieb, A Toro, JR Vabres, P Vahlquist, A Williams, M Traupe, H AF Oji, Vinzenz Tadini, Gianluca Akiyama, Masashi Bardon, Claudine Blanchet Bodemer, Christine Bourrat, Emmanuelle Coudiere, Philippe DiGiovanna, John J. Elias, Peter Fischer, Judith Fleckman, Philip Gina, Michal Harper, John Hashimoto, Takashi Hausser, Ingrid Hennies, Hans Christian Hohl, Daniel Hovnanian, Alain Ishida-Yamamoto, Akemi Jacyk, Witold K. Leachman, Sancy Leigh, Irene Mazereeuw-Hautier, Juliette Milstone, Leonard Morice-Picard, Fanny Paller, Amy S. Richard, Gabriele Schmuth, Matthias Shimizu, Hiroshi Sprecher, Eli Van Steensel, Maurice Taieb, Alain Toro, Jorge R. Vabres, Pierre Vahlquist, Anders Williams, Mary Traupe, Heiko TI Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Soreze 2009 SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE autosomal recessive congenital ichthyosis; epidermolytic ichthyosis; genetics; histology; keratinopathic ichthyosis; mendelian disorders of cornification; superficial epidermolytic ichthyosis; ultrastructure ID RECESSIVE CONGENITAL ICHTHYOSIS; BATHING-SUIT ICHTHYOSIS; EPIDERMAL PERMEABILITY BARRIER; HEALING COLLODION BABY; CHANARIN-DORFMAN-SYNDROME; SJOGREN-LARSSON-SYNDROME; LIPID STORAGE DISEASE; OF-FUNCTION MUTATIONS; PEELING-SKIN-SYNDROME; EPIDERMOLYTIC HYPERKERATOSIS AB Background: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification; typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. Objective: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. Methods: The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Soreze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. Results: It was agreed that currently the nosology should remain clinically based. "Syndromic" versus "nonsyndromic" forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, "keratinopathic ichthyosis"-under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. "Autosomal recessive congenital ichthyosis" is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. Limitations: As more becomes known about these diseases in the future, modifications will be needed. Conclusion: We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research. (I Am Acad Dermatol 2010;63:607-41.) C1 [Oji, Vinzenz; Traupe, Heiko] Univ Hosp Munster, Dept Dermatol, D-48149 Munster, Germany. [Tadini, Gianluca] Osped Maggiore, Ist Ricovero & Cura Carattere Sci, Ist Sci Dermatol, Ctr Malattie Cutanee Ereditarie, Milan, Italy. [Akiyama, Masashi; Shimizu, Hiroshi] Hokkaido Univ, Grad Sch Med, Dept Dermatol, Sapporo, Hokkaido, Japan. [Bardon, Claudine Blanchet; Bourrat, Emmanuelle] Hop St Louis, Dept Dermatol, Paris, France. [Bodemer, Christine] Univ Paris 05, Hop Necker Enfants Malad, APHP,Dept Dermatol, Natl Reference Ctr Genodermatoseis,Ctr Reference, F-75270 Paris 06, France. [Coudiere, Philippe] Pierre Fabre Dermatol, Lavaur, France. [DiGiovanna, John J.] Brown Univ, Warren Alpert Sch Med, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02912 USA. [Elias, Peter] Dept Vet Affairs Med Ctr, San Francisco, CA USA. [Fischer, Judith] Ctr Natl Genotypage, Evry, France. [Fleckman, Philip] Univ Washington, Div Dermatol, Seattle, WA 98195 USA. [Gina, Michal; Hohl, Daniel] CHU Vaudois, Serv Dermatol Hosp, Hosp Cantonaux, CH-1011 Lausanne, Switzerland. [Harper, John] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Hashimoto, Takashi] Kurume Univ, Sch Med, Dept Dermatol, Fukuoka, Japan. [Hausser, Ingrid] Univ Hosp Heidelberg, Dept Dermatol, Heidelberg, Germany. [Hennies, Hans Christian] Univ Cologne, Cologne Ctr Genom, Div Dermatogenet, Cologne, Germany. [Hovnanian, Alain] Univ Paris 05, Hop Necker Enfants Malad, APHP, Dept Genet, F-75270 Paris 06, France. [Hovnanian, Alain] Univ Paris 05, Hop Necker Enfants Malad, APHP, Dept Dermatol, F-75270 Paris 06, France. [Ishida-Yamamoto, Akemi] Asahikawa Med Coll, Dept Dermatol, Asahikawa, Hokkaido 078, Japan. [Hovnanian, Alain] Fac Med Toulouse, INSERM, U781, F-31073 Toulouse, France. [Jacyk, Witold K.] Univ Pretoria, Dept Dermatol, ZA-0002 Pretoria, South Africa. [Leachman, Sancy] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Leigh, Irene] Barts & London Med Sch Queen Mary, Inst Cell & Mol Sci, Ctr Cutaneous Res, London, England. [Mazereeuw-Hautier, Juliette] Purpan Hosp, Dept Dermatol, Reference Ctr Rare Skin Dis, Toulouse, France. [Milstone, Leonard] Yale Univ, New Haven, CT USA. [Morice-Picard, Fanny; Taieb, Alain] Hop St Andre, Natl Reference Ctr Rare Skin Dis, Dept Dermatol & Pediat Dermatol, Bordeaux, France. [Paller, Amy S.] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. [Paller, Amy S.] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. [Richard, Gabriele] GeneDx, Gaithersburg, MD USA. [Schmuth, Matthias; Williams, Mary] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schmuth, Matthias] Innsbruck Med Univ, Dept Dermatol, Innsbruck, Austria. [Sprecher, Eli] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Dermatol, IL-69978 Tel Aviv, Israel. [Van Steensel, Maurice] Maastricht Univ, Med Ctr, Dept Dermatol, Maastricht, Netherlands. [Van Steensel, Maurice] GROW Res Sch Oncol & Dev Biol, Maastricht, Netherlands. [Toro, Jorge R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Vabres, Pierre] Univ Bourgogne, Dept Dermatol, Hop Bocage, Dijon, France. [Vahlquist, Anders] Uppsala Univ, Dept Med Sci Dermatol & Venereol, Uppsala, Sweden. RP Oji, V (reprint author), Univ Hosp Munster, Dept Dermatol, Von Esmarch Str 58, D-48149 Munster, Germany. EM ojiv@uni-muenster.de RI MORICE-PICARD, Fanny/M-5125-2014; Fischer, Judith/E-6327-2016; OI Oji, Vinzenz/0000-0003-1380-4828 FU Network for lchthyoses and Related Keratinization Disorders (Bundesministerium fur Bildung und Forschung) [GFGM01143901]; Foundation for lchthyosis and Related Skin Types (United States); Ichthyosis Patient Organization of Germany FX The accommodation and travel costs of the participants and the conference rooms of the Ichthyosis Consensus Conference were sponsored by the Laboratories Pierre Fabre, Castres, France. Moreover, our work is supported by the Network for lchthyoses and Related Keratinization Disorders (Bundesministerium fur Bildung und Forschung, GFGM01143901), the Foundation for lchthyosis and Related Skin Types (United States), and the Ichthyosis Patient Organization of Germany (Selbsthilfe Ichthyose e. V.). NR 235 TC 184 Z9 192 U1 3 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2010 VL 63 IS 4 BP 607 EP 641 DI 10.1016/j.jaad.2009.11.020 PG 35 WC Dermatology SC Dermatology GA 653DZ UT WOS:000282069400008 PM 20643494 ER PT J AU Zhu, BP Han, JX Shi, J Shung, KK Wei, Q Huang, YH Kosec, M Zhou, QF AF Zhu, Benpeng Han, Jiangxue Shi, Jing Shung, Koping Krik Wei, Qing Huang, Yuhong Kosec, Marija Zhou, Qifa TI Lift-Off PMN-PT Thick Film for High-Frequency Ultrasonic Biomicroscopy SO JOURNAL OF THE AMERICAN CERAMIC SOCIETY LA English DT Article ID TRANSDUCERS AB Piezoelectric 0.65Pb(Mg(1/3)Nb(2/3))O(3)-0.35PbTiO(3) (PMN-35PT) thick film with a thickness of approximately 12 mu m has been deposited on the platinum-buffered Si substrate using a sol-gel composite method. The separation of the film from the substrate was achieved using a wet chemical method. The lifted-off PMN-35PT thick film exhibited good dielectric and ferroelectric properties. At 1 kHz, the dielectric constant and the dielectric loss were 3326 and 0.037, respectively, while the remnant polarization was 30.0 mu C/cm2. A high-frequency single-element acoustic transducer fabricated with this film showed a bandwidth at -6 dB of 63.6% at 110 MHz. C1 [Zhu, Benpeng; Han, Jiangxue; Shung, Koping Krik; Zhou, Qifa] Univ So Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Zhu, Benpeng] Huazhong Univ Sci & Technol, Dept Elect Sci & Technol, Wuhan 430074, Peoples R China. [Shi, Jing] Wuhan Univ, Dept Phys, Minist Educ, Key Lab Acoust & Photon Mat & Devices, Wuhan 430072, Peoples R China. [Wei, Qing; Huang, Yuhong] Chemat Technol Inc, Northridge, CA 91324 USA. [Kosec, Marija] Jozef Stefan Inst, SI-1000 Ljubljana, Slovenia. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu FU NIH [P41-EB2182]; NSF SBIR [IIP-0838881] FX This work was supported by the NIH grant P41-EB2182 and NSF SBIR Phase I IIP-0838881. NR 12 TC 13 Z9 13 U1 2 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-7820 J9 J AM CERAM SOC JI J. Am. Ceram. Soc. PD OCT PY 2010 VL 93 IS 10 BP 2929 EP 2931 DI 10.1111/j.1551-2916.2010.03873.x PG 3 WC Materials Science, Ceramics SC Materials Science GA 660JN UT WOS:000282637200002 PM 21170158 ER PT J AU Saldanha, LG Dwyer, JT Andrews, KW Bailey, RL Gahche, JJ Hardy, CJ Holden, JM Picciano, MF Roseland, JM Thomas, PR Wolf, WR AF Saldanha, Leila G. Dwyer, Johanna T. Andrews, Karen W. Bailey, Regan L. Gahche, Jaime J. Hardy, Constance J. Holden, Joanne M. Picciano, Mary Frances Roseland, Janet M. Thomas, Paul R. Wolf, Wayne R. TI Online Dietary Supplement Resources SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article C1 [Saldanha, Leila G.] NIH, Off Dietary Supplements, Alexandria, VA USA. [Dwyer, Johanna T.; Bailey, Regan L.; Picciano, Mary Frances; Thomas, Paul R.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Andrews, Karen W.; Holden, Joanne M.; Roseland, Janet M.] ARS, USDA, Nutrient Data Lab, Beltsville, MD USA. [Gahche, Jaime J.] CDC, Natl Hlth & Nutr Examinat Survey Planning Branch, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Hardy, Constance J.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Wolf, Wayne R.] Food Composit & Methods Dev Lab, Beltsville, MD USA. RP Saldanha, LG (reprint author), NIH, Off Dietary Supplements, Alexandria, VA USA. OI Dwyer, Johanna/0000-0002-0783-1769 FU Office of Dietary Supplements, National Institutes of Health; ODS FX Funds for the preparation of this article were provided by the Office of Dietary Supplements, National Institutes of Health.; Describes the ODS programs and offers links to research resources and research sponsored by ODS. NR 2 TC 7 Z9 8 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD OCT PY 2010 VL 110 IS 10 BP 1426 EP + DI 10.1016/j.jada.2010.08.013 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 657DJ UT WOS:000282392600003 PM 20869478 ER PT J AU Reedy, J Krebs-Smith, SM AF Reedy, Jill Krebs-Smith, Susan M. TI Dietary Sources of Energy, Solid Fats, and Added Sugars among Children and Adolescents in the United States SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID BODY-MASS INDEX; US CHILDREN; NUTRIENTS; HEALTH; ADULTS; TRENDS; AGE AB Objective The objective of this research was to identify top dietary sources of energy, solid fats, and added sugars among 2- to 18-year-olds in the United States. Methods Data from the National Health and Nutrition Examination Survey, a cross-sectional study, were used to examine food sources (percentage contribution and mean intake with standard errors) of total energy (data from 2005-2006) and energy from solid fats and added sugars (data from 2003-2004). Differences were investigated by age, sex, race/ethnicity, and family income, and the consumption of empty calories defined as the sum of energy from solid fats and added sugars was compared with the corresponding discretionary calorie allowance. Results The top sources of energy for 2- to 18-year-olds were grain desserts (138 kcal/day), pizza (136 kcal/day), and soda (118 kcal/day). Sugar-sweetened beverages (soda and fruit drinks combined) provided 173 kcal/day. Major contributors varied by age, sex, race/ethnicity, and income. Nearly 40% of total energy consumed (798 of 2,027 kcal/day) by 2- to 18-year-olds were in the form of empty calories (433 kcal from solid fat and 365 kcal from added sugars). Consumption of empty calories far exceeded the corresponding discretionary calorie allowance for all sex age groups (which range from 8% to 20%). Half of empty calories came from six foods: soda, fruit drinks, dairy desserts, grain desserts, pizza, and whole milk. Conclusions There is an overlap between the major sources of energy and empty calories: soda, grain desserts, pizza, and whole milk. The landscape of choices available to children and adolescents must change to provide fewer unhealthy foods and more healthy foods with less energy. Identifying top sources of energy and empty calories can provide targets for changes in the marketplace and food environment. However, product reformulation alone is not sufficient the flow of empty calories into the food supply must be reduced. J Am Diet Assoc. 2010;110:1477-1484. C1 [Reedy, Jill; Krebs-Smith, Susan M.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Reedy, J (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM reedyj@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 251 Z9 256 U1 3 U2 51 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD OCT PY 2010 VL 110 IS 10 BP 1477 EP 1484 DI 10.1016/j.jada.2010.07.010 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 657DJ UT WOS:000282392600012 PM 20869486 ER PT J AU Toner, CD Davis, CD Milner, JA AF Toner, Cheryl D. Davis, Cindy D. Milner, John A. TI The Vitamin D and Cancer Conundrum: Aiming at a Moving Target SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Review ID SERUM 25-HYDROXYVITAMIN D; D-RECEPTOR POLYMORPHISMS; PROSTATE-CANCER; BREAST-CANCER; D DEFICIENCY; MULTIPLE-SCLEROSIS; COLORECTAL-CANCER; D SUPPLEMENTATION; BLOOD-PRESSURE; BODY-FAT AB The case for the influence of vitamin D on health, including cancer prevention, is increasingly compelling. While some are calling for increases in the Tolerable Upper Intake Level, fortification, and dietary supplementation, questions regarding dose and individual response variability continue to merit attention. Colorectal cancer risk reduction with adequate vitamin D status is well documented. Protection has also been observed for cancer at all sites, skin, prostate, and breast. At the same time, some individuals may be adversely affected by elevated 25(OH)D concentrations with respect to risk of cancers of the prostate, breast, pancreas, and esophagus, and in some cases a U- or J-shaped association has been suggested. Future research should seek to clarify if and for whom there may be an increased risk for cancer at particular sites with high 25(OH)D concentrations, and the concentrations at which risk increases. Fundamentally, prospective longitudinal studies of these relationships are warranted. The health status, life stage, adiposity, estrogen exposure, and nutritional status of study participants should be taken into account. Continued investigation is necessary to ensure that vitamin D recommendations are appropriately targeted to individuals who stand to benefit most, while protecting vulnerable subgroups from risk of overexposure. J Am Diet Assoc. 2010;110:1492-1500. C1 [Toner, Cheryl D.; Davis, Cindy D.; Milner, John A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Toner, Cheryl D.] CDT Consulting LLC, Fairfax, VA USA. RP Milner, JA (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH,Dept Hlth & Human Serv, 6130 Execut Blvd,Execut Plaza N Suite 3164, Bethesda, MD 20892 USA. EM milnerj@mail.nih.gov NR 106 TC 39 Z9 43 U1 0 U2 11 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD OCT PY 2010 VL 110 IS 10 BP 1492 EP 1500 DI 10.1016/j.jada.2010.07.007 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 657DJ UT WOS:000282392600014 PM 20869488 ER PT J AU Chale-Rush, A Guralnik, JM Walkup, MP Miller, ME Rejeski, WJ Katula, JA King, AC Glynn, NW Manini, TM Blair, SN Fielding, RA AF Chale-Rush, Angela Guralnik, Jack M. Walkup, Michael P. Miller, Michael E. Rejeski, W. Jack Katula, Jeffrey A. King, Abby C. Glynn, Nancy W. Manini, Todd M. Blair, Steven N. Fielding, Roger A. TI Relationship Between Physical Functioning and Physical Activity in the Lifestyle Interventions and Independence for Elders Pilot SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE older adults; mobility disability; physical function performance ID PERIPHERAL ARTERIAL-DISEASE; LOWER-EXTREMITY FUNCTION; WALK 400 METERS; OLDER-ADULTS; ACTIVITY QUESTIONNAIRE; DEPRESSIVE SYMPTOMS; MOBILITY LIMITATION; BODY-COMPOSITION; MUSCLE STRENGTH; PERFORMANCE AB OBJECTIVES To determine whether participation in usual moderate-intensity or more-vigorous physical activity (MVPA) is associated with physical function performance and to identify sociodemographic, psychosocial, and disease-related covariates that may also compromise physical function performance. DESIGN Cross-sectional analysis of baseline variables of a randomized controlled intervention trial. SETTING Four academic research centers. PARTICIPANTS Four hundred twenty-four older adults aged 70 to 89 at risk for mobility disability (scoring < 10 on the Short Physical Performance Battery (SPPB)) and able to complete the 400-m walk test within 15 minutes. MEASUREMENTS Minutes of MVPA (dichotomized according to above or below 150 min/wk of MVPA) assessed according to the Community Healthy Activities Model Program for Seniors questionnaire, SPPB score, 400-m walk test, sex, body mass index (BMI), depressive symptoms, age, and number of medications. RESULTS The SPPB summary score was associated with minutes of MVPA (=0.16, P=.001). In multiple regression analyses, age, minutes of MVPA, number of medications, and depressive symptoms were associated with performance on the composite SPPB (P <.05). There was an association between 400-m walk time and minutes of MVPA (=-0.18; P <.001). In multiple regression analyses, age, sex, minutes of MVPA, BMI, and number of medications were associated with performance on the 400-m walk test (P <.05). CONCLUSION Minutes of MVPA, sex, BMI, depressive symptoms, age, and number of medications are associated with physical function performance and should all be taken into consideration in the prevention of mobility disability. C1 [Chale-Rush, Angela; Fielding, Roger A.] Tufts Univ, Nutr Exercise Physiol & Sarcopenia Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Walkup, Michael P.; Miller, Michael E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat, Winston Salem, NC USA. [Rejeski, W. Jack; Katula, Jeffrey A.] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [King, Abby C.] Stanford Univ, Dept Med, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Glynn, Nancy W.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Manini, Todd M.] Univ Florida, Coll Med, Dept Aging & Geriatr Res, Inst Aging, Gainesville, FL USA. [Blair, Steven N.] Univ S Carolina, Dept Exercise Sci & Epidemiol Biostat, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. RP Fielding, RA (reprint author), Tufts Univ, Nutr Exercise Physiol & Sarcopenia Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM roger.fielding@tufts.edu RI Katula, Jeffrey/K-5905-2013; OI Glynn, Nancy/0000-0003-2265-0162 FU U.S. Department of Agriculture [58-1950-7-707, DK007651]; Boston Claude D. Pepper Older Americans Independence Center [1P30AG031679]; National Institutes on Health (NIH), National Institute on Aging Cooperative Agreement [UO1 AG22376]; National Institute on Aging, NIH; Pittsburgh Claude D. Pepper Center [P30 AG024827]; National Institute on Aging [K24AG021507] FX Drs. Chale-Rush's and Fielding's contribution are supported by U.S. Department of Agriculture Grants 58-1950-7-707 and DK007651 and the Boston Claude D. Pepper Older Americans Independence Center (1P30AG031679). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.; The LIFE-P Study is funded by National Institutes on Health (NIH), National Institute on Aging Cooperative Agreement; UO1 AG22376 and sponsored in part by the Intramural Research Program, National Institute on Aging, NIH.; The Pittsburgh Field Center was partially supported by the Pittsburgh Claude D. Pepper Center P30 AG024827.; Dr. Gill is the recipient of a Midcareer Investigator Award in Patient-Oriented Research (K24AG021507) from the National Institute on Aging. NR 29 TC 22 Z9 22 U1 4 U2 11 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 OCT PY 2010 VL 58 IS 10 BP 1918 EP 1924 DI 10.1111/j.1532-5415.2010.03008.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 660ZP UT WOS:000282690900012 PM 20738437 ER PT J AU Guralnik, JM Kritchevsky, SB AF Guralnik, Jack M. Kritchevsky, Stephen B. TI Translating Research to Promote Healthy Aging: The Complementary Role of Longitudinal Studies and Clinical Trials SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE longitudinal studies; observational studies; clinical trials ID PROSTATE-CANCER; BLOOD-PRESSURE; OLDER PERSONS; MORTALITY; RISK; DISABILITY; DISEASE; ANEMIA; STROKE; HYPERTENSION AB An important challenge in epidemiology is the difficulty in inferring causality from observational studies. Even the best longitudinal studies have limitations in this regard, and when clinical trials are feasible, they will provide more-definite evidence of causality, but even when clinical trials are feasible, a large amount can be learned about the disease process, assessment techniques, subject selection criteria, and the effect of potential interventions from longitudinal studies. This review covers the theoretical issues supporting the value and limitations of longitudinal studies, the practical utilization in clinical trials of different aspects of knowledge that can be gained from longitudinal studies, critical issues in the translation of longitudinal observational studies into clinical trials, and the value of observational studies in broadening the applicability of specific trials. Relevant issues are illustrated with examples of unsuccessful and successful trials, with a major emphasis on clinical trials of physical activity in older persons. J Am Geriatr Soc 58:S337-S342, 2010. C1 [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. RP Guralnik, JM (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Room 3-C309, Bethesda, MD 20892 USA. EM jack.guralnik@nih.gov OI Kritchevsky, Stephen/0000-0003-3336-6781 FU Robert Wood Johnson Foundation; National Institute on Aging, National Institutes of Heatlh, Wake Forest University Claude D. Pepper Older Americans Independence Center [P30 AG21332] FX The article is based on a January 2009, conference on Longitudinal Studies in Aging supported by a grant from the Robert Wood Johnson Foundation.; Supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Heatlh, Wake Forest University Claude D. Pepper Older Americans Independence Center (P30 AG21332). NR 22 TC 14 Z9 14 U1 1 U2 7 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 OCT PY 2010 VL 58 SU 2 BP S337 EP S342 DI 10.1111/j.1532-5415.2010.02938.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 656YJ UT WOS:000282376700013 PM 21029064 ER PT J AU Kelly-Hayes, M AF Kelly-Hayes, Margaret TI Influence of Age and Health Behaviors on Stroke Risk: Lessons from Longitudinal Studies SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE stroke; prevention; risk factors; disability ID CORONARY-HEART-DISEASE; LARGE SOCIAL NETWORK; ISCHEMIC-STROKE; PHYSICAL-ACTIVITY; CIGARETTE-SMOKING; LIFETIME RISK; CARDIOVASCULAR HEALTH; DEPRESSIVE SYMPTOMS; NORTHERN MANHATTAN; BLOOD-PRESSURE AB Stroke is a major cause of death and serious neurological disability in older adults in the United States today. The most effective means available for reducing the burden of stroke involves risk factor modification. Given the growing number of older adults at risk for stroke, it is increasingly important to identify health behaviors that can produce significant change. Ongoing longitudinal studies have identified several behavioral factors that have been shown to improve overall health and reduce the risk of stroke, including effective management of hypertension, cessation of cigarette smoking for those who smoke, and maintaining a healthy diet and active physical lifestyle. Because modification of risk factors remains a primary intervention for effective prevention of stroke, community-based studies that address and institute stroke prevention strategies have the best opportunity to reduce or postpone the devastating effect of stroke. J Am Geriatr Soc 58:S325-S328, 2010. C1 [Kelly-Hayes, Margaret] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Kelly-Hayes, Margaret] NHLBI, Framingham Heart Study, Boston, MA USA. RP Kelly-Hayes, M (reprint author), Boston Univ, Sch Med, Dept Neurol, 72 E Concord St,B 610, Boston, MA 02118 USA. EM mkhayes@bu.edu FU Robert Wood Johnson Foundation; Framingham Heart Study National Heart, Lung, and Blood Institute [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [5 R01 NS17950] FX The article is based on a conference on longitudinal studies in aging held in January 2009 and sponsored by a grant from the Robert Wood Johnson Foundation.; Supported by Framingham Heart Study National Heart, Lung, and Blood Institute Contract N01-HC-25195 and Grant 5 R01 NS17950 from the National Institute of Neurological Disorders and Stroke. NR 39 TC 12 Z9 12 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2010 VL 58 SU 2 BP S325 EP S328 DI 10.1111/j.1532-5415.2010.02915.x PG 4 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 656YJ UT WOS:000282376700011 PM 21029062 ER PT J AU Schrack, JA Simonsick, EM Ferrucci, L AF Schrack, Jennifer A. Simonsick, Eleanor M. Ferrucci, Luigi TI The Energetic Pathway to Mobility Loss: An Emerging New Framework for Longitudinal Studies on Aging SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE energy; aging; physical function; gait speed; fatigue ID LOWER-EXTREMITY FUNCTION; HEALTHY OLDER-ADULTS; PHYSICAL PERFORMANCE BATTERY; DISTANCE CORRIDOR WALK; FUNCTIONAL PERFORMANCE; SUBSEQUENT DISABILITY; OVERGROUND WALKING; AEROBIC CAPACITY; ACTIVITY LEVEL; OXYGEN-UPTAKE AB The capacity to walk independently is a central component of independent living. Numerous large and well-designed longitudinal studies have shown that gait speed, a reliable marker of mobility, tends to decline with age and as a consequence of chronic disease. This decline in performance is of utmost importance because slow walking speed is a strong, independent predictor of disability, healthcare utilization, nursing home admission, and mortality. Based on these robust findings, it has been postulated that age-associated decline in walking speed is a reliable barometer of the effect of biological aging on health and functional status. Despite the extraordinary prognostic information that walking speed provides, which is often superior to traditional medical information, there is a limited understanding of the mechanisms that underlie age-and disease-related gait speed decline. Identifying the mechanisms that underlie the prognostic value of walking speed should be a central theme in the design of the next generation of longitudinal studies of aging, with appropriate measures introduced and analytical approaches incorporated. This study hypothesized that a scarcity of available energy induces the decline in customary walking speed with aging and disease. Based on work in the Baltimore Longitudinal Study of Aging, examples of measures, operationalized dimensions, and analytical models that may be implemented to address this are provided. The main premise is simple: the biochemical processes that maintain life, secure homeostatic equilibrium, and prevent the collapse of health require energy. If energy becomes deficient, adaptive behaviors develop to conserve energy. J Am Geriatr Soc 58:S329-S336, 2010. C1 [Schrack, Jennifer A.] Johns Hopkins Univ, Ctr Aging & Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Schrack, Jennifer A.; Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Schrack, JA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM jschrack@jhsph.edu FU Robert Wood Johnson Foundation; National Institutes of Health, National Institute on Aging (NIA) FX This paper is based on a conference on Longitudinal Studies in Aging held in January 2008 supported by a grant from the Robert Wood Johnson Foundation.; This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA). NR 47 TC 50 Z9 52 U1 0 U2 10 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 OCT PY 2010 VL 58 SU 2 BP S329 EP S336 DI 10.1111/j.1532-5415.2010.02913.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 656YJ UT WOS:000282376700012 PM 21029063 ER PT J AU Gates, MB Tomer, KB Deterding, LJ AF Gates, Matthew B. Tomer, Kenneth B. Deterding, Leesa J. TI Comparison of Metal and Metal Oxide Media for Phosphopeptide Enrichment Prior to Mass Spectrometric Analyses SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID HIGHLY SELECTIVE ENRICHMENT; TITANIUM-DIOXIDE; PHOSPHORYLATED PEPTIDES; AFFINITY-CHROMATOGRAPHY; PROTEIN-PHOSPHORYLATION; PROTEOLYTIC DIGESTS; HISTONE-H5; SITES; TIO2; H1 AB Several affinity resins consisting of ionic metals or metal oxides were investigated for their phosphopeptide enrichment capabilities with subsequent mass spectrometric analyses. Commercially-available enrichment metal oxide affinity chromatography (MOAC) resins using manufacturer's and/or published protocols were compared and evaluated for the most efficient and selective method that could be implemented as a standard enrichment procedure. From these comparative analyses, using a tryptic digest of casein proteins, it was determined that in our hands, two of the resins out-performed the others based on a variety of criteria, including the number of phosphorylation sites identified during MS analyses, the lower numbers of nonspecifically bound peptides observed, and the limits of detection. Applicability of these enrichment resins to a complex biological mixture was investigated. For this work, a mixture of avian histones was digested, subjected to titanium dioxide phosphopeptide enrichment, and analyzed by mass spectrometry. Eight phosphorylated tryptic peptides were observed following enrichment and subsequent LC/MS/MS analyses. Of note, seven of the eight phosphopeptides were not observed without titanium dioxide enrichment. From these analyses, four sites of phosphorylation were unequivocally determined, two of which have not been reported previously. Four additional phosphopeptides were observed; however, the site of phosphorylation could not be distinguished but was localized to one of two possible amino acids. These methods should aid in the investigation of proteins post-translationally modified with phosphate, especially those present at low concentrations as was demonstrated by successful enrichment at the femtomole level. (J Am Soc Mass Spectrom 2010, 21, 1649-1659) Published by Elsevier Inc. on behalf of American Society for Mass Spectrometry C1 [Gates, Matthew B.; Tomer, Kenneth B.; Deterding, Leesa J.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Deterding, LJ (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233,MD F0-03, Res Triangle Pk, NC 27709 USA. EM deterdi2@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU H, National Institute of Environmental Health Sciences [ES050171] FX The authors acknowledge support for this research by the Intra-mural Research Program of the NIH, National Institute of Environmental Health Sciences (ES050171). The authors thank Dr. Roxana Iacob and Dr. Jeffrey Kuhn for their assistance and thoughtful input, and Dr. Allison Schorzman and Dr. Jason Williams for critical review of this manuscript. NIEHS does not endorse or recommend any commercial products, processes, or services. The views and opinions expressed by authors affiliated with NIEHS do not necessarily state or reflect those of the U.S. Government, and they may not be used for advertising or product endorsement purposes. NR 33 TC 24 Z9 25 U1 1 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD OCT PY 2010 VL 21 IS 10 BP 1649 EP 1659 DI 10.1016/j.jasms.2010.06.005 PG 11 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 659EC UT WOS:000282548800003 PM 20634090 ER PT J AU Hager-Braun, C Hochleitner, EO Gorny, MK Zolla-Pazner, S Bienstock, RJ Tomer, KB AF Hager-Braun, Christine Hochleitner, Elisabeth O. Gorny, Miroslaw K. Zolla-Pazner, Susan Bienstock, Rachelle J. Tomer, Kenneth B. TI Characterization of a Discontinuous Epitope of the HIV Envelope Protein gp120 Recognized by a Human Monoclonal Antibody Using Chemical Modification and Mass Spectrometric Analysis SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IMMUNOGLOBULIN G1 B12; GLYCOPROTEIN GP120; NEUTRALIZING ANTIBODIES; ARGININE RESIDUES; SURFACE-TOPOLOGY; BINDING-SITE; RECEPTOR; RETROVIRUS; CORE AB A subset of the neutralizing anti-HIV antibodies recognize epitopes on the envelope protein gp120 of the human immunodeficiency virus. These epitopes are exposed during conformational changes when gp120 binds to its primary receptor CD4. Based on chemical modification of lysine and arginine residues followed by mass spectrometric analysis, we determined the epitope on gp120 recognized by the human monoclonal antibody 559/64-D, which was previously found to be specific for the CD4 binding domain. Twenty-four lysine and arginine residues in recombinant full-length glycosylated gp120 were characterized; the relative reactivities of two lysine residues and five arginine residues were affected by the binding of 559/64-D. The data show that the epitope is discontinuous and is located in the proximity of the CD4-binding site. Additionally, the reactivities of a residue that is located in the secondary receptor binding region and several residues distant from the CD4 binding site were also altered by Ab binding. These data suggest that binding of 559/64-D induced conformational changes which result in altered surface exposure of specific amino acids distant from the CD4-binding site. Consequently, binding of 559/64-D to gp120 affects not only the CD4-binding site, which is recognized as the epitope, but appears to have a global effect on surface exposed residues of the full-length glycosylated gp120. (J Am Soc Mass Spectrom 2010, 21, 1687-1698) (C) 2010 Published by Elsevier Inc. on behalf of American Society for Mass Spectrometry C1 [Hager-Braun, Christine; Hochleitner, Elisabeth O.; Bienstock, Rachelle J.; Tomer, Kenneth B.] Natl Inst Environm Hlth Sci, NIH, DHHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Gorny, Miroslaw K.; Zolla-Pazner, Susan] NYU, Sch Med, New York, NY USA. [Gorny, Miroslaw K.; Zolla-Pazner, Susan] Vet Affairs New York Harbor Healthcare Syst, New York, NY USA. RP Tomer, KB (reprint author), Natl Inst Environm Hlth Sci, NIH, DHHS, Struct Biol Lab, Bldg 101,MD F0-03,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM tomer@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013; OI Bienstock, Rachelle/0000-0001-5228-3610; Gorny, Miroslaw/0000-0002-2714-8780 FU National Institute of Environmental Health Sciences/National Institutes of Health [z050150]; NIH/NHLBI [HL59725] FX The authors acknowledge support in part for this research by the Intramural Research Program of the National Institute of Environmental Health Sciences/National Institutes of Health (z050150) and the NIH/NHLBI (grant HL59725 to S.Z.-P). NR 54 TC 7 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD OCT PY 2010 VL 21 IS 10 BP 1687 EP 1698 DI 10.1016/j.jasms.2010.03.031 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 659EC UT WOS:000282548800007 PM 20434359 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI HTLV-1 and Adult T-Cell Leukemia: Insights into Viral Transformation of Cells 30 Years After Virus Discovery SO JOURNAL OF THE FORMOSAN MEDICAL ASSOCIATION LA English DT Review DE adult T cell leukemia; aneuploidy; HTLV; p53; spindle assembly checkpoint ID NF-KAPPA-B; I TAX ONCOPROTEIN; INTERLEUKIN-2 RECEPTOR GENE; 1ST HUMAN RETROVIRUS; TYPE-1 TAX; RETINOBLASTOMA PROTEIN; CYCLE PROGRESSION; P53 INHIBITION; DNA-DAMAGE; G(1) PHASE AB Human T-cell leukemia virus type 1 (HTLV-1), the etiological agent of adult T-cell leukemia, was the first human retrovirus to be isolated It is now the 30(th) anniversary of the initial discovery of HTLV-1 This review discusses recent insights into the role of the HTLV-1 Tax oncoprotein in cellular proliferation and the abrogation of cellular checkpoints that lead to disease progression C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008 FU National Institute of Allergy and Infectious Diseases FX The views expressed in this review are the personal opinions of the author and do not reflect the views of his employer, the US National Institutes of Health. Work in KTJ's laboratory is supported by intramural funds from the National Institute of Allergy and Infectious Diseases. NR 82 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER TAIWAN PI TAIPEI PA RM N-412, 4F, CHIA HSIN BUILDING 11, NO 96, ZHONG SHAN N ROAD SEC 2, TAIPEI, 10449, TAIWAN SN 0929-6646 J9 J FORMOS MED ASSOC JI J. Formos. Med. Assoc. PD OCT PY 2010 VL 109 IS 10 BP 688 EP 693 DI 10.1016/S0929-6646(10)60112-X PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 673AQ UT WOS:000283630900002 PM 20970064 ER PT J AU Boyle, EW AF Boyle, Eric W. TI The History of American Homeopathy: From Rational Medicine to Holistic Care SO JOURNAL OF THE HISTORY OF MEDICINE AND ALLIED SCIENCES LA English DT Book Review C1 NIH, Off Hist, Bethesda, MD 20892 USA. RP Boyle, EW (reprint author), NIH, Off Hist, Bldg 45,Room 3,An 38,45 Ctr Dr,MSC 6330, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-5045 J9 J HIST MED ALL SCI JI J. Hist. Med. Allied Sci. PD OCT PY 2010 VL 65 IS 4 BP 589 EP 591 DI 10.1093/jhmas/jrq030 PG 3 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 669JW UT WOS:000283344700011 ER PT J AU Workman, TE Fiszman, M Hurdle, JF Rindflesch, TC AF Workman, T. Elizabeth Fiszman, Marcelo Hurdle, John F. Rindflesch, Thomas C. TI Biomedical text summarization to support genetic database curation: using Semantic MEDLINE to create a secondary database of genetic information SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID TRANSCRIPTION FACTORS; SYSTEMS BIOLOGY; LIBRARY AB Objective: This paper examines the development and evaluation of an automatic summarization system in the domain of molecular genetics. The system is a potential component of an advanced biomedical information management application called Semantic MEDLINE and could assist librarians in developing secondary databases of genetic information extracted from the primary literature. Methods: An existing summarization system was modified for identifying biomedical text relevant to the genetic etiology of disease. The summarization system was evaluated on the task of identifying data describing genes associated with bladder cancer in MEDLINE citations. A gold standard was produced using records from Genetics Home Reference and Online Mendelian Inheritance in Man. Genes in text found by the system were compared to the gold standard. Recall, precision, and F-measure were calculated. Results: The system achieved recall of 46%, and precision of 88% (F-measure=0.61) by taking Gene References into Function (GeneRIFs) into account. Conclusion: The new summarization schema for genetic etiology has potential as a component in Semantic MEDLINE to support the work of data curators. C1 [Workman, T. Elizabeth; Hurdle, John F.] Univ Utah, Dept Biomed Informat, Salt Lake City, UT 84112 USA. [Rindflesch, Thomas C.] Natl Lib Med, Semant Knowledge Representat Project, Bethesda, MD 20894 USA. RP Workman, TE (reprint author), Univ Utah, Dept Biomed Informat, 26 S 2000 E,HSEB 5700, Salt Lake City, UT 84112 USA. EM liz.workman@utah.edu; fiszmanm@mail.nih.gov; john.hurdle@utah.edu; tcr@nlm.nih.gov FU NLM NIH HHS [T15 LM007124, T15LM007123] NR 35 TC 6 Z9 6 U1 0 U2 4 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2010 VL 98 IS 4 BP 273 EP 281 DI 10.3163/1536-5050.98.4.003 PG 9 WC Information Science & Library Science SC Information Science & Library Science GA 661VY UT WOS:000282761900003 PM 20936065 ER PT J AU Hauptmann, M Stewart, PA Lubin, JH Freeman, LEB Hornung, RW Herrick, RF Hoover, RN Fraumeni, JF Blair, A Hayes, RB AF Hauptmann, M. Stewart, P. A. Lubin, J. H. Freeman, L. E. Beane Hornung, R. W. Herrick, R. F. Hoover, R. N. Fraumeni, J. F., Jr. Blair, A. Hayes, R. B. TI Re: Mortality From Lymphohematopoietic Malignancies and Brain Cancer Among Embalmers Exposed to Formaldehyde Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Hauptmann, M.; Stewart, P. A.; Lubin, J. H.; Freeman, L. E. Beane; Hoover, R. N.; Hayes, R. B.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hauptmann, M.] Netherlands Canc Inst, Dept Bioinformat & Stat, Amsterdam, Netherlands. [Stewart, P. A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Hornung, R. W.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Herrick, R. F.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hayes, R. B.] NYU Med Ctr, Dept Environm Med, New York, NY 10016 USA. RP Freeman, LEB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM freemala@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 3 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 OCT PY 2010 VL 102 IS 19 BP 1519 EP 1520 DI 10.1093/jnci/djq333 PG 2 WC Oncology SC Oncology GA 661TQ UT WOS:000282751400015 ER PT J AU Gage, JC Castle, PE AF Gage, Julia C. Castle, Philip E. TI Preventing Cervical Cancer Globally by Acting Locally: If Not Now, When? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS INFECTION; HIV ACQUISITION; QUADRIVALENT VACCINE; NEOPLASIA; DNA; WOMEN; RISK; REGRESSION; LESIONS; TESTS C1 [Gage, Julia C.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Castle, Philip E.] NCI, Hormone & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Castle, PE (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Executive Blvd,Rm 5026,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS NR 30 TC 13 Z9 13 U1 0 U2 0 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 OCT PY 2010 VL 102 IS 20 BP 1524 EP 1527 DI 10.1093/jnci/djq382 PG 4 WC Oncology SC Oncology GA 673PS UT WOS:000283676000002 PM 20884892 ER PT J AU Demenais, F Mohamdi, H Chaudru, V Goldstein, AM Bishop, JAN Bishop, DT Kanetsky, PA Hayward, NK Gillanders, E Elder, DE Avril, MF Azizi, E van Belle, P Bergman, W Bianchi-Scarra, G Bressac-de Paillerets, B Calista, D Carrera, C Hansson, J Harland, M Hogg, D Hoiom, V Holland, EA Ingvar, C Landi, MT Lang, JM Mackie, RM Mann, GJ Ming, ME Njauw, CJ Olsson, H Palmer, J Pastorino, L Puig, S Randerson-Moor, J Stark, M Tsao, H Tucker, MA van der Velden, P Yang, XR Gruis, N AF Demenais, F. Mohamdi, H. Chaudru, V. Goldstein, A. M. Bishop, J. A. Newton Bishop, D. T. Kanetsky, P. A. Hayward, N. K. Gillanders, E. Elder, D. E. Avril, M. F. Azizi, E. van Belle, P. Bergman, W. Bianchi-Scarra, G. Bressac-de Paillerets, B. Calista, D. Carrera, C. Hansson, J. Harland, M. Hogg, D. Hoiom, V. Holland, E. A. Ingvar, C. Landi, M. T. Lang, J. M. Mackie, R. M. Mann, G. J. Ming, M. E. Njauw, C. J. Olsson, H. Palmer, J. Pastorino, L. Puig, S. Randerson-Moor, J. Stark, M. Tsao, H. Tucker, M. A. van der Velden, P. Yang, X. R. Gruis, N. CA Melanoma Genetics Consortium TI Association of MC1R Variants and Host Phenotypes With Melanoma Risk in CDKN2A Mutation Carriers: A GenoMEL Study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HUMAN MELANOCORTIN-1 RECEPTOR; MULTIPLE PRIMARY MELANOMAS; STIMULATING HORMONE; CUTANEOUS MELANOMA; PRONE FAMILIES; GENE VARIANTS; RED HAIR; SKIN PIGMENTATION; HUMAN MELANOCYTES; WIDE ASSOCIATION AB Background Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. Methods We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, >= 2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. Results Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 x 10(-6) < P < .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 x 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 <= P <= .04), hair color (.006 <= P <= .06), and number of nevi (6.9 x 10(-6) <= P <= .02). Conclusion Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings. C1 [Demenais, F.; Mohamdi, H.; Chaudru, V.; Bressac-de Paillerets, B.] Fdn Jean Dausset CEPH, INSERM, U946, F-75010 Paris, France. [Demenais, F.; Mohamdi, H.] Univ Paris Diderot, Inst Univ Hematol, Paris, France. [Chaudru, V.] Univ Evry Val Essonne, Evry, France. [Goldstein, A. M.; Landi, M. T.; Tucker, M. A.; Yang, X. R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bishop, J. A. Newton; Bishop, D. T.; Harland, M.; Randerson-Moor, J.] St James Univ Hosp, Epidemiol & Biostat Sect, Leeds Inst Mol Med, Canc Res UK Clin Ctr, Leeds LS9 7TF, W Yorkshire, England. [Kanetsky, P. A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kanetsky, P. A.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Hayward, N. K.; Palmer, J.; Stark, M.] Queensland Inst Med Res, Oncogen Lab, Brisbane, Qld 4006, Australia. [Gillanders, E.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Elder, D. E.; van Belle, P.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Avril, M. F.] Univ Paris 05, Serv Dermatol, Hop Cochin, AP HP, Paris, France. [Azizi, E.] Tel Aviv Univ, Dept Dermatol, Sheba Med Ctr, Sackler Fac Med, Tel Aviv, Israel. [Bergman, W.; van der Velden, P.; Gruis, N.] Leiden Univ Med Ctr, Dept Dermatol, Leiden, Netherlands. [Bianchi-Scarra, G.; Pastorino, L.] Univ Genoa, Dept Oncol Biol & Genet, I-16126 Genoa, Italy. [Bianchi-Scarra, G.] San Martino Hosp, Lab Genet Rare Hereditary Canc, Genoa, Italy. [Bressac-de Paillerets, B.] Inst Canc Gustave Roussy, Dept Mol Genet, Villejuif, France. [Calista, D.] Maurizio Bufalini Hosp, Dermatol Unit, Cesena, Italy. [Gillanders, E.] Hosp Clin Barcelona, Dept Dermatol, Melanoma Unit, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain. [Carrera, C.; Puig, S.] Ctr Invest Biomed Red CIBER Enfermedades Rares, Barcelona, Spain. [Hansson, J.; Hoiom, V.] Karolinska Univ Hosp Solna, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Hogg, D.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Hogg, D.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Holland, E. A.; Mann, G. J.] Univ Sydney, Westmead Inst Canc Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Holland, E. A.; Mann, G. J.] Melanoma Inst Australia, Westmead, NSW, Australia. [Ingvar, C.] Univ Lund Hosp, Dept Surg, S-22185 Lund, Sweden. [Lang, J. M.; Mackie, R. M.] Univ Glasgow, Dept Med Genet, Glasgow, Lanark, Scotland. [Lang, J. M.; Mackie, R. M.] Univ Glasgow, Dept Publ Hlth, Glasgow, Lanark, Scotland. [Ming, M. E.] Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Ming, M. E.] Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Njauw, C. J.; Tsao, H.] Massachusetts Gen Hosp, Wellman Ctr Photomed, MGH Melanoma & Pigmented Les Ctr, Boston, MA 02114 USA. [Njauw, C. J.; Tsao, H.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Olsson, H.] Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. RP Demenais, F (reprint author), Fdn Jean Dausset CEPH, INSERM, U946, 27 Rue Juliette Dodu, F-75010 Paris, France. EM florence.demenais@inserm.fr RI Stark, Mitchell/E-3542-2010; Mann, Graham/G-4758-2014; Bianchi Scarra, Giovanna/G-8933-2014; Demenais, Florence/G-3298-2013; Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; Duffy, David/B-7392-2013; Marti, Rosa/A-2256-2010; Bruno, William/N-7477-2013; Hoiom, Veronica/F-4153-2012; bertazzi, pietro alberto/D-5039-2017 OI Bishop, Tim/0000-0002-8752-8785; Newton Bishop, Julia/0000-0001-9147-6802; Puig, Susana/0000-0003-1337-9745; CARRERA, CRISTINA/0000-0003-1608-8820; Badenas, Celia/0000-0002-0621-0477; Gruis, Nelleke/0000-0002-5210-9150; Stark, Mitchell/0000-0002-4510-2161; Mann, Graham/0000-0003-1301-405X; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; hayward, nicholas/0000-0003-4760-1033; Duffy, David/0000-0001-7227-632X; Marti, Rosa/0000-0001-6866-6114; Bruno, William/0000-0002-0337-0168; bertazzi, pietro alberto/0000-0003-3475-2449 FU European Community [LSH-CT-2006-018702]; National Institutes of Health [RO1 CA83115, RO1 CA88363, RO1 CA5558-01A2]; Ligue Nationale contre le Cancer [PRE05/FD, PRE09/FD]; Programme Hospitalier de Recherche Clinique [PHRC 2007-AOM-07-195]; French Institut National du Cancer [13]; National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health; Cancer Research UK Programme [C588/A4994]; Australian National Health and Medical Research Council; Cancer Councils of New South Wales, Victoria and Queensland; Cancer Institute NSW; Italian Ministry of Health [DGRST. 4/4235-P1.9. A. B]; Swedish Cancer Society; Radiumhemmet Research Funds; Swedish Research Council; Swedish Cancer foundation; Regional funds in Skane; University Hospital in Lund; Fondo de Investigaciones Sanitarias, Spain [03/0019, 05/0302, 06/0265] FX European Community FP6 Network of Excellence Award (LSH-CT-2006-018702 to J.A.N.B. and N.G.); the National Institutes of Health (RO1 CA83115 to D. E. E., RO1 CA88363 to N.K.H., RO1 CA5558-01A2 to M. T. L.); the Ligue Nationale contre le Cancer (PRE05/FD and PRE09/FD to F. D.); the Programme Hospitalier de Recherche Clinique (PHRC 2007-AOM-07-195 to F. D. and M. F. A.); the French Institut National du Cancer (Melanoma Network RS Number 13 to BB-dP); the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health to A. M. G, M. T. L., M. A. T and X.R.Y.; the Cancer Research UK Programme Award (C588/A4994 to J.A.N.B. and D. T. B.); the Australian National Health and Medical Research Council (to N.K.H. and to G.J.M.); the Cancer Councils of New South Wales, Victoria and Queensland to N.K.H. and G.J.M.; the Cancer Institute NSW to N.K.H. and G.J.M.; the Italian Ministry of Health (DGRST. 4/4235-P1.9. A. B to G. B-S.); the Swedish Cancer Society to J.H.: the Radiumhemmet Research Funds to J.H.; the Swedish Research Council to J.H; the Swedish Cancer foundation to C. I and H.O.; the Regional funds in Skane to C. I and H.O.; the funds at the University Hospital in Lund to C. I and H.O.; and Fondo de Investigaciones Sanitarias, Spain (03/0019, 05/0302, 06/0265 to S.P.). NR 59 TC 38 Z9 40 U1 0 U2 10 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 OCT PY 2010 VL 102 IS 20 BP 1568 EP 1583 DI 10.1093/jnci/djq363 PG 16 WC Oncology SC Oncology GA 673PS UT WOS:000283676000010 PM 20876876 ER PT J AU Howlader, N Ries, LAG Mariotto, AB Reichman, ME Ruhl, J Cronin, KA AF Howlader, Nadia Ries, Lynn A. G. Mariotto, Angela B. Reichman, Marsha E. Ruhl, Jennifer Cronin, Kathleen A. TI Improved Estimates of Cancer-Specific Survival Rates From Population-Based Data SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID DEATH CERTIFICATES; RELATIVE SURVIVAL; MORTALITY; US AB Background Accurate estimates of cancer survival are important for assessing optimal patient care and prognosis. Evaluation of these estimates via relative survival (a ratio of observed and expected survival rates) requires a population life table that is matched to the cancer population by age, sex, race and/or ethnicity, socioeconomic status, and ideally risk factors for the cancer under examination. Because life tables for all subgroups in a study may be unavailable, we investigated whether cause-specific survival could be used as an alternative for relative survival. Methods We used data from the Surveillance, Epidemiology, and End Results Program for 2 330 905 cancer patients from January 1, 1992, through December 31, 2004. We defined cancer-specific deaths according to the following variables: cause of death, only one tumor or the first of multiple tumors, site of the original cancer diagnosis, and comorbidities. Estimates of relative survival and cause-specific survival that were derived by use of an actuarial method were compared. Results Among breast cancer patients who were white, black, or of Asian or Pacific Islander descent and who were older than 65 years, estimates of 5-year relative survival (107.5%, 106.6%, and 103.0%, respectively) were higher than estimates of 5-year cause-specific survival (98.6%, 95% confidence interval [CI] = 98.4% to 98.8%; 97.4%, 95% CI = 96.2% to 98.2%; and 99.2%, 95% CI = 98.4%, 99.6%, respectively). Relative survival methods likely underestimated rates for cancers of the oral cavity and pharynx (eg, for white cancer patients aged >= 65 years, relative survival = 54.2%, 95% CI = 53.1% to 55.3%, and cause-specific survival = 60.1%, 95% CI = 59.1% to 60.9%) and the lung and bronchus (eg, for black cancer patients aged >65 years, relative survival = 10.5%, 95% CI = 9.9% to 11.2%, and cause-specific survival = 11.9%, 95% CI = 11.2 % to 12.6%), largely because of mismatches between the population with these diseases and the population used to derive the life table. Socioeconomic differences between groups with low and high status in relative survival estimates appeared to be inflated (eg, corpus and uterus socioeconomic status gradient was 13.3% by relative survival methods and 8.8% by cause-specific survival methods). Conclusion Although accuracy of the cause of death on a death certificate can be problematic for cause-specific survival estimates, cause-specific survival methods may be an alternative to relative survival methods when suitable life tables are not available. C1 [Howlader, Nadia] NCI, Data Anal & Interpretat Branch, Surveillance Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20892 USA. RP Howlader, N (reprint author), NCI, Data Anal & Interpretat Branch, Surveillance Res Program, Div Canc Control & Populat Sci,NIH, 6116 Executive Blvd,Ste 504, Bethesda, MD 20892 USA. EM howladern@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX Division of Cancer Control and Population Sciences, Surveillance Research Program, National Cancer Institute, National Institutes of Health. NR 28 TC 121 Z9 128 U1 0 U2 7 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 OCT PY 2010 VL 102 IS 20 BP 1584 EP 1598 DI 10.1093/jnci/djq366 PG 15 WC Oncology SC Oncology GA 673PS UT WOS:000283676000011 PM 20937991 ER PT J AU Raffensperger, S Kuczmarski, MF Hotchkiss, L Cotugna, N Evans, MK Zonderman, AB AF Raffensperger, Sarah Kuczmarski, Marie Fanelli Hotchkiss, Lawrence Cotugna, Nancy Evans, Michele K. Zonderman, Alan B. TI Effect of Race and Predictors of Socioeconomic Status on Diet Quality in the HANDLS Study Sample SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE race/ethnicity; socioeconomic status; antioxidants; free radicals; superoxides ID FOOD STORE AVAILABILITY; MISSISSIPPI-DELTA; NATIONAL-HEALTH; UNITED-STATES; US ADULTS; NUTRITION; PREVENTION; PATTERNS; NEIGHBORHOOD; POPULATION AB Purpose: To examine effects of race and predictors of socioeconomic status (SES) on nutrient-based diet quality and their contribution to health disparities in an urban population of low SES. Design: Data were analyzed from a sample of the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) Study participants examining effects of age, sex, race, income, poverty income ratio, education, employment, and smoking status on nutrient-based diet quality as measured by a micronutrient composite index of nutrient adequacy ratios and a mean adequacy ratio. Regression models were used to examine associations and t tests were used to look at racial differences. Subjects: African American and white adults ages 30 to 64 years residing in 12 predefined census tracts in Baltimore, Maryland. Results: Sex, age, education, poverty income ratio, and income were statistically significant predictors of diet quality for African Americans, while sex, education, and smoking status were statistically significant for whites. African Americans had lower mean adequacy ratio scores than whites (76.4 vs 79.1). Whites had significantly higher nutrient adequacy ratios scores for thiamin, riboflavin, folate, B(12), vitamins A and E, magnesium, copper, zinc, and calcium, while African Americans had higher vitamin C scores. Conclusion: Education significantly impacted diet quality in the HANDLS sample, but race cannot be discounted. Whether the racial differences in diet quality are indicative of cultural differences in food preferences, selection, preparation, and availability, or disparities in socioeconomic status remains unclear. C1 [Raffensperger, Sarah; Kuczmarski, Marie Fanelli; Cotugna, Nancy] Univ Delaware, Dept Hlth Nutr & Exercise Sci, Newark, DE 19716 USA. [Hotchkiss, Lawrence] Univ Delaware, Dept Informat Technol, Newark, DE 19716 USA. [Evans, Michele K.; Zonderman, Alan B.] NIA, Biomed Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. RP Cotugna, N (reprint author), Univ Delaware, Dept Hlth Nutr & Exercise Sci, Newark, DE 19716 USA. EM ncotugna@udel.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute of Aging, National Institutes of Health FX This research was funded by the Intramural Research Program of the National Institute of Aging, National Institutes of Health. NR 40 TC 20 Z9 20 U1 0 U2 12 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD OCT PY 2010 VL 102 IS 10 BP 923 EP 930 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 672VN UT WOS:000283615100009 PM 21053707 ER PT J AU Patz, EF Caporaso, NE Dubinett, SM Massion, PP Hirsch, FR Minna, JD Gatsonis, C Duan, FH Adams, A Apgar, C Medina, RM Aberle, DR AF Patz, Edward F., Jr. Caporaso, Neil E. Dubinett, Steven M. Massion, Pierre P. Hirsch, Fred R. Minna, John D. Gatsonis, Constantine Duan, Fenghai Adams, Amanda Apgar, Charles Medina, Rosa M. Aberle, Denise R. TI National Lung Cancer Screening Trial American College of Radiology Imaging Network Specimen Biorepository Originating from the Contemporary Screening for the Detection of Lung Cancer Trial (NLST, ACRIN 6654) Design, Intent, and Availability of Specimens for Validation of Lung Cancer Biomarkers SO JOURNAL OF THORACIC ONCOLOGY LA English DT Editorial Material ID OVERDIAGNOSIS BIAS; PROJECT; DIAGNOSIS; NODULES C1 [Patz, Edward F., Jr.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Patz, Edward F., Jr.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA. Vanderbilt Univ, Med Ctr, Div Pulm & Crit Care Med, Thorac Oncol Ctr, Nashville, TN USA. [Hirsch, Fred R.] Univ Colorado, Ctr Canc, Aurora, CO USA. [Minna, John D.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Gatsonis, Constantine; Duan, Fenghai; Adams, Amanda] Brown Univ, Ctr Stat Sci, Providence, RI 02912 USA. [Apgar, Charles; Medina, Rosa M.] Amer Coll Radiol, ACRIN Adm, Philadelphia, PA USA. [Aberle, Denise R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci Thorac Imaging & Bioengn, Los Angeles, CA 90095 USA. RP Patz, EF (reprint author), Duke Univ, Med Ctr, Dept Radiol, Box 3808, Durham, NC 27710 USA. EM patz0002@mc.duke.edu RI Duan, Fenghai/J-3709-2014 OI Duan, Fenghai/0000-0002-5084-0070 FU NCI NIH HHS [P50 CA070907, U01 CA079778, U01 CA080098] NR 14 TC 14 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2010 VL 5 IS 10 BP 1502 EP 1506 DI 10.1097/JTO.0b013e3181f1c634 PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 653UI UT WOS:000282122000004 PM 20871260 ER PT J AU Engels, EA AF Engels, Eric A. TI Epidemiology of Thymoma and Associated Malignancies SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article; Proceedings Paper CT 1st International Conference Thymic Malignancies CY AUG 20-21, 2009 CL Bethesda, MD DE Thymoma; Epidemiology; Secondary malignancies; Sarcomas; Cancer registries; Non-Hodgkin's lymphoma ID EPSTEIN-BARR-VIRUS; THYMIC EPITHELIAL TUMORS; IN-SITU HYBRIDIZATION; HUMAN FOAMY VIRUS; MYASTHENIA-GRAVIS; UNITED-STATES; CANCERS; RISK; NEOPLASMS; INFECTION AB Background: Thymoma is a rare malignancy of unknown etiology. Methods: The author examined patterns in thymoma incidence in the US general population using data from Surveillance, Epidemiology, and End Results (SEER) cancer registries. Prior studies concerning the risk of additional malignancies in thymoma patients were reviewed. Results: Based on cancer registry data, the overall incidence of thymoma in the US is 0.13 per 100,000 person-years. Thymoma is exceedingly uncommon in children and young adults, rises in incidence in middle age, and peaks in the seventh decade of life. Thymoma incidence is especially high among Asians and Pacific Islanders in the US. While several studies based at single treatment centers have suggested that thymoma patients have a broadly increased risk for other malignancies, follow up data from US cancer registries support a more limited spectrum of cancer risk. In particular, thymoma patients have a subsequently elevated risk for developing B-cell non-Hodgkin's lymphoma. Based on limited data, thymoma patients may also have an elevated risk for developing soft tissue sarcomas. Discussion: Thymoma is a rare malignancy. The excess risk for non-Hodgkin's lymphoma is consistent with an effect of immune disturbance arising from the thymoma or its treatment. While descriptive epidemiologic data may yield clues to the etiology of thymoma, large multi-center case-control studies will be required to formally evaluate environmental and genetic risk factors. C1 [Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Executive Blvd,EPS 7076, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov NR 34 TC 83 Z9 94 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2010 VL 5 SU 4 BP S260 EP S265 DI 10.1097/JTO.0b013e3181f1f62d PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 658PV UT WOS:000282502800002 PM 20859116 ER PT J AU Giaccone, G AF Giaccone, Giuseppe TI Foreword SO JOURNAL OF THORACIC ONCOLOGY LA English DT Editorial Material C1 [Giaccone, Giuseppe] NCI, Med Oncol & Affiliated Branches, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2010 VL 5 SU 4 BP S259 EP S259 DI 10.1097/JTO.0b013e3181f1f61c PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 658PV UT WOS:000282502800001 PM 20859115 ER PT J AU Lee, DK Hakim, FT Gress, RE AF Lee, Diana K. Hakim, Frances T. Gress, Ronald E. TI The Thymus and the Immune System Layered Levels of Control SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article; Proceedings Paper CT 1st International Conference Thymic Malignancies CY AUG 20-21, 2009 CL Bethesda, MD DE Thymopoiesis; Thymic epithelial cells; Thymocytes; IGF-1; KGF; Androgen withdrawal ID KERATINOCYTE GROWTH-FACTOR; T-CELL DEVELOPMENT; EPITHELIAL-CELLS; IN-VIVO; THYMOPOIESIS; INCREASES; EXPANSION; CONSEQUENCES; RECEPTOR; SUBSETS AB Control points of normal thymopoiesis may provide insights into strategies for interrupting cell interactions in thymomas which appear to maintain active T cell production. Thymus production of T cells represents one of two pathways by which peripheral T cell populations are maintained or, if lost, regenerated. The production of T cells by the thymus results from a series of thymus epithelial cell (TEC) - thymocyte interactions from entry of thymocyte precursors into the thymus to release of mature naive single positive T cells into the periphery. Within this series of interactions, certain control points have been identified, all of which act through TEC to modulate thymopoiesis. C1 [Gress, Ronald E.] NCI, NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Gress, RE (reprint author), NCI, NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, 10 Ctr Dr,Bldg 10,Room CRC3-3350, Bethesda, MD 20892 USA. EM gressr@mail.nih.gov NR 25 TC 5 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2010 VL 5 SU 4 BP S273 EP S276 DI 10.1097/JTO.0b013e3181f20474 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 658PV UT WOS:000282502800004 PM 20859118 ER PT J AU Rajan, A Giaccone, G AF Rajan, Arun Giaccone, Giuseppe TI Targeted Therapy for Advanced Thymic Tumors SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article; Proceedings Paper CT 1st International Conference Thymic Malignancies CY AUG 20-21, 2009 CL Bethesda, MD DE Thymoma; Thymic carcinoma; Targeted therapy; Gefitinib; Imatinib; Belinostat; Sorafenib; Cixutumumab; Octreotide ID SOLID TUMORS; THYMOMA; CARCINOMA; KIT; CETUXIMAB; IMATINIB AB The use of targeted therapies for the treatment of thymic malignancies is documented in the literature. However, only a few drugs have undergone evaluation in phase II trials. Most of the evidence for the benefit of biologic therapies for thymic malignancies is in the form of case reports and small case series. No major activity has been observed with any agent so far, likely due to the lack of selection of patients for targeted therapies and the small numbers studied. A better understanding of the biology of these tumors will be essential in furthering the field. C1 [Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov FU Intramural NIH HHS [ZID BC010951-02] NR 26 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2010 VL 5 SU 4 BP S361 EP S364 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 658PV UT WOS:000282502800020 PM 20859134 ER PT J AU Wright, CD AF Wright, Cameron D. TI Extended Resections for Thymic Malignancies SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article; Proceedings Paper CT 1st International Conference Thymic Malignancies CY AUG 20-21, 2009 CL Bethesda, MD DE Thymic malignancy; Superior vena cava resection; Pleuropneumonectomy ID SUPERIOR VENA-CAVA; STAGE IVA THYMOMA; MEDIASTINAL MALIGNANCIES; MULTIMODALITY THERAPY; TUMORS; MANAGEMENT; RECURRENCE; REPLACEMENT; PREDICTORS; INVASION AB Almost all series reporting on the results of resection in thymic tumors indicate that the performance of a complete resection is probably the most important prognostic factor. This issue is not a factor in Masaoka stage I and II tumors that are almost always easily completely resected and have an excellent prognosis. Masaoka stage III tumors that invade the pericardium, lungs, or great vessels have relatively higher incomplete resection rates, significantly higher recurrence rates, and thus a worse prognosis. There are several small reports on the efficacy of resection of the great veins when involved by a thymic malignancy with low morbidity and meaningful long-term survival. Superior vena cava reconstruction is commonly performed by a polytetrafluroethylene, venous, or pericardial graft. These cases can usually be identified preoperatively and, thus, considered for induction therapy. Because these types of cases are almost always of marginal respectability in terms of obtaining a true en bloc resection, there is an increasing enthusiasm for offering induction therapy in an effort to enhance resectability. Preliminary results suggest increased R0 resection rates and improved survival with induction therapy for locally advanced tumors. The optimal induction treatment is unknown. The ultimate extended surgery for advanced thymic tumors is an extrapleural pneumonectomy performed for extensive pleural disease (Masaoka stage IVA). These rarely performed operations are done for IVA disease found at initial presentation and for recurrent disease as a salvage procedure. Again these advanced patients are probably best managed by induction chemotherapy followed by resection. C1 [Wright, Cameron D.] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [Wright, Cameron D.] NCI, Dept Med Oncol, Bethesda, MD 20892 USA. RP Wright, CD (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,32 Fruit St, Boston, MA 02114 USA. EM cdwright@partners.org NR 22 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2010 VL 5 SU 4 BP S344 EP S347 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 658PV UT WOS:000282502800016 PM 20859130 ER PT J AU Crane, NJ Gillern, SM Tajkarimi, K Levin, IW Pinto, PA Elster, EA AF Crane, Nicole J. Gillern, Suzanne M. Tajkarimi, Kambiz Levin, Ira W. Pinto, Peter A. Elster, Eric A. TI Visual Enhancement of Laparoscopic Partial Nephrectomy With 3-Charge Coupled Device Camera: Assessing Intraoperative Tissue Perfusion and Vascular Anatomy by Visible Hemoglobin Spectral Response SO JOURNAL OF UROLOGY LA English DT Article DE kidney; nephrectomy; video-assisted surgery; laparoscopy; ischemia ID NEPHRON SPARING SURGERY; PATHOLOGICAL OUTCOMES; RENAL ISCHEMIA; WARM ISCHEMIA; HILAR TUMORS; SHORT-TERM; FEASIBILITY; TECHNOLOGY; IMPACT AB Purpose: We report the novel use of 3-charge coupled device camera technology to infer tissue oxygenation. The technique can aid surgeons to reliably differentiate vascular structures and noninvasively assess laparoscopic intraoperative changes in renal tissue perfusion during and after warm ischemia. Materials and Methods: We analyzed select digital video images from 10 laparoscopic partial nephrectomies for their individual 3-charge coupled device response. We enhanced surgical images by subtracting the red charge coupled device response from the blue response and overlaying the calculated image on the original image. Mean intensity values for regions of interest were compared and used to differentiate arterial and venous vasculature, and ischemic and nonischemic renal parenchyma. Results: The 3-charge coupled device enhanced images clearly delineated the vessels in all cases. Arteries were indicated by an intense red color while veins were shown in blue. Differences in mean region of interest intensity values for arteries and veins were statistically significant (p > 0.0001). Three-charge coupled device analysis of pre-clamp and post-clamp renal images revealed visible, dramatic color enhancement for ischemic vs nonischemic kidneys. Differences in the mean region of interest intensity values were also significant (p < 0.05). Conclusions: We present a simple use of conventional 3-charge coupled device camera technology in a way that may provide urological surgeons with the ability to reliably distinguish vascular structures during hilar dissection, and detect and monitor changes in renal tissue perfusion during and after warm ischemia. C1 [Crane, Nicole J.; Gillern, Suzanne M.; Elster, Eric A.] Uniformed Serv Univ Hlth Sci, Naval Med Res Ctr, Dept Regenerat Med, Silver Spring, MD 20910 USA. [Tajkarimi, Kambiz; Pinto, Peter A.] NCI, NIH, Bethesda, MD 20892 USA. [Levin, Ira W.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Elster, Eric A.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. [Gillern, Suzanne M.] Walter Reed Army Med Ctr, Dept Surg, Washington, DC 20307 USA. [Tajkarimi, Kambiz] George Washington Univ, Dept Urol, Washington, DC USA. RP Elster, EA (reprint author), Uniformed Serv Univ Hlth Sci, Naval Med Res Ctr, Dept Regenerat Med, 503 Robert Grant Ave,Suite 2W123, Silver Spring, MD 20910 USA. EM eric.elster@med.navy.mil FU United States Navy Bureau of Medicine and Surgery [PE 0604771N]; Office of Naval Research work unit [604771N.0933. 001.A0812]; Vibernet FX Supported by the United States Navy Bureau of Medicine and Surgery under the Medical Development Program (PE 0604771N), Office of Naval Research work unit No. 604771N.0933. 001.A0812, Combat Wound Initiative Program and intramural program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.; Financial interest and/or other relationship with Vibernet. NR 29 TC 18 Z9 18 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2010 VL 184 IS 4 BP 1279 EP 1285 DI 10.1016/j.juro.2010.06.010 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 660CB UT WOS:000282615400010 PM 20723937 ER PT J AU Rockx, B Bossart, KN Feldmann, F Geisbert, JB Hickey, AC Brining, D Callison, J Safronetz, D Marzi, A Kercher, L Long, D Broder, CC Feldmann, H Geisbert, TW AF Rockx, Barry Bossart, Katharine N. Feldmann, Friederike Geisbert, Joan B. Hickey, Andrew C. Brining, Douglas Callison, Julie Safronetz, David Marzi, Andrea Kercher, Lisa Long, Dan Broder, Christopher C. Feldmann, Heinz Geisbert, Thomas W. TI A Novel Model of Lethal Hendra Virus Infection in African Green Monkeys and the Effectiveness of Ribavirin Treatment SO JOURNAL OF VIROLOGY LA English DT Article ID NIPAH VIRUS; HAMSTER MODEL; FATAL ENCEPHALITIS; SUBUNIT VACCINE; PARAMYXOVIRUS; PATHOGENESIS; PROTECTION; ANTIBODY; HORSES; DEATH AB The henipaviruses, Hendra virus (HeV) and Nipah virus (NiV), are emerging zoonotic paramyxoviruses that can cause severe and often lethal neurologic and/or respiratory disease in a wide variety of mammalian hosts, including humans. There are presently no licensed vaccines or treatment options approved for human or veterinarian use. Guinea pigs, hamsters, cats, and ferrets, have been evaluated as animal models of human HeV infection, but studies in nonhuman primates (NHP) have not been reported, and the development and approval of any vaccine or antiviral for human use will likely require efficacy studies in an NHP model. Here, we examined the pathogenesis of HeV in the African green monkey (AGM) following intratracheal inoculation. Exposure of AGMs to HeV produced a uniformly lethal infection, and the observed clinical signs and pathology were highly consistent with HeV-mediated disease seen in humans. Ribavirin has been used to treat patients infected with either HeV or NiV; however, its utility in improving outcome remains, at best, uncertain. We examined the antiviral effect of ribavirin in a cohort of nine AGMs before or after exposure to HeV. Ribavirin treatment delayed disease onset by 1 to 2 days, with no significant benefit for disease progression and outcome. Together our findings introduce a new disease model of acute HeV infection suitable for testing antiviral strategies and also demonstrate that, while ribavirin may have some antiviral activity against the henipaviruses, its use as an effective standalone therapy for HeV infection is questionable. C1 [Geisbert, Joan B.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Geisbert, Joan B.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Rockx, Barry; Feldmann, Friederike; Callison, Julie; Safronetz, David; Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Brining, Douglas; Kercher, Lisa; Long, Dan] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Bossart, Katharine N.; Geisbert, Joan B.; Geisbert, Thomas W.] Boston Univ, Sch Med, Natl Emerging Infect Dis Labs Inst, Boston, MA 02118 USA. [Bossart, Katharine N.; Geisbert, Thomas W.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Hickey, Andrew C.; Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. RP Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab, 301 Univ Blvd, Galveston, TX 77555 USA. EM feldmannh@niaid.nih.gov; tom.geisbert@utmb.edu OI Bossart, Katharine/0000-0001-6886-6896 FU Department of Health and Human Services, NIH [AI082121, AI057159]; DIR, NIAID, NIH FX This study was supported in part by the Department of Health and Human Services, NIH, grants AI082121 and AI057159 to Thomas W. Geisbert and funding from DIR, NIAID, NIH, to the Laboratory of Virology. NR 30 TC 47 Z9 47 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 19 BP 9831 EP 9839 DI 10.1128/JVI.01163-10 PG 9 WC Virology SC Virology GA 660KQ UT WOS:000282641800017 PM 20660198 ER PT J AU Abram, ME Ferris, AL Shao, W Alvord, WG Hughes, SH AF Abram, Michael E. Ferris, Andrea L. Shao, Wei Alvord, W. Gregory Hughes, Stephen H. TI Nature, Position, and Frequency of Mutations Made in a Single Cycle of HIV-1 Replication SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RESISTANT REVERSE-TRANSCRIPTASE; RETROVIRAL SHUTTLE VECTOR; DEPENDENT DNA-SYNTHESIS; BOVINE LEUKEMIA-VIRUS; RNA-POLYMERASE-II; IN-VITRO; MUTANT FREQUENCIES; GENETIC-VARIATION; BROAD-SPECTRUM AB There is considerable HIV-1 variation in patients. The extent of the variation is due to the high rate of viral replication, the high viral load, and the errors made during viral replication. Mutations can arise from errors made either by host DNA-dependent RNA polymerase II or by HIV-1 reverse transcriptase (RT), but the relative contributions of these two enzymes to the mutation rate are unknown. In addition, mutations in RT can affect its fidelity, but the effect of mutations in RT on the nature of the mutations that arise in vivo is poorly understood. We have developed an efficient system, based on existing technology, to analyze the mutations that arise in an HIV-1 vector in a single cycle of replication. A lacZ alpha reporter gene is used to identify viral DNAs that contain mutations which are analyzed by DNA sequencing. The forward mutation rate in this system is 1.4 x 10(-5) mutations/bp/cycle, equivalent to the retroviral average. This rate is about 3-fold lower than previously reported for HIV-1 in vivo and is much lower than what has been reported for purified HIV-1 RT in vitro. Although the mutation rate was not affected by the orientation of lacZ alpha, the sites favored for mutations (hot spots) in lacZ alpha depended on which strand of lacZ alpha was present in the viral RNA. The pattern of hot spots seen in lacZ alpha in vivo did not match any of the published data obtained when purified RT was used to copy lacZ alpha in vitro. C1 [Abram, Michael E.; Ferris, Andrea L.; Hughes, Stephen H.] NCI Frederick, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Shao, Wei] SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD USA. [Alvord, W. Gregory] NCI Frederick, Data Management Serv, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI Frederick, HIV Drug Resistance Program, POB B,Bldg 539,Rm 130A, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 78 TC 82 Z9 85 U1 1 U2 21 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 19 BP 9864 EP 9878 DI 10.1128/JVI.00915-10 PG 15 WC Virology SC Virology GA 660KQ UT WOS:000282641800020 PM 20660205 ER PT J AU Burdick, R Smith, JL Chaipan, C Friew, Y Chen, JB Venkatachari, NJ Delviks-Frankenberry, KA Hu, WS Pathak, VK AF Burdick, Ryan Smith, Jessica L. Chaipan, Chawaree Friew, Yeshitila Chen, Jianbo Venkatachari, Narasimhan J. Delviks-Frankenberry, Krista A. Hu, Wei-Shau Pathak, Vinay K. TI P Body-Associated Protein Mov10 Inhibits HIV-1 Replication at Multiple Stages SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; STRESS GRANULES; GENOMIC RNA; VIF PROTEIN; 7SL RNA; APOBEC3G; BODIES; GENE; INFECTION; MICRORNA AB Recent studies have shown that APOBEC3G (A3G), a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication, is localized to cytoplasmic mRNA-processing bodies (P bodies). However, the functional relevance of A3G colocalization with P body marker proteins has not been established. To explore the relationship between HIV-1, A3G, and P bodies, we analyzed the effects of overexpression of P body marker proteins Mov10, DCP1a, and DCP2 on HIV-1 replication. Our results show that overexpression of Mov10, a putative RNA helicase that was previously reported to belong to the DExD superfamily and was recently reported to belong to the Upf1-like group of helicases, but not the decapping enzymes DCP1a and DCP2, leads to potent inhibition of HIV-1 replication at multiple stages. Mov10 overexpression in the virus producer cells resulted in reductions in the steady-state levels of the HIV-1 Gag protein and virus production; Mov10 was efficiently incorporated into virions and reduced virus infectivity, in part by inhibiting reverse transcription. In addition, A3G and Mov10 overexpression reduced proteolytic processing of HIV-1 Gag. The inhibitory effects of A3G and Mov10 were additive, implying a lack of functional interaction between the two inhibitors. Small interfering RNA (siRNA)-mediated knockdown of endogenous Mov10 by 80% resulted in a 2-fold reduction in virus production but no discernible impact on the infectivity of the viruses after normalization for the p24 input, suggesting that endogenous Mov10 was not required for viral infectivity. Overall, these results show that Mov10 can potently inhibit HIV-1 replication at multiple stages. C1 [Burdick, Ryan; Smith, Jessica L.; Chaipan, Chawaree; Friew, Yeshitila; Venkatachari, Narasimhan J.; Delviks-Frankenberry, Krista A.; Pathak, Vinay K.] NCI, HIV Drug Resistance Program, Viral Mutat Sect, Frederick, MD 21702 USA. [Chen, Jianbo; Hu, Wei-Shau] NCI, HIV Drug Resistance Program, Viral Recombinat Sect, Frederick, MD 21702 USA. RP Pathak, VK (reprint author), NCI, HIV Drug Resistance Program, Viral Mutat Sect, POB B,Bldg 535,Room 334, Frederick, MD 21702 USA. EM vinay.pathak@nih.gov RI Delviks-Frankenberry, Krista/M-4822-2013; Chen, Jianbo/N-3737-2014 OI Chen, Jianbo/0000-0001-6491-6577 FU NIH, Center for Cancer Research, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. NR 50 TC 69 Z9 73 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 19 BP 10241 EP 10253 DI 10.1128/JVI.00585-10 PG 13 WC Virology SC Virology GA 660KQ UT WOS:000282641800055 PM 20668078 ER PT J AU Kong, L Huang, CC Coales, SJ Molnar, KS Skinner, J Hamuro, Y Kwong, PD AF Kong, Leopold Huang, Chih-chin Coales, Stephen J. Molnar, Kathleen S. Skinner, Jeff Hamuro, Yoshitomo Kwong, Peter D. TI Local Conformational Stability of HIV-1 gp120 in Unliganded and CD4-Bound States as Defined by Amide Hydrogen/Deuterium Exchange SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HYDROGEN-DEUTERIUM EXCHANGE; CORECEPTOR-BINDING-SITE; MASS-SPECTROMETRY; ENVELOPE GLYCOPROTEIN; PROTEIN-STRUCTURE; ATOMIC-STRUCTURE; STRUCTURAL BASIS; HUMAN CD4; RECEPTOR AB The binding reaction of the HIV-1 gp120 envelope glycoprotein to the CD4 receptor involves exceptional changes in enthalpy and entropy. Crystal structures of gp120 in unliganded and various ligand-bound states, meanwhile, reveal an inner domain able to fold into diverse conformations, a structurally invariant outer domain, and, in the CD4-bound state, a bridging sheet minidomain. These studies, however, provide only hints as to the flexibility of each state. Here we use amide hydrogen/deuterium exchange coupled to mass spectrometry to provide quantifications of local conformational stability for HIV-1 gp120 in unliganded and CD4-bound states. On average, unliganded core gp120 displayed >10,000-fold slower exchange of backbone-amide hydrogens than a theoretically unstructured protein of the same composition, with binding by CD4 reducing the rate of gp120 amide exchange a further 10-fold. For the structurally constant CD4, alterations in exchange correlated well with alterations in binding surface (P value = 0.0004). For the structurally variable gp120, however, reductions in flexibility extended outside the binding surface, and regions of expected high structural diversity (inner domain/bridging sheet) displayed roughly 20-fold more rapid exchange in the unliganded state than regions of low diversity (outer domain). Thus, despite an extraordinary reduction in entropy, neither unliganded gp120 nor free CD4 was substantially unstructured, suggesting that most of the diverse conformations that make up the gp120 unliganded state are reasonably ordered. The results provide a framework for understanding how local conformational stability influences entropic change, conformational diversity, and structural rearrangements in the gp120-CD4 binding reaction. C1 [Kong, Leopold; Huang, Chih-chin; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kong, Leopold] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Coales, Stephen J.; Molnar, Kathleen S.; Hamuro, Yoshitomo] ExSAR Corp, Monmouth Jct 08852, NJ USA. [Skinner, Jeff] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 4508, Bethesda, MD 20892 USA. EM pdkwong@nih.gov OI Skinner, Jeff/0000-0001-5697-0442 FU NIH; Bill and Melinda Gates Foundation Grand Challenges in Global Heath Initiative; NIH/Oxford/Cambridge FX Support for this work was provided by the NIH Intramural Research Program, a grant from the Bill and Melinda Gates Foundation Grand Challenges in Global Heath Initiative, and the NIH/Oxford/Cambridge Graduate Partnerships Program. NR 49 TC 27 Z9 27 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 19 BP 10311 EP 10321 DI 10.1128/JVI.00688-10 PG 11 WC Virology SC Virology GA 660KQ UT WOS:000282641800061 PM 20660185 ER PT J AU Geisbert, TW Bailey, M Geisbert, JB Asiedu, C Roederer, M Grazia-Pau, M Custers, J Jahrling, P Goudsmit, J Koup, R Sullivan, NJ AF Geisbert, Thomas W. Bailey, Michael Geisbert, Joan B. Asiedu, Clement Roederer, Mario Grazia-Pau, Maria Custers, Jerome Jahrling, Peter Goudsmit, Jaap Koup, Richard Sullivan, Nancy J. TI Vector Choice Determines Immunogenicity and Potency of Genetic Vaccines against Angola Marburg Virus in Nonhuman Primates SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL RESPONSES; DNA VACCINES; EBOLA-VIRUS; HEMORRHAGIC-FEVER; GUINEA-PIGS; INFECTION; PROTECTION; PATHOGENESIS; VACCINATION; HUMANS AB The immunogenicity and durability of genetic vaccines are influenced by the composition of gene inserts and choice of delivery vector. DNA vectors are a promising vaccine approach showing efficacy when combined in prime-boost regimens with recombinant protein or viral vectors, but they have shown limited comparative efficacy as a stand-alone platform in primates, due possibly to suboptimal gene expression or cell targeting. Here, regimens using DNA plasmids modified for optimal antigen expression and recombinant adenovirus (rAd) vectors, all encoding the glycoprotein (GP) gene from Angola Marburg virus (MARV), were compared for their ability to provide immune protection against lethal MARV Angola infection. Heterologous DNA-GP/rAd5-GP prime-boost and single-modality rAd5-GP, as well as the DNA-GP-only vaccine, prevented death in all vaccinated subjects after challenge with a lethal dose of MARV Angola. The DNA/DNA vaccine induced humoral responses comparable to those induced by a single inoculation with rAd5-GP, as well as CD4(+) and CD8(+) cellular immune responses, with skewing toward CD4(+) T-cell activity against MARV GP. Vaccine regimens containing rAd-GP, alone or as a boost, exhibited cellular responses with CD8(+) T-cell dominance. Across vaccine groups, CD8(+) T-cell subset dominance comprising cells exhibiting a tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) double-positive functional phenotype was associated with an absence or low frequency of clinical symptoms, suggesting that both the magnitude and functional phenotype of CD8(+) T cells may determine vaccine efficacy against infection by MARV Angola. C1 [Bailey, Michael; Asiedu, Clement; Sullivan, Nancy J.] NIAID, Biodef Res Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Roederer, Mario; Koup, Richard] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Geisbert, Thomas W.; Geisbert, Joan B.] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Jahrling, Peter] NIAID, Integrated Res Facil, NIH, Bethesda, MD 20817 USA. [Grazia-Pau, Maria; Custers, Jerome; Goudsmit, Jaap] Crucell, NL-2333 CN Leiden, Netherlands. RP Sullivan, NJ (reprint author), NIAID, Biodef Res Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM nsullivan@nih.gov NR 28 TC 33 Z9 33 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 19 BP 10386 EP 10394 DI 10.1128/JVI.00594-10 PG 9 WC Virology SC Virology GA 660KQ UT WOS:000282641800068 PM 20660192 ER PT J AU Liu, JY Keele, BF Li, H Keating, S Norris, PJ Carville, A Mansfield, KG Tomaras, GD Haynes, BF Kolodkin-Gal, D Letvin, NL Hahn, BH Shaw, GM Barouch, DH AF Liu, Jinyan Keele, Brandon F. Li, Hui Keating, Sheila Norris, Philip J. Carville, Angela Mansfield, Keith G. Tomaras, Georgia D. Haynes, Barton F. Kolodkin-Gal, Dror Letvin, Norman L. Hahn, Beatrice H. Shaw, George M. Barouch, Dan H. TI Low-Dose Mucosal Simian Immunodeficiency Virus Infection Restricts Early Replication Kinetics and Transmitted Virus Variants in Rhesus Monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 INFECTION; DOUBLE-BLIND; VACCINE; RESPONSES; CHALLENGE; TRIAL; METAANALYSIS; SIVMAC251; MACAQUES; THAILAND AB Defining the earliest virologic events following human immunodeficiency virus type 1 (HIV-1) transmission may be critical for the design of vaccine strategies aimed at blocking acquisition of HIV-1 infection. In particular, the length of the eclipse phase and the number of transmitted virus variants may define the window in which a prophylactic vaccine must act. Here we show that the dose of the virus inoculum affects these key virologic parameters following intrarectal simian immunodeficiency virus (SIV) infection of rhesus monkeys. Low-dose SIV infection resulted in a lengthened eclipse phase, fewer transmitted virus variants, and decreased innate immune activation compared with these parameters in high-dose SIV infection. These data suggest a mechanism by which it may be considerably easier for a vaccine to protect against low-risk HIV-1 transmission than against high-risk HIV-1 transmission. These findings have implications for the design and interpretation of HIV-1 vaccine efficacy studies. C1 [Liu, Jinyan; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. [Kolodkin-Gal, Dror; Letvin, Norman L.] Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. [Keele, Brandon F.] NCI, SAIC Frederick, Frederick, MD 21702 USA. [Li, Hui; Hahn, Beatrice H.; Shaw, George M.] Univ Alabama, Birmingham, AL 35294 USA. [Keating, Sheila; Norris, Philip J.] Univ Calif San Francisco, San Francisco, CA 94118 USA. [Keating, Sheila; Norris, Philip J.] Blood Syst Res Inst, San Francisco, CA 94118 USA. [Carville, Angela; Mansfield, Keith G.] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. [Tomaras, Georgia D.; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Barouch, Dan H.] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. RP Barouch, DH (reprint author), Beth Israel Deaconess Med Ctr, Div Vaccine Res, E CLS 1047,330 Brookline Ave, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu RI Keating, Sheila/B-1652-2013; Tomaras, Georgia/J-5041-2016 FU National Institutes of Health Center for HIV/AIDS Vaccine Immunology [AI067854]; National Institutes of Health [AI066305, AI066924, AI078526, AI084794, AI087383, RR000168, HHSN266200400088C] FX We acknowledge support from the National Institutes of Health Center for HIV/AIDS Vaccine Immunology (AI067854), as well as from the National Institutes of Health (AI066305, AI066924, AI078526, AI084794, AI087383, RR000168, and HHSN266200400088C). The authors declare no competing financial interests. NR 21 TC 75 Z9 76 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 19 BP 10406 EP 10412 DI 10.1128/JVI.01155-10 PG 7 WC Virology SC Virology GA 660KQ UT WOS:000282641800071 PM 20686016 ER PT J AU Gosert, R Kardas, P Major, EO Hirsch, HH AF Gosert, Rainer Kardas, Piotr Major, Eugene O. Hirsch, Hans H. TI Rearranged JC Virus Noncoding Control Regions Found in Progressive Multifocal Leukoencephalopathy Patient Samples Increase Virus Early Gene Expression and Replication Rate SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN POLYOMAVIRUS JC; ACTIVE ANTIRETROVIRAL THERAPY; CEREBROSPINAL-FLUID; REGULATORY REGION; IMMUNE RECONSTITUTION; TAT PROTEIN; HUMAN BRAIN; IN-VIVO; SEQUENCES AB Polyomavirus JC (JCV) infects similar to 60% of the general population, followed by asymptomatic urinary shedding in similar to 20%. In patients with pronounced immunodeficiency, including HIV/AIDS, JCV can cause progressive multifocal leukoencephalopathy (PML), a devastating brain disease of high mortality. While JCV in the urine of healthy people has a linear noncoding control region called the archetype NCCR (at-NCCR), JCV in brain and cerebrospinal fluid (CSF) of PML patients bear rearranged NCCRs (rr-NCCRs). Although JCV NCCR rearrangements are deemed pathognomonic for PML, their role as a viral determinant is unclear. We sequenced JCV NCCRs found in CSF of eight HIV/AIDS patients newly diagnosed with PML and analyzed their effect on early and late gene expression using a bidirectional reporter vector recapitulating the circular polyomavirus early and late gene organization. The rr-NCCR sequences were highly diverse, but all increased viral early reporter gene expression in progenitor-derived astrocytes, glia-derived cells, and human kidney compared to the expression levels with the at-NCCR. The expression of simian virus 40 (SV40) large T antigen or HIV Tat expression in trans was associated with a strong increase of at-NCCR-controlled early gene expression, while rr-NCCRs were less responsive. The insertion of rr-NCCRs into the JCV genome backbone revealed higher viral replication rates for rr-NCCR compared to those of the at-NCCR JCV in human progenitor-derived astrocytes or glia cells, which was abrogated in SV40 large T-expressing COS-7 cells. We conclude that naturally occurring JCV rr-NCCR variants from PML patients confer increased early gene expression and higher replication rates compared to those of at-NCCR JCV and thereby increase cytopathology. C1 [Gosert, Rainer; Kardas, Piotr; Hirsch, Hans H.] Univ Basel, Dept Biomed, Inst Med Microbiol, CH-4003 Basel, Switzerland. [Major, Eugene O.] NINDS, NIH, Bethesda, MD 20892 USA. [Hirsch, Hans H.] Univ Basel Hosp, Infect Dis & Hosp Epidemiol, CH-4031 Basel, Switzerland. RP Hirsch, HH (reprint author), Univ Basel, Dept Biomed, Inst Med Microbiol, CH-4003 Basel, Switzerland. EM hans.hirsch@unibas.ch NR 60 TC 54 Z9 54 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 20 BP 10448 EP 10456 DI 10.1128/JVI.00614-10 PG 9 WC Virology SC Virology GA 660KW UT WOS:000282642600002 PM 20686041 ER PT J AU Liu, J Ruckwardt, TJ Chen, M Nicewonger, JD Johnson, TR Graham, BS AF Liu, Jie Ruckwardt, Tracy J. Chen, Man Nicewonger, John D. Johnson, Teresa R. Graham, Barney S. TI Epitope-Specific Regulatory CD4 T Cells Reduce Virus-Induced Illness while Preserving CD8 T-Cell Effector Function at the Site of Infection SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; TRANSCRIPTION FACTOR FOXP3; VIRAL-INFECTION; IMMUNODOMINANCE DISPARITIES; MICE; RESPONSES; DISEASE; SUBSETS; ANTIGEN; MODEL AB The role of epitope-specific regulatory CD4 T cells in modulating CD8 T-cell-mediated immunopathology during acute viral infection has not been well defined. In the murine model of respiratory syncytial virus (RSV) infection, CD8 T cells play an important role in both viral clearance and immunopathology. We have previously characterized two RSV epitope-specific CD4 T-cell responses with distinct phenotypic properties. One of them, the IA(b)M(209)-specific subset, constitutively expresses FoxP3 and modulates CD8 T-cell function in vitro. We show here that the IA(b)M(209)-specific CD4 T-cell response regulates CD8 T-cell function in vivo and is associated with diminished RSV-induced illness without affecting viral clearance at the site of infection. Achieving the optimal balance of regulatory and effector T-cell function is an important consideration for designing future vaccines. C1 [Liu, Jie; Ruckwardt, Tracy J.; Chen, Man; Nicewonger, John D.; Johnson, Teresa R.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU NIAID FX We thank the NIAID-sponsored tetramer core facility at Emory University (Atlanta, GA) for assisting in the construction of the class II tetramers and Mythreyi Shastri for her editorial work. NR 50 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 20 BP 10501 EP 10509 DI 10.1128/JVI.00963-10 PG 9 WC Virology SC Virology GA 660KW UT WOS:000282642600007 PM 20686045 ER PT J AU Radoshitzky, SR Dong, LA Chi, XO Clester, JC Retterer, C Spurgers, K Kuhn, JH Sandwick, S Ruthel, G Kota, K Boltz, D Warren, T Kranzusch, PJ Whelan, SPJ Bavari, S AF Radoshitzky, Sheli R. Dong, Lian Chi, Xiaoli Clester, Jeremiah C. Retterer, Cary Spurgers, Kevin Kuhn, Jens H. Sandwick, Sarah Ruthel, Gordon Kota, Krishna Boltz, Dutch Warren, Travis Kranzusch, Philip J. Whelan, Sean P. J. Bavari, Sina TI Infectious Lassa Virus, but Not Filoviruses, Is Restricted by BST-2/Tetherin SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN SORTING PATHWAY; HUMAN DENDRITIC CELLS; VALLEY FEVER VIRUS; EBOLA-VIRUS; MATRIX PROTEIN; NIPAH-VIRUS; SIGNAL PEPTIDE; INTERFERON RESPONSE; ZAIRE EBOLAVIRUS; IN-VITRO AB Bone marrow stromal antigen 2 (BST-2/tetherin) is a cellular membrane protein that inhibits the release of HIV-1. We show for the first time, using infectious viruses, that BST-2 also inhibits egress of arenaviruses but has no effect on filovirus replication and spread. Specifically, infectious Lassa virus (LASV) release significantly decreased or increased in human cells in which BST-2 was either stably expressed or knocked down, respectively. In contrast, replication and spread of infectious Zaire ebolavirus (ZEBOV) and Lake Victoria marburgvirus (MARV) were not affected by these conditions. Replication of infectious Rift Valley fever virus (RVFV) and cowpox virus (CPXV) was also not affected by BST-2 expression. Elevated cellular levels of human or murine BST-2 inhibited the release of virus-like particles (VLPs) consisting of the matrix proteins of multiple highly virulent NIAID Priority Pathogens, including arenaviruses (LASV and Machupo virus [MACV]), filoviruses (ZEBOV and MARV), and paramyxoviruses (Nipah virus). Although the glycoproteins of filoviruses counteracted the antiviral activity of BST-2 in the context of VLPs, they could not rescue arenaviral (LASV and MACV) VLP release upon BST-2 overexpression. Furthermore, we did not observe colocalization of filoviral glycoproteins with BST-2 during infection with authentic viruses. None of the arenavirus-encoded proteins rescued budding of VLPs in the presence of BST-2. Our results demonstrate that BST-2 might be a broad antiviral factor with the ability to restrict release of a wide variety of human pathogens. However, at least filoviruses, RVFV, and CPXV are immune to its inhibitory effect. C1 [Radoshitzky, Sheli R.; Dong, Lian; Chi, Xiaoli; Clester, Jeremiah C.; Retterer, Cary; Spurgers, Kevin; Sandwick, Sarah; Ruthel, Gordon; Kota, Krishna; Boltz, Dutch; Warren, Travis; Bavari, Sina] USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Kuhn, Jens H.] Tunnell Consulting, King Of Prussia, PA 19406 USA. [Kranzusch, Philip J.; Whelan, Sean P. J.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Bavari, S (reprint author), USA, Med Res Inst Infect Dis, 1425 Porter St,Natl Interagency Biodef Campus, Frederick, MD 21702 USA. EM sina.bavari@amedd.army.mil RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 FU Joint Science and Technology Office for Chemical and Biological Defense [4.10022_08_RD_B] FX Work performed at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) was supported by grant 4.10022_08_RD_B from the Joint Science and Technology Office for Chemical and Biological Defense. NR 66 TC 74 Z9 78 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 20 BP 10569 EP 10580 DI 10.1128/JVI.00103-10 PG 12 WC Virology SC Virology GA 660KW UT WOS:000282642600013 PM 20686043 ER PT J AU Karanam, B Peng, SW Li, T Buck, C Day, PM Roden, RBS AF Karanam, Balasubramanyam Peng, Shiwen Li, Tong Buck, Christopher Day, Patricia M. Roden, Richard B. S. TI Papillomavirus Infection Requires gamma Secretase SO JOURNAL OF VIROLOGY LA English DT Article ID MINOR CAPSID PROTEIN; POSITIVELY CHARGED TERMINI; AMYLOID PRECURSOR PROTEIN; VIRUS-LIKE PARTICLES; HUMAN KERATINOCYTES; HEPARAN-SULFATE; EXTRACELLULAR-MATRIX; L2; MEMBRANE; PATHWAY AB The mechanism by which papillomaviruses breach cellular membranes to deliver their genomic cargo to the nucleus is poorly understood. Here, we show that infection by a broad range of papillomavirus types requires the intramembrane protease gamma secretase. The gamma-secretase inhibitor (S, S)-2-[2-(3,5-difluorophenyl)-acetylamino]- N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4] diazepin-3-yl)-propionamide (compound XXI) inhibits infection in vitro by all types of papillomavirus pseudovirions tested, with a 50% inhibitory concentration (IC(50)) of 130 to 1,000 pM, regardless of reporter construct and without impacting cellular viability. Conversely, XXI does not inhibit in vitro infection by adenovirus or pseudovirions derived from the BK or Merkel cell polyomaviruses. Vaginal application of XXI prevents infection of the mouse genital tract by human papillomavirus type 16 (HPV16) pseudovirions. Nicastrin and presenilin-1 are essential components of the gamma-secretase complex, and mouse embryo fibroblasts deficient in any one of these components were not infected by HPV16, whereas wild-type and beta-secretase (BACE1)-deficient cells were susceptible. Neither the uptake of HPV16 into Lamp-1-positive perinuclear vesicles nor the disassembly of capsid to reveal both internal L1 and L2 epitopes and bromodeoxyuridine (BrdU)-labeled encapsidated DNA is dependent upon gamma-secretase activity. However, blockade of gamma-secretase activity by XXI prevents the BrdU-labeled DNA encapsidated by HPV16 from reaching the ND10 subnuclear domains. Since prior studies indicate that L2 is critical for endosomal escape and targeting of the viral DNA to ND10 and that gamma secretase is located in endosomal membranes, our findings suggest that either L2 or an intracellular receptor are cleaved by gamma secretase as papillomavirus escapes the endosome. C1 [Karanam, Balasubramanyam; Peng, Shiwen; Li, Tong; Roden, Richard B. S.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21231 USA. [Roden, Richard B. S.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21231 USA. [Roden, Richard B. S.] Johns Hopkins Univ, Dept Gynecol & Obstet, Baltimore, MD 21231 USA. [Buck, Christopher; Day, Patricia M.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Roden, RBS (reprint author), Johns Hopkins Univ, Dept Pathol, Room 308,Canc Res Bldg 2,1550 Orleans St, Baltimore, MD 21231 USA. EM roden@jhmi.edu FU National Institutes of Health, National Cancer Institute [R01CA118790, R01 CA133749]; SPORE in Cervical Cancer [P50 CA098252]; GlaxoSmithKline FX Funding for this study was provided by the National Institutes of Health, National Cancer Institute (grants R01CA118790 and R01 CA133749) and SPORE in Cervical Cancer (grant P50 CA098252 to R. B. S. R.).; R. B. S. R. has served as a paid consultant of Merck & Co, Inc., and Knobbe Martens Olson & Bear LLC. R. B. S. R. has received unrestricted educational grant funding from GlaxoSmithKline. R. B. S. R. is a coinventor on L2 patents licensed to Shantha Biotechnics, Ltd., PaxVax, Inc., and Acambis, Inc., and to GlaxoSmithKline. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. NR 53 TC 30 Z9 30 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 20 BP 10661 EP 10670 DI 10.1128/JVI.01081-10 PG 10 WC Virology SC Virology GA 660KW UT WOS:000282642600021 PM 20702627 ER PT J AU Schmeisser, H Mejido, J Balinsky, CA Morrow, AN Clark, CR Zhao, T Zoon, KC AF Schmeisser, H. Mejido, J. Balinsky, C. A. Morrow, A. N. Clark, C. R. Zhao, T. Zoon, K. C. TI Identification of Alpha Interferon-Induced Genes Associated with Antiviral Activity in Daudi Cells and Characterization of IFIT3 as a Novel Antiviral Gene SO JOURNAL OF VIROLOGY LA English DT Article ID INDUCED NUCLEAR FACTORS; STIMULATED GENES; IFN-ALPHA; IN-VITRO; ANTIPROLIFERATIVE ACTIVITY; PERIPHERAL-BLOOD; PROMOTER ELEMENT; MXA PROTEIN; FOAMY VIRUS; RIG-G AB A novel assay was developed for Daudi cells in which the antiviral (AV) and antiproliferative (AP) activities of interferon (IFN) can be measured simultaneously. Using this novel assay, conditions allowing IFN AV protection but no growth inhibition were identified and selected. Daudi cells were treated under these conditions, and gene expression microarray analyses were performed. The results of the analysis identified 25 genes associated with IFN-alpha AV activity. Upregulation of 23 IFN-induced genes was confirmed by using reverse transcription-PCR. Of 25 gene products, 17 were detected by Western blotting at 24 h. Of the 25 genes, 10 have not been previously linked to AV activity of IFN-alpha. The most upregulated gene was IFIT3 (for IFN-induced protein with tetratricopeptide repeats 3). The results from antibody neutralizing experiments suggested an association of the identified genes with IFN-alpha AV activity. This association was strengthened by results from IFIT3-small interfering RNA transfection experiments showing decreased expression of IFIT3 and a reduction in the AV activity induced by IFN-alpha. Overexpression of IFIT3 resulted in a decrease of virus titer. Transcription of AV genes after the treatment of cells with higher concentrations of IFN having an AP effect on Daudi cells suggested pleiotropic functions of identified gene products. C1 [Zoon, K. C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, Cytokine Biol Sect, NIH, MSC 8001,50 Ctr Dr,Bldg 50,Rm 5515, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU NIH (NIAID) FX This research was supported by the Intramural Research Program of the NIH (NIAID). NR 41 TC 33 Z9 35 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 20 BP 10671 EP 10680 DI 10.1128/JVI.00818-10 PG 10 WC Virology SC Virology GA 660KW UT WOS:000282642600022 PM 20686046 ER PT J AU Alpert, MD Rahmberg, AR Neidermyer, W Ng, SK Carville, A Camp, JV Wilson, RL Piatak, M Mansfield, KG Li, WJ Miller, CJ Lifson, JD Kozlowski, PA Evans, DT AF Alpert, Michael D. Rahmberg, Andrew R. Neidermyer, William Ng, Sharon K. Carville, Angela Camp, Jeremy V. Wilson, Robert L. Piatak, Michael, Jr. Mansfield, Keith G. Li, Wenjun Miller, Christopher J. Lifson, Jeffrey D. Kozlowski, Pamela A. Evans, David T. TI Envelope-Modified Single-Cycle Simian Immunodeficiency Virus Selectively Enhances Antibody Responses and Partially Protects against Repeated, Low-Dose Vaginal Challenge SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; RHESUS MACAQUES; ATTENUATED SIV; IN-VIVO; MEDIATED NEUTRALIZATION; MONOCLONAL-ANTIBODIES; REPLICATION-COMPETENT; GLYCOSYLATION SITES AB Immunization of rhesus macaques with strains of simian immunodeficiency virus (SIV) that are limited to a single cycle of infection elicits T-cell responses to multiple viral gene products and antibodies capable of neutralizing lab-adapted SIV, but not neutralization-resistant primary isolates of SIV. In an effort to improve upon the antibody responses, we immunized rhesus macaques with three strains of single-cycle SIV (scSIV) that express envelope glycoproteins modified to lack structural features thought to interfere with the development of neutralizing antibodies. These envelope-modified strains of scSIV lacked either five potential N-linked glycosylation sites in gp120, three potential N-linked glycosylation sites in gp41, or 100 amino acids in the V1V2 region of gp120. Three doses consisting of a mixture of the three envelope-modified strains of scSIV were administered on weeks 0, 6, and 12, followed by two booster inoculations with vesicular stomatitis virus (VSV) G trans-complemented scSIV on weeks 18 and 24. Although this immunization regimen did not elicit antibodies capable of detectably neutralizing SIV(mac)239 or SIV(mac)251(UCD), neutralizing antibody titers to the envelope-modified strains were selectively enhanced. Virus-specific antibodies and T cells were observed in the vaginal mucosa. After 20 weeks of repeated, low-dose vaginal challenge with SIV(mac)251(UCD), six of eight immunized animals versus six of six naive controls became infected. Although immunization did not significantly reduce the likelihood of acquiring immunodeficiency virus infection, statistically significant reductions in peak and set point viral loads were observed in the immunized animals relative to the naive control animals. C1 [Alpert, Michael D.; Rahmberg, Andrew R.; Neidermyer, William; Ng, Sharon K.; Evans, David T.] Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. [Carville, Angela; Mansfield, Keith G.] Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Dept Pathol, Southborough, MA 01772 USA. [Camp, Jeremy V.; Wilson, Robert L.; Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Gene Therapy Program, New Orleans, LA 70112 USA. [Camp, Jeremy V.; Wilson, Robert L.; Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA 70112 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI, SAIC Frederick, Frederick, MD 21702 USA. [Li, Wenjun] Univ Massachusetts, Worcester, MA 01655 USA. [Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. RP Evans, DT (reprint author), Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Dept Microbiol & Mol Genet, 1 Pine Hill Dr, Southborough, MA 01772 USA. EM david_evans@hms.harvard.edu RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 FU National Institutes of Health [AI063993, AI071306, RR000168]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Elizabeth Glaser Pediatric AIDS Foundation FX This work was supported by grants AI063993, AI071306, and RR000168 from the National Institutes of Health and by federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. D.T.E. is an Elizabeth Glaser Scientist supported by the Elizabeth Glaser Pediatric AIDS Foundation. NR 88 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 20 BP 10748 EP 10764 DI 10.1128/JVI.00945-10 PG 17 WC Virology SC Virology GA 660KW UT WOS:000282642600029 PM 20702641 ER PT J AU Kolokithas, A Rosenke, K Malik, F Hendrick, D Swanson, L Santiago, ML Portis, JL Hasenkrug, KJ Evans, LH AF Kolokithas, Angelo Rosenke, Kyle Malik, Frank Hendrick, Duncan Swanson, Lukas Santiago, Mario L. Portis, John L. Hasenkrug, Kim J. Evans, Leonard H. TI The Glycosylated Gag Protein of a Murine Leukemia Virus Inhibits the Antiretroviral Function of APOBEC3 SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VIVO; IDENTIFICATION; RETROVIRUS; CELLS; GENE; PATHOGENESIS; RESTRICTION; INFECTION; STRAINS; XMRV AB APOBEC proteins have evolved as innate defenses against retroviral infections. Human immunodeficiency virus (HIV) encodes the Vif protein to evade human APOBEC3G; however, mouse retroviruses do not encode a Vif homologue, and it has not been understood how they evade mouse APOBEC3. We report here a murine leukemia virus (MuLV) that utilizes its glycosylated Gag protein (gGag) to evade APOBEC3. gGag is critical for infection of in vitro cell lines in the presence of APOBEC3. Furthermore, a gGag-deficient virus restricted for replication in wild-type mice replicates efficiently in APOBEC3 knockout mice, implying a novel role of gGag in circumventing the action of APOBEC3 in vivo. C1 [Kolokithas, Angelo; Rosenke, Kyle; Malik, Frank; Hendrick, Duncan; Swanson, Lukas; Santiago, Mario L.; Portis, John L.; Hasenkrug, Kim J.; Evans, Leonard H.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Evans, LH (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM levans@niaid.nih.gov OI Santiago, Mario L./0000-0001-7792-2706 FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 35 TC 33 Z9 33 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD OCT PY 2010 VL 84 IS 20 BP 10933 EP 10936 DI 10.1128/JVI.01023-10 PG 4 WC Virology SC Virology GA 660KW UT WOS:000282642600048 PM 20702647 ER PT J AU Pinn, VW AF Pinn, Vivian W. TI Seventh Annual NIH Interdisciplinary Women's Health Research Symposium November 9, 2010 SO JOURNAL OF WOMENS HEALTH LA English DT Editorial Material C1 NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. EM orwh-research@od.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD OCT PY 2010 VL 19 IS 10 BP 1777 EP 1778 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 660WF UT WOS:000282676500001 ER PT J AU Kelly, TN Gu, DF Jaquish, CE Rao, DC Chen, J Cao, J Chen, JC Li, JX Lu, FH Ma, JX Mu, JJ Whelton, PK He, JA AF Kelly, Tanika N. Gu, Dongfeng Jaquish, Cashell E. Rao, D. C. Chen, Jing Cao, Jie Chen, Jichun Li, Jianxin Lu, Fanghong Ma, Jixiang Mu, Jianjun Whelton, Paul K. He, Jiang TI Maternal History of Hypertension Predicts Blood Pressure Response to Potassium in a Han Chinese Population: The GenSalt Study SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Kelly, Tanika N.; He, Jiang] Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. [Gu, Dongfeng; Cao, Jie; Chen, Jichun; Li, Jianxin] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100037, Peoples R China. [Gu, Dongfeng; Cao, Jie; Chen, Jichun; Li, Jianxin] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100037, Peoples R China. [Gu, Dongfeng; Cao, Jie; Chen, Jichun; Li, Jianxin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Dongfeng; Cao, Jie; Chen, Jichun; Li, Jianxin] Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing, Peoples R China. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD USA. [Rao, D. C.] Washington Univ, Div Biostat, Sch Med, St Louis, MO 63130 USA. [Chen, Jing] Tulane Univ, Dept Med, Sch Med, New Orleans, LA 70118 USA. [Mu, Jianjun] Xi An Jiao Tong Univ, Dept Med, Xian, Shanxi, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD OCT PY 2010 VL 19 IS 10 BP 1787 EP 1787 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 660WF UT WOS:000282676500033 ER PT J AU Madkour, AS Farhat, T Halpern, CT Godeau, E Gabhainn, SN AF Madkour, Aubrey Spriggs Farhat, Tilda Halpern, Carolyn Tucker Godeau, Emmanuelle Gabhainn, Saoirse Nic TI Early Adolescent Sexual Initiation and Physical/Psychological Symptoms: A Comparative Analysis of Five Nations SO JOURNAL OF YOUTH AND ADOLESCENCE LA English DT Article DE Sexual behavior; Adolescent; Gender differences; Depressive symptoms; Cross-national ID SCHOOL-AGED CHILDREN; DEPRESSIVE SYMPTOMS; NEIGHBORHOOD CONTEXT; DEVELOPED-COUNTRIES; HEALTH COMPLAINTS; FAMILY-STRUCTURE; DOUBLE-STANDARD; UNITED-STATES; BEHAVIOR; YOUTH AB Although most people in developed countries experience sexual initiation during adolescence, little is known about inter-country variability in the psychosocial correlates of early initiation. Population-based samples of 15-year-olds (n = 6,111, 52% female) who participated in the Health Behaviors in School-Aged Children Study (Finland, Scotland, France and Poland, 1997/1998) or the National Longitudinal Study of Adolescent Health (United States, 1996) self-reported sexual intercourse experience and physical (headaches, trouble sleeping) or psychological (unhappiness, loneliness, sadness, moodiness) symptoms. Analyses were conducted stratified by gender. Sexual initiation prevalence and symptoms scores varied significantly across nations. In adjusted models, sexual initiation was not related to symptoms among boys in any nation, but significantly positively related to symptoms among girls in Poland and the US. Results support variability by gender and nation in the relationship between adolescents' sexual initiation and physical/psychological symptoms. Empirically investigating specific features of national contexts that generate these differences should be explored further. C1 [Madkour, Aubrey Spriggs] Tulane Univ, Dept Community Hlth Sci, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. [Farhat, Tilda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Halpern, Carolyn Tucker] Univ N Carolina, Dept Maternal & Child Hlth, Chapel Hill, NC USA. [Halpern, Carolyn Tucker] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Godeau, Emmanuelle] Univ Toulouse 3, INSERM, UMR U558, F-31062 Toulouse, France. [Godeau, Emmanuelle] Acad Toulouse, Serv Med Rectorat, Toulouse, France. [Gabhainn, Saoirse Nic] Natl Univ Ireland Galway, Hlth Promot Res Ctr, Sch Hlth Sci, Galway, Ireland. RP Madkour, AS (reprint author), Tulane Univ, Dept Community Hlth Sci, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. EM aspriggs@tulane.edu FU NICHD NIH HHS [P01 HD031921, T32 HD007168, T32-HD07168, R24 HD050924, L40 HD066680] NR 66 TC 17 Z9 17 U1 0 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0047-2891 J9 J YOUTH ADOLESCENCE JI J. Youth Adolesc. PD OCT PY 2010 VL 39 IS 10 BP 1211 EP 1225 DI 10.1007/s10964-010-9521-x PG 15 WC Psychology, Developmental SC Psychology GA 635UG UT WOS:000280681600008 PM 20333456 ER PT J AU Le Couteur, DG Lakatta, EG AF Le Couteur, David G. Lakatta, Edward G. TI A Vascular Theory of Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID CARDIOVASCULAR-DISEASE ENTERPRISES; SUBCLINICAL ARTERIAL-DISEASE; MAJOR SHAREHOLDERS; HEART-DISEASE; LIFE-SPAN; HEALTH; ATHEROSCLEROSIS; RESTRICTION; RAT C1 [Le Couteur, David G.] Univ Sydney, ANZAC Res Inst, Concord RG Hosp, Sydney, NSW 2139, Australia. [Le Couteur, David G.] Univ Sydney, Ctr Educ & Res Ageing, Concord RG Hosp, Sydney, NSW 2139, Australia. [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Le Couteur, DG (reprint author), Univ Sydney, ANZAC Res Inst, Concord RG Hosp, Sydney, NSW 2139, Australia. EM david.lecouteur@sydney.edu.au NR 29 TC 11 Z9 11 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2010 VL 65 IS 10 BP 1025 EP 1027 DI 10.1093/gerona/glq135 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 651WK UT WOS:000281957800001 PM 20650862 ER PT J AU Ungvari, Z Kaley, G de Cabo, R Sonntag, WE Csiszar, A AF Ungvari, Zoltan Kaley, Gabor de Cabo, Rafael Sonntag, William E. Csiszar, Anna TI Mechanisms of Vascular Aging: New Perspectives SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review DE Vascular aging; Oxidative stress; Endothelial dysfunction; Atherosclerosis; Stroke; Myocardial infarction ID GROWTH-FACTOR-I; NF-KAPPA-B; ENDOTHELIAL PROGENITOR CELLS; TERM CALORIC RESTRICTION; NECROSIS-FACTOR-ALPHA; ACTIVATED PROTEIN-KINASE; AGE-DEPENDENT IMPAIRMENT; GLYCATION END-PRODUCT; NITRIC-OXIDE SYNTHASE; MUSCLE FEED ARTERIES AB This review focuses on molecular, cellular, and functional changes that occur in the vasculature during aging; explores the links between mitochondrial oxidative stress, inflammation, and development of vascular disease in the elderly patients; and provides a landscape of molecular mechanisms involved in cellular oxidative stress resistance, which could be targeted for the prevention or amelioration of unsuccessful vascular aging. Practical interventions for prevention of age-associated vascular dysfunction and disease in old age are considered here based on emerging knowledge of the effects of anti-inflammatory treatments, regular exercise, dietary interventions, and caloric restriction mimetics. C1 [Ungvari, Zoltan; Sonntag, William E.; Csiszar, Anna] Univ Oklahoma, Reynolds Oklahoma Ctr Aging, Dept Geriatr Med, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Kaley, Gabor] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [de Cabo, Rafael] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Ungvari, Z (reprint author), Univ Oklahoma, Reynolds Oklahoma Ctr Aging, Dept Geriatr Med, Hlth Sci Ctr, 975 NE 10th St,BRC 1303, Oklahoma City, OK 73104 USA. EM zoltan-ungvari@ouhsc.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU American Diabetes Association; American Federation for Aging Research; National Institutes of Health (NIH) [HL077256, HL43023, AG11370] FX This work was supported by grants from the American Diabetes Association, the American Federation for Aging Research, and the National Institutes of Health (NIH) (HL077256, HL43023, AG11370) and the Intramural Research Program of NIH (to R.d.C.). NR 188 TC 210 Z9 221 U1 4 U2 26 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2010 VL 65 IS 10 BP 1028 EP 1041 DI 10.1093/gerona/glq113 PG 14 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 651WK UT WOS:000281957800002 PM 20576649 ER PT J AU Lewis, TT Sutton-Tyrrell, K Penninx, BW Vogelzangs, N Harris, TB Vaidean, GD Ayonayon, HN Kim, L Lakatta, EG Newman, AB AF Lewis, Tene T. Sutton-Tyrrell, Kim Penninx, Brenda W. Vogelzangs, Nicole Harris, Tamara B. Vaidean, Georgeta D. Ayonayon, Hilsa N. Kim, Lauren Lakatta, Edward G. Newman, Anne B. TI Race, Psychosocial Factors, and Aortic Pulse Wave Velocity: The Health, Aging, and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Psychosocial; Social support; Arterial stiffness; Cardiovascular disease; African-Americans ID ARTERIAL STIFFNESS; DEPRESSIVE SYMPTOMS; EMOTIONAL SUPPORT; CARDIOVASCULAR REACTIVITY; MYOCARDIAL-INFARCTION; RACIAL-DIFFERENCES; AFRICAN-AMERICAN; SOCIAL NETWORKS; BLOOD-PRESSURE; OLDER-ADULTS AB Background. Increasingly, researchers have begun to explore pathways through which psychosocial factors might influence cardiovascular disease, with some emphasis on early markers. The current study examined the cross-sectional association between psychosocial factors and aortic pulse wave velocity (an early marker of cardiovascular disease) in a biracial cohort of older adults. We were particularly interested in determining whether the association between psychosocial factors and aortic pulse wave velocity differed for older blacks compared with whites. Methods. Participants were 2,488 (40% black and 52% female) older adults from the Health, Aging, and Body Composition Study. Carotid-femoral aortic pulse wave velocity was assessed using standard methodologies. Depressive symptoms, anxiety symptoms, negative life events, and inadequate emotional support were assessed, and a summary psychosocial risk index was created. Results. In multivariable linear regression models, psychosocial risk was not associated with aortic pulse wave velocity (Estimate [Est] = .00, p = .83), but there was a significant Race x Psychosocial risk interaction (Est = .07, p = .01), after adjusting for age, race, sex, and education. Further analyses revealed that this association was driven by the inadequate emotional support component of psychosocial risk (Race x Inadequate emotional support, p = .005). In race-stratified analyses, inadequate emotional support was associated with higher levels of arterial stiffness in older blacks (Est = .05, p = .04) but not whites (Est = -.04, p = .13). This association persisted after adjusting for demographics, cardiovascular risk factors, and social network characteristics. Conclusions. Findings suggest that older blacks may be particularly vulnerable to the effects of inadequate emotional support on vascular health. Interventions aimed at increasing social support among this population might be beneficial in reducing cardiovascular disease risk. C1 [Lewis, Tene T.] Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Sutton-Tyrrell, Kim; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. [Penninx, Brenda W.; Vogelzangs, Nicole] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Penninx, Brenda W.; Vogelzangs, Nicole] Vrije Univ Amsterdam, Med Ctr, Inst Res Extramural Med, Amsterdam, Netherlands. [Harris, Tamara B.; Kim, Lauren] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Vaidean, Georgeta D.] Univ Memphis, Dept Prevent Med, Memphis, TN 38152 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Bethesda, MD 20892 USA. RP Lewis, TT (reprint author), 60 Coll St,4th Floor, New Haven, CT 06520 USA. EM tene.lewis@yale.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Center for Minority Health and Health Disparities; National Heart, Lung, and Blood Institute [HL092591]; National Institutes of Health FX The Health, Aging, and Body Composition Study was funded by the National Institute on Aging (N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106). T.T.L. received additional support from a Visiting Scholar Award funded by the National Center for Minority Health and Health Disparities and a Career Development Award funded by the National Heart, Lung, and Blood Institute (HL092591). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 42 TC 7 Z9 7 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2010 VL 65 IS 10 BP 1079 EP 1085 DI 10.1093/gerona/glq089 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 651WK UT WOS:000281957800007 PM 20522528 ER PT J AU Watson, NL Rosano, C Boudreau, RM Simonsick, EM Ferrucci, L Sutton-Tyrrell, K Hardy, SE Atkinson, HH Yaffe, K Satterfield, S Harris, TB Newman, AB AF Watson, N. L. Rosano, C. Boudreau, R. M. Simonsick, E. M. Ferrucci, L. Sutton-Tyrrell, K. Hardy, S. E. Atkinson, H. H. Yaffe, K. Satterfield, S. Harris, T. B. Newman, A. B. CA Health ABC Study TI Executive Function, Memory, and Gait Speed Decline in Well-Functioning Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Cognitive function; Gait speed ID WHITE-MATTER HYPERINTENSITIES; DWELLING ELDERLY-PEOPLE; BODY-COMPOSITION; COGNITIVE FUNCTION; PHYSICAL PERFORMANCE; WOMENS HEALTH; WALKING SPEED; ASSOCIATION; DISEASE; DISABILITY AB Background. In community-dwelling older adults, global cognitive function predicts longitudinal gait speed decline. Few prospective studies have evaluated whether specific executive cognitive deficits in aging may account for gait slowing over time. Methods. Multiple cognitive tasks were administered at baseline in 909 participants in the Health, Aging, and Body Composition Study Cognitive Vitality Substudy (mean age 75.2 +/- 2.8 years, 50.6% women, 48.4% black). Usual gait speed (m/s) over 20 minutes was assessed at baseline and over a 5-year follow-up. Results. Poorer performance in each cognitive task was cross-sectionally associated with slower gait independent of demographic and health characteristics. In longitudinal analyses, each 1 SD poorer performance in global function, verbal memory, and executive function was associated with 0.003-0.004 m/s greater gait speed decline per year (p=.03-.05) after adjustment for baseline gait speed, demographic, and health characteristics. Conclusions. In this well-functioning cohort, several cognitive tasks were associated with gait speed cross-sectionally and predicted longitudinal gait speed decline. These data are consistent with a shared pathology underlying cognitive and motor declines but do not suggest that specific executive cognitive deficits account for slowing of usual gait in aging. C1 [Watson, N. L.; Rosano, C.; Boudreau, R. M.; Sutton-Tyrrell, K.; Newman, A. B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Simonsick, E. M.; Ferrucci, L.] NIA, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Hardy, S. E.; Newman, A. B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Atkinson, H. H.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Yaffe, K.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, K.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Satterfield, S.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Watson, NL (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 N Bellefield Ave,4th Floor, Pittsburgh, PA 15213 USA. EM watsonn@edc.pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institutes of Health, NIA FX This work was supported by National Institute on Aging (NIA) contract numbers N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 and in part by the Intramural Research Program of the National Institutes of Health, NIA. NR 52 TC 88 Z9 88 U1 3 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2010 VL 65 IS 10 BP 1093 EP 1100 DI 10.1093/gerona/glq111 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 651WK UT WOS:000281957800009 PM 20581339 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OD, HHS, Bethesda, MD 20892 USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OD, HHS, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD OCT PY 2010 VL 39 IS 10 BP 299 EP 299 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 660TP UT WOS:000282668300005 PM 20859274 ER PT J AU Pogribny, IP Starlard-Davenport, A Tryndyak, VP Han, T Ross, SA Rusyn, I Beland, FA AF Pogribny, Igor P. Starlard-Davenport, Athena Tryndyak, Volodymyr P. Han, Tao Ross, Sharon A. Rusyn, Ivan Beland, Frederick A. TI Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice SO LABORATORY INVESTIGATION LA English DT Article DE methyl-deficient diet; mice; microRNA; nonalcoholic steatohepatitis; strain difference. ID FATTY LIVER-DISEASE; BINDING-PROTEIN-BETA; HUMAN HEPATOCELLULAR-CARCINOMA; MITOCHONDRIAL-DNA DAMAGE; INDUCED OXIDATIVE STRESS; HUMAN BREAST-CANCER; GENE-EXPRESSION; DOWN-REGULATION; E-CADHERIN; C/EBP-BETA AB The importance of dysregulation of microRNA (miRNA) expression in nonalcoholic steatohepatitis (NASH) has been increasingly recognized; however, the association between altered expression of miRNAs and pathophysiological features of NASH and whether there is a connection between susceptibility to NASH and altered expression of miRNAs are largely unknown. In this study, male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet that causes liver injury similar to human NASH, and the expression of miRNAs and the level of proteins targeted by these miRNAs in the livers were determined. Administration of the methyl-deficient diet triggered NASH-specific changes in the livers of C57BL/6J and DBA/2J mice, with the magnitude being more severe in DBA/2J mice. This was evidenced by a greater extent of expression of fibrosis-related genes in the livers of methyl-deficient DBA/2J mice. The development of NASH was accompanied by prominent changes in the expression of miRNAs, including miR-29c, miR-34a, miR-155, and miR-200b. Interestingly, changes in the expression of these miRNAs and protein levels of their targets, including Cebp-b, Socs 1, Zeb-1, and E-cadherin, in the livers of DBA/2J mice fed a methyl-deficient diet were more pronounced as compared with those in C57BL/6J mice. These results show that alterations in the expression of miRNAs are a prominent event during development of NASH induced by methyl deficiency and strongly suggest that severity of NASH and susceptibility to NASH may be determined by variations in miRNA expression response. More important, our data provide a mechanistic link between alterations in miRNA expression and pathophysiological and pathomorphological features of NASH. Laboratory Investigation (2010) 90, 1437-1446; doi: 10.1038/labinvest.2010.113; published online 14 June 2010 C1 [Pogribny, Igor P.; Starlard-Davenport, Athena; Tryndyak, Volodymyr P.; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Han, Tao] Natl Ctr Toxicol Res, Div Syst Toxicol, Jefferson, AR 72079 USA. [Ross, Sharon A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Rusyn, Ivan] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3990 NCTR Rd,HFT-140, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov RI Rusyn, Ivan/S-2426-2016 FU NIEHS NIH HHS [R01 ES015241] NR 50 TC 87 Z9 95 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD OCT PY 2010 VL 90 IS 10 BP 1437 EP 1446 DI 10.1038/labinvest.2010.113 PG 10 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 655TY UT WOS:000282273900004 PM 20548288 ER PT J AU Stroeve, JHM Brufau, G Stellaard, F Gonzalez, FJ Staels, B Kuipers, F AF Stroeve, Johanna H. M. Brufau, Gemma Stellaard, Frans Gonzalez, Frank J. Staels, Bart Kuipers, Folkert TI Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice SO LABORATORY INVESTIGATION LA English DT Article DE bile acids; circadian rhythm; Cyp7A1; enterohepatic circulation; Fgf15; Fxr ID FARNESOID-X-RECEPTOR; NUCLEAR RECEPTOR; DEFICIENT MICE; CHOLESTEROL; METABOLISM; HOMEOSTASIS; LIVER; GENE; FIBROBLAST-GROWTH-FACTOR-19; TRANSCRIPTION AB Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute significantly to control of hepatic bile acid synthesis. However, scientific evidence supporting this assumption is primarily based on gene expression data. Using intestine-selective FXR knockout mice (iFXR-KO), we show that contribution of intestinal FXR-Fgf15 signalling in regulation of hepatic cholesterol 7a-hydroxylase (Cyp7A1) expression depends on time of the day with increased hepatic Cyp7A1 expression in iFXR-KO mice compared with controls exclusively during the dark phase. To assess the physiological relevance hereof, we determined effects of intestine-selective deletion of FXR on physiological parameters such as bile formation and kinetics of the enterohepatic circulation of bile acids. It appeared that intestinal FXR deficiency leads to a modest but significant increase in cholic acid pool size, without changes in fractional turnover rate. As a consequence, bile flow and biliary bile acid secretion rates were increased in iFXR-KO mice compared with controls. Feeding a bile acid-containing diet or treatment with a bile acid sequestrant similarly affected bile formation in iFXR-KO and control mice and induced similar changes in Cyp7A1 and Cyp8B1 expression patterns. In conclusion, this study is the first to demonstrate the physiological relevance of the contribution of the intestinal FXR-Fgf15 signalling pathway in control of hepatic bile acid synthesis. Fgf15 contributes to the regulation of hepatic bile acid synthesis in mice mainly during the dark phase. Expansion of the circulating bile acid pool as well as bile acid sequestration diminishes the contribution of intestinal FXR-Fgf15 signalling in control of hepatic bile acid synthesis and bile formation. Laboratory Investigation (2010) 90, 1457-1467; doi: 10.1038/labinvest.2010.107; published online 7 June 2010 C1 [Stroeve, Johanna H. M.] Univ Groningen, Univ Med Ctr Groningen, CMC V, Ctr Liver Digest & Metab Dis,Dept Pediat, NL-9700 RB Groningen, Netherlands. [Stellaard, Frans; Kuipers, Folkert] Univ Groningen, Univ Med Ctr Groningen, Ctr Liver Digest & Metab Dis, Dept Lab Med, NL-9700 RB Groningen, Netherlands. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Staels, Bart] Inst Pasteur, Dept Atherosclerose, Lille, France. [Staels, Bart] INSERM, UMR 545, F-59045 Lille, France. [Staels, Bart] Univ Lille 2, Fac Sci Pharmaceut & Biol, Lille, France. [Staels, Bart] Univ Lille 2, Fac Med, Lille, France. RP Stroeve, JHM (reprint author), Univ Groningen, Univ Med Ctr Groningen, CMC V, Ctr Liver Digest & Metab Dis,Dept Pediat, Hanzepl 1,POB 30-001, NL-9700 RB Groningen, Netherlands. EM J.H.M.Stroeve@med.umcg.nl OI Staels, Bart/0000-0002-3784-1503 FU European Commission [LSHM-CT-2005-018734]; Agence Nationale pour la Recherche (ANR) [LSHM-CT-2005-018734] FX We thank our colleagues for stimulating scientific discussions and advice. Our work is part of the project 'Hepatic and adipose tissue and functions in the metabolic syndrome' (HEPADIP, see http://www.hepadip.org/), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734). In addition, B.S. is recipient of a grant from 'Agence Nationale pour la Recherche' (ANR). Grant number: 'HEPADIP' (Contract LSHM-CT-2005-018734) and 'Agence Nationale pour la Recerche' (ANR). NR 26 TC 31 Z9 33 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD OCT PY 2010 VL 90 IS 10 BP 1457 EP 1467 DI 10.1038/labinvest.2010.107 PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 655TY UT WOS:000282273900006 PM 20531290 ER PT J AU Laaksovirta, H Peuralinna, T Schymick, JC Scholz, SW Lai, SL Myllykangas, L Sulkava, R Jansson, L Hernandez, DG Gibbs, JR Nalls, MA Heckerman, D Tienari, PJ Traynor, BJ AF Laaksovirta, Hannu Peuralinna, Terhi Schymick, Jennifer C. Scholz, Sonja W. Lai, Shaoi-Lin Myllykangas, Liisa Sulkava, Raimo Jansson, Lilja Hernandez, Dena G. Gibbs, J. Raphael Nalls, Michael A. Heckerman, David Tienari, Pentti J. Traynor, Bryan J. TI Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study SO LANCET NEUROLOGY LA English DT Article ID FRONTOTEMPORAL LOBAR DEGENERATION; MOTOR-NEURON DISEASE; DEMENTIA; POPULATION; ALS; SUSCEPTIBILITY; LINKAGE; PREVALENCE; VARIANTS; FAMILIES AB Background The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population. Methods We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus. Findings We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2. 58x10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9. 11x10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7.47x10(-33) when people with familial ALS were compared with controls, odds ratio 21.0,95% CI 11.2-39.1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37-9% (95% CI 27.7-48.1) and that for D90A homozygosity was 25.5% (16.9-34.1). Interpretation The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. Funding National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University. C1 [Schymick, Jennifer C.; Lai, Shaoi-Lin; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, Sonja W.; Hernandez, Dena G.; Nalls, Michael A.] NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Laaksovirta, Hannu; Peuralinna, Terhi; Jansson, Lilja; Tienari, Pentti J.] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Laaksovirta, Hannu; Peuralinna, Terhi; Jansson, Lilja; Tienari, Pentti J.] Univ Helsinki, Mol Neurol Programme, Biomedicum, Helsinki, Finland. [Scholz, Sonja W.] Georgetown Univ, Dept Neurosci, Washington, DC USA. [Lai, Shaoi-Lin] Chang Gung Univ Hosp, Chiayi, Taiwan. [Lai, Shaoi-Lin] Coll Med, Chiayi, Taiwan. [Myllykangas, Liisa] Univ Helsinki, Dept Pathol, Haartman Inst, Helsinki, Finland. [Myllykangas, Liisa] Folkhalsan Res Ctr, Helsinki, Finland. [Sulkava, Raimo] Univ Eastern Finland, Sect Geriatr, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Heckerman, David] Microsoft Res, Los Angeles, CA USA. [Traynor, Bryan J.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, 35 Convent Dr,Room 1A-1000, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI Tienari, Pentti/A-4893-2012; Traynor, Bryan/G-5690-2010; OI Scholz, Sonja/0000-0002-6623-0429 FU Sanofi-Aventis; Rhone-Poulenc Rorer; National Institutes of Health; National Institute on Aging [Z01-AG000949-02]; Microsoft Research; ALS Association; Helsinki University Central Hospital; Finnish Academy; Finnish Medical Society Duodecim; Kuopio University FX HL has received payment from Sanofi-Aventis and Rhone-Poulenc Rorer for development of educational presentations including services on speakers' bureaus, as well as travel and accommodation expenses from Rhone-Poulenc-Rorer. DH is senior director of the eScience Research Group at Microsoft Research. None of the other authors has any conflicts of interest.; This work was supported in part by the Intramural Research Program of the National Institutes of Health, and the National Institute on Aging (Z01-AG000949-02) and was also funded by Microsoft Research, the ALS Association, the Helsinki University Central Hospital, the Finnish Academy, the Finnish Medical Society Duodecim, and Kuopio University. We thank the DNA extraction and storage facility of the National Institute for Health and Welfare and Institute for Molecular Medicine in Finland (FIMM), Helsinki, Finland, and Tuomo Polvikoski, Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle University, UK, for their help with DNA extraction from the patients diagnosed with ALS. NR 32 TC 129 Z9 130 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD OCT PY 2010 VL 9 IS 10 BP 978 EP 985 DI 10.1016/S1474-4422(10)70184-8 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 672WC UT WOS:000283616700012 PM 20801718 ER PT J AU Shatunov, A Mok, K Newhouse, S Weale, ME Smith, B Vance, C Johnson, L Veldink, JH van Es, MA van den Berg, LH Robberecht, W Van Damme, P Hardiman, O Farmer, AE Lewis, CM Butler, AW Abel, O Andersen, PM Fogh, I Silani, V Chio, A Traynor, BJ Melki, J Meininger, V Landers, JE McGuffin, P Glass, JD Pall, H Leigh, PN Hardy, J Brown, RH Powell, JF Orrell, RW Morrison, KE Shaw, PJ Shaw, CE Al-Chalabi, A AF Shatunov, Aleksey Mok, Kin Newhouse, Stephen Weale, Michael E. Smith, Bradley Vance, Caroline Johnson, Lauren Veldink, Jan H. van Es, Michael A. van den Berg, Leonard H. Robberecht, Wim Van Damme, Philip Hardiman, Orla Farmer, Anne E. Lewis, Cathryn M. Butler, Amy W. Abel, Olubunmi Andersen, Peter M. Fogh, Isabella Silani, Vincenzo Chio, Adriano Traynor, Bryan J. Melki, Judith Meininger, Vincent Landers, John E. McGuffin, Peter Glass, Jonathan D. Pall, Hardev Leigh, P. Nigel Hardy, John Brown, Robert H., Jr. Powell, John F. Orrell, Richard W. Morrison, Karen E. Shaw, Pamela J. Shaw, Christopher E. Al-Chalabi, Ammar TI Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study SO LANCET NEUROLOGY LA English DT Article ID FRONTOTEMPORAL LOBAR DEGENERATION; COPY NUMBER VARIATION; SUSCEPTIBILITY; POPULATION; DEMENTIA; GENE; ALS; LINKAGE; LOCI; IRISH AB Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries. Methods We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0.05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2.20x10(-7). Findings After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2.22x10(-6); odds ratio [OR] 1.39, 95% CI 1.21-1.59) and rs2814707 (p=3.32x10(-6); 1.38, 1.20-1.58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4. 64x10(-10); OR 1.22, 95% CI 1.15-1.30) and rs2814707 (p=4.72x10(-10); 1.22, 1.15-1.30) were associated with ALS. Interpretation We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene. Funding ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). C1 [Al-Chalabi, Ammar] Kings Coll London, Med Res Council Ctr Neurodegenerat Res, Inst Psychiat, Dept Clin Neurosci, London SE5 8AF, England. [Weale, Michael E.; Lewis, Cathryn M.] Guys Hosp, Dept Med & Mol Genet, London SE1 9RT, England. [Farmer, Anne E.; Lewis, Cathryn M.; Butler, Amy W.; McGuffin, Peter] Inst Psychiat, Med Res Council Ctr Social Genet & Dev Psychiat, London, England. [Powell, John F.] Inst Psychiat, Dept Neurosci, London SE5 8AF, England. [Mok, Kin; Hardy, John; Orrell, Richard W.] UCL, Inst Neurol, London, England. [Veldink, Jan H.; van Es, Michael A.; van den Berg, Leonard H.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands. [Robberecht, Wim; Van Damme, Philip] Katholieke Univ Leuven Hosp, Dept Neurol, Louvain, Belgium. [Robberecht, Wim; Van Damme, Philip] Univ Louvain, Neurobiol Lab, Vesalius Res Ctr, VIB, Louvain, Belgium. [Hardiman, Orla] Beaumont Hosp, Dept Neurol, Dublin, Ireland. [Hardiman, Orla] Trinity Coll Dublin, Dublin, Ireland. [Andersen, Peter M.] Umea Univ, Dept Clin Neurosci, S-90187 Umea, Sweden. [Silani, Vincenzo] Univ Milan, Dept Neurol, Dino Ferrari Ctr, IRCCS,Ist Auxol Italiano, Milan, Italy. [Silani, Vincenzo] Univ Milan, Neurosci Lab, Dino Ferrari Ctr, IRCCS,Ist Auxol Italiano, Milan, Italy. [Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Chio, Adriano] Azienda Osped Univ San Giovanni Battista, Turin, Italy. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Melki, Judith] INSERM, UMR 788, Paris, France. [Melki, Judith] Univ Paris 11, Bicetre Hosp, Paris, France. [Meininger, Vincent] Univ Paris 06, Hop La Pitie Salpetriere, Assistance Publ Hop Paris, Paris, France. [Landers, John E.; Brown, Robert H., Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Glass, Jonathan D.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Pall, Hardev; Morrison, Karen E.] Univ Birmingham, Coll Med & Dent, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Pall, Hardev; Morrison, Karen E.] Univ Hosp Birmingham NHS Fdn Trust, Div Neurosci, Birmingham, W Midlands, England. [Shaw, Pamela J.] Univ Sheffield, Acad Neurol Unit, Dept Neurosci, Fac Med Dent & Hlth, Sheffield, S Yorkshire, England. RP Al-Chalabi, A (reprint author), Kings Coll London, Med Res Council Ctr Neurodegenerat Res, Inst Psychiat, Dept Clin Neurosci, PO41, London SE5 8AF, England. EM ammar.al-chalabi@kcl.ac.uk RI Vance, Caroline/C-3047-2012; McGuffin, Peter/A-1565-2012; Orrell, Richard/L-2123-2013; Smith, Bradley/H-6107-2013; Lewis, Cathryn/A-5225-2010; Al-Chalabi, Ammar/E-5361-2010; Shatunov, Aleksey/E-6946-2011; Powell, John/G-4412-2011; Van Damme, Philip/A-6464-2009; Hardy, John/C-2451-2009; Weale, Michael/F-2587-2010; Mok, Kin/F-5860-2012; Traynor, Bryan/G-5690-2010; Newhouse, Stephen/C-9330-2011; OI Vance, Caroline/0000-0001-5780-6951; McGuffin, Peter/0000-0002-9888-2907; Lewis, Cathryn/0000-0002-8249-8476; Al-Chalabi, Ammar/0000-0002-4924-7712; Powell, John/0000-0001-6124-439X; Van Damme, Philip/0000-0001-6384-0611; Weale, Michael/0000-0003-4593-1186; Newhouse, Stephen/0000-0002-1843-9842; Chio, Adriano/0000-0001-9579-5341; Silani, Vincenzo/0000-0002-7698-3854; Hardiman, Orla/0000-0003-2610-1291 FU Motor Neurone Disease Association [3/3]; Wellcome Trust [070122/A/02/Z, 068545/Z/02]; Angel Fund; ALS Therapy Alliance; Motor Neurone Disease Association for genotyping [10/57]; Medical Research Council [G0000934, G0701420]; Prinses Beatrix Fonds; VSB Fonda; Kersten Foundation; Netherlands ALS Foundation; Adessium Foundation (LHvdB); Brain Foundation of the Netherlands; University of Leuven (Methusalem); Belgian Federal Science Policy Office [P6/43]; Italian Ministry of Health [31]; National Institutes of Health; National Institute on Aging [Z01-AG000949-02]; Fondazione Vialli e Mauro per la SLA [3/2008]; Federazione Italians Giuoco Calcio [2/2008]; ALS Association; ALS Society of Canada; MNDA Iceland; National Institute for Health Research Biomedical Research Centre for Mental Health FX The independent study case samples were obtained from the UK DNA bank for Motor Neuron Disease Research, which was funded by the Motor Neurone Disease Association grant 3/3 and the Wellcome Trust grant 070122/A/02/Z, with additional support from the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). Genotyping of the independent study case samples was funded by grants from the Angel Fund and ALS Therapy Alliance, with additional funding to RO and JH from the Motor Neurone Disease Association for genotyping (grant 10/57). We acknowledge use of genotype data from the British 1958 birth cohort DNA collection, which was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Controls for the DeCC study and BACCS were genotyped under the Medical Research Council grant G0701420. This project has been supported by the Prinses Beatrix Fonds, VSB Fonda, The Kersten Foundation, The Netherlands ALS Foundation, and The Adessium Foundation (LHvdB). JHV is supported by grants from The Brain Foundation of the Netherlands. WR is supported by grants from the University of Leuven (Methusalem) and the Interuniversity Attraction Poles (IUAP) program P6/43 of the Belgian Federal Science Policy Office. VS is supported by the Italian Ministry of Health (Ricerca Finalizzata 2007 number 31). This work was supported in part by the Intramural Research Program of the National Institutes of Health, and the National Institute on Aging (Z01-AG000949-02). AC is supported by the Italian Ministry of Health (Ricerca Sanitaria Finalizzata, 2007, number 30), the Fondazione Vialli e Mauro per la SLA (grant 3/2008), and the Federazione Italians Giuoco Calcio (Grant 2/2008). We thank the ALS Association, the ALS Society of Canada, MNDA Iceland, and the National Institute for Health Research Biomedical Research Centre for Mental Health for support, and Kuang Lin for programming advice. NR 35 TC 117 Z9 118 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD OCT PY 2010 VL 9 IS 10 BP 986 EP 994 DI 10.1016/S1474-4422(10)70197-6 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 672WC UT WOS:000283616700013 PM 20801717 ER PT J AU Bible, KC Suman, VJ Molina, JR Smallridge, RC Maples, WJ Menefee, ME Rubin, J Sideras, K Morris, JC McIver, B Burton, JK Webster, KP Bieber, C Traynor, AM Flynn, PJ Goh, BC Tang, H Ivy, SP Erlichman, C AF Bible, Keith C. Suman, Vera J. Molina, Julian R. Smallridge, Robert C. Maples, William J. Menefee, Michael E. Rubin, Joseph Sideras, Kostandinos Morris, John C., III McIver, Bryan Burton, Jill K. Webster, Kevin P. Bieber, Carolyn Traynor, Anne M. Flynn, Patrick J. Goh, Boon Cher Tang, Hui Ivy, Susan Percy Erlichman, Charles CA Mayo Clinic Canc Ctr Mayo Phase 2 Consortium TI Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study SO LANCET ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; II TRIAL; INCREASED EXPRESSION; UNITED-STATES; CARCINOMA; SORAFENIB; STATISTICS; INHIBITOR; SURVIVAL AB Background Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. Methods This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. Findings 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0.40, p=0.021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Interpretation Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. C1 [Bible, Keith C.; Molina, Julian R.; Rubin, Joseph; Sideras, Kostandinos; Burton, Jill K.; Webster, Kevin P.; Erlichman, Charles] Mayo Clin, Div Med Oncol, Rochester, MN 55901 USA. [Suman, Vera J.; Tang, Hui] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55901 USA. [Morris, John C., III; McIver, Bryan] Mayo Clin, Div Endocrinol, Rochester, MN 55901 USA. [Smallridge, Robert C.] Mayo Clin Florida, Div Endocrinol, Jacksonville, FL USA. [Maples, William J.; Menefee, Michael E.; Bieber, Carolyn] Mayo Clin Florida, Div Med Oncol, Jacksonville, FL USA. [Traynor, Anne M.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Goh, Boon Cher] Natl Univ Singapore Hosp, Singapore, Singapore. [Ivy, Susan Percy] NCI, Ctr Translat Expt Therapeut, Bethesda, MD 20892 USA. RP Bible, KC (reprint author), Mayo Clin, Div Med Oncol, 200 First St SW, Rochester, MN 55901 USA. EM bible.keith@mayo.edu RI Tang, Hui/B-3643-2010; OI Sideras, Kostandinos/0000-0002-4698-2105 FU National Cancer Institute [NCI CA15083, CM62205] FX KCB, JAM. and CE were supported in part by the National Cancer Institute (grants CA15083 and CM62205).; National Cancer Institute, supported in part by NCI CA15083 and CM62205. NR 29 TC 203 Z9 207 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD OCT PY 2010 VL 11 IS 10 BP 962 EP 972 DI 10.1016/S1470-2045(10)70203-5 PG 11 WC Oncology SC Oncology GA 667RE UT WOS:000283210600022 PM 20851682 ER PT J AU Litzinger, MT Foon, KA Tsang, KY Schlom, J Palena, C AF Litzinger, Mary T. Foon, Kenneth A. Tsang, Kwong-Yok Schlom, Jeffrey Palena, Claudia TI Comparative analysis of MVA-CD40L and MVA-TRICOM vectors for enhancing the immunogenicity of chronic lymphocytic leukemia (CLL) cells SO LEUKEMIA RESEARCH LA English DT Article DE Immunotherapy; CLL; TRICOM; CD40L; Vaccine ID MODIFIED VACCINIA VIRUS; ANTIGEN-PRESENTING CELLS; HUMAN B-CELLS; COSTIMULATORY MOLECULES; RECOMBINANT VECTOR; THERAPEUTIC VACCINATION; INDUCE EXPRESSION; IMMUNE-RESPONSES; DENDRITIC CELLS; T-LYMPHOCYTES AB Adenoviral transduction with CD40L and poxviral transduction with B7-1, ICAM-1, and LFA-3 (TRICOM) have been used to enhance the antigen-presenting capacity of chronic lymphocytic leukemia (CLL) cells. This study compares the same vector (modified vaccinia virus strain Ankara (MVA)) encoding CD40L or TRICOM for its ability to enhance the immunogenicity of CLL cells. CLL cells from some patients showed differential responses to each vector in terms of induction of autologous T-cell responses. This study supports the rationale for the use of CLL cells modified ex vivo with pre-specified recombinant MVA vectors as a whole tumor-cell vaccine for immunotherapy in CLL patients. Published by Elsevier Ltd. C1 [Litzinger, Mary T.; Tsang, Kwong-Yok; Schlom, Jeffrey; Palena, Claudia] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Foon, Kenneth A.] Univ Pittsburgh, Div Hematol & Oncol, Inst Canc, Pittsburgh, PA USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. FU NIH; Center for Cancer Research; National Cancer Institute FX We acknowledge the technical assistance of Margie Duberstein and the editorial assistance of Debra Weingarten in the preparation of this manuscript. We thank Dr. James Hodge and Dr. Ravi Madan for critical reading of the manuscript. This research was supported by the NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute. NR 37 TC 4 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD OCT PY 2010 VL 34 IS 10 BP 1351 EP 1357 DI 10.1016/j.leukres.2009.12.013 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 642LI UT WOS:000281214700017 PM 20122733 ER PT J AU Reddy, P Naidoo, RN Robins, TG Mentz, G London, SJ Li, HL Naidoo, R AF Reddy, Poovendhree Naidoo, Rajen N. Robins, Thomas G. Mentz, Graciela London, Stephanie J. Li, Huiling Naidoo, Richard TI GSTM1, GSTP1, and NQO1 Polymorphisms and Susceptibility to Atopy and Airway Hyperresponsiveness among South African Schoolchildren SO LUNG LA English DT Article DE Genetic polymorphism; Glutathione-S-transferases; Nicotinamide quinone oxidoreductase; Oxidative stress; Atopy; AHR ID GLUTATHIONE-S-TRANSFERASE; BRONCHIAL HYPERRESPONSIVENESS; RISK-FACTORS; ASTHMA; GENE; INFLAMMATION; LOCUS; ASSOCIATION; PREVALENCE; CHILDREN AB Glutathione-S-transferases (GSTM1 and GSTP1) and nicotinamide quinone oxidoreductase (NQO1) genes play an important role in cellular protection against oxidative stress which has been linked to asthma pathogenesis. We investigated whether common, functional polymorphisms in GSTM1, GSTP1 and NQO1 influence airway hyperreactivity (AHR) and atopy among schoolchildren in South Africa. Genomic DNA was extracted from 317 primary schoolchildren, aged 9-11 years, from urban, low socioeconomic communities of Durban, South Africa. GSTM1 (null vs. present genotype), GSTP1 (Ile105Val; AA -> AG + GG), and NQO1 (Pro/187Ser; CC -> CT/TT) genotypes were determined using polymerase chain reaction (PCR) methods. Atopy was defined as a positive skin-prick test to any of several common allergens. Airway hyperreactivity (AHR) was evaluated by pulmonary function testing before and after methacholine challenge. Among the children, 30% were GSTM1 null, 65% carried the G allele for GSTP1, and 36% carried the C allele for NQO1. The frequency of GSTM1, GSTP1, and NQO1 variants among our South African sample was similar to frequencies found in similar ethnic groups worldwide. Marked airway reactivity (PC(20) a parts per thousand currency sign 2 mg/ml) was found in 10.3% of children and approximately 40% of them were atopic. No significant associations for GSTM1 and NQO1 with either AHR or atopy were identified. A significant protective effect against atopy was found among children with one or two copies of the GSTP1 G allele. C1 [Naidoo, Rajen N.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Dept Occupat & Environm Hlth, ZA-4013 Durban, South Africa. [Reddy, Poovendhree] Durban Univ Technol, Dept Community Hlth Studies, Durban, South Africa. [Robins, Thomas G.; Mentz, Graciela] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [London, Stephanie J.; Li, Huiling] NIEHS, Div Intramural Res, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Naidoo, Richard] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Pfizer Mol Biol Unit, ZA-4013 Durban, South Africa. RP Naidoo, RN (reprint author), Univ KwaZulu Natal, Nelson R Mandela Sch Med, Dept Occupat & Environm Hlth, Private Bag 7, ZA-4013 Durban, South Africa. EM naidoon@ukzn.ac.za RI Naidoo, Rajen/N-4712-2013; OI London, Stephanie/0000-0003-4911-5290 FU eThekwini Municipality; Durban University of Technology; National Research Foundation (NRF), South Africa; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, USA [Z01 49019] FX We thank the participants of the South Durban Health Study, both the children and parents, for their dedicated cooperation and commitment. Members of the study team, in particular Caron Jack, Joy Kistnasamy, and Pamela Nasirumbi, are gratefully acknowledged. We also thank Prof. Mary Lou Thompson for statistical advice and Zakeer Gafoor for assistance with geno-typing. This study was supported by the eThekwini Municipality, Durban University of Technology, and the National Research Foundation (NRF), South Africa. This work was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, USA (Z01 49019). NR 22 TC 9 Z9 13 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2040 J9 LUNG JI Lung PD OCT PY 2010 VL 188 IS 5 BP 409 EP 414 DI 10.1007/s00408-010-9246-3 PG 6 WC Respiratory System SC Respiratory System GA 650OU UT WOS:000281859800008 PM 20526719 ER PT J AU Sultan, F Hamodeh, S Murayama, Y Saleem, KS Logothetis, N AF Sultan, Fahad Hamodeh, Salah Murayama, Yusuke Saleem, Kadharbatcha S. Logothetis, Nikos TI Flat map areal topography in Macaca mulatta based on combined MRI and histology SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Primate; Visual cortex; Maps; Neocortex ID SUPERIOR TEMPORAL SULCUS; MEDIAL PREFRONTAL NETWORKS; CEREBRAL-CORTEX; MACAQUE MONKEYS; RHESUS-MONKEY; VISUAL AREAS; DIFFERENTIAL CONNECTIONS; CORTICAL CONNECTIONS; THALAMIC AFFERENTS; COORDINATE SYSTEM AB Flattened representations are a useful approach to represent the convoluted complex surface of the neocortex of primates and other large-brained mammals. In this study, we compared the flattened representation of neocortical areas obtained from the recently published MRI and histology atlas of the rhesus monkey brain (Saleem KS, Logothetis NK. A combined MRI and histology atlas of the rhesus monkey brain in stereotaxic coordinates. London: Academic; 2007) with other previously published maps. Our results confirm that flat map representations are advantageous due to their ease of use and that current flat maps are well comparable to each other. Some differences arise due to different distinguishing criteria and here too flat maps can help to reveal them. (C) 2010 Elsevier Inc. All rights reserved. C1 [Sultan, Fahad; Hamodeh, Salah] HIH Clin Brain Res, Dept Cognit Neurol, D-72076 Tubingen, Germany. [Murayama, Yusuke; Logothetis, Nikos] Max Planck Inst Biol Cybernet, D-72076 Tubingen, Germany. [Saleem, Kadharbatcha S.] NIMH, NIH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Sultan, F (reprint author), HIH Clin Brain Res, Dept Cognit Neurol, D-72076 Tubingen, Germany. EM fahad.sultan@uni-tuebingen.de OI Saleem, Kadharbatcha S/0000-0002-4450-9234 NR 48 TC 5 Z9 5 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD OCT PY 2010 VL 28 IS 8 SI SI BP 1159 EP 1164 DI 10.1016/j.mri.2010.03.023 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 658NZ UT WOS:000282498000015 PM 20471190 ER PT J AU Goense, J Logothetis, NK Merkle, H AF Goense, Jozien Logothetis, Nikos K. Merkle, Hellmut TI Flexible, phase-matched, linear receive arrays for high-field MRI in monkeys SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Monkey; Phased array; fMRI; Physiological noise ID OCULAR DOMINANCE COLUMNS; HIGH-RESOLUTION FMRI; FUNCTIONAL MRI; LAMINAR SPECIFICITY; SPIN-ECHO; PHYSIOLOGICAL NOISE; HEAD COIL; 1.5 T; DESIGN; SIGNAL AB High signal-to-noise ratios (SNR) are essential for high-resolution anatomical and functional MRI. Phased arrays are advantageous for this but have the drawback that they often have inflexible and bulky configurations. Particularly in experiments where functional MRI is combined with simultaneous electrophysiology, space constraints can be prohibitive. To this end we developed a highly flexible multiple receive element phased array for use on anesthetized monkeys. The elements are interchangeable and different sizes and combinations of coil elements can be used, for instance, combinations of single and overlapped elements. The preamplifiers including control electronics are detachable and can serve a variety of prefabricated and phase matched arrays of different configurations, allowing the elements to always be placed in close proximity to the area of interest. Optimizing performance of the individual elements ensured high SNR at the cortical surface as well as in deeper laying structures. Performance of a variety of arrangements of gapped linear arrays was evaluated at 4.7 and 7T in high-resolution anatomical and functional MRI. (C) 2010 Elsevier Inc. All rights reserved. C1 [Goense, Jozien; Logothetis, Nikos K.] Max Planck Inst Biol Cybernet, Dept Physiol Cognit Proc, D-72076 Tubingen, Germany. [Logothetis, Nikos K.] Univ Manchester, Div Imaging Sci & Biomed Engn, Manchester M13 9PT, Lancs, England. [Merkle, Hellmut] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Goense, J (reprint author), Max Planck Inst Biol Cybernet, Dept Physiol Cognit Proc, Spemannstr 38, D-72076 Tubingen, Germany. EM jozien.goense@tuebingen.mpg.de FU Max-Planck Society; National Institutes of Health, National Institute Neurological Disorders and Stroke, Bethesda, MD, USA FX This work was supported by the Max-Planck Society and in part by the Intramural Program of the National Institutes of Health, National Institute Neurological Disorders and Stroke, Bethesda, MD, USA. We thank Mark Augath for technical support and Alexander Rauch for comments on an earlier version of the manuscript. NR 36 TC 15 Z9 15 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD OCT PY 2010 VL 28 IS 8 SI SI BP 1183 EP 1191 DI 10.1016/j.mri.2010.03.026 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 658NZ UT WOS:000282498000018 PM 20456890 ER PT J AU Duyn, JH AF Duyn, Jozef H. TI Study of brain anatomy with high-field MRI: recent progress SO MAGNETIC RESONANCE IMAGING LA English DT Review DE High field MRI; Magnetic susceptibility; Brain; Contrast; Iron ID WHITE-MATTER CONTRAST; ARRAY HEAD COIL; IRON CONTENT; IN-VIVO; PHASED-ARRAY; 8 TESLA; 7.0 T; SUSCEPTIBILITY; IMAGES; MICROSCOPY AB Recent developments in high-field magnetic resonance imaging technology have led to improved contrast and resolution and are opening up new possibilities for the study of human brain anatomy. In particular, techniques sensitized to magnetic susceptibility contrast provide particular advantages at high field that have allowed visualization of brain structures that have been difficult to detect with conventional technology. In this review, some of these developments and techniques will be discussed, and an attempt will be made to interpret magnetic susceptibility contrast based on recent studies. Published by Elsevier Inc. C1 NINDS, Lab Adv MRI, LFMI, NIH, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), NINDS, Lab Adv MRI, LFMI, NIH, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov NR 50 TC 24 Z9 24 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD OCT PY 2010 VL 28 IS 8 SI SI BP 1210 EP 1215 DI 10.1016/j.mri.2010.02.007 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 658NZ UT WOS:000282498000021 PM 20392587 ER PT J AU Tyler, DJ Lopez, O Cole, MA Carr, CA Stuckey, DJ Lakatta, E Clarke, K Spencer, RG AF Tyler, Damian J. Lopez, Orlando Cole, Mark A. Carr, Carolyn A. Stuckey, Daniel J. Lakatta, Edward Clarke, Kieran Spencer, Richard G. TI Ongoing Dual-Angle Measurements for the Correction of Partial Saturation in (31)P MR Spectroscopy SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE cardiovascular; biochemistry; heart ID MAGNETIC-RESONANCE-SPECTROSCOPY; NEGLECTING CHEMICAL-EXCHANGE; GRAPHICAL USER-INTERFACE; LATTICE-RELAXATION TIMES; CREATINE-KINASE REACTION; ONE-PULSE EXPERIMENT; IN-VIVO NMR; METABOLITE CONCENTRATIONS; QUANTITATION ERRORS; MUSCLE AB Use of a repetition time similar to, or shorter than, metabolite T(1)s is common in NMR spectroscopy of biological samples to improve the signal-to-noise ratio. Conventionally, the partial saturation that results from this is corrected using saturation factors. However, this can lead to erroneous results in the presence of chemical exchange or nonconstant T(1)s. We describe an alternative approach to correction for saturation, based on ongoing dual-angle T(1) measurement. Using (31)P magnetic resonance spectroscopy of the perfused rat heart undergoing ischemia-reperfusion, we demonstrate that signal alternations in the data acquired by the dual-angle approach are eliminated by the ongoing dual-angle T(1) measurement correction scheme, meaning that metabolite concentration and T(1) measurement can be made throughout the course of the ischemia-reperfusion protocol. Simulations, based on parameters pertinent to the perfused rat heart, demonstrate that accurate saturation correction is possible with this method except at times of rapid concentration change. Additionally, compared to the conventional saturation factor correction method, the ongoing dual-angle T(1) measurement correction scheme results in improved accuracy in determining the [phosphocreatine] recovery time constant. Thus, the ongoing dual-angle T(1) measurements procedure permits accurate monitoring of metabolite concentrations even in the setting of chemical exchange and T(1) changes and allows more accurate analysis of bioenergetic status. Magn Reson Med 64:957-966, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Tyler, Damian J.; Cole, Mark A.; Carr, Carolyn A.; Stuckey, Daniel J.; Clarke, Kieran] Univ Oxford, Dept Physiol Anat & Genet, CMRG, Oxford OX1 3PT, England. [Lopez, Orlando; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. [Lakatta, Edward] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Tyler, DJ (reprint author), Univ Oxford, Dept Physiol Anat & Genet, CMRG, Sherrington Bldg,Parks Rd, Oxford OX1 3PT, England. EM damian.tyler@dpag.ox.ac.uk RI Tyler, Damian/E-6296-2011; OI Tyler, Damian/0000-0002-0780-8905; stuckey, daniel/0000-0001-8888-627X FU Medical Research Council (MRC) [G0601490]; British Heart Foundation (BHF) [PG/07/070/23365, RG/07/004/22659, RG/07/059/23259]; National Institute on Aging FX Grant sponsor: Medical Research Council (MRC); Grant number: G0601490; Grant sponsor: British Heart Foundation (BHF); Grant numbers: PG/07/070/23365, RG/07/004/22659, RG/07/059/23259; Grant sponsor: National Institute on Aging (Intramural Research Program of the NIH). NR 25 TC 4 Z9 4 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2010 VL 64 IS 4 BP 957 EP 966 DI 10.1002/mrm.22511 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 658FY UT WOS:000282477100004 PM 20740663 ER PT J AU Lui, JC Chen, WP Barnes, KM Baron, J AF Lui, Julian C. Chen, Weiping Barnes, Kevin M. Baron, Jeffrey TI Changes in gene expression associated with aging commonly originate during juvenile growth SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Aging; Postnatal growth; Microarray; Genetic program; Proliferation ID UBIQUITIN-CONJUGATING ENZYME; LIFE-SPAN EXTENSION; CALORIC RESTRICTION; STEM-CELL; IMPRINTED GENE; SOMATIC GROWTH; MICE; AGE; INFILTRATION; METABOLISM AB In mammals proliferation is rapid in many tissues during early postnatal life causing rapid somatic growth This robust proliferation is then suppressed as the animal approaches adult size bringing many tissues to a quiescent state where proliferation occurs only as needed to replace dying cells Recent evidence suggests that the mechanism responsible for this decline in proliferation involves a multi-organ genetic program We hypothesized that this genetic program continues to progress into later adult life eventually suppressing proliferation to levels below those needed for tissue renewal thus contributing to aging We therefore used expression microarray to compare the temporal changes in gene expression that occur in adult mouse organs during aging to those occurring as juvenile proliferation slows We found that many of the changes in gene expression that occur during the aging process originate during the period of juvenile growth deceleration Bioinformatic analyses of the genes that show persistent decline in expression throughout postnatal life indicated that cell-cycle-related genes are strongly over-represented Thus the findings support the hypothesis that the genetic program that slows juvenile growth to limit body size persists into adulthood and thus may eventually hamper tissue maintenance and repair contributing to the aging process (C) 2010 Elsevier Ireland Ltd All rights reserved C1 [Lui, Julian C.; Barnes, Kevin M.; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, Dev Endocrinol Branch, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDKD, Microarray Core Facil, NIH, Bethesda, MD 20892 USA. RP Lui, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, Dev Endocrinol Branch, Program Dev Endocrinol & Genet, NIH, CRC Room 1,3330 10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. RI Lui, Chun Kin Julian/E-2253-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH NR 63 TC 11 Z9 11 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD OCT PY 2010 VL 131 IS 10 BP 641 EP 649 DI 10.1016/j.mad.2010.08.010 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 686FD UT WOS:000284681300005 PM 20816690 ER PT J AU Jumpertz, R Thearle, MS Bunt, JC Krakoff, J AF Jumpertz, Reiner Thearle, Marie S. Bunt, Joy C. Krakoff, Jonathan TI Assessment of non insulin-mediated glucose uptake: association with body fat and glycemic status SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID DIABETES-MELLITUS; PIMA-INDIANS; MODEL; TOLERANCE; SENSITIVITY; RESISTANCE; DISPOSAL; NIDDM; RATES AB In the fasting state, approximately 83% of glucose uptake occurs via non-insulin-mediated mechanisms. A widely accepted static rate for NIMGU is 1.62 mg kg(-1).min(-1). To investigate the variability of NIMGU, we examined differences by glucose tolerance, sex, age, race (American Indian/African American/Caucasian), and adiposity in 616 volunteers (including individuals with normal glucose regulation [NGR] and impaired glucose regulation [IGR] and diabetes mellitus [DM]) using data from euglycemic-hyperinsulinemic clamp experiments. NIMGU was determined by plotting basal glucose output and insulin action against fasting and steady-state clamp insulin. The intercept with the y-axis after extrapolation was interpreted as NIMGU at zero insulin. Body composition was determined by dual-energy x-ray absorptiometry; and glucose regulation, by a 75-g oral glucose tolerance test. Energy expenditure was measured by indirect calorimetry in a metabolic chamber. In individuals with NGR (n = 385), NIMGU was 1.63 mg kg(estimated metabolic body size (fat free mass + 17.7 kg))(-1) min(-1) (95% confidence interval, 1.59-1.66). NIMGU increased with 1GR and DM (IGR: n = 189, 1.67 [1.62-1.72]; DM: n = 42, 2.39 [2.29-2.49]; P < .0001 across groups). NIMGU did not differ by sex (P = .13), age (P = .22), or race (P = .06); however, NIMGU was associated with percentage body fat (r(2) = 0.04, P < .0001). Furthermore, NIMGU was positively associated with 24-hour and sleep energy expenditure (r(2) = 0.002, P = .03; r(2) = 0.01, P < .01). Extrapolated NIMGU in individuals with NGR is remarkably consistent with previously published data. Our results indicate that NIMGU is associated with adiposity. NIMGU increases with declining glucose tolerance perhaps to preserve glucose uptake during increased insulin resistance. Published by Elsevier Inc. C1 [Jumpertz, Reiner; Thearle, Marie S.; Bunt, Joy C.; Krakoff, Jonathan] NIDDKD, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ 85016 USA. RP Jumpertz, R (reprint author), NIDDKD, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ 85016 USA. EM jumpertzr@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX We thank all study volunteers for their contribution to this study. We also thank the staff of the Clinical Research Unit on the fifth floor of the Phoenix Indian Medical Center. This study was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 25 TC 4 Z9 4 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2010 VL 59 IS 10 BP 1396 EP 1401 DI 10.1016/j.metabol.2010.01.006 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 656YG UT WOS:000282376400003 PM 20153490 ER PT J AU Lenfant, C AF Lenfant, Claude TI Chest pain of cardiac and noncardiac origin SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID CORONARY-ARTERY-DISEASE; EMERGENCY-DEPARTMENT; PRIMARY-CARE; MYOCARDIAL-INFARCTION; STABLE ANGINA; HEART-DISEASE; WOMEN; COHORT; PREVALENCE; PROGNOSIS AB Chest pain is one of the most common symptoms driving patients to a physician's office or the hospital's emergency department. In approximately half of the cases, chest pain is of cardiac origin, either ischemic cardiac or nonischemic cardiac disease. The other half is due to noncardiac causes, primarily esophageal disorder. Pain from either origin may occur in the same patient. In addition, psychological and psychiatric factors play a significant role in the perception and severity of the chest pain, irrespective of its cause. Chest pain of ischemic cardiac disease is called angina pectoris. Stable angina may be the prelude of ischemic cardiac disease; and for this reason, it is essential to ensure a correct diagnosis. In most cases, further testing, such as exercise testing and angiography, should be considered. The more severe form of chest pain, unstable angina, also requires a firm diagnosis because it indicates severe coronary disease and is the earliest manifestation of acute myocardial infarction. Once a diagnosis of stable or unstable angina is established, and if a decision is made not to use invasive therapy, such as coronary bypass, percutaneous transluminal coronary angioplasty, or stent insertion, effective medical treatment of associated cardiac risk factors is a must. Acute myocardial infarction occurring after a diagnosis of angina greatly increases the risk of subsequent death. Chest pain in women warrants added attention because women underestimate their likelihood to have coronary heart disease. A factor that complicates the clinical assessment of patients with chest pain (both cardiac and noncardiac in origin) is the relatively common presence of psychological and psychiatric conditions such as depression or panic disorder. These factors have been found to cause or worsen chest pain; but unfortunately, they may not be easily detected. Noncardiac chest pain represents the remaining half of all cases of chest pain. Although there are a number of causes, gastroesophageal disorders are by far the most prevalent, especially gastroesophageal reflux disease. Fortunately, this disease can be diagnosed and treated effectively by proton-pump inhibitors. The other types of non-gastroesophageal reflux disease related noncardiac chest pain are more difficult to diagnose and treat. In conclusion, the cause of chest pain must be accurately diagnosed; and treatment must be pursued according to the cause, especially if the cause is of cardiac origin. (C) 2010 Elsevier Inc. All rights reserved. C1 [Lenfant, Claude] NHLBI, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), POB 65278, Vancouver, WA 98665 USA. EM lenfantc@prodigy.net NR 49 TC 15 Z9 17 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2010 VL 59 IS 10 SU 1 BP S41 EP S46 DI 10.1016/j.metabol.2010.07.014 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 656YI UT WOS:000282376600010 PM 20837193 ER PT J AU Wang, YX Zuo, XB Wang, JB Yu, P Butcher, SE AF Wang, Yun-Xing Zuo, Xiaobing Wang, Jinbu Yu, Ping Butcher, Samuel E. TI Rapid global structure determination of large RNA and RNA complexes using NMR and small-angle X-ray scattering SO METHODS LA English DT Review DE RNA global structure in solution; SAXS; NMR; New methods ID RESIDUAL DIPOLAR COUPLINGS; TURNIP CRINKLE VIRUS; TETRALOOP-RECEPTOR COMPLEX; TRANSLATIONAL ENHANCER; RELATIVE ORIENTATION; SPIN SYSTEMS; BASE-PAIRS; SAXS DATA; RESOLUTION; DYNAMICS AB Among the greatest advances in biology today are the discoveries of various roles played by RNA in biological processes. However, despite significant advances in RNA structure determination using X-ray crystallography [1] and solution NMR [2-4], the number of bona fide RNA structures is very limited, in comparison with the growing number of known functional RNAs. This is because of great difficulty in growing crystals or/and obtaining phase information, and severe size constraints on structure determination by solution NMR spectroscopy. Clearly, there is an acute need for new methodologies for RNA structure determination. The prevailing approach for structure determination of RNA in solution is a "bottom-up" approach that was basically transplanted from the approach used for determining protein structures, despite vast differences in both structural features and chemical compositions between these two types of biomacromolecules. In this chapter, we describe a new method, which has been reported recently, for rapid global structure determination of RNAs using solution-based NMR spectroscopy and small-angle X-ray scattering. The method treats duplexes as major building blocks of RNA structures. By determining the global orientations of the duplexes and the overall shape, the global structure of an RNA can be constructed and further regularized using Xplor-NIH. The utility of the method was demonstrated in global structure determination of two RNAs, a 71-nt and 102-nt RNAs with an estimated backbone RMSD similar to 3.0 angstrom. The global structure opens door to high-resolution structure determination in solution. Published by Elsevier Inc. C1 [Wang, Yun-Xing; Zuo, Xiaobing; Wang, Jinbu; Yu, Ping] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Butcher, Samuel E.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. RP Wang, YX (reprint author), NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM wangyu@ncifcrf.gov RI Zuo, Xiaobing/F-1469-2010; OI Zuo, Xiaobing/0000-0002-0134-4804 FU NIGMS NIH HHS [R01 GM065166] NR 65 TC 28 Z9 28 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD OCT PY 2010 VL 52 IS 2 BP 180 EP 191 DI 10.1016/j.ymeth.2010.06.009 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 663RV UT WOS:000282907000009 PM 20554045 ER PT J AU Yahiro, K Morinaga, N Moss, J Noda, M AF Yahiro, Kinnosuke Morinaga, Naoko Moss, Joel Noda, Masatoshi TI Subtilase cytotoxin induces apoptosis in HeLa cells by mitochondrial permeabilization via activation of Bax/Bak, independent of C/EBF-homologue protein (CHOP), Ire1 alpha or JNK signaling SO MICROBIAL PATHOGENESIS LA English DT Article DE Subtilase cytotoxin; ER stress; Apoptosis; Bax; Bak ID ENDOPLASMIC-RETICULUM STRESS; TOXIGENIC ESCHERICHIA-COLI; CHAPERONE BIP; VERO CELLS; BAX; BCL-2; DEATH; FAMILY; MEMBRANE; POTENT AB Subtilase cytotoxin (SubAB) is an AB(5) cytotoxin produced by some strains of Shiga-toxigenic Escherichia colt The A subunit is a subtilase-like serine protease and cleaves an endoplasmic reticulum (ER) chaperone, BiP, leading to transient inhibition of protein synthesis and cell cycle arrest at G(1) phase, and inducing caspase-dependent apoptosis via mitochondrial membrane damage in Vero cells. Here we investigated the mechanism of mitochondrial permeabilization in HeLa cells SubAB-induced cytochrome c release into cytosol did not depend on mitochondrial permeability transition pore (PTP), since cyclosporine A did not suppress cytochrome c release SubAB did not change the expression of anti-apoptotic Bcl-2 or Bcl-XL and pro-apoptotic Box or Bak, but triggered Box and Bak conformational changes and association of Bax with Bak Silencing using siRNA of both bax and bak genes, but not bax, bak, or bun alone, resulted in reduction of cytochrome c release, caspase-3 activation. DNA ladder formation and cytotoxicity, indicating that Box and Bak were involved in apoptosis SubAB activated ER transmembrane transducers, Ire1 alpha, and cJun N-terminal kinase (JNK), and induced C/EBF-homologue protein (CHOP) To investigate whether these signals were involved in cytochrome c release by Bax activation, we silenced ire la, ink or chop. however, silencing did not decrease SubAB-induced cytochrome c release, suggesting that these signals were not necessary for SubAB-induced mitochondrial permeabilization by Bax activation (C) 2010 Elsevier Ltd All rights reserved C1 [Yahiro, Kinnosuke; Morinaga, Naoko; Noda, Masatoshi] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chuo Ku, Chiba 2608670, Japan. [Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Yahiro, K (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. FU Japan Society for the Promotion of Science; Japan Science and Technology Agency; National Institute of Health, National Heart, Lung and Blood Institute FX This work was supported by Grants-in Aid for Scientific Research from Japan Society for the Promotion of Science and for Improvement of Research Environment for Young Researchers from Japan Science and Technology Agency Joel Moss was supported by the Intramural Research Program, National Institute of Health, National Heart, Lung and Blood Institute. We thank Dr. Iwao Kato, the former professor of Chiba University, for useful discussions and critical review of the manuscript. We thank Dr. Eisuke Nishida and Dr. Hiroyuki Seimia for providing JNK expression vector. NR 40 TC 13 Z9 14 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD OCT PY 2010 VL 49 IS 4 BP 153 EP 163 DI 10.1016/j.micpath.2010.05.007 PG 11 WC Immunology; Microbiology SC Immunology; Microbiology GA 639AY UT WOS:000280944400003 PM 20561923 ER PT J AU Sastalla, I Maltese, LM Pomerantseva, OM Pomerantsev, AP Keane-Myers, A Leppla, SH AF Sastalla, Inka Maltese, Lauren M. Pomerantseva, Olga M. Pomerantsev, Andrei P. Keane-Myers, Andrea Leppla, Stephen H. TI Activation of the latent PlcR regulon in Bacillus anthracis SO MICROBIOLOGY-SGM LA English DT Article ID CHOLESTEROL-DEPENDENT CYTOLYSIN; PHOSPHOLIPASE-C; ANTHROLYSIN-O; CEREUS GROUP; NONHEMOLYTIC ENTEROTOXIN; GENOME SEQUENCE; THURINGIENSIS; VIRULENCE; IDENTIFICATION; EXPRESSION AB Many genes in Bacillus cereus and Bacillus thuringiensis are under the control of the transcriptional regulator PlcR and its regulatory peptide, PapR. In Bacillus anthracis, the causative agent of anthrax, PlcR is inactivated by truncation, and consequently genes having PlcR binding sites are expressed at very low levels when compared with B. cereus. We found that activation of the PlcR regulon in B. anthracis by expression of a PlcR-PapR fusion protein does not alter sporulation in strains containing the virulence plasmid pXO1 and thereby the global regulator AtxA. Using comparative 2D gel electrophoresis, we showed that activation of the PlcR regulon in B. anthracis leads to upregulation of many proteins found in the secretome of B. cereus, including phospholipases and proteases, such as the putative protease BA1995. Transcriptional analysis demonstrated expression of BA1995 to be dependent on PlcR-PapR, even though the putative PlcR recognition site of the BA1995 gene does not exactly match the PlcR consensus sequence, explaining why this protein had escaped recognition as belonging to the PlcR regulon. Additionally, while transcription of major PlcR-dependent haemolysins, sphingomyelinase and anthrolysin O is enhanced in response to PlcR activation in B. anthracis, only anthrolysin O contributes significantly to lysis of human erythrocytes. In contrast, the toxicity of bacterial culture supernatants from a PlcR-positive strain towards murine macrophages occurred independently of anthrolysin O expression in vitro and in vivo. C1 [Sastalla, Inka; Maltese, Lauren M.; Pomerantsev, Andrei P.; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Pomerantseva, Olga M.; Keane-Myers, Andrea] USN, Biol Def Res Directorate, Res Ctr, Rockville, MD USA. RP Leppla, SH (reprint author), NIAID, Lab Bacterial Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA. We thank Zachary Newman for supplying BMDM cells, Devorah Crown for assistance with animal experiments, the NIAID RTB for performing 2D SDS-PAGE and MS, and Dr Clinton Leysath for assistance with flow cytometry. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government. NR 46 TC 8 Z9 12 U1 0 U2 4 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD OCT PY 2010 VL 156 BP 2982 EP 2993 DI 10.1099/mic.0.041418-0 PN 10 PG 12 WC Microbiology SC Microbiology GA 670UZ UT WOS:000283454100010 PM 20688829 ER PT J AU Wang, SM Duyn, JH AF Wang, Shumin Duyn, Jeff H. TI A TOPOLOGY-BASED MULTILEVEL SCHEME FOR FAST INTEGRAL-EQUATION METHODS SO MICROWAVE AND OPTICAL TECHNOLOGY LETTERS LA English DT Article DE method of moments; fast integral methods; multilevel scheme ID ELECTROMAGNETIC SCATTERING; ALGORITHM; APPROXIMATION; MATRICES; MOMENTS AB A topology-based multilevel scheme is proposed for fast integral-equation simulations. Low-level subdomains are formed at first by exploring topological connectivity between basis functions: Profile reduction and quad-tree image compression are then applied to construct a heuristic multilevel scheme from a symbolic rank map. Numerical results verified this approach and demonstrated its computational efficiency. (C) 2010 Wiley Periodicals, Inc. Microwave Opt Technol Lett 52:2195-2198,2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.25468 C1 [Wang, Shumin; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. RP Wang, SM (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. EM wangshu@ninds.nih.gov RI Duyn, Jozef/F-2483-2010 NR 13 TC 2 Z9 2 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0895-2477 J9 MICROW OPT TECHN LET JI Microw. Opt. Technol. Lett. PD OCT PY 2010 VL 52 IS 10 BP 2195 EP 2198 DI 10.1002/mop.25468 PG 4 WC Engineering, Electrical & Electronic; Optics SC Engineering; Optics GA 636NN UT WOS:000280744100010 ER PT J AU Cuchalova, L Kouba, T Herrmannova, A Danyi, I Chiu, WL Valasek, L AF Cuchalova, Lucie Kouba, Tomas Herrmannova, Anna Danyi, Istvan Chiu, Wen-ling Valasek, Leos TI The RNA Recognition Motif of Eukaryotic Translation Initiation Factor 3g (eIF3g) Is Required for Resumption of Scanning of Posttermination Ribosomes for Reinitiation on GCN4 and Together with eIF3i Stimulates Linear Scanning SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID OPEN READING FRAMES; START CODON SELECTION; MESSENGER-RNA; SACCHAROMYCES-CEREVISIAE; IN-VIVO; 40S RIBOSOME; ESCHERICHIA-COLI; GENE-EXPRESSION; STOP CODONS; YEAST AB Recent reports have begun unraveling the details of various roles of individual eukaryotic translation initiation factor 3 (eIF3) subunits in translation initiation. Here we describe functional characterization of two essential Saccharomyces cerevisiae eIF3 subunits, g/Tif35 and i/Tif34, previously suggested to be dispensable for formation of the 48S preinitiation complexes (PICs) in vitro. A triple-Ala substitution of conserved residues in the RRM of g/Tif35 (g/tif35-KLF) or a single-point mutation in the WD40 repeat 6 of i/Tif34 (i/tif34-Q258R) produces severe growth defects and decreases the rate of translation initiation in vivo without affecting the integrity of eIF3 and formation of the 43S PICs in vivo. Both mutations also diminish induction of GCN4 expression, which occurs upon starvation via reinitiation. Whereas g/tif35-KLF impedes resumption of scanning for downstream reinitiation by 40S ribosomes terminating at upstream open reading frame 1 (uORF1) in the GCN4 mRNA leader, i/tif34-Q258R prevents full GCN4 derepression by impairing the rate of scanning of posttermination 40S ribosomes moving downstream from uORF1. In addition, g/tif35-KLF reduces processivity of scanning through stable secondary structures, and g/Tif35 specifically interacts with Rps3 and Rps20 located near the ribosomal mRNA entry channel. Together these results implicate g/Tif35 and i/Tif34 in stimulation of linear scanning and, specifically in the case of g/Tif35, also in proper regulation of the GCN4 reinitiation mechanism. C1 [Cuchalova, Lucie; Kouba, Tomas; Herrmannova, Anna; Danyi, Istvan; Valasek, Leos] Inst Microbiol AVCR, Lab Regulat Gene Express, Vvi, Prague, Czech Republic. [Chiu, Wen-ling] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Valasek, L (reprint author), Inst Microbiol AVCR, Lab Regulat Gene Express, Vvi, Videnska 1083, Prague, Czech Republic. EM valasekl@biomed.cas.cz RI Herrmannova, Anna/I-1745-2014; Valasek, Leos/I-5743-2014; Cuchalova, Lucie/H-4650-2014 FU Howard Hughes Medical Institute; Wellcome Trust [076456/Z/05/Z]; Academy of Sciences of the Czech Republic [AV0Z50200510] FX This research was supported by the Howard Hughes Medical Institute, The Wellcome Trust grant 076456/Z/05/Z, a Fellowship of Jan E. Purkyne from the Academy of Sciences of the Czech Republic, and Institutional Research Concept AV0Z50200510. NR 62 TC 40 Z9 41 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2010 VL 30 IS 19 BP 4671 EP 4686 DI 10.1128/MCB.00430-10 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 648VB UT WOS:000281721400010 PM 20679478 ER PT J AU Schug, TT Xu, Q Gao, HM Peres-da-Silva, A Draper, DW Fessler, MB Purushotham, A Li, XL AF Schug, Thaddeus T. Xu, Qing Gao, Huiming Peres-da-Silva, Ashwin Draper, David W. Fessler, Michael B. Purushotham, Aparna Li, Xiaoling TI Myeloid Deletion of SIRT1 Induces Inflammatory Signaling in Response to Environmental Stress SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NF-KAPPA-B; INDUCED INSULIN-RESISTANCE; CALORIE RESTRICTION; DEPENDENT TRANSCRIPTION; ALTERNATIVE ACTIVATION; PULMONARY INFLAMMATION; GENE-EXPRESSION; CELL-SURVIVAL; PROTEIN SIR2; LIFE-SPAN AB Macrophage activation and infiltration into resident tissues is known to mediate local inflammation and is a hallmark feature of metabolic syndrome. Members of the sirtuin family of proteins regulate numerous physiological processes, including those involved in nutrient regulation and the promotion of longevity. However, the important role that SIRT1, the leading sirtuin family member, plays in immune response remains unclear. In this study, we demonstrate that SIRT1 modulates the acetylation status of the RelA/p65 subunit of NF-kappa B and thus plays a pivotal role in regulating the inflammatory, immune, and apoptotic responses in mammals. Using a myeloid cell-specific SIRT1 knockout (Mac-SIRT1 KO) mouse model, we show that ablation of SIRT1 in macrophages renders NF-kappa B hyperacetylated, resulting in increased transcriptional activation of proinflammatory target genes. Consistent with increased proinflammatory gene expression, Mac-SIRT1 KO mice challenged with a high-fat diet display high levels of activated macrophages in liver and adipose tissue, predisposing the animals to development of systemic insulin resistance and metabolic derangement. In summary, we report that SIRT1, in macrophages, functions to inhibit NF-kappa B-mediated transcription, implying that myeloid cell-specific modulation of this sirtuin may be beneficial in the treatment of inflammation and its associated diseases. C1 [Schug, Thaddeus T.; Xu, Qing; Peres-da-Silva, Ashwin; Purushotham, Aparna; Li, Xiaoling] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Gao, Huiming] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Draper, David W.; Fessler, Michael B.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Li, XL (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM lix3@niehs.nih.gov RI gao, huiming/C-8454-2012 FU NIH, National Institute of Environmental Health Sciences [Z01 ES102205] FX This research was supported by a grant from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, to X. L. (Z01 ES102205). NR 44 TC 126 Z9 135 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2010 VL 30 IS 19 BP 4712 EP 4721 DI 10.1128/MCB.00657-10 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 648VB UT WOS:000281721400013 PM 20647536 ER PT J AU Arevalo, JC Wu, SH Takahashi, T Zhang, H Yu, T Yano, H Milner, TA Tessarollo, L Ninan, I Arancio, O Chao, MV AF Carlos Arevalo, Juan Wu, Synphen H. Takahashi, Takuya Zhang, Hong Yu, Tao Yano, Hiroko Milner, Teresa A. Tessarollo, Lino Ninan, Ipe Arancio, Ottavio Chao, Moses V. TI The ARMS/Kidins220 scaffold protein modulates synaptic transmission SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE ARMS-Kidins220; Scaffold; Synaptic transmission ID AMPA RECEPTOR TRAFFICKING; LONG-TERM POTENTIATION; GLUTAMATE RECEPTORS; MOLECULAR-MECHANISMS; PKA PHOSPHORYLATION; HIPPOCAMPAL-NEURONS; GLUR1 SUBUNIT; PLASTICITY; NEUROTROPHIN; RECTIFICATION AB Activity-dependent changes of synaptic connections are facilitated by a variety of scaffold proteins, including PSD-95, Shank, SAP97 and GRIP, which serve to organize ion channels, receptors and enzymatic activities and to coordinate the actin cytoskeleton. The abundance of these scaffold proteins raises questions about the functional specificity of action of each protein. Here we report that basal synaptic transmission is regulated in an unexpected manner by the ankyrin repeat-rich membrane-spanning (ARMS/Kidins220) scaffold protein. In particular, decreases in the levels of ARMS/Kidins220 in vivo led to an increase in basal synaptic transmission in the hippocampus, without affecting paired pulse facilitation. One explanation to account for the effects of ARMS/Kidins220 is an interaction with the AMPA receptor subunit. GluA1, which could be observed after immunoprecipitation. Importantly, shRNA and cell surface biotinylation experiments indicate that ARMS/Kidins220 levels have an impact on GluA1 phosphorylation and localization. Moreover, ARMS/Kidins220 is a negative regulator of AMPAR function, which was confirmed by inward rectification assays. These results provide evidence that modulation of ARMS/Kidins220 levels can regulate basal synaptic strength in a specific manner in hippocampal neurons. (C) 2010 Elsevier Inc. All rights reserved. C1 [Carlos Arevalo, Juan; Wu, Synphen H.; Yano, Hiroko; Ninan, Ipe; Chao, Moses V.] NYU, Sch Med, Skirball Inst Biomol Med, Mol Neurobiol Program,Dept Cell Biol, New York, NY 10016 USA. [Carlos Arevalo, Juan; Wu, Synphen H.; Yano, Hiroko; Ninan, Ipe; Chao, Moses V.] NYU, Sch Med, Skirball Inst Biomol Med, Mol Neurobiol Program,Dept Physiol & Neurosci, New York, NY 10016 USA. [Carlos Arevalo, Juan; Wu, Synphen H.; Yano, Hiroko; Ninan, Ipe; Chao, Moses V.] NYU, Sch Med, Skirball Inst Biomol Med, Mol Neurobiol Program,Dept Psychiat & Neural Sci, New York, NY 10016 USA. [Carlos Arevalo, Juan; Yu, Tao] Univ Salamanca, Inst Neurociencias Castilla & Leon INCyL, Salamanca 37007, Spain. [Takahashi, Takuya] Yokohama City Univ, Dept Physiol, Grad Sch Med, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. [Zhang, Hong; Arancio, Ottavio] Columbia Univ, Dept Pathol, Taub Inst, New York, NY 10032 USA. [Milner, Teresa A.] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. [Milner, Teresa A.] Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10065 USA. [Tessarollo, Lino] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Arevalo, JC (reprint author), NYU, Sch Med, Skirball Inst Biomol Med, Mol Neurobiol Program,Dept Cell Biol, New York, NY 10016 USA. EM arevalojc@usal.es; Moses.Chao@med.nyu.edu RI IBSAL, Secretaria/H-3719-2011; ArAvalo, Juan Carlos/J-8154-2014; OI ArAvalo, Juan Carlos/0000-0003-1994-3095; Ninan, Ipe/0000-0001-9774-6455; Chao, Moses/0000-0002-6969-3744 FU NIH [HL18974, DA08259, NS049442, NS21072, HD23315]; Medical Scientist Training Program; Ministerio de Ciencia e Innovacion [BFU2008-00162]; Junta Castilla y Leon [SA074A08]; Alzheimer's Association FX We thank G. Schiavo for the ARMS/Kidins220 monoclonal antibody; E. Ziff for the GluA1 construct; D. Trono for the lentiviral plasmids; members of the Moses V. Chao, Barbara L. Hempstead, and Francis S. Lee laboratories for the helpful discussions; Enrique Lopez-Poveda for his help writing the MatLab custom-program to quantify immunofluorescence images and Belen Dominguez for continuous support. This work was supported by NIH grants (HL18974 and DA08259) to T.A.M., NIH grant (NS049442) to O.A., NIH grants (NS21072 and HD23315) to M.V.C., the Intramural Research Program of the NIH (LT.), the Medical Scientist Training Program (S.H.W.), and by a Marie Curie International Reintegration Grant within the 7th European Community Framework Programme, by Ministerio de Ciencia e Innovacion Grant BFU2008-00162, and by Junta Castilla y Leon Grant SA074A08 to J.C.A. J.C.A. is a "Ramon y Cajal" Investigator from the University of Salamanca and a NARSAD 2007 Young Investigator Awardee. I.N. is a NARSAD 2008 Young Investigator and a recipient of Alzheimer's Association New Investigator Award. NR 42 TC 17 Z9 17 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD OCT PY 2010 VL 45 IS 2 BP 92 EP 100 DI 10.1016/j.mcn.2010.06.002 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 644CF UT WOS:000281347300002 PM 20547223 ER PT J AU Franchini, G AF Franchini, Genoveffa TI HTLV-1 and HIV-1 "Accessory" proteins: A Misleading Misnomer SO MOLECULAR ASPECTS OF MEDICINE LA English DT Editorial Material C1 NCI, Anim Models Retroviral Vaccine Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Anim Models Retroviral Vaccine Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov 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 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD OCT PY 2010 VL 31 IS 5 SI SI BP 331 EP 332 DI 10.1016/j.mam.2010.08.001 PG 2 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 694GV UT WOS:000285283900001 PM 20708638 ER PT J AU Van Prooyen, N Andresen, V Gold, H Bialuk, I Pise-Masison, C Franchini, G AF Van Prooyen, Nancy Andresen, Vibeke Gold, Heather Bialuk, Izabela Pise-Masison, Cynthia Franchini, Genoveffa TI Hijacking the T-cell communication network by the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) p12 and p8 proteins SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE HTLV-1; p12; p8; T-cells; orf-I; Virus transmission; Immunological synapse ID I-ASSOCIATED MYELOPATHY; OPEN READING FRAMES; VACUOLAR H+-ATPASE; LEUKEMIA-VIRUS; MESSENGER-RNA; NUCLEAR FACTOR; SIGNAL-TRANSDUCTION; MONONUCLEAR-CELLS; SJOGRENS-SYNDROME; HAM/TSP PATIENTS AB The non-structural proteins encoded by the orf-I, II, III, and IV genes of the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) genome, are critical for the modulation of cellular gene expression and T-cell proliferation, the escape from cytotoxic T-cells and natural killer cells, and virus expression. In here, we review the main functions of the HTLV-1 orf-I products. The 12 kDa product from orf-I (p12) is proteolytically cleaved within the endoplasmic reticulum (ER) to generate the 8 kDa protein (p8). At the steady state, both proteins are expressed at similar levels in transfected T-cells. The p12 protein remains in the ER and cis-Golgi, whereas the p8 protein traffics to the cell surface and is recruited to the immunological synapse. The p12 and the p8 proteins have seemingly opposite effects on T-cells; the ER resident p12, modulates T-cell activation and proliferation, whereas p8 induces T-cell anergy. The p8 protein also increases the formation of cellular conduits, is transferred to neighboring T-cells, and increases virus transmission. The requirement for HTLV-1 infectivity of orf-I is demonstrated by the loss of virus infectivity in macaques exposed to an engineered virus, whereby expression of orf-I was ablated. Altogether the current knowledge demonstrates that the concerted activity of p8 and p12 is essential for the persistence of virus infected cells in the host. Published by Elsevier Ltd. C1 [Van Prooyen, Nancy; Andresen, Vibeke; Gold, Heather; Bialuk, Izabela; Pise-Masison, Cynthia; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, Vaccine Branch, NIH, Bldg 41 Room D-804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Teresa Habina for editorial assistance. We are very grateful to Dustin Edwards and Shari Gordon for critical reading of the manuscript. NR 90 TC 23 Z9 23 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD OCT PY 2010 VL 31 IS 5 SI SI BP 333 EP 343 DI 10.1016/j.mam.2010.07.001 PG 11 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 694GV UT WOS:000285283900002 PM 20673780 ER PT J AU Silic-Benussi, M Biasiotto, R Andresen, V Franchini, G D'Agostino, DM Ciminale, V AF Silic-Benussi, Micol Biasiotto, Roberta Andresen, Vibeke Franchini, Genoveffa D'Agostino, Donna M. Ciminale, Vincenzo TI HTLV-1 p13, a small protein with a busy agenda SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE Mitochondria; K plus channel; HTLV-1; Apoptosis; Leukemia ID LEUKEMIA-VIRUS TYPE-1; ACTIVATED T-CELLS; THIOREDOXIN-BINDING PROTEIN-2; P13(II) PROTEIN; MEDIATED APOPTOSIS; ACCESSORY PROTEINS; GENE-EXPRESSION; NUCLEAR FACTOR; I TAX; DEATH AB Human T-cell leukemia virus type 1 (HTLV-1) infection is characterized by life-long persistence of the virus in the host. While most infected individuals remain asymptomatic, 3-5% will eventually develop adult T-cell leukemia/lymphoma (ATLL) or tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM) after a clinical latency that can span years (TSP/HAM) to decades (ATLL). The major oncogenic determinant among HTLV-1 proteins is the Tax transactivator, which influences the expression and function of a great number of cellular proteins, drives cell proliferation, reduces cell death, and induces genetic instability. The present review is focused on the current knowledge of p13, an HTLV-1 accessory protein targeted to the inner mitochondrial membrane and, under certain conditions, to the nucleus. In mitochondria, p13 produces an inward K+ current that results in an increased production of ROS by mitochondria. These effects are linked to the protein's effects on cell turnover which include activation of primary T-cells and reduced proliferation/sensitization to death of tumor cells. Recent findings suggest that in the presence of Tax, p13 is subjected to ubiquitylation and partly targeted to the nucleus. Nuclear p13 binds Tax and inhibits its transcriptional activity. These findings suggest that the protein might exert distinct functions depending on its intracellular localization and influence both the turnover of infected cells and the balance between viral latency and productive infection. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Silic-Benussi, Micol; Biasiotto, Roberta; D'Agostino, Donna M.; Ciminale, Vincenzo] Univ Padua, Dipartimento Sci Oncol & Chirurg, I-35128 Padua, Italy. [Andresen, Vibeke; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. [D'Agostino, Donna M.; Ciminale, Vincenzo] IRCCS, Ist Oncol Veneto, I-35128 Padua, Italy. RP Ciminale, V (reprint author), Univ Padua, Dipartimento Sci Oncol & Chirurg, Via Gattamelata 64, I-35128 Padua, Italy. EM v.ciminale@unipd.it RI Biasiotto, Roberta/G-2903-2012 FU Associazione Italiana per la Ricerca sul Cancro; European Union [2005-018704]; Ministero per l'Universita e la Ricerca Scientifica, e Tecnologica - Progetti di Ricerca di Interesse Nazionale; Ministero della Salute [RFPS-2006-2-342-010]; University of Padova; National Cancer Institute National Institutes of Health FX We thank Luigi Chieco-Bianchi, Paolo Bernardi, Fabio di Lisa and Ilaria Cavallari for valuable discussions. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (V.C.), the European Union ('The role of chronic infections in the development of cancer': Contract No. 2005-018704, to V.C.), the Ministero per l'Universita e la Ricerca Scientifica, e Tecnologica - Progetti di Ricerca di Interesse Nazionale (V.C.), the Ministero della Salute (progetto RFPS-2006-2-342-010), the University of Padova (D.M.D., V.C.), and National Cancer Institute National Institutes of Health intramural grants (V.A., G.F.). NR 47 TC 15 Z9 16 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD OCT PY 2010 VL 31 IS 5 SI SI BP 350 EP 358 DI 10.1016/j.mam.2010.03.001 PG 9 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 694GV UT WOS:000285283900004 PM 20332002 ER PT J AU Andrew, A Strebel, K AF Andrew, Amy Strebel, Klaus TI HIV-1 Vpu targets cell surface markers CD4 and BST-2 through distinct mechanisms SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE Vpu; Degradation of CD4; HIV-1 release; BST-2; beta-TrCP ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROTEIN-U VPU; CLATHRIN-MEDIATED ENDOCYTOSIS; VIRAL PARTICLE RELEASE; FULL-LENGTH VPU; CYTOPLASMIC DOMAIN; ENDOPLASMIC-RETICULUM; ENVELOPE GLYCOPROTEIN; TRANSMEMBRANE DOMAIN; DOWN-MODULATION AB Vpu is a small integral membrane protein encoded by HIV-1 and some SIV isolates. The protein is known to induce degradation of the viral receptor molecule CD4 and to enhance the release of newly formed virions from the cell surface. Vpu accomplishes these two functions through two distinct mechanisms. In the case of CD4, Vpu acts as a molecular adaptor to connect CD4 to an E3 ubiquitin ligase complex resulting in CD4 degradation by cellular proteasomes. This requires signals located in Vpu's cytoplasmic domain. Enhancement of virus release on the other hand involves the neutralization of a cellular host factor, BST-2 (also known as CD317, HM1.24, or tetherin) and requires Vpu's TM domain. The current review discusses recent advances on the role of Vpu in controlling degradation of CD4 and in regulating virus release. Published by Elsevier Ltd. C1 [Andrew, Amy; Strebel, Klaus] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bldg 4,Room 310,4 Ctr Dr MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU NIH; NIH, NIAID FX This work was supported in part by a Grant from the NIH Intramural AIDS Targeted Antiviral Program to K.S. and by the Intramural Research Program of the NIH, NIAID. NR 121 TC 25 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD OCT PY 2010 VL 31 IS 5 SI SI BP 407 EP 417 DI 10.1016/j.mam.2010.08.002 PG 11 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 694GV UT WOS:000285283900009 PM 20858517 ER PT J AU Renvoise, B Parker, RL Yang, D Bakowska, JC Hurley, JH Blackstone, C AF Renvoise, Benoit Parker, Rell L. Yang, Dong Bakowska, Joanna C. Hurley, James H. Blackstone, Craig TI SPG20 Protein Spartin Is Recruited to Midbodies by ESCRT-III Protein Ist1 and Participates in Cytokinesis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; TROYER-SYNDROME; STRUCTURAL BASIS; COMPLEX; VPS4; LOCALIZATION; RECOGNITION; MACHINERY; INTERACTS; FEATURES AB Hereditary spastic paraplegias (HSPs, SPG1-46) are inherited neurological disorders characterized by lower extremity spastic weakness. Loss-of-function SPG20 gene mutations cause an autosomal recessive HSP known as Troyer syndrome. The SPG20 protein spartin localizes to lipid droplets and endosomes, and it interacts with tail interacting protein 47 (TIP47) as well as the ubiquitin E3 ligases atrophin-1-interacting protein (AIP)4 and AIP5. Spartin harbors a domain contained within microtubule-interacting and trafficking molecules (MIT) at its N-terminus, and most proteins with MIT domains interact with specific ESCRT-III proteins. Using yeast two-hybrid and in vitro surface plasmon resonance assays, we demonstrate that the spartin MIT domain binds with micromolar affinity to the endosomal sorting complex required for transport (ESCRT)-III protein increased sodium tolerance (Ist)1 but not to ESCRT-III proteins charged multivesicular body proteins 1-7. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells by small interfering RNA significantly decreases the number of cells where spartin is present at midbodies. Depletion of spartin does not affect Ist1 localization to midbodies but markedly impairs cytokinesis. A structure-based amino acid substitution in the spartin MIT domain (F24D) blocks the spartin-Ist1 interaction. Spartin F24D does not localize to the midbody and acts in a dominant-negative manner to impair cytokinesis. These data suggest that Ist1 interaction is important for spartin recruitment to the midbody and that spartin participates in cytokinesis. C1 [Renvoise, Benoit; Parker, Rell L.; Blackstone, Craig] NINDS, Cellular Neurol Unit, Neurogenet Branch, Bethesda, MD 20892 USA. [Yang, Dong; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Parker, Rell L.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20814 USA. [Bakowska, Joanna C.] Loyola Univ, Dept Pharmacol & Expt Therapeut, Chicago Stritch Sch Med, Maywood, IL 60153 USA. RP Blackstone, C (reprint author), NINDS, Cellular Neurol Unit, Neurogenet Branch, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; National Institute of Diabetes and Digestive Diseases, National Institutes of Health; National Institutes of Health [NS-050137]; Howard Hughes Medical Institute-National Institutes of Health FX We thank J. Nagle and D. Kauffman (DNA Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD) for DNA sequencing. This research was supported by the Intramural Research programs of the National Institute of Neurological Disorders and Stroke (B. R., C. B.) and the National Institute of Diabetes and Digestive Diseases (D.Y., J. H. H.), National Institutes of Health; the National Institutes of Health Bench-to-Bedside Program (J. H. H., C. B.); the Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program (R. P.); and National Institutes of Health K22 training grant NS-050137 (to J. C. B.). NR 40 TC 34 Z9 38 U1 0 U2 5 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 OCT 1 PY 2010 VL 21 IS 19 BP 3293 EP 3303 DI 10.1091/mbc.E09-10-0879 PG 11 WC Cell Biology SC Cell Biology GA 655UJ UT WOS:000282275600002 PM 20719964 ER PT J AU Perez-Victoria, FJ Schindler, C Magadan, JG Mardones, GA Delevoye, C Romao, M Raposo, G Bonifacino, JS AF Perez-Victoria, F. Javier Schindler, Christina Magadan, Javier G. Mardones, Gonzalo A. Delevoye, Cedric Romao, Maryse Raposo, Graca Bonifacino, Juan S. TI Ang2/Fat-Free Is a Conserved Subunit of the Golgi-associated Retrograde Protein Complex SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MOTOR-NEURON DISEASE; SNARE TLG1P; WOBBLER MOUSE; GARP COMPLEX; VFT-COMPLEX; ESCRT-I; MICE; AUTOPHAGY; NEURODEGENERATION; IDENTIFICATION AB The Golgi-associated retrograde protein (GARP) complex mediates tethering and fusion of endosome-derived transport carriers to the trans-Golgi network (TGN). In the yeast Saccharomyces cerevisiae, GARP comprises four subunits named Vps51p, Vps52p, Vps53p, and Vps54p. Orthologues of the GARP subunits, except for Vps51p, have been identified in all other eukaryotes. A yeast two-hybrid screen of a human cDNA library yielded a phylogenetically conserved protein, Ang2/Fat-free, which interacts with human Vps52, Vps53 and Vps54. Human Ang2 is larger than yeast Vps51p, but exhibits significant homology in an N-terminal coiled-coil region that mediates assembly with other GARP subunits. Biochemical analyses show that human Ang2, Vps52, Vps53 and Vps54 form an obligatory 1: 1: 1: 1 complex that strongly interacts with the regulatory Habc domain of the TGN SNARE, Syntaxin 6. Depletion of Ang2 or the GARP subunits similarly impairs protein retrieval to the TGN, lysosomal enzyme sorting, endosomal cholesterol traffico and autophagy. These findings indicate that Ang2 is the missing component of the GARP complex in most eukaryotes. C1 [Perez-Victoria, F. Javier; Schindler, Christina; Magadan, Javier G.; Mardones, Gonzalo A.; Bonifacino, Juan S.] NIH, Cell Biol & Metab Program, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Delevoye, Cedric; Romao, Maryse; Raposo, Graca] CNRS, UMR 144, Inst Curie, F-75248 Paris, France. RP Bonifacino, JS (reprint author), NIH, Cell Biol & Metab Program, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU National Institute of Child Health and Human Development, NIH; Centre National de la Recherche Scientifique and Institut Curie; Deutsche Forschungsgemeinschaft FX We thank X. Zhu and N. Tsai for technical assistance, M. Krieger for antibody to Cog8, and J. Dacks for discussion. This work was funded by the National Institutes of Health (NIH) Intramural Program of National Institute of Child Health and Human Development, NIH (J. S. B), and the Centre National de la Recherche Scientifique and Institut Curie (G. R.). C. S. was supported by a fellowship from the Deutsche Forschungsgemeinschaft. NR 40 TC 32 Z9 37 U1 0 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 OCT 1 PY 2010 VL 21 IS 19 BP 3386 EP 3395 DI 10.1091/mbc.E10-05-0392 PG 10 WC Cell Biology SC Cell Biology GA 655UJ UT WOS:000282275600010 PM 20685960 ER PT J AU Afkarian, M Bhasin, M Dillon, ST Guerrero, MC Nelson, RG Knowler, WC Thadhani, R Libermann, TA AF Afkarian, Maryam Bhasin, Manoj Dillon, Simon T. Guerrero, Manuel C. Nelson, Robert G. Knowler, William C. Thadhani, Ravi Libermann, Towia A. TI Optimizing a Proteomics Platform for Urine Biomarker Discovery SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID SAMPLE PREPARATION; DIABETIC-NEPHROPATHY; 2-DIMENSIONAL ELECTROPHORESIS; GEL-ELECTROPHORESIS; PROTEINS; QUANTITATION; COLLECTION; PREDICT AB Biomarker discovery approaches in urine have been hindered by concerns for reproducibility and inadequate standardization of proteomics protocols. In this study, we describe an optimized quantitative proteomics strategy for urine biomarker discovery, which is applicable to fresh or long frozen samples. We used urine from healthy controls to standardize iTRAQ (isobaric tags for relative and absolute quantitation) for variation induced by protease inhibitors, starting protein and iTRAQ label quantities, protein extraction methods, and depletion of albumin and immunoglobulin G (IgG). We observed the following: (a) Absence of protease inhibitors did not affect the number or identity of the high confidence proteins. (b) Use of less than 20 mu g of protein per sample led to a significant drop in the number of identified proteins. (c) Use of as little as a quarter unit of an iTRAQ label did not affect the number or identity of the identified proteins. (d) Protein extraction by methanol precipitation led to the highest protein yields and the most reproducible spectra. (e) Depletion of albumin and IgG did not increase the number of identified proteins or deepen the proteome coverage. Applying this optimized protocol to four pairs of long frozen urine samples from diabetic Pima Indians with or without nephropathy, we observed patterns suggesting segregation of cases and controls by iTRAQ spectra. We also identified several previously reported candidate biomarkers that showed trends toward differential expression, albeit not reaching statistical significance in this small sample set. Molecular & Cellular Proteomics 9:2195-2204, 2010. C1 [Bhasin, Manoj; Dillon, Simon T.; Guerrero, Manuel C.; Libermann, Towia A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Genom & Prote Ctr, Sch Med, Boston, MA 02215 USA. [Bhasin, Manoj; Dillon, Simon T.; Guerrero, Manuel C.; Libermann, Towia A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dana Farber Harvard Canc Ctr Canc Prote Core, Sch Med, Boston, MA 02215 USA. [Afkarian, Maryam; Thadhani, Ravi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Nelson, Robert G.; Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. RP Libermann, TA (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Genom & Prote Ctr, Sch Med, Res N Bldg,Rm 380C,99 Brookline Ave, Boston, MA 02215 USA. EM tliberma@bidmc.harvard.edu RI Libermann, Towia/F-9866-2010; Nelson, Robert/B-1470-2012; OI Libermann, Towia/0000-0002-4006-8179 FU National Institutes of Health through NIDDK; Juvenile Diabetes Research Foundation FX This work was supported, in whole or in part, by the National Institutes of Health through the Intramural Research Program of the NIDDK. This work was also supported by a research grant from the Juvenile Diabetes Research Foundation (to R. T.). NR 25 TC 39 Z9 41 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2010 VL 9 IS 10 BP 2195 EP 2204 DI 10.1074/mcp.M110.000992 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 656VJ UT WOS:000282368900010 PM 20511394 ER PT J AU Fernandez-Irigoyen, J Santamaria, E Chien, YH Hwu, WL Korman, SH Faghfoury, H Schulze, A Hoganson, GE Stabler, SP Allen, RH Wagner, C Mudd, SH Corrales, FJ AF Fernandez-Irigoyen, Joaquin Santamaria, Enrique Chien, Yin-Hsiu Hwu, Wuh-Liang Korman, Stanley H. Faghfoury, Hanna Schulze, Andreas Hoganson, George E. Stabler, Sally P. Allen, Robert H. Wagner, Conrad Mudd, S. Harvey Corrales, Fernando J. TI Enzymatic activity of methionine adenosyltransferase variants identified in patients with persistent hypermethioninemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Methionine adenosyltransferase; Hypermethioninemia; S-adenosylmethionine; Tripolyphosphate ID S-ADENOSYLMETHIONINE SYNTHETASE; I/III DEFICIENCY; HEPATOCELLULAR-CARCINOMA; MOLECULAR-MECHANISMS; TOTAL HOMOCYSTEINE; LIVER; MUTATION; ADENOSYLHOMOCYSTEINE; METABOLISM; EXPRESSION AB Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been conserved with a high degree of homology among species. In the liver, MAT I and III, tetrameric and dimeric isoforms of the same catalytic subunit encoded by the gene MAT1A, account for the predominant portion of total body synthesis of S-adenosylmethionine (SAM), a versatile sulfonium ion-containing molecule involved in a variety of vital metabolic reactions and in the control of hepatocyte proliferation and differentiation. During the past 15 years 28 MAT1A mutations have been described in patients with elevated plasma methionines, total homocysteines at most only moderately elevated, and normal levels of tyrosine and other aminoacids. In this study we describe functional analyses that determine the MAT and tripolyphosphatase (PPPase) activities of 18 MAT1A variants, six of them novel, and none of them previously assayed for activity. With the exception of G69S and Y92H, all recombinant proteins showed impairment (usually severe) of MAT activity. Tripolyphosphate (PPPi) hydrolysis was decreased only in some mutant proteins but, when it was decreased MAT activity was always also impaired. (C) 2010 Elsevier Inc. All rights reserved. C1 [Fernandez-Irigoyen, Joaquin; Santamaria, Enrique; Corrales, Fernando J.] Univ Navarra, Ctr Appl Med Res CIMA, Prote Unit, Div Hepatol & Gene Therapy, Pamplona 31008, Spain. [Chien, Yin-Hsiu; Hwu, Wuh-Liang] Natl Taiwan Univ Hosp, Dept Med Genet, Taipei, Taiwan. [Korman, Stanley H.] Hadassah Hebrew Univ Med Ctr, Dept Human Genet & Metab Dis, Jerusalem, Israel. [Faghfoury, Hanna; Schulze, Andreas] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada. [Hoganson, George E.] Univ Illinois, Coll Med, Dept Pediat, Chicago, IL USA. [Faghfoury, Hanna; Schulze, Andreas] Univ Toronto, Toronto, ON, Canada. [Stabler, Sally P.; Allen, Robert H.] Univ Colorado, Hlth Sci Ctr, Div Hematol, Aurora, CO USA. [Wagner, Conrad] Vanderbilt Univ, Med Ctr, Dept Biochem, Nashville, TN USA. [Mudd, S. Harvey] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Corrales, FJ (reprint author), Univ Navarra, Ctr Appl Med Res CIMA, Prote Unit, Div Hepatol & Gene Therapy, Pamplona 31008, Spain. EM fjcorrales@unav.es OI HWU, WUH-LIANG/0000-0001-6690-4879; CHIEN, YIN-HSIU/0000-0001-8802-5728 FU Ministerio de Ciencia e Innovacion [ISCIII-RETIC RD06/0020] FX The technical assistance of Manuela Molina and Maria I. Mora is acknowledged. This work was supported by: the agreement between FIMA and the "UTE project CIMA"; grants Plan Nacional I+D+I SAF2008-0154 from Ministerio de Ciencia e Innovacion to FJC; ISCIII-RETIC RD06/0020 to MAA and FJC. NR 52 TC 15 Z9 15 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD OCT-NOV PY 2010 VL 101 IS 2-3 BP 172 EP 177 DI 10.1016/j.ymgme.2010.07.009 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 672TK UT WOS:000283609600014 PM 20675163 ER PT J AU Fu, R Yanjanin, NM Bianconi, S Pavan, WJ Porter, FD AF Fu, Rao Yanjanin, Nicole M. Bianconi, Simona Pavan, William J. Porter, Forbes D. TI Oxidative stress in Niemann-Pick disease, type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Neurodegenerative disease; Lysosomal storage disease; Oxidative stress; Coenzyme Q10; Trolox equivalent antioxidant capacity ID LOW-DENSITY-LIPOPROTEIN; COENZYME Q(10); CHOLESTEROL HOMEOSTASIS; MITOCHONDRIAL-FUNCTION; ALZHEIMERS-DISEASE; ALPHA-TOCOPHEROL; BINDING PROTEIN; METABOLISM; GENE; ACCUMULATION AB Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder due to impaired intracellular cholesterol and lipid transport. Increased oxidative stress has been reported in human NPC1 mutant fibroblasts and in tissues from Npc1 mutant mice. However, oxidative stress in NPC patients has not been established. In this study, we demonstrated increased oxidative stress in NPC patients. Evaluation of serum from 37 NPC patients, compared to control values, showed significant decreases (p<.01) in both the fraction of reduced coenzyme Q10 (CoQ10) and trolox equivalent antioxidant capacity (TEAC). Both findings are consistent with increased oxidative stress in NPC. Supplementation with CoQ10 was not effective in correcting the decreased fraction of reduced CoQ10. Increased oxidative stress may be a contributing factor to the pathology of NPC, and demonstration of increased oxidative stress in NPC patients provides both a rationale and the biomarkers necessary to test the efficacy of antioxidant therapy in NPC. Published by Elsevier Inc. C1 [Fu, Rao; Yanjanin, Nicole M.; Bianconi, Simona; Porter, Forbes D.] NICHD, Program Dev Endocrinol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Fu, Rao] Peking Univ, Hlth Sci Ctr, Beijing 100191, Peoples R China. [Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), Bld 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Human Genome Research Institute; Office of Rare Diseases; Ara Parseghian Medical Research Foundation; Dana's Angels Research Trust; Hadley Hope Foundation; Ed Cutler (Phlebotomy Services International) FX This work was supported by the intramural programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Human Genome Research Institute, and a Bench-to-Bedside grant from the Office of Rare Diseases. NY was supported by funding from the Ara Parseghian Medical Research Foundation and Dana's Angels Research Trust. Collection of control blood samples was organized and supported by Hadley Hope Foundation and Ed Cutler (Phlebotomy Services International). RF is a Ph.D. candidate of Health Science Center of Peking University. We would also like to acknowledge the contribution of the caretakers and patients who have participated in this study. NR 45 TC 52 Z9 52 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 OCT-NOV PY 2010 VL 101 IS 2-3 BP 214 EP 218 DI 10.1016/j.ymgme.2010.06.018 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 672TK UT WOS:000283609600021 PM 20667755 ER PT J AU Puri, A AF Puri, Anu TI Nanoparticles: Crossing barriers and membrane interactions FOREWORD SO MOLECULAR MEMBRANE BIOLOGY LA English DT Editorial Material C1 NCI, NIH, Frederick, MD 21701 USA. RP Puri, A (reprint author), NCI, NIH, Frederick, MD 21701 USA. EM apuri@helix.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0968-7688 J9 MOL MEMBR BIOL JI Mol. Membr. Biol. PD OCT PY 2010 VL 27 IS 7 BP 213 EP 214 DI 10.3109/09687688.2010.509115 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 672NE UT WOS:000283591200001 PM 20929338 ER PT J AU Rosenblum, LT Kosaka, N Mitsunaga, M Choyke, PL Kobayashi, H AF Rosenblum, Lauren T. Kosaka, Nobuyuki Mitsunaga, Makoto Choyke, Peter L. Kobayashi, Hisataka TI In vivo molecular imaging using nanomaterials: General in vivo characteristics of nano-sized reagents and applications for cancer diagnosis (Review) SO MOLECULAR MEMBRANE BIOLOGY LA English DT Review DE Molecular imaging; nanomaterial; quantum dot; dendrimer; iron oxide particle ID SENTINEL LYMPH-NODE; MRI CONTRAST AGENTS; MAGNETIC RESONANCE LYMPHANGIOGRAPHY; II QUANTUM DOTS; POLYAMIDOAMINE DENDRIMERS; REAL-TIME; CELL; NANOPARTICLES; MULTICOLOR; BIOCOMPATIBILITY AB Nanoparticles present a new collection of contrast agents for the field of in vivo molecular imaging. This review focuses on promising molecular imaging probes for optical and magnetic resonance imaging based on four representative nanomaterial(s) platforms: quantum dots, upconversion phosphors, superparamagnetic iron oxides, and dendrimer-based agents. Quantum dots are extremely efficient fluorescent nanoparticles with size-tunable emission properties, enabling high sensitivity and greater depth penetration. Their heavy metal composition and long retention in the body, however, pose concerns for clinical translational applications. Upconversion phosphors generate excellent signal-to-background contrast because they emit light with higher energy than the excitation photons and autofluorescence signals. For MRI, iron oxide particles also generate excellent signal and have been used in liver imaging and for cell tracking studies. As they are metabolized through endogenous iron salvage pathways, they have already been introduced as clinical contrast agents. Lastly, dendrimers, a 'soft' nanoparticle, can be used as a structural basis for the attachment of small molecule imaging agents and/or targeting groups. This array of nanoparticles should offer insights into the uses and potentials of nanoparticles for the molecular imaging. C1 [Rosenblum, Lauren T.; Kosaka, Nobuyuki; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,10 Ctr Dr, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 62 TC 29 Z9 32 U1 6 U2 61 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0968-7688 J9 MOL MEMBR BIOL JI Mol. Membr. Biol. PD OCT PY 2010 VL 27 IS 7 BP 274 EP 285 DI 10.3109/09687688.2010.481640 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 672NE UT WOS:000283591200006 PM 20455640 ER PT J AU Yavlovich, A Smith, B Gupta, K Blumenthal, R Puri, A AF Yavlovich, Amichai Smith, Brandon Gupta, Kshitij Blumenthal, Robert Puri, Anu TI Light-sensitive lipid-based nanoparticles for drug delivery: design principles and future considerations for biological applications SO MOLECULAR MEMBRANE BIOLOGY LA English DT Article DE Lipid-based nanoparticles; drug delivery; laser; cancer therapy; photodynamic therapy; liposomes; photo-triggering ID STERICALLY STABILIZED LIPOSOMES; BIOADHESIVE PATCH SYSTEMS; GOLD NANOPARTICLES; PHOTODYNAMIC THERAPY; PHOTOSENSITIVE LIPOSOMES; SOLUTE RELEASE; PHOTOINDUCED DESTABILIZATION; MULTILAMELLAR VESICLES; NUCLEAR-LOCALIZATION; METAL NANOPARTICLES AB Radiation-based therapies aided by nanoparticles have been developed for decades, and can be primarily categorized into two main platforms. First, delivery of payload of photo-reactive drugs (photosensitizers) using the conventional nanoparticles, and second, design and development of photo-triggerable nanoparticles (primarily liposomes) to attain light-assisted on-demand drug delivery. The main focus of this review is to provide an update of the history, current status and future applications of photo-triggerable lipid-based nanoparticles (light-sensitive liposomes). We will begin with a brief overview on the applications of liposomes for delivery of photosensitizers, including the choice of photosensitizers for photodynamic therapy, as well as the currently available light sources (lasers) used for these applications. The main segment of this review will encompass the details of strategies used to develop photo-triggerable liposomes for their drug delivery function. The principles underlying the assembly of photoreactive lipids into nanoparticles (liposomes) and photo-triggering mechanisms will be presented. We will also discuss factors that limit the applications of these liposomes for in vivo triggered drug delivery and emerging concepts that may lead to the biologically viable photo-activation strategies. We will conclude with our view point on the future perspectives of light-sensitive liposomes in the clinic. C1 [Yavlovich, Amichai; Smith, Brandon; Gupta, Kshitij; Blumenthal, Robert; Puri, Anu] NCI, CCR Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Puri, A (reprint author), NCI, CCR Nanobiol Program, NIH, Bldg 469,Rm 216A,POB B,Miller Dr, Frederick, MD 21702 USA. EM apuri@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 127 TC 47 Z9 49 U1 4 U2 38 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0968-7688 J9 MOL MEMBR BIOL JI Mol. Membr. Biol. PD OCT PY 2010 VL 27 IS 7 BP 364 EP 381 DI 10.3109/09687688.2010.507788 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 672NE UT WOS:000283591200013 PM 20939770 ER PT J AU Vecchiarelli, AG Han, YW Tan, X Mizuuchi, M Ghirlando, R Biertumpfel, C Funnell, BE Mizuuchi, K AF Vecchiarelli, Anthony G. Han, Yong-Woon Tan, Xin Mizuuchi, Michiyo Ghirlando, Rodolfo Biertuempfel, Christian Funnell, Barbara E. Mizuuchi, Kiyoshi TI ATP control of dynamic P1 ParA-DNA interactions: a key role for the nucleoid in plasmid partition SO MOLECULAR MICROBIOLOGY LA English DT Article ID BACTERIAL CHROMOSOME SEGREGATION; ESCHERICHIA-COLI; PROTEIN PARA; F-PLASMID; BACILLUS-SUBTILIS; PATTERN-FORMATION; DIVISION SITE; BINDING; SOPA; POLYMERIZATION AB P>P1 ParA is a member of the Walker-type family of partition ATPases involved in the segregation of plasmids and bacterial chromosomes. ATPases of this class interact with DNA non-specifically in vitro and colocalize with the bacterial nucleoid to generate a variety of reported patterns in vivo. Here, we directly visualize ParA binding to DNA using total internal reflection fluorescence microscopy. This activity depends on, and is highly specific for ATP. DNA-binding activity is not coupled to ATP hydrolysis. Rather, ParA undergoes a slow multi-step conformational transition upon ATP binding, which licenses ParA to bind non-specific DNA. The kinetics provide a time-delay switch to allow slow cycling between the DNA binding and non-binding forms of ParA. We propose that this time delay, combined with stimulation of ParA's ATPase activity by ParB bound to the plasmid DNA, generates an uneven distribution of the nucleoid-associated ParA, and provides the motive force for plasmid segregation prior to cell division. C1 Kyoto Univ, Present addresses Inst Integrated Cell Mat Sci, Sakyo Ku, Kyoto 6068501, Japan. [Vecchiarelli, Anthony G.; Funnell, Barbara E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Han, Yong-Woon; Tan, Xin; Mizuuchi, Michiyo; Ghirlando, Rodolfo; Biertuempfel, Christian; Mizuuchi, Kiyoshi] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Funnell, BE (reprint author), Univ Toronto, Dept Mol Genet, 100 Coll St, Toronto, ON M5S 1A8, Canada. EM b.funnell@utoronto.ca; Kmizu@helix.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; OI Biertumpfel, Christian/0000-0002-7528-6547; Vecchiarelli, Anna/0000-0002-3185-6720 FU University of Toronto; Eric Hani Fellowship; Canadian Institutes of Health Research [37997] FX We are grateful to Vassili Ivanov for his help with the microscope system, to Wei Yang for the use of instruments for stopped-flow and SEC/MALS experiments, and to Natalie Erdmann for construction of the parA-gfp fusion. This work was supported by the University of Toronto Open Fellowship and an Eric Hani Fellowship (to A.G.V.), by Grant 37997 from the Canadian Institutes of Health Research (to B.E.F.), and by intramural research fund for NIDDK, NIH, HHS, US Government (to K.M.). NR 46 TC 70 Z9 70 U1 2 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2010 VL 78 IS 1 BP 78 EP 91 DI 10.1111/j.1365-2958.2010.07314.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 654MR UT WOS:000282172900008 PM 20659294 ER PT J AU Peterson, JH Woolhead, CA Bernstein, HD AF Peterson, Janine H. Woolhead, Cheryl A. Bernstein, Harris D. TI The conformation of a nascent polypeptide inside the ribosome tunnel affects protein targeting and protein folding SO MOLECULAR MICROBIOLOGY LA English DT Article ID SIGNAL RECOGNITION PARTICLE; ESCHERICHIA-COLI RIBOSOME; EXIT TUNNEL; TRIGGER FACTOR; MEMBRANE-PROTEINS; CONDUCTING CHANNEL; PEPTIDE; CHAINS; SEQUENCE; L23 AB In this report, we describe insights into the function of the ribosome tunnel that were obtained through an analysis of an unusual 25 residue N-terminal motif (EspP(1-25)) associated with the signal peptide of the Escherichia coli EspP protein. It was previously shown that EspP(1-25) inhibits signal peptide recognition by the signal recognition particle, and we now show that fusion of EspP(1-25) to a cytoplasmic protein causes it to aggregate. We obtained two lines of evidence that both of these effects are attributable to the conformation of EspP(1-25) inside the ribosome tunnel. First, we found that mutations in EspP(1-25) that abolished its effects on protein targeting and protein folding altered the cross-linking of short nascent chains to ribosomal components. Second, we found that a mutation in L22 that distorts the tunnel mimicked the effects of the EspP(1-25) mutations on protein biogenesis. Our results provide evidence that the conformation of a polypeptide inside the ribosome tunnel can influence protein folding under physiological conditions and suggest that ribosomal mutations might increase the solubility of at least some aggregation-prone proteins produced in E. coli. C1 [Peterson, Janine H.; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Woolhead, Cheryl A.] Univ Glasgow, Fac Biomed & Life Sci, Div Biochem & Mol Biol, Glasgow G12 8QQ, Lanark, Scotland. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; BBSRC [BB/G011281] FX We thank Jim Bardwell, Bernd Bukau, Isabelle Iost, Rowena Matthews, Matthias Muller and Knud Nierhaus for gifts of strains and antisera. We also thank Manu Hegde and Frances Yap for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by BBSRC Grant BB/G011281 to C.A.W. NR 55 TC 14 Z9 14 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2010 VL 78 IS 1 BP 203 EP 217 DI 10.1111/j.1365-2958.2010.07325.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 654MR UT WOS:000282172900016 PM 20804452 ER PT J AU Oquendo, MA Canino, G Lehner, T Licinio, J AF Oquendo, M. A. Canino, G. Lehner, T. Licinio, J. TI Genetic repositories for the study of major psychiatric conditions: what do we know about ethnic minorities' genetic vulnerability? SO MOLECULAR PSYCHIATRY LA English DT Article DE diversity; race; DNA ID BIPOLAR AFFECTIVE-DISORDER; STORED BIOLOGICAL SAMPLES; UNITED-STATES; SEQUENCE VARIATIONS; MEXICAN-AMERICANS; AFRICAN-AMERICAN; ETHICAL-ISSUES; SCHIZOPHRENIA; ASSOCIATION; POPULATIONS AB In spite of considerable efforts, no genes of major effect have been found across an entire diagnostic category in psychiatry. Possible reasons for this may include difficulties in defining the phenotype, the complex relationship between genotype and gene expression and population stratification. This last problem has often been managed by restricting genetic sampling to only one ethnic group. An unintended consequence of using this strategy is that the major repositories of genetic material for the study of psychiatric conditions in the United States suffer from a paucity of genetic samples from non-Caucasian groups. Thus, these groups are being relatively understudied in terms of the genetic antecedents to psychiatric disease. The authors provide solutions including the need to augment the representation of African-American, Latino and Asian-Americans among research participants; a more nuanced approach to identify ancestry; and the development of analytic and genetic strategies to handle the issue of ethnic heterogeneity in samples. Molecular Psychiatry (2010) 15, 970-975; doi:10.1038/mp.2010.11; published online 23 February 2010 C1 [Oquendo, M. A.] New York State Psychiat Inst & Hosp, Dept Psychiat, New York, NY 10032 USA. [Oquendo, M. A.] Columbia Univ, New York, NY USA. [Canino, G.] Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA. [Lehner, T.] NIMH, Bethesda, MD 20892 USA. [Licinio, J.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. RP Oquendo, MA (reprint author), New York State Psychiat Inst & Hosp, Dept Psychiat, 1051 Riverside Dr,Unit 42, New York, NY 10032 USA. EM mao4@columbia.edu RI Licinio, Julio/L-4244-2013 OI Licinio, Julio/0000-0001-6905-5884 FU NIMH NIH HHS [R01 MH048514] NR 41 TC 5 Z9 5 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2010 VL 15 IS 10 BP 970 EP 975 DI 10.1038/mp.2010.11 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 653MS UT WOS:000282096200001 PM 20177407 ER PT J AU Rosenberg, SA AF Rosenberg, Steven A. TI Of Mice, Not Men: No Evidence for Graft-versus-Host Disease in Humans Receiving T-Cell Receptor-Transduced Autologous T Cells SO MOLECULAR THERAPY LA English DT Editorial Material ID CANCER REGRESSION; GENE-THERAPY C1 NCI, Surg Branch, NIH, CRC, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, CRC, 10 Ctr Dr,Room 3-3940, Bethesda, MD 20892 USA. EM sar@nih.gov NR 6 TC 37 Z9 38 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD OCT PY 2010 VL 18 IS 10 BP 1744 EP 1745 DI 10.1038/mt.2010.195 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 659BE UT WOS:000282541200003 PM 20885433 ER PT J AU Huang, X Guo, HF Tammana, S Jung, YC Mellgren, E Bassi, P Cao, Q Tu, ZJ Kim, YC Ekker, SC Wu, XL Wang, SM Zhou, XZ AF Huang, Xin Guo, Hongfeng Tammana, Syam Jung, Yong-Chul Mellgren, Emil Bassi, Preetinder Cao, Qing Tu, Zheng Jin Kim, Yeong C. Ekker, Stephen C. Wu, Xiaolin Wang, San Ming Zhou, Xianzheng TI Gene Transfer Efficiency and Genome-Wide Integration Profiling of Sleeping Beauty, Tol2, and PiggyBac Transposons in Human Primary T Cells SO MOLECULAR THERAPY LA English DT Article ID MAMMALIAN-CELLS; STEM-CELLS; EXPRESSION; THERAPY; SYSTEM; TRANSFORMATION; LYMPHOCYTES; EVOLUTION; MAP4K4; FISH AB In this study, we compared the genomic integration efficiencies and transposition site preferences of Sleeping Beauty (SB or SB11), Tol2, and piggyBac (PB) transposon systems in primary T cells derived from peripheral blood lymphocytes (PBL) and umbilical cord blood (UCB). We found that PB demonstrated the highest efficiency of stable gene transfer in PBL-derived T cells, whereas SB11 and Tol2 mediated intermediate and lowest efficiencies, respectively. Southern hybridization analysis demonstrated that PB generated the highest number of integrants when compared to SB and Tol2 in both PBL and UCB T cells. Tol2 and PB appeared more likely to promote clonal expansion than SB, which may be in part due to the dysregulated expression of cancer-related genes near the insertion sites. Genome-wide integration analysis demonstrated that SB, Tol2, and PB integrations occurred in all the chromosomes without preference. Additionally, Tol2 and PB integration sites were mainly localized near transcriptional start sites (TSSs), CpG islands and DNasel hypersensitive sites, whereas SB integrations were randomly distributed. These results suggest that SB may be a preferential choice of the delivery vector in T cells due to its random integration site preference and relatively high efficiency, and support continuing development of SB-mediated T-cell phase I trials. C1 [Huang, Xin; Guo, Hongfeng; Zhou, Xianzheng] Univ Minnesota, Sch Med, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Huang, Xin; Guo, Hongfeng; Zhou, Xianzheng] Univ Minnesota, Sch Med, Div Pediat Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Huang, Xin; Guo, Hongfeng; Zhou, Xianzheng] Univ Minnesota, Sch Med, Ctr Immunol, Minneapolis, MN 55455 USA. [Huang, Xin; Guo, Hongfeng; Zhou, Xianzheng] Univ Minnesota, Sch Med, Ctr Genome Engn, Minneapolis, MN 55455 USA. [Tammana, Syam; Zhou, Xianzheng] Univ Minnesota, Grad Sch, Grad Program Microbial Engn, Minneapolis, MN 55455 USA. [Jung, Yong-Chul; Kim, Yeong C.; Wang, San Ming] Northwestern Univ, Evanston NW Healthcare Res Inst, Ctr Funct Genom, Evanston, IL USA. [Mellgren, Emil] Macalester Coll, St Paul, MN 55105 USA. [Bassi, Preetinder] Univ Minnesota, Coll Biol Sci, Minneapolis, MN 55455 USA. [Cao, Qing] Univ Minnesota, Sch Med, Biostat & Informat Core Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Tu, Zheng Jin] Univ Minnesota, Inst Supercomp, Minneapolis, MN 55455 USA. [Ekker, Stephen C.] Mayo Clin, Rochester, MN USA. [Wu, Xiaolin] Natl Canc Inst Frederick, Lab Mol Technol, SAIC Frederick Inc, Frederick, MD USA. RP Zhou, XZ (reprint author), Univ Minnesota, Sch Med, Masonic Canc Ctr, MMC 366,420 Delaware St, Minneapolis, MN 55455 USA. EM zhoux058@umn.edu FU Children's Cancer Research Fund in Minneapolis, Alliance for Cancer Gene Therapy; Gabrielle's Angel (formerly G&P) Foundation for Cancer Research; Sidney Kimmel Foundation for Cancer Research; University of Minnesota; University Minnesota Medical School Dean's Commitment; Leukemia Research Fund; American Society of Hematology; Undergraduate Research Opportunity Program Award; Multicultural Summer Research Opportunities Award; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Sonja Nodland (University of Minnesota Masonic Cancer Center) for major editing, R. Scott McIvor, David Largaespada, and Perry Hackett (University of Minnesota Center for Genome Engineering, Minneapolis, MN) for critical review of the manuscript. We also thank John E. Wagner for providing cord blood, Malcolm J. Fraser (University of Notre Dame, Notre Dame, IN) for providing piggyBac vectors, Andrew C. Wilber (Southern Illinois University, Springfield, IL) for providing Sleeping Beauty transposon recoverable vector, Kevin A.T. Silverstein (Bioinformatics Core Facility at Masonic Cancer Center, University of Minnesota) for the independent evaluation on the data, and Linan Ma (Biostatistics and Informatics Core at the Masonic Cancer Center, University of Minnesota) for initial statistical analysis. This work was supported by grants from the Children's Cancer Research Fund in Minneapolis, Alliance for Cancer Gene Therapy, the Gabrielle's Angel (formerly G&P) Foundation for Cancer Research, the Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Program, the University of Minnesota Translational Research Grant, the University Minnesota Medical School Dean's Commitment (X.Z.), and Leukemia Research Fund. E.M. was a recipient of American Society of Hematology Research Trainee Award. P.B. was a recipient of the Undergraduate Research Opportunity Program Award and the Multicultural Summer Research Opportunities Award. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (X.W.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Contribution statement: X.H. designed and performed the research, analyzed the data, and wrote the paper; H.G., S.T., E.M., and P.B. performed the research. Y.-C.J. performed DNA sequencing and analyzed the data; Q.C. performed the statistical analyses; Z.J.T. and Y.C.K. performed integration site analysis; S.C.E. provided miniTol2 construct and discussed the research; X.W. preformed integration bioinformatic analyses and wrote the paper; S.M.W. analyzed the data and wrote the paper; X.Z. oversaw the research and wrote the paper. The authors declare no competitive financial interests. NR 45 TC 72 Z9 75 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD OCT PY 2010 VL 18 IS 10 BP 1803 EP 1813 DI 10.1038/mt.2010.141 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 659BE UT WOS:000282541200011 PM 20606646 ER PT J AU Bagnato, F Salman, Z Kane, R Auh, S Cantor, FK Ehrmantraut, M Gallo, A Ikonomidou, VN Ohayon, J Pellicano, C Stern, SK McFarland, HF AF Bagnato, Francesca Salman, Zeena Kane, Robert Auh, Sungyoung Cantor, Fredric K. Ehrmantraut, Mary Gallo, Antonio Ikonomidou, Vasiliki N. Ohayon, Joan Pellicano, Clelia Stern, Susan K. McFarland, Henry F. TI T(1) cortical hypointensities and their association with cognitive disability in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Article DE MRI; multiple sclerosis; T2 lesions ID INVERSION-RECOVERY; INTRACORTICAL LESIONS; FUNCTIONAL COMPOSITE; IMPAIRMENT; PATHOLOGY; ATROPHY AB Objective: To assess the incidence of T(1) hypointense NLs by 3.0-Tesla magnetic resonance imaging (MRI) in patients with MS and examine neocortical lesion association with cognitive impairment. Methods: In this case-control study, 21 MS patients and 21 age-, sex- and years of education-matched healthy volunteers underwent: (i) a neuropsychological examination rating cognitive impairment (Minimal Assessment of Cognitive Function in MS); (ii) a 3.0-Tesla MRI inclusive of an isotropic 1.0 mm(3) three-dimensional inversion prepared spoiled gradient-recalled-echo (3D-IRSPGR) image and T(1)- and T(2)-weighted images. Hypointensities on 3D-IRSPGR lying in the cortex, either entirely or partially were counted and association between NLs and cognitive impairment investigated. Results: A total of 95 NLs were observed in 14 (66.7%) patients. NL+ patients performed poorer (p = 0.020) than NLpatients only on the delayed recall component of the California Verbal Learning Test. This difference lost statistical significance when a correction for white matter lesion volume was employed. Conclusions: Although T(1) hypointense NLs may be present in a relatively high proportion of multiple sclerosis patients, the impact that they have in cognitive impairment is not independent from white matter disease. C1 [Bagnato, Francesca; Salman, Zeena; Cantor, Fredric K.; Ehrmantraut, Mary; Gallo, Antonio; Ikonomidou, Vasiliki N.; Ohayon, Joan; Pellicano, Clelia; Stern, Susan K.; McFarland, Henry F.] NINDS, NIB, NIH, Bethesda, MD 20892 USA. [Kane, Robert] Vet Affairs Med Ctr, MS Ctr Excellence, Baltimore, MD 21201 USA. [Auh, Sungyoung] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), NINDS, NIB, NIH, Bldg 10,Room 5C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM bagnatof@ninds.nih.gov RI Pellicano, Clelia/K-1062-2016 OI Pellicano, Clelia/0000-0002-3272-1094 NR 35 TC 14 Z9 14 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD OCT PY 2010 VL 16 IS 10 BP 1203 EP 1212 DI 10.1177/1352458510377223 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 656KG UT WOS:000282332100007 PM 20699284 ER PT J AU Jacobson, S AF Jacobson, S. TI Role of human herpesviruses in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT Conference on Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS) CY AUG 26-28, 2010 CL Bali, INDONESIA C1 [Jacobson, S.] NIH, Viral Immunol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD OCT PY 2010 VL 16 IS 10 BP 1268 EP 1268 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 656KG UT WOS:000282332100018 ER PT J AU Sena, LM Fishman, SJ Jenkins, KJ Xu, H Brechbiel, MW Regino, CAS Kosaka, N Bernardo, M Choyke, PL Kobayashi, H AF Sena, Laureen M. Fishman, Steven J. Jenkins, Kathy J. Xu, Heng Brechbiel, Martin W. Regino, Celeste A. S. Kosaka, Nobuyuki Bernardo, Marcelino Choyke, Peter L. Kobayashi, Hisataka TI Magnetic resonance lymphangiography with a nano-sized gadolinium-labeled dendrimer in small and large animal models SO NANOMEDICINE LA English DT Article DE dendrimer; magnetic resonance lymphangiography; nanomaterials; pig; thoracic duct ID IMAGING CONTRAST AGENTS; PERCUTANEOUS SCLEROTHERAPY; LYMPHATIC MALFORMATIONS; BREAST-CANCER; CELLS; VISUALIZATION; HORIZONS; DELIVERY; NODES; MICE AB Aim: Imaging of the lymphatic system is critical in preoperative planning of resections of complex lymphatic malformations. However, safe, effective imaging methods with sufficient resolution to identify the lymphatics have been lacking. In this study, we demonstrate the use of gadolinium-labeled dendrimers to image the lymphatics in small and large animal models during magnetic resonance lymphangiography. Methods: Polyamidoamine G6-Gd_1B4M_N-hydroxysuccinimide was synthesized and administered intradermally in the extremities of normal mice and pigs at several doses. Results: The lymphatics were well demonstrated in both animal models and there was rapid uptake in the deep lymphatic system, including the thoracic duct. A significant dose reduction was achieved (1 mu mol Gd/kg) in the 35-kg pig compared with mice, while still producing excellent results. No toxicity was observed and only minor inflammatory changes were observed at the injection site 30 days later. Conclusion: We demonstrate that a low dose of a macromolecular magnetic resonance contrast agent can provide rapid imaging of the deep lymphatic system in both small and large animals. This data provides a basis to consider a similar agent in clinical trials. C1 [Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Sena, Laureen M.; Fishman, Steven J.; Jenkins, Kathy J.] Boston Childrens Hosp, Boston, MA USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, NIH, Bldg 10,Room B9B69, Bethesda, MD 20892 USA. EM pchoyke@nih.gov 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. 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 24 TC 18 Z9 19 U1 0 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD OCT PY 2010 VL 5 IS 8 BP 1183 EP 1191 DI 10.2217/NNM.10.70 PG 9 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 679YM UT WOS:000284196700010 PM 21039196 ER PT J AU Satterlee, JS Schubeler, D Ng, HH AF Satterlee, John S. Schuebeler, Dirk Ng, Huck-Hui TI Tackling the epigenome: challenges and opportunities for collaboration SO NATURE BIOTECHNOLOGY LA English DT Article ID EMBRYONIC STEM-CELLS; DNA METHYLATION; HUMAN GENOME; DIFFERENTIATED CELLS; CHROMATIN; CANCER; EPIGENETICS; REVEALS; PLURIPOTENT; THERAPY C1 [Satterlee, John S.] US Natl Inst Drug Abuse, Bethesda, MD USA. [Schuebeler, Dirk] Friedrich Miescher Inst, CH-4002 Basel, Switzerland. [Ng, Huck-Hui] Genome Inst Singapore, Singapore, Singapore. RP Satterlee, JS (reprint author), US Natl Inst Drug Abuse, Bethesda, MD USA. EM satterleej@nida.nih.gov RI Ng, Huck Hui/A-1135-2009 NR 63 TC 49 Z9 51 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD OCT PY 2010 VL 28 IS 10 BP 1039 EP 1044 DI 10.1038/nbt1010-1039 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 663GF UT WOS:000282870500024 PM 20944594 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, Jennifer TI The long road: peering into live cells SO NATURE CELL BIOLOGY LA English DT Editorial Material C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD OCT PY 2010 VL 12 IS 10 BP 918 EP 918 DI 10.1038/ncb1010-918 PG 1 WC Cell Biology SC Cell Biology GA 656UJ UT WOS:000282363500002 PM 20885416 ER PT J AU McElhinny, SAN Kumar, D Clark, AB Watt, DL Watts, BE Lundstrom, EB Johansson, E Chabes, A Kunkel, TA AF McElhinny, Stephanie A. Nick Kumar, Dinesh Clark, Alan B. Watt, Danielle L. Watts, Brian E. Lundstrom, Else-Britt Johansson, Erik Chabes, Andrei Kunkel, Thomas A. TI Genome instability due to ribonucleotide incorporation into DNA SO NATURE CHEMICAL BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; POLYMERASE-EPSILON; ESCHERICHIA-COLI; SUBSTRATE-SPECIFICITY; REPLICATION FORK; YEAST; PURIFICATION; MUTATIONS; RESIDUE; SUGAR AB Maintaining the chemical identity of DNA depends on ribonucleotide exclusion by DNA polymerases. However, ribonucleotide exclusion during DNA synthesis in vitro is imperfect. To determine whether ribonucleotides are incorporated during DNA replication in vivo, we substituted leucine or glycine for an active-site methionine in yeast DNA polymerase epsilon ( Pol epsilon). Ribonucleotide incorporation in vitro was three-fold lower for M644L and 11-fold higher for M644G Pol epsilon compared to wildtype Pol epsilon. This hierarchy was recapitulated in vivo in yeast strains lacking RNase H2. Moreover, the pol2-M644G rnh201 Delta strain progressed more slowly through S phase, had elevated dNTP pools and generated 2-5-base-pair deletions in repetitive sequences at a high rate and in a gene orientation-dependent manner. The data indicate that ribonucleotides are incorporated during replication in vivo, that they are removed by RNase H2-dependent repair and that defective repair results in replicative stress and genome instability via DNA strand misalignment. C1 [McElhinny, Stephanie A. Nick; Clark, Alan B.; Watt, Danielle L.; Watts, Brian E.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [McElhinny, Stephanie A. Nick; Clark, Alan B.; Watt, Danielle L.; Watts, Brian E.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Kumar, Dinesh; Lundstrom, Else-Britt; Johansson, Erik; Chabes, Andrei] Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden. [Chabes, Andrei] Umea Univ, Lab Mol Infect Med Sweden, Umea, Sweden. RP McElhinny, SAN (reprint author), NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Chabes, Andrei/0000-0003-1708-8259 FU Division of Intramural Research of the US National Institutes of Health, National Institute of Environmental Health Sciences; Swedish Foundation for Strategic Research; Swedish Research Council; Swedish Cancer Society; Umea University FX We thank K. Bebenek and J. Williams for thoughtful comments on the manuscript and the National Institute of Environmental Health Sciences Molecular Genetics Core for technical support in DNA sequence analysis of ura3 mutants. This work was supported in part by Project Z01 ES065070 (to T. A. K.) from the Division of Intramural Research of the US National Institutes of Health, National Institute of Environmental Health Sciences, in part by the Swedish Foundation for Strategic Research, the Swedish Research Council and the Swedish Cancer Society (to A. C.) and in part by the Swedish Research Council, the Swedish Cancer Society, Smartafonden and the fund for Basic Science-oriented Biotechnology, Medical Faculty of Umea University (to E. J.). NR 37 TC 152 Z9 153 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2010 VL 6 IS 10 BP 774 EP 781 DI 10.1038/NCHEMBIO.424 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 651YM UT WOS:000281964100015 ER PT J AU Church, DM Lappalainen, I Sneddon, TP Hinton, J Maguire, M Lopez, J Garner, J Paschall, J DiCuccio, M Yaschenko, E Scherer, SW Feuk, L Flicek, P AF Church, Deanna M. Lappalainen, Ilkka Sneddon, Tam P. Hinton, Jonathan Maguire, Michael Lopez, John Garner, John Paschall, Justin DiCuccio, Michael Yaschenko, Eugene Scherer, Stephen W. Feuk, Lars Flicek, Paul TI Public data archives for genomic structural variation SO NATURE GENETICS LA English DT Letter ID COPY-NUMBER; SEGMENTAL DUPLICATION C1 [Church, Deanna M.; Sneddon, Tam P.; Lopez, John; Garner, John; Paschall, Justin; DiCuccio, Michael; Yaschenko, Eugene] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Lappalainen, Ilkka; Hinton, Jonathan; Maguire, Michael; Flicek, Paul] European Bioinformat Inst, Cambridge, England. [Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada. [Scherer, Stephen W.] Univ Toronto, McLaughlin Ctr, Toronto, ON, Canada. [Scherer, Stephen W.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Feuk, Lars] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. RP Church, DM (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM church@ncbi.nlm.nih.gov; flicek@ebi.ac.uk RI Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013; OI Scherer, Stephen /0000-0002-8326-1999; Sneddon, Tam Paterson/0000-0003-1137-8992; Lappalainen, Ilkka/0000-0001-5762-893X; Flicek, Paul/0000-0002-3897-7955 FU Intramural NIH HHS [Z99 LM999999] NR 15 TC 47 Z9 47 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2010 VL 42 IS 10 BP 813 EP 814 DI 10.1038/ng1010-813 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 655UO UT WOS:000282276600002 PM 20877315 ER PT J AU Goode, LL Chenevix-Trench, G Song, H Ramus, SJ Notaridou, M Lawrenson, K Widschwendter, M Vierkant, RA Larson, MC Kjaer, SK Birrer, MJ Berchuck, A Schildkraut, J Tomlinson, I Kiemeney, LA Cook, LS Gronwald, J Garcia-Closas, M Gore, ME Campbell, I Whittemore, AS Sutphen, R Phelan, C Anton-Culver, H Pearce, CL Lambrechts, D Rossing, MA Chang-Claude, J Moysich, KB Goodman, MT Dork, T Nevanlinna, H Ness, RB Rafnar, T Hogdall, C Hogdall, E Fridley, BL Cunningham, JM Sieh, W McGuire, V Godwin, AK Cramer, DW Hernandez, D Levine, D Lu, K Iversen, ES Palmieri, RT Houlston, R van Altena, AM Aben, KKH Massuger, LFAG Brooks-Wilson, A Kelemen, LE Le, ND Jakubowska, A Lubinski, J Medrek, K Stafford, A Easton, DF Tyrer, J Bolton, KL Harrington, P Eccles, D Chen, A Molina, AN Davila, BN Arango, H Tsai, Y Chen, ZH Risch, HA McLaughlin, J Narod, SA Ziogas, A Brewster, W Gentry-Maharaj, A Menon, U Wu, AH Stram, DO Pike, MC Beesley, J Webb, PM Chen, XQ Ekici, AB Thiel, FC Beckmann, MW Yang, H Wentzensen, N Lissowska, J Fasching, PA Despierre, E Amant, F Vergote, I Doherty, J Hein, R Wang-Gohrke, S Lurie, G Carney, ME Thompson, PJ Runnebaum, I Hillemanns, P Durst, M Antonenkova, N Bogdanova, N Leminen, A Butzow, R Heikkinen, T Stefansson, K Sulem, P Besenbacher, S Sellers, TA Gayther, SA Pharoah, PDP AF Goode, Llen L. Chenevix-Trench, Georgia Song, Honglin Ramus, Susan J. Notaridou, Maria Lawrenson, Kate Widschwendter, Martin Vierkant, Robert A. Larson, Melissa C. Kjaer, Susanne K. Birrer, Michael J. Berchuck, Andrew Schildkraut, Joellen Tomlinson, Ian Kiemeney, Lambertus A. Cook, Linda S. Gronwald, Jacek Garcia-Closas, Montserrat Gore, Martin E. Campbell, Ian Whittemore, Alice S. Sutphen, Rebecca Phelan, Catherine Anton-Culver, Hoda Pearce, Celeste Leigh Lambrechts, Diether Rossing, Mary Anne Chang-Claude, Jenny Moysich, Kirsten B. Goodman, Marc T. Doerk, Thilo Nevanlinna, Heli Ness, Roberta B. Rafnar, Thorunn Hogdall, Claus Hogdall, Estrid Fridley, Brooke L. Cunningham, Julie M. Sieh, Weiva McGuire, Valerie Godwin, Andrew K. Cramer, Daniel W. Hernandez, Dena Levine, Douglas Lu, Karen Iversen, Edwin S. Palmieri, Rachel T. Houlston, Richard van Altena, Anne M. Aben, Katja K. H. Massuger, Leon F. A. G. Brooks-Wilson, Angela Kelemen, Linda E. Le, Nhu D. Jakubowska, Anna Lubinski, Jan Medrek, Krzysztof Stafford, Anne Easton, Douglas F. Tyrer, Jonathan Bolton, Kelly L. Harrington, Patricia Eccles, Diana Chen, Ann Molina, Ashley N. Davila, Barbara N. Arango, Hector Tsai, Yu Chen, Zhihua Risch, Harvey A. McLaughlin, John Narod, Steven A. Ziogas, Argyrios Brewster, Wendy Gentry-Maharaj, Aleksandra Menon, Usha Wu, Anna H. Stram, Daniel O. Pike, Malcolm C. Beesley, Jonathan Webb, Penelope M. Chen, Xiaoqing Ekici, Arif B. Thiel, Falk C. Beckmann, Matthias W. Yang, Hannah Wentzensen, Nicolas Lissowska, Jolanta Fasching, Peter A. Despierre, Evelyn Amant, Frederic Vergote, Ignace Doherty, Jennifer Hein, Rebecca Wang-Gohrke, Shan Lurie, Galina Carney, Michael E. Thompson, Pamela J. Runnebaum, Ingo Hillemanns, Peter Duerst, Matthias Antonenkova, Natalia Bogdanova, Natalia Leminen, Arto Butzow, Ralf Heikkinen, Tuomas Stefansson, Kari Sulem, Patrick Besenbacher, Soeren Sellers, Thomas A. Gayther, Simon A. Pharoah, Paul D. P. CA Wellcome Trust Case-Control Conso Australian Canc Study Ovarian Canc Australian Ovarian Canc Study Grp OCAC TI A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24 SO NATURE GENETICS LA English DT Article ID COLORECTAL-CANCER; POLY(ADP-RIBOSE) POLYMERASE; EPITHELIAL-CELLS; MULTIPLE LOCI; IN-VITRO; GENE; METAANALYSIS; VARIANTS; CARRIERS AB Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2)(1). Here, we report on nine additional candidate loci (defined as having P <= 10(-4)) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P <= 5 x 10(-8) (8q24, P = 8.0 x 10(-15) and 2q31, P = 3.8 x 10(-14)) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 x 10(-8) and 17q21, P = 1.4 x 10(-7)). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development. C1 [Goode, Llen L.; Vierkant, Robert A.; Larson, Melissa C.; Fridley, Brooke L.] Mayo Clin Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Chenevix-Trench, Georgia; Beesley, Jonathan; Webb, Penelope M.; Chen, Xiaoqing; Australian Canc Study Ovarian Canc] Post Off Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld, Australia. [Song, Honglin; Stafford, Anne; Tyrer, Jonathan; Harrington, Patricia] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cancer Res United Kingdom, Cambridge, England. [Notaridou, Maria; Lawrenson, Kate; Widschwendter, Martin; Menon, Usha; Gayther, Simon A.] UCL, Dept Gynecol Oncol, Elizabeth Garrett Anderson EGA Inst Womens Hlt, London, England. [Kjaer, Susanne K.; Runnebaum, Ingo] Juliane Marie Ctr, Dept Gynecol & Obstet, Copenhagen, Denmark. [Kjaer, Susanne K.; Runnebaum, Ingo] Inst Canc Epidemiol, Dept Virus, Hormones & Canc, Danish Canc Soc, Copenhagen, Denmark. [Birrer, Michael J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Berchuck, Andrew; Schildkraut, Joellen] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC USA. [Tomlinson, Ian] London Sch Med & Dent, Inst Canc, Ctr Mol Oncol & Imaging, London, England. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol, Biostatist & Hlth Technol Assessment HTA, NL-6525 ED Nijmegen, Netherlands. [Lubinski, Jan] Univ New Mexico, Div Epidemiol & Biostatist, Albuquerque, NM 87131 USA. [Cook, Linda S.] Alberta Hlth Services Canc Care, Calgary, AB, Canada. [Gronwald, Jacek; Medrek, Krzysztof] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Garcia-Closas, Montserrat; Wentzensen, Nicolas] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Rockville, MD USA. [Gore, Martin E.] Royal Marsden Hosp, Gynecol Oncol Unit, London, England. [Campbell, Ian] Peter MacCallum Canc Inst, Ctr Canc Genom & Predict Med, Melbourne, Australia. [Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Whittemore, Alice S.; Molina, Ashley N.; Davila, Barbara N.] Stanford Univ, Sch Med, Div Epidemiol & Biostatist, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Sutphen, Rebecca; Sieh, Weiva; McGuire, Valerie] Univ S Florida, Coll Med, Pediat Epidemiol Ctr, Tampa, FL USA. [Phelan, Catherine] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Pearce, Celeste Leigh; Wu, Anna H.; Stram, Daniel O.; Pike, Malcolm C.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Brussels, Belgium. [Lambrechts, Diether] LU Leuven, Louvain, Belgium. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Chang-Claude, Jenny; Hein, Rebecca] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Goodman, Marc T.; Carney, Michael E.; Thompson, Pamela J.] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Doerk, Thilo] Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany. [Nevanlinna, Heli; Leminen, Arto; Heikkinen, Tuomas] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Rafnar, Thorunn; Stefansson, Kari; Sulem, Patrick; Besenbacher, Soeren] DeCODE Genet, Reykjavik, Iceland. [Hogdall, Claus] Juliane Marie Ctr, Dept Gynecol & Obstet, Copenhagen, Denmark. [Hogdall, Estrid] Hormones & Canc Inst Canc Epidemiol, Danish Canc Soc, Dept Virus, Copenhagen, Denmark. [Cunningham, Julie M.] Mayo Clin Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Godwin, Andrew K.] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA. [Cramer, Daniel W.] Brigham & Womens Hosp, Obstetr & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Hernandez, Dena] Natl Inst Hlth, NIA, Bethesda, MD USA. [Levine, Douglas] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lu, Karen] MD Anderson Canc Ctr, Houston, TX USA. [Iversen, Edwin S.] Duke Univ, Dept Stat, Durham, NC USA. [Palmieri, Rachel T.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Houlston, Richard] Inst Canc Res, Royal Canc Hosp, Mol & Populat Genet Team, London, England. [van Altena, Anne M.; Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja K. H.] Comprehens Canc Ctr E, Nijmegen, Netherlands. [Brooks-Wilson, Angela] Genome Sci Ctr, British Columbia Canc Agcy, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Calgary, AB, Canada. [Le, Nhu D.] British Columbia Canc Agcy, Cancer Control Res, Vancouver, BC V5Z 4E6, Canada. [Easton, Douglas F.] Univ Cambridge, Strangeways Res Lab, Canc Res United Kingdom Genet Epidemiol Unit, Cambridge, England. [Bolton, Kelly L.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. [Eccles, Diana] Univ Southampton, Sch Med, Wessex Clin Genet Serv Princess Anne Hosp, Southampton, Hants, England. [Arango, Hector] W Coast Gynecol Oncol, Clearwater, FL USA. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT USA. [McLaughlin, John] Canc Care Ontario, Toronto, ON, Canada. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Brewster, Wendy] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Inst, Melbourne, Australia. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-8520 Erlangen, Germany. [Thiel, Falk C.] Univ Breast Ctr Franconia, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany. [Beckmann, Matthias W.; Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Beckmann, Matthias W.; Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Despierre, Evelyn; Amant, Frederic; Vergote, Ignace] Univ Hosp Leuven, Dept Gynecol Oncol, Leuven, Belgium. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Duerst, Matthias] Friedrich Schiller Univ, Clin Obstet & Gynaecol, Jena, Germany. [Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandro N, Minsk, Byelarus. [Bogdanova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandro N, Minsk, Byelarus. [Bogdanova, Natalia] Hannover Med Sch, Clin Obstet & Gynaecol, D-3000 Hannover, Germany. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. [Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Canc Res United Kingdom Dept Oncol, Cambridge, England. [Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. RP Gayther, SA (reprint author), Mayo Clin Coll Med, Dept Hlth Sci Res, Rochester, MN USA. EM gayther@usc.edu RI Menon, Usha/C-4716-2008; Verdrengh, Evelien/H-4571-2012; Webb, Penelope/D-5736-2013; Ekici, Arif/C-3971-2013; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; van Altena, Anne/B-9824-2016; McLaughlin, John/E-4577-2013; Kiemeney, Lambertus/D-3357-2009; Tang, Macy/B-9798-2014; Brooks-Wilson, Angela/E-9399-2012; Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014; Dork, Thilo/J-8620-2012; Aben, Katja/G-9686-2016; Gronwald, Jacek/A-4576-2017; OI Webb, Penelope/0000-0003-0733-5930; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Kiemeney, Lambertus/0000-0002-2368-1326; Brooks-Wilson, Angela/0000-0003-1009-6408; Aben, Katja/0000-0002-0214-2147; Gronwald, Jacek/0000-0002-3643-2871; Vierkant, Robert/0000-0001-6242-5221; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799; Nevanlinna, Heli/0000-0002-0916-2976; Besenbacher, Soren/0000-0003-1455-1738; Houlston, Richard/0000-0002-5268-0242 FU Ovarian Cancer Research Fund; Mermaid 1; Danish Cancer Society; National Cancer Institute, Bethesda, Maryland, USA [R01-CA61107]; US National Institutes of Health; National Cancer Institute [R01CA- 122443, CA-58860, CA-92044, R01-CA58598, N01-CN-55424, N01-PC-67001, N01-PC-35137]; Mayo Foundation; US National Cancer Institute; Department of Health and Human Services; Ovarian Cancer Specialized Program of Research Excellence (SPORE) [P50 CA083638]; Cancer Research UK; Eastern Cancer Registration and Information Centre for subject recruitment; US National Institutes of Health [R01-CA106414, R01-CA-63682, R01CA- 63678, R01-CA112523, R01-CA-87538]; American Cancer Society [CRTG-00-196-01-CCE]; Advanced Cancer Detection Center; Department of Defense [DAMD17-98-1-8659]; Canadian Institutes for Health Research; Canadian Cancer Society; University of California, Irvine [R01-CA-114343]; Lon V Smith Foundation [LVS-39420]; OAK Foundation; National Health and Medical Research Council of Australia [199600]; US Army Medical Research and Materiel Command [DAMD17-01-1-0729, W81XWH-06-1-0220]; Cancer Council Tasmania; Cancer Foundation of Western Australia; ELAN Foundation; Erlangen University Hospital; German Federal Ministry of Education and Research of Germany; Programme of Clinical Biomedical Research [01 GB 9401]; University of Ulm; German Cancer Research Center; California Cancer Research Program [00-01389V-20170, 2110200]; Helsinki University Central Hospital; Academy of Finland; Finnish Cancer Society FX This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www. wtccc. org. uk/.Funding for the project was provided by the Wellcome Trust under award 076113. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith.; The MAL study is supported by grants from Mermaid 1, the Danish Cancer Society and the National Cancer Institute, Bethesda, Maryland, USA (R01-CA61107). The MAY study and the phase 3 and combined analyses were supported by the US National Institutes of Health, National Cancer Institute grants R01CA- 122443 and funding from the Mayo Foundation. The PBCS was funded by Intramural Research Funds of the US National Cancer Institute, Department of Health and Human Services. The Fox Chase Cancer Center ovarian cancer study, part of the National Cancer Institute collaboration, is supported by an Ovarian Cancer Specialized Program of Research Excellence (SPORE) (P50 CA083638). The NCO study is supported by the US National Institutes of Health, National Cancer Institute grant R01-CA-76016. The SEA study is funded by a programme grant from Cancer Research UK. We thank the SEARCH team and the Eastern Cancer Registration and Information Centre for subject recruitment. The TBO study was supported by the US National Institutes of Health (R01-CA106414); the American Cancer Society (CRTG-00-196-01-CCE); and the Advanced Cancer Detection Center Grant, Department of Defense (DAMD17-98-1-8659). The TOR study was supported by grants from the Canadian Institutes for Health Research, the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society and the US National Institutes of Health (R01-CA-63682 and R01CA- 63678). Additional support for the TOR, NCO, MAY, TBO and NCI studies was provided by the University of California, Irvine grant R01-CA-114343. The UCI study is supported by the US National Institutes of Health, National Cancer Institute grants CA-58860, CA-92044 and the Lon V Smith Foundation grant LVS-39420. The UKO study is supported by funding from Cancer Research UK, the Eve Appeal and the OAK Foundation. Some of this work was undertaken at University College London Hospital/University College London, who received a proportion of funding from the Department of Health's National Institutes for Health Research Biomedical Research Centre funding scheme. We particularly thank I. Jacobs, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. The AUS study is supported by the National Health and Medical Research Council of Australia (199600), US Army Medical Research and Materiel Command under DAMD17-01-1-0729 (award no. W81XWH-06-1-0220) and the Cancer Council Tasmania and Cancer Foundation of Western Australia. G. C.-M. T. and P. M. W. are Research Fellows of the National Health and Medical Research Council. The Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, A. deFazio, G. C.-T., D. G., A. K. G. and P. M. W.) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www. aocstudy. org/). The Australian Cancer Study (ACS) Management Group comprises P. D. P. P., P. M. W., A. Green, N. Hayward and D. Whiteman. The BAV study is supported by the ELAN Foundation and Erlangen University Hospital. The BEL study is supported by the National Cancer Plan-Action 29 for the support of Translational Research. The DOV study (Seattle Diseases of the Ovary) was supported by the US National Institutes of Health grants R01-CA112523 and R01-CA-87538. The GER study was supported by the German Federal Ministry of Education and Research of Germany, the Programme of Clinical Biomedical Research (01 GB 9401), and the genotyping was supported in part by the state of Baden-Wrttemberg through the Medical Faculty, University of Ulm (P. 685).; Data management wassupported by the German Cancer Research Center. The HAW study was supported by the US Public Health Service grant R01-CA58598 and contracts N01-CN-55424, N01-PC-67001 and N01-PC-35137 from the National Cancer Institute, US National Institutes of Health, Department of Health and Human Services. Funding for the USC study was received from the California Cancer Research Program grants 00-01389V-20170 and 2110200, US Public Health Service grants CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03CA113148 and the California Department of Health Services sub-contract 050E8709 as part of its statewide cancer reporting program (University of Southern California). The HJO study gratefully acknowledges the contribution of F. Kramer and W. Zheng to the recruitment of subjects at Hannover Medical School. The HMO study gratefully acknowledges the help of L. Gacucova in sample preparation. The HOC study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland and the Finnish Cancer Society. NR 30 TC 131 Z9 132 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2010 VL 42 IS 10 BP 874 EP + DI 10.1038/ng.668 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 655UO UT WOS:000282276600018 ER PT J AU Bolton, KL Tyrer, J Song, H Ramus, SJ Notaridou, M Jones, C Sher, T Gentry-Maharaj, A Wozniak, E Tsai, YY Weidhaas, J Paik, D Van den Berg, DJ Stram, DO Pearce, CL Wu, AH Brewster, W Anton-Culver, H Ziogas, A Narod, SA Levine, DA Kaye, SB Brown, R Paul, J Flanagan, J Sieh, W McGuire, V Whittemore, AS Campbell, I Gore, ME Lissowska, J Yang, HP Medrek, K Gronwald, J Lubinski, J Jakubowska, A Le, ND Cook, LS Kelemen, LE Brook-Wilson, A Massuger, LFAG Kiemeney, LA Aben, KKH van Altena, AM Houlston, R Tomlinson, I Palmieri, RT Moorman, PG Schildkraut, J Iversen, ES Phelan, C Vierkant, RA Cunningham, JM Goode, EL Fridley, BL Kruger-Kjaer, S Blaeker, J Hogdall, E Hogdall, C Gross, J Karlan, BY Ness, RB Edwards, RP Odunsi, K Moyisch, KB Baker, JA Modugno, F Heikkinenen, T Butzow, R Nevanlinna, H Leminen, A Bogdanova, N Antonenkova, N Doerk, T Hillemanns, P Duurst, M Runnebaum, I Thompson, PJ Carney, ME Goodman, MT Lurie, G Wang-Gohrke, S Hein, R Chang-Claude, J Rossing, MA Cushing-Haugen, KL Doherty, J Chen, C Rafnar, T Besenbacher, S Sulem, P Stefansson, K Birrer, MJ Terry, KL Hernandez, D Cramer, DW Vergote, I Amant, F Lambrechts, D Despierre, E Fasching, PA Beckmann, MW Thiel, FC Ekici, AB Chen, XQ Johnatty, SE Webb, PM Beesley, J Chanock, S Garcia-Closas, M Sellers, T Easton, DF Berchuck, A Chenevix-Trench, G Pharoah, PDP Gayther, SA AF Bolton, Kelly L. Tyrer, Jonathan Song, Honglin Ramus, Susan J. Notaridou, Maria Jones, Chris Sher, Tanya 3 Gentry-Maharaj, Aleksandra Wozniak, Eva Tsai, Ya-Yu Weidhaas, Joanne Paik, Daniel Van den Berg, David J. Stram, Daniel O. Pearce, Celeste Leigh Wu, Anna H. Brewster, Wendy Anton-Culver, Hoda Ziogas, Argyrios Narod, Steven A. Levine, Douglas A. Kaye, Stanley B. Brown, Robert Paul, Jim Flanagan, James Sieh, Weiva McGuire, Valerie Whittemore, Alice S. Campbell, Ian Gore, Martin E. Lissowska, Jolanta Yang, Hanna P. Medrek, Krzysztof Gronwald, Jacek Lubinski, Jan Jakubowska, Anna Le, Nhu D. Cook, Linda S. Kelemen, Linda E. Brook-Wilson, Angela Massuger, Leon F. A. G. Kiemeney, Lambertus A. Aben, Katja K. H. van Altena, Anne M. Houlston, Richard Tomlinson, Ian Palmieri, Rachel T. Moorman, Patricia G. Schildkraut, Joellen Iversen, Edwin S. Phelan, Catherine Vierkant, Robert A. Cunningham, Julie M. Goode, Ellen L. Fridley, Brooke L. Kruger-Kjaer, Susan Blaeker, Jan Hogdall, Estrid Hogdall, Claus Gross, Jenny Karlan, Beth Y. Ness, Roberta B. Edwards, Robert P. Odunsi, Kunle Moyisch, Kirsten B. Baker, Julie A. Modugno, Francesmary Heikkinenen, Tuomas Butzow, Ralf Nevanlinna, Heli Leminen, Arto Bogdanova, Natalia Antonenkova, Natalia Doerk, Thilo Hillemanns, Peter Duerst, Matthias Runnebaum, Ingo Thompson, Pamela J. Carney, Michael E. Goodman, Marc T. Lurie, Galina Wang-Gohrke, Shan Hein, Rebecca Chang-Claude, Jenny Rossing, Mary Anne Cushing-Haugen, Kara L. Doherty, Jennifer Chen, Chu Rafnar, Thorunn Besenbacher, Soren Sulem, Patrick Stefansson, Kari Birrer, Michael J. Terry, Kathryn L. Hernandez, Dena Cramer, Daniel W. Vergote, Ignace Amant, Frederic Lambrechts, Diether Despierre, Evelyn Fasching, Peter A. Beckmann, Matthias W. Thiel, Falk C. Ekici, Arif B. Chen, Xiaoqing Johnatty, Sharon E. Webb, Penelope M. Beesley, Jonathan Chanock, Stephen Garcia-Closas, Montserrat Sellers, Tom Easton, Douglas F. Berchuck, Andrew Chenevix-Trench, Georgia Pharoah, Paul D. P. Gayther, Simon A. CA Australian Ovarian Canc Study Grp Australian Canc Study Ovarian Canc Ovarian Canc Assoc Consortium TI Common variants at 19p13 are associated with susceptibility to ovarian cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BRCA1; GENOTYPES; COMPLEX; BREAST; CELLS AB Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women(1). We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 x 10(-4) and P = 6 x 10(-4), respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 x 10(-9) and P = 4 x 10(-11), respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development. C1 [Bolton, Kelly L.; Tyrer, Jonathan; Song, Honglin; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Bolton, Kelly L.; Yang, Hanna P.; Kiemeney, Lambertus A.; Chanock, Stephen; Garcia-Closas, Montserrat] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Rockville, MD USA. [Ramus, Susan J.; Notaridou, Maria; Jones, Chris; Sher, Tanya 3; Gentry-Maharaj, Aleksandra; Gayther, Simon A.] UCL, Inst Womens Hlth, Dept Gynecol Oncol, EGA, London, England. [Tsai, Ya-Yu] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Weidhaas, Joanne] Yale Univ, Dept Therapeut Radiol, New Haven, CT 06510 USA. [Paik, Daniel] Yale Univ, Dept Obstet & Gynecol, New Haven, CT USA. [Van den Berg, David J.; Stram, Daniel O.; Pearce, Celeste Leigh; Wu, Anna H.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Brewster, Wendy; Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Narod, Steven A.] Ctr Res Womens Hlth, Toronto, ON, Canada. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Kaye, Stanley B.] Inst Canc Res, Med Sect, Sutton, Surrey, England. [Brown, Robert; Flanagan, James] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. [Paul, Jim] Univ Glasgow, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland. [Sieh, Weiva; McGuire, Valerie; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Inst, Melbourne, Australia. [Campbell, Ian; Gore, Martin E.] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Medrek, Krzysztof; Gronwald, Jacek; Lubinski, Jan; Jakubowska, Anna] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Le, Nhu D.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 4E6, Canada. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostatist, Albuquerque, NM 87131 USA. [Cook, Linda S.; Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Calgary, AB, Canada. [Brook-Wilson, Angela] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brook-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Gynaecol, Nijmegen, Netherlands. [Aben, Katja K. H.] Comprehens Canc Ctr E, Nijmegen, Netherlands. [Houlston, Richard] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England. [Tomlinson, Ian] Wellcome Trust Ctr Human Genet, Populat & Funct Genet Lab, Oxford, England. [Palmieri, Rachel T.; Moorman, Patricia G.; Schildkraut, Joellen; Berchuck, Andrew] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC USA. [Iversen, Edwin S.] Duke Univ, Dept Stat, Durham, NC USA. [Vierkant, Robert A.; Goode, Ellen L.; Fridley, Brooke L.] Mayo Clin Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Cunningham, Julie M.] Mayo Clin Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Kruger-Kjaer, Susan; Hogdall, Estrid] Danish Canc Soc, Dept Virus, Copenhagen, Denmark. [Kruger-Kjaer, Susan; Hogdall, Estrid] Danish Canc Soc, Canc Inst Canc Epidemiol, Canc Inst Canc Epidemiol, Copenhagen, Denmark. [Blaeker, Jan] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Hogdall, Claus] Juliane Marie Ctr, Gynaecol Clin, Copenhagen, Denmark. [Gross, Jenny; Karlan, Beth Y.] Cedars Sinai Med Ctr, Womens Canc Res Inst, Samuel Oschin Comprehens Canc Ctr, Los Angeles, CA 90048 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Edwards, Robert P.] Magee Womens Hosp, Pittsburgh, PA USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Moyisch, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Baker, Julie A.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Modugno, Francesmary] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Heikkinenen, Tuomas; Butzow, Ralf; Nevanlinna, Heli; Leminen, Arto] Univ Helsinki, Cent Hosp, Dept Obstet & Gynaecol, Helsinki, Finland. [Bogdanova, Natalia; Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandro, Minsk, Byelarus. [Doerk, Thilo; Hillemanns, Peter] Hannover Med Sch, Clin Obstet & Gynaecol, D-3000 Hannover, Germany. [Duerst, Matthias; Runnebaum, Ingo] Friedrich Schiller Univ, Clin Obstet & Gynaecol, Jena, Germany. [Thompson, Pamela J.; Carney, Michael E.; Goodman, Marc T.; Lurie, Galina] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Hein, Rebecca; Chang-Claude, Jenny] Deutsch Krebsforschungszentrum, Div Canc Epidemiol, Unit Genet Epidemiol, D-6900 Heidelberg, Germany. [Rossing, Mary Anne; Cushing-Haugen, Kara L.; Doherty, Jennifer; Chen, Chu] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Rafnar, Thorunn; Besenbacher, Soren; Sulem, Patrick; Stefansson, Kari] DeCODE Genet, Reykjavik, Iceland. [Birrer, Michael J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Terry, Kathryn L.; Cramer, Daniel W.] Brigham & Womens Hosp, Obstetr & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Hernandez, Dena] Natl Inst Hlth, NIA, Bethesda, MD USA. [Vergote, Ignace; Amant, Frederic; Despierre, Evelyn] Univ Hosp Leuven, Dept Gynecol Oncol, Louvain, Belgium. [Lambrechts, Diether] Vesalius Res Ctr VIB & KU Leuven, Louvain, Belgium. [Fasching, Peter A.] David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA USA. [Beckmann, Matthias W.] Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Beckmann, Matthias W.] Inst Oncol, M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Thiel, Falk C.] Univ Hosp Erlangen, Dept Obstet & Gynaecol, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Chen, Xiaoqing; Johnatty, Sharon E.; Webb, Penelope M.; Beesley, Jonathan; Chenevix-Trench, Georgia; Australian Canc Study Ovarian Canc] Post Off Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld, Australia. RP Pharoah, PDP (reprint author), Univ Cambridge, Dept Oncol, Cambridge, England. EM paul1@srl.cam.ac.uk RI Bowtell, David/H-1007-2016; Johnatty, Sharon/R-8890-2016; Gronwald, Jacek/A-4576-2017; Brooks-Wilson, Angela/E-9399-2012; Verdrengh, Evelien/H-4571-2012; Lester, Jenny/B-5933-2012; Webb, Penelope/D-5736-2013; Ekici, Arif/C-3971-2013; Kiemeney, Lambertus/D-3357-2009; Tang, Macy/B-9798-2014; Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; campbell, Ian/F-6006-2011; van Altena, Anne/B-9824-2016; Aben, Katja/G-9686-2016 OI Bowtell, David/0000-0001-9089-7525; Johnatty, Sharon/0000-0002-7888-1966; Gronwald, Jacek/0000-0002-3643-2871; Brooks-Wilson, Angela/0000-0003-1009-6408; Vierkant, Robert/0000-0001-6242-5221; Weidhaas, Joanne/0000-0002-5096-3281; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799; Nevanlinna, Heli/0000-0002-0916-2976; Besenbacher, Soren/0000-0003-1455-1738; Houlston, Richard/0000-0002-5268-0242; Webb, Penelope/0000-0003-0733-5930; Kiemeney, Lambertus/0000-0002-2368-1326; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Aben, Katja/0000-0002-0214-2147 FU Cancer Research UK; Wellcome Trust [076113]; Ovarian Cancer Research Fund; Mermaid/Eve Appeal; National Health and Medical Research Council; Deutsche Krebshilfe; National Health Service; Danish Cancer Society; Ovarian Cancer Research Fund [PPD/RPCI.07]; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institute [CA58860, CA92044, P50CA105009, R01CA122443, R01CA126841-01, R01CA16056, R01CA61107, R01CA71766, R01CA054419, R01CA114343, R01CA87538, R01CA112523, R01CA58598, N01CN55424, N01PC35137]; US Army Medical Research and Material Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; University of Ulm [P. 685]; Mayo Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; University College Hospital National Institute for Health Research Biomedical Research Centre; Royal Marsden Hospital Biomedical Research Centre FX The genotyping and data analysis for this study was supported by a project grant from Cancer Research UK. We acknowledge the computational resources provided by the University of Cambridge (CamGrid). This study makes use of data generated by the Wellcome Trust Case-Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www. wtccc. org. uk/. Funding for the project was provided by the Wellcome Trust under award 076113. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of K. Sladek Smith. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome. nih. gov/. S.J.R. is supported by the Mermaid/Eve Appeal. G. C.-T. and P. M. W. are supported by the National Health and Medical Research Council. P. A. F. is supported by the Deutsche Krebshilfe. M. E. G. acknowledges National Health Service funding to the National Institutes of Health Research Centre at the Royal Marsden Hospital, and D. F. E. is a Principal Research Fellow of Cancer Research UK. Funding of the constituent studies was provided by the Danish Cancer Society, the Ovarian Cancer Research Fund (PPD/RPCI.07), the Roswell Park Cancer Institute Alliance Foundation, the US National Cancer Institute (CA58860, CA92044, P50CA105009, R01CA122443, R01CA126841-01, R01CA16056, R01CA61107, R01CA71766, R01CA054419, R01CA114343, R01CA87538, R01CA112523, R01CA58598, N01CN55424, N01PC35137 and Intramural research funds), the US Army Medical Research and Material Command (DAMD17-01-1-0729), Cancer Council Victoria, Cancer Council Queensland, Cancer Council New South Wales, Cancer Council South Australia, Cancer Council Tasmania and Cancer Foundation of Western Australia, the National Health and Medical Research Council of Australia (199600 and 400281), the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401), the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P. 685), the Mayo Foundation, the Lon V. Smith Foundation (LVS-39420), the Oak Foundation, the University College Hospital National Institute for Health Research Biomedical Research Centre and the Royal Marsden Hospital Biomedical Research Centre. NR 24 TC 144 Z9 148 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2010 VL 42 IS 10 BP 880 EP + DI 10.1038/ng.666 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 655UO UT WOS:000282276600019 PM 20852633 ER PT J AU Antoniou, AC Wang, XS Fredericksen, ZS McGuffog, L Tarrell, R Sinilnikova, OM Healey, S Morrison, J Kartsonaki, C Lesnick, T Ghoussaini, M Barrowdale, D Peock, S Cook, M Oliver, C Frost, D Eccles, D Evans, DG Eeles, R Izatt, L Chu, C Douglas, F Paterson, J Stoppa-Lyonnet, D Houdayer, C Mazoyer, S Giraud, S Lasset, C Remenieras, A Caron, O Hardouin, A Berthet, P Hogervorst, FBL Rookus, MA Jager, A van den Ouweland, A Hoogerbrugge, N van der Luijt, RB Meijers-Heijboer, H Garcia, EBG Devilee, P Vreeswijk, MPG Lubinski, J Jakubowska, A Gronwald, J Huzarski, T Byrski, T Gorski, B Cybulski, C Spurdle, AB Holland, H Goldgar, DE John, EM Hopper, JL Southey, M Buys, SS Daly, MB Terry, MB Schmutzler, RK Wappenschmidt, B Engel, C Meindl, A Preisler-Adams, S Arnold, N Niederacher, D Sutter, C Domchek, SM Nathanson, KL Rebbeck, T Blum, JL Piedmonte, M Rodriguez, GC Wakeley, K Boggess, JF Basil, J Blank, SV Friedman, E Kaufman, B Laitman, Y Milgrom, R Andrulis, IL Glendon, G Ozcelik, H Kirchhoff, T Vijai, J Gaudet, MM Altshuler, D Guiducci, C Loman, N Harbst, K Rantala, J Ehrencrona, H Gerdes, AM Thomassen, M Sunde, L Peterlongo, P Manoukian, S Bonanni, B Viel, A Radice, P Caldes, T de la Hoya, M Singer, CF Fink-Retter, A Greene, MH Mai, PL Loud, JT Guidugli, L Lindor, NM Hansen, TVO Nielsen, FC Blanco, I Lazaro, C Garber, J Ramus, SJ Gayther, SA Phelan, C Narod, S Szabo, CI Benitez, J Osorio, A Nevanlinna, H Heikkinen, T Caligo, MA Beattie, MS Hamann, U Godwin, AK Montagna, M Casella, C Neuhausen, SL Karlan, BY Tung, N Toland, AE Weitzel, J Olopade, O Simard, J Soucy, P Rubinstein, WS Arason, A Rennert, G Martin, NG Montgomery, GW Chang-Claude, J Flesch-Janys, D Brauch, H Severi, G Baglietto, L Cox, A Cross, SS Miron, P Gerty, SM Tapper, W Yannoukakos, D Fountzilas, G Fasching, PA Beckmann, MW Silva, IDS Peto, J Lambrechts, D Paridaens, R Rudiger, T Forsti, A Winqvist, R Pylkaas, K Diasio, RB Lee, AM Eckel-Passow, J Vachon, C Blows, F Driver, K Dunning, A Pharoah, PPD Offit, K Pankratz, VS Hakonarson, H Chenevix-Trench, G Easton, DF Couch, FJ AF Antoniou, Antonis C. Wang, Xianshu Fredericksen, Zachary S. McGuffog, Lesley Tarrell, Robert Sinilnikova, Olga M. Healey, Sue Morrison, Jonathan Kartsonaki, Christiana Lesnick, Timothy Ghoussaini, Maya Barrowdale, Daniel Peock, Susan Cook, Margaret Oliver, Clare Frost, Debra Eccles, Diana Evans, D. Gareth Eeles, Ros Izatt, Louise Chu, Carol Douglas, Fiona Paterson, Joan Stoppa-Lyonnet, Dominique Houdayer, Claude Mazoyer, Sylvie Giraud, Sophie Lasset, Christine Remenieras, Audrey Caron, Olivier Hardouin, Agnes Berthet, Pascaline Hogervorst, Frans B. L. Rookus, Matti A. Jager, Agnes van den Ouweland, Ans Hoogerbrugge, Nicoline van der Luijt, Rob B. Meijers-Heijboer, Hanne Garcia, Encarna B. Gomez Devilee, Peter Vreeswijk, Maaike P. G. Lubinski, Jan Jakubowska, Anna Gronwald, Jacek Huzarski, Tomasz Byrski, Tomasz Gorski, Bohdan Cybulski, Cezary Spurdle, Amanda B. Holland, Helene Goldgar, David E. John, Esther M. Hopper, John L. Southey, Melissa Buys, Saundra S. Daly, Mary B. Terry, Mary-Beth Schmutzler, Rita K. Wappenschmidt, Barbara Engel, Christoph Meindl, Alfons Preisler-Adams, Sabine Arnold, Norbert Niederacher, Dieter Sutter, Christian Domchek, Susan M. Nathanson, Katherine L. Rebbeck, Timothy Blum, Joanne L. Piedmonte, Marion Rodriguez, Gustavo C. Wakeley, Katie Boggess, John F. Basil, Jack Blank, Stephanie V. Friedman, Eitan Kaufman, Bella Laitman, Yael Milgrom, Roni Andrulis, Irene L. Glendon, Gord Ozcelik, Hilmi Kirchhoff, Tomas Vijai, Joseph Gaudet, Mia M. Altshuler, David Guiducci, Candace Loman, Niklas Harbst, Katja Rantala, Johanna Ehrencrona, Hans Gerdes, Anne-Marie Thomassen, Mads Sunde, Lone Peterlongo, Paolo Manoukian, Siranoush Bonanni, Bernardo Viel, Alessandra Radice, Paolo Caldes, Trinidad de la Hoya, Miguel Singer, Christian F. Fink-Retter, Anneliese Greene, Mark H. Mai, Phuong L. Loud, Jennifer T. Guidugli, Lucia Lindor, Noralane M. Hansen, Thomas V. O. Nielsen, Finn C. Blanco, Ignacio Lazaro, Conxi Garber, Judy Ramus, Susan J. Gayther, Simon A. Phelan, Catherine Narod, Stephen Szabo, Csilla I. Benitez, Javier Osorio, Ana Nevanlinna, Heli Heikkinen, Tuomas Caligo, Maria A. Beattie, Mary S. Hamann, Ute Godwin, Andrew K. Montagna, Marco Casella, Cinzia Neuhausen, Susan L. Karlan, Beth Y. Tung, Nadine Toland, Amanda E. Weitzel, Jeffrey Olopade, Olofunmilayo Simard, Jacques Soucy, Penny Rubinstein, Wendy S. Arason, Adalgeir Rennert, Gad Martin, Nicholas G. Montgomery, Grant W. Chang-Claude, Jenny Flesch-Janys, Dieter Brauch, Hiltrud Severi, Gianluca Baglietto, Laura Cox, Angela Cross, Simon S. Miron, Penelope Gerty, Sue M. Tapper, William Yannoukakos, Drakoulis Fountzilas, George Fasching, Peter A. Beckmann, Matthias W. Silva, Isabel dos Santos Peto, Julian Lambrechts, Diether Paridaens, Robert Ruediger, Thomas Foersti, Asta Winqvist, Robert Pylkaes, Katri Diasio, Robert B. Lee, Adam M. Eckel-Passow, Jeanette Vachon, Celine Blows, Fiona Driver, Kristy Dunning, Alison Pharoah, Paul P. D. Offit, Kenneth Pankratz, V. Shane Hakonarson, Hakon Chenevix-Trench, Georgia Easton, Douglas F. Couch, Fergus J. CA EMBRACE GEMO Study Collaborators HEBON KConFab SWE-BRCA MOD SQUAD GENICA TI A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ESTROGEN-RECEPTOR; COMMON VARIANTS; CONFER SUSCEPTIBILITY; OVARIAN-CANCER; NONSENSE; ALLELES; COMPLEX; 2Q35 AB Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 x 10(-7)). C1 [Antoniou, Antonis C.; McGuffog, Lesley; Morrison, Jonathan; Kartsonaki, Christiana; Barrowdale, Daniel; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Tung, Nadine; Blows, Fiona; Driver, Kristy; Dunning, Alison; Pharoah, Paul P. D.; Easton, Douglas F.; EMBRACE] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Wang, Xianshu; Guidugli, Lucia; Szabo, Csilla I.; Toland, Amanda E.; Couch, Fergus J.] Dept Lab Med & Pathol, Mayo Clin, Rochester, MN USA. [Fredericksen, Zachary S.; Tarrell, Robert; Lesnick, Timothy; Weitzel, Jeffrey; Eckel-Passow, Jeanette; Vachon, Celine; Pankratz, V. Shane] Dept Hlth Sci Res, Mayo Clin, Rochester, MN USA. [Sinilnikova, Olga M.; Giraud, Sophie; Olopade, Olofunmilayo] Univ Lyon Ctr Leon Berard, Ctr Hosp, Unit Mixte Genet Constitutionnelle Canc Frequents, Lyon, France. [Sinilnikova, Olga M.; Mazoyer, Sylvie; Simard, Jacques] Univ Lyon, Ctr Leon Berard, CNRS, Equipe Labellisee LIGUE 2008, Lyon, France. [Healey, Sue; Ghoussaini, Maya; Spurdle, Amanda B.; Holland, Helene; Simard, Jacques; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Eccles, Diana; Gerty, Sue M.; Tapper, William] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Evans, D. Gareth] Cent Manchester Univ Hosp, Manchester Acad Hlth Sci Ctr, NHSFT, Manchester, Lancs, England. [Eeles, Ros] Inst Canc Res & Royal Marsden NHS Fdn, Oncogenet Team, Sutton, Surrey, England. [Izatt, Louise; Soucy, Penny] Guys & St Thomas NHS Fdn Trust, Clin Genet, London, England. [Chu, Carol] Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Douglas, Fiona] Newcastle Tyne Hosp NHS Trust, Ctr Life, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. Addenbrookes Hosp, Dept Clin Genet, E Anglian Reg Genet Serv, Cambridge, England. [Stoppa-Lyonnet, Dominique; Houdayer, Claude] Univ Paris 05, Inst Curie, INSERM U509, Serv Genet Oncolog, Paris, France. [Lasset, Christine] Univ Lyon 1, CNRS, UMR5558, F-69365 Lyon, France. [Lasset, Christine] Ctr Leon Berard, Unit Prevent & Epidemiol Genet, Lyon, France. [Remenieras, Audrey] Inst Cancerol Gustave Roussy, Dept Genet, Villejuif, France. [Caron, Olivier] Inst Cancerol Gustave Roussy, Dept Med, Consultat Genet, Villejuif, France. [Hardouin, Agnes; Berthet, Pascaline; Miron, Penelope] Ctr Francois Baclesse, F-14021 Caen, France. [GEMO Study Collaborators] Federat Natl Ctr Lutte Contre Canc, Grp Genet & Canc, Canc Genet Network, GEMO Study, Paris, France. [Hogervorst, Frans B. L.] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Jager, Agnes] Erasmus Univ, Med Ctr, Rotterdam Family Canc Clin, Dept Clin Genet, Rotterdam, Netherlands. [van den Ouweland, Ans] Rotterdam Family Canc Clin, Erasmus Univ Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Meijers-Heijboer, Hanne] Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam, Netherlands. [Garcia, Encarna B. Gomez] Maastricht Univ, Med Ctr, Dept Clin Genet, Sch Oncol & Dev Biol, Maastricht, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Vreeswijk, Maaike P. G.] Leiden Univ, Med Ctr, Dept Toxicogenet, Leiden, Netherlands. [Lubinski, Jan; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Gorski, Bohdan; Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [KConFab] Peter MacCallum Canc Inst, Kathleen Cuningham Fdn Consortium Res Familial Br, kConFab, Melbourne, Vic 3000, Australia. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [John, Esther M.] Stanford Univ, Sch Med, Canc Prevent Inst Calif, Stanford, CA USA. [Hopper, John L.; Southey, Melissa] Univ Melbourne, Melbourne, Vic, Australia. [Buys, Saundra S.] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Salt Lake City, UT USA. [Daly, Mary B.; Godwin, Andrew K.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Terry, Mary-Beth] Columbia Univ, New York, NY USA. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Cologne, CIO, Cologne, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Meindl, Alfons] Tech Univ Munich, Dept Obstet & Gynaecol, Div Tumor Genet, Klinikum Rechts Isar, Munich, Germany. [Preisler-Adams, Sabine] Univ Munster, Inst Human Genet, Munster, Germany. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Kiel, Germany. [Niederacher, Dieter] Univ Dusseldorf, Univ Hosp Dusseldorf, Div Mol Genet, Dept Obstet & Gynaecol, Dusseldorf, Germany. [Sutter, Christian] Univ Heidelberg, Div Mol Diagnost, Inst Human Genet, Heidelberg, Germany. [Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy] Univ Penn, Philadelphia, PA 19104 USA. [Blum, Joanne L.] Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Gynecol Oncol Grp Stat & Data Ctr, Buffalo, NY 14263 USA. [Rodriguez, Gustavo C.] Northshore Univ Hlth Syst, Evanston NW Healthcare, Evanston, IL USA. [Wakeley, Katie] Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. [Boggess, John F.] Univ N Carolina, Chapel Hill, NC USA. [Basil, Jack] St Elizabeth Hosp, Edgewood, KY USA. [Blank, Stephanie V.] NYU, Sch Med, New York, NY USA. [Friedman, Eitan; Laitman, Yael; Milgrom, Roni] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel. [Kaufman, Bella] Inst Oncol, Sheba Med Ctr, Tel Hashomer, Israel. [Andrulis, Irene L.; Glendon, Gord] Ontario Canc Inst, Ontario Canc Genet Network, Toronto, ON M4X 1K9, Canada. [Ozcelik, Hilmi] Samuel Lunenfeld Res Inst, Fred Litwin Ctr Canc Genet, Toronto, ON, Canada. [Andrulis, Irene L.; Offit, Kenneth] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Kirchhoff, Tomas; Vijai, Joseph] Mem Hosp, Clin Genet Serv, New York, NY USA. [Kirchhoff, Tomas; Vijai, Joseph] Sloan Kettering Inst, Canc Biol & Genet Program, Mem Sloan Kettering Canc Ctr, New York, NY USA. [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, New York, NY USA. [Altshuler, David; Guiducci, Candace] Broad Inst Harvard, Cambridge, MA USA. [Altshuler, David; Guiducci, Candace] MIT, Cambridge, MA 02139 USA. [Loman, Niklas; Harbst, Katja] Lund Univ, Dept Oncol, Lund, Sweden. [Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [Ehrencrona, Hans] Uppsala Univ, Dept Genet & Pathol Rudbeck Lab, Uppsala, Sweden. [Gerdes, Anne-Marie] Dept Clin Genet, Copenhagen, Denmark. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Sunde, Lone] Aalborg & Aarhus Univ, Dept Clin Genet, Aalborg, Denmark. [Peterlongo, Paolo; Radice, Paolo] Fdn Inst Ricovero Cura Carattere Sci, Unit Genet Susceptibil Canc, Dept Expt Oncol & Mol Med, Ist Nazl Tumori, Milan, Italy. [Peterlongo, Paolo; Radice, Paolo] Fdn Ist Fdn Italiana Ricera Cancro FIRC Oncol Mol, IFOM, Milan, Italy. [Manoukian, Siranoush] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Bonanni, Bernardo; de la Hoya, Miguel] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Viel, Alessandra] Ctr Riferimento Oncol, Div Expt Oncol, IRCCS, I-33081 Aviano, PN, Italy. [Caldes, Trinidad] Hosp Clin San Carlos, Madrid, Spain. [Singer, Christian F.; Fink-Retter, Anneliese] Med Univ Vienna, Dept Obstet Gynecol, Vienna, Austria. [Greene, Mark H.; Mai, Phuong L.; Loud, Jennifer T.] Natl Canc Inst, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD USA. [Lindor, Noralane M.] Mayo Clin Rochester, Rochester, MN USA. [Hansen, Thomas V. O.; Nielsen, Finn C.] Copenhagen Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Blanco, Ignacio; Lazaro, Conxi] Gran Via Hosp, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain. [Garber, Judy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ramus, Susan J.; Gayther, Simon A.] UCL, Dept Gynecol Oncol, EGA, London, England. [Phelan, Catherine] Res Inst, Womens Coll, Toronto, ON, Canada. [Narod, Stephen] H Lee Moffitt Canc Ctr & Res Inst, Dept Epidemiol & Genet, Tampa, FL USA. [Benitez, Javier; Osorio, Ana] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Madrid, Spain. [Nevanlinna, Heli; Heikkinen, Tuomas] Univ Helsinki, Ctr Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Caligo, Maria A.] Univ Pisa, Dept Oncol, Div Surg Mol & Ultrastructural Pathol, Pisa, Italy. [Beattie, Mary S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Beattie, Mary S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Beattie, Mary S.] Univ Calif San Francisco, Canc Risk Program, Helen Diller Family Canc Ctr, San Francisco, CA 94143 USA. [Hamann, Ute; Foersti, Asta] German Canc Res Ctr, Heidelberg, Germany. [Montagna, Marco; Casella, Cinzia] Ist Oncol Veneto IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Karlan, Beth Y.] Canc Res Inst, Samuel Oschin Canc Inst, Div Gynecol Oncol, Cedars Sinai Med Ctr, Los Angeles, CA USA. [Karlan, Beth Y.] Univ Calif Los Angeles, Dept Obstet & Gynecol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Toland, Amanda E.] Ohio State Univ, Coll Med, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Weitzel, Jeffrey] City Hope Canc Ctr, Div Clin Canc Genet, Duarte, CA USA. [Olopade, Olofunmilayo] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Simard, Jacques] Univ Quebec, Ctr Hosp, Canc Genom Lab, Quebec City, PQ, Canada. [Simard, Jacques] Univ Laval, Ctr Rech Ctr Hosp Univ Quebec CHUQ, Quebec City, PQ G1K 7P4, Canada. [Rubinstein, Wendy S.] Northshore Univ Hlth Syst, Evanston, IL USA. [Arason, Adalgeir] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Rennert, Gad] Queensland Inst Med Res, QIMR GWAS Collect, Brisbane, Qld 4006, Australia. [Martin, Nicholas G.; Montgomery, Grant W.] B Rappaport Fac Med Techn, Haifa, Israel. [Martin, Nicholas G.; Montgomery, Grant W.] Carmel Hosp, Dept Commun Med & Epidemiol, Clalit Hlth Serv Natl Canc Control Ctr, Haifa, Israel. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Severi, Gianluca; Baglietto, Laura] Canc Epidemiol Ctr, MCCS, Melbourne, Australia. [Cox, Angela] Univ Sheffield, Dept Oncol, Fac Med Dent & Hlth, Inst Canc Studies, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Fac Med Dent & Hlth, Sheffield, S Yorkshire, England. [Miron, Penelope] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab Inst Radioisotopes & Radiodiagno, Athens, Greece. [Fountzilas, George] Aristotle Univ Thessaloniki, Papageorgiou Hosp, Dept Med Oncol, Thessaloniki, Greece. [Fountzilas, George] Aristotle Univ Thessaloniki, Papageorgiou Hosp, Dept Med Oncol, Thessaloniki, Greece. [Fasching, Peter A.] Calif State Univ Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90032 USA. [Beckmann, Matthias W.] Univers Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany. [Silva, Isabel dos Santos; Peto, Julian] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, Cancer Res UK Epidemiol & Genet Grp, London WC1, England. [Lambrechts, Diether] VRC, VIB, Leuven, Belgium. [Paridaens, Robert] Univ Hosp Leuven, Multidisciplinary Breast Ctr, Leuven, Belgium. [Ruediger, Thomas] Inst Pathol, Stadt Klinikum Karlsruhe, Karlsruhe, Germany. [Foersti, Asta] Lund Univ, Ctr Primary Hlth Care Res, Lund, Sweden. [Winqvist, Robert; Pylkaes, Katri] Univ Oulu, Dept Clin Genet & Biocenter Oulu, Canc Genet Lab, Oulu Univ Hosp, Oulu, Finland. [Diasio, Robert B.; Lee, Adam M.] Mayo Clin, Dept Pharmacol, Rochester, MN USA. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Gen, Philadelphia, PA 19104 USA. RP Couch, FJ (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. EM couch.fergus@mayo.edu RI Spurdle, Amanda/A-4978-2011; BYRSKI, Tomasz/I-2844-2014; Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; Montgomery, Grant/B-7148-2008; Gronwald, Jacek/A-4576-2017; manoukian, siranoush/E-7132-2017; Osorio, Ana/I-4324-2014; Altshuler, David/A-4476-2009; Arnold, Norbert/E-3012-2010; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Verdrengh, Evelien/H-4571-2012; Fink, Rainer/C-5333-2008; Andrulis, Irene/E-7267-2013; Sunde, Lone/H-7402-2013; Joseph, Vijai/J-9158-2013; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Blanco, Ignacio/D-2565-2013 OI Kirchhoff, Tomas/0000-0002-9055-2364; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166; Martin, Nicholas/0000-0003-4069-8020; Evans, Gareth/0000-0002-8482-5784; Ramus, Susan/0000-0003-0005-7798; Spurdle, Amanda/0000-0003-1337-7897; Barrowdale, Daniel/0000-0003-1661-3939; Cross, Simon/0000-0003-2044-1754; Sunde, Lone/0000-0002-8479-165X; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Ehrencrona, Hans/0000-0002-5589-3622; Montgomery, Grant/0000-0002-4140-8139; Gronwald, Jacek/0000-0002-3643-2871; manoukian, siranoush/0000-0002-6034-7562; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Osorio, Ana/0000-0001-8124-3984; Altshuler, David/0000-0002-7250-4107; Arnold, Norbert/0000-0003-4523-8808; montagna, marco/0000-0002-4929-2150; Fink, Rainer/0000-0002-6896-4266; Joseph, Vijai/0000-0002-7933-151X; Blanco, Ignacio/0000-0002-7414-7481 FU Breast Cancer Research Foundation (BCRF); US National Institutes of Health [CA128978]; Cancer Research UK FX Financial support for this study was provided by the Breast Cancer Research Foundation (BCRF), Susan G. Komen for the Cure and US National Institutes of Health grant CA128978 to F. J. C. and by Cancer Research UK to D. F. E. and A. C. A. A. C. A. is a Cancer Research UK Senior Cancer Research Fellow and D. F. E. is a Cancer Research UK Principal Research Fellow. The authors thank Cancer Genetic Markers of Susceptability (CGEMS) and Wellcome Trust Case Control Consortium (WTCCC) for provision of genotype data from controls. Study specific acknowledgments listed in Supplementary Note. NR 32 TC 180 Z9 185 U1 5 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2010 VL 42 IS 10 BP 885 EP + DI 10.1038/ng.669 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 655UO UT WOS:000282276600020 PM 20852631 ER PT J AU Jacobelli, J Friedman, RS Conti, MA Lennon-Dumenil, AM Piel, M Sorensen, CM Adelstein, RS Krummel, MF AF Jacobelli, Jordan Friedman, Rachel S. Conti, Mary Anne Lennon-Dumenil, Ana-Maria Piel, Matthieu Sorensen, Caitlin M. Adelstein, Robert S. Krummel, Matthew F. TI Confinement-optimized three-dimensional T cell amoeboid motility is modulated via myosin IIA-regulated adhesions SO NATURE IMMUNOLOGY LA English DT Article ID FIBROBLASTIC RETICULAR CELLS; LYMPH-NODE; LEUKOCYTE MIGRATION; CHAIN; SPEED; ADHESIVENESS; LYMPHOCYTES; CHEMOTAXIS; MICROSCOPY; LOCOMOTION AB During trafficking through tissues, T cells fine-tune their motility to balance the extent and duration of cell-surface contacts versus the need to traverse an entire organ. Here we show that in vivo, myosin IIA-deficient T cells had a triad of defects, including overadherence to high-endothelial venules, less interstitial migration and inefficient completion of recirculation through lymph nodes. Spatiotemporal analysis of three-dimensional motility in microchannels showed that the degree of confinement and myosin IIA function, rather than integrin adhesion (as proposed by the haptokinetic model), optimized motility rate. This motility occurred via a myosin IIA-dependent rapid 'walking' mode with multiple small and simultaneous adhesions to the substrate, which prevented spurious and prolonged adhesions. Adhesion discrimination provided by myosin IIA is thus necessary for the optimization of motility through complex tissues. C1 [Jacobelli, Jordan; Friedman, Rachel S.; Sorensen, Caitlin M.; Krummel, Matthew F.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Conti, Mary Anne; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Lennon-Dumenil, Ana-Maria; Piel, Matthieu] Inst Curie, Inst Natl Sante Rech Med, U653, Paris, France. RP Krummel, MF (reprint author), Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. EM matthew.krummel@ucsf.edu RI piel, matthieu/A-2956-2010; Lennon-Dumenil, Ana-Maria/I-6716-2016; OI Adelstein, Robert/0000-0002-8683-2144 FU National Institutes of Health [AI52116]; Larry L. Hillblom Foundation FX We thank P. Beemiller for help with two-photon data analysis with Imaris and Matlab software; S. Peck for assistance in maintenance of microscopes; M. Tang (Stanford Microfabrication Center) for Silicon Masters; S. Jiang for technical assistance with cell sorting; O. Khan and M. Werner for help with mouse genotyping; M. Heuze for assistance in setting up the microchannel system; and B. Sauer (Stowers Institute for Medical Research) for the pBS479 vector. Supported by the National Institutes of Health (AI52116 to M.F.K.) and the Larry L. Hillblom Foundation (R.S.F.). NR 40 TC 83 Z9 83 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2010 VL 11 IS 10 BP 953 EP U110 DI 10.1038/ni.1936 PG 12 WC Immunology SC Immunology GA 651KP UT WOS:000281926900015 PM 20835229 ER PT J AU Lovinger, DM AF Lovinger, David M. TI Endocannabinoids rein in pain outside the brain SO NATURE NEUROSCIENCE LA English DT Editorial Material ID CANNABINOID RECEPTORS; EFFICACY; BLOCKADE; OBESITY C1 NIAAA, Lab Integrat Neurosci, Bethesda, MD USA. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, Bethesda, MD USA. EM lovindav@mail.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2010 VL 13 IS 10 BP 1155 EP 1156 DI 10.1038/nn1010-1155 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 654MB UT WOS:000282171300003 PM 20877276 ER PT J AU Evers, DM Matta, JA Hoe, HS Zarkowsky, D Lee, SH Isaac, JT Pak, DTS AF Evers, Danielle M. Matta, Jose A. Hoe, Hyang-Sook Zarkowsky, Devin Lee, Sang Hyoung Isaac, John T. Pak, Daniel T. S. TI Plk2 attachment to NSF induces homeostatic removal of GluA2 during chronic overexcitation SO NATURE NEUROSCIENCE LA English DT Article ID AMPA RECEPTOR TRAFFICKING; ETHYLMALEIMIDE-SENSITIVE FACTOR; DOMAIN-CONTAINING PROTEINS; LONG-TERM POTENTIATION; POLO-LIKE KINASE; HIPPOCAMPAL-NEURONS; SYNAPTIC-TRANSMISSION; SURFACE EXPRESSION; SUBUNIT COMPOSITION; BINDING PROTEIN AB Trafficking of AMPA receptors (AMPARs) is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. We identified a direct interaction between N-ethylmaleimide-sensitive fusion protein (NSF), an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Polo-like kinase-2 (Plk2), an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted the interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adaptor proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a motif in the Plk2 protein that was independent of the canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2. C1 [Evers, Danielle M.; Matta, Jose A.; Zarkowsky, Devin; Pak, Daniel T. S.] Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. [Matta, Jose A.; Isaac, John T.] NIGMS, NIH, Bethesda, MD USA. [Hoe, Hyang-Sook] Georgetown Univ, Dept Neurosci, Washington, DC 20007 USA. [Lee, Sang Hyoung] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. RP Pak, DTS (reprint author), Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. EM dtp6@georgetown.edu FU US National Institutes of Health; National Institute of Neurological Disorders and Stroke (Biacore Molecular Interactions Shared Resource of Lombardi Comprehensive Cancer Center) [NS048085, F31NS061467, P30CA051008] FX We thank L. Bilello for technical assistance. This work was supported by US National Institutes of Health and National Institute of Neurological Disorders and Stroke grants NS048085 (D.T.S.P.), F31NS061467 (D.M.E.) and P30CA051008 (Biacore Molecular Interactions Shared Resource of Lombardi Comprehensive Cancer Center). NR 50 TC 36 Z9 39 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2010 VL 13 IS 10 BP 1199 EP 1207 DI 10.1038/nn.2624 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 654MB UT WOS:000282171300011 PM 20802490 ER PT J AU Chittajallu, R Isaac, JTR AF Chittajallu, Ramesh Isaac, John T. R. TI Emergence of cortical inhibition by coordinated sensory-driven plasticity at distinct synaptic loci SO NATURE NEUROSCIENCE LA English DT Article ID RAT BARREL CORTEX; THALAMOCORTICAL FEEDFORWARD INHIBITION; EXCITATORY NEURONAL NETWORK; FAST-SPIKING INTERNEURONS; RECEPTOR SUBUNIT NR3A; SPINY STELLATE CELLS; NMDA RECEPTORS; LAYER-IV; SOMATOSENSORY CORTEX; REGIONAL EXPRESSION AB Feedforward GABAergic inhibition sets the dendritic integration window, thereby controlling timing and output in cortical circuits. However, the manner in which feedforward inhibitory circuits emerge is unclear, despite this being a critical step for neocortical development and function. We found that sensory experience drove plasticity of the feedforward inhibitory circuit in mouse layer 4 somatosensory barrel cortex in the second postnatal week via two distinct mechanisms. First, sensory experience selectively strengthened thalamocortical-to-feedforward interneuron inputs via a presynaptic mechanism but did not regulate other inhibitory circuit components. Second, experience drove a postsynaptic mechanism in which a downregulation of a prominent thalamocortical NMDA excitatory postsynaptic potential in stellate cells regulated the final expression of functional feedforward inhibitory input. Thus, experience is required for specific, coordinated changes at thalamocortical synapses onto both inhibitory and excitatory neurons, producing a circuit plasticity that results in maturation of functional feedforward inhibition in layer 4. C1 [Chittajallu, Ramesh; Isaac, John T. R.] NINDS, Dev Synapt Plast Sect, NIH, Bethesda, MD 20892 USA. RP Chittajallu, R (reprint author), NINDS, Dev Synapt Plast Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM chittajallur@ninds.nih.gov; isaacj@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX We thank C. McBain for discussions and Y. Yanagawa (Gunma University) for providing GAD67-GFP knockin mouse. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Program. NR 42 TC 36 Z9 36 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2010 VL 13 IS 10 BP 1240 EP 1248 DI 10.1038/nn.2639 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 654MB UT WOS:000282171300016 PM 20871602 ER PT J AU Logothetis, NK Augath, M Murayama, Y Rauch, A Sultan, F Goense, J Oeltermann, A Merkle, H AF Logothetis, Nikos K. Augath, Mark Murayama, Yusuke Rauch, Alexander Sultan, Fahad Goense, Jozien Oeltermann, Axel Merkle, Hellmut TI The effects of electrical microstimulation on cortical signal propagation SO NATURE NEUROSCIENCE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; CAT VISUAL-CORTEX; FRONTAL EYE FIELD; STRIATE CORTEX; INTRACORTICAL MICROSTIMULATION; FUNCTIONAL MRI; RAT NEOCORTEX; MOTOR CORTEX; FMRI SIGNAL; AREA MT AB Electrical stimulation has been used in animals and humans to study potential causal links between neural activity and specific cognitive functions. Recently, it has found increasing use in electrotherapy and neural prostheses. However, the manner in which electrical stimulation-elicited signals propagate in brain tissues remains unclear. We used combined electrostimulation, neurophysiology, microinjection and functional magnetic resonance imaging (fMRI) to study the cortical activity patterns elicited during stimulation of cortical afferents in monkeys. We found that stimulation of a site in the lateral geniculate nucleus (LGN) increased the fMRI signal in the regions of primary visual cortex (V1) that received input from that site, but suppressed it in the retinotopically matched regions of extrastriate cortex. Consistent with previous observations, intracranial recordings indicated that a short excitatory response occurring immediately after a stimulation pulse was followed by a long-lasting inhibition. Following microinjections of GABA antagonists in V1, LGN stimulation induced positive fMRI signals in all of the cortical areas. Taken together, our findings suggest that electrical stimulation disrupts cortico-cortical signal propagation by silencing the output of any neocortical area whose afferents are electrically stimulated. C1 [Logothetis, Nikos K.; Augath, Mark; Murayama, Yusuke; Rauch, Alexander; Goense, Jozien; Oeltermann, Axel] Max Planck Inst Biol Cybernet, Tubingen, Germany. [Logothetis, Nikos K.] Univ Manchester, Manchester, Lancs, England. [Sultan, Fahad] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Cognit Neurol, Tubingen, Germany. [Merkle, Hellmut] NINDS, Lab Funct & Mol Imaging, US NIH, Bethesda, MD 20892 USA. RP Logothetis, NK (reprint author), Max Planck Inst Biol Cybernet, Tubingen, Germany. EM nikos.logothetis@tuebingen.mpg.de FU Max Planck Society; German Research Foundation [DFG SFB-A9]; US National Institutes of Health (National Institute Neurological Disorders and Stroke) FX We thank C. Kayser, O. Eschenko and M. Munk for reading the manuscript and for useful suggestions. Many thanks also go to D. Blaurock for editing, S. Weber for fine-mechanic work and T. Steudel and P. Douay for help with the alert monkey experiments. This research was supported by the Max Planck Society, the German Research Foundation (DFG SFB-A9) and by the intramural research program of the US National Institutes of Health (National Institute Neurological Disorders and Stroke, H.M.). NR 50 TC 128 Z9 131 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2010 VL 13 IS 10 BP 1283 EP 1291 DI 10.1038/nn.2631 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 654MB UT WOS:000282171300022 PM 20818384 ER PT J AU Makarova, KS Yutin, N Bell, SD Koonin, EV AF Makarova, Kira S. Yutin, Natalya Bell, Stephen D. Koonin, Eugene V. TI Evolution of diverse cell division and vesicle formation systems in Archaea SO NATURE REVIEWS MICROBIOLOGY LA English DT Article ID SULFOLOBUS-SOLFATARICUS; BACILLUS-SUBTILIS; ESCRT; FTSZ; EUKARYOTES; ORIGIN; CYTOSKELETON; GENOMICS; PROSTHECOBACTER; CRENARCHAEOTA AB Recently a novel cell division system comprised of homologues of eukaryotic ESCRT-III (endosomal sorting complex required for transport III) proteins was discovered in the hyperthermophilic crenarchaeote Sulfolobus acidocaldarius. On the basis of this discovery, we undertook a comparative genomic analysis of the machineries for cell division and vesicle formation in Archaea. Archaea possess at least three distinct membrane remodelling systems: the FtsZ-based bacterial-type system, the ESCRT-III-based eukaryote-like system and a putative novel system that uses an archaeal actin-related protein. Many archaeal genomes encode assortments of components from different systems. Evolutionary reconstruction from these findings suggests that the last common ancestor of the extant Archaea possessed a complex membrane remodelling apparatus, different components of which were lost during subsequent evolution of archaeal lineages. By contrast, eukaryotes seem to have inherited all three ancestral systems. C1 [Makarova, Kira S.; Yutin, Natalya; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Bell, Stephen D.] Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM stephen.bell@path.ox.ac.uk FU US National Institutes of Health; National Library of Medicine; Edward Penley Abraham Trust FX The authors thank Y. Wolf for useful discussions and help with the preparation of figure 3. The authors' research is supported by the Intramural Research Program of the US National Institutes of Health, National Library of Medicine (K.S.M., N.Y. and E.V.K.) and by the Edward Penley Abraham Trust (S.D.B.). NR 57 TC 89 Z9 92 U1 5 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD OCT PY 2010 VL 8 IS 10 BP 731 EP 741 DI 10.1038/nrmicro2406 PG 11 WC Microbiology SC Microbiology GA 651EU UT WOS:000281908700012 PM 20818414 ER PT J AU Merino, JG Warach, S AF Merino, Jose G. Warach, Steven TI Imaging of acute stroke SO NATURE REVIEWS NEUROLOGY LA English DT Review ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; MIDDLE CEREBRAL-ARTERY; DIGITAL-SUBTRACTION-ANGIOGRAPHY; NEPHROGENIC SYSTEMIC FIBROSIS; PERFUSION COMPUTED-TOMOGRAPHY; CONTRAST-INDUCED NEPHROPATHY; BRAIN-BARRIER DISRUPTION; TRANSCRANIAL DOPPLER ULTRASONOGRAPHY; PERIPHERAL VASCULAR-DISEASE AB Brain imaging provides an objective basis for the clinical inferences that direct individual patient management in the acute stroke setting. A brain CT or MRI scan is required for all patients with suspected stroke or transient ischemic attack. Thrombolytic therapy is arguably the most important aspect of acute stroke management; however, most decisions in acute stroke do not relate to this treatment. Stroke imaging must, therefore, provide information beyond the presence or absence of intracranial hemorrhage (ICH) and early evidence of a large infarct. Noncontrast CT and gradient-recalled echo MRI show comparable accuracy in the diagnosis of acute ICH. Diffusion-weighted MRI is more sensitive than noncontrast CT for differentiation of acute ischemic stroke from nonstroke conditions. Combined multimodal parenchymal, perfusion and vascular imaging with CT or MRI has the potential to identify patients with an ischemic penumbra that might be appropriate for acute reperfusion therapies. MRI identifies a broader range of acute and chronic cerebrovascular pathologies than does CT and, hence, could aid decisions about acute intervention, in-hospital management, and secondary prevention. Here, we present an overview of the diagnostic information that clinicians might gain from CT and MRI in the setting of acute stroke, along with the advantages and disadvantages of these techniques. C1 [Warach, Steven] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. [Merino, Jose G.] Suburban Hosp Stroke Program, Bethesda, MD 20007 USA. RP Warach, S (reprint author), Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, NIH, Room B1D-733,MSC 1063, Bethesda, MD 20892 USA. EM warachs@ninds.nih.gov OI Merino, Jose/0000-0002-6676-0008 FU Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH FX This work was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH. NR 155 TC 38 Z9 40 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD OCT PY 2010 VL 6 IS 10 BP 560 EP 571 DI 10.1038/nrneurol.2010.129 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 660LB UT WOS:000282643100008 PM 20842186 ER PT J AU Luo, LQ Rodriguez, E Jerbi, K Lachaux, JP Martinerie, J Corbetta, M Shulman, GL Piomelli, D Turrigiano, GG Nelson, SB Joels, M de Kloet, ER Holsboer, F Amodio, DM Frith, CD Block, ML Zecca, L Hong, JS Dantzer, R Kelley, KW Craig, AD AF Luo, Liqun Rodriguez, Eugenio Jerbi, Karim Lachaux, Jean-Philippe Martinerie, Jacques Corbetta, Maurizio Shulman, Gordon L. Piomelli, Daniele Turrigiano, Gina G. Nelson, Sacha B. Joels, Marian de Kloet, E. Ronald Holsboer, Florian Amodio, David M. Frith, Chris D. Block, Michelle L. Zecca, Luigi Hong, Jau-Shyong Dantzer, Robert Kelley, Keith W. Craig, A. D. (Bud) TI Ten years of Nature Reviews Neuroscience: insights from the highly cited SO NATURE REVIEWS NEUROSCIENCE LA English DT Article ID HOMEOSTATIC SYNAPTIC PLASTICITY; GLUCOCORTICOID-RECEPTOR GENE; STIMULUS-DRIVEN ATTENTION; VISUAL-CORTEX; SPATIAL ATTENTION; RHO-GTPASES; CANNABINOID RECEPTOR; HUMAN BRAIN; NEURODEGENERATIVE DISEASE; NEUROLOGICAL DISORDERS AB To celebrate the first 10 years of Nature Reviews Neuroscience, we invited the authors of the most cited article of each year to look back on the state of their field of research at the time of publication and the impact their article has had, and to discuss the questions that might be answered in the next 10 years. This selection of highly cited articles provides interesting snapshots of the progress that has been made in diverse areas of neuroscience. They show the enormous influence of neuroimaging techniques and highlight concepts that have generated substantial interest in the past decade, such as neuroimmunology, social neuroscience and the 'network approach' to brain function. These advancements will pave the way for further exciting discoveries that lie ahead. C1 [Luo, Liqun] Stanford Univ, Dept Biol, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Rodriguez, Eugenio] Pontificia Univ Catolica Chile, Santiago 8940000, Chile. [Rodriguez, Eugenio] Max Planck Inst Brain Res, D-60528 Frankfurt, Germany. [Jerbi, Karim; Lachaux, Jean-Philippe] Univ Lyon 1, INSERM, U821, F-69365 Lyon, France. [Martinerie, Jacques] Univ Paris 06, Hop La Pitie Salpetriere, Ctr Rech Inst Cerveau & Moelle Epiniere, COGIMAGE,CNRS,INSERM,U975, F-75651 Paris, France. [Corbetta, Maurizio; Shulman, Gordon L.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Piomelli, Daniele] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92697 USA. [Piomelli, Daniele] Italian Inst Technol, Unit Drug Discovery & Dev, I-16163 Genoa, Italy. [Turrigiano, Gina G.; Nelson, Sacha B.] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. [Turrigiano, Gina G.; Nelson, Sacha B.] Brandeis Univ, Natl Ctr Behav Genom, Waltham, MA 02454 USA. [Joels, Marian] UMC Utrecht, Div Neurosci, Rudolf Magnus Inst, Dept Neurosci & Pharmacol, NL-3584 CG Utrecht, Netherlands. [de Kloet, E. Ronald] LUMC, Leiden Amsterdam Ctr Drug Res, Dept Med Pharmacol, NL-2300 RA Leiden, Netherlands. [Holsboer, Florian] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Amodio, David M.] New York Univ, Dept Psychol, New York, NY 10003 USA. [Amodio, David M.] New York Univ, Ctr Neural Sci, New York, NY 10003 USA. [Frith, Chris D.] Aarhus Univ, Aarhus Univ Hosp, Ctr Functionally Integrat Neurosci, DK-8000 Aarhus C, Denmark. [Frith, Chris D.] UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Block, Michelle L.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA 23298 USA. [Zecca, Luigi] Italian Natl Res Council, Inst Biomed Technol, I-20090 Milan, Italy. [Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, NIH Res Triangle Pk, Res Triangle Pk, NC 27709 USA. [Dantzer, Robert; Kelley, Keith W.] Univ Illinois, Integrat Immunol & Behav Program, Dept Anim Sci, Coll Agr Consumer & Environm Sci, Urbana, IL 61801 USA. [Dantzer, Robert; Kelley, Keith W.] Univ Illinois, Coll Med, Dept Pathol, Urbana, IL 61801 USA. [Craig, A. D. (Bud)] Barrow Neurol Inst, Atkinson Res Lab, Phoenix, AZ 85013 USA. RP Luo, LQ (reprint author), Stanford Univ, Dept Biol, Howard Hughes Med Inst, Stanford, CA 94305 USA. RI Frith, Chris/A-2171-2009; Frank, David/E-8213-2012; Joels, Marian/P-6415-2016; OI Frith, Chris/0000-0002-8665-0690; Nelson, Sacha/0000-0002-0108-8599; Kelley, Keith W./0000-0002-6837-8793; Dantzer, Robert/0000-0001-9399-6107 FU National Institutes of Health (NIH); Howard Hughes Medical Institute; Comision Nacional de Investigacion Cientifica y Tecnologica; Deutscher Akademischer Austauschdienst; Fondation pour la Recherche Medicale; European Project [HEALTH-F2-2008-200728]; National Institute on Drug Abuse; National Alliance for Research on Schizophrenia and Depression; Royal Academy of Arts and Sciences (KNAW); American National Science Foundation [BCS 0847350]; Danish National Research Foundation; National Institute of Environmental Health Sciences (NIEHS)/NIH [R01ES016951]; Lombardia Region Department of Industry; NIEHS; NIH [R01 AG 029573, R01 MH 079829] FX L. L. thanks support from the National Institutes of Health (NIH) and the Howard Hughes Medical Institute. E. R. was partly supported by the Comision Nacional de Investigacion Cientifica y Tecnologica and the Deutscher Akademischer Austauschdienst. K.J. and J.P.L. were partly supported by the Fondation pour la Recherche Medicale and by the BrainSync FP7 European Project (grant HEALTH-F2-2008-200728). M. C. and G. L. S. thank S. Astafiev for assistance with figure 1. D. P. gratefully acknowledges support from the National Institute on Drug Abuse and the National Alliance for Research on Schizophrenia and Depression. G. G. T. and S.B.N. thank all members of their laboratories, past and present, as well as the many colleagues and collaborators who have contributed to the genesis of their ideas. E.R.d.K. gratefully acknowledges the support of the Royal Academy of Arts and Sciences (KNAW). D. M. A. is supported by grant BCS 0847350 from the American National Science Foundation and C. D. F. is supported by the Danish National Research Foundation. M. L. B. was supported by the National Institute of Environmental Health Sciences (NIEHS)/NIH Outstanding New Environmental Scientist Award (grant R01ES016951). L.Z. was supported by the Lombardia Region Department of Industry, Project Metadistretti. J.-S. H was partly funded by the Intramural Research Program of the NIEHS (part of the NIH). K. W. K. is supported by the NIH (grant R01 AG 029573) and R. D. is supported by the NIH (grant R01 MH 079829). A. D. C. is grateful to the James S. McDonnell Foundation and to the Barrow Neurological Foundation. NR 116 TC 16 Z9 16 U1 1 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD OCT PY 2010 VL 11 IS 10 BP 718 EP + DI 10.1038/nrn2912 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 651LF UT WOS:000281928500005 PM 20852655 ER PT J AU Tu, XY Das, K Han, QW Bauman, JD Clark, AD Hou, XR Frenkel, YV Gaffney, BL Jones, RA Boyer, PL Hughes, SH Sarafianos, SG Arnold, E AF Tu, Xiongying Das, Kalyan Han, Qianwei Bauman, Joseph D. Clark, Arthur D., Jr. Hou, Xiaorong Frenkel, Yulia V. Gaffney, Barbara L. Jones, Roger A. Boyer, Paul L. Hughes, Stephen H. Sarafianos, Stefan G. Arnold, Eddy TI Structural basis of HIV-1 resistance to AZT by excision SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 REVERSE-TRANSCRIPTASE; HIGH-LEVEL RESISTANCE; ATP-MEDIATED EXCISION; IN-VIVO MUTATION; PRIMER-UNBLOCKING; 3'-AZIDO-3'-DEOXYTHYMIDINE AZT; MOLECULAR-MECHANISMS; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE AB Human immunodeficiency virus (HIV-1) develops resistance to 3'-azido-2',3'-deoxythymidine (AZT, zidovudine) by acquiring mutations in reverse transcriptase that enhance the ATP-mediated excision of AZT monophosphate from the 3' end of the primer. The excision reaction occurs at the dNTP-binding site, uses ATP as a pyrophosphate donor, unblocks the primer terminus and allows reverse transcriptase to continue viral DNA synthesis. The excision product is AZT adenosine dinucleoside tetraphosphate ( AZTppppA). We determined five crystal structures: wild-type reverse transcriptase-double-stranded DNA (RT-dsDNA)-AZTppppA; AZT-resistant (AZTr; M41L D67N K70R T215Y K219Q) RT-dsDNA-AZTppppA; AZTr RT-dsDNA terminated with AZT at dNTP-and primer-binding sites; and AZTr apo reverse transcriptase. The AMP part of AZTppppA bound differently to wild-type and AZTr reverse transcriptases, whereas the AZT triphosphate part bound the two enzymes similarly. Thus, the resistance mutations create a high-affinity ATP-binding site. The structure of the site provides an opportunity to design inhibitors of AZT-monophosphate excision. C1 [Tu, Xiongying; Das, Kalyan; Bauman, Joseph D.; Clark, Arthur D., Jr.; Frenkel, Yulia V.; Sarafianos, Stefan G.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Tu, Xiongying; Das, Kalyan; Han, Qianwei; Bauman, Joseph D.; Clark, Arthur D., Jr.; Hou, Xiaorong; Frenkel, Yulia V.; Gaffney, Barbara L.; Jones, Roger A.; Sarafianos, Stefan G.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Biol, Piscataway, NJ 08854 USA. [Boyer, Paul L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu RI Tu, Xiongying/H-7983-2012; OI Sarafianos, Stefan G/0000-0002-5840-154X FU US National Institutes of Health (NIH) [AI 27690, P01 GM 066671]; US National Cancer Institute (NCI); Center for Cancer Research; US National Institute of General Medical Sciences FX We acknowledge personnel at the Cornell High Energy Synchrotron Source and the Advanced Photon Source for support of data collection, the members of our laboratories, including R. Bandwar and S. Martinez, for valuable conversations and assistance, and P. Clark for assistance with protein preparation. We are grateful to the US National Institutes of Health (NIH; grants R37 MERIT Award AI 27690 to E.A. and P01 GM 066671 to E.A. and R.A.J.) for support of reverse transcriptase structural studies. S. H. H. was supported by the Intramural Research Program of NIH, US National Cancer Institute (NCI), Center for Cancer Research and US National Institute of General Medical Sciences. This research was supported, in part, by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 60 TC 59 Z9 60 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD OCT PY 2010 VL 17 IS 10 BP 1202 EP + DI 10.1038/nsmb.1908 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 659JU UT WOS:000282563600009 PM 20852643 ER PT J AU Soderblom, C Stadler, J Jupille, H Blackstone, C Shupliakov, O Hanna, MC AF Soderblom, Cynthia Stadler, Julia Jupille, Henri Blackstone, Craig Shupliakov, Oleg Hanna, Michael C. TI Targeted disruption of the Mast syndrome gene SPG21 in mice impairs hind limb function and alters axon branching in cultured cortical neurons SO NEUROGENETICS LA English DT Article DE Maspardin; ACP33; CD4; Hereditary spastic paraplegia; Rab7 ID HEREDITARY SPASTIC PARAPLEGIA; MUTATIONS; DISEASE; ELONGATION; NEUROPATHY; DEMENTIA; ATLASTIN; FORM AB Mast syndrome (SPG21) is a childhood-onset, autosomal recessive, complicated form of hereditary spastic paraplegia (HSP) characterized by dementia, thin corpus callosum, white matter abnormalities, and cerebellar and extrapyramidal signs in addition to spastic paraparesis. A nucleotide insertion resulting in premature truncation of the SPG21 gene product maspardin underlies this disorder, likely leading to loss of protein function. In this study, we generated SPG21-/- knockout mice by homologous recombination as a possible animal model for SPG21. Though SPG21-/- mice appeared normal at birth, within several months they developed gradually progressive hind limb dysfunction. Cerebral cortical neurons cultured from SPG21-/- mice exhibited significantly more axonal branching than neurons from wild-type animals, while comprehensive neuropathological analysis of SPG21-/- mice did not reveal definitive abnormalities. Since alterations in axon branching have been seen in neurons derived from animal models of other forms of HSP as well as motor neuron diseases, this may represent a common cellular pathogenic theme. C1 [Hanna, Michael C.] Texas A&M Univ, Dept Biol & Environm Sci, Commerce, TX 75428 USA. [Soderblom, Cynthia] Karolinska Inst, Natl Inst Hlth, Grad Partnerships Program, S-17177 Stockholm, Sweden. [Soderblom, Cynthia; Shupliakov, Oleg] Karolinska Inst, DBRM, Dept Neurosci, S-17177 Stockholm, Sweden. [Soderblom, Cynthia; Stadler, Julia; Jupille, Henri; Blackstone, Craig; Hanna, Michael C.] NINDS, Cellular Neurol Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Hanna, MC (reprint author), Texas A&M Univ, Dept Biol & Environm Sci, Commerce, TX 75428 USA. EM michael_hanna@tamu-commerce.edu OI Shupliakov, Oleg/0000-0001-5352-6848 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health; National Institute of General Medical Sciences; Swedish Research Council [13473, 20587] FX The authors wish to thank James Nagle and Debbie Kauffman (NINDS DNA Sequencing Facility) for DNA sequencing and Dr. Peng-Peng Zhu for generation of the phylogenetic tree. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health [to C. S., J.S., H.J., C. B, and M. C. H.], the National Institute of General Medical Sciences Pharmacology Research Associate (PRAT) Program and the Swedish Research Council [grant numbers 13473, 20587 to O.S.]. NR 30 TC 11 Z9 13 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD OCT PY 2010 VL 11 IS 4 BP 369 EP 378 DI 10.1007/s10048-010-0252-7 PG 10 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 654QN UT WOS:000282183200001 PM 20661613 ER PT J AU Thambisetty, M Wan, J Carass, A An, Y Prince, JL Resnick, SM AF Thambisetty, Madhav Wan, Jing Carass, Aaron An, Yang Prince, Jerry L. Resnick, Susan M. TI Longitudinal changes in cortical thickness associated with normal aging SO NEUROIMAGE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; IMPLICIT SURFACE EVOLUTION; BRAIN VOLUME CHANGES; ALZHEIMERS-DISEASE; ENTORHINAL CORTEX; CEREBRAL-CORTEX; OLDER-ADULTS; IN-VIVO; PATTERN-CLASSIFICATION; SEX-DIFFERENCES AB Imaging studies of anatomic changes in regional gray matter volumes and cortical thickness have documented age effects in many brain regions, but the majority of such studies have been cross-sectional investigations of individuals studied at a single point in time. In this study, using serial imaging assessments of participants in the Baltimore Longitudinal Study of Aging (BLSA), we investigate longitudinal changes in cortical thickness during aging in a cohort of 66 older adults (mean age 68.78; sd. 6.6; range 60-84 at baseline) without dementia. We used the Cortical Reconstruction Using Implicit Surface Evolution CRUISE suite of algorithms to automatically generate a reconstruction of the cortical surface and identified twenty gyral based regions of interest per hemisphere. Using mixed effects regression, we investigated longitudinal changes in these regions over a mean follow-up interval of 8 years. The main finding in this study is that age-related decline in cortical thickness is widespread, but shows an anterior posterior gradient with frontal and parietal regions, in general, exhibiting greater rates of decline than temporal and occipital. There were fewer regions in the right hemisphere showing statistically significant age-associated longitudinal decreases in mean cortical thickness. Males showed greater rates of decline in the middle frontal, inferior parietal, parahippocampal, postcentral, and superior temporal gyri in the left hemisphere, right precuneus and bilaterally in the superior parietal and cingulate regions. Significant nonlinear changes over time were observed in the postcentral, precentral, and orbitofrontal gyri on the left and inferior parietal, cingulate, and orbitofrontal gyri on the right. Published by Elsevier Inc. C1 [Thambisetty, Madhav] NIA, Biomed Res Ctr, Lab Personal & Cognit, Baltimore, MD 21224 USA. [Wan, Jing; Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. RP Thambisetty, M (reprint author), NIA, Biomed Res Ctr, Lab Personal & Cognit, 04B311,251 Bayview Blvd, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov RI Prince, Jerry/A-3281-2010; OI Prince, Jerry/0000-0002-6553-0876; Carass, Aaron/0000-0003-4939-5085 FU NIH, National Institute on Aging; National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Health (NIH) [R01-NS37747, RO1-AG016324, R01-NS054255, R01 NS052585-01]; NCRR [P41-RR14075, R01 RR16594-01A1] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Partial support was provided by the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institute of Health (NIH), through grants R01-NS37747, RO1-AG016324 and R01-NS054255. The authors have no known conflicts of interest. The atlas data was provided by Dr. Bruce Fischl, Martinos Center for Biomedical Imaging, and supported by the NCRR through grants P41-RR14075 and R01 RR16594-01A1 and by the NIH/NINDS through grant R01 NS052585-01. We are grateful to the BLSA participants and neuroimaging staff NR 66 TC 88 Z9 88 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2010 VL 52 IS 4 BP 1215 EP 1223 DI 10.1016/j.neuroimage.2010.04.258 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 635YY UT WOS:000280695200009 PM 20441796 ER PT J AU Shin, WY Geng, XJ Gu, H Zhan, W Zou, QH Yang, YH AF Shin, Wanyong Geng, Xiujuan Gu, Hong Zhan, Wang Zou, Qihong Yang, Yihong TI Automated brain tissue segmentation based on fractional signal mapping from inversion recovery Look-Locker acquisition SO NEUROIMAGE LA English DT Article DE Magnetic resonance imaging; Automated segmentation; Brain tissue; Partial volume effect; Fractional volume; Fast T1 mapping ID MAGNETIC-RESONANCE IMAGES; WHITE-MATTER; MR-IMAGES; CEREBROSPINAL-FLUID; FUZZY CLASSIFIERS; RELAXATION-TIMES; GRAY-MATTER; VOLUME; CLASSIFICATION; QUANTIFICATION AB Most current automated segmentation methods are performed on T(1)- or T(2)-weighted MR images, relying on relative image intensity that is dependent on other MR parameters and sensitive to B(1) magnetic field inhomogeneity. Here, we propose an image segmentation method based on quantitative longitudinal magnetization relaxation time (T(1)) of brain tissues. Considering the partial volume effect, fractional volume maps of brain tissues (white matter, gray matter, and cerebrospinal fluid) were obtained by fitting the observed signal in an inversion recovery procedure to a linear combination of three exponential functions, which represents the relaxations of each of the tissue types. A Look-Locker acquisition was employed to accelerate the acquisition process. The feasibility and efficacy of this proposed method were evaluated using simulations and experiments. The potential applications of this method in the study of neurological disease as well as normal brain development and aging are discussed. Published by Elsevier Inc. C1 [Shin, Wanyong; Geng, Xiujuan; Gu, Hong; Zou, Qihong; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Zhan, Wang] Univ Calif San Francisco, Dept Radiol, VA Med Ctr, San Francisco, CA 94121 USA. RP Shin, WY (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM shinwa@nida.nih.gov; yihongyang@intra.nida.nih.gov RI Geng, Xiujuan/I-3852-2012 FU National Institute on Drug Abuse (NIDA), National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health. The authors would like to thank Dr. Thomas Ross and Dr. Annabelle Belcher of the NIDA for his helpful discussions and suggestions, and Dr. Leon Axel for suggesting the validation of FRASIER using the down-sampling approach. NR 35 TC 7 Z9 7 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2010 VL 52 IS 4 BP 1347 EP 1354 DI 10.1016/j.neuroimage.2010.05.001 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 635YY UT WOS:000280695200023 PM 20452444 ER PT J AU Green, S Ralph, MAL Moll, J Stamatakis, EA Grafman, J Zahn, R AF Green, Sophie Ralph, Matthew A. Lambon Moll, Jorge Stamatakis, Emmanuel A. Grafman, Jordan Zahn, Roland TI Selective functional integration between anterior temporal and distinct fronto-mesolimbic regions during guilt and indignation SO NEUROIMAGE LA English DT Article DE Moral emotions; fMRI; Psychophysiological interaction; Anterior temporal lobe; Subgenual cingulate cortex; Septal region; Orbitofrontal cortex; Semantics; Guilt; Indignation; Anger; Major depression ID FRONTOTEMPORAL LOBAR DEGENERATION; SEMANTIC DEMENTIA; HUMAN BRAIN; CINGULATE CORTEX; NEURAL BASIS; ORBITOFRONTAL CORTEX; MORAL COGNITION; FMRI; MEMORY; MRI AB It has been hypothesized that the experience of different moral sentiments such as guilt and indignation is underpinned by activation in temporal and fronto-mesolimbic regions and that functional integration between these regions is necessary for the differentiated experience of these moral sentiments. A recent fMRI study revealed that the right superior anterior temporal lobe (ATL) was activated irrespective of the context of moral feelings (guilt or indignation). This region has been associated with context-independent conceptual social knowledge which allows us to make fine-grained differentiations between qualities of social behaviours (e.g. "critical" and "faultfinding"). This knowledge is required to make emotional evaluations of social behaviour. In contrast to the context-independent activation of the ATL, there were context-dependent activations within different fronto-mesolimbic regions for guilt and indignation. However, it is unknown whether functional integration occurs between these regions and whether regional patterns of integration are distinctive for the experience of different moral sentiments. Here, we used fMRI and psychophysiological interaction analysis, an established measure of functional integration to investigate this issue. We found selective functional integration between the right superior ATL and a subgenual cingulate region during the experience of guilt and between the right superior ATL and the lateral orbitofrontal cortex for indignation. Our data provide the first evidence for functional integration of conceptual social knowledge representations in the right superior ATL with representations of different feeling contexts in fronto-mesolimbic regions. We speculate that this functional architecture allows for the conceptually differentiated experience of moral sentiments in healthy individuals. (C) 2010 Elsevier Inc. All rights reserved. C1 [Green, Sophie; Ralph, Matthew A. Lambon; Zahn, Roland] Univ Manchester, Sch Psychol Sci, Neurosci & Aphasia Res Unit, Manchester M13 9PL, Lancs, England. [Moll, Jorge] DOr Inst Res & Educ IDOR, Cognit & Behav Neurosci Unit, BR-22280080 Rio De Janeiro, Brazil. [Grafman, Jordan; Zahn, Roland] NINDS, NIH, Cognit Neurosci Sect, Bethesda, MD 20892 USA. [Stamatakis, Emmanuel A.] Univ Cambridge, Sch Clin Med, Div Anaesthesia, Cambridge, England. RP Zahn, R (reprint author), Univ Manchester, Sch Psychol Sci, Neurosci & Aphasia Res Unit, Manchester M13 9PL, Lancs, England. EM roland.zahn@manchester.ac.uk RI Zahn, Roland/C-4665-2008; Moll, Jorge/B-2654-2013; Neurociencia, Inct/I-1011-2013; Lambon Ralph, Matthew/A-1695-2009; OI Zahn, Roland/0000-0002-8447-1453; Lambon Ralph, Matthew/0000-0001-5907-2488; Moll, Jorge/0000-0002-4297-591X; Grafman, Jordan H./0000-0001-8645-4457 FU NINDS (USA); Federal Ministry of Education and Research [BMBF-LPD 9901/8-122]; MRC; Faculty of Medical and Human Sciences, The University of Manchester, UK; LABS-D'Or Hospital Network, Rio de Janeiro, Brazil; Queens' College, Cambridge, UK FX This study was supported by NINDS (USA) intramural funding to J.G. and a German National Academy of Sciences Leopoldina Fellowship funded by the Federal Ministry of Education and Research (BMBF-LPD 9901/8-122) to R.Z. S.G. was funded by an MRC PhD studentship. R.Z. was supported by a Stepping Stones Fellowship from the Faculty of Medical and Human Sciences, The University of Manchester, UK. J.M. was supported by the LABS-D'Or Hospital Network, Rio de Janeiro, Brazil. E.A.S. was funded by a Stephen Erskine Fellowship, Queens' College, Cambridge, UK. NR 71 TC 23 Z9 23 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2010 VL 52 IS 4 BP 1720 EP 1726 DI 10.1016/j.neuroimage.2010.05.038 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 635YY UT WOS:000280695200060 PM 20493953 ER PT J AU Cheng, J Zhou, XB Miller, EL Alvarez, VA Sabatini, BL Wong, STC AF Cheng, Jie Zhou, Xiaobo Miller, Eric L. Alvarez, Veronica A. Sabatini, Bernardo L. Wong, Stephen T. C. TI Oriented Markov Random Field Based Dendritic Spine Segmentation for Fluorescence Microscopy Images SO NEUROINFORMATICS LA English DT Article DE Dendritic spine; Segmentation; Automatic detection; Microscopy image ID FUNCTIONAL MRI DATA; DISORDERS; ALGORITHM AB Dendritic spines have been shown to be closely related to various functional properties of the neuron. Usually dendritic spines are manually labeled to analyze their morphological changes, which is very time-consuming and susceptible to operator bias, even with the assistance of computers. To deal with these issues, several methods have been recently proposed to automatically detect and measure the dendritic spines with little human interaction. However, problems such as degraded detection performance for images with larger pixel size (e.g. 0.125 mu m/pixel instead of 0.08 mu m/pixel) still exist in these methods. Moreover, the shapes of detected spines are also distorted. For example, the "necks" of some spines are missed. Here we present an oriented Markov random field (OMRF) based algorithm which improves spine detection as well as their geometric characterization. We begin with the identification of a region of interest (ROI) containing all the dendrites and spines to be analyzed. For this purpose, we introduce an adaptive procedure for identifying the image background. Next, the OMRF model is discussed within a statistical framework and the segmentation is solved as a maximum a posteriori estimation (MAP) problem, whose optimal solution is found by a knowledge-guided iterative conditional mode (KICM) algorithm. Compared with the existing algorithms, the proposed algorithm not only provides a more accurate representation of the spine shape, but also improves the detection performance by more than 50% with regard to reducing both the misses and false detection. C1 [Cheng, Jie; Zhou, Xiaobo; Wong, Stephen T. C.] Methodist Hosp, Res Inst, Ctr Bioengn & Informat, Houston, TX 77030 USA. [Cheng, Jie; Zhou, Xiaobo; Wong, Stephen T. C.] Methodist Hosp, Dept Radiol, Weill Cornell Med Coll, Houston, TX 77030 USA. [Alvarez, Veronica A.] NIAAA, SNS, LIN, NIH, Bethesda, MD 20892 USA. [Sabatini, Bernardo L.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Miller, Eric L.] Tufts Univ, Dept Elect & Comp Engn, Medford, MA 02155 USA. RP Wong, STC (reprint author), Methodist Hosp, Res Inst, Ctr Bioengn & Informat, Houston, TX 77030 USA. EM stwong@tmhs.org RI Miller, Eric/B-2546-2008; Cheng, Jie/F-6855-2013; Alvarez, Veronica /E-9745-2015 OI Miller, Eric/0000-0002-3156-6002; Cheng, Jie/0000-0003-4471-9087; Alvarez, Veronica /0000-0003-2611-8675 FU NIH [R01 LM008696] FX The testing images and manual results are provided by Bernardo L. Sabatini's lab. Thanks Dr. Fuhai Li for help testing the codes. This research is funded by a NIH R01 LM008696 Grant to STCW. Finally, the authors want to thank the reviewers for their many helpful comments. NR 31 TC 1 Z9 1 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 EI 1559-0089 J9 NEUROINFORMATICS JI Neuroinformatics PD OCT PY 2010 VL 8 IS 3 BP 157 EP 170 DI 10.1007/s12021-010-9073-y PG 14 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA 655AH UT WOS:000282212500003 PM 20585900 ER PT J AU Bonnemann, CG AF Bonnemann, C. G. TI Molecular therapeutic approaches to the extracellular matrix-related congenital muscular dystrophies SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 15th International Congress of the World-Muscle-Society CY OCT 12-16, 2010 CL Kumamoto, JAPAN SP World Muscle Soc C1 [Bonnemann, C. G.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2010 VL 20 IS 9-10 BP 597 EP 597 DI 10.1016/j.nmd.2010.07.009 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 659JO UT WOS:000282563000005 ER PT J AU Yardeni, T Manoli, I Ciccone, C Hoogstraten-Miller, S Darvish, D Anikster, Y Maples, P Jay, CM Gahl, WA Nemunaitis, J Huizing, M AF Yardeni, T. Manoli, I. Ciccone, C. Hoogstraten-Miller, S. Darvish, D. Anikster, Y. Maples, P. Jay, C. M. Gahl, W. A. Nemunaitis, J. Huizing, M. TI A non-viral, GNE-lipoplex treatment to correct sialylation defects in hereditary inclusion body myopathy (HIBM) SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 15th International Congress of the World-Muscle-Society CY OCT 12-16, 2010 CL Kumamoto, JAPAN SP World Muscle Soc C1 [Hoogstraten-Miller, S.] NHGRI, NIH, OLAM, Bethesda, MD 20892 USA. [Darvish, D.] HIBM Res Grp, Encino, NM USA. [Anikster, Y.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Maples, P.; Jay, C. M.; Nemunaitis, J.] Gradalis Inc, Dallas, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2010 VL 20 IS 9-10 BP 620 EP 621 DI 10.1016/j.nmd.2010.07.081 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 659JO UT WOS:000282563000077 ER PT J AU Olive, M Odgerel, Z Martinez, A Poza, JJ Garcia-Bragado, F Jerico, I Maravi, E Ramos-Arroyo, M Gonzalez-Mera, L Goldfarb, LG AF Olive, M. Odgerel, Z. Martinez, A. Poza, J. J. Garcia-Bragado, F. Jerico, I. Maravi, E. Ramos-Arroyo, M. Gonzalez-Mera, L. Goldfarb, L. G. TI Intranuclear rods in three Spanish families with ZASPopathy SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 15th International Congress of the World-Muscle-Society CY OCT 12-16, 2010 CL Kumamoto, JAPAN SP World Muscle Soc C1 [Olive, M.; Martinez, A.; Gonzalez-Mera, L.] IDIBELL Bellvitge Hosp, Inst Neuropathol, Barcelona, Spain. [Olive, M.] Hosp Llobregat, Neuromuscular Unit, Barcelona, Spain. [Odgerel, Z.; Goldfarb, L. G.] NINDS, NIH, Bethesda, MD 20892 USA. [Martinez, A.; Gonzalez-Mera, L.] IDIBELL Hosp Bellvitge, Neuromuscular Unit, Barcelona, Spain. [Poza, J. J.] Hosp Donostia, San Sebastian, Spain. [Garcia-Bragado, F.; Jerico, I.; Maravi, E.; Ramos-Arroyo, M.] Hosp Virgen Camino, Pamplona, Spain. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2010 VL 20 IS 9-10 BP 623 EP 623 DI 10.1016/j.nmd.2010.07.089 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 659JO UT WOS:000282563000085 ER PT J AU Sambuughin, N Kyle, SY Olive, M Duff, RM Bayarsaikhan, M Sivadorai, P Nowak, KJ Mastaglia, FL North, K Ilkovski, B van Engelen, B Lamont, P Davis, MR Laing, NG Goldfarb, LG AF Sambuughin, N. Kyle, S. Y. Olive, M. Duff, R. M. Bayarsaikhan, M. Sivadorai, P. Nowak, K. J. Mastaglia, F. L. North, K. Ilkovski, B. van Engelen, B. Lamont, P. Davis, M. R. Laing, N. G. Goldfarb, L. G. TI A new member of the BTB/Kelch family of proteins is mutated in nemaline myopathy type 6 (NEM6) SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 15th International Congress of the World-Muscle-Society CY OCT 12-16, 2010 CL Kumamoto, JAPAN SP World Muscle Soc C1 [Sambuughin, N.; Bayarsaikhan, M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Kyle, S. Y.; Duff, R. M.; Nowak, K. J.; Mastaglia, F. L.; Laing, N. G.] Univ Western Australia, Perth, WA 6009, Australia. [Olive, M.] Inst Neuropatol, Barcelona, Spain. [Sivadorai, P.; Lamont, P.; Davis, M. R.] Royal Perth Hosp, Perth, WA, Australia. [North, K.; Ilkovski, B.] Childrens Hosp Westmead, Sydney, NSW, Australia. [van Engelen, B.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Nijmegen, Netherlands. [Goldfarb, L. G.] NIH, Bethesda, MD 20892 USA. RI van Engelen, Baziel/D-3475-2009; Engelen, B.G.M./H-8027-2014 NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2010 VL 20 IS 9-10 BP 638 EP 638 DI 10.1016/j.nmd.2010.07.134 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 659JO UT WOS:000282563000130 ER PT J AU Guglieri, M Herr, B McColl, E Eagle, M Pandya, S McDermott, M Tawil, R Martens, W Annis, C Hirtz, D Kirschner, J Korinthenberg, R Hart, K Brown, M Rafferty, K Griggs, R Bushby, K AF Guglieri, M. Herr, B. McColl, E. Eagle, M. Pandya, S. McDermott, M. Tawil, R. Martens, W. Annis, C. Hirtz, D. Kirschner, J. Korinthenberg, R. Hart, K. Brown, M. Rafferty, K. Griggs, R. Bushby, K. TI FOR-DMD: double-blind randomized trial to optimize steroid regime in Duchenne Muscular Dystrophy (DMD) SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 15th International Congress of the World-Muscle-Society CY OCT 12-16, 2010 CL Kumamoto, JAPAN SP World Muscle Soc C1 [Guglieri, M.] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Herr, B.; Pandya, S.; McDermott, M.; Tawil, R.; Martens, W.; Annis, C.; Hart, K.; Brown, M.; Griggs, R.] Univ Rochester, Sch Med & Dent, Rochester, NY 14627 USA. [Hirtz, D.] Natl Inst Neurol Disorders & Storke, NIH, Bethesda, MD 20892 USA. [Kirschner, J.; Korinthenberg, R.] Univ Freiburg, Freiburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2010 VL 20 IS 9-10 BP 657 EP 657 DI 10.1016/j.nmd.2010.07.194 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 659JO UT WOS:000282563000190 ER PT J AU Keil, A Bradley, MM Ihssen, N Heim, S Vila, J Guerra, P Lang, PJ AF Keil, Andreas Bradley, Margaret M. Ihssen, Niklas Heim, Sabine Vila, Jaime Guerra, Pedro Lang, Peter J. TI Defensive engagement and perceptual enhancement SO NEUROPSYCHOLOGIA LA English DT Article DE Human; Dense array EEG; Cardiac defense; Emotion; Steady state potential ID MOTIVATED ATTENTION; CARDIAC DEFENSE; VISUAL-CORTEX; HEART-RATE; EMOTION; BRAIN; FEAR AB We tested whether visual cortical sensitivity to external cues in the context of an acute defensive reaction is heightened or attenuated A strong cardiac defense (fear) response was elicited by presenting an abrupt loud acoustic stimulus following a 10-min period of quiescence Electrocortical responses to aversive and neutral pictures following defensive stimulus onset were measured using dense-array EEG Pictures were flickered at 12 5 Hz to evoke steady-state visual evoked potentials (ssVEP) which can be reliably extracted on the basis of single trials Visual cortical activity indexing perceptual processing was substantially heightened when pictures were shown in temporal proximity to (i e 5s after) the defense stimulus Replicating previous studies aversive visual stimuli were associated with enhanced ssVEP amplitude compared to neutral stimuli Acute defense facilitates visual perception of external cues and preserves accurate discrimination between threatening and safe cues (C) 2010 Elsevier Ltd All rights reserved C1 [Keil, Andreas] Univ Florida, Dept Psychol, NIMH Ctr Study Emot & Attent, Gainesville, FL 32608 USA. [Ihssen, Niklas] Bangor Univ, Bangor, Gwynedd, Wales. [Heim, Sabine] Deutsch Inst Int Padag Forsch, Frankfurt, Germany. [Vila, Jaime; Guerra, Pedro] Univ Granada, Granada, Spain. RP Keil, A (reprint author), Univ Florida, Dept Psychol, NIMH Ctr Study Emot & Attent, POB 112766, Gainesville, FL 32608 USA. RI Keil, Andreas/F-9427-2011; Vila, Jaime/F-9719-2010; Ihssen, Niklas/B-6324-2012; Frank, David/E-8213-2012 OI Keil, Andreas/0000-0002-4064-1924; Vila, Jaime/0000-0002-1767-8606; Ihssen, Niklas/0000-0001-8386-1524; FU NIMH [P50-MH072850, R21 MH082702, R01 MH084392]; Deutsche Forschungsgememschaft FX This research was supported in part by NIMH grants P50-MH072850 and R21 MH082702 to P J Lang by NIMH grant R01 MH084392 to A Keil and by grants from the Deutsche Forschungsgememschaft The authors would like to thank Felix Bartsch for assistance in data reduction NR 28 TC 10 Z9 11 U1 2 U2 9 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 OCT PY 2010 VL 48 IS 12 BP 3580 EP 3584 DI 10.1016/j.neuropsychologia.2010.08.007 PG 5 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 677UM UT WOS:000284017300023 PM 20713075 ER PT J AU Tsai, LK Leng, Y Wang, ZF Leeds, P Chuang, DM AF Tsai, Li-Kai Leng, Yan Wang, Zhifei Leeds, Peter Chuang, De-Maw TI The Mood Stabilizers Valproic Acid and Lithium Enhance Mesenchymal Stem Cell Migration via Distinct Mechanisms SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE CXCR4; lithium; mesenchymal stem cells; migration; MMP-9; valproic acid ID HISTONE DEACETYLASE INHIBITORS; AMYOTROPHIC-LATERAL-SCLEROSIS; GLYCOGEN-SYNTHASE KINASE-3; MARROW STROMAL CELLS; HUMAN BONE-MARROW; NF-KAPPA-B; MOUSE MODEL; NEURODEGENERATIVE DISORDERS; MYOCARDIAL-INFARCTION; ISCHEMIC BRAIN AB Mesenchymal stem cells (MSCs) show high potential for the therapy of several human diseases; however, the effectiveness of MSC transplantation has been hampered by the relatively poor migratory capacity of these cells toward disease target sites. This study investigated whether treatment of MSCs with two mood stabilizers-valproic acid (VPA) and lithium-would enhance cell migration and, if so, to explore the mechanisms underlying their effects. Short-term (3h) exposure of MSCs to a relatively high concentration (2.5 mM) of VPA markedly increased the transcript and protein levels of CXC chemokine receptor 4 (CXCR4). VPA-induced CXCR4 expression required inhibition of histone deacetylases (HDACs), including the HDACI isoform, and involved histone hyperacetylation at the promoter region of the CXCR4 gene. Notably, VPA treatment enhanced stromal cell-derived factor-1 alpha (SDF-1 alpha)-mediated MSC migration, which was completely blocked by AMD3100, a CXCR4 antagonist. Treatment of MSCs with lithium (2.5mM for 1 day) selectively elevated the transcript and protein levels of matrix metalloproteinase-9 (MMP-9) and its enzymatic activity; these effects were mimicked by inhibition or gene silencing of glycogen synthase kinase-3 beta (GSK-3 beta). Lithium treatment also potentiated SDF-1 alpha-dependent MSC migration across the extracellular matrix, which was suppressed by two MMP-9 inhibitors, doxycycline and GM6001. Combining VPA and lithium treatment further increased MSC migration. Overall, VPA and lithium stimulated MSC migration through distinct targets and mediators: HDAC-CXCR4 and GSK-3 beta-MMP-9, respectively. Neuropsychopharmacology (2010) 35, 2225-2237; doi:10.1038/npp.2010.97; published online 7 July 2010 C1 [Tsai, Li-Kai; Leng, Yan; Wang, Zhifei; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Tsai, Li-Kai] Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan. [Tsai, Li-Kai] Natl Taiwan Univ Hosp, Stroke Ctr, Taipei, Taiwan. [Tsai, Li-Kai] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr,MSC1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov RI Wang, Zhifei/I-2787-2013; OI Tsai, Li-Kai/0000-0001-8420-6951 FU National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services (IRP-NIMH-NIH-DHHS); National Taiwan University Hospital; HSU FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services (IRP-NIMH-NIH-DHHS), by National Taiwan University Hospital, and by the HSU family gift fund. We thank Dr Chen-Hung Ting of Academia Sinica, Taiwan, for primer design in the ChIP assay, Mr Dave Luckenbaugh of the National Institute of Mental Health for assistance in statistical analysis, and Ms Ioline Henter and Dr Joshua Hunsberger of the National Institute of Mental Health for assistance in the preparation of the paper. NR 52 TC 34 Z9 42 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2010 VL 35 IS 11 BP 2225 EP 2237 DI 10.1038/npp.2010.97 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 650BB UT WOS:000281821200008 PM 20613717 ER PT J AU Senegas, J Liu, W Dahnke, H Song, H Jordan, EK Frank, JA AF Senegas, Julien Liu, Wei Dahnke, Hannes Song, Hotaek Jordan, E. Kay Frank, Joseph A. TI Fast T-2 Relaxometry with an Accelerated Multi-echo Spin-echo Sequence SO NMR IN BIOMEDICINE LA English DT Article DE T-2 relaxometry; undersampling; k-t BLAST; k-t GRAPPA; SPIO labeled cells ID IN-VIVO; ARTICULAR-CARTILAGE; R2 RELAXOMETRY; DYNAMIC MRI; T2; RELAXATION; GRAPPA; QUANTIFICATION; RECONSTRUCTION; FRACTION AB A new method has been developed to reduce the number of phase-encoding steps in a multi-echo spin-echo imaging sequence allowing fast 12 mapping without loss of spatial resolution. In the proposed approach, the k-space data at each echo time were undersampled and a reconstruction algorithm that exploited the temporal correlation of the MR signal in k-space was used to reconstruct alias-free images. A specific application of this algorithm with multiple-receiver acquisition, offering an alternative to existing parallel imaging methods, has also been introduced. The fast T-2 mapping method has been validated in human brain T-2 measurements in a group of nine volunteers with acceleration factors up to 3.4. The results demonstrated that the proposed method exhibited excellent linear correlation with the regular T-2 mapping with full sampling and achieved better image reconstruction and T-2 mapping with respect to SNR and reconstruction artifacts than the selected reference acceleration techniques. The new method has also been applied for quantitative tracking of injected magnetically labeled breast cancer cells in the rat brain with acceleration factors of 1.8 and 3.0. The proposed technique can provide an effective approach for accelerated T-2 quantification, especially for experiments with single-channel coil when parallel imaging is not applicable. Copyright (c) 2010 John Wiley & Sons, Ltd. C1 [Liu, Wei] Philips Res N Amer, Briarcliff Manor, NY 10510 USA. [Senegas, Julien; Dahnke, Hannes] Philips Res Europe, Hamburg, Germany. [Liu, Wei; Song, Hotaek; Jordan, E. Kay; Frank, Joseph A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Song, Hotaek] Yonsei Univ, Coll Med, Dept Radiol, Seoul 120749, South Korea. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Liu, W (reprint author), Philips Res N Amer, 345 Scarborough Rd, Briarcliff Manor, NY 10510 USA. EM wei.liu_1@philips.com FU Clinical Center at the National Institutes of Health; Philips Research North America FX The authors would like to acknowledge Dr Diane Palmieri for the generous donation and creation of the MDA-MB-231BRL-Luc breast cancer cell line and Dr Stefanie Remmele for valuable discussion. This work was sponsored in part by the Intramural Research Program at the Clinical Center at the National Institutes of Health and a cooperative research and development agreement with Philips Research North America. NR 33 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD OCT PY 2010 VL 23 IS 8 BP 958 EP 967 DI 10.1002/nbm.1521 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 666GP UT WOS:000283102800007 PM 20878973 ER PT J AU Li, SZ Zhang, Y Wang, SM Araneta, MF Johnson, CS Xiang, Y Innis, RB Shen, J AF Li, Shizhe Zhang, Yan Wang, Shumin Araneta, Maria Ferraris Johnson, Christopher S. Xiang, Yun Innis, Robert B. Shen, Jun TI C-13 MRS of occipital and frontal lobes at 3 T using a volume coil for stochastic proton decoupling SO NMR IN BIOMEDICINE LA English DT Article DE MRS; carbon-13; human brain; stochastic decoupling ID MAGNETIC-RESONANCE-SPECTROSCOPY; TRICARBOXYLIC-ACID CYCLE; HUMAN BRAIN; IN-VIVO; HUMAN HEAD; 4 TESLA; DIELECTRIC-PROPERTIES; GLUTAMATE METABOLISM; BIOLOGICAL TISSUES; DECONVOLUTION AB Previously, we devised a novel strategy for in vivo C-13 MRS using (2-C-13)glucose infusion and low-power proton decoupling, and proposed that this strategy could be used to acquire C-13 MR spectra from the frontal lobe of the human brain. Here, we demonstrate, for the first time, in vivo C-13 MRS of human frontal lobe acquired at 3 T. Because the primary metabolites of [2-C-13]glucose can be decoupled using very-low-radiofrequency power, we used a volume coil for proton decoupling in this study. The homogeneous B-1 field of the volume coil was found to significantly enhance the decoupling efficiency of the stochastic decoupling sequence. Detailed specific absorption rates inside the human head were analyzed using the finite difference time domain method to ensure experimental safety. In vivo C-13 spectra from the occipital and frontal lobes of the human brain were obtained. At a decoupling power of 30W (time-averaged power, 2.45W), the spectra from the occipital lobe showed well-resolved spectral resolution and excellent signal-to-noise ratio. Although frontal lobe C-13 spectra were affected by local B-0 field inhomogeneity, we demonstrated that the spectral quality could be improved using post-acquisition data processing. In particular, we showed that the frontal lobe glutamine C5 at 178.5 ppm and aspartate C4 at 178.3 ppm could be spectrally resolved with effective proton decoupling and B-0 field correction. Because of its large spatial coverage, volume coil decoupling provides the potential to acquire C-13 MRS from more than one brain region simultaneously. Copyright (c) 2010 John Wiley & Sons, Ltd. C1 [Araneta, Maria Ferraris; Johnson, Christopher S.; Xiang, Yun; Innis, Robert B.; Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Li, Shizhe; Zhang, Yan; Shen, Jun] NIMH, Magnet Resonance Spect Core Fac, NIH, Bethesda, MD 20892 USA. [Wang, Shumin] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health (NIMH-NIH) FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (NIMH-NIH). The authors have no conflict of interest to disclose, financial or otherwise. NR 42 TC 11 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD OCT PY 2010 VL 23 IS 8 BP 977 EP 985 DI 10.1002/nbm.1524 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 666GP UT WOS:000283102800009 PM 20878974 ER PT J AU Schneider, TD AF Schneider, Thomas D. TI 70% efficiency of bistate molecular machines explained by information theory, high dimensional geometry and evolutionary convergence SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ECORI RESTRICTION ENDONUCLEASE; REPLICATION INITIATOR REPA; DNA-BINDING SITES; SEQUENCE LOGOS; CHANNEL CAPACITY; QUANTUM YIELD; PROTEIN; RECOGNITION; P1; BASE AB The relationship between information and energy is key to understanding biological systems. We can display the information in DNA sequences specifically bound by proteins by using sequence logos, and we can measure the corresponding binding energy. These can be compared by noting that one of the forms of the second law of thermodynamics defines the minimum energy dissipation required to gain one bit of information. Under the isothermal conditions that molecular machines function this is epsilon(min) = k(B)T in 2 joules per bit (k(B) is Boltzmann's constant and T is the absolute temperature). Then an efficiency of binding can be computed by dividing the information in a logo by the free energy of binding after it has been converted to bits. The isothermal efficiencies of not only genetic control systems, but also visual pigments are near 70%. From information and coding theory, the theoretical efficiency limit for bistate molecular machines is ln 2 = 0.6931. Evolutionary convergence to maximum efficiency is limited by the constraint that molecular states must be distinct from each other. The result indicates that natural molecular machines operate close to their information processing maximum (the channel capacity), and implies that nanotechnology can attain this goal. C1 NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. RP Schneider, TD (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Bldg 469,Room 215,POB B, Frederick, MD 21702 USA. EM toms@alum.mit.edu OI Schneider, Thomas/0000-0002-9841-1531 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research. Funding for open acess charge: National Cancer Institute. NR 70 TC 13 Z9 13 U1 1 U2 8 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 OCT PY 2010 VL 38 IS 18 BP 5995 EP 6006 DI 10.1093/nar/gkq389 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 666LL UT WOS:000283116600011 PM 20562221 ER PT J AU Aniba, MR Poch, O Marchler-Bauer, A Thompson, JD AF Aniba, Mohamed Radhouene Poch, Olivier Marchler-Bauer, Aron Thompson, Julie Dawn TI AlexSys: a knowledge-based expert system for multiple sequence alignment construction and analysis SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DATABASE SEARCHES; PROTEIN SEQUENCES; T-COFFEE; ACCURACY; BIOINFORMATICS; DISCOVERY; BENCHMARK AB Multiple sequence alignment (MSA) is a cornerstone of modern molecular biology and represents a unique means of investigating the patterns of conservation and diversity in complex biological systems. Many different algorithms have been developed to construct MSAs, but previous studies have shown that no single aligner consistently outperforms the rest. This has led to the development of a number of 'meta-methods' that systematically run several aligners and merge the output into one single solution. Although these methods generally produce more accurate alignments, they are inefficient because all the aligners need to be run first and the choice of the best solution is made a posteriori. Here, we describe the development of a new expert system, AlexSys, for the multiple alignment of protein sequences. AlexSys incorporates an intelligent inference engine to automatically select an appropriate aligner a priori, depending only on the nature of the input sequences. The inference engine was trained on a large set of reference multiple alignments, using a novel machine learning approach. Applying AlexSys to a test set of 178 alignments, we show that the expert system represents a good compromise between alignment quality and running time, making it suitable for high throughput projects. AlexSys is freely available from http://www.w3.org/1999/xlink">http://alnitak.u-strasbg.fr/similar to aniba/alexsys. C1 [Aniba, Mohamed Radhouene; Poch, Olivier; Thompson, Julie Dawn] IGBMC, Dept Struct Biol & Genom, F-67400 Illkirch Graffenstaden, France. [Aniba, Mohamed Radhouene; Poch, Olivier; Thompson, Julie Dawn] INSERM, F-67400 Illkirch Graffenstaden, France. [Aniba, Mohamed Radhouene; Poch, Olivier; Thompson, Julie Dawn] CNRS, UMR7104, F-67400 Illkirch Graffenstaden, France. [Aniba, Mohamed Radhouene; Poch, Olivier; Thompson, Julie Dawn] Univ Strasbourg, F-67000 Strasbourg, France. [Marchler-Bauer, Aron] NCBI NLM NIH, Bethesda, MD 20894 USA. RP Thompson, JD (reprint author), IGBMC, Dept Struct Biol & Genom, F-67400 Illkirch Graffenstaden, France. EM julie.thompson@igbmc.fr RI Marchler-Bauer, Aron/A-9681-2009; Thompson, Julie/F-3208-2010; OI Marchler-Bauer, Aron/0000-0003-1516-0712 FU Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (INSERM); Universite de Strasbourg FX Institute funds from the Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (INSERM); Universite de Strasbourg. Funding for open access charge: CNRS (Centre National de la Recherche Scientifique). NR 54 TC 9 Z9 9 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2010 VL 38 IS 19 BP 6338 EP 6349 DI 10.1093/nar/gkq526 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673SA UT WOS:000283682100010 PM 20530533 ER PT J AU Ming, X Alam, MR Fisher, M Yan, YJ Chen, XY Juliano, RL AF Ming, Xin Alam, Md Rowshon Fisher, Michael Yan, Yongjun Chen, Xiaoyuan Juliano, Rudolph L. TI Intracellular delivery of an antisense oligonucleotide via endocytosis of a G protein-coupled receptor SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN PROSTATE ADENOCARCINOMA; PEPTIDE-RECEPTOR; SIRNA OLIGONUCLEOTIDES; NONHUMAN-PRIMATES; RNA-INTERFERENCE; BOMBESIN ANALOGS; GENE DELIVERY; CANCER-CELLS; TRAFFICKING; THERAPY AB Gastrin-releasing peptide receptor (GRPR), a member of the G protein-coupled receptor superfamily, has been utilized for receptor-mediated targeting of imaging and therapeutic agents; here we extend its use to oligonucleotide delivery. A splice-shifting antisense oligonucleotide was conjugated to a bombesin (BBN) peptide, and its intracellular delivery was tested in GRPR expressing PC3 cells stably transfected with a luciferase gene interrupted by an abnormally spliced intron. The BBN-conjugate produced significantly higher luciferase expression compared to unmodified oligonucleotide, and this increase was reversed by excess BBN peptide. Kinetic studies revealed a combination of saturable, receptor-mediated endocytosis and non-saturable pinocytosis for uptake of the conjugate. The K(m) value for saturable uptake was similar to the EC(50) value for the pharmacological response, indicating that receptor-mediated endocytosis was a primary contributor to the response. Use of pharmacological and molecular inhibitors of endocytosis showed that the conjugate utilized a clathrin-, actin- and dynamin-dependent pathway to enter PC3 cells. The BBN-conjugate partially localized in endomembrane vesicles that were associated with Rab7 or Rab9, demonstrating that it was transported to late endosomes and the trans-golgi network. These observations suggest that the BBN-oligonucleotide conjugate enters cells via a process of GRPR mediated endocytosis followed by trafficking to deep endomembrane compartments. C1 [Ming, Xin; Alam, Md Rowshon; Fisher, Michael; Juliano, Rudolph L.] Univ N Carolina, Div Mol Pharmaceut, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Yan, Yongjun; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20810 USA. RP Juliano, RL (reprint author), Univ N Carolina, Div Mol Pharmaceut, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. EM arjay@med.unc.edu RI Ming, Xin/M-6691-2013 OI Ming, Xin/0000-0001-8368-250X FU National Institutes of Health [P01GM059299] FX Grant P01GM059299 to R.L.J. Funding for open access charge: National Institutes of Health (grant P01GM059299). NR 45 TC 39 Z9 40 U1 2 U2 14 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 OCT PY 2010 VL 38 IS 19 BP 6567 EP 6576 DI 10.1093/nar/gkq534 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673SA UT WOS:000283682100029 PM 20551131 ER PT J AU Massad, LS Evans, CT Weber, KM Goderre, JL Hessol, NA Henry, D Colie, C Strickler, HD Watts, DH Wilson, TE AF Massad, L. Stewart Evans, Charlesnika T. Weber, Kathleen M. Goderre, Johanna L. Hessol, Nancy A. Henry, Donna Colie, Christine Strickler, Howard D. Watts, D. Heather Wilson, Tracey E. TI Changes in Knowledge of Cervical Cancer Prevention and Human Papillomavirus Among Women With Human Immunodeficiency Virus SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID INTERAGENCY HIV; PAPANICOLAOU SMEARS; HPV VACCINE; ABNORMALITIES; PREVALENCE; COLPOSCOPY AB OBJECTIVE: To estimate changes in high-risk women's knowledge of cervical cancer prevention, human papillomavirus (HPV), and HPV vaccination since introduction and marketing of HPV vaccines. METHODS: At study visits in 2007 and 2008-2009, women with the human immunodeficiency virus (HIV) and at-risk comparison women in a multicenter U.S. cohort study completed 44-item self-report questionnaires exploring their knowledge of cervical cancer prevention, HPV, and HPV vaccination. Results from 2007 were compared with those obtained in 2008-2009. Knowledge scores were correlated with demographic variables, measures of education and attention, and medical factors. Significant associations were assessed in multivariable models. RESULTS: HIV-seropositive women had higher knowledge scores than seronegative women at baseline (13.2 +/- 5.7 compared with 11.8 +/- 6.0, P<.001) and follow-up (14.1 +/- 5.3 compared with 13.2 +/- 5.5, P=.01), but the change in scores was similar (0.9 +/- 5.3 compared with 1.5 +/- 5.5, P=.13). Knowledge that cervical cancer is caused by a virus rose significantly (P=.005), but only to 24%. Belief that cervical cancer is preventable only rose from 52% to 55% (P=.04), but more than 90% of women in both periods believed regular Pap testing was important. In analysis of covariance models, higher baseline score, younger age, higher education level, higher income, and former-as opposed to never-drug users, but not HIV status, were associated with improved knowledge. CONCLUSION: High-risk women's understanding of cervical cancer and HPV has improved, but gaps remain. Improvement has been weakest for less educated and lower-income women. (Obstet Gynecol 2010;116:941-7) C1 Washington Univ, Sch Med, St Louis, MO USA. Hines VA Med Ctr, Dept Vet Affairs, Chicago, IL USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. John H Stroger Jr Hosp Cook Cty, CORE Ctr, Chicago, IL USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Georgetown Univ, Sch Med, Washington, DC USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. RP Massad, LS (reprint author), Div Gynecol Oncol, 4911 Barnes Jewish Hosp Plaza, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources [UL1 RR024131]; NCI [R01 CA85178-01] FX The Women's Interagency HIV Study (WIHS) is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). H.D.S. was supported by NCI R01 CA85178-01. NR 23 TC 8 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2010 VL 116 IS 4 BP 941 EP 947 DI 10.1097/AOG.0b013e3181f2dbae PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 653DO UT WOS:000282067700020 PM 20859159 ER PT J AU Huff, J AF Huff, James TI Predicting chemicals causing cancer in animals as human carcinogens SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Letter ID RISKS C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 7 TC 8 Z9 8 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD OCT PY 2010 VL 67 IS 10 BP 720 EP 720 DI 10.1136/oem.2009.054569 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 827ZJ UT WOS:000295469100012 PM 20837652 ER PT J AU Davies, MA Samuels, Y AF Davies, M. A. Samuels, Y. TI Analysis of the genome to personalize therapy for melanoma SO ONCOGENE LA English DT Review DE BRAF; NRAS; C-KIT; ERBB4; GN alpha Q ID MULTIKINASE INHIBITOR SORAFENIB; PHASE-II TRIAL; RECOMBINANT INTERLEUKIN-2 THERAPY; COOPERATIVE-ONCOLOGY-GROUP; KIT PROTEIN EXPRESSION; ACUTE MYELOID-LEUKEMIA; PRIMARY UVEAL MELANOMA; METASTATIC MELANOMA; CUTANEOUS MELANOMA; BRAF MUTATIONS AB The treatment of cancer is being revolutionized by an improved understanding of the genetic events that occur in tumors. Advances in the understanding of the prevalence and patterns of mutations in melanoma have recently led to impressive results in trials of personalized, targeted therapies for this disease. In this review, we will discuss the molecular targets that have been validated clinically, additional genetic events that are candidates for future trials, and the challenges that remain to improve outcomes further in this aggressive disease. Oncogene (2010) 29, 5545-5555; doi:10.1038/onc.2010.323; published online 9 August 2010 C1 [Samuels, Y.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Davies, M. A.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Davies, M. A.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. RP Samuels, Y (reprint author), NHGRI, Canc Genet Branch, NIH, 50 South Dr,MSC 8000,Bldg 50,Room 5140, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov FU ASCO; M D Anderson Cancer Center SPORE in Melanoma [5 P50 CA093459 03 PP-DRP3]; National Human Genome Research Institute, National Institutes of Health, USA FX We thank Darryl Leja for graphical expertize and Nature Genetics for permission to use figures from paper doi:10.1038/ng.438. This work was supported by grants from ASCO (Young Investigator Award) and M D Anderson Cancer Center SPORE in Melanoma (Developmental Research Grant; 5 P50 CA093459 03 PP-DRP3; to MAD) and the Intramural Research Programs of the National Human Genome Research Institute, National Institutes of Health, USA (to YS). NR 119 TC 55 Z9 59 U1 6 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT PY 2010 VL 29 IS 41 BP 5545 EP 5555 DI 10.1038/onc.2010.323 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 664FX UT WOS:000282946900001 PM 20697348 ER PT J AU Lu, C Everhart, L Tilan, J Kuo, L Sun, CCJ Munivenkatappa, RB Jonsson-Rylander, AC Sun, J Kuan-Celarier, A Li, L Abe, K Zukowska, Z Toretsky, JA Kitlinska, J AF Lu, C. Everhart, L. Tilan, J. Kuo, L. Sun, C-C J. Munivenkatappa, R. B. Jonsson-Rylander, A.-C. Sun, J. Kuan-Celarier, A. Li, L. Abe, K. Zukowska, Z. Toretsky, J. A. Kitlinska, J. TI Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy SO ONCOGENE LA English DT Article DE neuropeptide Y; neuroblastoma; angiogenesis ID BAX-DEPENDENT APOPTOSIS; SMOOTH-MUSCLE-CELLS; INDUCED ANGIOGENESIS; NEURO-BLASTOMA; ADRENAL-GLAND; YY2 RECEPTOR; EXPRESSION; BIM; TUMORS; PHOSPHORYLATION AB Neuroblastomas are pediatric tumors that develop from sympathetic precursors and express neuronal proteins, such as neuropeptide Y (NPY). NPY is a sympathetic neurotransmitter acting via multiple receptors (Y1-Y5R). Both NPY and Y2Rs are commonly expressed in neuroblastoma cell lines and tissues. The peptide secreted from neuroblastomas stimulates tumor cell proliferation and angiogenesis. As both processes are Y2R-mediated, the aim of this study was to assess Y2R as a potential therapeutic target for neuroblastoma. In vitro, Y2R antagonist (BIIE0246) prevented activation of p44/42 mitogen-activated protein kinase (MAPK) induced by endogenous NPY, which resulted in decreased proliferation and induction of Bim-mediated apoptosis. Similar growth-inhibitory effects were achieved with NPY small interfering RNA (siRNA) and Y2R siRNA. In vivo, Y2R antagonist significantly inhibited growth of SK-N-BE(2) and SK-N-AS xenografts, which was associated with decreased activation of p44/42 MAPK, as well as reduced proliferation (Ki67) and increased apoptosis (TdT-mediated dUTP nick end labeling; TUNEL). The Y2R antagonist also exerted an antiangiogenic effect. In vitro, it reduced the proliferation of endothelial cells induced by neuroblastoma-conditioned media. Consequently, the Y2R antagonist-treated xenografts had decreased vascularization and a high degree of focal fibrosis. In human neuroblastoma tissues, the expression of Y2R was observed in both tumor and endothelial cells, while NPY was predominantly expressed in neuroblastoma cells. In summary, Y2R is a promising new target for neuroblastoma therapy affecting both cancer cells and tumor vasculature. Oncogene (2010) 29, 5630-5642; doi:10.1038/onc.2010.301; published online 2 August 2010 C1 [Lu, C.; Everhart, L.; Tilan, J.; Kuo, L.; Kuan-Celarier, A.; Li, L.; Zukowska, Z.; Kitlinska, J.] Georgetown Univ, Dept Physiol & Biophys, Washington, DC 20057 USA. [Sun, C-C J.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Munivenkatappa, R. B.] Univ Maryland, Sch Med, Dept Surg, Div Transplantat, Baltimore, MD 21201 USA. [Jonsson-Rylander, A.-C.] AstraZeneca, Dept Biosci, Molndal, Sweden. [Sun, J.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Abe, K.] NHLBI, NIH, Bethesda, MD 20892 USA. [Toretsky, J. A.] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Kitlinska, J (reprint author), Georgetown Univ, Dept Physiol & Biophys, BSB 231A,3900 Reservoir Rd NW, Washington, DC 20057 USA. EM jbk4@georgetown.edu RI Lu, Congyi/G-3984-2013 FU NIH [1R01CA123211-01]; Children's Cancer Foundation (Baltimore, MD, USA) FX This work was supported by NIH Grant 1R01CA123211-01 and funding from Children's Cancer Foundation (Baltimore, MD, USA) to Joanna Kitlinska. The authors would like to thank John Styliaris and David Hur for help in performing experiments. We also thank the Flow Cytometry/Cell Sorting Shared Resources of Lombardi Comprehensive Cancer Center for technical assistance and Children's Oncology Group for providing human samples. NR 42 TC 25 Z9 25 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT PY 2010 VL 29 IS 41 BP 5630 EP 5642 DI 10.1038/onc.2010.301 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 664FX UT WOS:000282946900009 PM 20676138 ER PT J AU Cheng, L Zhou, Z Flesken-Nikitin, A Toshkov, IA Wang, W Camps, J Ried, T Nikitin, AY AF Cheng, L. Zhou, Z. Flesken-Nikitin, A. Toshkov, I. A. Wang, W. Camps, J. Ried, T. Nikitin, A. Y. TI Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency SO ONCOGENE LA English DT Article DE breast cancer; genomic maintenance; mouse; models of cancer; oncogenomics; tumor suppressor ID CONDITIONAL MOUSE MODEL; HUMAN BREAST-CANCER; TUMOR SUPPRESSION; SOMATIC INACTIVATION; LIVER TUMORIGENESIS; GENOME INTEGRITY; PROSTATE-CANCER; TRANSGENIC MICE; HIGH-FREQUENCY; NEURAL CREST AB Genetically defined mouse models offer an important tool to identify critical secondary genetic alterations with relevance to human cancer pathogenesis. We used newly generated MMTV-Cre105Ayn mice to inactivate p53 and/or Rb strictly in the mammary epithelium, and to determine recurrent genomic changes associated with deficiencies of these genes. p53 inactivation led to formation of estrogen receptor-positive raloxifene-responsive mammary carcinomas with features of luminal subtype B. Rb deficiency was insufficient to initiate carcinogenesis but promoted genomic instability and growth rate of neoplasms associated with p53 inactivation. Genome-wide analysis of mammary carcinomas identified a recurrent amplification at chromosome band 9A1, a locus orthologous to human 11q22, which contains protooncogenes cIAP1 (Birc2), cIAP2 (Birc3) and Yap1. It is interesting that this amplicon was preferentially detected in carcinomas carrying wild-type Rb. However, all three genes were overexpressed in carcinomas with p53 and Rb inactivation, likely due to E2F-mediated transactivation, and cooperated in carcinogenesis according to gene knockdown experiments. These findings establish a model of luminal subtype B mammary carcinoma, identify critical role of cIAP1, cIAP2 and Yap1 co-expression in mammary carcinogenesis and provide an explanation for the lack of recurrent amplifications of cIAP1, cIAP2 and Yap1 in some tumors with frequent Rb deficiency, such as mammary carcinoma. Oncogene (2010) 29, 5700-5711; doi:10.1038/onc.2010.300; published online 2 August 2010 C1 [Cheng, L.; Zhou, Z.; Flesken-Nikitin, A.; Toshkov, I. A.; Nikitin, A. Y.] Cornell Univ, Dept Biomed Sci, Ithaca, NY 14853 USA. [Wang, W.] Cornell Univ, Microarray Core Facil, Ithaca, NY 14853 USA. [Camps, J.; Ried, T.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Nikitin, AY (reprint author), Cornell Univ, Dept Biomed Sci, T2 014A VRT Campus Rd, Ithaca, NY 14853 USA. EM an58@cornell.edu FU NIH/NCI [R01 CA96823]; NYSTEM [C023050] FX We thank David C Corney for critical reading of this paper and Dr Anton Berns (Netherlands Cancer Institute, Amsterdam, The Netherlands) for the generous gift of the p53floxP/floxP and RbfloxP/floxP mice. This work was supported by grants R01 CA96823 (NIH/NCI) and C023050 (NYSTEM) to AYN. NR 50 TC 16 Z9 16 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT PY 2010 VL 29 IS 42 BP 5700 EP 5711 DI 10.1038/onc.2010.300 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 668IT UT WOS:000283262500006 PM 20676140 ER PT J AU Herbert, BS Chanoux, RA Liu, YL Baenziger, PH Goswami, CP McClintick, JN Edenberg, HJ Pennington, RE Lipkin, SM Kopelovich, L AF Herbert, Brittney-Shea Chanoux, Rebecca A. Liu, Yunlong Baenziger, Peter H. Goswami, Chirayu P. McClintick, Jeanette N. Edenberg, Howard J. Pennington, Robert E. Lipkin, Steven M. Kopelovich, Levy TI A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers SO ONCOTARGET LA English DT Article DE one-hit effects; gene expression profiling; Li-Fraumeni Syndrome; chemoprevention; breast cancer ID TUMOR-SUPPRESSOR GENE; FALSE DISCOVERY RATE; ONE-HIT; PROMOTER HYPERMETHYLATION; P53 RESTORATION; CANCER FAMILY; MUTANT P53; CYCLIN D2; EXPRESSION; MICE AB Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited "hit" in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry "one-hit" p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well. C1 [Herbert, Brittney-Shea; Chanoux, Rebecca A.; Liu, Yunlong; Edenberg, Howard J.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Herbert, Brittney-Shea] Indiana Univ Sch Med, Melvin & Bren Simon Canc Ctr, Indianapolis, IN USA. [Liu, Yunlong; Baenziger, Peter H.; Goswami, Chirayu P.] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA. [Liu, Yunlong] Indiana Univ Sch Med, Dept Med, Div Biostat, Indianapolis, IN USA. [Liu, Yunlong; McClintick, Jeanette N.; Edenberg, Howard J.] Indiana Univ Sch Med, Ctr Med Genom, Indianapolis, IN USA. [McClintick, Jeanette N.; Edenberg, Howard J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA. [Pennington, Robert E.] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN USA. [Lipkin, Steven M.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Lipkin, Steven M.] Weill Cornell Med Coll, Dept Med Genet, New York, NY USA. [Kopelovich, Levy] Natl Canc Inst, Canc Prevent Div, Bethesda, MD USA. RP Herbert, BS (reprint author), Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. EM brherber@iupui.edu; kopelovl@mail.nih.gov RI Baenziger, Peter/C-6490-2014; OI Baenziger, Peter/0000-0002-9109-6954; Edenberg, Howard/0000-0003-0344-9690 FU Indiana Genomics Initiative at Indiana University (INGEN Registered Trademark); Lilly Endowment, Inc.; National Cancer Institute [N01 CN-43300]; IU Simon Cancer Center; INGEN FX We thank M. Fox, E. Gentry, A. Hochreiter-Hufford, and C.B. Smith for technical assistance, and J.W. Shay for LFS-50 and WT cell lines. The microarray studies were carried out using the facilities of the Center for Medical Genomics at Indiana University School of Medicine. The Center for Medical Genomics is supported in part by the Indiana Genomics Initiative at Indiana University (INGEN (R), which is supported in part by the Lilly Endowment, Inc.). This work was supported by National Cancer Institute N01 CN-43300, IU Simon Cancer Center, and INGEN. NR 57 TC 21 Z9 21 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT PY 2010 VL 1 IS 6 BP 405 EP 422 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 802JC UT WOS:000293504900004 PM 21311097 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI Human T cell leukemia virus type 1 (HTLV-1) and oncogene or oncomiR addiction? SO ONCOTARGET LA English DT Article DE HTLV; ATL; MicroRNAs; Leukemia; oncogene ID 1ST HUMAN RETROVIRUS; TAX GENE; I PX; LYMPHOCYTES; MECHANISMS; EXPRESSION; MICRORNAS; DISCOVERY; DISEASE; PROTEIN AB The mechanism of HTLV-1 transformation of cells to Adult T cell leukemia (ATL) remains not fully understood. Currently, the viral Tax oncoprotein is known to be required to initiate transformation. Emerging evidence suggests that Tax is not needed to maintain the transformed ATL phenotype. Recent studies have shown that HTLV-1 transformed cells show deregulated expression of cellular microRNAs (miRNAs). Here we discuss the possibility that early ATL cells are Tax-oncogene-addicted while late ATL cells are oncogenic microRNA (oncomiR) - addicted. The potential utility of interrupting oncomiR addiction as a cancer treatment is broached. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM kjeang@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU National Institute of Allergy and Infectious Diseases FX The views expressed here are the personal opinions of the author and do not reflect the views of his employer, the US National Institutes of Health. Work in KTJ's laboratory is supported by intramural funds from the National Institute of Allergy and Infectious Diseases. The author thanks Daniel Schmidt and Lauren Lee for help with manuscript and figure preparations. NR 33 TC 15 Z9 16 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 OCT PY 2010 VL 1 IS 6 BP 453 EP 456 PG 4 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 802JC UT WOS:000293504900008 PM 21311101 ER PT J AU Heimpel, H Kratz, CP Flotho, C Brittinger, G Konig, E Lauenstein, T Duhrsen, U AF Heimpel, H. Kratz, C. P. Flotho, C. Brittinger, G. Koenig, E. Lauenstein, T. Duehrsen, U. TI Congenital dyserythropoietic anemia with thrombocytopenia and extramedullary erythropoiesis due to a germline GATA-1 mutation SO ONKOLOGIE LA English DT Meeting Abstract C1 [Heimpel, H.] Univ Ulm, Zentrum Innere Med, Innere Med Klin 3, Ulm, Germany. [Kratz, C. P.] NCI, Clin Genet Branch, Rockville, MD USA. [Flotho, C.] Univ Freiburg, Zentrum Kinderheilkunde & Jugendmed, Klin Hamatol & Onkol 4, Freiburg, Germany. [Brittinger, G.; Koenig, E.; Duehrsen, U.] Univ Klinikum Essen, Klin Hamatol, Essen, Germany. [Lauenstein, T.] Univ Klinikum Essen, Inst Diagnost & Intervent Radiol & Neuroradiol, Essen, Germany. RI Lauenstein, Thomas/H-4239-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X J9 ONKOLOGIE JI Onkologie PD OCT PY 2010 VL 33 SU 6 BP 112 EP 112 PG 1 GA 664UN UT WOS:000282988400309 ER PT J AU Gerbitz, A Sukumar, M Helm, F Wilke, A Friese, C Fahrenwaldt, C Lehmann, F Loddenkemper, C Kammertons, T Mautner, J Blankenstein, T Bornkamm, G AF Gerbitz, A. Sukumar, M. Helm, F. Wilke, A. Friese, C. Fahrenwaldt, C. Lehmann, F. Loddenkemper, C. Kammertoens, T. Mautner, J. Blankenstein, T. Bornkamm, G. TI Host interferon-gamma signaling and cross-presentation is required for elimination of antigen-loss variants of high-grade B cell lymphomas: Implications for adoptive T-cell therapy SO ONKOLOGIE LA English DT Meeting Abstract C1 [Gerbitz, A.] Univ Erlangen Nurnberg, Erlangen, Germany. [Sukumar, M.] NIH, Surg Branch, Bethesda, MD 20892 USA. [Helm, F.; Wilke, A.; Friese, C.; Fahrenwaldt, C.; Kammertoens, T.; Blankenstein, T.] Charite CBF, Inst Immunol, Berlin, Germany. [Lehmann, F.; Bornkamm, G.] Helmholtz Zentrum Munchen, Inst Klin Mol Biol & Tumorgenet, Munich, Germany. [Loddenkemper, C.] Tech Univ Munich, Inst Pathol, Munich, Germany. [Mautner, J.] Tech Univ Munich, Kinderklin, Klin Kooperat Grp, Munich, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X J9 ONKOLOGIE JI Onkologie PD OCT PY 2010 VL 33 SU 6 BP 288 EP 288 PG 1 GA 664UN UT WOS:000282988401367 ER PT J AU Young, N AF Young, N. TI Human bone marrow failure and the role of telomere biology in human disease SO ONKOLOGIE LA English DT Meeting Abstract C1 [Young, N.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X J9 ONKOLOGIE JI Onkologie PD OCT PY 2010 VL 33 SU 6 BP 294 EP 294 PG 1 GA 664UN UT WOS:000282988401387 ER PT J AU Barnett, ML Pihlstrom, BL AF Barnett, M. L. Pihlstrom, B. L. TI Considerations in establishing an oral disease clinical research center SO ORAL DISEASES LA English DT Review DE clinical research; research center; human subject protections; research training; industry-sponsored research AB High quality clinical research is necessary to improve oral health and translate research findings to the practice of dentistry. This has led many academic institutions to consider establishing a formal clinical research center. This is not a trivial undertaking and requires that the center have an appropriate physical infrastructure, trained investigators with recognized expertise in the planning and conduct of high quality clinical research, and very importantly, a financial plan to assure its long-term sustainability. The purpose of this paper is to provide some guidance and practical advice with respect to factors that should be considered in developing and maintaining a successful oral disease clinical research center. C1 [Barnett, M. L.] SUNY Buffalo, Sch Dent Med, Buffalo, NY 14260 USA. [Pihlstrom, B. L.] Univ Minnesota, Sch Dent, Bethesda, MD USA. [Pihlstrom, B. L.] Natl Inst Dent & Craniofacial Res, Div Clin Res & Hlth Promot, NIH, Bethesda, MD USA. RP Barnett, ML (reprint author), 289 Sayre Dr, Princeton, NJ 08540 USA. EM mlbgums@aol.com FU United States National Institutes of Health (NIH) FX The main source of government funding for oral health research worldwide is the United States National Institutes of Health (NIH), specifically the National Institute of Dental and Craniofacial Research (NIDCR). All applications for U.S. government funding must be submitted in response to a Funding Opportunity Announcement (FOA) posted on the Grants.gov website (http://www.grants.gov/applicants/ find_grant_opportunities.jsp) or the websites of specific granting agencies. Oral health FOAs can be found at three locations: (1) the Grants.gov website, (2) the NIH Guide for Grants and Contracts (http://grants.nih.gov/grants/guide/) and, (3) the NIDCR website (http://www.nidcr.nih.gov/). Most NIH funding is awarded to U.S. investigators, but the NIH supports research in other countries if resources such as investigator expertise, instrumentation, or patient populations are not available in the U.S and if the findings are applicable to people living in the U.S. Investigators who are interested in obtaining government funding from other countries should consult public health agencies in those countries for funding opportunities. NR 5 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD OCT PY 2010 VL 16 IS 7 BP 586 EP 591 DI 10.1111/j.1601-0825.2010.01673.x PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 650EI UT WOS:000281831600002 PM 20846148 ER PT J AU Oladeinde, OA Hong, SY Holland, RJ Maciag, AE Keefer, LK Saavedra, JE Nandurdikar, RS AF Oladeinde, Oyebola A. Hong, Sam Y. Holland, Ryan J. Maciag, Anna E. Keefer, Larry K. Saavedra, Joseph E. Nandurdikar, Rahul S. TI "Click" Reaction in Conjunction with Diazeniumdiolate Chemistry: Developing High-Load Nitric Oxide Donors SO ORGANIC LETTERS LA English DT Article ID AZIDE-ALKYNE CYCLOADDITION; 1,3-DIPOLAR CYCLOADDITIONS; NOBEL LECTURE; DISCOVERY; PRODRUG; ANALOGS; TRENDS; DRUGS AB The use of Cu(I)-catalyzed "click" reactions of alkyne-substituted diazeniumdiolate prodrugs with bis- and tetrakis-azido compounds is described. The "click" reaction for the bis-azide using CuSO(4)/Na-ascorbate predominantly gave the expected bis-triazole. However, CuI/diisopropylethylamine predominantly gave uncommon triazolo-triazole products as a result of oxidative coupling. Neither set of "click" conditions showed evidence of compromising the integrity of the diazeniumdiolate groups. The chemistry developed has applications in the synthesis of polyvalent and dendritic nitric oxide donors. C1 [Maciag, Anna E.; Saavedra, Joseph E.] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Oladeinde, Oyebola A.; Hong, Sam Y.; Holland, Ryan J.; Keefer, Larry K.; Nandurdikar, Rahul S.] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Saavedra, JE (reprint author), NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. EM saavedjo@mail.nih.gov; nandurdikarr@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr. Sergey Tarasov and Ms. Marzena A. Dyba of the Biophysics Resource in the Structural Biophysics Laboratory, NCI-Frederick, for assistance with the high-resolution mass spectrometry studies. NR 25 TC 13 Z9 13 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD OCT 1 PY 2010 VL 12 IS 19 BP 4256 EP 4259 DI 10.1021/ol101645k PG 4 WC Chemistry, Organic SC Chemistry GA 652WP UT WOS:000282041900011 PM 20812718 ER PT J AU Berger, VW AF Berger, V. W. TI Assessing the quality of randomization and allocation concealment SO OSTEOARTHRITIS AND CARTILAGE LA English DT Letter C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 4 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2010 VL 18 IS 10 BP 1361 EP 1361 DI 10.1016/j.joca.2010.05.022 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 670UK UT WOS:000283452600019 PM 20650327 ER PT J AU Gabay, OH Lee, E Booth, R Gagarina, V Dvir-Ginzberg, M Hall, DJ AF Gabay, O. H. Lee, E. Booth, R. Gagarina, V. Dvir-Ginzberg, M. Hall, D. J. TI INCREASED EXPRESSION OF ARTHRITIC MARKER GENES IN THE CARTILAGE OF SIRT1 NULL MICE SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the OsteoArthritis-Research-Society-International CY SEP 23-26, 2010 CL Brussels, BELGIUM SP OsteoArthritis Res Soc Int C1 [Gabay, O. H.; Lee, E.; Booth, R.; Gagarina, V.; Hall, D. J.] NIH, Bethesda, MD 20892 USA. [Dvir-Ginzberg, M.] Hebrew Univ Hadassah Ein Kerem, Fac Med Dent, Lab Cartilage Biol, Inst Dent Sci, Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2010 VL 18 SU 2 BP S49 EP S49 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 670UN UT WOS:000283452900117 ER PT J AU Gabay, OH Lee, E Booth, R Gagarina, V Dvir-Ginzberg, M Hall, DJ AF Gabay, O. H. Lee, E. Booth, R. Gagarina, V. Dvir-Ginzberg, M. Hall, D. J. TI A POSITIVE ROLE OF DBC1, A SIRT1 REPRESSOR, IN THE ARTHRITIC RESPONSE IN HUMAN CHONDROCYTES SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the OsteoArthritis-Research-Society-International CY SEP 23-26, 2010 CL Brussels, BELGIUM SP OsteoArthritis Res Soc Int C1 [Gabay, O. H.; Lee, E.; Booth, R.; Gagarina, V.; Hall, D. J.] NIH, Bethesda, MD 20892 USA. [Dvir-Ginzberg, M.] Hebrew Univ Hadassah Ein Kerem, Lab Cartilage Biol, Inst Dent Sci, Fac Med Dent, Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2010 VL 18 SU 2 BP S17 EP S17 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 670UN UT WOS:000283452900042 ER PT J AU Jonsson, H Helgadottir, GP Aspelund, T Eiriksdottir, G Sigurdsson, S Siggeirsdottir, K Ingvarsson, T Harris, TB Launer, L Gudnason, V AF Jonsson, H. Helgadottir, G. P. Aspelund, T. Eiriksdottir, G. Sigurdsson, S. Siggeirsdottir, K. Ingvarsson, T. Harris, T. B. Launer, L. Gudnason, V. TI THE PRESENCE OF TOTAL KNEE OR HIP REPLACEMENTS DUE TO OA STRENGTHENS THE POSITIVE ASSOCIATION BETWEEN HAND OA AND ATHEROSCLEROSIS IN FEMALES: THE AGES-REYKJAVIK STUDY SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the OsteoArthritis-Research-Society-International CY SEP 23-26, 2010 CL Brussels, BELGIUM SP OsteoArthritis Res Soc Int C1 [Jonsson, H.; Helgadottir, G. P.; Aspelund, T.; Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Aspelund, T.; Eiriksdottir, G.; Sigurdsson, S.; Siggeirsdottir, K.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Ingvarsson, T.] Cent Hosp, Akureyri, Iceland. [Harris, T. B.; Launer, L.] Inst Aging, Bethesda, MD USA. RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2010 VL 18 SU 2 BP S127 EP S127 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 670UN UT WOS:000283452900306 ER PT J AU Sigurjonsdottir, K Bjorgulfsson, TM Aspelund, T Eiriksdottir, G Sigurdsson, S Ingvarsson, T Harris, TB Launer, L Gudnason, V Jonsson, H AF Sigurjonsdottir, K. Bjorgulfsson, T. M. Aspelund, T. Eiriksdottir, G. Sigurdsson, S. Ingvarsson, T. Harris, T. B. Launer, L. Gudnason, V. Jonsson, H. TI TYPE 3 FINGER LENGTH PATTERN IS ASSOCIATED WITH TOTAL KNEE (TKR) BUT NOT WITH HIP REPLACEMENTS (THR) IN THE ELDERLY: THE AGES-REYKJAVIK STUDY SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the OsteoArthritis-Research-Society-International CY SEP 23-26, 2010 CL Brussels, BELGIUM SP OsteoArthritis Res Soc Int C1 [Sigurjonsdottir, K.; Bjorgulfsson, T. M.; Aspelund, T.; Gudnason, V.; Jonsson, H.] Univ Iceland, Reykjavik, Iceland. [Aspelund, T.; Eiriksdottir, G.; Sigurdsson, S.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Ingvarsson, T.] Ctr Hosp, Akureyri, Iceland. [Harris, T. B.; Launer, L.] NIA, Bethesda, MD 20892 USA. RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2010 VL 18 SU 2 BP S33 EP S33 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 670UN UT WOS:000283452900079 ER PT J AU Portnoy, DB Roter, D Erby, LH AF Portnoy, David B. Roter, Debra Erby, Lori H. TI The role of numeracy on client knowledge in BRCA genetic counseling SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Numeracy; Patient-provider interaction; Genetic counseling; Patient learning ID DECISIONAL CONFLICT SCALE; ORAL LITERACY DEMAND; BREAST-CANCER; HEALTH LITERACY; RISK; COMMUNICATION; INFORMATION; EDUCATION; DIALOGUE; OUTCOMES AB Objective: To assess the impact of numeracy and health literacy on client's ability to learn information orally communicated during a BRCA 1/2 genetic counseling session. Methods: Fifty-nine videotaped simulated genetic counseling sessions were shown to 246 analogue clients (AC) recruited to imagine themselves as the client in the genetic counseling session. AC numeracy, genetic literacy, state and trait anxiety, and decisional conflict were assessed. The primary outcome was AC learning about BRCA 1/2. Results: Health literacy and numeracy were moderately correlated, and each independently predicted learning. Higher numeracy was associated with higher knowledge scores only among ACs with adequate literacy. Decisional conflict was not related to literacy, numeracy, or knowledge acquisition. It was, however, inversely related to state anxiety so that the higher post-session state anxiety, the lower the AC's decisional conflict. Conclusion: Numeracy and health literacy are associated with learning of orally communicated information during genetic counseling. It appears that numeracy can facilitate learning for literate subjects: it does not, however, make any difference in learning ability of clients with significant literacy deficits. Practice implications: Numeracy plays an important role in client's ability to learn information communicated during medical sessions, especially among clients who are otherwise regarded as literate. Published by Elsevier Ireland Ltd. C1 [Portnoy, David B.] NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [Roter, Debra; Erby, Lori H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. RP Portnoy, DB (reprint author), NCI, Canc Prevent Fellowship Program, NIH, Execut Plaza N,6130 Execut Blvd,Room 4051, Bethesda, MD 20892 USA. EM portnoydb@mail.nih.gov RI Roter, Debra/N-8830-2014; OI Portnoy, David/0000-0003-2175-9457 FU National Human Genome Research Institute of the NIH [1R01HG002688-01A1] FX This research was supported by grant 1R01HG002688-01A1 (PI D.Roter), Genetic Counseling Processes and Analogue Client Outcome, funded by the National Human Genome Research Institute of the NIH. NR 30 TC 17 Z9 17 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD OCT PY 2010 VL 81 IS 1 BP 131 EP 136 DI 10.1016/j.pec.2010.09.036 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 653EL UT WOS:000282070900022 PM 19854023 ER PT J AU Kolb, EA Gorlick, R Houghton, PJ Morton, CL Neale, G Keir, ST Carol, H Lock, R Phelps, D Kang, MH Reynolds, CP Maris, JM Billups, C Smith, MA AF Kolb, E. Anders Gorlick, Richard Houghton, Peter J. Morton, Christopher L. Neale, Geoffrey Keir, Stephen T. Carol, Hernan Lock, Richard Phelps, Doris Kang, Min H. Reynolds, C. Patrick Maris, John M. Billups, Catherine Smith, Malcolm A. TI Initial Testing (Stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE AZD6244; developmental therapeutics; preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; KINASE KINASE-1/2 INHIBITOR; PATHWAY ACTIVATION; BRAF GENE; IN-VIVO; B-RAF; PILOCYTIC ASTROCYTOMAS; MAMMALIAN TARGET; CANCER MODELS; MAPK PATHWAY AB Background. AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development Procedures. AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 mu M) In vivo AZD6244 was tested at a close of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting Results. At the highest concentration used in vitro (10 mu M) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines Against the in vivo tumor panels, AZD6244 induced significant differences in FFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models There were no objective responses Pharmacodynamic studies indicated at this close and schedule AZD6244 completely inhibited ERK1/2 phosphorylation AZD6244 was evaluated against two IPA xenografts, BT-35 (wild-type BRAF) and BT 40 (mutant [V600E] BRAF) BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment Conclusions. At the close and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions Pediatr Blood Cancer 2010,55 668-677 (C) 2010 Wiley-Liss, Inc C1 [Kolb, E. Anders] AI duPont Hosp tor Children, Nemours Ctr Childhood Canc Res, Wilmington, DE 19803 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Houghton, Peter J.; Morton, Christopher L.; Neale, Geoffrey; Phelps, Doris; Billups, Catherine] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Carol, Hernan; Lock, Richard] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Kang, Min H.; Reynolds, C. Patrick] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Smith, Malcolm A.] NCI, Cancer Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Kolb, EA (reprint author), AI duPont Hosp tor Children, Nemours Ctr Childhood Canc Res, 1600 Rockland Rd, Wilmington, DE 19803 USA. RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NOI-CM-42216, CA21765, CA108786] FX Grant sponsor National Cancer Institute, Grant numbers NOI-CM-42216, CA21765, CA108786 NR 33 TC 30 Z9 30 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2010 VL 55 IS 4 BP 668 EP 677 DI 10.1002/pbc.22576 PG 10 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 646LU UT WOS:000281542900016 PM 20806365 ER PT J AU Chao, MM Todd, MA Kontny, U Neas, K Sullivan, MJ Hunter, AG Picketts, DJ Kratz, CP AF Chao, Mwe Mwe Todd, Matthew A. Kontny, Udo Neas, Katherine Sullivan, Michael J. Hunter, Alasdair G. Picketts, David J. Kratz, Christian P. TI T-Cell Acute Lymphoblastic Leukemia in Association With Borjeson-Forssman-Lehmann Syndrome Due To a Mutation in PHF6 SO PEDIATRIC BLOOD & CANCER LA English DT Article DE Borjeson-Forssman-Lehmann syndrome; PHF6; T-cell ALL/lymphoma ID GERMLINE MUTATIONS; GENE; THROMBOCYTOPENIA; PROTEIN AB Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked mental retardation syndrome that is caused by germline mutations in PHF6 We describe a 9-year-old male with BFLS, who developed T-cell acute lymphoblastic leukemia (T-ALL) The PHF6 gene is located on the X chromosome and encodes a protein with two PHD-type zinc finger domains and four nuclear localization sequences Previously, overexpression of Phf6 was observed in murine T-cell lymphomas Our observation indicates that BEES may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-ALL Pediatr Blood Cancer 2010,55 722-724 (C) 2010 Wiley-Liss, Inc C1 [Kratz, Christian P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Chao, Mwe Mwe] Childrens Natl Med Ctr, Div Pediat Hematol Oncol, Washington, DC 20010 USA. [Todd, Matthew A.; Picketts, David J.] Univ Ottawa, Ottawa Hlth Res Inst, Ottawa, ON, Canada. [Kontny, Udo] Univ Freiburg, Div Pediat Hematol Oncol, Dept Pediat & Adolescent Med, Freiburg, Germany. [Neas, Katherine] Capital & Coast Dist Hlth Board, Cent & So Reg Genet Serv, Wellington, New Zealand. [Sullivan, Michael J.] Univ Otago, Dept Paediat, Childrens Canc Res Grp, Childrens Haematol Oncol Ctr,Chrsitchurch Sch Med, Christchurch, New Zealand. [Hunter, Alasdair G.] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada. RP Kratz, CP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room EPS 7030, Rockville, MD 20852 USA. RI Sullivan, Michael/B-5459-2012 FU National Cancer Institute, National Institutes of Health; Canadian Institutes of Health Research FX C P K 's work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. D J P's work is funded by grants from the Canadian Institutes of Health Research We thank Lemuel Racacho for technical assistance NR 13 TC 18 Z9 18 U1 3 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2010 VL 55 IS 4 BP 722 EP 724 DI 10.1002/pbc.22574 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 646LU UT WOS:000281542900023 PM 20806366 ER PT J AU Moon, SS Wang, YH Shane, AL Trang, N Ray, P Dennehy, P Baek, LJ Parashar, U Glass, RI Jiang, BM AF Moon, Sung-Sil Wang, Yuhuan Shane, Andi L. Trang Nguyen Ray, Pratima Dennehy, Penelope Baek, Luck Ju Parashar, Umesh Glass, Roger I. Jiang, Baoming TI Inhibitory Effect of Breast Milk on Infectivity of Live Oral Rotavirus Vaccines SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE rotavirus; RV1; RV5; neutralizing activity; breast milk ID INFANTS; DIARRHEA; EFFICACY; SAFETY; IMMUNOGENICITY; CHILDREN; RIX4414; PROTECTION; SEROTYPES; RIT-4237 AB Background: Live oral rotavirus vaccines have been less immunogenic and efficacious among children in poor developing countries compared with middle income and industrialized countries for reasons that are not yet completely understood. We assessed whether the neutralizing activity of breast milk could lower the titer of vaccine virus and explain this difference in vitro. Methods: Breast milk samples were collected from mothers who were breast-feeding infants 4 to 29 weeks of age (ie, vaccine eligible age) in India (N = 40), Vietnam (N = 77), South Korea (N = 34), and the United States (N = 51). We examined breast milk for rotavirus-specific IgA and neutralizing activity against 3 rotavirus vaccine strains-RV1, RV5 G1, and 116E using enzyme immunoassays. The inhibitory effect of breast milk on RV1 was further examined by a plaque reduction assay. Findings: Breast milk from Indian women had the highest IgA and neutralizing titers against all 3 vaccine strains, while lower but comparable median IgA and neutralizing titers were detected in breast milk from Korean and Vietnamese women, and the lowest titers were seen in American women. Neutralizing activity was greatest against the 2 vaccine strains of human origin, RV1 and 116E. This neutralizing activity in one half of the breast milk specimens from Indian women could reduce the effective titer of RV1 by similar to 2 logs, of 116E by 1.5 logs, and RV5 G1 strain by similar to 1 log more than that of breast milk from American women. Interpretation: The lower immunogenicity and efficacy of rotavirus vaccines in poor developing countries could be explained, in part, by higher titers of IgA and neutralizing activity in breast milk consumed by their infants at the time of immunization that could effectively reduce the potency of the vaccine. Strategies to overcome this negative effect, such as delaying breast-feeding at the time of immunization, should be evaluated. C1 [Jiang, Baoming] Ctr Dis Control & Prevent, Gastroenteritis & Resp Viruses Lab Branch, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Shane, Andi L.] Emory Univ, Div Pediat Infect Dis, Atlanta, GA 30322 USA. [Trang Nguyen] Natl Inst Hyg & Epidemiol, Hanoi, Vietnam. [Ray, Pratima] All India Inst Med Sci, Dept Pediat, Delhi, India. [Dennehy, Penelope] Rhode Isl Hosp, Dept Pediat, Providence, RI USA. [Baek, Luck Ju] Korea Univ, Coll Med, Dept Microbiol, Seoul 136705, South Korea. [Glass, Roger I.] NIH, Fogarty Int Ctr, Rockville, MD USA. RP Jiang, BM (reprint author), Ctr Dis Control & Prevent, Gastroenteritis & Resp Viruses Lab Branch, Natl Ctr Immunizat & Resp Dis, MS G04,1600 Clifton Rd NE, Atlanta, GA 30333 USA. EM bxj4@cdc.gov OI Dennehy, Penelope/0000-0002-2259-5370; Ray, Pratima/0000-0002-2182-2279 FU CDC; NIH National Center for Research Resources [K12RR017643, 1KL2RR025009] FX Supported (in part) by CDC program funds. Also supported (in part) by the NIH National Center for Research Resources, grants K12RR017643 and 1KL2RR025009 (to S.A.L.). NR 25 TC 57 Z9 57 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2010 VL 29 IS 10 BP 919 EP 923 DI 10.1097/INF.0b013e3181e232ea PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 653EC UT WOS:000282069700005 PM 20442687 ER PT J AU Vanprapar, N Cressey, TR Chokephaibulkit, K Muresan, P Plipat, N Sirisanthana, V Prasitsuebsai, W Hongsiriwan, S Chotpitayasunondh, T Eksaengsri, A Toye, M Smith, ME McIntosh, K Capparelli, E Yogev, R AF Vanprapar, Nirun Cressey, Tim R. Chokephaibulkit, Kulkanya Muresan, Petronella Plipat, Nottasorn Sirisanthana, Virat Prasitsuebsai, Wasana Hongsiriwan, Suchat Chotpitayasunondh, Tawee Eksaengsri, Achara Toye, MariPat Smith, Mary Elizabeth McIntosh, Kenneth Capparelli, Edmund Yogev, Ram CA IMPAACT P1056 Team TI A Chewable Pediatric Fixed-dose Combination Tablet of Stavudine, Lamivudine, and Nevirapine Pharmacokinetics and Safety Compared With the Individual Liquid Formulations in Human Immunodeficiency Virus-infected Children in Thailand SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT 16th Conference on Retroviruses and Opportunistic Infections (CROI) CY FEB 08-11, 2009 CL Montreal, CANADA DE pharmacokinetics; antiretrovirals; fixed-dose combinations; children; Thailand ID HIV-INFECTED CHILDREN; ACTIVE ANTIRETROVIRAL THERAPY; PLASMA-CONCENTRATIONS; EFFICACY; 2',3'-DIDEHYDRO-3'-DEOXYTHYMIDINE; THAILAND; PROGRAM AB Background: Pediatric fixed-dose combinations (FDCs) are needed to facilitate antiretroviral therapy in children. We evaluated the relative bioavailability, safety, and therapeutic adequacy of a novel chewable pediatric FDC tablet of stavudine (7 mg), lamivudine (30 mg), and nevirapine (50 mg), referred to as GPO-VIR S7, and compared it with the individual original brand-name liquid formulations in human immunodeficiency virus-infected Thai children. Methods: The International Maternal Pediatric Adolescent AIDS Clinical Trials group (IMPAACT) P1056 study was a phase I/II, 2-arm, randomized, open-label, multidose pharmacokinetic cross-over study. Children >= 6 to <= 30 kg receiving nevirapine-based HAART for at least 4 weeks were randomized to receive GPO-VIR S7 chewable tablets or the equivalent liquid formulations. Children were stratified by weight and dosing was weight-based. Intensive 12-hour blood sampling was performed on day 28, and subjects then crossed-over to the alternate formulation at equal doses with identical 12-hour sampling on day 56. Pharmacokinetic indices were determined by noncompartmental analysis. Results: Thirty-four children completed the study. While taking Government Pharmaceutical Organization (GPO)-VIR S7 the geometric mean (90% CI) area under the curve was 1.54 mu g.hr/mL (1.42-1.67) for stavudine, 6.39 (5.82-7.00) for lamivudine, and 74.06 (65.62-83.60) for nevirapine. Nevirapine drug exposure for GPO-VIR S7 was therapeutically adequate. Geometric mean area under the curve ratios (90% CI) of GPO-VIR S7/liquid formulation for stavudine, lamivudine, and nevirapine were 0.97 (0.92-1.02), 1.41 (1.30-1.53), and 1.08 (1.04-1.13), respectively. No serious drug-related toxicity was reported. Conclusions: The chewable FDC was safe and provided therapeutically adequate plasma drug exposures in human immunodeficiency virus-infected children. Substituting the FDC for liquid formulations can simplify antiretroviral therapy. C1 [Vanprapar, Nirun; Chokephaibulkit, Kulkanya; Prasitsuebsai, Wasana] Mahidol Univ, Dept Pediat, Fac Med, Siriraj Hosp, Bangkok 10700, Thailand. [Cressey, Tim R.] Chiang Mai Univ, Dept Med Technol, Program HIV Prevent & Treatment IRD, Fac Associated Med Sci, Chiang Mai 50000, Thailand. [Cressey, Tim R.; Muresan, Petronella; McIntosh, Kenneth] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Plipat, Nottasorn] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Sirisanthana, Virat; McIntosh, Kenneth] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [Hongsiriwan, Suchat] Chonburi Reg Hosp, Dept Pediat, Chon Buri, Thailand. [Chotpitayasunondh, Tawee] QSNICH, Bangkok, Thailand. [Eksaengsri, Achara] GPO, Bangkok, Thailand. [Toye, MariPat] Baystate Med Ctr, Dept Pediat, Springfield, MA 01199 USA. [Smith, Mary Elizabeth] NIAID, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Pediat Pharmacol Res Unit, Boston, MA 02115 USA. [Capparelli, Edmund] Univ Calif San Diego, San Diego, CA 92103 USA. [Yogev, Ram] Chicago Childrens Mem Hosp, Chicago, IL USA. RP Chokephaibulkit, K (reprint author), Mahidol Univ, Dept Pediat, Fac Med, Siriraj Hosp, 2 Prannok Rd, Bangkok 10700, Thailand. EM sikch@mahidol.ac.th FU NIAID NIH HHS [U01 AI068632-03, 1 U01 AI068616, 5 U01 AI41110, AI068632, U01 AI041110, U01 AI068616, U01 AI068632, U01 AI069429, U01AI069429, UM1 AI068632]; NICHD NIH HHS [HHSN267200800001C]; NIDDK NIH HHS [HHSN267200800001G] NR 31 TC 18 Z9 18 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2010 VL 29 IS 10 BP 940 EP 944 DI 10.1097/INF.0b013e3181e2189d PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 653EC UT WOS:000282069700009 PM 20453709 ER PT J AU Walsh, TJ Maertens, JA Madero, L Reilly, AF Lehrnbecher, T Groll, AH Jafri, HS Green, M Nania, JJ Bourque, MR Wise, BA Strohmaier, KM Taylor, AF Kartsonis, NA Chow, JW Arndt, CAS dePauw, B AF Walsh, Thomas J. Maertens, Johan A. Madero, Luis Reilly, Anne F. Lehrnbecher, Thomas Groll, Andreas H. Jafri, Hasan S. Green, Michael Nania, Joseph J. Bourque, Michael R. Wise, Beth Ann Strohmaier, Kim M. Taylor, Arlene F. Kartsonis, Nicholas A. Chow, Joseph W. Arndt, Carola A. S. dePauw, Ben E. TI Caspofungin Versus Liposomal Amphotericin B Are They Really Comparable? Reply SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Letter ID PEDIATRIC-PATIENTS; ANTIFUNGAL THERAPY; PERSISTENT FEVER; MULTICENTER; NEUTROPENIA; INFECTIONS; CHILDREN C1 [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Walsh, Thomas J.] Cornell Univ, Transplantat Oncol Infect Dis Program, Weill Cornell Med Coll, New York, NY 10021 USA. [Maertens, Johan A.] Katholieke Univ Leuven Hosp, Acute Leukemia & Stem Cell Transplantat Unit, Dept Hematol, Leuven, Belgium. [Madero, Luis] Hosp Univ Nino Jesus, Madrid, Spain. [Reilly, Anne F.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA USA. [Lehrnbecher, Thomas] Goethe Univ Frankfurt, Frankfurt, Germany. [Groll, Andreas H.] Univ Childrens Hosp Munster, Infect Dis Res Program, Dept Pediat Hematol Oncol, Munster, Germany. [Jafri, Hasan S.] Univ Texas SW Med Ctr Dallas, Div Pediat Infect Dis, Dept Pediat, Dallas, TX 75390 USA. [Jafri, Hasan S.] MedImmune, Clin Dev, Gaithersburg, MD USA. [Green, Michael] Childrens Hosp Pittsburgh, Dept Pediat Surg & Clin, Div Infect Dis, Pittsburgh, PA 15213 USA. [Green, Michael] Childrens Hosp Pittsburgh, Dept Translat Sci, Div Infect Dis, Pittsburgh, PA 15213 USA. [Nania, Joseph J.] Vanderbilt Univ, Dept Pediat, Div Pediat Infect Dis, Nashville, TN USA. [Bourque, Michael R.; Wise, Beth Ann; Strohmaier, Kim M.; Taylor, Arlene F.; Kartsonis, Nicholas A.; Chow, Joseph W.] Merck Res Labs, N Wales, PA USA. [Arndt, Carola A. S.] Mayo Clin, Rochester, MN USA. [dePauw, Ben E.] Radboud Univ Nijmegen, Nijmegen Med Ctr, NL-6525 ED Nijmegen, Netherlands. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2010 VL 29 IS 10 BP 986 EP 987 DI 10.1097/INF.0b013e3181f2d88c PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 653EC UT WOS:000282069700025 ER PT J AU Staber, J Burnightt, E Korsakov, P Sarvida, ME McCaffrey, A Kaminski, J McCray, P AF Staber, Janice Burnightt, Erin Korsakov, Pasha Sarvida, Marie-Ellen McCaffrey, Anton Kaminski, Joseph McCray, Paul TI A GENE TRANSFER APPROACH TOWARDS HEMOPHILIA A CORRECTION USING THE PIGGYBAC TRANSPOSON VECTOR SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT 51st Scientific Meeting on Annual Midwest Society-for-Pediatric-Research CY OCT 21-22, 2010 CL Iowa City, IA SP Midwest Soc Pediat Res C1 [Staber, Janice; Burnightt, Erin; Korsakov, Pasha] UIHC, Dept Pediat, Iowa City, IA USA. [Sarvida, Marie-Ellen] Loyola Univ Hlth Syst, Maywood, IL USA. [McCaffrey, Anton] UIHC, Iowa City, IA USA. [Kaminski, Joseph] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2010 VL 68 IS 4 MA 10 BP 356 EP 356 PG 1 WC Pediatrics SC Pediatrics GA 653FO UT WOS:000282074100026 ER PT J AU Benjamin, DK Stoll, BJ Gantz, MG Walsh, MC Sanchez, PJ Das, A Shankaran, S Higgins, RD Auten, KJ Miller, NA Walsh, TJ Laptook, AR Carlo, WA Kennedy, KA Finer, NN Duara, S Schibler, K Chapman, RL Van Meurs, KP Frantz, ID Phelps, DL Poindexter, BB Bell, EF O'Shea, TM Watterberg, KL Goldberg, RN AF Benjamin, Daniel K., Jr. Stoll, Barbara J. Gantz, Marie G. Walsh, Michele C. Sanchez, Pablo J. Das, Abhik Shankaran, Seetha Higgins, Rosemary D. Auten, Kathy J. Miller, Nancy A. Walsh, Thomas J. Laptook, Abbot R. Carlo, Waldemar A. Kennedy, Kathleen A. Finer, Neil N. Duara, Shahnaz Schibler, Kurt Chapman, Rachel L. Van Meurs, Krisa P. Frantz, Ivan D., III Phelps, Dale L. Poindexter, Brenda B. Bell, Edward F. O'Shea, T. Michael Watterberg, Kristi L. Goldberg, Ronald N. CA Eunice Kennedy Shriver Natl Inst TI Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment SO PEDIATRICS LA English DT Article DE candidiasis; premature infant; risk factors ID BIRTH-WEIGHT INFANTS; FLUCONAZOLE PROPHYLAXIS; INVASIVE CANDIDIASIS; FUNGAL COLONIZATION; CANDIDEMIA; INFECTION; SUSCEPTIBILITY; MULTICENTER; THERAPY AB OBJECTIVE: Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight (< 1000-g) infants. We quantified risk factors that predict infection in premature infants at high risk and compared clinical judgment with a prediction model of invasive candidiasis. METHODS: The study involved a prospective observational cohort of infants < 1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis. RESULTS: Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from >= 1 of these sources: blood (n = 96); cerebrospinal fluid (n = 9); urine obtained by catheterization (n = 52); or other sterile body fluid (n = 10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled >= 50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. CONCLUSION: Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment. Pediatrics 2010;126:e865-e873 C1 [Stoll, Barbara J.] Emory Univ & Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA USA. [Gantz, Marie G.] RTI Int, Statist Epidemiol Unit, Res Triangle Pk, NC USA. [Walsh, Michele C.] Case Western Reserve Univ, Dept Pediat, Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Sanchez, Pablo J.; Miller, Nancy A.] Univ Texas Dallas, Dept Pediat, SW Med Ctr, Dallas, TX 75230 USA. [Das, Abhik] RTI Int, Statist & Epidemiol Unit, Rockville, MD USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Walsh, Thomas J.] Human Dev & Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Women & Infants Hosp, Providence, RI 02912 USA. [Carlo, Waldemar A.] Univ Alabama, Dept Pediat, Birmingham, AL USA. [Kennedy, Kathleen A.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Finer, Neil N.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Duara, Shahnaz] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Schibler, Kurt] Cincinnati Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH USA. [Chapman, Rachel L.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Frantz, Ivan D., III] Tufts Med Ctr, Boston, MA USA. [Phelps, Dale L.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Poindexter, Brenda B.] Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Bell, Edward F.] Univ Iowa, Iowa City, IA USA. [O'Shea, T. Michael] Wake Forest Univ, Winston Salem, NC 27109 USA. [Watterberg, Kristi L.] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Auten, Kathy J.; Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. RP Benjamin, DK (reprint author), Duke Clin, Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM danny.benjamin@duke.edu FU Thrasher Research Fund; NICHD [HD044799]; National Institutes of Health FX Dr Benjamin received support from the Thrasher Research Fund and the NICHD (grant HD044799). The National Institutes of Health and NICHD provided grant support for the Neonatal Research Network's candidiasis study (recruitment 2004-2007). Data collected at participating sites of the NICHD NRN were transmitted to RTI International, the data-coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the NRN, Drs Das (DCC principal investigator) and Gantz (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. Dr Benjamin also had full access to all of the data in the study through RTI International and had final responsibility for the decision to submit for publication.; The NRN steering committee chairs were Alan H. Jobe, MD, PhD (University of Cincinnati) (2001-2006) and Michael S. Caplan, MD (University of Chicago Pritzker School of Medicine) (2006-2011). The following investigators (and NIH/NICHD grant numbers), in addition to those listed as authors, participated in this study: William Oh, MD, and Angelita Hensman, BSN, RNC (Brown University, Women & Infants Hospital of Rhode Island) (U10 HD27904); Nancy S. Newman, BA, RN (Case Western Reserve University and Rainbow Babies & Children's Hospital) (CCTS UL1 RR24989, GCRC M01 RR80, and U10 HD21364); C. Michael Cotten, MD, and Katherine A. Foy, RN (Duke University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital) (CCTS UL1 RR24128, GCRC M01 RR30, and U10 HD40492); Ellen C. Hale, RN, BS, CCRC, Ann M. Blackwelder, RNC, MS, and Michelle Tidwell, BSN (Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory Hospital Midtown) (CCTS UL1 RR25008, GCRC M01 RR39, and U10 HD27851); Stephanie Wilson Archer, MA (NICHD); Brenda L. MacKinnon, RNC, Ellen Nylen, RN, and Anne Furey, MPH (Floating Hospital for Children at Tufts Medical Center) (GCRC M01 RR54 and U10 HD53119); James A. Lemons, MD, Dianne Herron, RN, Lucy Miller, RN, BSN, CCRC, and Leslie D. Wilson, RN, BSN (Indiana University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services) (GCRC M01 RR750 and U10 HD27856); W. Kenneth Poole, PhD, Betty Hastings, Carolyn Petrie Huitema, MS, Kristin M. Zaterka-Baxter, RN, Scott E. Schaefer, MS, and Jeanette O'Donnell Auman, BS (RTI International) (U10 HD36790); David K. Stevenson, MD, M. Bethany Ball, BS, CCRC, and Melinda S. Proud, RCP (Lucile Packard Children's Hospital) (GCRC M01 RR70 and U10 HD27880); Monica V. Collins, RN, BSN, MaEd, and Shirley S. Cosby, RN, BSN (University of Alabama at Birmingham Health System and Children's Hospital of Alabama) (GCRC M01 RR32 and U10 HD34216); Maynard R. Rasmussen, MD, David Kaegi, MD, Kathy Arnell, RNC, Clarence Demetrio, RN, Chris Henderson, RCP, CRTT, and Wade Rich, BSHS, RRT (University of California-San Diego Medical Center and Sharp Mary Birch Hospital for Women) (U10 HD40461); Kurt Schibler, MD, Edward F. Donovan, MD, Kathleen Bridges, MD, Barbara Alexander, RN, Cathy Grisby, BSN, CCRC, Holly L. Mincey, RN, BSN, and Jody Hessing, RN (Cincinnati Children's Hospital Medical Center, University of Cincinnati Hospital, and Good Samaritan Hospital) (GCRC M01 RR8084 and U10 HD27853); Karen J. Johnson, RN, BSN (University of Iowa Children's Hospital) (CTSA UL1 RR24979, GCRC M01 RR59, and U10 HD53109); Ruth Everett-Thomas, RN, MSN (University of Miami Holtz Children's Hospital) (GCRC M01 RR16587 and U10 HD21397); Conra Backstrom Lacy, RN (University of New Mexico Health Sciences Center) (GCRC M01 RR997 and U10 HD53089); Linda J. Reubens, RN, CCRC, Erica Burnell, RN, Cassandra A. Horihan, MS, and Rosemary L. Jensen (University of Rochester Golisano Children's Hospital) (GCRC M01 RR44 and U10 HD40521); Walid A. Salhab, MD, Charles R. Rosenfeld, MD, Gaynelle Hensley, RN, and Melissa H. Leps, RN, and Alicia Guzman (University of Texas Southwestern Medical Center at Dallas Parkland Health & Hospital System and Children's Medical Center Dallas) (CCTS UL1 RR24982, GCRC M01 RR633, and U10 HD40689); Jon E. Tyson, MD, MPH, Esther G. Akpa, RN, BSN, Beverly Harris, RN, BSN, Anna E. Lis, RN, BSN, Georgia E. McDavid, RN, Sarah Martin, RN, BSN, and Patti L.; Pierce Tate, RCP (University of Texas Health Science Center at Houston Medical School and Childrens Memorial Hermann Hospital) (U10 HD21373); Roger G. Faix, MD, Bradley A. Yoder, MD, Karen A. Osborne, RN, BSN, Jennifer J. Jensen, RN, BSN, Cynthia Spencer, RNC, R. Edison Steele, RN, Karena Strong, RN, BSN, and Kimberlee Weaver-Lewis, RN, BSN (University of Utah University Hospital, LDS Hospital, and Primary Children's Medical Center) (CTSA UL1 RR25764, GCRC M01 RR64, and U10 HD53124); Nancy J. Peters, RN, CCRP (Wake Forest University Baptist Medical Center, Forsyth Medical Center, and Brenner Children's Hospital) (GCRC M01 RR7122 and U10 HD40498); Rebecca Bara, RN, BSN (Wayne State University, Hutzel Women's Hospital and Children's Hospital of Michigan) (U10 HD21385); and Richard A. Ehrenkranz, MD, Rachel L. Chapman, MD, Patricia Gettner, RN, and Monica Konstantino, RN, BSN (Yale University and Yale-New Haven Children's Hospital) (CCTS UL1 RR24139, GCRC M01 RR6022, and U10 HD27871). NR 24 TC 90 Z9 92 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2010 VL 126 IS 4 BP E865 EP E873 DI 10.1542/peds.2009-3412 PG 9 WC Pediatrics SC Pediatrics GA 658WW UT WOS:000282526100014 PM 20876174 ER PT J AU Choi, SH Aid, S Choi, U Bosetti, F AF Choi, S-H Aid, S. Choi, U. Bosetti, F. TI Cyclooxygenases-1 and-2 differentially modulate leukocyte recruitment into the inflamed brain SO PHARMACOGENOMICS JOURNAL LA English DT Article DE LPS; cyclooxygenase; neuroinflammation; leukocyte ID CENTRAL-NERVOUS-SYSTEM; NONSTEROIDAL ANTIINFLAMMATORY AGENTS; EXPERIMENTAL PNEUMOCOCCAL MENINGITIS; DENDRITIC CELL-MIGRATION; NECROSIS-FACTOR-ALPHA; PROSTAGLANDIN E-2; INFLAMMATORY RESPONSE; BARRIER PERMEABILITY; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE AB Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Cyclooxygenase (COX)-derived prostaglandins promote the migration of several immune cells in vitro, however, the specific roles of COX-1 and -2 on leukocyte recruitment in vivo have not been investigated. To examine the specific effects of COX-1 or COX-2 deficiency on neuroinflammation-induced leukocyte infiltration, we used a model of intracerebroventricular lipopolysaccharide (LPS)-induced neuroinflammation in COX-1(-/-), COX-2(-/-), and their respective wild-type (WT) ((+/+)) mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1(-/-) and increased in COX-2(-/-) mice, compared with their respective WT controls. This influx of leukocytes was accompanied by a marked disruption of blood-brain barrier and differential expression of chemokines. These results indicate that COX-1 and COX-2 deletion differentially modulate leukocyte recruitment during neuroinflammation, and suggest that inhibition of COX-1 activity is beneficial, whereas COX-2 inhibition is detrimental, during a primary neuroinflammatory response. The Pharmacogenomics Journal (2010) 10, 448-457; doi:10.1038/tpj.2009.68; published online 29 December 2009 C1 [Choi, S-H; Aid, S.; Bosetti, F.] NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Choi, U.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, 9 Mem Dr,Bldg 9,Rm 1S126, Bethesda, MD 20892 USA. EM frances@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX We thank Dr Robert Langenbach (Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health) for providing COX-1 / , COX-2 / , and their WT mice. This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 70 TC 25 Z9 27 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD OCT PY 2010 VL 10 IS 5 BP 448 EP 457 DI 10.1038/tpj.2009.68 PG 10 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 660DM UT WOS:000282619700008 PM 20038958 ER PT J AU Ohlmann, P de Castro, S Brown, GG Gachet, C Jacobson, KA Harden, TK AF Ohlmann, Philippe de Castro, Sonia Brown, Garth G., Jr. Gachet, Christian Jacobson, Kenneth A. Harden, T. Kendall TI Quantification of recombinant and platelet P2Y(1) receptors utilizing a [I-125]-labeled high-affinity antagonist 2-iodo-N-6-methyl-(N)-methanocarba-2 '-deoxyadenosine-3 ',5 '-bisphosphate ([I-126]MRS2500) SO PHARMACOLOGICAL RESEARCH LA English DT Article DE P2Y1 receptor; Competitive antagonist; Radioligand; MRS2500; Platelet ID GENETIC POLYMORPHISMS; P2Y1 RECEPTOR; ACTIVATION; ADP; AGGREGATION; AGONIST; PATHOPHYSIOLOGY; DESENSITIZATION; CLOPIDOGREL; DIMORPHISM AB The ADP-activated P2Y(1) receptor is broadly expressed and plays a crucial role in ADP-promoted platelet aggregation. We previously synthesized 2-iodo-N6-methy1-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate (MR52500), as a selective, high-affinity, competitive antagonist of this receptor. Here we report utilization of a trimethylstannyl precursor molecule for the multi-step radiochemical synthesis of a [I-125]-labeled form of MRS2500. [I-125]MRS2500 bound selectively to Sf9 insect cell membranes expressing the human P2Y(1) receptor but did not specifically bind to membranes isolated from empty vector-infected cells. Binding of [I-125]MRS2500 to P2Y(1) receptors was saturable with a Kd of 1.2 nM. Known agonists and antagonists of the P2Y(1) receptor inhibited [I-125]MRS2500 binding to P2Y(1) receptor-expressing membranes with potencies in agreement with those previously observed in functional assays of this receptor. A high-affinity binding site for [I-125]MRS2500 also was observed on intact human platelets (Kd = 0.61 nM) and mouse platelets (Kd =1.20 nM) that exhibited the pharmacological selectivity of the P2Y(1) receptor. The densities of sites observed were 151 sites/platelet and 229 sites/platelet in human and mouse platelets, respectively. In contrast, specific binding was not observed in platelets isolated from P2Y(1) receptor(-/-) mice. Taken together, these data illustrate the synthesis and characterization of a novel P2Y(1) receptor radioligand and its utility for examining P2Y(1) receptors natively expressed on human and mouse platelets. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Ohlmann, Philippe; Gachet, Christian] INSERM, UMR S949, F-67087 Strasbourg, France. [Ohlmann, Philippe; Gachet, Christian] Univ Strasbourg, F-67087 Strasbourg, France. [de Castro, Sonia; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. [Brown, Garth G., Jr.] PerkinElmer Inc, Waltham, MA 02451 USA. RP Harden, TK (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, CB 7365, Chapel Hill, NC 27599 USA. EM tkh@med.unc.edu RI de castro, sonia/E-7303-2012; Jacobson, Kenneth/A-1530-2009; Gachet, Christian/H-9156-2016 OI de castro, sonia/0000-0002-3838-6856; Jacobson, Kenneth/0000-0001-8104-1493; FU National Institutes of Health [GM38213]; NIDDK; Ministerio de Educacion y Ciencia, Spain FX We thank Anthony Joseph (PerkinElmer) for technical assistance. This work was supported by National Institutes of Health grant GM38213 and by the NIDDK Intramural Research Program. S. de Castro thanks Ministerio de Educacion y Ciencia, Spain for financial support. NR 27 TC 13 Z9 13 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD OCT PY 2010 VL 62 IS 4 BP 344 EP 351 DI 10.1016/j.phrs.2010.05.007 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 644IN UT WOS:000281368600008 PM 20594939 ER PT J AU Arko, L Katsyv, I Park, GE Luan, WP Park, JK AF Arko, Leopold Katsyv, Igor Park, Grace E. Luan, William Patrick Park, John K. TI Experimental approaches for the treatment of malignant gliomas SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Malignant glioma; Glioblastoma; Anaplastic astrocytoma; Chemotherapy; Biologic therapy; Immunotherapy; Clinical trial ID GROWTH-FACTOR RECEPTOR; PHASE-II TRIAL; RECURRENT GLIOBLASTOMA-MULTIFORME; TYROSINE KINASE INHIBITOR; HIGH-GRADE GLIOMA; NEWLY-DIAGNOSED GLIOBLASTOMA; BRAIN-TUMOR CONSORTIUM; ACTIVATED KILLER-CELLS; CENTRAL-NERVOUS-SYSTEM; LONG-TERM SURVIVAL AB Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review. Published by Elsevier Inc. C1 [Arko, Leopold; Katsyv, Igor; Luan, William Patrick; Park, John K.] NINDS, Surg & Mol Neurooncol Unit, NIH, Bethesda, MD 20892 USA. [Arko, Leopold] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. [Arko, Leopold] Univ New Mexico Sch Med, Albuquerque, NM USA. [Park, Grace E.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Park, JK (reprint author), 35 Convent Dr,Rm 2B-1002, Bethesda, MD 20892 USA. EM parkjk@ninds.nih.gov OI Arko, Leopold/0000-0003-1052-5671; Luan, William Patrick/0000-0003-4731-937X FU National Institute of Neurological Disorders and Stroke, NIH; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; Howard Hughes Medical Institute-National Institutes of Health FX This work was supported by the intramural research programs of the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, and the Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program. NR 446 TC 46 Z9 46 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD OCT PY 2010 VL 128 IS 1 BP 1 EP 36 DI 10.1016/j.pharmthera.2010.04.015 PG 36 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662XE UT WOS:000282846800001 PM 20546782 ER PT J AU Lopez-Novoa, JM Martinez-Salgado, C Rodriguez-Pena, AB Hernandez, FJL AF Lopez-Novoa, Jose M. Martinez-Salgado, Carlos Rodriguez-Pena, Ana B. Lopez Hernandez, Francisco J. TI Common pathophysiological mechanisms of chronic kidney disease: Therapeutic perspectives SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Chronic renal disease; Animal models; Hypertension; Diabetes; Ureteral obstruction; Renal mass reduction; Therapy ID ANGIOTENSIN-CONVERTING-ENZYME; RENAL INTERSTITIAL FIBROSIS; PLATELET-ACTIVATING-FACTOR; SPONTANEOUSLY HYPERTENSIVE-RATS; GROWTH-FACTOR-BETA; UNILATERAL URETERAL OBSTRUCTION; II RECEPTOR BLOCKERS; SMOOTH-MUSCLE-CELLS; FACTOR-KAPPA-B; GLOMERULAR MESANGIAL CELLS AB It is estimated that over 10% of the adult population in developed countries have some degree of chronic kidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function that results in implementation of renal replacement therapy in the form of dialysis or renal transplant, which may also lead to death. CKD poses a growing problem to society as the incidence of the disease increases at an annual rate of 8%, and consumes up to 2% of the global health expenditure. CKD is caused by a variety of factors including diabetes, hypertension, infection, reduced blood supply to the kidneys, obstruction of the urinary tract and genetic alterations. The nephropathies associated with some of these conditions have been modeled in animals, this being crucial to understanding their pathophysiological mechanism and assessing prospective treatments at the preclinical level. This article reviews and updates the pathophysiological knowledge acquired primarily from experimental models and human studies of CKD. It also highlights the common mechanism(s) underlying the most relevant chronic nephropathies which lead to the appearance of a progressive, common renal phenotype regardless of aetiology. Based on this knowledge, a therapeutic horizon for the treatment of CKD is described. Present therapy primarily based upon renin-angiotensin inhibition, future diagnostics and therapeutic perspectives based upon anti-inflammatory, anti-fibrotic and hemodynamic approaches, new drugs targeting specific signaling pathways, and advances in gene and cell therapies, are all elaborated. (C) 2010 Elsevier Inc. All rights reserved. C1 [Martinez-Salgado, Carlos; Lopez Hernandez, Francisco J.] Hosp Univ Salamanca, Unidad Invest, Salamanca 37007, Spain. [Lopez-Novoa, Jose M.; Martinez-Salgado, Carlos; Lopez Hernandez, Francisco J.] Univ Salamanca, Unidad Fisiopatol Renal & Cardiovasc, Dept Fisiol & Farmacol, E-37008 Salamanca, Spain. [Rodriguez-Pena, Ana B.] NIH, Bethesda, MD 20892 USA. [Lopez-Novoa, Jose M.; Martinez-Salgado, Carlos; Lopez Hernandez, Francisco J.] Fdn Inigo Alvarez de Toledo, Inst Reina Sofia Invest Nefrol, Toledo, Spain. RP Hernandez, FJL (reprint author), Hosp Univ Salamanca, Unidad Invest, Paseo San Vicente 58-182, Salamanca 37007, Spain. EM flopezher@usal.es RI IBSAL, Secretaria/H-3719-2011; Martinez-Salgado, Carlos/E-7299-2012; OI Lopez-Novoa, Jose M./0000-0002-6211-7269 NR 322 TC 29 Z9 31 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD OCT PY 2010 VL 128 IS 1 BP 61 EP 81 DI 10.1016/j.pharmthera.2010.05.006 PG 21 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662XE UT WOS:000282846800003 PM 20600306 ER PT J AU Gerstenblith, MR Shi, JX Landi, MT AF Gerstenblith, Meg R. Shi, Jianxin Landi, Maria Teresa TI Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE GWAS (genome-wide association study); pigmentation; skin cancer; melanoma; basal cell carcinoma; nevi; meta-analysis ID MELANOCORTIN-1 RECEPTOR MC1R; BASAL-CELL CARCINOMA; CUTANEOUS MALIGNANT-MELANOMA; GENE VARIANTS; KIT-LIGAND; EYE-COLOR; SUSCEPTIBILITY LOCI; PANCREATIC-CANCER; GERMLINE MUTATION; SEQUENCE VARIANTS AB P>Recent genome-wide association studies (GWAS) identified genetic loci associated with pigmentation, nevi, and skin cancer. We performed a review and meta-analysis of GWAS results, grouping them into four categories: (i) loci associated with pigmentation (hair, eye, and/or skin color), cutaneous UV-response (sun sensitivity and/or freckling), and skin cancer; (ii) loci associated with nevi and melanoma; (iii) loci associated with pigmentation and/or cutaneous UV-response but not skin cancer; and (iv) loci associated distinctly with skin cancer, mostly basal cell carcinoma, but not pigmentation or cutaneous UV-response. These findings suggest at least two pathways for melanoma development (via pigmentation and via nevi), and two pathways for basal cell carcinoma development (via pigmentation and independent of pigmentation). However, further work is necessary to separate the association with skin cancer from the association with pigmentation. As with any GWAS, the identified loci may not include the causal variants and may need confirmation by direct genome sequencing. C1 [Gerstenblith, Meg R.; Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Shi, Jianxin] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. 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 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This study was supported by the Intramural Research Program of NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The authors thank Drs. David Duffy, Hongmei Nan, Jiali Han, Mario Falchi, and Patrick Sulem for sharing data that allowed meta-analysis and refined associations for specific loci, and Barbara Rogers, William Wheeler, and Sara De Matteis for help with the graphical items. NR 76 TC 51 Z9 54 U1 2 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD OCT PY 2010 VL 23 IS 5 BP 587 EP 606 DI 10.1111/j.1755-148X.2010.00730.x PG 20 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 646OO UT WOS:000281552100007 PM 20546537 ER PT J AU Kauffman, GB Pentimalli, R Doldi, S Hall, MD AF Kauffman, George B. Pentimalli, Raffaele Doldi, Sandro Hall, Matthew D. TI Michele Peyrone (1813-1883), Discoverer of Cisplatin SO PLATINUM METALS REVIEW LA English DT Article AB The Italian chemist Michele Peyrone (1813-1883) was the first to synthesise cisplatin (cis-diamminedichloro-platinum (II)), the basis of today's most widely used family of anticancer drugs. This biographical article aims to present, for the first time in the English language, a summary of his life and the achievements that he made during his scientific career. Originally trained in medicine, Peyrone moved to chemistry and attended some of the most prestigious institutions in Europe in his time. He wrote several publications describing his work on 'Peyrone's chloride' (PtCl(2)(NH(3))(2)) and Magnus' green salt ([Pt(NH(3))(4)][PtCl(4)]). He later turned his attention to agricultural science where he defended important advances in the understanding of plant growth. Michele Peyrone's dedication to science is best summarised in the English translation of his first report on the synthesis of cisplatin: "I am determined to pursue this subject with all my energies, without having regard for the difficulties to be encountered at every step in so expensive and delicate a research". C1 [Kauffman, George B.] Calif State Univ Fresno, Dept Chem, Fresno, CA 93740 USA. [Pentimalli, Raffaele] Univ Valle Aosta, I-11100 Aosta, Italy. [Hall, Matthew D.] NCI, NIH, Dr Michael M Gottesmans Lab, Bethesda, MD 20892 USA. RP Kauffman, GB (reprint author), Calif State Univ Fresno, Dept Chem, Fresno, CA 93740 USA. EM georgek@csufresno.edu; raffaele.pentimalli@virgilio.it; hallma@mail.nih.gov FU National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA FX This research was partly supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. NR 40 TC 10 Z9 10 U1 5 U2 23 PU JOHNSON MATTHEY PUBL LTD CO PI LONDON PA HATTON GARDEN, LONDON EC1N 8EE, ENGLAND SN 1471-0676 J9 PLATIN MET REV JI Platin. Met. Rev. PD OCT PY 2010 VL 54 IS 4 BP 250 EP 256 DI 10.1595/147106710X534326 PG 7 WC Chemistry, Physical SC Chemistry GA 663IX UT WOS:000282878400007 ER PT J AU Babayan, SA Read, AF Lawrence, RA Bain, O Allen, JE AF Babayan, Simon A. Read, Andrew F. Lawrence, Rachel A. Bain, Odile Allen, Judith E. TI Filarial Parasites Develop Faster and Reproduce Earlier in Response to Host Immune Effectors That Determine Filarial Life Expectancy SO PLOS BIOLOGY LA English DT Article ID VACCINE-INDUCED PROTECTION; BLOOD FLUKE DEVELOPMENT; MURINE FILARIASIS; LITOMOSOIDES-SIGMODONTIS; BRUGIA-MALAYI; SCHISTOSOMA-MANSONI; PRIMARY INFECTION; T-CELLS; MICE; INTERLEUKIN-5 AB Humans and other mammals mount vigorous immune assaults against helminth parasites, yet there are intriguing reports that the immune response can enhance rather than impair parasite development. It has been hypothesized that helminths, like many free-living organisms, should optimize their development and reproduction in response to cues predicting future life expectancy. However, immune-dependant development by helminth parasites has so far eluded such evolutionary explanation. By manipulating various arms of the immune response of experimental hosts, we show that filarial nematodes, the parasites responsible for debilitating diseases in humans like river blindness and elephantiasis, accelerate their development in response to the IL-5 driven eosinophilia they encounter when infecting a host. Consequently they produce microfilariae, their transmission stages, earlier and in greater numbers. Eosinophilia is a primary host determinant of filarial life expectancy, operating both at larval and at late adult stages in anatomically and temporally separate locations, and is implicated in vaccine-mediated protection. Filarial nematodes are therefore able to adjust their reproductive schedules in response to an environmental predictor of their probability of survival, as proposed by evolutionary theory, thereby mitigating the effects of the immune attack to which helminths are most susceptible. Enhancing protective immunity against filarial nematodes, for example through vaccination, may be less effective at reducing transmission than would be expected and may, at worst, lead to increased transmission and, hence, pathology. C1 [Babayan, Simon A.; Allen, Judith E.] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. [Babayan, Simon A.; Read, Andrew F.; Allen, Judith E.] Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Edinburgh, Midlothian, Scotland. [Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Read, Andrew F.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lawrence, Rachel A.] Univ London Royal Vet Coll, London, England. [Bain, Odile] Museum Natl Hist Nat, USM 307, F-75231 Paris, France. RP Babayan, SA (reprint author), Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. EM s.babayan@ed.ac.uk RI Allen, Judith/C-9198-2011; Babayan, Simon/E-1807-2011 OI Allen, Judith/0000-0002-3829-066X; Babayan, Simon/0000-0002-4949-1117 FU European Union [ICA4-CT- 1999-10002, INCO-CT-2006-03232]; Fogarty International Center; National Institutes of Health; BBSRC; Wellcome Trust FX This work was funded by a European Union Marie-Curie Fellowship, EU grants "VARBO" (INCO-DEV contract ICA4-CT- 1999-10002) and "SCOOTT" (INCO-CT-2006-03232), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, the BBSRC, and the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 45 Z9 45 U1 2 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD OCT PY 2010 VL 8 IS 10 AR e1000525 DI 10.1371/journal.pbio.1000525 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 671IQ UT WOS:000283495100021 PM 20976099 ER PT J AU Conze, DB Zhao, YG Ashwell, JD AF Conze, Dietrich B. Zhao, Yongge Ashwell, Jonathan D. TI Non-Canonical NF-kappa B Activation and Abnormal B Cell Accumulation in Mice Expressing Ubiquitin Protein Ligase-Inactive c-IAP2 SO PLOS BIOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; LYMPHOID-TISSUE LYMPHOMAS; MALT LYMPHOMA; TNF-ALPHA; DEPENDENT APOPTOSIS; SIGNALING PATHWAY; MULTIPLE-MYELOMA; NF-KAPPA-B2 P100; SURVIVAL SIGNALS; TRAF2 AB Chromosomal translocations between loci encoding MALT1 and c-IAP2 are common in MALT lymphomas. The resulting fusion proteins lack the c-IAP2 RING domain, the region responsible for its ubiquitin protein ligase (E3) activity. Ectopic expression of the fusion protein activates the canonical NF-kappa B signaling cascade, but how it does so is controversial and how it promotes MALT lymphoma is unknown. Considering recent reports implicating c-IAP1 and c-IAP2 E3 activity in repression of non-canonical NF-kappa B signaling, we asked if the c-IAP2/ MALT fusion protein can initiate non-canonical NF-kappa B activation. Here we show that in addition to canonical activation, the fusion protein stabilizes NIK and activates non-canonical NF-kappa B. Canonical but not non-canonical activation depended on MALT1 paracaspase activity, and expression of E3-inactive c-IAP2 activated non-canonical NF-kappa B. Mice in which endogenous c-IAP2 was replaced with an E3-inactive mutant accumulated abnormal B cells with elevated non-canonical NF-kappa B and had increased numbers of B cells with a marginal zone phenotype, gut-associated lymphoid hyperplasia, and other features of MALT lymphoma. Thus, the c-IAP2/MALT1 fusion protein activates NF-kappa B by two distinct mechanisms, and loss of c-IAP2 E3 activity in vivo is sufficient to induce abnormalities common to MALT lymphoma. C1 [Conze, Dietrich B.; Zhao, Yongge; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Conze, DB (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU National Institutes of Health; Center for Cancer Research, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 32 Z9 32 U1 0 U2 1 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 OCT PY 2010 VL 8 IS 10 AR e1000518 DI 10.1371/journal.pbio.1000518 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 671IQ UT WOS:000283495100016 PM 21048983 ER PT J AU Goldfarb, T Lichten, M AF Goldfarb, Tamara Lichten, Michael TI Frequent and Efficient Use of the Sister Chromatid for DNA Double-Strand Break Repair during Budding Yeast Meiosis SO PLOS BIOLOGY LA English DT Article ID SYNAPTONEMAL COMPLEX-FORMATION; MEIOTIC RECOMBINATION; SACCHAROMYCES-CEREVISIAE; HOLLIDAY JUNCTIONS; JOINT MOLECULES; INTERHOMOLOG RECOMBINATION; CROSSOVER INTERFERENCE; CHROMOSOME SYNAPSIS; CROSSING-OVER; GENE ENCODES AB Recombination between homologous chromosomes of different parental origin (homologs) is necessary for their accurate segregation during meiosis. It has been suggested that meiotic inter-homolog recombination is promoted by a barrier to inter-sister-chromatid recombination, imposed by meiosis-specific components of the chromosome axis. Consistent with this, measures of Holliday junction-containing recombination intermediates (joint molecules [JMs]) show a strong bias towards inter-homolog and against inter-sister JMs. However, recombination between sister chromatids also has an important role in meiosis. The genomes of diploid organisms in natural populations are highly polymorphic for insertions and deletions, and meiotic double-strand breaks (DSBs) that form within such polymorphic regions must be repaired by inter-sister recombination. Efforts to study inter-sister recombination during meiosis, in particular to determine recombination frequencies and mechanisms, have been constrained by the inability to monitor the products of inter-sister recombination. We present here molecular-level studies of inter-sister recombination during budding yeast meiosis. We examined events initiated by DSBs in regions that lack corresponding sequences on the homolog, and show that these DSBs are efficiently repaired by inter-sister recombination. This occurs with the same timing as inter-homolog recombination, but with reduced (2- to 3-fold) yields of JMs. Loss of the meiotic-chromosome-axis-associated kinase Mek1 accelerates inter-sister DSB repair and markedly increases inter-sister JM frequencies. Furthermore, inter-sister JMs formed in mek1 Delta mutants are preferentially lost, while inter-homolog JMs are maintained. These findings indicate that inter-sister recombination occurs frequently during budding yeast meiosis, with the possibility that up to one-third of all recombination events occur between sister chromatids. We suggest that a Mek1-dependent reduction in the rate of inter-sister repair, combined with the destabilization of inter-sister JMs, promotes inter-homolog recombination while retaining the capacity for inter-sister recombination when inter-homolog recombination is not possible. C1 [Goldfarb, Tamara; Lichten, Michael] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Goldfarb, T (reprint author), NCI, Biochem & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM lichten@helix.nih.gov RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 FU National Cancer Institute; National Institutes of Health FX This work was supported by the Intramural Research Program at the National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 65 Z9 65 U1 2 U2 5 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 OCT PY 2010 VL 8 IS 10 AR e1000520 DI 10.1371/journal.pbio.1000520 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 671IQ UT WOS:000283495100018 PM 20976044 ER PT J AU Andres, AM Dennis, MY Kretzschmar, WW Cannons, JL Lee-Lin, SQ Hurle, B Schwartzberg, PL Williamson, SH Bustamante, CD Nielsen, R Clark, AG Green, ED AF Andres, Aida M. Dennis, Megan Y. Kretzschmar, Warren W. Cannons, Jennifer L. Lee-Lin, Shih-Queen Hurle, Belen Schwartzberg, Pamela L. Williamson, Scott H. Bustamante, Carlos D. Nielsen, Rasmus Clark, Andrew G. Green, Eric D. CA NISC Comparative Sequencing Progra TI Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation SO PLOS GENETICS LA English DT Article ID ENDOPLASMIC-RETICULUM AMINOPEPTIDASES; CLASS-I MOLECULES; HISTOCOMPATIBILITY COMPLEX LOCI; GENOME-WIDE ASSOCIATION; ANKYLOSING-SPONDYLITIS; PROCESSING MACHINERY; CERVICAL-CARCINOMA; NATURAL-SELECTION; NUCLEOTIDE SUBSTITUTION; OVERDOMINANT SELECTION AB A remarkable characteristic of the human major histocompatibility complex (MHC) is its extreme genetic diversity, which is maintained by balancing selection. In fact, the MHC complex remains one of the best-known examples of natural selection in humans, with well-established genetic signatures and biological mechanisms for the action of selection. Here, we present genetic and functional evidence that another gene with a fundamental role in MHC class I presentation, endoplasmic reticulum aminopeptidase 2 (ERAP2), has also evolved under balancing selection and contains a variant that affects antigen presentation. Specifically, genetic analyses of six human populations revealed strong and consistent signatures of balancing selection affecting ERAP2. This selection maintains two highly differentiated haplotypes (Haplotype A and Haplotype B), with frequencies 0.44 and 0.56, respectively. We found that ERAP2 expressed from Haplotype B undergoes differential splicing and encodes a truncated protein, leading to nonsense-mediated decay of the mRNA. To investigate the consequences of ERAP2 deficiency on MHC presentation, we correlated surface MHC class I expression with ERAP2 genotypes in primary lymphocytes. Haplotype B homozygotes had lower levels of MHC class I expressed on the surface of B cells, suggesting that naturally occurring ERAP2 deficiency affects MHC presentation and immune response. Interestingly, an ERAP2 paralog, endoplasmic reticulum aminopeptidase 1 (ERAP1), also shows genetic signatures of balancing selection. Together, our findings link the genetic signatures of selection with an effect on splicing and a cellular phenotype. Although the precise selective pressure that maintains polymorphism is unknown, the demonstrated differences between the ERAP2 splice forms provide important insights into the potential mechanism for the action of selection. C1 [Andres, Aida M.; Dennis, Megan Y.; Kretzschmar, Warren W.; Lee-Lin, Shih-Queen; Hurle, Belen; Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Cannons, Jennifer L.; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Williamson, Scott H.; Bustamante, Carlos D.] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY USA. [Nielsen, Rasmus] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA. RP Andres, AM (reprint author), Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Leipzig, Germany. EM aida.andres@eva.mpg.de RI Nielsen, Rasmus/D-4405-2009; Andres, Aida/B-4088-2014 OI Nielsen, Rasmus/0000-0003-0513-6591; Andres, Aida/0000-0002-8590-9672 FU National Human Genome Research Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 85 TC 72 Z9 72 U1 0 U2 7 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 OCT PY 2010 VL 6 IS 10 AR e1001157 DI 10.1371/journal.pgen.1001157 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 673GP UT WOS:000283647800028 PM 20976248 ER PT J AU Gaudet, MM Kirchhoff, T Green, T Vijai, J Korn, JM Guiducci, C Segre, AV McGee, K McGuffog, L Kartsonaki, C Morrison, J Healey, S Sinilnikova, OM Stoppa-Lyonnet, D Mazoyer, S Gauthier-Villars, M Sobol, H Longy, M Frenay, M Hogervorst, FBL Rookus, MA Collee, JM Hoogerbrugge, N van Roozendaal, KEP Piedmonte, M Rubinstein, W Nerenstone, S Van Le, L Blank, SV Caldes, T de la Hoya, M Nevanlinna, H Aittomaki, K Lazaro, C Blanco, I Arason, A Johannsson, OT Barkardottir, RB Devilee, P Olopade, OI Neuhausen, SL Wang, XS Fredericksen, ZS Peterlongo, P Manoukian, S Barile, M Viel, A Radice, P Phelan, CM Narod, S Rennert, G Lejbkowicz, F Flugelman, A Andrulis, IL Glendon, G Ozcelik, H Toland, AE Montagna, M D'Andrea, E Friedman, E Laitman, Y Borg, A Beattie, M Ramus, SJ Domchek, SM Nathanson, KL Rebbeck, T Spurdle, AB Chen, XQ Holland, H John, EM Hopper, JL Buys, SS Daly, MB Southey, MC Terry, MB Tung, N Hansen, TVO Nielsen, FC Greene, MI Mai, PL Osorio, A Duran, M Andres, R Benitez, J Weitzel, JN Garber, J Hamann, U Peock, S Cook, M Oliver, C Frost, D Platte, R Evans, DG Lalloo, F Eeles, R Izatt, L Walker, L Eason, J Barwell, J Godwin, AK Schmutzler, RK Wappenschmidt, B Engert, S Arnold, N Gadzicki, D Dean, M Gold, B Klein, RJ Couch, FJ Chenevix-Trench, G Easton, DF Daly, MJ Antoniou, AC Altshuler, DM Offit, K AF Gaudet, Mia M. Kirchhoff, Tomas Green, Todd Vijai, Joseph Korn, Joshua M. Guiducci, Candace Segre, Ayellet V. McGee, Kate McGuffog, Lesley Kartsonaki, Christiana Morrison, Jonathan Healey, Sue Sinilnikova, Olga M. Stoppa-Lyonnet, Dominique Mazoyer, Sylvie Gauthier-Villars, Marion Sobol, Hagay Longy, Michel Frenay, Marc Hogervorst, Frans B. L. Rookus, Matti A. Collee, J. Margriet Hoogerbrugge, Nicoline van Roozendaal, Kees E. P. Piedmonte, Marion Rubinstein, Wendy Nerenstone, Stacy Van Le, Linda Blank, Stephanie V. Caldes, Trinidad de la Hoya, Miguel Nevanlinna, Heli Aittomaki, Kristiina Lazaro, Conxi Blanco, Ignacio Arason, Adalgeir Johannsson, Oskar T. Barkardottir, Rosa B. Devilee, Peter Olopade, Olofunmilayo I. Neuhausen, Susan L. Wang, Xianshu Fredericksen, Zachary S. Peterlongo, Paolo Manoukian, Siranoush Barile, Monica Viel, Alessandra Radice, Paolo Phelan, Catherine M. Narod, Steven Rennert, Gad Lejbkowicz, Flavio Flugelman, Anath Andrulis, Irene L. Glendon, Gord Ozcelik, Hilmi Toland, Amanda E. Montagna, Marco D'Andrea, Emma Friedman, Eitan Laitman, Yael Borg, Ake Beattie, Mary Ramus, Susan J. Domchek, Susan M. Nathanson, Katherine L. Rebbeck, Tim Spurdle, Amanda B. Chen, Xiaoqing Holland, Helene John, Esther M. Hopper, John L. Buys, Saundra S. Daly, Mary B. Southey, Melissa C. Terry, Mary Beth Tung, Nadine Hansen, Thomas V. Overeem Nielsen, Finn C. Greene, Mark I. Mai, Phuong L. Osorio, Ana Duran, Mercedes Andres, Raquel Benitez, Javier Weitzel, Jeffrey N. Garber, Judy Hamann, Ute Peock, Susan Cook, Margaret Oliver, Clare Frost, Debra Platte, Radka Evans, D. Gareth Lalloo, Fiona Eeles, Ros Izatt, Louise Walker, Lisa Eason, Jacqueline Barwell, Julian Godwin, Andrew K. Schmutzler, Rita K. Wappenschmidt, Barbara Engert, Stefanie Arnold, Norbert Gadzicki, Dorothea Dean, Michael Gold, Bert Klein, Robert J. Couch, Fergus J. Chenevix-Trench, Georgia Easton, Douglas F. Daly, Mark J. Antoniou, Antonis C. Altshuler, David M. Offit, Kenneth CA GEMO Study Collaborators HEBON Study Collaborators OCGN kConFab TI Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer SO PLOS GENETICS LA English DT Article ID BRCA2 MUTATION CARRIERS; SUSCEPTIBILITY GENES; RECURRENT BRCA1; RISK; POPULATION; MODEL; PREDISPOSITION; ASSOCIATION; PHENOTYPE; FREQUENCY AB The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. C1 [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, New York, NY USA. [Kirchhoff, Tomas; Vijai, Joseph; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Sloan Kettering Inst, Clin Genet Serv, New York, NY 10021 USA. [Kirchhoff, Tomas] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10021 USA. [Green, Todd; Korn, Joshua M.; Guiducci, Candace; Daly, Mark J.; Altshuler, David M.] Harvard Univ, Sch Med, Broad Inst Harvard, Boston, MA USA. [Green, Todd; Korn, Joshua M.; Guiducci, Candace; Daly, Mark J.; Altshuler, David M.] Harvard Univ, Sch Med, MIT, Boston, MA USA. [Segre, Ayellet V.] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Segre, Ayellet V.] MIT, Cambridge, MA 02139 USA. [Segre, Ayellet V.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Segre, Ayellet V.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [McGee, Kate; Dean, Michael; Gold, Bert] NCI, Ctr Canc Res, Canc Inflammat Program, Human Genet Sect, Frederick, MD 21701 USA. [McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Sinilnikova, Olga M.] CHU Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Sinilnikova, Olga M.; Mazoyer, Sylvie] Univ Lyon, Ctr Leon Berard, CNRS UMR5201, Equipe Labellisee LIGUE 2008, Lyon, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, INSERM U830, Serv Genet, Inst Curie, F-75248 Paris, France. [Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion] Inst Curie, Serv Genet Oncol, Paris, France. [Sobol, Hagay] Univ Aix Marseille 2, Inst J Paoli I Calmettes, INSERM CIC P9502, Dept Oncol Genet Prevent & Depistage, F-13284 Marseille 07, France. [Longy, Michel] Inst Bergonie, Bordeaux, France. [Frenay, Marc] Ctr Antoine Lacassagne, F-06054 Nice, France. [GEMO Study Collaborators] Fed Natl Ctr Lutte Contre Canc, GEMO Study Canc Genet Network Grp Genet & Canc, Paris, France. [Hogervorst, Frans B. L.; HEBON Study Collaborators] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Med Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Hoogerbrugge, Nicoline] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [van Roozendaal, Kees E. P.] Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Piedmonte, Marion] Roswell Pk Canc Inst, Gynecol Oncol Grp Stat, Buffalo, NY 14263 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Ctr Data, Buffalo, NY 14263 USA. [Rubinstein, Wendy] NorthShore Univ Hlth Syst, Evanston, IL USA. [Nerenstone, Stacy] Hartford Hosp, Cent Connecticut Canc Consortium, Hartford, CT 06115 USA. [Van Le, Linda] Univ N Carolina, Chapel Hill, NC USA. [Blank, Stephanie V.] NYU, Sch Med, New York, NY USA. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Lazaro, Conxi; Blanco, Ignacio] Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain. [Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.] Landspitali LSH, Dept Oncol, Reykjavik, Iceland. [Arason, Adalgeir; Barkardottir, Rosa B.] Landspitali LSH, Dept Pathol, Reykjavik, Iceland. [Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Olopade, Olofunmilayo I.] Univ Chicago, Med Ctr, Dept Med, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Wang, Xianshu; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Fredericksen, Zachary S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Expt Oncol & Mol Med, Unit Genet Susceptibil Canc, Milan, Italy. [Peterlongo, Paolo; Radice, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Manoukian, Siranoush] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Barile, Monica] IEO, Div Canc Prevent & Genet, Milan, Italy. [Viel, Alessandra] IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Narod, Steven] Womens Coll Res Inst, Toronto, ON, Canada. [Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath] CHS Natl Canc Control Ctr, Haifa, Israel. [Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Andrulis, Irene L.; Ozcelik, Hilmi] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; OCGN] Univ Toronto, Ontario Canc Genet Network, Toronto, ON, Canada. [Toland, Amanda E.] Ohio State Univ, Dept Mol Virol, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Dept Immunol, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Dept Med Genet & Internal Med, Columbus, OH 43210 USA. [Montagna, Marco; D'Andrea, Emma] IRCCS, Ist Oncol Veneto, Immunol & Mol Oncol Unit, Padua, Italy. [D'Andrea, Emma] Univ Padua, Dept Oncol & Surg Sci, Padua, Italy. [Friedman, Eitan; Laitman, Yael] Sheba Med Ctr, Inst Genet, Susan Levy Gertner Oncogenet Unit, Tel Hashomer, Israel. [Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Beattie, Mary] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Ramus, Susan J.] UCL, UCL EGA Inst Womens Hlth, Gynaecol Oncol Unit, London WC1E 6BT, England. [Domchek, Susan M.] Hosp Univ Penn, Dept Oncol, Philadelphia, PA 19104 USA. [Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Cell & Mol Biol, Philadelphia, PA 19104 USA. [Rebbeck, Tim] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene] Queensland Inst Med Res, Genet & Populat Hlth Div, Brisbane, Qld 4006, Australia. [Chenevix-Trench, Georgia; kConFab] Peter MacCallum Canc Ctr, Melbourne, Australia. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Hopper, John L.] Univ Melbourne, Ctr Genet Epidemiol, Melbourne, Vic, Australia. [Buys, Saundra S.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Southey, Melissa C.] Univ Melbourne, Ctr Genet Epidemiol, Melbourne, Vic, Australia. [Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Hansen, Thomas V. Overeem; Nielsen, Finn C.] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Greene, Mark I.; Mai, Phuong L.] NCI, Clin Genet Branch, Rockville, MD USA. [Osorio, Ana; Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Duran, Mercedes] Univ Valladolid IBGM UVA, Inst Biol & Mol Genet, Valladolid, Spain. [Andres, Raquel] Hosp Clin Univ Lozano Blesa, Oncol Serv, Zaragoza, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain. [Weitzel, Jeffrey N.] City Hope Canc Ctr, Duarte, CA USA. [Garber, Judy] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamann, Ute] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. [Evans, D. Gareth; Lalloo, Fiona] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Ros] Inst Canc Res, Oncogenet Team, London SW3 6JB, England. [Eeles, Ros] Royal Marsden NHS Fdn Trust, London, England. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, London, England. [Walker, Lisa] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Eason, Jacqueline] Nottingham Univ Hosp NHS Trust, Nottingham Clin Genet Serv, Nottingham, England. [Barwell, Julian] Univ Hosp Leicester NHS Trust, Leicestershire Clin Genet Serv, Leicester, Leics, England. [Godwin, Andrew K.] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, CIO, Cologne, Germany. [Engert, Stefanie] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Obstet & Gynaecol, D-8000 Munich, Germany. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Kiel, Germany. [Gadzicki, Dorothea] Hannover Med Sch, Inst Cell & Mol Pathol, D-3000 Hannover, Germany. RP Gaudet, MM (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. EM offitk@mskcc.org RI Spurdle, Amanda/A-4978-2011; Radice, Paolo/O-3119-2013; Blanco, Ignacio/D-2565-2013; Osorio, Ana/I-4324-2014; GLADIEFF, Laurence/O-5129-2014; Ligtenberg, Marjolijn/N-9666-2013; manoukian, siranoush/E-7132-2017; Altshuler, David/A-4476-2009; Klein, Robert/K-1888-2013; Hoogerbrugge, Nicoline/O-1016-2013; Segre, Ayellet/E-9800-2010; Arnold, Norbert/E-3012-2010; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Dean, Michael/G-8172-2012; D'Andrea, Emma/B-4374-2013; Andrulis, Irene/E-7267-2013; Joseph, Vijai/J-9158-2013 OI Evans, Gareth/0000-0002-8482-5784; Ramus, Susan/0000-0003-0005-7798; Spurdle, Amanda/0000-0003-1337-7897; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364; Blanco, Ignacio/0000-0002-7414-7481; Osorio, Ana/0000-0001-8124-3984; GLADIEFF, Laurence/0000-0002-6980-9719; Ligtenberg, Marjolijn/0000-0003-1290-1474; manoukian, siranoush/0000-0002-6034-7562; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Altshuler, David/0000-0002-7250-4107; Klein, Robert/0000-0003-3539-5391; Arnold, Norbert/0000-0003-4523-8808; montagna, marco/0000-0002-4929-2150; Dean, Michael/0000-0003-2234-0631; Joseph, Vijai/0000-0002-7933-151X FU Starr Cancer Research Consortium; Breast Cancer Research Foundation; NIH NCI [P20CA103694-3]; Lymphoma Foundation; Robert and Kate Niehaus Clinical Cancer Genetics Initiative at MSKCC FX This study was supported by the Starr Cancer Research Consortium and the Breast Cancer Research Foundation, as well as by NIH NCI: P20CA103694-3 and the Lymphoma Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The LUMC study would like to thank Hans Vasen, Inge van Leeuwen, and Hanne Meijers for patient accrual. For the CNIO study, the authors would like to thank R. M. Alonso, G. Pita and R. M. Milne for their assistance. We thank IBGM, Universidad de Valladolid and Consejeria de Sanidad Junta de Castilla y Leon. For the SWE-BRCA, the authors would like to also acknowledge the contribution of Per Karlsson, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren Linkoping University Hospital; Ake Borg, Niklas Loman, Hakan Olsson, Ulf Kristoffersson, Helena Jernstrom, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Gronberg, Eva-Lena Stattin and Monica Emanuelsson, Umea University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital. Douglas F. Easton is the PI of the EMBRACE study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare Oliver, Debra Frost. North of Scotland Regional Genetics Service, Aberdeen: Helen Gregory, Zosia Miedzybrodzka. Northern Ireland Regional Genetics Service, Belfast: Patrick J. Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown, Kai-Ren Ong, Laura Boyes. South Western Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson. All Wales Medical Genetics Services, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous. Peninsula Clinical Genetics Service. Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Gabriella Pichert, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Carol Chu, Tim Bishop, Julie Miller. Merseyside & Cheshire Clinical Genetics Service. Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Felicity Holt. North East Thames Regional Genetics Service, North East Thames: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durrell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins. Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South Essex Cancer Research Network, Southend: Anne Robinson.; South West Thames Regionl Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester. Wessex Clinical Genetics Service. Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Emma Tyler, Donna McBride. HEBCS thanks Dr. Carl Blomqvist and Tuomas Heikkinen for their help with the patient data and samples. Fox Chase Cancer Center (FCCC) thanks Ms. JoEllen Weaver and Mr. John Malick for expert technical assistance. The UCSF study would like to acknowledge Ms. Salina Chan for her database management assistance. CONsorzio Studi Italiani Tumori Ereditari Alla Mammella, CONSIT TEAM acknowledges Marco Pierotti, Bernard Peissel, Daniela Zaffaroni and Carla B. Ripamonti of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Bernardo Bonanni of the Istituto Europeo di Oncologia, Milan, Italy and Loris Bernard of the Cogentech, Consortium for Genomic Technologies, Milan, Italy. CBCS would like to thank Bent Ejlerten, Mette K. Andersen, Susanne Kjaergaard and Anne-Marie Gerdes for clinical data. The authors wish to thank Nichole Hansen for help in manuscript preparation. The authors also acknowledge support of the Robert and Kate Niehaus Clinical Cancer Genetics Initiative at MSKCC. NR 43 TC 56 Z9 58 U1 0 U2 8 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 OCT PY 2010 VL 6 IS 10 AR e1001183 DI 10.1371/journal.pgen.1001183 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 673GP UT WOS:000283647800014 PM 21060860 ER PT J AU Ikram, MK Xueling, S Jensen, RA Cotch, MF Hewitt, AW Ikram, MA Wang, JJ Klein, R Klein, BEK Breteler, MMB Cheung, N Liew, G Mitchell, P Uitterlinden, AG Rivadeneira, F Hofman, A de Jong, PTVM van Duijn, CM Kao, L Cheng, CY Smith, AV Glazer, NL Lumley, T McKnight, B Psaty, BM Jonasson, F Eiriksdottir, G Aspelund, T Harris, TB Launer, LJ Taylor, KD Li, XH Iyengar, SK Xi, QS Sivakumaran, TA Mackey, DA MacGregor, S Martin, NG Young, TL Bis, JC Wiggins, KL Heckbert, SR Hammond, CJ Andrew, T Fahy, S Attia, J Holliday, EG Scott, RJ Islam, FMA Rotter, JI McAuley, AK Boerwinkle, E Tai, ES Gudnason, V Siscovick, DS Vingerling, JR Wong, TY AF Ikram, M. Kamran Xueling, Sim Jensen, Richard A. Cotch, Mary Frances Hewitt, Alex W. Ikram, M. Arfan Wang, Jie Jin Klein, Ronald Klein, Barbara E. K. Breteler, Monique M. B. Cheung, Ning Liew, Gerald Mitchell, Paul Uitterlinden, Andre G. Rivadeneira, Fernando Hofman, Albert de Jong, Paulus T. V. M. van Duijn, Cornelia M. Kao, Linda Cheng, Ching-Yu Smith, Albert Vernon Glazer, Nicole L. Lumley, Thomas McKnight, Barbara Psaty, Bruce M. Jonasson, Fridbert Eiriksdottir, Gudny Aspelund, Thor Harris, Tamara B. Launer, Lenore J. Taylor, Kent D. Li, Xiaohui Iyengar, Sudha K. Xi, Quansheng Sivakumaran, Theru A. Mackey, David A. MacGregor, Stuart Martin, Nicholas G. Young, Terri L. Bis, Josh C. Wiggins, Kerri L. Heckbert, Susan R. Hammond, Christopher J. Andrew, Toby Fahy, Samantha Attia, John Holliday, Elizabeth G. Scott, Rodney J. Islam, F. M. Amirul Rotter, Jerome I. McAuley, Annie K. Boerwinkle, Eric Tai, E. Shyong Gudnason, Vilmundur Siscovick, David S. Vingerling, Johannes R. Wong, Tien Y. CA Global BPgen Consortium TI Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo SO PLOS GENETICS LA English DT Article ID RETINAL VASCULAR CALIBER; GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; ANTIHYPERTENSIVE DRUG THERAPIES; GENOME-WIDE ASSOCIATION; VESSEL DIAMETERS; ATHEROSCLEROSIS RISK; CHARGE CONSORTIUM; DISEASE; METAANALYSIS; AGE AB There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0x10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61x10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25x10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15x10(-13), in the region of ATXN2, SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32x10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease. C1 [Ikram, M. Kamran; Ikram, M. Arfan; Breteler, Monique M. B.; Uitterlinden, Andre G.; Rivadeneira, Fernando; Hofman, Albert; van Duijn, Cornelia M.; Vingerling, Johannes R.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Kamran; Vingerling, Johannes R.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Ikram, M. Kamran] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Xueling, Sim] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Mol Epidemiol, Singapore 117595, Singapore. [Jensen, Richard A.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Hewitt, Alex W.; Wang, Jie Jin; Cheung, Ning; Islam, F. M. Amirul; McAuley, Annie K.; Wong, Tien Y.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Wang, Jie Jin; Liew, Gerald; Mitchell, Paul; Mackey, David A.] Univ Sydney, Ctr Vision Res, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Wang, Jie Jin; Liew, Gerald; Mitchell, Paul; Mackey, David A.] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Clin Chem, Rotterdam, Netherlands. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci, Amsterdam, Netherlands. [de Jong, Paulus T. V. M.] Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. [Kao, Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Cheng, Ching-Yu] Taipei Vet Gen Hosp, Dept Ophthalmol, Taipei, Taiwan. [Cheng, Ching-Yu] Natl Yang Ming Univ, Sch Med, Dept Ophthalmol, Taipei 112, Taiwan. [Smith, Albert Vernon; Eiriksdottir, Gudny; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Bis, Josh C.; Wiggins, Kerri L.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Lumley, Thomas; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Jonasson, Fridbert] Univ Iceland, Dept Ophthalmol, Reykjavik, Iceland. [Jonasson, Fridbert] Landspitalinn Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Aspelund, Thor] Univ Iceland, Dept Stat, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Taylor, Kent D.; Li, Xiaohui; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Iyengar, Sudha K.; Xi, Quansheng; Sivakumaran, Theru A.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Mackey, David A.] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Lions Eye Inst, Perth, WA 6009, Australia. [MacGregor, Stuart; Martin, Nicholas G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Young, Terri L.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Hammond, Christopher J.; Andrew, Toby; Fahy, Samantha] Kings Coll London, Sch Med, St Thomas Hosp, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Attia, John; Holliday, Elizabeth G.; Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci, Callaghan, NSW 2308, Australia. [Attia, John; Holliday, Elizabeth G.; Scott, Rodney J.] Hunter Med Res Inst, Newcastle, NSW, Australia. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol & Publ Hlth, Singapore 117595, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117595, Singapore. [Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore, Singapore. [Wong, Tien Y.] Singapore Eye Res Inst, Singapore, Singapore. [Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore 117595, Singapore. RP Ikram, MK (reprint author), Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. EM ophwty@nus.edu.sg RI Mackey, David/H-5340-2014; Bochud, Murielle/A-3981-2010; Grobbee, Diederick/C-7651-2014; van der Schouw, Yvonne/F-8327-2014; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Laan, Maris/A-4100-2011; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Hewitt, Alex/D-1936-2013; Smith, Albert/K-5150-2015; Matullo, Giuseppe/K-6383-2016; Fahy, Samantha/F-7966-2012; Pfeufer, Arne/B-6634-2013; Altshuler, David/A-4476-2009; Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Lucas, Gavin/D-4346-2012; Macgregor, Stuart/C-6442-2009; Colaus, PsyColaus/K-6607-2013; Attia, John/F-5376-2013 OI Luben, Robert/0000-0002-5088-6343; Sacerdote, Carlotta/0000-0002-8008-5096; Klein, Ronald/0000-0002-4428-6237; Hammond, Christopher/0000-0002-3227-2620; Ikram, Mohammad Kamran/0000-0003-0173-9571; Tai, E Shyong/0000-0003-2929-8966; Martin, Nicholas/0000-0003-4069-8020; Wain, Louise/0000-0003-4951-1867; Mackey, David/0000-0001-7914-4709; Bochud, Murielle/0000-0002-5727-0218; Seedorf, Udo/0000-0003-4652-5358; McAuley, Annie/0000-0002-6252-6185; Zeggini, Eleftheria/0000-0003-4238-659X; Cotch, Mary Frances/0000-0002-2046-4350; Org, Elin/0000-0003-1451-9375; Andrew, Toby/0000-0001-8838-4384; Ikram, Mohammad Arfan/0000-0003-0372-8585; Grobbee, Diederick/0000-0003-4472-4468; van der Schouw, Yvonne/0000-0002-4605-435X; Wang, Jie Jin/0000-0001-9491-4898; Laan, Maris/0000-0002-8519-243X; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Hewitt, Alex/0000-0002-5123-5999; Smith, Albert/0000-0003-1942-5845; Fahy, Samantha/0000-0002-2013-6154; Altshuler, David/0000-0002-7250-4107; Aspelund, Thor/0000-0002-7998-5433; Macgregor, Stuart/0000-0001-6731-8142; Attia, John/0000-0001-9800-1308 FU National Institute on Aging [Z01AG007380]; NIH [N01-AG-12100, Z01EY000426]; National Eye Institute [Z01EY000401]; Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652, T32HL007902]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; National Center for Research Resources [M01RR00069]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for scientific research (NWO); Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European commission; Municipality of Rotterdam; Australian National Health and Medical Research Council (NHMRC) FX Age Gene/Environment Susceptibility - Reykjavik Study: Age, Gene/Environment Susceptibility - Reykjavik Study received funding from the Intramural Research Program of the National Institute on Aging (Z01AG007380, NIH contract N01-AG-12100) and the National Eye Institute (Z01EY000401) at the National Institutes of Health, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Atherosclerosis Risk in Communities Study: The Atherosclerosis Risk in Communities is supported by the National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and R01HL087641; National Human Genome Research Institute award U01HG004402; NIH Intramural Research award Z01EY000426 from the National Eye Institute; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study: The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00069 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Additional support included the National Heart, Lung, and Blood Institute Training Grant T32HL007902 (RAJ). Rotterdam Study: The GWA database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (no. 175.010.2005.011). This study was further supported by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank Dr. Michael Moorhouse, Pascal Arp, and Mila Jhamai for their help in creating the database. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for scientific research (NWO); the Netherlands Organization for the Health Research and Development (ZonMw); The Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; The European commission (DG XII); and the Municipality of Rotterdam. The ophthalmic part of the Rotterdam Study was supported by Lijf en Leven, Krimpen a/d Lek; MD Fonds, Utrecht. Oogfonds Nederland, Utrecht; Stichting Nederlands Oogheelkundig Onderzoek, Nijmegen/Rotterdam; Swart van Essen, Rotterdam; Netherlands Organisation for Scientific Research (NWO); Bevordering van Volkskracht, Rotterdam; Blindenhulp, The Hague; Rotterdamse Vereniging Blindenbelangen, Rotterdam; OOG, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn; Blinden-Penning, Amsterdam; Blindenhulp, Gravenzande; Henkes Stichting, Rotterdam; Topcon Europe BV, Capelle aan de IJssel; Medical Workshop BV, Groningen; all in the Netherlands; Heidelberg Engineering, Dossenheim, Germany.; Australian Twins Study: The Australian Twin Registry is supported by an Australian National Health and Medical Research Council (NHMRC) Enaling Grant (2004-2009). We also thank the following organisations for their financial support: Clifford Craig Medical Research Trust, Ophthalmic Research Institute of Australia, Glaucoma Australia, American Health Assistance Foundation, Peggy and Leslie Cranbourne Foundation, Foundation for Children, NHMRC project grant (2005-2007), Jack Brockhoff Foundation, NEI Project Grant (2007-2010). NR 47 TC 64 Z9 67 U1 0 U2 9 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 OCT PY 2010 VL 6 IS 10 AR e1001184 DI 10.1371/journal.pgen.1001184 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 673GP UT WOS:000283647800015 PM 21060863 ER PT J AU Lefevre, GM Patel, SR Kim, D Tessarollo, L Dressler, GR AF Lefevre, Gaelle M. Patel, Sanjeevkumar R. Kim, Doyeob Tessarollo, Lino Dressler, Gregory R. TI Altering a Histone H3K4 Methylation Pathway in Glomerular Podocytes Promotes a Chronic Disease Phenotype SO PLOS GENETICS LA English DT Article ID CONTAINING PROTEIN PTIP; BRCT-DOMAIN; METHYLTRANSFERASE ACTIVITY; TRANSGENIC MICE; MESSENGER-RNA; STEM-CELLS; EXPRESSION; CHROMATIN; POLYCOMB; GROWTH AB Methylation of specific lysine residues in core histone proteins is essential for embryonic development and can impart active and inactive epigenetic marks on chromatin domains. The ubiquitous nuclear protein PTIP is encoded by the Paxip1 gene and is an essential component of a histone H3 lysine 4 (H3K4) methyltransferase complex conserved in metazoans. In order to determine if PTIP and its associated complexes are necessary for maintaining stable gene expression patterns in a terminally differentiated, non-dividing cell, we conditionally deleted PTIP in glomerular podocytes in mice. Renal development and function were not impaired in young mice. However, older animals progressively exhibited proteinuria and podocyte ultra structural defects similar to chronic glomerular disease. Loss of PTIP resulted in subtle changes in gene expression patterns prior to the onset of a renal disease phenotype. Chromatin immunoprecipitation showed a loss of PTIP binding and lower H3K4 methylation at the Ntrk3 (neurotrophic tyrosine kinase receptor, type 3) locus, whose expression was significantly reduced and whose function may be essential for podocyte foot process patterning. These data demonstrate that alterations or mutations in an epigenetic regulatory pathway can alter the phenotypes of differentiated cells and lead to a chronic disease state. C1 [Lefevre, Gaelle M.; Kim, Doyeob; Dressler, Gregory R.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Patel, Sanjeevkumar R.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Tessarollo, Lino] NCI, Neural Dev Sect, Frederick, MD 21701 USA. RP Lefevre, GM (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM dressler@umich.edu FU NIH [DK073722, DK054740] FX This work was supported by NIH grant DK073722 and DK054740 to GRD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 25 Z9 26 U1 0 U2 0 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 OCT PY 2010 VL 6 IS 10 AR e1001142 DI 10.1371/journal.pgen.1001142 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 673GP UT WOS:000283647800002 PM 21060806 ER PT J AU Cheung, GYC Rigby, K Wang, R Queck, SY Braughton, KR Whitney, AR Teintze, M Deleo, FR Otto, M AF Cheung, Gordon Y. C. Rigby, Kevin Wang, Rong Queck, Shu Y. Braughton, Kevin R. Whitney, Adeline R. Teintze, Martin DeLeo, Frank R. Otto, Michael TI Staphylococcus epidermidis Strategies to Avoid Killing by Human Neutrophils SO PLOS PATHOGENS LA English DT Article ID PHENOL-SOLUBLE MODULIN; POLYSACCHARIDE INTERCELLULAR ADHESIN; PEPTIDE-SENSING SYSTEM; AUREUS DELTA-TOXIN; IMMUNE EVASION; ANTIMICROBIAL PEPTIDES; BIOFILM FORMATION; VIRULENCE; EXPRESSION; ACID AB Staphylococcus epidermidis is a leading nosocomial pathogen. In contrast to its more aggressive relative S. aureus, it causes chronic rather than acute infections. In highly virulent S. aureus, phenol-soluble modulins (PSMs) contribute significantly to immune evasion and aggressive virulence by their strong ability to lyse human neutrophils. Members of the PSM family are also produced by S. epidermidis, but their role in immune evasion is not known. Notably, strong cytolytic capacity of S. epidermidis PSMs would be at odds with the notion that S. epidermidis is a less aggressive pathogen than S. aureus, prompting us to examine the biological activities of S. epidermidis PSMs. Surprisingly, we found that S. epidermidis has the capacity to produce PSM delta, a potent leukocyte toxin, representing the first potent cytolysin to be identified in that pathogen. However, production of strongly cytolytic PSMs was low in S. epidermidis, explaining its low cytolytic potency. Interestingly, the different approaches of S. epidermidis and S. aureus to causing human disease are thus reflected by the adaptation of biological activities within one family of virulence determinants, the PSMs. Nevertheless, S. epidermidis has the capacity to evade neutrophil killing, a phenomenon we found is partly mediated by resistance mechanisms to antimicrobial peptides (AMPs), including the protease SepA, which degrades AMPs, and the AMP sensor/resistance regulator, Aps (GraRS). These findings establish a significant function of SepA and Aps in S. epidermidis immune evasion and explain in part why S. epidermidis may evade elimination by innate host defense despite the lack of cytolytic toxin expression. Our study shows that the strategy of S. epidermidis to evade elimination by human neutrophils is characterized by a passive defense approach and provides molecular evidence to support the notion that S. epidermidis is a less aggressive pathogen than S. aureus. C1 [Cheung, Gordon Y. C.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Rigby, Kevin; Wang, Rong; Queck, Shu Y.; Braughton, Kevin R.; Whitney, Adeline R.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT USA. [Teintze, Martin] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. RP Cheung, GYC (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov RI Cheung, Yiu Chong /K-3565-2012; OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. 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 57 TC 64 Z9 66 U1 4 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2010 VL 6 IS 10 AR e1001133 DI 10.1371/journal.ppat.1001133 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 673IG UT WOS:000283652200009 PM 20949069 ER PT J AU Porotto, M Rockx, B Yokoyama, CC Talekar, A DeVito, I Palermo, LM Liu, J Cortese, R Lu, M Feldmann, H Pessi, A Moscona, A AF Porotto, Matteo Rockx, Barry Yokoyama, Christine C. Talekar, Aparna DeVito, Ilaria Palermo, Laura M. Liu, Jie Cortese, Riccardo Lu, Min Feldmann, Heinz Pessi, Antonello Moscona, Anne TI Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry SO PLOS PATHOGENS LA English DT Article ID HUMAN PARAINFLUENZA VIRUS; HEMAGGLUTININ-NEURAMINIDASE PROTEIN; EMERGENT DEADLY PARAMYXOVIRUS; HN-RECEPTOR INTERACTION; MEMBRANE-FUSION; POTENT INHIBITORS; HAMSTER MODEL; CELL-FUSION; 4-GU-DANA ZANAMIVIR; FATAL ENCEPHALITIS AB In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F) leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC) regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol-tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses. C1 [Porotto, Matteo; Yokoyama, Christine C.; Talekar, Aparna; DeVito, Ilaria; Palermo, Laura M.; Moscona, Anne] Cornell Univ, Weill Med Coll, Dept Pediat, New York, NY 10021 USA. [Porotto, Matteo; Yokoyama, Christine C.; Talekar, Aparna; DeVito, Ilaria; Palermo, Laura M.; Moscona, Anne] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. [Rockx, Barry; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Liu, Jie; Lu, Min] Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA. [Cortese, Riccardo] CEINGE, Naples, Italy. [Pessi, Antonello] PeptiPharma, Rome, Italy. RP Porotto, M (reprint author), Cornell Univ, Weill Med Coll, Dept Pediat, New York, NY 10021 USA. EM Map2028@med.Cornell.edu; anm2047@med.Cornell.edu FU National Institutes of Health (NIAID) [AI31971, AI076335, AI090354, AI079771]; NIH (NIAID) Northeast Center of Excellence for Bio-defense and Emerging Infectious Disease Research [U54AI057158]; Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work was supported by Public Health Service grants AI31971, AI076335, and AI090354 from the National Institutes of Health (NIAID) to AM, AI079771 to ML, NIH (NIAID) Northeast Center of Excellence for Bio-defense and Emerging Infectious Disease Research U54AI057158 grants to AM and MP (PI of Center of Excellence grant: W. I. Lipkin), and Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) to HF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 95 TC 47 Z9 47 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2010 VL 6 IS 10 AR e1001168 DI 10.1371/journal.ppat.1001168 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 673IG UT WOS:000283652200040 PM 21060819 ER PT J AU Talbi, C Lemey, P Suchard, MA Abdelatif, E Elharrak, M Jalal, N Faouzi, A Echevarria, JE Moron, SV Rambaut, A Campiz, N Tatem, AJ Holmes, EC Bourhy, H AF Talbi, Chiraz Lemey, Philippe Suchard, Marc A. Abdelatif, Elbia Elharrak, Mehdi Jalal, Nourlil Faouzi, Abdellah Echevarria, Juan E. Vazquez Moron, Sonia Rambaut, Andrew Campiz, Nicholas Tatem, Andrew J. Holmes, Edward C. Bourhy, Herve TI Phylodynamics and Human-Mediated Dispersal of a Zoonotic Virus SO PLOS PATHOGENS LA English DT Article ID DOG RABIES VIRUS; TRANSMISSION DYNAMICS; VACCINATION CAMPAIGN; POPULATION-DYNAMICS; MOLECULAR SEQUENCES; BITE INJURIES; CANINE RABIES; AFRICA; EVOLUTION; DISEASE AB Understanding the role of humans in the dispersal of predominately animal pathogens is essential for their control. We used newly developed Bayesian phylogeographic methods to unravel the dynamics and determinants of the spread of dog rabies virus (RABV) in North Africa. Each of the countries studied exhibited largely disconnected spatial dynamics with major geopolitical boundaries acting as barriers to gene flow. Road distances proved to be better predictors of the movement of dog RABV than accessibility or raw geographical distance, with occasional long distance and rapid spread within each of these countries. Using simulations that bridge phylodynamics and spatial epidemiology, we demonstrate that the contemporary viral distribution extends beyond that expected for RABV transmission in African dog populations. These results are strongly supportive of human-mediated dispersal, and demonstrate how an integrated phylogeographic approach will turn viral genetic data into a powerful asset for characterizing, predicting, and potentially controlling the spatial spread of pathogens. C1 [Talbi, Chiraz; Bourhy, Herve] Inst Pasteur, Unit Lyssavirus Dynam & Host Adaptat, WHO Collaborating Ctr Reference & Res Rabies, Paris, France. [Lemey, Philippe] Katholieke Univ Leuven, Rega Inst, Louvain, Belgium. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Elharrak, Mehdi] Biopharma Lab, Rabat, Morocco. [Abdelatif, Elbia] Inst Pasteur, Lab Rage Rech & Diagnost, Algiers, Algeria. [Jalal, Nourlil; Faouzi, Abdellah] Inst Pasteur Maroc, Med Virol Lab, Casablanca, Morocco. [Echevarria, Juan E.; Vazquez Moron, Sonia] Inst Salud Carlos III, Serv Microbiol Diagnost, Madrid, Spain. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Campiz, Nicholas; Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. RP Talbi, C (reprint author), Inst Pasteur, Unit Lyssavirus Dynam & Host Adaptat, WHO Collaborating Ctr Reference & Res Rabies, Paris, France. EM herve.bourhy@pasteur.fr RI Vazquez Moron, Sonia/H-7019-2013; Echevarria, Juan E./F-7913-2016; OI Vazquez Moron, Sonia/0000-0002-0977-741X; Echevarria, Juan E./0000-0001-7522-850X; Rambaut, Andrew/0000-0003-4337-3707; Holmes, Edward/0000-0001-9596-3552 FU European Union [INCO-CT-2006-517727]; Fund for Scientific Research (FWO) Flanders; National Institutes of Health (NIH) [R01 GM080533, R01 GM086887]; National Science Foundation [DMS 0856099]; European Community [260864] FX This work was supported by the European Union Project RABMEDCONTROL (FP6 Project: INCO-CT-2006-517727). PL was supported by a postdoctoral fellowship from the Fund for Scientific Research (FWO) Flanders. ECH was supported by National Institutes of Health (NIH) grant R01 GM080533, while MAS was partially supported by NIH grant R01 GM086887 and National Science Foundation grant DMS 0856099. The European Research Council has provided financial support under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no \#260864. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 68 Z9 68 U1 3 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2010 VL 6 IS 10 AR e1001166 DI 10.1371/journal.ppat.1001166 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 673IG UT WOS:000283652200038 PM 21060816 ER PT J AU Zaitseva, E Yang, ST Melikov, K Pourmal, S Chernomordik, LV AF Zaitseva, Elena Yang, Sung-Tae Melikov, Kamran Pourmal, Sergei Chernomordik, Leonid V. TI Dengue Virus Ensures Its Fusion in Late Endosomes Using Compartment-Specific Lipids SO PLOS PATHOGENS LA English DT Article ID SEMLIKI-FOREST-VIRUS; FLAVIVIRUS MEMBRANE-FUSION; PH-DEPENDENT FUSION; VESICULAR STOMATITIS-VIRUS; SINDBIS VIRUS; INFLUENZA HEMAGGLUTININ; CELL-FUSION; MONOCLONAL-ANTIBODIES; TARGET MEMBRANE; WEST-NILE AB Many enveloped viruses invade cells via endocytosis and use different environmental factors as triggers for virus-endosome fusion that delivers viral genome into cytosol. Intriguingly, dengue virus (DEN), the most prevalent mosquito-borne virus that infects up to 100 million people each year, fuses only in late endosomes, while activation of DEN protein fusogen glycoprotein E is triggered already at pH characteristic for early endosomes. Are there any cofactors that time DEN fusion to virion entry into late endosomes? Here we show that DEN utilizes bis(monoacylglycero) phosphate, a lipid specific to late endosomes, as a co-factor for its endosomal acidification-dependent fusion machinery. Effective virus fusion to plasma-and intracellular-membranes, as well as to protein-free liposomes, requires the target membrane to contain anionic lipids such as bis(monoacylglycero) phosphate and phosphatidylserine. Anionic lipids act downstream of low-pH-dependent fusion stages and promote the advance from the earliest hemifusion intermediates to the fusion pore opening. To reach anionic lipid-enriched late endosomes, DEN travels through acidified early endosomes, but we found that low pH-dependent loss of fusogenic properties of DEN is relatively slow in the presence of anionic lipid-free target membranes. We propose that anionic lipid-dependence of DEN fusion machinery protects it against premature irreversible restructuring and inactivation and ensures viral fusion in late endosomes, where the virus encounters anionic lipids for the first time during entry. Currently there are neither vaccines nor effective therapies for DEN, and the essential role of the newly identified DEN-bis(monoacylglycero) phosphate interactions in viral genome escape from the endosome suggests a novel target for drug design. C1 [Zaitseva, Elena; Yang, Sung-Tae; Melikov, Kamran; Pourmal, Sergei; Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. RP Zaitseva, E (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. EM chernoml@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; NIAID, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health and by an NIAID, National Institutes of Health Intramural Biodefense Research grant (both to L.V.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 96 Z9 98 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2010 VL 6 IS 10 AR e1001131 DI 10.1371/journal.ppat.1001131 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 673IG UT WOS:000283652200007 PM 20949067 ER PT J AU Huang, J Sun, LG Huang, W Wang, XM Wang, YH AF Huang, Jing Sun, Liguang Huang, Wen Wang, Xinming Wang, Yuhong TI The ecosystem evolution of penguin colonies in the past 8,500 years on Vestfold Hills, East Antarctica SO POLAR BIOLOGY LA English DT Article DE Antarctica; Penguin colony; Ecosystem evolution; Molecular marker; Ornithogenic sediment; Fecal sterol ID DIATOM ASSEMBLAGES; ICE-SHEET; SALINE LAKES; PRYDZ BAY; ACE LAKE; HOLOCENE; ISLAND; SEA; POPULATIONS; OCCUPATION AB Penguin colony is one of the Earth's simplest ecosystems. As the seabird with the largest population in Antarctica, penguin is a unique indicator of Antarctic environment and climate changes. In this study, we collected an ornithogenic sediment core from Gardner Island in Vestfold Hills, East Antarctica, reconstructed an 8,500 years variation history of penguin population and vegetation abundance on this island, and examined the evolution of the penguin colony. We used the levels of two molecular markers cholesterol and cholestanol as the proxy indicators of penguin population size. Other molecular markers, including C(24:0) alkenoic acid, C(18) n-alkanol and phytol were used as the proxy indicators of aquatic moss, algae, and general vegetation, respectively. It is shown that the growth of algae was mainly affected by the nutritional supply from penguin droppings, so their abundance was positively linked with penguin population. The growth of aquatic moss, however, was controlled more by the degree of water body transparency than by nutrient availability. Because the pollution of water body increased as penguin population grew, aquatic moss abundance showed a seesaw-like relationship with penguin population. These results suggested that penguins played a dominant role in this simple ecosystem in the Antarctic environment. The reconstructed relationship between penguin population and vegetation abundance may offer new insights to understand ancient Antarctic environment and ecology. C1 [Huang, Jing; Sun, Liguang] Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Anhui, Peoples R China. [Huang, Jing; Wang, Xinming] Chinese Acad Sci, Guangzhou Inst Geochem, Guangzhou 510640, Guangdong, Peoples R China. [Huang, Wen] Univ Wisconsin, Dept Dairy Sci, Madison, WI 53706 USA. [Wang, Yuhong] NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. RP Sun, LG (reprint author), Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Anhui, Peoples R China. EM slg@ustc.edu.cn RI Huang, Wen/B-5005-2011; Wang, Xinming/A-7388-2014 OI Wang, Xinming/0000-0002-1982-0928 FU National Natural Science Foundation of China [40730107]; National Science and Technology [2006BAB18B07]; State Key Laboratory of Organic Geochemistry foundation [OGL-200606]; Australia Antarctic Division Science Project [AAD2873] FX We thank the Chinese Arctic and Antarctic Administration, Australian Antarctic Division, CHINARE22 team in Zhongshan Station and the members of Davis Station for their support and assistance in the field working. We thank Prof. Renbin Zhu for sample collection. This study was funded by the National Natural Science Foundation of China (No. 40730107), the National Science and Technology Supporting Program (2006BAB18B07), the State Key Laboratory of Organic Geochemistry foundation (OGL-200606) and the Australia Antarctic Division Science Project (AAD2873). NR 44 TC 11 Z9 14 U1 4 U2 35 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0722-4060 J9 POLAR BIOL JI Polar Biol. PD OCT PY 2010 VL 33 IS 10 BP 1399 EP 1406 DI 10.1007/s00300-010-0832-x PG 8 WC Biodiversity Conservation; Ecology SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 649BD UT WOS:000281740300011 ER PT J AU Louis, SNS Chow, L Rezmann, L Krezel, MA Catt, KJ Tikellis, C Frauman, AG Louis, WJ AF Louis, Simon N. S. Chow, Laurie Rezmann, Linda Krezel, Michael A. Catt, Kevin J. Tikellis, Chris Frauman, Albert G. Louis, William J. TI Expression and Function of ATIP/MTUSI in Human Prostate Cancer Cell Lines SO PROSTATE LA English DT Article DE AT(2)-receptor; AT(2)-receptor interacting protein; prostate cancer cell line; epidermal growth factor ID GROWTH-FACTOR RECEPTOR; ANGIOTENSIN-II RECEPTORS; CONVERTING-ENZYME; AT2 RECEPTOR; ANTIPROLIFERATIVE ACTIVITY; INTERACTING PROTEIN; TUMOR-GROWTH; CARCINOMA; IDENTIFICATION; HYPERPLASIA AB BACKGROUND. We have previously demonstrated Ang II type 2 (AT(2)-) receptor-mediated inhibition of EGF-induced prostate cancer cell growth in androgen-dependent (LNCaP) and independent (PC3) prostate cancer cell lines. METHODS. To explore the signaling pathways involved in this inhibitory effect, we examined the interaction of the AT(2)-receptor with its novel regulatory partner ATIP using real time PCR, over-expression, siRNA and [(3)H] thymidine incorporation assays. RESULTS. The results in human prostate cancer cell lines demonstrate the presence of ATIP in both cell lines examined, and suggest that (i) the AT(2)-receptor through an interaction with ATIP mediates an anti-growth factor effect in both androgen-dependent and androgen-independent cell lines; (ii) ATIP expression decreases as the rate of cell growth and androgen-independence increase; and (iii) EGF may act on cell growth in part by reducing the content of ATIP present in the cells. CONCLUSIONS. The results support our earlier proposal in normal cell lines that ATIP is an important component of the cellular response to AT(2)-receptor activation. The results further suggest that a critical level of ATIP is required to mediate the effect of AT(2)-receptor activation to inhibit EGF mediated increases in cell growth. They also suggest that EGF may in part induce cell growth by suppressing the level of ATIP expression. Prostate 70: 1563-1574, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Louis, Simon N. S.; Chow, Laurie; Rezmann, Linda; Krezel, Michael A.; Frauman, Albert G.; Louis, William J.] Univ Melbourne, Clin Pharmacol & Therapeut Unit, Dept Med, Austin Hlth, Heidelberg, Vic 3084, Australia. [Catt, Kevin J.] NICHD, Sect Hormonal Regulat, PEDGEN, NIH, Bethesda, MD USA. [Tikellis, Chris] Baker Heart Res Inst, Melbourne, Vic, Australia. RP Louis, SNS (reprint author), Univ Melbourne, Clin Pharmacol & Therapeut Unit, Dept Med, Austin Hlth, Studley Rd,Level 5 Lance Townsend Bldg, Heidelberg, Vic 3084, Australia. EM simonnsl@unimelb.edu.au FU INSERM/NHMRC; Sir Edward Dunlop Medical Research Foundation; Austin Hospital Medical Research Foundation; University of Melbourne FX This work has been kindly supported by the INSERM/NH&MRC, Sir Edward Dunlop Medical Research Foundation, the Austin Hospital Medical Research Foundation and the University of Melbourne. The authors would also like to thank Dr. Clara Nahmias and Professor Pam Russell for their help in preparing this manuscript. NR 38 TC 14 Z9 15 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD OCT 1 PY 2010 VL 70 IS 14 BP 1563 EP 1574 DI 10.1002/pros.21192 PG 12 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 657IF UT WOS:000282405700009 PM 20687230 ER PT J AU Yan, JS Hereld, D Jin, T AF Yan, Jianshe Hereld, Dale Jin, Tian TI Chemotaxis: new role for Ras revealed SO PROTEIN & CELL LA English DT News Item C1 [Yan, Jianshe; Jin, Tian] NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Hereld, Dale] NIAAA, Div Metab & Hlth Effects, NIH, Rockville, MD 20852 USA. RP Yan, JS (reprint author), NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM yanjia@niaid.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU HIGHER EDUCATION PRESS PI BEIJING PA SHATANHOU ST 55, BEIJING 100009, PEOPLES R CHINA SN 1674-800X J9 PROTEIN CELL JI Protein Cell PD OCT PY 2010 VL 1 IS 10 BP 879 EP 880 DI 10.1007/s13238-010-0119-6 PG 2 WC Cell Biology SC Cell Biology GA V25XV UT WOS:000208511600001 PM 21204012 ER PT J AU Lu, JX Sharpe, S Ghirlando, R Yau, WM Tycko, R AF Lu, Jun-Xia Sharpe, Simon Ghirlando, Rodolfo Yau, Wai-Ming Tycko, Robert TI Oligomerization state and supramolecular structure of the HIV-1 Vpu protein transmembrane segment in phospholipid bilayers SO PROTEIN SCIENCE LA English DT Article DE solid-state NMR; analytical ultracentrifugation; photochemical crosslinking; membrane protein structure ID PHOTOINDUCED CROSS-LINKING; ION-CHANNEL ACTIVITY; VIRUS TYPE-1 VPU; MOLECULAR-DYNAMICS; BETA-TRCP; SEDIMENTATION-VELOCITY; MEMBRANE-PROTEINS; NMR-SPECTROSCOPY; ANALYTICAL ULTRACENTRIFUGATION; 3-DIMENSIONAL STRUCTURE AB HIV-1 Vpu is an 81-residue protein with a single N-terminal transmembrane (TM) helical segment that is involved in the release of new virions from host cell membranes. Vpu and its TM segment form ion channels in phospholipid bilayers, presumably by oligomerization of TM helices into a pore-like structure. We describe measurements that provide new constraints on the oligomerization state and supramolecular structure of residues 1-40 of Vpu (Vpu(1-40)), including analytical ultracentrifugation measurements to investigate oligomerization in detergent micelles, photo-induced crosslinking experiments to investigate oligomerization in bilayers, and solid-state nuclear magnetic resonance measurements to obtain constraints on intermolecular contacts between and orientations of TM helices in bilayers. From these data, we develop molecular models for Vpu TM oligomers. The data indicate that a variety of oligomers coexist in phospholipid bilayers, so that a unique supramolecular structure can not be defined. Nonetheless, since oligomers of various sizes have similar intermolecular contacts and orientations, molecular models developed from our data are most likely representative of Vpu TM oligomers that exist in host cell membranes. C1 [Lu, Jun-Xia; Yau, Wai-Ming; Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Sharpe, Simon] Hosp Sick Children, Program Mol Struct & Funct, Toronto, ON M5G 1X8, Canada. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Ghirlando, Rodolfo/A-8880-2009 FU Intramural Research Program; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX Grant sponsors: Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, NIH Intramural AIDS Targeted Antiviral Program. NR 74 TC 35 Z9 35 U1 0 U2 16 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2010 VL 19 IS 10 BP 1877 EP 1896 DI 10.1002/pro.474 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661HO UT WOS:000282716900007 PM 20669237 ER PT J AU Flynn, KE Shelby, RA Mitchell, SA Fawzy, MR Hardy, NC Husain, AM Keefe, FJ Krystal, AD Porter, LS Reeve, BB Weinfurt, KP AF Flynn, Kathryn E. Shelby, Rebecca A. Mitchell, Sandra A. Fawzy, Maria R. Hardy, N. Chantelle Husain, Aatif M. Keefe, Francis J. Krystal, Andrew D. Porter, Laura S. Reeve, Bryce B. Weinfurt, Kevin P. TI Sleep-wake functioning along the cancer continuum: focus group results from the Patient-Reported Outcomes Measurement Information System (PROMIS (R)) SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; focus groups; oncology; qualitative research; quality of life; sleep ID BREAST-CANCER; INSOMNIA SECONDARY; FATIGUE; DISTURBANCE; SURVIVORS; SYMPTOMS; EFFICACY; THERAPY; CONTEXT; PEOPLE AB Objective: Cancer and its treatments disturb sleep wake functioning; however, there is little information available on the characteristics and consequences of sleep problems associated with cancer. As part of an effort to improve measurement of sleep wake functioning, we explored the scope of difficulties with sleep in a diverse group of patients diagnosed with cancer. Methods: We conducted 10 focus groups with patients recruited from the Duke University tumor registry and oncology/hematology clinics. Separate groups were held with patients scheduled to begin or currently undergoing treatment for breast, prostate, lung, colorectal, hematological, and other cancer types and with patients who were in posttreatment follow-up. The content of the focus group discussions was transcribed and analyzed for major themes by independent coders. Results: Participants not only reported causes of sleep disturbance common in other populations, such as pain and restless legs, but they also reported causes that may be unique to cancer populations, including abnormal dreams, anxiety about cancer diagnosis and recurrence, night sweats, and problems with sleep positioning. Many participants felt that sleep problems reduced their productivity, concentration, social interactions, and overall quality of life. Many also shared beliefs about the increased importance of sleep when fighting cancer. Conclusions: The findings underscore the need for interventions that minimize the negative impact of cancer and its treatments on sleep. This study will inform efforts now underway to develop a patient-reported measure of sleep wake functioning that reflects the breadth of concepts considered important by patients with cancer. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Flynn, Kathryn E.; Fawzy, Maria R.; Hardy, N. Chantelle; Weinfurt, Kevin P.] Duke Univ, Ctr Clin & Genet Econ, Sch Med, Duke Clin Res Inst, Durham, NC 27715 USA. [Flynn, Kathryn E.; Keefe, Francis J.; Krystal, Andrew D.; Porter, Laura S.; Weinfurt, Kevin P.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27715 USA. [Shelby, Rebecca A.; Weinfurt, Kevin P.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27715 USA. [Mitchell, Sandra A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Husain, Aatif M.] Duke Univ, Dept Med, Sch Med, Durham, NC 27715 USA. [Reeve, Bryce B.] NCI, Bethesda, MD 20892 USA. RP Flynn, KE (reprint author), Duke Univ, Ctr Clin & Genet Econ, Sch Med, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM kathryn.flynn@duke.edu RI Krystal, Andrew/J-7109-2013; Flynn, Kathryn/M-5346-2013 OI Krystal, Andrew/0000-0002-6702-781X; Flynn, Kathryn/0000-0002-4427-3583 FU National Institutes of Health [U01AR052186] FX This work was supported by a National Cancer Institute supplement to grant U01AR052186 from the National Institutes of Health. NR 37 TC 12 Z9 12 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD OCT PY 2010 VL 19 IS 10 BP 1086 EP 1093 DI 10.1002/pon.1664 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 670FC UT WOS:000283405600009 PM 20013938 ER PT J AU Eddy, KT Swanson, SA Crosby, RD Franko, DL Engel, S Herzog, DB AF Eddy, K. T. Swanson, S. A. Crosby, R. D. Franko, D. L. Engel, S. Herzog, D. B. TI How should DSM-V classify eating disorder not otherwise specified (EDNOS) presentations in women with lifetime anorexia or bulimia nervosa? SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Anorexia nervosa; bulimia nervosa; classification; eating disorder not otherwise specified; longitudinal ID DIAGNOSTIC CROSSOVER; PURGING DISORDER; VALIDITY; RELAPSE AB Objective. Anorexia nervosa (AN) and bulimia nervosa (BN) are marked by longitudinal symptom fluctuations. DSM-IV-TR does not address how to classify eating disorder (ED) presentations in individuals who no longer meet full criteria for these disorders. To consider this issue, we examined subthreshold presentations in women with initial diagnoses of AN and BN. Method. A total of 246 women with AN or BN were followed for a median of 9 years; weekly symptom data were collected at frequent intervals using the Longitudinal Interval Follow-up Evaluation of Eating Disorders (LIFE-EAT-II). Outcomes were ED presentations that were subthreshold for >= 3 months, including those narrowly missing full criteria for AN or BN, along with binge eating disorder (BED) and purging disorder. Results. During follow-up, most women (77.6%) experienced a subthreshold presentation. Subthreshold presentation was related to intake diagnosis (Wald chi(2)=8.065, df=2, p=0.018). Individuals with AN most often developed subthreshold presentations resembling AN; those with BN were more likely to develop subthreshold BN. Purging disorder was experienced by half of those with BN and one-quarter of those with AN binge/purge type (ANBP); BED occurred in 20% with BN. Transition from AN or BN to most subthreshold types was associated with improved psychosocial functioning (p<0.001). Conclusions. Subthreshold presentations in women with lifetime AN and BN were common, resembled the initial diagnosis, and were associated with modest improvements in psychosocial functioning. For most with lifetime AN and BN, subthreshold presentations seem to represent part of the course of illness and to fit within the original AN or BN diagnosis. C1 [Eddy, K. T.; Franko, D. L.; Herzog, D. B.] Massachusetts Gen Hosp, Dept Psychiat, Harris Ctr, Boston, MA 02214 USA. [Swanson, S. A.] NIMH, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. [Crosby, R. D.; Engel, S.] Neuropsychiat Res Inst, Fargo, ND USA. [Crosby, R. D.; Engel, S.] Univ N Dakota, Sch Med & Hlth Sci, Dept Clin Neurosci, Fargo, ND USA. [Franko, D. L.] Northwestern Univ, Dept Counseling & Appl Educ Psychol, Boston, MA USA. RP Eddy, KT (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Harris Ctr, 2 Longfellow Pl,Ste 200, Boston, MA 02214 USA. EM keddy@partners.org OI Crosby, Ross/0000-0001-9131-1629 FU [RO1 MH038333]; [F32 MH084396] FX Support for this research was provided by RO1 MH038333 (PI D.B.H.) and F32 MH084396 (PI K.T.E.). NR 17 TC 10 Z9 10 U1 1 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD OCT PY 2010 VL 40 IS 10 BP 1735 EP 1744 DI 10.1017/S0033291709992200 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 644VF UT WOS:000281408700015 PM 20047706 ER PT J AU Clauser, SB Brazier, J Feeny, D Revicki, DA Kind, P AF Clauser, Steven B. Brazier, John Feeny, David Revicki, Dennis A. Kind, Paul TI Development and Comparisons of Alternative Preference-Based Measures of Health SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Clauser, Steven B.] NCI, Outcomes Res Branch, Bethesda, MD 20892 USA. [Brazier, John] Sch Hlth & Related Res, Sheffield, S Yorkshire, England. [Feeny, David] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Revicki, Dennis A.] United BioSource Corp, Ctr Hlth Outcomes Res, Bethesda, MD USA. [Kind, Paul] Univ York, Ctr Hlth Econ, York YO10 5DD, N Yorkshire, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 BP 2 EP 2 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700002 ER PT J AU Maringwa, JT Coens, C Quinten, C Martinelli, F Ringash, J Osoba, D Reeve, BB King, M Cleeland, CS Flechtner, H Gotay, C Greimel, E Taphoorn, MJ Schumucker-von Koch, J Weis, J Smit, EF van Meerbeeck, JP Bottomley, A AF Maringwa, John T. Coens, Corneel Quinten, Chantal Martinelli, Francesca Ringash, Jolie Osoba, David Reeve, Bryce B. King, Madeleine Cleeland, Charles S. Flechtner, Henning Gotay, Carolyn Greimel, Eva Taphoorn, Martin J. Schumucker-von Koch, Joseph Weis, Joachim Smit, Egbert F. van Meerbeeck, Jan P. Bottomley, Andrew TI Effect of Time Windows in Analysis of Health-Related Quality of Life (HRQOL) Outcomes SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Maringwa, John T.; Coens, Corneel; Quinten, Chantal; Martinelli, Francesca; Bottomley, Andrew] EORTC, Qual Life, Brussels, Belgium. [Ringash, Jolie] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Osoba, David] Qual Life Consulting, West Vancourver, BC, Canada. [Reeve, Bryce B.] NCI, Div Canc Control & Populat Studies, NIH, Bethesda, MD 20892 USA. [King, Madeleine] Univ Sydney, PoCoG, Sydney, NSW 2006, Australia. [Cleeland, Charles S.] Univ Texas Houston, Symptom Res, Houston, TX USA. [Flechtner, Henning] Otto Von Guericke Univ, Fac Med, Magdeburg, Germany. [Gotay, Carolyn] Sch Populat & Publ Hlth, Primary Prevent, Vancouver, BC, Canada. [Greimel, Eva] Med Univ Graz, Obstet & Gynecol, Graz, Austria. [Taphoorn, Martin J.] Vrije Univ Amsterdam Med Ctr, Neurol, Amsterdam, Netherlands. [Schumucker-von Koch, Joseph] Univ Regensburg, Med Eth, D-93053 Regensburg, Germany. [Weis, Joachim] Univ Freiburg, Tumor Biol Ctr, D-79106 Freiburg, Germany. [Smit, Egbert F.] Vrije Univ VUMC, Pulm Dis, Amsterdam, Netherlands. [van Meerbeeck, Jan P.] Univ Ziekenhuis Gent, Thoracale Oncol, Ghent, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 1369 BP 19 EP 20 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700060 ER PT J AU Johnson, LL Kurland, BF Egleston, BL Diehr, P AF Johnson, Laura L. Kurland, Brenda F. Egleston, Brian L. Diehr, Paula TI Longitudinal data with follow-up truncated by death: Matching statistical analysis to research, clinical and policy aims SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Johnson, Laura L.] US Natl Inst Hlth, NCCAM, Bethesda, MD USA. [Kurland, Brenda F.] Fred Hutchinson Canc Res Ctr, Clin Stat, Seattle, WA 98104 USA. [Egleston, Brian L.] Fox Chase Canc Ctr, Biostat & Bioinformat, Philadelphia, PA 19111 USA. [Diehr, Paula] Univ Washington, Biostat & Hlth Serv, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 1714 BP 20 EP 20 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700061 ER PT J AU Treadwell, MJ Levine, R Keller, S Hassell, K Werner, E AF Treadwell, Marsha J. Levine, Roger Keller, San Hassell, Kathryn Werner, Ellen TI Understanding Perspectives of Adults with Sickle Cell Disease in Developing a Disease Specific Quality of Life Measurement System SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Treadwell, Marsha J.] Childrens Hosp & Res Ctr Oakland, Hematol Oncol, Oakland, CA USA. [Levine, Roger] Amer Inst Res, San Mateo, CA USA. [Keller, San] Amer Inst Res, Chapel Hill, NC USA. [Hassell, Kathryn] Univ Colorado, Sickle Cell Treatment & Res Ctr, Denver, CO 80202 USA. [Werner, Ellen] NHLBI, Blood Dis & Resources, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 1666 BP 23 EP 23 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700071 ER PT J AU Bruner, DW Hanisch, LJ Reeve, BB Minasian, LM Rowland, JH O'Mara, AM Sit, L Sloan, JA Cleeland, CS Denicoff, AM Trimble, EL Clauser, SB Geoghegan, C Paul, DB Abernethy, AP Schrag, D Basch, EM AF Bruner, Deborah Watkins Hanisch, Laura J. Reeve, Bryce B. Minasian, Lori M. Rowland, Julia H. O'Mara, Ann M. Sit, Laura Sloan, Jeff A. Cleeland, Charles S. Denicoff, Andrea M. Trimble, Edward L. Clauser, Steven B. Geoghegan, Cindy Paul, Diane B. Abernethy, Amy P. Schrag, Deborah Basch, Ethan M. TI Perceived Barriers to Implementing the Patient-Reported Outcomes-Common Toxicity Criteria Adverse Event (PRO-CTCAE) System in Cancer Clinical Trials SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Bruner, Deborah Watkins] Univ Penn, Sch Nursing, Biobehav Hlth Sci Div, Philadlephia, PA USA. [Hanisch, Laura J.] Univ Penn, Psychiat, Philadelphia, PA 19104 USA. [Reeve, Bryce B.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Minasian, Lori M.; O'Mara, Ann M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Rowland, Julia H.; Clauser, Steven B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Sit, Laura; Basch, Ethan M.] Mem Sloan Kettering Canc Ctr, Epidemiol & Biostat, New York, NY 10021 USA. [Sloan, Jeff A.] Mayo Clin, Hlth Sci Res, Rochester, MN USA. [Cleeland, Charles S.] Univ Texas MD Anderson Canc Ctr, Symptom Res, Houston, TX 77030 USA. [Denicoff, Andrea M.; Trimble, Edward L.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Geoghegan, Cindy] Patient & Partners LLC, Madison, CT USA. [Paul, Diane B.] Patient Advocate, Brooklyn, NY USA. [Abernethy, Amy P.] Duke Univ, Sch Med, Med, Durham, NC USA. [Schrag, Deborah] Dana Farber Canc Inst, Med, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 1006 BP 31 EP 32 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700096 ER PT J AU Basch, E Reeve, B Cleeland, CS Sloan, JA Schrag, D Atkinson, TM Mendoza, TR Hay, JL Abernethy, AP Minasian, L Kwitkowski, V Trentacosti, AM Burke, L Sit, L Bruner, DW AF Basch, Ethan Reeve, Bryce Cleeland, Charles S. Sloan, Jeff A. Schrag, Deborah Atkinson, Thomas M. Mendoza, Tito R. Hay, Jennifer L. Abernethy, Amy P. Minasian, Lori Kwitkowski, Virginia Trentacosti, Ann Marie Burke, Laurie Sit, Laura Bruner, Deborah W. TI Development of the Patient-Reported Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Basch, Ethan; Sit, Laura] Mem Sloan Kettering Canc Ctr, Epidemiol & Biostat, New York, NY 10021 USA. [Reeve, Bryce] NCI, Outcomes Res, Bethesda, MD 20892 USA. [Cleeland, Charles S.; Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Symptom Res, Houston, TX 77030 USA. [Sloan, Jeff A.] Mayo Clin, Biomed Stat & Informat, Rochester, MN USA. [Schrag, Deborah] Dana Farber Canc Inst, Med, Boston, MA 02115 USA. [Atkinson, Thomas M.; Hay, Jennifer L.] Mem Sloan Kettering Canc Ctr, Psychiat & Behav Sci, New York, NY 10021 USA. [Abernethy, Amy P.] Duke Univ, Sch Med, Med, Durham, NC USA. [Minasian, Lori] NCI, Canc Prevent, Rockville, MD USA. [Kwitkowski, Virginia] US FDA, Drug Oncol Prod, Silver Spring, MD USA. [Burke, Laurie] US FDA, Study Endpoints & Labeling Dev, Silver Spring, MD USA. [Bruner, Deborah W.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 161439 BP 50 EP 51 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700153 ER PT J AU Quinten, C Martinelli, F Maringwa, J Coens, C Reeve, B Gotay, C Flechtner, H Ringash, J Greimel, E King, M Osoba, D Taphoorn, MJ Cleeland, C Weis, J Schmucker-von Koch, J Bottomley, A AF Quinten, Chantal Martinelli, Francesca Maringwa, John Coens, Corneel Reeve, Bryce Gotay, Caroline Flechtner, Henning Ringash, Jolie Greimel, Eva King, Madeleine Osoba, David Taphoorn, Martin J. Cleeland, Charles Weis, Joachim Schmucker-von Koch, Joseph Bottomley, Andrew TI Prognostic significance of patient heterogeneity in a dataset of 10,108 cancer patients SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Quinten, Chantal; Martinelli, Francesca; Maringwa, John; Coens, Corneel; Bottomley, Andrew] EORTC, Qual Life Dept, Brussels, Belgium. [Reeve, Bryce] NCI, Div Canc Control & Populat Studies, NIH, Bethesda, MD 20892 USA. [Gotay, Caroline] Univ British Columbia, Primary Prevent Sch Populat, Vancouver, BC V5Z 1M9, Canada. [Flechtner, Henning] Univ Magdeburg, Fac Med, D-39106 Magdeburg, Germany. [Ringash, Jolie] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Greimel, Eva] Med Univ Graz, Obstet & Gynecol, Graz, Austria. [King, Madeleine] Univ Sydney, Psychooncol Cooperat Res Grp, Sydney, NSW 2006, Australia. [Osoba, David] Qual Life Consulting, Vancouver, BC, Canada. [Taphoorn, Martin J.] VU Med Ctr MC Haaglanden, Neurol, The Hague, Netherlands. [Cleeland, Charles] Univ Texas Houston, Symptom Res, Houston, TX USA. [Weis, Joachim] Univ Freiburg, Psychooncol, D-79106 Freiburg, Germany. [Schmucker-von Koch, Joseph] Univ Regensburg, Philosoph Fac, D-93053 Regensburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 150/1291 BP 93 EP 93 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700287 ER PT J AU Victorson, D Cavazos, J Cella, D Nowinski, C Wortman, K Moy, C AF Victorson, David Cavazos, Jose Cella, David Nowinski, Cindy Wortman, Katy Moy, Claudia TI Validation of Neuro-QOL Measures for People Diagnosed with Epilepsy SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Victorson, David; Cella, David; Nowinski, Cindy; Wortman, Katy] Northwestern Univ, Feinberg Sch Med, Med Social Sci, Evanston, IL 60208 USA. [Cavazos, Jose] Univ Texas Hlth Sci Ctr San Anto, Neurol, San Antonio, TX 78229 USA. [Moy, Claudia] NINDS, Extramural Res, NIH, Bethesda, MD 20892 USA. RI Cavazos, Jose/J-4122-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 160/1327 BP 96 EP 97 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700297 ER PT J AU Miller, D Bethoux, F Nowinski, C Victorson, D Moy, C Wortman, K Cella, D AF Miller, Deborah Bethoux, Francois Nowinski, Cindy Victorson, David Moy, Claudia Wortman, Katy Cella, David TI Validation of Neuro-QOL Measures for People Diagnosed with Multiple Sclerosis SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Miller, Deborah] Cleveland Clin Fdn, Neurol, Cleveland, OH USA. [Bethoux, Francois] Cleveland Clin, Neurol, Cleveland, OH USA. [Nowinski, Cindy; Victorson, David; Wortman, Katy; Cella, David] Northwestern Univ, Feinberg Sch Med, Med Social Sci, Evanston, IL 60208 USA. [Moy, Claudia] NINDS, Extramural Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 162/1325 BP 97 EP 97 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700299 ER PT J AU Flynn, KE Jeffery, DD Reeve, BB Lin, L Smith, AW Abernethy, A Reese, J Weinfurt, K AF Flynn, Kathryn E. Jeffery, Diana D. Reeve, Bryce B. Lin, L. Smith, Ashley Wilder Abernethy, A. Reese, J. Weinfurt, Kevin TI Progress on the PROMIS (R) Sexual Function Measure SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Flynn, Kathryn E.] Duke Univ, Sch Med, Psychiat & Behav Sci, Durham, NC USA. [Reeve, Bryce B.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Lin, L.] Duke Clin Res Inst, Durham, NC USA. [Smith, Ashley Wilder] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Abernethy, A.] Duke Clin Res Inst, Durham, NC USA. [Reese, J.] Johns Hopkins Univ, Baltimore, MD USA. [Weinfurt, Kevin] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 166/1170 BP 98 EP 99 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700303 ER PT J AU Nowinski, C Siderowf, A Victorson, D Cella, D Wortman, K Moy, C AF Nowinski, Cindy Siderowf, Andrew Victorson, David Cella, David Wortman, Katy Moy, Claudia TI Clinical Validation of Neuro-QOL Measurement Tools in Parkinson's Disease SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Nowinski, Cindy; Victorson, David; Cella, David; Wortman, Katy] Northwestern Univ, Feinberg Sch Med, Med Social Sci, Evanston, IL 60208 USA. [Siderowf, Andrew] Univ Penn Hlth Syst, Neurol, Philadelphia, PA USA. [Moy, Claudia] NINDS, Extramural Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 164/1326 BP 98 EP 98 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700301 ER PT J AU Martinelli, F Quinten, C Maringwa, J Coens, C Cleeland, C Gotay, C Reeve, B Ringash, J Flechtner, H Greimel, E Osoba, D King, M Schmucker-Von Koch, J Taphoorn, M Weis, J Fossa, S Albrecht, W Van Poppel, H Powell, P Johnson, M Bottomley, A AF Martinelli, Francesca Quinten, Chantal Maringwa, John Coens, Corneel Cleeland, Charles Gotay, Carolyn Reeve, Bryce Ringash, Jolie Flechtner, Henning Greimel, Eva Osoba, David King, Madeleine Schmucker-Von Koch, Joseph Taphoorn, Martin Weis, Joachim Fossa, Sophie Albrecht, Walter Van Poppel, Hendrik Powell, Philip Johnson, Mark Bottomley, Andrew TI Clustering of Health-Related Quality of Life (HRQoL) items in metastatic prostate cancer patients SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Martinelli, Francesca; Quinten, Chantal; Maringwa, John; Coens, Corneel; Bottomley, Andrew] EORTC, Qual Life, Brussels, Belgium. [Cleeland, Charles] UT MD Anderson Canc Ctr, Symptom Res, Houston, TX USA. [Gotay, Carolyn] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Reeve, Bryce] NCI, Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ringash, Jolie] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Flechtner, Henning] Otto Von Guericke Univ, Fac Med, Child & Adolescent Psychiat & Psychotherapy, Magdeburg, Germany. [Greimel, Eva] Graz Univ, Obstet & Gynecol, Graz, Austria. [Osoba, David] Consulting, Qual Life, W Vancouver, BC, Canada. [King, Madeleine] Univ Sydney, Psychooncol Cooperat Res Grp, Sidney, BC, Canada. [Schmucker-Von Koch, Joseph] Univ Regensburg, Med Eth Philosoph Fac, D-93053 Regensburg, Germany. [Taphoorn, Martin] Med Ctr Haaglanden, VU Med Ctr, The Hague, Netherlands. [Weis, Joachim] Univ Freiburg, Psychooncol, D-79106 Freiburg, Germany. [Fossa, Sophie] Oslo Univ Hosp, Clin Res, Oslo, Norway. [Albrecht, Walter] Landesklinikum Weinviertel Mistelbach, Urol, Mistelbach, Austria. [Van Poppel, Hendrik] Univ Hosp Leuven, Urol, Leuven, Belgium. [Powell, Philip; Johnson, Mark] Freeman Rd Hosp, Urol, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 SU 1 MA 259/1630 BP 127 EP 127 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QU UT WOS:000209358700396 ER PT J AU Hays, RD Bode, R Rothrock, N Riley, W Cella, D Gershon, R AF Hays, Ron D. Bode, Rita Rothrock, Nan Riley, William Cella, David Gershon, Richard TI The impact of next and back buttons on time to complete and measurement reliability in computer-based surveys SO QUALITY OF LIFE RESEARCH LA English DT Article DE Computer-based surveys; Social/role activities; PROMIS AB To assess the impact of including next and back buttons on response burden and measurement reliability of computer-based surveys. A sample of 807 participants (mean age of 53; 64% women, 83% non-Hispanic white; 81% some college or college graduates) from the YouGov Polimetrix panel was administered 56 items assessing performance of social/role activities and 56 items measuring satisfaction with social/role activities. Participants were randomly assigned to either (1) automatic advance to the next question with no opportunity to go back (auto/no back); (2) automatic advance to the next questions with an opportunity to go back (auto/back); (3) next button to go to the next question with no opportunity to go back (next/no back); or (4) next button to go to the next question with an opportunity to go back (next/back). We found no difference in missing data, internal consistency reliability, and domain scores by group. Time to complete the survey was about 50% longer when respondents were required to use a next button to go on. Given the similarity in missing data, reliability and mean scale scores with or without use of the next button, we recommend automatic advancement to the next item with the option to go back to the previous item. C1 [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Bode, Rita; Rothrock, Nan; Cella, David; Gershon, Richard] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Riley, William] NHLBI, Bethesda, MD 20892 USA. RP Hays, RD (reprint author), Univ Calif Los Angeles, Dept Med, 911 Broxton Ave,Room 110, Los Angeles, CA 90024 USA. EM drhays@ucla.edu RI Hays, Ronald/D-5629-2013 FU Northwestern University [U01AR52177]; Duke University [U01AR52186]; University of North Carolina [U01AR52181]; University of Pittsburgh [U01AR52155]; Stanford University [U01AR52158]; Stony Brook University, PI [U01AR52170]; University of Washington, PI [U01AR52171]; National Institute on Aging [AG020679-01, P30AG021684]; NCMHD [2P20MD000182]; UCLA Older Americans Independence Center [P30-AG028748] FX The Patient-Reported Outcomes Measurement Information System (PROMIS) is a US National Institutes of Health (NIH) Roadmap initiative to develop a computerized system measuring patient-reported outcomes in respondents with a wide range of chronic diseases and demographic characteristics. PROMIS was funded by cooperative agreements to a Statistical Coordinating Center (Northwestern University, PI: David Cella, PhD, U01AR52177) and six Primary Research Sites (Duke University, PI: Kevin Weinfurt, PhD, U01AR52186; University of North Carolina, PI: Darren DeWalt, MD, MPH, U01AR52181; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, U01AR52155; Stanford University, PI: James Fries, MD, U01AR52158; Stony Brook University, PI: Arthur Stone, PhD, U01AR52170; and University of Washington, PI: Dagmar Amtmann, PhD, U01AR52171). NIH Science Officers on this project are Deborah Ader, PhD, Susan Czajkowski, PhD, Lawrence Fine, MD, DrPH, Louis Quatrano, PhD, Bryce Reeve, PhD, William Riley, PhD, and Susana Serrate-Sztein, PhD. Ron D. Hays, PhD, was also supported by grants from the National Institute on Aging (AG020679-01, P30AG021684), NCMHD (2P20MD000182), and the UCLA Older Americans Independence Center (P30-AG028748). See the web site at www.nihpromis.org for additional information on the PROMIS cooperative group. NR 4 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2010 VL 19 IS 8 BP 1181 EP 1184 DI 10.1007/s11136-010-9682-9 PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 651CS UT WOS:000281902800011 PM 20552282 ER PT J AU John-Aryankalayil, M Palayoor, ST Cerna, D Simone, CB Falduto, MT Magnuson, SR Coleman, CN AF John-Aryankalayil, Molykutty Palayoor, Sanjeewani T. Cerna, David Simone, Charles B., II Falduto, Michael T. Magnuson, Scott R. Coleman, C. Norman TI Fractionated Radiation Therapy Can Induce a Molecular Profile for Therapeutic Targeting SO RADIATION RESEARCH LA English DT Article ID GENE-EXPRESSION PROFILES; HUMAN SUBCUTANEOUS FIBROBLASTS; HUMAN GLIOMA-CELLS; IONIZING-RADIATION; CANCER-CELLS; TRANSCRIPTIONAL RESPONSE; SYNTHETIC LETHALITY; MICROARRAY ANALYSIS; GAMMA-RAYS; IN-VIVO AB To examine the possibility of using fractionated radiation in a unique way with molecular targeted therapy, gene expression profiles of prostate carcinoma cells treated with 10 Gy radiation administered either as a single dose or as fractions of 2 Gy X 5 and 1 Gy X 10 were examined by microarray analysis. Compared to the single dose, the fractionated irradiation resulted in significant increases in differentially expressed genes in both cell lines, with more robust changes in PC3 cells than in DU145 cells. The differentially expressed genes (>twofold change; P < 0.05) were clustered and their ontological annotations evaluated. In PC3 cells genes regulating immune and stress response, cell cycle and apoptosis were significantly up-regulated by multifractionated radiation compared to single-dose radiation. Ingenuity Pathway Analysis (IPA) of the differentially expressed genes revealed that immune response and cardiovascular genes were in the top functional category in PC3 cells and cell-to-cell signaling in DU145 cells. RT-PCR analysis showed that a flexure point for gene expression occurred at the 6th-8th fraction and AKT inhibitor perifosine produced enhanced cell killing after 1 Gy x 8 fractionated radiation in PC3 and DU145 cells compared to single dose. This study suggests that fractionated radiation may be a uniquely exploitable, non-oncogene-addiction stress pathway for molecular therapeutic targeting. (C) 2010 by Radiation Research Society C1 [John-Aryankalayil, Molykutty; Palayoor, Sanjeewani T.; Cerna, David; Simone, Charles B., II; Coleman, C. Norman] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Falduto, Michael T.; Magnuson, Scott R.] Gen Us BioSyst Inc, Northbrook, IL USA. RP John-Aryankalayil, M (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Rm B3 B 406,Bldg 10, Bethesda, MD 20892 USA. EM Aryankalayilm@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research. NR 41 TC 21 Z9 24 U1 0 U2 0 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD OCT PY 2010 VL 174 IS 4 BP 446 EP 458 DI 10.1667/RR2105.1 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 659BO UT WOS:000282542200005 PM 20726711 ER PT J AU El Touny, LH Henderson, F Djakiew, D AF El Touny, Lara H. Henderson, Fraser Djakiew, Daniel TI Biochanin A Reduces Drug-Induced p75NTR Expression and Enhances Cell Survival: A New In Vitro Assay for Screening Inhibitors of p75NTR Expression SO REJUVENATION RESEARCH LA English DT Article ID SPINAL-CORD-INJURY; PROSTATE TUMOR-CELLS; NERVE GROWTH-FACTOR; CASPASE-MEDIATED APOPTOSIS; NF-KAPPA-B; NEUROTROPHIN RECEPTOR; PROTEIN-KINASE; CANCER CELL; P75(NTR); METHYLPREDNISOLONE AB Following spinal cord injury (SCI) or peripheral neuropathy, increased levels of the p75(NTR) death receptor initiate the signal transduction cascade leading to cell death Investigations of compounds that may ameliorate neuronal cell death have largely used rodent models, which are time consuming, expensive, and cumbersome to perform Previous studies had demonstrated that steroids, particularly dexamethasone and its analog methylprednisolone sodium succinate, exhibit limited neuroprotective effects against neuronal injury Significantly, many naturally occurring nonsteroidal plant compounds exhibit structural overlap with steroids In this report, we present an in vitro cellular screen model to practically examine the efficacy of various phytoestrogens in modulating the ibuprofen-induced expression of p75(NTR) and reduced cell survival of CCFSTTG1 and U87MG cells in a rescue (postinjury) or prevention (preinjury) regimen We show that the phytoestrogen, biochanin A, and, to a lesser extent, genistein are more effective than dexamethasone at reducing p75(NTR) expression and improving the viability of U87MG and CCFSTTG1 before and after p75(NTR) induction Furthermore, these studies implicate biochanin A's inactivation of p38-MAPK as a possible contributor to reducing p75(NTR) with associated increased cell survival This new in vitro assay facilitates a more time-efficient screening of compounds to suppress p75(NTR) expression and increase neuronal cell viability prior to their evaluation in animal models of neurological diseases C1 [Djakiew, Daniel] Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Med Ctr, Washington, DC 20057 USA. [El Touny, Lara H.] NCI, Canc Biol Lab, Bethesda, MD 20892 USA. [Henderson, Fraser] Georgetown Univ, Dept Radiol, Med Ctr, Washington, DC 20057 USA. [Henderson, Fraser] Doctors Community Hosp, Lanham, MD USA. RP Djakiew, D (reprint author), Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Med Ctr, 3900 Reservoir Rd NW,Med Dent Bldg,Room C406C, Washington, DC 20057 USA. FU U S Army [W81XWH-07-1-0366] FX This work was funded by U S Army grant W81XWH-07-1-0366 and administered by the Telemedicine and Advanced Technology Research Center (TATRC), Fort Detrick, Maryland, MD The content of this paper does not necessarily reflect the position or policy of the U S Government NR 48 TC 1 Z9 1 U1 0 U2 3 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 OCT PY 2010 VL 13 IS 5 BP 527 EP 537 DI 10.1089/rej.2009.1006 PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 689XU UT WOS:000284965100004 PM 20818983 ER PT J AU Manuck, TA Price, TM Thom, E Meis, PJ Dombrowski, MP Sibai, B Spong, CY Rouse, DJ Iams, JD Simhan, HN O'Sullivan, MJ Miodovnik, M Leveno, KJ Conway, D Wapner, RJ Carpenter, M Mercer, B Ramin, SM Thorp, JM Peaceman, AM AF Manuck, Tracy A. Price, Thomas M. Thom, Elizabeth Meis, Paul J. Dombrowski, Mitchell P. Sibai, Baha Spong, Catherine Y. Rouse, Dwight J. Iams, Jay D. Simhan, Hyagriv N. O'Sullivan, Mary J. Miodovnik, Menachem Leveno, Kenneth J. Conway, Deborah Wapner, Ronald J. Carpenter, Marshall Mercer, Brian Ramin, Susan M. Thorp, John M. Peaceman, Alan M. TI Absence of Mitochondrial Progesterone Receptor Polymorphisms in Women With Spontaneous Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Article DE mitochondria; prematurity; progesterone ID SMOOTH-MUSCLE-CELLS; GLUCOCORTICOID-RECEPTOR; PR-M; EXPRESSION; DELIVERY; ALPHA; BETA; MYOMETRIUM; ISOFORMS; RISK AB Objective: The truncated mitochondrial progesterone receptor (PR-M) is homologous to nuclear PRs with the exception of an amino terminus hydrophobic membrane localization sequence, which localizes PR-M to mitochondria. Given the matrilineal inheritance of both spontaneous preterm birth (SPTB) and the mitochondrial genome, we hypothesized that (a) PR-M is polymorphic and (b) PR-M localization sequence polymorphisms could result in variable progesterone-mitochondrial effects and variable responsiveness to progesterone prophylaxis. Methods: Secondary analysis of DNA from women enrolled in a multicenter, prospective, study of 17 alpha-hydroxyprogesterone caproate (17OHPC) versus placebo for the prevention of recurrent SPTB. DNA was extracted from stored saliva. Results: The PR-M localization sequence was sequenced on 344 patients. Sequences were compared with the previously published 48 base-pair sequence, and all were identical. Conclusions: We did not detect genetic variation in the mitochondrial localization sequence of the truncated PR-M in a group of women at high risk for SPTB. C1 [Manuck, Tracy A.; Price, Thomas M.; Thom, Elizabeth; Meis, Paul J.; Dombrowski, Mitchell P.; Sibai, Baha; Spong, Catherine Y.; Rouse, Dwight J.; Iams, Jay D.; Simhan, Hyagriv N.; O'Sullivan, Mary J.; Miodovnik, Menachem; Leveno, Kenneth J.; Conway, Deborah; Wapner, Ronald J.; Carpenter, Marshall; Mercer, Brian; Ramin, Susan M.; Thorp, John M.; Peaceman, Alan M.] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. RP Manuck, TA (reprint author), 30 N 1900 E,Rm 2B200, Salt Lake City, UT 84132 USA. EM tracy.manuck@hsc.utah.edu OI Peaceman, Alan/0000-0002-4515-4850 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD27860, HD36801, HD27917, HD21414, HD27861, HD27869, HD27905, HD34208, HD34116, HD21410, HD27915, HD34136, HD34120, HD34122, HD40500, HD40544, HD40560, HD40512] FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD27860, HD36801, HD27917, HD21414, HD27861, HD27869, HD27905, HD34208, HD34116, HD21410, HD27915, HD34136, HD34210, HD34122, HD40500, HD40544, HD34116, HD40560, HD40512) and its contents do not necessarily represent the official view of NICHD or NIH. NR 27 TC 3 Z9 3 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD OCT PY 2010 VL 17 IS 10 BP 913 EP 916 DI 10.1177/1933719110374365 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 652JQ UT WOS:000282003100005 PM 20693499 ER PT J AU Kagan, JM Rosas, S Trochim, WMK AF Kagan, Jonathan M. Rosas, Scott Trochim, William M. K. TI Integrating utilization-focused evaluation with business process modeling for clinical research improvement SO RESEARCH EVALUATION LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; TRIALS; CANCER AB New discoveries in basic science are creating extraordinary opportunities to design novel biomedical preventions and therapeutics for human disease. But the clinical evaluation of these new interventions is, in many instances, being hindered by a variety of legal, regulatory, policy and operational factors, few of which enhance research quality, the safety of study participants or research ethics. With the goal of helping increase the efficiency and effectiveness of clinical research, we have examined how the integration of utilization-focused evaluation with elements of business process modeling can reveal opportunities for systematic improvements in clinical research. Using data from the NW global HIV/AIDS clinical trials networks, we analyzed the absolute and relative times required to traverse defined phases associated with specific activities within the clinical protocol lifecycle. Using simple median duration and Kaplan-Meyer survival analysis, we show how such time-based analyses can provide a rationale for the prioritization of research process analysis and re-engineering, as well as a means for statistically assessing the impact of policy modifications, resource utilization, re-engineered processes and best practices. Successfully applied, this approach can help researchers be more efficient in capitalizing on new science to speed the development of improved interventions for human disease. C1 [Kagan, Jonathan M.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Rosas, Scott] Concept Syst Inc, Ithaca, NY 14850 USA. [Trochim, William M. K.] Cornell Univ, Dept Policy Anal & Management, Ithaca, NY 14853 USA. RP Kagan, JM (reprint author), NIAID, Div Clin Res, NIH, 6700 B Rockledge Dr,Room 1102,MSC 7609, Bethesda, MD 20892 USA. EM jkagan@niaid.nih.gov; srosas@conceptsystems.com; wmt1@cornell.edu OI Rosas, Scott/0000-0001-5212-1478 FU NCRR NIH HHS [UL1 RR024996, UL1 RR024996-01]; NIAID NIH HHS [N01 AI030060-11, N01 AI050022, N01AI30020, N01AI50022] NR 33 TC 4 Z9 4 U1 2 U2 7 PU BEECH TREE PUBLISHING PI GUILDFORD PA 10 WATFORD CLOSE,, GUILDFORD GU1 2EP, SURREY, ENGLAND SN 0958-2029 J9 RES EVALUAT JI Res. Evaluat. PD OCT PY 2010 VL 19 IS 4 BP 239 EP 250 DI 10.3152/095820210X12827366906607 PG 12 WC Information Science & Library Science SC Information Science & Library Science GA 716SU UT WOS:000286994600002 PM 21552512 ER PT J AU Flaxel, CJ Edwards, AR Aiello, LP Arrigg, PG Beck, RW Bressler, NM Bressler, SB Ferris, FL Gupta, SK Haller, JA Lazarus, HS Qin, HJ AF Flaxel, Christina J. Edwards, Allison R. Aiello, Lloyd Paul Arrigg, Paul G. Beck, Roy W. Bressler, Neil M. Bressler, Susan B. Ferris, Frederick L., III Gupta, Shailesh K. Haller, Julia A. Lazarus, Howard S. Qin, Haijing TI FACTORS ASSOCIATED WITH VISUAL ACUITY OUTCOMES AFTER VITRECTOMY FOR DIABETIC MACULAR EDEMA Diabetic Retinopathy Clinical Research Network SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE diabetic macular edema; retinal thickness; visual acuity; vitrectomy ID VITREOMACULAR TRACTION AB Purpose: To evaluate factors associated with favorable outcomes after vitrectomy for diabetic macular edema. Methods: Data were collected prospectively on 241 eyes undergoing vitrectomy for diabetic macular edema. Multivariate models were used to evaluate associations of 20 preoperative and intraoperative factors with 6-month outcomes of visual acuity and retinal thickness. Results: Median central subfield thickness decreased from 412 mu m to 278 mu m at 6 months, butmedian visual acuity remained unchanged (20/80, Snellen equivalent). Greater visual acuity improvement occurred in eyes with worse baseline acuity (P < 0.001) and in eyes in which an epiretinal membrane was removed (P = 0.006). Greater reduction in central subfield thickness occurred with worse baseline visual acuity (P < 0.001), greater preoperative retinal thickness (P = 0.001), removal of internal limiting membrane (P = 0.003), and optical coherence tomography evidence of vitreoretinal abnormalities (P = 0.006). No associations with clinician's preoperative assessments of the posterior vitreous were identified. Conclusion: These results suggest that the removal of epiretinal membranes may favorably affect visual outcome after vitrectomy. Preoperative presence of vitreoretinal abnormalities appeared to be associated with somewhat greater reductions in retinal thickness but not with visual acuity outcome. These results may be useful for future studies evaluating vitrectomy for diabetic macular edema. RETINA 30: 1488-1495, 2010 C1 [Edwards, Allison R.; Beck, Roy W.; Qin, Haijing] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Flaxel, Christina J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Aiello, Lloyd Paul] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02115 USA. [Bressler, Neil M.; Bressler, Susan B.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Ferris, Frederick L., III] NEI, Bethesda, MD 20892 USA. [Ferris, Frederick L., III] NIH, Bethesda, MD 20892 USA. [Gupta, Shailesh K.] Univ Florida, Coll Med, Dept Ophthalmol, Jacksonville, FL USA. [Haller, Julia A.] Wills Eye Inst, Philadelphia, PA USA. [Lazarus, Howard S.] Amer Eye Inst, Los Angeles, CA USA. RP Edwards, AR (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM drcrstat1@jaeb.org FU National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and Department of Health and Human Services [EY14231, EY018817, EY14229] FX Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and Department of Health and Human Services (EY14231, EY018817, and EY14229). NR 11 TC 35 Z9 36 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD OCT PY 2010 VL 30 IS 9 BP 1488 EP 1495 DI 10.1097/IAE.0b013e3181e7974f PG 8 WC Ophthalmology SC Ophthalmology GA 659JC UT WOS:000282561800018 PM 20924264 ER PT J AU Davis, BR Candotti, F AF Davis, Brian R. Candotti, Fabio TI Mosaicism-Switch or Spectrum? SO SCIENCE LA English DT Editorial Material ID WISKOTT-ALDRICH-SYNDROME; REVERTANT MOSAICISM; 2ND-SITE MUTATIONS; EPIDERMOLYSIS-BULLOSA; SOMATIC MOSAICISM; PATIENT; LYMPHOCYTES; SIBLINGS C1 [Davis, Brian R.] Univ Texas Hlth Sci Ctr, Brown Fdn Inst Mol Med, Ctr Stem Cell Res, Houston, TX 77030 USA. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Davis, BR (reprint author), Univ Texas Hlth Sci Ctr, Brown Fdn Inst Mol Med, Ctr Stem Cell Res, Houston, TX 77030 USA. EM brian.r.davis@uth.tmc.edu NR 12 TC 6 Z9 7 U1 0 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 1 PY 2010 VL 330 IS 6000 BP 46 EP 47 DI 10.1126/science.1195991 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 656KW UT WOS:000282334500026 PM 20929800 ER PT J AU Arensburger, P Megy, K Waterhouse, RM Abrudan, J Amedeo, P Antelo, B Bartholomay, L Bidwell, S Caler, E Camara, F Campbell, CL Campbell, KS Casola, C Castro, MT Chandramouliswaran, I Chapman, SB Christley, S Costas, J Eisenstadt, E Feschotte, C Fraser-Liggett, C Guigo, R Haas, B Hammond, M Hansson, BS Hemingway, J Hill, SR Howarth, C Ignell, R Kennedy, RC Kodira, CD Lobo, NF Mao, CH Mayhew, G Michel, K Mori, A Liu, NN Naveira, H Nene, V Nguyen, N Pearson, MD Pritham, EJ Puiu, D Qi, YM Ranson, H Ribeiro, JMC Roberston, HM Severson, DW Shumway, M Stanke, M Strausberg, RL Sun, C Sutton, G Tu, ZJ Tubio, JMC Unger, MF Vanlandingham, DL Vilella, AJ White, O White, JR Wondji, CS Wortman, J Zdobnov, EM Birren, B Christensen, BM Collins, FH Cornel, A Dimopoulos, G Hannick, LI Higgs, S Lanzaro, GC Lawson, D Lee, NH Muskavitch, MAT Raikhel, AS Atkinson, PW AF Arensburger, Peter Megy, Karine Waterhouse, Robert M. Abrudan, Jenica Amedeo, Paolo Antelo, Beatriz Bartholomay, Lyric Bidwell, Shelby Caler, Elisabet Camara, Francisco Campbell, Corey L. Campbell, Kathryn S. Casola, Claudio Castro, Marta T. Chandramouliswaran, Ishwar Chapman, Sinead B. Christley, Scott Costas, Javier Eisenstadt, Eric Feschotte, Cedric Fraser-Liggett, Claire Guigo, Roderic Haas, Brian Hammond, Martin Hansson, Bill S. Hemingway, Janet Hill, Sharon R. Howarth, Clint Ignell, Rickard Kennedy, Ryan C. Kodira, Chinnappa D. Lobo, Neil F. Mao, Chunhong Mayhew, George Michel, Kristin Mori, Akio Liu, Nannan Naveira, Horacio Nene, Vishvanath Nguyen, Nam Pearson, Matthew D. Pritham, Ellen J. Puiu, Daniela Qi, Yumin Ranson, Hilary Ribeiro, Jose M. C. Roberston, Hugh M. Severson, David W. Shumway, Martin Stanke, Mario Strausberg, Robert L. Sun, Cheng Sutton, Granger Tu, Zhijian (Jake) Tubio, Jose Manuel C. Unger, Maria F. Vanlandingham, Dana L. Vilella, Albert J. White, Owen White, Jared R. Wondji, Charles S. Wortman, Jennifer Zdobnov, Evgeny M. Birren, Bruce Christensen, Bruce M. Collins, Frank H. Cornel, Anthony Dimopoulos, George Hannick, Linda I. Higgs, Stephen Lanzaro, Gregory C. Lawson, Daniel Lee, Norman H. Muskavitch, Marc A. T. Raikhel, Alexander S. Atkinson, Peter W. TI Sequencing of Culex quinquefasciatus Establishes a Platform for Mosquito Comparative Genomics SO SCIENCE LA English DT Article ID AEDES-AEGYPTI; PIPIENS; VECTOR AB Culex quinquefasciatus (the southern house mosquito) is an important mosquito vector of viruses such as West Nile virus and St. Louis encephalitis virus, as well as of nematodes that cause lymphatic filariasis. C. quinquefasciatus is one species within the Culex pipiens species complex and can be found throughout tropical and temperate climates of the world. The ability of C. quinquefasciatus to take blood meals from birds, livestock, and humans contributes to its ability to vector pathogens between species. Here, we describe the genomic sequence of C. quinquefasciatus: Its repertoire of 18,883 protein-coding genes is 22% larger than that of Aedes aegypti and 52% larger than that of Anopheles gambiae with multiple gene-family expansions, including olfactory and gustatory receptors, salivary gland genes, and genes associated with xenobiotic detoxification. C1 [Arensburger, Peter; Raikhel, Alexander S.; Atkinson, Peter W.] Univ Calif Riverside, Ctr Dis Vector Res, Riverside, CA 92521 USA. [Megy, Karine; Hammond, Martin; Vilella, Albert J.; Lawson, Daniel] European Bioinformat Inst EMBL EBI, Cambridge CB10 1SD, England. [Waterhouse, Robert M.; Zdobnov, Evgeny M.] Univ Geneva, Sch Med, CH-1211 Geneva, Switzerland. [Waterhouse, Robert M.] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Abrudan, Jenica; Christley, Scott; Kennedy, Ryan C.; Lobo, Neil F.; Mori, Akio; Severson, David W.; Unger, Maria F.; Collins, Frank H.] Univ Notre Dame, Notre Dame, IN 46556 USA. [Amedeo, Paolo; Caler, Elisabet; Chandramouliswaran, Ishwar; Eisenstadt, Eric; Hannick, Linda I.] J Craig Venter Inst, Rockville, MD 20850 USA. [Tubio, Jose Manuel C.] Univ Santiago, Complexo Hosp, Santiago De Compostela 15706, Spain. [Bartholomay, Lyric] Iowa State Univ, Ames, IA 50011 USA. [Bidwell, Shelby; Camara, Francisco; Guigo, Roderic] Univ Pompeu Fabra, Ctr Gene Regulat, E-08003 Barcelona, Catalonia, Spain. [Campbell, Corey L.] Colorado State Univ, Ft Collins, CO 80523 USA. [Campbell, Kathryn S.] Harvard Univ, Cambridge, MA 02138 USA. [Casola, Claudio] Indiana Univ, Bloomington, IN 47405 USA. [Castro, Marta T.] Hosp Llobregat, Programa Epigenet & Biol Canc, Hosp Duran & Reynals, Barcelona 08907, Spain. [Chapman, Sinead B.; Haas, Brian; Howarth, Clint; Pearson, Matthew D.; White, Jared R.; Birren, Bruce; Muskavitch, Marc A. T.] Broad Inst, Cambridge, MA 02142 USA. [Costas, Javier] Fdn Publ Galega Med Xenomica Servizo Galego Saude, Santiago De Compostela 15706, Spain. [Feschotte, Cedric; Nguyen, Nam; Pritham, Ellen J.; Sun, Cheng] Univ Texas Arlington, Arlington, TX 76019 USA. [Fraser-Liggett, Claire; White, Owen; Wortman, Jennifer] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Hansson, Bill S.] Max Planck Inst Chem Ecol, D-07749 Jena, Germany. [Hemingway, Janet; Ranson, Hilary; Wondji, Charles S.] Univ Liverpool Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Hill, Sharon R.; Ignell, Rickard] Swedish Univ Agr Sci, S-23053 Alnarp, Sweden. [Kodira, Chinnappa D.] Roche Grp, Branford, CT 06405 USA. [Mao, Chunhong; Qi, Yumin; Tu, Zhijian (Jake)] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Mayhew, George; Christensen, Bruce M.] Univ Wisconsin, Madison, WI 53706 USA. [Michel, Kristin] Kansas State Univ, Manhattan, KS 66506 USA. [Liu, Nannan] Auburn Univ, Auburn, AL 36849 USA. [Naveira, Horacio] Univ A Coruna, Dept Bioloxia Celular & Mol, Coruna 15071 A, Spain. [Nene, Vishvanath] Int Livestock Res Inst, Nairobi, Kenya. [Puiu, Daniela] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Ribeiro, Jose M. C.; Shumway, Martin] Natl Inst Hlth, Bethesda, MD 20892 USA. [Roberston, Hugh M.] Univ Illinois, Urbana, IL 61801 USA. [Stanke, Mario] Univ Gottingen, D-37077 Gottingen, Germany. [Cornel, Anthony] Univ Texas Galveston, Med Branch, Galveston, TX 77555 USA. [Vanlandingham, Dana L.; Zdobnov, Evgeny M.; Higgs, Stephen] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Zdobnov, Evgeny M.; Lanzaro, Gregory C.] Univ Calif Davis, Parlier, CA 93648 USA. [Dimopoulos, George] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Lee, Norman H.] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Muskavitch, Marc A. T.] Boston Coll, Chestnut Hill, MA 02467 USA. [Muskavitch, Marc A. T.] Harvard Sch Publ Hlth, Boston, MA 02115 USA. RP Arensburger, P (reprint author), Univ Calif Riverside, Ctr Dis Vector Res, Riverside, CA 92521 USA. EM arensburger@gmail.com RI Costas, Javier/B-5016-2008; Feschotte, Cedric/C-4048-2011; Michel, Kristin/F-3400-2011; Zdobnov, Evgeny/K-1133-2012; Hansson, Bill/G-2774-2013; Naveira, Horacio/H-7249-2014; Camara Ferreira, Francisco/G-9841-2015; Guigo, Roderic/D-1303-2010; Tubio, Jose/H-5076-2015; Mayhew, George/B-4042-2016; Waterhouse, Robert/A-1858-2010; OI Costas, Javier/0000-0003-0306-3990; Hannick, Linda/0000-0002-8018-8466; Wortman, Jennifer/0000-0002-8713-1227; Hansson, Bill/0000-0002-4811-1223; Naveira, Horacio/0000-0002-3840-1569; Camara Ferreira, Francisco/0000-0002-1971-5466; Guigo, Roderic/0000-0002-5738-4477; Tubio, Jose/0000-0003-3540-2459; Mayhew, George/0000-0003-0609-6018; Waterhouse, Robert/0000-0003-4199-9052; Vilella, Albert/0000-0002-2005-2516; Lawson, Daniel/0000-0001-7765-983X; Megy, Karyn/0000-0002-2826-3879; Fraser, Claire/0000-0003-1462-2428; Ranson, Hilary/0000-0003-2332-8247; Hill, Sharon Rose/0000-0002-6474-0214; Dimopoulos, George/0000-0001-6755-8111; Hemingway, Janet/0000-0002-3200-7173; Ribeiro, Jose/0000-0002-9107-0818 FU NIH [HHSN266200400039C]; National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services [N01-AI-30071, HHSN266200400001C] FX This work was supported by NIH grant HHSN266200400039C and by the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services under contract numbers N01-AI-30071 and HHSN266200400001C. The assembled genome was deposited in the GenBank database with accession number AAWU00000000. NR 12 TC 207 Z9 219 U1 5 U2 60 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 1 PY 2010 VL 330 IS 6000 BP 86 EP 88 DI 10.1126/science.1191864 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 656KW UT WOS:000282334500040 PM 20929810 ER PT J AU Arana, ME Kunkel, TA AF Arana, Mercedes E. Kunkel, Thomas A. TI Mutator phenotypes due to DNA replication infidelity SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE Fidelity; DNA polymerase; DNA replication; Mutator phenotypes; Microsatellite instability ID XERODERMA-PIGMENTOSUM VARIANT; POLYMERASE-ETA; MISMATCH REPAIR; TRANSLESION SYNTHESIS; SOMATIC HYPERMUTATION; MICROSATELLITE INSTABILITY; SACCHAROMYCES-CEREVISIAE; AFFINITY MATURATION; COLORECTAL-CANCER; ESCHERICHIA-COLI AB This article considers the fidelity of DNA replication performed by eukaryotic DNA polymerases involved in replicating the nuclear genome. DNA replication fidelity can vary widely depending on the DNA polymerase, the composition of the error, the flanking sequence, the presence of DNA damage and the ability to correct errors. As a consequence, defects in processes that determine DNA replication fidelity can confer strong mutator phenotypes whose specificity can help determine the molecular nature of the defect. Published by Elsevier Ltd. C1 [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, 111 TW Alexander Dr,Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01 ES065070, Z01 ES065089] FX We thank Katarzyna Bebenek and Jessica Williams for thoughtful comments on the manuscript. The research conducted in Thomas Kunkel's laboratory is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Projects Z01 ES065070 and Z01 ES065089). NR 91 TC 36 Z9 36 U1 1 U2 9 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 OCT PY 2010 VL 20 IS 5 BP 304 EP 311 DI 10.1016/j.semcancer.2010.10.003 PG 8 WC Oncology SC Oncology GA 704DL UT WOS:000286031200004 PM 20934516 ER PT J AU Singer, A AF Singer, Alfred TI Molecular and cellular basis of T cell lineage commitment: An overview SO SEMINARS IN IMMUNOLOGY LA English DT Editorial Material C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM singera@mail.nih.gov NR 7 TC 1 Z9 1 U1 0 U2 1 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 OCT PY 2010 VL 22 IS 5 BP 253 EP 253 DI 10.1016/j.smim.2010.06.001 PG 1 WC Immunology SC Immunology GA 647BG UT WOS:000281590100001 PM 20655758 ER PT J AU Wang, L Xiong, YM Bosselut, R AF Wang, Lie Xiong, Yumei Bosselut, Remy TI Tenuous paths in unexplored territory: From T cell receptor signaling to effector gene expression during thymocyte selection SO SEMINARS IN IMMUNOLOGY LA English DT Review DE T cell development; Thymus; Transcription; Signaling ID NF-KAPPA-B; DOUBLE-POSITIVE THYMOCYTES; CD8 LINEAGE COMMITMENT; ERK MAPK CASCADE; TRANSCRIPTION FACTORS; NEGATIVE SELECTION; ANTIGEN RECEPTOR; THYMIC SELECTION; DNA-BINDING; TCR SIGNALS AB During the last step of alpha beta T cell development, thymocytes that have rearranged genes encoding TCR chains and express CD4 and CD8 coreceptors are selected on the basis of their TCR reactivity to escape programmed cell death and become mature CD4 or CD8 T cells. This process is triggered by intrathymic TCR signaling, that activates 'sensor' transcription factors 'constitutively' expressed in DP thymocytes. Eventually, TCR-signaled thymocytes evolve effector transcriptional circuits that control basal metabolism, migration, survival and initiation of lineage-specific gene expression. This review examines how components of the 'sensing' transcription apparatus responds to positive selection signals, and highlights important differences with mature T cell responses. In a second part, we evaluate current observations and hypotheses on the connections between sensing transcription factors and effector circuitries. (C) 2010 Published by Elsevier Ltd. C1 [Wang, Lie; Xiong, Yumei; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bldg 37,Room 3015,37 Convent Dr, Bethesda, MD 20892 USA. EM remy@helix.nih.gov FU National Cancer Institute, Center for Cancer Research, NIH FX We thank Jon Ashwell, Dietz Conze, Ellen Rothenberg and Murty Shrinivasula for stimulating discussions, and Jon Ashwell and Paul Love for critical reading of the manuscript. Research work in the authors' laboratory is supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 158 TC 12 Z9 12 U1 0 U2 3 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 OCT PY 2010 VL 22 IS 5 BP 294 EP 302 DI 10.1016/j.smim.2010.04.013 PG 9 WC Immunology SC Immunology GA 647BG UT WOS:000281590100007 PM 20537906 ER PT J AU Signore, C Spong, CY AF Signore, Caroline Spong, Catherine Y. TI Vaginal Birth After Cesarean: New Insights Manuscripts from an NIH Consensus Development Conference, March 8-10, 2010 SO SEMINARS IN PERINATOLOGY LA English DT Editorial Material C1 [Signore, Caroline; Spong, Catherine Y.] NIH, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. RP Signore, C (reprint author), NIH, Pregnancy & Perinatol Branch, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HD999999] NR 0 TC 7 Z9 7 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD OCT PY 2010 VL 34 IS 5 BP 309 EP 310 DI 10.1053/j.semperi.2010.05.002 PG 2 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 662TI UT WOS:000282835100001 PM 20869544 ER PT J AU Bolla, KI Lesage, SR Gamaldo, CE Neubauer, DN Wang, NY Funderburk, FR Allen, RP David, PM Cadet, JL AF Bolla, Karen I. Lesage, Suzanne R. Gamaldo, Charlene E. Neubauer, David N. Wang, Nae-Yuh Funderburk, Frank R. Allen, Richard P. David, Paula M. Cadet, Jean Lud TI Polysomnogram changes in marijuana users who report sleep disturbances during prior abstinence SO SLEEP MEDICINE LA English DT Article DE Sleep; Polysomnography; Periodic leg movements; Marijuana; Abstinence; Substance abuse; Withdrawal ID CANNABIS WITHDRAWAL; SEX-DIFFERENCES; COCAINE USERS; DEPENDENCE; QUESTIONNAIRE; TOLERANCE; SEVERITY; PATTERNS; VALIDITY; RELAPSE AB Background: Abrupt discontinuation of heavy marijuana (MJ) use is associated with self-reports of sleep difficulty. Disturbed sleep is clinically important because MJ users experiencing sleep problems may relapse to MJ use to improve their sleep quality. Few studies have used polysomnography (PSG) to characterize changes in sleep architecture during abrupt abstinence from heavy MJ use. Methods: We recorded PSG measures on nights 1, 2, 7, 8, and 13 after abrupt MJ discontinuation in 18 heavy MJ users residing in an inpatient unit. Results: Across abstinence, Total Sleep Time (TST), Sleep Efficiency (SEff), and amount of REM sleep declined, while Wake after Sleep Onset (WASO) and Periodic Limb Movements (PLM) increased. Furthermore, quantity (joints/week) and duration (years) of MJ use were positively associated with more PLMs. Conclusion: The treatment of sleep disturbance is a potential target for the management of cannabis use disorders since poor sleep could contribute to treatment failure in heavy MJ users. (C) 2010 Elsevier B.V. All rights reserved. C1 [Bolla, Karen I.; Gamaldo, Charlene E.; Allen, Richard P.; David, Paula M.] Johns Hopkins Med Inst, Dept Neurol, Bayview Med Ctr, Baltimore, MD 21205 USA. [Bolla, Karen I.; Neubauer, David N.] Johns Hopkins Med Inst, Dept Psychiat & Behav Sci, Bayview Med Ctr, Baltimore, MD 21205 USA. [Bolla, Karen I.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Lesage, Suzanne R.] Univ Maryland, Sleep Disorders Ctr, Baltimore, MD 21201 USA. [Wang, Nae-Yuh] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Wang, Nae-Yuh] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Funderburk, Frank R.] InCompass Syst, Columbia, MD USA. [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Branch, DHHS, NIH,Intramural Res Program, Baltimore, MD USA. RP Bolla, KI (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave,B Bldg,Room 123, Baltimore, MD 21224 USA. EM kbolla@jhmi.edu OI Wang, Nae-Yuh/0000-0001-6513-9730 FU NIH [DA 17122]; JHBMC-GCRC-CTSA [MO1 RR02719, UL1 RR 025005]; DHH NIDA FX Supported by NIH grants DA 17122(KB), the JHBMC-GCRC-CTSA (MO1 RR02719, UL1 RR 025005) and the DHH NIDA Intramural Research Program. NR 38 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 J9 SLEEP MED JI Sleep Med. PD OCT PY 2010 VL 11 IS 9 BP 882 EP 889 DI 10.1016/j.sleep.2010.02.013 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 663EL UT WOS:000282865700014 PM 20685163 ER PT J AU McAreavey, D Vidal, JS Aspelund, T Owens, DS Hughes, T Garcia, M Sigurdsson, S Bjornsdottir, H Harris, TB Gudnason, V Launer, LJ Plehn, JF AF McAreavey, Dorothea Vidal, Jean-Sebastien Aspelund, Thor Owens, David S. Hughes, Timothy Garcia, Melissa Sigurdsson, Sigurdur Bjornsdottir, Halldora Harris, Tamara B. Gudnason, Vilmundur Launer, Lenore J. Plehn, Jonathan F. TI Correlation of Echocardiographic Findings With Cerebral Infarction in Elderly Adults The AGES-Reykjavik Study SO STROKE LA English DT Article DE aging; cerebral infarction; echocardiography; epidemiology; magnetic resonance imaging ID LEFT-VENTRICULAR HYPERTROPHY; MITRAL ANNULAR CALCIFICATION; HEART-FAILURE; EJECTION FRACTION; STROKE; DISEASE; RISK; COHORT; PREVALENCE; PREDICTOR AB Background and Purpose-Chronic effects of hypertension may be observed in multiple end organs. Previous reports suggest that cardiovascular morphological features can mirror cerebral infarction. In this cross-sectional analysis of elderly subjects, we investigated the relationship of a comprehensive set of echocardiographic measures with cerebral infarction detected by MRI. Methods-We compared echocardiographically determined left ventricular (LV) mass, left atrial volume, aortic root diameter, mitral annular calcification, and measures of diastolic function with cerebral infarction determined by MRI using logistic regression in a random sample drawn from the Age Gene/Environment Susceptibility-Reykjavik Study cohort. The model was first adjusted for age and gender, and then for age, gender, and vascular risk factors. Results-Among 692 subjects aged 75 (standard deviation, 6) years, 28% had at least 1 cerebral infarct. When adjusted for age and gender, the presence of cerebral infarction was modestly related to LV mass (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02) and left atrial volume (OR, 1.03; 95% CI, 1.01-1.05), as well as the lowest quartile of early-to-late pulsed Doppler velocity ratio (early-to-late pulsed Doppler velocity ratio <0.75; OR, 1.87; 95% CI, 1.22-2.87). The latter relation remained significant after adjustment for vascular risk factors and LV ejection fraction (OR, 1.82; 95% CI, 1.16-2.86). Conclusion-Of all echocardiographic parameters, LV filling abnormality as indicated by low early-to-late pulsed Doppler velocity ratio displayed the strongest association with cerebral infarction and this relationship was independent of vascular risk factors. This simple marker of cerebral infarction may be useful when evaluating older patients. (Stroke. 2010;41:2223-2228.) C1 [McAreavey, Dorothea] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Vidal, Jean-Sebastien; Hughes, Timothy; Garcia, Melissa; Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Owens, David S.; Plehn, Jonathan F.] NHLBI, NIH, Bethesda, MD 20892 USA. [Aspelund, Thor; Sigurdsson, Sigurdur; Bjornsdottir, Halldora; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. RP McAreavey, D (reprint author), 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM dmcareavey@cc.nih.gov RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; Vidal, Jean-Sebastien/D-1941-2016; OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Vidal, Jean-Sebastien/0000-0001-6770-0720; Owens, David/0000-0002-7293-9688 FU National Institutes of Health [N01-AG-1-2100]; National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study was supported by a contract from the National Institutes of Health (N01-AG-1-2100), National Institute on Aging Intramural Research Program, the Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). NR 29 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2010 VL 41 IS 10 BP 2223 EP 2228 DI 10.1161/STROKEAHA.110.590430 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 655CY UT WOS:000282221700029 PM 20798368 ER PT J AU Taylor, A Castle, A Merino, JG Hsia, A Kidwell, CS Warach, S AF Taylor, Alexis Castle, Amanda Merino, Jose G. Hsia, Amie Kidwell, Chelsea S. Warach, Steven TI Optimizing Stroke Clinical Trial Design Estimating the Proportion of Eligible Patients SO STROKE LA English DT Article DE acute ischemic stroke; age; clinical trial; National Institutes of Health Stroke Scale; time factors AB Background and Purpose-Clinical trial planning and site selection require an accurate estimate of the number of eligible patients at each site. In this study, we developed a tool to calculate the proportion of patients who would meet a specific trial's age, baseline severity, and time to treatment inclusion criteria. Methods-From a sample of 1322 consecutive patients with acute ischemic cerebrovascular syndromes, we developed regression curves relating the proportion of patients within each range of the 3 variables. We used half the patients to develop the model and the other half to validate it by comparing predicted vs actual proportions who met the criteria for 4 current stroke trials. Results-The predicted proportion of patients meeting inclusion criteria ranged from 6% to 28% among the different trials. The proportion of trial-eligible patients predicted from the first half of the data were within 0.4% to 1.4% of the actual proportion of eligible patients. This proportion increased logarithmically with National Institutes of Health Stroke Scale score and time from onset; lowering the baseline limits of the National Institutes of Health Stroke Scale score and extending the treatment window would have the greatest impact on the proportion of patients eligible for a stroke trial. Conclusions-This model helps estimate the proportion of stroke patients eligible for a study based on different upper and lower limits for age, stroke severity, and time to treatment, and it may be a useful tool in clinical trial planning. (Stroke. 2010;41:2236-2238.) C1 [Taylor, Alexis; Merino, Jose G.; Hsia, Amie; Warach, Steven] NINDS, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. [Castle, Amanda; Hsia, Amie; Kidwell, Chelsea S.] Georgetown Univ Hosp, Dept Neurol, Washington, DC 20007 USA. [Merino, Jose G.] Suburban Hosp Stroke Program, Bethesda, MD USA. [Hsia, Amie; Kidwell, Chelsea S.] Washington Hosp Ctr, Stroke Ctr, Washington, DC 20010 USA. RP Warach, S (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, 10 Ctr Dr,Room B1D733,MSC 1063, Bethesda, MD 20892 USA. EM Warachs@ninds.nih.gov OI Merino, Jose/0000-0002-6676-0008 FU Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This research was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 6 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2010 VL 41 IS 10 BP 2236 EP 2238 DI 10.1161/STROKEAHA.110.578252 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 655CY UT WOS:000282221700031 PM 20798375 ER PT J AU Lima, FO Furie, KL Silva, GS Lev, MH Camargo, ECS Singhal, AB Harris, GJ Halpern, EF Koroshetz, WJ Smith, WS Yoo, AJ Nogueira, RG AF Lima, Fabricio O. Furie, Karen L. Silva, Gisele S. Lev, Michael H. Camargo, Erica C. S. Singhal, Aneesh B. Harris, Gordon J. Halpern, Elkan F. Koroshetz, Walter J. Smith, Wade S. Yoo, Albert J. Nogueira, Raul G. TI The Pattern of Leptomeningeal Collaterals on CT Angiography Is a Strong Predictor of Long-Term Functional Outcome in Stroke Patients With Large Vessel Intracranial Occlusion SO STROKE LA English DT Article DE acute stroke; brain imaging; brain ischemia; leptomeningeal collaterals; outcome ID ACUTE ISCHEMIC-STROKE; INTRAARTERIAL THROMBOLYSIS; PROACT-II; RECANALIZATION; CIRCULATION; PERFUSION; INFARCT; EXTENT; TRIAL; SCORE AB Background and Purpose-The role of noninvasive methods in the evaluation of collateral circulation has yet to be defined. We hypothesized that a favorable pattern of leptomeningeal collaterals, as identified by CT angiography, correlates with improved outcomes. Methods-Data from a prospective cohort study at 2 university-based hospitals where CT angiography was systematically performed in the acute phase of ischemic stroke were analyzed. Patients with complete occlusion of the intracranial internal carotid artery and/or the middle cerebral artery (M1 or M2 segments) were selected. The leptomeningeal collateral pattern was graded as a 3-category ordinal variable (less, equal, or greater than the unaffected contralateral hemisphere). Univariate and multivariate analyses were performed to define the independent predictors of good outcome at 6 months (modified Rankin Scale score <= 2). Results-One hundred ninety-six patients were selected. The mean age was 69 +/- 17 years and the median National Institute of Health Stroke Scale score was 13 (interquartile range, 6 to 17). In the univariate analysis, age, baseline National Institute of Health Stroke Scale score, prestroke modified Rankin Scale score, Alberta Stroke Programme Early CT score, admission blood glucose, history of hypertension, coronary artery disease, congestive heart failure, atrial fibrillation, site of occlusion, and collateral pattern were predictors of outcome. In the multivariate analysis, age (OR, 0.95; 95% CI, 0.93 to 0.98; P=0.001), baseline National Institute of Health Stroke Scale (OR, 0.75; 0.69 to 0.83; P<0.001), prestroke modified Rankin Scale score (OR, 0.41; 0.22 to 0.76; P=0.01), intravenous recombinant tissue plasminogen activator (OR, 4.92; 1.83 to 13.25; P=0.01), diabetes (OR, 0.31; 0.01 to 0.98; P=0.046), and leptomeningeal collaterals (OR, 1.93; 1.06 to 3.34; P=0.03) were identified as independent predictors of good outcome. Conclusion-Consistent with angiographic studies, leptomeningeal collaterals on CT angiography are also a reliable marker of good outcome in ischemic stroke. (Stroke. 2010;41:2316-2322.) C1 [Lima, Fabricio O.; Furie, Karen L.; Silva, Gisele S.; Camargo, Erica C. S.; Singhal, Aneesh B.; Nogueira, Raul G.] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. [Nogueira, Raul G.] Massachusetts Gen Hosp, Dept Neurol, Neurocrit Care Serv, Boston, MA 02114 USA. [Nogueira, Raul G.] Massachusetts Gen Hosp, Dept Neurol, Intervent Neuroradiol Serv, Boston, MA 02114 USA. [Nogueira, Raul G.] Massachusetts Gen Hosp, Dept Radiol, Stroke Serv, Boston, MA 02114 USA. [Nogueira, Raul G.] Massachusetts Gen Hosp, Dept Radiol, Neurocrit Care Serv, Boston, MA 02114 USA. [Nogueira, Raul G.] Massachusetts Gen Hosp, Dept Radiol, Intervent Neuroradiol Serv, Boston, MA 02114 USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. [Smith, Wade S.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yoo, Albert J.] Massachusetts Gen Hosp, Dept Radiol, Diagnost & Intervent Neuroradiol Serv, Boston, MA 02114 USA. RP Nogueira, RG (reprint author), Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Blake 12,55 Fruit St, Boston, MA 02114 USA. EM rnogueira@partners.org RI Lima, Fabricio/E-6507-2015 OI Lima, Fabricio/0000-0002-0383-4145 FU Department of Health and Human Services, Agency for Healthcare Research and Quality [RO1-HS011392-01A1]; GE Healthcare; National Institutes of Health (NIH) [P50NS051343, R01NS051412, R01NS38477, R01NS059775]; Penumbra Inc FX This research was funded by a grant from the Department of Health and Human Services, Agency for Healthcare Research and Quality, grant number RO1-HS011392-01A1.; M.H.L. is a speaker for GE Healthcare, receives educational support from GE Healthcare, serves on a medical advisory board for CoAxia Inc, is a research consultant for Vernalis Ltd (modest), and is supported by National Institutes of Health (NIH) grant P50NS051343 (significant). A.B.S. is supported by NIH grants P50NS051343, R01NS051412, R01NS38477 (significant), and R01NS059775 (modest). W.S.S. has significant ownership interests and has served as a consultant to Concentric Medical Inc (significant). A.J.Y. is supported by a research grant from Penumbra Inc (significant). R.G.N. is a member of the Scientific Advisory Board for Concentric Medical Inc, ev3 Neurovascular Inc, and Coaxia Inc (modest). NR 24 TC 109 Z9 115 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2010 VL 41 IS 10 BP 2316 EP 2322 DI 10.1161/STROKEAHA.110.592303 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 655CY UT WOS:000282221700044 PM 20829514 ER PT J AU Kernan, WN Launer, LJ Goldstein, LB AF Kernan, Walter N. Launer, Lenore J. Goldstein, Larry B. TI What Is the Future of Stroke Prevention? Debate: Polypill Versus Personalized Risk Factor Modification SO STROKE LA English DT Article; Proceedings Paper CT 27th Princeton Conference 2010 CY APR 22-24, 2010 CL Boston, MA DE cerebrovascular disorders; primary prevention ID CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; OUTCOMES; TRIAL; HEALTH; METAANALYSIS; ASSOCIATION; OPPORTUNITY; NUTRITION; MORTALITY AB Background and Purpose-The control of stroke risk factors remains challenging. The "polypill" concept represents a novel approach for reducing stroke and cardiovascular risk factors in the entire population. The polypill would include several components and be provided without prescription to all adults of a certain age. Results-A polypill aimed at lowering blood pressure and cholesterol levels is estimated to potentially reduce the risk of a first ischemic stroke by 53%; this would translate to about 400 000 fewer strokes each year in the United States alone. Recommending a polypill for the entire older adult population would, however, include many individuals without the multiple risk factors targeted by its components, putting them at risk for drug-related side effects and responsible for the costs of a medication from which they would not derive benefit. Additional arguments for and against the polypill approach are discussed. Conclusions-Only clinical trials can provide the evidence needed to determine the usefulness of the polypill approach. Issues related to defining the components of the polypill, evaluating the pharmacodynamics and pharmacokinetics of a multiple-component formulation, and establishing safety and cost-effectiveness when given to large populations, however, are not trivial. (Stroke. 2010;41[suppl 1]:S35-S38.) C1 [Launer, Lenore J.] NIA, Neuroepidemiol Sect, NIH, Bethesda, MD 20892 USA. [Kernan, Walter N.] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Goldstein, Larry B.] Duke Univ, Duke Stroke Ctr, Dept Med Neurol, Durham, NC 27710 USA. Durham Dept Vet Affairs Med Ctr, Durham, NC USA. RP Goldstein, LB (reprint author), Duke Univ, Med Ctr, Box 3651, Durham, NC 27710 USA. EM golds004@mc.duke.edu FU Intramural NIH HHS [Z01 AG007270-08] NR 30 TC 10 Z9 10 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD OCT PY 2010 VL 41 IS 10 SU 1 BP S35 EP S38 DI 10.1161/STROKEAHA.110.592022 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 655DR UT WOS:000282224300010 PM 20876501 ER PT J AU Yuan, NP Eaves, ER Koss, MP Polacca, M Bletzer, K Goldman, D AF Yuan, Nicole P. Eaves, Emery R. Koss, Mary P. Polacca, Mona Bletzer, Keith Goldman, David TI "Alcohol is Something That Been With Us Like a Common Cold": Community Perceptions of American Indian Drinking SO SUBSTANCE USE & MISUSE LA English DT Article DE American Indian; alcohol; prevention; qualitative research ID MENTAL-HEALTH DISPARITIES; RESERVATION POPULATIONS; DISORDERS; DEPENDENCE; PREVENTION; PREVALENCE; CULTURE; TRIBES AB This study examined tribal members' perspectives on alcohol, risk factors, consequences, and community responses. Focus groups were conducted with five American Indian tribes between 1997 and 2001. Participants were knowledgeable of the cultural lives of their reservation communities. Although there was agreement regarding the pervasiveness of heavy drinking, participants reported different opinions about the meaning of alcohol and appropriate intervention strategies. Three dilemmas were identified, suggesting that community ambivalence may serve as a barrier to reducing problem drinking. Implications, limitations, and future research directions are discussed. The study was funded by the National Institute on Alcohol Abuse and Alcoholism. C1 [Yuan, Nicole P.; Koss, Mary P.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ 85724 USA. [Bletzer, Keith] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ USA. [Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Eaves, Emery R.] Univ Arizona, Dept Family & Community Med, Tucson, AZ 85724 USA. RP Yuan, NP (reprint author), Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, 1295 N Martin Ave,POB 245209, Tucson, AZ 85724 USA. EM nyuan@email.arizona.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism [K23AA014606, N01AA51012] FX This paper was supported by Grant Number K23AA014606 from the National Institute on Alcohol Abuse and Alcoholism to the first author. The Ten Tribes Study was funded by Contract Number N01AA51012 from the same institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism or the National Institutes of Health. We express sincere gratitude to the tribal members who shared their opinions and experiences to inform the main study design and the tribes for providing tribal council support. Appreciation also goes to Christiane Pretzinger and JoLene Unruh for transcribing the interviews and Dr. Nicky Teufel-Shone for consultation on qualitative analysis. Thanks are also due to Dr. Bonnie Duran for her insightful reading of the manuscript. NR 29 TC 7 Z9 7 U1 0 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PD OCT PY 2010 VL 45 IS 12 BP 1909 EP 1929 DI 10.3109/10826081003682115 PG 21 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 633RP UT WOS:000280522500005 PM 20380555 ER PT J AU Scheidweiler, KB Spargo, EAK Kelly, TL Cone, EJ Barnes, AJ Huestis, MA AF Scheidweiler, Karl B. Spargo, Erin A. Kolbrich Kelly, Tamsin L. Cone, Edward J. Barnes, Allan J. Huestis, Marilyn A. TI Pharmacokinetics of Cocaine and Metabolites in Human Oral Fluid and Correlation With Plasma Concentrations After Controlled Administration SO THERAPEUTIC DRUG MONITORING LA English DT Article DE cocaine; oral fluid; clinical study; pharmacokinetics ID HUMAN VOLUNTEERS; SALIVA; DISPOSITION; COLLECTION; CODEINE; URINE; DRUGS; SWEAT AB Oral fluid is an attractive alternative matrix for drug testing with a noninvasive and directly observed collection, but there are few controlled cocaine administration studies to guide interpretation. Materials and Methods: While residing on a closed research unit for up to 10 weeks under constant medical supervision, 19 participants were administered 75 wmg/70 kg subcutaneous cocaine and 14 received 150 mg/70 kg. The disposition of cocaine, benzoylecgonine (BE), and ecgonine methyl ester (EME) into oral fluid was determined by gas chromatography-mass spectrometry for 0.08 to 48 hours after administration. Results: In oral fluid collected by citric acid candy-stimulated expectoration, cocaine first appeared in oral fluid 0.08 to 0.32 hours after dosing and was rapidly eliminated with half-lives of 1.1 to 3.8 hours. BE and EME were first detected 0.08 to 1.0 hours after dosing with longer half-lives of 3.4 to 13.8 (BE) and 2.4 to 15.5 hours (EME) (P < 0.05). Oral fluid and plasma concentrations were significantly correlated for cocaine, BE, and EME (P < 0.0001). There were no significant differences (P. 0.05) in first and last detection times with the 8-mu g/L cutoff proposed by the Substance Abuse and Mental Health Services Administration or the 10-mu g/L cutoff from the European initiative, Driving Under the Influence of Drugs, Alcohol and Medicines. Metabolite: cocaine ratios increased after cocaine administration, potentially helpful for interpreting time of last use. Comparison of oral fluid collection through citric acid candy-stimulated expectoration, citric acid-treated Salivette, and neutral cotton Salivette devices did not reveal significant differences between devices for areas under the curve for cocaine, BE, or EME (P > 0.05). Discussion and Conclusion: These results provide additional evidence for interpreting cocaine and metabolite concentrations in oral fluid and oral fluid's usefulness as an alternative matrix for drug testing. C1 [Scheidweiler, Karl B.; Spargo, Erin A. Kolbrich; Barnes, Allan J.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kelly, Tamsin L.] Univ Canberra, Fac Sci Appl, Canberra, ACT 2601, Australia. [Cone, Edward J.] Johns Hopkins Sch Med, Baltimore, MD USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI Kelly, Tamsin/A-2456-2009 OI Kelly, Tamsin/0000-0002-8946-9686 FU National Institutes of Health, National Institute on Drug Abuse FX This research was supported by funds from the National Institutes of Health, Intramural Research Program, National Institute on Drug Abuse. NR 26 TC 26 Z9 27 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD OCT PY 2010 VL 32 IS 5 BP 628 EP 637 DI 10.1097/FTD.0b013e3181f2b729 PG 10 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 653NY UT WOS:000282099700014 PM 20814350 ER PT J AU Yende, S van der Poll, T Lee, M Huang, DT Newman, AB Kong, L Kellum, JA Harris, TB Bauer, D Satterfield, S Angus, DC AF Yende, Sachin van der Poll, Tom Lee, MinJae Huang, David T. Newman, Anne B. Kong, Lan Kellum, John A. Harris, Tamara B. Bauer, Doug Satterfield, Suzanne Angus, Derek C. CA GenIMS Hlth ABC Study TI The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies SO THORAX LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; ACUTE-RENAL-FAILURE; INFLAMMATORY MARKERS; LONG-TERM; MORTALITY; SEPSIS; RISK; PREDICTION; HYPERGLYCEMIA; DISEASE AB Background Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear. Methods A retrospective analysis of two multicentre cohorts was carried out. The effect of pre-existing diabetes on the host immune response, acute organ function and mortality in patients hospitalised with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalisations in the population-based cohort study, Health ABC (n=1639) was determined. Measurements included the mortality rate within the first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumour necrosis factor, interleukin 6, interleukin 10), coagulation (Factor IX, thrombin-antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1 and D-dimer) and cell surface markers (CD120a, CD120b, human leucocyte antigen (HLA)-DR, Toll-like receptor-2 and Toll-like receptor-4). Results In GenIMS, diabetes increased the mortality rate within the first year after CAP (unadjusted HR 1.41, 95% CI 1.12 to 1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR 1.3, 95% CI 1.03 to 1.65, p=0.02). In Health ABC, diabetes increased the mortality rate within the first year following CAP hospitalisation, but not after hospitalisation for non-infectious illnesses (significant interaction for diabetes and reason for hospitalisation (p=0.04); HR for diabetes on mortality over the first year after CAP 1.87, 95% CI 0.76 to 4.6, p=0.16, and after non-infectious hospitalisation 1.16, 95% CI 0.8 to 1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels, in the emergency department and during the first week. Those with diabetes had a higher risk of acute kidney injury during hospitalisation (39.3% vs 31.7%, p-0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs 26.8% and 10.4% vs 4.5%, p=0.03). Conclusions Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease. C1 [Yende, Sachin; Lee, MinJae; Huang, David T.; Kellum, John A.; Angus, Derek C.] Univ Pittsburgh, Clin Res Invest & Syst Modeling Acute Illness Lab, Pittsburgh, PA 15261 USA. [Yende, Sachin] Univ Pittsburgh, Dept Crit Care Med, CRISMA Lab, Pittsburgh, PA 15261 USA. [van der Poll, Tom] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, NL-1105 AZ Amsterdam, Netherlands. [van der Poll, Tom] Univ Amsterdam, Acad Med Ctr, Ctr Expt & Mol Med, NL-1105 AZ Amsterdam, Netherlands. [Lee, MinJae; Kong, Lan] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Huang, David T.] Univ Pittsburgh, Dept Emergency Med, Pittsburgh, PA 15261 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Bauer, Doug] Univ Calif San Francisco, Dept Epidemiol & Biostat & Med, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. RP Yende, S (reprint author), Univ Pittsburgh, Dept Crit Care Med, CRISMA Lab, 642A Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM yendes@upmc.edu RI Angus, Derek/E-9671-2012; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NIGMS [R01 GM61992]; GlaxoSmithKline; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NHLBI [R01HL74104]; NIAID [27913, 39482]; NIH, National Institute on Ageing; [K23GM083215] FX GenIMS was funded by NIGMS R01 GM61992 with additional support from GlaxoSmithKline for enrolment and clinical data collection, and Diagnostic Products Corporation for the cytokine assays. Health ABC was funded by NIA (N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106), NHLBI (R01HL74104) and NIAID (27913 and 39482). Health ABC was supported in part by the Intramural Research Program of the NIH, National Institute on Ageing. SY is supported by K23GM083215. NR 35 TC 36 Z9 38 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD OCT PY 2010 VL 65 IS 10 BP 870 EP 877 DI 10.1136/thx.2010.136317 PG 8 WC Respiratory System SC Respiratory System GA 653GI UT WOS:000282076700008 PM 20861291 ER PT J AU Hatsukami, DK Perkins, KA LeSage, MG Ashley, DL Henningfield, JE Benowitz, NL Backinger, CL Zeller, M AF Hatsukami, Dorothy K. Perkins, Kenneth A. LeSage, Mark G. Ashley, David L. Henningfield, Jack E. Benowitz, Neal L. Backinger, Cathy L. Zeller, Mitch TI Nicotine reduction revisited science and future directions SO TOBACCO CONTROL LA English DT Article ID DISCRIMINATIVE STIMULUS PROPERTIES; CONDITIONED PLACE PREFERENCE; BEHAVIORAL ECONOMIC-ANALYSIS; MONOAMINE-OXIDASE INHIBITOR; CIGARETTE-SMOKING; TOBACCO DEPENDENCE; ADULT RATS; SEX-DIFFERENCES; DENICOTINIZED CIGARETTES; ACETYLCHOLINE-RECEPTORS AB Regulation of nicotine levels in cigarettes and other tobacco products is now possible with the passage of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) in 2009 giving the US Food and Drug Administration (FDA) authority to regulate tobacco products and with Articles 911 of the WHO Framework Convention on Tobacco Control Both regulatory approaches allow establishing product standards for tobacco constituents including nicotine The FSPTCA does not allow nicotine levels to be decreased to rem although the FDA has the authority to reduce nicotine yields to very low presumably non addicting levels The proposal to reduce levels of nicotine to a level that is non addicting was originally suggested in 1994 Reduction of nicotine in tobacco products could potentially have a profound impact on reducing tobacco related morbidity and mortality To examine this issue two meetings were convened in the US with non tobacco industry scientists of varied disciplines tobacco control policymakers and representatives of government agencies This article provides an overview of the current science in the area of reduced nicotine content cigarettes and key conclusions and recommendations for research and policy that emerged from the deliberations of the meeting members C1 [Hatsukami, Dorothy K.] Univ Minnesota, Tobacco Use Res Ctr, Dept Psychiat, Minneapolis, MN 55414 USA. [Perkins, Kenneth A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [LeSage, Mark G.] Univ Minnesota, Minneapolis Med Res Fdn, Dept Med, Minneapolis, MN 55414 USA. [Ashley, David L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. [Henningfield, Jack E.; Zeller, Mitch] Pinney Associates, Bethesda, MD USA. [Benowitz, Neal L.] Univ Calif San Francisco, Dept Med & Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Backinger, Cathy L.] Natl Canc Inst, Tobacco Control Res Branch, Rockville, MD USA. RP Hatsukami, DK (reprint author), Univ Minnesota, Tobacco Use Res Ctr, Dept Psychiat, 717 Delaware St SE, Minneapolis, MN 55414 USA. FU National Institute on Drug Abuse Rockville Maryland USA; National Cancer Institute Rockville Maryland USA; Nabi Biopharmaceuticals FX National Institute on Drug Abuse Rockville Maryland USA National Cancer Institute Rockville Maryland USA Other Funders American Legacy Foundation Washington DC USA; DKH has received grant funding from Nabi Biopharmaceuticals to conduct nicotine vaccine clinical trials JEH provides consulting support for GlaxoSmithKline Consumer Health through Pinney Associates on an exclusive basis on issues related to tobacco dependence treatment has financial interest in a potential new oral nicotine replacement product and serves as an expert witness in litigation against tobacco companies NLB serves as a consultant for Pfizer and as an expert witness in litigation against tobacco companies MZ provides consulting support to GlaxoSmithKline Consumer Health through Pinney Associates on an exclusive basis on issues related to tobacco dependence treatment KAP has served as a consultant to Cypress Bioscience NR 154 TC 45 Z9 45 U1 1 U2 11 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD OCT PY 2010 VL 19 IS 5 AR e1 DI 10.1136/tc.7009.035584 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 691HN UT WOS:000285071000024 PM 20876072 ER PT J AU Crawford, LW Foley, JF Elmore, SA AF Crawford, Laura Wilding Foley, Julie F. Elmore, Susan A. TI Histology Atlas of the Developing Mouse Hepatobiliary System with Emphasis on Embryonic Days 9.5-18.5 SO TOXICOLOGIC PATHOLOGY LA English DT Article DE liver; embryo; mouse; development; phenotype; atlas; hematopoiesis ID MURINE FETAL LIVER; T-CELL PROGENITORS; HEMATOPOIETIC STEM-CELLS; INTRAHEPATIC BILE-DUCTS; HOMEOBOX GENE HEX; B-CELL; TRANSCRIPTION FACTOR; MICE LACKING; YOLK-SAC; ERYTHROBLASTIC ISLANDS AB Animal model phenotyping, in utero exposure toxicity studies, and investigation into causes of embryonic, fetal, or perinatal deaths have required pathologists to recognize and diagnose developmental disorders in spontaneous and engineered mouse models of disease. In mammals, the liver is the main site of hematopoiesis during fetal development, has endocrine and exocrine functions important for maintaining homeostasis in fetal and adult life; and performs other functions including waste detoxification, production and removal of glucose, glycogen storage, triglyceride and fatty acid processing, and serum protein production. Due to its role in many critical functions, alterations in the size, morphology, or function(s) of the liver often lead to embryonic lethality. Many publications and websites describe individual aspects of hepatobiliary development at defined stages. However, no single resource provides a detailed histological evaluation of H&E-stained sections of the developing murine liver and biliary systems using high-magnification and high-resolution color images. The work herein provides a histology atlas of hepatobiliary development between embryonic days 9.5-18.5. Although the focus of this work is normal hepatobiliary development, common defects in liver development are also described as a reference for pathologists who may be asked to phenotype mice with congenital, inherited, or treatment-related hepatobiliary defects. Authors' note: All digital images can be viewed online at https://niehsimagesepl-inc.com with the username "ToxPathLiver" and the password "embryolivers." C1 [Crawford, Laura Wilding; Foley, Julie F.; Elmore, Susan A.] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Elmore, Susan A.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Elmore, SA (reprint author), NIEHS, Cellular & Mol Pathol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX This research was supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 107 TC 19 Z9 20 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD OCT PY 2010 VL 38 IS 6 BP 872 EP 906 DI 10.1177/0192623310374329 PG 35 WC Pathology; Toxicology SC Pathology; Toxicology GA 707VA UT WOS:000286315700004 PM 20805319 ER PT J AU Auerbach, SS Thomas, R Shah, R Xu, H Vallant, MK Nyska, A Dunnick, JK AF Auerbach, Scott S. Thomas, Reuben Shah, Ruchir Xu, Hong Vallant, Molly K. Nyska, Abraham Dunnick, June K. TI Comparative Phenotypic Assessment of Cardiac Pathology, Physiology, and Gene Expression in C3H/HeJ, C57BL/6J, and B6C3F1/J Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE heart; genetic susceptibly; genomics; cardiomyopathy; electrophysiology ID ACTIVATED PROTEIN-KINASE; NATIONAL TOXICOLOGY PROGRAM; LONG-QT SYNDROME; HEART-FAILURE; ATHEROSCLEROSIS SUSCEPTIBILITY; MICROARRAY ANALYSIS; FAILING HEART; DISEASE; IDENTIFICATION; MITOCHONDRIAL AB Human cardiomyopathies often lead to heart failure, a major cause of morbidity and mortality in industrialized nations. Described here is a phenotypic characterization of cardiac function and genome-wide expression from C3H/HeJ, C57BL/6J, and B6C3F1/J male mice. Histopathologic analysis identified a low-grade background cardiomyopathy (murine progressive cardiomyopathy) in eight of nine male C3H/HeJ mice (age nine to ten weeks), but not in male C57BL/6J and in only of ten male B6C3F1/J mice. The C3H/HeJ mouse had an increased heart rate and a shorter RR interval compared to the B6C3F1/J and C57BL/6J mice. Cardiac genomic studies indicated the B6C3F1/J mice exhibited an intermediate gene expression phenotype relative to the 2 parental strains. Disease-centric enrichment analysis indicated a number of cardiomyopathy-associated genes were induced in B6C3F1/J and C3H/HeJ mice, including Myh7, My14, and Lmna and also indicated differential expression of genes associated with metabolic (e. g., Pdk2) and hypoxic stress (e. g. Hif1a). A novel coexpression and integrated pathway network analysis indicated Prkaa2, Pdk2, Rhoj, and Sgcb are likely to play a central role in the pathophysiology of murine progressive cardiomyopathy in C3H/HeJ mice. Our studies indicate that genetically determined baseline differences in cardiac phenotype have the potential to influence the results of cardiotoxicity studies. C1 [Auerbach, Scott S.; Thomas, Reuben; Xu, Hong; Vallant, Molly K.; Nyska, Abraham; Dunnick, June K.] NIEHS, Natl Toxicol Program, Div Intramural Res, Res Triangle Pk, NC 27709 USA. [Shah, Ruchir] SRA Int, Durham, NC USA. RP Dunnick, JK (reprint author), NIEHS, Natl Toxicol Program, Div Intramural Res, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov OI Xu, Hong/0000-0003-1995-4675 FU National Institute of Environmental Health Sciences, Research Triangle Park, NC; NIEHS [N01-ES-55536, ES 55547] FX We thank Dr. Jef French, NIEHS, and Dr. K. Shockley, NIEHS, for their excellent review of the manuscript. We would also like to thank Dr. Vincent VanBuren and Dr. Daniel C. Jupiter for generously providing the cardiac gene expression correlation matrix used in the creation of the coexpression network analysis. This work was supported by the intramural program of the National Institute of Environmental Health Sciences Intramural Program, Research Triangle Park, NC. The in-life portion of this study was conducted under NIEHS contract N01-ES-55536. Statistical support was provided under NIEHS contract ES 55547. NR 70 TC 5 Z9 5 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD OCT PY 2010 VL 38 IS 6 BP 923 EP 942 DI 10.1177/0192623310382864 PG 20 WC Pathology; Toxicology SC Pathology; Toxicology GA 707VA UT WOS:000286315700006 PM 21037199 ER PT J AU Szabo, DT Diliberto, JJ Hakk, H Huwe, JK Birnbaum, LS AF Szabo, David T. Diliberto, Janet J. Hakk, Heldur Huwe, Janice K. Birnbaum, Linda S. TI Toxicokinetics of the Flame Retardant Hexabromocyclododecane Gamma: Effect of Dose, Timing, Route, Repeated Exposure, and Metabolism SO TOXICOLOGICAL SCIENCES LA English DT Article DE mouse; metabolism; diastereomer; pharmacokinetics; stereoisomerization; HBCD; ADME; risk assessment; persistent organic pollutant; brominated flame retardant ID POLYBROMINATED DIPHENYL ETHERS; INDOOR DUST; WISTAR RATS; ACCUMULATION; SPECTROMETRY; TRENDS; HBCDS; MICE AB Hexabromocyclododecane-gamma (gamma-HBCD) is the predominate diastereoisomer in the commercial HBCD mixture used as a flame retardant in a wide variety of consumer products. Three main diastereoisomers, alpha (alpha), beta (beta), and gamma (gamma), comprise the mixture. Despite the gamma-diastereoisomer being the major diastereoisomer in the mixture and environmental samples, the alpha-diastereoisomer predominates human tissue and wildlife. This study was conducted to characterize absorption, distribution, metabolism, and excretion parameters of gamma-HBCD with respect to dose and time following a single acute exposure and repeated exposure in adult female C57BL/6 mice. Results suggest that 85% of the administered dose (3 mg/kg) was absorbed after po exposure. Disposition was dose independent and did not significantly change after 10 days of exposure. Liver was the major depot (< 0.3% of dose) 4 days after treatment followed by blood, fat, and then brain. gamma-HBCD was rapidly metabolized and eliminated in the urine and feces. For the first time, in vivo stereoisomerization was observed of the gamma-diastereoisomer to the beta-diastereoisomer in liver and brain tissues and to the alpha- and beta-diastereoisomer in fat and feces. Polar metabolites in the blood and urine were a major factor in determining the initial whole-body half-life (1 day) after a single po exposure. Elimination, both whole-body and from individual tissues, was biphasic. Initial half-lives were approximately 1 day, whereas terminal half-lives were up to 4 days, suggesting limited potential for gamma-diastereoisomer bioaccumulation. The toxicokinetic behavior reported here has important implications for the extrapolation of toxicological studies of the commercial HBCD mixture to the assessment of risk. C1 [Szabo, David T.] Univ N Carolina, Curriculum Toxicol, US EPA, Res Triangle Pk, NC 27711 USA. [Szabo, David T.; Diliberto, Janet J.] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Hakk, Heldur; Huwe, Janice K.] USDA ARS, Biosci Res Lab, Fargo, ND 58105 USA. [Birnbaum, Linda S.] NIEHS, NCI, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Szabo, DT (reprint author), Univ N Carolina, Curriculum Toxicol, US EPA, MD B143-01,109 TW Alexander Dr, Durham, NC 27703 USA. EM szabo@email.unc.edu FU University of North Carolina in Chapel Hill; United States Environmental Protection Agency [CR 833237] FX University of North Carolina in Chapel Hill and the United States Environmental Protection Agency predoctoral training grants (CR 833237). NR 32 TC 56 Z9 57 U1 8 U2 38 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2010 VL 117 IS 2 BP 282 EP 293 DI 10.1093/toxsci/kfq183 PG 12 WC Toxicology SC Toxicology GA 653AZ UT WOS:000282055900005 PM 20562218 ER PT J AU Thackaberry, EA Kopytek, S Sherratt, P Trouba, K McIntyre, B AF Thackaberry, Evan A. Kopytek, Stephen Sherratt, Phillip Trouba, Kevin McIntyre, Barry TI Comprehensive Investigation of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl-Beta-Cyclodextrin for use in General Toxicology Studies SO TOXICOLOGICAL SCIENCES LA English DT Article DE propylene glycol; polysorbate 80; hydroxypropyl-beta-cyclodextrin; Tween 80; HP beta CD; safety assessment ID SAFETY ASSESSMENT; RATS; TOXICITY; DOGS AB This study was conducted to assess the safety and tolerability of the alternative formulation vehicles polysorbate 80 (PS80), propylene glycol (PG), and hydroxypropyl-beta-cyclodextrin (HP beta CD) in general toxicology studies in the mouse, rat, dog, and monkey. Twenty (20) mg/kg of hydroxypropyl methylcellulose (MC, control), 10 mg/kg PS80, 1000 mg/kg PG, 500 mg/kg HP beta CD, or 1000 mg/kg HP beta CD were administered by oral gavage to mice, rats, dogs, and cynomolgus monkeys for approximately 90 days. The effects of these formulations on clinical observations, body weight and food consumption parameters, clinical pathology, and histopathology were evaluated across all species. The suitability of formulations containing up to 20 mg/kg MC, 10 mg/kg PS80, and 1000 mg/kg PG for use in preclinical safety studies was confirmed by a lack of effects on all parameters examined. However, formulations containing HP beta CD produced elevated transaminase (aspartate and alanine aminotransferase) levels in rats and mice and fecal changes (loose and soft stool) in large animals. Although the etiology and toxicological significance of the transaminase elevations in rats and mice is uncertain, this finding could represent a significant liability for a preclinical formulation because of the critical importance of these biomarkers in the risk assessment of novel therapeutic agents. Based on these data, PS80 and PG are considered to be practical alternatives to MC in preclinical toxicology studies. However, formulations containing HP beta CD should be used with caution because of the elevations in rodent transaminase levels. C1 [Thackaberry, Evan A.] Merck Res Labs, Dept Safety Assessment, Lafayette, NJ 07848 USA. [Kopytek, Stephen; Sherratt, Phillip] Merck Res Labs, Dept Safety Assessment, Summit, NJ 07901 USA. [Trouba, Kevin] Bristol Myers Squibb, Drug Safety Evaluat, Mount Vernon, IN 47630 USA. [McIntyre, Barry] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Thackaberry, EA (reprint author), Merck Res Labs, Dept Safety Assessment, 44 Route 94 S, Lafayette, NJ 07848 USA. EM methack@gmail.com FU Merck Research Laboratories FX Merck Research Laboratories. NR 36 TC 20 Z9 20 U1 5 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2010 VL 117 IS 2 BP 485 EP 492 DI 10.1093/toxsci/kfq207 PG 8 WC Toxicology SC Toxicology GA 653AZ UT WOS:000282055900023 PM 20643750 ER PT J AU Hayakawa, J Joyal, EG Gildner, JF Washington, KN Phang, OA Uchida, N Hsieh, MM Tisdale, JF AF Hayakawa, Jun Joyal, Elizabeth G. Gildner, Jean F. Washington, Kareem N. Phang, Oswald A. Uchida, Naoya Hsieh, Matthew M. Tisdale, John F. TI 5% Dimethyl sulfoxide (DMSO) and pentastarch improves cryopreservation of cord blood cells over 10% DMSO SO TRANSFUSION LA English DT Article ID HEMATOPOIETIC STEM-CELLS; SEVERE RESPIRATORY DEPRESSION; SCID IL2R-GAMMA(NULL) MICE; PLASMA-VOLUME EXPANSION; PERIPHERAL-BLOOD; UNRELATED DONORS; HYDROXYETHYL STARCH; PROGENITOR CELLS; SPINAL-ANESTHESIA; CLINICAL TOXICITY AB BACKGROUND: Cell number and viability are important in cord blood (CB) transplantation. While 10% dimethyl sulfoxide (DMSO) is the standard medium, adding a starch to freezing medium is increasingly utilized as a cytoprotectant for the thawing process. Similar to hetastarch, pentastarch has the advantages of faster renal clearance and less effect on the coagulation system. STUDY DESIGN AND METHODS: We compared a lower DMSO concentration (5%) containing pentastarch with 10% DMSO and performed cell viability assay, colony-forming units (CFUs), and transplantation of CB cells in NOD/SCID IL2R gamma null mice. RESULTS: CB cells in 5% DMSO/pentastarch had similar CD34+, CD3+, and CD19+ cell percentages after thawing as fresh CB cells. CB cells in 5% DMSO/pentastarch had higher viability (83.3 +/- 9.23%) than those frozen in 10% DMSO (75.3 +/- 11.0%, p < 0.05). We monitored cell viability postthaw every 30 minutes. The mean loss in the first 30 minutes was less in the 5% DMSO/pentastarch group. At the end of 3 hours, the viability decreased by a mean of 7.75% for the 5% DMSO/pentastarch and 17.5% for the 10% DMSO groups. CFUs were similar between the two cryopreserved groups. Frozen CB cells engrafted equally well in IL2R gamma null mice compared to fresh CB cells up to 24 weeks, and CB cells frozen in 5% DMSO/pentastarch engrafted better than those in 10% DMSO. CONCLUSION: Our data indicate that the lower DMSO concentration with pentastarch represents an improvement in the CB cryopreservation process and could have wider clinical application as an alternate freezing medium over 10% DMSO. C1 NIH, MCHB, Bethesda, MD 20892 USA. NIDDK, NIH, Bethesda, MD USA. NHLBI, NIH, Bethesda, MD 20892 USA. NIH, Charles S Carter Cellular Therapy Lab, Dept Transfus Med, Bethesda, MD USA. RP Tisdale, JF (reprint author), 9000 Rockville Pike,Bldg 10,Room 9N 116, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU National Institute of Diabetes, Digestive, and Kidney diseases and the National Heart, Lung, and Blood Institute at NIH FX We appreciate the statistical help by Richard Chen. This work is supported by the intramural research program of the National Institute of Diabetes, Digestive, and Kidney diseases and the National Heart, Lung, and Blood Institute at NIH. NR 50 TC 18 Z9 18 U1 4 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD OCT PY 2010 VL 50 IS 10 BP 2158 EP 2166 DI 10.1111/j.1537-2995.2010.02684.x PG 9 WC Hematology SC Hematology GA 661AF UT WOS:000282693500013 PM 20492608 ER PT J AU Chang, CM Quinlan, SC Warren, JL Engels, EA AF Chang, Cindy M. Quinlan, Scott C. Warren, Joan L. Engels, Eric A. TI Blood transfusions and the subsequent risk of hematologic malignancies SO TRANSFUSION LA English DT Article ID NON-HODGKINS-LYMPHOMA; POPULATION; CANCER; DONOR; ASSOCIATION; PREVALENCE; RECIPIENTS; HEPATITIS; COHORT; WOMEN AB BACKGROUND: Blood transfusions are associated with viral transmission and immunomodulation, perhaps increasing subsequent risk of hematologic malignancies (HMs). Prior studies of transfusion recipients have lacked details on specific HM subtypes. STUDY DESIGN AND METHODS: Risk of HM after blood transfusion was evaluated in a US population-based case-control study (77,488 elderly HM cases identified through cancer registries, 154,509 controls). Transfusions were identified using linked Medicare hospitalization claims. Polytomous logistic regression was used to calculate odds ratios (ORs) associating transfusion and HM subtypes by features suggestive of a causal relationship. RESULTS: A history of transfusion was present in 7.9% of HM cases versus 5.9% of controls. Associations for most HM subtypes suggested reverse causality: ORs were elevated only during the shortest latency periods; ORs for unspecified anemia and gastrointestinal bleeding, which may be related to undiagnosed HM, were stronger than for surgeries, which are unlikely to be related to HM; and/or there was no dose response. In contrast, risk for lymphoplasmacytic lymphoma (1397 cases) was elevated at long latency (OR, 1.56 at 10+ years after transfusion), after transfusions related to surgeries (OR, 1.22-1.47), and in a dose-response relationship with number of transfusion-related hospitalizations (OR, 1.53 with one hospitalization; OR, 1.80 with two or more hospitalizations, p trend < 0.0001). Risk for marginal zone lymphoma (1915 cases) was also elevated at 10+ years after transfusion (OR, 1.80). CONCLUSION: Consistent with prior studies, blood transfusions did not increase risk of most HM subtypes. Patterns of elevated risk for lymphoplasmacytic and marginal zone lymphomas suggest an etiologic role for transfusion. C1 [Chang, Cindy M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, DHHS, Rockville, MD 20892 USA. NIH, Div Canc Control & Populat Sci, Rockville, MD USA. RP Chang, CM (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, DHHS, 6120 Execut Blvd,EPS 7074, Rockville, MD 20892 USA. EM changcm@mail.nih.gov RI Chang, Cindy/G-4514-2010 FU National Cancer Institute FX This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, National Cancer Institute (NCI); the Office of Research, Development, and Information, Centers for Medicare and Medicaid Services; Information Management Services (IMS), Inc.; and the SEER Program tumor registries in the creation of the SEER-Medicare database. The authors thank Winnie Ricker (Information Management Services, Rockville, MD) for assistance with database management. This research was supported by the Intramural Research Program of the National Cancer Institute. NR 40 TC 10 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2010 VL 50 IS 10 BP 2249 EP 2257 DI 10.1111/j.1537-2995.2010.02692.x PG 9 WC Hematology SC Hematology GA 661AF UT WOS:000282693500023 PM 20497517 ER PT J AU Blajchman, MA Glynn, SA Josephson, CD Kleinman, SH AF Blajchman, Morris A. Glynn, Simone A. Josephson, Cassandra D. Kleinman, Steve H. CA State-Of-The Sci TI Clinical Trial Opportunities in Transfusion Medicine: Proceedings of a National Heart, Lung, and Blood Institute State-of-the-Science Symposium SO TRANSFUSION MEDICINE REVIEWS LA English DT Review ID ACUTE NORMOVOLEMIC HEMODILUTION; ACUTE CORONARY SYNDROMES; PROPHYLACTIC PLATELET TRANSFUSIONS; RADICAL RETROPUBIC PROSTATECTOMY; CHEMOTHERAPY-INDUCED ANEMIA; ARTERY-BYPASS SURGERY; BIRTH-WEIGHT INFANTS; VERSUS-HOST-DISEASE; DARBEPOETIN ALPHA; SEVERE THROMBOCYTOPENIA AB The use of blood products to support patients undergoing the large variety of medical and surgical interventions requiring such support has continued to escalate very significantly over time. Relevantly, significant practice variation in the use of blood products exists among practitioners and institutions, largely because of the lack of robust clinical trial data, in many instances, which are critical for providing practitioners with evidence-based guidelines for appropriate blood product utilization. Recognizing this gap, the National Heart, Lung, and Blood Institute recently established a State-of-the-Science Symposium to help define areas of clinical trial research that would enhance the opportunity for developing appropriate practice guidelines for both Transfusion Medicine and Hemostasis/Thrombosis. Such a Symposium was held in September 2009 to identify important clinical trial research issues in these 2 subject areas of endeavor. The aims of this Symposium were to specifically identify phase 2 and 3 clinical trials that, if conducted over the next 5 to 10 years, could impact the treatment of patients with hemostatic and other disorders as well as to optimize the use of blood products in patients who need such interventions. This article reports on the deliberations that were held relating to the various clinical trial concepts developed by 7 Transfusion Medicine subcommittees. This Symposium generated a rich assortment of clinical trial proposals that will undergo further refinement before final implementation into pilot or full randomized clinical trials. The various proposals identified many opportunities for clinical trial research and most importantly underscored the ongoing need for well-developed evidence-based clinical trial research in the field of Transfusion Medicine. (C) 2010 Elsevier Inc. All rights reserved. C1 [Blajchman, Morris A.] McMaster Univ, Dept Pathol, Hamilton, ON L8N 3Z5, Canada. NHLBI, Bethesda, MD 20892 USA. Emory Univ, Atlanta, GA 30322 USA. Univ British Columbia, Victoria, BC, Canada. RP Blajchman, MA (reprint author), McMaster Univ, Dept Pathol, 1200 Main St W,HSC-4N67, Hamilton, ON L8N 3Z5, Canada. EM blatchma@mcmaster.ca RI Szczepiorkowski, Zbigniew/A-1359-2007; Winters, Jeffrey/A-2000-2013 OI Szczepiorkowski, Zbigniew/0000-0003-2357-9564; Winters, Jeffrey/0000-0001-8654-3732 NR 76 TC 16 Z9 16 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0887-7963 J9 TRANSFUS MED REV JI Transf. Med. Rev. PD OCT PY 2010 VL 24 IS 4 BP 259 EP 285 DI 10.1016/j.tmrv.2010.05.002 PG 27 WC Hematology SC Hematology GA 656PP UT WOS:000282349000001 PM 20851330 ER PT J AU Csermely, P Palotai, R Nussinov, R AF Csermely, Peter Palotai, Robin Nussinov, Ruth TI Induced fit, conformational selection and independent dynamic segments: an extended view of binding events SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID PROTEIN COMPLEXES; HYDROGEN-BONDS; ENERGY LANDSCAPES; FOLDING FUNNELS; MECHANISM; NETWORKS; WATER; RNA; FLUCTUATIONS; RECOGNITION AB Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here, we describe an extended conformational selection model that embraces a repertoire of selection and adjustment processes. Induced fit can be viewed as a subset of this repertoire, whose contribution is affected by the bond types stabilizing the interaction and the differences between the interacting partners. We argue that protein segments whose dynamics are distinct from the rest of the protein ('discrete breathers') can govern conformational transitions and allosteric propagation that accompany binding processes and, as such, might be more sensitive to mutational events. Additionally, we highlight the dynamic complexity of binding scenarios as they relate to events such as aggregation and signalling, and the crowded cellular environment. C1 [Csermely, Peter; Palotai, Robin] Semmelweis Univ, Dept Med Chem, H-1444 Budapest, Hungary. [Nussinov, Ruth] NCI Frederick, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Csermely, P (reprint author), Semmelweis Univ, Dept Med Chem, POB 260, H-1444 Budapest, Hungary. EM csermely@eok.sote.hu FU EU [FP6-518230]; Hungarian National Science Foundation [OTKA K69105]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX The authors thank the anonymous referees for their helpful suggestions and we thank Mark Bathe and Do-Nyun Kim (Massachusetts Institute of Technology, Cambridge, MA), as well as Zaida Luthey-Shulten and John Eargle (University of Illinois at Urbana-Champaign, Urbana IL) for the images in Figure 2. P.C. thanks Francesco Piazza (University of Portsmouth, UK), Yves-Henri Sanejouand (University of Nantes, France) and Gabor Simko (Semmelweis University, Budapest, Hungary) for helpful discussions. Funding has been provided by the EU (FP6-518230) and by the Hungarian National Science Foundation (OTKA K69105). This project has been funded, in part, with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The 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 70 TC 348 Z9 352 U1 10 U2 113 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 2010 VL 35 IS 10 BP 539 EP 546 DI 10.1016/j.tibs.2010.04.009 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 670HF UT WOS:000283411100002 PM 20541943 ER PT J AU Rohani, P King, AA AF Rohani, Pejman King, Aaron A. TI Never mind the length, feel the quality: the impact of long-term epidemiological data sets on theory, application and policy SO TRENDS IN ECOLOGY & EVOLUTION LA English DT Review ID INFECTIOUS-DISEASES; POPULATION BIOLOGY; DYNAMICS; CYCLES AB Infectious diseases have been a prime testing ground for ecological theory. However, the ecological perspective is increasingly recognized as essential in epidemiology. Long-term, spatially resolved reliable data on disease incidence and the ability to test them using mechanistic models have been critical in this cross-fertilization. Here, we review some of the key intellectual developments in epidemiology facilitated by long-term data. We identify research frontiers at the interface of ecology and epidemiology and their associated data needs. C1 [Rohani, Pejman; King, Aaron A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman; King, Aaron A.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [Rohani, Pejman; King, Aaron A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Rohani, P (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM rohani@umich.edu RI King, Aaron/B-8092-2012 OI King, Aaron/0000-0001-6159-3207 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation FX We thank Marc Choisy and two anonymous reviewers for comments on the manuscript. We are grateful to Matt Ferrari and Natalia Mantilla-Beniers for graciously sharing Figures 1 and 2, respectively. The authors are supported by the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. PR was also supported by the Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation. NR 27 TC 15 Z9 15 U1 0 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0169-5347 J9 TRENDS ECOL EVOL JI Trends Ecol. Evol. PD OCT PY 2010 VL 25 IS 10 SI SI BP 611 EP 616 DI 10.1016/j.tree.2010.07.010 PG 6 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 663CM UT WOS:000282860600010 PM 20800928 ER PT J AU Singleton, AB Hardy, J Traynor, BJ Houlden, H AF Singleton, Andrew B. Hardy, John Traynor, Bryan J. Houlden, Henry TI Towards a complete resolution of the genetic architecture of disease SO TRENDS IN GENETICS LA English DT Review ID GENOME-WIDE ASSOCIATION; FAMILIAL ALZHEIMERS-DISEASE; CYSTIC-FIBROSIS GENE; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; PARKINSONS-DISEASE; IDENTIFIES VARIANTS; MISSENSE MUTATIONS; CLONING; RISK AB After years of linear gains in the genetic dissection of human disease we are now in a period of exponential discovery. This is particularly apparent for complex disease. Genome-wide association studies (GWAS) have provided myriad associations between common variability and disease, and have shown that common genetic variability is unlikely to explain the entire genetic predisposition to disease. Here we detail how one can expand on this success and systematically identify genetic risks that lead or predispose to disease using next-generation sequencing. Geneticists have had for many years a protocol to identify Mendelian disease. A similar set of tools is now available for the identification of rare moderate-risk loci and common low-risk variants. Whereas major challenges undoubtedly remain, particularly regarding data handling and the functional classification of variants, we suggest that these will be largely practical and not conceptual. C1 [Singleton, Andrew B.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hardy, John; Houlden, Henry] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John; Houlden, Henry] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England. [Houlden, Henry] Inst Neurol, Ctr Neuromuscular Dis, MRC, London WC1N 3BG, England. RP Singleton, AB (reprint author), NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Sincan, Murat /A-3794-2010; Hardy, John/C-2451-2009; Traynor, Bryan/G-5690-2010; Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 FU Medical Research Council [G0601943, G0701075, G0802760] NR 47 TC 53 Z9 54 U1 0 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD OCT PY 2010 VL 26 IS 10 BP 438 EP 442 DI 10.1016/j.tig.2010.07.004 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 657HG UT WOS:000282403200003 PM 20813421 ER PT J AU Ahlers, JD Belyakov, IM AF Ahlers, Jeffrey D. Belyakov, Igor M. TI Molecular pathways regulating CD4(+) T cell differentiation, anergy and memory with implications for vaccines SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID HUMAN DENDRITIC CELLS; ARYL-HYDROCARBON RECEPTOR; GROWTH-FACTOR-BETA; HUMAN TH17 CELLS; ROR-GAMMA-T; IN-VIVO; TRANSCRIPTION FACTOR; CUTTING EDGE; LINEAGE COMMITMENT; HELPER-CELLS AB CD4(+) T cells occupy a central role in the induction and regulation of adaptive immune responses. Activated CD4(+) T helper (Th) cells exert immediate effector functions by producing cytokines and chemokines, providing help for the induction of CD8(+) cytotoxic T lymphocyte responses and memory, and providing help for immunoglobulin class switching, affinity maturation of antibody and B cell memory. Inherent in naive CD4(+) T cells is the flexibility to adopt alternate lineage potentials, which depend upon regulatory mechanisms that change with tissue microenvironment and upon infection. Here, we discuss lineage instructive programs that regulate CD4(+) T cell differentiation and memory and how to translate this knowledge into vaccines and immunotherapies that promote protective immune responses. C1 [Ahlers, Jeffrey D.] NIAID, NIH, Bethesda, MD 20817 USA. [Belyakov, Igor M.] Midwest Res Inst, Frederick, MD 21702 USA. RP Ahlers, JD (reprint author), NIAID, NIH, Bethesda, MD 20817 USA. EM jeffreyahlers@hotmail.com NR 157 TC 15 Z9 17 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 EI 1471-499X J9 TRENDS MOL MED JI Trends Mol. Med PD OCT PY 2010 VL 16 IS 10 BP 478 EP 491 DI 10.1016/j.molmed.2010.07.007 PG 14 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 673QS UT WOS:000283678700005 PM 20739220 ER PT J AU Vaisbuch, E Romero, R Erez, O Kusanovic, JP Mazaki-Tovi, S Gotsch, F Romero, V Ward, C Chaiworapongsa, T Mittal, P Sorokin, Y Hassan, SS AF Vaisbuch, E. Romero, R. Erez, O. Kusanovic, J. P. Mazaki-Tovi, S. Gotsch, F. Romero, V. Ward, C. Chaiworapongsa, T. Mittal, P. Sorokin, Y. Hassan, S. S. TI Clinical significance of early (< 20 weeks) vs. late (20-24 weeks) detection of sonographic short cervix in asymptomatic women in the mid-trimester SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE amniotic fluid sludge; cervical length; pregnancy; preterm delivery; preterm labor; transvaginal; ultrasound ID SPONTANEOUS PRETERM DELIVERY; AMNIOTIC-FLUID SLUDGE; TRANSVAGINAL ULTRASONOGRAPHY; GESTATIONAL-AGE; OBSTETRIC HISTORY; HIGH-RISK; DEMOGRAPHIC CHARACTERISTICS; LENGTH MEASUREMENT; CONTROLLED-TRIAL; PREGNANCY LOSS AB Objective The aim of this study was to determine whether the risk of early spontaneous preterm delivery (PTD) in asymptomatic women with a sonographic cervical length of <= 15 mm in the mid-trimester changes as a function of gestational age at diagnosis. Methods This cohort study included 109 asymptomatic patients with a sonographic cervical length of <= 15 mm diagnosed at 14-24 weeks of gestation. Women with a multifetal gestation, cerclage and a cervical dilatation of > 2 cm were excluded. The study population was stratified by gestational age at diagnosis (< 20 weeks vs. 20-24 weeks) and by cervical length (<= 10 mm vs. 11-15 mm). The primary outcome variables were PTD at < 28 and < 32 weeks of gestation and the diagnosis-to-delivery interval. Results The median gestational age at diagnosis of a short cervix before 20 weeks and at 20-24 weeks was 18.9 and 22.7 weeks, respectively. Women diagnosed before 20 weeks had a higher rate of PTD at < 28 weeks (76.9% vs. 30.9%; P < 0.001) and at < 32 weeks (80.8% vs. 48.1%; P = 0.004), and a shorter median diagnosis-to-delivery interval (21 vs. 61.5 days, P 0.003) than those diagnosed at 20-24 weeks. The rate of amniotic fluid sludge was higher among patients diagnosed with a short cervix at < 20 weeks of gestation than in those in whom it was diagnosed between 20 and 24 weeks (92.3% vs. 48.2%; P < 0.001). Conclusions Asymptomatic women with a sonographic cervical length of < 15 mm diagnosed before 20 weeks of gestation have a dramatic and significantly higher risk of early preterm delivery than women diagnosed at 20-24 weeks. These findings can be helpful to physicians in counseling these patients, and may suggest different mechanisms of disease leading to a sonographic short cervix before or after 20 weeks of gestation. Copyright (C) 2010 ISUOG. Published by John Wiley & Sons, Ltd. C1 [Vaisbuch, E.; Romero, R.; Erez, O.; Kusanovic, J. P.; Mazaki-Tovi, S.; Gotsch, F.; Chaiworapongsa, T.; Mittal, P.; Hassan, S. S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD NIH DHHS, Bethesda, MD USA. [Vaisbuch, E.; Erez, O.; Kusanovic, J. P.; Mazaki-Tovi, S.; Romero, V.; Ward, C.; Chaiworapongsa, T.; Mittal, P.; Sorokin, Y.; Hassan, S. S.] Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, R.; Gotsch, F.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Vaisbuch, E.; Romero, R.; Erez, O.; Kusanovic, J. P.; Mazaki-Tovi, S.; Gotsch, F.; Chaiworapongsa, T.; Mittal, P.; Hassan, S. S.] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS,Intramural Div, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS,Intramural Div, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. The authors wish to acknowledge the contributions of the Registered Diagnostic Medical Sonographers staff and the Research Nurses of the Perinatology Research Branch. NR 82 TC 27 Z9 27 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD OCT PY 2010 VL 36 IS 4 BP 471 EP 481 DI 10.1002/uog.7673 PG 11 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 669ZZ UT WOS:000283390200014 PM 20503224 ER PT J AU Menotti-Raymond, M David, VA Pflueger, S Roelke, ME Kehler, J O'Brien, SI Narfstrom, K AF Menotti-Raymond, M. David, V. A. Pflueger, S. Roelke, M. E. Kehler, J. O'Brien, S. I. Narfstrom, K. TI Widespread retinal degenerative disease mutation (rdAc) discovered among a large number of popular cat breeds SO VETERINARY JOURNAL LA English DT Article DE Retinal degeneration; Cat breeds; Mutation; CEP290; Photoreceptors ID ROD-CONE DEGENERATION; GENETIC-LINKAGE MAP; ABYSSINIAN CAT; DOMESTIC CAT; FELIS-CATUS; JOUBERT-SYNDROME; CENTROSOMAL PROTEIN; RADIATION HYBRID; ATROPHY; DYSTROPHY AB The recent discovery of a mutational variant in the CEP290 gene (CEP290 IVS50 + 9T>G) conferring recessive retinal degeneration in Abyssinian and Somali (long-haired Abyssinian) cats (rdAc) prompted a survey among 41 cat breeds (846 individuals) to assess the incidence frequency and clinical consequence of rdAc The rdAc allele displayed widespread distribution observed in 16/43 (37%) breeds exhibiting a high allele frequency (similar to 33%) in North American and European Siamese populations Clinical evaluations demonstrated high concordance between rdAc pathology and the CEP290 (IV550 + 9T>G) homozygous genotype (P = 1 1E-6) with clinical disease similar to affected Abyssinians/Somalis This retinal degener anon has not been reported in breeds other than the Abyssinian/Somali and poses a significant health risk particularly in the Siamese breed group Alertness of the veterinary community and the present availability of commercial diagnostic testing could synergistically enable breeders to reduce the incidence of rdAc blindness in pure-bred cat populations Published by Elsevier Ltd C1 [Menotti-Raymond, M.; Roelke, M. E.] NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. [Pflueger, S.] Baystate Med Ctr, Springfield, MA 01199 USA. [Narfstrom, K.] Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Columbia, MO 65211 USA. RP Menotti-Raymond, M (reprint author), NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. FU National Cancer Institute National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute National Institutes of Health under contract N01-CO-12400 The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names commercial products or organizations imply endorsement by the US Government NR 55 TC 11 Z9 11 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1090-0233 J9 VET J JI Vet. J. PD OCT PY 2010 VL 186 IS 1 BP 32 EP 38 DI 10.1016/j.tvjl.2009.08.010 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA 686XL UT WOS:000284732200008 PM 19747862 ER PT J AU Roberts, A Lamirande, EW Vogel, L Baras, B Goossens, G Knott, I Chen, J Ward, JM Vassilev, V Subbarao, K AF Roberts, Anjeanette Lamirande, Elaine W. Vogel, Leatrice Baras, Benoit Goossens, Genevieve Knott, Isabelle Chen, Jun Ward, Jerrold M. Vassilev, Ventzislav Subbarao, Kanta TI Immunogenicity and Protective Efficacy in Mice and Hamsters of a beta-Propiolactone Inactivated Whole Virus SARS-CoV Vaccine SO VIRAL IMMUNOLOGY LA English DT Article ID ACUTE RESPIRATORY SYNDROME; GOLDEN-SYRIAN-HAMSTERS; T-CELL RESPONSES; SYNDROME CORONAVIRUS; IMMUNE-RESPONSES; NEUTRALIZING ANTIBODY; INFLUENZA VACCINE; ADJUVANT SYSTEMS; HEALTHY-ADULTS; FLOW-CYTOMETRY AB The immunogenicity and efficacy of beta-propiolactone (BPL) inactivated whole virion SARS-CoV (WI-SARS) vaccine was evaluated in BALB/c mice and golden Syrian hamsters. The vaccine preparation was tested with or without adjuvants. Adjuvant Systems AS01(B) and AS03(A) were selected and tested for their capacity to elicit high humoral and cellular immune responses to WI-SARS vaccine. We evaluated the effect of vaccine dose and each adjuvant on immunogenicity and efficacy in mice, and the effect of vaccine dose with or without the AS01(B) adjuvant on the immunogenicity and efficacy in hamsters. Efficacy was evaluated by challenge with wild-type virus at early and late time points (4 and 18 wk post-vaccination). A single dose of vaccine with or without adjuvant was poorly immunogenic in mice; a second dose resulted in a significant boost in antibody levels, even in the absence of adjuvant. The use of adjuvants resulted in higher antibody titers, with the AS01(B)-adjuvanted vaccine being slightly more immunogenic than the AS03(A)-adjuvanted vaccine. Two doses of WI-SARS with and without Adjuvant Systems were highly efficacious in mice. In hamsters, two doses of WI-SARS with and without AS01(B) were immunogenic, and two doses of 2 mu g of WI-SARS with and without the adjuvant provided complete protection from early challenge. Although antibody titers had declined in all groups of vaccinated hamsters 18 wk after the second dose, the vaccinated hamsters were still partially protected from wild-type virus challenge. Vaccine with adjuvant provided better protection than non-adjuvanted WI-SARS vaccine at this later time point. Enhanced disease was not observed in the lungs or liver of hamsters following SARS-CoV challenge, regardless of the level of serum neutralizing antibodies. C1 [Roberts, Anjeanette; Lamirande, Elaine W.; Vogel, Leatrice; Chen, Jun; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Ward, Jerrold M.] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Baras, Benoit; Goossens, Genevieve; Knott, Isabelle; Vassilev, Ventzislav] GlaxoSmithKline Biol, Rixensart, Belgium. [Roberts, Anjeanette; Ward, Jerrold M.] Univ Virginia, Charlottesville, VA USA. [Roberts, Anjeanette; Ward, Jerrold M.] NIH, Immunopathol Lab, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU NIAID, NIH FX We thank Jadon Jackson and the staff of the Comparative Medicine Branch, NIAID, for excellent technical support for animal studies performed at the NIH. This research was supported in part by the Intramural Research Program of NIAID, NIH. NR 35 TC 7 Z9 7 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0882-8245 J9 VIRAL IMMUNOL JI Viral Immunol. PD OCT PY 2010 VL 23 IS 5 BP 509 EP 519 DI 10.1089/vim.2010.0028 PG 11 WC Immunology; Virology SC Immunology; Virology GA 656UD UT WOS:000282362300007 PM 20883165 ER PT J AU Cmarik, J Ruscetti, S AF Cmarik, Joan Ruscetti, Sandra TI Friend Spleen Focus-Forming Virus Activates the Tyrosine Kinase sf-Stk and the Transcription Factor PU.1 to Cause a Multi-Stage Erythroleukemia in Mice SO VIRUSES-BASEL LA English DT Review DE friend spleen focus-forming virus; leukemia; tyrosine kinases; sf-Stk; Epo receptor; PU.1; signal transduction pathways ID COMPLETE NUCLEOTIDE-SEQUENCE; ERYTHROID PROGENITOR CELLS; CELLULAR P53 GENE; ERYTHROPOIETIN RECEPTOR; MEMBRANE GLYCOPROTEIN; PHOSPHATIDYLINOSITOL 3-KINASE; TRANSMEMBRANE DOMAIN; ENVELOPE PROTEIN; LEUKEMIA VIRUS; TRUNCATED FORM AB Hematological malignancies in humans typically involve two types of genetic changes: those that promote hematopoietic cell proliferation and survival (often the result of activation of tyrosine kinases) and those that impair hematopoietic cell differentiation (often the result of changes in transcription factors). The multi-stage erythroleukemia induced in mice by Friend spleen focus-forming virus (SFFV) is an excellent animal model for studying the molecular basis for both of these changes. Significant progress has been made in understanding the molecular basis for the multi-stage erythroleukemia induced by Friend SFFV. In the first stage of leukemia, the envelope protein encoded by SFFV interacts with and activates the erythropoietin (Epo) receptor and the receptor tyrosine kinase sf-Stk in erythroid cells, causing their Epo-independent proliferation, differentiation and survival. In the second stage, SFFV integration into the Sfpi1 locus activates the myeloid transcription factor PU.1, blocking erythroid cell differentiation, and in conjunction with the loss of p53 tumor suppressor activity, results in the outgrowth of malignant cells. In this review, we discuss the current level of understanding of how SFFV alters the growth and differentiation of erythroid cells and results in the development of erythroleukemia. Our knowledge of how SFFV causes erythroleukemia in mice may give us clues as to how the highly related human retrovirus XMRV causes malignancies in humans. C1 [Cmarik, Joan; Ruscetti, Sandra] NCI, Lab Canc Prevent, Frederick, MD 21702 USA. RP Ruscetti, S (reprint author), NCI, Lab Canc Prevent, Frederick, MD 21702 USA. EM cmarikj@mail.nih.gov; ruscetts@mail.nih.gov NR 94 TC 6 Z9 6 U1 1 U2 4 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD OCT PY 2010 VL 2 IS 10 BP 2235 EP 2257 DI 10.3390/v2102235 PG 23 WC Virology SC Virology GA 684VQ UT WOS:000284581900006 PM 21994618 ER PT J AU Brister, JR Bao, YM Kuiken, C Lefkowitz, EJ Le Mercier, P Leplae, R Madupu, R Scheuermann, RH Schobel, S Seto, D Shrivastava, S Sterk, P Zeng, QD Klimke, W Tatusova, T AF Brister, James Rodney Bao, Yiming Kuiken, Carla Lefkowitz, Elliot J. Le Mercier, Philippe Leplae, Raphael Madupu, Ramana Scheuermann, Richard H. Schobel, Seth Seto, Donald Shrivastava, Susmita Sterk, Peter Zeng, Qiandong Klimke, William Tatusova, Tatiana TI Towards Viral Genome Annotation Standards, Report from the 2010 NCBI Annotation Workshop SO VIRUSES-BASEL LA English DT Editorial Material DE virus; genome; annotation ID PROTEIN-CODING GENES; BACTERIAL; SYSTEM; DATABASE; ZCURVE AB Improvements in DNA sequencing technologies portend a new era in virology and could possibly lead to a giant leap in our understanding of viral evolution and ecology. Yet, as viral genome sequences begin to fill the world's biological databases, it is critically important to recognize that the scientific promise of this era is dependent on consistent and comprehensive genome annotation. With this in mind, the NCBI Genome Annotation Workshop recently hosted a study group tasked with developing sequence, function, and metadata annotation standards for viral genomes. This report describes the issues involved in viral genome annotation and reviews policy recommendations presented at the NCBI Annotation Workshop. C1 [Brister, James Rodney; Bao, Yiming; Klimke, William; Tatusova, Tatiana] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Kuiken, Carla] Los Alamos Natl Lab, Los Alamos, NM 87545 USA. [Lefkowitz, Elliot J.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35222 USA. [Le Mercier, Philippe] Swiss Inst Bioinformat, CH-1211 Geneva 4, Switzerland. [Leplae, Raphael] Univ Libre Brussels, Lab Bioinformat Genomes & Reseaux, B-1050 Brussels, Belgium. [Madupu, Ramana; Schobel, Seth; Shrivastava, Susmita] J Craig Venter Inst, Rockville, MD 20850 USA. [Scheuermann, Richard H.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Scheuermann, Richard H.] Univ Texas SW Med Ctr Dallas, Div Biomed Informat, Dallas, TX 75390 USA. [Seto, Donald] George Mason Univ, Dept Bioinformat & Computat Biol, Manassas, VA 20110 USA. [Sterk, Peter] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Zeng, Qiandong] Broad Inst, Cambridge, MA 02141 USA. RP Brister, JR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM jamesbr@ncbi.nlm.nih.gov; bao@ncbi.nlm.nih.gov; kuiken@lanl.gov; elliotl@uab.edu; philippe.lemercier@isb-sib.ch; raphael@bigre.ulb.ac.be; rmadupu@jcvi.org; richard.scheuermann@utsouthwestern.edu; sschobel@jcvi.org; dseto@gmu.edu; sshrivastava@jcvi.org; ps8@sanger.ac.uk; qzeng@broadinstitute.org; klimke@ncbi.nlm.nih.gov; tatiana@ncbi.nlm.nih.gov OI Lefkowitz, Elliot/0000-0002-4748-4925; Sterk, Peter/0000-0003-1668-7778; Scheuermann, Richard/0000-0003-1355-892X NR 25 TC 11 Z9 11 U1 0 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD OCT PY 2010 VL 2 IS 10 BP 2258 EP 2268 DI 10.3390/v2102258 PG 11 WC Virology SC Virology GA 684VQ UT WOS:000284581900007 PM 21994619 ER PT J AU Song, SH Kim, A Ragoczy, T Bender, MA Groudine, M Dean, A AF Song, Sang-Hyun Kim, AeRi Ragoczy, Tobias Bender, M. A. Groudine, Mark Dean, Ann TI Multiple functions of Ldb1 required for beta-globin activation during erythroid differentiation SO BLOOD LA English DT Article ID LOCUS-CONTROL REGION; RNA-POLYMERASE-II; EMBRYONIC STEM-CELLS; CHROMATIN DOMAIN; IN-VIVO; HYPERSENSITIVE SITES; DOWNSTREAM PROMOTER; ENHANCER-BLOCKING; GENE-EXPRESSION; TRANSCRIPTION AB Ldb1 and erythroid partners SCL, GATA-1, and LMO2 form a complex that is required to establish spatial proximity between the beta-globin locus control region and gene and for transcription activation during erythroid differentiation. Here we show that Ldb1 controls gene expression at multiple levels. Ldb1 stabilizes its erythroid complex partners on beta-globin chromatin, even though it is not one of the DNA-binding components. In addition, Ldb1 is necessary for enrichment of key transcriptional components in the locus, including P-TEFb, which phosphorylates Ser2 of the RNA polymerase C-terminal domain for efficient elongation. Furthermore, reduction of Ldb1 results in the inability of the locus to migrate away from the nuclear periphery, which is necessary to achieve robust transcription of beta-globin in nuclear transcription factories. Ldb1 contributes these critical functions at both embryonic and adult stages of globin gene expression. These results implicate Ldb1 as a factor that facilitates nuclear relocation for transcription activation. (Blood. 2010;116(13):2356-2364) C1 [Song, Sang-Hyun; Dean, Ann] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Kim, AeRi] Pusan Natl Univ, Coll Nat Sci, Pusan 609735, South Korea. [Ragoczy, Tobias; Groudine, Mark] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA. [Bender, M. A.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. RP Dean, A (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bldg 50,Rm 3154,50 S Dr,MSC 8028, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov FU National Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institutes of Health [DK44746, HL65440] FX This work was supported by the Intra-mural program of the National Diabetes and Digestive and Kidney Diseases, National Institutes of Health (A.D.) and extramural National Institutes of Health (grants DK44746 and HL65440; M.G.). NR 48 TC 47 Z9 47 U1 0 U2 4 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 SEP 30 PY 2010 VL 116 IS 13 BP 2356 EP 2364 DI 10.1182/blood-2010-03-272252 PG 9 WC Hematology SC Hematology GA 656VR UT WOS:000282369700024 PM 20570862 ER PT J AU Buonanno, A AF Buonanno, Andres TI The neuregulin signaling pathway and schizophrenia: From genes to synapses and neural circuits SO BRAIN RESEARCH BULLETIN LA English DT Review DE ErbB4; Neuregulin; GABAergic interneuron; Schizophrenia; Bipolar depression; Hypoglutamatergic; Gamma oscillations; LTP; Depotentiation ID LONG-TERM POTENTIATION; CENTRAL-NERVOUS-SYSTEM; PARVALBUMIN-POSITIVE INTERNEURONS; NMDA RECEPTOR HYPOFUNCTION; EARLY-ONSET PSYCHOSIS; DOPAMINE D1 RECEPTOR; HIPPOCAMPUS IN-VITRO; SIZED SPINY NEURONS; ADULT HUMAN BRAIN; TYROSINE KINASE AB Numerous genetic linkage and association studies implicate members of the Neuregulin-ErbB receptor (NRG-ErbB) signaling pathway as schizophrenia "at risk" genes An emphasis of this review is to propose plausible neurobiological mechanisms, regulated by the Neuregulin-ErbB signaling network, that may be altered in schizophrenia and contribute to its etiology To this end, the distinct neurotransmitter pathways, neuronal subtypes and neural network systems altered in schizophrenia are initially discussed. Next, the review focuses on the possible significance of genetic studies associating NRG1 and ErbB4 with schizophrenia, in light of the functional role of this signaling pathway in regulating glutamatergic, GABAergic and dopaminergic neurotransmission, as well as modulating synaptic plasticity and gamma oscillations The Importance of restricted ErbB4 receptor expression in GABAergic interneurons is emphasized, particularly their expression at glutamatergic synapses of parvalbumin-positive fast-spiking interneurons where modulation of inhibitory drive could account for the dramatic effects of NRG-ErbB signaling on gamma oscillations and pyramidal neuron output A case is made for reasons that the NRG-ErbB signaling pathway constitutes a "biologically plausible" system for understanding the pathogenic mechanisms that may underlie the complex array of positive, negative and cognitive deficits associated with schizophrenia during development. Published by Elsevier Inc C1 Eunice Kennedy Shriver NICHD, NIH, Mol Neurobiol Sect, Program Dev Neurobiol, Bethesda, MD 20892 USA. RP Buonanno, A (reprint author), Eunice Kennedy Shriver NICHD, NIH, Mol Neurobiol Sect, Program Dev Neurobiol, 35 Lincoln Dr, Bethesda, MD 20892 USA. FU Eunice Shriver Kennedy National Institute of Child Health and Human Development FX The author thanks Drs. Irina Karavanova and Detlef Vullhorst for assistance with figures, and Drs. Vullhorst and Neddens for critical reading of the manuscript. The author appreciates the continued financial support from the Eunice Shriver Kennedy National Institute of Child Health and Human Development Intramural Research Program. NR 164 TC 67 Z9 70 U1 5 U2 19 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 SEP 30 PY 2010 VL 83 IS 3-4 SI SI BP 122 EP 131 DI 10.1016/j.brainresbull.2010.07.012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 665MJ UT WOS:000283039300006 PM 20688137 ER PT J AU Shew, WL Bellay, T Plenz, D AF Shew, Woodrow L. Bellay, Timothy Plenz, Dietmar TI Simultaneous multi-electrode array recording and two-photon calcium imaging of neural activity SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Electrophysiology; Two-photon imaging; Multi-electrode array; Calcium imaging; Spontaneous activity; Local field potential; Acute slice; Cortex; Rat ID IN-VIVO; POTENTIALS; MICROSCOPY; ELECTRODES; CORTEX AB A complete understanding of how brain circuits function will require measurement techniques which monitor large-scale network activity simultaneously with the activity of local neural populations at a small scale. Here we present a useful step towards achieving this aim: simultaneous two-photon calcium imaging and multi-electrode array (MEA) recordings. The primary challenge of this method is removing an electrical artifact from the MEA signals that is caused by the imaging laser. Here we show that artifact removal can be achieved with a simple filtering scheme. As a demonstration of this technique we compare large-scale local field potential signals to single-neuron activity in a small-scale group of cells recorded from rat acute slices under two conditions: suppressed vs. intact inhibitory interactions between neurons. Published by Elsevier B.V. C1 [Shew, Woodrow L.; Bellay, Timothy; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Shew, WL (reprint author), NIMH, Sect Crit Brain Dynam, Porter Neurosci Res Ctr, Rm 3A-1003,35 Convent Dr, Bethesda, MD 20892 USA. EM sheww@mail.nih.gov OI Shew, Woodrow/0000-0003-0679-1766 FU National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. The authors declare no competing financial interests. NR 13 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD SEP 30 PY 2010 VL 192 IS 1 BP 75 EP 82 DI 10.1016/j.jneumeth.2010.07.023 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 671CM UT WOS:000283477500009 PM 20659501 ER PT J AU Crea, F Hurt, EM Farrar, WL AF Crea, Francesco Hurt, Elaine M. Farrar, William L. TI Clinical significance of Polycomb gene expression in brain tumors SO MOLECULAR CANCER LA English DT Article ID STEM-CELLS; INITIATING CELLS; CANCER; EPIDEMIOLOGY; RENEWAL; GLIOMAS; BMI1 AB Polycomb group (PcG) proteins are crucial for neural cancer stem cell (NCSC) self-renewal. However, the relative expression levels of PcG genes in different subtypes of brain tumors, their prognostic role and their effects on cellular pathways have not been investigated. For this purpose, we queried the Oncomine database and found that 4 PcG genes (EZH2, RBBP7, SUZ12, YY1) are specifically expressed in brain tumors. EZH2 expression increases with tumor grade in adult and pediatric brain tumors, and is a poor prognostic factor. In glioblastoma, EZH2 inhibits differentiation, and activates cancer-, cell cycle- and cellular movement-related genes. In keeping with previously published data, our results suggest that EZH2 is both a prognostic factor and a promising therapy target in brain tumors. C1 [Crea, Francesco; Hurt, Elaine M.; Farrar, William L.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. [Crea, Francesco] Scuola Super StAnna, Pisa, Italy. RP Farrar, WL (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. EM farrar@mail.ncifcrf.gov RI Crea, Francesco /I-8383-2015; OI Crea, Francesco/0000-0002-4903-2973 FU National Cancer Institute; National Institutes of Health NIH [N01-CO-12400]; Center for Cancer Research FX This publication has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract No. N01-CO-12400. This research was supported in part 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 US Government. NR 23 TC 42 Z9 46 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD SEP 30 PY 2010 VL 9 AR 265 DI 10.1186/1476-4598-9-265 PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 668II UT WOS:000283261400001 PM 20920292 ER PT J AU Yu, AL Gilman, AL Ozkaynak, MF London, WB Kreissman, SG Chen, HX Smith, M Anderson, B Villablanca, JG Matthay, KK Shimada, H Grupp, SA Seeger, R Reynolds, CP Buxton, A Reisfeld, RA Gillies, SD Cohn, SL Maris, JM Sondel, PM AF Yu, Alice L. Gilman, Andrew L. Ozkaynak, M. Fevzi London, Wendy B. Kreissman, Susan G. Chen, Helen X. Smith, Malcolm Anderson, Barry Villablanca, Judith G. Matthay, Katherine K. Shimada, Hiro Grupp, Stephan A. Seeger, Robert Reynolds, C. Patrick Buxton, Allen Reisfeld, Ralph A. Gillies, Steven D. Cohn, Susan L. Maris, John M. Sondel, Paul M. CA Children's Oncology Grp TI Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHILDRENS ONCOLOGY GROUP; HIGH-RISK NEUROBLASTOMA; ANTIGANGLIOSIDE GD2 ANTIBODY; BONE-MARROW-TRANSPLANTATION; COLONY-STIMULATING FACTOR; C-RECEPTOR POLYMORPHISMS; PHASE-I; RECOMBINANT INTERLEUKIN-2; REFRACTORY NEUROBLASTOMA; 13-CIS-RETINOIC ACID AB Background: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. Methods: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-csf and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. Results: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66+/-5% vs. 46+/-5% at 2 years, P=0.01) and overall survival (86+/-4% vs. 75+/-5% at 2 years, P=0.02 without adjustment for interim analyses). Conclusions: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.) N Engl J Med 2010;363:1324-34. C1 [Yu, Alice L.] Univ Calif San Diego, San Diego, CA 92103 USA. [Yu, Alice L.] Moores Canc Ctr, San Diego, CA 92103 USA. [Yu, Alice L.] Acad Sinica, Genom Res Ctr, Taipei, Taiwan. [Gilman, Andrew L.] Levine Childrens Hosp, Charlotte, NC USA. [Kreissman, Susan G.] Duke Univ, Med Ctr, Durham, NC USA. [Ozkaynak, M. Fevzi] New York Med Coll, Valhalla, NY 10595 USA. [London, Wendy B.] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [London, Wendy B.] Childrens Oncol Grp Stat & Data Ctr, Boston, MA USA. [Chen, Helen X.; Smith, Malcolm; Anderson, Barry] NCI, Bethesda, MD 20892 USA. [Villablanca, Judith G.; Shimada, Hiro; Seeger, Robert] Univ So Calif, Childrens Hosp Los Angeles, Los Angeles, CA USA. [Matthay, Katherine K.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Matthay, Katherine K.] Univ Calif San Francisco, Childrens Hosp, San Francisco, CA 94143 USA. [Grupp, Stephan A.; Maris, John M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Grupp, Stephan A.; Maris, John M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Sch Med, Lubbock, TX 79430 USA. [Buxton, Allen] Childrens Oncol Grp Stat & Data Ctr, Arcadia, CA USA. [Reisfeld, Ralph A.] Scripps Res Inst, La Jolla, CA 92037 USA. [Gillies, Steven D.] Provenance Biopharmaceut, Waltham, MA USA. [Cohn, Susan L.] Univ Chicago, Chicago, IL 60637 USA. [Sondel, Paul M.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53706 USA. RP Yu, AL (reprint author), Univ Calif San Diego, 200 W Arbor Dr, San Diego, CA 92103 USA. EM aliceyu@ucsd.edu OI Cohn, Susan/0000-0001-5749-7650 FU National Institutes of Health [U10-CA98543, U10-CA98413, U10-CA29139]; Food and Drug Administration [FD-R-002319] FX Supported by grants from the National Institutes of Health (U10-CA98543, U10-CA98413, and U10-CA29139) and the Food and Drug Administration (FD-R-002319). NR 40 TC 454 Z9 465 U1 1 U2 39 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 SEP 30 PY 2010 VL 363 IS 14 BP 1324 EP 1334 DI 10.1056/NEJMoa0911123 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 655TD UT WOS:000282271500006 PM 20879881 ER PT J AU Rivera, J Colbert, RA AF Rivera, Juan Colbert, Robert A. TI Healing the Syk through Kinase Inhibitors. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TYROSINE KINASE; RHEUMATOID-ARTHRITIS; THERAPY C1 [Rivera, Juan; Colbert, Robert A.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. NR 11 TC 13 Z9 14 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 30 PY 2010 VL 363 IS 14 BP 1362 EP 1364 DI 10.1056/NEJMe1006527 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 655TD UT WOS:000282271500013 PM 20879886 ER PT J AU Tokar, EJ Diwan, BA Waalkes, MP AF Tokar, Erik J. Diwan, Bhalchandra A. Waalkes, Michael P. TI Early life inorganic lead exposure induces testicular teratoma and renal and urinary bladder preneoplasia in adult metallothionein-knockout mice but not in wild type mice SO TOXICOLOGY LA English DT Article DE Lead; Carcinogenesis; Mice; Metallothionein; Testes ID INCLUSION-BODY FORMATION; POSTNATAL DIETHYLSTILBESTROL; ARSENIC EXPOSURE; TRANSGENIC MICE; MESSENGER-RNA; HUMAN-LIVER; II GENES; CARCINOGENESIS; SENSITIVITY; CADMIUM AB Inorganic lead compounds are carcinogenic in animals and have carcinogenic potential in humans. In mice, lead (Pb) is a transplacental carcinogen in the kidney. Metallothionein (MT) is a metal-binding protein that can reduce the toxicity of various metals, including Pb, either by direct sequestration or as an antioxidant for metals that generate reactive oxygen species. Although MT appears to reduce Pb carcinogenicity in adult mice it is unknown how MT deficiency may affect Pb carcinogenicity from early life exposure. Thus, groups (n = 10) of pregnant MT-I/II double knockout (MT-null) or 129/SVJ MT wild type (WT) mice were exposed to Pb acetate in the drinking water (0, 2000, 4000 ppm Pb) from gestation day 8 through birth and during lactation. Maternal drinking water Pb exposure continued to wean at 4 weeks of age and the male offspring were then directly exposed to Pb until 8 weeks of age and observed until 2 years old. High dose (4000 ppm) but not low dose (2000 ppm) Pb reduced survival in the latter part of the study in both MT-null and WT mice. In MT-null mice, but not WT, early life Pb exposure caused a dose-related increase in testicular teratomas, to a maximum incidence of 28% compared to control (4%). Pb-induced renal cystic hyperplasia, considered preneoplastic, was a prominent occurrence in MT-null mice but nearly absent in WT mice. Pb dose-related increases in renal cystic hyperplasia occurred in adult MT-null with early life exposure with maximal incidence of 52%. Pb-treated MT-null mice also showed dose-related increases in urinary bladder hyperplasia with occasional papilloma that were absent in WT mice. Thus, MT deficiency made mice more sensitive to early life Pb exposure with regard to testes tumors, and renal and urinary bladder preneoplastic lesions. Published by Elsevier Ireland Ltd. C1 [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. [Tokar, Erik J.; Waalkes, Michael P.] NCI, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis, NIEHS, Res Triangle Pk, NC 27709 USA. [Diwan, Bhalchandra A.] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. RP Waalkes, MP (reprint author), NIEHS, NTP, 111 Alexander Dr,POB 12233,MD F0-09, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS); NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors wish to thank Drs. L. Keefer, W. Qu, and Y. Sun for critical evaluation of this manuscript, Dr. J. Liu for assistance with the MT-null mice, and D. Logsdon and the Pathology and Histotechnology Laboratory of SAIC-Frederick for expert technical assistance. This research was supported in part by the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS) and by the Intramural Research program of the NIH, National Cancer Institute, Center for Cancer Research. This article may be the work product of an employee or group of employees of the NIEHS, National Institutes of Health (NIEL), however, the statements contained herein do not necessarily represent the statements, opinions or conclusions of the NIEHS, NIH or the U.S. Government. This project was also supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or the 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 38 TC 14 Z9 16 U1 0 U2 3 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 SEP 30 PY 2010 VL 276 IS 1 BP 5 EP 10 DI 10.1016/j.tox.2010.06.006 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 647NI UT WOS:000281624800002 PM 20600549 ER PT J AU Palkar, PS Anderson, CR Ferry, CH Gonzalez, FJ Peters, JM AF Palkar, Prajakta S. Anderson, Cherie R. Ferry, Christina H. Gonzalez, Frank J. Peters, Jeffrey M. TI Effect of prenatal peroxisome proliferator-activated receptor alpha (PPAR alpha) agonism on postnatal development SO TOXICOLOGY LA English DT Article DE Peroxisome proliferator-activated receptor-alpha; Postnatal development; Nuclear receptor; Prenatal exposure ID PERFLUOROOCTANOIC ACID; LACTATING RATS; DIFFERENTIAL EXPRESSION; MORPHOMETRIC-ANALYSIS; TISSUE DISTRIBUTION; KIDNEY PEROXISOMES; LIVER; MOUSE; EXPOSURE; PUPS AB Recent work indicates that PPAR alpha is required for perfluorooctanoic acid (PFOA)-induced postnatal lethality resulting from prenatal exposure. The present study tested the hypothesis that relatively modest activation of PPAR alpha during prenatal development will cause postnatal lethality, similar to that observed with PFOA, a relatively low affinity PPAR alpha agonist. Female wild-type and Ppar alpha-null mice were mated overnight with males of the same genotype. The presence of a copulatory plug on the morning after mating was indicative of pregnancy and considered gestation day (GD) 0. Plugged female mice were fed either a control diet or one containing clofibrate (0.5%) or Wy-14,643 (0.005%) until GD18 or until parturition. Mice were examined on GD18 or on postnatal day (PND) 20 following the prenatal exposure period. Dietary administration of clofibrate or Wy-14,643 did not affect maternal weight or weight gain, the average number of implantations, the percentage of litter loss, the average number of live/dead fetuses, average crown-rump length, or the average fetal weight on GD18 in either genotype. An increase in relative maternal liver weight and elevated expression of PPAR alpha target genes in maternal and fetal livers on GD18 were observed, indicative of PPAR alpha-dependent changes in both the maternal and fetal compartments. However, no defects in postnatal development were observed by either clofibrate or Wy-14,643 in either genotype by PND20. These results demonstrate that relatively low level activation of PPAR alpha by clofibrate or Wy-14,643 during prenatal development does not cause postnatal lethality. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Palkar, Prajakta S.; Anderson, Cherie R.; Ferry, Christina H.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Palkar, Prajakta S.; Anderson, Cherie R.; Ferry, Christina H.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, 312 Life Sci Bldg, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Peters, Jeffrey/D-8847-2011 NR 40 TC 8 Z9 8 U1 0 U2 5 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 SEP 30 PY 2010 VL 276 IS 1 BP 79 EP 84 DI 10.1016/j.tox.2010.07.008 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 647NI UT WOS:000281624800012 PM 20637823 ER PT J AU Easley, R Carpio, L Dannenberg, L Choi, S Alani, D Van Duyne, R Guendel, I Klase, Z Agbottah, E Kehn-Hall, K Kashanchi, F AF Easley, Rebecca Carpio, Lawrence Dannenberg, Luke Choi, Soyun Alani, Dowser Van Duyne, Rachel Guendel, Irene Klase, Zachary Agbottah, Emmanuel Kehn-Hall, Kylene Kashanchi, Fatah TI Transcription through the HIV-1 nucleosomes: Effects of the PBAF complex in Tat activated transcription SO VIROLOGY LA English DT Article DE HW-1; Chromatin; BAF; PBAF; FACT; Transcription; Remodel ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHROMATIN-REMODELING COMPLEX; LONG TERMINAL REPEAT; RNA-POLYMERASE-II; ELONGATION-FACTORS; IN-VIVO; SACCHAROMYCES-CEREVISIAE; CHD1 INTERACTS; N-COR; PROTEIN AB The SWI/SNF complex remodels nucleosomes, allowing RNA Polymerase II access to the HIV-1 proviral DNA. It has not been determined which SWI/SNF complex (BAF or PBAF) remodels nucleosomes at the transcription start site. These complexes differ in only three subunits and determining which subunit(s) is required could explain the regulation of Tat activated transcription. We show that PBAF is required for chromatin remodeling at the nuc-1 start site and transcriptional elongation. We find that Baf200 is required to ensure activation at the LTR level and for viral production. Interestingly, the BAF complex was observed on the LTR whereas PBAF was present on both LTR and Env regions. We found that Tat activated transcription facilitates removal of histones H2A and H2B at the LTR, and that the FACT complex may be responsible for their removal. Finally, the BAF complex may play an important role in regulating splicing of the HIV-1 genome. (C) 2010 Elsevier Inc. All rights reserved. C1 [Kehn-Hall, Kylene; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. [Klase, Zachary] NIAID, NIH, Bethesda, MD 20892 USA. RP Kashanchi, F (reprint author), George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Discovery Hall,Room 306,10900 Univ Blvd,MS 1H8, Manassas, VA 20110 USA. EM rleasl@gmail.com; lawrence.carpio@gmail.com; luke.dannenberg@roche.com; choysters@gmail.com; dalani@gmu.edu; rachel.vanduyne@gmail.com; mtmixg@gwumc.edu; klaseza@niaid.nih.gov; bcmeta@gwumc.edu; kkehnhal@gmu.edu; fkashanc@gmu.edu RI Kehn-Hall, Kylene/I-5752-2013 FU George Washington University [AI043894, AI074410] FX This work was supported by grants from the George Washington University REF funds to FK and NIH grant AI043894 and AI074410. NR 59 TC 15 Z9 16 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 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2010 VL 405 IS 2 BP 322 EP 333 DI 10.1016/j.virol.2010.06.009 PG 12 WC Virology SC Virology GA 641MJ UT WOS:000281130500007 PM 20599239 ER PT J AU Wu, TY Datta, SAK Mitra, M Gorelick, RJ Rein, A Levin, JG AF Wu, Tiyun Datta, Siddhartha A. K. Mitra, Mithun Gorelick, Robert J. Rein, Alan Levin, Judith G. TI Fundamental differences between the nucleic acid chaperone activities of HIV-1 nucleocapsid protein and Gag or Gag-derived proteins: Biological implications SO VIROLOGY LA English DT Article DE Nucleic acid chaperone; HIV-1; Gag; Nucleocapsid protein; Capsid protein; Reverse transcription; Nucleic acid-driven multimerization; Retrovirus; Minus-strand transfer ID IMMUNODEFICIENCY-VIRUS TYPE-1; STRONG-STOP DNA; ZINC-FINGER STRUCTURES; REVERSE TRANSCRIPTION; IN-VITRO; STRAND TRANSFER; GENOMIC RNA; CAPSID PROTEIN; VIRAL REPLICATION; MATRIX DOMAIN AB The HIV-1 Gag polyprotein precursor has multiple domains including nucleocapsid (NC). Although mature NC and NC embedded in Gag are nucleic acid chaperones (proteins that remodel nucleic acid structure), few studies include detailed analysis of the chaperone activity of partially processed Gag proteins and comparison with NC and Gag. Here we address this issue by using a reconstituted minus-strand transfer system. NC and NC-containing Gag proteins exhibited annealing and duplex destabilizing activities required for strand transfer. Surprisingly, unlike NC, with increasing concentrations. Gag proteins drastically inhibited the DNA elongation step. This result is consistent with "nucleic acid-driven multimerization" of Gag and the reported slow dissociation of Gag from bound nucleic acid, which prevent reverse transcriptase from traversing the template ("roadblock" mechanism). Our findings illustrate one reason why NC (and not Gag) has evolved as a critical cofactor in reverse transcription, a paradigm that might also extend to other retrovirus systems. Published by Elsevier Inc. C1 [Wu, Tiyun; Mitra, Mithun; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Datta, Siddhartha A. K.; Rein, Alan] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, Program Genom Differentiat, NIH, Bldg 6B,Room 216,6 Ctr Dr, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov RI Mitra, Mithun/A-2133-2015; OI Datta, Siddhartha/0000-0002-4098-7490 FU NIH; National Cancer Institute, Center for Cancer Research; National Cancer Institute [N01-CO-12400, HHSN261200800001E] FX We thank Christopher Aiken for the Gag cleavage mutants, David Ott for the HIV-1 PR mutant PRD25G, Malcolm Martin for the pNL4-3 clone, which was obtained from the NIH AIDS Research and Reference Reagent Program, and Hans Luecke, who generously allowed us to use his Spectromax M5 instrument for the Kd determinations. We are also indebted to Christopher Jones, Ioulia Rouzina, and Karin Musier-Forsyth for valuable discussion and for sharing unpublished data. This work was supported by the Intramural Research Program of the NIH (Eunice Kennedy Shriver National Institute of Child Health and Human Development [J.G.L.] and the National Cancer Institute, Center for Cancer Research [A.R.]) and was funded in part with federal funds from the National Cancer Institute under contract numbers N01-CO-12400 and HHSN261200800001E (R.J.G.). 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 79 TC 30 Z9 30 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2010 VL 405 IS 2 BP 556 EP 567 DI 10.1016/j.virol.2010.06.042 PG 12 WC Virology SC Virology GA 641MJ UT WOS:000281130500032 PM 20655566 ER PT J AU Yassine, HM Khatri, M Lee, CW Saif, YM AF Yassine, Hadi M. Khatri, Mahesh Lee, Chang W. Saif, Yehia M. TI Characterization of an H3N2 triple reassortant influenza virus with a mutation at the receptor binding domain (D190A) that occurred upon virus transmission from turkeys to pigs SO VIROLOGY JOURNAL LA English DT Article ID A VIRUSES; INTERSPECIES TRANSMISSION; AVIAN INFLUENZA; ACID CHANGE; HEMAGGLUTININ; SPECIFICITY; CELLS; RECOGNITION; GENERATION; MAMMALS AB The hemagglutinin (HA) protein of influenza virus mediates essential viral functions including the binding to host receptor and virus entry. It also has the antigenic sites required for virus neutralization by host antibodies. Here, we characterized an H3N2 triple reassortant (TR) influenza virus (A/turkey/Ohio/313053/04) with a mutation at the receptor binding domain (Asp190Ala) that occurred upon virus transmission from turkeys to pigs in an experimental infection study. The mutant virus replicated less efficiently than the parental virus in human, pig and turkey primary tracheal/bronchial epithelial cells, with more than 3-log10 difference in virus titer at 72 hours post infection. In addition, the mutant virus demonstrated lower binding efficiency to plasma membrane preparations from all three cell types compared to the parental virus. Antisera raised against the parental virus reacted equally to both homologous and heterlogous viruses, however, antisera raised against the mutant virus showed 4-8 folds lower reactivity to the parental virus. C1 [Yassine, Hadi M.; Khatri, Mahesh; Lee, Chang W.; Saif, Yehia M.] Ohio State Univ, Food Anim Hlth Res Program, Ohio Agr Res & Dev Ctr, Wooster, OH 44691 USA. [Yassine, Hadi M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Saif, YM (reprint author), Ohio State Univ, Food Anim Hlth Res Program, Ohio Agr Res & Dev Ctr, 1680 Madison Ave, Wooster, OH 44691 USA. EM saif.1@osu.edu FU United States Department of Agriculture,; Ohio Agricultural Research and Development Center, The Ohio State University; CSREES FX This work was partially supported by funds from the United States Department of Agriculture, CSREES AI-CAP project, and the Ohio Agricultural Research and Development Center, The Ohio State University. NR 34 TC 6 Z9 6 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD SEP 30 PY 2010 VL 7 AR 258 DI 10.1186/1743-422X-7-258 PG 7 WC Virology SC Virology GA 670LN UT WOS:000283423300001 PM 20920297 ER PT J AU Gonzalez-Islas, C Chub, N Garcia-Bereguiain, MA Wenner, P AF Gonzalez-Islas, Carlos Chub, Nikolai Garcia-Bereguiain, Miguel Angel Wenner, Peter TI GABAergic Synaptic Scaling in Embryonic Motoneurons Is Mediated by a Shift in the Chloride Reversal Potential SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SPONTANEOUS NETWORK ACTIVITY; NEOCORTICAL NEURONS; QUANTAL AMPLITUDE; CHICK-EMBRYO; PLASTICITY; SYNAPSES; GABA; COTRANSPORTERS; AVAILABILITY; TRANSMISSION AB Homeostatic synaptic plasticity ensures that networks maintain specific levels of activity by regulating synaptic strength in a compensatory manner. When spontaneous network activity was blocked in vivo in the embryonic spinal cord, compensatory increases in excitatory GABAergic synaptic inputs were observed. This homeostatic synaptic strengthening was observed as an increase in the amplitude of GABAergic miniature postsynaptic currents. We find that this process is mediated by an increase in chloride accumulation, which produces a depolarizing shift in the GABAergic reversal potential (E(GABA)). The findings demonstrate a previously unrecognized mechanism underlying homeostatic synaptic scaling. Similar shifts in E(GABA) have been described following various forms of neuronal injury, introducing the possibility that these shifts in E(GABA) represent a homeostatic response. C1 [Gonzalez-Islas, Carlos; Garcia-Bereguiain, Miguel Angel; Wenner, Peter] Emory Univ, Sch Med, Dept Physiol, Atlanta, GA 30322 USA. [Chub, Nikolai] Natl Inst Neurol Disorders & Stroke, Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Wenner, P (reprint author), Emory Univ, Sch Med, Dept Physiol, Room 601,Whitehead Bldg, Atlanta, GA 30322 USA. EM pwenner@emory.edu OI Wenner, Peter/0000-0002-7072-2194 FU National Institute of Neurological Disorders and Stroke [NS046510]; National Science Foundation [0616097] FX This research was supported by National Institute of Neurological Disorders and Stroke Grant NS046510 and National Science Foundation Grant 0616097 to P.W. and by the Intramural Program of the National Institutes of Neurological Disorders and Stroke. We thank Drs. Michael O'Donovan and Mark Rich for their comments on the manuscript, and Dr. Porfirio Nava for assistance with Western blots. NR 30 TC 15 Z9 15 U1 1 U2 1 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 SEP 29 PY 2010 VL 30 IS 39 BP 13016 EP 13020 DI 10.1523/JNEUROSCI.1659-10.2010 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 659MY UT WOS:000282571800012 PM 20881119 ER PT J AU Kikuchi, Y Horwitz, B Mishkin, M AF Kikuchi, Yukiko Horwitz, Barry Mishkin, Mortimer TI Hierarchical Auditory Processing Directed Rostrally along the Monkey's Supratemporal Plane SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTROLATERAL PREFRONTAL CORTEX; SUPERIOR TEMPORAL REGION; RHESUS-MONKEY; MACAQUE MONKEYS; CORTICAL CONNECTIONS; BELT CORTEX; FUNCTIONAL SPECIALIZATION; TONOTOPIC ORGANIZATION; RESPONSE PROPERTIES; MARMOSET MONKEYS AB Connectional anatomical evidence suggests that the auditory core, containing the tonotopic areas A1, R, and RT, constitutes the first stage of auditory cortical processing, with feedforward projections from core outward, first to the surrounding auditory belt and then to the parabelt. Connectional evidence also raises the possibility that the core itself is serially organized, with feedforward projections from A1 to R and with additional projections, although of unknown feed direction, from R to RT. We hypothesized that area RT together with more rostral parts of the supratemporal plane (rSTP) form the anterior extension of a rostrally directed stimulus quality processing stream originating in the auditory core area A1. Here, we analyzed auditory responses of single neurons in three different sectors distributed caudorostrally along the supratemporal plane (STP): sector I, mainly area A1; sector II, mainly area RT; and sector III, principally RTp (the rostrotemporal polar area), including cortex located 3 mm from the temporal tip. Mean onset latency of excitation responses and stimulus selectivity to monkey calls and other sounds, both simple and complex, increased progressively from sector I to III. Also, whereas cells in sector I responded with significantly higher firing rates to the "other" sounds than to monkey calls, those in sectors II and III responded at the same rate to both stimulus types. The pattern of results supports the proposal that the STP contains a rostrally directed, hierarchically organized auditory processing stream, with gradually increasing stimulus selectivity, and that this stream extends from the primary auditory area to the temporal pole. C1 [Kikuchi, Yukiko] Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20057 USA. [Kikuchi, Yukiko; Mishkin, Mortimer] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Kikuchi, Yukiko; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD 20892 USA. RP Kikuchi, Y (reprint author), Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Res Bldg WP15,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM yk254@georgetown.edu FU National Institute of Mental Health; National Institute on Deafness and Other Communication Disorders; Japan Society for the Promotion of Science; National Institutes of Health [R01 NS052494]; National Science Foundation Partnerships for International Research and Education [OISE-0730255] FX This work was supported by the Intramural Research Programs of the National Institute of Mental Health and the National Institute on Deafness and Other Communication Disorders, by the Japan Society for the Promotion of Science, and by National Institutes of Health Grant R01 NS052494 and National Science Foundation Partnerships for International Research and Education Grant OISE-0730255. We thank R. C. Saunders and M. Malloy for assisting with the surgeries and the structural MRI, O. Castillo-Aguiar for animal care and testing, K. King for audiological screening, K. Saleem for neuroanatomical advice, and M. D. Hauser and A. Poremba for providing monkey vocalizations. NR 36 TC 53 Z9 53 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 29 PY 2010 VL 30 IS 39 BP 13021 EP 13030 DI 10.1523/JNEUROSCI.2267-10.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 659MY UT WOS:000282571800013 PM 20881120 ER PT J AU Iwahara, J Clore, GM AF Iwahara, Junji Clore, G. Marius TI Structure-Independent Analysis of the Breadth of the Positional Distribution of Disordered Groups in Macromolecules from Order Parameters for Long, Variable-Length Vectors Using NMR Paramagnetic Relaxation Enhancement SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MOLECULAR-STRUCTURE DETERMINATION; TRANSIENT ENCOUNTER COMPLEXES; PROTEIN-PROTEIN ASSOCIATION; PAIR CORRELATION-FUNCTIONS; SPIN-LATTICE RELAXATION; TRANSLATIONAL DIFFUSION; PROTON RELAXATION; CROSS-RELAXATION; XPLOR-NIH; DYNAMICS AB Quantitative information regarding structurally disordered groups is crucial for a complete understanding of the relationship between structure, dynamics, and function in biological macromolecules. Experimental analysis, however, of the positional distribution of disordered groups in the macromolecular frame is extremely difficult. While NMR order parameters, S(2), for fixed-length bond vectors such as N-H and C-H are commonly used for investigations of conformational dynamics of macromolecules, these order parameters provide only angular information about internal motions and are totally insensitive to translational motions. Although analysis of S(2) for bond vectors permits identification of disordered groups in macromolecules, this type of order parameter cannot provide any information about the distribution radii of disordered groups. Here we describe an NMR approach to directly determine the distribution radius of a disordered group independent of any structural knowledge. This approach makes use of order parameters for long, variable-length vectors (including proton paramagnetic center and proton proton vectors) between a disordered group and a rigid portion of the macromolecule. We demonstrate the application of this formalism to paramagnetic relaxation enhancement vectors. In addition, the potential utility of the same formalism to (1)H-(1)H cross-relaxation rates is considered as an alternative approach for analyzing the breadth of the positional distribution of disordered groups. C1 [Iwahara, Junji] Univ Texas Med Branch, Dept Biochem & Mol Biol, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA. [Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Iwahara, J (reprint author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA. EM j.iwahara@utmb.edu; mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 FU Welch Foundation [H-1683]; National Science Foundation [MCB-0920238]; National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Office of the Director of the NIH FX We thank Dr. Attila Szabo for stimulating discussions and for originally pointing out to us that < r-6> S2 = R-6 to order R-10 for any spherical distribution centered on R. This work was supported by Grant H-1683 from the Welch Foundation (to J.I.), Grant MCB-0920238 from the National Science Foundation (to J.I.), the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH (to G.M.C.), and the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 48 TC 19 Z9 19 U1 1 U2 5 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 SEP 29 PY 2010 VL 132 IS 38 BP 13346 EP 13356 DI 10.1021/ja1048187 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 656CQ UT WOS:000282304000059 PM 20795737 ER PT J AU De, S Zhang, YQ Garner, JR Wang, SA Becker, KG AF De, Supriyo Zhang, Yongqing Garner, John R. Wang, S. Alex Becker, Kevin G. TI Disease and phenotype gene set analysis of disease-based gene expression in mouse and human SO PHYSIOLOGICAL GENOMICS LA English DT Article DE genome-wide association; microarray; common disease; disease ontology; data integration ID GENOME-WIDE ASSOCIATION; ENRICHMENT ANALYSIS; PATHWAYS; DATABASE; ARCHIVE; BIOLOGY; ATLAS AB De S, Zhang Y, Garner JR, Wang SA, Becker KG. Disease and phenotype gene set analysis of disease-based gene expression in mouse and human. Physiol Genomics 42A: 162-167, 2010. First published August 3, 2010; doi:10.1152/physiolgenomics.00008.2010.-The genetic contributions to common disease and complex disease phenotypes are pleiotropic, multifactorial, and combinatorial. Gene set analysis is a computational approach used in the analysis of microarray data to rapidly query gene combinations and multifactorial processes. Here we use novel gene sets based on population-based human genetic associations in common human disease or experimental genetic mouse models to analyze disease-related microarray studies. We developed a web-based analysis tool that uses these novel disease-and phenotype-related gene sets to analyze microarray-based gene expression data. These gene sets show disease and phenotype specificity in a species-specific and cross-species fashion. In this way, we integrate population-based common human disease genetics, mouse genetically determined phenotypes, and disease or phenotype structured ontologies, with gene expression studies relevant to human disease. This may aid in the translation of large-scale high-throughput datasets into the context of clinically relevant disease phenotypes. C1 [De, Supriyo; Zhang, Yongqing; Garner, John R.; Becker, Kevin G.] NIA, Biomed Res Ctr, NIH, Gene Express & Genom Unit, Baltimore, MD 21224 USA. [Wang, S. Alex] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Becker, KG (reprint author), NIA, Biomed Res Ctr, NIH, Gene Express & Genom Unit, Ste 100,Rm 4B122,251 Bayview Blvd, Baltimore, MD 21224 USA. EM beckerk@grc.nia.nih.gov OI De, Supriyo/0000-0002-2075-7655; Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health (NIH); National Institute on Aging; NIH Center for Information Technology FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging, and the NIH Center for Information Technology. NR 26 TC 11 Z9 11 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD SEP 29 PY 2010 VL 42A IS 2 BP 162 EP 167 DI 10.1152/physiolgenomics.00008.2010 PG 6 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 656BY UT WOS:000282302000009 PM 20682848 ER PT J AU Moore, SC Gierach, GL Schatzkin, A Matthews, CE AF Moore, S. C. Gierach, G. L. Schatzkin, A. Matthews, C. E. TI Physical activity, sedentary behaviours, and the prevention of endometrial cancer SO BRITISH JOURNAL OF CANCER LA English DT Review DE sedentary behaviour; physical activity; endometrial cancer; epidemiology ID LIFE-STYLE; US WOMEN; RISK; COHORT; MECHANISMS; OBESITY; HEALTH; TIME; OVERWEIGHT; HORMONES AB Physical activity has been hypothesised to reduce endometrial cancer risk, but this relationship has been difficult to confirm because of a limited number of prospective studies. However, recent publications from five cohort studies, which together comprise 2663 out of 3463 cases in the published literature for analyses of recreational physical activity, may help resolve this question. To synthesise these new data, we conducted a meta-analysis of prospective studies published through to December 2009. We found that physical activity was clearly associated with reduced risk of endometrial cancer, with active women having an approximately 30% lower risk than inactive women. Owing to recent interest in sedentary behaviour, we further investigated sitting time in relation to endometrial cancer risk using data from the NIH-AARP Diet and Health Study. We found that, independent of the level of moderate-vigorous physical activity, greater sitting time was associated with increased endometrial cancer risk. Thus, limiting time in sedentary behaviours may complement increasing level of moderate-vigorous physical activity as a means of reducing endometrial cancer risk. Taken together with the established biological plausibility of this relation, the totality of evidence now convincingly indicates that physical activity prevents or reduces risk of endometrial cancer. British Journal of Cancer (2010) 103, 933-938. doi:10.1038/sj.bjc.6605902 www.bjcancer.com (C) 2010 Cancer Research UK C1 [Moore, S. C.; Gierach, G. L.; Schatzkin, A.; Matthews, C. E.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Moore, SC (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM moorest@mail.nih.gov RI matthews, Charles/E-8073-2015; Gierach, Gretchen/E-1817-2016; Moore, Steven/D-8760-2016 OI matthews, Charles/0000-0001-8037-3103; Gierach, Gretchen/0000-0002-0165-5522; Moore, Steven/0000-0002-8169-1661 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. NR 29 TC 49 Z9 50 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 28 PY 2010 VL 103 IS 7 BP 933 EP 938 DI 10.1038/sj.bjc.6605902 PG 6 WC Oncology SC Oncology GA 655DB UT WOS:000282222000002 PM 20877336 ER PT J AU Dores, GM Anderson, WF Freeman, LEB Fraumeni, JF Curtis, RE AF Dores, G. M. Anderson, W. F. Freeman, L. E. Beane Fraumeni, J. F. Curtis, R. E. TI Risk of breast cancer according to clinicopathologic features among long-term survivors of Hodgkin's lymphoma treated with radiotherapy SO BRITISH JOURNAL OF CANCER LA English DT Article DE Hodgkin's lymphoma; second breast cancer; radiation-related breast cancer ID END RESULTS DATABASE; ESTROGEN-RECEPTOR; DISEASE; SURVEILLANCE; RADIATION; WOMEN; EPIDEMIOLOGY AB BACKGROUND: It is unknown whether breast cancer (BC) characteristics among young women treated with radiotherapy (RT) for Hodgkin's lymphoma (HL) differ from sporadic BC. METHODS: Using population-based data, we calculated BC risk following HL according to clinicopathologic features. RESULTS: Compared with BC in the general population, risks of oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive and ER-negative/PR-negative BC in young, irradiated HL survivors were increased five-fold (95% confidence interval (CI) = 3.81-6.35) and nine-fold (95% CI = 6.93-12.25), respectively. Among 15-year survivors, relative risk of ER-negative/PR-negative BC exceeded by two-fold (P = 0.002) than that of ER-positive/PR-positive BC. CONCLUSION: Radiotherapy may disproportionately contribute to the development of BC with adverse prognostic features among young HL survivors. British Journal of Cancer (2010) 103, 1081-1084. doi:10.1038/sj.bjc.6605877 www.bjcancer.com Published online 14 September 2010 (C) 2010 Cancer Research UK C1 [Dores, G. M.] Med Serv, Dept Vet Affairs Med Ctr, Oklahoma City, OK 73104 USA. [Dores, G. M.; Anderson, W. F.; Freeman, L. E. Beane; Fraumeni, J. F.; Curtis, R. E.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Dores, GM (reprint author), Med Serv, Dept Vet Affairs Med Ctr, 921 NE 13th St, Oklahoma City, OK 73104 USA. EM doresg@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Veterans Affairs Medical Center in Oklahoma City, OK, USA FX This work was supported by the Intramural Research Programme of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, and by the Department of Veterans Affairs Medical Center in Oklahoma City, OK, USA. We are grateful to Nathan Appel, Information Management Systems Inc., Silver Spring, Maryland, USA, for computer support. NR 22 TC 18 Z9 19 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 28 PY 2010 VL 103 IS 7 BP 1081 EP 1084 DI 10.1038/sj.bjc.6605877 PG 4 WC Oncology SC Oncology GA 655DB UT WOS:000282222000020 PM 20842115 ER PT J AU Major, JM Stolzenberg-Solomon, RZ Pollak, MN Snyder, K Virtamo, J Albanes, D AF Major, J. M. Stolzenberg-Solomon, R. Z. Pollak, M. N. Snyder, K. Virtamo, J. Albanes, D. TI Insulin-like growth factors and liver cancer risk in male smokers SO BRITISH JOURNAL OF CANCER LA English DT Article DE insulin-like growth factor; IGF-I; incidence; men ID IGF-BINDING PROTEIN-3; C VIRUS-INFECTION; FACTOR-I; HEPATOCELLULAR-CARCINOMA; PROSTATE-CANCER; REGRESSION ANALYSIS; FACTOR (IGF)-I; SERUM-LEVELS; MEN; EPIDEMIOLOGY AB BACKGROUND: The liver is the primary source of circulating insulin-like growth factor (IGF)-I, yet the relation between IGFs and liver cancer is uncertain. METHODS: In a case-cohort study within a cohort of 29 133 male smokers we examined associations of serum IGF-I and IGF binding protein (IGFBP)-3 with liver cancer (50 cases). RESULTS: Nonlinear associations between liver cancer and IGF-I and IGFBP-3 were observed (P = 0.04 and P<0.01, respectively), strongest association at lowest levels (odds ratio (OR) = 0.2, 95% confidence interval (CI) = 0.1-0.7 for 80 vs 30 ng ml(-1) of IGF-I; OR = 0.2, 95% CI = 0.1-0.6 for 1400 vs 700 ng ml(-1) of IGFBP-3). CONCLUSIONS: Low IGF-I and IGFBP-3 levels in male smokers are associated with increased risk of liver cancer. British Journal of Cancer (2010) 103, 1089-1092. doi:10.1038/sj.bjc.6605842 www.bjcancer.com Published online 17 August 2010 (C) 2010 Cancer Research UK C1 [Major, J. M.; Stolzenberg-Solomon, R. Z.; Albanes, D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Pollak, M. N.] Jewish Gen Hosp, Dept Oncol, Montreal, PQ H3T 1E2, Canada. [Pollak, M. N.] McGill Univ, Montreal, PQ H3T 1E2, Canada. [Snyder, K.] Informat Management Serv Inc, Silver Spring, MD 20904 USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00300, Finland. RP Major, JM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. EM Jacqueline.major@nih.gov RI Pollak, Michael/G-9094-2011; Albanes, Demetrius/B-9749-2015 OI Pollak, Michael/0000-0003-3047-0604; NR 34 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 28 PY 2010 VL 103 IS 7 BP 1089 EP 1092 DI 10.1038/sj.bjc.6605842 PG 4 WC Oncology SC Oncology GA 655DB UT WOS:000282222000022 PM 20717109 ER PT J AU Faupel-Badger, JM Sherman, ME Garcia-Closas, M Gaudet, MM Falk, RT Andaya, A Pfeiffer, RM Yang, XR Lissowska, J Brinton, LA Peplonska, B Vonderhaar, BK Figueroa, JD AF Faupel-Badger, J. M. Sherman, M. E. Garcia-Closas, M. Gaudet, M. M. Falk, R. T. Andaya, A. Pfeiffer, R. M. Yang, X. R. Lissowska, J. Brinton, L. A. Peplonska, B. Vonderhaar, B. K. Figueroa, J. D. TI Prolactin serum levels and breast cancer: relationships with risk factors and tumour characteristics among pre- and postmenopausal women in a population-based case-control study from Poland SO BRITISH JOURNAL OF CANCER LA English DT Article DE lobular carcinoma; molecular subtypes; prolactin; breast cancer ID HORMONE REPLACEMENT THERAPY; PLASMA PROLACTIN; PREMENOPAUSAL WOMEN; SEX-HORMONES; REPRODUCTIVE FACTORS; PITUITARY-FUNCTION; MENOPAUSAL WOMEN; FAMILY-HISTORY; ENERGY-BALANCE; NURSES HEALTH AB BACKGROUND: Previous prospective studies have found an association between prolactin (PRL) levels and increased risk of breast cancer. Using data from a population-based breast cancer case-control study conducted in two cities in Poland (2000-2003), we examined the association of PRL levels with breast cancer risk factors among controls and with tumour characteristics among the cases. METHODS: We analysed PRL serum levels among 773 controls without breast cancer matched on age and residence to 776 invasive breast cancer cases with available pretreatment serum. Tumours were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis. Breast cancer risk factors, assessed by interview, were related to serum PRL levels among controls using analysis of variance. Mean serum PRL levels by tumour characteristics are reported. These associations also were evaluated using polytomous logistic regression. RESULTS: Prolactin levels were associated with nulliparity in premenopausal (P = 0.05) but not in postmenopausal women. Associations in postmenopausal women included an inverse association with increasing body mass index (P = 0.0008) and direct association with use of recent/current hormone therapy (P = 0.0006). In case-only analyses, higher PRL levels were more strongly associated with lobular compared with ductal carcinoma among postmenopausal women (P = 0.02). Levels were not different by tumour size, grade, node involvement or oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status. CONCLUSIONS: Our analysis demonstrates that PRL levels are higher among premenopausal nulliparous as compared with parous women. Among postmenopausal women, levels were higher among hormone users and lower among obese women. These results may have value in understanding the mechanisms underlying several breast cancer risk factor associations. British Journal of Cancer (2010) 103, 1097-1102. doi:10.1038/sj.bjc.6605844 www.bjcancer.com Published online 24 August 2010 (C) 2010 Cancer Research UK C1 [Faupel-Badger, J. M.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, Bethesda, MD 20892 USA. [Sherman, M. E.; Garcia-Closas, M.; Falk, R. T.; Andaya, A.; Brinton, L. A.; Figueroa, J. D.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gaudet, M. M.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY 10461 USA. [Pfeiffer, R. M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Yang, X. R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, J.] Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, J.] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Peplonska, B.] Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. [Vonderhaar, B. K.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Faupel-Badger, JM (reprint author), NCI, Canc Prevent Fellowship Program, Ctr Canc Training, 6120 Execut Blvd EPS,Suite 150E,MSC 7105, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Pfeiffer, Ruth /F-4748-2011; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU National Cancer Institute, Department of Health and Human Services, USA; Division of Cancer Epidemiology and Genetics and Center for Cancer Research of the National Cancer Institute; Center for Cancer Training, NCI FX We thank Drs Neonila Szeszenia-Dabrowska of the Nofer Institute of Occupational Medicine (Lodz, Poland), Witold Zatonski of the Department of Cancer Epidemiology and Prevention, the M Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland), and Pei Chao and Michael Stagner from Information Management Services (Sliver Spring, MD, USA), for their valuable contributions to the study. We also thank the participants, physicians, pathologists, nurses, and interviewers from participating centres in Poland for their efforts during field-work. The study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. This research was supported by the Intramural Research Programs of the Division of Cancer Epidemiology and Genetics and Center for Cancer Research of the National Cancer Institute. Dr Faupel-Badger's research also was supported by the Cancer Prevention Fellowship Program, Center for Cancer Training, NCI. NR 42 TC 22 Z9 24 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 28 PY 2010 VL 103 IS 7 BP 1097 EP 1102 DI 10.1038/sj.bjc.6605844 PG 6 WC Oncology SC Oncology GA 655DB UT WOS:000282222000024 PM 20736944 ER PT J AU de Vathaire, F Drozdovitch, V Brindel, P Rachedi, F Boissin, JL Sebbag, J Shan, L Bost-Bezeaud, F Petitdidier, P Paoaafaite, J Teuri, J Iltis, J Bouville, A Cardis, E Hill, C Doyon, F AF de Vathaire, F. Drozdovitch, V. Brindel, P. Rachedi, F. Boissin, J-L Sebbag, J. Shan, L. Bost-Bezeaud, F. Petitdidier, P. Paoaafaite, J. Teuri, J. Iltis, J. Bouville, A. Cardis, E. Hill, C. Doyon, F. TI Thyroid cancer following nuclear tests in French Polynesia SO BRITISH JOURNAL OF CANCER LA English DT Article DE differentiated thyroid carcinoma; nuclear test; French Polynesia; radiation-induced cancer ID CHERNOBYL ACCIDENT; MARSHALL-ISLANDS; CHILDHOOD EXPOSURE; TEST-SITE; RADIATION; RISK; I-131; UKRAINE; RECONSTRUCTION; DOSIMETRY AB BACKGROUND: Between 1966 and 1974, France conducted 41 atmospheric nuclear tests in Polynesia, but their potential health effects have not previously been investigated. METHODS: In a case-control study, we compared the radiation exposure of almost all the French Polynesians diagnosed with differentiated thyroid carcinoma between 1981 and 2003 (n = 229) to the exposure of 373 French Polynesian control individuals without cancer from the general population. Radiation exposures were estimated using measurements after the nuclear tests, age at time of each test, residential and dietary information. RESULTS: The average thyroid dose before 15 years of age was about 1.8 mGy, and 5% of the cases and 3% of the controls received a dose above 10 mGy. Despite this low level of dose, and after adjusting for ethnic group, level of education, body surface area, family history of thyroid cancer and number of pregnancies for women, we observed an increasing risk (P = 0.04) of thyroid cancer with increasing thyroid dose received before age of 15 years, which remained after excluding non-aggressive differentiated thyroid micro-carcinomas. This increase of risk per unit of thyroid radiation dose was higher (P = 0.03) in women who later experienced four or more pregnancies than among other women. CONCLUSION: The risk estimate is low, but is based on limited exposure data. The release of information on exposure, currently classified, would greatly improve the reliability of the risk estimation. British Journal of Cancer (2010) 103, 1115-1121. doi: 10.1038/sj.bjc.6605862 www.bjcancer.com Published online 31 August 2010 (c) 2010 Cancer Research UK C1 [de Vathaire, F.; Brindel, P.; Doyon, F.] INSERM, U1018, Inst Gustave Roussy, Radiat Epidemiol Grp, F-94800 Villejuif, France. [de Vathaire, F.; Brindel, P.; Doyon, F.] Univ Paris 11, F-94800 Villejuif, France. [Drozdovitch, V.; Cardis, E.] Int Agcy Res Canc, F-69008 Lyon, France. [Drozdovitch, V.; Bouville, A.] DHHS NIH NCI Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rachedi, F.; Bost-Bezeaud, F.] Ctr Hosp Terr Mamao, Tahiti, Fr Polynesia. [Petitdidier, P.] Lab Boz, Tahiti, Fr Polynesia. [Paoaafaite, J.; Teuri, J.; Iltis, J.] Inst Rech Dev, Tahiti, Fr Polynesia. RP de Vathaire, F (reprint author), INSERM, U1018, Inst Gustave Roussy, Radiat Epidemiol Grp, 39 Rue Camille Desmoulins, F-94800 Villejuif, France. EM florent.devathaire@igr.fr RI de Vathaire, Florent/L-2983-2016; Cardis, Elisabeth/C-3904-2017 FU Association pour la Recherche contre le Cancer; Ligue Nationale Contre le Cancer; Direction Generale de la Sante; Comite de radioprotection de Electricite de France, Agence Francaise de Securite Sanitaire et Environnementale et du Travail; CHILD-THYR FX This study was supported by the Association pour la Recherche contre le Cancer, the Ligue Nationale Contre le Cancer, the Direction Generale de la Sante, the Comite de radioprotection de Electricite de France, Agence Francaise de Securite Sanitaire et Environnementale et du Travail and CHILD-THYR EEC programme. We thank Dr Ph Morales, Dr P Giraud, Dr P Didiergeorge, Dr M Brisard, Dr G Soubiran, Dr B Caillou, JM Bidard, A Merceron, ML Vanizette, P Dupire, M Berges, Dr J Ienfa, Dr G de Clermont, N Cerf, B Oddo, M Bambridge, C Baron, A Mouchard- Rachet, Dr O Simonet, Dr D Lamarque, Dr Vabret, Dr J Delacre, MP Darquier and J Leninger. NR 36 TC 17 Z9 17 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 28 PY 2010 VL 103 IS 7 BP 1115 EP 1121 DI 10.1038/sj.bjc.6605862 PG 7 WC Oncology SC Oncology GA 655DB UT WOS:000282222000027 PM 20808313 ER PT J AU Minami, SS Sidahmed, E Aid, S Shimoji, M Niikura, T Mocchetti, I Rebeck, GW Prendergast, JS Dealwis, C Wetzel, R Bosetti, F Matsuoka, Y Hoe, HS Turner, RS AF Minami, S. Sakura Sidahmed, Elkhansa Aid, Saba Shimoji, Mika Niikura, Takako Mocchetti, Italo Rebeck, G. William Prendergast, Jay S. Dealwis, Chris Wetzel, Ronald Bosetti, Francesca Matsuoka, Yasuji Hoe, Hyang-Sook Turner, R. Scott TI Therapeutic versus neuroinflammatory effects of passive immunization is dependent on A beta/amyloid burden in a transgenic mouse model of Alzheimer's disease SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID AMYLOID-BETA-PROTEIN; PATHOLOGY; MICE; CLEARANCE; PLAQUES; INHIBITION; IMPAIRMENT; ANTIBODIES; DEPOSITION; TERMINUS AB Background: Passive immunization with antibodies directed to A beta decreases brain A beta/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD). This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema). Methods: We intravenously administered the monoclonal A beta protofibril antibody PFA1 to aged (22 month) male and female 3 x tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum A beta and CNS cytokine levels. We also examined 17 month old 3 x tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization. Results: The 22 month old male mice immunized with PFA1 had decreased brain A beta, increased serum A beta, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain A beta, decreased serum A beta, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 x tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain A beta and increased serum A beta accompanied by a decrease in CNS MCP-1. Conclusions: These data suggest that passive immunization with PFA1 in 3 x tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain A beta. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines. C1 [Sidahmed, Elkhansa; Niikura, Takako; Matsuoka, Yasuji; Hoe, Hyang-Sook; Turner, R. Scott] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20057 USA. [Minami, S. Sakura; Shimoji, Mika; Mocchetti, Italo; Rebeck, G. William; Hoe, Hyang-Sook] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. [Aid, Saba; Bosetti, Francesca] NIH, Bethesda, MD 20892 USA. [Prendergast, Jay S.; Dealwis, Chris] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA. [Wetzel, Ronald] Dept Biol Struct, Pittsburgh, PA 15260 USA. [Wetzel, Ronald] Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15260 USA. RP Turner, RS (reprint author), Georgetown Univ, Med Ctr, Dept Neurol, Bldg D,Suite 177,4000 Reservoir Rd NW, Washington, DC 20057 USA. EM rst36@georgetown.edu RI Wetzel, Ronald/G-7453-2011; Turner, Raymond/G-2263-2011 OI Turner, Raymond/0000-0001-7534-2935 FU NIH [NS059178, R01 AG026478]; NIH, National Institute on Aging FX We thank Dr. Paul Patterson, Jan Ko, and Susan Ou at Caltech for production of the PFA1. This work was supported by NIH grants NS059178 (SSM), R01 AG026478 (RST), and the Intramural Research Program of the NIH, National Institute on Aging (FB). NR 32 TC 14 Z9 14 U1 0 U2 1 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 SEP 28 PY 2010 VL 7 AR 57 DI 10.1186/1742-2094-7-57 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 668SM UT WOS:000283290100001 PM 20920207 ER PT J AU Negrete, A Ng, WI Shiloach, J AF Negrete, Alejandro Ng, Weng-Ian Shiloach, Joseph TI Glucose uptake regulation in E. coli by the small RNA SgrS: comparative analysis of E. coli K-12 (JM109 and MG1655) and E. coli B (BL21) SO MICROBIAL CELL FACTORIES LA English DT Article ID ESCHERICHIA-COLI; MESSENGER-RNA; POSTTRANSCRIPTIONAL REGULATION; ACETATE ACCUMULATION; TRANSPORTER GENE; METABOLISM; DESTABILIZATION; MICROARRAYS; EXPRESSION; MECHANISM AB Background: The effect of high glucose concentration on the transcription levels of the small RNA SgrS and the messenger RNA ptsG, (encoding the glucose transporter IICB(Glc)), was studied in both E. coli K-12 (MG1655 and JM109) and E. coli B (BL21). It is known that the transcription level of sgrS increases when E. coli K-12 (MG1655 and JM109) is exposed to the non-metabolized glucose alpha methyl glucoside (alpha MG) or when the bacteria with a defective glycolysis pathway is grown in presence of glucose. The increased level of sRNA SgrS reduces the level of the ptsG mRNA and consequently lowers the level of the glucose transporter IICBGlc. The suggested trigger for this action is the accumulation of the corresponding phospho-sugars. Results: In the course of the described work, it was found that E. coli B (BL21) and E. coli K-12 (JM109 and MG1655) responded similarly to aMG: both strains increased SgrS transcription and reduced ptsG transcription. However, the two strains reacted differently to high glucose concentration (40 g/L). E. coli B (BL21) reacted by increasing sgrS transcription and reducing ptsG transcription while E. coli K-12 (JM109 and MG1655) did not respond to the high glucose concentration, and, therefore, transcription of sgrS was not detected and ptsG mRNA level was not affected. Conclusions: The results suggest that E. coli B (BL21) tolerates high glucose concentration not only by its more efficient central carbon metabolism, but also by controlling the glucose transport into the cells regulated by the sRNA SgrS, which may suggest a way to control glucose consumption and increase its efficient utilization. C1 [Negrete, Alejandro; Ng, Weng-Ian; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD USA. [Ng, Weng-Ian] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD USA. EM yossi@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding was provided by the Intramural program at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The authors would like to thank Prof. Nam Sun Wang for the academic support of Ms Weng, Dr. Young-Jin Son for his help in the metabolites analysis and Dr. N. Majdalani for his help in setting up the sRNA detecting method. NR 23 TC 11 Z9 11 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2859 J9 MICROB CELL FACT JI Microb. Cell. Fact. PD SEP 28 PY 2010 VL 9 AR 75 DI 10.1186/1475-2859-9-75 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 664NY UT WOS:000282970000001 PM 20920177 ER PT J AU Raznahan, A Lee, Y Stidd, R Long, R Greenstein, D Clasen, L Addington, A Gogtay, N Rapoport, JL Giedd, JN AF Raznahan, Armin Lee, Yohan Stidd, Reva Long, Robert Greenstein, Dede Clasen, Liv Addington, Anjene Gogtay, Nitin Rapoport, Judith L. Giedd, Jay N. TI Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE sex differences; brain; cortex; development; androgen receptor ID POLYCYSTIC-OVARY-SYNDROME; CEREBRAL-CORTEX; RECEPTOR GENE; HUMAN BRAIN; TESTOSTERONE; CHILDHOOD; BEHAVIOR; LENGTH; TRACT; MRI AB Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating "movies" of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with "masculinization" of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors. C1 [Raznahan, Armin; Lee, Yohan; Stidd, Reva; Long, Robert; Greenstein, Dede; Clasen, Liv; Addington, Anjene; Gogtay, Nitin; Rapoport, Judith L.; Giedd, Jay N.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Raznahan, Armin] Kings Coll London, Dept Child & Adolescent Psychiat, Inst Psychiat, London SE5 8A8, England. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/A-3080-2008; Gogtay, Nitin/A-3035-2008; Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU National Institutes of Health and National Institute of Health Intramural Research; United Kingdom Medical Research CouncilFellowship [G0701370] FX We thank the participants who took part in this study. This study was funded through the National Institutes of Health and National Institute of Health Intramural Research and by United Kingdom Medical Research Council Clinical Research Training Fellowship G0701370 (to A.R.). NR 53 TC 109 Z9 109 U1 1 U2 12 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 SEP 28 PY 2010 VL 107 IS 39 BP 16988 EP 16993 DI 10.1073/pnas.1006025107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 655AA UT WOS:000282211700047 PM 20841422 ER PT J AU Lee, SE Simons, SB Heldt, SA Zhao, ML Schroeder, JP Vellano, CP Cowan, DP Ramineni, S Yates, CK Feng, Y Smith, Y Sweatt, D Weinshenker, D Ressler, KJ Dudek, SM Hepler, JR AF Lee, Sarah Emerson Simons, Stephen B. Heldt, Scott A. Zhao, Meilan Schroeder, Jason P. Vellano, Christopher P. Cowan, D. Patrick Ramineni, Suneela Yates, Cindee K. Feng, Yue Smith, Yoland Sweatt, David Weinshenker, David Ressler, Kerry J. Dudek, Serena M. Hepler, John R. TI RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE long-term potentiation; hippocampus; G protein signaling; RGS proteins; ERK ID LONG-TERM POTENTIATION; SIGNAL-REGULATED KINASE; K+ CHANNELS; MOLECULAR-MECHANISMS; PYRAMIDAL NEURONS; RAT HIPPOCAMPUS; IMPAIRS MEMORY; PROTEIN; RECEPTORS; CORTEX AB Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2-7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG-CA3-CA1 circuit. C1 [Lee, Sarah Emerson; Vellano, Christopher P.; Cowan, D. Patrick; Ramineni, Suneela; Yates, Cindee K.; Feng, Yue; Hepler, John R.] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. [Heldt, Scott A.; Ressler, Kerry J.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Schroeder, Jason P.; Weinshenker, David] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Heldt, Scott A.; Ressler, Kerry J.] Emory Univ, Sch Med, Ctr Behav Neurosci, Atlanta, GA 30322 USA. [Smith, Yoland; Ressler, Kerry J.] Emory Univ, Sch Med, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Smith, Yoland] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Simons, Stephen B.; Zhao, Meilan; Dudek, Serena M.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Sweatt, David] Univ Alabama, Sch Med, Dept Neurobiol, Birmingham, AL 35294 USA. RP Hepler, JR (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. EM jhepler@pharm.emory.edu OI Ressler, Kerry/0000-0002-5158-1103; Feng, Yue/0000-0002-7905-2182; Dudek, Serena M./0000-0003-4094-8368; Sweatt, J. David/0000-0003-3567-485X FU National Institutes of Health [R01 NS037112, R01 NS049195, R01 DA017963, R01 DA019624, P30 NS57098]; Burroughs Wellcome Fund; Yerkes Primate Center [RR00165]; Emory National Institute of Neurological Disorders and Stroke Neuroscience [P30 NS055077, 5 T32 GM008602]; National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES100221] FX We thank Susan Campbell and Jing Wang for technical assistance with electrophysiological studies of CA1 hippocampus and Susan Jenkins and Jean-Francois Pare for technical assistance with the electron microscopy immunocytochemistry experiments. This work was supported by National Institutes of Health Grants R01 NS037112 and R01 NS049195 (to J.R.H.), Grant R01 DA017963 (to D.W.), Grant R01 DA019624 and the Burroughs Wellcome Fund (to K.J.R.), the Yerkes Primate Center Base Grant RR00165 (to Y.S.), Emory National Institute of Neurological Disorders and Stroke Neuroscience Core Facilities Grant P30 NS055077, Training Grant 5 T32 GM008602 to the Emory Molecular and Systems Pharmacology graduate program, and the National Institutes of Health Neuroscience Blueprint Core Grant P30 NS57098 (to J.D.S.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES100221, to S.M.D.). Monoclonal antibodies were generated in collaboration with the University of California-Davis/National Institutes of Health Neuro Mab Facility, and RGS14-KO mice were generated and made available by the NIH Mutant Mouse Regional Resource Center/Lexicon Genetics. NR 48 TC 47 Z9 49 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 28 PY 2010 VL 107 IS 39 BP 16994 EP 16998 DI 10.1073/pnas.1005362107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 655AA UT WOS:000282211700048 PM 20837545 ER PT J AU Xu, XH Meckel, T Brzostowski, JA Yan, JS Meier-Schellersheim, M Jin, TA AF Xu, Xuehua Meckel, Tobias Brzostowski, Joseph A. Yan, Jianshe Meier-Schellersheim, Martin Jin, Tian TI Coupling Mechanism of a GPCR and a Heterotrimeric G Protein During Chemoattractant Gradient Sensing in Dictyostelium SO SCIENCE SIGNALING LA English DT Article ID CONTROLLING MULTICELLULAR DEVELOPMENT; LIVING CELLS; SIGNALING EVENTS; CHEMOTAXIS; RECEPTOR; ACTIVATION; DYNAMICS; MICROSCOPY; DISCOIDEUM; MODEL AB The coupling of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) with G proteins is fundamental for GPCR signaling; however, the mechanism of coupling is still debated. Moreover, how the proposed mechanisms affect the dynamics of downstream signaling remains unclear. Here, through experiments involving fluorescence recovery after photobleaching and single-molecule imaging, we directly measured the mobilities of cyclic adenosine monophosphate (cAMP) receptor 1 (cAR1), a chemoattractant receptor, and a G protein beta gamma subunit in live cells. We found that cAR1 diffused more slowly in the plasma membrane than did G beta gamma. Upon binding of ligand to the receptor, the mobility of cAR1 was unchanged, whereas the speed of a fraction of the faster-moving G beta gamma subunits decreased. Our measurements showed that cAR1 was relatively immobile and G beta gamma diffused freely, suggesting that chemoattractant-bound cAR1 transiently interacted with G proteins. Using models of possible coupling mechanisms, we computed the temporal kinetics of G protein activation. Our fluorescence resonance energy transfer imaging data showed that fully activated cAR1 induced the sustained dissociation of G protein alpha and beta gamma subunits, which indicated that ligand-bound cAR1 activated G proteins continuously. Finally, simulations indicated that a high-affinity coupling of ligand-bound receptors and G proteins was essential for cAR1 to translate extracellular gradient signals into directional cellular responses. We suggest that chemoattractant receptors use a ligand-induced coupling rather than a precoupled mechanism to control the activation of G proteins during chemotaxis. C1 [Xu, Xuehua; Meckel, Tobias; Yan, Jianshe; Jin, Tian] NIH, Chemotaxis Signal Sect, Rockville, MD 20852 USA. [Brzostowski, Joseph A.] NIH, Lab Immunogenet Imaging Facil, Immunogenet Lab, Rockville, MD 20852 USA. [Meier-Schellersheim, Martin] NIAID, Program Syst Immunol & Infect Dis Modeling, NIH, Rockville, MD 20852 USA. RP Jin, TA (reprint author), NIH, Chemotaxis Signal Sect, Rockville, MD 20852 USA. EM tjin@niaid.nih.gov RI Meckel, Tobias/F-4372-2010 OI Meckel, Tobias/0000-0003-0759-2072 FU National Institute of Allergy and Infectious Diseases; NIH; American Heart Association [AHA0930127N] FX Funding: This work was supported by the intramural fund of National Institute of Allergy and Infectious Diseases and the NIH Intramural AIDS Targeted Antiviral Program. X. X. is supported by the American Heart Association (AHA0930127N). NR 44 TC 17 Z9 17 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD SEP 28 PY 2010 VL 3 IS 141 AR ra71 DI 10.1126/scisignal.2000980 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 655TQ UT WOS:000282272800003 PM 20876874 ER PT J AU Pontari, MA Krieger, JN Litwin, MS White, PC Anderson, RU McNaughton-Collins, M Nickel, JC Shoskes, DA Alexander, RB O'Leary, M Zeitlin, S Chuai, S Landis, JR Cen, LY Propert, KJ Kusek, JW Nyberg, LM Schaeffer, AJ AF Pontari, Michel A. Krieger, John N. Litwin, Mark S. White, Paige C. Anderson, Rodney U. McNaughton-Collins, Mary Nickel, J. Curtis Shoskes, Daniel A. Alexander, Richard B. O'Leary, Michael Zeitlin, Scott Chuai, Shannon Landis, J. Richard Cen, Liyi Propert, Kathleen J. Kusek, John W. Nyberg, Leroy M., Jr. Schaeffer, Anthony J. CA Chronic Prostatitis Collaborative TI Pregabalin for the Treatment of Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome A Randomized Controlled Trial SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; INTERSTITIAL CYSTITIS; SYMPTOM INDEX; RESPONSIVENESS; DESIGN; SCALES AB Background: Evidence suggests that the urogenital pain of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may be neuropathic. Methods: This randomized, double-blind, placebo-controlled trial was conducted across 10 tertiary care centers in North America to determine whether pregabalin, which has been proved effective in other chronic pain syndromes, is effective in reducing CP/CPPS symptoms. In 2006-2007, 324 men with pelvic pain for at least 3 of the previous 6 months were enrolled in this study. Men were randomly assigned to receive pregabalin or placebo in a 2:1 ratio and were treated for 6 weeks. Pregabalin dosage was increased from 150 to 600 mg/d during the first 4 weeks. The primary outcome was a 6-point decrease in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score. Multiple secondary outcomes were assessed. Results: Of 218 men assigned to receive pregabalin, 103 (47.2%) reported at least a 6-point decrease in the NIH-CPSI total score at 6 weeks compared with 35.8% (38 of 106 men) assigned to receive placebo (P = .07, exact Mantel-Haenszel test, adjusting for clinical sites). Compared with the placebo group, men assigned to receive pregabalin experienced reductions in the NIH-CPSI total score and subscores (P < .05), a higher Global Response Assessment response rate (31.2% and 18.9%; P = .02), and improvement in total McGill Pain Questionnaire score (P = .01). Results for the other outcomes did not differ between groups. Conclusion: Pregabalin therapy for 6 weeks was not superior to placebo use in the rate of a 6-point decrease (improvement) in the NIH-CPSI total score in men with CP/CPPS. C1 [Pontari, Michel A.] Temple Univ, Sch Med, Dept Urol, Philadelphia, PA 19140 USA. [Krieger, John N.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Litwin, Mark S.; Zeitlin, Scott] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Litwin, Mark S.; Zeitlin, Scott] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Litwin, Mark S.; Zeitlin, Scott] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA 90095 USA. [Litwin, Mark S.; Zeitlin, Scott] Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA 90095 USA. [White, Paige C.] Univ Mississippi, Dept Surg, Gulfport, MS USA. [White, Paige C.] Coast Urol Ctr, Gulfport, MS USA. [Anderson, Rodney U.] Stanford Univ, Med Ctr, Dept Urol, Stanford, CA 94305 USA. [McNaughton-Collins, Mary] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Nickel, J. Curtis] Queens Univ, Dept Urol, Kingston, ON K7L 3N6, Canada. [Shoskes, Daniel A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Alexander, Richard B.] Univ Maryland, Dept Urol, Baltimore, MD 21201 USA. [O'Leary, Michael] Brigham & Womens Hosp, Div Urol, Boston, MA 02115 USA. [O'Leary, Michael] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Chuai, Shannon; Landis, J. Richard; Cen, Liyi; Propert, Kathleen J.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. [Schaeffer, Anthony J.] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. RP Pontari, MA (reprint author), Temple Univ, Sch Med, Dept Urol, 3401 N Broad St,Ste 330, Philadelphia, PA 19140 USA. EM Pontarm@tuhs.temple.edu FU Sanofi-Aventis; Pfizer; GlaxoSmithKline; Merck; Allergan; Watson; American Medical Systems; Boehringer Ingelheim; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [DK65209, U01 DK65268, U01 DK65297, U01 DK65187, U01 DK65277, U01 DK65189, U01 DK65174, U01 DK65266, U01 DK65257, U01 DK65186, U01 DK65287]; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Minority Health and Health Disparities FX Dr Pontari received consulting fees from Sanofi-Aventis, Pfizer, and GlaxoSmithKline and reported clinical trial participation with Pfizer; Dr Krieger received consulting and advising fees from Pfizer; Dr Litwin received consulting fees from Sanofi-Aventis; Dr Anderson received consulting fees from Bioness Inc, investigator fees from Boston Scientific and Allergan, and speaker fees from GlaxoSmithKline and Astella; Dr Nickel reports receiving consulting fees from Merck, GlaxoSmithKline, Pfizer, Ortho Women's Health, Fan Labs, Watson, Medtronic, NeurAxon, and Genyous Biomed and research support from Merck, GlaxoSmithKline, Allergan, Watson, Pfizer, and American Medical Systems; Dr Shoskes received consulting fees from Roche, is on the advisory board of Fan Labs, and has a financial interest in Triurol; Dr Alexander received lecture fees from Boehringer Ingelheim; Dr O'Leary received consulting fees from Sanofi-Aventis; Dr Landis received consulting fees from Sanofi-Aventis; Dr Kusek holds stock in Decode Genetics; and Dr Schaeffer was a consultant for Alita Pharmaceuticals, American Medical Systems, NovaBay Pharmaceuticals, Regeneron Pharm Inc, IMS Health, Exoxemis Inc, CombinatoRx Inc, Monitor Company Group LP, and Advanstar Communications and received meeting honorarium from the Scientific Consulting Group.; No author received compensation for the performance of this study except as salary support from a grant from the National Institutes of Health. This study was supported by cooperative agreements U01 DK65209, U01 DK65268, U01 DK65297, U01 DK65187, U01 DK65277, U01 DK65189, U01 DK65174, U01 DK65266, U01 DK65257, U01 DK65186, and U01 DK65287 from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Minority Health and Health Disparities. Pregabalin and matching placebo capsules were provided by Pfizer Inc. Previous Presentation: This study was presented at the meeting of the American Urological Association; April 26, 2009; Chicago, Illinois. NR 28 TC 31 Z9 32 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 27 PY 2010 VL 170 IS 17 BP 1586 EP 1593 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 655WQ UT WOS:000282286700011 PM 20876412 ER PT J AU El-Bassel, N Jemmott, JB Landis, JR Pequegnat, W Wingood, GM Wyatt, GE Bellamy, SL AF El-Bassel, Nabila Jemmott, John B. Landis, J. Richard Pequegnat, Willo Wingood, Gina M. Wyatt, Gail E. Bellamy, Scarlett L. CA Nimh Multisite HIV STD Prevention TI National Institute of Mental Health Multisite Eban HIV/STD Prevention Intervention for African American HIV Serodiscordant Couples A Cluster Randomized Trial SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RISK-REDUCTION INTERVENTION; CHILD SEXUAL-ABUSE; UNITED-STATES; HETEROSEXUAL COUPLES; ADOLESCENT GIRLS; POSITIVE WOMEN; CONDOM USE; EFFICACY; BEHAVIOR; SEROCONVERSION AB Background: Human immunodeficiency virus (HIV) has disproportionately affected African Americans. Couple-level interventions may be a promising intervention strategy. Methods: To determine if a behavioral intervention can reduce HIV/sexually transmitted disease (STD) risk behaviors among African American HIV serodiscordant couples, a cluster randomized controlled trial (Eban) was conducted in Atlanta, Georgia; Los Angeles, California; New York, New York; and Philadelphia, Pennsylvania; with African American HIV serodiscordant heterosexual couples who were eligible if both partners were at least 18 years old and reported unprotected intercourse in the previous 90 days and awareness of each other's serostatus. One thousand seventy participants were enrolled (mean age, 43 years; 40% of male participants were HIV positive). Couples were randomized to 1 of 2 interventions: couple-focused Eban HIV/STD risk-reduction intervention or attention-matched individual-focused health promotion comparison. The primary outcomes were the proportion of condom-protected intercourse acts and cumulative incidence of STDs (chlamydia, gonorrhea, or trichomonas). Data were collected preintervention and postintervention, and at 6- and 12-month follow-ups. Results: Data were analyzed for 535 randomized couples: 260 in the intervention group and 275 in the comparison group; 81.9% were retained at the 12-month follow-up. Generalized estimating equation analyses revealed that the pro-portion of condom-protected intercourse acts was larger among couples in the intervention group (0.77) than in the comparison group (0.47; risk ratio, 1.24; 95% confidence interval [CI], 1.09 to 1.41; P=.006) when adjusted for the baseline criterion measure. The adjusted percentage of couples using condoms consistently was higher in the intervention group (63%) than in the comparison group (48%; risk ratio, 1.45; 95% CI, 1.24 to 1.70; P<.001). The adjusted mean number of (log)unprotected intercourse acts was lower in the intervention group than in the comparison group (mean difference, -1.52; 95% CI, -2.07 to -0.98; P<.001). The cumulative STD incidence over the 12-month follow-up did not differ between couples in the intervention and comparison groups. The overall HIV seroconversion at the 12-month follow-up was 5 (2 in the intervention group, 3 in the comparison group) of 535 individuals, which translates to 935 per 100 000 population. Conclusion: To our knowledge, this is the first randomized controlled intervention trial to report significant reductions in HIV/STD risk behaviors among African American HIV serodiscordant couples. C1 [Pequegnat, Willo] NIMH, Div Aids, Natl Inst Hlth, Bethesda, MD 20852 USA. [El-Bassel, Nabila] Columbia Univ, Sch Social Work, Social Intervent Grp, New York, NY USA. [Jemmott, John B.] Univ Penn, Annenberg Sch Commun, Philadelphia, PA 19104 USA. [Jemmott, John B.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Landis, J. Richard; Bellamy, Scarlett L.] Univ Penn, Dept Biostat & Engn, Philadelphia, PA 19104 USA. [Wingood, Gina M.] Emory Univ, Dept Behav Sci & Hlth Educ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Wyatt, Gail E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RP Pequegnat, W (reprint author), NIMH, Div Aids, Natl Inst Hlth, 6001 Executive Blvd,Room 6219B, Bethesda, MD 20852 USA. EM wpequegn@mail.nih.gov FU National Institute of Mental Health (NIMH) of the US National Institutes of Health; NIMH [U10 MH064395, 2 U10 MH64394, U10 MH078819, U10 MH064393, 5 U10 MH064404] FX This trial was funded by research grants from the National Institute of Mental Health (NIMH) of the US National Institutes of Health. This trial was supported by NIMH funds to Dr El-Bassel (U10 MH064395), Dr Jemmott (2 U10 MH64394), Dr Landis (U10 MH078819), Dr Wingood (U10 MH064393), and Dr Wyatt (5 U10 MH064404). Dr Pequegnat was the federal principal investigator (the NIMH staff collaborator) and her involvement on the study did not present a financial conflict. NR 41 TC 52 Z9 52 U1 3 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 27 PY 2010 VL 170 IS 17 BP 1594 EP 1601 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 655WQ UT WOS:000282286700012 PM 20625011 ER PT J AU Pastina, I Giovannetti, E Chioni, A Sissung, TM Crea, F Orlandini, C Price, DK Cianci, C Figg, WD Ricci, S Danesi, R AF Pastina, Ilaria Giovannetti, Elisa Chioni, Aldo Sissung, Tristan M. Crea, Francesco Orlandini, Cinzia Price, Douglas K. Cianci, Claudia Figg, William D. Ricci, Sergio Danesi, Romano TI Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients SO BMC CANCER LA English DT Article ID CELL LUNG-CANCER; P4501B1 VARIANTS; DRUG-RESISTANCE; GENE-EXPRESSION; CHEMOTHERAPY; METABOLISM; MITOXANTRONE; PREDNISONE; HAPLOTYPES; ESTRADIOL AB Background: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. Methods: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson chi(2) test, Kaplan-Meier curves and Log-rank test. Results: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. Conclusions: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment. C1 [Giovannetti, Elisa; Crea, Francesco; Danesi, Romano] Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, I-56100 Pisa, Italy. [Pastina, Ilaria; Chioni, Aldo; Orlandini, Cinzia; Cianci, Claudia; Ricci, Sergio] Pisa Univ Hosp, Dept Med Oncol, Pisa, Italy. [Pastina, Ilaria; Chioni, Aldo] Grosseto Civ Hosp, Grosseto, Italy. [Giovannetti, Elisa] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands. [Sissung, Tristan M.; Price, Douglas K.; Figg, William D.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Giovannetti, E (reprint author), Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, Via Roma 55, I-56100 Pisa, Italy. EM elisa.giovannetti@gmail.com RI Crea, Francesco /I-8383-2015; Figg Sr, William/M-2411-2016; OI Crea, Francesco/0000-0002-4903-2973; Giovannetti, Elisa/0000-0002-7565-7504 NR 34 TC 19 Z9 20 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 27 PY 2010 VL 10 AR 511 DI 10.1186/1471-2407-10-511 PG 9 WC Oncology SC Oncology GA 665WN UT WOS:000283067300001 PM 20875115 ER PT J AU Trinchieri, G AF Trinchieri, Giorgio TI Type I interferon: friend or foe? SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Review ID TOLL-LIKE RECEPTORS; LISTERIA-MONOCYTOGENES INFECTION; PLASMACYTOID DENDRITIC CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; VIRUS-TRANSFORMED CELLS; DOUBLE-STRANDED-RNA; MYCOBACTERIUM-TUBERCULOSIS; IFN-ALPHA; RIG-I; CHLAMYDIA-TRACHOMATIS AB Although the role of type I interferon (IFN) in the protection against viral infections has been known and studied for decades, its role in other immunologically relevant scenarios, including bacterial infections, shock, autoimmunity, and cancer, is less well defined and potentially much more complicated. C1 NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM trinchig@mail.nih.gov NR 112 TC 342 Z9 348 U1 2 U2 32 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 27 PY 2010 VL 207 IS 10 BP 2053 EP 2063 DI 10.1084/jem.20101664 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 660NH UT WOS:000282649800003 PM 20837696 ER PT J AU Kofinger, J Dellago, C AF Koefinger, Juergen Dellago, Christoph TI Single-file water as a one-dimensional Ising model SO NEW JOURNAL OF PHYSICS LA English DT Article ID CARBON NANOTUBE MEMBRANES; ICE-NANOTUBES; ORDERED WATER; CONDUCTION; PERMEATION; TRANSPORT; CHANNEL; PORES AB We show that single-file water in nanopores can be viewed as a one-dimensional (1D) Ising model, and we investigate, on the basis of this, the static dielectric response of a chain of hydrogen-bonded water molecules to an external field. To achieve this, we use a recently developed dipole lattice model that accurately captures the free energetics of nanopore water. In this model, the total energy of the system can be expressed as the sum of the effective interactions of chain ends and orientational defects. Neglecting these interactions, we essentially obtain the 1D Ising model, which allows us to derive analytical expressions for the free energy as a function of the total dipole moment and for the dielectric susceptibility. Our expressions, which agree very well with simulation results, provide the basis for the interpretation of future dielectric spectroscopy experiments on water-filled nanopore membranes. C1 [Koefinger, Juergen] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Dellago, Christoph] Univ Vienna, Fac Phys, A-1090 Vienna, Austria. RP Kofinger, J (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM koefingerj@mail.nih.gov RI Dellago, Christoph/E-1625-2011 FU Austrian Science Fund (FWF) [P20942-N16, W004]; University of Vienna; NIH, NIDDK FX We thank Gerhard Hummer and Georg Menzl for useful discussions. We acknowledge support from the Austrian Science Fund (FWF) under grants P20942-N16 and W004 and from the University of Vienna through the Focus Research Area Materials Science. JK was supported by the Intramural Research Program of the NIH, NIDDK. The simulations presented in this paper were carried out on the Vienna Scientific Cluster (VSC). NR 35 TC 10 Z9 10 U1 0 U2 9 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1367-2630 J9 NEW J PHYS JI New J. Phys. PD SEP 27 PY 2010 VL 12 AR 093044 DI 10.1088/1367-2630/12/9/093044 PG 17 WC Physics, Multidisciplinary SC Physics GA 687FV UT WOS:000284765300001 ER PT J AU Njajou, OT Blackburn, EH Pawlikowska, L Mangino, M Damcott, CM Kwok, PY Spector, TD Newman, AB Harris, TB Cummings, SR Cawthon, RM Shuldiner, AR Valdes, AM Hsueh, WC AF Njajou, Omer T. Blackburn, Elizabeth H. Pawlikowska, Ludmila Mangino, Massimo Damcott, Coleen M. Kwok, Pui-Yan Spector, Timothy D. Newman, Anne B. Harris, Tamara B. Cummings, Steven R. Cawthon, Richard M. Shuldiner, Alan R. Valdes, Ana M. Hsueh, Wen-Chi TI A Common Variant in the Telomerase RNA Component Is Associated with Short Telomere Length SO PLOS ONE LA English DT Article ID DYSKERATOSIS-CONGENITA; GENE TERC; DISEASE; CELLS; MUTATIONS; PEDIGREES; BIOLOGY; HTERC AB Background: Telomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS). Methodology: Five variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects. Results: The adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69 +/- 0.05 kbp vs. 4.86 +/- 0.04 kbp, measured by quantitative PCR, p = 0.005). This association was replicated in another white sample from the TwinsUK Study (6.90 +/- 0.03 kbp in 301 carriers compared to 7.06 +/- 0.03 kbp in 395 non-carriers, measured by Southern blots, p = 0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (beta = -0.19 +/- 0.04 kbp, p = 0.001). Conclusion: Our study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis. C1 [Njajou, Omer T.; Hsueh, Wen-Chi] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Pawlikowska, Ludmila] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Blackburn, Elizabeth H.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Mangino, Massimo; Spector, Timothy D.; Valdes, Ana M.] Kings Coll London, St Thomas Hosp, Twin Res & Genet Epidemiol Unit, London WC2R 2LS, England. [Damcott, Coleen M.; Shuldiner, Alan R.] Univ Maryland, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Cawthon, Richard M.] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. RP Njajou, OT (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM wen-chi.hsueh@ucsf.edu RI Kwok, Pui-Yan/F-7725-2014; Newman, Anne/C-6408-2013; mangino, massimo/F-5134-2011 OI Kwok, Pui-Yan/0000-0002-5087-3059; Newman, Anne/0000-0002-0106-1150; mangino, massimo/0000-0002-2167-7470 FU National Institutes of Health (NIH) [N01 AG-6-2101, N01 AG-6-2103, N01 AG-6-2106, K01 AG022782, R01 AG023692, U19 AG023122]; NIH, National Institute on Aging; Wellcome Trust; NIHR (TDS), NIHR Biomedical Research Centre; National Cancer Institute [R25 CA112355] FX This study was supported in part by the National Institutes of Health (NIH) contracts (N01 AG-6-2101, N01 AG-6-2103 and N01 AG-6-2106) and grants (K01 AG022782, R01 AG023692 and U19 AG023122). This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by the Wellcome Trust; NIHR (TDS), NIHR Biomedical Research Centre (grant to Guys' and St. Thomas' Hospitals and King's College London). Dr. Omer T. Njajou is supported by the Training in Molecular and Genetic Epidemiology of Cancer grant from the National Cancer Institute (R25 CA112355). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 21 Z9 23 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 SEP 27 PY 2010 VL 5 IS 9 AR e13048 DI 10.1371/journal.pone.0013048 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 654KL UT WOS:000282167100030 PM 20885959 ER PT J AU von Marschall, Z Fisher, LW AF von Marschall, Zofia Fisher, Larry W. TI Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Wnt3a; sFRP2; Wnt signaling; LRP6/5; beta-Catenin ID BETA-CATENIN; RECEPTOR; INHIBITION; EXPRESSION; PATHWAY; DISEASE; CELLS; ANTAGONISTS; MECHANISMS; MESODERM AB Secreted Frizzled-related proteins (sFRP) are involved in embryonic development as well as pathological conditions including bone and myocardial disorders and cancer Because of their sequence homology with the Writ-binding domain of Frizzled, they have generally been considered antagonists of canonical Wnt signaling However, additional activities of various sFRPs including both synergism and mimicry of Wilt signaling as well as functions other than modulation of Writ signaling have been reported Using human embryonic kidney cells (HEK293A), we found that sFRP2 enhanced Wnt3a-dependent phosphorylation of LRP6 as well as both cytosolic beta-catenin levels and its nuclear translocation. While addition of recombinant sFRP2 had no activity by itself, Top/Fop luciferase reporter assays showed a dose-dependent increase of Wnt3a-mediated transcriptional activity sFRP2 enhancement of Wnt3a signaling was abolished by treatment with the Writ antagonist, Dickkopf-1 (DKK1) Wnt-signaling pathway qPCR arrays showed that sFRP2 enhanced the Wnt3a-mediated transcriptional up-regulation of several genes regulated by Wnt3a including its antagonists, DKK1, and Naked cuticle-1 homolog (NKD1). These results support sFRP2's role as an enhancer of Wnt/beta-catenin signaling, a result with biological impact for both normal development and diverse pathologies such as tumorigenesis. Published by Elsevier Inc. C1 [von Marschall, Zofia; Fisher, Larry W.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD USA. RP Fisher, LW (reprint author), Room 228,Bldg 30,9000 Rockville Pike, Bethesda, MD 20892 USA. FU Division of Intramural Research, NIDCR; NIH; DHHS FX This work was supported by the Division of Intramural Research, NIDCR, of the Intramural Research Program, NIH, DHHS. NR 34 TC 34 Z9 34 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 24 PY 2010 VL 400 IS 3 BP 299 EP 304 DI 10.1016/j.bbrc.2010.08.043 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 660CH UT WOS:000282616200002 PM 20723538 ER PT J AU Raifman, O Kolusheva, S El Kazzouli, S Sigano, DM Kedei, N Lewin, NE Lopez-Nicolas, R Ortiz-Espin, A Gomez-Fernandez, JC Blumberg, PM Marquez, VE Corbalan-Garcia, S Jelinek, R AF Raifman, Or Kolusheva, Sofiya El Kazzouli, Said Sigano, Dina M. Kedei, Noemi Lewin, Nancy E. Lopez-Nicolas, Ruben Ortiz-Espin, Ana Gomez-Fernandez, Juan C. Blumberg, Peter M. Marquez, Victor E. Corbalan-Garcia, Senena Jelinek, Raz TI Membrane-Surface Anchoring of Charged Diacylglycerol-Lactones Correlates with Biological Activities SO CHEMBIOCHEM LA English DT Article DE diacylglycerol (DAG)-lactones; membrane anchoring; membranes; protein kinases; vesicles ID PROTEIN-KINASE-C; DAG-LACTONES; EPSILON; DOMAINS; CELLS; DELTA; ASSAY AB Synthetic diacylglycerol-lactones (DAG-lactones) are effective modulators of critical cellular signaling pathways, downstream of the lipophilic second messenger diacylglycerol, that activate a host of protein kinase C (PKC) isozymes and other nonkinase proteins that share similar C1 membrane-targeting domains with PKC. A fundamental determinant of the biological activity of these amphiphilic molecules is the nature of their interactions with cellular membranes. This study examines the biological properties of charged DAG-lactones exhibiting different alkyl groups attached to the heterocyclic nitrogen of an alpha-pyridylalkylidene chain, and particularly the relationship between membrane interactions of the substituted DAG-lactones and their respective biological activities. Our results suggest that bilayer interface localization of the N-alkyl chain in the R(2) position of the DAG-lactones inhibits translocation of PKC isoenzymes onto the cellular membrane. However, the orientation of a branched alkyl chain at the bilayer surface facilitates PKC binding and translocation. This investigation emphasizes that bilayer localization of the aromatic side residues of positively charged DAG-lactone derivatives play a central role in determining biological activity, and that this factor contributes to the diversity of biological actions of these synthetic biomimetic ligands. C1 [El Kazzouli, Said; Sigano, Dina M.; Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Raifman, Or; Kolusheva, Sofiya; Jelinek, Raz] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Kedei, Noemi; Lewin, Nancy E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Lopez-Nicolas, Ruben; Ortiz-Espin, Ana; Gomez-Fernandez, Juan C.; Corbalan-Garcia, Senena] Univ Murcia, Dept Biochem & Mol Biol A, Sch Vet, E-30100 Murcia, Spain. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov; senena@um.es; razj@bgu.ac.il RI JELINEK, RAZ/F-2023-2012; Sigano, Dina/M-6144-2014; CORBALAN-GARCIA, SENENA/C-6477-2009; OI Sigano, Dina/0000-0001-7489-9555; CORBALAN-GARCIA, SENENA/0000-0003-1840-5578; jelinek, raz/0000-0002-0336-1384 FU National Institutes of Health, Center for Cancer Research, National Cancer Institute; Fundacion Medica Mutua Madrilena-Spain; Fundacion Seneca Spain [08700/PI/08]; MICINN-Direccion General de Investigacion Spain [BFU2008-01010] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. Grants from the Fundacion Medica Mutua Madrilena-Spain, Fundacion Seneca Spain 08700/PI/08 and MICINN-Direccion General de Investigacion Spain (BFU2008-01010). NR 19 TC 2 Z9 2 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD SEP 24 PY 2010 VL 11 IS 14 BP 2003 EP 2009 DI 10.1002/cbic.201000343 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 659WD UT WOS:000282596900013 PM 20715268 ER PT J AU Li, DHS Chung, YS Gloyd, M Joseph, E Ghirlando, R Wright, GD Cheng, YQ Maurizi, MR Guarne, A Ortega, J AF Li, Dominic Him Shun Chung, Yu Seon Gloyd, Melanie Joseph, Ebenezer Ghirlando, Rodolfo Wright, Gerard D. Cheng, Yi-Qiang Maurizi, Michael R. Guarne, Alba Ortega, Joaquin TI Acyldepsipeptide Antibiotics Induce the Formation of a Structured Axial Channel in CIpP: A Model for the CIpX/CIpA-Bound State of CIpP SO CHEMISTRY & BIOLOGY LA English DT Article ID DEPENDENT CLP PROTEASE; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; SEDIMENTATION-VELOCITY; COMPLEX-FORMATION; DEGRADATION; CHAPERONE; TRANSLOCATION; PROTEOLYSIS; PEPTIDASE AB In CIpXP and CIpAP complexes, CIpA and CIpX use the energy of ATP hydrolysis to unfold proteins and translocate them into the self-compartmentalized CIpP protease. CIpP requires the ATPases to degrade folded or unfolded substrates, but binding of acyldepsipeptide antibiotics (ADEPs) to CIpP bypasses this requirement with unfolded proteins. We present the crystal structure of Escherichia coli CIpP bound to ADEP1 and report the structural changes underlying CIpP activation. ADEP1 binds in the hydrophobic groove that serves as the primary docking site for CIpP ATPases. Binding of ADEP1 locks the N-terminal loops of CIpP in a beta-hairpin conformation, generating a stable pore through which extended polypeptides can be threaded. This structure serves as a model for CIpP in the holoenzyme CIpAP and CIpXP complexes and provides critical information to further develop this class of antibiotics. C1 [Li, Dominic Him Shun; Chung, Yu Seon; Gloyd, Melanie; Wright, Gerard D.; Guarne, Alba; Ortega, Joaquin] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada. [Li, Dominic Him Shun; Wright, Gerard D.; Ortega, Joaquin] McMaster Univ, MG DeGroote Inst Infect Dis Res, Hamilton, ON L8N 3Z5, Canada. [Joseph, Ebenezer; Maurizi, Michael R.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Cheng, Yi-Qiang] Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53211 USA. [Cheng, Yi-Qiang] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. RP Ortega, J (reprint author), McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada. EM ortegaj@mcmaster.ca FU Canadian Institutes of Health Research [MOP-82930, MT-14981]; Canada Research Chair in Antibiotic Biochemistry; Ontario Ministry of Research Innovation; Center for Cancer Research, NCI; National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD FX We are grateful to Walid A. Houry for providing the pT9a-CIpP plasmid. We are in debt with M. Junop and the staff at the X25 beam line (BNL, NSLS) for assistance during data collection. This work was supported by a grant from the Canadian Institutes of Health Research to J.O. (MOP-82930) and G.D.W. (MT-14981), by a Canada Research Chair in Antibiotic Biochemistry (to G.D.W.) and an Early Researcher Award to A.G. (Ontario Ministry of Research Innovation). J.O. and A.G. are supported by the New Investigators program from CIHR. This work was also supported by the intramural research program of the Center for Cancer Research, NCI (M.R.M. and E.J.) and the National Institute of Diabetes and Digestive and Kidney Diseases (R.G.), NIH, Bethesda, MD. NR 44 TC 55 Z9 57 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD SEP 24 PY 2010 VL 17 IS 9 BP 959 EP 969 DI 10.1016/j.chembiol.2010.07.008 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 668PY UT WOS:000283283200010 PM 20851345 ER PT J AU Umehara, T Nakamura, Y Wakamori, M Ozato, K Yokoyama, S Padmanabhan, B AF Umehara, Takashi Nakamura, Yoshihiro Wakamori, Masatoshi Ozato, Keiko Yokoyama, Shigeyuki Padmanabhan, Balasundaram TI Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2 SO FEBS LETTERS LA English DT Article DE BET family; Bromodomain; Cell cycle; Chromatin; Crystal structure; Papilloma virus; Transcription ID X-RAY-DIFFRACTION; PROTEIN BRD4; LIVING CELLS; BINDING; CHROMATIN; TRANSCRIPTION; ACETYLATION; DOMAIN; TAILS AB The BET family proteins recognize acetylated chromatin through their two bromodomains, acting as transcriptional activators or tethering viral genomes to the mitotic chromosomes of their host. The structural mechanism for how the N-terminal bromodomain of human BRD2 (BRD2-BD1) deciphers the mono-acetylated status of histone H4 tail was recently reported. Here we show the crystal structure of the second bromodomain of BRD2 (BRD2-BD2) in complex with the di-acetylated histone H4 tail (H4K5ac/K12ac). To our surprise, a single K5ac/K12ac peptide interacts with two BRD2-BD2 molecules simultaneously:the K5ac residue binds to one BRD2-BD2 molecule while the K12ac residue binds to another. These results provide a structural basis for the recognition of two different patterns of the histone acetylation status by a single bromodomain. Structured summary: MINT-7989882, MINT-7989824, MINT-7989846, MINT-7989865:H4 (uniprotkb:P62805) binds (MI:0407) to BRD2 (uniprotkb:P25440) by surface plasmon resonance (MI:0107) MINT-7989539: H4 (uniprotkb:P62805) and BRD2 (uniprotkb:P25440) bind (MI:0407) by X-ray crystallography (MI:0114) (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved. C1 [Umehara, Takashi; Nakamura, Yoshihiro; Wakamori, Masatoshi; Yokoyama, Shigeyuki; Padmanabhan, Balasundaram] RIKEN Syst & Struct Biol Ctr, Yokohama, Kanagawa 2300045, Japan. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. [Yokoyama, Shigeyuki] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Bunkyo Ku, Tokyo 1130033, Japan. RP Yokoyama, S (reprint author), RIKEN Syst & Struct Biol Ctr, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. EM yokoyama@biochem.s.u-tokyo.ac.jp; bpadma-nabhan@hotmail.com RI Umehara, Takashi/N-5683-2015; OI Umehara, Takashi/0000-0003-3464-2960; Yokoyama, Shigeyuki/0000-0003-3133-7338 FU National Institute of Biomedical Innovation (NIBIO) of Japan; Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [19790083, 22790101]; RIKEN Structural Genomics/Proteomics Initiative (RSGI); MEXT FX We thank Drs. M. K. Jang, K. Nakano and C. Shang for initial experiments of this study, S. Wakatsuki and N. Igarashi (AR-NW12A, Photon Factory, KEK) for help in data collection, and T. Nakayama and A. Ishii for clerical assistance. This work was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) of Japan to T.U., by Grants-in-Aid for Young Scientists from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan to T.U. (Nos. 19790083 and 22790101), and by the RIKEN Structural Genomics/Proteomics Initiative (RSGI), the National Project on Protein Structural and Functional Analyses of MEXT to S.Y. NR 30 TC 21 Z9 23 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 24 PY 2010 VL 584 IS 18 BP 3901 EP 3908 DI 10.1016/j.febslet.2010.08.013 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 654SE UT WOS:000282187500013 PM 20709061 ER PT J AU Xu, LL Kitani, A Stuelten, C McGrady, G Fuss, I Strober, W AF Xu, Lili Kitani, Atsushi Stuelten, Christina McGrady, George Fuss, Ivan Strober, Warren TI Positive and Negative Transcriptional Regulation of the Foxp3 Gene is Mediated by Access and Binding of the Smad3 Protein to Enhancer I SO IMMUNITY LA English DT Article ID T-CELLS; RETINOIC-ACID; TH17 CELLS; EXPRESSION; INDUCTION; DRIVEN AB The molecular mechanisms underlying retinoic acid (RA) augmentation of T cell receptor (TCR) and transforming growth factor-beta (TGF-beta)-induced Foxp3 transcription and inhibition of the latter by cytokines such as IL-27 were here shown to be related processes involving modifications of baseline (TGF-beta-induced) phosphorylated Smad3 (pSmad3) binding to a conserved enhancer region (enhancer l). RA augmentation involved the binding of retinoic acid receptor (RAR) and retinoid X receptor (RXR) to a dominant site in enhancer I and a subordinate site in the promoter. This led to increased histone acetylation in the region of the Smad3 binding site and increased binding of pSmad3. Cytokine (IL-27) inhibition involved binding of pStat3 to a gene silencer in a second conserved enhancer region (enhancer II) downstream from enhancer I; this led to loss of pSmad3 binding to enhancer I. Thus, control of accessibility and binding of pSmad3 provides a common framework for positive and negative regulation of TGF-beta-induced Foxp3 transcription. C1 [Xu, Lili; Fuss, Ivan; Strober, Warren] NIAID, Mucosal Immun Sect, Lab Host Defenses, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kitani, Atsushi] NCI, Cell & Canc Biol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [McGrady, George] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Lab Host Defenses, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov FU NIAID; NIH FX We thank J.J. O'Shea (Molecular Immunology and Inflammation Branch, NIAMS/NIH) for kindly providing us Stat3fl/fl and Stat3fl/fl;; MMTV-Cre mice and Socs3fl/fl and Socs3fl/fl; MMTV-Cre mice. We thank S. Wahl (Oral Infection and Immunity Branch, NIDCR/NIH) for Smad3-deficient mice. We thank M. Oukka (Harvard Medical School) for kindly providing us Foxp3-IRES-GFP gene-targeted mice. We thank M. Tone (University of Pennsylvania) for EL4 clone LAF cells. This research was supported by the Intramural Research Program of NIAID and NIH. NR 24 TC 80 Z9 83 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 24 PY 2010 VL 33 IS 3 BP 313 EP 325 DI 10.1016/j.immuni.2010.09.001 PG 13 WC Immunology SC Immunology GA 662HP UT WOS:000282798500007 PM 20870174 ER PT J AU Longley, MJ Humble, MM Sharief, FS Copeland, WC AF Longley, Matthew J. Humble, Margaret M. Sharief, Farida S. Copeland, William C. TI Disease Variants of the Human Mitochondrial DNA Helicase Encoded by C10orf2 Differentially Alter Protein Stability, Nucleotide Hydrolysis, and Helicase Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; SINGLE-STRANDED-DNA; ONSET SPINOCEREBELLAR ATAXIA; RECESSIVE TWINKLE MUTATIONS; STRUCTURE-FUNCTION DEFECTS; PRIMASE-HELICASE; GENE MUTATION; MTDNA MAINTENANCE; BACTERIOPHAGE T7; LINKER REGION AB Missense mutations in the human C10orf2 gene, encoding the mitochondrial DNA (mtDNA) helicase, co-segregate with mitochondrial diseases such as adult-onset progressive external ophthalmoplegia, hepatocerebral syndrome with mtDNA depletion syndrome, and infantile-onset spinocerebellar ataxia. To understand the biochemical consequences of C10orf2 mutations, we overproduced wild type and 20 mutant forms of human mtDNA helicase in Escherichia coli and developed novel schemes to purify the recombinant enzymes to near homogeneity. A combination of molecular crowding, non-ionic detergents, Mg(2+) ions, and elevated ionic strength was required to combat insolubility and intrinsic instability of certain mutant variants. Asystematic biochemical assessment of the enzymes included analysis of DNA binding affinity, DNA helicase activity, the kinetics of nucleotide hydrolysis, and estimates of thermal stability. In contrast to other studies, we found that all 20 mutant variants retain helicase function under optimized in vitro conditions despite partial reductions in DNA binding affinity, nucleotide hydrolysis, or thermal stability for some mutants. Such partial defects are consistent with the delayed presentation of mitochondrial diseases associated with mutation of C10orf2. C1 [Longley, Matthew J.; Humble, Margaret M.; Sharief, Farida S.; Copeland, William C.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU National Institutes of Health through the NIEHS [ES 065078] FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health through the NIEHS (Grant ES 065078) (to W.C.C.). NR 62 TC 27 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 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 24 PY 2010 VL 285 IS 39 BP 29690 EP 29702 DI 10.1074/jbc.M110.151795 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 652EK UT WOS:000281984300004 PM 20659899 ER PT J AU Tchigvintsev, A Xu, XH Singer, A Chang, C Brown, G Proudfoott, M Cui, H Flick, R Anderson, WF Joachimiak, A Galperin, MY Savchenko, A Yakunin, AF AF Tchigvintsev, Anatoli Xu, Xiaohui Singer, Alexander Chang, Changsoo Brown, Greg Proudfoott, Michael Cui, Hong Flick, Robert Anderson, Wayne F. Joachimiak, Andrzej Galperin, Michael Y. Savchenko, Alexei Yakunin, Alexander F. TI Structural Insight into the Mechanism of c-di-GMP Hydrolysis by EAL Domain Phosphodiesterases SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE EAL domain; c-di-GMP; phosphodiesterase; X-ray crystallography; Thiobacillus denitrificans ID II RESTRICTION ENDONUCLEASES; REGULATES BIOFILM FORMATION; 3'-5' EXONUCLEASE ACTIVITY; METAL-ION MECHANISM; CYCLIC DIGUANYLATE; ESCHERICHIA-COLI; PSEUDOMONAS-AERUGINOSA; CATALYTIC MECHANISM; ACETOBACTER-XYLINUM; CELLULOSE SYNTHESIS AB Cyclic diguanylate (or bis-(3'-5') cyclic dimeric guanosine monophosphate; c-di-GMP) is a ubiquitous second messenger that regulates diverse cellular functions, including motility, biofilm formation, cell cycle progression, and virulence in bacteria. In the cell, degradation of c-di-GMP is catalyzed by highly specific EAL domain phosphodiesterases whose catalytic mechanism is still unclear. Here, we purified 13 EAL domain proteins from various organisms and demonstrated that their catalytic activity is associated with the presence of 10 conserved EAL domain residues. The crystal structure of the TBD1265 EAL domain was determined in free state (1.8 angstrom) and in complex with c-di-GMP (2.35 angstrom), and unveiled the role of conserved residues in substrate binding and catalysis. The structure revealed the presence of two metal ions directly coordinated by six conserved residues, two oxygens of c-di-GMP phosphate, and potential catalytic water molecule. Our results support a two-metal-ion catalytic mechanism of c-di-GMP hydrolysis by EAL domain phosphodiesterases. (c) 2010 Elsevier Ltd. All rights reserved. C1 [Tchigvintsev, Anatoli; Xu, Xiaohui; Singer, Alexander; Brown, Greg; Proudfoott, Michael; Cui, Hong; Flick, Robert; Savchenko, Alexei; Yakunin, Alexander F.] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada. [Tchigvintsev, Anatoli; Xu, Xiaohui; Singer, Alexander; Brown, Greg; Proudfoott, Michael; Cui, Hong; Flick, Robert; Savchenko, Alexei; Yakunin, Alexander F.] Univ Toronto, Dept Chem Engn & Appl Chem, Toronto, ON M5G 1L6, Canada. [Chang, Changsoo; Joachimiak, Andrzej] Argonne Natl Lab, Midwest Ctr Struct Genom & Struct Biol Ctr, Biosci Div, Argonne, IL 60439 USA. [Anderson, Wayne F.] Northwestern Univ, Feinberg Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. [Anderson, Wayne F.] Northwestern Univ, Feinberg Sch Med, Midwest Ctr Struct Genom, Chicago, IL 60611 USA. [Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Yakunin, AF (reprint author), Univ Toronto, Banting & Best Dept Med Res, 112 Coll St, Toronto, ON M5G 1L6, Canada. EM a.iakounine@utoronto.ca RI Galperin, Michael/B-5859-2013; Yakunin, Alexander/J-1519-2014; OI Galperin, Michael/0000-0002-2265-5572; Yakunin, Alexander/0000-0003-0813-6490 FU Genome Canada (through the Ontario Genomics Institute); Office of Biological and Environmental Research [DE-AC02-06CH11357]; National Library of Medicine, National Institutes of Health FX We thank all members of the Ontario Center for Structural Proteomics in Toronto for help with the conduct of experiments and for discussions. We acknowledge the support of Genome Canada (through the Ontario Genomics Institute) and the Protein Structure Initiative of the National Institutes of Health (Midwest Center for Structural Genomics, National Institutes of Health grant GM074942 to A.J.). The use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science. The use of Structural Biology Center beamlines was supported by the Office of Biological and Environmental Research under contract DE-AC02-06CH11357. M. Y.G. was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 56 TC 48 Z9 49 U1 1 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 24 PY 2010 VL 402 IS 3 BP 524 EP 538 DI 10.1016/j.jmb.2010.07.050 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 663YZ UT WOS:000282927400003 PM 20691189 ER PT J AU Mitchell, SF Walker, SE Algire, MA Park, EH Hinnebusch, AG Lorsch, JR AF Mitchell, Sarah F. Walker, Sarah E. Algire, Mikkel A. Park, Eun-Hee Hinnebusch, Alan G. Lorsch, Jon R. TI The 5 '-7-Methylguanosine Cap on Eukaryotic mRNAs Serves Both to Stimulate Canonical Translation Initiation and to Block an Alternative Pathway SO MOLECULAR CELL LA English DT Article ID FACTOR 4G EIF4G; SACCHAROMYCES-CEREVISIAE; PROTEIN-SYNTHESIS; SECONDARY STRUCTURE; BINDING-PROTEIN; FACTOR EIF-4-GAMMA; RIBOSOMAL-SUBUNIT; 40S SUBUNITS; POLY(A) TAIL; YEAST AB Translational control is frequently exerted at the stage of mRNA recruitment to the initiating ribosome. We have reconstituted mRNA recruitment to the 43S preinitiation complex (PIG) using purified S. cerevisiae components. We show that elF3 and the elF4 factors not only stabilize binding of mRNA to the PIG, they also dramatically increase the rate of recruitment. Although capped mRNAs require elF3 and the elF4 factors for efficient recruitment to the PIC, uncapped mRNAs can be recruited in the presence of elF3 alone. The cap strongly inhibits this alternative recruitment pathway, imposing a requirement for the elF4 factors for rapid and stable binding of natural mRNA. Our data suggest that the 5' cap serves as both a positive and negative element in mRNA recruitment, promoting initiation in the presence of the canonical group of mRNA handling factors while preventing binding to the ribosome via an aberrant, alternative pathway requiring only elF3. C1 [Mitchell, Sarah F.; Walker, Sarah E.; Algire, Mikkel A.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Park, Eun-Hee; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. EM jlorsch@jhmi.edu OI Lorsch, Jon/0000-0002-4521-4999; Walker, Sarah/0000-0002-9983-2485 FU National Institutes of Health (NIH) [GM62128]; NIH/NICHD FX We thank Patrick Linder, Stewart Shuman, and Alan Sachs for providing plasmids; and Roy Parker, members of our labs, and the reviewers for comments on this manuscript. This work was supported by a grant from the National Institutes of Health (NIH) to J.R.L. (GM62128) and the intramural research program of the NIH/NICHD (A.G.H.). NR 54 TC 44 Z9 44 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 24 PY 2010 VL 39 IS 6 BP 950 EP 962 DI 10.1016/j.molcel.2010.08.021 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 656YO UT WOS:000282377200014 PM 20864040 ER PT J AU Johnson, WE Onorato, DP Roelke, ME Land, ED Cunningham, M Belden, RC McBride, R Jansen, D Lotz, M Shindle, D Howard, J Wildt, DE Penfold, LM Hostetler, JA Oli, MK O'Brien, SJ AF Johnson, Warren E. Onorato, David P. Roelke, Melody E. Land, E. Darrell Cunningham, Mark Belden, Robert C. McBride, Roy Jansen, Deborah Lotz, Mark Shindle, David Howard, JoGayle Wildt, David E. Penfold, Linda M. Hostetler, Jeffrey A. Oli, Madan K. O'Brien, Stephen J. TI Genetic Restoration of the Florida Panther SO SCIENCE LA English DT Article ID FELIS-CONCOLOR-CORYI; CONSERVATION BIOLOGY; DEPLETION; PUMAS AB The rediscovery of remnant Florida panthers (Puma concolor coryi) in southern Florida swamplands prompted a program to protect and stabilize the population. In 1995, conservation managers translocated eight female pumas (P. c. stanleyana) from Texas to increase depleted genetic diversity, improve population numbers, and reverse indications of inbreeding depression. We have assessed the demographic, population-genetic, and biomedical consequences of this restoration experiment and show that panther numbers increased threefold, genetic heterozygosity doubled, survival and fitness measures improved, and inbreeding correlates declined significantly. Although these results are encouraging, continued habitat loss, persistent inbreeding, infectious agents, and possible habitat saturation pose new dilemmas. This intensive management program illustrates the challenges of maintaining populations of large predators worldwide. C1 [Johnson, Warren E.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Onorato, David P.; Land, E. Darrell; Cunningham, Mark; Lotz, Mark; Shindle, David] Florida Fish & Wildlife Conservat Commiss, Naples, FL 34114 USA. [Roelke, Melody E.] NCI, SAIC Frederick, Lab Genom Divers, Frederick, MD 21702 USA. [Belden, Robert C.] US Fish & Wildlife Serv, Vero Beach, FL 32960 USA. [McBride, Roy] Livestock Protect Co, Alpine, TX 79832 USA. [Jansen, Deborah] Big Cypress Natl Preserve, Ochopee, FL 34141 USA. [Howard, JoGayle; Wildt, David E.] Smithsonian Conservat Biol Inst, Front Royal, VA 22630 USA. [Penfold, Linda M.] White Oak Conservat Ctr, Yulee, FL 32046 USA. [Hostetler, Jeffrey A.; Oli, Madan K.] Univ Florida, Dept Wildlife Ecol & Conservat, Gainesville, FL 32611 USA. RP Johnson, WE (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM warjohns@mail.nih.gov; Dave.Onorato@MyFWC.com; stephenobrien@nih.gov RI Hostetler, Jeffrey/A-3345-2011; Johnson, Warren/D-4149-2016 OI Hostetler, Jeffrey/0000-0003-3669-1758; Johnson, Warren/0000-0002-5954-186X FU Florida Fish and Wildlife Conservation Commission (FWC); Everglades National Park (EVER); BCNP; U.S. Fish and Wildlife Service; National Cancer Institute, National Institutes of Health (NIH) [N01-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research; Florida Panther Research and Management Trust FX We dedicate this study to the memory of Ulysses Seal and Ernst Mayr, important heroes in the conservation struggle of the Florida panther. Funded by the Florida Fish and Wildlife Conservation Commission (FWC) via purchases of Florida panther license plates. Other major funding for the field work was provided by Everglades National Park (EVER), the BCNP, and federal funds from the U.S. Fish and Wildlife Service (especially in the early years) as well as from the National Cancer Institute, National Institutes of Health (NIH), under contract number N01-CO-12400. This research was supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research, and the Florida Panther Research and Management Trust Fund. All panther captures, sampling, and radio collaring were authorized by U. S. Fish and Wildlife Service Endangered Species Permits TE01553-3 (FWC) and TE146761-1 (BCNP). We thank many individuals for their help in this project, who are named in SOM reference S25. NR 22 TC 136 Z9 139 U1 36 U2 285 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 SEP 24 PY 2010 VL 329 IS 5999 BP 1641 EP 1645 DI 10.1126/science.1192891 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 653NK UT WOS:000282098100040 PM 20929847 ER PT J AU Knox, SM Lombaert, IMA Reed, X Vitale-Cross, L Gutkind, JS Hoffman, MP AF Knox, S. M. Lombaert, I. M. A. Reed, X. Vitale-Cross, L. Gutkind, J. S. Hoffman, M. P. TI Parasympathetic Innervation Maintains Epithelial Progenitor Cells During Salivary Organogenesis SO SCIENCE LA English DT Article ID GLAND BRANCHING MORPHOGENESIS; SUBMANDIBULAR-GLAND; STEM-CELLS; CONDITIONAL EXPRESSION; K-RAS; DIFFERENTIATION; MECHANISMS; NERVES; LIVER; SKIN AB The maintenance of a progenitor cell population as a reservoir of undifferentiated cells is required for organ development and regeneration. However, the mechanisms by which epithelial progenitor cells are maintained during organogenesis are poorly understood. We report that removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin 5-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. We demonstrate that acetylcholine signaling, via the muscarinic M1 receptor and epidermal growth factor receptor, increased epithelial morphogenesis and proliferation of the keratin 5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis. This mechanism for epithelial progenitor cell maintenance may be targeted for organ repair or regeneration. C1 [Knox, S. M.; Lombaert, I. M. A.; Reed, X.; Hoffman, M. P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Unit, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Vitale-Cross, L.; Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Hoffman, MP (reprint author), Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Unit, Lab Cell & Dev Biol, NIH, 30 Convent Dr, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU National Institute of Dental and Craniofacial Research, NIH FX The authors would like to thank V. N. Patel, I. T. Rebustini, L. M. Angerer, K. G. Ten-Hagen, K. M. Yamada, and S. Powers for discussions and critical reading of this manuscript. The study was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH. NR 24 TC 109 Z9 110 U1 1 U2 16 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 SEP 24 PY 2010 VL 329 IS 5999 BP 1645 EP 1647 DI 10.1126/science.1192046 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 653NK UT WOS:000282098100041 PM 20929848 ER PT J AU Ludek, OR Gu, WL Gildersleeve, JC AF Ludek, Olaf R. Gu, Wenlu Gildersleeve, Jeffrey C. TI Activation of glycosyl trichloroacetimidates with perchloric acid on silica (HClO4-SiO2) provides enhanced alpha-selectivity SO CARBOHYDRATE RESEARCH LA English DT Article DE Glycosylation; Trichloroacetimidates; Stereoselectivity; Perchloric acid on silica ID BUILDING-BLOCKS; CHEMOENZYMATIC SYNTHESIS; HIGHLY EFFICIENT; DONORS; TN; OLIGOSACCHARIDES; GLYCOPEPTIDES; ACETYLATION; CHEMISTRY; ALCOHOLS AB Obtaining high stereoselectivity in glycosylation reactions is often challenging in the absence of neighboring group participation. In this study, we demonstrate that activation of glycosyl trichloroacetimidate donors with immobilized perchloric acid on silica (HClO4-SiO2) provides higher alpha-selectivity than trimethylsilyl triflate (TMSOTf) for reactions that do not involve neighboring group participation. Published by Elsevier Ltd. C1 [Ludek, Olaf R.; Gu, Wenlu; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. RP Gildersleeve, JC (reprint author), NCI, Biol Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. EM gildersj@mail.nih.gov RI Gildersleeve, Jeffrey/N-3392-2014 FU NIH, NCI FX This research was supported by the Intramural Research Program of the NIH, NCI. NR 36 TC 11 Z9 11 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD SEP 23 PY 2010 VL 345 IS 14 BP 2074 EP 2078 DI 10.1016/j.carres.2010.07.030 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 671DW UT WOS:000283481500012 PM 20692651 ER PT J AU Holmes, EC AF Holmes, Edward C. TI MALARIA The gorilla connection SO NATURE LA English DT Editorial Material ID PLASMODIUM-FALCIPARUM; ORIGIN; POPULATIONS C1 [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM echolmes@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 9 TC 7 Z9 7 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 23 PY 2010 VL 467 IS 7314 BP 404 EP 405 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 653KO UT WOS:000282090200025 PM 20864986 ER PT J AU Anderson, RV McGill, J Legge, KL AF Anderson, Rebecca VanOosten McGill, Jodi Legge, Kevin L. TI Quantification of the Frequency and Multiplicity of Infection of Respiratory- and Lymph Node-Resident Dendritic Cells During Influenza Virus Infection SO PLOS ONE LA English DT Article ID CD8(+) T-CELLS; ANTIGEN PRESENTATION; RESPONSES; PROLIFERATION; ACTIVATION; SUBSETS; LUNG; MICE; MIGRATION; HYBRIDS AB Background: Previous studies have demonstrated that DC differentially regulate influenza A virus (IAV)-specific CD8 T cell responses in vivo during high and low dose IAV infections. Furthermore, in vitro infection of DC with IAV at low versus high multiplicities of infection (MOI) results in altered cytokine production and a reduced ability to prime naive CD8 T cell responses. Flow cytometric detection of IAV proteins within DC, a commonly used method for detection of cellular IAV infection, does not distinguish between the direct infection of these cells or their uptake of viral proteins from dying epithelial cells. Methods/Principal Findings: We have developed a novel, sensitive, single-cell RT-PCR-based approach to assess the infection of respiratory DC (rDC) and lymph node (LN)-resident DC (LNDC) following high and low dose IAV infections. Our results show that, while a fraction of both rDC and LNDC contain viral mRNA following IAV infection, there is little correlation between the percentage of rDC containing viral mRNA and the initial IAV inoculum dose. Instead, increasing IAV inoculums correlate with augmented rDC MOI. Conclusion/Significance: Together, our results demonstrate a novel and sensitive method for the detection of direct IAV infection at the single-cell level and suggest that the previously described ability of DC to differentially regulate IAV-specific T cell responses during high and low dose IAV infections could relate to the MOI of rDC within the LN rather than the percentage of rDC infected. C1 [Anderson, Rebecca VanOosten; McGill, Jodi; Legge, Kevin L.] Univ Iowa, Dept Pathol, Interdisciplinary Grad Program Immunol, Iowa City, IA 52242 USA. RP Anderson, RV (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. EM kevin-legge@uiowa.edu OI Legge, Kevin/0000-0001-9800-6854 FU National Institutes of Health (NIH) [AI-071085]; Department of Pathology FX This work was supported by National Institutes of Health (NIH) grant AI-071085 and Department of Pathology Start-Up Funds to KLL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 5 Z9 5 U1 0 U2 2 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 SEP 23 PY 2010 VL 5 IS 9 AR e12902 DI 10.1371/journal.pone.0012902 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 653KV UT WOS:000282091100012 ER PT J AU Tan, W Dean, M Law, AJ AF Tan, Wei Dean, Michael Law, Amanda J. TI Molecular Cloning and Characterization of the Human ErbB4 Gene: Identification of Novel Splice Isoforms in the Developing and Adult Brain SO PLOS ONE LA English DT Article ID SCHIZOPHRENIA; EXPRESSION; NEUREGULIN-1; TRANSLATION; VARIANTS; DISEASE; CODE AB ErbB4 is a growth factor receptor tyrosine kinase essential for neurodevelopment. Genetic variation in ErbB4 is associated with schizophrenia and risk-associated polymorphisms predict overexpression of ErbB4 CYT-1 isoforms in the brain in the disorder. The molecular mechanism of association is unclear because the polymorphisms flank exon 3 of the gene and reside 700 kb distal to the CYT-1 defining exon. We hypothesized that the polymorphisms are indirectly associated with ErbB4 CYT-1 via splicing of exon 3 on the CYT-1 background. We report via cloning and sequencing of adult and fetal human brain cDNA libraries the identification of novel splice isoforms of ErbB4, whereby exon 3 is skipped (del. 3). ErbB4 del. 3 transcripts exist as CYT-2 isoforms and are predicted to produce truncated proteins. Furthermore, our data refine the structure of the human ErbB4 gene, clarify that juxtamembrane (JM) splice variants of ErbB4, JM-a and JM-b respectively, are characterized by the replacement of a 75 nucleotide (nt) sequence with a 45-nt insertion, and demonstrate that there are four alternative exons in the gene. Our analyses reveal that novel splice variants of ErbB4 exist in the developing and adult human brain and, given the failure to identify ErbB4 del. 3 CYT-1 transcripts, suggest that the association of risk polymorphisms in the ErbB4 gene with CYT-1 transcript levels is not mediated via an exon 3 splicing event. C1 [Tan, Wei] Natl Canc Inst Frederick, Basic Sci Program, Sci Applicat Int Corp Frederick, Frederick, MD USA. [Dean, Michael] Natl Canc Inst Frederick, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD USA. [Law, Amanda J.] NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Tan, W (reprint author), Natl Canc Inst Frederick, Basic Sci Program, Sci Applicat Int Corp Frederick, Frederick, MD USA. EM lawa@mail.nih.gov RI Law, Amanda/G-6372-2012; Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Law, Amanda/0000-0002-2574-1564 FU National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD 20892, USA and federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 8 Z9 8 U1 0 U2 1 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 SEP 23 PY 2010 VL 5 IS 9 AR e12924 DI 10.1371/journal.pone.0012924 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 653KV UT WOS:000282091100028 PM 20886074 ER PT J AU Scheinberg, P Cooper, JN Sloand, EM Wu, CO Calado, RT Young, NS AF Scheinberg, Phillip Cooper, James N. Sloand, Elaine M. Wu, Colin O. Calado, Rodrigo T. Young, Neal S. TI Association of Telomere Length of Peripheral Blood Leukocytes With Hematopoietic Relapse, Malignant Transformation, and Survival in Severe Aplastic Anemia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ANTI-THYMOCYTE GLOBULIN; ANTITHYMOCYTE GLOBULIN; ULCERATIVE-COLITIS; CYCLOSPORINE; CANCER; DISEASE; INSTABILITY; PROGRESSION; MUTATIONS; CARCINOMA AB Context Critically short telomeres produce apoptosis, cell senescence, and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia but their clinical significance is unknown. Objective To investigate the relationship between telomere length and clinical outcomes in severe aplastic anemia. Design, Setting, and Patients Single institution analysis of 183 patients with severe aplastic anemia who were treated in sequential prospective protocols at the National Institutes of Health from 2000 to 2008. The pretreatment leukocyte age-adjusted telomere length of patients with severe aplastic anemia consecutively enrolled in immunosuppression protocols with antithymocyte globulin plus cyclosporine for correlation with clinical outcomes were analyzed. Main Outcome Measures Hematologic response, relapse, clonal evolution, and survival. Results There was no relationship between hematologic response and telomere length with response rates of 56.5% of 46 patients in the first, 54.3% of 46 in the second, 60% of 45 in the third, and 56.5% of 46 in the fourth quartiles. Multivariate analysis demonstrated that telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.03-0.69; P=.01). The probability of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7%-37.5%) than in quartiles 2 through 4 (8.4%; 95% CI, 3.2%-13.3%; P=.009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%-31.6%) than in quartiles 2 through 4 (4.5%; 95% CI, 0.5%-8.2%; P=.002). Survival between these 2 groups differed, with 66% (95% CI, 52.9%-82.5%) surviving 6 years in the first quartile compared with 83.8% (95% CI, 77.3%-90.9%) in quartiles 2 through 4 (P=.008). Conclusion In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response but was associated with risk of relapse, clonal evolution, and overall survival. JAMA. 2010; 304(12): 1358-1364 C1 [Scheinberg, Phillip; Cooper, James N.; Sloand, Elaine M.; Calado, Rodrigo T.; Young, Neal S.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Cooper, James N.] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. RP Scheinberg, P (reprint author), NHLBI, Hematol Branch, 10 Ctr Dr,Bldg 10 CRC,Room 3-5140,MSC 1202, Bethesda, MD 20892 USA. EM scheinbp@mail.nih.gov RI Calado, Rodrigo/G-2619-2011; OI Scheinberg, Phillip/0000-0002-9047-4538 FU National Institutes of Health; National Heart, Lung, and Blood Institute; Pfizer Inc FX This research was supported by the Intramural Research Program of the National Institutes of Health; the National Heart, Lung, and Blood Institute. Dr Cooper's research year was made possible through the Clinical Research Training Program (CRTP), a public-private partnership supported jointly by the National Institutes of Health and Pfizer Inc (via a grant to the Foundation for National Institutes of Health from Pfizer Inc). NR 31 TC 77 Z9 92 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 22 PY 2010 VL 304 IS 12 BP 1358 EP 1364 DI 10.1001/jama.2010.1376 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 652LK UT WOS:000282007900019 PM 20858879 ER PT J AU Wang, ACJ Hara, Y Janssen, WGM Rapp, PR Morrison, JH AF Wang, Athena C. J. Hara, Yuko Janssen, William G. M. Rapp, Peter R. Morrison, John H. TI Synaptic Estrogen Receptor-alpha Levels in Prefrontal Cortex in Female Rhesus Monkeys and Their Correlation with Cognitive Performance SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HORMONE-THERAPY; RAT HIPPOCAMPUS; COMPUTER-PROGRAM; PROTEIN-KINASE; AGING AFFECT; WOMEN; EXPRESSION; PLASTICITY; ESTRADIOL; BRAIN AB In rat hippocampus, estrogen receptor-alpha (ER-alpha) can initiate nongenomic signaling mechanisms that modulate synaptic plasticity in response to either circulating or locally synthesized estradiol (E). Here we report quantitative electron microscopic data demonstrating that ER-alpha is present within excitatory synapses in dorsolateral prefrontal cortex (dlPFC) of young and aged ovariectomized female rhesus monkeys with and without E treatment. There were no treatment or age effects on the percentage of excitatory synapses containing ER-alpha, nor were there any group differences in distribution of ER-alpha within the synapse. However, the mean size of synapses containing ER-alpha was larger than that of unlabeled excitatory synapses. All monkeys were tested on delayed response (DR), a cognitive test of working memory that requires dlPFC. In young ovariectomized monkeys without E treatment, presynaptic ER-alpha correlated with DR accuracy across memory delays. In aged monkeys that received E treatment, ER-alpha within the postsynaptic density (30-60 nm from the synaptic membrane) positively correlated with DR performance. Thus, although the lack of group effects suggests that ER-alpha is primarily in synapses that are stable across age and treatment, synaptic abundance of ER-alpha is correlated with individual performance in two key age/treatment groups. These data have important implications for individual differences in the cognitive outcome among menopausal women and promote a focus on cortical estrogen receptors for therapeutic efficacy with respect to cognition. C1 [Wang, Athena C. J.; Hara, Yuko; Janssen, William G. M.; Morrison, John H.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Rapp, Peter R.] NIA, Lab Expt Gerontol, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Morrison, JH (reprint author), Mt Sinai Sch Med, Dept Neurosci, Box 1065,1 Gustave L Levy Pl, New York, NY 10029 USA. EM john.morrison@mssm.edu RI Hara, Yuko/B-9172-2012; Morrison, John/F-9229-2012 OI Hara, Yuko/0000-0001-5828-442X; FU National Institutes of Health [AG16765, AG00647]; National Institute on Aging FX This work was supported by National Institutes of Health Grants AG16765 and AG00647, and supported in part by the Intramural Research Program of the National Institute on Aging. We thank Dr. Wendy Lou for expert assistance with the statistical analyses. We also thank Tweithy Oung, Anne Canfield, Don Canfield, Mary Roberts, Sania Fong, Deborah Kent, and Heather McKay for technical assistance. In addition, we thank Drs. Mark Baxter and Bruce McEwen and Erik Bloss for critical discussion and helpful comments on the manuscript, and Dr. Patrick Hof for neuroanatomic expertise and helpful discussions throughout this project. NR 47 TC 41 Z9 42 U1 1 U2 4 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 SEP 22 PY 2010 VL 30 IS 38 BP 12770 EP 12776 DI 10.1523/JNEUROSCI.3192-10.2010 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 653NG UT WOS:000282097600021 PM 20861381 ER PT J AU Schwieters, CD Suh, JY Grishaev, A Ghirlando, R Takayama, Y Clore, GM AF Schwieters, Charles D. Suh, Jeong-Yong Grishaev, Alexander Ghirlando, Rodolfo Takayama, Yuki Clore, G. Marius TI Solution Structure of the 128 kDa Enzyme I Dimer from Escherichia coli and Its 146 kDa Complex with HPr Using Residual Dipolar Couplings and Small- and Wide-Angle X-ray Scattering SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SUGAR PHOSPHOTRANSFERASE SYSTEM; N-TERMINAL DOMAIN; MACROMOLECULAR STRUCTURE DETERMINATION; PARAMAGNETIC RELAXATION ENHANCEMENT; MOLECULAR-STRUCTURE DETERMINATION; SMALL ALPHA/BETA PROTEIN; RIGID-BODY MINIMIZATION; NMR STRUCTURES; BIOLOGICAL MACROMOLECULES; SALMONELLA-TYPHIMURIUM AB The solution structures of free Enzyme I (EI, similar to 128 kDa, 575 x 2 residues), the first enzyme in the bacterial phosphotransferase system, and its complex with HPr (similar to 146 kDa) have been solved using novel methodology that makes use of prior structural knowledge (namely, the structures of the dimeric EIC domain and the isolated EIN domain both free and complexed to HPr), combined with residual dipolar coupling (RDC), small- (SAXS) and wide- (WAXS) angle X-ray scattering and small-angle neutron scattering (SANS) data. The calculational strategy employs conjoined rigid body/torsion/Cartesian simulated annealing, and incorporates improvements in calculating and refining against SAXS/WAXS data that take into account complex molecular shapes in the description of the solvent layer resulting in a better representation of the SAXS/WAXS data. The RDC data orient the symmetrically related EIN domains relative to the C(2) symmetry axis of the EIC dimer, while translational, shape, and size information is provided by SAXS/WAXS. The resulting structures are independently validated by SANS. Comparison of the structures of the free El and the EI HPr complex with that of the crystal structure of a trapped phosphorylated EI intermediate reveals large (similar to 70-90 degrees) hinge body rotations of the two subdomains comprising the EIN domain, as well as of the EIN domain relative to the dimeric EIC domain. These large-scale interdomain motions shed light on the structural transitions that accompany the catalytic cycle of EI. C1 [Suh, Jeong-Yong; Grishaev, Alexander; Takayama, Yuki; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008; Ghirlando, Rodolfo/A-8880-2009 OI Clore, G. Marius/0000-0003-3809-1027; FU NIDDK; CIT of the NIH; Office of the Director of the NIH; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-ENG-38]; National Institute of Standards and Technology; National Science Foundation [DMR-0454672] FX We thank Ad Bax and Markus Zweckstetter for useful discussions. This work was supported by the intramural programs of NIDDK (G.M.C.) and CIT (C.D.S.) of the NIH, and by the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-ENG-38. The authors acknowledge shared scattering beamline resource allocated under the PUP-77 agreement between the National Cancer Institute, NIH and the Argonne National Laboratory. We thank X. Zuo (NCI, NIH) for assistance with SAXS/WAXS data processing and S. Seifert (Basic Energy Sciences Synchrotron Radiation Center, Advanced Photon Source, Argonne National Laboratory) for his support for the synchrotron experiments. We acknowledge the support of the National Institute of Standards and Technology, U.S. Department of Commerce in providing the neutron research facilities used in this work. This neutron scattering measurements utilized facilities supported in part by the National Science Foundation under agreement no. DMR-0454672. We would like to thank Boualem Hammouda (National Institute of Standard and Technology) for assistance with neutron instrumentation. NR 76 TC 56 Z9 57 U1 0 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 SEP 22 PY 2010 VL 132 IS 37 BP 13026 EP 13045 DI 10.1021/ja105485b PG 20 WC Chemistry, Multidisciplinary SC Chemistry GA 652NL UT WOS:000282013700054 PM 20731394 ER PT J AU Ferrari, MJ Djibo, A Grais, RF Bharti, N Grenfell, BT Bjornstad, ON AF Ferrari, Matthew J. Djibo, Ali Grais, Rebecca F. Bharti, Nita Grenfell, Bryan T. Bjornstad, Ottar N. TI Rural-urban gradient in seasonal forcing of measles transmission in Niger SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE seasonality; Niger; critical community size; TSIR model; epidemic metapopulation ID METAPOPULATION DYNAMICS; INFECTIOUS-DISEASES; CHILDHOOD DISEASES; MASS VACCINATION; COMMUNITY SIZE; EPIDEMICS; MODEL; PERSISTENCE; DETERMINISM; HIERARCHIES AB Seasonally driven cycles of incidence have been consistently observed for a range of directly transmitted pathogens. Though frequently observed, the mechanism of seasonality for directly transmitted human pathogens is rarely well understood. Despite significant annual variation in magnitude, measles outbreaks in Niger consistently begin in the dry season and decline at the onset of the seasonal rains. We estimate the seasonal fluctuation in measles transmission rates for the 38 districts and urban centres of Niger, from 11 years of weekly incidence reports. We show that transmission rates are consistently in anti-phase to the rainfall patterns across the country. The strength of the seasonal forcing of transmission is not correlated with the latitudinal rainfall gradient, as would be expected if transmission rates were determined purely by environmental conditions. Rather, seasonal forcing is correlated with the population size, with larger seasonal fluctuation in more populous, urban areas. This pattern is consistent with seasonal variation in human density and contact rates due to agricultural cycles. The stronger seasonality in large cities drives deep inter-epidemic troughs and results in frequent local extinction of measles, which contrasts starkly to the conventional observation that large cities, by virtue of their size, act as reservoirs of measles. C1 [Ferrari, Matthew J.; Bjornstad, Ottar N.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Djibo, Ali] Minist Hlth, Niamey, Niger. [Grais, Rebecca F.] Epicentre, F-75011 Paris, France. [Bharti, Nita; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.; Bjornstad, Ottar N.] Natl Inst Hlth, Fogerty Ctr Int Hlth, Bethesda, MD 20892 USA. RP Ferrari, MJ (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM mferrari@psu.edu RI Bjornstad, Ottar/I-4518-2012 FU Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation; National Institutes of Health [R01 GM083 983-01] FX We would like to acknowledge the support of the Niger Ministry of Health and Medicins Sans Frontieres for access to the Nigerien surveillance data. M.F., B.G. and O.B. were funded by RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health and a grant from the Bill and Melinda Gates Foundation. B.G. was additionally funded by the National Institutes of Health (R01 GM083 983-01). NR 41 TC 24 Z9 24 U1 0 U2 14 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD SEP 22 PY 2010 VL 277 IS 1695 BP 2775 EP 2782 DI 10.1098/rspb.2010.0536 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 636YE UT WOS:000280779700005 PM 20427338 ER PT J AU Cheng, S Cohen, KS Shaw, SY Larson, MG Hwang, SJ McCabe, EL Martin, RP Klein, RJ Hashmi, B Hoffmann, U Fox, CS Vasan, RS O'Donnell, CJ Wang, TJ AF Cheng, Susan Cohen, Kenneth S. Shaw, Stanley Y. Larson, Martin G. Hwang, Shih-Jen McCabe, Elizabeth L. Martin, Roderick P. Klein, Rachael J. Hashmi, Basma Hoffmann, Udo Fox, Caroline S. Vasan, Ramachandran S. O'Donnell, Christopher J. Wang, Thomas J. TI Association of Colony-Forming Units With Coronary Artery and Abdominal Aortic Calcification SO CIRCULATION LA English DT Article DE angiogenesis; atherosclerosis; epidemiology; risk factors; vasculature ID ENDOTHELIAL PROGENITOR CELLS; SOUTH ASIAN MEN; CARDIOVASCULAR RISK; CAROTID ATHEROSCLEROSIS; COMPUTED-TOMOGRAPHY; HEART-DISEASE; DYSFUNCTION; CALCIUM; NUMBER; POPULATION AB Background-Certain bone marrow-derived cell populations, called endothelial progenitor cells, have been reported to possess angiogenic activity. Experimental data suggest that depletion of these angiogenic cell populations may promote atherogenesis, but limited data are available on their relation to subclinical atherosclerotic cardiovascular disease in humans. Methods and Results-We studied 889 participants of the Framingham Heart Study who were free of clinically apparent cardiovascular disease (mean age, 65 years; 55% women). Participants underwent endothelial progenitor cell phenotyping with an early-outgrowth colony-forming unit assay and cell surface markers. Participants also underwent noncontrast multidetector computed tomography to assess the presence of subclinical atherosclerosis, as reflected by the burden of coronary artery calcification and abdominal aortic calcification. Across decreasing tertiles of colony-forming units, there was a progressive increase in median coronary artery calcification and abdominal aortic calcification scores. In multivariable analyses adjusting for traditional cardiovascular risk factors, each 1-SD increase in colony-forming units was associated with a approximate to 16% decrease in coronary artery calcification (P=0.02) and 17% decrease in abdominal aortic calcification (P=0.03). In contrast, neither CD34(+) /KDR(+) nor CD34(+) variation was associated with significant differences in coronary or aortic calcification. Conclusions-In this large, community-based sample of men and women, lower colony-forming unit number was associated with a higher burden of subclinical atherosclerosis in the coronary arteries and aorta. Decreased angiogenic potential could contribute to the development of atherosclerosis in humans. (Circulation. 2010;122:1176-1182.) C1 [Cheng, Susan; Shaw, Stanley Y.; McCabe, Elizabeth L.; O'Donnell, Christopher J.; Wang, Thomas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cohen, Kenneth S.; Martin, Roderick P.; Klein, Rachael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Shaw, Stanley Y.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Cheng, Susan; Larson, Martin G.; Hwang, Shih-Jen; McCabe, Elizabeth L.; Fox, Caroline S.; Vasan, Ramachandran S.; O'Donnell, Christopher J.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Cheng, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02114 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Metab & Diabet,Dept Med, Boston, MA 02114 USA. [Cheng, Susan] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Clin Investigator Training Program, Boston, MA 02114 USA. [Cohen, Kenneth S.] Univ Chicago, Med Ctr, Hematol Oncol Sect, Chicago, IL 60637 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hwang, Shih-Jen; Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Martin, Roderick P.] Genzyme Corp, Cambridge, MA USA. [Hashmi, Basma] Harvard Univ, Dept Bioengn, Boston, MA 02114 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. RP Wang, TJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, GRB-800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Ellison Medical Foundation; Harvard-MIT/BIDMC; [R01-HL083197]; [R01-HL93328] FX This work was supported in part by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195), grant R01-HL083197 (Dr Wang), grant R01-HL93328 (Dr Vasan), the Ellison Medical Foundation (Dr Cheng), and the Harvard-MIT/BIDMC Clinical Investigator Training Program (Dr Cheng). NR 49 TC 17 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 21 PY 2010 VL 122 IS 12 BP 1176 EP 1182 DI 10.1161/CIRCULATIONAHA.109.931279 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 652WR UT WOS:000282042100007 PM 20823386 ER PT J AU Gujja, P Rosing, DR Tripodi, DJ Shizukuda, Y AF Gujja, Pradeep Rosing, Douglas R. Tripodi, Dorothy J. Shizukuda, Yukitaka TI Iron Overload Cardiomyopathy Better Understanding of an Increasing Disorder SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE calcium channel blockers; chelation; hemochromatosis; hemosiderosis; iron overload cardiomyopathy; T2*MRI ID SICKLE-CELL-DISEASE; BETA-THALASSEMIA MAJOR; T2-ASTERISK-CARDIOVASCULAR MAGNETIC-RESONANCE; BONE-MARROW-TRANSPLANTATION; HEREDITARY HEMOCHROMATOSIS; MYOCARDIAL IRON; IDIOPATHIC HEMOCHROMATOSIS; CARDIAC IRON; ENDOMYOCARDIAL BIOPSY; SERUM FERRITIN AB The prevalence of iron overload cardiomyopathy (IOC) is increasing. The spectrum of symptoms of IOC is varied. Early in the disease process, patients may be asymptomatic, whereas severely overloaded patients can have terminal heart failure complaints that are refractory to treatment. It has been shown that early recognition and intervention may alter outcomes. Biochemical markers and tissue biopsy, which have traditionally been used to diagnose and guide therapy, are not sensitive enough to detect early cardiac iron deposition. Newer diagnostic modalities such as magnetic resonance imaging are noninvasive and can assess quantitative cardiac iron load. Phlebotomy and chelating drugs are suboptimal means of treating IOC; hence, the roles of gene therapy, hepcidin, and calcium channel blockers are being actively investigated. There is a need for the development of clinical guidelines in order to improve the management of this emerging complex disease. (J Am Coll Cardiol 2010; 56: 1001-12) (C) 2010 by the American College of Cardiology Foundation C1 [Gujja, Pradeep; Shizukuda, Yukitaka] Univ Cincinnati, Div Cardiovasc Dis, Dept Internal Med, Cincinnati, OH 45267 USA. [Rosing, Douglas R.; Tripodi, Dorothy J.; Shizukuda, Yukitaka] NHLBI, Translat Med Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Gujja, P (reprint author), Univ Cincinnati, Div Cardiovasc Dis, Dept Internal Med, 231 Albert Sabin Way,ML 0542, Cincinnati, OH 45267 USA. EM Pradeepg001@hotmail.com FU NHLBI/NIH FX Tripodi is supported by a fund from the intramural research programs of the NHLBI/NIH. Dr. Shizukuda is a special volunteer investigator of the National Heart, Lung, and Blood Institute of the National Institutes of Health (NHLBI/NIH), and his research is in part supported by a fund from the intramural research programs of the NHLBI/NIH. NR 138 TC 57 Z9 59 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 21 PY 2010 VL 56 IS 13 BP 1001 EP 1012 DI 10.1016/j.jacc.2010.03.083 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 651LO UT WOS:000281929400002 PM 20846597 ER PT J AU Hendrickson, SL Lautenberger, JA Chinn, LW Malasky, M Sezgin, E Kingsley, LA Goedert, JJ Kirk, GD Gomperts, ED Buchbinder, SP Troyer, JL O'Brien, SJ AF Hendrickson, Sher L. Lautenberger, James A. Chinn, Leslie Wei Malasky, Michael Sezgin, Efe Kingsley, Lawrence A. Goedert, James J. Kirk, Gregory D. Gomperts, Edward D. Buchbinder, Susan P. Troyer, Jennifer L. O'Brien, Stephen J. TI Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; HIV-1 INFECTION; EXPRESSION; DNA; IDENTIFICATION; ASSOCIATION; HEMOPHILIA; CARCINOMA; ISOMERASE AB Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. Methodology/Principal Findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3, D2-enoyl-CoA isomerase (PECI) on chromosome 6. Conclusions: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis. C1 [Hendrickson, Sher L.; Lautenberger, James A.; Chinn, Leslie Wei; Sezgin, Efe; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Malasky, Michael; Troyer, Jennifer L.] SAIC Frederick Inc, Lab Genom Divers, Frederick, MD USA. [Kingsley, Lawrence A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Kingsley, Lawrence A.] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Bethesda, MD 20892 USA. [Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gomperts, Edward D.] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Buchbinder, Susan P.] San Francisco City Clin, Dept Publ Hlth, San Francisco, CA USA. RP Hendrickson, SL (reprint author), NCI, Lab Genom Divers, Frederick, MD 21701 USA. EM hendricksons@mail.nih.gov RI Sezgin, Efe/B-8418-2012; Troyer, Jennifer/B-8415-2012 OI Sezgin, Efe/0000-0002-8000-7485; FU National Cancer Institute [N02-CP-55504, UO1-AI-35042, 5-MO1-RR-00722, UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041]; National Institutes of Health [UO1-AI-35042, 5-MO1-RR-00722, UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041, HHSN261200800001E, N01-CO-12400, R01-DA-04334, R01-DA-12568, M01 RR00425]; National Center for Research Resources at Harbor-UCLA Research and Education Institute; National Institute of Child Health; Human Development [1 R01 HD41224] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). ALIVE was supported by NIH grants R01-DA-04334 and R01-DA-12568. MACS work was supported by NIH grants UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041 and M01 RR00425 (National Center for Research Resources grant awarded to the GCRC at Harbor-UCLA Research and Education Institute). The MHCS is supported by National Cancer Institute contract N02-CP-55504 with RTI International. The HGDS is funded by the National Institutes of Health, National Institute of Child Health and Human Development, 1 R01 HD41224. National Cancer Institute contracts include: UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 20 Z9 22 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 SEP 21 PY 2010 VL 5 IS 9 AR e12862 DI 10.1371/journal.pone.0012862 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 652JO UT WOS:000282002900012 PM 20877624 ER PT J AU Jaoko, W Karita, E Kayitenkore, K Omosa-Manyonyi, G Allen, S Than, S Adams, EM Graham, BS Koup, RA Bailer, RT Smith, C Dally, L Farah, B Anzala, O Muvunyi, CM Bizimana, J Tarragona-Fiol, T Bergin, PJ Hayes, P Ho, M Loughran, K Komaroff, W Stevens, G Thomson, H Boaz, MJ Cox, JH Schmidt, C Gilmour, J Nabel, GJ Fast, P Bwayo, J AF Jaoko, Walter Karita, Etienne Kayitenkore, Kayitesi Omosa-Manyonyi, Gloria Allen, Susan Than, Soe Adams, Elizabeth M. Graham, Barney S. Koup, Richard A. Bailer, Robert T. Smith, Carol Dally, Len Farah, Bashir Anzala, Omu Muvunyi, Claude M. Bizimana, Jean Tarragona-Fiol, Tony Bergin, Philip J. Hayes, Peter Ho, Martin Loughran, Kelley Komaroff, Wendy Stevens, Gwynneth Thomson, Helen Boaz, Mark J. Cox, Josephine H. Schmidt, Claudia Gilmour, Jill Nabel, Gary J. Fast, Patricia Bwayo, Job TI Safety and Immunogenicity Study of Multiclade HIV-1 Adenoviral Vector Vaccine Alone or as Boost following a Multiclade HIV-1 DNA Vaccine in Africa SO PLOS ONE LA English DT Article ID CANDIDATE VACCINE; T-CELLS; NEUTRALIZING ANTIBODIES; CLINICAL-TRIALS; PHASE-1 SAFETY; IMMUNITY; INFECTION; ASSAY; REPLICATION; GAG AB Background: We conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replication-defective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIV-uninfected African adults. Methodology/Principal Findings: Volunteers were randomized to 4 groups receiving the rAd5 vaccine intramuscularly at dosage levels of 1x10(10) or 1x10(11) particle units (PU) either alone or as boost following 3 injections of the DNA vaccine given at 4 mg/dose intramuscularly by needle-free injection using Biojector (R) 2000. Safety and immunogenicity were evaluated for 12 months. Both vaccines were well-tolerated. Overall, 62% and 86% of vaccine recipients in the rAd5 alone and DNA prime - rAd5 boost groups, respectively, responded to the HIV-1 proteins by an interferon-gamma (IFN-gamma) ELISPOT. The frequency of immune responses was independent of rAd5 dosage levels. The highest frequency of responses after rAd5 alone was detected at 6 weeks; after DNA prime - rAd5 boost, at 6 months (end of study). At baseline, neutralizing antibodies against Ad5 were present in 81% of volunteers; the distribution was similar across the 4 groups. Pre-existing immunity to Ad5 did not appear to have a significant impact on reactogenicity or immune response rates to HIV antigens by IFN-gamma ELISPOT. Binding antibodies against Env were detected in up to 100% recipients of DNA prime - rAd5 boost. One volunteer acquired HIV infection after the study ended, two years after receipt of rAd5 alone. Conclusions/Significance: The HIV-1 rAd5 vaccine, either alone or as a boost following HIV-1 DNA vaccine, was well-tolerated and immunogenic in African adults. DNA priming increased the frequency and magnitude of cellular and humoral immune responses, but there was no effect of rAd5 dosage on immunogenicity endpoints. Trial Registration: ClinicalTrials.gov NCT00124007 C1 [Jaoko, Walter; Omosa-Manyonyi, Gloria; Farah, Bashir; Anzala, Omu; Bwayo, Job] Kenya AIDS Vaccine Initiat KAVI, Nairobi, Kenya. [Karita, Etienne; Kayitenkore, Kayitesi; Muvunyi, Claude M.; Bizimana, Jean] Rwanda Zambia HIV Res Project, PSF, Kigali, Rwanda. [Allen, Susan] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Than, Soe; Komaroff, Wendy; Stevens, Gwynneth; Thomson, Helen; Boaz, Mark J.; Cox, Josephine H.; Schmidt, Claudia; Fast, Patricia] Int AIDS Vaccine Initiat IAVI, New York, NY USA. [Adams, Elizabeth M.] NIAID, VCRB, VRP, DAIDS,NIH, Bethesda, MD 20892 USA. [Graham, Barney S.; Koup, Richard A.; Bailer, Robert T.; Nabel, Gary J.] NIAID, VRC, NIH, Bethesda, MD 20892 USA. [Smith, Carol; Dally, Len; Ho, Martin; Loughran, Kelley] EMMES Corp, Rockville, MD USA. [Tarragona-Fiol, Tony; Bergin, Philip J.; Hayes, Peter; Gilmour, Jill] Univ London Imperial Coll Sci Technol & Med, IAVI Human Immunol, London, England. RP Jaoko, W (reprint author), Kenya AIDS Vaccine Initiat KAVI, Nairobi, Kenya. EM pfast@iavi.org OI Bergin, Philip/0000-0001-5522-8350 FU International AIDS Vaccine Initiative FX This study was funded by the International AIDS Vaccine Initiative and its donors, including the generous support of the American people through the United States Agency for International Development (USAID; USAID Cooperative Agreement Number GPO-A-00-06-00006-00). The contents of this manuscript are the responsibility of IAVI and do not necessarily reflect the views of USAID or the US government. The following organizations/institutions played a direct role in study design, data collection and analysis, decision to publish, and preparation of this manuscript: i) the International AIDS Vaccine Initiative, ii) the Vaccine Clinical Research Branch/DAIDS/NIAID/NIH, iii) the Vaccine Research Center/NIAID/NIH. The EMMES Corporation is a Contract Research Organization (CRO). IAVI subcontracted data coordination, management and analysis for the V001 study to the EMMES Corporation. NR 31 TC 63 Z9 63 U1 1 U2 7 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 SEP 21 PY 2010 VL 5 IS 9 AR e12873 DI 10.1371/journal.pone.0012873 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 652JO UT WOS:000282002900014 PM 20877623 ER PT J AU Liu, D Meckel, T Long, EO AF Liu, Dongfang Meckel, Tobias Long, Eric O. TI Distinct Role of Rab27a in Granule Movement at the Plasma Membrane and in the Cytosol of NK Cells SO PLOS ONE LA English DT Article ID NATURAL-KILLER-CELLS; REFLECTION FLUORESCENCE MICROSCOPY; SINGLE SECRETORY GRANULES; CYTOTOXIC T-LYMPHOCYTES; IMMUNOLOGICAL SYNAPSE; LYTIC GRANULES; F-ACTIN; MEDIATED CYTOTOXICITY; MELANOSOME TRANSPORT; EPITHELIAL-CELLS AB Protocols were developed to automate image analysis and to track the movement of thousands of vesicular compartments in live cells. Algorithms were used to discriminate among different types of movement (e. g. random, caged, and directed). We applied these tools to investigate the steady-state distribution and movement of lytic granules (LG) in live natural killer (NK) cells by high-speed 3-dimensional (3D) spinning disc confocal and 2-dimensional total internal reflection fluorescence microscopy. Both mouse NK cells and a human NK cell line deficient in the small GTPase Rab27a were examined. The unbiased analysis of large datasets led to the following observations and conclusions. The majority of LG in the cytosol and at the plasma membrane of unstimulated NK cells are mobile. The use of inhibitors indicated that movement in the cytosol required microtubules but not actin, whereas movement at the plasma membrane required both. Rab27a deficiency resulted in fewer LG, and in a reduced fraction of mobile LG, at the plasma membrane. In contrast, loss of Rab27a increased the fraction of mobile LG and the extent of their movement in the cytosol. Therefore, in addition to its documented role in LG delivery to the plasma membrane, Rab27a may restrict LG movement in the cytosol. C1 [Liu, Dongfang; Meckel, Tobias; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Liu, D (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM eLong@nih.gov RI Meckel, Tobias/F-4372-2010; Long, Eric/G-5475-2011 OI Meckel, Tobias/0000-0003-0759-2072; Long, Eric/0000-0002-7793-3728 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work 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 63 TC 21 Z9 21 U1 0 U2 2 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 SEP 21 PY 2010 VL 5 IS 9 AR e12870 DI 10.1371/journal.pone.0012870 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 652JO UT WOS:000282002900013 PM 20877725 ER PT J AU Vagenas, P Aravantinou, M Williams, VG Jasny, E Piatak, M Lifson, JD Salazar, AM Blanchard, JL Gettie, A Robbiani, M AF Vagenas, Panagiotis Aravantinou, Meropi Williams, Vennansha G. Jasny, Edith Piatak, Michael, Jr. Lifson, Jeffrey D. Salazar, Andres M. Blanchard, James L. Gettie, Agegnehu Robbiani, Melissa TI A Tonsillar PolyICLC/AT-2 SIV Therapeutic Vaccine Maintains Low Viremia Following Antiretroviral Therapy Cessation SO PLOS ONE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-LYMPHOCYTE RESPONSES; DENDRITIC-CELL VACCINE; RHESUS MACAQUES; DISEASE PROGRESSION; INFECTED MACAQUES; SIVMAC251 INFECTION; ANTIBODY-RESPONSES; PARTIAL PROTECTION; IMMUNE-RESPONSES AB Background: HIV-infected individuals rely on antiretroviral therapy (ART) to control viral replication. Despite abundant demonstrable benefits, the multiple limitations of ART point to the potential advantages of therapeutic vaccination approaches that could provide sustained host control of viral replication after discontinuation of ART. We provide evidence from a non-human primate model that a therapeutic vaccine applied to the tonsils can maintain low viral loads after cessation of ART. Methodology/Principal Findings: Animals received 40 weeks of ART initiated 9 weeks after rectal SIVmac239 infection. During ART, animals were vaccinated (or not) with AT-2 inactivated SIVmac239 using CpG-C ISS-ODN (C274) or polyICLC as adjuvants. PolyICLC/AT-2 SIV vaccinated animals maintained viral loads <3x10(3) copies/ml for up to 16 weeks post-ART, whereas the C274/AT-2 SIV vaccinated and non-vaccinated animals' viremia ranged between 1x10(4)-4x10(5) copies/ml (p<0.03). Neutralizing Ab activity in plasma was increased by polyICLC/AT-2 tonsillar vaccination under ART, compared to controls (p<0.03). Subsequent vaccination of all animals with polyICLC/AT-2 SIV in the absence of ART did not alter viral loads. Other immune parameters measured in blood and tissues were comparable between groups. Conclusions/Significance: These results provide support for the potential benefit of mucosally delivered vaccines in therapeutic immunization strategies for control of AIDS virus infection. C1 [Vagenas, Panagiotis; Aravantinou, Meropi; Williams, Vennansha G.; Jasny, Edith; Robbiani, Melissa] Populat Council, Ctr Biomed Res, HIV AIDS Program, New York, NY 10021 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Salazar, Andres M.] Oncovir Inc, Washington, DC USA. [Blanchard, James L.] Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. RP Vagenas, P (reprint author), Populat Council, Ctr Biomed Res, HIV AIDS Program, 1230 York Ave, New York, NY 10021 USA. EM mrobbiani@popcouncil.org RI Vagenas, Panagiotis/H-7850-2013 OI Vagenas, Panagiotis/0000-0003-2107-0377 FU National Institutes of Health [R01 DE016256, RR00164]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project was funded by the National Institutes of Health grant R01 DE016256, the base grant RR00164, and in part with Federal Funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. MR was a 2002 Elizabeth Glaser Scientist. Oncovir Inc. provided the PolyICLC (Hiltonol). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 12 Z9 12 U1 0 U2 0 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 SEP 21 PY 2010 VL 5 IS 9 AR e12891 DI 10.1371/journal.pone.0012891 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 652JO UT WOS:000282002900020 PM 20877632 ER PT J AU Tsai, YC Maditz, R Kuo, CL Fishman, PS Shoemaker, CB Oyler, GA Weissman, AM AF Tsai, Yien Che Maditz, Rhyan Kuo, Chueh-ling Fishman, Paul S. Shoemaker, Charles B. Oyler, George A. Weissman, Allan M. TI Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE botulinum toxin; HECT domain; synaptic transmission; Clostridium; SNAP25 ID CLOSTRIDIAL NEUROTOXINS; CHROMAFFIN CELLS; VESICLE DOCKING; LIGHT-CHAIN; SNAP-25; DEGRADATION; EXOCYTOSIS; PROTEINS; IDENTIFICATION; LOCALIZATION AB Botulinum neurotoxins (BoNTs) are the most potent natural toxins known. The effects of BoNT serotype A (BoNT/A) can last several months, whereas the effects of BoNT serotype E (BoNT/E), which shares the same synaptic target, synaptosomal-associated protein 25 (SNAP25), last only several weeks. The long-lasting effects or persistence of BoNT/A, although desirable for therapeutic applications, presents a challenge for medical treatment of BoNT intoxication. Although the mechanisms for BoNT toxicity are well known, little is known about the mechanisms that govern the persistence of the toxins. We show that the recombinant catalytic light chain (LC) of BoNT/E is ubiquitylated and rapidly degraded in cells. In contrast, BoNT/A LC is considerably more stable. Differential susceptibility of the catalytic LCs to ubiquitin-dependent proteolysis therefore might explain the differential persistence of BoNT serotypes. In this regard we show that TRAF2, a RING finger protein implicated in ubiquitylation, selectively associates with BoNT/E LC and promotes its proteasomal degradation. Given these data, we asked whether BoNT/A LC could be targeted for rapid proteasomal degradation by redirecting it to characterized ubiquitin ligase domains. We describe chimeric SNAP25-based ubiquitin ligases that target BoNT/A LC for degradation, reducing its duration in a cellular model for toxin persistence. C1 [Oyler, George A.] Synapt Res LLC, Baltimore, MD 21227 USA. [Tsai, Yien Che; Maditz, Rhyan; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Kuo, Chueh-ling; Shoemaker, Charles B.] Tufts Cummings Sch Vet Med, Dept Biomed Sci Infect Dis, North Grafton, MA 01536 USA. [Fishman, Paul S.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Fishman, Paul S.] Maryland Dept Vet Affairs Hlth Care Syst, Neurol Serv, Baltimore, MD 21201 USA. RP Oyler, GA (reprint author), Synapt Res LLC, Baltimore, MD 21227 USA. EM george@synapticresearch.com; amw@nih.gov OI Tsai, Yien Che/0000-0001-9624-1092 FU National Institutes of Health/NCI; Veterans Affairs Biomedical and Laboratory Research Service; National Institute of Allergy and Infectious Diseases [N01-AI-30050]; Department of Defense Defense Threat Reduction Agency FX We thank K. Lorick and members of the Laboratory of Protein Dynamics and Signaling for helpful discussions; M. Metzger and Z. Kostova for critical reading of the manuscript; M. Zhou and T. Veenstra [Biomedical Proteomics Program, National Cancer Institute (NCI)] for mass spectrometry analysis; S. Lockett (Optical Microscopy Analysis Laboratory, NCI) for confocal imaging support; S. Zou, J. Shi, D. Yarnell, R. Kincaid, and E. Sum for excellent technical support; J. Lippincott- Schwartz (National Institute of Child Health and Human Development) for mRFP plasmids, J. M. Mukherjee (Tufts University) for monoclonal antibody against BoNT/A LC; and J.D. Ashwell (NCI) for TRAF2 plasmids. This research is supported in part by the Intramural Research Program of the National Institutes of Health/NCI (Y.C.T.,R.M., and A.M.W.), by the Veterans Affairs Biomedical and Laboratory Research Service (P.S.F.), by National Institute of Allergy and Infectious Diseases Grant N01-AI-30050 (to C.K., C.B.S., and G.A.O.), and by a Department of Defense Defense Threat Reduction Agency contract (G.A.O.). NR 28 TC 36 Z9 36 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 SEP 21 PY 2010 VL 107 IS 38 BP 16554 EP 16559 DI 10.1073/pnas.1008302107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 652JW UT WOS:000282003700033 PM 20823219 ER PT J AU Pancewicz, J Taylor, JM Datta, A Baydoun, HH Waldmann, TA Hermine, O Nicot, C AF Pancewicz, Joanna Taylor, John M. Datta, Abhik Baydoun, Hicham H. Waldmann, Thomas A. Hermine, Olivier Nicot, Christophe TI Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; GAMMA-SECRETASE INHIBITORS; MOLECULAR PATHOGENESIS; ACTIVATION; MUTATIONS; PATHWAY; RESISTANCE; MASTERMIND; MECHANISMS; APOPTOSIS AB The Notch signaling pathway plays an important role in cellular proliferation, differentiation, and apoptosis. Unregulated activation of Notch signaling can result in excessive cellular proliferation and cancer. Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). The disease has a dismal prognosis and is invariably fatal. In this study, we report a high frequency of constitutively activated Notch in ATL patients. We found activating mutations in Notch in more than 30% of ATL patients. These activating mutations are phenotypically different from those previously reported in T-ALL leukemias and may represent polymorphisms for activated Notch in human cancers. Compared with the exclusive activating frameshift mutations in the proline, glutamic acid, serine, and threonine (PEST) domain in T-ALLs, those in ATLs have, in addition, single-substitution mutations in this domain leading to reduced CDC4/Fbw7-mediated degradation and stabilization of the intracellular cleaved form of Notch1 (ICN1). Finally, we demonstrated that inhibition of Notch signaling by gamma-secretase inhibitors reduced tumor cell proliferation and tumor formation in ATL-engrafted mice. These data suggest that activated Notch may be important to ATL pathogenesis and reveal Notch1 as a target for therapeutic intervention in ATL patients. C1 [Waldmann, Thomas A.] NIH, Metab Branch, Bethesda, MD 20892 USA. [Pancewicz, Joanna; Taylor, John M.; Datta, Abhik; Baydoun, Hicham H.; Nicot, Christophe] Univ Kansas, Med Ctr, Dept Pathol, Kansas City, KS 66160 USA. [Hermine, Olivier] Hop Necker Enfants Malad, CNRS, UMR 8603, F-75743 Paris 15, France. RP Waldmann, TA (reprint author), NIH, Metab Branch, Bldg 10, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov; cnicot@kumc.edu FU National Cancer Institute [CA106258, CA115398]; University of Kansas Medical Center Research Institute, Inc. FX We thank Dr. J. Aster (Brigham and Women's Hospital) for providing the MIG-ICN and MIGR1-MAML1 dominant-negative construct. ATL-derived HTLV-I-transformed cells MT1, TL-Om1, and ED40515(-) were provided by Dr. Michiyuki Maeda (University Sakyo-ku). SLB1 ATL-derived HTLV-I-transformed cells were provided by Dr. G. Feuer (State University of New York Upstate Medical University). The authors thank Elizabeth Jenkins for editorial assistance. This work was supported by Grants CA106258 and CA115398 from the National Cancer Institute (to C.N.) and by funds from the University of Kansas Medical Center Research Institute, Inc. (to C.N.). NR 31 TC 49 Z9 55 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 21 PY 2010 VL 107 IS 38 BP 16619 EP 16624 DI 10.1073/pnas.1010722107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 652JW UT WOS:000282003700044 PM 20823234 ER PT J AU Goldstein, RZ Woicik, PA Maloney, T Tomasi, D Alia-Klein, N Shan, JT Honorio, J Samaras, D Wang, RL Telang, F Wang, GJ Volkow, ND AF Goldstein, Rita Z. Woicik, Patricia A. Maloney, Thomas Tomasi, Dardo Alia-Klein, Nelly Shan, Juntian Honorio, Jean Samaras, Dimitris Wang, Ruiliang Telang, Frank Wang, Gene-Jack Volkow, Nora D. TI Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE prefrontal cortex; behavioral intervention; dopamine agonist; functional MRI blood oxygen level-dependent; emotional Stroop ID MEDIAL PREFRONTAL CORTEX; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; POSTTRAUMATIC-STRESS-DISORDER; ANTERIOR CINGULATE; ORBITOFRONTAL CORTEX; EMOTIONAL CONFLICT; BRAIN ACTIVATION; FRONTAL-CORTEX; DOPAMINE; ABUSE AB Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested. C1 [Goldstein, Rita Z.; Woicik, Patricia A.; Maloney, Thomas; Alia-Klein, Nelly; Wang, Ruiliang; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med Res, Ctr Translat Neuroimaging, Upton, NY 11973 USA. [Tomasi, Dardo; Telang, Frank; Volkow, Nora D.] NIAAA, Intramural Program, Rockville, MD 20857 USA. [Shan, Juntian; Honorio, Jean; Samaras, Dimitris] SUNY Stony Brook, Dept Comp Sci, Stony Brook, NY 11794 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, Dept Med Res, Ctr Translat Neuroimaging, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU National Institute on Drug Abuse [R01DA023579, R21DA02062, R01DA020949]; General Clinical Research Center [5-MO1-RR-10710] FX This study was supported by National Institute on Drug Abuse Grants R01DA023579 (to R.Z.G.), R21DA02062 (to R.Z.G.), and R01DA020949 (to D.S.), General Clinical Research Center Grant 5-MO1-RR-10710, and the Office of Biological and Environmental Research, Department of Energy (for infrastructure support). NR 59 TC 63 Z9 64 U1 2 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 SEP 21 PY 2010 VL 107 IS 38 BP 16667 EP 16672 DI 10.1073/pnas.1011455107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 652JW UT WOS:000282003700052 PM 20823246 ER PT J AU Ayanian, JZ Zaslavsky, AM Arora, NK Kahn, KL Malin, JL Ganz, PA van Ryn, M Hornbrook, MC Kiefe, CI He, YL Urmie, JM Weeks, JC Harrington, DP AF Ayanian, John Z. Zaslavsky, Alan M. Arora, Neeraj K. Kahn, Katherine L. Malin, Jennifer L. Ganz, Patricia A. van Ryn, Michelle Hornbrook, Mark C. Kiefe, Catarina I. He, Yulei Urmie, Julie M. Weeks, Jane C. Harrington, David P. TI Patients' Experiences With Care for Lung Cancer and Colorectal Cancer: Findings From the Cancer Care Outcomes Research and Surveillance Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-CARE; LANGUAGE CONCORDANCE; ASIAN-AMERICANS; SATISFACTION; BREAST AB Purpose To assess patients' experiences with cancer care, ratings of their quality of care, and correlates of these assessments. Patients and Methods For 4,093 patients with lung cancer and 3,685 patients with colorectal cancer in multiple US regions and health care delivery systems, we conducted telephone surveys of patients or their surrogates in English, Spanish, or Chinese at 4 to 7 months after diagnosis. The surveys assessed ratings of the overall quality of cancer care and experiences with three domains of interpersonal care (physician communication, nursing care, and coordination and responsiveness of care). Results English-speaking Asian/Pacific Islander patients and Chinese-speaking patients and those in worse health reported significantly worse adjusted experiences with all three domains of interpersonal care, whereas white, black, and Hispanic patients reported generally similar experiences with interpersonal care. The overall quality of cancer care was rated as excellent by 44.4% of patients with lung cancer and 53.0% of patients with colorectal cancer, and these ratings were most strongly correlated with positive experiences with coordination and responsiveness of care (Spearman rank coefficients of 0.49 and 0.42 for lung and colorectal cancer, respectively). After multivariate adjustment, excellent ratings were less common for each cancer among black patients, English-speaking Asian/Pacific Islander patients, Chinese-speaking patients, and patients reporting worse health status (all P <= .05). Conclusion Patients' reports and ratings of care differed significantly by race, language, and health status. Efforts to improve patients' experiences with cancer care should focus on problems affecting Asian and Pacific Islander patients and those in worse health. C1 [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Worcester, MA USA. NCI, Rockville, MD USA. Univ Calif Los Angeles, Los Angeles, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. RAND Corp, Santa Monica, CA USA. Univ Minnesota, Minneapolis, MN USA. NW Hawaii SE Kaiser Permanente NW, Portland, OR USA. Univ Iowa, Iowa City, IA USA. RP Ayanian, JZ (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM ayanian@hcp.med.harvard.edu FU National Cancer Institute [U01 CA093344, U01 CA093324, U01 CA093332, U01 CA093348, U01 CA093329, U01 CA093339, U01 CA093326]; Department of Veterans Affairs [U01 CDA093344]; HARQ [03-438MO-03] FX The Cancer Care Outcomes Research and Surveillance Consortium was supported by National Cancer Institute Grants No. U01 CA093344 to the Statistical Coordinating Center at the Dana-Farber Cancer Institute; U01 CA093324 to Harvard Medical School and Northern California Cancer Center; U01 CA093332 to the Dana-Farber Cancer Institute and Cancer Research Network; U01 CA093348 to the RAND Corporation and University of California, Los Angeles; U01 CA093329 to the University of Alabama at Birmingham; U01 CA093339 to the University of Iowa; and U01 CA093326 to the University of North Carolina; also supported by Department of Veterans Affairs Grants No. U01 CDA093344 (MOU) and HARQ 03-438MO-03 to the Durham Veterans Affairs Medical Center. NR 29 TC 50 Z9 50 U1 2 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 SEP 20 PY 2010 VL 28 IS 27 BP 4154 EP 4161 DI 10.1200/JCO.2009.27.3268 PG 8 WC Oncology SC Oncology GA 651FB UT WOS:000281909700011 PM 20713876 ER PT J AU Stadler, ZK Thom, P Robson, ME Weitzel, JN Kauff, ND Hurley, KE Devlin, V Gold, B Klein, RJ Offit, K AF Stadler, Zsofia K. Thom, Peter Robson, Mark E. Weitzel, Jeffrey N. Kauff, Noah D. Hurley, Karen E. Devlin, Vincent Gold, Bert Klein, Robert J. Offit, Kenneth TI Genome-Wide Association Studies of Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID COMMON SEQUENCE VARIANTS; POSITIVE BREAST-CANCER; BASAL-CELL CARCINOMA; 5 GENETIC-VARIANTS; PROSTATE-CANCER; COLORECTAL-CANCER; SUSCEPTIBILITY LOCI; LUNG-CANCER; POPULATION STRATIFICATION; CONFER SUSCEPTIBILITY AB Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited. C1 [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10021 USA. City Hope Natl Med Ctr, Div Clin Canc Genet, Duarte, CA USA. NCI, Ctr Canc Res, Canc Inflammat Program, Human Genet Sect, Frederick, MD 21701 USA. RP Offit, K (reprint author), Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Box 192,1275 York Ave, New York, NY 10021 USA. EM offitk@mskcc.org RI Klein, Robert/K-1888-2013; OI Klein, Robert/0000-0003-3539-5391; Robson, Mark/0000-0002-3109-1692; Kauff, Noah/0000-0001-7242-6156 FU Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Lymphoma Foundation; Breast Cancer Research Foundation; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported in part by The Robert and Kate Niehaus Clinical Cancer Genetics Initiative, The Lymphoma Foundation, the Breast Cancer Research Foundation, and funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 104 TC 57 Z9 58 U1 0 U2 2 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 SEP 20 PY 2010 VL 28 IS 27 BP 4255 EP 4267 DI 10.1200/JCO.2009.25.7816 PG 13 WC Oncology SC Oncology GA 651FB UT WOS:000281909700024 PM 20585100 ER PT J AU Gunderson, LL Jessup, JM Greene, FL AF Gunderson, Leonard L. Jessup, J. Milburn Greene, Frederick L. TI Conflicting Finding on Intramucosal Colon Cancers Based on National Survival Outcomes Data Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Gunderson, Leonard L.] Mayo Clin, Ctr Canc, Scottsdale, AZ USA. [Jessup, J. Milburn] NCI, Bethesda, MD 20892 USA. [Greene, Frederick L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. RP Gunderson, LL (reprint author), Mayo Clin, Ctr Canc, Scottsdale, AZ USA. NR 2 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 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2010 VL 28 IS 27 BP E470 EP E470 DI 10.1200/JCO.2010.29.3480 PG 1 WC Oncology SC Oncology GA 651FB UT WOS:000281909700038 ER PT J AU Brichacek, B Vanpouille, C Kiselyeva, Y Biancotto, A Merbah, M Hirsch, I Lisco, A Grivel, JC Margolis, L AF Brichacek, Beda Vanpouille, Christophe Kiselyeva, Yana Biancotto, Angelique Merbah, Melanie Hirsch, Ivan Lisco, Andrea Grivel, Jean Charles Margolis, Leonid TI Contrasting Roles for TLR Ligands in HIV-1 Pathogenesis SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN LYMPHOID-TISSUE; TOLL-LIKE RECEPTORS; T-CELL-ACTIVATION; PATTERN-RECOGNITION RECEPTORS; TROPICAL INFECTIOUS-DISEASES; MEROZOITE SURFACE PROTEIN-1; X-C-CHEMOKINE; INNATE IMMUNITY; CXCR4-TROPIC HIV-1 AB The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs). Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs) 5 and 9, we examined their effect on human immunodeficiency virus (HIV)-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist) treatment enhanced replication of CC chemokine receptor 5 (CCR 5)-tropic and CXC chemokine receptor 4 (CXCR4)-tropic HIV-1, treatment with oligodeoxynucleotide (ODN) M362 (TLR9 agonist) suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD) 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA)-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention. C1 [Brichacek, Beda; Vanpouille, Christophe; Kiselyeva, Yana; Biancotto, Angelique; Merbah, Melanie; Lisco, Andrea; Grivel, Jean Charles; Margolis, Leonid] NICHHD, Sect Intercellular Interact, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Hirsch, Ivan] Univ Mediterrane, Inst Paoli Calmettes, INSERM, Ctr Rech Cancerol Marseille,UMR 891, Marseille, France. RP Brichacek, B (reprint author), NICHHD, Sect Intercellular Interact, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM bricbeda@mail.nih.gov RI Hirsch, Ivan/J-7726-2015; OI Hirsch, Ivan/0000-0003-1701-1438 FU National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 96 TC 16 Z9 16 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2010 VL 5 IS 9 AR e12831 DI 10.1371/journal.pone.0012831 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 651YH UT WOS:000281963200013 ER PT J AU Miller, MA Conrad, PA Harris, M Hatfield, B Langlois, G Jessup, DA Magargal, SL Packham, AE Toy-Choutka, S Melli, AC Murray, MA Gulland, FM Grigg, ME AF Miller, Melissa A. Conrad, Patricia A. Harris, Michael Hatfield, Brian Langlois, Gregg Jessup, David A. Magargal, Spencer L. Packham, Andrea E. Toy-Choutka, Sharon Melli, Ann C. Murray, Michael A. Gulland, Frances M. Grigg, Michael E. TI A protozoal-associated epizootic impacting marine wildlife: Mass-mortality of southern sea otters (Enhydra lutris nereis) due to Sarcocystis neurona infection SO VETERINARY PARASITOLOGY LA English DT Article DE Sea otter; Enhydra lutris; Sarcocystis neurona; 18S rDNA; ITS-1; Epizootic ID PHOCA-VITULINA-RICHARDSI; TOXOPLASMA-GONDII; COASTAL CALIFORNIA; DRINKING-WATER; DOMOIC ACID; MUSSELS; SPP.; MENINGOENCEPHALITIS; CRYPTOSPORIDIUM; CONTAMINATION AB During April 2004,40 sick and dead southern sea otters (Enhydra lutris nereis) were recovered over 18 km of coastline near Morro Bay, California. This event represented the single largest monthly spike in mortality ever recorded during 30 years of southern sea otter stranding data collection. Because of the point-source nature of the event and clinical signs consistent with severe, acute neurological disease, exposure to a chemical or marine toxin was initially considered. However, detailed postmortem examinations revealed lesions consistent with an infectious etiology, and further investigation confirmed the protozoan parasite Sarcocystis neurona as the underlying cause. Tissues from 94% of examined otters were PCR-positive for S. neurona, based on DNA amplification and sequencing at the ITS-1 locus, and 100% of tested animals (n = 14) had elevated IgM and IgG titers to S. neurona. Evidence to support the point-source character of this event include the striking spatial and temporal clustering of cases and detection of high concentrations of anti-S. neurona IgM in serum of stranded animals. Concurrent exposure to the marine biotoxin domoic acid may have enhanced susceptibility of affected otters to S. neurona and exacerbated the neurological signs exhibited by stranded animals. Other factors that may have contributed to the severity of this epizootic include a large rainstorm that preceded the event and an abundance of razor clams near local beaches, attracting numerous otters close to shore within the affected area. This is the first report of a localized epizootic in marine wildlife caused by apicomplexan protozoa. (C) 2010 Elsevier B.V. All rights reserved. C1 [Miller, Melissa A.; Harris, Michael; Jessup, David A.; Toy-Choutka, Sharon] CDFG OSPR, Marine Wildlife Vet Care & Res Ctr, Santa Cruz, CA 95060 USA. [Conrad, Patricia A.; Packham, Andrea E.; Melli, Ann C.] Univ Calif Davis, Dept Pathol Microbiol & Immunol, Sch Vet Med, Davis, CA 95616 USA. [Hatfield, Brian] US Geol Survey, San Simeon, CA 93452 USA. [Langlois, Gregg] Calif Dept Hlth Serv, Environm Management Branch, Richmond, CA 94804 USA. [Magargal, Spencer L.; Grigg, Michael E.] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Murray, Michael A.] Monterey Bay Aquarium, Monterey, CA 93940 USA. [Gulland, Frances M.] Marine Mammal Ctr, Sausalito, CA 94965 USA. RP Miller, MA (reprint author), CDFG OSPR, Marine Wildlife Vet Care & Res Ctr, Santa Cruz, CA 95060 USA. EM mmiller@ospr.dfg.ca.gov FU NIH; NIAID; CDFG-OSPR; USGS; Monterey Bay Aquarium; United States Fish and Wildlife Service FX We thank J. Ames, E. Berberich, D. Brownstein, E. Dodd, E. Dorfmeier, J. Mazet and W. Miller for assistance. The Microbial Diseases Laboratory and the Food and Drug Laboratory, CDPH, for DA analyses. This research was supported in part by the Intramural Research Program of the NIH and NIAID (MEG), CDFG-OSPR, USGS, Monterey Bay Aquarium and the United States Fish and Wildlife Service. This manuscript is dedicated to Dr Peter Kennedy, an outstanding pathologist, mentor and lifelong student who believed in doing good things for sea otters. NR 44 TC 23 Z9 25 U1 4 U2 46 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 J9 VET PARASITOL JI Vet. Parasitol. PD SEP 20 PY 2010 VL 172 IS 3-4 BP 183 EP 194 DI 10.1016/j.vetpar.2010.05.019 PG 12 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA 652FY UT WOS:000281989700002 PM 20615616 ER PT J AU Zhang, RX Zhang, FB Wang, CJ Wang, SX Shiao, YH Guo, ZJ AF Zhang, Ruixing Zhang, Fengbin Wang, Cuiju Wang, Shunxiang Shiao, Yih-Horng Guo, Zhanjun TI Identification of sequence polymorphism in the D-Loop region of mitochondrial DNA as a risk factor for hepatocellular carcinoma with distinct etiology SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Article ID CANCER RISK; PANCREATIC-CANCER; SOMATIC MUTATIONS; HEPATITIS-B; TRANSCRIPTION; DISEASE; CHINA; EPIDEMIOLOGY; REPLICATION; MAINTENANCE AB Background: Hepatocellular carcinoma (HCC) is frequently preceded by hepatitis virus infection or alcohol abuse. Genetic backgrounds may increase susceptibility to HCC from these exposures. Methods: Mitochondrial DNA (mtDNA) of peripheral blood, tumor, and/or adjacent non-tumor tissue from 49 hepatitis B virus-related and 11 alcohol-related HCC patients, and from 38 controls without HCC were examined for single nucleotide polymorphisms (SNPs) and mutations in the D-Loop region. Results: Single nucleotide polymorphisms (SNPs) in the D-loop region of mt DNA were examined in HCC patients. Individual SNPs, namely the 16266C/T, 16293A/G, 16299A/G, 16303G/A, 242C/T, 368A/G, and 462C/T minor alleles, were associated with increased risk for alcohol-HCC, and the 523A/del was associated with increased risks of both HCC types. The mitochondrial haplotypes under the M haplogroup with a defining 489C polymorphism were detected in 27 (55.1%) of HBV-HCCand 8 (72.7%) of alcohol-HCC patients, and in 15 (39.5%) of controls. Frequencies of the 489T/152T, 489T/523A, and 489T/525C haplotypes were significantly reduced in HBV-HCC patients compared with controls. In contrast, the haplotypes of 489C with 152T, 249A, 309C, 523Del, or 525Del associated significantly with increase of alcohol-HCC risk. Mutations in the D-Loop region were detected in 5 adjacent non-tumor tissues and increased in cancer stage (21 of 49 HBV-HCC and 4 of 11 alcohol-HCC, p < 0.002). Conclusions: In sum, mitochondrial haplotypes may differentially predispose patients to HBV-HCC and alcohol-HCC. Mutations of the mitochondrial D-Loop sequence may relate to HCC development. C1 [Shiao, Yih-Horng] NCI, Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. [Zhang, Ruixing; Zhang, Fengbin; Guo, Zhanjun] Hebei Med Univ, Hosp 4, Dept Gastroenterol & Hepatol, Shijiazhuang, Peoples R China. [Wang, Cuiju] Hebei Med Univ, Hosp 4, Dept Gynecol Ultrasound, Shijiazhuang, Peoples R China. [Wang, Shunxiang] Hebei Med Univ, Hosp 4, Dept Hepatobiliary Surg, Shijiazhuang, Peoples R China. RP Shiao, YH (reprint author), NCI, Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. EM shiaoy@mail.nih.gov; zjguo5886@yahoo.com.cn FU National Natural Science Foundation of PR China [30801384]; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by National Natural Science Foundation of PR China No. 30801384. The research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 30 TC 27 Z9 28 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-9966 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD SEP 18 PY 2010 VL 29 AR 130 DI 10.1186/1756-9966-29-130 PG 7 WC Oncology SC Oncology GA 656OQ UT WOS:000282346500001 PM 20849651 ER PT J AU Vinogradova, TM Brochet, DXP Sirenko, S Li, Y Spurgeon, H Lakatta, EG AF Vinogradova, Tatiana M. Brochet, Didier X. P. Sirenko, Syevda Li, Yue Spurgeon, Harold Lakatta, Edward G. TI Sarcoplasmic Reticulum Ca2+ Pumping Kinetics Regulates Timing of Local Ca2+ Releases and Spontaneous Beating Rate of Rabbit Sinoatrial Node Pacemaker Cells SO CIRCULATION RESEARCH LA English DT Article ID PROTEIN-KINASE-A; RYANODINE RECEPTOR; DIASTOLIC DEPOLARIZATION; CYCLOPIAZONIC ACID; PHOSPHOLAMBAN GENE; CALCIUM; STIMULATION; PHOSPHORYLATION; INHIBITION; MECHANISM AB Rationale: Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR) during late diastolic depolarization. LCRs activate an inward Na+-Ca2+ exchange current (I-NCX), which accelerates diastolic depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca2+ transient and LCR appearance, defines the time of late diastolic depolarization I-NCX activation. Mechanisms that control the LCR period, however, are still unidentified. Objective: To determine dependence of the LCR period on SR Ca2+ refilling kinetics and establish links between regulation of SR Ca2+ replenishment, LCR period, and spontaneous cycle length. Methods and Results: Spontaneous APs and SR luminal or cytosolic Ca2+ were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca2+ following AP-induced Ca2+ transient was highly correlate C1 [Lakatta, Edward G.] NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU National Institutes of Health, National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 36 TC 32 Z9 33 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 17 PY 2010 VL 107 IS 6 BP 767 EP U224 DI 10.1161/CIRCRESAHA.110.220517 PG 20 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 652ME UT WOS:000282010000009 PM 20651285 ER PT J AU Tian, P Bernstein, HD AF Tian, Pu Bernstein, Harris D. TI Molecular Basis for the Structural Stability of an Enclosed beta-Barrel Loop SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE beta barrel; loop; stability; geometrical constraint; MD simulation ID TITIN IMMUNOGLOBULIN DOMAINS; BACTERIAL OUTER-MEMBRANE; CONFORMATIONAL-CHANGES; DYNAMICS CALCULATIONS; MECHANICAL STABILITY; TRANSITION-STATE; EXTERNAL FORCES; SINGLE-PROTEIN; UBIQUITIN; SIMULATION AB We present molecular dynamics simulation studies of the structural stability of an enclosed loop in the beta domain of the Escherichia coli O157: H7 autotransporter EspP. Our investigation revealed that, in addition to its excellent resistance to thermal perturbations, EspP loop 5 (L5) also has remarkable mechanical stability against pulling forces along the membrane norm. These findings are consistent with the experimental report that EspP L5 helps to maintain the permeability barrier in the outer membrane. In contrast to the major secondary structure elements of globular proteins such as ubiquitin, whose resistance to thermal and mechanical perturbations depends mainly on backbone hydrogen bonds and hydrophobic interactions, the structural stability of EspP L5 can be attributed mainly to geometric constraints and side-chain interactions dominated by hydrogen bonds. Examination of B-factors from available high-resolution structures of membrane-embedded beta barrels indicates that most of the enclosed loops have stable structures. This finding suggests that loops stabilized by geometric constraints and side-chain interactions might be used more generally to restrict beta-barrel channels for various functional purposes. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Tian, Pu; Bernstein, Harris D.] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Tian, P (reprint author), Jilin Univ, Coll Life Sci, 2699 QianJin St, Changchun 130012, Peoples R China. EM tianpu@jlu.edu.cn RI TIAN, PU/F-5739-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This study was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Computational resources for this study were provided by the National Institutes of Health Biowulf cluster. We thank Bertram Canagarajah and Emanuele Paci for helpful comments on the manuscript. NR 47 TC 8 Z9 8 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 17 PY 2010 VL 402 IS 2 BP 475 EP 489 DI 10.1016/j.jmb.2010.07.035 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 667QM UT WOS:000283208700014 PM 20655928 ER PT J AU Zhang, FL Saha, S Shabalina, SA Kashina, A AF Zhang, Fangliang Saha, Sougata Shabalina, Svetlana A. Kashina, Anna TI Differential Arginylation of Actin Isoforms Is Regulated by Coding Sequence-Dependent Degradation SO SCIENCE LA English DT Article ID N-END RULE; RNA-PROTEIN TRANSFERASE; CELLS; IDENTIFICATION; TRANSLATION; RIBOSOME; PATHWAY AB The mammalian cytoskeletal proteins beta- and gamma-actin are highly homologous, but only beta-actin is amino-terminally arginylated in vivo, which regulates its function. We examined the metabolic fate of exogenously expressed arginylated and nonarginylated actin isoforms. Arginylated gamma-actin, unlike beta-, was highly unstable and was selectively ubiquitinated and degraded in vivo. This instability was regulated by the differences in the nucleotide coding sequence between the two actin isoforms, which conferred different translation rates. gamma-actin was translated more slowly than beta-actin, and this slower processing resulted in the exposure of a normally hidden lysine residue for ubiquitination, leading to the preferential degradation of gamma-actin upon arginylation. This degradation mechanism, coupled to nucleotide coding sequence, may regulate protein arginylation in vivo. C1 [Zhang, Fangliang; Saha, Sougata; Kashina, Anna] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. [Shabalina, Svetlana A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Kashina, A (reprint author), Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. EM akashina@vet.upenn.edu RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 FU NIH [5R01HL084419]; W. W. Smith Charitable Trust; Philip Morris Research Management Group; NIH, National Center for Biotechnology Information FX We thank R. Dominguez for help with actin structure analysis and the preparation of fig. S15; D. Volgin for helpful suggestions on quantitative polymerase chain reaction; S. Fuchs, Y. Goldman, and J. M. Murray for helpful discussions; and S. Kurosaka for critical reading of the manuscript. This work was supported by NIH grant 5R01HL084419 and W. W. Smith Charitable Trust and Philip Morris Research Management Group awards to A. K. and by the Intramural Research Program of NIH, National Center for Biotechnology Information, to S.A.S. NR 22 TC 73 Z9 74 U1 0 U2 6 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 SEP 17 PY 2010 VL 329 IS 5998 BP 1534 EP 1537 DI 10.1126/science.1191701 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 650RK UT WOS:000281869000045 PM 20847274 ER PT J AU Zhang, XQ Matsui, K Krohmal, B Abou Zeid, A Muthuswamy, V Koo, YM Kita, Y Lie, RK AF Zhang, Xinqing Matsui, Kenji Krohmal, Benjamin Abou Zeid, Alaa Muthuswamy, Vasantha Koo, Young Mo Kita, Yoshikuni Lie, Reidar K. TI Attitudes towards transfers of human tissue samples across borders: An international survey of researchers and policy makers in five countries SO BMC MEDICAL ETHICS LA English DT Article AB Background: Sharing of tissue samples for research and disease surveillance purposes has become increasingly important. While it is clear that this is an area of intense, international controversy, there is an absence of data about what researchers themselves and those involved in the transfer of samples think about these issues, particularly in developing countries. Methods: A survey was carried out in a number of Asian countries and in Egypt to explore what researchers and others involved in research, storage and transfer of human tissue samples thought about some of the issues related to sharing of such samples. Results: The results demonstrated broad agreement with the positions taken by developing countries in the current debate, favoring quite severe restrictions on the use of samples by developed countries. Conclusions: It is recommended that an international agreement is developed on what conditions should be attached to any sharing of human tissue samples across borders. C1 [Lie, Reidar K.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Zhang, Xinqing] Peking Union Med Coll, Ctr Bioeth, Beijing, Peoples R China. [Matsui, Kenji] Toyama Univ, Ctr Clin Bioeth, Toyama, Japan. [Matsui, Kenji; Kita, Yoshikuni] Shiga Univ Med Sci, Dept Hlth Sci, Shiga, Japan. [Abou Zeid, Alaa] Cairo Univ, Fac Med, Cairo, Egypt. [Koo, Young Mo] Univ Ulsan, Dept Med Humanities & Social Sci, Coll Med, Ulsan, South Korea. [Lie, Reidar K.] Univ Bergen, Dept Philosophy, N-5020 Bergen, Norway. RP Lie, RK (reprint author), NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. EM reidar.lie@fil.uib.no FU NIH Clinical Center; [19602001] FX This research was supported by the Intramural Research Program of the NIH Clinical Center. The opinions expressed are the author's own. They do not reflect any position or policy of the National Institutes of Health, Public Health Service, or Department of Health and Human Services. This research was also supported by the Grant-in-Aid for Scientific Research (C) of Japan (no. 19602001) NR 13 TC 6 Z9 6 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6939 J9 BMC MED ETHICS JI BMC Med. Ethics PD SEP 16 PY 2010 VL 11 AR 16 DI 10.1186/1472-6939-11-16 PG 7 WC Ethics; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Biomedical Social Sciences GA 667ET UT WOS:000283176200001 PM 20843366 ER PT J AU Day, PM Kines, RC Thompson, CD Jagu, S Roden, RB Lowy, DR Schiller, JT AF Day, Patricia M. Kines, Rhonda C. Thompson, Cynthia D. Jagu, Subhashini Roden, Richard B. Lowy, Douglas R. Schiller, John T. TI In Vivo Mechanisms of Vaccine-Induced Protection against HPV Infection SO CELL HOST & MICROBE LA English DT Article ID MINOR CAPSID PROTEIN; VIRUS-LIKE PARTICLES; COTTONTAIL RABBIT PAPILLOMAVIRUS; HEPARAN-SULFATE; BASEMENT-MEMBRANE; HUMAN SERA; NEUTRALIZATION; L2; IMMUNIZATION; INHIBITION AB Using a human papillomavirus (HPV) cervicovaginal murine challenge model, we microscopically examined the in vivo mechanisms of L1 virus-like particle (VLP) and L2 vaccine-induced inhibition of infection. In vivo HPV infection requires an initial association with the acellular basement membrane (BM) to induce conformational changes in the virion that permit its association with the keratinocyte cell surface. By passive transfer of immune serum, we determined that anti-L1 antibodies can interfere with infection at two stages. Similarly to active VLP immunization, transfer of high L1 antibody concentrations prevented BM binding. However, in the presence of low concentrations of anti-L1, virions associated with the BM, but to the epithelial cell surface was not detected. Regardless of the concentration, L2 vaccine-induced antibodies allow BM association but prevent association with the cell surface. Thus, we have revealed distinct mechanisms of vaccine-induced inhibition of virus infection in vivo. C1 [Day, Patricia M.; Kines, Rhonda C.; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.] NCI, Lab Cellular Oncol, NIH, Bethesda, MD 20892 USA. [Jagu, Subhashini; Roden, Richard B.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21231 USA. [Roden, Richard B.] Johns Hopkins Sch Med, Dept Oncol Gynecol & Obstet, Baltimore, MD 21231 USA. RP Schiller, JT (reprint author), NCI, Lab Cellular Oncol, NIH, Bethesda, MD 20892 USA. EM schillej@dc37a.nci.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute; SPORE in Cervical Cancer [P50 CA098252, CA118790]; GlaxoSmithKline FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and by National Cancer Institute, SPORE in Cervical Cancer, P50 CA098252 and CA118790 to R.B.R. and a Prevent Cancer Foundation, Alexandria, VA fellowship to S.J.; D.R.L. and J.T.S. are inventors of intellectual property owned by the US government for the L1 vaccine. D.R.L., J.T.S., S.J. and R.B.R. are inventors of intellectual property owned by the US government and Johns Hopkins University for the L2 vaccine. R.B.R. has been a paid consultant of Merck & Co, Inc., and both S.J. and R.B.R. have received unrestricted educational grant funding from GlaxoSmithKline. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. NR 43 TC 71 Z9 73 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD SEP 16 PY 2010 VL 8 IS 3 BP 260 EP 270 DI 10.1016/j.chom.2010.08.003 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 660GA UT WOS:000282626900007 PM 20833377 ER PT J AU Beltramello, M Williams, KL Simmons, CP Macagno, A Simonelli, L Quyen, NTH Sukupolvi-Petty, S Navarro-Sanchez, E Young, PR de Silva, AM Rey, FA Varani, L Whitehead, SS Diamond, MS Harris, E Lanzavecchia, A Sallusto, F AF Beltramello, Martina Williams, Katherine L. Simmons, Cameron P. Macagno, Annalisa Simonelli, Luca Quyen, Nguyen Than Ha Sukupolvi-Petty, Soila Navarro-Sanchez, Erika Young, Paul R. de Silva, Aravinda M. Rey, Felix A. Varani, Luca Whitehead, Stephen S. Diamond, Michael S. Harris, Eva Lanzavecchia, Antonio Sallusto, Federica TI The Human Immune Response to Dengue Virus Is Dominated by Highly Cross-Reactive Antibodies Endowed with Neutralizing and Enhancing Activity SO CELL HOST & MICROBE LA English DT Article ID WEST-NILE-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; IMMUNOGLOBULIN G1 ANTIBODY; CHIMPANZEE FAB FRAGMENTS; BORNE ENCEPHALITIS-VIRUS; PROTEIN DOMAIN-III; ENVELOPE GLYCOPROTEIN; DEPENDENT ENHANCEMENT; HEMORRHAGIC-FEVER; MEDIATED NEUTRALIZATION AB Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fc gamma receptors (Fc gamma R). We immortalized memory B cells from individuals after primary or secondary infection and analyzed anti-DENV monoclonal antibodies (mAbs) thus generated. MAbs to envelope (E) protein domain III (DIII) were either serotype specific or cross-reactive and potently neutralized DENV infection. DI/DII- or viral membrane protein prM-reactive mAbs neutralized poorly and showed broad cross-reactivity with the four DENV serotypes. All mAbs enhanced infection at subneutralizing concentrations. Three mAbs targeting distinct epitopes on the four DENV serotypes and engineered to prevent Fc gamma R binding did not enhance infection and neutralized DENV in vitro and in vivo as postexposure therapy in a mouse model of lethal DENV infection. Our findings reveal an unexpected degree of cross-reactivity in human antibodies against DENV and illustrate the potential for an antibody-based therapy to control severe dengue. C1 [Beltramello, Martina; Macagno, Annalisa; Simonelli, Luca; Varani, Luca; Lanzavecchia, Antonio; Sallusto, Federica] Inst Res Biomed, CH-6500 Bellinzona, Switzerland. [Williams, Katherine L.; Harris, Eva] Univ Calif Berkeley, Div Infect Dis, Berkeley, CA 94720 USA. [Simmons, Cameron P.; Quyen, Nguyen Than Ha] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Sukupolvi-Petty, Soila; Diamond, Michael S.] Washington Univ, Dept Med, Sch Med, St Louis, MO 63110 USA. [Sukupolvi-Petty, Soila; Diamond, Michael S.] Washington Univ, Dept Mol Microbiol, Sch Med, St Louis, MO 63110 USA. [Sukupolvi-Petty, Soila; Diamond, Michael S.] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA. [Navarro-Sanchez, Erika; Rey, Felix A.] Inst Pasteur, Dept Virol, F-75724 Paris, France. [Young, Paul R.] Univ Queensland, Sch Chem & Mol Biosci, Ctr Infect Dis Res, Brisbane, Qld 4072, Australia. [de Silva, Aravinda M.] Univ N Carolina, Dept Microbiol & Immunol, Sch Med, Chapel Hill, NC 27599 USA. [Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Lanzavecchia, A (reprint author), Inst Res Biomed, CH-6500 Bellinzona, Switzerland. EM lanzavecchia@irb.unisi.ch; federica.sallusto@irb.unisi.ch RI Young, Paul/A-6176-2010; Rey, Felix/B-6497-2012; OI Young, Paul/0000-0002-2040-5190; Simmons, Cameron P./0000-0002-9039-7392; varani, luca/0000-0002-0963-0987; Rey, Felix/0000-0002-9953-7988 FU Gottfried and Julia Bangerter-Rhyner-Stiftung; Swiss National Science Foundation [126027]; Swiss Vaccine Research Institute; Wellcome Trust; Pediatric Dengue Vaccine Initiative [CRA14]; NIH [R01-AI077955, AI65359, U19-AI 057266]; Helmut Horten Foundation FX We thank Michel Nussenzweig for providing vectors to clone and express Ig genes, David Jarrossay for cell sorting, Catriona McElnea for the NS1 screening, and Ruben Lachica for his excellent technical assistance with the in vivo experiments. This research was supported in part by the Gottfried and Julia Bangerter-Rhyner-Stiftung (to F.S.), the Swiss National Science Foundation Grant N. 126027 (to A.L.), the Swiss Vaccine Research Institute (to L.V.), the Wellcome Trust (to C.P.S.), the Pediatric Dengue Vaccine Initiative (CRA14 to E.H.), NIH grant R01-AI077955 (to M.S.D.), AI65359 (to E.H.), and U19-AI 057266 (to A.L.) and by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, NIH (to S.S.W.). The Institute for Research in Biomedicine is supported by the Helmut Horten Foundation. A.L. is the scientific founder of Humabs LLC and a member of its Board of Directors. A.L. and F.S. are shareholders of Humabs. NR 64 TC 227 Z9 230 U1 4 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD SEP 16 PY 2010 VL 8 IS 3 BP 271 EP 283 DI 10.1016/j.chom.2010.08.007 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 660GA UT WOS:000282626900008 PM 20833378 ER PT J AU Maxwell, SK Airola, M Nuckols, JR AF Maxwell, Susan K. Airola, Matthew Nuckols, John R. TI Using Landsat satellite data to support pesticide exposure assessment in California SO INTERNATIONAL JOURNAL OF HEALTH GEOGRAPHICS LA English DT Article ID RESIDENTIAL EXPOSURE; VEGETATION INDEXES; CROPS; PROXIMITY; CHILDREN; GAPS; ETM+; CORN AB Background: The recent U. S. Geological Survey policy offering Landsat satellite data at no cost provides researchers new opportunities to explore relationships between environment and health. The purpose of this study was to examine the potential for using Landsat satellite data to support pesticide exposure assessment in California. Methods and Results: We collected a dense time series of 24 Landsat 5 and 7 images spanning the year 2000 for an agricultural region in Fresno County. We intersected the Landsat time series with the California Department of Water Resources (CDWR) land use map and selected field samples to define the phenological characteristics of 17 major crop types or crop groups. We found the frequent overpass of Landsat enabled detection of crop field conditions (e. g., bare soil, vegetated) over most of the year. However, images were limited during the winter months due to cloud cover. Many samples designated as single-cropped in the CDWR map had phenological patterns that represented multi-cropped or non-cropped fields, indicating they may have been misclassified. Conclusions: We found the combination of Landsat 5 and 7 image data would clearly benefit pesticide exposure assessment in this region by 1) providing information on crop field conditions at or near the time when pesticides are applied, and 2) providing information for validating the CDWR map. The Landsat image time-series was useful for identifying idle, single-, and multi-cropped fields. Landsat data will be limited during the winter months due to cloud cover, and for years prior to the Landsat 7 launch (1999) when only one satellite was operational at any given time. We suggest additional research to determine the feasibility of integrating CDWR land use maps and Landsat data to derive crop maps in locations and time periods where maps are not available, which will allow for substantial improvements to chemical exposure estimation. C1 [Maxwell, Susan K.] BioMedware Inc, Ann Arbor, MI USA. [Airola, Matthew; Nuckols, John R.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Airola, Matthew] Westat Corp, Rockville, MD USA. [Nuckols, John R.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Maxwell, SK (reprint author), BioMedware Inc, Ann Arbor, MI USA. EM maxwell@biomedware.com FU NCI NIH HHS [R01 CA92683-01] NR 34 TC 11 Z9 11 U1 0 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-072X J9 INT J HEALTH GEOGR JI Int. J. Health Geogr. PD SEP 16 PY 2010 VL 9 AR 46 DI 10.1186/1476-072X-9-46 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 656FJ UT WOS:000282311300001 PM 20846438 ER PT J AU Evans, JP Dale, DC Fomous, C AF Evans, James P. Dale, David C. Fomous, Cathy TI Preparing for a Consumer-Driven Genomic Age. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Evans, James P.; Dale, David C.] Secretarys Advisory Comm Genet Hlth & Soc, Washington, DC USA. [Evans, James P.] Univ N Carolina, Chapel Hill, NC USA. [Dale, David C.] Univ Washington, Seattle, WA 98195 USA. [Fomous, Cathy] NIH, Off Biotechnol Act, Bethesda, MD 20892 USA. RP Evans, JP (reprint author), Secretarys Advisory Comm Genet Hlth & Soc, Washington, DC USA. NR 3 TC 28 Z9 30 U1 1 U2 5 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 SEP 16 PY 2010 VL 363 IS 12 BP 1099 EP 1103 DI 10.1056/NEJMp1006202 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 649TD UT WOS:000281795800002 PM 20843241 ER PT J AU Factor, VM Seo, D Ishikawa, T Kaposi-Novak, P Marquardt, JU Andersen, JB Conner, EA Thorgeirsson, SS AF Factor, Valentina M. Seo, Daekwan Ishikawa, Tsuyoshi Kaposi-Novak, Pal Marquardt, Jens U. Andersen, Jesper B. Conner, Elizabeth A. Thorgeirsson, Snorri S. TI Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice SO PLOS ONE LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; MITOTIC CHROMOSOME CONDENSATION; SIGNAL-REGULATED KINASE; CELL-CYCLE PROGRESSION; EGF RECEPTOR; HISTONE H3; PATHWAY; PHOSPHORYLATION; MITOSIS; ACTIVATION AB Background: Previous work has established that HGF/c-Met signaling plays a pivotal role in regulating the onset of S phase following partial hepatectomy (PH). In this study, we used Met(fl/fl); Alb-Cre(+/-) conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration. Methodology/Principal Finding: The priming events appeared to be intact in Met(fl/fl); Alb-Cre(+/-) livers. Up-regulation of stress response (MAFK, IKBZ, SOCS3) and early growth response (c-Myc, c-Jun, c-Fos, DUSP1 and 6) genes as assessed by RT-qPCR and/or microarray profiling was unchanged. This was consistent with an early induction of MAPK/Erk and STAT3. However, after a successful completion of the first round of DNA replication, c-Met deficient hepatocytes were blocked in early/mid G2 phase as shown by staining with phosphorylated form of histone H3. Furthermore, loss of c-Met in hepatocytes diminished the subsequent G1/S progression and delayed liver recovery after partial hepatectomy. Upstream signaling pathways involved in the blockage of G2/M transition included lack of persistent Erk1/2 activation and inability to up-regulate the levels of Cdk1, Plk1, Aurora A and B, and Mad2 along with a defective histone 3 phosphorylation and lack of chromatin condensation. Continuous supplementation with EGF in vitro increased proliferation of Met(fl/fl); Alb-Cre(+/-) primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures. Conclusion/Significance: In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration. C1 [Factor, Valentina M.; Seo, Daekwan; Ishikawa, Tsuyoshi; Kaposi-Novak, Pal; Marquardt, Jens U.; Andersen, Jesper B.; Conner, Elizabeth A.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Factor, VM (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244 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 funders had no role in study design, data collection and analysis, decision to publish or preparation of manuscript. NR 46 TC 19 Z9 20 U1 0 U2 8 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 SEP 16 PY 2010 VL 5 IS 9 AR e12739 DI 10.1371/journal.pone.0012739 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 650QH UT WOS:000281864100007 ER PT J AU Gowen, BB Julander, JG London, NR Wong, MH Larson, D Morrey, JD Li, DY Bray, M AF Gowen, Brian B. Julander, Justin G. London, Nyall R. Wong, Min-Hui Larson, Deanna Morrey, John D. Li, Dean Y. Bray, Mike TI Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever SO VIROLOGY JOURNAL LA English DT Article ID INDUCED LETHAL DISEASE; VIRUS-INFECTION; MESOCRICETUS-AURATUS; BLOOD-VOLUME; LASSA FEVER; EVANS BLUE; DENGUE; RIBAVIRIN AB Background: A number of RNA viruses cause viral hemorrhagic fever (VHF), in which proinflammatory mediators released from infected cells induce increased permeability of the endothelial lining of blood vessels, leading to loss of plasma volume, hypotension, multi-organ failure, shock and death. The optimal treatment of VHF should therefore include both the use of antiviral drugs to inhibit viral replication and measures to prevent or correct changes in vascular function. Although rodent models have been used to evaluate treatments for increased vascular permeability (VP) in bacterial sepsis, such studies have not been performed for VHF. Results: Here, we use an established model of Pichinde virus infection of hamsters to demonstrate how changes in VP can be detected by intravenous infusion of Evans blue dye (EBD), and compare those measurements to changes in hematocrit, serum albumin concentration and serum levels of proinflammatory mediators. We show that EBD injected into sick animals in the late stage of infection is rapidly sequestered in the viscera, while in healthy animals it remains within the plasma, causing the skin to turn a marked blue color. This test could be used in live animals to detect increased VP and to assess the ability of antiviral drugs and vasoactive compounds to prevent its onset. Finally, we describe a multiplexed assay to measure levels of serum factors during the course of Pichinde arenavirus infection and demonstrate that viremia and subsequent increase in white blood cell counts precede the elaboration of inflammatory mediators, which is followed by increased VP and death. Conclusions: This level of model characterization is essential to the evaluation of novel interventions designed to control the effects of virus-induced hypercytokinemia on host vascular function in VHF, which could lead to improved survival. C1 [Gowen, Brian B.; Julander, Justin G.; Wong, Min-Hui; Larson, Deanna; Morrey, John D.] Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA. [Gowen, Brian B.; Julander, Justin G.; Wong, Min-Hui; Larson, Deanna; Morrey, John D.] Utah State Univ, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA. [London, Nyall R.; Li, Dean Y.] Univ Utah, Program Mol Med, Salt Lake City, UT USA. [Bray, Mike] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. RP Gowen, BB (reprint author), Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA. EM brian.gowen@usu.edu FU Virology Branch, NIAID, NIH [N01-AI-15435, N01-AI-30063] FX This work was supported by contract grant N01-AI-15435 and N01-AI-30063 (awarded to Southern Research Institute) from the Virology Branch, NIAID, NIH. NR 25 TC 24 Z9 24 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD SEP 16 PY 2010 VL 7 AR 240 DI 10.1186/1743-422X-7-240 PG 13 WC Virology SC Virology GA 659ZP UT WOS:000282606500009 PM 20846417 ER PT J AU Grulich, AE Vajdic, CM Falster, MO Kane, E Smedby, KE Bracci, PM de Sanjose, S Becker, N Turner, J Martinez-Maza, O Melbye, M Engels, EA Vineis, P Costantini, AS Holly, EA Spinelli, JJ La Vecchia, C Zheng, TZ Chiu, BCH Franceschi, S Cocco, P Maynadie, M Foretova, L Staines, A Brennan, P Davis, S Severson, RK Cerhan, JR Breen, EC Birmann, B Cozen, W AF Grulich, Andrew E. Vajdic, Claire M. Falster, Michael O. Kane, Eleanor Smedby, Karin Ekstrom Bracci, Paige M. de Sanjose, Silvia Becker, Nikolaus Turner, Jenny Martinez-Maza, Otoniel Melbye, Mads Engels, Eric A. Vineis, Paolo Costantini, Adele Seniori Holly, Elizabeth A. Spinelli, John J. La Vecchia, Carlo Zheng, Tongzhang Chiu, Brian C. H. Franceschi, Silvia Cocco, Pierluigi Maynadie, Marc Foretova, Lenka Staines, Anthony Brennan, Paul Davis, Scott Severson, Richard K. Cerhan, James R. Breen, Elizabeth C. Birmann, Brenda Cozen, Wendy TI Birth Order and Risk of Non-Hodgkin Lymphoma-True Association or Bias? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE birth order; case-control studies; lymphoma; non-Hodgkin; selection bias; social class ID CHILDHOOD SOCIAL-ENVIRONMENT; FRANCISCO BAY AREA; SELECTION BIAS; MAGNETIC-FIELDS; SIBSHIP SIZE; DISEASE; SIBLINGS; NUMBER; CANCER; PARTICIPATION AB There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983-2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL. C1 [Grulich, Andrew E.] Univ New S Wales, HIV Epidemiol & Prevent Program, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2052, Australia. [Vajdic, Claire M.; Falster, Michael O.] Univ New S Wales, UNSW Canc Res Ctr, Prince Wales Clin Sch, Sydney, NSW 2052, Australia. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, UCLA AIDS Inst, Los Angeles, CA 90095 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [de Sanjose, Silvia] Inst Catala Oncol, Barcelona, Spain. [de Sanjose, Silvia] CIBERESP, Barcelona, Spain. [Becker, Nikolaus] German Canc Res Ctr, Div Clin Epidemiol, D-6900 Heidelberg, Germany. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Turner, Jenny] St Vincents Hosp, Dept Anat Pathol, Sydney, NSW 2010, Australia. [Kane, Eleanor] Univ York, Epidemiol & Genet Unit, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Smedby, Karin Ekstrom] Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden. [Smedby, Karin Ekstrom] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, Fac Med, London, England. [Costantini, Adele Seniori] Canc Prevent & Res Inst, Occupat & Environm Epidemiol Unit, Florence, Italy. [Spinelli, John J.] British Columbia Canc Agcy, Canc Control Res Program, Vancouver, BC V5Z 4E6, Canada. [La Vecchia, Carlo] Univ Milan, Ist Ric Farmacol Mario Negri, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Ist Stat Med & Biometria, I-20122 Milan, Italy. [Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Chiu, Brian C. H.] Univ Chicago, Div Biol Sci, Dept Hlth Studies, Chicago, IL 60637 USA. [Franceschi, Silvia; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth, Occupat Hlth Sect, Cagliari, Italy. [Maynadie, Marc] Dijon Univ Hosp, Registry Hematol Malignancies Cote dOr, Dijon, France. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Staines, Anthony] Dublin City Univ, Sch Nursing, Dublin 9, Ireland. [Davis, Scott] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Davis, Scott] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Severson, Richard K.] Wayne State Univ, Sch Med, Dept Family Med, Detroit, MI USA. [Severson, Richard K.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA. [Cerhan, James R.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Breen, Elizabeth C.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Birmann, Brenda] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Birmann, Brenda] Harvard Univ, Sch Med, Boston, MA USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Grulich, AE (reprint author), Univ New S Wales, HIV Epidemiol & Prevent Program, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2052, Australia. EM agrulich@nchecr.unsw.edu.au RI Spinelli, John/B-6210-2013; Martinez-Maza, Otoniel/B-2667-2009; de Sanjose Llongueras, Silvia/H-6339-2014; OI Martinez-Maza, Otoniel/0000-0003-1364-0675; Vajdic, Claire/0000-0002-3612-8298; Cerhan, James/0000-0002-7482-178X; Staines, Anthony/0000-0001-9161-1357; La Vecchia, Carlo/0000-0003-1441-897X; Falster, Michael/0000-0001-6444-7272 FU Leukaemia Foundation of Australia [24]; Italian Association for Cancer Research; Italian League Against Cancer (Aviano-Napoli, Northern Italy); Canadian Cancer Society; Canadian Institutes for Health Research (British Columbia); US National Cancer Institute (NCI) [CA62006]; European Commission [QLK4-CT-2000-00422]; Ministry of Health of the Czech Republic (EpiLymph-Czech Republic) [MZO MOU 2005]; Association pour la Recherche contre le Cancer [5111]; Fondation de France (EpiLymph-France) [1999 008471]; Compagnia di San Paolo di Torino (EpiLymph-Italy); Health Research Board and Cancer Research Ireland (EpiLymph-Ireland); Spanish Ministry of Health, Fondo de Investigaciones Sanitarias [PI 081555]; CIBER-ESP (EpiLymph-Spain) [06/06/0073]; German Federal Office for Radiation Protection (EpiLymph-Germany) [StSch4261, StSch4420]; NCI [CA51086, CA92153, PC65064, PC67008, PC67009, PC67010, PC71105, CA69269-02]; European Community; Italian League against Cancer (Italy); American Institute for Cancer Research (Nebraska) [99B083]; National Health and Medical Research Council of Australia (New South Wales) [990920, 568819, 510346]; Swedish Cancer Society (SCALE) [04 0458]; NCI (University of California, San Francisco) [CA45614, CA89745, CA87014, CA104682]; Leukaemia Research Fund of Great Britain (United Kingdom) FX The current data pooling project was supported by the Leukaemia Foundation of Australia (grant 24). Individual studies (listed in Table 1) were supported by the Italian Association for Cancer Research and the Italian League Against Cancer (Aviano-Napoli, Northern Italy); the Canadian Cancer Society and the Canadian Institutes for Health Research (British Columbia); the US National Cancer Institute (NCI) (grant CA62006) (Connecticut); the European Commission (grant QLK4-CT-2000-00422) (EpiLymph); the Ministry of Health of the Czech Republic (grant MZO MOU 2005) (EpiLymph-Czech Republic), the Association pour la Recherche contre le Cancer (grant 5111) and the Fondation de France (grant 1999 008471) (EpiLymph-France); the Compagnia di San Paolo di Torino, Programma Oncologia 2001 (EpiLymph-Italy); the Health Research Board and Cancer Research Ireland (EpiLymph-Ireland); the Spanish Ministry of Health, Fondo de Investigaciones Sanitarias (grant PI 081555) and CIBER-ESP (grant 06/06/0073) (EpiLymph-Spain); the German Federal Office for Radiation Protection (grants StSch4261 and StSch4420) (EpiLymph-Germany); the NCI (grant CA51086), the European Community, and the Italian League against Cancer (Italy); the NCI (grant CA92153) (Mayo Clinic); the NCI (grants PC65064, PC67008, PC67009, PC67010, and PC71105) (NCI-SEER); the American Institute for Cancer Research (grant 99B083) (Nebraska); the National Health and Medical Research Council of Australia (grant 990920 (New South Wales), grant 568819 to A. E. G., and grant 510346 to C. M. V.); the NCI (grant CA69269-02) and the Swedish Cancer Society (grant 04 0458) (SCALE); the NCI (grants CA45614, CA89745, CA87014, and CA104682) (University of California, San Francisco); and the Leukaemia Research Fund of Great Britain (United Kingdom). Publication of this article was funded by the Australian Government Department of Health and Ageing. NR 58 TC 18 Z9 18 U1 0 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 SEP 15 PY 2010 VL 172 IS 6 BP 621 EP 630 DI 10.1093/aje/kwq167 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 651TD UT WOS:000281949100001 PM 20720098 ER PT J AU O'Reilly, EJ Gao, XA Weisskopf, MG Chen, HL Schwarzschild, MA Spiegelman, D Ascherio, A AF O'Reilly, Ellis J. Gao, Xiang Weisskopf, Marc G. Chen, Honglei Schwarzschild, Michael A. Spiegelman, Donna Ascherio, Alberto TI Plasma Urate and Parkinson's Disease in Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; Parkinson disease; uric acid ID URIC-ACID LEVELS; RISK; CONSUMPTION; PREDICTOR; CAFFEINE; ESTROGEN; NEURONS; HEALTH AB Plasma urate has been consistently associated with a lower risk of Parkinson's disease in men, but it is less clear if this relation exists in women. Between 1990 and 2004, the authors conducted a nested case-control study among participants of the female-only Nurses' Health Study. In controls (n = 504), plasma urate was positively associated with age, body mass index, alcohol consumption, hypertension, and use of diuretics and was inversely associated with physical activity and postmenopausal hormone use, as expected. Mean urate levels were 5.04 mg/dL for cases (n = 101) and 4.86 mg/dL for controls (P = 0.17). The age-, smoking-, and caffeine-adjusted rate ratio comparing women in the highest (>= 5.8 mg/dL) with those in the lowest (<4.0 mg/dL) quartile was 1.33 (95% confidence interval: 0.69, 2.57; P(trend) = 0.4). Further adjustment for body mass index, physical activity, history of hypertension, and postmenopausal hormone use did not change the results. Unlike in men, these findings do not support the hypothesis that urate is strongly associated with lower rates of Parkinson's disease among women. C1 [O'Reilly, Ellis J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [O'Reilly, Ellis J.; Weisskopf, Marc G.; Spiegelman, Donna; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Weisskopf, Marc G.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gao, Xiang; Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. RP O'Reilly, EJ (reprint author), Room 305,Bldg 2,655 Huntington Ave, Boston, MA 02115 USA. EM eoreilly@hsph.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Institutes of Health [K24NS060991]; National Institute of Environmental Health Sciences [Z01-ES-101986] FX The study was supported in part by grant K24NS060991 (M. A. S.) and the Intramural Research Program of the National Institutes of Health and by grant Z01-ES-101986 (H. C.) from the National Institute of Environmental Health Sciences. NR 20 TC 24 Z9 27 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2010 VL 172 IS 6 BP 666 EP 670 DI 10.1093/aje/kwq195 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 651TD UT WOS:000281949100008 PM 20682521 ER PT J AU Ober, C Butte, AJ Elias, JA Lusis, AJ Gan, WN Banks-Schlegel, S Schwartz, D AF Ober, Carole Butte, Atul J. Elias, Jack A. Lusis, A. Jake Gan, Weiniu Banks-Schlegel, Susan Schwartz, David TI Getting from Genes to Function in Lung Disease A National Heart, Lung, and Blood Institute Workshop Report SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE genetics; epigenetics; genomics; bioinformatics; lung disease ID GENOME-WIDE ASSOCIATION; ASTHMA; VARIANTS; SUSCEPTIBILITY; RISK AB Genome-wide association studies (GWAS) have revealed novel genes and pathways involved in lung disease, many of which are potential targets for therapy. However, despite numerous successes, a large proportion of the genetic variance in disease risk remains unexplained, and the function of the associated genetic variations identified by GWAS and the mechanisms by which they alter individual risk for disease or pathogenesis are still largely unknown. The National Heart, Lung, and Blood Institute (NHLBI) convened a 2-day workshop to address these shortcomings and to make recommendations for future research areas that will move the scientific community beyond gene discovery. Topics of individual sessions ranged from data integration and systems genetics to functional validation of genetic variations in humans and model systems. There was broad consensus among the participants for five high-priority areas for future research, including the following: (1) integrated approaches to characterize the function of genetic variations, (2) studies on the role of environment and mechanisms of transcriptional and post-transcriptional regulation, (3) development of model systems to study gene function in complex biological systems, (4) comparative phenomic studies across lung diseases, and (5) training in and applications of bioinformatic approaches for comprehensive mining of existing data sets. Last, it was agreed that future research on lung diseases should integrate approaches across "-omic" technologies and to include ethnically/racially diverse populations in human studies of lung disease whenever possible. C1 [Gan, Weiniu; Banks-Schlegel, Susan] NHLBI, Airway Biol & Dis Branch, Div Lung Dis, NIH, Bethesda, MD 20892 USA. [Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Butte, Atul J.] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Butte, Atul J.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Elias, Jack A.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Lusis, A. Jake] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Schwartz, David] Natl Jewish Hlth, Dept Med, Denver, CO USA. RP Banks-Schlegel, S (reprint author), NHLBI, Airway Biol & Dis Branch, Div Lung Dis, NIH, 2 Rockledge Ctr,Suite 10042,6701 Rockledge Dr,MSC, Bethesda, MD 20892 USA. EM schleges@nih.gov FU Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services; Tercicia; Lilly; Johnson and Johnson; Numedii; Genstruct; Siemens; Hewlett Packard Foundation; MIT Press; American Medical Informatics Association; Intermune Inc.; Merck; Intermune; Wallace; Brayton; Purcell; Weitz; Luxemberg; Graham FX Sponsored by the Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services.; C.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.J.B. received $1,001-$5,000 from Tercicia and $1,001-$5,000 from Lilly in consultancy fees; $50,001-$100,000 from Johnson and Johnson, up to $1,000 from Numedii, and $10,001-$50,000 from Genstruct in advisory board fees; $5,001-$10,000 from Siemens in lecture fees; more than $100,001 from the Hewlett Packard Foundation in institutional grants; holds a patent from Stanford University for biomarkers and therapeutics (not related to submitted paper); and received up to $1,000 from MIT Press in royalties and up to $1,000 from the American Medical Informatics Association for serving on an advisory board. J.A.E. received $1,001-$5,000 from Intermune Inc. for serving on a scientific advisory board; holds patents from Yale University on chitinases in lung Inflammation, mir-1 in VEGF tissue responses, IL-18 in COPD, and VEGF in asthma; and holds $1,001-$5,000 from Merck $5,001-$10,000 from Intermune in stock ownership or options. A.J.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.B-S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.S. received $10,001-$50,000 from Wallace and Graham for serving as an expert witness on workers compensation evaluations; received $5,001-$10,000 from Brayton and Purcell, $50,001-$100,000 from Weitz and Luxemberg, and $10,001-$50,000 from Waters and Kraus for serving as an expert witness on determination of asbestos induced lung disease; holds a patent from MedImmune for TLR4 hyporesponsive polymorphisms used in RSV vaccine research (less than $10,000); and is employed by the NIH as a Director, NIEHS, and National Jewish Health as a professor. NR 16 TC 7 Z9 7 U1 0 U2 2 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 SEP 15 PY 2010 VL 182 IS 6 BP 732 EP 737 DI 10.1164/rccm.201002-0180PP PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 654IQ UT WOS:000282162100005 PM 20558629 ER PT J AU Reyes-Hernandez, OD Mejia-Garcia, A Sanchez-Ocampo, EM Cabanas-Cortes, MA Ramirez, P Chavez-Gonzalez, L Gonzalez, FJ Elizondo, G AF Reyes-Hernandez, O. D. Mejia-Garcia, A. Sanchez-Ocampo, E. M. Cabanas-Cortes, M. A. Ramirez, P. Chavez-Gonzalez, L. Gonzalez, F. J. Elizondo, G. TI Ube213 gene expression is modulated by activation of the aryl hydrocarbon receptor: Implications for p53 ubiquitination SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE AhR; Ubiquitin-proteasome system; Ube213; p53; TCDD ID GROWTH-FACTOR-BETA; AHR-NULL MICE; PROTEOLYTIC SYSTEM; CELL-CYCLE; PROTEIN; DEGRADATION; MECHANISMS; LIGASE; LIVER; PROTEASOME AB Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a halogenated aromatic hydrocarbon and environmental contaminant, results in several deleterious effects, including fetal malformation and cancer. These effects are mediated by the aryl hydrocarbon receptor (AhR), a ligand-activated receptor that regulates the expression of genes encoding xenobiotic-metabolizing enzymes. Several reports suggest that AhR function is beyond the adaptive chemical response In the present study, we analyzed and compared gene expression profiles of C57BL/6N wild-type (WT) and Ahr-null mice DNA microarray and quantitative RT-PCR analyses revealed changes in the expression of genes involved in the ubiquitin-proteasome system (UPS) UPS has an important role in cellular homeostasis control and dysfunction of this pathway has been implicated in the development of several human pathologies. Protein ubiquitination is a multi-step enzymatic process that regulates the stability, function, and/or localization of the modified proteins. This system is highly regulated post-translationally by covalent modifications However, little information regarding the transcriptional regulation of the genes encoding ubiquitin (Ub) proteins is available Therefore, we investigated the role of the AhR in modulation of the UPS and regulation of Ube213 transcription, an E2 ubiquitin-conjugating enzyme, as well as the effects on p53 degradation Our results indicate that AhR inactivation decreases on liver proteasome activity, probably due to a down-regulation on the expression of several proteasome subunits On the other hand, AhR activation increases Ube213 mRNA and protein levels by controlling Ube213 gene expression, resulting in increased p53 ubiquitination and degradation In agreement with this, induction of apoptosis was attenuated by the AhR activation (C) 2010 Elsevier Inc. All rights reserved C1 [Mejia-Garcia, A.; Sanchez-Ocampo, E. M.; Cabanas-Cortes, M. A.; Elizondo, G.] IPN, CINVESTAV, Dept Biol Celular, Zacatenco Mexico 07360, DF, Mexico. [Reyes-Hernandez, O. D.] IPN, CINVESTAV, Dept Toxicol, Mexico City 07360, DF, Mexico. [Ramirez, P.] UNAM, Fac Estudios Super Cuautitlan, Lab Toxicol & Genet, Unidad Invest Multidisciplinaria, Cuautitlan, Mexico. [Chavez-Gonzalez, L.] UNAM, DNA Microarray Unit, Cuautitlan, Mexico. [Gonzalez, F. J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Elizondo, G (reprint author), IPN, CINVESTAV, Dept Biol Celular, Av IPN 2508, Zacatenco Mexico 07360, DF, Mexico. FU CONACYT [48786] FX We thank Simon Guzman Leon, Jose Luis Santillan Torres and Jorge Ramirez for technical assistance with the microarrays, and Gerardo Coello, Gustavo Corral and Ana Patricia Gomez for assistance with the genArise software. We also thank Samia Fattel Fazenda for technical assistance with the TUNEL assay. This work was supported by CONACYT grant 48786. NR 39 TC 16 Z9 17 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 15 PY 2010 VL 80 IS 6 BP 932 EP 940 DI 10.1016/j.bcp.2010.05.007 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 635YC UT WOS:000280692800019 PM 20478272 ER PT J AU Warner-Schmidt, JL Chen, EY Zhang, XQ Marshall, JJ Morozov, A Svenningsson, P Greengard, P AF Warner-Schmidt, Jennifer L. Chen, Emily Y. Zhang, Xiaoqun Marshall, John J. Morozov, Alexei Svenningsson, Per Greengard, Paul TI A Role for p11 in the Antidepressant Action of Brain-Derived Neurotrophic Factor SO BIOLOGICAL PSYCHIATRY LA English DT Article DE BDNF; depression; 5-HT1B; neurogenesis; neurotrophin; S100A10 ID MESSENGER-RNA EXPRESSION; SEROTONERGIC NEURONAL PHENOTYPE; HIPPOCAMPAL NEUROGENESIS; RAT-BRAIN; DRUG TREATMENTS; MOOD DISORDERS; BDNF LEVELS; DEPRESSION; RECEPTOR; ACTIVATION AB Background: The protein p11 (also called S100A10) is downregulated in human and rodent depressive-like states. Considerable experimental evidence also implicates p11 in the mechanism of action of antidepressant drugs and electroconvulsive seizures, in part due to its interaction with specific serotonin receptors. Brain-derived neurotrophic factor (BDNF) has been linked to the therapeutic activity of antidepressants in rodent models and humans. In the current study, we investigated whether BDNF regulates p11 in vitro and in vivo. Methods: We utilized primary neuronal cultures, in vivo analyses of transgenic mice, and behavioral techniques to assess the effects of BDNF on p11. Results: Results indicate that BDNF stimulates p11 expression through tropomyosin-related kinase B (trkB) receptors and via the mitogen-activated protein kinase signaling pathway. Brain-derived neurotrophic factor-induced changes in p11 in vivo correlate with changes in ligand binding to the 5-hydroxytryptamine receptor 1B, the subcellular localization of which is known to be regulated by p11. Behavioral studies demonstrate that p11 knockout mice are insensitive to the antidepressant actions of BDNF. Conclusions: Taken together, our data demonstrate that p11 levels are regulated by BDNF in vitro and in vivo and that the antidepressant-like effect of BDNF in two well-established behavioral models requires p11. These data support a role for p11 in the antidepressant activity of neurotrophins. C1 [Warner-Schmidt, Jennifer L.; Chen, Emily Y.; Marshall, John J.; Svenningsson, Per; Greengard, Paul] Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. [Zhang, Xiaoqun; Svenningsson, Per] Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden. [Morozov, Alexei] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RP Warner-Schmidt, JL (reprint author), 1230 York Ave,Box 296, New York, NY 10065 USA. EM jschmidt@rockefeller.edu FU Skirball Foundation; Calvin Klein Family Foundation; Zilkha Foundation; United States Army Medical Research Acquisition Activity (USAMRAA) [W81XWH-08-1-0111, W81XWH-09-1-0401]; National Institutes of Health/National Institute of Mental Health [MH074866]; Vetenskapsradet and Soderberg's stiftelse FX This work has been supported by The Skirball Foundation, The Calvin Klein Family Foundation; the Zilkha Foundation; United States Army Medical Research Acquisition Activity (USAMRAA) Giants W81XWH-08-1-0111 and W81XWH-09-1-0401, National Institutes of Health/National Institute of Mental Health Grant MH074866 and Vetenskapsradet and Soderberg's stiftelse. NR 38 TC 32 Z9 33 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2010 VL 68 IS 6 BP 528 EP 535 DI 10.1016/j.biopsych.2010.04.029 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 647NP UT WOS:000281625500005 PM 20591415 ER PT J AU Rietschel, M Mattheisen, M Frank, J Treutlein, J Degenhardt, F Breuer, R Steffens, M Mier, D Esslinger, C Walter, H Kirsch, P Erk, S Schnell, K Herms, S Wichmann, HE Schreiber, S Jockel, KH Strohmaier, J Roeske, D Haenisch, B Gross, M Hoefels, S Lucae, S Binder, EB Wienker, TF Schulze, TG Schmal, C Zimmer, A Juraeva, D Brors, B Bettecken, T Meyer-Lindenberg, A Muller-Myhsok, B Maier, W Nothen, MM Cichon, S AF Rietschel, Marcella Mattheisen, Manuel Frank, Josef Treutlein, Jens Degenhardt, Franziska Breuer, Rene Steffens, Michael Mier, Daniela Esslinger, Christine Walter, Henrik Kirsch, Peter Erk, Susanne Schnell, Knut Herms, Stefan Wichmann, H. -Erich Schreiber, Stefan Joeckel, Karl-Heinz Strohmaier, Jana Roeske, Darina Haenisch, Britta Gross, Magdalena Hoefels, Susanne Lucae, Susanne Binder, Elisabeth B. Wienker, Thomas F. Schulze, Thomas G. Schmael, Christine Zimmer, Andreas Juraeva, Dilafruz Brors, Benedikt Bettecken, Thomas Meyer-Lindenberg, Andreas Mueller-Myhsok, Bertram Maier, Wolfgang Noethen, Markus M. Cichon, Sven TI Genome-Wide Association-, Replication-, and Neuroimaging Study Implicates HOMER1 in the Etiology of Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Carboxypeptidase M; CPM; gene-wide; HOMER1; major depression; neuroimaging ID MACROPHAGE MATURATION; FRONTAL-CORTEX; SCHIZOPHRENIA; DISORDER; HERITABILITY; DYSFUNCTION; PARADIGM; GENETICS; DISEASE; LINKAGE AB Background: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression. Methods: We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects. Results: Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER I. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward. Conclusion: Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes. C1 [Rietschel, Marcella; Frank, Josef; Treutlein, Jens; Breuer, Rene; Strohmaier, Jana; Schmael, Christine] Univ Heidelberg, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68159 Mannheim, Germany. [Mattheisen, Manuel; Degenhardt, Franziska; Herms, Stefan; Haenisch, Britta; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Mattheisen, Manuel; Degenhardt, Franziska; Herms, Stefan; Haenisch, Britta; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Mattheisen, Manuel; Steffens, Michael; Wienker, Thomas F.] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany. [Mier, Daniela; Esslinger, Christine; Kirsch, Peter; Meyer-Lindenberg, Andreas] Univ Heidelberg, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-68159 Mannheim, Germany. [Walter, Henrik; Erk, Susanne; Schnell, Knut] Univ Bonn, Dept Psychiat & Psychotherapy, Div Med Psychol, D-5300 Bonn, Germany. [Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum, Inst Epidemiol, Neuherberg, Germany. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat, Chair Epidemiol, Munich, Germany. [Wichmann, H. -Erich] Munich Univ Hosp Campus Grosshadern, Munich, Germany. [Schreiber, Stefan] Univ Kiel, Inst Clin Mol Biol, D-24098 Kiel, Germany. [Schreiber, Stefan] Univ Kiel, Dept Gen Internal Med, D-24098 Kiel, Germany. [Joeckel, Karl-Heinz] Univ Essen Gesamthsch, Inst Med Informat, Heinz Nixdorf Study Grp, Essen, Germany. [Roeske, Darina; Lucae, Susanne; Binder, Elisabeth B.; Bettecken, Thomas; Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Gross, Magdalena; Hoefels, Susanne; Maier, Wolfgang] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. [Schulze, Thomas G.] NIMH, Bethesda, MD 20892 USA. [Zimmer, Andreas] Univ Bonn, Inst Mol Psychiat, D-5300 Bonn, Germany. [Juraeva, Dilafruz; Brors, Benedikt] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Cichon, Sven] Struct & Funct Org Brain, Res Ctr, Inst Neurosci & Med, Julich, Germany. RP Rietschel, M (reprint author), Univ Heidelberg, Cent Inst Mental Hlth Mannheim CIMH, Dept Genet Epidemiol Psychiat, J5, D-68159 Mannheim, Germany. EM marcella.rietschel@zi-mannheim.de RI Schreiber, Stefan/B-6748-2008; Muller-Myhsok, Bertram/A-3289-2013; Herms, Stefan/J-1949-2014; Zimmer, Andreas/B-8357-2009; Brors, Benedikt/E-5620-2013; Schulze, Thomas/H-2157-2013; Walter, Henrik/O-2612-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Binder, Elisabeth/K-8905-2014; Mattheisen, Manuel/B-4949-2012; Meyer-Lindenberg, Andreas/H-1076-2011; OI Schreiber, Stefan/0000-0003-2254-7771; Herms, Stefan/0000-0002-2786-8200; Brors, Benedikt/0000-0001-5940-3101; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Mattheisen, Manuel/0000-0002-8442-493X; Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Mier, Daniela/0000-0003-2518-7492; Kirsch, Peter/0000-0002-0817-1248; Nothen, Markus/0000-0002-8770-2464; Steffens, Michael/0000-0002-6445-8593 FU German Federal Ministry of Education and Research within German National Genome Research Network; Alfried Krupp von Bohlen und Halbach-Stiftung; Heinz Nixdorf Foundation FX This work was supported by the German Federal Ministry of Education and Research within the context of the German National Genome Research Network (NGFN-2 and NGFN-plus) by grants to MR, HW, H-EW, SS, TGS, CS, AZ, TB, AML, BMM, WM, BB, Mini, and SC. MMN and SC received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. The Heinz Nixdorf Recall Study was supported by a grant from the Heinz Nixdorf Foundation. NR 36 TC 80 Z9 81 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2010 VL 68 IS 6 BP 578 EP 585 DI 10.1016/j.biopsych.2010.05.038 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 647NP UT WOS:000281625500011 PM 20673876 ER PT J AU Suzuki, S Maddali, K Hashimoto, C Urano, E Ohashi, N Tanaka, T Ozaki, T Arai, H Tsutsumi, H Narumi, T Nomura, W Yamamoto, N Pommier, Y Komano, JA Tamamura, H AF Suzuki, Shintaro Maddali, Kasthuraiah Hashimoto, Chie Urano, Emiko Ohashi, Nami Tanaka, Tomohiro Ozaki, Taro Arai, Hiroshi Tsutsumi, Hiroshi Narumi, Tetsuo Nomura, Wataru Yamamoto, Naoki Pommier, Yves Komano, Jun A. Tamamura, Hirokazu TI Peptidic HIV integrase inhibitors derived from HIV gene products: Structure-activity relationship studies SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE HIV integrase; Inhibitory peptide; Glu-Lys pairs; Ala-scan ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE; VIRAL INTEGRASE; IN-VITRO; PROTEIN; DETERMINANTS; RALTEGRAVIR; VPR AB Structure-activity relationship studies were conducted on HIV integrase (IN) inhibitory peptides which were found by the screening of an overlapping peptide library derived from HIV-1 gene products. Since these peptides located in the second helix of Vpr are considered to have an alpha-helical conformation, Glu-Lys pairs were introduced into the i and i + 4 positions to increase the helicity of the lead compound possessing an octa-arginyl group. Ala-scan was also performed on the lead compound for the identification of the amino acid residues responsible for the inhibitory activity. The results indicated the importance of an a-helical structure for the expression of inhibitory activity, and presented a binding model of integrase and the lead compound. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Suzuki, Shintaro; Hashimoto, Chie; Ohashi, Nami; Tanaka, Tomohiro; Ozaki, Taro; Arai, Hiroshi; Tsutsumi, Hiroshi; Narumi, Tetsuo; Nomura, Wataru; Tamamura, Hirokazu] Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Chiyoda Ku, Tokyo 1010062, Japan. [Maddali, Kasthuraiah; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Urano, Emiko; Yamamoto, Naoki; Komano, Jun A.] Natl Inst Infect Dis, AIDS Res Ctr, Shinjuku Ku, Tokyo 1628640, Japan. [Yamamoto, Naoki] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Microbiol, Singapore 117597, Singapore. RP Tamamura, H (reprint author), Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Chiyoda Ku, Tokyo 1010062, Japan. EM tamamura.mr@tmd.ac.jp RI Nomura, Wataru/F-5812-2015; Tsutsumi, Hiroshi/L-8761-2016; OI Tsutsumi, Hiroshi/0000-0003-3780-7871; Nomura, Wataru/0000-0001-8348-7544 FU JSPS; Mitsui Life Social Welfare Foundation; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japanese Ministry of Health, Labor, and Welfare; NIH; Center for Cancer Research; US National Cancer Institute FX N.O. and T.T. are supported by JSPS research fellowships for young scientists. This work was supported by Mitsui Life Social Welfare Foundation, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Health and Labour Sciences Research Grants from Japanese Ministry of Health, Labor, and Welfare, and by the NIH Intramural Program, Center for Cancer Research, US National Cancer Institute. NR 18 TC 9 Z9 9 U1 0 U2 2 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 SEP 15 PY 2010 VL 18 IS 18 BP 6771 EP 6775 DI 10.1016/j.bmc.2010.07.050 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 646FW UT WOS:000281524700020 PM 20708407 ER PT J AU da Fonseca, RR Johnson, WE O'Brien, SJ Vasconcelos, V Antunes, A AF da Fonseca, Rute R. Johnson, Warren E. O'Brien, Stephen J. Vasconcelos, Vitor Antunes, Agostinho TI Molecular evolution and the role of oxidative stress in the expansion and functional diversification of cytosolic glutathione transferases SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID S-TRANSFERASE; MAXIMUM-LIKELIHOOD; DRUG-RESISTANCE; FAMILY; POLYMORPHISMS; SELECTION; CANCER; PERSPECTIVES; PHYLOGENIES; ALIGNMENTS AB Background: Cytosolic glutathione transferases (cGST) are a large group of ubiquitous enzymes involved in detoxification and are well known for their undesired side effects during chemotherapy. In this work we have performed thorough phylogenetic analyses to understand the various aspects of the evolution and functional diversification of cGSTs. Furthermore, we assessed plausible correlations between gene duplication and substrate specificity of gene paralogs in humans and selected species, notably in mammalian enzymes and their natural substrates. Results: We present a molecular phylogeny of cytosolic GSTs that shows that several classes of cGSTs are more ubiquitous and thus have an older ancestry than previously thought. Furthermore, we found that positive selection is implicated in the diversification of cGSTs. The number of duplicate genes per class is generally higher for groups of enzymes that metabolize products of oxidative damage. Conclusions: 1) Protection against oxidative stress seems to be the major driver of positive selection in mammalian cGSTs, explaining the overall expansion pattern of this subfamily; 2) Given the functional redundancy of GSTs that metabolize xenobiotic chemicals, we would expect the loss of gene duplicates, but by contrast we observed a gene expansion of this family, which likely has been favored by: i) the diversification of endogenous substrates; ii) differential tissue expression; and iii) increased specificity for a particular molecule; 3) The increased availability of sequence data from diversified taxa is likely to continue to improve our understanding of the early origin of the different cGST classes. C1 [da Fonseca, Rute R.; Vasconcelos, Vitor; Antunes, Agostinho] Univ Porto, Ctr Interdisciplinar Invest Marinha & Ambiental, CIMAR CIIMAR, P-4050123 Oporto, Portugal. [Johnson, Warren E.; O'Brien, Stephen J.; Antunes, Agostinho] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Vasconcelos, Vitor] Univ Porto, Fac Ciencias, Dept Biol, Oporto, Portugal. RP da Fonseca, RR (reprint author), Univ Porto, Ctr Interdisciplinar Invest Marinha & Ambiental, CIMAR CIIMAR, Rua Bragas 177, P-4050123 Oporto, Portugal. EM rute.r.da.fonseca@gmail.com; aantunes@nih.gov RI Vasconcelos, Vitor/A-8933-2008; da Fonseca, Rute/F-9143-2013; Scientific output, CIIMAR/E-5122-2012; Johnson, Warren/D-4149-2016; OI Vasconcelos, Vitor/0000-0003-3585-2417; da Fonseca, Rute/0000-0002-2805-4698; Scientific output, CIIMAR/0000-0001-6270-2153; Johnson, Warren/0000-0002-5954-186X; Antunes, Agostinho/0000-0002-1328-1732 FU FCT [SFRH/BPD/26769/2006]; Portuguese Foundation for Science and Technology (FCT) [PTDC/BIA-BDE/69144/2006, PTDC/AAC-AMB/104983/2008] FX RRF was funded by FCT (SFRH/BPD/26769/2006). This work was funded in part by the Portuguese Foundation for Science and Technology (FCT) project PTDC/BIA-BDE/69144/2006 and PTDC/AAC-AMB/104983/2008. NR 48 TC 13 Z9 13 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD SEP 15 PY 2010 VL 10 AR 281 DI 10.1186/1471-2148-10-281 PG 11 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 661YP UT WOS:000282769900002 PM 20843339 ER PT J AU Ferrucci, LM Sinha, R Ward, MH Graubard, BI Hollenbeck, AR Kilfoy, BA Schatzkin, A Michaud, DS Cross, AJ AF Ferrucci, Leah M. Sinha, Rashmi Ward, Mary H. Graubard, Barry I. Hollenbeck, Albert R. Kilfoy, Briseis A. Schatzkin, Arthur Michaud, Dominique S. Cross, Amanda J. TI Meat and Components of Meat and the Risk of Bladder Cancer in the NIH-AARP Diet and Health Study SO CANCER LA English DT Article DE diet; bladder cancer; meat; nitrate; nitrite ID FOOD-FREQUENCY QUESTIONNAIRE; HETEROCYCLIC AROMATIC-AMINES; MUNICIPAL DRINKING-WATER; RETIRED-PERSONS DIET; LOWER URINARY-TRACT; UROTHELIAL CANCER; NITROSO-COMPOUNDS; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; PROSPECTIVE COHORT AB BACKGROUND: Meat could be involved in bladder carcinogenesis via multiple potentially carcinogenic meat-related compounds related to cooking and processing, including nitrate, nitrite, heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs). The authors comprehensively investigated the association between meat and meat components and bladder cancer. METHODS: During 7 years of follow-up, 854 transitional cell bladder-cancer cases were identified among 300,933 men and women who had completed a validated food-frequency questionnaire in the large prospective NIH-AARP Diet and Health Study. The authors estimated intake of nitrate and nitrite from processed meat and HCAs and PAHs from cooked meat by using quantitative databases of measured values. Total dietary nitrate and nitrite were calculated based on literature values. RESULTS: The hazard ratios (HR) and 95% confidence intervals (CI) for red meat (HR for fifth quintile compared with first quintile, 1.22; 95% CI, 0.96-1.54; P-trend = .07) and the HCA 2-amino-1 methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) (HR, 1.19; 95% CI, 0.95-1.48; P-trend = .06) conferred a borderline statistically significant increased risk of bladder cancer. Positive associations were observed in the top quintile for total dietary nitrite (HR, 1.28; 95% CI, 1.02-1.61; P-trend = .06) and nitrate plus nitrite intake from processed meat (HR, 1.29; 95% CI, 1.00-1.67; P-trend = .11). CONCLUSIONS: These findings provided modest support for an increased risk of bladder cancer with total dietary nitrite and nitrate plus nitrite from processed meat. Results also suggested a positive association between red meat and PhIP and bladder carcinogenesis. Cancer 2010;116:4345-53. (C) 2010 American Cancer Society C1 [Ferrucci, Leah M.; Sinha, Rashmi; Ward, Mary H.; Graubard, Barry I.; Kilfoy, Briseis A.; Schatzkin, Arthur; Cross, Amanda J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Serv, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Michaud, Dominique S.] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. RP Cross, AJ (reprint author), 6120 Execut Blvd, Rockville, MD 20852 USA. EM crossa@mail.nih.gov RI Aschebrook-Kilfoy, Briseis/A-2537-2012; Michaud, Dominique/I-5231-2014; Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This research was supported (in part) by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 58 TC 28 Z9 29 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2010 VL 116 IS 18 BP 4345 EP 4353 DI 10.1002/cncr.25463 PG 9 WC Oncology SC Oncology GA 646AS UT WOS:000281507900019 PM 20681011 ER PT J AU Weaver, KE Rowland, JH Alfano, CM McNeel, TS AF Weaver, Kathryn E. Rowland, Julia H. Alfano, Catherine M. McNeel, Timothy S. TI Parental Cancer and the Family A Population-Based Estimate of the Number of US Cancer Survivors Residing With Their Minor Children SO CANCER LA English DT Article DE cancer survivors; parents; children; adolescents ID IMPACT; ADOLESCENTS; ADJUSTMENT AB BACKGROUND: Cancer diagnosis and treatment of a parent has considerable impact on the lives of their minor children, family caregivers, and patients themselves. Understanding the number and characteristics of the population of cancer survivors with children younger than 18 years of age would help to better target services for these survivors and their children and to stimulate and inform research on these understudied families. METHODS: This study identified adults with a history of cancer (n=13,385) who participated in the United States National Health Interview Survey (NHIS) between 2000 and 2007. The authors examined the prevalence and characteristics of survivors residing with their minor children, both in the total sample and among survivors diagnosed within the last 2 years. RESULTS: Among these adult survivors, 18.3% (95%CI, 16.3-20.5) of those recently diagnosed and 14.0% (95%CI 13.3-14.8) of the total sample reported living with a minor child. Most of these survivors were female (78.9%), married (69.8%), and younger than age 50 years (85.8%). Of the 3193 identified children of survivors, 30.5% were younger than age 6 years at the time of their parent's cancer diagnosis; 33.4% were born after the diagnosis. By using population-based weights, the authors estimated that 1.58 million US cancer survivors reside with their minor children, representing 2.85 million children. Furthermore, an estimated 562,000 US minor children are living with a parent in the early phases of cancer treatment and recovery. CONCLUSIONS: There is a large population of families for whom cancer may pose special challenges and for whom assessment of needs and referral to resources are essential. Cancer 2010;116:4395-401. Published 2010 by the American Cancer Society*. C1 [Weaver, Kathryn E.; Rowland, Julia H.; Alfano, Catherine M.] Natl Canc Inst, Off Canc Survivorship, Div Canc Control & Populat Sci, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD USA. [Weaver, Kathryn E.] Natl Canc Inst, Canc Prevent Fellowship Program, Off Prevent Oncol, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD USA. [McNeel, Timothy S.] Informat Management Serv Inc, Silver Spring, MD USA. RP Weaver, KE (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Social Sci & Hlth Policy, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM keweaver@wfubmc.edu FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [HHSN261200900553P] NR 15 TC 48 Z9 48 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2010 VL 116 IS 18 BP 4395 EP 4401 DI 10.1002/cncr.25368 PG 7 WC Oncology SC Oncology GA 646AS UT WOS:000281507900025 PM 20586037 ER PT J AU Tauler, J Zudaire, E Liu, HT Shih, J Mulshine, JL AF Tauler, Jordi Zudaire, Enrique Liu, Huaitian Shih, Joanna Mulshine, James L. TI hnRNP A2/B1 Modulates Epithelial-Mesenchymal Transition in Lung Cancer Cell Lines SO CANCER RESEARCH LA English DT Article ID NUCLEAR RIBONUCLEOPROTEIN A2/B1; DETECTION MARKER; EXPRESSION; PROTEIN; A2; ANTIGEN; RNA; P53; OVEREXPRESSION; IDENTIFICATION AB Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) has been reported to be overexpressed in lung cancer and in other cancers such as breast, pancreas, and liver. However, a mechanism linking hnRNP A2/B1 overexpression and progression to cancer has not yet been definitively established. To elucidate this mechanism, we have silenced hnRNPA2/B1 mRNA in non-small-cell lung cancer cell lines A549, H1703, and H358. These cell lines present different levels of expression of epithelial-to-mesenchymal transition (EMT) markers such as E-cadherin, fibronectin, and vimentin. Microarray expression analysis was performed to evaluate the effect of silencing hnRNP A2/B1 in A549 cells. We identified a list of target genes, affected by silencing of hnRNP A2/B1, that are involved in regulation of migration, proliferation, survival, and apoptosis. Silencing hnRNP A2/B1 induced formation of cell clusters and increased proliferation. In the anchorage-independent assay, silencing hnRNP A2/B1 increased colony formation by 794% in A549 and 174% in H1703 compared with a 25% increase in proliferation, in both cell lines, in a two-dimensional proliferation assay. Silencing hnRNP A2/B1 decreased migration in intermediate cell line A549 and mesenchymal cell line H1703; however, no changes in proliferation were observed in epithelial cell line H358. Silencing hnRNP A2/B1 in A549 and H1703 cells correlated with an increase of E-cadherin expression and downregulation of the E-cadherin inhibitors Twist1 and Snai1. These data suggest that expression of hnRNP A2/B1 may play a role in EMT, in nonepithelial lung cancer cell lines A549 and H1703, through the regulation of E-cadherin expression. Cancer Res; 70(18); 7137-47. (C)2010 AACR. C1 [Tauler, Jordi; Mulshine, James L.] Rush Univ, Med Ctr, Sect Med Oncol, Lab Lung Canc Biol, Chicago, IL 60612 USA. [Zudaire, Enrique] NCI, Angiogenesis Core Facil, NIH, Adv Technol Ctr, Gaithersburg, MD USA. [Liu, Huaitian] Sci Applicat Int Corp, Rockville, MD USA. [Shih, Joanna] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Tauler, J (reprint author), Rush Univ, Med Ctr, Sect Med Oncol, Lab Lung Canc Biol, Room 1413,Jelke Bldg,1750 W Harrison St, Chicago, IL 60612 USA. EM Jordi_Tauler@rush.edu FU NCI; Rush University; Charles J. & Margaret Roberts Fund FX This research was supported in part by intramural NCI funds, Rush University, and the Charles J. & Margaret Roberts Fund. NR 43 TC 45 Z9 50 U1 2 U2 6 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 SEP 15 PY 2010 VL 70 IS 18 BP 7137 EP 7147 DI 10.1158/0008-5472.CAN-10-0860 PG 11 WC Oncology SC Oncology GA 651GI UT WOS:000281914900014 PM 20807810 ER PT J AU Li, CI Nishi, N McDougall, JA Semmens, EO Sugiyama, H Soda, M Sakata, R Hayashi, M Kasagi, F Suyama, A Mabuchi, K Davis, S Kodama, K Kopecky, KJ AF Li, Christopher I. Nishi, Nobuo McDougall, Jean A. Semmens, Erin O. Sugiyama, Hiromi Soda, Midori Sakata, Ritsu Hayashi, Mikiko Kasagi, Fumiyoshi Suyama, Akihiko Mabuchi, Kiyohiko Davis, Scott Kodama, Kazunori Kopecky, Kenneth J. TI Relationship between Radiation Exposure and Risk of Second Primary Cancers among Atomic Bomb Survivors SO CANCER RESEARCH LA English DT Article ID PRIMARY BREAST-CANCER; TESTICULAR CANCER; ESOPHAGEAL CANCER; CHILDHOOD-CANCER; LUNG-CARCINOMA; RADIOTHERAPY; THERAPY; CHEMOTHERAPY; MORTALITY; LYMPHOMA AB Radiation exposure is related to risk of numerous types of cancer, but relatively little is known about its effect on risk of multiple primary cancers. Using follow-up data through 2002 from 77,752 Japanese atomic bomb survivors, we identified 14,048 participants diagnosed with a first primary cancer, of whom 1,088 were diagnosed with a second primary cancer. Relationships between radiation exposure and risks of first and second primary cancers were quantified using Poisson regression. There was a similar linear dose-response relationship between radiation exposure and risks of both first and second primary solid tumors [excess relative risk (ERR)/Gy = 0.65; 95% confidence interval (CI), 0.57-0.74 and ERR/Gy = 0.56; 95% CI, 0.33-0.80, respectively] and risk of both first and second primary leukemias (ERR/Gy = 2.65; 95% CI, 1.78-3.78 and ERR/Gy = 3.65; 95% CI, 0.96-10.70, respectively). Background incidence rates were higher for second solid cancers, compared with first solid cancers, until about age 70 years for men and 80 years for women (P < 0.0001), but radiation-related ERRs did not differ between first and second primary solid cancers (P = 0.70). Radiation dose was most strongly related to risk of solid tumors that are radiation-sensitive including second primary lung, colon, female breast, thyroid, and bladder cancers. Radiation exposure confers equally high relative risks of second primary cancers as first primary cancers. Radiation is a potent carcinogen and those with substantial exposures who are diagnosed with a first primary cancer should be carefully screened for second primary cancers, particularly for cancers that are radiation-sensitive. Cancer Res; 70(18); 7187-98. (C)2010 AACR. C1 [Li, Christopher I.; McDougall, Jean A.; Semmens, Erin O.; Davis, Scott; Kopecky, Kenneth J.] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [McDougall, Jean A.; Semmens, Erin O.; Davis, Scott] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA. [Kopecky, Kenneth J.] Univ Washington, Dept Biostat, Seattle, WA 98109 USA. [Nishi, Nobuo; Sugiyama, Hiromi; Soda, Midori; Sakata, Ritsu; Hayashi, Mikiko; Kasagi, Fumiyoshi; Suyama, Akihiko; Kodama, Kazunori] Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima, Japan. [Mabuchi, Kiyohiko] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Li, CI (reprint author), Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M4-C308,POB 19024, Seattle, WA 98109 USA. EM cili@fhcrc.org FU Japanese Ministry of Health, Labour and Welfare; U.S. Department of Energy; RERF [RP2-06]; U.S. NIH, National Cancer Institute [N01-CP-31012]; NIH; Division of Cancer Epidemiology and Genetics FX The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a private, nonprofit foundation funded by the Japanese Ministry of Health, Labour and Welfare and the U.S. Department of Energy, the latter in part through the National Academy of Sciences. This publication was supported by RERF Research Protocol RP2-06. This research was also supported by the U.S. NIH, National Cancer Institute contract N01-CP-31012 and in part by the Intramural Research Program of the NIH, and the Division of Cancer Epidemiology and Genetics. NR 24 TC 14 Z9 15 U1 2 U2 4 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 SEP 15 PY 2010 VL 70 IS 18 BP 7187 EP 7198 DI 10.1158/0008-5472.CAN-10-0276 PG 12 WC Oncology SC Oncology GA 651GI UT WOS:000281914900019 PM 20843820 ER PT J AU Rambold, AS Lippincott-Schwartz, J AF Rambold, Angelika S. Lippincott-Schwartz, Jennifer TI Starved cells use mitochondria for autophagosome biogenesis SO CELL CYCLE LA English DT Editorial Material ID ENDOPLASMIC-RETICULUM; PHOSPHORYLATION; STARVATION C1 [Rambold, Angelika S.; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. EM lippincj@mail.nih.gov NR 14 TC 9 Z9 9 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2010 VL 9 IS 18 BP 3633 EP 3634 DI 10.4161/cc.9.18.13170 PG 2 WC Cell Biology SC Cell Biology GA 651FD UT WOS:000281909900001 PM 20855967 ER PT J AU Arthur, LM Demarest, RM Clark, L Gourevitch, D Bedelbaeva, K Anderson, R Snyder, A Capobianco, AJ Lieberman, P Feigenbaum, L Heber-Katz, E AF Arthur, L. Matthew Demarest, Renee M. Clark, Lise Gourevitch, Dmitri Bedelbaeva, Kamila Anderson, Rhonda Snyder, Andrew Capobianco, Anthony J. Lieberman, Paul Feigenbaum, Lionel Heber-Katz, E. TI Epimorphic regeneration in mice is p53-independent SO CELL CYCLE LA English DT Article DE mouse; regeneration; p53; p21; MRL; ear-hole; Tgf beta ID DNA-DAMAGE RESPONSE; GROWTH-FACTOR-BETA; TGF-BETA; CELLULAR SENESCENCE; BLASTEMA FORMATION; STEM-CELLS; HUMAN FIBROBLASTS; TUMOR-SUPPRESSOR; P21 EXPRESSION; KNOCKOUT MICE AB The process of regeneration is most readily studied in species of sponge, hydra, planarian and salamander (i.e., newt and axolotl). The closure of MRL mouse ear pinna through-and-through holes provides a mammalian model of unusual wound healing/regeneration in which a blastema-like structure closes the ear hole and cartilage and hair follicles are replaced. Recent studies, based on a broad level of DNA damage and a cell cycle pattern of G(2)/M "arrest," showed that p21(Cip1/Waf1) was missing from the MRL mouse ear and that a p21-null mouse could close its ear holes. Given the p53/p21 axis of control of DNA damage, cell cycle arrest, apoptosis and senescence, we tested the role of p53 in the ear hole regenerative response. Using backcross mice, we found that loss of p53 in MRL mice did not show reduced healing. Furthermore, cross sections of MRL. p53(-/-) mouse ears at 6 weeks post-injury showed an increased level of adipocytes and chondrocytes in the region of healing whereas MRL or p21(-/-) mice showed chondrogenesis alone in this same region, though at later time points. In addition, we also investigated other cell cycle-related mutant mice to determine how p21 was being regulated. We demonstrate that p16 and Gadd45 null mice show little healing capacity. Interestingly, a partial healing phenotype in mice with a dual Tgf beta/Rag2 knockout mutation was seen. These data demonstrate an independence of p53 signaling for mouse appendage regeneration and suggest that the role of p21 in this process is possibly through the abrogation of the Tgf beta/Smad pathway. C1 [Arthur, L. Matthew; Demarest, Renee M.; Clark, Lise; Gourevitch, Dmitri; Bedelbaeva, Kamila; Lieberman, Paul; Heber-Katz, E.] NCI, Wistar Inst, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. [Bedelbaeva, Kamila; Anderson, Rhonda; Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. [Snyder, Andrew] TargAnox Inc, Cambridge, MA USA. [Capobianco, Anthony J.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. RP Heber-Katz, E (reprint author), NCI, Wistar Inst, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. EM heberkatz@wistar.org FU F.M. Kirby Foundation, Inc.; G. Harold and Leila Y. Mathers Foundation; NIGMS; NCI Cancer Center [P30 CA10815]; Lab Animal Sciences Program, Frederick; Training Program Grant in Basic Cancer Biology [5T32CA09171] FX We would like to thank N. Dahmane for useful discussions and Keith Smith, Dawn Crummkitt, Nicole Roberts for their help with the MMHCC studies. Support for these studies came from the F.M. Kirby Foundation, Inc., the G. Harold and Leila Y. Mathers Foundation, an NIH ARRA grant from NIGMS, NCI Cancer Center Grant (P30 CA10815) and from the Lab Animal Sciences Program, Frederick. L.M.A. was supported by the Training Program Grant in Basic Cancer Biology 5T32CA09171. NR 74 TC 12 Z9 13 U1 0 U2 9 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2010 VL 9 IS 18 BP 3667 EP 3673 DI 10.4161/cc.9.18.13119 PG 7 WC Cell Biology SC Cell Biology GA 651FD UT WOS:000281909900014 PM 20855943 ER PT J AU Bates, SE AF Bates, Susan E. TI DNA Repair: A Reinvigorated Therapeutic Target SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2010 VL 16 IS 18 BP 4510 EP 4510 DI 10.1158/1078-0432.CCR-10-2086 PG 1 WC Oncology SC Oncology GA 651FF UT WOS:000281910400004 PM 20823139 ER PT J AU Annunziata, CM O'Shaughnessy, J AF Annunziata, Christina M. O'Shaughnessy, Joyce TI Poly (ADP-Ribose) Polymerase as a Novel Therapeutic Target in Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; DNA-REPAIR; HOMOLOGOUS RECOMBINATION; SPORADIC BREAST; STRAND BREAKS; MECHANISMS; INHIBITORS; BRCA1; GENE; INSTABILITY AB Cancer chemotherapy exploits limitations in repairing DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Poly (ADP-ribose) polymerase (PARP) and BRCA proteins are central to the repair of DNA strand breaks and, when defective, lead to the accumulation of mutations introduced by error-prone DNA repair. Breast, ovarian, and other cancers develop in the setting of BRCA deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in BRCA-pathway-deficient tumors. Future studies must seek to identify sporadic cancers that harbor genomic instability, rendering susceptibility to agents that induce additional and lethal DNA damage. Clin Cancer Res; 16(18); 4517-26. (c) 2010 AACR. C1 [O'Shaughnessy, Joyce] US Oncol, Baylor Sammons Canc Ctr, Texas Oncol, Dallas, TX 75246 USA. [Annunziata, Christina M.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP O'Shaughnessy, J (reprint author), US Oncol, Baylor Sammons Canc Ctr, Texas Oncol, 3535 Worth St,Collins 5, Dallas, TX 75246 USA. EM joyce.oshaughnessy@usoncology.com RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU Intramural NIH HHS [Z99 CA999999] NR 49 TC 63 Z9 64 U1 3 U2 7 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 SEP 15 PY 2010 VL 16 IS 18 BP 4517 EP 4526 DI 10.1158/1078-0432.CCR-10-0526 PG 10 WC Oncology SC Oncology GA 651FF UT WOS:000281910400006 PM 20823142 ER PT J AU Redon, CE Nakamura, AJ Zhang, YW Ji, JP Bonner, WM Kinders, RJ Parchment, RE Doroshow, JH Pommier, Y AF Redon, Christophe E. Nakamura, Asako J. Zhang, Yong-Wei Ji, Jiuping (Jay) Bonner, William M. Kinders, Robert J. Parchment, Ralph E. Doroshow, James H. Pommier, Yves TI Histone yH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers SO CLINICAL CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; ADP-RIBOSE POLYMERASE; I CLEAVAGE COMPLEXES; H2AX PHOSPHORYLATION; TOPOISOMERASE-I; ATAXIA-TELANGIECTASIA; GENOMIC INSTABILITY; MAMMALIAN-CELLS; CANCER-CELLS AB Tumor cells are often deficient in DNA damage response (DDR) pathways, and anticancer therapies are commonly based on genotoxic treatments using radiation and/or drugs that damage DNA directly or interfere with DNA metabolism, leading to the formation of DNA double-strand breaks (DSB), and ultimately to cell death. Because DSBs induce the phosphorylation of histone H2AX (gamma H2AX) in the chromatin flanking the break site, an antibody directed against gamma H2AX can be employed to measure DNA damage levels before and after patient treatment. Poly(ADP-ribose) polymerases (PARP1 and PARP2) are also activated by DNA damage, and PARP inhibitors show promising activity in cancers with defective homologous recombination (HR) pathways for DSB repair. Ongoing clinical trials are testing combinations of PARP inhibitors with DNA damaging agents. Poly(ADP-ribosylation), abbreviated as PAR, can be measured in clinical samples and used to determine the efficiency of PARP inhibitors. This review summarizes the roles of gamma H2AX and PAR in the DDR, and their use as biomarkers to monitor drug response and guide clinical trials, especially phase 0 clinical trials. We also discuss the choices of relevant samples for gamma H2AX and PAR analyses. Clin Cancer Res; 16(18); 4532-42. (c) 2010 AACR. C1 [Redon, Christophe E.; Nakamura, Asako J.; Zhang, Yong-Wei; Bonner, William M.; Doroshow, James H.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Ji, Jiuping (Jay)] NCI, Natl Clin Target Validat Lab, SAIC Frederick Inc, Frederick, MD USA. [Kinders, Robert J.; Parchment, Ralph E.] NCI, Lab Human Toxicol & Pharmacol, SAIC Frederick Inc, Frederick, MD 21701 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI ZHANG, YONGWEI/E-6252-2012 FU Division of Cancer Treatment and Diagnosis of the National Cancer Institute; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland FX This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute and by the Center for Cancer Research, Intramural Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. NR 84 TC 128 Z9 131 U1 3 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2010 VL 16 IS 18 BP 4532 EP 4542 DI 10.1158/1078-0432.CCR-10-0523 PG 11 WC Oncology SC Oncology GA 651FF UT WOS:000281910400008 PM 20823146 ER PT J AU Burns, DN Dieffenbach, CW Vermund, SH AF Burns, David N. Dieffenbach, Carl W. Vermund, Sten H. TI Rethinking Prevention of HIV Type 1 Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; UNITED-STATES; SEXUAL TRANSMISSION; GENITAL-TRACT; TUBERCULOSIS; HIV/AIDS; EPIDEMIC; EFFICACY; AFRICA; PEOPLE AB Research on the prevention of human immunodeficiency virus (HIV)-1 infection is at a critical juncture. Major methodological challenges to performing prevention trials have emerged, and one after another promising biomedical interventions have failed to reduce the incidence of HIV-1 infection. Nevertheless, there is growing optimism that progress can be achieved in the near term. Mathematical modeling indicates that 2 new strategies, "test and treat" and preexposure prophylaxis, could have a major impact on the incidence of HIV-1 infection. Will our hopes be justified? We review the potential strengths and limitations of these antiretroviral "treatment as prevention" strategies and outline other new options for reducing the incidence of HIV-1 infection in the near term. By maximizing the potential of existing interventions, developing other effective strategies, and combining them in an optimal manner, we have the opportunity to bring the HIV-1 epidemic under control. C1 [Burns, David N.; Dieffenbach, Carl W.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Inst Global Hlth, Nashville, TN 37212 USA. RP Burns, DN (reprint author), NIAID, Div Aids, NIH, 6700B Rockledge Dr, Bethesda, MD 20892 USA. EM burnsda@niaid.nih.gov OI Vermund, Sten/0000-0001-7289-8698 FU National Institutes of Health [U01AI068619] FX National Institutes of Health (U01AI068619 to S.H.V.). NR 63 TC 68 Z9 69 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2010 VL 51 IS 6 BP 725 EP 731 DI 10.1086/655889 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 641QA UT WOS:000281143400014 PM 20707698 ER PT J AU Outterson, K Powers, JH Gould, IM Kesselheim, AS AF Outterson, Kevin Powers, John H., III Gould, Ian M. Kesselheim, Aaron S. TI Questions about the 10 x '20 Initiative SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID DRUGS C1 [Outterson, Kevin] Boston Univ, Sch Law, Boston, MA 02215 USA. [Kesselheim, Aaron S.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Kesselheim, Aaron S.] Harvard Univ, Sch Med, Boston, MA USA. [Powers, John H., III] NIH, Sci Applicat Int Corp, Bethesda, MD 20892 USA. [Gould, Ian M.] Aberdeen Royal Infirm, Dept Med Microbiol, Aberdeen, Scotland. RP Outterson, K (reprint author), Boston Univ, Sch Law, 765 Commonwealth Ave, Boston, MA 02215 USA. EM mko@bu.edu FU AHRQ HHS [K08HS18465-01] NR 8 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2010 VL 51 IS 6 BP 751 EP 752 DI 10.1086/655955 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 641QA UT WOS:000281143400018 PM 20731566 ER PT J AU Dutta, S Dawid, IB AF Dutta, Sunit Dawid, Igor B. TI Kctd15 inhibits neural crest formation by attenuating Wnt/beta-catenin signaling output SO DEVELOPMENT LA English DT Article DE Neural crest; Neural plate border; Wnt signaling; Pigmentation; BTB domain; Zebrafish; Xenopus ID XENOPUS EMBRYOS; HOMEOBOX GENE; OTIC PLACODE; BTB DOMAIN; CELL FATE; ZEBRAFISH; WNT; EXPRESSION; INDUCTION; VERTEBRATE AB Neural crest (NC) precursors are stem cells that are capable of forming many cell types after migration to different locations in the embryo. NC and placodes form at the neural plate border (NPB). The Wnt pathway is essential for specifying NC versus placodal identity in this cell population. Here we describe the BTB domain-containing protein Potassium channel tetramerization domain containing 15 (Kctd15) as a factor expressed in the NPB that efficiently inhibits NC induction in zebrafish and frog embryos. Whereas overexpression of Kctd15 inhibited NC formation, knockdown of Kctd15 led to expansion of the NC domain. Likewise, NC induction by Wnt3a plus Chordin in Xenopus animal explants was suppressed by Kctd15, but constitutively active beta-catenin reversed Kctd15-mediated suppression of NC induction. Suppression of NC induction by inhibition of Wnt8.1 was rescued by reduction of Kctd15 expression, linking Kctd15 action to the Wnt pathway. We propose that Kctd15 inhibits NC formation by attenuating the output of the canonical Wnt pathway, thereby restricting expansion of the NC domain beyond its normal range. C1 [Dutta, Sunit; Dawid, Igor B.] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM idawid@nih.gov FU NICHD, NIH FX We thank Hyunju Ro for the beta-catenin mutant and other reagents, Martha Rebbert for technical support, Robert Cornell (University of Iowa) for plasmids, Brian Brooks for support and members of the Dawid laboratory for discussion. This research was supported by the Intramural Research Program of the NICHD, NIH. Deposited in PMC for release after 12 months. NR 51 TC 20 Z9 23 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 15 PY 2010 VL 137 IS 18 BP 3013 EP 3018 DI 10.1242/dev.047548 PG 6 WC Developmental Biology SC Developmental Biology GA 642HY UT WOS:000281200800005 PM 20685732 ER PT J AU Mandin, P Gottesman, S AF Mandin, Pierre Gottesman, Susan TI Integrating anaerobic/aerobic sensing and the general stress response through the ArcZ small RNA SO EMBO JOURNAL LA English DT Article DE ArcA; ArcZ; Hfq; RpoS ID ESCHERICHIA-COLI; MESSENGER-RNA; RPOS TRANSLATION; 2-COMPONENT SYSTEM; SOLUBLE-RNA; SALMONELLA-TYPHIMURIUM; GENETIC-EVIDENCE; REGULATORY RNAS; SIGMA-FACTOR; HOST FACTOR AB The alternative sigma factor RpoS responds to multiple stresses and activates a large number of genes that allow bacteria to adapt to changing environments. The accumulation of RpoS is regulated at multiple levels, including the regulation of its translation by small regulatory RNAs (sRNAs). A library of plasmids expressing each of 26 Escherichia coli sRNAs that bind Hfq was created to globally and rapidly analyse regulation of an rpoS-lacZ translational fusion. The approach can be easily applied to any gene of interest. When overexpressed, four sRNAs, including OxyS, previously shown to repress rpoS, were observed to repress the expression of the rpoS-lacZ fusion. Along with DsrA and RprA, two previously defined activators of rpoS translation, a third new sRNA activator, ArcZ, was identified. The expression of arcZ is repressed by the aerobic/anaerobic-sensing ArcA-ArcB two-component system under anaerobic conditions and adds translational regulation to the ArcA-ArcB regulon. ArcZ directly represses, and is repressed by, arcB transcription, providing a negative feedback loop that may affect functioning of the ArcA-ArcB regulon. C1 [Mandin, Pierre; Gottesman, Susan] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37,Room 5132, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX We thank Maude Guillier and Kyung Moon for providing plasmids. We thank members of our laboratory and Gisela Storz for comments on the paper. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 71 TC 109 Z9 111 U1 5 U2 17 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 SEP 15 PY 2010 VL 29 IS 18 BP 3094 EP 3107 DI 10.1038/emboj.2010.179 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 664VT UT WOS:000282991900007 PM 20683441 ER PT J AU Xu, DY Muniandy, P Leo, E Yin, JH Thangavel, S Shen, X Ii, M Agama, K Guo, R Fox, D Meetei, AR Wilson, L Nguyen, H Weng, NP Brill, SJ Li, L Vindigni, A Pommier, Y Seidman, M Wang, WD AF Xu, Dongyi Muniandy, Parameswary Leo, Elisabetta Yin, Jinhu Thangavel, Saravanabhavan Shen, Xi Ii, Miki Agama, Keli Guo, Rong Fox, David, III Meetei, Amom Ruhikanta Wilson, Lauren Nguyen, Huy Weng, Nan-ping Brill, Steven J. Li, Lei Vindigni, Alessandro Pommier, Yves Seidman, Michael Wang, Weidong TI Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication SO EMBO JOURNAL LA English DT Article DE BLM; Bloom syndrome; replication; Rif1; RMI ID TOPOISOMERASE-III-ALPHA; HOLLIDAY JUNCTION DISSOLVASOME; SYNDROME HELICASE; FANCONI-ANEMIA; GENOME STABILITY; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; TRANSLESION SYNTHESIS; ESSENTIAL COMPONENT; PROTEIN COMPLEXES AB BLM, the helicase defective in Bloom syndrome, is part of a multiprotein complex that protects genome stability. Here, we show that Rif1 is a novel component of the BLM complex and works with BLM to promote recovery of stalled replication forks. First, Rif1 physically interacts with the BLM complex through a conserved C-terminal domain, and the stability of Rif1 depends on the presence of the BLM complex. Second, Rif1 and BLM are recruited with similar kinetics to stalled replication forks, and the Rif1 recruitment is delayed in BLM-deficient cells. Third, genetic analyses in vertebrate DT40 cells suggest that BLM and Rif1 work in a common pathway to resist replication stress and promote recovery of stalled forks. Importantly, vertebrate Rif1 contains a DNA-binding domain that resembles the alpha CTD domain of bacterial RNA polymerase a; and this domain preferentially binds fork and Holliday junction (HJ) DNA in vitro and is required for Rif1 to resist replication stress in vivo. Our data suggest that Rif1 provides a new DNA-binding interface for the BLM complex to restart stalled replication forks. C1 [Xu, Dongyi; Yin, Jinhu; Guo, Rong; Fox, David, III; Meetei, Amom Ruhikanta; Wilson, Lauren; Wang, Weidong] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Muniandy, Parameswary; Seidman, Michael] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Leo, Elisabetta; Agama, Keli; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Thangavel, Saravanabhavan; Vindigni, Alessandro] Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy. [Shen, Xi; Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. [Shen, Xi; Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. [Ii, Miki; Brill, Steven J.] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08855 USA. [Nguyen, Huy; Weng, Nan-ping] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM wangw@grc.nia.nih.gov OI Xu, Dongyi/0000-0001-5711-2618; Wilson, Lauren/0000-0002-5953-2293 FU National Institute on Aging [Z01 AG000657-08]; National Institute of Health; NIH [GM071268]; AIRC FX We thank Drs E Blackburn and L Xu for hRif1 cDNA, I Hickson for Topo 3 alpha antibody, S Takeda for Ovalbumin-DRGFP plasmid, M Takata for FANCC-targeting vector, KJ Patel for FANCM-/- DT40 cells, S Buonomo for Rif1-/- mouse cells, and S Fuggman for reagents and advice. This work was supported in part by the Intramural Research Program of the National Institute on Aging (Z01 AG000657-08), National Institute of Health, and NIH grant GM071268 (to SJB). It is also supported by an AIRC grant (to AV). NR 56 TC 40 Z9 40 U1 0 U2 2 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 SEP 15 PY 2010 VL 29 IS 18 BP 3140 EP 3155 DI 10.1038/emboj.2010.186 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 664VT UT WOS:000282991900011 PM 20711169 ER PT J AU Murga-Zamalloa, CA Atkins, SJ Peranen, J Swaroop, A Khanna, H AF Murga-Zamalloa, Carlos A. Atkins, Stephen J. Peranen, Johan Swaroop, Anand Khanna, Hemant TI Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration SO HUMAN MOLECULAR GENETICS LA English DT Article ID GUANINE-NUCLEOTIDE-EXCHANGE; INTRAFLAGELLAR TRANSPORT PROTEIN; CYCLIC-GMP PHOSPHODIESTERASE; VERTEBRATE PRIMARY CILIUM; RETINAL DEGENERATION; OUTER SEGMENTS; (RPGR)-INTERACTING PROTEIN; SENSORY ORGANELLE; MUTATION ANALYSIS; CLINICAL FINDINGS AB Defects in biogenesis or function(s) of primary cilia are associated with numerous inherited disorders (called ciliopathies) thatmay include retinal degeneration phenotype. The cilia-expressed gene RPGR (retinitis pigmentosa GTPase regulator) is mutated in patients with X-linked retinitis pigmentosa (XLRP) and encodes multiple protein isoforms with a common N-terminal domain homologous to regulator of chromosome condensation 1 (RCC1), a guanine nucleotide exchange factor (GEF) for Ran GTPase. RPGR interacts with several ciliopathy proteins, such as RPGRIP1L and CEP290; however, its physiological role in cilia-associated functions has not been delineated. Here, we report that RPGRinteractswith the smallGTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/ GTP nucleotide exchange. Disease-causing mutations in RPGR diminish its interaction with RAB8A and reduce the GEF activity. Depletion of RPGR in hTERT-RPE1 cells interferes with ciliary localization of RAB8A and results in shorter primary cilia. Our data suggest that RPGR modulates intracellular localization and function of RAB8A. We propose that perturbation of RPGR-RAB8A interaction, at least in part, underlies the pathogenesis of photoreceptor degeneration in XLRP caused by RPGR mutations. C1 [Murga-Zamalloa, Carlos A.; Atkins, Stephen J.; Khanna, Hemant] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Peranen, Johan] Univ Helsinki, Inst Biotechnol, Helsinki, Finland. [Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. RP Khanna, H (reprint author), 381 Plantat St,Biotech 5,Suite 250, Worcester, MA 01605 USA. EM hemant.khanna@umassmed.edu OI Swaroop, Anand/0000-0002-1975-1141 FU Intramural NIH HHS; NEI NIH HHS [EY07003, R01-EY007961]; NIDDK NIH HHS [5P60 DK20572] NR 75 TC 48 Z9 49 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 SEP 15 PY 2010 VL 19 IS 18 BP 3591 EP 3598 DI 10.1093/hmg/ddq275 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 644AU UT WOS:000281343600009 PM 20631154 ER PT J AU Melton, PE Rutherford, S Voruganti, VS Goring, HHH Laston, S Haack, K Comuzzie, AG Dyer, TD Johnson, MP Kent, JW Curran, JE Moses, EK Blangero, J Barac, A Lee, ET Best, LG Fabsitz, RR Devereux, RB Okin, PM Bella, JN Broeckel, U Howard, BV MacCluer, JW Cole, SA Almasy, L AF Melton, Phillip E. Rutherford, Sue Voruganti, Venkata Saroja Goering, Harald H. H. Laston, Sandra Haack, Karin Comuzzie, Anthony G. Dyer, Thomas D. Johnson, Matthew P. Kent, Jack W., Jr. Curran, Joanne E. Moses, Eric K. Blangero, John Barac, Ana Lee, Elisa T. Best, Lyle G. Fabsitz, Richard R. Devereux, Richard B. Okin, Peter M. Bella, Jonathan N. Broeckel, Uli Howard, Barbara V. MacCluer, Jean W. Cole, Shelley A. Almasy, Laura TI Bivariate genetic association of KIAA1797 with heart rate in American Indians: the Strong Heart Family Study SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; QUANTITATIVE-TRAIT LOCUS; CHROMOSOME 9P21; CARDIOVASCULAR-DISEASE; RATE-VARIABILITY; LINKAGE ANALYSIS; 4 SNPS; MYOCARDIAL-INFARCTION; MEXICAN-AMERICANS AB Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians (AIs) from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2248 single-nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL [logarithm of odds (LOD) = 4.83; genome-wide P = 0.0003] on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488 and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (P = 7.14 x 10(-6)). This SNP (rs7875153) is rare (minor allele frequency = 0.02) in AIs and is located within intron 9 of the gene KIAA1797. To support this association, we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (P = 0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study. C1 [Melton, Phillip E.; Rutherford, Sue; Voruganti, Venkata Saroja; Goering, Harald H. H.; Laston, Sandra; Haack, Karin; Comuzzie, Anthony G.; Dyer, Thomas D.; Johnson, Matthew P.; Kent, Jack W., Jr.; Curran, Joanne E.; Moses, Eric K.; Blangero, John; MacCluer, Jean W.; Cole, Shelley A.; Almasy, Laura] SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78245 USA. [Barac, Ana; Howard, Barbara V.] MedStar Res Inst, Washington, DC USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Coll Publ Hlth, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Fabsitz, Richard R.] NHLBI, Epidemiol Branch, Bethesda, MD 20892 USA. [Devereux, Richard B.; Okin, Peter M.; Bella, Jonathan N.] Weill Cornell Med Coll New York, Dept Med, New York, NY USA. [Broeckel, Uli] Med Coll Wisconsin, Milwaukee, WI 53226 USA. RP Melton, PE (reprint author), SW Fdn Biomed Res, Dept Genet, POB 760549, San Antonio, TX 78245 USA. EM pmelton@sfbrgenetics.org RI Melton, Phillip/C-4773-2012; Melton, Phillip/A-5012-2013; OI Melton, Phillip/0000-0003-4026-2964; Barac, Ana/0000-0002-9935-8904; Kent, Jack/0000-0002-0758-7639 FU National Institute of Health [U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521, R01 HL45522, MH59490]; Research Facilities Improvement Program [C06 RR013556, C06 RR017515]; SBC Foundation FX This research was funded by National Institute of Health Grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521 and R01 HL45522. Development of SOLAR was supported by National Institute of Health grant MH59490. This investigation was conducted in part in facilities constructed with the support from the Research Facilities Improvement Program under grants numbered C06 RR013556 and C06 RR017515. The AT&T Genomics Computing Center supercomputing facilities used for statistical genetic analyses were supported in part by a gift from the SBC Foundation. NR 51 TC 14 Z9 14 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 SEP 15 PY 2010 VL 19 IS 18 BP 3662 EP 3671 DI 10.1093/hmg/ddq274 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 644AU UT WOS:000281343600016 PM 20601674 ER PT J AU Jacobs, EJ Chanock, SJ Fuchs, CS LaCroix, A McWilliams, RR Steplowski, E Stolzenberg-Solomon, RZ Arslan, AA Bueno-de-Mesquita, HB Gross, M Helzlsouer, K Petersen, G Zheng, W Agalliu, I Allen, NE Amundadottir, L Boutron-Ruault, MC Buring, JE Canzian, F Clipp, S Dorronsoro, M Gaziano, JM Giovannucci, EL Hankinson, SE Hartge, P Hoover, RN Hunter, DJ Jacobs, KB Jenab, M Kraft, P Kooperberg, C Lynch, SM Sund, M Mendelsohn, JB Mouw, T Newton, CC Overvad, K Palli, D Peeters, PHM Rajkovic, A Shu, XO Thomas, G Tobias, GS Trichopoulos, D Virtamo, J Wactawski-Wende, J Wolpin, BM Yu, K Zeleniuch-Jacquotte, A AF Jacobs, Eric J. Chanock, Stephen J. Fuchs, Charles S. LaCroix, Andrea McWilliams, Robert R. Steplowski, Emily Stolzenberg-Solomon, Rachael Z. Arslan, Alan A. Bueno-de-Mesquita, H. Bas Gross, Myron Helzlsouer, Kathy Petersen, Gloria Zheng, Wei Agalliu, Ilir Allen, Naomi E. Amundadottir, Laufey Boutron-Ruault, Marie-Christine Buring, Julie E. Canzian, Federico Clipp, Sandra Dorronsoro, Miren Gaziano, J. Michael Giovannucci, Edward L. Hankinson, Susan E. Hartge, Patricia Hoover, Robert N. Hunter, David J. Jacobs, Kevin B. Jenab, Mazda Kraft, Peter Kooperberg, Charles Lynch, Shannon M. Sund, Malin Mendelsohn, Julie B. Mouw, Tracy Newton, Christina C. Overvad, Kim Palli, Domenico Peeters, Petra H. M. Rajkovic, Aleksandar Shu, Xiao-Ou Thomas, Gilles Tobias, Geoffrey S. Trichopoulos, Dimitrios Virtamo, Jarmo Wactawski-Wende, Jean Wolpin, Brian M. Yu, Kai Zeleniuch-Jacquotte, Anne TI Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan) SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID BASE-LINE CHARACTERISTICS; SINGLE BRCA2 MUTATION; COLORECTAL-CANCER; HIGH PREVALENCE; WOMENS HEALTH; BREAST; ADENOCARCINOMA; MORTALITY; DESIGN; POLYMORPHISMS AB A family history of pancreatic cancer has consistently been associated with increased risk of pancreatic cancer. However, uncertainty remains about the strength of this association. Results from previous studies suggest a family history of select cancers (i.e., ovarian, breast and colorectal) could also be associated, although not as strongly, with increased risk of pancreatic cancer. We examined the association between a family history of 5 types of cancer (pancreas, prostate, ovarian, breast and colorectal) and risk of pancreatic cancer using data from a collaborative nested case-control study conducted by the Pancreatic Cancer Cohort Consortium. Cases and controls were from cohort studies from the United States, Europe and China, and a case-control study from the Mayo Clinic. Analyses of family history of pancreatic cancer included 1,183 cases and 1,205 controls. A family history of pancreatic cancer in a parent, sibling or child was associated with increased risk of pancreatic cancer [multivariate-adjusted odds ratios (ORs) = 1.76, 95% confidence interval (Cl) = 1.19-2.61]. A family history of prostate cancer was also associated with increased risk (OR = 1.45, 95% Cl = 1.12-1.89). There were no statistically significant associations with a family history of ovarian cancer (OR = 0.82, 95% Cl = 0.52-1.31), breast cancer (OR = 1.21, 95% Cl = 0.97-1.51) or colorectal cancer (OR = 1.17, 95% Cl = 0.93-1.47). Our results confirm a moderate sized association between a family history of pancreatic cancer and risk of pancreatic cancer and also provide evidence for an association with a family history of prostate cancer worth further study. C1 [Jacobs, Eric J.; Newton, Christina C.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Chanock, Stephen J.; Amundadottir, Laufey] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Wolpin, Brian M.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [LaCroix, Andrea; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [McWilliams, Robert R.] Mayo Clin, Coll Med, Dept Oncol, Rochester, MN USA. [Steplowski, Emily] Informat Management Serv Inc, Silver Spring, MD USA. [Arslan, Alan A.] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, RIVM, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Gross, Myron] Univ Minnesota, Sch Med, Dept Lab Med Pathol, Minneapolis, MN 55455 USA. [Helzlsouer, Kathy] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Petersen, Gloria] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Agalliu, Ilir] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Allen, Naomi E.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Boutron-Ruault, Marie-Christine] INSERM, F-75654 Paris 13, France. [Boutron-Ruault, Marie-Christine] Inst Gustave Roussy, Villejuif, France. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med & Aging, Boston, MA 02115 USA. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Clipp, Sandra] George W Comstock Ctr Publ Hlth Res & Prevent, Hagerstown, MD USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Phys Hlth Study, Div Aging Cardiovasc Dis & Prevent Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Med, Dept Nutr, Boston, MA USA. [Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Kraft, Peter; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Jacobs, Kevin B.] BioInformed LLC, Gaithersburg, MD USA. [Jacobs, Kevin B.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jenab, Mazda] Int Agcy Res Canc, F-69372 Lyon, France. [Lynch, Shannon M.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Sund, Malin] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Mouw, Tracy; Peeters, Petra H. M.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Overvad, Kim] Aarhus Univ Hosp, Dept Cardiol, Aalborg Hosp, Aalborg, Denmark. [Overvad, Kim] Aarhus Univ Hosp, Dept Clin Epidemiol, Aalborg Hosp, Aalborg, Denmark. [Palli, Domenico] Canc Res & Prevent Inst ISPO Florence, Mol & Nutr Epidemiol Unit, Florence, Italy. [Peeters, Petra H. M.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Rajkovic, Aleksandar] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Trichopoulos, Dimitrios] Univ Athens, Sch Med, Dept Hyg & Epidemiol, Athens, Greece. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Jacobs, EJ (reprint author), Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. EM ejacobs@cancer.org RI Boutron Ruault, Marie-Christine/G-3705-2013; Boutron, Marie-Christine/K-8168-2013; Boutron-Ruault, Marie-Christine/H-3936-2014; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; OI Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; Sund, Malin/0000-0002-7516-9543; PALLI, Domenico/0000-0002-5558-2437; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU NCI NIH HHS [R01 CA082729, R01 CA097193, R01 CA124908, R37 CA070867, U01 CA098710-04] NR 36 TC 37 Z9 37 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2010 VL 127 IS 6 BP 1421 EP 1428 DI 10.1002/ijc.25148 PG 8 WC Oncology SC Oncology GA 643ZL UT WOS:000281340100017 PM 20049842 ER PT J AU Bhatia, K Goedert, JJ Modali, R Preiss, L Ayers, LW AF Bhatia, Kishor Goedert, James J. Modali, Rama Preiss, Liliana Ayers, Leona W. TI Immunological detection of viral large T antigen identifies a subset of Merkel cell carcinoma tumors with higher viral abundance and better clinical outcome SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID POLYOMAVIRUS INFECTION; EXPRESSION; ABSENCE; MCV C1 [Bhatia, Kishor; Goedert, James J.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. [Modali, Rama] Bioserve, Laurel, MD USA. [Preiss, Liliana] RTI Int, Rockville, MD USA. [Ayers, Leona W.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. RP Bhatia, K (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. EM bhatiak@mail.nih.gov FU Intramural NIH HHS [Z01 CP010176-08] NR 21 TC 49 Z9 49 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2010 VL 127 IS 6 BP 1493 EP 1496 DI 10.1002/ijc.25136 PG 4 WC Oncology SC Oncology GA 643ZL UT WOS:000281340100025 PM 20041469 ER PT J AU Wadgaonkar, AD Schneider, EC Bhattacharyya, T AF Wadgaonkar, Ajay D. Schneider, Eric C. Bhattacharyya, Timothy TI Physician Tiering by Health Plans in Massachusetts SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID SURGEON PROCEDURE VOLUME; HIP FRACTURE; REPLACEMENT; ASSOCIATION; MORTALITY; OUTCOMES AB Background: Physician tiering is an emerging health-care strategy that purports to grade physicians on the basis of cost-efficiency and quality-performance measures. We investigated the consistency of tiering of orthopaedic surgeons by examining tier agreement between health plans and physician factors associated with top-tier ranking. Methods: Health plan tier, demographic, and training data were collected on 615 licensed orthopaedic surgeons who accepted one or more of three health plans and practiced in Massachusetts. We then computed the concordance of physician tier rankings between the health plans. We further examined the factors associated with top-tier ranking, such as malpractice claims and socioeconomic conditions of the practice area. Results: The concordance of physician tiering between health plans was poor to fair (range, 8% to 28%, kappa = 0.06 to 0.25). The percentage of physicians ranked as top-tier varied widely among the health plans, from 21% to 62%. Thirty-eight percent of physicians were not rated top-tier by any of the health plans, whereas only 5.2% of physicians were rated top-tier by all three health plans. Multivariate analysis showed that board certification, accepting Medicaid, and practicing in a suburban location were the independent factors associated with being ranked in the top tier. More years in practice or fewer malpractice claims were not related to tier. Conclusions: Current methods of physician tiering have low consistency and manifest evidence of geographic and demographic biases. C1 [Wadgaonkar, Ajay D.; Schneider, Eric C.; Bhattacharyya, Timothy] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Wadgaonkar, AD (reprint author), 950 25th St NW,Apartment 707 S, Washington, DC 20037 USA. EM Timothy.bhattacharyya@nih.gov OI Schneider, Eric/0000-0002-1132-5084 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health FX In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants of less than $10,000 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits of less than $10,000 or a commitment or agreement to provide such benefits from commercial entities (Stryker, AO North America, and Best Doctors, Inc.). NR 16 TC 7 Z9 7 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD SEP 15 PY 2010 VL 92A IS 12 BP 2204 EP 2209 DI 10.2106/JBJS.I.01080 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 649PQ UT WOS:000281785100009 PM 20844163 ER PT J AU Choi, W Wolber, R Gerwat, W Mann, T Batzer, J Smuda, C Liu, HF Kolbe, L Hearing, VJ AF Choi, Wonseon Wolber, Rainer Gerwat, Wolfram Mann, Tobias Batzer, Jan Smuda, Christoph Liu, Hongfang Kolbe, Ludger Hearing, Vincent J. TI The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin SO JOURNAL OF CELL SCIENCE LA English DT Article DE Pigmentation; Skin; Melanocyte; Fibroblast; Color ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE; IN-VITRO; ULTRAVIOLET-RADIATION; INHIBITOR CI-1033; ERBB RECEPTORS; CANCER-CELLS; DNA-DAMAGE; PIGMENTATION; EXPRESSION AB Interactions between melanocytes and neighboring cells in the skin are important in regulating skin color in humans. We recently demonstrated that the less pigmented and thicker skin on the palms and soles is regulated by underlying fibroblasts in those areas, specifically via a secreted factor (DKK1) that modulates Wnt signaling. In this study, we tested the hypothesis that dermal fibroblasts regulate the constitutive skin color of individuals ranging from very light to very dark. We used microarray analysis to compare gene expression patterns in fibroblasts derived from lighter skin types compared to darker skin types, with a focus on secreted proteins. We identified a number of genes that differ dramatically in expression and, among the expressed proteins, neuregulin-1, which is secreted by fibroblasts derived from dark skin, effectively increases the pigmentation of melanocytes in tissue culture and in an artificial skin model and regulates their growth, suggesting that it is one of the major factors determining human skin color. C1 [Choi, Wonseon; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Wolber, Rainer; Gerwat, Wolfram; Mann, Tobias; Batzer, Jan; Smuda, Christoph; Kolbe, Ludger] Beiersdorf AG, Skin Res, R&D, D-20245 Hamburg, Germany. [Liu, Hongfang] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM hearingv@nih.gov FU NIH, National Cancer Institute FX The authors thank Yuji Yamaguchi (Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan) for his helpful discussions and critical review of the manuscript. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. Deposited in PMC for release after 12 months. NR 55 TC 41 Z9 42 U1 0 U2 4 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 SEP 15 PY 2010 VL 123 IS 18 BP 3102 EP 3111 DI 10.1242/jcs.064774 PG 10 WC Cell Biology SC Cell Biology GA 646WN UT WOS:000281575100009 PM 20736300 ER PT J AU Schwartz, CM Cheng, A Mughal, MR Mattson, MP Yao, PJ AF Schwartz, Catherine M. Cheng, Aiwu Mughal, Mohamed R. Mattson, Mark P. Yao, Pamela J. TI Clathrin Assembly Proteins AP180 and CALM in the Embryonic Rat Brain SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE intracellular trafficking; neural stem cells; postmitotic neurons; dopaminergic ID SYNAPTIC VESICLE ENDOCYTOSIS; MONOCLONAL-ANTIBODIES; STEM-CELLS; ALPHA-APPENDAGE; TERMINAL DOMAIN; EXPRESSION; NEURONS; BINDING; LOCALIZATION; AP-3 AB Clathrin-coated vesicles are known to play diverse and pivotal roles in cells. The proper formation of clathrin-coated vesicles is dependent on, and highly regulated by, a large number of clathrin assembly proteins. These assembly proteins likely determine the functional specificity of clathrin-coated vesicles, and together they control a multitude of intracellular trafficking pathways, including those involved in embryonic development. In this study, we focus on two closely related clathrin assembly proteins, AP180 and CALM (clathrin assembly lymphoid myeloid leukemia protein), in the developing embryonic rat brain. We find that AP180 begins to be expressed at embryonic day 14 (E14), but only in postmitotic cells that have acquired a neuronal fate. CALM, on the other hand, is expressed as early as E12, by both neural stem cells and postmitotic neurons. In vitro loss-of-function studies using RNA interference (RNAi) indicate that AP180 and CALM are dispensable for some aspects of embryonic neurogenesis but are required for the growth of postmitotic neurons. These results identify the developmental stage of AP180 and CALM expression and suggest that each protein has distinct functions in neural development. J. Comp. Neurol. 518:3803-3818, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Yao, Pamela J.] NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Schwartz, Catherine M.] Karolinska Inst, Mol Neurobiol Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden. [Cheng, Aiwu] MedStar Res Inst, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, Room 05C226,251 Bayview Blvd, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging, MedStar Research Institute FX Grant sponsors: Intramural Research Program of the National Institute on Aging, MedStar Research Institute (R&D contract). NR 66 TC 9 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD SEP 15 PY 2010 VL 518 IS 18 BP 3803 EP 3818 DI 10.1002/cne.22425 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 634RD UT WOS:000280600400009 PM 20653035 ER PT J AU Kitamura, K Farber, JM Kelsall, BL AF Kitamura, Kazuya Farber, Joshua M. Kelsall, Brian L. TI CCR6 Marks Regulatory T Cells as a Colon-Tropic, IL-10-Producing Phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; DENDRITIC CELLS; INTESTINAL INFLAMMATION; CHEMOKINE RECEPTORS; TGF-BETA; RHEUMATOID-ARTHRITIS; EXPERIMENTAL COLITIS; EXPRESSION DEFINES; PROTEIN 3-ALPHA; CROHNS-DISEASE AB Expression of CCR6 and its ligand, CCL20, are increased in the colon of humans with inflammatory bowel diseases and mice with experimental colitis; however, their role in disease pathogenesis remains obscure. In this study, we demonstrate a role for CCR6 on regulatory T (Treg) cells in the T cell-transfer model of colitis. Rag2(-/-) mice given Ccr6(-/-) CD4(+)CD45RB(high) T cells had more severe colitis with increased IFN-gamma-producing T cells, compared with the mice given wild-type cells. Although an equivalent frequency of induced/acquired Treg (iTreg) cells was observed in mesenteric lymph nodes and colon from both groups, the suppressive capacity of Ccr6(-/-) iTreg cells was impaired. Cotransfer studies of wild-type or Ccr6(-/-) Treg cells with CD4(+)CD45RB(high) T cells also showed a defect in suppression by Ccr6(-/-) Treg cells. CCR6(+) Treg cells were characterized as Ag-activated and IL-10-producing in the steady-state and preferentially migrated to the colon during inflammation. Thus, we conclude that CCR6 expression on Treg cells was required for the full function of Treg cell-mediated suppression in the T cell-transfer model of colitis. CCR6 may contribute to the regulation of colitis by directing its function in Ag-specific, IL-10-producing iTreg cells to the inflamed colon. The Journal of Immunology, 2010, 185: 3295-3304. C1 [Kitamura, Kazuya; Kelsall, Brian L.] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Farber, Joshua M.] NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kitamura, Kazuya] Kanazawa Univ Hosp, Dept Gastroenterol, Kanazawa, Ishikawa, Japan. RP Kelsall, BL (reprint author), NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, 10-11N104,10 Ctr Dr, Bethesda, MD 20892 USA. EM bkelsall@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by research funds from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 69 TC 42 Z9 43 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2010 VL 185 IS 6 BP 3295 EP 3304 DI 10.4049/jimmunol.1001156 PG 10 WC Immunology SC Immunology GA 646RI UT WOS:000281559300021 PM 20720211 ER PT J AU Hoshi, M Saito, K Hara, A Taguchi, A Ohtaki, H Tanaka, R Fujigaki, H Osawa, Y Takemura, M Matsunami, H Ito, H Seishima, M AF Hoshi, Masato Saito, Kuniaki Hara, Akira Taguchi, Ayako Ohtaki, Hirofumi Tanaka, Ryo Fujigaki, Hidetsugu Osawa, Yosuke Takemura, Masao Matsunami, Hidetoshi Ito, Hiroyasu Seishima, Mitsuru TI The Absence of IDO Upregulates Type I IFN Production, Resulting in Suppression of Viral Replication in the Retrovirus-Infected Mouse SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL PROLIFERATION; PLASMACYTOID DENDRITIC CELLS; NONOBESE DIABETIC MICE; INDOLEAMINE 2,3-DIOXYGENASE; TRYPTOPHAN CATABOLISM; MURINE AIDS; EXPRESSION; INHIBITION; INDUCTION; VIRUS AB Indoleamine 2,3-dioxygenase, the L-tryptophan-degrading enzyme, plays a key role in the powerful immunomodulatory effects on several different types of cells. Because modulation of IDO activities after viral infection may have great impact on disease progression, we investigated the role of IDO following infection with LP-BM5 murine leukemia virus. We found suppressed BM5 provirus copies and increased type I IFNs in the spleen from IDO knockout (IDO(-/-)) and 1-methyl-D-L-tryptophan-treated mice compared with those from wild-type (WT) mice. Additionally, the number of plasmacytoid dendritic cells in IDO(-/-) mice was higher in the former than in the WT mice. In addition, neutralization of type I IFNs in IDO(-/-) mice resulted in an increase in LP-BM5 viral replication. Moreover, the survival rate of IDO(-/-) mice or 1-methyl-D-L-tryptophan-treated mice infected with LP-BM5 alone or with both Toxoplasma gondii and LP-BM5 was clearly greater than the survival rate of WT mice. To our knowledge, the present study is the first report to observe suppressed virus replication with upregulated type I IFN in IDO(-/-) mice, suggesting that modulation of the IDO pathway may be an effective strategy for treatment of virus infection. The Journal of Immunology, 2010, 185: 3305-3312. C1 [Saito, Kuniaki] Kyoto Univ, Grad Sch Med, Kyoto 6068507, Japan. [Hoshi, Masato; Saito, Kuniaki; Ohtaki, Hirofumi; Tanaka, Ryo; Osawa, Yosuke; Takemura, Masao; Ito, Hiroyasu; Seishima, Mitsuru] Gifu Univ, Grad Sch Med, Dept Informat Clin Med, Gifu, Japan. [Hara, Akira; Taguchi, Ayako] Gifu Univ, Grad Sch Med, Dept Tumor Pathol, Gifu, Japan. [Saito, Kuniaki] Kyoto Univ, Fac Med, Kyoto, Japan. [Matsunami, Hidetoshi] Matsunami Gen Hosp, Kasamatsu, Gifu, Japan. [Fujigaki, Hidetsugu] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Saito, K (reprint author), Kyoto Univ, Grad Sch Med, Kyoto 6068507, Japan. EM saito-k@hs.med.kyoto-u.ac.jp FU Ministry for Education, Culture, Sports, Science and Technology of Japan [20390167] FX This work was supported by Grant-in-Aid for Scientific Research 20390167 from the Ministry for Education, Culture, Sports, Science and Technology of Japan. NR 42 TC 47 Z9 48 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2010 VL 185 IS 6 BP 3305 EP 3312 DI 10.4049/jimmunol.0901150 PG 8 WC Immunology SC Immunology GA 646RI UT WOS:000281559300022 PM 20693424 ER PT J AU von Gegerfelt, A Valentin, A Alicea, C Van Rompay, KKA Marthas, ML Montefiori, DC Pavlakis, GN Felber, BK AF von Gegerfelt, Agneta Valentin, Antonio Alicea, Candido Van Rompay, Koen K. A. Marthas, Marta L. Montefiori, David C. Pavlakis, George N. Felber, Barbara K. TI Emergence of Simian Immunodeficiency Virus-Specific Cytotoxic CD4(+) T Cells and Increased Humoral Responses Correlate with Control of Rebounding Viremia in CD8-Depleted Macaques Infected with Rev-Independent Live-Attenuated Simian Immunodeficiency Virus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) LYMPHOCYTE DEPLETION; NATURAL-KILLER-CELLS; REPLICATION IN-VITRO; VIRAL MESSENGER-RNA; RHESUS MACAQUES; IMMUNE-RESPONSES; POSTTRANSCRIPTIONAL REGULATION; MONOCLONAL-ANTIBODY; RETROVIRUS TYPE-1; NEONATAL MACAQUES AB Indian rhesus macaques infected with the Rev-independent live-attenuated SIVmac239 strains control viremia to undetectable levels, have persistent but low cellular and humoral anti-SIV responses, and show no signs of immune deficiency. To analyze the immune mechanisms responsible for viral control, five macaques infected at day 1 after birth were subjected to CD8(+) cell depletion at 6.7 y postinfection. This resulted in viremia increases to 3.7-5.5 log(10) RNA copies, supporting a role of CD8-mediated responses in the control of viral replication. The rebounding viremia was rapidly controlled to levels below the threshold of detection, and occurred in the absence of SIV-specific CD8(+) T cells and significant CD8(+) T cell recovery in four of the five animals, suggesting that other mechanisms are involved in the immunological control of viremia. Monitoring immune responses at the time of viral control demonstrated a burst of circulating SIV-specific CD4(+) T cells characterized as CD45RA(-)CD28(+)CD95(+)CCR7(-) and also granzyme B+, suggesting cytotoxic ability. Control of viremia was also concomitant with increases in humoral responses to Gag and Env, including a transient increase in neutralizing Abs against the neutralization-resistant SIVmac239 in four of five animals. These data demonstrate that a combination of cellular responses mediated by CD4(+) T cells and humoral responses was associated with the rapid control of the rebounding viremia in macaques infected by the Rev-independent live-attenuated SIV, even in the absence of measurable SIV-specific CD8(+) T cells in the blood, emphasizing the importance of different components of the immune response for full control of SIV infection. The Journal of Immunology, 2010, 185: 3348-3358. C1 [Alicea, Candido; Felber, Barbara K.] NCI, Vaccine Branch, Ctr Canc Res, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. [von Gegerfelt, Agneta; Valentin, Antonio; Pavlakis, George N.] NCI, Human Retrovirus Sect, Frederick, MD 21702 USA. [Van Rompay, Koen K. A.; Marthas, Marta L.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. RP Felber, BK (reprint author), NCI, Vaccine Branch, Ctr Canc Res, Human Retrovirus Pathogenesis Sect, POB B,Bldg 535,Room 206, Frederick, MD 21702 USA. EM pavlakig@mail.nih.gov; felberb@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Center for Research Resources, National Institutes of Health [RR-00169] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Part of this work was supported by Grant RR-00169 from the National Center for Research Resources, National Institutes of Health to the California National Primate Research Center. NR 67 TC 10 Z9 10 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2010 VL 185 IS 6 BP 3348 EP 3358 DI 10.4049/jimmunol.1000572 PG 11 WC Immunology SC Immunology GA 646RI UT WOS:000281559300026 PM 20702730 ER PT J AU Kucirka, LM Farzadegan, H Feld, JJ Mehta, SH Winters, M Glenn, JS Kirk, GD Segev, DL Nelson, KE Marks, M Heller, T Golub, ET AF Kucirka, Lauren M. Farzadegan, Homayoon Feld, Jordan J. Mehta, Shruti H. Winters, Mark Glenn, Jeffrey S. Kirk, Gregory D. Segev, Dorry L. Nelson, Kenrad E. Marks, Morgan Heller, Theo Golub, Elizabeth T. TI Prevalence, Correlates, and Viral Dynamics of Hepatitis Delta among Injection Drug Users SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID B SURFACE-ANTIGEN; VIRUS-INFECTION; UNITED-STATES; HBSAG-CARRIERS; DISEASE; AGENT; SUPERINFECTION; EPIDEMIOLOGY; ASSOCIATION; COINFECTION AB Background. Most hepatitis delta virus (HDV) prevalence estimates from the United States are 110 years old, and HDV has shown significant temporal variation in other populations. HDV-hepatitis B virus (HBV) dual infection progresses rapidly, has more complications, and has a different treatment regimen than HBV infection alone. Accurate estimates of prevalence and risk factors are important to help clinicians decide who to screen. Methods. Injection drug users in Baltimore, Maryland, who were positive for HBV serologic markers were tested for hepatitis delta antibody (HDAb) at 2 time periods: 1988-1989 (194 participants) and 2005-2006 (258 participants). Those who were HDAb positive in 2005-2006, plus a random sample of HDAb negative, HBV-positive participants were tested for HDV RNA, HBV DNA, and HCV RNA. Characteristics associated with HDV exposure and viremia were identified. Results. HDV prevalence declined from 15% in 1988-1989 to 11% in 2005-2006. Among those with chronic HBV infection, prevalence increased from 29% (14 of 48 participants) to 50% (19 of 38 participants) (P=.05). Visiting a "shooting gallery" (a location where people gather to inject illegal drugs) was a strong correlate of HDAb positivity (relative risk, 3.08; P=.01). Eight (32%) of those who were HDAb positive had HDV viremia. Viremic participants had elevated liver enzyme levels and more emergency room visits. Conclusions. The temporal increase in HDV prevalence among those with chronic HBV infection is troubling; understanding this change should be a priority to prevent the burden from increasing. C1 [Kucirka, Lauren M.; Segev, Dorry L.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Farzadegan, Homayoon; Mehta, Shruti H.; Kirk, Gregory D.; Segev, Dorry L.; Nelson, Kenrad E.; Marks, Morgan; Golub, Elizabeth T.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Heller, Theo] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Winters, Mark; Glenn, Jeffrey S.] Stanford Univ, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Palo Alto, CA 94304 USA. [Feld, Jordan J.] Univ Toronto, Toronto Western Hosp, Ctr Liver, Univ Hlth Network, Toronto, ON M5S 1A1, Canada. RP Kucirka, LM (reprint author), Johns Hopkins Univ, Sch Med, Dept Surg, 771 Ross Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM lkucirka@jhsph.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; National Institute on Drug Abuse [R01DA04334, R01DA12568]; Johns Hopkins Bloomberg Infectious Disease Program Laboratory FX Hepatitis Delta antibody enzyme-linked immunosorbent assay (ELISA) kits were donated by International Immunodiagnostics (California). Associated laboratory expenses were supported by the Johns Hopkins Bloomberg Infectious Disease Program Laboratory. This research was partially supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health. The AIDS-Linked Intravenous Experience (ALIVE) study was supported by the National Institute on Drug Abuse (grants R01DA04334 and R01DA12568). NR 35 TC 31 Z9 33 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2010 VL 202 IS 6 BP 845 EP 852 DI 10.1086/655808 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 640YV UT WOS:000281091200004 PM 20701536 ER PT J AU Chary, A Winters, MA Kottilil, S Murphy, AA Polis, MA Holodniy, M AF Chary, Aarthi Winters, Mark A. Kottilil, Shyam Murphy, Alison A. Polis, Michael A. Holodniy, Mark TI Impact of Interferon-Ribavirin Treatment on Hepatitis C Virus (HCV) Protease Quasispecies Diversity in HIV- and HCV-Coinfected Patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PEGYLATED-INTERFERON; INFECTED PATIENTS; THERAPY; NS3; PEGINTERFERON; TELAPREVIR; RESPONSES; GENE AB Patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection for whom prior treatment of HCV with interferon-ribavirin has failed may require subsequent treatment with new HCV protease inhibitors (PIs). We evaluated the diversity of HCV nonstructural protein 3 (NS3) in 26 HCV- and HIV-coinfected patients receiving stable antiretroviral therapy (ART) who were treated with interferon-ribavirin. Plasma HCV RNA clonal analysis was performed. There was greater baseline NS3 diversity in patients with nonresponse or relapse than in those with sustained virologic response. Interferon-ribavirin treatment did not result in significant changes in HCV protease gene diversity or significant HCV PI resistance mutations. The effect of prior interferon-ribavirin treatment on HCV NS3 will likely not impact HCV PI efficacy in HIV-coinfected patients receiving ART. C1 [Chary, Aarthi; Winters, Mark A.; Holodniy, Mark] VA Palo Alto Hlth Care Syst, AIDS Res Ctr, Palo Alto, CA 94304 USA. [Chary, Aarthi; Winters, Mark A.; Holodniy, Mark] Stanford Univ, Div Infect Dis, Stanford, CA 94305 USA. [Kottilil, Shyam; Murphy, Alison A.] NIAID, Immunopathogenesis Sect, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Kottilil, Shyam; Polis, Michael A.] NIAID, Immunoregulat Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Chary, A (reprint author), VA Palo Alto Hlth Care Syst, AIDS Res Ctr, 3801 Miranda Ave 132, Palo Alto, CA 94304 USA. EM charya@stanford.edu OI Polis, Michael/0000-0002-9151-2268 FU Department of Veterans Affairs; National Institutes of Health (National Institute of Allergy and Infectious Diseases and National Institutes of Health Clinical Center) [Z01 AI000390-25, ZIA AI00390-26] FX Department of Veterans Affairs; Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases and National Institutes of Health Clinical Center; project Z01 AI000390-25 and ZIA AI00390-26 to S. K.). NR 16 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2010 VL 202 IS 6 BP 889 EP 893 DI 10.1086/655784 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 640YV UT WOS:000281091200010 PM 20677940 ER PT J AU Burbelo, PD Kovacs, JA Ching, KH Issa, AT Iadarola, MJ Murphy, AA Schlaak, JF Masur, H Polis, MA Kottilil, S AF Burbelo, Peter D. Kovacs, Joseph A. Ching, Kathryn H. Issa, Alexandra T. Iadarola, Michael J. Murphy, Alison A. Schlaak, Joerg F. Masur, Henry Polis, Michael A. Kottilil, Shyam TI Proteome-Wide Anti-Hepatitis C Virus (HCV) and Anti-HIV Antibody Profiling for Predicting and Monitoring the Response to HCV Therapy in HIV-Coinfected Patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTION; PREVALENCE AB We quantified antibody responses to the hepatitis C virus (HCV) proteome that are associated with sustained virologic response (SVR) in human immunodeficiency virus (HIV)/HCV-coinfected patients treated with pegylated interferon and ribavirin. Analysis of pre- and posttreatment samples revealed significant decreases in the combined anti-core, anti-E1, and anti-NS4 HCV antibody titers in those with SVRs but not in those who experienced relapse or who did not respond. Furthermore, anti-HIV p24 antibody titers inversely correlated with treatment response. These results suggest that profiling anti-HCV antibody is useful for monitoring HCV therapy, especially in discriminating between those who experience relapse and those who have SVRs at 48 weeks. C1 [Murphy, Alison A.; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Schlaak, Joerg F.] Univ Hosp Essen, Essen, Germany. [Burbelo, Peter D.; Ching, Kathryn H.; Issa, Alexandra T.; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, Bethesda, MD USA. [Kovacs, Joseph A.; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Room 11N 204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov OI Schlaak, Joerg/0000-0002-9499-1014; Polis, Michael/0000-0002-9151-2268 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH); NIH Clinical Research Center FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), and in part by a Bench-to-Bedside Award from the NIH Clinical Research Center. NR 14 TC 10 Z9 10 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2010 VL 202 IS 6 BP 894 EP 898 DI 10.1086/655780 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 640YV UT WOS:000281091200011 PM 20684729 ER PT J AU Limou, S Coulonges, C Herbeck, JT van Manen, D An, P Le Clerc, S Delaneau, O Diop, G Taing, L Montes, M van't Wout, AB Gottlieb, GS Therwath, A Rouzioux, C Delfraissy, JF Lelievre, JD Levy, Y Hercberg, S Dina, C Phair, J Donfield, S Goedert, JJ Buchbinder, S Estaquier, J Schachter, F Gut, I Froguel, P Mullins, JI Schuitemaker, H Winkler, C Zagury, JF AF Limou, Sophie Coulonges, Cedric Herbeck, Joshua T. van Manen, Danielle An, Ping Le Clerc, Sigrid Delaneau, Olivier Diop, Gora Taing, Lieng Montes, Matthieu van't Wout, Angelique B. Gottlieb, Geoffrey S. Therwath, Amu Rouzioux, Christine Delfraissy, Jean-Francois Lelievre, Jean-Daniel Levy, Yves Hercberg, Serge Dina, Christian Phair, John Donfield, Sharyne Goedert, James J. Buchbinder, Susan Estaquier, Jerome Schaechter, Francois Gut, Ivo Froguel, Philippe Mullins, James I. Schuitemaker, Hanneke Winkler, Cheryl Zagury, Jean-Francois TI Multiple-Cohort Genetic Association Study Reveals CXCR6 as a New Chemokine Receptor Involved in Long-Term Nonprogression to AIDS SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID WHOLE-GENOME ASSOCIATION; HIV-1 DISEASE PROGRESSION; WIDE ASSOCIATION; INFECTION; EXPRESSION; EXTREME; INDIVIDUALS; ACTIVATION; RESISTANCE; INFERENCE AB Background. The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS. Methods. To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (<100 copies/mL). Results. The rs2234358 polymorphism in the CXCR6 gene was the strongest signal (P=2.5x10(-7); odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of P(combined) = 9.7x10(-10). This association with LTNP is independent of the CCR2-CCR5 locus and the HCP5 polymorphisms. Conclusions. The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation. C1 [Limou, Sophie; Coulonges, Cedric; Le Clerc, Sigrid; Delaneau, Olivier; Diop, Gora; Taing, Lieng; Montes, Matthieu; Schaechter, Francois; Zagury, Jean-Francois] Chaire Bioinformat Conservatoire Natl Arts & Meti, Paris, France. [Coulonges, Cedric; Le Clerc, Sigrid; Rouzioux, Christine; Delfraissy, Jean-Francois; Zagury, Jean-Francois] French Agcy Res AIDS & Hepatitis, Agence Natil Rech, SIDA & Hepatites Virales Genom Grp, Paris, France. [Therwath, Amu] Univ Paris 07, Oncol Mol Lab, Paris, France. [Limou, Sophie; Le Clerc, Sigrid; Lelievre, Jean-Daniel; Levy, Yves; Estaquier, Jerome; Zagury, Jean-Francois] Univ Paris 12, INSERM, U955, Creteil, France. [Estaquier, Jerome] Hop Henri Mondor, AP HP, F-94010 Creteil, France. [Limou, Sophie; Gut, Ivo] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Hercberg, Serge] UP13, Ctr Rech Nutr Humaine Ile de France, UMR U557, INSERM,U1125,Inra, Bobigny, France. [Dina, Christian; Froguel, Philippe] Inst Pasteur, UMR 8090, CNRS, F-59019 Lille, France. [van Manen, Danielle; van't Wout, Angelique B.] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Landsteiner Lab,Ctr Infect Dis & Immun Amsterdam, NL-1105 AZ Amsterdam, Netherlands. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [Herbeck, Joshua T.; Gottlieb, Geoffrey S.; Mullins, James I.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. [An, Ping; Winkler, Cheryl] NCI, Lab Genom Div, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Phair, John] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Donfield, Sharyne] Rho, Dept Biostat, Chapel Hill, NC USA. [Buchbinder, Susan] San Francisco Dept Publ Hlth, HIV Res Sect, San Francisco, CA USA. RP Zagury, JF (reprint author), 292 Rue St Martin, F-75003 Paris, France. EM zagury@cnam.fr RI Dina, Christian/D-3535-2015; OI Dina, Christian/0000-0002-7722-7348; Estaquier, Jerome/0000-0002-9432-8044; Montes, Matthieu/0000-0001-5921-460X FU Agence Nationale de Recherche sur le SIDA; AIDS Cancer Vaccine Development Foundation; Neovacs SA; US National Institutes of Health [AI047734]; National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Netherlands Organization for Scientific Research [9120.6046]; National Institutes of Health, National Institute of Child Health and Human Development [1 R01 HD41224]; Netherlands National Institute for Public Health and the Environment FX Agence Nationale de Recherche sur le SIDA, Sidaction, Innovation 2007 program of Conservatoire National des Arts et Metiers, AIDS Cancer Vaccine Development Foundation, Neovacs SA, Vax-consulting, and R37 (grant AI047734) from the US National Institutes of Health. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH; contract HHSN261200800001E) and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors acknowledge funding from the Netherlands Organization for Scientific Research (TOP; registration number 9120.6046). The Hemophilia Growth and Development Study is funded by the National Institutes of Health, National Institute of Child Health and Human Development, 1 R01 HD41224. The Amsterdam Cohort Studies on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic-Medical Center of the University of Amsterdam, Sanquin Research, and the University Medical Center Utrecht, are part of the Netherlands HIV Monitoring Foundation and are financially supported by the Netherlands National Institute for Public Health and the Environment. NR 41 TC 39 Z9 39 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2010 VL 202 IS 6 BP 908 EP 915 DI 10.1086/655782 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 640YV UT WOS:000281091200013 PM 20704485 ER PT J AU Marina, N Abdala, AP Trapp, S Li, AH Nattie, EE Hewinson, J Smith, JC Paton, JFR Gourine, AV AF Marina, Nephtali Abdala, Ana P. Trapp, Stefan Li, Aihua Nattie, Eugene E. Hewinson, James Smith, Jeffrey C. Paton, Julian F. R. Gourine, Alexander V. TI Essential Role of Phox2b-Expressing Ventrolateral Brainstem Neurons in the Chemosensory Control of Inspiration and Expiration SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RESPIRATORY RHYTHM GENERATION; CENTRAL-NERVOUS-SYSTEM; RETROTRAPEZOID NUCLEUS; VENTRAL MEDULLA; IN-VIVO; RAT; PHOX2B; CO2; HOMEOSTASIS; CHANNELS AB Phox2b-expressing neurons of the retrotrapezoid nucleus (RTN), located in the ventrolateral brainstem, are sensitive to changes in PCO(2)/pH, have excitatory projections to the central respiratory rhythm/pattern generator, and their activation enhances central respiratory drive. Using in vivo (conscious and anesthetized rats) and in situ (arterially perfused rat brainstem-spinal cord preparations) models, we evaluated the functional significance of this neuronal population for both resting respiratory activity and the CO(2)-evoked respiratory responses by reversibly inhibiting these neurons using the insect peptide allatostatin following transduction with a lentiviral construct to express the G-protein-coupled Drosophila allatostatin receptor. Selective inhibition of the Phox2b-expressing neurons in the ventrolateral brainstem, including the RTN, using allatostatin was without effect on resting respiratory activity in conscious rats, but decreased the amplitude of the phrenic nerve discharge in anesthetized rats and the in situ rat preparations. Postinspiratory activity was also reduced in situ. In the absence or presence of the peripheral chemoreceptor input, inhibiting the Phox2b-expressing neurons during hypercapnia abolished the CO(2)-evoked abdominal expiratory activity in anesthetized rats and in situ preparations. Inspiratory responses evoked by rising levels of CO(2) in the breathing air were also reduced in anesthetized rats with denervated carotid bodies and conscious rats with peripheral chemoreceptors intact (by 28% and 60%, respectively). These data indicate a crucial dependence of central expiratory drive upon Phox2b-expressing neurons of the ventrolateral brainstem and support the hypothesis that these neurons contribute in a significant manner to CO(2)-evoked increases of inspiratory activity. C1 [Abdala, Ana P.; Hewinson, James; Paton, Julian F. R.] Univ Bristol, Bristol Heart Inst, Dept Physiol & Pharmacol, Bristol BS8 1TD, Avon, England. [Marina, Nephtali; Gourine, Alexander V.] UCL, London WC1E 6BT, England. [Trapp, Stefan] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, Biophys Sect, London SW7 2AZ, England. [Li, Aihua; Nattie, Eugene E.] Dartmouth Med Sch, Dept Physiol, Lebanon, NH 03756 USA. [Smith, Jeffrey C.] Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Paton, JFR (reprint author), Univ Bristol, Bristol Heart Inst, Dept Physiol & Pharmacol, Bristol BS8 1TD, Avon, England. EM Julian.F.R.Paton@Bristol.ac.uk; a.gourine@ucl.ac.uk RI Trapp, Stefan/D-9240-2011; Hewinson, Glyn/J-1902-2014; Abdala, Ana Paula/G-9104-2014; OI Trapp, Stefan/0000-0003-0665-4948; Abdala, Ana Paula/0000-0001-6051-2591; Paton, Julian/0000-0001-7410-2913 FU The Wellcome Trust [079040]; National Institute of Neurological Disorders and Stroke (NINDS); National Heart, Lung, and Blood Institute [HL 28066]; Medical Research Council [G0600928]; Royal Society FX This study was supported by The Wellcome Trust and the National Institute of Neurological Disorders and Stroke (NINDS). E.E.N. and A.L. are supported by National Heart, Lung, and Blood Institute Grant HL 28066. S.T. is supported by the Medical Research Council (Grant G0600928). J.F.R.P. is the recipient of a Royal Society Wolfson Research Merit Award, and A.V.G. is a Wellcome Trust Senior Research Fellow (Grant 079040). NR 30 TC 71 Z9 72 U1 0 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 15 PY 2010 VL 30 IS 37 BP 12466 EP 12473 DI 10.1523/JNEUROSCI.3141-10.2010 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 649UF UT WOS:000281798700024 PM 20844141 ER PT J AU Zhang, AX Murelli, RP Barinka, C Michel, J Cocleaza, A Jorgensen, WL Lubkowski, J Spiegel, DA AF Zhang, Andrew X. Murelli, Ryan P. Barinka, Cyril Michel, Julien Cocleaza, Alexandra Jorgensen, William L. Lubkowski, Jacek Spiegel, David A. TI A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID GLUTAMATE-CARBOXYPEPTIDASE-II; UREA-BASED INHIBITORS; AROMATIC STACKING INTERACTIONS; NATURAL ANTIBODIES; IMMUNE-RESPONSE; PSMA INHIBITOR; CANCER-THERAPY; DESIGN; CELLS; IMMUNOGLOBULINS AB Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody-recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment; more broadly, the presence of similar arene-binding sites throughout the proteome could prove widely enabling in the optimization of small molecule protein interactions. C1 [Zhang, Andrew X.; Murelli, Ryan P.; Michel, Julien; Cocleaza, Alexandra; Jorgensen, William L.; Spiegel, David A.] Yale Univ, Dept Chem, New Haven, CT 06510 USA. [Barinka, Cyril] Inst Biotechnol AS CR, VVI, Struct Biol Lab, Prague 14200 4, Czech Republic. [Lubkowski, Jacek] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Spiegel, David A.] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. RP Spiegel, DA (reprint author), Yale Univ, Dept Chem, 225 Prospect St,POB 208107, New Haven, CT 06510 USA. EM david.spiegel@yale.edu RI Barinka, Cyril/G-9803-2014 FU National Institutes of Health [DP22OD002913, GM32136]; EMBO [1978]; IBT [CEZ:AV0Z50520701]; U.S. Department of Energy [W-31-109-Eng38]; National Cancer Institute, Center for Cancer Research; National Science Foundation [TG-CHE090106]; European Community [FP7-PEOPLE-2008-16704-1-IOF, 234796-PPIdesign] FX This work was funded by the National Institutes of Health through the NIH Director's New Innovator Award Program (DP22OD002913 to D.A.S.), and through NIH Grant GM32136 (to W.L.J.). C.B. acknowledges financial support from the EMBO Installation Grant (#1978) and the Institutional Research Support of the IBT (CEZ:AV0Z50520701). The use of the Advanced Photon Source was supported by the U.S. Department of Energy (W-31-109-Eng38). J.L. acknowledges financial support from the National Cancer Institute, Center for Cancer Research. This research was partially supported by the National Science Foundation through Teragrid resources provided by the Texas Advanced Computing Center under grant number TG-CHE090106 (to J.M.), and by a Marie Curie International Outgoing Fellowship (J.M.) within the 7th European Community Framework Programme (FP7-PEOPLE-2008-16704-1-IOF, 234796-PPIdesign). NR 68 TC 54 Z9 55 U1 4 U2 23 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 SEP 15 PY 2010 VL 132 IS 36 BP 12711 EP 12716 DI 10.1021/ja104591m PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 653FP UT WOS:000282074200036 PM 20726553 ER PT J AU Knox, KS Vinton, C Hage, CA Kohli, LM Twigg, HL Klatt, NR Zwickl, B Waltz, J Goldman, M Douek, DC Brenchley, JM AF Knox, Kenneth S. Vinton, Carol Hage, Chadi A. Kohli, Lisa M. Twigg, Homer L., III Klatt, Nichole R. Zwickl, Beth Waltz, Jeffrey Goldman, Mitchell Douek, Daniel C. Brenchley, Jason M. TI Reconstitution of CD4 T Cells in Bronchoalveolar Lavage Fluid after Initiation of Highly Active Antiretroviral Therapy SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; GASTROINTESTINAL-TRACT; TYPE-1 INFECTION; HIV-1 INFECTION; SIV INFECTION; IMMUNE RECONSTITUTION; COLLAGEN DEPOSITION; VIRAL SUPPRESSION; LYMPHOID-TISSUE; DEPLETION AB The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells. C1 [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Knox, Kenneth S.] Univ Arizona, So Arizona VA Healthcare Syst, Tucson, AZ 85723 USA. [Knox, Kenneth S.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ 85723 USA. [Knox, Kenneth S.] Univ Arizona, Div Pulm & Crit Care Med, Tucson, AZ 85723 USA. [Vinton, Carol; Klatt, Nichole R.; Brenchley, Jason M.] NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Hage, Chadi A.; Kohli, Lisa M.; Twigg, Homer L., III] Indiana Univ, Div Pulm & Crit Care Med, Indianapolis, IN 46202 USA. [Hage, Chadi A.] Richard L Roudebush VA Med Ctr, Indianapolis, IN 46202 USA. [Hage, Chadi A.; Zwickl, Beth; Waltz, Jeffrey; Goldman, Mitchell] Indiana Univ, Div Infect Dis, Indianapolis, IN 46202 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov; jbrenchl@niaid.nih.gov FU Indiana Clinical and Translational Sciences Institute; National Institutes of Health [RR025761, R01 HL083468, U01 HL098960]; NIAID, NIH FX This project was supported by the Indiana Clinical and Translational Sciences Institute, funded in part by grant RR025761 from the National Institutes of Health, Clinical and Translational Sciences Award. K. S. K. is supported by NIH grant R01 HL083468. H. L. T. is supported by NIH grant U01 HL098960. This work was supported in part by intramural funding from NIAID, NIH. NR 31 TC 15 Z9 15 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP 15 PY 2010 VL 84 IS 18 BP 9010 EP 9018 DI 10.1128/JVI.01138-10 PG 9 WC Virology SC Virology GA 641FP UT WOS:000281110500002 PM 20610726 ER PT J AU Yozwiak, NL Skewes-Cox, P Gordon, A Saborio, S Kuan, G Balmaseda, A Ganem, D Harris, E DeRisi, JL AF Yozwiak, Nathan L. Skewes-Cox, Peter Gordon, Aubree Saborio, Saira Kuan, Guillermina Balmaseda, Angel Ganem, Don Harris, Eva DeRisi, Joseph L. TI Human Enterovirus 109: a Novel Interspecies Recombinant Enterovirus Isolated from a Case of Acute Pediatric Respiratory Illness in Nicaragua SO JOURNAL OF VIROLOGY LA English DT Article ID MOLECULAR-IDENTIFICATION; CODING REGION; COXSACKIE-A; POLIOVIRUS; RNA; EVOLUTION; SEROTYPES; CHILDREN; SEQUENCE; VIRUSES AB Enteroviruses (Picornaviridae family) are a common cause of human illness worldwide and are associated with diverse clinical syndromes, including asymptomatic infection, respiratory illness, gastroenteritis, and meningitis. In this study, we report the identification and complete genome sequence of a novel enterovirus isolated from a case of acute respiratory illness in a Nicaraguan child. Unbiased deep sequencing of nucleic acids from a nose and throat swab sample enabled rapid recovery of the full-genome sequence. Phylogenetic analysis revealed that human enterovirus 109 (EV109) is most closely related to serotypes of human enterovirus species C (HEV-C) in all genomic regions except the 5' untranslated region (5' UTR). Bootstrap analysis indicates that the 5' UTR of EV109 is likely the product of an interspecies recombination event between ancestral members of the HEV-A and HEV-C groups. Overall, the EV109 coding region shares 67 to 72% nucleotide sequence identity with its nearest relatives. EV109 isolates were detected in 5/310 (1.6%) of nose and throat swab samples collected from children in a pediatric cohort study of influenza-like illness in Managua, Nicaragua, between June 2007 and June 2008. Further experimentation is required to more fully characterize the pathogenic role, disease associations, and global distribution of EV109. C1 [Yozwiak, Nathan L.; Gordon, Aubree; Harris, Eva] Univ Calif Berkeley, Sch Publ Hlth, Div Infect Dis & Vaccinol, Berkeley, CA 94720 USA. [Skewes-Cox, Peter] Univ Calif San Francisco, Biol & Med Informat Program, San Francisco, CA 94143 USA. [Ganem, Don; DeRisi, Joseph L.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [DeRisi, Joseph L.] Univ Calif San Francisco, Dept Biochem, San Francisco, CA 94143 USA. [Ganem, Don; DeRisi, Joseph L.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Saborio, Saira; Balmaseda, Angel] Ctr Nacl Diagnost & Referencia, Dept Virol, Managua, Nicaragua. [Gordon, Aubree] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Kuan, Guillermina] Minist Salud, Ctr Salud Socrates Flores Vivas, Managua, Nicaragua. RP DeRisi, JL (reprint author), UCSF Biochem & Biophys, 1700 4th St,QB3 Room 403, San Francisco, CA 94143 USA. EM joe@derisilab.ucsf.edu OI Gordon, Aubree/0000-0002-9352-7877; Skewes-Cox, Peter/0000-0003-1633-5190 FU Pacific Southwest Regional Center of Excellence, NIH [U54-AI65359]; Pediatric Dengue Vaccine Initiative [VE-1]; Howard Hughes Medical Institute; Doris Duke Foundation; Packard Foundation FX This work was supported in part by a grant from the Pacific Southwest Regional Center of Excellence, NIH grant U54-AI65359, the Pediatric Dengue Vaccine Initiative (VE-1 to E. H.), the Howard Hughes Medical Institute, the Doris Duke Foundation, and the Packard Foundation. Joseph DeRisi and Don Ganem are supported by the Howard Hughes Medical Institute. NR 51 TC 73 Z9 76 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP 15 PY 2010 VL 84 IS 18 BP 9047 EP 9058 DI 10.1128/JVI.00698-10 PG 12 WC Virology SC Virology GA 641FP UT WOS:000281110500006 PM 20592079 ER PT J AU Emerson, SU Nguyen, HT Torian, U Burke, D Engle, R Purcell, RH AF Emerson, Suzanne U. Nguyen, Hanh T. Torian, Udana Burke, Danielle Engle, Ronald Purcell, Robert H. TI Release of Genotype 1 Hepatitis E Virus from Cultured Hepatoma and Polarized Intestinal Cells Depends on Open Reading Frame 3 Protein and Requires an Intact PXXP Motif SO JOURNAL OF VIROLOGY LA English DT Article ID CIS-REACTIVE ELEMENT; ORF3 PROTEIN; IN-VITRO; REPLICATION; INTERACTS; INFECTION; PARTICLES; ENCODES; GENOMES; SYSTEM AB Hepatitis E virus genotype 1 strain Sar55 replicated in subcloned Caco-2 intestinal cells and Huh7 hepatoma cells that had been transfected with in vitro transcribed viral genomes, and hepatitis E virions were released into the culture medium of both cell lines. Virus egress from cells depended on open reading frame 3 (ORF3) protein, and a proline-rich sequence in ORF3 was important for egress from cultured cells and for infection of macaques. Both intracellular ORF3 protein accumulation and virus release occurred at the apical membrane of polarized Caco-2 cells. ORF3 protein and lipids were intimately associated with virus particles produced in either cell line; ORF2 epitopes were masked in these particles and could not be immunoprecipitated with anti-ORF2. C1 [Emerson, Suzanne U.; Nguyen, Hanh T.; Torian, Udana; Burke, Danielle; Engle, Ronald; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Emerson, SU (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr,MSC 8009, Bethesda, MD 20892 USA. EM semerson@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 32 TC 67 Z9 68 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP 15 PY 2010 VL 84 IS 18 BP 9059 EP 9069 DI 10.1128/JVI.00593-10 PG 11 WC Virology SC Virology GA 641FP UT WOS:000281110500007 PM 20610720 ER PT J AU Sundling, C O'Dell, S Douagi, I Forsell, MN Morner, A Lore, K Mascola, JR Wyatt, RT Hedestam, GBK AF Sundling, Christopher O'Dell, Sijy Douagi, Iyadh Forsell, Mattias N. Morner, Andreas Lore, Karin Mascola, John R. Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI Immunization with Wild-Type or CD4-Binding-Defective HIV-1 Env Trimers Reduces Viremia Equivalently following Heterologous Challenge with Simian-Human Immunodeficiency Virus SO JOURNAL OF VIROLOGY LA English DT Article ID CORECEPTOR BINDING-SITE; T-CELL RESPONSES; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; RHESUS MACAQUES; SHIV CHALLENGE; HYPERVARIABLE REGION; MUCOSAL TRANSMISSION; RECEPTOR-BINDING; NO EVIDENCE AB We recently reported that rhesus macaques inoculated with CD4-binding-competent and CD4-binding-defective soluble YU2-derived HIV-1 envelope glycoprotein (Env) trimers in adjuvant generate comparable levels of Env-specific binding antibodies (Abs) and T cell responses. We also showed that Abs directed against the Env coreceptor binding site (CoRbs) were elicited only in animals immunized with CD4-binding-competent trimers and not in animals immunized with CD4-binding-defective trimers, indicating that a direct interaction between Env and CD4 occurs in vivo. To investigate both the overall consequences of in vivo Env-CD4 interactions and the elicitation of CoRbs-directed Abs for protection against heterologous simian-human immunodeficiency virus (SHIV) challenge, we exposed rhesus macaques immunized with CD4-binding-competent and CD4-binding-defective trimers to the CCR5-tropic SHIV-SF162P4 challenge virus. Compared to unvaccinated controls, all vaccinated animals displayed improved control of plasma viremia, independent of the presence or absence of CoRbs-directed Abs prior to challenge. Immunization resulted in plasma responses that neutralized the heterologous SHIV challenge stock in vitro, with similar neutralizing Ab titers elicited by the CD4-binding-competent and CD4-binding-defective trimers. The neutralizing responses against both the SHIV-SF162P4 stock and a recombinant virus pseudotyped with a cloned SHIV-SF162P4-derived Env were significantly boosted by the SHIV challenge. Collectively, these results suggest that the capacity of soluble Env trimers to interact with primate CD4 in vivo and to stimulate the production of moderate titers of CoRbs-directed Abs did not influence the magnitude of the neutralizing Ab recall response after viral challenge or the subsequent control of viremia in this heterologous SHIV challenge model. C1 [Sundling, Christopher; Douagi, Iyadh; Morner, Andreas; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. [Sundling, Christopher; Douagi, Iyadh; Morner, Andreas; Hedestam, Gunilla B. Karlsson] Swedish Inst Infect Dis Control, Solna, Sweden. [O'Dell, Sijy; Forsell, Mattias N.; Mascola, John R.; Wyatt, Richard T.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Lore, Karin] Karolinska Inst, Ctr Infect Med, S-17177 Stockholm, Sweden. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Box 280, S-17177 Stockholm, Sweden. EM Gunilla.Karlsson.Hedestam@ki.se OI Morner, Andreas/0000-0002-3654-1728; Sundling, Christopher/0000-0002-6138-690X FU International AIDS Vaccine Initiative; Swedish International Development Agency (Sida)/Department of Research Cooperation (SAREC); National Institute of Allergy and Infectious Diseases; National Institutes of Health; Karolinska Institutet FX This study was supported by grants from the International AIDS Vaccine Initiative and the Swedish International Development Agency (Sida)/Department of Research Cooperation (SAREC), the National Institute of Allergy and Infectious Diseases, the National Institutes of Health intramural research program, and the Karolinska Institutet. NR 67 TC 13 Z9 13 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP 15 PY 2010 VL 84 IS 18 BP 9086 EP 9095 DI 10.1128/JVI.01015-10 PG 10 WC Virology SC Virology GA 641FP UT WOS:000281110500010 PM 20610729 ER PT J AU Sukupolvi-Petty, S Austin, SK Engle, M Brien, JD Dowd, KA Williams, KL Johnson, S Rico-Hesse, R Harris, E Pierson, TC Fremont, DH Diamond, MS AF Sukupolvi-Petty, Soila Austin, S. Kyle Engle, Michael Brien, James D. Dowd, Kimberly A. Williams, Katherine L. Johnson, Syd Rico-Hesse, Rebeca Harris, Eva Pierson, Theodore C. Fremont, Daved H. Diamond, Michael S. TI Structure and Function Analysis of Therapeutic Monoclonal Antibodies against Dengue Virus Type 2 SO JOURNAL OF VIROLOGY LA English DT Article ID WEST-NILE-VIRUS; PROTEIN DOMAIN-III; FLAVIVIRUS ENVELOPE PROTEIN; CROSS-REACTIVE EPITOPES; HUMAN DENDRITIC CELLS; ENCEPHALITIS-VIRUS; MEMBRANE-FUSION; NEUTRALIZING EPITOPES; CRYSTAL-STRUCTURE; B-CELLS AB Dengue virus (DENV) is the most prevalent insect-transmitted viral disease in humans globally, and currently no specific therapy or vaccine is available. Protection against DENV and other related flaviviruses is associated with the development of antibodies against the viral envelope (E) protein. Although prior studies have characterized the neutralizing activity of monoclonal antibodies (MAbs) against DENV type 2 (DENV-2), none have compared simultaneously the inhibitory activity against a genetically diverse range of strains in vitro, the protective capacity in animals, and the localization of epitopes. Here, with the goal of identifying MAbs that can serve as postexposure therapy, we investigated in detail the functional activity of a large panel of new anti-DENV-2 mouse MAbs. Binding sites were mapped by yeast surface display and neutralization escape, cell culture inhibition assays were performed with homologous and heterologous strains, and prophylactic and therapeutic activity was evaluated with two mouse models. Protective MAbs localized to epitopes on the lateral ridge of domain I (DI), the dimer interface, lateral ridge, and fusion loop of DII, and the lateral ridge, C-C' loop, and A strand of DIII. Several MAbs inefficiently inhibited at least one DENV-2 strain of a distinct genotype, suggesting that recognition of neutralizing epitopes varies with strain diversity. Moreover, antibody potency generally correlated with a narrowed genotype and serotype specificity. Five MAbs functioned efficiently as postexposure therapy when administered as a single dose, even 3 days after intracranial infection of BALB/c mice. Overall, these studies define the structural and functional complexity of antibodies against DENV-2 with protective potential. C1 [Sukupolvi-Petty, Soila; Engle, Michael; Brien, James D.; Diamond, Michael S.] Washington Univ, Dept Med, Sch Med, St Louis, MO 63110 USA. [Austin, S. Kyle; Fremont, Daved H.; Diamond, Michael S.] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Dept Mol Microbiol, Sch Med, St Louis, MO 63110 USA. [Fremont, Daved H.] Washington Univ, Dept Biochem & Mol Biophys, Sch Med, St Louis, MO 63110 USA. [Fremont, Daved H.; Diamond, Michael S.] Washington Univ, Midwest Reg Ctr Excellence Biodef & Emerging Infe, Sch Med, St Louis, MO 63110 USA. [Dowd, Kimberly A.; Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. [Williams, Katherine L.; Harris, Eva] Univ Calif Berkeley, Sch Publ Hlth, Div Infect Dis & Vaccinol, Berkeley, CA 94720 USA. [Johnson, Syd] MacroGenics Inc, Rockville, MD USA. [Rico-Hesse, Rebeca] SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX USA. RP Diamond, MS (reprint author), Washington Univ, Dept Med, Sch Med, 660 S Euclid Ave,Box 8051, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu RI Rico-Hesse, Rebeca/C-5294-2011 OI Rico-Hesse, Rebeca/0000-0001-6216-1000 FU Burroughs Wellcome Fund; Pediatric Dengue Vaccine Initiative; NIH, Midwest and Pacific Southwest Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research [R01-AI077955, U01-AI061373, U54-AI057160, U54-AI65359, R01-AI050123] FX This work was supported by the Burroughs Wellcome Fund, the Pediatric Dengue Vaccine Initiative, and NIH grants R01-AI077955, U01-AI061373, U54-AI057160, and U54-AI65359 (Midwest and Pacific Southwest Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research) and R01-AI050123. NR 73 TC 113 Z9 118 U1 3 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP 15 PY 2010 VL 84 IS 18 BP 9227 EP 9239 DI 10.1128/JVI.01087-10 PG 13 WC Virology SC Virology GA 641FP UT WOS:000281110500024 PM 20592088 ER PT J AU Zhang, ZS Sun, E Ou, JHJ Liang, TJ AF Zhang, Zhensheng Sun, Eun Ou, Jing-Hsiung James Liang, T. Jake TI Inhibition of Cellular Proteasome Activities Mediates HBX-Independent Hepatitis B Virus Replication In Vivo SO JOURNAL OF VIROLOGY LA English DT Article ID X-GENE PRODUCT; TRANSGENIC MICE; VIRAL EVASION; PROTEIN; COMPLEX; SYSTEM; DISEASE; CELLS AB The X protein (HBX) of the hepatitis B virus (HBV) is essential for HBV productive infection in vivo. Our previous study (Z. Hu, Z. Zhang, E. Doo, O. Coux, A. L. Goldberg, and T. J. Liang, J. Virol. 73: 7231-7240, 1999) shows that interaction of HBX with the proteasome complex may underlie the pleiotropic functions of HBX. Previously, we demonstrated that HBX affects hepadnaviral replication through a proteasome-dependent pathway in cell culture models. In the present study, we studied the effect of the proteasome inhibitor MLN-273 in two HBV mouse models. We demonstrated that administration of MLN-273 to transgenic mice containing the replication-competent HBV genome with the defective HBX gene substantially enhanced HBV replication, while the compound had a minor effect on wild-type HBV transgenic mice. Similar results were obtained by using C57BL/6 mice infected with recombinant adenoviruses expressing the replicating HBV genome. Our data suggest that HBV replication is subjected to regulation by cellular proteasome and HBX functions through the inhibition of proteasome activities to enhance HBV replication in vivo. C1 [Zhang, Zhensheng; Sun, Eun; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Ou, Jing-Hsiung James] Univ So Calif, Dept Microbiol & Immunol, Los Angeles, CA USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr,Room 9B16, Bethesda, MD 20892 USA. EM JLiang@nih.gov FU NIH [P01CA123328]; National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX J.-H.J.O. was supported by NIH grant P01CA123328. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 32 TC 9 Z9 10 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP 15 PY 2010 VL 84 IS 18 BP 9326 EP 9331 DI 10.1128/JVI.00579-10 PG 6 WC Virology SC Virology GA 641FP UT WOS:000281110500033 PM 20592087 ER PT J AU Bellani, MA Boateng, KA McLeod, D Camerini-Otero, RD AF Bellani, Marina A. Boateng, Kingsley A. McLeod, Dianne Camerini-Otero, R. Daniel TI The Expression Profile of the Major Mouse SPO11 Isoforms Indicates that SPO11 beta Introduces Double Strand Breaks and Suggests that SPO11 alpha Has an Additional Role in Prophase in both Spermatocytes and Oocytes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MEIOTIC RECOMBINATION; CHROMOSOME SYNAPSIS; TOPOISOMERASE-VI; MICE; ARABIDOPSIS; DEFICIENT; GERMLINE; DEFECTS; HOMOLOG; PROTEIN AB Both in mice and humans, two major SPO11 isoforms are generated by alternative splicing: SPO11 alpha (exon 2 skipped) and SPO11 beta. Thus, the alternative splicing event must have emerged before the mouse and human lineages diverged and was maintained during 90 million years of evolution, arguing for an essential role for both isoforms. Here we demonstrate that developmental regulation of alternative splicing at the Spo11 locus governs the sequential expression of SPO11 isoforms in male meiotic prophase. Protein quantification in juvenile mice and in prophase mutants indicates that early spermatocytes synthesize primarily SPO11 beta. Estimation of the number of SPO11 dimers (beta beta/alpha beta/alpha alpha) in mutants in which spermatocytes undergo a normal number of double strand breaks but arrest in midprophase due to inefficient repair argues for a role for SPO11 beta-containing dimers in introducing the breaks in leptonema. Expression kinetics in males suggested a role for SPO11 alpha in pachytene/diplotene spermatocytes. Nevertheless, we found that both alternative transcripts can be detected in oocytes throughout prophase I, arguing against a male-specific function for this isoform. Altogether, our data support a role for SPO11 alpha in mid-to late prophase, presumably acting as a topoisomerase, that would be conserved in male and female meiocytes. C1 [Bellani, Marina A.; Boateng, Kingsley A.; McLeod, Dianne; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM rdcamerini@mail.nih.gov FU NIDDK, NIH FX The Intramural Research Program of the NIDDK, NIH, supported this research. NR 36 TC 28 Z9 29 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP 15 PY 2010 VL 30 IS 18 BP 4391 EP 4403 DI 10.1128/MCB.00002-10 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 643ID UT WOS:000281287900003 PM 20647542 ER PT J AU Chiu, WL Wagner, S Herrmannova, A Burela, L Zhang, F Saini, AK Valasek, L Hinnebusch, AG AF Chiu, Wen-Ling Wagner, Susan Herrmannova, Anna Burela, Laxminarayana Zhang, Fan Saini, Adesh K. Valasek, Leos Hinnebusch, Alan G. TI The C-Terminal Region of Eukaryotic Translation Initiation Factor 3a (eIF3a) Promotes mRNA Recruitment, Scanning, and, Together with eIF3j and the eIF3b RNA Recognition Motif, Selection of AUG Start Codons SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID 40S RIBOSOMAL-SUBUNIT; SACCHAROMYCES-CEREVISIAE; IN-VIVO; PREINITIATION COMPLEX; MULTIFACTOR COMPLEX; MOLECULAR-GENETICS; ESCHERICHIA-COLI; SITE SELECTION; YEAST EIF3; BINDING AB The C-terminal domain (CTD) of the a/Tif32 subunit of budding yeast eukaryotic translation initiation factor 3 (eIF3) interacts with eIF3 subunits j/Hcr1 and b/Prt1 and can bind helices 16 to 18 of 18S rRNA, suggesting proximity to the mRNA entry channel of the 40S subunit. We have identified substitutions in the conserved Lys-Glu-Arg-Arg (KERR) motif and in residues of the nearby box6 element of the a/Tif32 CTD that impair mRNA recruitment by 43S preinitiation complexes (PICs) and confer phenotypes indicating defects in scanning and start codon recognition. The normally dispensable CTD of j/Hcr1 is required for its binding to a/Tif32 and to mitigate the growth defects of these a/Tif32 mutants, indicating physical and functional interactions between these two domains. The a/Tif32 CTD and the j/Hcr1 N-terminal domain (NTD) also interact with the RNA recognition motif (RRM) in b/Prt1, and mutations in both subunits that disrupt their interactions with the RRM increase leaky scanning of an AUG codon. These results, and our demonstration that the extreme CTD of a/Tif32 binds to Rps2 and Rps3, lead us to propose that the a/Tif32 CTD directly stabilizes 43S subunit-mRNA interaction and that the b/Prt1-RRM-j/Hcr1-a/Tif32-CTD module binds near the mRNA entry channel and regulates the transition between scanning-conducive and initiation-competent conformations of the PIC. C1 [Chiu, Wen-Ling; Burela, Laxminarayana; Zhang, Fan; Saini, Adesh K.; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Wagner, Susan; Herrmannova, Anna; Valasek, Leos] Inst Microbiol AVCR, Lab Regulat Gene Express, Prague 14220, Czech Republic. RP Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM valasekl@biomed.cas.cz; ahinnebusch@nih.gov RI Herrmannova, Anna/I-1745-2014; Valasek, Leos/I-5743-2014; Wagner, Susan/K-8240-2014 FU NIH; Wellcome Trusts [076456/Z/05/Z]; Fogarty International Center [R01 TW007271]; Czech Science Foundation [305/10/0335]; Inst. Research Concept [AV0Z50200510] FX This work was supported in part by the Intramural Research Program of the NIH (A. G. H.) and by The Wellcome Trusts grant 076456/Z/05/Z, NIH research grant R01 TW007271 funded by Fogarty International Center, Czech Science Foundation 305/10/0335, and Inst. Research Concept AV0Z50200510 to L. V. NR 53 TC 43 Z9 43 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP 15 PY 2010 VL 30 IS 18 BP 4415 EP 4434 DI 10.1128/MCB.00280-10 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 643ID UT WOS:000281287900005 PM 20584985 ER PT J AU Hamza, M Wang, XM Wu, T Brahim, JS Rowan, JS Dionne, RA AF Hamza, May Wang, Xiao-Min Wu, Tongtong Brahim, Jaime S. Rowan, Janet S. Dionne, Raymond A. TI Nitric oxide is negatively correlated to pain during acute inflammation SO MOLECULAR PAIN LA English DT Article ID INDUCED THERMAL HYPERALGESIA; PROSTAGLANDIN E-2 RELEASE; CONTROLLED CLINICAL-TRIAL; ASPIRIN-LIKE DRUGS; LOW-BACK-PAIN; GENE-EXPRESSION; INOS-DEFICIENT; DOUBLE-BLIND; MODEL; SYNTHASE AB Background: The role that nitric oxide (NO) plays in modulating pain in the periphery is unclear. We show here, the results of two independent clinical studies (microdialysis and gene expression studies) and a pilot dose finding study (glyceryl trinitrate study), to study the role of NO in the early phase of acute inflammatory pain following oral surgery. The effect of ketorolac on NO production and nitric oxide synthase (NOS) gene expression was also studied. Results: Microdialysis samples showed significantly higher levels of NO at the first 100 min compared to the last 80 minutes in the placebo treated group. In the ketorolac group, on the other hand, NO levels gradually decreased over the first 60 min but were similar to placebo over the later 100-180 min, with no significant change in NO level over time. The levels of NO were negatively correlated to pain intensity scores. Local infusion of the NO donor glyceryl trinitrate at the site of surgery, showed a small analgesic effect that did not reach statistical significance in the sample size used. While the gene expression of iNOS and eNOS were not up-regulated, 3 hours after surgery, nNOS was downregulated in both treatment groups and eNOS gene expression was significantly lower in the ketorolac group compared to the placebo group. Further, there was a positive correlation between the change in gene expression of nNOS and eNOS in the placebo goup but not in the ketorolac group. Conclusion: We suggest that at this early stage of inflammatory pain in man, NO is analgesic in the periphery. Further, ketorolac down-regulates eNOS gene expression. C1 [Hamza, May; Wang, Xiao-Min; Dionne, Raymond A.] NINR, NIH, Bethesda, MD 20892 USA. [Wu, Tongtong] Univ Maryland, Dept Epidemiol & Biostat, College Pk, MD 20742 USA. [Brahim, Jaime S.] Univ Maryland, Baltimore Dent Sch, Dept Oral Maxillofacial Surg, Baltimore, MD USA. [Rowan, Janet S.] NIH, Dept Nursing, Magnuson Clin Res Ctr, Bethesda, MD 20892 USA. [Hamza, May] Ain Shams Univ, Fac Med, Dept Pharmacol, Cairo 11566, Egypt. RP Dionne, RA (reprint author), NINR, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov RI Hamza, May/A-5053-2010 OI Hamza, May/0000-0002-7637-3060 FU Division of Intramural Research, National Institute of Nursing Research; National Institute of Dental and Craniofacial Research, NIH FX This work was supported by Division of Intramural Research, National Institute of Nursing Research and National Institute of Dental and Craniofacial Research, NIH. We are grateful to Mary Oke for helping in data entry. NR 49 TC 10 Z9 11 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD SEP 15 PY 2010 VL 6 AR 55 DI 10.1186/1744-8069-6-55 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 658KB UT WOS:000282487800001 PM 20843331 ER PT J AU Paisan-Ruiz, C Guevara, R Federoff, M Hanagasi, H Sina, F Elahi, E Schneider, SA Schwingenschuh, P Bajaj, N Emre, M Singleton, AB Hardy, J Bhatia, KP Brandner, S Lees, AJ Houlden, H AF Paisan-Ruiz, Coro Guevara, Rocio Federoff, Monica Hanagasi, Hasmet Sina, Fardaz Elahi, Elahe Schneider, Susanne A. Schwingenschuh, Petra Bajaj, Nin Emre, Murat Singleton, Andrew B. Hardy, John Bhatia, Kailash P. Brandner, Sebastian Lees, Andrew J. Houlden, Henry TI Early-Onset L-dopa-Responsive Parkinsonism with Pyramidal Signs Due to ATP13A2, PLA2G6, FBXO7 and Spatacsin Mutations SO MOVEMENT DISORDERS LA English DT Article DE parkinsonism; recessive; ATP13A2; PLA2G6; FBXO7; Spatacsin ID SUPRANUCLEAR UPGAZE PARESIS; GTP CYCLOHYDROLASE-I; KUFOR-RAKEB-SYNDROME; SPASTIC PARAPLEGIA; JUVENILE PARKINSONISM; DYSTONIA-PARKINSONISM; BRAIN IRON; DISEASE; DEMENTIA; GENE AB Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido- pyramidal syndrome. (C) 2010 Movement Disorder Society C1 [Paisan-Ruiz, Coro; Guevara, Rocio; Federoff, Monica; Hardy, John; Lees, Andrew J.; Houlden, Henry] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Paisan-Ruiz, Coro; Guevara, Rocio; Federoff, Monica; Hardy, John; Lees, Andrew J.; Houlden, Henry] UCL Inst Neurol, Reta Lila Weston Inst, London, England. [Hanagasi, Hasmet; Emre, Murat] Istanbul Univ, Dept Neurol, Behav Neurol & Movement Disorders Unit, Istanbul Fac Med, Istanbul, Turkey. [Sina, Fardaz] Iran Univ Med Sci, Hazrat Rasool Hosp, Tehran, Iran. [Elahi, Elahe] Univ Tehran, Dept Biotechnol, Tehran, Iran. [Elahi, Elahe] Univ Tehran, Univ Coll Sci, Sch Biol, Tehran, Iran. [Elahi, Elahe] Univ Tehran, Ctr Excellence Biomath, Sch Math Stat & Comp Sci, Coll Sci, Tehran, Iran. [Schneider, Susanne A.; Bhatia, Kailash P.] Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Schneider, Susanne A.; Schwingenschuh, Petra; Bhatia, Kailash P.] Univ Lubeck, Schilling Sect Clin & Mol Neurogenet, Dept Neurol, Lubeck, Germany. [Bajaj, Nin] Univ Nottingham, Queens Med Ctr, Dept Neurol, Nottingham NG7 2RD, England. [Singleton, Andrew B.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Singleton, Andrew B.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Brandner, Sebastian] UCL Inst Neurol, Div Neuropathol, London WC1N 3BG, England. RP Bhatia, KP (reprint author), Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, Queen Sq, London WC1N 3BG, England. EM k.bhatia@ion.ucl.ac.uk RI Paisan-Ruiz, Coro/C-2912-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Lees, Andrew/A-6605-2009; Schwingenschuh, Petra/J-7887-2012; Houlden, Henry/C-1532-2008; OI Houlden, Henry/0000-0002-2866-7777; Bhatia, Kailash/0000-0001-8185-286X FU The Bachmann Strauss Foundation; The Medical Research Council; The Brain Research Trust; Ataxia UK; The BMA Vera Down Award; Iran National Science Foundation; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000958-05]; NIHR UCLH/UCL Comprehensive Biomedical Research Centre FX We are grateful to the patients and families who support the donation of tissue for research and to the following for essential grant support; The Bachmann Strauss Foundation (CPR, JH), The Medical Research Council (MRC) HH (MRC clinician scientist fellowship) and JH, The Michael J Fox Foundation (HH, CPR and JH), The Brain Research Trust (BRT) (HH, JH, SAS), Ataxia UK (HH) and The BMA Vera Down Award (HH), and the Iran National Science Foundation (EE). We thank The NICHD Brain and Tissue Bank for Developmental Disorder at the University of Maryland, Baltimore, MD. The role of NICHD Brain and Tissue Bank is to distribute tissue, and, therefore, does not endorse the studies performed or the interpretation of results. This work was supported in part by the Intramural Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000958-05. This study was clinically supported by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre. None of the funders had any input into the writing of this manuscript. NR 39 TC 90 Z9 93 U1 1 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 IS 12 BP 1791 EP 1800 DI 10.1002/mds.23221 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 655VN UT WOS:000282283100004 PM 20669327 ER PT J AU Simon, KC Gao, XA Chen, HL Schwarzschild, MA Ascherio, A AF Simon, Kelly Claire Gao, Xiang Chen, Honglei Schwarzschild, Michael A. Ascherio, Alberto TI Calcium Channel Blocker Use and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE calcium channel blockers; Parkinson's disease; antihypertensive ID NEURONAL VULNERABILITY; ANTIHYPERTENSIVES AB We investigated whether the use of calcium channel blockers (CCBs) was associated with a reduced risk of Parkinson's disease (PD) in two large prospective cohorts: the Nurses' Health Study (NHS) and Health Professionals' Follow- Up Study (HPFS). Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) to assess the association between use of CCBs and risk of PD adjusting for potential confounders. We identified 514 incident cases of PD during follow-up. No association between baseline use of CCBs (RR 5 1.18, 95% CI: 0.731.92), frequency of use or duration of use of CCBs and PD risk was observed (P > 0.2 for all). These findings do not support a role for CCBs in providing neuroprotection against development of PD. (C) 2010 Movement Disorder Society C1 [Simon, Kelly Claire; Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp,Dept Med, Boston, MA 02115 USA. [Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Simon, KC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,3rd Floor, Boston, MA 02115 USA. EM ksimon@hsph.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU NIH/NINDS [R01 NS048517]; National Institute of Environmental Health Sciences; National Institute of Health [Z01ES101986]; National Institute of Health/National Research Service [T32 ES016645-01]; NHI/NINDS [R01 NS062879-01A2]; National Institute of Environmental Health Sciences, NIH [Z01ES101986]; Department of Defense/USAMRAA; RJG Foundation; Fox Foundation; American Parkinson's Disease Association; Parkinson's Disease Foundation; The Parkinson Study Group; University of Rochester; Harvard University; DoD (Department of the Army) [W81XWH-05-1-0117; 20052009] FX This work was supported by grant NIH/NINDS R01 NS048517 and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institute of Health (Z01ES101986).; K.C.S. was supported in 2009 by a National Institute of Health/National Research Service Award grant (T32 ES016645-01). X.G.: Advisory boards: Monitoring Committee of the Parkinson Study Group; Employment: Instructor in Medicine at Harvard Medical School; Research Scientist at Harvard School of Public Health; Associate Epidemiologist, Brigham and Women's Hospital; Grants: NHI/NINDS grant "Prospective study of restless legs syndrome'' (R01 NS062879-01A2), role: PI. H.C. is an employee of the federal government and has received funding from the intramural research program of the National Institute of Environmental Health Sciences, NIH (Z01ES101986). M.A.S.: Employment: Massachusetts General Hospital, Harvard University; Grant support: NIH/NINDS, Department of Defense/USAMRAA, RJG Foundation, Hartford Foundation/American Federation for Aging Research, Michael J. Fox Foundation, American Parkinson's Disease Association, Parkinson's Disease Foundation, The Parkinson Study Group, University of Rochester, Harvard University; Honoraria: Emory University, University of Pennsylvania. A.A.: Scientific advisory boards: Michael J. Fox Foundation 2008-2009; Editorial advisory boards: Neurology, Associate Editor 2008-2009; Annals of Neurology, Associate Editor 2008-2009; Honoraria: From Merck-Serono for scientific presentation 2009-12-15; Grants: DoD (Department of the Army) W81XWH-05-1-0117; 20052009; Role: PI; NIH R01 NS045893; 2006-2011; Role: PI; NIH R01 NS047467; 2005-2009; Role: PI; NIH R01 NS48517; 2005-2010; Role: PI; NIH/NINDS R01 NS042194; 2005-2010; Role: PI; NIH R01 NS046635; 2008-2013; Role: PI; DoD: No Award Number; 2008-2011; Role: PI; Michael J. Fox Foundation: No Award Number; 2008-2012; Role: Co-PI. NR 11 TC 20 Z9 20 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 IS 12 BP 1818 EP 1822 DI 10.1002/mds.23191 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 655VN UT WOS:000282283100007 PM 20669249 ER PT J AU Shahar, A Patel, KV Semba, RD Bandinelli, S Shahar, DR Ferrucci, L Guralnik, JM AF Shahar, Avner Patel, Kushang V. Semba, Richard D. Bandinelli, Stefania Shahar, Danit R. Ferrucci, Louigi Guralnik, Jack M. TI Plasma Selenium is Positively Related to Performance in Neurological Tasks Assessing Coordination and Motor Speed SO MOVEMENT DISORDERS LA English DT Article DE selenium; trace elements; Parkinson's disease; antioxidants; elderly ID PARKINSONS-DISEASE; OLDER WOMEN; INCHIANTI; MICRONUTRIENT; EPIDEMIOLOGY; NEUROMELANIN; SUPEROXIDE; COMMUNITY; STRENGTH; NEURONS AB Parkinson's disease (PD) is a degenerative process affecting the striato nigral system (SN). Its etiology, although obscure, may involve oxidative damage. Selenium, an antioxidant, was shown to protect the SN in animal models. In the current study, we investigate the association between plasma selenium concentrations and the presence of "soft'' neurological signs related to the SN. Plasma selenium concentration was assessed in participants of age >= 65 years in the InCHIANTI study, a population-based cohort study in Tuscany, Italy. PD was defined based on standard criteria. "Soft'' neurological signs were ascertained by physical examination. A total of 1,012 participants were included. No association was found between the presence of PD and plasma selenium. There was, however, a strong association between plasma selenium and timed performance-based assessments. Lower levels of selenium were significantly associated with decreased performance in neurological tests of coordination among older adults. Prospective studies are needed to further investigate the effects of selenium on SN dysfunction. (C) 2010 Movement Disorder Society C1 [Shahar, Avner; Patel, Kushang V.; Shahar, Danit R.; Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Shahar, Avner] Minist Hlth, Beer Sheva, Israel. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Shahar, Danit R.] Ben Gurion Univ Negev, S Daniel Abraham Int Ctr Hlth & Nutr, IL-84105 Beer Sheva, Israel. [Ferrucci, Louigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Shahar, A (reprint author), 5 Kibbutz Galuyot St, IL-70700 Gedera, Israel. EM dvsst@netvision.net.il RI Shahar, Danit/B-4280-2012 FU Italian Ministry of Health [ICS110.1/RF97.71]; US National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; National Institute on Aging, National Institutes of Health; Baltimore, MD FX 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 US National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-ups 2 and 3 studies (2004-2010) were financed by the US National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, MD. The study conformed to the ethical principles contained in the Declaration of Helsinki, and the InCHIANTI Study protocol was approved by the Ethical Committee of the Italian National Institute of Research and Care of Aging. NR 32 TC 26 Z9 26 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 IS 12 BP 1909 EP 1915 DI 10.1002/mds.23218 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 655VN UT WOS:000282283100020 PM 20687175 ER PT J AU Alpan, GO Masdeu, J Kohn, P Lopez, G Eisenberg, D Groden, C Chalfin, M Ianni, A Berman, KF Sidransky, E AF Alpan, Goker-O. Masdeu, J. Kohn, P. Lopez, G. Eisenberg, D. Groden, C. Chalfin, M. Ianni, A. Berman, K. F. Sidransky, E. TI The Neurobiology of Glucocerebrosidase Associated PD: Studies of Dopamine Synthesis and RCBF in GBA Mutation Carriers with and Without Parkinsonism SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Alpan, Goker-O.; Masdeu, J.; Eisenberg, D.; Chalfin, M.; Ianni, A.; Berman, K. F.] NIH, Bethesda, MD 20892 USA. [Kohn, P.; Lopez, G.; Groden, C.; Sidransky, E.] NHGRI, Bethesda, MD 20892 USA. RI Eisenberg, Daniel/C-7432-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S723 EP S724 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300506 ER PT J AU Civiero, L Taymans, JM Beilina, A Cookson, MR Baekelandt, V Bubacco, L Greggio, E AF Civiero, L. Taymans, J. M. Beilina, A. Cookson, M. R. Baekelandt, V. Bubacco, L. Greggio, E. TI Biochemical Characterization of Full-Length Human Recombinant LRRK1 and LRRK2 SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Civiero, L.; Bubacco, L.; Greggio, E.] Univ Padua, I-35100 Padua, Italy. [Taymans, J. M.; Baekelandt, V.] Katholieke Univ Leuven, Louvain, Belgium. [Beilina, A.; Cookson, M. R.] NIH, Bethesda, MD USA. RI Bubacco, Luigi/B-5602-2012; Greggio, Elisa/H-6119-2013 OI Greggio, Elisa/0000-0002-8172-3598 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S634 EP S634 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300235 ER PT J AU Cookson, M AF Cookson, M. TI Biology and Protein Biochemistry SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Cookson, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S594 EP S594 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300096 ER PT J AU Goldstein, D AF Goldstein, D. TI Cardiovascular Features in PD SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Goldstein, D.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S603 EP S603 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300128 ER PT J AU Schulz, G Bradberry, TJ Hosey, LA Stager, S Li-Ching, L Pawha, R Lyons, K Verhagen, L Braun, A AF Schulz, G. Bradberry, T. J. Hosey, L. A. Stager, S. Li-Ching, L. Pawha, R. Lyons, K. Verhagen, L. Braun, A. TI Dissociated Effects of Left, Right, and Bilateral Stimulation of the Subthalamic Nucleus on Motor, Speech, and Language Function in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Stager, S.] George Washington Univ, Med Ctr, Washington, DC 20052 USA. [Bradberry, T. J.; Hosey, L. A.; Braun, A.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Pawha, R.; Lyons, K.] Univ Kansas, Med Ctr, Lawrence, KS 66045 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S671 EP S672 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300346 ER PT J AU Sidransky, E AF Sidransky, E. TI Gaucher Disease and Parkinsonism SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Sidransky, E.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S579 EP S580 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300043 ER PT J AU Singleton, A AF Singleton, A. TI GWAS SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Singleton, A.] NIH, Bethesda, MD USA. RI Singleton, Andrew/C-3010-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S579 EP S579 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300042 ER PT J AU Xu, Q Park, Y Huang, X Umbach, D Hollenbeck, A Blair, A Schatzkin, A Chen, H AF Xu, Q. Park, Y. Huang, X. Umbach, D. Hollenbeck, A. Blair, A. Schatzkin, A. Chen, H. TI Diabetes Mellitus and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Park, Y.; Blair, A.; Schatzkin, A.] NCI, Bethesda, MD 20892 USA. [Umbach, D.; Chen, H.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. 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 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S615 EP S615 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300172 ER PT J AU Xu, Q Park, Y Huang, X Hollenbeck, A Blair, A Schatzkin, A Chen, H AF Xu, Q. Park, Y. Huang, X. Hollenbeck, A. Blair, A. Schatzkin, A. Chen, H. TI Multivitamin Use and Risk of Parkinson's Disease Among Older Adults SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Xu, Q.] Beijing Union Med Univ, Beijing, Peoples R China. [Park, Y.; Blair, A.; Schatzkin, A.] NCI, Bethesda, MD 20892 USA. [Huang, X.] Penn State Univ, University Pk, PA 16802 USA. [Chen, H.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. 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 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2010 VL 25 SU 3 BP S615 EP S616 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 655WO UT WOS:000282286300173 ER PT J AU Pickens, CL Navarre, BM Nair, SG AF Pickens, C. L. Navarre, B. M. Nair, S. G. TI INCUBATION OF CONDITIONED FEAR IN THE CONDITIONED SUPPRESSION MODEL IN RATS: ROLE OF FOOD-RESTRICTION CONDITIONS, LENGTH OF CONDITIONED STIMULUS, AND GENERALITY TO CONDITIONED FREEZING SO NEUROSCIENCE LA English DT Article DE fear conditioning; anxiety; incubation; post-traumatic stress disorder; conditioned freezing; conditioned suppression ID POSTTRAUMATIC-STRESS-DISORDER; WATER RESTRICTION; ANXIETY; AMYGDALA; BEHAVIOR; LESIONS; MEMORY; INHIBITION; IMMEDIATE; RESPONSES AB We recently adapted the conditioned suppression of operant responding method to study fear incubation. We found that food-restricted rats show low fear 2 days after extended (10 d; 100 30-s tone-shock pairings) fear training and high fear after 1-2 months. Here, we studied a potential mechanism of fear incubation: extended food-restriction stress. We also studied whether fear incubation is observed after fear training with a prolonged-duration (6-min) tone conditioned stimulus (CS), and whether conditioned freezing incubates after extended training in rats with or without a concurrent operant task. Conditioned fear was assessed 2 days and 1 month after training. In the conditioned suppression method, fear incubation was reliably observed in rats under moderate food-restriction conditions (18-20 g food/day) that allowed for weight gain, and after extended (10 d), but not limited (1 d), fear training with the 6-min CS. Incubation of conditioned freezing was observed after extended fear training in rats lever-pressing for food and, to a lesser degree, in rats not performing an operant task. Results indicate that prolonged hunger-related stress does not account for fear incubation in the conditioned suppression method, and that fear incubation occurs to a longer-duration (6-min) fear CS. Extended training also leads to robust fear incubation of conditioned freezing in rats performing an operant task and weaker fear incubation in rats not performing an operant task. Published by Elsevier Ltd on behalf of IBRO. C1 [Pickens, C. L.; Navarre, B. M.; Nair, S. G.] NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, Baltimore, MD 21218 USA. RP Pickens, CL (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21218 USA. EM pickensc@mail.nih.gov RI Pickens, Charles/E-8984-2010 FU National Institute on Drug Abuse FX Research was supported by the National Institute on Drug Abuse's Intramural Research Program. We thank Dr. Yavin Shaham for helpful comments on the manuscript, Dr. Michael McDannald for useful discussions and Tristan Adams-Deutsch for technical assistance. We also thank Mary Dallman for suggesting alternative mechanisms of fear incubation that led us to perform Exp. 1 in this report and Anna Stern for scoring the freezing data in Exp. 3. The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript. NR 42 TC 13 Z9 14 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD SEP 15 PY 2010 VL 169 IS 4 BP 1501 EP 1510 DI 10.1016/j.neuroscience.2010.06.036 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 640KR UT WOS:000281050600002 PM 20600654 ER PT J AU Holt, SK Kwon, EM Koopmeiners, JS Lin, DW Feng, ZD Ostrander, EA Peters, U Stanford, JL AF Holt, Sarah K. Kwon, Erika M. Koopmeiners, Joseph S. Lin, Daniel W. Feng, Ziding Ostrander, Elaine A. Peters, Ulrike Stanford, Janet L. TI Vitamin D Pathway Gene Variants and Prostate Cancer Prognosis SO PROSTATE LA English DT Article DE vitamin D receptor; 1-alpha-hydroxylase; 24-hydroxylase; prostatic neoplasms; outcomes ID D-RECEPTOR GENE; RADICAL PROSTATECTOMY; 25-HYDROXYVITAMIN D-1-ALPHA-HYDROXYLASE; UNITED-STATES; COLON-CANCER; RISK; POLYMORPHISMS; ASSOCIATION; EXPRESSION; DIAGNOSIS AB BACKGROUND. Observational studies linking vitamin D deficiency with increased prostate cancer (PCa) mortality and the pleiotropic anticancer effects of vitamin D in malignant prostate cell lines have initiated trials examining potential therapeutic benefits of vitamin D metabolites. There have been some successes but efforts have been hindered by risk of inducing hypercalcemia. A limited number of studies have investigated associations between variants in vitamin D pathway genes with aggressive forms of PCa. Increased understanding of relevant germline genetic variation with disease outcome could aid in the development of vitamin-D-based therapies. METHODS. We undertook a comprehensive analysis of 48 tagging single-nucleotide polymorphisms (tagSNPs) in genes encoding for vitamin D receptor (VDR), vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) in a cohort of 1,294 Caucasian cases with an average of 8 years of follow-up. Disease recurrence/progression and PCa-specific mortality risks were estimated using adjusted Cox proportional hazards regression. RESULTS. There were 139 cases with recurrence/progression events and 57 cases who died of PCa. Significantly altered risks of recurrence/progression were observed in relation to genotype for two VDR tagSNPs (rs6823 and rs2071358) and two CYP24A1 tagSNPs (rs927650 and rs2762939). Three VDR tagSNPs (rs3782905, rs7299460, and rs11168314), one CYP27B1 tagSNP (rs3782130), and five CYP24A1 tagSNPs (rs3787557, rs4809960, rs2296241, rs2585428, and rs6022999) significantly altered risks of PCa death. CONCLUSIONS. Genetic variations in vitamin D pathway genes were found to alter both risk of recurrence/progression and PCa-specific mortality. Prostate 70: 1448-1460, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Holt, Sarah K.; Koopmeiners, Joseph S.; Feng, Ziding; Peters, Ulrike; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Kwon, Erika M.] Johns Hopkins Univ, Sch Med, Program Human Genet & Mol Biol, Baltimore, MD USA. [Lin, Daniel W.] Univ Washington, Dept Urol, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Feng, Ziding] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Peters, Ulrike; Stanford, Janet L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Holt, SK (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Mailstop M4-A402,POB 19024, Seattle, WA 98109 USA. EM skholt@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute [RO1-CA056678, RO1-CA092579, RO1-CA082664, P50-CA097186] FX Grant sponsor: National Cancer Institute; Grant numbers: RO-CA056678, RO1-CA092579, RO1-CA082664, P50-CA097186.; This work was supported by grants RO1-CA056678, RO1-CA092579, RO1-CA082664, and P50-CA097186 from the National Cancer Institute; additional support was provided by the Fred Hutchinson Cancer Research Center, the Intramural Program of the National Human Genome Research Institute, and the Prostate Cancer Foundation Young Investigator Award Grant. NR 50 TC 40 Z9 40 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD SEP 15 PY 2010 VL 70 IS 13 BP 1448 EP 1460 DI 10.1002/pros.21180 PG 13 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 646LM UT WOS:000281542100009 PM 20687218 ER PT J AU Borner, K Contractor, N Falk-Krzesinski, HJ Fiore, SM Hall, KL Keyton, J Spring, B Stokols, D Trochim, W Uzzi, B AF Boerner, Katy Contractor, Noshir Falk-Krzesinski, Holly J. Fiore, Stephen M. Hall, Kara L. Keyton, Joann Spring, Bonnie Stokols, Daniel Trochim, William Uzzi, Brian TI A Multi-Level Systems Perspective for the Science of Team Science SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TRANSDISCIPLINARY RESEARCH; COLLABORATION; INTERDISCIPLINARY; READINESS; KNOWLEDGE; NETWORKS; CENTERS AB This Commentary describes recent research progress and professional developments in the study of scientific teamwork, an area of inquiry termed the "science of team science" (SciTS, pronounced "sahyts"). It proposes a systems perspective that incorporates a mixed-methods approach to SciTS that is commensurate with the conceptual, methodological, and translational complexities addressed within the SciTS field. The theoretically grounded and practically useful framework is intended to integrate existing and future lines of SciTS research to facilitate the field's evolution as it addresses key challenges spanning macro, meso, and micro levels of analysis. C1 [Boerner, Katy] Indiana Univ, Sch Lib & Informat Sci, Cyberinfrastruct Network Sci Ctr, Bloomington, IN 47401 USA. [Contractor, Noshir] Northwestern Univ, Dept Ind Engn & Management Sci, Evanston, IL 60208 USA. [Falk-Krzesinski, Holly J.] Northwestern Univ, NW Univ Clin & Translat Sci NUCATS Inst, Chicago, IL 60611 USA. [Fiore, Stephen M.] Univ Cent Florida, Dept Philosophy, Orlando, FL 32826 USA. [Hall, Kara L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20850 USA. [Keyton, Joann] N Carolina State Univ, Dept Commun, Raleigh, NC 27695 USA. [Spring, Bonnie] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Stokols, Daniel] Univ Calif Irvine, Dept Planning Policy & Design, Irvine, CA 92697 USA. [Stokols, Daniel] Univ Calif Irvine, Dept Psychol & Social Behav, Irvine, CA 92697 USA. [Trochim, William] Cornell Univ, Dept Policy Anal & Management, Ithaca, NY 14853 USA. [Uzzi, Brian] Northwestern Univ, Kellogg Sch Management, Evanston, IL 60208 USA. [Uzzi, Brian] Northwestern Univ, NW Inst Complex Syst, Evanston, IL 60208 USA. RP Borner, K (reprint author), Indiana Univ, Sch Lib & Informat Sci, Cyberinfrastruct Network Sci Ctr, Bloomington, IN 47401 USA. EM katy@indiana.edu RI Contractor, Noshir/B-7456-2009; Falk-Krzesinski, Holly/E-8870-2011; OI Falk-Krzesinski, Holly/0000-0001-8112-2445; Fiore, Stephen/0000-0003-3529-1322 FU National Institutes of Health (National Center for Research Resources) [UL1RR025741, NIH U24RR029822]; National Science Foundation (Social & Economic Sciences, Social, Behavioral & Economic Sciences Directorate) [0915602] FX This publication was made possible by grant awards UL1RR025741 and NIH U24RR029822 from the National Institutes of Health (National Center for Research Resources CTSA and American Recovery and Reinvestment Act programs) and by grant award 0915602 from the National Science Foundation (Social & Economic Sciences, Social, Behavioral & Economic Sciences Directorate). NR 36 TC 41 Z9 42 U1 1 U2 34 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 SEP 15 PY 2010 VL 2 IS 49 AR 49cm24 DI 10.1126/scitranslmed.3001399 PG 5 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735SJ UT WOS:000288437200001 PM 20844283 ER PT J AU Feinberg, AP Irizarry, RA Fradin, D Aryee, MJ Murakami, P Aspelund, T Eiriksdottir, G Harris, TB Launer, L Gudnason, V Fallin, MD AF Feinberg, Andrew P. Irizarry, Rafael A. Fradin, Delphine Aryee, Martin J. Murakami, Peter Aspelund, Thor Eiriksdottir, Gudny Harris, Tamara B. Launer, Lenore Gudnason, Vilmundur Fallin, M. Daniele TI Personalized Epigenomic Signatures That Are Stable Over Time and Covary with Body Mass Index SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID COMMON HUMAN-DISEASE; DNA METHYLATION; EPIGENETICS; CANCER; SUSCEPTIBILITY; OBESITY; AGE; OVERWEIGHT; EXPRESSION; SORCS1 AB The epigenome consists of non-sequence-based modifications, such as DNA methylation, that are heritable during cell division and that may affect normal phenotypes and predisposition to disease. Here, we have performed an unbiased genome-scale analysis of similar to 4 million CpG sites in 74 individuals with comprehensive array-based relative methylation (CHARM) analysis. We found 227 regions that showed extreme interindividual variability [variably methylated regions (VMRs)] across the genome, which are enriched for developmental genes based on Gene Ontology analysis. Furthermore, half of these VMRs were stable within individuals over an average of 11 years, and these VMRs defined a personalized epigenomic signature. Four of these VMRs showed covariation with body mass index consistently at two study visits and were located in or near genes previously implicated in regulating body weight or diabetes. This work suggests an epigenetic strategy for identifying patients at risk of common disease. C1 [Feinberg, Andrew P.; Irizarry, Rafael A.; Fradin, Delphine; Aryee, Martin J.; Murakami, Peter; Fallin, M. Daniele] Johns Hopkins Sch Med, Ctr Epigenet, Baltimore, MD 21205 USA. [Feinberg, Andrew P.; Fradin, Delphine; Murakami, Peter] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Irizarry, Rafael A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Aryee, Martin J.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore] NIA, Intramural Res Program, Baltimore, MD 21205 USA. [Fallin, M. Daniele] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Feinberg, AP (reprint author), Johns Hopkins Sch Med, Ctr Epigenet, Baltimore, MD 21205 USA. EM afeinberg@jhu.edu; dfallin@jhsph.edu RI Gudnason, Vilmundur/K-6885-2015; Fradin, Delphine/K-7181-2015; Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008 OI Gudnason, Vilmundur/0000-0001-5696-0084; Fradin, Delphine/0000-0001-6231-2649; Aspelund, Thor/0000-0002-7998-5433 FU NIH [1R01ES015211, 2P50HG003323, N01-AG-12100]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NIH, National Institute on Aging FX Supported by NIH grants 1R01ES015211 (D.F.) and 2P50HG003323 (A.P.F.). The AGES Reykjavik Study is funded by NIH contract N01-AG-12100, Hjartavernd (the Icelandic Heart Association), and Althingi (the Icelandic Parliament). This research was funded in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 35 TC 146 Z9 152 U1 1 U2 22 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 SEP 15 PY 2010 VL 2 IS 49 AR 49ra67 DI 10.1126/scitranslmed.3001262 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735SJ UT WOS:000288437200004 PM 20844285 ER PT J AU Pastrana, DV Pumphrey, KA Cuburu, N Schowalter, RM Buck, CB AF Pastrana, Diana V. Pumphrey, Katherine A. Cuburu, Nicolas Schowalter, Rachel M. Buck, Christopher B. TI Characterization of monoclonal antibodies specific for the Merkel cell polyomavirus capsid SO VIROLOGY LA English DT Article DE MCV; MCPyV; Merkel Cell Carcinoma; Polyomavirus; PyV; HPyV; mAb; Neutralization ID VIRUS-LIKE PARTICLES; MEDIATED NEUTRALIZATION; HUMAN-PAPILLOMAVIRUS; CARCINOMA; PROTEINS; DNA; IMMUNOASSAYS; INFECTION; EPITOPES; TISSUES AB Merkel cell polyomavirus (MCV) has been implicated as a causative agent in Merkel cell carcinoma. Robust polyclonal antibody responses against MCV have been documented in human subjects, but monoclonal antibodies (mAbs) specific for the VP1 capsid protein have not yet been characterized We generated 12 mAbs capable of binding recombinant MCV virus-like particles. The use of a short immunogenic priming schedule was important for production of the mAbs Ten of the 12 mAbs were highly effective for immunofluorescent staining of cells expressing capsid proteins. An overlapping set of 10 mAbs were able to neutralize the infectivity of MCV-based reporter vectors, with 50% effective doses in the low picomolar range. Three mAbs interfered with the binding of MCV virus-like particles to cells This panel of anti-capsid antibodies should provide a useful set of tools for the study of MCV Published by Elsevier Inc C1 [Pastrana, Diana V.; Pumphrey, Katherine A.; Cuburu, Nicolas; Schowalter, Rachel M.; Buck, Christopher B.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Buck, CB (reprint author), Bldg 37 Room 4118,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Buck, Christopher/0000-0003-3165-8094 FU Intramural NIH HHS [ZIA BC011090-02] NR 42 TC 8 Z9 8 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 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2010 VL 405 IS 1 BP 20 EP 25 DI 10.1016/j.virol.2010.06.022 PG 6 WC Virology SC Virology GA 635XR UT WOS:000280691700004 PM 20598728 ER PT J AU Shinoda, K Wyatt, LS Moss, B AF Shinoda, Kaori Wyatt, Linda S. Moss, Bernard TI The neutralizing antibody response to the vaccinia virus A28 protein is specifically enhanced by its association with the H2 protein SO VIROLOGY LA English DT Article DE Poxvirus immunity; Neutralizing antibody; Membrane proteins; Protein interactions; Enhancing immunogenicity ID CELL-CELL-FUSION; SURFACE HEPARAN-SULFATE; VIRION MEMBRANE-PROTEIN; 2 INFECTIOUS FORMS; SMALLPOX VACCINATION; MATURE VIRION; L1 PROTEIN; MONOCLONAL-ANTIBODIES; PROTECTIVE ANTIBODIES; ENTRY/FUSION COMPLEX AB The vaccinia virus (VACV) entry-fusion complex (EFC) is composed of at least nine membrane proteins Immunization of mice with individual EFC genes induced corresponding protein-binding antibody but failed to protect against VACV intranasal challenge and only DNA encoding A28 elicited low neutralizing antibody. Because the A28 and H2 proteins interact, we determined the effect of immunizing with both genes simultaneously This procedure greatly enhanced the amount of antibody that bound intact virions, neutralized infectivity, and provided partial protection against respiratory challenge Neither injection of A28 and H2 plasmids at different sites or mixing A28 and H2 sera enhanced neutralizing antibody The neutralizing antibody could be completely removed by binding to the A28 protein alone and the epitope was located in the C-terminal segment These data suggest that the interaction of H2 with A28 stabilizes the immunogenic form of A28. mimicking an exposed region of the entry-fusion complex on infectious virions Published by Elsevier Inc C1 [Shinoda, Kaori; Wyatt, Linda S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The excellent assistance of Norman Cooper and Catherine Cotter in preparation of cells and purification of VACV is greatly appreciated. We thank Gary Nabel of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases for providing the VRC8400 plasmid, and Wolfgang Leitner/Dermatology Branch, National Cancer Institute for the gold particles used in the gene gun experiments. The studies were supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 68 TC 7 Z9 9 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 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2010 VL 405 IS 1 BP 41 EP 49 DI 10.1016/j.virol.2010.05.025 PG 9 WC Virology SC Virology GA 635XR UT WOS:000280691700007 PM 20673745 ER PT J AU Rippinger, CM Patton, JT McDonald, SM AF Rippinger, Christine M. Patton, John T. McDonald, Sarah M. TI Complete genome sequence analysis of candidate human rotavirus vaccine strains RV3 and 116E SO VIROLOGY LA English DT Article DE Rotavirus; Neonatal; Vaccine; Attenuated; Genome; RV3; 116E ID GROUP-A ROTAVIRUSES; NONSTRUCTURAL PROTEIN; GENE CONSTELLATIONS; PORCINE ROTAVIRUS; CONTROLLED-TRIAL; YOUNG-CHILDREN; NSP4 GENES; NEW-DELHI; VP4; SAFETY AB Rotaviruses (RVs) cause severe gastroenteritis in infants and young children, yet, several strains have been isolated from newborns showing no signs of clinical illness Two of these neonatal strains, RV3 (G3P[6]) and 116E (G9P[11]), are currently being developed as live-attenuated vaccines In this study, we sequenced the eleven-segmented double-stranded RNA genomes of cell culture-adapted RV3 and 116E and compared their genes and protein products to those of other RVs Using amino acid alignments and structural predictions, we identified residues of RV3 or 116E that may contribute to attenuation or influence vaccine efficacy We also discovered residues of the VP4 attachment protein that correlate with the capacity of some P[6] strains. including RV3, to infect newborns versus older infants. The results of this study enhance our understanding of the molecular determinants of RV3 and 116E attenuation and are expected to aid in the ongoing development of these vaccine candidates Published by Elsevier Inc. C1 [Rippinger, Christine M.; Patton, John T.; McDonald, Sarah M.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP McDonald, SM (reprint author), 50 South Dr,Room 6311, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We would like to thank Carl Kirkwood and Taka Hoshino for providing the viruses sequenced in this study and for reviewing the manuscript. We also thank Kristen Guglielmi, Jelle Matthijnssens, and Al Kapikian for important scientific and editorial comments This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 56 TC 22 Z9 22 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2010 VL 405 IS 1 BP 201 EP 213 DI 10.1016/j.virol.2010.06.005 PG 13 WC Virology SC Virology GA 635XR UT WOS:000280691700023 PM 20580391 ER PT J AU Engel, AR Rumyantsev, AA Maximova, OA Speicher, JM Heiss, B Murphy, BR Pletnev, AG AF Engel, Amber R. Rumyantsev, Alexander A. Maximova, Olga A. Speicher, James M. Heiss, Brian Murphy, Brian R. Pletnev, Alexander G. TI The neurovirulence and neuroinvasiveness of chimeric tick-borne encephalitis/dengue virus can be attenuated by introducing defined mutations into the envelope and NS5 protein genes and the 3 ' non-coding region of the genome SO VIROLOGY LA English DT Article DE Flavivirus; Tick-borne encephalitis virus; Live attenuated vaccine; Neurovirulence ID DENGUE TYPE-4 VIRUSES; HUMAN LIVER-CELLS; VACCINE CANDIDATE; NEUTRALIZING ANTIBODIES; 3'-UNTRANSLATED REGION; VERO CELLS; HOST-RANGE; MICE; IMMUNOGENICITY; REPLICATION AB Tick-borne encephalitis (TBE) is a severe disease affecting thousands of people throughout Eurasia Despite the use of formalin-inactivated vaccines in endemic areas, an increasing incidence of TBE emphasizes the need for an alternative vaccine that will induce a more durable immunity against TBE virus (TBEV) The chimeric attenuated virus vaccine candidate containing the structural protein genes of TBEV on a dengue virus genetic background (TBEV/DEN4) retains a high level of neurovirulence in both mice and monkeys. Therefore, attenuating mutations were introduced into the envelope (E(315)) and N55 (NS5(654 655)) proteins, and into the 3' non-coding region (Delta 30) of TBEV/DEN4. The variant that contained all three mutations (v Delta 30/E(315)/N5(654.655)) was significantly attenuated for neuroinvasiveness and neurovirtilence and displayed a reduced level of replication and virus-induced histopathology in the brains of mice The high level of safety in the central nervous system indicates that v Delta 30/E(315)/NS5(654 655) should be further evaluated as a TBEV vaccine Published by Elsevier Inc C1 [Engel, Amber R.; Rumyantsev, Alexander A.; Maximova, Olga A.; Speicher, James M.; Heiss, Brian; Murphy, Brian R.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 33,Room 3W10A,33 N Dr,MSC 3203, Bethesda, MD 20892 USA. FU NIH, NIAID FX We would like to thank Dr Stephen Whitehead (NIH, NIAID) for review of the manuscript and Jeff Skinner for statistical analysis support (NIH, NIAID, Bioinformatics and Computational Biosciences Branch).; This work was supported by the Intramural Research Program of the NIH, NIAID. NR 41 TC 21 Z9 21 U1 1 U2 7 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 SEP 15 PY 2010 VL 405 IS 1 BP 243 EP 252 DI 10.1016/j.virol.2010.06.014 PG 10 WC Virology SC Virology GA 635XR UT WOS:000280691700027 PM 20594569 ER PT J AU Arispe, N Diaz, J Durell, SR Shafrir, Y Guy, HR AF Arispe, Nelson Diaz, Juan Durell, Stewart R. Shafrir, Yinon Guy, H. Robert TI Polyhistidine Peptide Inhibitor of the A beta Calcium Channel Potently Blocks the A beta-Induced Calcium Response in Cells. Theoretical Modeling Suggests a Cooperative Binding Process SO BIOCHEMISTRY LA English DT Article ID RAPID CELLULAR DEGENERATION; ALZHEIMERS-DISEASE; ION CHANNELS; PROTEIN; CYTOTOXICITY; MECHANISM; TOXICITY; NEURONS; FRESH AB On the basis of the consistent demonstrations that the A beta peptide of Alzheimer's disease forms calcium permeant channels in artificial membranes, we have proposed that the intracellular calcium increase observed in cells exposed to A beta is initiated by calcium fluxes through A beta channels. We have found that a small four-histidine peptide, NAHis04, potently inhibits the A beta-induced calcium channel currents in artificial lipid membranes. Here we report that NaHis04 also potently blocks the intracellular calcium increase which is observed in cells exposed to A beta. PC12 cells loaded with Fura-2AM show a rapid increase in fluorescence and a rapid return to baseline after A beta is added to the medium. This fluorescence change occurs even when the medium contains nitrendipine, a voltage-gated calcium channel blocker, but fails to occur when application of A beta is preceded by addition of NAHis04. Steep dose-response curves of the percentage of responding cells and cell viability show that NAHis04 inhibits in the micromolar range in an apparently cooperative manner. We have developed numerous models of A beta pores in which the first part of the A beta sequence forms a large beta-barrel ending at His 13. We have modeled how up to four NAHis04 peptides may block these types of pores by binding to side chains of A beta residues Glu 11, His 13, and His 14. C1 [Arispe, Nelson; Diaz, Juan] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Durell, Stewart R.; Shafrir, Yinon; Guy, H. Robert] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Arispe, N (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM narispe@usuhs.mil; bg4y@nih.gov FU Alzheimer's Association of America; Uniformed Services University of the Health Sciences FX This work was supported by grants from The Alzheimer's Association of America and The Uniformed Services University of the Health Sciences. NR 25 TC 8 Z9 9 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 14 PY 2010 VL 49 IS 36 BP 7847 EP 7853 DI 10.1021/bi1006833 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 645OH UT WOS:000281471600011 PM 20690616 ER PT J AU Semenyuk, A Darian, E Liu, J Majumdar, A Cuenoud, B Miller, PS MacKerell, AD Seidman, MM AF Semenyuk, A. Darian, E. Liu, J. Majumdar, A. Cuenoud, B. Miller, P. S. MacKerell, A. D., Jr. Seidman, M. M. TI Targeting of an Interrupted Polypurine:Polypyrimidine Sequence in Mammalian Cells by a Triplex-Forming Oligonucleotide Containing a Novel Base Analogue SO BIOCHEMISTRY LA English DT Article ID DOUBLE-HELICAL DNA; DOUBLE-STRANDED DNA; MOLECULAR-DYNAMICS; NUCLEIC-ACIDS; GENE KNOCKOUT; 2'-AMINOETHOXY-MODIFIED OLIGONUCLEOTIDES; 2'-O-(2-AMINOETHYL) RESIDUES; SELECTIVE RECOGNITION; NUCLEOSIDE ANALOGS; DUAL RECOGNITION AB The DNA triple helix consists of a third strand of nucleic acid lying in the major groove of an intact DNA duplex. The most stable triplexes form on polypurine:polypyrimidine sequences, and pyrimidine interruptions in the purine strand are destabilizing. Sequence stringency is imparted by specific Hoogsteen hydrogen bonds between third strand bases and the purine bases in the duplex. Appropriate base and sugar modifications of triple helix-forming oligonucleotides (TFOs) confer chromosome targeting activity in living cells. However, broad utilization of TFOs as gene targeting reagents in mammalian cells has been limited by the requirement for homopurine target sequences. Although there have been a number of base analogues described that appear to be promising as candidates for triplex target expansion, none has been examined in a biological system. We have employed a postsynthetic strategy to prepare a collection of TFOs with base analogues at a defined position. Following assessment of affinity for a triplex target with a single C:G inversion, TFOs with a second generation of analogues were synthesized. One of these, TFO-5a, with 2'-OMe-guanidinylethyl-5-methylcytosine at the position corresponding to the C:G interruption in the target sequence, was further modified to confer bioactivity. The activity of this TFO, linked to psoralen, was measured in a mammalian cell line that was engineered by directed sequence conversion to carry a triplex target with a single C:G interruption. TFO-5a was active against this target and inactive against the corresponding target with an uninterrupted polypurine:polypyrimidine sequence. C1 [Seidman, M. M.] NIA, LMG, NIH, Baltimore, MD 21224 USA. [Darian, E.; MacKerell, A. D., Jr.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Miller, P. S.] Johns Hopkins Sch Med, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Cuenoud, B.] Merck Serono SA, CH-1202 Geneva, Switzerland. RP Seidman, MM (reprint author), NIA, LMG, NIH, 251 Bayview Blvd,5B133, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov OI MacKerell, Alex/0000-0001-8287-6804 FU National Institutes of Health, National Institute on Aging [Z01 AG000746-10]; National Institutes of Health [GM051501] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Grant Z01 AG000746-10), and by National Institutes of Health Grant GM051501 (A.D.M.). NR 63 TC 30 Z9 30 U1 2 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 14 PY 2010 VL 49 IS 36 BP 7867 EP 7878 DI 10.1021/bi100797z PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 645OH UT WOS:000281471600013 PM 20701359 ER PT J AU Force, T Bonow, RO Houser, SR Solaro, RJ Hershberger, RE Adhikari, B Anderson, ME Boineau, R Byrne, BJ Cappola, TP Kalluri, R LeWinter, MM Maron, MS Molkentin, JD Ommen, SR Regnier, M Tang, WHW Tian, R Konstam, MA Maron, BJ Seidman, CE AF Force, Thomas Bonow, Robert O. Houser, Steven R. Solaro, R. John Hershberger, Ray E. Adhikari, Bishow Anderson, Mark E. Boineau, Robin Byrne, Barry J. Cappola, Thomas P. Kalluri, Raghu LeWinter, Martin M. Maron, Martin S. Molkentin, Jeffery D. Ommen, Steve R. Regnier, Michael Tang, W. H. Wilson Tian, Rong Konstam, Marvin A. Maron, Barry J. Seidman, Christine E. TI Research Priorities in Hypertrophic Cardiomyopathy Report of a Working Group of the National Heart, Lung, and Blood Institute SO CIRCULATION LA English DT Article DE calcium; genetics; cardiomyopathy, hypertrophic; hypertrophy; tachyarrhythmias ID CARDIAC TROPONIN-T; PLURIPOTENT STEM-CELLS; CARDIOVASCULAR MAGNETIC-RESONANCE; LEFT-VENTRICULAR MASS; BINDING PROTEIN-C; CORONARY MICROVASCULAR DYSFUNCTION; PRESSURE-OVERLOAD HYPERTROPHY; DELAYED CONTRAST ENHANCEMENT; BRAIN NATRIURETIC PEPTIDE; ALCOHOL SEPTAL ABLATION C1 [Force, Thomas] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA. [Force, Thomas] Thomas Jefferson Univ, Div Cardiol, Philadelphia, PA 19107 USA. [Bonow, Robert O.] Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. [Houser, Steven R.] Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19122 USA. [Solaro, R. John] Univ Illinois, Sch Med, Dept Physiol, Chicago, IL USA. [Hershberger, Ray E.] Univ Miami, Miller Sch Med, Dept Med, Div Cardiovasc, Miami, FL 33136 USA. [Adhikari, Bishow; Boineau, Robin] NHLBI, NIH, Bethesda, MD 20892 USA. [Anderson, Mark E.] Univ Iowa, Dept Med, Carver Coll Med, Iowa City, IA 52242 USA. [Byrne, Barry J.] Univ Florida, Coll Med, Powell Gene Therapy Ctr, Gainesville, FL USA. [Cappola, Thomas P.] Univ Penn, Sch Med, Div Cardiovasc, Philadelphia, PA 19104 USA. [Kalluri, Raghu] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Matrix Biol,Dept Med, Boston, MA USA. [LeWinter, Martin M.] Univ Vermont, Coll Med, Dept Med, Cardiol Unit, Burlington, VT 05405 USA. [Maron, Martin S.; Konstam, Marvin A.] Tufts Univ, Sch Med, Tufts Med Ctr, Boston, MA 02111 USA. [Molkentin, Jeffery D.] Univ Cincinnati, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45221 USA. [Ommen, Steve R.] Mayo Clin, Rochester, MN USA. [Regnier, Michael] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Tang, W. H. Wilson] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Tian, Rong] Univ Washington, Mitochondrial & Metab Ctr, Seattle, WA USA. [Maron, Barry J.] Minneapolis Heart Inst Fdn, Hypertroph Cardiomyopathy Ctr, Minneapolis, MN USA. [Seidman, Christine E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Force, T (reprint author), Thomas Jefferson Univ, Ctr Translat Med, Coll Bldg,Room 315,1025 Walnut St, Philadelphia, PA 19107 USA. EM thomas.force@jefferson.edu RI Tang, Wai Hong/I-1238-2013; Kalluri, Raghu/E-2677-2015; OI Force, Thomas/0000-0002-0450-8659; Kalluri, Raghu/0000-0002-2190-547X; Tian, Rong/0000-0002-3676-3830 FU National Institutes of Health (NIH); Howard Hughes Medical Institute (HHMI); Fondation Leducq (FL); American Heart Association (AHA); Kahn Foundation; Scarperi Family; Abbott Diagnostics; Abbott Labs; Medtronic, Inc; Merck and Co; Boehringer-Ingelheim; Johnson and Johnson; Trevena FX The following receive research grants from the National Institutes of Health (NIH), Howard Hughes Medical Institute (HHMI), the Fondation Leducq (FL), The American Heart Association (AHA), or other sources: Dr Force (NIH, The Kahn Foundation, the Scarperi Family, and AHA), Dr Anderson (NIH, FL), Dr Houser (NIH), Dr LeWinter (NIH), Dr Molkentin (NIH, HHMI, and FL), Dr Seidman (NIH, HHMI, and FL), Dr Solaro (NIH), Dr Byrne (NIH), Dr Maron (NIH), Dr Tang (NIH), Dr Tian (NIH), Dr Regnier (NIH), Dr Hershberger (NIH), Dr Bonow (NIH), Dr Cappola (NIH), and Dr Kalluri (NIH).; Dr Solaro serves on the scientific advisory board of Cytokinetics, Inc. Dr Byrne has received honoraria from Amicus Therapeutics and has ownership interest in AGTC, Inc. Dr Cappola has received other research support from Abbott Diagnostics. Dr M. Maron serves as a consultant/advisory board member for PGX Health and Genzyme. Dr Tang has received other research support from Abbott Labs and has served as a consultant to Medtronic Inc. Dr B. Maron received a research grant and honoraria from Medtronic, Inc and has served as a consultant to Gene Dx. Dr Konstam has served as a consultant for or received research support from Merck and Co, Boehringer-Ingelheim, Johnson and Johnson, and Trevena. The remaining authors report no conflicts. NR 179 TC 57 Z9 60 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 14 PY 2010 VL 122 IS 11 BP 1130 EP 1133 DI 10.1161/CIRCULATIONAHA.110.950089 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 650UJ UT WOS:000281877800011 PM 20837938 ER PT J AU Censor, N Dimyan, MA Cohen, LG AF Censor, Nitzan Dimyan, Michael A. Cohen, Leonardo G. TI Modification of Existing Human Motor Memories Is Enabled by Primary Cortical Processing during Memory Reactivation SO CURRENT BIOLOGY LA English DT Article ID DIRECT-CURRENT STIMULATION; MAGNETIC STIMULATION; CONSOLIDATION; RECONSOLIDATION; CORTEX; PLASTICITY; EXCITABILITY; SLEEP; BRAIN AB One of the most challenging tasks of the brain is to constantly update the internal neural representations of existing memories. Animal studies have used invasive methods such as direct microfusion of protein inhibitors to designated brain areas, in order to study the neural mechanisms underlying modification of already existing memories after their reactivation during recall [1-4]. Because such interventions are not possible in humans, it is not known how these neural processes operate in the human brain. In a series of experiments we show here that when an existing human motor memory is reactivated during recall, modification of the memory is blocked by virtual lesion [5] of the related primary cortical human brain area. The virtual lesion was induced by noninvasive repetitive transcranial magnetic stimulation guided by a frameless stereotactic brain navigation system and each subject's brain image. The results demonstrate that primary cortical processing in the human brain interacting with pre-existing reactivated memory traces is critical for successful modification of the existing related memory. Modulation of reactivated memories by noninvasive cortical stimulation may have important implications for human memory research and have far-reaching clinical applications. C1 [Censor, Nitzan; Dimyan, Michael A.; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. EM cohen1@ninds.nih.gov RI Dimyan, Michael/B-1715-2012; OI Dimyan, Michael/0000-0002-9715-9741 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX We thank Mark Hallett for reading an earlier version of the manuscript. This research was supported by the Intramural Research Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 24 TC 45 Z9 45 U1 0 U2 8 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 SEP 14 PY 2010 VL 20 IS 17 SI SI BP 1545 EP 1549 DI 10.1016/j.cub.2010.07.047 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 651QB UT WOS:000281941100031 PM 20817532 ER PT J AU Ramamurthi, KS AF Ramamurthi, Kumaran S. TI Signal Transduction: Bacterial Thermometer Works by Measuring Membrane Thickness SO CURRENT BIOLOGY LA English DT Editorial Material ID BACILLUS-SUBTILIS; LENGTH; 2-COMPONENT; CURVATURE; MECHANISM; RULER AB Cells detect external chemical stimuli by directly binding a signaling molecule, but the strategies used by cells to detect and respond to non-chemical cues have been mysterious. Recent work suggests that a bacterial protein detects changes in environmental temperature by physically measuring membrane thickness. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ramamurthi, KS (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Bldg 37,Room 5132, Bethesda, MD 20892 USA. EM ramamurthiks@mail.nih.gov RI Ramamurthi, Kumaran/P-3516-2015 NR 12 TC 0 Z9 0 U1 0 U2 1 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 SEP 14 PY 2010 VL 20 IS 17 SI SI BP R707 EP R709 DI 10.1016/j.cub.2010.07.010 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 651QB UT WOS:000281941100012 PM 20833311 ER PT J AU Smith, MA Blankman, E Gardel, ML Luettjohann, L Waterman, CM Beckerle, MC AF Smith, Mark A. Blankman, Elizabeth Gardel, Margaret L. Luettjohann, Laura Waterman, Clare M. Beckerle, Mary C. TI A Zyxin-Mediated Mechanism for Actin Stress Fiber Maintenance and Repair SO DEVELOPMENTAL CELL LA English DT Article ID FOCAL ADHESIONS; ALPHA-ACTININ; EXTRACELLULAR-MATRIX; CELL-MIGRATION; PROTEINS; FORCES; MECHANOTRANSDUCTION; POLYMERIZATION; LOCALIZATION; ORGANIZATION AB To maintain mechanical homeostasis, cells must recognize and respond to changes in cytoskeletal integrity. By imaging live cells expressing fluorescently tagged cytoskeletal proteins, we observed that actin stress fibers undergo local, acute, force-induced elongation and thinning events that compromise their stress transmission function, followed by stress fiber repair that restores this capability. The LIM protein zyxin rapidly accumulates at sites of strain-induced stress fiber damage and is essential for stress fiber repair and generation of traction force. Zyxin promotes recruitment of the actin regulatory proteins alpha-actinin and VASP to compromised stress fiber zones. alpha-Actinin plays a critical role in restoration of actin integrity at sites of local stress fiber damage, whereas both alpha-actinin and VASP independently contribute to limiting stress fiber elongation at strain sites, thus promoting stabilization of the stress fiber. Our findings demonstrate a mechanism for rapid repair and maintenance of the structural integrity of the actin cytoskeleton. C1 [Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD USA. [Smith, Mark A.; Blankman, Elizabeth; Luettjohann, Laura; Beckerle, Mary C.] Univ Utah, Huntsman Canc Inst, Dept Biol, Salt Lake City, UT 84112 USA. [Smith, Mark A.; Blankman, Elizabeth; Luettjohann, Laura; Beckerle, Mary C.] Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. [Gardel, Margaret L.] Univ Chicago, Dept Phys, Chicago, IL 60637 USA. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD USA. EM watermancm@nhlbi.nih.gov; mary.beckerle@hci.utah.edu RI Gardel, Margaret/D-1703-2012; OI Waterman, Clare/0000-0001-6142-6775 FU NIH [RO1GM50877, 5 DP1 OD003354-02]; Huntsman Cancer Foundation; Cancer Center [2 P30 CA042014-21]; Burroughs Wellcome Career Award at the Scientific Interfaces; NHLBI FX We thank Frank Gertler (Massachusetts Institute of Technology), Michael Davidson (Florida State University), Carol Otey (University of North Carolina, Chapel Hill), and Ke Hu (Indiana University) for reagents. We also thank Laura Hoffman and Chris Jensen for the zyx4F > A cell line, the zyx Delta 1-42 construct, and for helpful discussions, Jonathan Stricker for technical advice, and Diana Lim for graphic design. Supported by NIH RO1GM50877 (M.C.B.), the Huntsman Cancer Foundation, and shared resources from the Cancer Center Support Grant (2 P30 CA042014-21), the NIH multidisciplinary cancer research training grant (M.A.S.), the Burroughs Wellcome Career Award at the Scientific Interfaces and NIH Director's Pioneer Award 5 DP1 OD003354-02 (M.L.G), and NHLBI (C.M.W.). NR 46 TC 80 Z9 80 U1 0 U2 11 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 SEP 14 PY 2010 VL 19 IS 3 BP 365 EP 376 DI 10.1016/j.devcel.2010.08.008 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 654WZ UT WOS:000282203100006 PM 20833360 ER PT J AU Hernandez, L Roux, KJ Wong, ESM Mounkes, LC Mutalif, R Navasankari, R Rai, B Cool, S Jeong, JW Wang, HH Lee, HS Kozlov, S Grunert, M Keeble, T Jones, CM Meta, MD Young, SG Daar, IO Burke, B Perantoni, AO Stewart, CL AF Hernandez, Lidia Roux, Kyle J. Wong, Esther Sook Miin Mounkes, Leslie C. Mutalif, Rafidah Navasankari, Raju Rai, Bina Cool, Simon Jeong, Jae-Wook Wang, Honghe Lee, Hyun-Shik Kozlov, Serguei Grunert, Martin Keeble, Thomas Jones, C. Michael Meta, Margarita D. Young, Stephen G. Daar, Ira O. Burke, Brian Perantoni, Alan O. Stewart, Colin L. TI Functional Coupling between the Extracellular Matrix and Nuclear Lamina by Wnt Signaling in Progeria SO DEVELOPMENTAL CELL LA English DT Article ID HUTCHINSON-GILFORD-PROGERIA; BETA-CATENIN; PRELAMIN-A; MUSCULAR-DYSTROPHY; LMNA MUTATIONS; MICE DEFICIENT; MOUSE EMBRYO; COLON-CANCER; CELL-CYCLE; STEM-CELLS AB The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/ lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging. C1 [Hernandez, Lidia; Mounkes, Leslie C.; Wang, Honghe; Kozlov, Serguei; Perantoni, Alan O.; Stewart, Colin L.] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Lee, Hyun-Shik; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Hernandez, Lidia] NCI, Mol Signalling Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Roux, Kyle J.; Navasankari, Raju; Burke, Brian] Univ Florida, Coll Med, Dept Anat & Cell Biol, Gainesville, FL 32606 USA. [Wong, Esther Sook Miin; Mutalif, Rafidah; Navasankari, Raju; Rai, Bina; Cool, Simon; Grunert, Martin; Keeble, Thomas; Jones, C. Michael; Stewart, Colin L.] Immunos, Inst Med Biol, Singapore 138648, Singapore. [Jeong, Jae-Wook] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Meta, Margarita D.; Young, Stephen G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Stewart, CL (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM colin.stewart@imb.a-star.edu.sg RI Lee, Hyun-Shik/G-3555-2011; OI Daar, Ira/0000-0003-2657-526X FU Center for Cancer Research, NCI; NIH [R01HD057873] FX We thank T. Yamaguchi, J. Pollard, and J. Campisi for advice, C. B. DeMille for guidance, M. Gelb for PB-43, R. Frederickson, A. Kane for producing the figures, K. Rogers for histology, and anonymous reviewers for helpful suggestions. These studies were funded in part by the Center for Cancer Research, NCI, and NIH and NIH Grant R01HD057873 to J.-W.J. We report no conflict of interest. NR 83 TC 75 Z9 75 U1 2 U2 17 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 SEP 14 PY 2010 VL 19 IS 3 BP 413 EP 425 DI 10.1016/j.devcel.2010.08.013 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 654WZ UT WOS:000282203100010 PM 20833363 ER PT J AU Linard, C Alegana, VA Noor, AM Snow, RW Tatem, AJ AF Linard, Catherine Alegana, Victor A. Noor, Abdisalan M. Snow, Robert W. Tatem, Andrew J. TI A high resolution spatial population database of Somalia for disease risk mapping SO INTERNATIONAL JOURNAL OF HEALTH GEOGRAPHICS LA English DT Article ID ACCURACY; KENYA; MAPS AB Background: Millions of Somali have been deprived of basic health services due to the unstable political situation of their country. Attempts are being made to reconstruct the health sector, in particular to estimate the extent of infectious disease burden. However, any approach that requires the use of modelled disease rates requires reasonable information on population distribution. In a low-income country such as Somalia, population data are lacking, are of poor quality, or become outdated rapidly. Modelling methods are therefore needed for the production of contemporary and spatially detailed population data. Results: Here land cover information derived from satellite imagery and existing settlement point datasets were used for the spatial reallocation of populations within census units. We used simple and semi-automated methods that can be implemented with free image processing software to produce an easily updatable gridded population dataset at 100 x 100 meters spatial resolution. The 2010 population dataset was matched to administrative population totals projected by the UN. Comparison tests between the new dataset and existing population datasets revealed important differences in population size distributions, and in population at risk of malaria estimates. These differences are particularly important in more densely populated areas and strongly depend on the settlement data used in the modelling approach. Conclusions: The results show that it is possible to produce detailed, contemporary and easily updatable settlement and population distribution datasets of Somalia using existing data. The 2010 population dataset produced is freely available as a product of the AfriPop Project and can be downloaded from: http://www.afripop.org. C1 [Linard, Catherine] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Linard, Catherine] Univ Libre Brussels, B-1050 Brussels, Belgium. [Alegana, Victor A.; Noor, Abdisalan M.; Snow, Robert W.] Univ Oxford, Kenyatta Natl Hosp Grounds NASCOP, Wellcome Trust Collaborat Programme,KEMRI, Malaria Publ Hlth & Epidemiol Grp,Ctr Geog Med, Nairobi, Kenya. [Noor, Abdisalan M.; Snow, Robert W.] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford OX3 7LJ, England. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Linard, C (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,S Parks Rd, Oxford OX1 3PS, England. EM catherine.linard@zoo.ox.ac.uk RI Linard, Catherine/A-8533-2011 NR 21 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-072X J9 INT J HEALTH GEOGR JI Int. J. Health Geogr. PD SEP 14 PY 2010 VL 9 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 656FI UT WOS:000282311200001 ER PT J AU Barr, TL Conley, Y Ding, J Dillman, A Warach, S Singleton, A Matarin, M AF Barr, T. L. Conley, Y. Ding, J. Dillman, A. Warach, S. Singleton, A. Matarin, M. TI Genomic biomarkers and cellular pathways of ischemic stroke by RNA gene expression profiling SO NEUROLOGY LA English DT Article ID BLOOD MONONUCLEAR-CELLS; MICROARRAY; MONOCYTES; GLYCOPROTEIN; DISEASE; GTPASES; DAMPS AB Objective: The objective of this study was to provide insight into the molecular mechanisms of acute ischemic cerebrovascular syndrome (AICS) through gene expression profiling and pathway analysis. Methods: Peripheral whole blood samples were collected from 39 MRI-diagnosed patients with AICS and 25 nonstroke control subjects >18 years of age. Total RNA was extracted from whole blood stabilized in Paxgene RNA tubes, amplified, and hybridized to Illumina HumanRef-8v2 bead chips. Gene expression was compared in a univariate manner between stroke patients and control subjects using t test in GeneSpring. The significant genes were tested in a logistic regression model controlling for age, hypertension, and dyslipidemia. Inflation of type 1 error was corrected by Bonferroni and Ingenuity Systems Pathway analysis was performed. Validation was performed by QRT-PCR using Taqman gene expression assays. Results: A 9-gene profile was identified in the whole blood of ischemic stroke patients using gene expression profiling. Five of these 9 genes were identified in a previously published expression profiling study of stroke and are therefore likely biomarkers of stroke. Pathway analysis revealed toll-like receptor signaling as a highly significant canonical pathway present in the peripheral whole blood of patients with AICS. Conclusions: Our study highlights the relevance of the innate immune system through toll-like receptor signaling as a mediator of response to ischemic stroke and supports the claim that gene expression profiling can be used to identify biomarkers of ischemic stroke. Further studies are needed to validate and refine these biomarkers for their diagnostic potential. Neurology (R) 2010;75:1009-1014 C1 [Barr, T. L.] NINR, Tissue Injury Unit, Hatfield Clin Res Ctr 10, Bethesda, MD 20812 USA. [Conley, Y.] Univ Pittsburgh, Sch Nursing, Dept Hlth Promot & Dev, Pittsburgh, PA 15261 USA. [Ding, J.; Dillman, A.; Singleton, A.; Matarin, M.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Warach, S.] NINDS, Bethesda, MD 20892 USA. [Matarin, M.] UCL, Inst Neurol, Dept Mol Neurosci, London WC1E 6BT, England. [Matarin, M.] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London WC1E 6BT, England. RP Barr, TL (reprint author), NINR, Tissue Injury Unit, Hatfield Clin Res Ctr 10, Tissue Injury Unit Bldg,Room 2-1339, Bethesda, MD 20812 USA. EM barrt@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Matarin, Mar/F-1771-2016 OI Matarin, Mar/0000-0002-4717-5735 FU NIH/NINDS/NIA [Z01 AG000957-05]; NINR; NIH [NINR R01NR008424-01, NINDS P01NS030318, NEI R01EY09859, NICHD R01HD048162, NINR R01NR004339, NINR F31NR011379, NINR T32NR009759, NICHD T32HD040686]; US Department of Defense [W81XWH-07-0701, W81XWH-09-2-0128]; Oncology Nursing Society; NIH/NINDS, Division of Intramural Research FX Dr. Barr has a patent pending re: diagnosis of ischemic stroke using gene expression profiling and receives research support from the Division of Intramural Research of the NIH/NINDS/NIA and a predoctoral training fellowship from NINR. Dr. Conley serves on the editorial board of Biological Research for Nursing; has a patent pending re: panel of markers to diagnose stroke and receives royalties (Optherion, Inc.) for a patent re: susceptibility genes for age-related maculopathy; receives research support from the NIH (NINR R01NR008424-01 [coinvestigator], NINDS P01NS030318 [coinvestigator], NEI R01EY09859 [coinvestigator], NICHD R01HD048162 [subcontract PI], NINR R01NR004339 [sponsor], NINR F31NR011379 [codirector], NINR T32NR009759 [training faculty], and NICHD T32HD040686 [PI]), the US Department of Defense (W81XWH-07-0701 [coinvestigator]), and the Oncology Nursing Society. Dr. Ding and A. Dillman report no disclosures. Dr. Warach serves on the editorial boards of the Journal of Cerebral Blood Flow and Metabolism, Stroke, The Lancet Neurology, the International Journal of Stroke, and Cerebrovascular Diseases and receives research support from the NIH/NINDS, Division of Intramural Research. Dr. Singleton serves on the editorial boards of Annals of Neurology, The Lancet Neurology, Neurogenetics, and Neurodegenerative Diseases; has a patent pending re: panel of markers to diagnose stroke; and receives NIH Intramural funding (Department of Defense W81XWH-09-2-0128 [PI]). Dr. Matarin reports no disclosures.; Supported by the Division of Intramural Research of the NIH/NINDS/NIA (Z01 AG000957-05) and by a predoctoral Intramural Research Training Award via the Graduate Partnerships Program through the National Institute of Nursing Research, NIH (to T.L.B.). NR 31 TC 53 Z9 53 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 14 PY 2010 VL 75 IS 11 BP 1009 EP 1014 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 653BP UT WOS:000282058600012 PM 20837969 ER PT J AU Shin, YK Martin, B Kim, W White, CM Ji, SG Sun, YX Smith, RG Sevigny, J Tschop, MH Maudsley, S Egan, JM AF Shin, Yu-Kyong Martin, Bronwen Kim, Wook White, Caitlin M. Ji, Sunggoan Sun, Yuxiang Smith, Roy G. Sevigny, Jean Tschoep, Matthias H. Maudsley, Stuart Egan, Josephine M. TI Ghrelin Is Produced in Taste Cells and Ghrelin Receptor Null Mice Show Reduced Taste Responsivity to Salty (NaCl) and Sour (Citric Acid) Tastants SO PLOS ONE LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; GROWTH-HORMONE RELEASE; COEXPRESSION PATTERNS; MAMMALIAN TASTE; SODIUM TASTE; BUDS; RAT; EXPRESSION; MOUSE; AMILORIDE AB Background: The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved. Methodology/Principal Findings: Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3), ghrelin, its cognate receptor (GHSR), and ghrelin-O-acyltransferase (GOAT, the enzyme that activates ghrelin) are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid) and salty (sodium chloride) tastants. Conclusions/Significance: These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity. C1 [Shin, Yu-Kyong; Martin, Bronwen; Kim, Wook; White, Caitlin M.; Ji, Sunggoan; Maudsley, Stuart; Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. [Sun, Yuxiang] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. [Smith, Roy G.] Scripps Res Inst, Dept Metab & Aging, Jupiter, FL USA. [Sevigny, Jean] Univ Laval, Ctr Hosp Univ Quebec, Ctr Rech Rhumatol & Immunol, Quebec City, PQ, Canada. [Tschoep, Matthias H.] Univ Cincinnati, Div Endocrinol, Coll Med, Dept Med,Metab Dis Inst, Cincinnati, OH USA. [Tschoep, Matthias H.] Univ Cincinnati, Div Endocrinol, Coll Med, Dept Psychiat,Metab Dis Inst, Cincinnati, OH USA. RP Shin, YK (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM eganj@mail.nih.gov RI Sevigny, Jean/E-8039-2012; Tschoep, Matthias/I-5443-2014; OI Sevigny, Jean/0000-0003-2922-1600; Tschoep, Matthias/0000-0002-4744-371X FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 39 Z9 40 U1 0 U2 12 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 SEP 14 PY 2010 VL 5 IS 9 AR e12729 DI 10.1371/journal.pone.0012729 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 649ZO UT WOS:000281815700016 PM 20856820 ER PT J AU Wang, J Sarkar, TR Zhou, M Sharan, S Ritt, DA Veenstra, TD Morrison, DK Huang, AM Sterneck, E AF Wang, Jun Sarkar, Tapasree Roy Zhou, Ming Sharan, Shikha Ritt, Daniel A. Veenstra, Timothy D. Morrison, Deborah K. Huang, A-Mei Sterneck, Esta TI CCAAT/enhancer binding protein delta (C/EBP delta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Fanconi anemia; DNA repair; mitomycin C; importin 4; protein adaptor ID FANCONI-ANEMIA PATHWAY; HUMAN BREAST-CANCER; GENE-EXPRESSION; TUMOR-SUPPRESSOR; REPAIR; GAMMA-H2AX; TRANSPORT; GENOME AB Maintenance of genomic integrity is an essential cellular function. We previously reported that the transcription factor and tumor suppressor CCAAT/enhancer binding protein delta (C/EBP delta, CEBPD; also known as "NFIL-6 beta") promotes genomic stability. However, the molecular mechanism was not known. Here, we show that C/EBPd is a DNA damage-induced gene, which supports survival of mouse bone marrow cells, mouse embryo fibroblasts (MEF), human fibroblasts, and breast tumor cells in response to the DNA cross-linking agent mitomycin C (MMC). Using gene knockout, protein depletion, and overexpression studies, we found that C/EBP delta promotes monoubiquitination of the Fanconi anemia complementation group D2 protein (FANCD2), which is necessary for its function in replication-associated DNA repair. C/EBPd interacts with FANCD2 and importin 4 (IPO4, also known as "Imp4" and "RanBP4") via separate domains, mediating FANCD2-IPO4 association and augmenting nuclear import of FANCD2, a prerequisite for its monoubiquitination. This study identifies a transcription-independent activity of C/EBP delta in the DNA damage response that may in part underlie its tumor suppressor function. Furthermore, we report a function of IPO4 and nuclear import in the Fanconi anemia pathway of DNA repair. C1 [Wang, Jun; Sarkar, Tapasree Roy; Sharan, Shikha; Ritt, Daniel A.; Morrison, Deborah K.; Huang, A-Mei; Sterneck, Esta] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Zhou, Ming; Veenstra, Timothy D.] SAIC Frederick, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD 21702 USA. RP Sterneck, E (reprint author), NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21702 USA. EM sternecg@mail.nih.gov FU National Institutes of Health, National Cancer Institute [HHSN261200800001E] FX BD69319 mouse monoclonal antibody against C/EBP delta was provided by BD Biosciences Pharmingen through an Antibody Codevelopment Collaboration between the National Cancer Institute and BD Bioscience. The cell lines PD20, PD20-D2, PD220, and PD220RV and FANCD2 (9700) and FANCA (R6512) antibodies were kindly provided by the Fanconi Anemia Research Fund (Eugene, OR). We thank Dr. J. Keller for advice on bone marrow cell colony assays; Drs. Stephen Lockett and Thomas Turbyville for kind help with confocal microscopy; and Glenn Summers, Jennifer Beachley, and Linda Miller for outstanding assistance with mouse work. We thank Drs. Alan D'Andrea (Dana-Faber Cancer Institute) and Shyam Sharan (National Cancer Institute) for reagents and discussion. We are indebted to Dr. Nigel Jones for expert advice. We thank Drs. Shyam Sharan, Nigel Jones, Ira Daar, Kuppusamy Balamurugan, Tom Misteli, Stephen Lockett, and Thomas Turbyville for constructive comments on the manuscript and Jiro Wada for preparation of the figures. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and in part with federal funds under Contract HHSN261200800001E. NR 41 TC 13 Z9 13 U1 0 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 SEP 14 PY 2010 VL 107 IS 37 BP 16131 EP 16136 DI 10.1073/pnas.1002603107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 649UI UT WOS:000281799000030 PM 20805509 ER PT J AU Rimoin, AW Mulembakani, PM Johnston, SC Lloyd-Smith, JO Kisalu, NK Kinkela, TL Blumberg, S Thomassen, HA Pike, BL Fair, JN Wolfe, ND Shongo, RL Graham, BS Formenty, P Okitolonda, E Hensley, LE Meyer, H Wright, LL Muyembe, JJ AF Rimoin, Anne W. Mulembakani, Prime M. Johnston, Sara C. Lloyd-Smith, James O. Kisalu, Neville K. Kinkela, Timothee L. Blumberg, Seth Thomassen, Henri A. Pike, Brian L. Fair, Joseph N. Wolfe, Nathan D. Shongo, Robert L. Graham, Barney S. Formenty, Pierre Okitolonda, Emile Hensley, Lisa E. Meyer, Hermann Wright, Linda L. Muyembe, Jean-Jacques TI Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE active surveillance; orthopoxvirus; zoonosis; eradication ID ROCHE LIGHTCYCLER; VIRUS DETECTION; PRAIRIE DOGS; WEST-AFRICA; TRANSMISSION; ZAIRE; INDIVIDUALS; INFECTION; EFFICACY; ASSAYS AB Studies on the burden of human monkeypox in the Democratic Republic of the Congo (DRC) were last conducted from 1981 to 1986. Since then, the population that is immunologically naive to orthopoxviruses has increased significantly dueto cessation of mass smallpox vaccination campaigns. To assess the current risk of infection, we analyzed human monkeypox incidence trends in a monkeypox-enzootic region. Active, population-based surveillance was conducted in nine health zones in central DRC. Epidemiologic data and biological samples were obtained from suspected cases. Cumulative incidence (per 10,000 population) and major determinants of infection were compared with data from active surveillance in similar regions from 1981 to 1986. Between November 2005 and November 2007, 760 laboratory-confirmed human monkeypox cases were identified in participating health zones. The average annual cumulative incidence across zones was 5.53 per 10,000 (2.18-14.42). Factors associated with increased risk of infection included: living in forested areas, male gender, age < 15, and no prior smallpox vaccination. Vaccinated persons had a 5.2-fold lower risk of monkeypox than unvaccinated persons (0.78 vs. 4.05 per 10,000). Comparison of active surveillance data in the same health zone from the 1980s (0.72 per 10,000) and 2006-07 (14.42 per 10,000) suggests a 20-fold increase in human monkeypox incidence. Thirty years after mass smallpox vaccination campaigns ceased, human monkeypox incidence has dramatically increased in rural DRC. Improved surveillance and epidemiological analysis is needed to better assess the public health burden and develop strategies for reducing the risk of wider spread of infection. C1 [Rimoin, Anne W.] Univ Calif Los Angeles, Los Angeles Sch Publ Hlth, Los Angeles, CA 90095 USA. [Rimoin, Anne W.; Lloyd-Smith, James O.; Blumberg, Seth] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Mulembakani, Prime M.; Kinkela, Timothee L.; Okitolonda, Emile] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Johnston, Sara C.; Hensley, Lisa E.] USA, Res Inst Infect Dis, Frederick, MD 21702 USA. [Lloyd-Smith, James O.; Blumberg, Seth] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Kisalu, Neville K.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90095 USA. [Thomassen, Henri A.] Univ Calif Los Angeles, Ctr Trop Res, Inst Environm, Los Angeles, CA 90095 USA. [Pike, Brian L.; Fair, Joseph N.; Wolfe, Nathan D.] Global Viral Forecasting Initiat, San Francisco, CA 94105 USA. [Shongo, Robert L.] Minist Hlth, Kinshasa, Zaire. [Graham, Barney S.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Formenty, Pierre] WHO, Dept Global Alert & Response, CH-1211 Geneva 27, Switzerland. [Meyer, Hermann] Bundeswehr Inst Microbiol, D-80937 Munich, Germany. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Muyembe, Jean-Jacques] Natl Inst Biomed Res, Kinshasa, Zaire. RP Rimoin, AW (reprint author), Univ Calif Los Angeles, Los Angeles Sch Publ Hlth, Los Angeles, CA 90095 USA. EM arimoin@ucla.edu RI Lloyd-Smith, James/K-4080-2012; Valle, Ruben/A-7512-2013 OI Lloyd-Smith, James/0000-0001-7941-502X; FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Global Network for Women's and Children's Health Research; National Institute of Allergy and Infectious Disease, Division of Infectious Diseases and Microbiology; National Institutes of Health Director's Office; Fogarty International Center; Skoll Foundation; Department of Homeland Security; Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious Disease; Defense Threat Reduction Agency; Global Viral Forecasting Initiative; US Agency for International Development Emerging Pandemic Threats Program; Faucett Family Foundation FX Many individuals contributed to the design of this manuscript and data collection in the field. We thank the Congolese health workers in the Sankuru District for their surveillance efforts and the DRC Ministry of Health and World Health Organization Country office in Kinshasa. We also thank Drs. Joel G. Breman, Donald A. Henderson, Onyebuchi Arah, Roger Detels, Harout Armenian, and Robert W. Ryder for their comments and suggestions on the manuscript and Eric Wilkinson, Erick Mucker, Carly Wlazlowski, and Jay Goff for organizational and technical laboratory support. Funding for this work was provided by: the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Global Network for Women's and Children's Health Research; National Institute of Allergy and Infectious Disease, Division of Infectious Diseases and Microbiology; National Institutes of Health Director's Office [through a National Institutes of Health Director's Pioneer Award (N.D.W.)]; Fogarty International Center, Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious Disease; Defense Threat Reduction Agency; the Global Viral Forecasting Initiative (supported by Google.org, the Skoll Foundation, and the US Agency for International Development Emerging Pandemic Threats Program); and the Faucett Family Foundation. NR 33 TC 110 Z9 112 U1 1 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 14 PY 2010 VL 107 IS 37 BP 16262 EP 16267 DI 10.1073/pnas.1005769107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 649UI UT WOS:000281799000053 PM 20805472 ER PT J AU Shi, Y Suh, YH Milstein, AD Isozaki, K Schmid, SM Roche, KW Nicoll, RA AF Shi, Yun Suh, Young Ho Milstein, Aaron D. Isozaki, Kaname Schmid, Sabine M. Roche, Katherine W. Nicoll, Roger A. TI Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE stargazin; synapse; auxiliary subunit; hippocampus ID 2 DISTINCT MECHANISMS; AUXILIARY SUBUNITS; GLUTAMATE RECEPTORS; ENDOPLASMIC-RETICULUM; STARGAZIN; DESENSITIZATION; DROSOPHILA; PROTEINS; MOUSE; BLOCK AB Glutamate receptors of the AMPA subtype (AMPARs) mediate fast synaptic transmission in the brain. These ionotropic receptors rely on auxiliary subunits known as transmembrane AMPAR regulatory proteins (TARPs) for both trafficking and gating. Recently, a second family of AMPAR binding proteins, referred to as cornichons, were identified and also proposed to function as auxiliary subunits. Cornichons are transmembrane proteins that modulate AMPAR function in expression systems much like TARPs. In the present study we compare the role of cornichons in controlling AMPA receptor function in neurons and HEK cells to that of TARPs. Cornichons mimic some, but not all, of the actions of TARPs in HEK cells; their role in neurons, however, is more limited. Although expressed cornichons can affect the trafficking of AMPARs, they were not detected on the surface of neurons and failed to alter the kinetics of endogenous AMPARs. This neuronal role is more consistent with that of an endoplasmic reticulum (ER) chaperone rather than a bona fide auxiliary subunit. C1 [Shi, Yun; Milstein, Aaron D.; Schmid, Sabine M.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Milstein, Aaron D.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. [Suh, Young Ho; Isozaki, Kaname; Roche, Katherine W.] NINDS, NIH, Bethesda, MD 20892 USA. RP Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. EM nicoll@cmp.ucsf.edu RI Shi, Yun/B-5623-2009; OI Roche, Katherine/0000-0001-7282-6539 FU NIMH NIH HHS [R01 MH080379] NR 29 TC 55 Z9 64 U1 0 U2 9 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 SEP 14 PY 2010 VL 107 IS 37 BP 16315 EP 16319 DI 10.1073/pnas.1011706107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 649UI UT WOS:000281799000062 PM 20805473 ER PT J AU Anderson, RV Crane, DD Bosio, CM AF Anderson, Rebecca V. Crane, Deborah D. Bosio, Catharine M. TI Long lived protection against pneumonic tularemia is correlated with cellular immunity in peripheral, not pulmonary, organs SO VACCINE LA English DT Article DE Tularemia; Lung; Vaccine ID FRANCISELLA-TULARENSIS-LVS; DELAYED-TYPE HYPERSENSITIVITY; CD8(+) T-CELLS; MEDIATED-IMMUNITY; VACCINE STRAIN; INTRACELLULAR BACTERIUM; SALMONELLA-TYPHIMURIUM; RESPIRATORY-INFECTION; GUINEA PIG; MICE AB Protection against the intracellular bacterium Francisella tularensis within weeks of vaccination is thought to involve both cellular and humoral immune responses. However, the relative roles for cellular and humoral immunity in long lived protection against virulent F. tularensis are not well established. Here, we dissected the correlates of immunity to pulmonary infection with virulent F. tularensis strain SchuS4 in mice challenged 30 and 90 days after subcutaneous vaccination with LVS. Regardless of the time of challenge. LVS vaccination protected approximately 90% of SchuS4 infected animals. Surprisingly, control of bacterial replication in the lung during the first 7 days of infection was not required for survival of SchuS4 infection in vaccinated mice. Control and survival of virulent F. tularensis strain SchuS4 infection within 30 days of vaccination was associated with high titers of SchuS4 agglutinating antibodies, and IFN-gamma production by multiple cell types in both the lung and spleen. In contrast, survival of SchuS4 infection 90 days after vaccination was correlated only with IFN-gamma producing splenocytes and activated T cells in the spleen. Together these data demonstrate that functional agglutinating antibodies and strong mucosal immunity are correlated with early control of pulmonary infections with virulent F. tularensis. However, early mucosal immunity may not be required to survive F. tularensis infection. Instead, survival of SchuS4 infection at extended time points after immunization was only associated with production of IFN-gamma and activation of T cells in peripheral organs. Published by Elsevier Ltd. C1 [Anderson, Rebecca V.; Crane, Deborah D.; Bosio, Catharine M.] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Bosio, CM (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The authors would like to thank Dr. Rong Wang, Ms. Jennifer Chase, and Ms. Robin Ireland for their excellent technical help in the execution of experiments described herein. We also thank Dr. Harlan Caldwell for his comments and suggestions pertaining to this manuscript. NR 49 TC 15 Z9 15 U1 0 U2 1 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 SEP 14 PY 2010 VL 28 IS 40 BP 6562 EP 6572 DI 10.1016/j.vaccine.2010.07.072 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 656ZF UT WOS:000282379000003 PM 20688042 ER PT J AU Kleinerman, RA Weinstock, RM Mabuchi, K AF Kleinerman, Ruth A. Weinstock, Robert M. Mabuchi, Kiyohiko TI High-Dose Abdominal Radiotherapy and Risk of Diabetes Mellitus SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID RADIATION-THERAPY; PEPTIC-ULCER; SURVIVORS C1 [Kleinerman, Ruth A.; Mabuchi, Kiyohiko] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Weinstock, Robert M.] RTI Int, Rockville, MD USA. RP Mabuchi, K (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7038,MSC 7238, Rockville, MD 20852 USA. EM mabuchik@mail.nih.gov OI Kleinerman, Ruth/0000-0001-7415-2478 FU Intramural NIH HHS NR 6 TC 5 Z9 5 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 13 PY 2010 VL 170 IS 16 BP 1506 EP 1507 DI 10.1001/archinternmed.2010.285 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 649JE UT WOS:000281764100017 PM 20837842 ER PT J AU Largent, EA Miller, FG AF Largent, Emily A. Miller, Franklin G. TI Is Emergency Research Without Initial Consent Justified? The Consent Substitute Model Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Largent, Emily A.; Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 13 PY 2010 VL 170 IS 16 BP 1509 EP 1509 DI 10.1001/archinternmed.2010.296 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 649JE UT WOS:000281764100021 ER PT J AU Rosa, EC Dickinson, D Apud, J Weinberger, DR Elvevag, B AF Rosa, Elise C. Dickinson, Dwight Apud, Jose Weinberger, Daniel R. Elvevag, Brita TI COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination SO BEHAVIORAL AND BRAIN FUNCTIONS LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; WORKING-MEMORY; PREFRONTAL CORTEX; GENETIC-VARIATION; SCHIZOPHRENIA; GENOTYPE; MODULATION; HYPOTHESIS; SYSTEM; BRAIN AB Background: Dopamine in prefrontal cortex (PFC) modulates core cognitive processes, notably working memory and executive control. Dopamine regulating genes and polymorphisms affecting PFC-including Catechol-O-Methyltransferase (COMT) Val158Met - are crucial to understanding the molecular genetics of cognitive function and dysfunction. A mechanistic account of the COMT Val158Met effect associates the Met allele with increased tonic dopamine transmission underlying maintenance of relevant information, and the Val allele with increased phasic dopamine transmission underlying the flexibility of updating new information. Thus, consistent with some earlier work, we predicted that Val carriers would display poorer performance when the maintenance component was taxed, while Met carriers would be less efficient when rapid updating was required. Methods: Using a Stroop task that manipulated level of required cognitive stability and flexibility, we examined reaction time performance of patients with schizophrenia (n = 67) and healthy controls (n = 186) genotyped for the Val/Met variation. Results: In both groups we found a Met advantage for tasks requiring cognitive stability, but no COMT effect when a moderate level of cognitive flexibility was required, or when a conflict cost measure was calculated. Conclusions: Our results do not support a simple stability/flexibility model of dopamine COMT Val/Met effects and suggest a somewhat different conceptualization and experimental operationalization of these cognitive components. C1 [Rosa, Elise C.; Dickinson, Dwight; Apud, Jose; Weinberger, Daniel R.; Elvevag, Brita] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. EM brita@elvevaag.net FU National Institute of Mental Health, National Institutes of Health FX This research was funded by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 23 TC 19 Z9 19 U1 5 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-9081 J9 BEHAV BRAIN FUNCT JI Behav. Brain Funct. PD SEP 13 PY 2010 VL 6 AR 53 DI 10.1186/1744-9081-6-53 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 660GY UT WOS:000282629400002 PM 20836853 ER PT J AU Rolli, J Rosenblatt-Velin, N Li, JH Loukili, N Levrand, S Pacher, P Waeber, B Feihl, F Ruchat, P Liaudet, L AF Rolli, Joelle Rosenblatt-Velin, Nathalie Li, Jianhui Loukili, Noureddine Levrand, Sandra Pacher, Pal Waeber, Bernard Feihl, Francois Ruchat, Patrick Liaudet, Lucas TI Bacterial Flagellin Triggers Cardiac Innate Immune Responses and Acute Contractile Dysfunction SO PLOS ONE LA English DT Article ID TOLL-LIKE RECEPTOR-5; MYOCARDIAL INFLAMMATION; SIGNALING PATHWAY; SEPTIC SHOCK; CUTTING EDGE; SEPSIS; PEROXYNITRITE; EXPRESSION; HEART; LIPOPOLYSACCHARIDE AB Background: Myocardial contractile failure in septic shock may develop following direct interactions, within the heart itself, between molecular motifs released by pathogens and their specific receptors, notably those belonging to the toll-like receptor (TLR) family. Here, we determined the ability of bacterial flagellin, the ligand of mammalian TLR5, to trigger myocardial inflammation and contractile dysfunction. Methodology/Principal Findings: TLR5 expression was determined in H9c2 cardiac myoblasts, in primary rat cardiomyocytes, and in whole heart extracts from rodents and humans. The ability of flagellin to activate pro-inflammatory signaling pathways (NF-kappaB and MAP kinases) and the expression of inflammatory cytokines was investigated in H9c2 cells, and, in part, in primary cardiomyocytes, as well as in the mouse myocardium in vivo. The influence of flagellin on left ventricular function was evaluated in mice by a conductance pressure-volume catheter. Cardiomyoyctes and intact myocardium disclosed significant TLR5 expression. In vitro, flagellin activated NF-kappaB, MAP kinases, and the transcription of inflammatory genes. In vivo, flagellin induced cardiac activation of NF-kappaB, expression of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, MIP-2 and MCP-1), and provoked a state of reversible myocardial dysfunction, characterized by cardiac dilation, reduced ejection fraction, and decreased end-systolic elastance. Conclusion/Significance: These results are the first to indicate that flagellin has the ability to trigger cardiac innate immune responses and to acutely depress myocardial contractility. C1 [Rolli, Joelle; Li, Jianhui; Loukili, Noureddine; Levrand, Sandra; Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Dept Intens Care Med, Lausanne, Switzerland. [Rolli, Joelle; Rosenblatt-Velin, Nathalie; Li, Jianhui; Loukili, Noureddine; Levrand, Sandra; Waeber, Bernard; Feihl, Francois; Ruchat, Patrick; Liaudet, Lucas] Fac Biol & Med, Lausanne, Switzerland. [Rosenblatt-Velin, Nathalie; Levrand, Sandra; Waeber, Bernard; Feihl, Francois; Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Div Pathophysiol, Lausanne, Switzerland. [Ruchat, Patrick] Univ Lausanne Hosp, Med Ctr, Dept Cardiovasc Surg, Lausanne, Switzerland. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Li, Jianhui] Zhejiang Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Coll Med, Hangzhou 310003, Zhejiang, Peoples R China. RP Rolli, J (reprint author), Univ Lausanne Hosp, Med Ctr, Dept Intens Care Med, Lausanne, Switzerland. EM lucas.liaudet@chuv.ch RI Pacher, Pal/B-6378-2008; Liaudet, Lucas/E-1322-2017 OI Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930 FU Swiss National Fund for Scientific Research [PP00B-68882/1, 320000-118174/1] FX This work was supported by grants from the Swiss National Fund for Scientific Research (PP00B-68882/1 and 320000-118174/1) to Lucas Liaudet. URL: www.snf.ch. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 19 Z9 19 U1 0 U2 2 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 SEP 13 PY 2010 VL 5 IS 9 AR e12687 DI 10.1371/journal.pone.0012687 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 648ZZ UT WOS:000281735700012 PM 20856884 ER PT J AU Yu, YL Zeng, PY Xiong, JB Liu, ZY Berger, SL Merlino, G AF Yu, Yanlin Zeng, Pingyao Xiong, Jingbo Liu, Ziyang Berger, Shelley L. Merlino, Glenn TI Epigenetic Drugs Can Stimulate Metastasis through Enhanced Expression of the Pro-Metastatic Ezrin Gene SO PLOS ONE LA English DT Article ID TUMOR-SUPPRESSOR GENES; ERM PROTEINS; PROSTATE-CANCER; DNA METHYLATION; CARCINOMA CELLS; MELANOMA-CELLS; LINKER EZRIN; THERAPY; MIGRATION; MECHANISM AB Ezrin has been reported to be upregulated in many tumors and to participate in metastatic progression. No study has addressed epigenetic modification in the regulation of Ezrin gene expression, the importance of which is unknown. Here, we report that highly metastatic rhabdomyosarcoma (RMS) cells with high levels of Ezrin have elevated acetyl-H3-K9 and tri-methyl-H3-K4 as well as reduced DNA methylation at the Ezrin gene promoter. Conversely, poorly metastatic RMS cells with low levels of Ezrin have reduced acetyl-H3-K9 and elevated methylation. Thus epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, which in fact can be regulated by epigenetic mechanisms. Notably, treatment with histone deacetylase (HDAC) inhibitors or DNA demethylating agents could restore Ezrin expression and stimulate the metastatic potential of poorly metastatic RMS cells characterized by low Ezrin levels. However, the ability of epigenetic drugs to stimulate metastasis in RMS cells was inhibited by expression of an Ezrin-specific shRNA. Our data demonstrate the potential risk associated with clinical application of broadly acting covalent epigenetic modifiers, and highlight the value of combination therapies that include agents specifically targeting potent pro-metastatic genes. C1 [Yu, Yanlin; Liu, Ziyang; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Zeng, Pingyao; Berger, Shelley L.] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Xiong, Jingbo] So Med Univ, Dept Cell Biol, Guangzhou, Guangdong, Peoples R China. RP Yu, YL (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM YuY@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 22 Z9 23 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 SEP 13 PY 2010 VL 5 IS 9 AR e12710 DI 10.1371/journal.pone.0012710 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 648ZZ UT WOS:000281735700022 PM 20856924 ER PT J AU Doria-Rose, VP Vinden, C Ransohoff, DF Prorok, PC AF Doria-Rose, V. Paul Vinden, Chris Ransohoff, David F. Prorok, Philip C. TI Flexible sigmoidoscopy to prevent colorectal cancer SO LANCET LA English DT Letter C1 [Doria-Rose, V. Paul; Prorok, Philip C.] NCI, Biometry Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Doria-Rose, V. Paul] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, NIH, Bethesda, MD 20892 USA. [Vinden, Chris] Univ Western Ontario, Dept Surg, London, ON N6A 3K7, Canada. [Ransohoff, David F.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Ransohoff, David F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Doria-Rose, VP (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM doriarop@mail.nih.gov NR 2 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD SEP 11 PY 2010 VL 376 IS 9744 BP 871 EP 871 DI 10.1016/S0140-6736(10)61407-9 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 653DW UT WOS:000282069100021 PM 20833296 ER PT J AU Tomescu, C Duh, FM Lanier, MA Kapalko, A Mounzer, KC Martin, MP Carrington, M Metzger, DS Montaner, LJ AF Tomescu, Costin Duh, Fuh-Mei Lanier, Michael A. Kapalko, Angela Mounzer, Karam C. Martin, Maureen P. Carrington, Mary Metzger, David S. Montaner, Luis J. TI Increased plasmacytoid dendritic cell maturation and natural killer cell activation in HIV-1 exposed, uninfected intravenous drug users SO AIDS LA English DT Article DE Exposed/Uninfected; HIV/AIDS; IDU; NK cells; plasmacytoid DC ID INFECTED FIBROBLASTS; ACCESSORY CELLS; INNATE IMMUNITY; NK CELLS; HLA-B; DISEASE; INDIVIDUALS; RECEPTORS; VIRUS; LYSIS AB Background: Increased natural killer (NK) activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected individuals. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1(high)) has also been observed in a subset of HIV-1 exposed, uninfected individuals. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intravenous drug users (EU-IDU) remains to be elucidated. Objective: We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU individuals and 15 control, uninfected donors from Philadelphia. Design: We assessed the activation status of NK cells and dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU individuals. Results: As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU individuals compared with control uninfected donors (P = 0.0056, n = 13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*801 ligands was not enriched in our cohort of EU-IDU individuals. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared with control uninfected donors (P = 0.0011, n = 12). When stimulated in vitro, both PDCs and NK cells from EU-IDU individuals maintained strong effector cell function and did not exhibit signs of exhaustion. Conclusion: Increased maturation of PDCs is associated with heightened NK activation in EU-IDU individuals suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU. (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Tomescu, Costin; Montaner, Luis J.] Wistar Inst Anat & Biol, HIV Immunopathogenesis Lab, Philadelphia, PA 19104 USA. [Duh, Fuh-Mei; Martin, Maureen P.; Carrington, Mary] NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Duh, Fuh-Mei; Martin, Maureen P.; Carrington, Mary] MGH MIT & Harvard, Ragon Inst, Boston, MA USA. [Lanier, Michael A.; Metzger, David S.] Univ Penn, Dept Psychiat, HIV Prevent Div, Philadelphia, PA 19104 USA. [Kapalko, Angela; Mounzer, Karam C.] Jonathan Lax Treatment Ctr, Philadelphia FIGHT, Philadelphia, PA USA. RP Montaner, LJ (reprint author), Wistar Inst Anat & Biol, HIV Immunopathogenesis Lab, 3601 Spruce St,Room 480, Philadelphia, PA 19104 USA. EM Montaner@wistar.org FU National Institutes of Health (NIDA) [R01 DA028775, R01 AI073219, RO1 AI065279, P30 CA10815]; Philadelphia Foundation; Pennsylvania Commonwealth Universal Research Enhancement Program; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX We thank Jonathan Davis at the Jonathan Lax Treatment center at Philadelphia FIGHT for his contribution as phlebotomist specializing in drawing blood from IDU individuals. We thank Deborah Davis at The Wistar Institute for the recruitment of control donors and her contribution as phlebotomist for this study. We also thank David E. Ambrose, Daniel Hussey, and Jeffrey S. Faust at The Wistar Institute Flow Cytometry Core facility. This study was supported by grants from the National Institutes of Health (NIDA R01 DA028775, R01 AI073219, RO1 AI065279, Core grant P30 CA10815), the Philadelphia Foundation, and funds from the Pennsylvania Commonwealth Universal Research Enhancement Program.; This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. There are no conflicts of interest. NR 44 TC 16 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2010 VL 24 IS 14 BP 2151 EP 2160 DI 10.1097/QAD.0b013e32833dfc20 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 642VN UT WOS:000281249200002 PM 20647906 ER PT J AU Flores, R Goedert, JJ AF Flores, Roberto Goedert, James J. TI Reconstitution of immune responses against Kaposi sarcoma-associated herpesvirus SO AIDS LA English DT Editorial Material DE combination antiretroviral therapy; HIV/AIDS; Kaposi sarcoma associated herpes virus ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTED INDIVIDUALS; PERIPHERAL-BLOOD; HOMOSEXUAL-MEN; RISK-FACTORS; HUMAN-HERPESVIRUS-8; HIV; PROGRESSION; ANTIBODIES C1 [Flores, Roberto; Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Rockville, MD 20852 USA. [Flores, Roberto] NCI, Canc Prevent Fellowship Program, Rockville, MD 20852 USA. RP Goedert, JJ (reprint author), NCI, Infect & Immunoepidemiol Branch, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov FU Intramural NIH HHS [ZIA CP010176-08] NR 31 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2010 VL 24 IS 14 BP 2279 EP 2281 DI 10.1097/QAD.0b013e32833c7bb8 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 642VN UT WOS:000281249200017 PM 20616696 ER PT J AU Sugarman, J Grace, WC AF Sugarman, Jeremy Grace, William C. TI Ethics and the standards of prevention in HIV prevention trials SO AIDS LA English DT Letter C1 [Sugarman, Jeremy] Johns Hopkins Univ, Berman Inst Bioeth, Baltimore, MD 21205 USA. [Sugarman, Jeremy] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Grace, William C.] NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP Sugarman, J (reprint author), Johns Hopkins Univ, Berman Inst Bioeth, Hampton House 351,624 N Broadway, Baltimore, MD 21205 USA. EM jsugarm1@jhmi.edu FU NIAID NIH HHS [U01AI068619] NR 2 TC 3 Z9 3 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2010 VL 24 IS 14 BP 2298 EP 2299 DI 10.1097/QAD.0b013e32833d4364 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 642VN UT WOS:000281249200024 PM 20736687 ER PT J AU Awadalla, P Gauthier, J Myers, RA Casals, F Hamdan, FF Griffing, AR Cote, M Henrion, E Spiegelman, D Tarabeux, J Piton, A Yang, Y Boyko, A Bustamante, C Xiong, L Rapoport, JL Addington, AM DeLisi, JLE Krebs, MO Joober, R Millet, B Fombonne, E Mottron, L Zilversmit, M Keebler, J Daoud, H Marineau, C Roy-Gagnon, MH Dube, MP Eyre-Walker, A Drapeau, P Stone, EA Lafreniere, RG Rouleau, GA AF Awadalla, Philip Gauthier, Julie Myers, Rachel A. Casals, Ferran Hamdan, Fadi F. Griffing, Alexander R. Cote, Melanie Henrion, Edouard Spiegelman, Dan Tarabeux, Julien Piton, Amelie Yang, Yan Boyko, Adam Bustamante, Carlos Xiong, Lan Rapoport, Judith L. Addington, Aniene M. DeLisi, J. Lynn E. Krebs, Marie-Odile Joober, Ridha Millet, Bruno Fombonne, Eric Mottron, Laurent Zilversmit, Martine Keebler, Jon Daoud, Hussein Marineau, Claude Roy-Gagnon, Marie-Helene Dube, Marie-Pierre Eyre-Walker, Adam Drapeau, Pierre Stone, Eric A. Lafreniere, Ronald G. Rouleau, Guy A. TI Direct Measure of the De Novo Mutation Rate in Autism and Schizophrenia Cohorts SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SPECTRUM DISORDERS; PROTEIN FUNCTION; ASSOCIATION; DISEASES; DATABASE; HUMANS; NUCLEOTIDE; CHILDHOOD; FAMILY; SHANK3 AB The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (mu) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of -430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 x 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants. C1 [Awadalla, Philip; Myers, Rachel A.; Casals, Ferran; Zilversmit, Martine; Keebler, Jon; Rouleau, Guy A.] Univ Montreal, Dept Pediat, Montreal, PQ H3T 1C5, Canada. [Awadalla, Philip; Hamdan, Fadi F.; Roy-Gagnon, Marie-Helene; Rouleau, Guy A.] Univ Montreal, Ctr Hosp Univ St Justine Res Ctr, Montreal, PQ H3C 1G7, Canada. [Awadalla, Philip; Gauthier, Julie; Hamdan, Fadi F.; Cote, Melanie; Henrion, Edouard; Spiegelman, Dan; Tarabeux, Julien; Piton, Amelie; Yang, Yan; Xiong, Lan; Daoud, Hussein; Marineau, Claude; Lafreniere, Ronald G.; Rouleau, Guy A.] Univ Montreal, Ctr Excellence Neur, Ctr Hosp Univ Montreal, Montreal, PQ H2L 2W5, Canada. [Awadalla, Philip; Gauthier, Julie; Hamdan, Fadi F.; Cote, Melanie; Henrion, Edouard; Spiegelman, Dan; Tarabeux, Julien; Piton, Amelie; Yang, Yan; Xiong, Lan; Daoud, Hussein; Marineau, Claude; Lafreniere, Ronald G.; Rouleau, Guy A.] Univ Montreal, Dept Med, Montreal, PQ H2L 2W5, Canada. [Mottron, Laurent] Univ Montreal, Dept Psychiat, Hop Riviere Des Prairies, Montreal, PQ HIE 1A4, Canada. [Dube, Marie-Pierre] Univ Montreal, Dept Pharmacol, Ctr Rech Inst Cardiol Montreal, Montreal, PQ H1T 1C8, Canada. [Drapeau, Pierre] Univ Montreal, Grp Rech Syst Nerveux Cent, Dept Pathol & Cell Biol, Montreal, PQ H3C 3J7, Canada. [Myers, Rachel A.; Griffing, Alexander R.; Keebler, Jon; Stone, Eric A.] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27606 USA. [Boyko, Adam; Bustamante, Carlos] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Rapoport, Judith L.; Addington, Aniene M.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [DeLisi, J. Lynn E.] Nathan S Kline Inst Psychiat Res, Ctr Adv Brain Imaging, Orangeburg, NY 10962 USA. [Krebs, Marie-Odile; Millet, Bruno] Univ Paris 05, INSERM, Lab Physiopathol Malad Psychiat, Ctr Psychiat & Neurosci,St Anne Hosp,U894, F-75014 Paris, France. [Joober, Ridha; Fombonne, Eric] McGill Univ, Dept Psychiat, Montreal, PQ H3A 1A1, Canada. [Joober, Ridha] Douglas Hosp, Montreal, PQ H3A 1A1, Canada. [Fombonne, Eric] Montreal Childrens Hosp, Montreal, PQ H3Z 1P2, Canada. [Eyre-Walker, Adam] Univ Sussex, Sch Life Sci, Ctr Study Evolut, Brighton BN1 9QG, E Sussex, England. RP Awadalla, P (reprint author), Univ Montreal, Dept Pediat, Montreal, PQ H3T 1C5, Canada. EM philip.awadalla@umontreal.ca; guy.rouleau@umontreal.ca RI Eyre-Walker, Adam/G-6216-2011; Dube, Marie-Pierre/B-9364-2008; Stone, Eric/Q-7840-2016; OI Dube, Marie-Pierre/0000-0001-8442-4393; Piton, Amelie/0000-0003-0408-7468; Eyre-Walker, Adam/0000-0001-5527-8729; Fombonne, Eric/0000-0002-8605-3538 FU Genome Canada; Genome Quebec; Universite de Montreal; Canadian Foundation for Innovation; Ministre de Exploration, Innovation et Economique of Quebec; Fonds de Recherche Sante Quebec FX We would like to thank all the families and individuals who participated in this study. We are thankful for the efforts of the members of the Genome Quebec Innovation Centre Sequencing and Bioinformatic groups. This work was supported by Genome Canada and Genome Quebec and received cofunding from Universite de Montreal for the Synapse-to-Disease (S2D) Project, funding from the Canadian Foundation for Innovation to both G.A.R and RA., and cofunding from the Ministre de Exploration, Innovation et Economique of Quebec. G.A.R. holds the Canada Research Chair in Genetics of the Nervous System; P.A. holds career awards from the Fonds de Recherche Sante Quebec and Genome Quebec. NR 37 TC 125 Z9 127 U1 6 U2 23 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 SEP 10 PY 2010 VL 87 IS 3 BP 316 EP 324 DI 10.1016/j.ajhg.2010.07.019 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 651JH UT WOS:000281923500001 PM 20797689 ER PT J AU Li, L Nakaya, N Chavali, VRM Ma, ZW Jiao, XD Sieving, PA Riazuddin, S Tomarev, SI Ayyagari, R Riazuddin, SA Hejtmancik, JF AF Li, Lin Nakaya, Naoki Chavali, Venkata R. M. Ma, Zhiwei Jiao, Xiaodong Sieving, Paul A. Riazuddin, Sheikh Tomarev, Stanislav I. Ayyagari, Radha Riazuddin, S. Amer Hejtmancik, J. Fielding TI A Mutation in ZNF513, a Putative Regulator of Photoreceptor Development, Causes Autosomal-Recessive Retinitis Pigmentosa SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MACULAR DEGENERATION; MOLECULAR-GENETICS; CRX; ROD; TRANSCRIPTION; PROTEIN; GENES; REGENERATION; DYSTROPHIES; PREVALENCE AB Retinitis pigmentosa (RP) is a phenotypically and genetically heterogeneous group of inherited retinal degenerations characterized clinically by night blindness, progressive constriction of the visual fields, and loss of vision, and pathologically by progressive loss of rod and then cone photoreceptors. Autosomal-recessive RP (arRP) in a consanguineous Pakistani family previously linked to chromosome 2p22.3-p24.1 is shown to result from a homozygous missense mutation (c.1015T>C [p.C33912]) in ZNF513, encoding a presumptive transcription factor. znf513 is expressed in the retina, especially in the outer nuclear layer, inner nuclear layer, and photoreceptors. Knockdown of znf513 in zebrafish reduces eye size, retinal thickness, and expression of rod and cone opsins and causes specific loss of photoreceptors. These effects are rescued by coinjection with wild-type (WT) but not p.C339R-znf5/3 mRNA. Both normal and p.C339R mutant ZNF513 proteins expressed in COS-7 cells localize to the nucleus. ChIP analysis shows that only the wild-type but not the mutant ZNF513 binds to the Pax6, Sp4, Arr3, Irbp, and photoreceptor opsin promoters. These results suggest that the ZNF513 p.C339R mutation is responsible for RP in this family and that ZNF513 plays a key role in the regulation of photoreceptor-specific genes in retinal development and photoreceptor maintenance. C1 [Li, Lin; Ma, Zhiwei; Jiao, Xiaodong; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Nakaya, Naoki; Tomarev, Stanislav I.] NEI, Sect Mol Mech Glaucoma, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. [Li, Lin] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. [Chavali, Venkata R. M.; Ayyagari, Radha] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92037 USA. [Riazuddin, Sheikh; Riazuddin, S. Amer] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Riazuddin, Sheikh] Allama lqbal Med Coll, Lahore 54550, Pakistan. Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov FU National Eye Institute [EY13198]; Foundation Fighting Blindness; Research to Prevent Blindness, Inc. FX We thank Dr. David Hyde and Dr. James Fadool for the generous gifts of zebrafish cone opsin and 1D1 monoclonal antibodies, respectively. Supported by National Eye Institute Grant EY13198 (R.A.); Foundation Fighting Blindness (R.A.); and Research to Prevent Blindness, Inc. (R.A.). NR 33 TC 20 Z9 22 U1 0 U2 3 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 SEP 10 PY 2010 VL 87 IS 3 BP 400 EP 409 DI 10.1016/j.ajhg.2010.08.003 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 651JH UT WOS:000281923500010 PM 20797688 ER PT J AU Shen, L Chepelev, I Liu, J Wang, W AF Shen, Li Chepelev, Iouri Liu, Jie Wang, Wei TI Prediction of quantitative phenotypes based on genetic networks: a case study in yeast sporulation SO BMC SYSTEMS BIOLOGY LA English DT Article ID TRANSCRIPTIONAL REGULATION; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; MEIOSIS; INFERENCE; CELL AB Background: An exciting application of genetic network is to predict phenotypic consequences for environmental cues or genetic perturbations. However, de novo prediction for quantitative phenotypes based on network topology is always a challenging task. Results: Using yeast sporulation as a model system, we have assembled a genetic network from literature and exploited Boolean network to predict sporulation efficiency change upon deleting individual genes. We observe that predictions based on the curated network correlate well with the experimentally measured values. In addition, computational analysis reveals the robustness and hysteresis of the yeast sporulation network and uncovers several patterns of sporulation efficiency change caused by double gene deletion. These discoveries may guide future investigation of underlying mechanisms. We have also shown that a hybridized genetic network reconstructed from both temporal microarray data and literature is able to achieve a satisfactory prediction accuracy of the same quantitative phenotypes. Conclusions: This case study illustrates the value of predicting quantitative phenotypes based on genetic network and provides a generic approach. C1 [Shen, Li; Chepelev, Iouri; Liu, Jie; Wang, Wei] Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92093 USA. [Shen, Li] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Chepelev, Iouri] NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Wang, W (reprint author), Univ Calif San Diego, Dept Chem & Biochem, 9500 Gilman Dr, San Diego, CA 92093 USA. EM wei-wang@ucsd.edu FU NIH [R01GM072856] FX This study was partially supported by NIH (R01GM072856 to W.W.). NR 24 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 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD SEP 10 PY 2010 VL 4 AR 128 DI 10.1186/1752-0509-4-128 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 655PD UT WOS:000282261000001 PM 20828418 ER PT J AU Zwolak, A Uruno, T Piszczek, G Hammer, JA Tjandra, N AF Zwolak, Adam Uruno, Takehito Piszczek, Grzegorz Hammer, John A., III Tjandra, Nico TI Molecular Basis for Barbed End Uncapping by CARMIL Homology Domain 3 of Mouse CARMIL-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIN-CAPPING PROTEIN; NMR CHEMICAL-SHIFTS; STRUCTURAL BASIS; MULTIDIMENSIONAL NMR; FILAMENT NUCLEATION; CELL MORPHOLOGY; ARP2/3 COMPLEX; BINDING SITE; MYOSIN-I; IDENTIFICATION AB Capping protein (CP) is a ubiquitously expressed, 62-kDa heterodimer that binds the barbed end of the actin filament with similar to 0.1 nM affinity to prevent further monomer addition. CARMIL is a multidomain protein, present from protozoa to mammals, that binds CP and is important for normal actin dynamics in vivo. The CARMIL CP binding site resides in its CAH3 domain (CARMIL homology domain 3) located at or near the protein's C terminus. CAH3 binds CP with similar to 1 nM affinity, resulting in a complex with weak capping activity (30-200 nM). Solution assays and single-molecule imaging show that CAH3 binds CP already present on the barbed end, causing a 300-fold increase in the dissociation rate of CP from the end (i.e. uncapping). Here we used nuclear magnetic resonance (NMR) to define the molecular interaction between the minimal CAH3 domain (CAH3a/b) of mouse CARMIL-1 and CP. Specifically, we show that the highly basic CAH3a subdomain is required for the high affinity interaction of CAH3 with a complementary "acidic groove" on CP opposite its actin-binding surface. This CAH3a-CP interaction orients the CAH3b subdomain, which we show is also required for potent anti-CP activity, directly adjacent to the basic patch of CP, shown previously to be required for CP association to and high affinity interaction with the barbed end. The importance of specific residue interactions between CP and CAH3a/b was confirmed by site-directed mutagenesis of both proteins. Together, these results offer a mechanistic explanation for the barbed end uncapping activity of CARMIL, and they identify the basic patch on CP as a crucial regulatory site. C1 [Uruno, Takehito; Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biophys Core Facil, NIH, Bethesda, MD 20892 USA. [Zwolak, Adam] NYU, Sch Med, Sackler Inst Biomed Sci, New York, NY 10016 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, 50 S Dr,Bldg 50,Rm 2306, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov; tjandran@nhlbi.nih.gov OI Hammer, John/0000-0002-2496-5179 FU NHLBI, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, NHLBI (to J. A. H. and N. T.). NR 56 TC 12 Z9 12 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 SEP 10 PY 2010 VL 285 IS 37 BP 29014 EP 29026 DI 10.1074/jbc.M110.134221 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 647CR UT WOS:000281594000066 PM 20630878 ER PT J AU Hays, JL Kim, G Giuroiu, I Kohn, EC AF Hays, John L. Kim, Geoffrey Giuroiu, Iulia Kohn, Elise C. TI Proteomics and ovarian cancer: Integrating proteomics information into clinical care SO JOURNAL OF PROTEOMICS LA English DT Review DE Ovarian cancer; Proteomics; Clinical trials ID DISTAL FALLOPIAN-TUBE; CARCINOMA CELL-LINE; PHASE-II CONSORTIA; RECURRENT OVARIAN; PRIMARY PERITONEAL; MASS-SPECTROMETRY; BREAST-CANCER; LUNG-CANCER; PELVIC MASS; BEVACIZUMAB AB The power of proteomics allows unparalleled opportunity to query the molecular mechanisms of a malignant cell and the tumor microenvironment in patients with ovarian cancer and other solid tumors. This information has given us insight into the perturbations of signaling pathways within tumor cells and has aided the discovery of new drug targets for the tumor and possible prognostic indicators of outcome and disease response to therapy. Proteomics analysis of serum and ascites has also given us sources with which to discover possible early markers for the presence of new disease and for the progression of established cancer throughout the course of treatment. Unfortunately, this wealth of information has yielded little to date in changing the clinical care of these patients from a diagnostic, prognostic, or treatment perspective. The rational examination and translation of proteomics data in the context of past clinical trials and the design of future clinical trials must occur before we can march forward into the future of personalized medicine. Published by Elsevier B.V. C1 [Hays, John L.; Kim, Geoffrey; Giuroiu, Iulia; Kohn, Elise C.] Natl Canc Inst, Mol Signaling Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD USA. RP Hays, JL (reprint author), 10 Ctr Dr MSC 1906,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM haysjl@mail.nih.gov RI Hays, John/H-3968-2012 FU NIH, National Cancer Institute, Center for Cancer Research; Howard Hughes Medical Institute at the NIH FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. I. G. was supported by the Research Scholars Program of the Howard Hughes Medical Institute at the NIH. NR 73 TC 10 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD SEP 10 PY 2010 VL 73 IS 10 SI SI BP 1864 EP 1872 DI 10.1016/j.jprot.2010.05.013 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 659DR UT WOS:000282547700007 PM 20561909 ER PT J AU Rodrigues, J Brayner, FA Alves, LC Dixit, R Barillas-Mury, C AF Rodrigues, Janneth Brayner, Fabio Andre Alves, Luiz Carlos Dixit, Rajnikant Barillas-Mury, Carolina TI Hemocyte Differentiation Mediates Innate Immune Memory in Anopheles gambiae Mosquitoes SO SCIENCE LA English DT Article ID RED FLOUR BEETLE; TRIBOLIUM-CASTANEUM; INSECT; DROSOPHILA; PARASITE; INVASION AB Mosquito midgut invasion by ookinetes of the malaria parasite Plasmodium disrupts the barriers that normally prevent the gut microbiota from coming in direct contact with epithelial cells. This triggers a long-lived response characterized by increased abundance of granulocytes, a subpopulation of hemocytes that circulates in the insect's hemocoel, and enhanced immunity to bacteria that indirectly reduces survival of Plasmodium parasites upon reinfection. In mosquitoes, differentiation of hemocytes was necessary and sufficient to confer innate immune memory. C1 [Rodrigues, Janneth; Brayner, Fabio Andre; Alves, Luiz Carlos; Dixit, Rajnikant; 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, Rockville, MD 20892 USA. EM cbarillas@niaid.nih.gov RI DIXIT, RAJNIKANT/D-2566-2009 OI DIXIT, RAJNIKANT/0000-0002-3536-8329 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; Conselho Nacionale de Desenvolvimento Cientifico e Tecnologico; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior Brazilian government agencies FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. We thank A. Laughinghouse and K. Lee for insectary support; C. Ortega for experimental support; L. Koo for confocal assistance; J. Ribeiro and J. Valenzuela for their comments and insight; and B. R. Marshall for editorial assistance. F. A. B. and L. C. A. were funded by the Conselho Nacionale de Desenvolvimento Cientifico e Tecnologico and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior Brazilian government agencies, respectively. NR 18 TC 165 Z9 167 U1 8 U2 49 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 SEP 10 PY 2010 VL 329 IS 5997 BP 1353 EP 1355 DI 10.1126/science.1190689 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647YR UT WOS:000281657300041 PM 20829487 ER PT J AU De Ravin, SS Zarember, KA Long-Priel, D Chan, KC Fox, SD Gallin, JI Kuhns, DB Malech, HL AF De Ravin, Suk See Zarember, Kol A. Long-Priel, Debra Chan, King C. Fox, Stephen D. Gallin, John I. Kuhns, Douglas B. Malech, Harry L. TI Tryptophan/kynurenine metabolism in human leukocytes is independent of superoxide and is fully maintained in chronic granulomatous disease SO BLOOD LA English DT Article ID INDOLEAMINE 2,3-DIOXYGENASE; INTERFERON-GAMMA; TRYPTOPHAN CATABOLISM; DEGRADE TRYPTOPHAN; INFLAMMATION; MODEL; INFECTION; P47(PHOX); INDUCTION; ANION AB In chronic granulomatous disease (CGD), defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity causes reduced superoxide anion (O(2)(sic)) radical production leading to frequent infections as well as granulomas and impaired wound healing indicative of excessive inflammation. Based on recent mouse studies, the lack of O(2)(radical anion)-dependent interferon gamma (IFN gamma)-induced synthesis of kynurenine (kyn), an anti-inflammatory tryptophan metabolite produced by indolamine 2,3 deoxygenase (IDO), was proposed as a cause of hyperinflammation in CGD and this pathway has been considered for clinical intervention. Here, we show that IFN gamma induces normal levels of kynurenine in cultures of O(2)(radical anion)-deficient monocytes, dendritic cells, and polymorphonuclear leukocytes from gp91(PHOX)- or p47(PHOX)-deficient human CGD donors. Kynurenine accumulation was dose-and time-dependent as was that of a downstream metabolite, anthranilic acid. Furthermore, urinary and serum levels of kynurenine and a variety of other tryptophan metabolites were elevated rather than suppressed in CGD donors. Although we did not specifically evaluate kyn metabolism in local tissue or inflamed sites in humans, our data demonstrates that O(2)(radical anion) anion is dispensable for the rate-limiting step in tryptophan degradation, and CGD patients do not appear to have either hematopoietic cell or systemic deficits in the production of the anti-inflammatory kynurenine molecule. (Blood. 2010; 116(10):1755-1760) C1 [De Ravin, Suk See; Zarember, Kol A.; Gallin, John I.; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Long-Priel, Debra; Kuhns, Douglas B.] NCI, Neutrophil Monitoring Lab, Clin Serv Program, Bethesda, MD 20892 USA. [Chan, King C.; Fox, Stephen D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick, Bethesda, MD 20892 USA. RP De Ravin, SS (reprint author), NIAID, Host Def Lab, NIH, 10CRC-5W-3816,10 Ctr Dr, Bethesda, MD 20892 USA. EM sderavin@niaid.nih.gov OI Malech, Harry/0000-0001-5874-5775 FU National Institute of Allergy and Infectious Diseases Division of Intramural Research; Clinical Center of the National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research and the Clinical Center of the National Institutes of Health (NIH). This project has been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. NR 24 TC 23 Z9 23 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 9 PY 2010 VL 116 IS 10 BP 1755 EP 1760 DI 10.1182/blood-2009-07-233734 PG 6 WC Hematology SC Hematology GA 649GY UT WOS:000281757400020 PM 20511543 ER PT J AU Lee, DJ Wynveen, A Kornyshev, AA Leikin, S AF Lee, D. J. Wynveen, A. Kornyshev, A. A. Leikin, S. TI Undulations Enhance the Effect of Helical Structure on DNA Interactions SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID EQUATION-OF-STATE; LIQUID-CRYSTALS; ELECTROSTATIC INTERACTION; NUCLEIC-ACIDS; COMPUTER-SIMULATION; PHASE-TRANSITIONS; HYDRATION FORCES; MODELING DNA; MOLECULES; LONG AB During the past decade, theory and experiments have provided clear evidence that specific helical patterns of charged groups and adsorbed (condensed) counterions on the DNA surface are responsible for many important features of DNA-DNA interactions in hydrated aggregates. The effects of helical structure on DNA-DNA interactions result from a preferential juxtaposition of the negatively charged sugar phosphate backbone with counterions bound within the grooves of the opposing molecule. Analysis of X-ray diffraction experiments confirmed the mutual alignment of parallel molecules in hydrated aggregates required for such juxtaposition. However, it remained unclear how this alignment and molecular interactions might be affected by intrinsic and thermal fluctuations, which cause structural deviations away from an ideal double helical conformation. We previously argued that the torsional flexibility of DNA allows the molecules to adapt their structure to accommodate a more electrostatically favorable alignment between molecules, partially compensating disruptive fluctuation effects. In the present work, we develop a more comprehensive theory, incorporating also stretching and bending fluctuations of DNA. We found the effects of stretching to be qualitatively and quantitatively similar to those of twisting fluctuations. However, this theory predicts more dramatic and surprising effects of bending. Undulations of DNA in hydrated aggregates strongly amplify rather than weaken the helical structure effects. They enhance the structural adaptation, leading to better alignment of neighboring molecules and pushing the geometry of the DNA backbone closer to that of an ideal helix. These predictions are supported by a quantitative comparison of the calculated and measured osmotic pressures in DNA. C1 [Lee, D. J.; Kornyshev, A. A.] Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England. [Lee, D. J.] Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany. [Wynveen, A.] Univ Dusseldorf, Inst Theoret Phys Soft Matter 2, D-40225 Dusseldorf, Germany. [Wynveen, A.] Univ Minnesota, Sch Phys & Astron, Minneapolis, MN 55455 USA. [Leikin, S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, NIH, DHHS, Bethesda, MD 20892 USA. RP Lee, DJ (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England. EM domolee@hotmail.com; a.wynveen@googlemail.com; a.kornyshev@ic.ac.uk; leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU Max-Planck Society; Alexander von Humboldt Foundation; Leverhulme Trust [F/0758/AE]; EPSRC [EP/H010106/1]; NICHD, NIH FX We acknowledge useful, stimulating discussions with Adrian Parsegian, Rudy Podgornik, Don Rau, and Loren Willams. This was a long-term, five year project, for which we gratefully acknowledge financial support from the Max-Planck Society (D.J.L.); the Alexander von Humboldt Foundation (A.W.); the Leverhulme Trust, Grant F/0758/AE and EPSRC, Grant EP/H010106/1 (A.A.K.); and the Intramural Research Program of NICHD, NIH (S.L.). NR 72 TC 16 Z9 16 U1 0 U2 8 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 SEP 9 PY 2010 VL 114 IS 35 BP 11668 EP 11680 DI 10.1021/jp104552u PG 13 WC Chemistry, Physical SC Chemistry GA 686YQ UT WOS:000284738600039 PM 20718454 ER PT J AU Giedd, JN Rapoport, JL AF Giedd, Jay N. Rapoport, Judith L. TI Structural MRI of Pediatric Brain Development: What Have We Learned and Where Are We Going? SO NEURON LA English DT Review ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CHILDHOOD-ONSET SCHIZOPHRENIA; QUANTITATIVE MORPHOLOGY; CORTICAL DEVELOPMENT; CHILDREN; ADOLESCENTS; CORTEX; ABNORMALITIES; CEREBELLUM AB Magnetic resonance imaging (MRI) allows unprecedented access to the anatomy and physiology of the developing brain without the use of ionizing radiation. Over the past two decades, thousands of brain MRI scans from healthy youth and those with neuropsychiatric illness have been acquired and analyzed with respect to diagnosis, sex, genetics, and/or psychological variables such as IQ. Initial reports comparing size differences of various brain components averaged across large age spans have given rise to longitudinal studies examining trajectories of development over time and evaluations of neural circuitry as opposed to structures in isolation. Although MRI is still not of routine diagnostic utility for evaluation of pediatric neuropsychiatric disorders, patterns of typical versus atypical development have emerged that may elucidate pathologic mechanisms and suggest targets for intervention. In this review we summarize general contributions of structural MRI to our understanding of neurodevelopment in health and illness. C1 [Giedd, Jay N.; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Giedd, JN (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. EM jg@nih.gov RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS [Z99 MH999999, ZIA MH002581-21] NR 58 TC 285 Z9 290 U1 9 U2 47 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 9 PY 2010 VL 67 IS 5 BP 728 EP 734 DI 10.1016/j.neuron.2010.08.040 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 651PF UT WOS:000281938900008 PM 20826305 ER PT J AU Bonham, VL Dover, GJ Brody, LC AF Bonham, Vence L. Dover, George J. Brody, Lawrence C. TI Screening Student Athletes for Sickle Cell Trait - A Social and Clinical Experiment SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Bonham, Vence L.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Dover, George J.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. RP Bonham, VL (reprint author), NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. NR 5 TC 41 Z9 42 U1 0 U2 6 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 SEP 9 PY 2010 VL 363 IS 11 BP 997 EP 999 DI 10.1056/NEJMp1007639 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 647HS UT WOS:000281609700001 PM 20825310 ER PT J AU Baratz, KH Tosakulwong, N Ryu, E Brown, WL Branham, K Chen, W Tran, KD Schmid-Kubista, KE Heckenlively, JR Swaroop, A Abecasis, G Bailey, KR Edwards, AO AF Baratz, Keith H. Tosakulwong, Nirubol Ryu, Euijung Brown, William L. Branham, Kari Chen, Wei Tran, Khoa D. Schmid-Kubista, Katharina E. Heckenlively, John R. Swaroop, Anand Abecasis, Goncalo Bailey, Kent R. Edwards, Albert O. TI E2-2 Protein and Fuchs's Corneal Dystrophy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SNOWFLAKE VITREORETINAL DEGENERATION; TYROSINE-PHOSPHATASE-GAMMA; ENDOTHELIAL DYSTROPHY; MACULAR DEGENERATION; TRANSCRIPTION FACTOR; MISSENSE MUTATIONS; IN-SITU; LINKAGE; FAMILY; EXPRESSION AB BACKGROUND Fuchs's corneal dystrophy (FCD) is a leading cause of corneal transplantation and affects 5% of persons in the United States who are over the age of 40 years. Clinically visible deposits called guttae develop under the corneal endothelium in patients with FCD. A loss of endothelial cells and deposition of an abnormal extracellular matrix are observed microscopically. In advanced disease, the cornea swells and becomes cloudy because the remaining endothelial cells are not sufficient to keep the cornea dehydrated and clear. Although rare genetic variation that contributes to both early-onset and typical late-onset forms of FCD has been identified, to our knowledge, no common variants have been reported. METHODS We performed a genomewide association study and replicated the most significant observations in a second, independent group of subjects. RESULTS Alleles in the transcription factor 4 gene (TCF4), encoding a member of the E-protein family (E2-2), were associated with typical FCD (P = 2.3x10(-26)). The association increased the odds of having FCD by a factor of 30 for persons with two copies of the disease variants (homozygotes) and discriminated between case subjects and control subjects with about 76% accuracy. At least two regions of the TCF4 locus were associated independently with FCD. Alleles in the gene encoding protein tyrosine phosphatase receptor type G (PTPRG) were associated with FCD (P = 4.0x10(-7)), but the association did not reach genomewide significance. CONCLUSIONS Genetic variation in TCF4 contributes to the development of FCD. (Funded by the National Eye Institute and others.) C1 [Tran, Khoa D.; Edwards, Albert O.] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. [Baratz, Keith H.; Brown, William L.; Schmid-Kubista, Katharina E.] Mayo Clin, Dept Ophthalmol, Rochester, MN USA. [Tosakulwong, Nirubol; Ryu, Euijung; Bailey, Kent R.] Mayo Clin, Dept Biomed Stat & Informat, Rochester, MN USA. [Branham, Kari; Heckenlively, John R.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Chen, Wei; Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Swaroop, Anand] NEI, Bethesda, MD 20892 USA. RP Edwards, AO (reprint author), Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. EM edwardsa@uoregon.edu RI Abecasis, Goncalo/B-7840-2010; OI Abecasis, Goncalo/0000-0003-1509-1825; Swaroop, Anand/0000-0002-1975-1141 FU National Institutes of Health [EY014467, EY016862, HHSN268200782096C]; Foundation Fighting Blindness; American Health Assistance Foundation; Research to Prevent Blindness; Max Kade Foundation FX Supported by grants from the National Institutes of Health (EY014467, EY016862, and HHSN268200782096C), the Foundation Fighting Blindness, the American Health Assistance Foundation, Research to Prevent Blindness, and the Max Kade Foundation. NR 42 TC 92 Z9 94 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 9 PY 2010 VL 363 IS 11 BP 1016 EP 1024 DI 10.1056/NEJMoa1007064 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 647HS UT WOS:000281609700005 PM 20825314 ER PT J AU Baker, SG AF Baker, Stuart G. TI Simple and flexible classification of gene expression microarrays via Swirls and Ripples SO BMC BIOINFORMATICS LA English DT Article ID RELATIVE UTILITY CURVES; DISCRIMINANT-ANALYSIS; RISK PREDICTION; CANCER; TUMOR; CARCINOGENESIS; PERSPECTIVE; DISCOVERY; SELECTION; CELLS AB Background: A simple classification rule with few genes and parameters is desirable when applying a classification rule to new data. One popular simple classification rule, diagonal discriminant analysis, yields linear or curved classification boundaries, called Ripples, that are optimal when gene expression levels are normally distributed with the appropriate variance, but may yield poor classification in other situations. Results: A simple modification of diagonal discriminant analysis yields smooth highly nonlinear classification boundaries, called Swirls, that sometimes outperforms Ripples. In particular, if the data are normally distributed with different variances in each class, Swirls substantially outperforms Ripples when using a pooled variance to reduce the number of parameters. The proposed classification rule for two classes selects either Swirls or Ripples after parsimoniously selecting the number of genes and distance measures. Applications to five cancer microarray data sets identified predictive genes related to the tissue organization theory of carcinogenesis. Conclusion: The parsimonious selection of classifiers coupled with the selection of either Swirls or Ripples provides a good basis for formulating a simple, yet flexible, classification rule. Open source software is available for download. 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 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov FU National Cancer Institute FX This work was supported by the National Cancer Institute. The author thanks the investigators who collected the microarray data and made it publicly available. NR 30 TC 15 Z9 15 U1 0 U2 0 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 SEP 8 PY 2010 VL 11 AR 452 DI 10.1186/1471-2105-11-452 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 660PP UT WOS:000282655900001 PM 20825641 ER PT J AU Gray, MM Sutter, NB Ostrander, EA Wayne, RK AF Gray, Melissa M. Sutter, Nathan B. Ostrander, Elaine A. Wayne, Robert K. TI The IGF1 small dog haplotype is derived from Middle Eastern grey wolves (vol 8, 2010) SO BMC BIOLOGY LA English DT Correction C1 [Gray, Melissa M.; Wayne, Robert K.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90024 USA. [Gray, Melissa M.] Univ Wisconsin, Genet Lab, Madison, WI 53706 USA. [Sutter, Nathan B.] Cornell Univ, Coll Vet Med, Dept Clin Sci, Ithaca, NY 14853 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gray, MM (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90024 USA. EM mgray9@ucla.edu RI Gray, Melissa/B-5025-2008 OI Gray, Melissa/0000-0002-1756-5468 NR 2 TC 2 Z9 2 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD SEP 8 PY 2010 VL 8 AR 118 DI 10.1186/1741-7007-8-118 PG 2 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 672IU UT WOS:000283577300001 ER PT J AU Kim, HS Xiao, CY Wang, RH Lahusen, T Xu, XL Vassilopoulos, A Vazquez-Ortiz, G Jeong, WI Park, O Ki, SH Gao, B Deng, CX AF Kim, Hyun-Seok Xiao, Cuiying Wang, Rui-Hong Lahusen, Tyler Xu, Xiaoling Vassilopoulos, Athanassios Vazquez-Ortiz, Guelaguetza Jeong, Won-Il Park, Ogyi Ki, Sung Hwan Gao, Bin Deng, Chu-Xia TI Hepatic-Specific Disruption of SIRT6 in Mice Results in Fatty Liver Formation Due to Enhanced Glycolysis and Triglyceride Synthesis SO CELL METABOLISM LA English DT Article ID DEPENDENT GENE-EXPRESSION; IN-VIVO; NUTRIENT AVAILABILITY; TRANSCRIPTION FACTORS; GLUCOSE-HOMEOSTASIS; TUMOR-SUPPRESSOR; DEACETYLASE; MITOCHONDRIA; METABOLISM; STEATOSIS AB Under various conditions, mammals have the ability to maintain serum glucose concentration within a narrow range. SIRT1 plays an important role in regulating gluconeogenesis and fat metabolism; however, the underlying mechanisms remain elusive. Here, we show that SIRT1 forms a complex with FOXO3a and NRF1 on the SIRT6 promoter and positively regulates expression of SIRT6, which, in turn, negatively regulates glycolysis, triglyceride synthesis, and fat metabolism by deacetylating histone H3 lysine 9 in the promoter of many genes involved in these processes. Liver-specific deletion of SIRT6 in mice causes profound alterations in gene expression, leading to increased glycolysis, triglyceride synthesis, reduced 13 oxidation, and fatty liver formation. Human fatty liver samples exhibited significantly lower levels of SIRT6 than did normal controls. Thus, SIRT6 plays a critical role in fat metabolism and may serve as a therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction in humans. C1 [Kim, Hyun-Seok; Xiao, Cuiying; Wang, Rui-Hong; Lahusen, Tyler; Xu, Xiaoling; Vassilopoulos, Athanassios; Vazquez-Ortiz, Guelaguetza; Deng, Chu-Xia] NIAAA, Genet Dev & Dis Branch, NIDDK, NIH, Bethesda, MD 20892 USA. [Jeong, Won-Il; Park, Ogyi; Ki, Sung Hwan; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIAAA, Genet Dev & Dis Branch, NIDDK, NIH, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI JEONG, WON IL/B-6615-2011; deng, chuxia/N-6713-2016 FU National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health FX We thank Drs. E. Mueller, J. Wess, S. Tydlacka, and C. Chisholm for critical reading of the manuscript, and Drs. O. Gavrilova, W. Jou, D. Simon, and C. Li for technical assistance. This work was supported by the intramural Research Program of National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health. NR 42 TC 143 Z9 151 U1 5 U2 24 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 SEP 8 PY 2010 VL 12 IS 3 BP 224 EP 236 DI 10.1016/j.cmet.2010.06.009 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 648OH UT WOS:000281703300007 PM 20816089 ER PT J AU Stenkula, KG Lizunov, VA Cushman, SW Zimmerberg, J AF Stenkula, Karin G. Lizunov, Vladimir A. Cushman, Samuel W. Zimmerberg, Joshua TI Insulin Controls the Spatial Distribution of GLUT4 on the Cell Surface through Regulation of Its Postfusion Dispersal SO CELL METABOLISM LA English DT Article ID RAT ADIPOSE-CELLS; PLASMA-MEMBRANE; STORAGE-VESICLES; SUBCELLULAR TRAFFICKING; FUSION; TRANSLOCATION; ENDOCYTOSIS; ADIPOCYTES; TRACKING; SINGLE AB While the glucose transporter-4 (GLUT4) is fundamental to insulin-regulated glucose metabolism, its dynamic spatial organization in the plasma membrane (PM) is unclear. Here, using multicolor TIRF microscopy in transfected adipose cells, we demonstrate that insulin regulates not only the exocytosis of GLUT4 storage vesicles but also PM distribution of GLUT4 itself. In the basal state, domains (clusters) of GLUT4 molecules in PM are created by an exocytosis that retains GLUT4 at the fusion site. Surprisingly, when insulin induces a burst of GLUT4 exocytosis, it does not merely accelerate this basal exocytosis but rather stimulates similar to 60-fold another mode of exocytosis that disperses GLUT4 into PM. In contradistinction, internalization of most GLUT4, regardless of insulin, occurs from pre-existing clusters via the subsequent recruitment of clathrin. The data fit a new kinetic model that features multifunctional clusters as intermediates of exocytosis and endocytosis. C1 [Lizunov, Vladimir A.; Zimmerberg, Joshua] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Lab Cellular & Mol Biophys, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Stenkula, Karin G.; Cushman, Samuel W.] NIDDK, Expt Diabet Metab & Nutr Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Lab Cellular & Mol Biophys, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM joshz@mail.nih.gov RI Lizunov, Vladimir/B-5468-2009 FU Swedish Research Council; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Child Health and Human Development, National Institutes of Health FX The authors thank Dr. Kamran Melikov for useful discussions and Dena R. Yver for expert technical assistance. This work was supported in part by a Postdoctoral Fellowship to K.G.S. from the Swedish Research Council, and by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Child Health and Human Development, National Institutes of Health. NR 33 TC 41 Z9 43 U1 0 U2 5 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 SEP 8 PY 2010 VL 12 IS 3 BP 250 EP 259 DI 10.1016/j.cmet.2010.08.005 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 648OH UT WOS:000281703300009 PM 20816091 ER PT J AU Grady, C AF Grady, Christine TI Do IRBs Protect Human Research Participants? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10-1C118, Bethesda, MD 20892 USA. EM cgrady@nih.gov NR 9 TC 30 Z9 30 U1 0 U2 1 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 SEP 8 PY 2010 VL 304 IS 10 BP 1122 EP 1123 DI 10.1001/jama.2010.1304 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 646RM UT WOS:000281559800026 PM 20823440 ER PT J AU Milescu, LS Yamanishi, T Ptak, K Smith, JC AF Milescu, Lorin S. Yamanishi, Tadashi Ptak, Krzysztof Smith, Jeffrey C. TI Kinetic Properties and Functional Dynamics of Sodium Channels during Repetitive Spiking in a Slow Pacemaker Neuron SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PERSISTENT NA+ CURRENT; PYRAMIDAL NEURONS; PURKINJE NEURONS; MEMBRANE-PROPERTIES; ION CHANNELS; GATING MODES; IN-VITRO; INACTIVATION; MECHANISMS; CURRENTS AB We examined the kinetic properties of voltage-gated Na(+) channels and their contribution to the repetitive spiking activity of medullary raphe neurons, which exhibit slow pacemaking and strong spiking adaptation. The study is based on a combination of whole-cell patch-clamp, modeling and real-time computation. Na(+) currents were recorded from neurons in brain slices obtained from male and female neonatal rats, using voltage-clamp protocols designed to reduce space-clamp artifacts and to emphasize functionally relevant kinetic features. A detailed kinetic model was formulated to explain the broad range of transient and stationary voltage-dependent properties exhibited by Na(+) currents. The model was tested by injecting via dynamic clamp a model-based current as a substitute for the native TTX-sensitive Na(+) currents, which were pharmacologically blocked. The model-based current reproduced well the native spike shape and spiking frequency. The dynamics of Na(+) channels during repetitive spiking were indirectly examined through this model. By comparing the spiking activities generated with different kinetic models in dynamic-clamp experiments, we determined that state-dependent slow inactivation contributes significantly to spiking adaptation. Through real-time manipulation of the model-based current, we established that suprathreshold Na(+) current mainly controls spike shape, whereas subthreshold Na(+) current modulates spiking frequency and contributes to the pacemaking mechanism. Since the model-based current was injected in the soma, the results also suggest that somatic Na(+) channels are sufficient to establish the essential spiking properties of raphe neurons in vitro. C1 [Milescu, Lorin S.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Milescu, Lorin S.; Yamanishi, Tadashi; Ptak, Krzysztof; Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Milescu, LS (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave,Goldenson Bldg,Room 420, Boston, MA 02115 USA. EM Lorin_Milescu@hms.harvard.edu FU National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke. We thank our colleagues for discussing the experiments and the manuscript, particularly Drs. Mirela Milescu and Shai Silberberg (NIH, Bethesda, MD), Andrew Plested (Max Delbruck Center for Molecular Medicine, Berlin, Germany), and Joel Tabak (Florida State University, Tallahassee, FL). Dr. Ruli Zhang (NIH, Bethesda, MD) helped with experimental procedures. We are grateful to Dr. Bruce Bean (Harvard Medical School, Boston, MA) for suggestions and support. NR 49 TC 19 Z9 19 U1 1 U2 3 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 SEP 8 PY 2010 VL 30 IS 36 BP 12113 EP 12127 DI 10.1523/JNEUROSCI.0445-10.2010 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 649KM UT WOS:000281768000023 PM 20826674 ER PT J AU Rozycki, B Lipowsky, R Weikl, TR AF Rozycki, B. Lipowsky, R. Weikl, T. R. TI Segregation of receptor-ligand complexes in cell adhesion zones: phase diagrams and the role of thermal membrane roughness SO NEW JOURNAL OF PHYSICS LA English DT Article ID 2-DIMENSIONAL DISSOCIATION-CONSTANT; IMMUNOLOGICAL SYNAPSE; T-CELLS; UNBINDING TRANSITIONS; DOMAIN FORMATION; FLUID MEMBRANES; MODEL MEMBRANE; CONTACT AREA; MONTE-CARLO; ACTIVATION AB The adhesion zone of immune cells, the 'immunological synapse', exhibits characteristic domains of receptor-ligand complexes. The domain formation is probably caused by a length difference of the receptor-ligand complexes, and has been investigated in experiments in which T cells adhere to supported membranes with anchored ligands. For supported membranes with two types of anchored ligands, MHCp and ICAM1, which bind to the T-cell receptor (TCR) and the receptor LFA1 in the cell membrane, the coexistence of domains of the TCR-MHCp and LFA1-ICAM1 complexes in the cell adhesion zone has been observed for a wide range of ligand concentrations and affinities. For supported membranes with long and short ligands that bind to the same cell receptor CD2, in contrast, domain coexistence has been observed for a quite narrow ratio of ligand concentrations. In this paper, we determine detailed phase diagrams for cells adhering to supported membranes with a statistical-physical model of cell adhesion. We find a characteristic difference between the adhesion scenarios in which two types of ligands in a supported membrane bind (i) to the same cell receptor or (ii) to two different cell receptors, which helps us to explain the experimental observations. Our phase diagrams fully include thermal shape fluctuations of the cell membranes on nanometer scales, which lead to a critical point for the domain formation and to a cooperative binding of the receptors and ligands. C1 [Rozycki, B.; Lipowsky, R.; Weikl, T. R.] Max Planck Inst Colloids & Interfaces, Dept Theory & Biosyst, D-14424 Potsdam, Germany. [Rozycki, B.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Rozycki, B (reprint author), Max Planck Inst Colloids & Interfaces, Dept Theory & Biosyst, D-14424 Potsdam, Germany. EM bartosz.rozycki@mpikg.mpg.de; thomas.weikl@mpikg.mpg.de RI Rozycki, Bartosz/B-7005-2009; Weikl, Thomas/G-8572-2016 OI Rozycki, Bartosz/0000-0001-5938-7308; Weikl, Thomas/0000-0002-0911-5328 NR 72 TC 17 Z9 17 U1 0 U2 12 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1367-2630 J9 NEW J PHYS JI New J. Phys. PD SEP 8 PY 2010 VL 12 AR 095003 DI 10.1088/1367-2630/12/9/095003 PG 22 WC Physics, Multidisciplinary SC Physics GA 651CL UT WOS:000281902100003 ER PT J AU Moulaei, T Shenoy, SR Giomarelli, B Thomas, C McMahon, JB Dauter, Z O'Keefe, BR Wlodawer, A AF Moulaei, Tinoush Shenoy, Shilpa R. Giomarelli, Barbara Thomas, Cheryl McMahon, James B. Dauter, Zbigniew O'Keefe, Barry R. Wlodawer, Alexander TI Monomerization of Viral Entry Inhibitor Griffithsin Elucidates the Relationship between Multivalent Binding to Carbohydrates and anti-HIV Activity SO STRUCTURE LA English DT Article ID ANTIVIRAL PROTEIN GRIFFITHSIN; INACTIVATING PROTEIN; CRYSTAL-STRUCTURE; CYANOVIRIN-N; STRUCTURAL BASIS; BANANA LECTIN; SPECIFICITY; MANNOSE; GLYCOPROTEINS; DOMAIN AB Mutations were introduced to the domain-swapped homodimer of the antiviral lectin griffithsin (GRFT). Whereas several single and double mutants remained dimeric, insertion of either two or four amino acids at the dimerization interface resulted in a monomeric form of the protein (mGRFT). Monomeric character of the modified proteins was confirmed by sedimentation equilibrium ultracentrifugation and by their high resolution X-ray crystal structures, whereas their binding to carbohydrates was assessed by isothermal titration calorimetry. Cell-based antiviral activity assays utilizing different variants of mGRFT indicated that the monomeric form of the lectin had greatly reduced activity against HIV-1, suggesting that the antiviral activity of GRFT stems from crosslinking and aggregation of viral particles via multivalent interactions between GRFT and oligosaccharides present on HIV envelope glycoproteins. Atomic resolution crystal structure of a complex between mGRFT and nonamannoside revealed that a single mGRFT molecule binds to two different nonamannoside molecules through all three carbohydrate-binding sites present on the monomer. C1 [Shenoy, Shilpa R.; Giomarelli, Barbara; Thomas, Cheryl; McMahon, James B.; O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Moulaei, Tinoush; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Shenoy, Shilpa R.] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. [Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Natl Canc Inst, Argonne, IL 60439 USA. RP O'Keefe, BR (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM okeefeba@mail.nih.gov; wlodawer@nih.gov FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HNSN26120080001E]; National Institutes of Health FX We thank Chi-Huey Wong and Sheng-Kai Wang (Scripps) for the gift of the nonamannoside, Nikolay V. Dokholyan (University of North Carolina) for suggesting several mutations of GRFT, Nicole LaRonde-LeBlanc (University of Maryland) for her assistance with ultracentrifugation experiments and helpful discussions, and David Eisenberg (UCLA) for discussion of the phenomenon of domain swapping. We would also like to thank Jennifer Wilson (MTL, CCR, NCI) for anti-HIV bioassay support, and Marzena Dyba (SBL, SAIC-Frederick, CCR, NCI) and Sergei Tarasov (SBL, CCR, NCI) for their assistance with dynamic light scattering experiments. We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health grant to A.W. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HNSN26120080001E. 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 36 TC 42 Z9 42 U1 3 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP 8 PY 2010 VL 18 IS 9 BP 1104 EP 1115 DI 10.1016/j.str.2010.05.016 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 650GE UT WOS:000281836400007 PM 20826337 ER PT J AU Hoadley, KA Xu, DY Xue, YT Satyshur, KA Wang, WD Keck, JL AF Hoadley, Kelly A. Xu, Dongyi Xue, Yutong Satyshur, Kenneth A. Wang, Weidong Keck, James L. TI Structure and Cellular Roles of the RMI Core Complex from the Bloom Syndrome Dissolvasome SO STRUCTURE LA English DT Article ID REPLICATION PROTEIN-A; HOLLIDAY JUNCTION DISSOLVASOME; TOPOISOMERASE-III-ALPHA; SINGLE-STRANDED-DNA; SYNDROME HELICASE; HOMOLOGOUS RECOMBINATION; FANCONI-ANEMIA; OB-FOLD; ESSENTIAL COMPONENT; GENOME STABILITY AB BLM, the protein product of the gene mutated in Bloom syndrome, is one of five human RecQ helicases. It functions to separate double Holliday junction DNA without genetic exchange as a component of the "dissolvasome," which also includes topoisomerase Ill alpha and the RMI (RecQ-mediated genome instability) subcomplex (RMI1 and RMI2). We describe the crystal structure of the RMI core complex, comprising RMI2 and the C-terminal OB domain of RMI1. The overall RMI core structure strongly resembles two-thirds of the trimerization core of the eukaryotic single-stranded DNA-binding protein, Replication Protein A. Immunoprecipitation experiments with RMI2 variants confirm key interactions that stabilize the RMI core interface. Disruption of this interface leads to a dramatic increase in cellular sister chromatid exchange events similar to that seen in BLM-deficient cells. The RMI core interface is therefore crucial for BLM dissolvasome assembly and may have additional cellular roles as a docking hub for other proteins. C1 [Xu, Dongyi; Xue, Yutong; Wang, Weidong] NIA, Genet Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Hoadley, Kelly A.; Satyshur, Kenneth A.; Keck, James L.] Univ Wisconsin, Dept Biomol Chem, Sch Med & Publ Hlth, Madison, WI 53706 USA. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd 10B113, Baltimore, MD 21224 USA. EM wangw@grc.nia.nih.gov; jlkeck@wisc.edu OI Xu, Dongyi/0000-0001-5711-2618 FU NIH [GM068061, GM07215]; National Institute on Aging [Z01 AG000657-08] FX We thank Advanced Photon Source staff (LS-CAT beamline) for assistance with data collection, and Dr. David Schlessinger, James Berger, David Fox, and members of the Keck Lab for critical reading of this manuscript. This work was funded by a grant from the NIH (GM068061, J.L.K.) and by the Intramural Research Program of the National Institute on Aging (Z01 AG000657-08, W.W.). K.A.H. was supported in part by an NIH training grant in Molecular Biosciences (GM07215). NR 41 TC 18 Z9 19 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP 8 PY 2010 VL 18 IS 9 BP 1149 EP 1158 DI 10.1016/j.str.2010.06.009 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 650GE UT WOS:000281836400011 PM 20826341 ER PT J AU Wang, F Yang, YT Singh, TR Busygina, V Guo, R Wan, K Wang, WD Sung, P Meetei, AR Lei, M AF Wang, Feng Yang, Yuting Singh, Thiyam Ramsing Busygina, Valeria Guo, Rong Wan, Ke Wang, Weidong Sung, Patrick Meetei, Amom Ruhikanta Lei, Ming TI Crystal Structures of RMI1 and RMI2, Two OB-Fold Regulatory Subunits of the BLM Complex SO STRUCTURE LA English DT Article ID REPLICATION PROTEIN-A; SINGLE-STRANDED-DNA; BLOOMS-SYNDROME HELICASE; TOPOISOMERASE-III-ALPHA; HOLLIDAY JUNCTION DISSOLVASOME; SYNDROME GENE-PRODUCT; ZINC-FINGER; ESSENTIAL COMPONENT; GENOME STABILITY; RECQ HELICASES AB Mutations in BLM, a RecQ-like helicase, are linked to the autosomal recessive cancer-prone disorder Bloom's syndrome. BLM associates with topoisomerase (Topo) Ill alpha, RMI1, and RMI2 to form the BLM complex that is essential for genome stability. The RMI1-RMI2 heterodimer stimulates the dissolution of double Holliday junction into non-crossover recombinants mediated by BLM-Topo Ill alpha and is essential for stabilizing the BLM complex. However, the molecular basis of these functions of RMI1 and RMI2 remains unclear. Here we report the crystal structures of multiple domains of RMI1-RMI2, providing direct confirmation of the existence of three oligonucleotide/oligosaccharide binding (OB)-folds in RMI1-RMI2. Our structural and biochemical analyses revealed an unexpected insertion motif in RMI1N-OB, which is important for stimulating the dHJ dissolution. We also revealed the structural basis of the interaction between RMI1C-OB and RMI2-OB and demonstrated the functional importance of the RMI1-RMI2 interaction in genome stability maintenance. C1 [Wang, Feng; Yang, Yuting; Wan, Ke; Lei, Ming] Univ Michigan, Sch Med, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Wang, Feng; Yang, Yuting; Wan, Ke; Lei, Ming] Univ Michigan, Dept Biol Chem, Sch Med, Ann Arbor, MI 48109 USA. [Singh, Thiyam Ramsing; Meetei, Amom Ruhikanta] Univ Cincinnati, Coll Med, Cincinnati, OH 45229 USA. [Singh, Thiyam Ramsing; Meetei, Amom Ruhikanta] Cincinnati Childrens Res Fdn, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Busygina, Valeria; Sung, Patrick] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Guo, Rong; Wang, Weidong] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Lei, M (reprint author), Univ Michigan, Sch Med, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. EM leim@umich.edu RI Wang, Feng/B-2474-2012 FU NIH [GM 083015-01, HL084082, ES015632, ES07061]; American Cancer Society; National Institute on Aging [AG000688-07]; National Cancer Institute [Y1-00-1020]; National Institute of General Medical Science [Y1-GM-1104]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX We thank Y. Chen and J. Sun for help at various stages of the project. M.L. is a Howard Hughes Medical Institute Early Career Scientist. This work was supported by NIH grants (GM 083015-01 to M.L., HL084082 to ARM., and ES015632 and ES07061 to P.S.), an American Cancer Society Research Scholar Award (to M.L.), and the Intramural Research Program of the National Institute on Aging (AG000688-07 to W.W.). The General Medicine and Cancer Institutes Collaborative Access Team has been funded in whole or in part with federal funds from the National Cancer Institute (grant Y1-00-1020) and the National Institute of General Medical Science (grant Y1-GM-1104). 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 no. DE-AC02-06CH11357. NR 48 TC 20 Z9 21 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP 8 PY 2010 VL 18 IS 9 BP 1159 EP 1170 DI 10.1016/j.str.2010.06.008 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 650GE UT WOS:000281836400012 PM 20826342 ER PT J AU McAlister, VJ Owens, RA AF McAlister, Victor J. Owens, Roland A. TI Substitution of adeno-associated virus Rep protein binding and nicking sites with human Chromosome 19 sequences SO VIROLOGY JOURNAL LA English DT Article ID ADENO-ASSOCIATED VIRUS; DNA HELICASE ACTIVITY; ATPASE ACTIVITIES; CAP SEQUENCES; WILD-TYPE; BIOCHEMICAL-CHARACTERIZATION; INTEGRATION SITE; TERMINAL REPEATS; GENE-PRODUCT; HUMAN GENOME AB Background: Adeno-associated virus type 2 (AAV2) preferentially integrates its DNA at a similar to 2 kb region of human chromosome 19, designated AAVS1 (also known as MBS85). Integration at AAVS1 requires the AAV2 replication (Rep) proteins and a DNA sequence within AAVS1 containing a 16 bp Rep recognition sequence (RRS) and closely spaced Rep nicking site (also referred to as a terminal resolution site, or trs). The AAV2 genome is flanked by inverted terminal repeats (ITRs). Each ITR contains an RRS and closely spaced trs, but the sequences differ from those in AAVS1. These ITR sequences are required for replication and packaging. Results: In this study we demonstrate that the AAVS1 RRS and trs can function in AAV2 replication, packaging and integration by replacing a 61 bp region of the AAV2 ITR with a 49 bp segment of AAVS1 DNA. Modifying one or both ITRs did not have a large effect on the overall virus titers. These modifications did not detectably affect integration at AAVS1, as measured by semi-quantitative nested PCR assays. Sequencing of integration junctions shows the joining of the modified ITRs to AAVS1 sequences. Conclusions: The ability of these AAVS1 sequences to substitute for the AAV2 RRS and trs provides indirect evidence that the stable secondary structure encompassing the trs is part of the AAV2 packaging signal. C1 [Owens, Roland A.] NIDDKD, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Owens, RA (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM owensrol@mail.nih.gov FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Robert Kotin, Richard Smith, Cara Heller, Anthony Furano and John Hanover for their critical reading of the manuscript. We thank R. Jude Samulski for providing pSub201(-). This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 63 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD SEP 8 PY 2010 VL 7 AR 218 DI 10.1186/1743-422X-7-218 PG 11 WC Virology SC Virology GA 659ZJ UT WOS:000282605900004 PM 20825662 ER PT J AU Lubitz, SA Sinner, MF Lunetta, KL Makino, S Pfeufer, A Rahman, R Veltman, CE Barnard, J Bis, JC Danik, SP Sonni, A Shea, MA del Monte, F Perz, S Muller, M Peters, A Greenberg, SM Furie, KL van Noord, C Boerwinkle, E Stricker, BHC Witteman, J Smith, JD Chung, MK Heckbert, SR Benjamin, EJ Rosand, J Arking, DE Alonso, A Kaab, S Ellinor, PT AF Lubitz, Steven A. Sinner, Moritz F. Lunetta, Kathryn L. Makino, Seiko Pfeufer, Arne Rahman, Rosanna Veltman, Caroline E. Barnard, John Bis, Joshua C. Danik, Stephan P. Sonni, Akshata Shea, Marisa A. del Monte, Federica Perz, Siegfried Mueller, Martina Peters, Annette Greenberg, Steven M. Furie, Karen L. van Noord, Charlotte Boerwinkle, Eric Stricker, Bruno H. C. Witteman, Jacqueline Smith, Jonathan D. Chung, Mina K. Heckbert, Susan R. Benjamin, Emelia J. Rosand, Jonathan Arking, Dan E. Alonso, Alvaro Kaeaeb, Stefan Ellinor, Patrick T. TI Independent Susceptibility Markers for Atrial Fibrillation on Chromosome 4q25 SO CIRCULATION LA English DT Article DE atrial fibrillation; electrophysiology; genetics; epidemiology; risk factors ID ATHEROSCLEROSIS RISK; COMMON VARIANTS; HUMAN GENOME; PR INTERVAL; ASSOCIATION; POPULATION; DESIGN; METAANALYSIS; OBJECTIVES; ROTTERDAM AB Background-Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. Methods and Results-Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P = 1.2x10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. Conclusions-We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF. (Circulation. 2010;122:976-984.) C1 [Danik, Stephan P.; Shea, Marisa A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.; Makino, Seiko; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Lubitz, Steven A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Sinner, Moritz F.; Mueller, Martina; Kaeaeb, Stefan] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Mueller, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Lunetta, Kathryn L.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Pfeufer, Arne] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, Munich, Germany. [Pfeufer, Arne] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Perz, Siegfried] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Neuherberg, Germany. [Mueller, Martina; Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Rahman, Rosanna; Sonni, Akshata; Greenberg, Steven M.; Furie, Karen L.; Rosand, Jonathan] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. [Veltman, Caroline E.; van Noord, Charlotte; Stricker, Bruno H. C.; Witteman, Jacqueline] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Barnard, John] Cleveland Clin, Dept Quantitat Hlth Sci, Inst Heart & Vasc, Dept Mol Cardiol,Lerner Res Inst, Cleveland, OH 44106 USA. [Smith, Jonathan D.] Cleveland Clin, Dept Cell Biol, Inst Heart & Vasc, Dept Mol Cardiol,Lerner Res Inst, Cleveland, OH 44106 USA. [Chung, Mina K.] Cleveland Clin, Dept Cardiovasc Med, Inst Heart & Vasc, Dept Mol Cardiol,Lerner Res Inst, Cleveland, OH 44106 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA USA. [del Monte, Federica] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [van Noord, Charlotte] Dutch Med Evaluat Board, The Hague, Netherlands. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Stricker, Bruno H. C.] Inspectorate Hlth Care, The Hague, Netherlands. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. EM pellinor@partners.org RI Alonso, Alvaro/A-4917-2010; Kaab, Stefan/H-3915-2012; Pfeufer, Arne/B-6634-2013; Peters, Annette/A-6117-2011; OI Alonso, Alvaro/0000-0002-2225-8323; Lunetta, Kathryn/0000-0002-9268-810X; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health (NIH) [R01NS059727, P50NS051343, T32HL007575, RO1HL092577, RC1HL101056, DA027021]; German Federal Ministry of Education and Research (BMBF); German National Competence Network on Atrial Fibrillation (AFNET); Leducq Foundation [07-CVD 03, 01GS0499, 01GI0204, 01GS0838]; Helmholtz Zentrum Munchen; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, RC1 HL101056]; National Human Genome Research Institute [U01HG004402]; NIH [HHSN268200625226C]; American Heart Association [09SDG2280087]; NHLBI/NIH [1RC1HL099452]; NHLBI [R01 HL090620, 1UL-RR024989, P50 HL077107, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01HL087652]; Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic; National Center for Research [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Netherlands Organization of Scientific Research [175.010.2005.011]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam FX MGH: This study was funded by grants to Dr Ellinor from the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke and grants from the National Institutes of Health (NIH) to Dr Rosand (R01NS059727), Dr Furie (P50NS051343), Dr Lubitz (T32HL007575), and Drs Ellinor and Benjamin (RO1HL092577, RC1HL101056, and DA027021). AFNET: The study was also supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN), the German National Competence Network on Atrial Fibrillation (AFNET), the Leducq Foundation (07-CVD 03) by grants to Dr Kaab (01GS0499, 01GI0204, and 01GS0838). KORA S4: The KORA platform is funded by the Helmholtz Zentrum Munchen, the BMBF partly in the context of the NGFN, and the State of Bavaria, and as part of LMUinnovativ. ARIC: ARIC is conducted as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, and RC1 HL101056; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. The present analysis was also supported by American Heart Association grant 09SDG2280087 and NHLBI/NIH grant 1RC1HL099452. CCAF: The CCAF is supported by R01 HL090620 from the NHLBI (Drs Chung, Barnard, and Smith); NIH/National Center for Research Resources, Clinical Translational Science Award 1UL-RR024989 (Dr Chung); Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic (Dr Chung); and P50 HL077107 from the NHLBI (Dr Barnard). CHS: The CHS research reported in this article was supported by contract Nos. N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grant Nos. U01 HL080295 and R01HL087652 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. DNA handling and genotyping were supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping Core and by National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. RS: The genome-wide association database of the RS was funded through the Netherlands Organization of Scientific Research (No. 175.010.2005.011). The RS is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. NR 35 TC 76 Z9 81 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 7 PY 2010 VL 122 IS 10 BP 976 EP U66 DI 10.1161/CIRCULATIONAHA.109.886440 PG 21 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 652PJ UT WOS:000282020600006 PM 20733104 ER PT J AU Kim, B Kan, R Anguish, L Nelson, LM Coonrod, SA AF Kim, Boram Kan, Rui Anguish, Lynne Nelson, Lawrence M. Coonrod, Scott A. TI Potential Role for MATER in Cytoplasmic Lattice Formation in Murine Oocytes SO PLOS ONE LA English DT Article ID MOUSE EMBRYO; EFFECT GENE; MAMMALIAN EGGS; LIPID DROPLETS; PROTEIN; EXPRESSION; STORAGE; EMBRYOGENESIS; COMPETENCE; TRANSITION AB Background: Mater and Padi6 are maternal effect genes that are first expressed during oocyte growth and are required for embryonic development beyond the two-cell stage in the mouse. We have recently found that PADI6 localizes to, and is required for the formation of, abundant fibrillar Triton X-100 (Triton) insoluble structures termed the oocyte cytoplasmic lattices (CPLs). Given their similar expression profiles and mutant mouse phenotypes, we have been testing the hypothesis that MATER also plays a role in CPL formation and/or function. Methodology/Findings: Herein, we show that PADI6 and MATER co-localize throughout the oocyte cytoplasm following Triton extraction, suggesting that MATER co-localizes with PADI6 at the CPLs. Additionally, the solubility of PADI6 was dramatically increased in Mater(tm/tm) oocytes following Triton extraction, suggesting that MATER is involved in CPL nucleation. This prediction is supported by transmission electron microscopic analysis of Mater(+/+) and Mater(tm/tm) germinal vesicle stage oocytes which illustrated that volume fraction of CPLs was reduced by 90% in Mater(tm/tm) oocytes compared to Mater(+/+) oocytes. Conclusions: Taken together, these results suggest that, similar to PADI6, MATER is also required for CPL formation. Given that PADI6 and MATER are essential for female fertility, these results not only strengthen the hypothesis that the lattices play a critical role in mediating events during the oocyte-to-embryo transition but also increase our understanding of the molecular nature of the CPLs. C1 [Kim, Boram; Kan, Rui; Anguish, Lynne; Coonrod, Scott A.] Cornell Univ, Coll Vet Med, James A Baker Inst Anim Hlth, Ithaca, NY 14853 USA. [Nelson, Lawrence M.] NICHHD, Intramural Res Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. RP Kim, B (reprint author), Cornell Univ, Coll Vet Med, James A Baker Inst Anim Hlth, Ithaca, NY 14853 USA. EM sac269@cornell.edu FU National Institute of Child Health and Human Development [RO1 38353]; Intramural Research Program on Reproductive and Adult Endocrinology; National Science Foundation [DMR-0520404] FX This work was supported by National Institute of Child Health and Human Development grant RO1 38353 to SAC and by the Intramural Research Program on Reproductive and Adult Endocrinology to LMN. This study also made use of the Cornell Center for Materials Research Facilities supported by the National Science Foundation under Award Number DMR-0520404. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 22 Z9 22 U1 0 U2 2 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 SEP 7 PY 2010 VL 5 IS 9 AR e12587 DI 10.1371/journal.pone.0012587 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647PO UT WOS:000281631300016 PM 20830304 ER PT J AU Sripadi, P Shrestha, B Easley, RL Carpio, L Kehn-Hall, K Chevalier, S Mahieux, R Kashanchi, F Vertes, A AF Sripadi, Prabhakar Shrestha, Bindesh Easley, Rebecca L. Carpio, Lawrence Kehn-Hall, Kylene Chevalier, Sebastien Mahieux, Renaud Kashanchi, Fatah Vertes, Akos TI Direct Detection of Diverse Metabolic Changes in Virally Transformed and Tax-Expressing Cells by Mass Spectrometry SO PLOS ONE LA English DT Article ID ABLATION ELECTROSPRAY-IONIZATION; VIRUS TYPE-I; ATMOSPHERIC-PRESSURE; AMBIENT CONDITIONS; GLUTATHIONE METABOLISM; ANTIVIRAL THERAPY; PROSTATE-CANCER; HIGH-THROUGHPUT; ENERGY-CHARGE; FATTY-ACIDS AB Background: Viral transformation of a cell starts at the genetic level, followed by changes in the proteome and the metabolome of the host. There is limited information on the broad metabolic changes in HTLV transformed cells. Methods and Principal Findings: Here, we report the detection of key changes in metabolites and lipids directly from human T-lymphotropic virus type 1 and type 3 (HTLV1 and HTLV3) transformed, as well as Tax1 and Tax3 expressing cell lines by laser ablation electrospray ionization (LAESI) mass spectrometry (MS). Comparing LAESI-MS spectra of non-HTLV1 transformed and HTLV1 transformed cells revealed that glycerophosphocholine (PC) lipid components were dominant in the non-HTLV1 transformed cells, and PC(O-32:1) and PC(O-34:1) plasmalogens were displaced by PC(30: 0) and PC(32: 0) species in the HTLV1 transformed cells. In HTLV1 transformed cells, choline, phosphocholine, spermine and glutathione, among others, were downregulated, whereas creatine, dopamine, arginine and AMP were present at higher levels. When comparing metabolite levels between HTLV3 and Tax3 transfected 293T cells, there were a number of common changes observed, including decreased choline, phosphocholine, spermine, homovanillic acid, and glycerophosphocholine and increased spermidine and N-acetyl aspartic acid. These results indicate that the lipid metabolism pathway as well as the creatine and polyamine biosynthesis pathways are commonly deregulated after expression of HTLV3 and Tax3, indicating that the noted changes are likely due to Tax3 expression. N-acetyl aspartic acid is a novel metabolite that is upregulated in all cell types and all conditions tested. Conclusions and Significance: We demonstrate the high throughput in situ metabolite profiling of HTLV transformed and Tax expressing cells, which facilitates the identification of virus-induced perturbations in the biochemical processes of the host cells. We found virus type-specific (HTLV1 vs. HTLV3), expression-specific (Tax1 vs. Tax3) and cell-type-specific (T lymphocytes vs. kidney epithelial cells) changes in the metabolite profiles. The new insight on the affected metabolic pathways can be used to better understand the molecular mechanisms of HTLV induced transformation, which in turn can result in new treatment strategies. C1 [Sripadi, Prabhakar; Shrestha, Bindesh; Vertes, Akos] George Washington Univ, Dept Chem, WM Keck Inst Prote Techol & Applicat, Washington, DC 20052 USA. [Easley, Rebecca L.; Carpio, Lawrence] George Washington Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20052 USA. [Kehn-Hall, Kylene; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA USA. [Chevalier, Sebastien] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Mahieux, Renaud] INSERM, Ecole Normale Super Lyon, U758, Equipe Oncogenese Retrovirale, F-69008 Lyon, France. RP Sripadi, P (reprint author), Indian Inst Chem Technol, Natl Ctr Mass Spectrometry, Hyderabad 500007, Andhra Pradesh, India. EM vertes@gwu.edu RI Vertes, Akos/B-7159-2008; Shrestha, Bindesh/B-8821-2008; Kehn-Hall, Kylene/I-5752-2013 OI Vertes, Akos/0000-0001-5186-5352; Shrestha, Bindesh/0000-0002-7595-3506; FU National Science Foundation [0719232]; W. M. Keck Foundation [041904]; Protea Biosciences, Inc.; George Washington University (GWU) FX This work was supported, in whole and in part, by the National Science Foundation (Grant 0719232), the W. M. Keck Foundation (Grant 041904), Protea Biosciences, Inc., and the George Washington University (GWU) Selective Excellence Funds. The opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the funding organizations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 18 Z9 18 U1 1 U2 24 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 SEP 7 PY 2010 VL 5 IS 9 AR e12590 DI 10.1371/journal.pone.0012590 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647PO UT WOS:000281631300018 PM 20830293 ER PT J AU White, JF Grisshammer, R AF White, Jim F. Grisshammer, Reinhard TI Stability of the Neurotensin Receptor NTS1 Free in Detergent Solution and Immobilized to Affinity Resin SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; LARGE-SCALE PURIFICATION; HIGH-LEVEL EXPRESSION; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; BINDING-SITE; STRUCTURAL INSTABILITY; BOVINE RHODOPSIN; CRYSTALLIZATION; ACTIVATION AB Background: Purification of recombinant membrane receptors is commonly achieved by use of an affinity tag followed by an additional chromatography step if required. This second step may exploit specific receptor properties such as ligand binding. However, the effects of multiple purification steps on protein yield and integrity are often poorly documented. We have previously reported a robust two-step purification procedure for the recombinant rat neurotensin receptor NTS1 to give milligram quantities of functional receptor protein. First, histidine-tagged receptors are enriched by immobilized metal affinity chromatography using Ni-NTA resin. Second, remaining contaminants in the Ni-NTA column eluate are removed by use of a subsequent neurotensin column yielding pure NTS1. Whilst the neurotensin column eluate contained functional receptor protein, we observed in the neurotensin column flow-through misfolded NTS1. Methods and Findings: To investigate the origin of the misfolded receptors, we estimated the amount of functional and misfolded NTS1 at each purification step by radio-ligand binding, densitometry of Coomassie stained SDS-gels, and protein content determination. First, we observed that correctly folded NTS1 suffers damage by exposure to detergent and various buffer compositions as seen by the loss of [3 H] neurotensin binding over time. Second, exposure to the neurotensin affinity resin generated additional misfolded receptor protein. Conclusion: Our data point towards two ways by which misfolded NTS1 may be generated: Damage by exposure to buffer components and by close contact of the receptor to the neurotensin affinity resin. Because NTS1 in detergent solution is stabilized by neurotensin, we speculate that the occurrence of aggregated receptor after contact with the neurotensin resin is the consequence of perturbations in the detergent belt surrounding the NTS1 transmembrane core. Both effects reduce the yield of functional receptor protein. C1 [White, Jim F.; Grisshammer, Reinhard] NINDS, NIH, US Dept HHS, Rockville, MD USA. RP White, JF (reprint author), NINDS, NIH, US Dept HHS, Rockville, MD USA. EM rkgriss@helix.nih.gov RI Grisshammer, Reinhard/C-3089-2015 FU NIH, National Institute of Neurological Disorders and Stroke FX The research of JFW and RG was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 3 Z9 3 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 SEP 7 PY 2010 VL 5 IS 9 AR e12579 DI 10.1371/journal.pone.0012579 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647PO UT WOS:000281631300011 PM 20830205 ER PT J AU Prakash, GKS Zibinsky, M Upton, TG Kashemirov, BA McKenna, CE Oertell, K Goodman, MF Batra, VK Pedersen, LC Beard, WA Shock, DD Wilson, SH Olah, GA AF Prakash, G. K. Surya Zibinsky, Mikhail Upton, Thomas G. Kashemirov, Boris A. McKenna, Charles E. Oertell, Keriann Goodman, Myron F. Batra, Vinod K. Pedersen, Lars C. Beard, William A. Shock, David D. Wilson, Samuel H. Olah, George A. TI Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA polymerase beta; nonhydrolyzable nucleotides; fluorinated triphosphate; pentabasic acid; isopolarity and bioisotericity ID DNA-POLYMERASE-BETA; VIRUS-1 REVERSE-TRANSCRIPTASE; TRIPHOSPHATE ANALOGS; EFFICIENT SYNTHESIS; NUCLEOSIDE; 5'-TRIPHOSPHATES; INHIBITORS; THYMIDINE; NUCLEOTIDES; PHOSPHONATE AB It is difficult to overestimate the importance of nucleoside triphosphates in cellular chemistry: They are the building blocks for DNA and RNA and important sources of energy. Modifications of biologically important organic molecules with fluorine are of great interest to chemists and biologists because the size and electronegativity of the fluorine atom can be used to make defined structural alterations to biologically important molecules. Although the concept of nonhydrolyzable nucleotides has been around for some time, the progress in the area of modified triphosphates was limited by the lack of synthetic methods allowing to access bisCF(2)-substituted nucleotide analogs-one of the most interesting classes of nonhydrolyzable nucleotides. These compounds have "correct" polarity and the smallest possible steric perturbation compared to natural nucleotides. No other known nucleotides have these advantages, making bisCF(2)-substituted analogs unique. Herein, we report a concise route for the preparation of hitherto unknown highly acidic and polybasic bis(difluoromethylene) triphosphoric acid 1 using a phosphorous(III)/phosphorous( V) interconversion approach. The analog 1 compared to triphosphoric acid is enzymatically nonhydrolyzable due to substitution of two bridging oxygen atoms with CF(2) groups, maintaining minimal perturbations in steric bulkiness and overall polarity of the triphosphate polyanion. The fluorinated triphosphoric acid 1 was used for the preparation of the corresponding fluorinated deoxy-nucleotides (dNTPs). One of these dNTP analogs (dT) was demonstrated to fit into DNA polymerase beta (DNA pol beta) binding pocket by obtaining a 2.5 angstrom resolution crystal structure of a ternary complex with the enzyme. Unexpected dominating effect of triphosphate/Mg(2+) interaction over Watson-Crick hydrogen bonding was found and discussed. C1 [Prakash, G. K. Surya; Zibinsky, Mikhail; Upton, Thomas G.; Kashemirov, Boris A.; McKenna, Charles E.; Oertell, Keriann; Goodman, Myron F.; Olah, George A.] Univ So Calif, Loker Hydrocarbon Res Inst, Dept Chem, Los Angeles, CA 90089 USA. [Prakash, G. K. Surya; Zibinsky, Mikhail; Upton, Thomas G.; Kashemirov, Boris A.; McKenna, Charles E.; Oertell, Keriann; Goodman, Myron F.; Olah, George A.] Univ So Calif, Dept Biol, Los Angeles, CA 90089 USA. [Batra, Vinod K.; Pedersen, Lars C.; Beard, William A.; Shock, David D.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Prakash, GKS (reprint author), Univ So Calif, Loker Hydrocarbon Res Inst, Dept Chem, 837 Bloom Walk, Los Angeles, CA 90089 USA. EM gprakash@usc.edu; olah@usc.edu RI Upton, Thomas/E-3749-2012 FU National Institutes of Health (NIH) [5-U19-CA105010, Z01 ES050158, Z01 ES050161]; Loker Hydrocarbon Institute; NIH, National Institute of Environmental Health Sciences FX We are indebted to Dr. J.M. Krahn for his help in preparing the analog parameters and topology files for structure determination. Financial support from the National Institutes of Health (NIH) and the Loker Hydrocarbon Institute is greatly appreciated. This research was supported by NIH program grant project 5-U19-CA105010 and in part by Research Project Numbers Z01 ES050158 and Z01 ES050161 to Dr. S.H. Wilson in the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 42 TC 17 Z9 17 U1 3 U2 19 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 SEP 7 PY 2010 VL 107 IS 36 BP 15693 EP 15698 DI 10.1073/pnas.1007430107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647RY UT WOS:000281637800014 ER PT J AU Lo, SC Pripuzova, N Li, BJ Komaroff, AL Hung, GC Wang, R Alter, HJ AF Lo, Shyh-Ching Pripuzova, Natalia Li, Bingjie Komaroff, Anthony L. Hung, Guo-Chiuan Wang, Richard Alter, Harvey J. TI Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors (Retracted article. See vol. 109, pg. 346, 2012) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Retracted Publication DE xenotropic murine leukemia virus-related virus; murine leukemia virus-like virus; viral gag gene sequence; polytropic; mouse mitochondria DNA PCR ID MURINE LEUKEMIA-VIRUS; PROSTATE-CANCER; RETROVIRUS XMRV; PATHOGENESIS; PREVALENCE; RELEASE; ABSENCE; RNA AB Chronic fatigue syndrome (CFS) is a serious systemic illness of unknown cause. A recent study identified DNA from a xenotropic murine leukemia virus-related virus (XMRV) in peripheral blood mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested PCR, as compared with 8 of 218 (3.7%) healthy controls. However, four subsequent reports failed to detect any murine leukemia virus (MLV)-related virus gene sequences in blood of CFS patients. We examined 41 PBMC-derived DNA samples from 37 patients meeting accepted diagnostic criteria for CFS and found MLV-like virus gag gene sequences in 32 of 37 (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors. No evidence of mouse DNA contamination was detected in the PCR assay system or the clinical samples. Seven of 8 gag-positive patients tested again positive in a sample obtained nearly 15 y later. In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs. Further studies are needed to determine whether the same strong association with MLV-related viruses is found in other groups of patients with CFS, whether these viruses play a causative role in the development of CFS, and whether they represent a threat to the blood supply. C1 [Lo, Shyh-Ching; Pripuzova, Natalia; Li, Bingjie; Hung, Guo-Chiuan] US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. [Lo, Shyh-Ching; Pripuzova, Natalia; Li, Bingjie; Hung, Guo-Chiuan] US FDA, Off Cellular Tissue & Gene Therapy, Div Human Tissues, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Komaroff, Anthony L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Wang, Richard; Alter, Harvey J.] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Lo, SC (reprint author), US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. EM shyhching.lo@FDA.hhs.gov; halter@mail.nih.gov FU National Institute of Allergy and Infectious Diseases [R01-A127314, U01-A132246]; De Young Foundation FX We thank Richard Schacterle, Ph.D., and Jennifer Redd, who helped collect the specimens and clinical data. Drs. Jakob Reiser and Paolo Lusso kindly helped to review the manuscript. Support for this work was provided in part by National Institute of Allergy and Infectious Diseases Grants R01-A127314 and U01-A132246 and by a gift from the De Young Foundation to A.L.K. NR 22 TC 138 Z9 141 U1 5 U2 27 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 SEP 7 PY 2010 VL 107 IS 36 BP 15874 EP 15879 DI 10.1073/pnas.1006901107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647RY UT WOS:000281637800046 PM 20798047 ER PT J AU Hargus, G Cooper, O Deleidi, M Levy, A Lee, K Marlow, E Yow, A Soldner, F Hockemeyer, D Hallett, PJ Osborn, T Jaenisch, R Isacson, O AF Hargus, Gunnar Cooper, Oliver Deleidi, Michela Levy, Adam Lee, Kristen Marlow, Elizabeth Yow, Alyssa Soldner, Frank Hockemeyer, Dirk Hallett, Penelope J. Osborn, Teresia Jaenisch, Rudolf Isacson, Ole TI Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell replacement therapy; dopaminergic neurons; Parkinson's disease; reprogramming; transplantation ID DOPAMINERGIC-NEURONS; DISEASE; MIDBRAIN; MODEL; NEUROBLASTS; PROGENITORS; MORPHOLOGY; DERIVATION; DEFICIT; TISSUE AB Recent advances in deriving induced pluripotent stem(iPS) cells from patients offer new possibilities for biomedical research and clinical applications, as these cells could be used for autologous transplantation. We differentiated iPS cells from patients with Parkinson's disease (PD) into dopaminergic (DA) neurons and show that these DA neurons can be transplanted without signs of neurodegeneration into the adult rodent striatum. The PD patient iPS (PDiPS) cell-derived DA neurons survived at high numbers, showed arborization, and mediated functional effects in an animal model of PD as determined by reduction of amphetamine-and apomorphine-induced rotational asymmetry, but only a few DA neurons projected into the host striatum at 16 wk after transplantation. We next applied FACS for the neural cell adhesion molecule NCAM on differentiated PDiPS cells before transplantation, which resulted in surviving DA neurons with functional effects on amphetamine-induced rotational asymmetry in a 6-OHDA animal model of PD. Morphologically, we found that PDiPS cell-derived non-DA neurons send axons along white matter tracts into specific close and remote gray matter target areas in the adult brain. Such findings establish the transplantation of human PDiPS cell-derived neurons as a long-term in vivo method to analyze potential disease-related changes in a physiological context. Our data also demonstrate proof of principle of survival and functional effects of PDiPS cell-derived DA neurons in an animal model of PD and encourage further development of differentiation protocols to enhance growth and function of implanted PDiPS cell-derived DA neurons in regard to potential therapeutic applications. C1 [Soldner, Frank; Hockemeyer, Dirk; Jaenisch, Rudolf] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Hargus, Gunnar; Cooper, Oliver; Deleidi, Michela; Levy, Adam; Lee, Kristen; Marlow, Elizabeth; Yow, Alyssa; Hallett, Penelope J.; Osborn, Teresia; Isacson, Ole] Harvard Univ, Sch Med, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. [Hargus, Gunnar; Cooper, Oliver; Deleidi, Michela; Levy, Adam; Lee, Kristen; Marlow, Elizabeth; Yow, Alyssa; Hallett, Penelope J.; Osborn, Teresia; Isacson, Ole] Harvard Univ, Sch Med, McLean Hosp, Ctr Neuroregenerat Res, Belmont, MA 02478 USA. RP Jaenisch, R (reprint author), MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM jaenisch@wi.mit.edu; isacson@hms.harvard.edu OI Cooper, Oliver/0000-0001-6567-7491; Hallett, Penelope/0000-0002-8858-9096 FU Udall Parkinson's Disease Center of Excellence [P50 NS39793] FX We thank Andrew Kartunen for excellent technical help. This study was supported by the Udall Parkinson's Disease Center of Excellence Grant P50 NS39793 (to O.I.), Michael Stern Foundation Grant WX81XWH-05-1-0555 (to O. I.), Parkinson's Disease iPS Cell Line Research Consortium Grant 1RC2NS070276-01 (to O. I.), Orchard Foundation (O. I.), the Consolidated Anti-Aging Foundation (O. I.), Harold and Ronna Cooper Family (O. I.); National Institutes of Health Grants R01-HD045022 (to R. J.) and R01 CA098959-01 (to R. J.), a Collaborative Innovation Award from the Howard Hughes Medical Institute (R. J.), postdoctoral fellowship HA5589/ 11 from the Deutsche Forschungsgemeinschaft (to G. H.), and Training Award T32AG000222-17 from the National Institute on Aging (to T. O.). D. H. is a Merck Fellow of the Life Science Research Foundation. NR 33 TC 237 Z9 246 U1 7 U2 45 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 SEP 7 PY 2010 VL 107 IS 36 BP 15921 EP 15926 DI 10.1073/pnas.1010209107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647RY UT WOS:000281637800054 PM 20798034 ER PT J AU Lau, AG Irier, HA Gu, JP Tian, DH Ku, L Liu, GL Xia, MJ Fritsch, B Zheng, JQ Dingledine, R Xu, BJ Lu, B Feng, Y AF Lau, Anthony G. Irier, Hasan A. Gu, Jiaping Tian, Donghua Ku, Li Liu, Guanglu Xia, Mingjing Fritsch, Brita Zheng, James Q. Dingledine, Raymond Xu, Baoji Lu, Bai Feng, Yue TI Distinct 3 ' UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE alternative 3'UTR; tropomyosin-related kinase receptor B; hippocampal mossy fiber; epilepsy ID MENTAL-RETARDATION PROTEIN; MESSENGER-RNA; HIPPOCAMPAL-NEURONS; UNTRANSLATED REGIONS; SPINE MORPHOLOGY; SPLICE VARIANTS; TRKB; PHOSPHORYLATION; EPILEPTOGENESIS; EXPRESSION AB Expression of the brain-derived neurotrophic factor (BDNF) is under tight regulation to accommodate its intricate roles in controlling brain function. Transcription of BDNF initiates from multiple promoters in response to distinct stimulation cues. However, regardless which promoter is used, all BDNF transcripts are processed at two alternative polyadenylation sites, generating two pools of mRNAs that carry either a long or a short 3'UTR, both encoding the same BDNF protein. Whether and how the two distinct 3'UTRs may differentially regulate BDNF translation in response to neuronal activity changes is an intriguing and challenging question. We report here that the long BDNF 3'UTR is a bona fide cis-acting translation suppressor at rest whereas the short 3'UTR mediates active translation to maintain basal levels of BDNF protein production. Upon neuronal activation, the long BDNF 3'UTR, but not the short 3'UTR, imparts rapid and robust activation of translation from a reporter. Importantly, the endogenous long 3'UTR BDNF mRNA specifically undergoes markedly enhanced polyribosome association in the hippocampus in response to pilocarpine induced-seizure before transcriptional up-regulation of BDNF. Furthermore, BDNF protein level is quickly increased in the hippocampus upon seizure-induced neuronal activation, accompanied by a robust activation of the tropomyosin-related receptor tyrosine kinase B. These observations reveal a mechanism for activity-dependent control of BDNF translation and tropomyosin-related receptor tyrosine kinase B signaling in brain neurons. C1 [Lau, Anthony G.; Irier, Hasan A.; Tian, Donghua; Ku, Li; Liu, Guanglu; Xia, Mingjing; Dingledine, Raymond; Feng, Yue] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. [Gu, Jiaping; Zheng, James Q.] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. [Fritsch, Brita] Natl Inst Neurol Disorders & Stroke, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. [Xu, Baoji] Georgetown Univ, Sch Med, Dept Pharmacol, Washington, DC 20007 USA. [Lu, Bai] NICHHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Feng, Y (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. EM yfeng@emory.edu RI dingledine, Ray/F-5173-2011; OI Fritsch, Brita/0000-0003-4884-9049; Feng, Yue/0000-0002-7905-2182 FU National Institutes of Health [NS056532, 5T32GM008602, HD061344, NS050596, NS036604] FX We thank Geidy Serrano (Emory University, Atlanta, GA) for her assistance with primary hippocampal neuron cultures and pilocapine-induced SE in mice. The anti-pY816-TrkB antibody was a gift from Dr. Moses Chao (Skirball Institute at New York University, New York, NY). The d2EGFP reporter was provided by Dr. Gary Bassell (Emory University, Atlanta, GA). This study was supported by National Institutes of Health Grants NS056532, 5T32GM008602 (to A. L.), HD061344 (to Y.F.), NS050596 (to B. X.), and NS036604 (to R. D.). NR 36 TC 82 Z9 83 U1 2 U2 9 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 SEP 7 PY 2010 VL 107 IS 36 BP 15945 EP 15950 DI 10.1073/pnas.1002929107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647RY UT WOS:000281637800058 PM 20733072 ER PT J AU Mulkidjanian, AY Galperin, MY AF Mulkidjanian, Armen Y. Galperin, Michael Y. TI On the abundance of zinc in the evolutionarily old protein domains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID SULFIDE C1 [Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. [Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119992, Russia. [Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Mulkidjanian, AY (reprint author), Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. EM amulkid@uos.de RI Galperin, Michael/B-5859-2013; Mulkidjanian, Armen/J-8086-2013 OI Galperin, Michael/0000-0002-2265-5572; Mulkidjanian, Armen/0000-0001-5844-3064 FU Intramural NIH HHS [Z99 LM999999] NR 5 TC 3 Z9 4 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 7 PY 2010 VL 107 IS 36 BP E137 EP E137 DI 10.1073/pnas.1008745107 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647RY UT WOS:000281637800001 PM 20693418 ER PT J AU Koelle, K Khatri, P Kamradt, M Kepler, TB AF Koelle, Katia Khatri, Priya Kamradt, Meredith Kepler, Thomas B. TI A two-tiered model for simulating the ecological and evolutionary dynamics of rapidly evolving viruses, with an application to influenza SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE disease dynamics; viral evolution; multi-strain model; influenza; phylodynamics ID 2 DISTINCT LINEAGES; B-VIRUS; MONOCLONAL-ANTIBODIES; A VIRUS; TIME-SERIES; GENETIC-CHARACTERIZATION; ANTIGENIC VARIATION; POSITIVE SELECTION; EPOCHAL EVOLUTION; DISEASE DYNAMICS AB Understanding the epidemiological and evolutionary dynamics of rapidly evolving pathogens is one of the most challenging problems facing disease ecologists today. To date, many mathematical and individual-based models have provided key insights into the factors that may regulate these dynamics. However, in many of these models, abstractions have been made to the simulated sequences that limit an effective interface with empirical data. This is especially the case for rapidly evolving viruses in which de novo mutations result in antigenically novel variants. With this focus, we present a simple two-tiered 'phylodynamic' model whose purpose is to simulate, along with case data, sequence data that will allow for a more quantitative interface with observed sequence data. The model differs from previous approaches in that it separates the simulation of the epidemiological dynamics (tier 1) from the molecular evolution of the virus's dominant antigenic protein (tier 2). This separation of phenotypic dynamics from genetic dynamics results in a modular model that is computationally simpler and allows sequences to be simulated with specifications such as sequence length, nucleotide composition and molecular constraints. To illustrate its use, we apply the model to influenza A (H3N2) dynamics in humans, influenza B dynamics in humans and influenza A (H3N8) dynamics in equine hosts. In all three of these illustrative examples, we show that the model can simulate sequences that are quantitatively similar in pattern to those empirically observed. Future work should focus on statistical estimation of model parameters for these examples as well as the possibility of applying this model, or variants thereof, to other host-virus systems. C1 [Koelle, Katia; Khatri, Priya; Kamradt, Meredith] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Kepler, Thomas B.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Ctr Computat Immunol, Durham, NC 27705 USA. RP Koelle, K (reprint author), Duke Univ, Dept Biol, POB 90338, Durham, NC 27708 USA. EM katia.koelle@duke.edu OI Kepler, Thomas/0000-0002-1383-6865 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; [NSF-EF-08-27416] FX We thank the three reviewers for their thoughtful comments and suggestions and members of the Koelle research group for detailed feedback. Support for K. K., P. K. and M. K. was provided by grant NSF-EF-08-27416 and by the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 70 TC 31 Z9 31 U1 1 U2 11 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD SEP 6 PY 2010 VL 7 IS 50 BP 1257 EP 1274 DI 10.1098/rsif.2010.0007 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 631FT UT WOS:000280332700002 PM 20335193 ER PT J AU Volkov, I Pepin, KM Lloyd-Smith, JO Banavar, JR Grenfell, BT AF Volkov, Igor Pepin, Kim M. Lloyd-Smith, James O. Banavar, Jayanth R. Grenfell, Bryan T. TI Synthesizing within-host and population-level selective pressures on viral populations: the impact of adaptive immunity on viral immune escape SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE immune escape; within-host evolution; viral evolution; adaptive immune response; cross-scale dynamics; viral quasi-species ID EVOLUTION; INFECTION; PATHOGENS; DYNAMICS; VIRULENCE; HUMANS AB The evolution of viruses to escape prevailing host immunity involves selection at multiple integrative scales, from within-host viral and immune kinetics to the host population level. In order to understand how viral immune escape occurs, we develop an analytical framework that links the dynamical nature of immunity and viral variation across these scales. Our epidemiological model incorporates within-host viral evolutionary dynamics for a virus that causes acute infections (e. g. influenza and norovirus) with changes in host immunity in response to genetic changes in the virus population. We use a deterministic description of the within-host replication dynamics of the virus, the pool of susceptible host cells and the host adaptive immune response. We find that viral immune escape is most effective at intermediate values of immune strength. At very low levels of immunity, selection is too weak to drive immune escape in recovered hosts, while very high levels of immunity impose such strong selection that viral subpopulations go extinct before acquiring enough genetic diversity to escape host immunity. This result echoes the predictions of simpler models, but our formulation allows us to dissect the combination of within-host and transmission-level processes that drive immune escape. C1 [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. [Lloyd-Smith, James O.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Volkov, Igor; Banavar, Jayanth R.] Penn State Univ, Dept Phys, University Pk, PA 16802 USA. [Volkov, Igor; Pepin, Kim M.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. RP Grenfell, BT (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM grenfell@princeton.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU NSF [0742373]; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This research was supported by NSF grant 0742373. B. T. G. and J.O.L.-S. were also supported by the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 24 TC 9 Z9 9 U1 0 U2 13 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD SEP 6 PY 2010 VL 7 IS 50 BP 1311 EP 1318 DI 10.1098/rsif.2009.0560 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 631FT UT WOS:000280332700006 PM 20335194 ER PT J AU Holleran, JL Parise, RA Yellow-Duke, AE Egorin, MJ Eiseman, JL Covey, JM Beumer, JH AF Holleran, Julianne L. Parise, Robert A. Yellow-Duke, Archibong E. Egorin, Merrill J. Eiseman, Julie L. Covey, Joseph M. Beumer, Jan H. TI Liquid chromatography-tandem mass spectrometric assay for the quantitation in human plasma of the novel indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC 725776 SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Indenoisoquinolines; Tandem mass spectrometry; Topoisomerase; Assay; Validation ID NSC-725776 AB Topoisomerase (Topo I) is a recognized target for ovarian, lung, and colorectal came therapy The FDA-approved camptothecin (CPT) Topo I inhibitors, topotecan and irinotecan are labile and their effects are rapidly reversible The indenoisoquinoline topoisomerase I inhibitors. NSC 743400 and NSC 725776, have been developed as a new generation of Topo I inhibitors and ale being advanced to clinical evaluation To support the clinical development of NSC 743400 and NSC 725776, we developed and validated, according to FDA guidelines, LC-MS/MS assays for the sensitive, accurate and precise quantitation of NSC 743400 and NSC 725776 in 0 2 mL human plasma After ethyl acetate extraction, separation was achieved with a Synergi Polar RI, column and a gradient of 0 1% formic acid in acetonnide water NSC 743400 and NSC 725776 eluted at approximately 3 min, and the total run time was 14 min Detection consisted of electrospray, positive-mode ionization mass spectrometi y Between 3 and 1000 ng/mL, accuracy was 969-108.2% for NSC 743400 and 95.1-106 7% for NSC 725776, and pi easion was <11 4% for NSC 743400 and <5 9% foi NSC 725776 Extraction recovery was >80% foi both analytes, and ton suppression ranged from 46.7 to 5.7%. The use of isotopically labeled Intel nal standards and a wash phase at the end of the run were necessary to achieve adequate assay pet rot mance Pi tem binding in human plasma as assessed by equilibrium dialysis showed both indenoisoquinolines to be mote than 98% protein bound (C) 2010 Elsevier B V All rights reserved. C1 [Holleran, Julianne L.; Parise, Robert A.; Yellow-Duke, Archibong E.; Egorin, Merrill J.; Eiseman, Julie L.; Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA 15213 USA. [Egorin, Merrill J.] Univ Pittsburgh, Div Hematol Oncol, Dept Med, Sch Med, Pittsburgh, PA 15232 USA. [Egorin, Merrill J.; Eiseman, Julie L.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15261 USA. [Covey, Joseph M.] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Beumer, Jan H.] Univ Pittsburgh, Dept Pharmaceut Sci, Sch Pharm, Pittsburgh, PA 15261 USA. RP Beumer, JH (reprint author), Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Room G27D,Hillman Res Pavil,5117 Ctr Ave, Pittsburgh, PA 15213 USA. OI Beumer, Jan/0000-0002-8978-9401 FU NCI [NO1-CM-52202, P30-CA47904]; ASCO Cancer Foundation; Hillman Fellows for Innovative Cancer Research Award FX Grant support. contracts NO1-CM-52202, and grant P30-CA47904, NCI. MJE is the recipient of an ASCO Cancer Foundation Translational Research Professorship. JHB is the recipient of a Hillman Fellows for Innovative Cancer Research Award. The study sponsor (represented by JMC) provided scientific advice with regards to data interpretation and the writing of the report. NR 7 TC 7 Z9 8 U1 2 U2 5 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 SEP 5 PY 2010 VL 52 IS 5 BP 714 EP 720 DI 10.1016/j.jpba.2010.02.020 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 584WU UT WOS:000276785400011 PM 20236781 ER PT J AU DeLeo, FR Otto, M Kreiswirth, BN Chambers, HF AF DeLeo, Frank R. Otto, Michael Kreiswirth, Barry N. Chambers, Henry F. TI Community-associated meticillin-resistant Staphylococcus aureus Reply SO LANCET LA English DT Letter C1 [DeLeo, Frank R.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Kreiswirth, Barry N.] Univ Med & Dent New Jersey, Int Ctr Publ Hlth, Publ Hlth Res Inst, TB Ctr, Newark, NJ 07103 USA. [Chambers, Henry F.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Infect Dis, San Francisco, CA USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 3 TC 1 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD SEP 4 PY 2010 VL 376 IS 9743 BP 767 EP 767 DI 10.1016/S0140-6736(10)61370-0 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 650EC UT WOS:000281831000018 ER PT J AU Shu, S Liu, XO Kriebel, PW Hong, MS Daniels, MP Parent, CA Korn, ED AF Shu, Shi Liu, Xiong Kriebel, Paul W. Hong, Myoung-Soon Daniels, Mathew P. Parent, Carole A. Korn, Edward D. TI Expression of Y53A-Actin in Dictyostelium Disrupts the Cytoskeleton and Inhibits Intracellular and Intercellular Chemotactic Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIN TYROSINE PHOSPHORYLATION; COLLECTIVE CELL-MIGRATION; II-INDEPENDENT PROCESSES; HEAVY-CHAIN GENE; MYOSIN-II; ADENYLYL-CYCLASE; IN-VIVO; ACANTHAMOEBA MYOSIN; DISCOIDEUM CELLS; CLEAVAGE FURROW AB We showed previously that phosphorylation of Tyr(53), or its mutation to Ala, inhibits actin polymerization in vitro with formation of aggregates of short filaments, and that expression of Y53A-actin in Dictyostelium blocks differentiation and development at the mound stage (Liu, X., Shu, S., Hong, M. S., Levine, R. L., and Korn, E. D. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 13694-13699; Liu, X., Shu, S., Hong, M. S., Yu, B., and Korn, E. D. (2010) J. Biol. Chem. 285, 9729-9739). We now show that expression of Y53A-actin, which does not affect cell growth, phagocytosis, or pinocytosis, inhibits the formation of head-to-tail cell streams during cAMP-induced aggregation, although individual amoebae chemotax normally. We show that expression of Y53A-actin causes a 50% reduction of cell surface cAMP receptors, and inhibits cAMP-induced increases in adenylyl cyclase A activity, phosphorylation of ERK2, and actin polymerization. Trafficking of vesicles containing adenylyl cyclase A to the rear of the cell and secretion of the ACA vesicles are also inhibited. The actin cytoskeleton of cells expressing Y53A-actin is characterized by numerous short filaments, and bundled and aggregated filaments similar to the structures formed by copolymerization of purified Y53A-actin and wild-type actin in vitro. This disorganized actin cytoskeleton may be responsible for the inhibition of intracellular and intercellular cAMP signaling in cells expressing F-Y53A-actin. C1 [Shu, Shi; Liu, Xiong; Korn, Edward D.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Kriebel, Paul W.; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hong, Myoung-Soon; Daniels, Mathew P.] NHLBI, Electtron Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), Bldg 50,Rm 2517,9000 Rockville Pike, Bethesda, MD 20892 USA. EM edk@nih.gov RI Korn, Edward/F-9929-2012 FU National Institutes of Health, NHLBI; NCI, Center for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Programs of the National Institute of Health, NHLBI, and NCI, Center for Cancer Research. NR 65 TC 13 Z9 13 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 3 PY 2010 VL 285 IS 36 BP 27713 EP 27725 DI 10.1074/jbc.M110.116277 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 644TL UT WOS:000281404100027 PM 20610381 ER PT J AU Yang, JL Tadokoro, T Keijzers, G Mattson, MP Bohr, VA AF Yang, Jenq-Lin Tadokoro, Takashi Keijzers, Guido Mattson, Mark P. Bohr, Vilhelm A. TI Neurons Efficiently Repair Glutamate-induced Oxidative DNA Damage by a Process Involving CREB-mediated Up-regulation of Apurinic Endonuclease 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; EXTRACELLULAR-SUPEROXIDE DISMUTASE; ELEMENT-BINDING PROTEIN; LONG-TERM POTENTIATION; HIPPOCAMPAL-NEURONS; POLYMERASE-BETA; MITOCHONDRIAL DYSFUNCTION; PERMEABILITY TRANSITION; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE AB Glutamate, the major excitatory neurotransmitter in the brain, activates receptors coupled to membrane depolarization and Ca(2+) influx that mediates functional responses of neurons including processes such as learning and memory. Here we show that reversible nuclear oxidative DNA damage occurs in cerebral cortical neurons in response to transient glutamate receptor activation using non-toxic physiological levels of glutamate. This DNA damage was prevented by intracellular Ca(2+) chelation, the mitochondrial superoxide dismutase mimetic MnTMPyP (Mn-5,10,15,20-tetra(4-pyridyl)-21H, 23H-porphine chloride tetrakis( methochloride)), and blockade of the permeability transition pore. The repair of glutamate-induced DNA damage was associated with increased DNA repair activity and increased mRNA and protein levels of apurinic endonuclease 1 (APE1). APE1 knockdown induced accumulation of oxidative DNA damage after glutamate treatment, suggesting that APE1 is a key repair protein for glutamate-induced DNA damage. A cAMP-response element-binding protein (CREB) binding sequence is present in the Ape1 gene (encodes APE1 protein) promoter and treatment of neurons with a Ca(2+)/calmodulin-dependent kinase inhibitor (KN-93) blocked the ability of glutamate to induce CREB phosphorylation and APE1 expression. Selective depletion of CREB using RNA interference prevented glutamate-induced up-regulation of APE1. Thus, glutamate receptor stimulation triggers Ca(2+)- and mitochondrial reactive oxygen species-mediated DNA damage that is then rapidly repaired by a mechanism involving Ca(2+)-induced, CREB-mediated APE1 expression. Our findings reveal a previously unknown ability of neurons to efficiently repair oxidative DNA lesions after transient activation of glutamate receptors. C1 [Yang, Jenq-Lin; Tadokoro, Takashi; Keijzers, Guido; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. [Yang, Jenq-Lin; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), 251 Bayview Blvd,Ste 100, Baltimore, MD 21224 USA. EM bohrv@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institutes of Health FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, NIA. NR 63 TC 51 Z9 51 U1 0 U2 0 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 SEP 3 PY 2010 VL 285 IS 36 BP 28191 EP 28199 DI 10.1074/jbc.M109.082883 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 644TL UT WOS:000281404100062 PM 20573957 ER PT J AU Daly, MJ Gaidamakova, EK Matrosova, VY Kiang, JG Fukumoto, R Lee, DY Wehr, NB Viteri, GA Berlett, BS Levine, RL AF Daly, Michael J. Gaidamakova, Elena K. Matrosova, Vera Y. Kiang, Juliann G. Fukumoto, Risaku Lee, Duck-Yeon Wehr, Nancy B. Viteri, Gabriela A. Berlett, Barbara S. Levine, Rodney L. TI Small-Molecule Antioxidant Proteome-Shields in Deinococcus radiodurans SO PLOS ONE LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; RADIATION-RESISTANCE; IONIZING-RADIATION; HYDROGEN-PEROXIDE; ESCHERICHIA-COLI; MICROCOCCUS-RADIODURANS; SALMONELLA-TYPHIMURIUM; SHEWANELLA-ONEIDENSIS; SUPEROXIDE-DISMUTASE; COMPARATIVE GENOMICS AB For Deinococcus radiodurans and other bacteria which are extremely resistant to ionizing radiation, ultraviolet radiation, and desiccation, a mechanistic link exists between resistance, manganese accumulation, and protein protection. We show that ultrafiltered, protein-free preparations of D. radiodurans cell extracts prevent protein oxidation at massive doses of ionizing radiation. In contrast, ultrafiltrates from ionizing radiation-sensitive bacteria were not protective. The D. radiodurans ultrafiltrate was enriched in Mn, phosphate, nucleosides and bases, and peptides. When reconstituted in vitro at concentrations approximating those in the D. radiodurans cytosol, peptides interacted synergistically with Mn(2+) and orthophosphate, and preserved the activity of large, multimeric enzymes exposed to 50,000 Gy, conditions which obliterated DNA. When applied ex vivo, the D. radiodurans ultrafiltrate protected Escherichia coli cells and human Jurkat T cells from extreme cellular insults caused by ionizing radiation. By establishing that Mn(2+)-metabolite complexes of D. radiodurans specifically protect proteins against indirect damage caused by gamma-rays delivered in vast doses, our findings provide the basis for a new approach to radioprotection and insight into how surplus Mn budgets in cells combat reactive oxygen species. C1 [Daly, Michael J.; Gaidamakova, Elena K.; Matrosova, Vera Y.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. [Kiang, Juliann G.; Fukumoto, Risaku] Uniformed Serv Univ Hlth Sci, Armed Forces Radiobiol Res Inst, Bethesda, MD 20814 USA. [Lee, Duck-Yeon; Wehr, Nancy B.; Viteri, Gabriela A.; Berlett, Barbara S.; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, MJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mdaly@usuhs.edu; rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Air Force Office of Scientific Research [FA9550-07-1-0218]; National Heart, Lung, and Blood Institute, National Institutes of Health; National Institute of Allergy and Infectious Diseases; AFRRI FX The work of E.K.G., V.Y.M. and M.J.D. was supported by the Air Force Office of Scientific Research (Grant FA9550-07-1-0218). The work of B.S.B., G.A.V., N.B.W., D.-Y.L. and R.L.L. was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. The work of J.G.K. and R.F. was supported by the National Institute of Allergy and Infectious Diseases, and the Intramural Program of the AFRRI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 97 Z9 98 U1 1 U2 23 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 SEP 3 PY 2010 VL 5 IS 9 AR e12570 DI 10.1371/journal.pone.0012570 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 647OL UT WOS:000281627700017 PM 20838443 ER PT J AU Horkay, F Magda, J Alcoutlabi, M Atzet, S Zarembinski, T AF Horkay, Ferenc Magda, Jules Alcoutlabi, Mataz Atzet, Sarah Zarembinski, Thomas TI Structural, mechanical and osmotic properties of injectable hyaluronan-based composite hydrogels SO POLYMER LA English DT Article DE Elasticity; Biopolymer; Hydrogel ID PHYSIOLOGICAL SALT-SOLUTIONS; ENTANGLED POLYMER-SOLUTIONS; POLYELECTROLYTE SOLUTIONS; NEUTRON-SCATTERING; CHAIN; NETWORKS; DYNAMICS; GELS AB The osmotic and scattering properties of hyaluronan-based composite hydrogels composed of stiff biopolymer chains (carboxymethylated thiolated hyaluronan (CMHA-S)) crosslinked by a flexible polymer (polyethylene glycol diacrylate (PEGDA)) are investigated and analyzed in terms of the scaling theory The total pre-gel polymer weight concentration is varied between 0 5 wt.% and 3 2 wt %, while the mole ratio between the reactive PEG chain ends and the thiolated HA moieties is changed between 015 and 1 0. The shear modulus G of the fully-swollen gels exhibits a stronger dependence on pre-gel concentration than on the crosslink density. Osmotic deswelling measurements reveal that the osmotic mixing pressure depends on the weight ratio CMHA-S/PEGDA, and is practically unaffected by the pre-gel concentration Small-angle neutron scattering observations indicate that the thermodynamic properties of these composite gels are governed by total polymer concentration, i e., specific interactions between the two polymeric components do not play a significant role (C) 2010 Elsevier Ltd. All rights reserved C1 [Magda, Jules; Alcoutlabi, Mataz] Univ Utah, Dept Chem Engn, Salt Lake City, UT 84112 USA. [Atzet, Sarah; Zarembinski, Thomas] Glycosan Biosyst Inc, Salt Lake City, UT 84108 USA. [Horkay, Ferenc] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. RP Magda, J (reprint author), Univ Utah, Dept Chem Engn, 50 S Cent Campus Dr,Rm 3290, Salt Lake City, UT 84112 USA. OI Magda, Jules/0000-0002-1063-6526 FU NICHD, NIH; National Institutes of Health [5R21EB4947]; National Science Foundation [DMR-0454672] FX F.H. acknowledges the support of the Intramural Research Program of the NICHD, NIH. This work was partially supported by a grant from the National Institutes of Health, grant number 5R21EB4947. We acknowledge the support of the National Institute of Standards and Technology, U.S. Department of Commerce, in providing the neutron research facilities used in this work. This work utilized facilities supported in part by the National Science Foundation under Agreement No. DMR-0454672. NR 36 TC 5 Z9 5 U1 5 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0032-3861 J9 POLYMER JI Polymer PD SEP 3 PY 2010 VL 51 IS 19 BP 4424 EP 4430 DI 10.1016/j.polymer.2010.06.027 PG 7 WC Polymer Science SC Polymer Science GA 646AA UT WOS:000281506100018 PM 20824199 ER PT J AU Milhollen, MA Traore, T Adams-Duffy, J Thomas, MP Berger, AJ Dang, L Dick, LR Garnsey, JJ Koenig, E Langston, SP Manfredi, M Narayanan, U Rolfe, M Staudt, LM Soucy, TA Yu, J Zhang, JL Bolen, JB Smith, PG AF Milhollen, Michael A. Traore, Tary Adams-Duffy, Jennifer Thomas, Michael P. Berger, Allison J. Dang, Lenny Dick, Lawrence R. Garnsey, James J. Koenig, Erik Langston, Steven P. Manfredi, Mark Narayanan, Usha Rolfe, Mark Staudt, Louis M. Soucy, Teresa A. Yu, Jie Zhang, Julie Bolen, Joseph B. Smith, Peter G. TI MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-kappa B-dependent lymphoma SO BLOOD LA English DT Article ID GENE-EXPRESSION; ACTIVATION; CANCER; MUTATIONS; PATHWAY; PROTEIN; ALPHA; UBIQUITINATION; REREPLICATION; MECHANISMS AB MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pI kappa B alpha, decrease in nuclear p65 content, reduction of nuclear factor-kappa B (NF-kappa B) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappa B pathway inhibition. Treatment of germinal-center B cell-like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-kappa B pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-kappa B pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-kappa B-dependent lymphomas. (Blood. 2010;116(9):1515-1523) C1 [Milhollen, Michael A.; Traore, Tary; Adams-Duffy, Jennifer; Thomas, Michael P.; Berger, Allison J.; Dang, Lenny; Dick, Lawrence R.; Garnsey, James J.; Koenig, Erik; Langston, Steven P.; Manfredi, Mark; Narayanan, Usha; Rolfe, Mark; Soucy, Teresa A.; Yu, Jie; Zhang, Julie; Bolen, Joseph B.; Smith, Peter G.] Millennium Pharmaceut Inc, Cambridge, MA 02139 USA. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Smith, PG (reprint author), Millennium Pharmaceut Inc, 40 Landsdowne St, Cambridge, MA 02139 USA. EM Peter.G.Smith@MPI.com NR 34 TC 141 Z9 141 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 SEP 2 PY 2010 VL 116 IS 9 BP 1515 EP 1523 DI 10.1182/blood-2010-03-272567 PG 9 WC Hematology SC Hematology GA 646VT UT WOS:000281572700019 PM 20525923 ER EF