FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Faulhaber-Walter, R Chen, L Oppermann, M Kim, SM Huang, Y Hiramatsu, N Mizel, D Kajiyama, H Zerfas, P Briggs, JP Kopp, JB Schnermann, J AF Faulhaber-Walter, Robert Chen, Limeng Oppermann, Mona Kim, Soo Mi Huang, Yuning Hiramatsu, Noriyuki Mizel, Diane Kajiyama, Hiroshi Zerfas, Patricia Briggs, Josephine P. Kopp, Jeffrey B. Schnermann, Jurgen TI Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID TUBULOGLOMERULAR FEEDBACK; MICE LACKING; TUBULAR HYPOTHESIS; FILTRATION-RATE; DEFICIENT MICE; NEPHROPATHY; MELLITUS; AKITA; MOUSE; EXPRESSION AB Intraglomerular hypertension and glomerular hyperfiltration likely contribute to the pathogenesis of diabetic nephropathy, and tubuloglomerular feedback (TGF) has been suggested to play a role in diabetic hyperfiltration. A1 adenosine receptor (A1AR) null mice lack a TGIF response, so this model was used to investigate the contribution of TGF to hyperfiltration in diabetic Ins2(+/-) Akita mice. TGF responses in Ins2(+/-) A1AR(-/-) double mutants were abolished, whereas they were attenuated in Ins2(+/-) mice. GFR, assessed at 14, 24, and 33 wk, was approximately 30% higher in Ins2(+/-) than in wild-type (WT) mice and increased further in Ins2(+/-) A1AR(-/-) mutants (P < 0.01 versus both WT and Ins2(+/-) mice at all ages). Histologic evidence of glomerular injury and urinary albumin excretion were more pronounced in double-mutant than single-mutant or WT mice. In summary, the marked elevation of GFR in diabetic mice that lack a TGF response indicates that TGF is not required to cause hyperfiltration in the Akita model of diabetes. Rather, an A1AR-dependent mechanism, possibly TGF, limits the degree of diabetic hyperfiltration and nephropathy. C1 [Faulhaber-Walter, Robert; Chen, Limeng; Oppermann, Mona; Kim, Soo Mi; Huang, Yuning; Hiramatsu, Noriyuki; Mizel, Diane; Kajiyama, Hiroshi; Kopp, Jeffrey B.; Schnermann, Jurgen] NIDDK, NIH, Bethesda, MD 20892 USA. [Zerfas, Patricia] NIDDK, Vet Resources Program, Bethesda, MD USA. [Briggs, Josephine P.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Schnermann, J (reprint author), NIDDK, NIH, Blgd 10,Room 4D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov RI Briggs, Josephine/B-9394-2009; OI Briggs, Josephine/0000-0003-0798-1190; Faulhaber-Walter, Robert/0000-0002-7769-9652; Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS NR 38 TC 53 Z9 57 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD APR PY 2008 VL 19 IS 4 BP 722 EP 730 DI 10.1681/ASN.2007060721 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 283TJ UT WOS:000254659100014 PM 18256360 ER PT J AU Grefsheim, SF Rankin, JA Perry, GJ McKibbon, KA AF Grefsheim, Suzanne F. Rankin, Jocelyn A. Perry, Gerald J. McKibbon, K. Ann TI Affirming our commitment to research: the Medical Library Association's research policy statement: the process and findings SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article AB Purpose: Building on its 1995 research policy statement, the Medical Library Association (MLA) has issued a new research policy, The Research Imperative. This paper shares the background research that informed the new policy. Methods: Semi-structured interviews were conducted with fifty-one key informants representing various library types, functions, geographic locations, ages, and ethnicities. The grounded theory approach was used to analyze the resulting textual database. Additionally, to gather input from the membership as a whole, two open forums were held at MLA annual meetings. Results: Key informant data indicated that the policy should provide roles for MLA in leadership, advocacy, collaboration, services, education, publishing, and development of a research agenda. Evidence-based library and information practice was emphasized. Six themes emerged to center the new policy: creation of a research culture, challenges, domains of research, research skills set, roles of stakeholders, and measurement of progress. Conclusion: Reflecting the interests and beliefs of the membership, The Research Imperative challenges MLA members to build a supportive culture that values and contributes to a research base that is recognized as an essential tool for future practice. C1 [Grefsheim, Suzanne F.] NIH, Div Lib Serv, Bethesda, MD 20892 USA. [Rankin, Jocelyn A.] CDC Informat Ctr, Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Perry, Gerald J.] Univ Colorado, Denison Mem Lib, Denver, CO 80262 USA. [McKibbon, K. Ann] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON L8N 3Z5, Canada. RP Grefsheim, SF (reprint author), NIH, Div Lib Serv, 10 Ctr Dr,MSC-1150, Bethesda, MD 20892 USA. EM grefshes@nih.gov; jrankin@cdc.gov; jerry.perry@uchsc.edu; mckib@mcmaster.ca NR 12 TC 8 Z9 8 U1 0 U2 3 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 APR PY 2008 VL 96 IS 2 BP 114 EP 120 DI 10.3163/1536-5050.96.2.114 PG 7 WC Information Science & Library Science SC Information Science & Library Science GA 289QL UT WOS:000255068900005 PM 18379666 ER PT J AU Smith, KA AF Smith, Kent A. TI Laws, leaders, and legends of the modern National Library of Medicine SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article AB Purpose: The paper is an expanded version of the 2007 Joseph Leiter National Library of Medicine ( NLM)/Medical Library Association Lecture presented at MLA '07, the Medical Library Association annual meeting in Philadelphia in May 2007. It presents an historical accounting of four major pieces of legislation, beginning with the NLM Act of 1956 up through the creation of the National Center for Biotechnology Information. Brief Description: The transition from the United States Armed Forces Medical Library to the United States National Library of Medicine in 1956 was a major turning point in NLM's history, scope, and direction. The succeeding landmark legislative achievements - namely, the 1965 Medical Library Assistance Act, the 1968 Joint Resolution forming the Lister Hill National Center for Biomedical Communications, and the 1988 authorization for the National Center for Biotechnology Information transformed the library into a major biomedical communications institution and a leader and supporter of an effective national network of libraries of medicine. The leaders of the library and its major advocates - including Dr. Michael DeBakey, Senator Lister Hill, and Senator Claude Pepper - together contributed to the creation of the modern NLM. C1 Natl Lib Med, NIH, US Dept HHS, Bethesda, MD 20894 USA. RP Smith, KA (reprint author), Natl Lib Med, NIH, US Dept HHS, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ksmith@kasenterprise.com NR 40 TC 3 Z9 3 U1 0 U2 2 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 APR PY 2008 VL 96 IS 2 BP 121 EP 133 DI 10.3163/1536-5050.96.2.121 PG 13 WC Information Science & Library Science SC Information Science & Library Science GA 289QL UT WOS:000255068900006 PM 18379667 ER PT J AU Mullins, C Lucia, MS Hayward, SW Lee, JY Levitt, JM Lin, VK Liu, BCS Chinnaiyan, AM Rubin, MA Slawin, K Star, RA Getzenberg, RH AF Mullins, Chris Lucia, M. Scott Hayward, Simon W. Lee, Jeannette Y. Levitt, Jonathan M. Lin, Victor K. Liu, Brian C. -S. Chinnaiyan, Arul M. Rubin, Mark A. Slawin, Kevin Star, Robert A. Getzenberg, Robert H. CA MPSA Consortium TI A comprehensive approach toward novel serum biomarkers for benign prostatic hyperplasia: The MPSA consortium SO JOURNAL OF UROLOGY LA English DT Review DE prostatic hyperplasia; urologic diseases; biological markers ID CAPTURE AUTOANTIBODY MICROARRAY; ACUTE URINARY RETENTION; III DUTASTERIDE TRIALS; ANTIGEN; MEN; CANCER; PROGRESSION; BPH; THERAPY; JM-27 AB Purpose: Clinical benign prostatic hyperplasia is primarily diagnosed based on a diverse array of progressive lower. urinary tract symptoms and is likely distinct from histological benign prostatic hyperplasia, which is detected by the presence of nonmalignant proliferation of prostate cells but may or may not be associated with symptoms. Pharmacological management of lower urinary tract symptoms has emerged as an effective initial treatment for clinical benign prostatic hyperplasia due to the introduction of new drug therapies shown to be effective in recent large clinical trials. Despite advances in symptom management and research into disease pathology, diagnostic strategies for the prediction of benign prostatic hyperplasia progression and response to drug modalities are lacking, and questions remain as to the molecular differences underlying clinical (symptomatic) vs histological (nonsymptomatic) benign prostatic hyperplasia. Materials and Methods: As part of the Medical Therapy of Prostatic Symptoms (MTOPS) clinical trial, which demonstrated the effectiveness of combination drug therapy in slowing benign prostatic hyperplasia progression, an archive of biological specimens linked to clinical data was collected for future profiling of disease pathology and changes associated with response to drug therapy. The MTOPS Prostatic Samples Analysis (MPSA) Consortium was established to identify and validate molecular markers that may better define benign prostatic hyperplasia related pathologies, identify risk of progression of lower urinary tract symptoms, and predict response to drug therapy using the MTOPS archive. The cooperating MPSA Biomarker Discovery Sites and Pathology Coordinating Center use diverse methodologies and scientific approaches as well as unique expertise to address the goals of the Consortium. Results: To date the MPSA has identified a number of promising biomarkers as well as other molecular and cellular changes associated with benign prostatic hyperplasia. Conclusions: These findings and ongoing Consortium discovery efforts have the potential to provide a greater understanding of the defects underlying disease pathology, and may lead to the development of early and more effective pharmacological treatment strategies for benign prostatic hyperplasia. C1 [Getzenberg, Robert H.] Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA. [Mullins, Chris; Star, Robert A.] NIH, NIDDK, Bethesda, MD 20892 USA. [Lucia, M. Scott] Univ Colorado, Prostrate Diagnost Lab, Aurora, CO USA. [Lucia, M. Scott] Univ Colorado, Dept Pathol, MPSA Pathol Coordinat Ctr, Aurora, CO USA. [Lucia, M. Scott] Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. RP Getzenberg, RH (reprint author), Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, 600 N Wolfe St Marburg 121, Baltimore, MD 21287 USA. EM rgetzen1@bmi.edu OI Rubin, Mark/0000-0002-8321-9950 FU NIA NIH HHS [AG022312, U01 AG022312]; NIDDK NIH HHS [DK63587, DK63593, DK63594, DK63597, DK63661, DK63665, U01 DK063587, U01 DK063593, U01 DK063593-04, U01 DK063594, U01 DK063597, U01 DK063661, U01 DK063665] NR 50 TC 9 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 0022-5347 J9 J UROLOGY JI J. Urol. PD APR PY 2008 VL 179 IS 4 BP 1243 EP 1256 DI 10.1016/j.juro.2007.11.049 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 276WS UT WOS:000254175000007 PM 18280515 ER PT J AU Nager, CW FitzGerald, M Kraus, SR Chai, TC Zyczynski, H Siris, L Lemack, GE Lloyd, LK Litman, HJ Stoddard, AM Baker, J Steersil, W AF Nager, Charles W. FitzGerald, MaryPat Kraus, Stephen R. Chai, Toby C. Zyczynski, Halina Siris, Larry Lemack, Gary E. Lloyd, L. Keith Litman, Heather J. Stoddard, Anne M. Baker, Jan Steersil, William CA Urinary Incontinence Treatment Net TI Urodynamic measures do not predict stress continence outcomes after surgery for stress urinary incontinence in selected women SO JOURNAL OF UROLOGY LA English DT Article DE urinary incontinence; stress; urodynamics; urinary bladder; surgery ID LEAK-POINT PRESSURE; BURCH COLPOSUSPENSION; DETRUSOR OVERACTIVITY; DIAGNOSIS; SUCCESS AB Purpose: We determined the prognostic value of preoperative urodynamic results in patients with stress urinary incontinence. Materials and Methods: In a 9-center surgical trial, women with stress urinary incontinence were randomized to a Burch or pubovaginal sling procedure. Women were eligible for the study if they had predominant stress urinary incontinence symptoms, a positive cough stress test, a bladder capacity more than 200 ml and urethral hypermobility. Preoperative free uroflowmetry, filling cystometry and pressure flow studies were performed in all. Overall treatment success required a negative pad test, no urinary incontinence on a 3-day diary, a negative stress test, no self-reported stress urinary incontinence symptoms and no re-treatment for stress urinary incontinence. Stress specific success required all of the last 3 criteria. We examined urodynamic measures, and whether the presence of urodynamic stress incontinence, the presence of detrusor overactivity and Valsalva leak point pressure would predict surgical success. Results: Subjects with urodynamic stress incontinence had a 2-fold greater odds of overall success when compared with the No urodynamic stress incontinence group, but this trend did not quite reach statistical significance (OR 2.26; 95% C.I. 0.99, 5.17). Odds of stress specific success did not differ by urodynamic stress incontinence status. Subjects with detrusor overactivity did not have significantly worse success rates. Stratifying by treatment group, there was no difference in mean Valsalva leak point pressure values between surgical successes and failures. Conclusions: We found a nearly statistically significant trend that women with urodynamic stress incontinence are twice as likely to have a successful overall outcome from surgical management of stress urinary incontinence as women without urodynamic stress incontinence. The level of Valsalva leak point pressure and the presence of detrusor overactivity do not predict the success outcomes after the Burch or autologous fascia sling procedures in women with pure or predominant stress urinary incontinence. The impact of urodynamic studies on surgical outcomes needs further investigation. C1 [FitzGerald, MaryPat] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Nager, Charles W.] Univ Calif San Diego, San Diego, CA 92103 USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Lemack, Gary E.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Chai, Toby C.] Univ Maryland, Baltimore, MD USA. [Urinary Incontinence Treatment Net] NIDDK, NIH, Bethesda, MD USA. [Zyczynski, Halina] Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. [Siris, Larry] Beaumont Hosp, Ctr Med, Royal Oak, MI USA. [Lloyd, L. Keith] Univ Alabama, Birmingham, AL USA. [Litman, Heather J.; Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. [Baker, Jan] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Steersil, William] Univ Virginia Hlth Syst, Charlottesville, VA USA. RP Nager, CW (reprint author), 9350 Campus Point,Dr Perlman Suite 2A,Mail Code 0, La Jolla, CA 92037 USA. EM cnager@ucsd.edu OI Wadie, Bassem/0000-0002-6977-6849 FU NIDDK NIH HHS [U01 DK60379, U01 DK 58225, U01 DK58229, U01 DK58231, U01 DK58234, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01 DK60401] NR 20 TC 65 Z9 67 U1 0 U2 5 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 APR PY 2008 VL 179 IS 4 BP 1470 EP 1474 DI 10.1016/j.juro.2007.11.077 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 276WS UT WOS:000254175000065 PM 18295276 ER PT J AU Matthijnssens, J Ciarlet, M Heiman, E Arijs, I Delbeke, T McDonald, SM Palombo, EA Iturriza-Gomara, M Maes, P Patton, JT Rahman, M Van Ranst, M AF Matthijnssens, Jelle Ciarlet, Max Heiman, Erica Arijs, Ingrid Delbeke, Thomas McDonald, Sarah M. Palombo, Enzo A. Iturriza-Gomara, Miren Maes, Piet Patton, John T. Rahman, Mustafizur Van Ranst, Marc TI Full genome-based classification of rotaviruses reveals a common origin between human Wa-like and porcine rotavirus strains and human DS-1-like and bovine rotavirus strains SO JOURNAL OF VIROLOGY LA English DT Article ID RNA-RNA HYBRIDIZATION; GENE SUBSTITUTION REASSORTANT; HOST-RANGE RESTRICTION; GROUP-A ROTAVIRUS; MOLECULAR CHARACTERIZATION; SEQUENCE-ANALYSIS; MURINE ROTAVIRUS; INTERSPECIES TRANSMISSION; P-GENOTYPE; NEUTRALIZATION EPITOPES AB Group A rotavirus classification is currently based on the molecular properties of the two outer layer proteins, VP7 and VP4, and the middle layer protein, VP6. As reassortment of all the 11 rotavirus gene segments plays a key role in generating rotavirus diversity in nature, a classification system that is based on all the rotavirus gene segments is desirable for determining which genes influence rotavirus host range restriction, replication, and virulence, as well as for studying rotavirus epidemiology and evolution. Toward establishing such a classification system, gene sequences encoding VP1 to VP3, VP6, and NSP1 to NSP5 were determined for human and animal rotavirus strains belonging to different G and P genotypes in addition to those available in databases, and they were used to define phylogenetic relationships among all rotavirus genes. Based on these phylogenetic analyses, appropriate identity cutoff values were determined for each gene. For the VP4 gene, a nucleotide identity cutoff value of 80% completely correlated with the 27 established P genotypes. For the VP7 gene, a nucleotide identity cutoff value of 80% largely coincided with the established G genotypes but identified four additional distinct genotypes comprised of murine or avian rotavirus strains. Phylogenetic analyses of the VP1 to VP3, VP6, and NSP1 to NSP5 genes showed the existence of 4, 5, 6, 11, 14, 5, 7, 11, and 6 genotypes, respectively, based on nucleotide identity cutoff values of 83%, 84%, 81%, 85%, 79%, 85%, 85%, 85%, and 91%, respectively. In accordance with these data, a revised nomenclature of rotavirus strains is proposed. The novel classification system allows the identification of (i) distinct genotypes, which probably followed separate evolutionary paths; (ii) interspecies transmissions and a plethora of reassortment events; and (iii) certain gene constellations that revealed (a) a common origin between human Wa-like rotavirus strains and porcine rotavirus strains and (b) a common origin between human DS-1-like rotavirus strains and bovine rotaviruses. These close evolutionary links between human and animal rotaviruses emphasize the need for close simultaneous monitoring of rotaviruses in animals and humans. C1 [Matthijnssens, Jelle; Arijs, Ingrid; Delbeke, Thomas; Maes, Piet; Rahman, Mustafizur; Van Ranst, Marc] Katholieke Univ Leuven, Rega Inst Med Res, Lab Clin & Epidemiol Virol, Dept Microbiol & Immunol, B-3000 Louvain, Belgium. [Ciarlet, Max] Merck & Co Inc, Vaccine & Biol Clin Res, N Wales, PA 19454 USA. [Heiman, Erica; McDonald, Sarah M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Palombo, Enzo A.] Swinburne Univ Technol, Fac Life & Social Sci, Environm & Biotechnol Ctr, Hawthorn, Vic 3122, Australia. [Iturriza-Gomara, Miren] Hlth Protect Agcy, Ctr Infect, Enter Virus Unit, Virus Reference Dept, London, England. [Rahman, Mustafizur] ICDDR B Mohakhali, Virol Lab, Dhaka 1212, Bangladesh. RP Matthijnssens, J (reprint author), Katholieke Univ Leuven, Rega Inst Med Res, Lab Clin & Epidemiol Virol, Dept Microbiol & Immunol, Minderbroedersstr 10, B-3000 Louvain, Belgium. EM jelle.matthijnssens@uz.kuleuven.ac.be RI rahman, mustafizur/E-6918-2010; Iturriza Gomara, Miren/B-4351-2013; Patton, John/P-1390-2014; Matthijnssens, Jelle/A-6770-2015; Matthijnssens, Jelle/B-8634-2016; OI Iturriza Gomara, Miren/0000-0001-5816-6423; Van Ranst, Marc/0000-0002-1674-4157; Palombo, Enzo/0000-0001-5889-1393 FU Intramural NIH HHS NR 78 TC 415 Z9 494 U1 5 U2 25 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 APR PY 2008 VL 82 IS 7 BP 3204 EP 3219 DI 10.1128/JVI.02257-07 PG 16 WC Virology SC Virology GA 276KL UT WOS:000254139800004 PM 18216098 ER PT J AU Barth, H Schnober, EK Neumann-Haefelin, C Thumann, C Zeisel, MB Diepolder, HM Hu, ZY Liang, TJ Blum, HE Thimme, R Lambotin, M Baumert, TF AF Barth, Heidi Schnober, Eva K. Neumann-Haefelin, Christoph Thumann, Christine Zeisel, Mirjam B. Diepolder, Helmut M. Hu, Zongyi Liang, T. Jake Blum, Hubert E. Thimme, Robert Lambotin, Melanie Baumert, Thomas F. TI Scavenger receptor class B is required for hepatitis C virus uptake and cross-presentation by human dendritic cells SO JOURNAL OF VIROLOGY LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CELLULAR IMMUNE-RESPONSES; ANTIGEN-PRESENTING CELLS; NEUTRALIZING ANTIBODIES; VIRAL REPLICATION; ADAPTIVE IMMUNITY; IN-VITRO; PARTICLES; INFECTION; BINDING AB Class B scavenger receptors (SR-Bs) bind lipoproteins and play an important role in lipid metabolism. Most recently, SR-B type I (SR-BI) and its splicing variant SR-BII have been found to mediate bacterial adhesion and cytosolic bacterial invasion in mammalian cells. In this study, we demonstrate that SR-BI is a key host factor required for hepatitis C virus (HCV) uptake and cross-presentation by human dendritic cells (DCs). Whereas monocytes and T and B cells were characterized by very low or undetectable SR-BI expression levels, human DCs demonstrated a high level of cell surface expression of SR-BI similar to that of primary human hepatocytes. Antibodies targeting the extracellular loop of SR-BI efficiently inhibited HCV-like particle binding, uptake, and cross-presentation by human DCs. Moreover, human high-density lipoprotein specifically modulated HCV-like particle binding to DCs, indicating an interplay of HCV with the lipid transfer function of SR-BI in DCs. Finally, we demonstrate that anti-SR-BI antibodies inhibit the uptake of cell culture-derived HCV (HCVcc) in DCs. In conclusion, these findings identify a novel function of SR-BI for viral antigen uptake and recognition and may have an important impact on the design of HCV vaccines and immunotherapeutic approaches aiming at the induction of efficient antiviral immune responses. C1 [Barth, Heidi; Hu, Zongyi; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Barth, Heidi; Schnober, Eva K.; Neumann-Haefelin, Christoph; Blum, Hubert E.; Thimme, Robert; Baumert, Thomas F.] Univ Freiburg, Dept Med 2, Freiburg, Germany. [Schnober, Eva K.; Thumann, Christine; Zeisel, Mirjam B.; Lambotin, Melanie; Baumert, Thomas F.] INSERM, U748, Strasbourg, France. [Schnober, Eva K.] Univ Freiburg, Fac Biol, Freiburg, Germany. [Thumann, Christine; Lambotin, Melanie; Baumert, Thomas F.] Univ Strasbourg, Strasbourg, France. [Diepolder, Helmut M.] Univ Munich, Klinikum Grosshadern, Dept Med 2, D-8000 Munich, Germany. [Baumert, Thomas F.] Univ Strasbourg, Ctr Hosp, Serv Hepatogastroenterol, Strasbourg, France. RP Barth, H (reprint author), NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM barthh@niddk.nih.gov; Thomas.Baumert@viro-ulp.u-strasbg.fr RI Neumann-Haefelin, Christoph/E-5550-2011; Zeisel, Mirjam/E-9205-2016 OI Zeisel, Mirjam/0000-0003-1606-0131 FU Intramural NIH HHS NR 71 TC 59 Z9 61 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2008 VL 82 IS 7 BP 3466 EP 3479 DI 10.1128/JVI.02478-07 PG 14 WC Virology SC Virology GA 276KL UT WOS:000254139800025 PM 18216094 ER PT J AU Benhnia, MREI McCausland, MM Su, HP Singh, K Hoffmann, J Davies, DH Felgner, PL Head, S Sette, A Garboczi, DN Crotty, S AF Benhnia, Mohammed Rafii-El-Idrissi McCausland, Megan M. Su, Hua-Poo Singh, Kavita Hoffmann, Julia Davies, D. Huw Felgner, Philip L. Head, Steven Sette, Alessandro Garboczi, David N. Crotty, Shane TI Redundancy and plasticity of neutralizing antibody responses are cornerstone attributes of the human immune response to the smallpox vaccine SO JOURNAL OF VIROLOGY LA English DT Article ID ENTRY-FUSION COMPLEX; 2 INFECTIOUS FORMS; MONOCLONAL-ANTIBODIES; GAMMA-GLOBULIN; MATURE VIRION; VIRUS L1R; PENETRATION PROTEIN; PROTECTIVE IMMUNITY; ENVELOPE PROTEIN; DRYVAX VACCINE AB The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective Immoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a "safety net" of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine. C1 [Benhnia, Mohammed Rafii-El-Idrissi; McCausland, Megan M.; Sette, Alessandro; Crotty, Shane] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. [Su, Hua-Poo; Singh, Kavita; Garboczi, David N.] NIAID, Immunogenet Lab, Struct Biol Sect, Rockville, MD 20852 USA. [Hoffmann, Julia; Head, Steven] Scripps Res Inst, DNA Array Core Facil & Consortium Funct Glycom, La Jolla, CA 92037 USA. [Davies, D. Huw; Felgner, Philip L.] Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92697 USA. RP Crotty, S (reprint author), La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, 9420 Athena Circle, La Jolla, CA 92037 USA. EM shane@liai.org RI rafii el idrissi benhnia, mohammed/F-3019-2015 OI rafii el idrissi benhnia, mohammed/0000-0001-7405-9476 FU NIAID NIH HHS [R01 AI063107, R01 AI56268, R01 AI63107, R01 AI056268] NR 61 TC 58 Z9 59 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 APR PY 2008 VL 82 IS 7 BP 3751 EP 3768 DI 10.1128/JVI.02244-07 PG 18 WC Virology SC Virology GA 276KL UT WOS:000254139800053 PM 18234801 ER PT J AU Tilton, JC Manion, MM Luskin, MR Johnson, AJ Patamwenu, AA Hallahan, CW Cogliano-Shutta, NA Mican, JM Davey, RT Kottilil, S Lifson, JD Metcalf, JA Lempicki, RA Connors, M AF Tilton, John C. Manion, Maura M. Luskin, Marlise R. Johnson, Alison J. Patamwenu, Andy A. Hallahan, Claire W. Cogliano-Shutta, Nancy A. Mican, Joann M. Davey, Richard T., Jr. Kottilil, Shyam Lifson, Jeffrey D. Metcalf, Julia A. Lempicki, Richard A. Connors, Mark TI Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-INFECTED INDIVIDUALS; IMMUNE-DEFICIENCY-SYNDROME; BLOOD MONONUCLEAR-CELLS; CD4(+) T-CELLS; ANTIRETROVIRAL THERAPY; IFN-ALPHA; PERIPHERAL-BLOOD; FUNCTIONAL DEFICIENCIES; ADAPTIVE IMMUNITY; RNA VIRUS AB Human immunodeficiency virus type 1 (HIV-1) infection has been associated with perturbations of plasmacytoid dendritic cells (PDC), including diminished frequencies in the peripheral blood and reduced production of type I interferons (IFNs) in response to in vitro stimulation. However, recent data suggest a paradoxical increase in production of type 1 interferons in vivo in HIV-infected patients compared to uninfected controls. Using a How cytometric assay to detect IFN-alpha-producing cells within unseparated peripheral blood mononuclear cells, we observed that short-term interruptions of antiretroviral therapy are sufficient to result in significantly reduced IFN-alpha production by PDC in vitro in response to CpG A ligands or inactivated HIV particles. The primary cause of diminished IFN-alpha production was reduced responsiveness of PDC to de novo stimulation, not diminished per cell IFN-alpha production or migration of cells to lymphoid organs. Real-time PCR analysis of purified PDC from patients prior to and during treatment interruptions revealed that active HIV-1 replication is associated with upregulation of type I IFN-stimulated gene expression. Treatment of hepatitis C virus-infected patients with IFN-alpha 2b and ribavirin for hepatitis C virus infection resulted in a profound suppression of de novo IFN-alpha production in response to CpG A or inactivated HIV particles, similar to the response observed in HIV-infected patients. Together, these results suggest that diminished production of type I interferons in vitro by PDC from HIV-1-infected patients may not represent diminished interferon production in vivo. Rather, diminished function in vitro is likely a consequence of prior activation via type I interferons or HIV virions in vivo. C1 [Tilton, John C.; Manion, Maura M.; Luskin, Marlise R.; Johnson, Alison J.; Patamwenu, Andy A.; Hallahan, Claire W.; Cogliano-Shutta, Nancy A.; Mican, Joann M.; Davey, Richard T., Jr.; Kottilil, Shyam; Metcalf, Julia A.; Connors, Mark] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Lifson, Jeffrey D.; Lempicki, Richard A.] NCI, Frederick Inc, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Connors, M (reprint author), NIAID, LIR, NIH, Bldg 10,Rm 11B-09,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM mconnors@niaid.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU Intramural NIH HHS NR 67 TC 57 Z9 59 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 APR PY 2008 VL 82 IS 8 BP 3997 EP 4006 DI 10.1128/JVI.01545-07 PG 10 WC Virology SC Virology GA 284QQ UT WOS:000254721300018 PM 18256146 ER PT J AU Daucher, M Price, DA Brenchley, JM Lamoreaux, L Metcalf, JA Rehm, C Nies-Kraske, E Urban, E Yoder, C Rock, D Gumkowski, J Betts, MR Dybul, MR Douek, DC AF Daucher, Marybeth Price, David A. Brenchley, Jason M. Lamoreaux, Laurie Metcalf, Julia A. Rehm, Catherine Nies-Kraske, Elizabeth Urban, Elizabeth Yoder, Christian Rock, Diane Gumkowski, Julie Betts, Michael R. Dybul, Mark R. Douek, Daniel C. TI Virological outcome after structured interruption of antiretroviral therapy for human immunodeficiency virus infection is associated with the functional profile of virus-specific CD8(+) T cells SO JOURNAL OF VIROLOGY LA English DT Article ID ACUTE HIV-1 INFECTION; CELLULAR IMMUNE-RESPONSES; LYMPHOCYTE RESPONSES; VIRAL LOAD; HIV-1-SPECIFIC CD4(+); TYPE-1 INFECTION; HLA ALLELES; CTL ESCAPE; VIREMIA; EPITOPE AB A clear understanding of the antiviral effects of CD8(+) T cells in the context of chronic human immunodeficiency virus (HIV) infection is critical for the development of prophylactic vaccines and therapeutics designed to support T-cell-mediated immunity. However, defining the potential correlates of effective CD8(+) T-cell immunity has proven difficult; notably, comprehensive analyses have demonstrated that the size and shape of the CD8(+) T-cell response are not necessarily indicative of efficacy determined by measures of plasma viral load. Here, we conducted a detailed quantitative and qualitative analysis of CD8(+) T-cell responses to autologous virus in a cohort of six HIV-infected individuals with a history of structured interruption of antiretroviral therapy (ART) (SIT). The magnitude and breadth of the HIV-specific response did not, by themselves, explain the changes observed in plasma virus levels after the cessation of ART. Furthermore, mutational escape from targeted epitopes could not account for the differential virological outcomes in this cohort. However, the functionality of HIV-specific CD8(+) T-cell populations upon antigen encounter, determined by the simultaneous and independent measurement of five CD8(+) T-cell functions (degranulation and gamma interferon, macrophage inflammatory protein 10, tumor necrosis factor alpha, and interleukin-2 levels) reflected the emergent level of plasma virus, with multiple functions being elicited in those individuals with lower levels of viremia after SIT. These data show that the quality of the HIV-specific CD8(+) T-cell response, rather than the quantity, is associated with the dynamics of viral replication in the absence of ART and suggest that the effects of SIT can be assessed by measuring the functional profile of HIV-specific CD8(+) T cells. C1 [Daucher, Marybeth; Metcalf, Julia A.; Rehm, Catherine; Nies-Kraske, Elizabeth; Urban, Elizabeth; Yoder, Christian; Rock, Diane; Gumkowski, Julie; Dybul, Mark R.] NIAID, Natl Inst Hlth, Immunoregulat Lab, Bethesda, MD 20892 USA. [Daucher, Marybeth] George Washington Univ, Grad Program Genet, Washington, DC 20522 USA. [Price, David A.; Brenchley, Jason M.; Douek, Daniel C.] NIAID, NIH, Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD 20892 USA. [Lamoreaux, Laurie] NIAID, NIH, Vaccine Res Ctr, Immunol Lab, Bethesda, MD 20892 USA. [Price, David A.] Cardiff Univ, Dept Med Biochem & Immunol, Cardiff CF14 4XN, Wales. [Betts, Michael R.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Dybul, Mark R.] US Dept State, Off US Global AIDS Coordinator, Washington, DC 20522 USA. RP Daucher, M (reprint author), NIAID, Natl Inst Hlth, Immunoregulat Lab, Bldg 10-Rm 11B13, Bethesda, MD 20892 USA. EM mdaucher@niaid.nih.gov RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Medical Research Council [G0501963] NR 56 TC 40 Z9 42 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 APR PY 2008 VL 82 IS 8 BP 4102 EP 4114 DI 10.1128/JVI.02212-07 PG 13 WC Virology SC Virology GA 284QQ UT WOS:000254721300028 PM 18234797 ER PT J AU Cao, D Santos, N Jones, RW Tatsumi, M Gentsch, JR Hoshino, Y AF Cao, Dianjun Santos, Norma Jones, Ronald W. Tatsumi, Masatoshi Gentsch, Jon R. Hoshino, Yasutaka TI The VP7 genes of two g9 rotaviruses isolated in 1980 from diarrheal stool samples collected in Washington, DC, are unique molecularly and serotypically SO JOURNAL OF VIROLOGY LA English DT Article ID G9 ROTAVIRUS STRAINS; GLOBAL COLLECTION; VACCINE; GASTROENTERITIS; EXPRESSION; PHENOTYPES; SEROTYPES; CHILDREN; JAPAN AB In a retrospective study of archival diarrheal stool samples collected from 1974 to 1991 at Children's Hospital National Medical Center, Washington, DC, we detected three genotype G9P[8] viruses in specimens collected in 1980, which represented the earliest human G9 viruses ever isolated. The VP7 genes of two culture-adapted 1980 G9 viruses were phylogenetically related closely to the lineage 2 G9 virus VP7 gene. Unexpectedly, however, the VP7s of the 1980 G9 viruses were more closely related serotypically to lineage 3 VP7s than to lineage 2 VP7, which may be supported by amino acid sequence analyses of the VP7 proteins. C1 [Cao, Dianjun; Santos, Norma; Jones, Ronald W.; Tatsumi, Masatoshi; Hoshino, Yasutaka] NIAID, NIH, Infect Dis Lab, Epidemiol Sect, Bethesda, MD 20892 USA. [Santos, Norma] Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, BR-21941 Rio De Janeiro, Brazil. [Gentsch, Jon R.] Ctr Dis Control & Prevent, Gastroenteritis & Resp Viruses Lab Branch, Atlanta, GA 30333 USA. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bldg 50,Room 6308, Bethesda, MD 20902 USA. EM thoshino@niaid.nih.gov RI Santos, Norma/H-6986-2015 OI Santos, Norma/0000-0002-5123-9172 FU Intramural NIH HHS NR 24 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 APR PY 2008 VL 82 IS 8 BP 4175 EP 4179 DI 10.1128/JVI.02537-07 PG 5 WC Virology SC Virology GA 284QQ UT WOS:000254721300037 PM 18234798 ER PT J AU Lauretani, F Semba, RD Bandinelli, S Dayhoff-Brannigan, M Giacomini, V Corsi, AM Guralnik, JM Ferrucci, L AF Lauretani, Fulvio Semba, Richard D. Bandinelli, Stefania Dayhoff-Brannigan, Margaret Giacomini, Vittoria Corsi, Anna Maria Guralnik, Jack M. Ferrucci, Luigi TI Low plasma carotenoids and skeletal muscle strength decline over 6 years SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE carotenoid; fruit; vegetable; Sarcopenia; InCHIANTI study ID MEDITERRANEAN-STYLE DIET; OXIDATIVE STRESS; GRIP STRENGTH; OLDER-ADULTS; SARCOPENIA; INCHIANTI; DISABILITY; EXERCISE; AGE; ANTIOXIDANTS AB Background. Higher intake of fruits and vegetables appears to protect against inflammation, poor physical performance, and disability, but its relationship with muscle strength is unclear. We examined the association between total plasma carotenoids, an indicator of fruit and vegetable intake, and changes in muscle strength over a 6-year follow-up in the participants aged 65 years and older in the InCHIANTI study, a population-based study in Tuscany, Italy. Methods. Plasma carotenoids were measured at enrollment (1998-2000). Hip, knee, and grip strength were measured at enrollment and 6 years later (2004-2006) in 628 of the 948 participants evaluated at baseline. Poor muscle strength was defined as the lowest sex-specific quartile of hip, knee, and grip strength at enrollment. The main outcome was poor muscle strength at the 6-year follow-up visit among those participants originally in the upper three quartiles of strength at enrollment. Results. Overall, 24.9% (110/441), 25.0% (111/444), and 24.9% (118/474) participants developed poor hip, knee, and grip strength, respectively. After adjusting for potential confounders, participants in the lowest versus the highest quartile of total plasma carotenoids at enrollment were at higher risk of developing poor hip (odds ratio [OR] = 3.01, 95% CI, 1.43-6.31, p =.004), knee (OR = 2.89, 95% CI, 1.38-6.02, p =.005), and grip (OR=1.88, 95% CI, 0.93-3.56, p =.07) muscle strength at the 6-year follow-up visit. Conclusion. These findings suggest that older community-dwelling adults with lower plasma carotenoids levels, a marker of poor fruit and vegetable intake, are at a higher risk of decline in skeletal muscle strength over time. C1 [Lauretani, Fulvio; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit, Baltimore, MD 21225 USA. [Lauretani, Fulvio; Giacomini, Vittoria; Corsi, Anna Maria] Tuscany Reg Hlth Agcy, Florence, Italy. [Semba, Richard D.; Dayhoff-Brannigan, Margaret] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Florence, Italy. [Corsi, Anna Maria] Univ Florence, Thrombosis Ctr, Dept Med & Surg Crit Care, I-50121 Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit, Harbor Hosp 5th floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-916413, N01-AG-5-0002, N01-AG-821336, R01 AG027012] NR 30 TC 35 Z9 37 U1 0 U2 2 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2008 VL 63 IS 4 BP 376 EP 383 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 294SO UT WOS:000255426100005 PM 18426961 ER PT J AU Walston, J Fedarko, N Yang, H Leng, S Beamer, B Espinoza, S Lipton, A Zheng, HW Becker, K AF Walston, Jeremy Fedarko, Neal Yang, Huanle Leng, Sean Beamer, Brock Espinoza, Sara Lipton, Anne Zheng, Howie Becker, Kevin TI The physical and biological characterization of a frail mouse model SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE frailty; mouse model ID INTERLEUKIN-10-DEFICIENT MICE; SERUM INTERLEUKIN-6; GERIATRIC SYNDROME; OLDER PERSONS; MUSCLE MASS; INFLAMMATION; APOPTOSIS; PERFORMANCE; MICROARRAY; STRENGTH AB Background. The development of animal models that approximate human frailty is necessary to facilitate etiologic and treatment-focused frailty research. The genetically altered IL-10(tm/tm) mouse does not express the antiinflammatory cytokine interleukin 10 (IL-10) and is, like frail humans, more susceptible to inflammatory pathway activation. We hypothesized that with increasing age, IL-10(tm/tm) mice would develop physical and biological characteristics similar to those of human frailty as compared to C57BL/6J control mice. Methods. Strength, activity, serum IL-6, and skeletal muscle gene expression were compared between age-matched and gender-matched IL-10(tm/tm) mice on C57BL/6J background and C57BL/6J control mice using a longitudinal design for physical characteristics and cross-sectional design for biological characteristics. Results. Strength levels declined significantly faster in IL-10(tm/tm) compared to control mice with increasing age. Serum IL-6 levels were significantly higher in older compared to younger IL-10(tm/tm) mice and were significantly higher in older IL-10(tm/tm) compared to age- and gender-matched C57BL/6J control mice. One hundred twenty-five genes, many related to mitochondrial biology and apoptosis, were differentially expressed in skeletal muscle between 50-week-old IL-10(tm/tm) and 50-week-old C57BL/6J mice. No expression differences between IL-10(tm/tm) age groups were identified by quantitative polymerase chain reaction. Conclusion. These physical and biological findings suggest that the IL-10(tm/tm) mouse develops inflammation and strength decline consistent with human frailty at an earlier age compared to C57BL/6J control type mice. This finding provides rationale for the further development and utilization of the IL-10(tm/tm) mouse to study the biological basis of frailty. C1 [Walston, Jeremy; Fedarko, Neal; Yang, Huanle; Leng, Sean; Beamer, Brock; Espinoza, Sara; Lipton, Anne; Zheng, Howie] Johns Hopkins Univ, Div Geriatr Med & Gerontol, Biol Frailty Working Grp, Baltimore, MD USA. [Becker, Kevin] NIA, Baltimore, MD 21224 USA. RP Walston, J (reprint author), John R Burton Pavil,5505 Bayview Circle, Baltimore, MD 21224 USA. EM jwalston@jhmi.edu OI Becker, Kevin/0000-0002-6794-6656 FU NIA NIH HHS [P30 AG021334] NR 27 TC 60 Z9 62 U1 0 U2 5 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2008 VL 63 IS 4 BP 391 EP 398 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 294SO UT WOS:000255426100007 PM 18426963 ER PT J AU You, TJ Nicklas, BJ Ding, JZ Penninx, BWJH Goodpaster, BH Bauer, DC Tylavsky, FA Harris, TB Kritchevsky, SB AF You, Tongjian Nicklas, Barbara J. Ding, Jingzhong Penninx, Brenda W. J. H. Goodpaster, Bret H. Bauer, Douglas C. Tylavsky, Frances A. Harris, Tamara B. Kritchevsky, Stephen B. CA Hlth Aging Body Composition Study TI The metabolic syndrome is associated with circulating adipokines in older adults across a wide range of adiposity SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE metabolic syndrome; adipokines; adiposity; aging ID C-REACTIVE PROTEIN; CARDIOVASCULAR EVENTS; INTERLEUKIN-10 LEVELS; POSTMENOPAUSAL WOMEN; OBESE SUBJECTS; VISCERAL FAT; TISSUE; INFLAMMATION; ADIPONECTIN; MARKERS AB Background. Circulating levels of adipokines are elevated with adiposity and are closely linked with the clustering of traditional metabolic risk factors for cardiovascular disease. The purpose of this study was to examine the relationship of metabolic syndrome to several adipokines and the role of total and visceral adiposity in influencing this relationship in older adults. Methods. A cross-sectional analysis was conducted including 1914 individuals aged 70-79 years without cardiovascular disease or type 2 diabetes. The metabolic syndrome was defined by the updated Adult Treatment Panel III criteria. Circulating levels of leptin, adiponectin, plasminogen activator inhibitor type 1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) were measured. Body composition and abdominal visceral fat area were determined. Results. Both the presence of metabolic syndrome and the number of metabolic syndrome components were associated with higher levels of leptin, PAI-1, IL-6, TNF-a, and CRP and with lower levels of adiponectin (all p < .0001). The odds ratios for the prevalence of metabolic syndrome associated with adipokines were attenuated after adjustment for total fat mass and/or visceral fat area, but remained significant. Levels of leptin, PAI-1, IL-6, and TNF-alpha were higher (all p < .05 to p < .0001), and adiponectin was lower (all p < .0001), in persons with, compared to those without, metabolic syndrome within each tertile of percent body fat. Conclusion. The metabolic syndrome is associated with adipokines in older adults across a wide range of adiposity, including in those with low or normal overall fatness. C1 [You, Tongjian] SUNY Buffalo, Dept Exercise & Nutr Sci, Buffalo, NY 14214 USA. [Nicklas, Barbara J.; Ding, Jingzhong; Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Goodpaster, Bret H.] Univ Pittsburgh, Dept Med, Div Endocrinol & Metab, Pittsburgh, PA 15260 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Tylavsky, Frances A.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Kritchevsky, Stephen B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP You, TJ (reprint author), SUNY Buffalo, Dept Exercise & Nutr Sci, 214A Kimball Tower, Buffalo, NY 14214 USA. EM tyou@buffalo.edu FU Intramural NIH HHS; NIA NIH HHS [N01-AG-62106, N01-AG-62101, N01-AG-62103, P30-AG-21332, R01-AG/DK-20583] NR 31 TC 55 Z9 61 U1 0 U2 0 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2008 VL 63 IS 4 BP 414 EP 419 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 294SO UT WOS:000255426100010 PM 18426966 ER PT J AU Alpers, C Bloom, RD Fabrizi, F Izopet, J Jadoul, M Lindley, E Martin, P Morales, JM Natov, S Pol, S Reddy, KR Rostaing, L Roth, D Wei, L Alter, M Lavanchy, D Meyers, C Seeff, L Eknoyan, G Lameire, N Balk, E Craig, J Earley, A Gordon, C Ioannidis, J Jadoul, M Roth, D AF Alpers, Charles Bloom, Roy D. Fabrizi, Fabrizio Izopet, Jacques Jadoul, Michel Lindley, Elizabeth Martin, Paul Morales, Jose M. Natov, Svetlozar Pol, Stanislas Reddy, K. Rajender Rostaing, Lionel Roth, David Wei, Lai Alter, Miriam Lavanchy, Daniel Meyers, Catherine Seeff, Leonard Eknoyan, Garabed Lameire, Norbert Balk, Ethan Craig, Jonathan Earley, Amy Gordon, Craig Ioannidis, John Jadoul, Michel Roth, David TI KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease - Introduction SO KIDNEY INTERNATIONAL LA English DT Review ID RENAL-TRANSPLANT RECIPIENTS; POSTTRANSPLANT DIABETES-MELLITUS; INTERFERON-ALPHA TREATMENT; LONG-TERM IMPACT; CHRONIC-HEMODIALYSIS PATIENTS; POLYMERASE-CHAIN-REACTION; CHRONIC DIALYSIS PATIENTS; CHRONIC ACTIVE HEPATITIS; VIRUS-ASSOCIATED GLOMERULONEPHRITIS; FIBROSING CHOLESTATIC HEPATITIS C1 [Alpers, Charles] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Bloom, Roy D.] Univ Penn, Philadelphia, PA 19104 USA. [Fabrizi, Fabrizio] Maggiore Hosp, IRCCS, Milan, Italy. [Izopet, Jacques; Rostaing, Lionel] CHU Toulouse, Organ Transplantat Unit, Toulouse, France. [Jadoul, Michel] Clin Univ St Luc, Dept Nephrol, St Louis, France. [Jadoul, Michel] Univ Catholique Louvain, Louvain, Belgium. [Lindley, Elizabeth] Leeds Teaching Hosp NHS Trust, Leeds, W Yorkshire, England. [Martin, Paul] Mt Sinai Sch Med, New York, NY 10029 USA. [Morales, Jose M.] Hosp 12 Octubre, Dept Nephrol, Renal Transplant Unit, E-28041 Madrid, Spain. [Natov, Svetlozar] Kindred Hosp NE, Waltham, MA USA. [Pol, Stanislas] Hop Cochin, Paris, France. [Reddy, K. Rajender] UPHS, Div Gastroenterol, Philadelphia, PA USA. [Reddy, K. Rajender] Liver Transplantat Penn Transplant Inst, Philadelphia, PA USA. [Roth, David] Univ Miami, Sch Med, Div Nephrol & Hypertens, Coral Gables, FL 33124 USA. [Wei, Lai] Peking Univ, Peoples Hosp, Inst Hepatol, Beijing, Peoples R China. [Lavanchy, Daniel] WHO, Dept Communicalbe Dis Surveillance & Response, Washington, DC USA. [Meyers, Catherine] NIDDK, NIH, Bethesda, MD 20892 USA. [Meyers, Catherine] NIDDKD, Bethesda, MD USA. [Seeff, Leonard] NIH, Bethesda, MD 20892 USA. [Seeff, Leonard] US FDA, Rockville, MD 20857 USA. [Seeff, Leonard] VA Med Ctr, Bethesda, MD USA. [Seeff, Leonard] Georgetown Univ, Washington, DC 20057 USA. [Seeff, Leonard] Amer Assoc Study Liver Dis, New York, NY USA. [Eknoyan, Garabed] Baylor Coll Med, Nephrol Sect, Houston, TX 77030 USA. [Lameire, Norbert] State Univ Ghent Hosp, Ghent, Belgium. [Balk, Ethan] Tufts Univ, Medford, MA 02155 USA. [Balk, Ethan; Earley, Amy] Tufts Univ New England Med Ctr, CPG, NKF, Dev & Implementat, Boston, MA USA. [Craig, Jonathan] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Craig, Jonathan] Childrens Hosp Westmead, Westmead, NSW, Australia. [Ioannidis, John] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Ioannidis, John] Fdn Res & Technol Hellas, Biomed Res Inst, Ioannina, Greece. [Ioannidis, John] Tufts Univ New England Med Ctr, Dept Med, Boston, MA USA. RP Alpers, C (reprint author), Univ Washington, Med Ctr, Seattle, WA 98195 USA. RI Jadoul, Michel/B-8779-2008; Ioannidis, John/G-9836-2011; IZOPET, Jacques/L-5756-2014; Craig, Jonathan/E-2813-2013 OI Craig, Jonathan/0000-0002-2548-4035 NR 416 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD APR PY 2008 VL 73 SU 109 BP S6 EP S99 DI 10.1038/ki.2008.83 PG 94 WC Urology & Nephrology SC Urology & Nephrology GA 282HT UT WOS:000254559200002 ER PT J AU Shin, JW Jin, P Stroncek, D AF Shin, Jeung Won Jin, Ping Stroncek, David TI Effect of leukapheresis on gene expression profiles of donor's peripheral blood mononuclear cells SO KOREAN JOURNAL OF LABORATORY MEDICINE LA Korean DT Article DE leukapheresis; gene expression profile; cDNA microarray; PBMC ID MATURE DENDRITIC CELLS; COBE-SPECTRA; STEM-CELLS; COLLECTION; PLUS AB Background : Leukapheresis has commonly been used to obtain the cell products intended for clinical cell therapy. Hypocalcemia related to citrate toxicity and some circulatory effects such as hypovolemia and hypotension are well-known complications of leukapheresis. In this study, we analyzed the gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained before and after leukapheresis to determine if the hemodynamic changes can affect the gene expression profiles of leukocyles. Methods : PBMCs were isolated from EDTA blood from 5 healthy donors collected before and immediately after apheresis. RNA was isolated, amplified, and analyzed using a cDNA microarray with 17,500 genes. Hierarchical clustering analysis was performed to evaluate the differences of gene expression profiling. Results : Hierarchical clustering separated PBMCs from different donors with each other, but did not separate PBMCs collected before and after leukapheresis. Comparison of gene expression by PBMCs collected before and after leukapheresis found only 25 genes were differentially expressed (15 were up-regulated and 10 were down-regulated after leukapheresis) (F-test, P<0.005). Stress induced apoptosis-related genes, ANXA3, DEDD, and A TXN2L, and cytokine-related genes, IL 13RA1 and K which were also related to stress, were up-regulated after leukapheresis. Genes involved in DNA and protein binding, such as CLSTN3, LRBA, SATB2, and HSPA8, were down-regulated. Conclusions : Leukapheresis had little effect on gene expression of PBMCs. Some genes showing differences between before and after leukapheresis were mainly involved in stress-related reactions. C1 [Shin, Jeung Won] Soonchunhyang Univ Hosp, Dept Lab Med, Seoul, South Korea. [Jin, Ping; Stroncek, David] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Shin, JW (reprint author), Soonchunhyang Univ Hosp, Dept Lab Med, Seoul, South Korea. EM jwshin@hosp.sch.ac.kr NR 19 TC 0 Z9 0 U1 0 U2 1 PU KOREAN SOC LABORATORY MEDICINE PI SEOUL PA KOREAN MEDICAL ASSOC BLDG, RM 602,302-75 ICHON 1-DONG, YONGSAN-GU, SEOUL, 140-721, SOUTH KOREA SN 1598-6535 J9 KOR J LAB MED JI Kor. J. Lab. Med. PD APR PY 2008 VL 28 IS 2 BP 130 EP 135 DI 10.3343/kjlm.2008.28.2.130 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 300QU UT WOS:000255841100007 PM 18458509 ER PT J AU Kim, SS Romero, R Kim, JS Abbas, A Espinoza, J Kusanovic, JP Hassan, S Yoon, BH Kim, CJ AF Kim, Sung-Su Romero, Roberto Kim, Jung-Sun Abbas, Asad Espinoza, Jimmy Kusanovic, Juan Pedro Hassan, Sonia Yoon, Bo Hyun Kim, Chong Jai TI Coexpression of myofibroblast and macrophage markers: novel evidence for an in vivo plasticity of chorioamniotic mesodermal cells of the human placenta SO LABORATORY INVESTIGATION LA English DT Article DE chorioamniotic membranes; mesodermal layer; myofibroblast; macrophage; PU.1 ID HUMAN FETAL MEMBRANES; CIRCULATING CD14(+) MONOCYTES; DR-POSITIVE CELLS; CLINICAL-SIGNIFICANCE; INTACT MEMBRANES; PRETERM LABOR; DIFFERENTIATION; TERM; PROGENITORS; INFECTION AB Human chorioamniotic membranes generate temporary but large mucosal surfaces. Due to lack of fetal vessels, macrophages represent the only subset of immunocytes of fetal origin available in the chorioamniotic mesodermal layer. This layer contains two distinct groups of cells: the fibroblasts/myofibroblasts and the macrophages; however, the relative contribution of these two cell populations has been a point of contention. In addressing various discrepancies, we hypothesized that cells in the chorioamniotic mesodermal layer have plasticity. Immunophenotyping of these cells using a panel of antibodies (CD14, CD68, CD163, HLA-DR, type I procollagen, a-smooth muscle actin, desmin, vimentin) revealed coexpression of both myofibroblast and macrophage markers. The proportion of CD14+ macrophages was higher in inflamed chorioamniotic membranes (P<0.05). Cells immunoreactive to the macrophage markers showed nuclear expression of PU.1, a hematopoietic cell-specific transcription factor. Furthermore, treatment with proinflammatory cytokines (IL-1 beta and TNF alpha) or Toll-like receptor-4 overexpression upregulated PU.1 mRNA expression in chorioamniotic mesodermal cells. Overexpression of PU.1 in chorionic mesodermal cells increased the expression of CD14 mRNA and protein. A reporter gene assay and chromatin immunoprecipitation demonstrated binding of PU.1 to the CD14 promoter region. This study reports that chorioamniotic mesodermal cells display plasticity ranging from overt transformation of fibroblast/myofibroblast to macrophages, and that PU.1 plays a role in macrophage differentiation. Chorioamniotic mesodermal cells are another novel example of phenotypic switching between fibroblast/myofibroblast and macrophage. The findings reported herein suggest that the plasticity of mesodermal cells is an effective mechanism of the chorioamniotic membranes to manage several biological needs, such as mucosal immune defense and the maintenance/disruption of physical integrity, with a limited pool of cells. C1 [Kim, Sung-Su; Romero, Roberto; Kim, Jung-Sun; Abbas, Asad; Espinoza, Jimmy; Kusanovic, Juan Pedro; Hassan, Sonia; Kim, Chong Jai] NICHD NIH DHHS, Perinatol Res Branch, Bethesda, MD USA. [Romero, Roberto] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Kim, Jung-Sun; Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI USA. [Kim, Jung-Sun; Espinoza, Jimmy; Hassan, Sonia] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI USA. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD NIH DHHS, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; cjkim@med.wayne.edu RI Yoon, Bo Hyun/H-6344-2011 FU Intramural NIH HHS NR 42 TC 15 Z9 16 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD APR PY 2008 VL 88 IS 4 BP 365 EP 374 DI 10.1038/labinvest.3700749 PG 10 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 278QA UT WOS:000254300200004 PM 18227805 ER PT J AU Moore, LE Pfeiffer, RM Poscablo, C Real, FX Kogevinas, M Silverman, D Garcia-Closas, R Chanock, S Tardon, A Serra, C Carrato, A Dosemeci, M Garcia-Closas, M Esteller, M Fraga, M Rothman, N Malats, N AF Moore, Lee E. Pfeiffer, Ruth M. Poscablo, Cristina Real, Francisco X. Kogevinas, Manolis Silverman, Debra Garcia-Closas, Reina Chanock, Stephen Tardon, Adonina Serra, Consol Carrato, Alfredo Dosemeci, Mustafa Garcia-Closas, Montserrat Esteller, Manel Fraga, Mario Rothman, Nathaniel Malats, Nuria TI Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case-control study SO LANCET ONCOLOGY LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; CHROMOSOMAL-ABERRATIONS; GENETIC INSTABILITY; METHYLATION LEVEL; URINARY-BLADDER; LYMPHOCYTES; RISK; POLYMORPHISMS; METABOLISM; SEQUENCES AB Background DNA hypomethylation has been suggested to cause genomic instability and increase cancer risk. aimed to test the hypothesis that DNA hypomethylation is associated with increased risk of bladder cancer. We Methods We measured cytosine methylation (5-mC) content in genomic DNA from blood cells from patients with bladder cancer enrolled in a large case-control study in Spain between Jan 1, 1998, and Dec 31, 2001. Cases were men and women with newly diagnosed and histologically confirmed urothelial carcinoma of the bladder. Controls were selected from patients admitted to the same hospital for diseases or conditions unrelated to smoking or other known risk factors for bladder cancer. Controls were individually matched to cases on age (within 5 years), sex, race, and area of hospital referral. 5-mC content was measured in leucocyte DNA by use of a combination of high-performance capillary electrophoresis, Hpa II digestion, and densitometry. Data on demographics, 34 polymorphisms in nine folate metabolism genes, and nutritional intake of six B vitamins (including folate), alcohol, and smoking were assessed as potential confounders. Relative 5-mC content was expressed as a percentage (%5-mC) with respect to the total cytosine content (the sum of methylated and non-methylated cytosines). The primary endpoint was median %5-mC DNA content. Findings %5-mC was measured in leucocyte DNA from 775 cases and 397 controls. Median %5-mC DNA was significantly lower in cases (3-03% [IQR 2.17-3-56]) than in controls (3-19% [2-46-3-681, p=0.0002). All participants were subsequently categorised into quartiles by %5-mC content in controls. When the highest quartile of %5-mC content was used as the reference category (Q4), the following adjusted odds ratios (OR) and 95% CI were recorded for decreasing methylation quartiles: OR(Q3) 2.05 (95% CI 1.37-3-06); OR(Q2) 1.62 (1.07-2.44); and OR(Q1) 2.67 (1.77-4.03), p for trend <0.0001. The lowest cancer risk was noted in never smokers in the highest methylation quartile (never smokers in Q4). By comparison with never smokers in the highest quartile, current smokers in the lowest methylation quartile had the highest risk of bladder cancer (Q1: OR 25.51 [9.61-67.76], p for interaction 0.06). In analyses stratified by smoking, hypomethylation was a strong risk factor in never smokers (OR 6.39 [2.37-17.22]). Amount of methylation in controls were not associated with baseline characteristics, micronutrients, or selected genotypes in folate metabolism pathways. Interpretation For the first time, to our knowledge, we have shown in a large case-control study that leucocyte DNA hypomethylation is associated with increased risk of developing bladder cancer, and this association is independent of smoking and the other assessed risk factors. Amount of global methylation in genomic DNA could provide a useful biomarker of susceptibility to certain cancer types and further research is warranted. Funding Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA, and Fondo de Investigacion Sanitaria, Spain (G03/174). C1 [Moore, Lee E.; Pfeiffer, Ruth M.; Poscablo, Cristina; Silverman, Debra; Dosemeci, Mustafa; Garcia-Closas, Montserrat; Rothman, Nathaniel] NIH, Div Can Epidemiol & Genet, Natl Canc Inst, Dept Hlth & Human Serv, Rockville, MD USA. [Chanock, Stephen] Natl Canc Inst, Core Genotyping Facility, Adv Technol Ctr, Dept Hlth & Human Serv, Rockville, MD USA. [Real, Francisco X.; Esteller, Manel; Fraga, Mario; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Kogevinas, Manolis] Med Res Inst IMIM, Res Ctr Environm Epidemiol, Barcelona, Spain. [Kogevinas, Manolis] CIBER Epidemiol & Publ Hlth, Barcelona, Spain. [Kogevinas, Manolis] Univ Crete, Sch Med, Iraklion, Greece. [Garcia-Closas, Reina] Univ Hosp Canarias, San Cristobal la Laguna, Spain. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Serra, Consol] Univ Pompeu Frabra, Barcelona, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Carrato, Alfredo] Univ Hosp Elche, Elche, Spain. RP Moore, LE (reprint author), NIH, Div Can Epidemiol & Genet, Natl Canc Inst, Dept Hlth & Human Serv, Rockville, MD USA. EM moorele@mail.nih.gov RI Serra, C/E-6879-2014; Garcia-Closas, Montserrat /F-3871-2015; Esteller, Manel/L-5956-2014; Kogevinas, Manolis/C-3918-2017 OI Serra, C/0000-0001-8337-8356; Garcia-Closas, Montserrat /0000-0003-1033-2650; Esteller, Manel/0000-0003-4490-6093; FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 148 Z9 153 U1 0 U2 28 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2008 VL 9 IS 4 BP 359 EP 366 DI 10.1016/51470-2045(08)70038-X PG 8 WC Oncology SC Oncology GA 284EL UT WOS:000254689000023 PM 18339581 ER PT J AU Caudell, D Aplan, PD AF Caudell, D. Aplan, P. D. TI The role of CALM-AF10 gene fusion in acute leukemia SO LEUKEMIA LA English DT Review DE CALM-AF10; acute leukemia; chromosomal translocations; t(10;11) ID ACUTE MYELOID-LEUKEMIA; ACUTE MEGAKARYOBLASTIC LEUKEMIA; CLATHRIN ASSEMBLY PROTEIN; ACUTE LYMPHOBLASTIC LEUKEMIAS; HEMATOPOIETIC STEM-CELLS; MLL-REARRANGED LEUKEMIAS; LEUCINE-ZIPPER; HEMATOLOGICAL MALIGNANCIES; MOLECULAR CHARACTERIZATION; CHROMOSOME TRANSLOCATIONS AB Chromosomal translocations are important genetic perturbations frequently associated with hematologic malignancies; characterization of these events has been a rich source of insights into the mechanisms that lead to malignant transformation. The t(10; 11)(p13; q14-21) results in a recently identified rare but recurring chromosomal translocation seen in patients with ALL as well as AML, and results in the production of a CALM-AF10 fusion gene. Although the details by which the CALM-AF10 fusion protein exerts its leukemogenic effect remain unclear, emerging data suggests that the CALM-AF10 fusion impairs differentiation of hematopoietic cells, at least in part via an upregulation of HOXA cluster genes. This review discusses the normal structure and function of CALM and AF10, describes the spectrum of clinical findings seen in patients with CALM-AF10 fusions, summarizes recently published CALM-AF10 mouse models and highlights the role of HOXA cluster gene activation in CALM-AF10 leukemia. C1 [Caudell, D.; Aplan, P. D.] NCI, NIH, Genet Branch, Bethesda, MD 20889 USA. [Caudell, D.] NCI, NIH, Comparat Mol Pathol Unit, Bethesda, MD USA. [Caudell, D.] Univ Maryland, Dept Vet Med Sci, College Pk, MD 20742 USA. RP Aplan, PD (reprint author), NCI, NIH, Genet Branch, NNMC Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Aplan, Peter/K-9064-2016 FU Intramural NIH HHS [Z01 SC010378-06] NR 74 TC 29 Z9 29 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD APR PY 2008 VL 22 IS 4 BP 678 EP 685 DI 10.1038/sj.leu.2405074 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 288SR UT WOS:000255006600003 PM 18094714 ER PT J AU Rizzatti, EG Mora-Jensen, H Weniger, MA Gibellini, F Lee, E Daibata, M Lai, R Wiestner, A AF Rizzatti, Edgar Gil Mora-Jensen, Helena Weniger, Marc Andree Gibellini, Federica Lee, Elinor Daibata, Masanori Lai, Raymond Wiestner, Adrian TI Noxa mediates bortezomib induced apoptosis in both sensitive and intrinsically resistant mantle cell lymphoma cells and this effect is independent of constitutive activity of the AKT and NF-kappa B pathways SO LEUKEMIA & LYMPHOMA LA English DT Article; Proceedings Paper CT Conference on Targets and Targeted Drugs in Chronic Myeloid Leukemia CY OCT 26-28, 2007 CL Vienna, AUSTRIA DE mantle cell lymphoma; bortezomib; proteasome inhibitor; Noxa; Akt; NF-kappa B ID PROTEASOME INHIBITOR BORTEZOMIB; NON-HODGKINS-LYMPHOMA; BH3-ONLY PROTEIN BIM; MYELOMA CELLS; BREAST-CANCER; PHASE-II; HOMOZYGOUS DELETIONS; LEUKEMIA-CELLS; ACTIVATION; GENES AB Bortezomib is more active against mantle cell lymphoma (MCL) than against most other lymphoma subtypes. Nevertheless, up to half of patients with MCL have bortezomib resistant disease. Factors contributing to intrinsic resistance to bortezomib have not been determined. Here we used a panel of eight bortezomib sensitive (median IC(50) 5.9 nM) and three relatively bortezomib resistant cell lines (median IC(50) 12.9 nM) to investigate differences in tumor biology that could determine sensitivity to bortezomib. Bortezomib effectively inhibited high baseline proteasome activity and induced a comparable degree of proteasome inhibition in both sensitive and resistant cells. At 10 nM, bortezomib induced the proapoptotic BH3-only protein Noxa in sensitive but not resistant cells. At higher concentrations of bortezomib, however, Noxa was also upregulated in resistant cells and this effect was sufficient to induce apoptosis. Silencing of Noxa with siRNA rescued these cells from apoptosis, arguing against a defect in Noxa regulation or function as the basis of bortezomib resistance. Bortezomib was equally effective against cells with high and low constitutive NF-kappa B signaling. Also, sensitive and resistant MCL cell lines showed comparable activation of the AKT pathway. We conclude that bortezomib can overcome classic mechanisms of resistance to apoptosis and that determinants of bortezomib sensitivity in MCL are due to differences in signaling or stress pathways upstream of Noxa. C1 [Rizzatti, Edgar Gil; Mora-Jensen, Helena; Weniger, Marc Andree; Gibellini, Federica; Lee, Elinor; Wiestner, Adrian] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Daibata, Masanori] Kochi Med Sch, Dept Hematol & Resp Med, Kochi, Japan. [Lai, Raymond] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, Bldg 10 CRC,Room 3-5140,10 Ctr Dr,MSC 1202, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov FU Intramural NIH HHS NR 40 TC 44 Z9 44 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD APR PY 2008 VL 49 IS 4 BP 798 EP 808 DI 10.1080/10428190801910912 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 304GU UT WOS:000256098800034 PM 18398749 ER PT J AU Gross, C Holler, E Stangl, S Dickinson, A Pockley, AG Asea, AA Mallappa, N Multhoff, G AF Gross, Catharina Holler, Ernst Stangl, Stefan Dickinson, Anne Pockley, A. Graham Asea, Alexzander A. Mallappa, Nagaraj Multhoff, Gabriele TI An Hsp70 peptide initiates NK cell killing of leukemic blasts after stem cell transplantation SO LEUKEMIA RESEARCH LA English DT Article DE hsp70 peptide TKD; HLA-E; NK cells; stem cell transplantation; cytotoxicity ID NATURAL-KILLER-CELLS; HEAT-SHOCK-PROTEIN; BONE-MARROW TRANSPLANTATION; HUMAN TUMOR-CELLS; CYTOLYTIC ACTIVITY; SURFACE EXPRESSION; THERAPY; CANCER; LYMPHOCYTES AB In contrast to solid tumors, leukemic blasts frequently present both Hsp70 and HLA-E on their cell Surface and thereby present activating and inhibitory signals to CD94(+) NK cells. In the first 12 months after stem cell trail splantation (SCT) CD94(+) NK cells clearly dominate over CD3(+)/CD16(-)/56(-) T and CD3(+)/CD16(+)/56(+) NK-like T cells. An incubation of post-SCT-derived peripheral blood lymphocytes with the Hsp70 peptide TKD and IL-15 enhances the cell surface density of CD56/CD94 and initiates the cytolytic activity of NK cells against Hsp70/HLA-E double-positive autologous and allogeneic leukemic blasts. Hsp70 was identified as the target structure for TKD-activated NK cells. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Multhoff, Gabriele] KKG Innate Immun & Tumor Biol, Inst Pathol, GSF, D-81675 Munich, Germany. [Gross, Catharina] NIAID, NIH, Rockville, MD USA. [Holler, Ernst] Univ Hosp, Dept Hematol & Oncol, Regensburg, Germany. [Stangl, Stefan; Pockley, A. Graham; Mallappa, Nagaraj; Multhoff, Gabriele] Tech Univ Munich, Dept Radiotherapy Radiooncol, D-81675 Munich, Germany. [Stangl, Stefan; Pockley, A. Graham; Mallappa, Nagaraj; Multhoff, Gabriele] Tech Univ Munich, Inst Pathol, GSF, D-81675 Munich, Germany. [Dickinson, Anne] Univ Newcastle Upon Tyne, Sch Clin Lab Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Pockley, A. Graham] Univ Sheffield, Sch Med & Biomed Sci, Immunobiol Res Unit, Sheffield, S Yorkshire, England. [Asea, Alexzander A.; Mallappa, Nagaraj] Scott & White Mem Hosp & Clin, Div Investigat Pathol, Temple, TX USA. [Asea, Alexzander A.; Mallappa, Nagaraj] Texas A&M Univ Syst, Coll Med, Hlth Sci Ctr, Temple, TX USA. RP Multhoff, G (reprint author), Tech Univ Munich, Univ Hosp Rechts Isar, Dept Radiotherapy Radiooncol, Ismaningerstr 22, D-81675 Munich, Germany. EM gabriele.multhoff@lrz.tu-muenchen.de RI Asea, Alexzander/I-4112-2013; OI Asea, Alexzander/0000-0003-3592-3481; Pockley, Alan/0000-0001-9593-6431 NR 29 TC 8 Z9 9 U1 0 U2 7 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 APR PY 2008 VL 32 IS 4 BP 527 EP 534 DI 10.1016/j.leukres.2007.03.027 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 284RU UT WOS:000254724300003 PM 17543383 ER PT J AU Xu, S Yang, JH Shen, J AF Xu, Su Yang, Jehoon Shen, Jun TI Inverse polarization transfer for detecting in vivo C-13 magnetization transfer effect of specific enzyme reactions in H-1 spectra SO MAGNETIC RESONANCE IMAGING LA English DT Article DE proton detection; carbon-13; magnetization transfer effect ID TRANSFER KINETIC MEASUREMENTS; RAT-BRAIN; DEHYDROGENASE REACTION; INCOMPLETE SATURATION; CROSS-POLARIZATION; 11.7 TESLA; NMR; SPECTROSCOPY; EXCHANGE; ENHANCEMENT AB The wide chemical shift dispersion and long T-1 of C-13 have allowed determination of in vivo magnetization transfer effects caused by aspartate aminotransferase and lactate dehydrogenase reactions using 13C magnetic resonance spectroscopy. In this report, we demonstrate that these effects can be observed in the proton spectra by transferring the equilibrium magnetization of 13C via the one-bond scalar coupling between 13 C and 1 H using an inverse insensitive nuclei enhanced by polarization transfer-based heteronuclear polarization transfer method. This inverse method allows a combination of the advantages of the long 13 C T, for maximum magnetization transfer and the high sensitivity of proton detection. The feasibility of this in vivo inverse polarization transfer approach was evaluated for detecting the 13C magnetization transfer effect of aspartate aminotransferase and lactate dehydrogenase reactions from a 72.5-mu l voxel in the rat brain at 11.7 T. Published by Elsevier Inc. C1 [Xu, Su; Yang, Jehoon; Shen, Jun] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU Intramural NIH HHS [NIH0011550095]; PHS HHS [NIH0011550095] NR 33 TC 2 Z9 2 U1 1 U2 2 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 APR PY 2008 VL 26 IS 3 BP 413 EP 419 DI 10.1016/j.mri.2007.07.010 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 276ZD UT WOS:000254181300013 PM 18063339 ER PT J AU Kellman, P Chefd'hotel, C Lorenz, CH Mancini, C Arai, AE McVeigh, ER AF Kellman, Peter Chefd'hotel, Christophe Lorenz, Christine H. Mancini, Christine Arai, Andrew E. McVeigh, Elliot R. TI Fully automatic, retrospective enhancement of real-time acquired cardiac cine MR images using image-based navigators and respiratory motion-corrected averaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; heart; real-time; parallel MRI; SENSE; navigator; motion correction; nonrigid; myocardial function; regional wall motion ID LEFT-VENTRICULAR FUNCTION; MYOCARDIAL-INFARCTION; RAPID EVALUATION; BREATH-HOLD; RECONSTRUCTION; ANGIOGRAPHY; GRAPPA; MASS AB Real-time imaging may be clinically important in patients with congestive heart failure, arrhythmias, or in pediatric cases. However, real-time imaging typically has compromised spatial and temporal resolution compared with gated, segmented studies. To combine the best features of both types of imaging, a new method is proposed that uses parallel imaging to improve temporal resolution of real-time acquired images at the expense of signal-to-noise ratio (SNR), but then produces an SNR-enhanced cine by means of respiratory motion-corrected averaging of images acquired in real-time over multiple heartbeats while free-breathing. The retrospective processing based on image-based navigators and nonrigid image registration is fully automated. The proposed method was compared with conventional cine images in 21 subjects. The resultant image quality for the proposed method (3.9 +/- 0.44) was comparable to the conventional cine (4.2 +/- 0.99) on a 5-point scale (P = not significant [n.s.]). The conventional method exhibited degraded image quality in cases of arrhythmias whereas the proposed method had uniformly good quality. Motion-corrected averaging of real-time acquired cardiac images provides a means of attaining high-quality cine images with many of the benefits of real-time imaging, such as free-breathing acquisition and tolerance to arrhythmias. C1 [Kellman, Peter; Mancini, Christine; Arai, Andrew E.] NHLBI, Cardiac Energet Lab, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chefd'hotel, Christophe] Siemens Corp Res, Princeton, NJ USA. [Lorenz, Christine H.] Siemens Corp Res, Baltimore, MD USA. [McVeigh, Elliot R.] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. RP Kellman, P (reprint author), NHLBI, Cardiac Energet Lab, Dept Hlth & Human Serv, 10 Ctr Dr,MSC-1061,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM kellman@nih.gov FU Intramural NIH HHS NR 23 TC 45 Z9 45 U1 0 U2 4 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 APR PY 2008 VL 59 IS 4 BP 771 EP 778 DI 10.1002/mrm.21509 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 283OI UT WOS:000254645500013 PM 18302227 ER PT J AU van Gelderen, P de Zwart, JA Duyn, JH AF van Gelderen, P. de Zwart, J. A. Duyn, J. H. TI Pittfalls of MRI measurement of white matter perfusion based on arterial spin labeling SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE arterial spin labeling; white matter; perfusion; transit time; cerebral blood flow ID CEREBRAL-BLOOD-FLOW; NORMAL-PRESSURE HYDROCEPHALUS; POSITRON-EMISSION-TOMOGRAPHY; TRANSIT-TIME; 3.0 TESLA; BRAIN; CONTRAST; QUANTIFICATION; SENSITIVITY; RELAXATION AB Although arterial spin labeling (ASL) MRI has been successfully applied to measure gray matter (GM) perfusion in vivo, accurate detection of white matter (WM) perfusion has proven difficult. Reported literature values are not consistent with each other or with perfusion measured with other modalities. In this work, the cause of these inconsistencies is investigated. The results suggest that WM perfusion values are substantially affected by the limited image resolution and by signal losses caused by the long transit times in WM, which significantly affect the label. From gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) bolus-tracking experiments (N = 6), it is estimated that the transit time can be several seconds long in deep WM. Furthermore, simulations show that even at a spatial resolution of 7 mu l voxel size, contamination by the GM signals can exceed 40% of the actual WM signal. From 10-min long flow-sensitive alternating inversion recovery ASL (FAIR-ASL) measurements at 3T in normal subjects (N = 7), using highly sensitive detectors, it is shown that single-voxel (7 mu l) deep WM perfusion values have an signal-to-noise ratio (SNR) less than 1. The poor sensitivity and heterogeneous transit time limit the applicability of ASL for measurement of perfusion in WM. C1 [van Gelderen, P.; de Zwart, J. A.; Duyn, J. H.] NINDS, Adv MRI, LFMI, NIH, Bethesda, MD 20892 USA. RP van Gelderen, P (reprint author), NINDS, Adv MRI, LFMI, NIH, 10 Ctr Dr,Bldg 10,Rm B1D-725, Bethesda, MD 20892 USA. EM gelderen@nih.gov RI Duyn, Jozef/F-2483-2010 FU Intramural NIH HHS NR 36 TC 70 Z9 70 U1 1 U2 2 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 APR PY 2008 VL 59 IS 4 BP 788 EP 795 DI 10.1002/mrm.21515 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 283OI UT WOS:000254645500015 PM 18383289 ER PT J AU Komlosh, ME Lizak, MJ Horkay, F Freidlin, RZ Basser, PJ AF Komlosh, M. E. Lizak, M. J. Horkay, F. Freidlin, R. Z. Basser, P. J. TI Observation of microscopic diffusion anisotropy in the spinal cord using double-pulsed gradient spin echo MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; double; pulsed gradient; diffusion; anisotropy; multiple scattering; white matter; gray matter; spinal cord; phantom; filter; DTI ID GRAY-MATTER; WEIGHTED MR; FIELD-GRADIENT; PGSE NMR; SYSTEM; WATER AB A double-pulsed gradient spin echo (d-PGSE) filtered MRI sequence is proposed to detect microscopic diffusion anisotropy in heterogeneous specimen. The technique was developed, in particular, to characterize local microscopic anisotropy in specimens that are macroscopically isotropic, such as gray matter. In such samples, diffusion tensor MRI (DTI) produces an isotropic or nearly isotropic diffusion tensor despite the fact that the medium may be anisotropic at a microscopic length scale. Using d-PGSE filtered MRI, microscopic anisotropy was observed in a "gray matter" phantom consisting of randomly oriented tubes filled with water, as well as in fixed pig spinal cord, within a range of b-values that can be readily achieved on clinical and small animal MR scanners. These findings suggest a potential use for this new contrast mechanism in clinical studies and biological research applications. C1 [Komlosh, M. E.; Horkay, F.; Basser, P. J.] NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. [Lizak, M. J.] NINDS, NIH, Bethesda, MD USA. [Freidlin, R. Z.] NIH, Ctr Informat Technol, Computat Biosci & Engn Lab, Bethesda, MD 20892 USA. RP Komlosh, ME (reprint author), NICHHD, Sect Tissue Biophys & Biomimet, NIH, 13 S Dr,MSC 5772,Bldg 13,Rm 3W16, Bethesda, MD 20892 USA. EM komloshm@yahoo.com RI Basser, Peter/H-5477-2011 FU Intramural NIH HHS NR 22 TC 45 Z9 45 U1 0 U2 7 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 APR PY 2008 VL 59 IS 4 BP 803 EP 809 DI 10.1002/mrm.21528 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 283OI UT WOS:000254645500017 PM 18383293 ER PT J AU de Zwart, JA van Gelderen, P Fukunaga, M Duyn, JH AF de Zwart, Jacco A. van Gelderen, Peter Fukunaga, Masaki Duyn, Jeff H. TI Reducing correlated noise in fMRI data SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE fMRI; temporal signal correlation; filtering; postprocessing; regression analysis; noise reduction ID FUNCTIONAL CONNECTIVITY; SERIAL CORRELATION; BRAIN; MRI; MOTION; REGRESSION; CONTRAST; SIGNAL; IMAGE AB The sensitivity of functional MRI (fMRI) in detecting neuronal activation is dependent on the relative levels of signal and noise in the time-series data. The temporal noise level within a single voxel is generally substantially higher than the intrinsic NMR (thermal) noise, and the noise is often correlated between voxels. This work introduces and evaluates a method that allows fMRI sensitivity improvement by reduction of these correlated noise sources. The method allows model-free estimation of the correlated noise from brain regions not activated by the functional paradigm using a short (1-2 min) reference scan. A single regressor representing this noise-source estimate is added to the design matrix used in the data analysis. Results obtained from five volunteers show an average t-score improvement of 11.3% and a 24.2% increase in the size of the activated area. C1 [de Zwart, Jacco A.; van Gelderen, Peter; Fukunaga, Masaki; Duyn, Jeff H.] NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. RP de Zwart, JA (reprint author), NINDS, Adv MRI Sect, LFMI, NIH, Bldg 10,Room B1D-728,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Jacco.deZwart@nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 FU Intramural NIH HHS [Z99 NS999999, ] NR 20 TC 15 Z9 15 U1 0 U2 1 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 APR PY 2008 VL 59 IS 4 BP 939 EP 945 DI 10.1002/mrm.21507 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 283OI UT WOS:000254645500035 PM 18383291 ER PT J AU Berezovskaya, F Camacho, E Wirkus, S Karev, G AF Berezovskaya, Faina Camacho, Erika Wirkus, Stephen Karev, Georgy TI "Traveling Wave" solutions of FitzHugh model with cross-diffusion SO MATHEMATICAL BIOSCIENCES AND ENGINEERING LA English DT Article DE FitzHugh; traveling wave solutions; cross-diffusion ID NAGUMO EQUATIONS; NERVE AXON; FAMILY AB The FitzHugh-Nagumo equations have been used as a caricature of the Hodgkin-Huxley equations of neuron firing and to capture, qualitatively, the general properties of an excitable membrane. In this paper, we utilize a modified version of the FitzHugh-Nagumo equations to model the spatial propagation of neuron firing; we assume that this propagation is (at least, partially) caused by the cross-diffusion connection between the potential and recovery variables. We show that the cross-diffusion version of the model, besides giving rise to the typical fast traveling wave solution exhibited in the original "diffusion" FitzHugh-Nagumo equations, additionally gives rise to a slow traveling wave solution. We analyze all possible traveling wave solutions of the model and show that there exists a threshold of the cross-diffusion coefficient (for a given speed of propagation), which bounds the area where "normal" impulse propagation is possible. C1 [Berezovskaya, Faina] Howard Univ, Dept Math, Washington, DC 20059 USA. [Camacho, Erika; Wirkus, Stephen] Arizona State Univ, Dept Math Sci & Appl Comp, Glendale, AZ 85306 USA. [Karev, Georgy] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Berezovskaya, F (reprint author), Howard Univ, Dept Math, Washington, DC 20059 USA. EM fsberezo@hotmail.com RI Wirkus, Stephen/G-3633-2016 OI Wirkus, Stephen/0000-0001-9141-3756 NR 40 TC 3 Z9 3 U1 1 U2 1 PU AMER INST MATHEMATICAL SCIENCES PI SPRINGFIELD PA PO BOX 2604, SPRINGFIELD, MO 65801-2604 USA SN 1547-1063 J9 MATH BIOSCI ENG JI Math. Biosci. Eng. PD APR PY 2008 VL 5 IS 2 BP 239 EP 260 PG 22 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 279TQ UT WOS:000254378000002 PM 18613732 ER PT J AU Kuznetsova, SA Mahoney, DJ Martin-Manso, G Ali, T Nentwich, HA Sipes, JM Zeng, B Vogel, T Day, AJ Roberts, DD AF Kuznetsova, Svetlana A. Mahoney, David J. Martin-Manso, Gema Ali, Tariq Nentwich, Hilke A. Sipes, John M. Zeng, Bixi Vogel, Tikva Day, Anthony J. Roberts, David D. TI TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly SO MATRIX BIOLOGY LA English DT Article DE matrix assembly; TSG-6; fibronectin; CUB domains ID LINK MODULE; HEAVY-CHAINS; INTEGRIN; THROMBOSPONDIN-1; ADHESION; FIBRILLOGENESIS; INFLAMMATION; INHIBITOR; PEPTIDES; PROTEINS AB Human plasma fibronectin binds with high affinity to the inflammation-induced secreted protein TSG-6. Fibronectin binds to the CUB-C domain of TSG-6 but not to its Link module. TSG-6 can thus act as a bridging molecule to facilitate fibronectin association with the TSG-6 Link module ligand thrombospondin-1. Fibronectin binding to TSG-6 is divalent cation-independent and is conserved in cellular fibronectins. Based on competition binding studies using recombinant and proteolytic fragments of ftbronectin, TSG-6 binding localizes to type III repeats 9-14 of fibronectin. This region of fibronectin contains the Arg-Gly-Asp sequence recognized by alpha 5 beta 1 integrin, but deletion of that sequence does not prevent TSG-6 binding, and TSG-6 does not inhibit cell adhesion on fibronectin substrates mediated by this integrin. This region of fibronectin is also involved in fibronectin matrix assembly, and addition of TSG-6 enhances exogenous and endogenous fibronectin matrix assembly by human fibroblasts. Therefore, TSG-6 is a high affinity ligand that can mediate fibronectin interactions with other matrix components and modulate some interactions of fibronectin with cells. (C) Published by Elsevier B.V./International Society of Matrix Biology. C1 [Kuznetsova, Svetlana A.; Martin-Manso, Gema; Sipes, John M.; Zeng, Bixi; Vogel, Tikva; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mahoney, David J.; Ali, Tariq; Nentwich, Hilke A.; Day, Anthony J.] Univ Oxford, Dept Biochem, MRC Immunochem Unit, Oxford OX1 3QU, England. [Ali, Tariq; Day, Anthony J.] Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Fac Life Sci, Manchester M13 9PT, Lancs, England. RP Roberts, DD (reprint author), NIH, Bldg 10,Room 2A33,10 Ctr Dr MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; Martin Manso, Maria Gema/D-4612-2013; Day, Anthony/O-1658-2015 OI Roberts, David/0000-0002-2481-2981; Day, Anthony/0000-0002-1415-3134 FU Arthritis Research UK; Intramural NIH HHS [Z01 SC009172-03]; Wellcome Trust NR 34 TC 27 Z9 29 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD APR PY 2008 VL 27 IS 3 BP 201 EP 210 DI 10.1016/j.matbio.2007.10.003 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 288NL UT WOS:000254993000006 PM 18042364 ER PT J AU Wang, SJ Yao, JH Summers, RM AF Wang, Shijun Yao, Jianhua Summers, Ronald M. TI Improved classifier for computer-aided polyp detection in CT Colonography by nonlinear dimensionality reduction SO MEDICAL PHYSICS LA English DT Article DE computed tomographic colonography; computer-aided detection; dimensionality reduction; diffusion map; locally linear embedding; FROC analysis ID SUPPORT VECTOR MACHINES; DIFFUSION MAPS; COLONIC POLYPS; SEGMENTATION; FRAMEWORK; ALGORITHM AB Computer-aided detection (CAD) has been shown to be feasible for polyp detection on computed tomography (CT) scans. After initial detection, the dataset of colonic polyp candidates has large-scale and high dimensional characteristics. In this article, we propose a nonlinear dimensionality reduction method based on diffusion map and locally linear embedding (DMLLE) for large-scale datasets. By selecting partial data as landmarks, we first map these points into a low dimensional embedding space using the diffusion map. The embedded landmarks can be viewed as a skeleton of whole data in the low dimensional space. Then by using the locally linear embedding algorithm, nonlandmark samples are mapped into the same low dimensional space according to their nearest landmark samples. The local geometry is preserved in both the original high dimensional space and the embedding space. In addition, DMLLE provides a faithful representation of the original high dimensional data at coarse and fine scales. Thus, it can capture the intrinsic distance relationship between samples and reduce the influence of noisy features, two aspects that are crucial to achieving high classifier performance. We applied the proposed DMLLE method to a colonic polyp dataset of 175 269 polyp candidates with 155 features. Visual inspection shows that true polyps with similar shapes are mapped to close vicinity in the low dimensional space. We compared the performance of a support vector machine (SVM) classifier in the low dimensional embedding space with that in the original high dimensional space, SVM with principal component analysis dimensionality reduction and SVM committee using feature selection technology. Free-response receiver operating characteristic analysis shows that by using our DMLLE dimensionality reduction method, SVM achieves higher sensitivity with a lower false positive rate compared with other methods. For 6-9 mm polyps (193 true polyps contained in test set), when the number of false positives per patient is 9, SVM with DMLLE improves the average sensitivity from 70% to 83% compared with that of an SVM committee classifier which is a state-of-the-art method for colonic polyp detection (p<0.001). C1 [Wang, Shijun; Yao, Jianhua; Summers, Ronald M.] Natl Inst Hlth Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), Natl Inst Hlth Clin Ctr, Dept Diagnost Radiol, Bldg 10,Room 1C368X,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov RI Wang, Shijun/E-5005-2010 FU Intramural NIH HHS [Z99 CL999999] NR 24 TC 17 Z9 18 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD APR PY 2008 VL 35 IS 4 BP 1377 EP 1386 DI 10.1118/1.2870218 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 281PN UT WOS:000254510700026 PM 18491532 ER PT J AU Dorwny, CA Cho, L Akohoue, SA Chen, KY Buchowski, MS AF Dorwny, Cindy A. Cho, Leena Akohoue, Sylvie A. Chen, Kong Y. Buchowski, Maciej S. TI Validity of a multisensor armband in estimating 24-h energy expenditure in children SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE activity monitor; whole-room; indirect calorimet'ry; physical activity; SenseWear Armband ID BONE-MINERAL DENSITY; PHYSICAL-ACTIVITY; ACTIVITY MONITORS; BODY-COMPOSITION; ACCELEROMETER; EXERCISE; MASS; ADOLESCENTS; FIELD; RACE AB Physical activity (PA) and energy expenditure (EE) in children are frequently assessed using portable activity monitors. Algorithms used to predict EE by these monitors are often based on adult populations and may not be accurate for children. Purpose: To evaluate the accuracy of the SenseWear Pro Armband (SWA) for assessing EE in African American children during treadmill exercise, sedentary activities, rest, sleep, and total 24-h EE, using indirect room calorimetry (IRC) as a reference standard. Methods: Participants were healthy African American children (10 boys, 11 girls; age: 11.6 +/- 0.9 yr; weight: 47.3 +/- 13.0 kg; height: 151.6 +/- 8.8 cm; BMI: 20.4 +/- 4.8 kg.m(-2)). EE was measured simultaneously using IRC and SWA during a 24-h stay in the IRC. Recorded activities included sedentary behaviors, treadmill exercise, rest periods, and sleep. Results from both methods were matched minute-by-minute and compared by Bland-Altman plot. Multiple linear regression analysis was used to describe the relationship between EE assessed by both methods and children's descriptive characteristics. Results: SWA overestimated EE compared with IRC during all activities and time periods, ranging from 116% during sleep to 143 % during rest after treadmill exercise. The SWA-predicted EE was improved by using linear regression modeling. Simple equations for sedentary activities and treadmill exercise were EE [kcal.min(-1)] = 0.462EE (SWA) [kcal.min(-1)] + 0.015 x body weight [kg], and EE [kcal.min(-1)] = 0.637EE (SWA) [kcal.min(-1)]+ 0.034 x body weight [kg], respectively. The prediction equation for RMR was RMR [kcal.min(-1)] = 0.453EE (SWA) [kcal.min(-1)] + 0.011 x body weight [kg]. Conclusion: EE estimated using SWA was significantly higher than EE measured using IRC in African American children ages 10-14 yr. Bias in individual EE estimated using SWA could be improved by an adjustment for the body weight of a child. The SWA manufacturer should work with researchers on improving existing algorithms for children. C1 [Dorwny, Cindy A.; Akohoue, Sylvie A.; Chen, Kong Y.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Cho, Leena] Vanderbilt Univ, Dept Biostat, Nashville, TN 37232 USA. [Dorwny, Cindy A.; Buchowski, Maciej S.] Vanderbilt Univ, Gen Clin Res Ctr, Nashville, TN 37232 USA. [Akohoue, Sylvie A.; Buchowski, Maciej S.] Meharry Med Coll, Dept Family & Community Med, Nashville, TN 37208 USA. [Chen, Kong Y.] NIDDK, Clin Endocrinol Branch, Div Intramural Res, NIH, Bethesda, MD USA. RP Buchowski, MS (reprint author), Vanderbilt Univ, Dept Med, 1161 21st Ave S, Nashville, TN 37232 USA. EM maciej.buchowski@vanderbilt.edu RI Buchowski, Maciej/A-2683-2008; OI Buchowski, Maciej/0000-0002-0566-1743; Chen, Kong/0000-0002-0306-1904 NR 31 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD APR PY 2008 VL 40 IS 4 BP 699 EP 706 DI 10.1249/MSS.0b013e318161ea8f PG 8 WC Sport Sciences SC Sport Sciences GA 278BU UT WOS:000254259300017 ER PT J AU Horwitz, B Smith, JF AF Horwitz, Barry Smith, Jason F. TI A link between neuroscience and informatics: Large-scale modeling of memory processes SO METHODS LA English DT Review DE brain; human; functional magnetic resonance imaging; positron emission tomography; neural network; neural modeling; memory; working memory; visual processing; auditory processing ID SHORT-TERM-MEMORY; PRIMATE PREFRONTAL CORTEX; INFERIOR TEMPORAL CORTEX; SPATIAL WORKING-MEMORY; DELAY-PERIOD ACTIVITY; NEUROCOMPUTATIONAL MODEL; EFFECTIVE CONNECTIVITY; INFEROTEMPORAL CORTEX; NEURONAL-ACTIVITY; CEREBRAL-CORTEX AB Utilizing advances in functional neuroimaging and computational neural modeling, neuroscientists have increasingly sought to investigate how distributed networks, composed of functionally defined subregions, combine to produce cognition. Large-scale, biologically realistic neural models, which integrate data from cellular, regional, whole brain, and behavioral sources, delineate specific hypotheses about how these interacting neural populations might carry out high-level cognitive tasks. In this review, we discuss neuroimaging, neural modeling, and the utility of large-scale biologically realistic models using modeling of short-term memory as an example. We present a sketch of the data regarding the neural basis of short-term memory from non-human electrophysiological, computational and neuroimaging perspectives, highlighting the multiple interacting brain regions believed to be involved. Through a review of several efforts, including our own, to combine neural modeling and neuroimaging data, we argue that large scale neural models provide specific advantages in understanding the distributed networks underlying cognition and behavior. (c) 2007 Elsevier Inc. All rights reserved. C1 [Horwitz, Barry; Smith, Jason F.] Natl Inst Deafness & Other Commun Disorders, NIH, Brain Imaging & Modeling Sect, Bethesda, MD 20892 USA. RP Horwitz, B (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Brain Imaging & Modeling Sect, Bldg 10,Rm 8S235,MSC 1407, Bethesda, MD 20892 USA. EM horwitz@helix.nih.gov FU Intramural NIH HHS [Z01 DC000057-08] NR 123 TC 6 Z9 7 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 1046-2023 J9 METHODS JI Methods PD APR PY 2008 VL 44 IS 4 BP 338 EP 347 DI 10.1016/j.ymeth.2007.02.007 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 295CG UT WOS:000255452000007 PM 18374277 ER PT J AU Kim, YS Kang, HS Herbert, R Beak, JY Collins, JB Grissom, SF Jetten, AM AF Kim, Yong-Sik Kang, Hong Soon Herbert, Ronald Beak, Ju Youn Collins, Jennifer B. Grissom, Sherry F. Jetten, Anton M. TI Kruppel-like zinc finger protein Glis2 is essential for the maintenance of normal renal functions SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; CHRONIC KIDNEY-DISEASE; ZIC GENES; FIBROSIS; MECHANISMS; CHEMOKINES; REPRESSOR; NEPHRONOPHTHISIS; DIFFERENTIATION; IDENTIFICATION AB To obtain insight into the physiological functions of the Kruppel-like zinc finger protein Gli-similar 2 (Glis2), mice deficient in Glis2 expression were generated. Glis2 mutant (Glis2(mut)) mice exhibit significantly shorter life spans than do littermate wild-type (WT) mice due to the development of progressive chronic kidney disease with features resembling nephronophthisis. Glis2(mut) mice develop severe renal atrophy involving increased cell death and basement membrane thickening in the proximal convoluted tubules. This development is accompanied by infiltration of lymphocytic inflammatory cells and interstitial/glomerular fibrosis. The severity of the fibrosis, inflammatory infiltrates, and glomerular and tubular changes progresses with age. Blood urea nitrogen and creatinine increase, and Glis2(mut) mice develop proteinuria and ultimately die prematurely of renal failure. A comparison of the gene expression profiles of kidneys from 25-day-old/60-day-old WT and Glis2(mut) mice by microarray analysis showed increased expressions of many genes involved in immune responses/inflammation and fibrosis/tissue remodeling in kidneys of Glis2(mut) mice, including several cytokines and adhesion and extracellular matrix proteins. Our data demonstrate that a deficiency in Glis2 expression leads to tubular atrophy and progressive fibrosis, similar to nephronophthisis, that ultimately results in renal failure. Our study indicates that Glis2 plays a critical role in the maintenance of normal kidney architecture and functions. C1 [Kim, Yong-Sik; Kang, Hong Soon; Beak, Ju Youn; Jetten, Anton M.] NIEHS, Div Intramural Res, Cell Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. [Herbert, Ronald] NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. [Collins, Jennifer B.; Grissom, Sherry F.] NIEHS, Microarray Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Div Intramural Res, Cell Biol Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural NIH HHS NR 50 TC 26 Z9 26 U1 0 U2 3 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 APR PY 2008 VL 28 IS 7 BP 2358 EP 2367 DI 10.1128/MCB.01722-07 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 276ZE UT WOS:000254181400022 PM 18227149 ER PT J AU Endo, Y Beauchamp, E Woods, D Taylor, WG Toretsky, JA Uren, A Rubin, JS AF Endo, Yoshimi Beauchamp, Elspeth Woods, David Taylor, William G. Toretsky, Jeffrey A. Uren, Aykut Rubin, Jeffrey S. TI Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing tumor cells via a Frizzled3-and c-Jun n-terminal kinase-dependent mechanism SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BETA-CATENIN; WNT/BETA-CATENIN; AXON GUIDANCE; SARCOMA; RYK; DIFFERENTIATION; POLARITY; MICROTUBULES; ACTIVATION; GSK-3-BETA AB Recombinant Wnt-3a stimulated the rapid formation of elongated processes in Ewing sarcoma family tumor (ESFT) cells that were identified as neurites. The processes stained positively for polymerized actin and microtubulles as well as synapsin I and growth-associated protein 43. Inhibition of the Wnt receptor, Frizzled3 (Fzd3), with antiserum or by short interfering RNA (siRNA) markedly reduced neurite extension. Knockdown of Dishevelled-2 (Dvl-2) and Dvl-3 also suppressed neurite outgrowth. Surprisingly, disruption of the Wnt/ Fzd/lipoprotein receptor-related protein (LRP) complex and the associated P-catenin signaling by treating cells either with the Wnt antagonist Dickkopf-1 (Dkk1) or LRP5/LRP6 siRNA enhanced neuritogenesis. Neurite outgrowth induced by Dkk1 or with LRP5/LRP6 siRNA was inhibited by secreted Fzd-related protein 1, a Wnt antagonist that binds directly to Wnt. Moreover, Dkk1 stimulation of neurite outgrowth was blocked by Fzd3 siRNA. These results suggested that Dkk1 shifted endogenous Wnt activity from the beta-catenin pathway to Fzd3-mediated, noncanonical signaling that is responsible for neurite formation. In particular, c-Jun amino-terminal kinase (JNK) was important for neurite outgrowth stimulated by both Wnt-3a and Dkk1. Our data demonstrate that Fzd3, Dv1, and JNK activity mediate Wnt-dependent neurite outgrowth and that ESFT cell lines will be useful experimental models for the study of Wnt-dependent neurite extension. C1 [Endo, Yoshimi; Woods, David; Taylor, William G.; Rubin, Jeffrey S.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Beauchamp, Elspeth; Toretsky, Jeffrey A.; Uren, Aykut] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20057 USA. RP Rubin, JS (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37,Room 2042,37 Convent Dr,MSC 4256, Bethesda, MD 20892 USA. EM rubinj@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [T32 CA009686, R01 CA088004, R01 CA088004-08] NR 46 TC 56 Z9 61 U1 0 U2 5 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 APR PY 2008 VL 28 IS 7 BP 2368 EP 2379 DI 10.1128/MCB.01780-07 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 276ZE UT WOS:000254181400023 PM 18212053 ER PT J AU Cho, H Park, C Hwang, IY Han, SB Schimel, D Despres, D Kehrl, JH AF Cho, Hyeseon Park, Chung Hwang, Il-Young Han, Sang-Bae Schimel, Dan Despres, Daryl Kehrl, John H. TI Rgs5 targeting leads to chronic low blood pressure and a lean body habitus SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SMOOTH-MUSCLE-CELLS; END RULE PATHWAY; ESSENTIAL-HYPERTENSION; ANGIOTENSIN-II; EXPRESSION; REGULATOR; RECEPTOR; MICE; PHOSPHORYLATION; OVEREXPRESSION AB RGS5 is a potent GTPase-activating protein for Gi. and G.. that is expressed strongly in pericytes and is present in vascular smooth muscle cells. To study the role of RGS5 in blood vessel physiology, we generated Rgs5-deficient mice. The Rgs(5-/-) mice developed normally, without obvious defects in cardiovascular development or function. Surprisingly, Rgs5(-/-) mice had persistently low blood pressure, lower in female mice than in male mice, without concomitant cardiac dysfunction, and a lean body habitus. The examination of the major blood vessels revealed that the aortas of Rgs5(-/-) mice were dilated compared to those of control mice, without altered wall thickness. Isolated aortic smooth muscle cells from the Rgs5(-/-) mice exhibited exaggerated levels of phosphorylation of vasodilator-stimulated phosphoprotein and extracellular signal-regulated kinase in response to stimulation with either sodium nitroprusside or sphingosine 1-phosphate. The results of this study, along with those of previous studies demonstrating that RGS5 stability is under the control of nitric oxide via the N-end rule pathway, suggest that RGS5 may balance vascular tone by attenuating vasodilatory signaling in vivo in opposition to RGS2, another RGS (regulator of G protein signaling) family member known to inhibit G protein-coupled receptor-mediated vasoconstrictor signaling. Blocking the function or the expression of RGS5 may provide an alternative approach to treat hypertension. C1 [Cho, Hyeseon; Park, Chung; Hwang, Il-Young; Kehrl, John H.] NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. [Schimel, Dan; Despres, Daryl] Natl Inst Neurol Disorders & Stroke, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Han, Sang-Bae] Chungbuk Natl Univ, Coll Pharm, Cheongju, South Korea. RP Cho, H (reprint author), NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, NIH, Bldg 10,Room 11B08,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM hcho@niaid.nih.gov; jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU Intramural NIH HHS NR 29 TC 56 Z9 59 U1 0 U2 3 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 APR PY 2008 VL 28 IS 8 BP 2590 EP 2597 DI 10.1128/MCB.01889-07 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 284LS UT WOS:000254708500009 PM 18268011 ER PT J AU Roy, SW Irimia, M AF Roy, Scott William Irimia, Manuel TI Rare genomic characters do not support coelomata: Intron loss/gain SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Letter ID BRANCH ATTRACTION ARTIFACTS; AMINO-ACID REPLACEMENTS; EUKARYOTIC EVOLUTION; ANIMAL PHYLOGENY; CLADE; ECDYSOZOA; GENES; CONSERVATION; PATTERN; GAIN AB Recently, a new phylogenetic method employing intron position sharing across species was proposed and support for a Coelomate clade reported (Zheng et al. 2007. A rigorous analysis of the pattern of intron conservation supports the Coelomata clade of animals. Mol Biol Evol. 24:2583-2592.). Here, we show that the previous analysis depends on: 1) an idiosyncratic definition of "conserved" introns, 2) exclusion of all phylogenetically informative introns present in outgroups, 3) incorrect inference of change along the critical branch, and 4) lack of variation in rates across branches. The method thus seems unlikely to give accurate results. In addition, we address differences in rates of loss across intron sites, which Zheng et al. claimed invalidates our previous analysis that supported Ecdysozoa (Roy and Gilbert. 2005a. Resolution of a deep animal divergence by the pattern of intron conservation. Proc Natl Acad Sci USA. 102:4403-4408.). Instead, we show that our conclusions are likely to be robust to such concerns. C1 [Roy, Scott William] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. [Irimia, Manuel] Univ Barcelona, Dept Genet, Barcelona, Spain. RP Roy, SW (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM scottwroy@gmail.com RI Irimia, Manuel/E-3040-2010; OI Irimia, Manuel/0000-0002-2179-2567 FU Intramural NIH HHS NR 29 TC 13 Z9 14 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD APR PY 2008 VL 25 IS 4 BP 620 EP 623 DI 10.1093/molbev/msn035 PG 4 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 274MH UT WOS:000254004900002 PM 18281272 ER PT J AU Shim, M Eling, TE AF Shim, Minsub Eling, Thomas E. TI Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ALPHA-TOCOPHERYL-SUCCINATE; PROSTATE-CANCER CELLS; BETA SUPERFAMILY MEMBER; ACTIVATED GENE NAG-1; GROWTH-FACTOR-BETA; MAP KINASE; PROTEIN-KINASE; MESSENGER-RNA; TRIGGERED APOPTOSIS; MEDIATED APOPTOSIS AB NAG-1 (nonsteroidal anti-inflammatory drug-activated gene), a member of the transforming growth factor-beta superfamily, is involved in many cellular processes, such as inflammation, apoptosis/survival, and tumorigenesis. Vitamin E succinate (VES) is the succinate derivative of alpha-tocopherol and has antitumorigenic activity in a variety of cell culture and animal models. In the current study, the regulation and role of NAG-1 expression in PC-3 human prostate carcinoma cells by VIES was examined. VIES treatment induced growth arrest and apoptosis as well as an increase in NAG-1 protein and mRNA levels in a time- and concentration-dependent manner. VES treatment induced nuclear translocation and activation of p38 kinase. Pretreatment with p38 kinase inhibitor blocked the VES-induced increase in NAG-1 protein and mRNA levels, whereas an inhibition of protein kinase C, Akt, c-Jun NH2-terminal kinase, or MEK activity had no effect on VES-induced NAG-1 levels. Forced expression of constitutively active MKK6, an upstream kinase for p38, induced an increase in NAG-1 promoter activity, whereas p38 kinase inhibitor blocked MKK6-induced increase in NAG-1 promoter activity. VIES treatment resulted in >3-fold increase in the half-life of NAG-1 mRNA in a p38 kinase-dependent manner and transient transfection experiment showed that VIES stabilizes NAG-1 mRNA through AU-rich elements in 3'-untranslated region of NAG-1 mRNA. The inhibition of NAG-1 expression by small interfering RNA significantly blocked VES-induced poly(ADP-ribose) polymerase cleavage, suggesting that NAG-1 may play an important role in VIES-induced apoptosis. These results indicate that VIES-induced expression of NAG-1 mRNA/protein is regulated by transcriptional/post-transcriptional mechanism in a p38 kinase-dependent manner and NAG-1 can be chemopreventive/therapeutic target in prostate cancer. C1 [Shim, Minsub; Eling, Thomas E.] NIEHS, Mol Carcinogenesis Lab, Eicosanoids Biochem Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, Eicosanoids Biochem Sect, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov FU Intramural NIH HHS [Z01 ES010016-09] NR 50 TC 11 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD APR PY 2008 VL 7 IS 4 BP 961 EP 971 DI 10.1158/1535-7163.MCT-07-0470 PG 11 WC Oncology SC Oncology GA 288SW UT WOS:000255007100025 PM 18413810 ER PT J AU Lubet, RA Szabo, E Christov, K Bode, AM Ericson, ME Steele, VE Juliana, MM Grubbs, CJ AF Lubet, Ronald A. Szabo, Eva Christov, Konstantin Bode, Ann M. Ericson, Marna E. Steele, Vernon E. Juliana, M. Margaret Grubbs, Clinton J. TI Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID GROWTH-FACTOR-RECEPTOR; METASTATIC BREAST-CANCER; SPRAGUE-DAWLEY RATS; PHASE-II; AROMATASE INHIBITORS; EXPRESSION; THERAPY; TUMORS; MODEL; ANASTROZOLE AB The ability of the epidermal growth factor receptor inhibitor gefitinib (Iressa) to prevent/treat methylnitrosourea (MNU)-induced mammary cancers and to modulate biomarkers in female Sprague-Dawley rats was examined. Rats were given a single dose of MNU (75 mg/kg body weight) at 50 days of age. In the prevention studies, continual treatment with Iressa at 10, 3, or 1 mg/kg body weight per day beginning 5 days after MNU reduced tumor multiplicity by 93%, 43%, and 20%, respectively. Treatment of rats bearing small palpable cancers with Iressa (10 mg/kg body weight per day) resulted in the complete regression of 70% of the tumors. Short-term treatment of tumor-bearing rats with Iressa caused decreases in cell proliferation and phosphorylated epidermal growth factor receptor and increases in apoptosis. To examine treatment regimens that might decrease the skin toxicity associated with Iressa, both intermittent treatments and combinations of lower doses of Iressa with other effective agents were evaluated. Treatment with Iressa (10 mg/kg body weight per day) continually or intermittently (either "3 weeks on/3 weeks off" or "4 days on/3 days off") reduced cancer multiplicity by 91%, 24%, and 68%, respectively. However, all regimens reduced tumor weights > 85 %. Finally, combining suboptimal doses of Iressa with suboptimal doses of vorozole (an aromatase inhibitor) or targretin (a retinoid X receptor agonist) yielded greater chemopreventive efficacy than any of these agents given alone. C1 [Lubet, Ronald A.; Szabo, Eva; Steele, Vernon E.] NCI, Canc Prevent Div, Bethesda, MD 20852 USA. [Christov, Konstantin] Univ Illinois, Dept Surg Oncol, Chicago, IL USA. [Bode, Ann M.] Hormel Inst, Austin, MN USA. [Ericson, Marna E.] Univ Minnesota, Dept Dermatol, Minneapolis, MN USA. [Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama, Dept Surg, Birmingham, AL USA. [Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama, Dept Genet, Birmingham, AL USA. RP Lubet, RA (reprint author), NCI, Canc Prevent Div, Execut Plaza N,Suite 2110 6130 Execut Blvd, Bethesda, MD 20852 USA. EM lubetr@mail.nih.gov FU NCI NIH HHS [N01-CN-15123, N01-CN-25003, N01-CN-43301] NR 29 TC 11 Z9 12 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD APR PY 2008 VL 7 IS 4 BP 972 EP 979 DI 10.1158/1535-7163.MCT-07-2141 PG 8 WC Oncology SC Oncology GA 288SW UT WOS:000255007100026 PM 18375820 ER PT J AU Ohta, S Lai, EW Morris, JC Pang, ALY Watanabe, M Yazawa, H Zhang, R Green, JE Chan, WY Sirajuddin, P Taniguchi, S Powers, JF Tischler, AS Pacak, K AF Ohta, Shoichiro Lai, Edwin W. Morris, John C. Pang, Alan L. Y. Watanabe, Morihiro Yazawa, Hiroshi Zhang, Richard Green, Jeffery E. Chan, Wai-Yee Sirajuddin, Paul Taniguchi, Shun'ichiro Powers, James F. Tischler, Arthur S. Pacak, Karel TI Metastasis-associated gene expression profile of liver and subcutaneous lesions derived from mouse pheochromocytoma cells SO MOLECULAR CARCINOGENESIS LA English DT Article DE pheochromocytoma; metastasis; superarray; catecholamines ID METHIONINE AMINOPEPTIDASE-2; OSTEOSARCOMA CELLS; DOWN-REGULATION; PARAGANGLIOMAS; INHIBITION; MALIGNANCY; LINES; RECK; MICE AB The development of metastatic cancer is associated with overexpression or downregulation of specific genes and cell regulatory pathways. Some of these genes and pathways may be involved in invasion and dissemination of tumor cells, while others may promote seeding, survival or growth of cells at specific distant sites. In this investigation, gene expression profiles of nonmetastasizing tumors generated by injecting mouse pheochromocytoma cells (MPCs) subcutaneously were compared to those of liver tumors generated by injecting the cells intravenously. Both were compared to the cultured parental cell line. Tumors in the liver have a route of spread, anatomical distribution, and growth environment similar to naturally metastasizing pheochromocytomas, while intravenous injection of cells bypasses the initial steps of metastasis occurring spontaneously from a primary tumor. Eight genes were upregulated in liver tumors, 15 in subcutaneous tumors and seven in both compared to the cultured cells. Using quantitative real-time PCR, expression of five genes (Metap2, Reck, S100a4, Timp2, and Timp3) was verified as significantly lower in liver tumors than in subcutaneous tumors. Downregulation of these genes has been previously been associated with malignancy of pheochromocytomas. These findings indicate that different microenvironments can differentially affect the expression of metastasis-related genes in pheochromocytomas, and that overexpression or underexpression of these genes need not be present when the tumor cells are initially disseminated. The hepatic localization of tumors formed by intravenously injected MPC cells and the tumors' gene expression profile resembling that of naturally occurring pheochromocytoma metastases support the use of this model to study pheochromocytoma metastasis. (C) 2007 Wiley-Liss, Inc. C1 [Pacak, Karel] NICHHD, Sect Med Neuroendocrinol, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. [Morris, John C.] NCI, Metab Branch, Canc Res Ctr, Bethesda, MD 20892 USA. [Pang, Alan L. Y.; Chan, Wai-Yee] NICHHD, Lab Clin Genom, Bethesda, MD 20892 USA. [Watanabe, Morihiro; Yazawa, Hiroshi] NCI, Canc Res Ctr, Lab Expt Immunotherapy, Frederick, MD 21701 USA. [Sirajuddin, Paul] NCI, Lab Cell Regulat & Carcinogenesis, Canc Res Ctr, Bethesda, MD 20892 USA. [Taniguchi, Shun'ichiro] Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Mol Oncol, Matsumoto, Nagano 390, Japan. [Powers, James F.; Tischler, Arthur S.] Tufts Univ, Sch Med, Tufts New England Med Ctr, Dept Pathol, Boston, MA 02111 USA. [Green, Jeffery E.] NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHHD, Sect Med Neuroendocrinol, Reprod Biol & Med Branch, NIH, Bldg 10,Room 1E-3140,10 Ctr Dr MSC-1109, Bethesda, MD 20892 USA. FU Intramural NIH HHS; NINDS NIH HHS [NS37685] NR 24 TC 9 Z9 9 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD APR PY 2008 VL 47 IS 4 BP 245 EP 251 DI 10.1002/mc.20388 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 285MJ UT WOS:000254780600001 PM 17957724 ER PT J AU Jenkins, LMM Mazur, SJ Rossi, M Gaidarenko, O Xu, Y Appella, E AF Jenkins, Lisa M. Miller Mazur, Sharlyn J. Rossi, Matteo Gaidarenko, Olga Xu, Yang Appella, Ettore TI Quantitative proteomics analysis of the effects of ionizing radiation in wild type and p53(K317R) knock-in mouse thymocytes SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID TUMOR-NECROSIS-FACTOR; GENE-EXPRESSION PROFILES; TANDEM MASS-SPECTROMETRY; NEGATIVE CROSS-TALK; NF-KAPPA-B; GLUCOCORTICOID RECEPTOR; DNA-DAMAGE; TNF-ALPHA; C-MYC; POSTTRANSLATIONAL MODIFICATIONS AB The tumor suppressor protein p53 is a sequence-specific transcription factor that has crucial roles in apoptosis, cell cycle arrest, cellular senescence, and DNA repair. Following exposure to a variety of stresses, p53 becomes post-translationally modified with concomitant increases in activity and stability. To better understand the role of acetylation of Lys-317 in mouse p53, the effect of ionizing radiation (IR) on the thymocytes of p53(K317R) knock-in mice was studied at the global level. Using cleavable ICAT quantitative mass spectrometry, the effect of IR on protein levels in either the wild type or p53(K317R) thymocytes was determined. We found 102 proteins to be significantly affected by IR in the wild type thymocytes, including several whose expression has been shown to be directly regulated by p53. When the effects of IR in the wild type and p53(K317R) samples were compared, 46 proteins were found to be differently affected (p < 0.05). The p53(K317R) mutation has widespread effects on specific protein levels following IR, including the levels of proteins involved in apoptosis, transcription, and translation. Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53(K317R) thymocytes as well as a decrease in tumor necrosis factor a signaling. These results suggest that acetylation of Lys-317 modulates the functions of p53 and influences the cross-talk between the DNA damage response and other signaling pathways. C1 [Jenkins, Lisa M. Miller; Mazur, Sharlyn J.; Rossi, Matteo; Appella, Ettore] NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. [Gaidarenko, Olga; Xu, Yang] Univ Calif San Diego, Div Biol Sci, Mol Biol Sect, La Jolla, CA 92093 USA. RP Appella, E (reprint author), NCI, NIH, Cell Biol Lab, 37 Convent Dr,Rm 2140, Bethesda, MD 20892 USA. EM appellae@pop.nci.nih.gov FU Intramural NIH HHS; NCI NIH HHS [CA94254, R01 CA094254] NR 69 TC 9 Z9 10 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD APR PY 2008 VL 7 IS 4 BP 716 EP 727 DI 10.1074/mcp.M700482-MCP200 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 286XK UT WOS:000254879200008 PM 18178582 ER PT J AU Park, JJ Cawley, NX Loh, YP AF Park, Joshua J. Cawley, Niamh X. Loh, Y. Peng TI Carboxypeptidase e cytoplasmic tail-driven vesicle transport is key for activity-dependent secretion of peptide hormones SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROHORMONE SORTING RECEPTOR; KINESIN SUPERFAMILY PROTEIN; CAENORHABDITIS-ELEGANS; ORGANELLE TRANSPORT; CONVERTING-ENZYME; DYNACTIN; MOTOR; GRANULES; DYNEIN; PURIFICATION AB Vesicular transport of peptide hormones from the cell body to the plasma membrane for activity-dependent secretion is important for endocrine function, but how it is achieved is unclear. Here we uncover a mechanism in which the cytoplasmic tail of transmembrane carboxypeptidase E (CPE) found in proopiomelanocotin (POMC)/ACTH vesicles interacts with microtubule-based motors to control transport of these vesicles to the release site in pituitary cells. Overexpression of the CPE tail in live cells significantly reduced the velocity and distance of POMC/ACTH- and CPE-containing vesicle movement into the cell processes. Biochemical studies showed that the CPE tail interacted with dynactin, which, in turn, recruited microtubule plus-end motors kinesin 2 and kinesin 3. Overexpression of the CPE tail inhibited the stimulated secretion of ACTH from AtT20 cells. Thus, the CPE cytoplasmic tail interaction with dynactin-kinesin 2/kinesin 3 plays an important role in the transport of POMC vesicles for activity-dependent secretion. C1 [Park, Joshua J.; Cawley, Niamh X.; Loh, Y. Peng] NICHHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), NICHHD, Cellular Neurobiol Sect, NIH, Bldg 49,Rm 5A22,49 Convent Dr, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov NR 43 TC 24 Z9 24 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD APR 1 PY 2008 VL 22 IS 4 BP 989 EP 1005 DI 10.1210/me.2007-0473 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 280JC UT WOS:000254421500017 PM 18202146 ER PT J AU Gopal, AAR Fugmann, SD AF Gopal, Anjali R. Fugmann, Sebastian D. TI AID-mediated diversification within the IgL locus of chicken DT40 cells is restricted to the transcribed IgL gene SO MOLECULAR IMMUNOLOGY LA English DT Article DE somatic hypermutation; gene conversion; immunoglobulin; DT40 ID CLASS SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; SINGLE-STRANDED-DNA; HEAVY-CHAIN LOCUS; SOMATIC HYPERMUTATION; B-CELLS; ANTIBODY HEAVY; CONVERSION; EXPRESSION; CHROMATIN AB Somatic hypermutation (SHM) and gene conversion (GCV) are closely related processes that increase the diversity the primary immunoglobulin repertoire. In both processes the activation-induced cytidine deaminase (AID) converts cytosine residues to uracils within the DNA of the immunoglobulin (Ig) genes in a transcription-dependent manner, and subsequent error-prone repair processes lead to changes in the antigen recognition site of the encoded receptors. This activity is specifically recruited to the Ig loci by unknown mechanisms. Our analyses of the chicken B-cell line DT40, and derivatives thereof, now revealed that even the closest neighbors of the Ig light chain (IgL) gene are protected from AID activity, albeit being transcribed and thus acting as potential targets of AID. Our findings are in support of a model in which cis-acting DNA boundary elements restrict AID activity to the IgL locus and guard the genome in the vicinity of the IgL gene from deleterious mutations. Published by Elsevier Ltd. C1 [Gopal, Anjali R.; Fugmann, Sebastian D.] NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, NIH,Mol Immunol Unit, Baltimore, MD 21224 USA. RP Fugmann, SD (reprint author), NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, NIH,Mol Immunol Unit, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM fugmanns@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000387-03] NR 30 TC 6 Z9 6 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD APR PY 2008 VL 45 IS 7 BP 2062 EP 2068 DI 10.1016/j.molimm.2007.10.017 PG 7 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 278CG UT WOS:000254260500025 PM 18023479 ER PT J AU Guiraldelli, MF Berenstein, EH Grodzki, ACG Siraganian, RP Jamur, MC Oliver, C AF Guiraldelli, Michel F. Berenstein, Elsa H. Grodzki, Ana Cristina G. Siraganian, Reuben P. Jamur, Maria Celia Oliver, Constance TI The low affinity IgG receptor Fc gamma RIIB contributes to the binding of the mast cell specific antibody, mAb BGD6 SO MOLECULAR IMMUNOLOGY LA English DT Article DE mast cells; precursor; CD32; expression cloning ID BONE-MARROW; MONOCLONAL-ANTIBODIES; EPSILON-RI; IMMUNOGLOBULIN; HETEROGENEITY; IDENTIFICATION; SEQUENCE; CLONING; CLONES; GENES AB The mast cell specific monoclonal antibody, mAb BGD6, is a mast cell lineage marker [Jamur, M.C., Grodzki, A.C., Berenstein, E.H., Hamawy, M.M., Siraganian, R.P., Oliver, C., 2005. Identification and characterization of undifferentiated mast cells in mouse bone marrow. Blood 105, 4282-4289]. In rat basophilic leukemia (RBL-2H3) cells, mAb BGD6 precipitates cell-surface proteins of similar to 110 and 40-60 kDa. An expression cloning strategy was used to identify proteins that interact with mAb BGD6. A RBL-2H3 cDNA library in plasmids was transfected into PEAK cells, which do not bind mAb BGD6, and positive cells were selected with mAb BGD6. The plasmids recovered from the positive cells were amplified; retransfected into PEAK cells and after several screening cycles a positive clone was identified. This clone showed almost complete identity to Fc gamma RIIB (CD32), the low affinity IgG receptor. However, in contrast to the sequence in GenBank, this clone had an insert of 141 bp which codes for a longer isoform of this molecule with an extra 47 aa in its cytoplasmic domain. In RBL-2H3 cells both isoforms were expressed, with higher expression of the shorter form. The mechanism of binding of mAB BGD6 on both RBL-2H3 and CD32 transfected PEAK cells was then examined. Intact mAb BGD6 bound to both RBL-2H3 and CD32 expressing PEAK cells, but F(ab)2 fragments bound only to RBL-2H3 cells demonstrating that mAb BGD6 binds to Fc gamma RIIB only through its Fc portion. On RBL-2H3 cells, the Fab of an anti-CD32 mAb partially inhibited the binding of intact mAb BGD6. The binding pattern of mAb BGD6 inhibited with anti-CD32 resembled that of the F(ab')(2) fragment of the antibody suggesting that the Fc portion of mAb BGD6 contributes to its binding on cells that have Fc gamma RIIB. These results are consistent with a model where mAb BGD6 binds through its Fab portion to a similar to 110 kDa protein and the Fc tail interacts with Fc gamma RIIB (CD32). (c) 2008 Published by Elsevier Ltd. C1 [Guiraldelli, Michel F.; Jamur, Maria Celia; Oliver, Constance] USP, Dept Cell & Mol Biol & Pathogen Bioagents, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP, Brazil. [Guiraldelli, Michel F.; Berenstein, Elsa H.; Grodzki, Ana Cristina G.; Siraganian, Reuben P.] Natl Inst Dent & Craniofacial Res, NIH, Receptors & Signal Transduct Sect, Bethesda, MD 20892 USA. RP Oliver, C (reprint author), USP, Dept Cell & Mol Biol & Pathogen Bioagents, Fac Med Ribeirao Preto, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. EM coliver@fmrp.usp.br RI Guiraldelli, Michel/H-1710-2013; Jamur, Maria Celia/L-5520-2016 OI Jamur, Maria Celia/0000-0001-7065-8543 FU Intramural NIH HHS NR 40 TC 6 Z9 7 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD APR PY 2008 VL 45 IS 8 BP 2411 EP 2418 DI 10.1016/j.molimm.2007.07.041 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 287UQ UT WOS:000254942400031 PM 18295888 ER PT J AU Egan, JM Margolskee, RF AF Egan, Josephine M. Margolskee, Robert F. TI Taste cells of the gut and gastrointestinal chemosensation SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID ENTEROENDOCRINE STC-1 CELLS; SOFT DRINK CONSUMPTION; METABOLIC SYNDROME; SWEET TASTE; US ADULTS; GUSTDUCIN; OBESITY; EXPRESSION; RECEPTORS; RISK C1 [Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. [Margolskee, Robert F.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. RP Egan, JM (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM robert.margolskee@mssm.edu RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 FU Intramural NIH HHS [Z01 AG000962-02]; NIDCD NIH HHS [R01 DC003055, R01 DC003155] NR 25 TC 49 Z9 56 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD APR 1 PY 2008 VL 8 IS 2 BP 78 EP 81 DI 10.1124/mi.8.2.5 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 308YJ UT WOS:000256426500004 PM 18403652 ER PT J AU Rokney, A Kobiler, O Amir, A Court, DL Stavans, J Adhya, S Oppenheim, AB AF Rokney, Assaf Kobiler, Oren Amir, Amnon Court, Donald L. Stavans, Joel Adhya, Sankar Oppenheim, Amos B. TI Host responses influence on the induction of lambda prophage SO MOLECULAR MICROBIOLOGY LA English DT Article ID OOP ANTISENSE RNA; BACTERIOPHAGE-LAMBDA; ESCHERICHIA-COLI; PHAGE-LAMBDA; FTSH HFLB; GENE; PROTEIN; MUTANT; PROTEOLYSIS; SIGMA(32) AB Inactivation of bacteriophage lambda CI repressor leads almost exclusively to lytic development. Prophage induction can be initiated either by DNA damage or by heat treatment of a temperature-sensitive repressor. These two treatments also cause a concurrent activation of either the host SOS or heat-shock stress responses respectively. We studied the effects of these two methods of induction on the lytic pathway by monitoring the activation of different lambda promoters, and found that the lambda genetic network co-ordinates information from the host stress response networks. Our results show that the function of the CII transcriptional activator, which facilitates the lysogenic developmental pathway, is not observed following either method of induction. Mutations in the cro gene restore the CII function irrespective of the induction method. Deletion of the heat-shock protease gene ftsH can also restore CII function following heat induction but not following SOS induction. Our findings highlight the importance of the elimination of CII function during induction as a way to ensure an efficient lytic outcome. We also show that, despite the common inhibitory effect on CII function, there are significant differences in the heat- and SOS-induced pathways leading to the lytic cascade. C1 [Rokney, Assaf; Kobiler, Oren; Oppenheim, Amos B.] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Genet & Biotechnol, IL-91010 Jerusalem, Israel. [Amir, Amnon; Stavans, Joel] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel. [Court, Donald L.; Oppenheim, Amos B.] Natl Canc Inst, Gene Regulat & Chromosome Biol Lab, Frederick, MD USA. [Adhya, Sankar; Oppenheim, Amos B.] Natl Canc Inst, Mol Biol Lab, Bethesda, MD USA. RP Rokney, A (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Genet & Biotechnol, IL-91010 Jerusalem, Israel. EM assafr@ekmd.huji.ac.il RI Kobiler, Oren/J-2268-2012 OI Kobiler, Oren/0000-0001-9914-3770 FU Intramural NIH HHS NR 32 TC 22 Z9 22 U1 2 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD APR PY 2008 VL 68 IS 1 BP 29 EP 36 DI 10.1111/j.1365-2958.2008.06119.x PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 272VS UT WOS:000253889700004 PM 18298445 ER PT J AU Kozmin, SG Leroy, P Pavlov, YI Schaaper, RM AF Kozmin, Stanislav G. Leroy, Prune Pavlov, Youri I. Schaaper, Roel M. TI YcbX and yiiM, two novel determinants for resistance of Escherichia coli to N-hydroxylated base analogues SO MOLECULAR MICROBIOLOGY LA English DT Article ID BIOTIN SULFOXIDE REDUCTASE; SALMONELLA-TYPHIMURIUM; SACCHAROMYCES-CEREVISIAE; MUTAGENIC-ACTIVITY; MOLYBDENUM; COFACTOR; 6-N-HYDROXYLAMINOPURINE; GENE; PROTEIN; IDENTIFICATION AB We have shown previously that lack of molybdenum cofactor (MoCo) in Escherichia coli leads to hypersensitivity to the mutagenic and toxic effects of N-hydroxylated base analogues, such as 6-N-hydroxylaminopurine (HAP). However, the nature of the MoCo-dependent mechanism is unknown, as inactivation of all known and putative E. coli molybdoenzymes does not produce any sensitivity. Presently, we report on the isolation and characterization of two novel HAP-hypersensitive mutants carrying defects in the ycbX or yiiM open reading frames. Genetic analysis suggests that the two genes operate within the MoCo-dependent pathway. In the absence of the ycbX- and yiiM-dependent pathways, biotin sulfoxide reductase plays also a role in the detoxification pathway. YcbX and YiiM are hypothetical members of the MOSC protein superfamily, which contain the C-terminal domain (MOSC) of the eukaryotic MoCo sulphurases. However, deletion of ycbX or yiiM did not affect the activity of human xanthine dehydrogenase expressed in E. coli, suggesting that the role of YcbX and YiiM proteins is not related to MoCo sulphuration. Instead, YcbX and YiiM may represent novel MoCo-dependent enzymatic activities. We also demonstrate that the MoCo/YcbX/YiiM-dependent detoxification of HAP proceeds by reduction to adenine. C1 [Kozmin, Stanislav G.; Leroy, Prune; Pavlov, Youri I.; Schaaper, Roel M.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Kozmin, Stanislav G.] St Petersburg State Univ, Dept Genet, St Petersburg 199034, Russia. [Pavlov, Youri I.] Nebraska Med Ctr, Eppley Inst Res Canc, Omaha, NE 68198 USA. RP Schaaper, RM (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov RI Kozmin, Stanislav/J-6849-2012 OI Kozmin, Stanislav/0000-0002-4128-4447 FU Intramural NIH HHS [Z01 ES050170-08] NR 61 TC 33 Z9 35 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD APR PY 2008 VL 68 IS 1 BP 51 EP 65 DI 10.1111/j.1365-2958.2008.06128.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 272VS UT WOS:000253889700006 PM 18312271 ER PT J AU Dionne, I Brown, NJ Woodgate, R Bell, SD AF Dionne, Isabelle Brown, Nicola J. Woodgate, Roger Bell, Stephen D. TI On the mechanism of loading the PCNA sliding clamp by RFC SO MOLECULAR MICROBIOLOGY LA English DT Article ID CELL NUCLEAR ANTIGEN; REPLICATION FACTOR-C; DNA-POLYMERASE; SULFOLOBUS-SOLFATARICUS; HETEROTRIMERIC PCNA; COMPLEX; SUBUNIT; LOADER AB Sliding clamps play central roles in a broad range of DNA replication and repair processes. The clamps form circular molecules that must be opened and resealed around DNA by the clamp loader complex to fulfil their function. While most eukaryotes and many archea possess a homo-trimeric PCNA, the PCNA of Sulfolobus solfataricus is a heterotrimer. Here, we exploit the asymmetry of S. solfataricus PCNA to create a series of circularly permuted PCNA subunit fusions, thereby covalently closing defined interfaces within the heterotrimer. Using these concatamers, we investigate the requirements for loading the clamp onto DNA and reveal that a single defined interface within the heterotrimer is opened during the loading process. Subunit-specific interactions between S. solfataricus RFC clamp loader and PCNA permit us to superimpose our data upon the structure of yeast RFC-PCNA complex, thereby presenting a general model for PCNA loading by RFC in archaea and eukaryotes. C1 [Dionne, Isabelle; Brown, Nicola J.; Bell, Stephen D.] Hutchinson MRC Res Ctr, MRC, Canc Cell Unit, Cambridge CB2 0XZ, England. [Woodgate, Roger] NICHHD, Lab Genom Integrit, Natl Inst Hlth, Rockville, MD 20854 USA. RP Bell, SD (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM stephen.bell@path.ox.ac.uk OI Dynes, Nicola J/0000-0002-1400-8455 FU Intramural NIH HHS NR 16 TC 30 Z9 30 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD APR PY 2008 VL 68 IS 1 BP 216 EP 222 DI 10.1111/j.1365-2958.2008.06150.x PG 7 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 272VS UT WOS:000253889700018 PM 18312273 ER PT J AU Bougdour, A Cunning, C Baptiste, PJ Elliott, T Gottesman, S AF Bougdour, Alexandre Cunning, Christofer Baptiste, Patrick Jean Elliott, Thomas Gottesman, Susan TI Multiple pathways for regulation of sigma(S) (RpoS) stability in Escherichia coli via the action of multiple anti-adaptors SO MOLECULAR MICROBIOLOGY LA English DT Article ID CYX-APPA OPERON; RESPONSE REGULATOR; SALMONELLA-TYPHIMURIUM; RNA-POLYMERASE; STATIONARY-PHASE; GROWTH-PHASE; TRANSCRIPTIONAL ACTIVATOR; 2-COMPONENT SYSTEM; ACETYL PHOSPHATE; GENE-EXPRESSION AB sigma(S), the stationary phase sigma factor of Escherichia coli and Salmonella, is regulated at multiple levels. The sigma(S) protein is unstable during exponential growth and is stabilized during stationary phase and after various stress treatments. Degradation requires both the ClpXP protease and the adaptor RssB. The small antiadaptor protein IraP is made in response to phosphate starvation and interacts with RssB, causing sigma(S) stabilization under this stress condition. IraP is essential for sigma(S) stabilization in some but not all starvation conditions, suggesting the existence of other anti-adaptor proteins. We report here the identification of new regulators of sigma(S) stability, important under other stress conditions. IraM (inhibitor of RssB activity during Magnesium starvation) and IraD (inhibitor of RssB activity after DNA damage) inhibit sigma(S) proteolysis both in vivo and in vitro. Our results reveal that multiple anti-adaptor proteins allow the regulation of sigma(S) stability through the regulation of RssB activity under a variety of stress conditions. C1 [Bougdour, Alexandre; Baptiste, Patrick Jean; Gottesman, Susan] NCI, Natl Inst Hlth, Mol Biol Lab, Bethesda, MD 20892 USA. [Cunning, Christofer; Elliott, Thomas] W Virginia Univ, Hlth Sci Ctr, Dept Microbiol, Morgantown, WV 26506 USA. RP Gottesman, S (reprint author), NCI, Natl Inst Hlth, Mol Biol Lab, Bethesda, MD 20892 USA. EM susang@helix.nih.gov RI Bougdour, Alexandre/K-3795-2014 OI Bougdour, Alexandre/0000-0002-5895-0020 FU Intramural NIH HHS NR 66 TC 78 Z9 87 U1 1 U2 24 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD APR PY 2008 VL 68 IS 2 BP 298 EP 313 DI 10.1111/j.1365-2958.2008.06146.x PG 16 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 278SI UT WOS:000254306200007 PM 18383615 ER PT J AU Yu, WP Jia, L Wang, P Lawson, KA Simmons-Menchaca, M Park, SK Sun, LZ Sanders, BG Kline, K AF Yu, Weiping Jia, Li Wang, Pei Lawson, Karla A. Simmons-Menchaca, Marla Park, Sook-Kyung Sun, Luzhe Sanders, Bob G. Kline, Kimberly TI In vitro and in vivo evaluation of anticancer actions of natural and synthetic vitamin E forms SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE anticancer actions; apoptosis; human breast cancer; natural vitamin E; synthetic vitamin E ID BREAST-CANCER CELLS; ALPHA-TOCOPHERYL SUCCINATE; GAMMA-TOCOPHEROL; COLON-CANCER; MDA-MB-435 CELLS; PROSTATE-CANCER; MELANOMA-CELLS; E ANALOGS; APOPTOSIS; TOCOTRIENOLS AB The goal of these studies was to investigate the potential anticancer properties of two naturally occurring plant sources and two manufactured synthetic forms of vitamin E, i.e., RRR-alpha-tocopherol (UT), RRR-alpha-tocopherol (alpha T), all-rac-alpha-tocopherol (all-rac-alpha T), and all-rac-alpha-tocopheryl acetate (all-rac-alpha TAc) in breast cancer models. Vitamin F compounds were evaluated in vitro for inhibition of colony formation and induction of apoptosis in human MDA-MB-435 and MCF-7 breast cancer cells and murine 66cl-4 mammary cancer cells and in vivo for ability to reduce tumor growth and lung and lymph node metastases using the transplantable syngeneic BALB/c mouse 66cl-4-GFP mammary cancer model. gamma T inhibited colony formation and induced apoptosis in all three cancer cell lines. alpha T and all-rac-aT were less effective and all-rac-alpha TAc was ineffective. gamma T-induced apoptosis was correlated with activation of caspases-8 and -9 and down-regulation of protein expression of c-FLIP and survivin. In vivo study 1 analyses showed that all-rac-alpha T and all-rac-alpha TAc significantly inhibited tumor growth and inhibited both visible and microscopic size lung metastases. In vivo study 2 analyses showed that alpha T and gamma T reduced tumor growth, but only gamma T reduced tumor growth significantly in comparison to control. In conclusion, synthetic, but not natural, vitamin E exhibits promising anticancer properties in vivo. C1 [Yu, Weiping; Kline, Kimberly] Univ Texas Austin, Div Nutr A2703, Austin, TX 78712 USA. [Yu, Weiping; Jia, Li; Wang, Pei; Simmons-Menchaca, Marla; Park, Sook-Kyung; Sanders, Bob G.] Univ Texas Austin, Sch Biol Sci, Austin, TX 78712 USA. [Lawson, Karla A.] Canc Prevent Fellowship Program, Natl Canc Inst, Bethesda, MD USA. [Sun, Luzhe] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. RP Kline, K (reprint author), Univ Texas Austin, Div Nutr A2703, Austin, TX 78712 USA. EM k.kline@mail.utexas.edu FU NCI NIH HHS [CA59739, CA79683]; NIEHS NIH HHS [ES07784] NR 41 TC 15 Z9 16 U1 1 U2 10 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1613-4125 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD APR PY 2008 VL 52 IS 4 BP 447 EP 456 DI 10.1002/mnfr.200700254 PG 10 WC Food Science & Technology SC Food Science & Technology GA 292VP UT WOS:000255294500007 PM 18381678 ER PT J AU Sueyoshi, T Moore, R Sugatani, J Matsumura, Y Negishi, M AF Sueyoshi, Tatsuya Moore, Rick Sugatani, Junko Matsumura, Yonehiro Negishi, Masahiko TI PPP1R16A, the membrane subunit of protein phosphatase 1 beta, signals nuclear translocation of the nuclear receptor constitutive active/androstane receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID PREGNANE-X-RECEPTOR; MOUSE-LIVER; ANDROSTANE RECEPTOR; PROTEIN PHOSPHATASE-1; DRUG-METABOLISM; GENE-EXPRESSION; CYP2B6 GENE; CAR; INDUCTION; PXR AB Constitutive active/androstane receptor (CAR), a member of the nuclear steroid/thyroid hormone receptor family, activates transcription of numerous hepatic genes upon exposure to therapeutic drugs and environmental pollutants. Sequestered in the cytoplasm, this receptor signals xenobiotic exposure, such as phenobarbital (PB), by translocating into the nucleus. Unlike other hormone receptors, translocation can be triggered indirectly without binding to xenobiotics. We have now identified a membrane-associated subunit of protein phosphatase 1 (PPP1R16A, or abbreviated as R16A) as a novel CAR-binding protein. When CAR and R16A are coexpressed in mouse liver, CAR translocates into the nucleus. Close association of R16A and CAR molecule on liver membrane was shown by fluorescence resonance energy transfer (FRET) analysis using expressed yellow fluorescent protein (YFP)-CAR and CFP-R16A fusion proteins. R16A can form dimer through its middle region, where protein kinase A phosphorylation sites are recently identified. Translocation of CAR by R16A correlates with the ability of R16A to form an intermolecular interaction via the middle region. Moreover, this interaction is enhanced by PB treatment in mouse liver. R16A specifically interacted with PP1 beta in HepG2 cells despite the highly conserved structure of PP1 family molecules. PP1 beta activity was inhibited by R16A in vitro and coexpression of PP1 beta in liver can prevent YFP-CAR translocation into mouse liver. Taken together, R16A at the membrane may mediate the PB signal to initiate CAR nuclear translocation, through a mechanism including its dimerization and inhibition of PP1 beta activity, providing a novel model for the translocation of nuclear receptors in which direct interaction of ligands and the receptors may not be crucial. C1 [Sueyoshi, Tatsuya; Moore, Rick; Sugatani, Junko; Matsumura, Yonehiro; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Sueyoshi, T (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM sueyoshi@niehs.nih.gov FU Intramural NIH HHS NR 43 TC 31 Z9 33 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD APR PY 2008 VL 73 IS 4 BP 1113 EP 1121 DI 10.1124/mol.107.042960 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 275IK UT WOS:000254064900009 PM 18202305 ER PT J AU Parnas, ML Gaffaney, JD Zou, MF Lever, JR Newman, AH Vaughan, RA AF Parnas, M. Laura Gaffaney, Jon D. Zou, Mu Fa Lever, John R. Newman, Amy Hauck Vaughan, Roxanne A. TI Labeling of dopamine transporter transmembrane domain 1 with the tropane ligand N-[4-(4-Azido-3-[I-125]iodophenyl)butyl]-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane implicates proximity of cocaine and substrate active sites SO MOLECULAR PHARMACOLOGY LA English DT Article ID HUMAN SEROTONIN TRANSPORTERS; HIGH-AFFINITY RECOGNITION; NEUROTRANSMITTER TRANSPORTERS; PHOTOAFFINITY LIGANDS; IRREVERSIBLE LIGANDS; DIFFERENTIALLY ALTER; BACTERIAL HOMOLOG; UPTAKE INHIBITORS; BINDING DOMAINS; BENZTROPINE AB The novel photoaffinity ligand N-[4-(4-azido-3-I-125-iodophenyl)-butyl]-2-beta-carbomethoxy-3 beta-(4- chlorophenyl) tropane ([I-125] MFZ 2-24) was used to investigate the site for cocaine binding on the dopamine transporter (DAT). [I-125] MFZ 2-24 irreversibly labeled both rat striatal and expressed human DAT with high affinity and appropriate pharmacological specificity. Tryptic proteolysis of [I-125] MFZ 2-24 labeled DAT followed by epitope-specific immunoprecipitation demonstrated that the ligand becomes adducted almost exclusively to transmembrane domains (TMs) 1-2. Further localization of [I-125] MFZ 2-24 incorporation achieved by proteolyzing labeled wild-type and methionine mutant DATs with cyanogen bromide identified the sequence between residues 68 and 80 in TM1 as the ligand adduction site. This is in marked contrast to the previously identified attachment of the photoaffinity label [I-125] RTI 82 in TM6. Because [I-125] MFZ 2-24 and [I-125] RTI 82 possess identical tropane pharmacophores and differ only in the placement of the reactive azido moieties, their distinct incorporation profiles identify the regions of the protein adjacent to different aspects of the cocaine molecule. These findings thus strongly support the direct interaction of cocaine on DAT with TM1 and TM6, both of which have been implicated by mutagenesis and homology to a bacterial leucine transporter as active sites for substrates. These results directly establish the proximity of TMs 1 and 6 in DAT and suggest that the mechanism of transport inhibition by cocaine involves close interactions with multiple regions of the substrate permeation pathway. C1 [Parnas, M. Laura; Gaffaney, Jon D.; Vaughan, Roxanne A.] Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Grand Forks, ND 58202 USA. [Zou, Mu Fa; Newman, Amy Hauck] Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, Baltimore, MD USA. [Lever, John R.] Univ Missouri, Dept Radiopharmaceut, Columbia, MO USA. RP Vaughan, RA (reprint author), Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Grand Forks, ND 58202 USA. EM rvaughan@medicine.nodak.edu FU Intramural NIH HHS; NIDA NIH HHS [DA15175] NR 40 TC 19 Z9 20 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD APR PY 2008 VL 73 IS 4 BP 1141 EP 1150 DI 10.1124/mol.107.043679 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 275IK UT WOS:000254064900012 PM 18216182 ER PT J AU Elbaz, B Alperovitch, A Gottesman, MM Kimchi-Sarfaty, C Rahamimoff, H AF Elbaz, Benayahu Alperovitch, Ariella Gottesman, Michael M. Kimchi-Sarfaty, Chava Rahamimoff, Hannah TI Modulation of Na+-Ca2+ exchanger expression by immunosuppressive drugs is isoform-specific SO MOLECULAR PHARMACOLOGY LA English DT Article ID SODIUM-CALCIUM EXCHANGE; BLOOD-BRAIN-BARRIER; CIS-TRANS ISOMERASE; CYCLOSPORINE-A; SURFACE EXPRESSION; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; NA+/CA2+ EXCHANGER; PROLYL ISOMERASE; DOWN-REGULATION AB The Na+-Ca2+ exchanger (NCX) is a major Ca2+-regulating protein encoded by three genes: NCX1, NCX2, and NCX3. They share a sequence homology of approximately 65%. NCX1 protein is expressed ubiquitously, and NCX2 and NCX3 are expressed almost exclusively in the brain. We have shown previously (Kimchi-Sarfaty et al., 2002) that treatment of NCX1-transfected human embryonic kidney (HEK) 293 cells with the immunosuppressive cyclosporin A (CsA) and its nonimmunosuppressive analog PSC833 (valspodar) results in down-regulation of surface expression and transport activity of the protein without a decrease in expression of cell NCX1 protein. In this study, we show that cyclosporin A and PSC833 treatment of NCX2- and NCX3-transfected HEK 293 cells also resulted in dose-dependent down-regulation of surface expression and transport activity of the two brain NCX proteins; however, whereas CsA had no effect on total cell NCX protein expression, PSC833 reduced mRNA and cell protein expression of NCX2 and NCX3. Moreover, tacrolimus (FK506), which had no effect on NCX1 protein expression, down-regulated NCX2 and NCX3 surface expression and transport activity without any significant effect on cell protein expression. Sirolimus (rapamycin) had no effect on NCX2 and NCX3 protein expression, yet it reduced NCX2 and NCX3 transport activity. Because all of the experimental conditions in our studies were identical, presumably the different drug response is related to structural differences between NCX isoforms. Clinical studies suggested that immunosuppressive regimes of patients who have received transplants resulted in complications related to Ca2+. Expression of NCX genes is tissue-specific. Hence, our results can potentially provide a tool for choosing the immunosuppressive protocol to be used. C1 [Elbaz, Benayahu; Alperovitch, Ariella; Rahamimoff, Hannah] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, IL-91120 Jerusalem, Israel. [Elbaz, Benayahu; Gottesman, Michael M.; Rahamimoff, Hannah] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Kimchi-Sarfaty, Chava] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Rahamimoff, H (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, POB 12272, IL-91120 Jerusalem, Israel. EM hannah.rahamimoff@huji.ac.il OI Elbaz, Benayahu/0000-0001-5202-4598 FU Intramural NIH HHS NR 50 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD APR PY 2008 VL 73 IS 4 BP 1254 EP 1263 DI 10.1124/mol.107.041582 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 275IK UT WOS:000254064900023 PM 18182482 ER PT J AU Giovannetti, E Lemos, C Tekle, C Smid, K Nannizzi, S Rodriguez, JA Ricciardi, S Danesi, R Giaccone, G Peters, GJ AF Giovannetti, Elisa Lemos, Clara Tekle, Christina Smid, Kees Nannizzi, Sara Rodriguez, Jose A. Ricciardi, Simona Danesi, Romano Giaccone, Giuseppe Peters, Godefridus J. TI Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID PHASE-III TRIAL; MESSENGER-RNA EXPRESSION; THYMIDYLATE SYNTHASE; DETERMINES RESPONSE; ANTITUMOR-ACTIVITY; COLORECTAL-CANCER; CLINICAL-RESPONSE; CYCLIN D1; GEFITINIB; GEMCITABINE AB Because the epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitor erlotinib and the multitargeted antifolate pemetrexed are registered in the treatment of second-line non small-cell lung cancer ( NSCLC), empirical combinations of these drugs are being tested. This study investigated molecular mechanisms underlying their combination in six NSCLC cell lines. Cells were characterized by heterogeneous expression of pemetrexed determinants, including thymidylate synthase ( TS) and dihydrofolate reductase ( DHFR), and mutations potentially affecting chemosensitivity. Pharmacological interaction was studied using the combination index ( CI) method, whereas cell cycle, apoptosis induction, and EGFR, extracellular signal-regulated kinases 1 and 2, and Akt phosphorylation were studied by flow cytometry, fluorescence microscopy, and enzyme-linked immunosorbent assays. Reverse-transcriptase polymerase chain reaction ( RT-PCR), Western blot, and activity assays were performed to assess whether erlotinib influenced TS. 3-( 4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium assays demonstrated that EGFR and k-Ras mutations were related to erlotinib sensitivity, whereas TS and DHFR expression were related to pemetrexed sensitivity. Synergistic cytotoxicity was found in all cells, most pronounced with pemetrexed + erlotinib ( 24 h) -> erlotinib ( 48 h) sequence ( CI, 0.09-0.40), which was associated with a significant induction of apoptosis. Pemetrexed increased EGFR phosphorylation and reduced Akt phosphorylation, which was additionally reduced by drug combination (-70.6% in H1650). Erlotinib significantly reduced TS expression and activity, possibly via E2F-1 reduction, as detected by RT-PCR and Western blot, and the combination decreased TS in situ activity in all cells. Erlotinib and pemetrexed showed a strong synergism in NSCLC cells, regardless of their genetic characteristics. Induction of apoptosis, modulation of EGFR and Akt phosphorylation, and changes in the expression of critical genes involved in pemetrexed activity contribute to this synergistic interaction and support the clinical investigation of these markers. C1 [Giovannetti, Elisa; Lemos, Clara; Tekle, Christina; Smid, Kees; Rodriguez, Jose A.; Peters, Godefridus J.] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Giovannetti, Elisa; Nannizzi, Sara; Ricciardi, Simona; Danesi, Romano] Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, I-56126 Pisa, Italy. [Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Giovannetti, E (reprint author), Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, 55 Via Roma, I-56126 Pisa, Italy. EM elisa.giovannetti@gmail.com RI Giovannetti, Elisa/F-4261-2011; Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Giovannetti, Elisa/0000-0002-7565-7504 NR 47 TC 95 Z9 102 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD APR PY 2008 VL 73 IS 4 BP 1290 EP 1300 DI 10.1124/mol.107.042382 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 275IK UT WOS:000254064900027 PM 18187583 ER PT J AU Nakamura, N Shibata, H O'Brien, DA Mori, C Eddy, EM AF Nakamura, Noriko Shibata, Haruna O'Brien, Deborah A. Mori, Chisato Eddy, Edward M. TI Spermatogenic cell-specific type 1 hexokinase is the predominant hexokinase in sperm SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE spermatogenesis; isozyme; gene expression; glycolysis; testis ID GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE-S; MESSENGER-RIBONUCLEIC-ACID; PORIN-BINDING DOMAIN; LACTATE-DEHYDROGENASE; MOUSE SPERMATOGENESIS; MALE-FERTILITY; TESTIS; GENE; LOCALIZATION; KINASE AB Hexokinase is the first enzyme in the glycolytic pathway and utilizes ATP to convert glucose to glucose-6-phosphate (G6P). We previously identified three variant transcripts of Hk1 that are expressed specifically in spermatogenic cells, have different 5 ' untranslated regions, and encode a protein (HK1S, spermatogenic cell-specific type 1 hexokinase) in which the porin-binding domain (PBD) of HK1 is replaced by a novel N-terminal spermatogenic cell-specific region (SSR). However, the level of expression of the individual variant transcripts or of the other members of the hexokinase gene family (Hk2, Hk3, and Gck) in spermatogenic cells remains uncertain. We show that Hk1, Hk2, and Hk3 transcripts levels are quite low in spermatocytes and spermatids and Gck transcripts are relatively abundant in spermatids, but that glucokinase (GCK) is not detected in spermatozoa. Using real time RT-PCR (qPCR) with primers specific for each of the three variant forms and RNA from whole testis and isolated germ cells, we found that transcripts for Hk1_v2 and Hk1_v3, but not for Hk1_v1, are relatively high in spermatids. Similar results were seen using spermatogenic cells isolated by laser-capture microdissection (LCM). Immunoblotting studies found that HK1S is abundant in sperm, and immunostaining confirmed that HK1S is located mainly in the principal piece of the sperm flagellum, where other spermatogenic cell-specific glycolytic enzymes have been found. These results strongly suggest that HK1, HK2, HK3, and GCK are unlikely to have a role in glycolysis in sperm and that HK1S encoded by Hk1_v2 and Hk1_v3 serves this role. C1 [Nakamura, Noriko; Eddy, Edward M.] NIEHS, NIH, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Shibata, Haruna; Mori, Chisato] Chiba Univ, Grad Sch Med, Dept Bioenvironm Med, Chuo Ku, Chiba, Japan. [O'Brien, Deborah A.] Univ N Carolina, Sch Med, Dept Cell & Dev Biol, Chapel Hill, NC USA. RP Eddy, EM (reprint author), NIEHS, NIH, Reprod & Dev Toxicol Lab, C4-01,Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov FU Intramural NIH HHS [Z01 ES070076-21]; NICHD NIH HHS [U54 HD035041, U54HD35041] NR 44 TC 24 Z9 25 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD APR PY 2008 VL 75 IS 4 BP 632 EP 640 DI 10.1002/mrd.20791 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 269QZ UT WOS:000253665400008 PM 17924400 ER PT J AU Bai, X Son, SJ Zhang, SX Liu, W Jordan, EK Frank, JA Venkatesan, T Lee, SB AF Bai, Xia Son, Sang Jun Zhang, Shixiong Liu, Wei Jordan, Elaine K. Frank, Joseph A. Venkatesan, Thirumalai Lee, Sang Bok TI Synthesis of superparamagnetic nanotubes as MRI contrast agents and for cell labeling SO NANOMEDICINE LA English DT Article DE cell labeling; cytotoxiciry; magnetic nanotubes; MRI contrast agent; polyol method; superparamagnetic iron oxide; nanoparticles; T(1)relaxation; T(2) relaxation ID IRON-OXIDE NANOPARTICLES; CODED SILICA NANOTUBES; MAGNETIC-PROPERTIES; BIOMEDICAL APPLICATIONS; SMART NANOTUBES; ANODIC ALUMINA; DRUG-DELIVERY; POLYOL MEDIUM; STEM-CELLS; SURFACE AB Aims: Magnetic nanoparticles have been studied widely as MR1 contrast agents to increase the sensitivity of this technique. This work describes the synthesis and characterization of magnetic nanotubes (MNTs) as a novel Mill contrast agent. Methods: MNTs with high saturation magnetization were fabricated by the synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) directly in the pores of silica nanotubes (SNTs). The MNTs were characterized by electron microscopy, superconducting quantum interference device and MR1. Preliminary studies on in vitro cytotoxicity and cell labeling were carried out. Results: The MNTs retained the superparamagnetic characteristics in bulk solutions with a considerably high saturation magnetization of 95 emu/gFe. The nuclear magnetic resonance (NMR) relaxivities for MNTs of 500 nm in length and of 60 nm in diameter were r(1) = 1.6 +/- 0.3 mM(-1)s(-1) and r(2) = 264 +/- 56 mM(-1)s(-1) and, for the MNTs of 2 pm in length and 70 nm in diameter, the r, and r2 were 3.0 +/- 1.3 and 358 +/- 65 mM(-1)s(-1), respectively. In vitro cell labeling showed promising results with excellent labeling efficiency. No cellular toxicity was observed in vitro. Conclusions: The integration of SPIONs with SNTs imparts the superparamagnetic characteristics of SPIONs onto the SNTs, creating unique magnetic nanoparticles with multifunctionality. The MNTs showed promising results as a MRI contrast agent with high NMR relaxivities, little cytotoxicity and high cell-labeling efficiency. C1 [Bai, Xia; Son, Sang Jun; Lee, Sang Bok] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Son, Sang Jun] Kyungwon Univ, Gachon BioNano Res Inst, Songnam 461701, Kyeonggi Do, South Korea. [Zhang, Shixiong; Venkatesan, Thirumalai] Univ Maryland, Ctr Superconduct Res, College Pk, MD 20742 USA. [Liu, Wei] Philips Res N Amer, Clin Sites Res Program, Briarcliff Manor, NY 10510 USA. [Jordan, Elaine K.; Frank, Joseph A.] NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. [Lee, Sang Bok] Univ Maryland, Maryland Nanoctr, College Pk, MD 20742 USA. RP Lee, SB (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. EM slee@umd.edu RI Lee, Sang Bok/B-4421-2009; Son, Sang Jun/E-2714-2012; Venkatesan, Thirumalai/E-1667-2013 FU Intramural NIH HHS NR 51 TC 39 Z9 39 U1 2 U2 20 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 APR PY 2008 VL 3 IS 2 BP 163 EP 174 DI 10.2217/17435889.3.2.163 PG 12 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 331EG UT WOS:000257994900007 PM 18373423 ER PT J AU Scaffidi, P Misteli, T AF Scaffidi, Paola Misteli, Tom TI Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing SO NATURE CELL BIOLOGY LA English DT Article ID HUTCHINSON-GILFORD-PROGERIA; NOTCH; PROTEIN; DIFFERENTIATION; TRANSCRIPTION; ACTIVATION; PHENOTYPE; HES; INHIBITION; EXPRESSION AB The premature-ageing disease Hutchinson-Gilford Progeria Syndrome ( HGPS) is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A(1,2). Progerin is also expressed sporadically in wildtype cells and has been linked to physiological ageing(3). Cells from HGPS patients exhibit extensive nuclear defects, including abnormal chromatin structure(4,5) and increased DNA damage(6). At the organismal level, HGPS affects several tissues, particularly those of mesenchymal origin(7). How the cellular defects of HGPS cells lead to the organismal defects has been unclear. Here, we provide evidence that progerin interferes with the function of human mesenchymal stem cells ( hMSCs). We find that expression of progerin activates major downstream effectors of the Notch signalling pathway. Induction of progerin in hMSCs changes their molecular identity and differentiation potential. Our results support a model in which accelerated ageing in HGPS patients, and possibly also physiological ageing, is the result of adult stem cell dysfunction and progressive deterioration of tissue functions. C1 [Scaffidi, Paola; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Scaffidi, P (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM scaffidp@mail.nih.gov FU Intramural NIH HHS [Z01 BC010309-09] NR 35 TC 247 Z9 254 U1 6 U2 33 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 APR PY 2008 VL 10 IS 4 BP 452 EP U167 DI 10.1038/ncb1708 PG 16 WC Cell Biology SC Cell Biology GA 282IS UT WOS:000254561700016 PM 18311132 ER PT J AU Polozov, IV Bezrukov, L Gawrisch, K Zimmerberg, J AF Polozov, Ivan V. Bezrukov, Ludmila Gawrisch, Klaus Zimmerberg, Joshua TI Progressive ordering with decreasing temperature of the phospholipids of influenza virus SO NATURE CHEMICAL BIOLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; ELECTRON-SPIN RESONANCE; PLASMA-MEMBRANE; LATERAL DIFFUSION; BIOLOGICAL-MEMBRANES; LIPID-MEMBRANES; CELL-MEMBRANES; RAFT FORMATION; LINE TENSION; MAS NMR AB Using linewidth and spinning sideband intensities of lipid hydrocarbon chain resonances in proton magic angle spinning NMR spectra, we detected the temperature-dependent phase state of naturally occurring lipids of intact influenza virus without exogenous probes. Increasingly, below 41 degrees C ordered and disordered lipid domains coexisted for the viral envelope and extracts thereof. At 22 degrees C much lipid was in a gel phase, the fraction of which reversibly increased with cholesterol depletion. Diffusion measurements and fluorescence microscopy independently confirmed the existence of gel-phase domains. Thus the existence of ordered regions of lipids in biological membranes is now demonstrated. Above the physiological temperatures of influenza infection, the physical properties of viral envelope lipids, regardless of protein content, were indistinguishable from those of the disordered fraction. Viral fusion appears to be uncorrelated to ordered lipid content. Lipid ordering may contribute to viral stability at lower temperatures, which has recently been found to be critical for airborne transmission. C1 [Polozov, Ivan V.; Bezrukov, Ludmila; Zimmerberg, Joshua] NICHHD, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. [Gawrisch, Klaus] NIAAA, NIH, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, 10D14,10 Ctr Dr MSC 1855, Bethesda, MD 20892 USA. EM joshz@helix.nih.gov FU Intramural NIH HHS NR 50 TC 83 Z9 83 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2008 VL 4 IS 4 BP 248 EP 255 DI 10.1038/nchembio.77 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278EY UT WOS:000254268300012 PM 18311130 ER PT J AU Steeg, PS Theodorescu, D AF Steeg, Patricia S. Theodorescu, Dan TI Metastasis: a therapeutic target for cancer SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Review DE angiogenesis; bone; colonization; metastasis; tumorigenesis ID GROWTH-FACTOR-BETA; ADJUVANT CLODRONATE TREATMENT; HER2-POSITIVE BREAST-CANCER; RANDOMIZED CONTROLLED-TRIAL; TYROSINE KINASE INHIBITOR; GENE-EXPRESSION PROFILES; LYMPH-NODE METASTASIS; FACTOR-KAPPA-B; PROSTATE-CANCER; BONE METASTASIS AB Metastasis remains the major driver of mortality in patients with cancer. Our growing body of knowledge regarding this process provides the basis for the development of molecularly targeted therapeutics aimed at the tumor cell or its interaction with the host microenvironment. Here we discuss the similarity and differences between primary tumors and metastases, pathways controlling the colonization of a distant organ, and incorporation of antimetastatic therapies into clinical testing. C1 [Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Theodorescu, Dan] Univ Virginia, Paul Mellon Urol Canc Inst, Charlottesville, VA 22908 USA. RP Steeg, PS (reprint author), NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Room 1122,Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov; theodorescu@virginia.edu FU Intramural NIH HHS [Z01 SC000892-24]; NCI NIH HHS [CA075115, CA104106, P01 CA104106, R01 CA075115, R29 CA075115] NR 98 TC 156 Z9 166 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD APR PY 2008 VL 5 IS 4 BP 206 EP 219 DI 10.1038/ncponc1066 PG 14 WC Oncology SC Oncology GA 280FY UT WOS:000254412300009 PM 18253104 ER PT J AU Roescher, N Illei, GG AF Roescher, Nienke Illei, Gabor G. TI Can quantified salivary gland scintigraphy results aid diagnosis of patients with sicca symptoms? SO NATURE CLINICAL PRACTICE RHEUMATOLOGY LA English DT Editorial Material ID SJOGRENS-SYNDROME; QUANTITATIVE-EVALUATION C1 [Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, NIH, Sjogren Syndrome Clin, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. RP Illei, GG (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Sjogren Syndrome Clin, Mol Physiol & Therapeut Branch, Bldg 10,Room 1N-114, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8382 J9 NAT CLIN PRACT RHEUM JI Nat. Clin. Pract. Rheumatol. PD APR PY 2008 VL 4 IS 4 BP 178 EP 179 DI 10.1038/ncprheum0759 PG 2 WC Rheumatology; Social Issues SC Rheumatology; Social Issues GA 282ID UT WOS:000254560200004 PM 18268547 ER PT J AU Nikolov, NP Pavletic, SZ AF Nikolov, Nikolay P. Pavletic, Steven Z. TI Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease SO NATURE CLINICAL PRACTICE RHEUMATOLOGY LA English DT Review DE allogeneic; autoimmunity; autologous; conditioning; hematopoietic stem cell transplantation ID DOSE IMMUNOSUPPRESSIVE THERAPY; VERSUS-HOST-DISEASE; TERM-FOLLOW-UP; LUPUS-ERYTHEMATOSUS; AUTOIMMUNE-DISEASES; MULTIPLE-SCLEROSIS; MARROW-TRANSPLANTATION; SCLERODERMA; ARTHRITIS; BLOOD AB Hematopoietic stem cells (HSCs) have the capacity for self-renewal and the potential to differentiate into all types of hematopoietic and immune system cells. These features have been successfully used to treat a multitude of hematologic malignancies and nonmalignant diseases such as aplastic anemia, hemoglobinopathies, inborn errors of metabolism and congenital immunodeficiency states. The application of HSC transplantation has been expanded over the past decade to include immune-mediated diseases such as multiple sclerosis, treatment-refractory rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Transplantation of HSCs for the treatment of autoimmune diseases aims to fundamentally correct the dysregulated immune system, which could result in sustained clinical remission or potential cure. The use of this approach is currently restricted to clinical research, as there is no standard conditioning regimen to attain these aims in autoimmune diseases. HSC transplantation is associated with inherent morbidity and mortality, both treatment-related and disease-related, and selecting the correct group of patients with the best risk: benefit ratio is a challenging task. C1 [Nikolov, Nikolay P.] NIDCR, NIH, Sjogren Syndrome Clin, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. [Pavletic, Steven Z.] NCI, Graft Versus Host & Autoimmunity Unit, Expt Transplantat & Immunol Branch, Bethesda, MD USA. RP Nikolov, NP (reprint author), NIDCR, NIH, Sjogren Syndrome Clin, Mol Physiol & Therapeut Branch, Bldg 10,Room 1N-114, Bethesda, MD 20892 USA. EM nikolovn@mail.nih.gov NR 46 TC 5 Z9 8 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8382 J9 NAT CLIN PRACT RHEUM JI Nat. Clin. Pract. Rheumatol. PD APR PY 2008 VL 4 IS 4 BP 184 EP 191 DI 10.1038/ncprheum0756 PG 8 WC Rheumatology; Social Issues SC Rheumatology; Social Issues GA 282ID UT WOS:000254560200007 PM 18285764 ER PT J AU Neaton, JD Lane, HC AF Neaton, James D. Lane, H. Clifford TI Getting personal about treating HIV SO NATURE MEDICINE LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY AB Genetic variants have been identified that may predict the response to HIV treatment ( pages 413 - 420). C1 [Neaton, James D.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55414 USA. [Lane, H. Clifford] US NIH, Bethesda, MD 20892 USA. RP Neaton, JD (reprint author), Univ Minnesota, Sch Publ Hlth, Div Biostat, 2221 Univ Ave SE,Room 200, Minneapolis, MN 55414 USA. EM jim@ccbr.umn.edu NR 11 TC 1 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2008 VL 14 IS 4 BP 369 EP 370 DI 10.1038/nm0408-369 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 283ZD UT WOS:000254674100010 PM 18391933 ER PT J AU Sayed, AA Simeonov, A Thomas, CJ Inglese, J Austin, CP Williams, DL AF Sayed, Ahmed A. Simeonov, Anton Thomas, Craig J. Inglese, James Austin, Christopher P. Williams, David L. TI Identification of oxadiazoles as new drug leads for the control of schistosomiasis SO NATURE MEDICINE LA English DT Article ID TROPICAL DISEASES; MANSONI; RESISTANCE; INFECTION; PRAZIQUANTEL; THIOREDOXIN; FUROXANS; METAANALYSIS; GLUTATHIONE; LIBRARIES AB Treatment for schistosomiasis, which is responsible for more than 280,000 deaths annually, depends almost exclusively on praziquantel. Millions of people are treated annually with praziquantel, and drug- resistant parasites thus are likely to evolve. Phosphinic amides and oxadiazole 2- oxides, identified from a quantitative high- throughput screen, were shown to inhibit a parasite enzyme, thioredoxin glutathione reductase ( TGR), with activities in the low micromolar to low nanomolar range. Incubation of parasites with these compounds led to rapid inhibition of TGR activity and parasite death. The activity of the oxadiazole 2- oxides was associated with a donation of nitric oxide. Treatment of schistosome- infected mice with 4- phenyl- 1,2,5- oxadiazole- 3-carbonitrile- 2- oxide led to marked reductions in worm burdens from treatments against multiple parasite stages and egg- associated pathologies. The compound was active against the three major schistosome species infecting humans. These protective effects exceed benchmark activity criteria set by the World Health Organization for lead compound development for schistosomiasis. C1 [Sayed, Ahmed A.; Williams, David L.] Illinois State Univ, Dept Biol Sci, Normal, IL 61790 USA. [Simeonov, Anton; Thomas, Craig J.; Inglese, James; Austin, Christopher P.] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Williams, DL (reprint author), Illinois State Univ, Dept Biol Sci, Normal, IL 61790 USA. EM austinc@mail.nih.gov; dlwilli@ilstu.edu FU Intramural NIH HHS [Z01 HG200319-04]; NIAID NIH HHS [N01AI30026, R01 AI065622, R01 AI065622-02, R01AI065622]; NIMH NIH HHS [R03 MH076449, R03MH076449] NR 36 TC 162 Z9 177 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2008 VL 14 IS 4 BP 407 EP 412 DI 10.1038/nm1737 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 283ZD UT WOS:000254674100027 PM 18345010 ER PT J AU Jones, KS Petrow-Sadowski, C Huang, YK Bertolette, DC Ruscetti, FW AF Jones, Kathryn S. Petrow-Sadowski, Cari Huang, Ying K. Bertolette, Daniel C. Ruscetti, Francis W. TI Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells SO NATURE MEDICINE LA English DT Article ID LYMPHOTROPIC VIRUS TYPE-1; MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; HEPARAN-SULFATE PROTEOGLYCANS; BLOOD MONONUCLEAR-CELLS; I TAX; ASYMPTOMATIC CARRIERS; IMMUNE SUPPRESSION; VIRAL REPLICATION; MESSENGER-RNA; LEUKEMIA AB Cell- free human T- lymphotropic virus type 1 ( HTLV- 1) virions are poorly infectious in vitro for their primary target cells, CD4(+) T cells. Here, we show that HTLV- 1 can efficiently infect myeloid and plasmacytoid dendritic cells ( DCs). Moreover, DCs exposed to HTLV- 1, both before and after being productively infected, can rapidly, efficiently and reproducibly transfer virus to autologous primary CD4(+) T cells. This DC- mediated transfer of HTLV-1 involves heparan sulfate proteoglycans and neuropilin-1 and results in long- term productive infection and interleukin-2- independent transformation of the CD4(+) T cells. These studies, along with observations of HTLV-1- infected DCs in the peripheral blood of infected individuals, indicate that DCs have a central role in HTLV-1 transmission, dissemination and persistence in vivo. In addition to altering the current paradigm concerning how HTLV-1 transmission occurs, these studies suggest that impairment of DC function after HTLV- 1 infection plays a part in pathogenesis. C1 [Jones, Kathryn S.; Petrow-Sadowski, Cari] Sci Applicat Int Corp, Basic Res Program, Frederick, MD USA. [Huang, Ying K.; Bertolette, Daniel C.; Ruscetti, Francis W.] NCI, Ctr Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD 21702 USA. RP Jones, KS (reprint author), Sci Applicat Int Corp, Basic Res Program, Frederick, MD USA. EM joneska@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 50 TC 137 Z9 140 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2008 VL 14 IS 4 BP 429 EP 436 DI 10.1038/nm1745 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 283ZD UT WOS:000254674100030 PM 18376405 ER PT J AU Jones, CA London, NR Chen, H Park, KW Sauvaget, D Stockton, RA Wythe, JD Suh, W Larrieu-Lahargue, F Mukouyama, YS Lindblom, P Seth, P Frias, A Nishiya, N Ginsberg, MH Gerhardt, H Zhang, K Li, DY AF Jones, Christopher A. London, Nyall R. Chen, Haoyu Park, Kye Won Sauvaget, Dominique Stockton, Rebecca A. Wythe, Joshua D. Suh, Wonhee Larrieu-Lahargue, Frederic Mukouyama, Yoh-Suke Lindblom, Per Seth, Pankaj Frias, Antonio Nishiya, Naoyuki Ginsberg, Mark H. Gerhardt, Holger Zhang, Kang Li, Dean Y. TI Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability SO NATURE MEDICINE LA English DT Article ID OXYGEN-INDUCED RETINOPATHY; MACULAR DEGENERATION; AXON GUIDANCE; SLIT; MOUSE; RECEPTOR; MIDLINE; GROWTH; NEOVASCULARIZATION; MORPHOGENESIS AB The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures(1). The Roundabout ( Robo) proteins are guidance receptors with well- established functions in the nervous system(2,3); however, their role in the mammalian vasculature remains ill defined(4-8). Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor ( VEGF)- 165 - induced migration, tube formation and permeability in vitro and VEGF- 165 - stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/ or vascular leak. C1 Univ Utah, Dept Oncol Sci, Salt Lake City, UT 84112 USA. Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. [Jones, Christopher A.; London, Nyall R.; Park, Kye Won; Wythe, Joshua D.; Suh, Wonhee; Larrieu-Lahargue, Frederic; Frias, Antonio; Zhang, Kang; Li, Dean Y.] Univ Utah, Program Human Mol Biol & Genet, Salt Lake City, UT 84112 USA. [Chen, Haoyu; Stockton, Rebecca A.; Zhang, Kang] Univ Utah, Dept Ophthalmol, Salt Lake City, UT 84112 USA. [Sauvaget, Dominique; Lindblom, Per; Gerhardt, Holger] London Res Inst Canc Res, Vasc Biol Lab, London WC2A 3PX, England. [Nishiya, Naoyuki; Ginsberg, Mark H.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Mukouyama, Yoh-Suke] NHLBI, Stem Cell & Neuro Vasc Dev & Patterning Sect, Dev Biol Lab, Genet & Dev Biol Ctr,NIH, Bethesda, MD 20892 USA. [Seth, Pankaj] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Renal Div, Boston, MA 02215 USA. [Seth, Pankaj] Harvard Univ, Sch Med, Ctr Study Tumor Microenvironm, Boston, MA 02215 USA. RP Li, DY (reprint author), Univ Utah, Dept Oncol Sci, 15 North 2030 East, Salt Lake City, UT 84112 USA. EM Kang.Zhang@hmbg.utah.edu; Dean.Li@hmbg.utah.edu RI Gerhardt, Holger/G-4610-2011; Xiao, Yang/B-5668-2012; Chen, Haoyu/A-7432-2013; Chu, Kai On/E-2325-2016; OI Gerhardt, Holger/0000-0001-9228-7472; Chen, Haoyu/0000-0003-0676-4610; Gerhardt, Holger/0000-0002-3030-0384 FU Cancer Research UK; Intramural NIH HHS [Z01 HL005702-02]; NHLBI NIH HHS [R01 HL077671-03, R01 HL065648, R01 HL068873, R01 HL068873-05, R01 HL068873-06, R01 HL077671, R01 HL077671-04, R01 HL084516, R01 HL084516-01A1, R01 HL084516-02] NR 29 TC 196 Z9 212 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2008 VL 14 IS 4 BP 448 EP 453 DI 10.1038/nm1742 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 283ZD UT WOS:000254674100033 PM 18345009 ER PT J AU Bleyer, A Barr, R Hayes-Lattin, B Thomas, D Ellis, C Anderson, B AF Bleyer, Archie Barr, Ronald Hayes-Lattin, Brandon Thomas, David Ellis, Chad Anderson, Barry CA Biol TI The distinctive biology of cancer in adolescents and young adults SO NATURE REVIEWS CANCER LA English DT Review ID ACUTE LYMPHOBLASTIC-LEUKEMIA; COOPERATIVE EWINGS-SARCOMA; COLORECTAL-CANCER; PROGNOSTIC-FACTORS; BREAST-CANCER; CHILDREN; TUMORS; CHEMOTHERAPY; CHILDHOOD; MELANOMA AB One explanation for the relative lack of progress in treating cancer in adolescents and young adults is that the biology of malignant diseases in this age group is different than in younger and older persons, not only in the spectrum of cancers but also within individual cancer types and within the patient ( host). Molecular, epidemiological and therapeutic outcome comparisons offer clues to this distinctiveness in most of the common cancers of adolescents and young adults. Translational and clinical research should not assume that the biology of cancers and patients is the same as in other age groups, and treatment strategies should be tailored to the differences. C1 [Bleyer, Archie] St Charles Hosp, Bend, OR 97701 USA. [Bleyer, Archie] Natl Childhood Canc Fdn, Arcadia, CA 91006 USA. [Barr, Ronald] McMaster Univ, Hamilton, ON L8S 4J9, Canada. [Hayes-Lattin, Brandon] Oregon Hlth & Sci Univ, Inst Canc, Portland, OR 97239 USA. [Thomas, David] Peter MacCallum Canc Inst, Melbourne, Vic 3002, Australia. [Ellis, Chad; Anderson, Barry] NCI, Canc Ctr Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Bleyer, A (reprint author), St Charles Hosp, 2500 NE Neff Rd, Bend, OR 97701 USA. EM ableyer@scmc.org FU NCI NIH HHS [U10 CA98543] NR 59 TC 181 Z9 184 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD APR PY 2008 VL 8 IS 4 BP 288 EP 298 DI 10.1038/nrc2349 PG 11 WC Oncology SC Oncology GA 276IC UT WOS:000254133500017 PM 18354417 ER PT J AU Rosenberg, SA Restifo, NP Yang, JC Morgan, RA Dudley, ME AF Rosenberg, Steven A. Restifo, Nicholas P. Yang, James C. Morgan, Richard A. Dudley, Mark E. TI Adoptive cell transfer: a clinical path to effective cancer immunotherapy SO NATURE REVIEWS CANCER LA English DT Review ID TUMOR-INFILTRATING LYMPHOCYTES; CD8(+) T-CELLS; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE; BONE-MARROW-TRANSPLANTATION; ENHANCED ANTITUMOR-ACTIVITY; IN-VIVO PERSISTENCE; METASTATIC MELANOMA; TRANSFER THERAPY; RECOMBINANT INTERLEUKIN-2; GENE-TRANSFER AB Adoptive cell therapy (ACT) using autologous tumour-infiltrating lymphocytes has emerged as the most effective treatment for patients with metastatic melanoma and can mediate objective cancer regression in approximately 50% of patients. The use of donor lymphocytes for ACT is an effective treatment for immunosuppressed patients who develop post-transplant lymphomas. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment. C1 [Rosenberg, Steven A.; Restifo, Nicholas P.; Yang, James C.; Morgan, Richard A.; Dudley, Mark E.] NCI, Surg Branch, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Ctr Canc Res, Natl Inst Hlth, 10 Ctr Dr, Bethesda, MD 20892 USA. EM sar@nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 SC003811-33] NR 79 TC 716 Z9 747 U1 18 U2 142 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD APR PY 2008 VL 8 IS 4 BP 299 EP 308 DI 10.1038/nrc2355 PG 10 WC Oncology SC Oncology GA 276IC UT WOS:000254133500018 PM 18354418 ER PT J AU Duffy, S Shackelton, LA Holmes, EC AF Duffy, Siobain Shackelton, Laura A. Holmes, Edward C. TI Rates of evolutionary change in viruses: patterns and determinants SO NATURE REVIEWS GENETICS LA English DT Review ID RNA VIRUS; SPONTANEOUS MUTATION; MOLECULAR EVOLUTION; LETHAL MUTAGENESIS; ERROR CATASTROPHE; GENETIC DIVERSITY; MOSAIC-VIRUS; PHYLOGENETIC EVIDENCE; REPLICATION FIDELITY; POPULATION-DYNAMICS AB Understanding the factors that determine the rate at which genomes generate and fix mutations provides important insights into key evolutionary mechanisms. We review our current knowledge of the rates of mutation and substitution, as well as their determinants, in RNA viruses, DNA viruses and retroviruses. We show that the high rate of nucleotide substitution in RNA viruses is matched by some DNA viruses, suggesting that evolutionary rates in viruses are explained by diverse aspects of viral biology, such as genomic architecture and replication speed, and not simply by polymerase fidelity. C1 [Duffy, Siobain; Shackelton, Laura A.; Holmes, Edward C.] Penn State Univ, Mueller Lab, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Mueller Lab, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu RI Duffy, Siobain/A-9104-2009; OI Duffy, Siobain/0000-0003-0753-223X; Holmes, Edward/0000-0001-9596-3552 NR 105 TC 522 Z9 539 U1 11 U2 100 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD APR PY 2008 VL 9 IS 4 BP 267 EP 276 DI 10.1038/nrg2323 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 275PM UT WOS:000254084100010 PM 18319742 ER PT J AU Margulies, EH Birney, E AF Margulies, Elliott H. Birney, Ewan TI Approaches to comparative sequence analysis: towards a functional view of vertebrate genomes SO NATURE REVIEWS GENETICS LA English DT Review ID REGULATORY ELEMENTS; ALIGNMENT; IDENTIFICATION; REGIONS; DISCOVERY; ENHANCER; EVOLUTIONARY; UNCERTAINTY; CONSTRAINT; 1-PERCENT AB The comparison of genomic sequences is now a common approach to identifying and characterizing functional regions in vertebrate genomes. However, for theoretical reasons and because of practical issues, the generation of these data sets is non-trivial and can have many pitfalls. We are currently seeing an explosion of comparative sequence data, the benefits and limitations of which need to be disseminated to the scientific community. This Review provides a critical overview of the different types of sequence data that are available for analysis and of contemporary comparative sequence analysis methods, highlighting both their strengths and limitations. Approaches to determining the biological significance of constrained sequence are also explored. C1 [Margulies, Elliott H.] NHGRI, Genome Technol Branch, Genome Informat Sect, NIH, Bethesda, MD 20892 USA. [Birney, Ewan] European Bioinformat Inst, Cambridge CB10 1SD, England. RP Margulies, EH (reprint author), NHGRI, Genome Technol Branch, Genome Informat Sect, NIH, Fishers Lane,Room 5N-01 N,MSC9400, Bethesda, MD 20892 USA. EM elliott@nhgri.nih.gov RI Sincan, Murat /A-3794-2010; OI Birney, Ewan/0000-0001-8314-8497 NR 65 TC 44 Z9 45 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD APR PY 2008 VL 9 IS 4 BP 303 EP 313 DI 10.1038/nrg2185 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 275PM UT WOS:000254084100013 PM 18347593 ER PT J AU Seder, RA Darrah, PA Roederer, M AF Seder, Robert A. Darrah, Patricia A. Roederer, Mario TI T-cell quality in memory and protection: implications for vaccine design SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID NECROSIS-FACTOR-ALPHA; LEISHMANIA-MAJOR; INTERFERON-GAMMA; MYCOBACTERIUM-TUBERCULOSIS; VIRAL-INFECTION; ANTIGEN LOAD; IFN-GAMMA; LINEAGE RELATIONSHIP; MURINE MACROPHAGES; CYTOKINE RESPONSES AB T cells mediate effector functions through a variety of mechanisms. Recently, multiparameter flow cytometry has allowed a simultaneous assessment of the phenotype and multiple effector functions of single T cells; the delineation of T cells into distinct functional populations defines the quality of the response. New evidence suggests that the quality of T-cell responses is crucial for determining the disease outcome to various infections. This Review highlights the importance of using multiparameter flow cytometry to better understand the functional capacity of effector and memory T-cell responses, thereby enabling the development of preventative and therapeutic vaccine strategies for infections. C1 [Seder, Robert A.; Darrah, Patricia A.; Roederer, Mario] NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Seder, RA (reprint author), NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Roederer, Mario/G-1887-2011 FU Intramural NIH HHS NR 73 TC 776 Z9 785 U1 5 U2 62 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD APR PY 2008 VL 8 IS 4 BP 247 EP 258 DI 10.1038/nri2274 PG 12 WC Immunology SC Immunology GA 278MC UT WOS:000254289100011 PM 18323851 ER PT J AU Zhang, K Mosch, K Fischle, W Grewal, SIS AF Zhang, Ke Mosch, Kerstin Fischle, Wolfgang Grewal, Shiv I. S. TI Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID H3 LYSINE-9 METHYLATION; RNA-POLYMERASE-II; FISSION YEAST; HISTONE H3; EPIGENETIC CONTROL; UBIQUITIN LIGASE; SCHIZOSACCHAROMYCES-POMBE; CHROMODOMAIN PROTEIN; BINDING-PROTEIN; CHROMATIN AB Heterochromatin assembly, involving methylation of histone H3 lysine 9 (H3K9me), regulates various chromosomal processes. In fission yeast, heterochromatin targeted to specific repeat loci in an RNAi-dependent manner spreads across extended domains to exert regional epigenetic control. The Clr4 methyltransferase complex (ClrC) is responsible for nucleation and spreading of heterochromatin; however, its recruitment to heterochromatic repeats is poorly understood. Here we demonstrate that ClrC components are distributed throughout heterochromatic domains. To nucleate heterochromatin, Rik1, a WD domain containing subunit of ClrC, is loaded onto the transcribed repeats via RNAi machinery including the RNA-induced transcriptional silencing (RITS) complex. Furthermore, we show that the chromodomain of Clr4 binds specifically to H3K9me that is essential for the spreading of heterochromatin. Our analyses delineate sequential steps for the assembly of heterochromatic domains and suggest that the ability of Clr4 to both 'write' and 'read' H3K9me facilitates heterochromatin maintenance through successive cell divisions. C1 [Zhang, Ke; Grewal, Shiv I. S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Mosch, Kerstin; Fischle, Wolfgang] Max Planck Inst Biophys Chem, Lab Chromatin Biochem, D-37077 Gottingen, Germany. RP Grewal, SIS (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov FU Intramural NIH HHS NR 60 TC 157 Z9 158 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2008 VL 15 IS 4 BP 381 EP 388 DI 10.1038/nsmb.1406 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 283FG UT WOS:000254621500010 PM 18345014 ER PT J AU Miller, MT Higgin, JJ Hall, TMT AF Miller, Matthew T. Higgin, Joshua J. Hall, Traci M. Tanaka TI Basis of altered RNA-binding specificity by PUF proteins revealed by crystal structures of yeast Puf4p SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID PUMILIO-HOMOLOGY DOMAIN; MESSENGER-RNA; TRANSLATIONAL REGULATOR; IDENTIFICATION; PUM2; LIFE AB Pumilio/FBF (PUF) family proteins are found in eukaryotic organisms and regulate gene expression post-transcriptionally by binding to sequences in the 3' untranslated region of target transcripts. PUF proteins contain an RNA binding domain that typically comprises eight alpha-helical repeats, each of which recognizes one RNA base. Some PUF proteins, including yeast Puf4p, have altered RNA binding specificity and use their eight repeats to bind to RNA sequences with nine or ten bases. Here we report the crystal structures of Puf4p alone and in complex with a 9-nucleotide (nt) target RNA sequence, revealing that Puf4p accommodates an 'extra' nucleotide by modest adaptations allowing one base to be turned away from the RNA binding surface. Using structural information and sequence comparisons, we created a mutant Puf4p protein that preferentially binds to an 8-nt target RNA sequence over a 9-nt sequence and restores binding of each protein repeat to one RNA base. C1 [Miller, Matthew T.; Higgin, Joshua J.; Hall, Traci M. Tanaka] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,Bldg 101,Room F363, Res Triangle Pk, NC 27709 USA. EM hall4@niehs.nih.gov FU Intramural NIH HHS [Z01 ES050165-10] NR 36 TC 61 Z9 61 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2008 VL 15 IS 4 BP 397 EP 402 DI 10.1038/nsmb.1390 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 283FG UT WOS:000254621500012 PM 18327269 ER PT J AU Pearce, LV Toth, A Ryu, H Kang, DW Choi, HK Jin, MK Lee, J Blumberg, PM AF Pearce, Larry V. Toth, Attila Ryu, HyungChul Kang, Dong Wook Choi, Hyun-Kyung Jin, Mi-Kyoung Lee, Jeewoo Blumberg, Peter M. TI Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Article DE TRPV1; capsaicin; resiniferatoxin; vanilloid; cyclosporin A; protein phosphatase ID VANILLOID RECEPTOR TRPV1; ROOT GANGLION NEURONS; CAPSAICIN RECEPTOR; CALCIUM RESPONSE; OKADAIC ACID; CALYCULIN-A; KINASE; CALCINEURIN; PHOSPHORYLATION; DESENSITIZATION AB The transient receptor potential V1 channel (vanilloid receptor, TRPV1) represents a promising therapeutic target for inflammatory pain and other conditions involving C-fiber sensory afferent neurons. Sensitivity of TRPV1 is known to be subject to modulation by numerous signaling pathways, in particular by phosphorylation, and we wished to determine whether TRPV1 structure activity relations could be differentially affected. We demonstrate here that the structure activity relations of TRPV1, as determined by Ca-45(2) uptake, were substantially altered by treatment of the cells with cyclosporin A, an inhibitor of protein phosphatase 2B. Whereas the potency of resiniferatoxin for stimulation of Ca-45(2) was not altered by cyclosporin A treatment, the potencies of some other agonists were increased up to 8-fold. Among the antagonists examined, potencies were reduced to a lesser extent, ranging from 1- to 2.5-fold. Finally, the efficacy of partial agonists was increased. In contrast to cyclosporin A, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, had little effect on agonist potencies, and calyculin A, an inhibitor of protein phosphatases 1 and 2A but with somewhat different selectivity from that of okadaic acid, caused changes in structure activity relations distinct from those induced by cyclosporin A. Because phosphatase activity differentially modulates the structure activity relations of TRPV1 agonists and antagonists, our findings predict that it may be possible to design agonists and antagonists selective for TRPV1 in a specific regulatory environment. A further implication is that it may be desirable to tailor screening approaches for drug discovery to reflect the desired regulatory state of the targeted TRPV1. C1 [Blumberg, Peter M.] NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. [Pearce, Larry V.; Toth, Attila; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Toth, Attila] Univ Debrecen, Div Clin Physiol, Inst Cardiol, H-4032 Debrecen, Hungary. [Ryu, HyungChul; Kang, Dong Wook; Choi, Hyun-Kyung; Jin, Mi-Kyoung; Lee, Jeewoo] Seoul Natl Univ, Med Chem Lab, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37,Room 4048,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov RI Toth, Attila/F-4859-2010 OI Toth, Attila/0000-0001-6503-3653 FU Intramural NIH HHS [Z01 BC005270-26] NR 42 TC 10 Z9 10 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 EI 1432-1912 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2008 VL 377 IS 2 BP 149 EP 157 DI 10.1007/s00210-007-0258-3 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 277IB UT WOS:000254204800005 PM 18259730 ER PT J AU Lamborn, KR Yung, WKA Chang, SM Wen, PY Cloughesy, TF DeAngelis, LM Robins, HI Lieberman, FS Fine, HA Fink, KL Junck, L Abrey, L Gilbert, MR Mehta, M Kuhn, JG Aldape, KD Hibberts, J Peterson, PM Prados, MD AF Lamborn, Kathleen R. Yung, W. K. Alfred Chang, Susan M. Wen, Patrick Y. Cloughesy, Timothy F. DeAngelis, Lisa M. Robins, H. Ian Lieberman, Frank S. Fine, Howard A. Fink, Karen L. Junck, Larry Abrey, Lauren Gilbert, Mark R. Mehta, Minesh Kuhn, John G. Aldape, Kenneth D. Hibberts, Janelle Peterson, Pamela M. Prados, Michael D. CA N Amer Brain Tumor Consortium TI Progression-free survival: An important end point in evaluating therapy for recurrent high-grade gliomas SO NEURO-ONCOLOGY LA English DT Article DE brain tumors; clinical trial end points; glioma; progression-free survival ID PHASE-II; GLIOBLASTOMA-MULTIFORME; TRIALS AB The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials. C1 [Lamborn, Kathleen R.; Chang, Susan M.; Prados, Michael D.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Yung, W. K. Alfred; Gilbert, Mark R.; Aldape, Kenneth D.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX USA. [Hibberts, Janelle; Peterson, Pamela M.] Univ Texas MD Anderson Canc Ctr, Data Management Ctr, Houston, TX USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA USA. [DeAngelis, Lisa M.; Abrey, Lauren] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Robins, H. Ian; Mehta, Minesh] Univ Wisconsin Hosp, Madison, WI USA. [Lieberman, Frank S.] Univ Pittsburgh, Med Ctr, Div Neurooncol, Pittsburgh, PA USA. [Fine, Howard A.] Natl Canc Inst, Natl Inst Hlth, Neurooncol Branch, Bethesda, MD USA. [Fink, Karen L.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Junck, Larry] Univ Michigan Hosp, Dept Neurol, Ann Arbor, MI 48109 USA. [Kuhn, John G.] Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. RP Lamborn, KR (reprint author), Univ Calif San Francisco, Dept Neurol Surg, UC Clin 808, San Francisco, CA 94143 USA. EM lambornk@neurosurg.ucsf.edu RI leng, xianwei/F-9073-2011; Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; mehta, minesh/0000-0002-4812-5713 FU NCI NIH HHS [CA 16672, CA 62399, CA 62412, CA 62422, CA 62426, CA 62455-08, P30 CA016672, U01 CA 62399 022030, U01 CA 62405, U01 CA 62407-08, U01 CA 62421-08, U01 CA062399, U01 CA062405, U01 CA062407, U01 CA062412, U01 CA062421, U01 CA062422, U01 CA062426]; NCRR NIH HHS [M01 RR 00042, M01 RR 00056, M01 RR 00079, M01 RR 00633, M01 RR 03186, M01 RR 0865, M01 RR000042, M01 RR000056, M01 RR000079, M01 RR000633, M01 RR000865, M01 RR003186] NR 7 TC 223 Z9 228 U1 0 U2 4 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD APR PY 2008 VL 10 IS 2 BP 162 EP 170 DI 10.1215/15228517-2007-062 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 286NT UT WOS:000254853300007 PM 18356283 ER PT J AU Beason-Held, LL Kraut, MA Resnick, SM AF Beason-Held, L. L. Kraut, M. A. Resnick, S. M. TI Longitudinal changes in aging brain function SO NEUROBIOLOGY OF AGING LA English DT Article DE positron emission tomography; functional imaging; neuroimaging; brain function; age; aging; verbal; spatial; memory ID CEREBRAL BLOOD-FLOW; AGE-RELATED-CHANGES; POSITRON-EMISSION-TOMOGRAPHY; WORKING-MEMORY; OLDER-ADULTS; RECOGNITION MEMORY; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX; NEURAL MECHANISMS; SPATIAL VISION AB Changes in brain activity over time were evaluated in a group of older adults in the Baltimore Longitudinal Study of Aging who maintained good physical and cognitive health. Participants underwent PET scans during rest and delayed verbal and figural recognition memory performance at year I baseline and at year 9. While memory performance remained stable over the 8 years, longitudinal changes in regional cerebral blood flow were observed within each scan condition. Further analyses revealed distinctive patterns of change related specifically to verbal or figural recognition, as well as longitudinal changes common to all scan conditions. These findings demonstrate that the older brain undergoes functional reorganization with increasing age in healthy, cognitively stable individuals. In view of the stable memory performance, the task-dependent results suggest that age-related changes in brain activity help maintain cognitive function with advancing age. (C) 2006 Elsevier Inc. All rights reserved. C1 [Beason-Held, L. L.; Resnick, S. M.] NIA, NIH, Lab Personal & Cognit, Baltimore, MD 21224 USA. [Kraut, M. A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21218 USA. RP Beason-Held, LL (reprint author), NIA, NIH, Lab Personal & Cognit, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM heldlo@grc.nia.nih.gov FU Intramural NIH HHS [Z99 AG999999, Z01 AG000191-11]; NIA NIH HHS [N01-AG-3-2124] NR 75 TC 26 Z9 26 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD APR PY 2008 VL 29 IS 4 BP 483 EP 496 DI 10.1016/j.neurobiolaging.2006.10.031 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 275MV UT WOS:000254077200001 PM 17184881 ER PT J AU Beason-Held, LL Kraut, MA Resnick, SM AF Beason-Held, L. L. Kraut, M. A. Resnick, S. M. TI Temporal patterns of longitudinal change in aging brain function SO NEUROBIOLOGY OF AGING LA English DT Article DE positron emission tomography; functional imaging; neuroimaging; brain function; age; aging; verbal; spatial; memory ID CEREBRAL-BLOOD-FLOW; ADULT AGE-DIFFERENCES; OLDER-ADULTS; ALZHEIMERS-DISEASE; WORKING-MEMORY; VISUAL-ATTENTION; NEURAL ACTIVITY; LIFE-SPAN; RETRIEVAL; PET AB Time-dependent changes in brain activity were assessed in a group of older adults who maintained good physical and cognitive health at years 1, 3, 5, 7, and 9 of the Baltimore Longitudinal Study of Aging neuroimaging study. Each year, these participants underwent PET scans during rest and delayed verbal and figural recognition memory conditions. While memory performance remained stable over the 8 years, both generalized and modality-specific patterns of time-dependent changes in regional cerebral blood flow (rCBF) were found. Many brain regions showed steady, progressive changes in rCBF over the 8 years while others maintained rCBF for a number of years before showing incremental declines or increases in activity. These temporal patterns of change were observed in many regions of the brain, particularly in the frontal and temporal lobes, suggesting that there are distinctive patterns of age-related functional decline and compensatory activity over time. The precise patterns of regional involvement and the temporal dynamics of rCBF change within specific regions vary based on cognitive processing demands. (C) 2006 Elsevier Inc. All rights reserved. C1 [Beason-Held, L. L.; Resnick, S. M.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Kraut, M. A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21218 USA. RP Beason-Held, LL (reprint author), NIA, Lab Personal & Cognit, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM heldlo@gre.nia.nih.gov FU Intramural NIH HHS [Z01 AG000191-11, Z99 AG999999]; NIA NIH HHS [AG-93-07, N01-AG-3-2124] NR 61 TC 16 Z9 16 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD APR PY 2008 VL 29 IS 4 BP 497 EP 513 DI 10.1016/j.neurobiolaging.2006.11.011 PG 17 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 275MV UT WOS:000254077200002 PM 17178430 ER PT J AU Davatzikos, C Fan, Y Wu, X Shen, D Resnick, SM AF Davatzikos, Christos Fan, Yong Wu, Xiaoying Shen, Dinggang Resnick, Susan M. TI Detection of prodromal Alzheimer's disease via pattern classification of magnetic resonance imaging SO NEUROBIOLOGY OF AGING LA English DT Article DE prodromal Alzheimer's disease; MCI; pattern recognition; MRI ID MILD COGNITIVE IMPAIRMENT; MACHINE LEARNING-METHODS; VOXEL-BASED MORPHOMETRY; GRAY-MATTER LOSS; HIPPOCAMPAL-FORMATION; ENTORHINAL CORTEX; TEMPORAL-LOBE; OLDER-ADULTS; MRI; ATROPHY AB We report evidence that computer-based high-dimensional pattern classification of magnetic resonance imaging (MRI) detects patterns of brain structure characterizing mild cognitive impairment (MCI), often a prodromal phase of Alzheimer's disease (AD). Ninety percent diagnostic accuracy was achieved, using cross-validation, for 30 participants in the Baltimore Longitudinal Study of Aging. Retrospective evaluation of serial scans obtained during prior years revealed gradual increases in structural abnormality for the MCI group, often before clinical symptoms, but slower increase for individuals remaining cognitively normal. Detecting complex patterns of brain abnormality in very early stages of cognitive impairment has pivotal importance for the detection and management of AD. (C) 2006 Elsevier Inc. All rights reserved. C1 [Davatzikos, Christos; Fan, Yong; Wu, Xiaoying; Shen, Dinggang] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Resnick, Susan M.] NIA, Lab Personal & Cognit, Bethesda, MD 20892 USA. RP Davatzikos, C (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, 3600 Market St,Suite 380, Philadelphia, PA 19104 USA. EM christos@rad.upenn.edu OI Fan, Yong/0000-0001-9869-4685 FU Intramural NIH HHS [Z01 AG000191-11]; NIA NIH HHS [N01 AG032124, N01-AG-3-2124, R01 AG014971, R01 AG014971-04, R01-AG14971] NR 49 TC 173 Z9 177 U1 2 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD APR PY 2008 VL 29 IS 4 BP 514 EP 523 DI 10.1016/j.neurobiolaging.2006.11.010 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 275MV UT WOS:000254077200003 PM 17174012 ER PT J AU Birn, RM Smith, MA Jones, TB Bandettini, PA AF Birn, Rasmus M. Smith, Monica A. Jones, Tyler B. Bandettini, Peter A. TI The respiration response function: The temporal dynamics of fMRI signal fluctuations related to changes in respiration SO NEUROIMAGE LA English DT Article ID CEREBRAL-BLOOD-FLOW; BOLD SIGNAL; HUMAN BRAIN; MRI; VARIABILITY; HYPERCAPNIA; HUMANS; NORMALIZATION; ACTIVATION AB Changes in the subject's breathing rate or depth, such as a breath-hold challenge, can cause significant MRI signal changes. However, the response function that best models breath-holding-induced signal changes, as well as those resulting from a wider range of breathing variations including those occurring during rest, has not yet been determined. Respiration related signal changes appear to be slower than neuronally induced BOLD signal changes and are not modeled accurately using the typical hemodynamic response functions used in fMRI. In this study, we derive a new response function to model the average MRI signal changes induced by variations in the respiration volume (breath-to-breath changes in the respiration depth and rate). This was done by averaging the response to a series of single deep breaths performed once every 40 s amongst otherwise constant breathing. The new "respiration response function" consists of an early overshoot followed by a later undershoot (peaking at approximately 16 s), and accurately models the MRI signal changes resulting from breath-holding as well as cued depth and rate changes. Published by Elsevier Inc. C1 [Birn, Rasmus M.; Smith, Monica A.; Jones, Tyler B.; Bandettini, Peter A.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Birn, RM (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Bldg 10,Rm 1D80, Bethesda, MD 20892 USA. EM rbim@mail.nih.gov FU Intramural NIH HHS [NIH0010390944] NR 28 TC 176 Z9 177 U1 3 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 APR 1 PY 2008 VL 40 IS 2 BP 644 EP 654 DI 10.1016/j.neuroimage.2007.11.059 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 283HQ UT WOS:000254627700025 PM 18234517 ER PT J AU Meyer-Lindenberg, A Nicodemus, KK Egan, MF Callicott, JH Mattay, V Weinberger, DR AF Meyer-Lindenberg, Andreas Nicodemus, Kristin K. Egan, Michael F. Callicott, Joseph H. Mattay, Venkata Weinberger, Daniel R. TI False positives in imaging genetics SO NEUROIMAGE LA English DT Article DE genetics; neuroimaging; false positives ID STATISTICAL SOFTWARE PACKAGES; VOXEL-BASED MORPHOMETRY; SEROTONIN TRANSPORTER; HUMAN AMYGDALA; SCHIZOPHRENIA; RISK; FMRI; POLYMORPHISM; MECHANISMS; STRATEGIES AB Imaging genetics provides an enormous amount of functional-structural data on gene effects in living brain, but the sheer quantity of potential phenotypes raises concerns about false discovery. Here, we provide the first empirical results on false positive rates in imaging genetics. We analyzed 720 frequent coding SNPs without significant association with schizophrenia and a subset of 492 of these without association with cognitive function. Effects on brain structure (using voxel-based morphometry, VBM) and brain function, using two archival imaging tasks, the n-back working memory task and an emotional face matching task, were studied in whole brain and regions of interest and corrected for multiple comparisons using standard neuroimaging procedures. Since these variants are unlikely to impact relevant brain function, positives obtained provide an upper empirical estimate of the false positive association rate. In a separate analysis, we randomly permuted genotype labels across subjects, removing any true genotype-phenotype association in the data, to derive a lower empirical estimate. At a set correction level of 0.05, in each region of interest and data set used, the rate of positive findings was well below 5% (0.2-4.1%). There was no relationship between the region of interest and the false positive rate. Permutation results were in the same range as empirically derived rates. The observed low rates of positives provide empirical evidence that the type I error rate is well controlled by current commonly used correction procedures in imaging genetics, at least in the context of the imaging paradigms we have used. In fact, our observations indicate that these statistical thresholds are conservative. Published by Elsevier Inc. C1 [Meyer-Lindenberg, Andreas] NIMH, NIH, DHHS, Unit Syst Neurosci Psychiat, Bethesda, MD 20892 USA. [Meyer-Lindenberg, Andreas; Mattay, Venkata] NIMH, NIH, DHHS, Neuroimaging Core Facil, Bethesda, MD 20892 USA. [Meyer-Lindenberg, Andreas; Nicodemus, Kristin K.; Egan, Michael F.; Callicott, Joseph H.; Mattay, Venkata; Weinberger, Daniel R.] NIMH, NIH, Clin Brain Disorders Branch, DHHS,Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, D-68159 Mannheim, Germany. RP Meyer-Lindenberg, A (reprint author), NIMH, NIH, DHHS, Unit Syst Neurosci Psychiat, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM a.meyer-lindenberg@zi-mannheim.de; weinberd@mail.nih.gov RI Callicott, Joseph/C-9102-2009; Meyer-Lindenberg, Andreas/H-1076-2011 OI Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 NR 31 TC 81 Z9 83 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2008 VL 40 IS 2 BP 655 EP 661 DI 10.1016/j.neuroimage.2007.11.058 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 283HQ UT WOS:000254627700026 PM 18201908 ER PT J AU Dunsmoor, JE Bandettini, PA Knight, DC AF Dunsmoor, Joseph E. Bandettini, Peter A. Knight, David C. TI Neural correlates of unconditioned response diminution during Pavlovian conditioning SO NEUROIMAGE LA English DT Article DE UCR diminution; fear; conditioning; fMRI; learning; amygdala ID ANTERIOR CINGULATE CORTEX; HUMAN AMYGDALA ACTIVITY; FUNCTIONAL MRI; UCR DIMINUTION; FEAR RESPONSES; BRAIN; TRACE; ACTIVATION; PRECEPTION; INTERVAL AB Pavlovian conditioning research has shown that unconditioned responses (UCR) to aversive unconditioned stimuli (UCS) are reduced when a UCS is predictable. This effect is known as UCR diminution. In the present study, we examined UCR diminution in the functional magnetic resonance imaging (fMRI) signal by varying the rate at which a neutral conditioned stimulus (CS) was paired with an aversive UCS. UCR diminution was observed within several brain regions associated with fear learning, including the amygdala, anterior cingulate, auditory cortex, and dorsolateral prefrontal cortex when a CS continuously relative to intermittently predicted the UCS. In addition, an inverse relationship between UCS expectancy and UCR magnitude was observed within the amygdala, anterior cingulate, and dorsolateral prefrontal cortex, such that as UCS expectancy increased the UCR decreased. These findings demonstrate UCR diminution within the fMRI signal, and suggest that UCS expectancies modulate UCR magnitude. Published by Elsevier Inc. C1 [Dunsmoor, Joseph E.; Bandettini, Peter A.; Knight, David C.] NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. RP Knight, DC (reprint author), Univ Alabama, Dept Psychol, Civitan Int Res Ctr, 1719 6th Ave S,CIRC 235H, Birmingham, AL 35294 USA. EM knightdc@uab.edu FU Intramural NIH HHS [, NIH0011354362]; PHS HHS [NIH0011354362] NR 44 TC 55 Z9 55 U1 2 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2008 VL 40 IS 2 BP 811 EP 817 DI 10.1016/j.neuroimage.2007.11.042 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 283HQ UT WOS:000254627700042 PM 18203622 ER PT J AU Mitchell, DGV Luo, Q Mondillo, K Vythilingam, M Finger, EC Blair, RJR AF Mitchell, D. G. V. Luo, Q. Mondillo, K. Vythilingam, M. Finger, E. C. Blair, R. J. R. TI The interference of operant task performance by emotional distracters: An antagonistic relationship between the amygdala and frontoparietal cortices SO NEUROIMAGE LA English DT Article DE amygdala; emotional attention; emotional bias; conditioned suppression; biased competition model of attention ID EVENT-RELATED FMRI; PREFRONTAL CORTEX; CONDITIONED SUPPRESSION; NEURAL MECHANISMS; ATTENTIONAL BIAS; VOLUNTARY SUPPRESSION; NEGATIVE AFFECT; FRONTAL-CORTEX; VISUAL-STIMULI; ANXIETY AB This fMRI study investigates neural activity associated with the interfering effects of emotional distracters. While in the scanner, participants made simple motor responses to target stimuli that were preceded and followed by positive, negative, or neutral images. Despite instructions to disregard the pictorial images, participants were slower to respond in the presence of positive or negative relative to neutral distracters, and significantly slower for negative relative to positive distracters. Enhanced activity in the amygdala and visual cortex was evident during trials that included positive and negative distracters. In contrast, increased activity in inferior frontal gyrus (BA 47) was only observed during trials that involved negative distracters. Connectivity analysis showed that activity in right amygdala correlated with activity in cingulate gyrus, posterior cingulate, middle temporal cortex, and was negatively correlated with activity in lateral superior frontal gyrus, middle frontal/orbital gyrus, and parietal cortex. The pattern of neural activity observed was interpreted within the framework of current cognitive models of attention. During a task demonstrating behavioural interference in the context of emotional distracters, increased activity in neural regions implicated in emotional processing (the amygdala) was associated with reduced activity in regions thought to be involved in exerting attentional control over task-relevant sensory representations (a frontoparietal network). (c) 2007 Elsevier Inc. All rights reserved. C1 [Mitchell, D. G. V.] Univ Western Ontario, Schulich Sci Med & Dent, Dept Psychiat, London, ON, Canada. [Mitchell, D. G. V.] Univ Western Ontario, Dept Cell Biol & Anat, London, ON, Canada. [Mitchell, D. G. V.; Luo, Q.; Mondillo, K.; Vythilingam, M.; Finger, E. C.; Blair, R. J. R.] NIMH, NIH, Dept Hlth & Human Serv, Mood & Anxiety Program, Bethesda, MD 20892 USA. RP Mitchell, DGV (reprint author), Univ Western Ontario, Schulich Sci Med & Dent, Dept Psychiat, 339 Windermere Rd, London, ON, Canada. EM dmitch8@uwo.ca RI Finger, Elizabeth/B-6453-2015 FU Intramural NIH HHS [Z99 MH999999] NR 69 TC 52 Z9 53 U1 5 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 APR 1 PY 2008 VL 40 IS 2 BP 859 EP 868 DI 10.1016/j.neuroimage.2007.08.002 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 283HQ UT WOS:000254627700047 PM 18234519 ER PT J AU Pierson, TM Zimmerman, RA Tennekoon, GI Boennemann, CG AF Pierson, T. M. Zimmerman, R. A. Tennekoon, G. I. Boennemann, C. G. TI Mega-corpus callosum, polymicrogyria, and psychomotor retardation: Confirmation of a syndromic entity SO NEUROPEDIATRICS LA English DT Article DE mega-corpus callosum; megalencephaly; delayed motor function; MEG-PMG-MegaCC ID MENTAL-RETARDATION; COHEN-SYNDROME; NEUROFIBROMATOSIS TYPE-1; MOTOR DEVELOPMENT; BRAIN; MRI; METABOLITES; DIAGNOSIS; DOPAMINE; FEATURES AB A mega-corpus callosum (CC) is not a common manifestation of neurological disease. Previous reports of patients with a constellation of findings including megalencephaly, perisylvian polymicrogyria, distinct facies, psychomotor retardation and mega-corpus callosum were designated as having megalencephaly, mega-corpus callosum, and complete lack of motor development [OMIM 603387; also referred to as megalencephaly-polymicrogyria-mega-corpus callosum (MEG-PMG-MegaCC)] syndrome. Three patients were initially reported with this syndrome, and a fourth was reported recently. Another case had similar findings in utero and upon autopsy. We present an additional patient who conforms to this phenotype; however, he is not megalencephalic, but has a normal head circumference in the setting of short stature. This patient is also noted to have abnormal saccades and mask-like facies. His motor function is more developed than in the other reported patients and was further improved by treatment with 1-DOPA/carbidopa, which was started because of his extrapryramidal symptoms and signs which were associated with low cerebral spinal fluid (CSF) catecholamine levels. C1 [Pierson, T. M.] NINDS NIH, Neurogenet Branch, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Dept Neuroradiol, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Neurol & Pediat, Philadelphia, PA 19104 USA. RP Pierson, TM (reprint author), NINDS NIH, Neurogenet Branch, 35 Convent Dr,MSC 3705 Bldg 35,Room 2A, Bethesda, MD 20892 USA. EM pierson@ninds.nih.gov FU NIAMS NIH HHS [R01AR051999]; NICHD NIH HHS [T32-HD043021-04] NR 25 TC 7 Z9 7 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0174-304X J9 NEUROPEDIATRICS JI Neuropediatrics PD APR PY 2008 VL 39 IS 2 BP 123 EP 127 DI 10.1055/s-2008-1081218 PG 5 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 336OK UT WOS:000258374300006 PM 18671190 ER PT J AU Engert, S Wendland, JR Schwab, A Petersen, M AF Engert, Sabine Wendland, Jens R. Schwab, Albrecht Petersen, Marlen TI Leukemia inhibitory factor differentially regulates capsaicin and heat sensitivity in cultured rat dorsal root ganglion neurons SO NEUROPEPTIDES LA English DT Article DE TRPV-1; nerve growth factor (NGF); LIF; dorsal root ganglion (DRG); heat receptors; galanin ID NERVE GROWTH-FACTOR; PRIMARY SENSORY NEURONS; GALANIN-LIKE IMMUNOREACTIVITY; IN-SITU HYBRIDIZATION; NEUROPEPTIDE EXPRESSION; SCIATIC-NERVE; AXOTOMY; RECEPTOR; CELLS; INJURY AB Thermal hyperalgesia is one hallmark of neuropathic pain conditions. Although the exact pathophysiological mechanisms remain elusive, nerve growth factor (NGF) and leukemia inhibitory factor (LIF) are considered key mediators. Their local availability or synthesis are altered by nerve damage and, in turn, they entail changes in phenotype of affected neurons. We examined the effects of LIF on capsaicin sensitivity, heat responsiveness, and galanin immuno reactivity in rat dorsal root ganglion neurons cultured for up to 6 days without supplemented NGF. Using double labeling, the proportions of heat-sensitive/galanin-immunoreactive (GAL-IR) and capsaicin-sensitive/GAL-IR neurons were compared over time in culture with galanin immunoreactivity being a marker for nociceptive neurons. The time course of the proportions of neurons responding to heat (44 degrees C) or capsaicin (1 mu M) which also were GAL-IR was differently affected by LIF. In the absence of LIF, within the population of heat-sensitive neurons, the proportion of neurons also GAL-IR increased from 17% to 32% between 6 h and 1 day in culture to stay at this level. For the capsaicin-sensitive neurons, the proportion of neurons also GAL-IR increased from 10% after 6 h to 18% at day 2 and then decreased to 4% at day 4. In contrast, LIF prevented the increase in the proportion of heat-sensitive/GAL-IR neurons and the decrease of capsaicin-sensitive/GAL-IR neurons. The results suggest that LIF partially prevents TRPV-1 downregulation in NGF-deprived nociceptive galaninergic DRG neurons. Furthermore, there is evidence that LIF regulates the expression of a heat receptor distinct from TRPV-1. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Petersen, Marlen] Univ Heidelberg, Dept Anesthesiol & Intens Care Med, D-68167 Mannheim, Germany. [Engert, Sabine] Univ Wurzburg, Dept Obstet & Gynecol, D-97080 Wurzburg, Germany. [Wendland, Jens R.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. [Schwab, Albrecht] Univ Munster, Inst Phys 2, D-48149 Munster, Germany. RP Petersen, M (reprint author), Univ Heidelberg, Dept Anesthesiol & Intens Care Med, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany. EM marlen.petersen@anaes.ma.uni-heidelberg.de RI Wendland, Jens/A-1809-2012 NR 31 TC 3 Z9 3 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD APR PY 2008 VL 42 IS 2 BP 193 EP 197 DI 10.1016/j.npep.2007.12.005 PG 5 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 285LX UT WOS:000254779400007 PM 18258298 ER PT J AU Tonelli, LH Holmes, A Postolache, TT AF Tonelli, Leonardo H. Holmes, Andrew Postolache, Teodor T. TI Intranasal immune challenge induces sex-dependent depressive-like behavior and cytokine expression in the brain SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE forced swim test; real-time RT-PCR; hippocampus; brainstem; corticosterone; cytokines; depression ID FORCED-SWIMMING TEST; TUMOR-NECROSIS-FACTOR; ACUTE RESPIRATORY ILLNESS; INDUCED SICKNESS BEHAVIOR; MAJOR DEPRESSION; INTERFERON-ALPHA; MOOD DISORDERS; RAT-BRAIN; NORADRENERGIC ANTIDEPRESSANTS; GLUCOCORTICOID-RECEPTOR AB The association between activation of the immune system and mood disorders has been reported by several studies. However, the mechanisms by which the immune system affects mood are only partially understood. In the present study, we detected depressive-like behavior in a rat animal model which involves the induction of inflammation in the nasal cavities by intranasal (i.n.) instillation of bacterial lipopolysaccharides (LPS). Female rats showed depressive-like behavior as evidenced by the forced swim test after repeated i.n. administration of LPS. These responses were not paralleled by alterations in motor activity as measured by the open field test. In the same animals, corticosterone responses after the swimming sessions were the highest of all the groups evaluated. Real-time RT PCR was used to analyze the transcriptional regulation of the cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6 in several brain regions. Increased tumor necrosis factor-a was detected in the hippocampus and brainstem of female rats challenged with i.n. LPS. These results suggest that peripheral inflammation in the upper respiratory tract is an immune challenge capable of inducing depressive-like behavior, promoting exaggerated glucocorticoid responses to stress, and increasing cytokine transcription in the brain. These results further our understanding of the role that the immune system may play in the pathophysiology of depression. C1 [Tonelli, Leonardo H.] Univ Maryland, Sch Med, Dept Psychiat, Lab Neuro Immunol,Mood & Anxiety Program, Baltimore, MD 21201 USA. [Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, Bethesda, MD USA. [Postolache, Teodor T.] Univ Maryland, Sch Med, Dept Psychiat, Lab Expt Chronobiol,Mood & Anxiety Program, Baltimore, MD 21201 USA. RP Tonelli, LH (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Lab Neuro Immunol,Mood & Anxiety Program, 685 W Baltimore St,MSTF Bldg,Room 502, Baltimore, MD 21201 USA. EM Ltonelli@psych.umaryland.edu FU NICHD NIH HHS [K12 HD43489, K12 HD043489]; NIMH NIH HHS [R21 MH075905, R21 MH075905-01A1, R21MH075905-01A1] NR 94 TC 54 Z9 59 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2008 VL 33 IS 5 BP 1038 EP 1048 DI 10.1038/sj.npp.1301488 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 273UQ UT WOS:000253957600009 PM 17593929 ER PT J AU Elkashef, AM Rawson, RA Anderson, AL Li, SH Holmes, T Smith, EV Chiang, N Kahn, R Vocci, F Ling, W Pearce, VJ McCann, M Campbell, J Gorodetzky, C Haning, W Carlton, B Mawhinney, J Weis, D AF Elkashef, Ahmed M. Rawson, Richard A. Anderson, Ann L. Li, Shou-Hua Holmes, Tyson Smith, Edwina V. Chiang, Nora Kahn, Roberta Vocci, Frank Ling, Walter Pearce, Valerie J. McCann, Michael Campbell, Jan Gorodetzky, Charles Haning, William Carlton, Barry Mawhinney, Joseph Weis, Dennis TI Bupropion for the treatment of methamphetamine dependence SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE bupropion; methamphetamine; addiction; drug abuse; risk factors; severity of illness index ID COCAINE DEPENDENCE; CLINICAL-TRIALS; PLACEBO; DISORDER; METHYLPHENIDATE; ARIPIPRAZOLE; INDIVIDUALS; MULTICENTER; ABSTINENCE; ADDICTION AB Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p = 0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (p<0.0001). Comorbid depression and attention-deficit/ hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition. C1 [Elkashef, Ahmed M.; Anderson, Ann L.; Smith, Edwina V.; Chiang, Nora; Kahn, Roberta; Vocci, Frank] Natl Inst Drug Abuse, NIH, Medications Dev Div, DPMC, Bethesda, MD 20892 USA. [Rawson, Richard A.; Pearce, Valerie J.] Univ Calif Los Angeles, Dept Psychiat, Integrated Substance Abuse Program, Los Angeles, CA USA. [Holmes, Tyson] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [McCann, Michael] Matrix Inst Addict, Dept Psychiat, Costa Mesa, CA USA. [Campbell, Jan] Univ Missouri, Dept Psychiat, Kansas City, MO 64110 USA. [Gorodetzky, Charles] Quintiles Inc, Dept Psychiat, Kansas City, MO USA. [Haning, William; Carlton, Barry] Univ Hawaii, John A Burns Sch Med, Dept Psychiat, Honolulu, HI 96822 USA. [Mawhinney, Joseph] S Bay Treatment Ctr, San Diego, CA USA. [Weis, Dennis] Lutheran Hosp, Dept Addict Med, Powell Addict Res Ctr, Des Moines, IA USA. RP Elkashef, AM (reprint author), Natl Inst Drug Abuse, NIH, Medications Dev Div, DPMC, Neyrosci Bldg,6001 Execut Blvd,Rm 4151, Bethesda, MD 20892 USA. EM ae8a@nih.gov FU NIDA NIH HHS [N01-DA-0-8804, N01-DA-3-8824] NR 45 TC 102 Z9 106 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2008 VL 33 IS 5 BP 1162 EP 1170 DI 10.1038/sj.npp.1301481 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 273UQ UT WOS:000253957600019 PM 17581531 ER PT J AU Heishman, SJ Singleton, EG Pickworth, WB AF Heishman, Stephen J. Singleton, Edward G. Pickworth, Wallace B. TI Reliability and validity of a short form of the tobacco craving questionnaire SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE DEPENDENCE; SMOKING; SMOKERS; VALIDATION; WITHDRAWAL; IMAGERY; REACTIVITY; INDUCTION; SYMPTOMS; DURATION AB The Tobacco Craving Questionnaire (TCQ) is a valid and reliable 47-item self-report instrument that assesses tobacco craving in four dimensions: emotionality, expectancy, compulsivity, and purposefulness. For use in research and clinical settings, we constructed a 12-item version of the TCQ by selecting three items from each of the four factors that exhibited optimal within-factor reliability (Cronbach's alpha coefficient) and inter-item correlation. Smokers (N=196) completed the TCQ-Short Form (TCQ-SF) after overnight tobacco deprivation and on a separate day during ad libitum smoking. Confirmatory factor analyses indicated acceptable model fit for a 4-factor model, with congruence coefficients suggesting high to very high similarity in factor patterns and magnitude of factor loadings between the TCQ and TCQ-SF in both conditions. Scores on each factor were significantly greater after tobacco deprivation than ad libitum smoking, were associated with measures of tobacco withdrawal, and varied with degree of nicotine dependence. Cronbach's alpha coefficients and average inter-item correlations were similar in both conditions and were consistent with reliability values obtained in the initial validation of the TCQ. Test-retest correlation coefficients were also similar to those found in a previous study. These findings suggest that the TCQ-SF is as valid and reliable as the 47-item TCQ in measuring tobacco craving. C1 [Heishman, Stephen J.] NIDA, Nicotine Psychopharmacol Unit, Clin Pharmacol & Therapeut Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Singleton, Edward G.] MayaTech Corp, Ctr Prevent & Treatment Res, Silver Spring, MD USA. [Pickworth, Wallace B.] Battelle Ctr Publ Hlth Res & Evaluat, Baltimore, MD USA. RP Heishman, SJ (reprint author), NIDA, Nicotine Psychopharmacol Unit, Clin Pharmacol & Therapeut Branch, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM heishman@nih.gov OI Singleton, Edward G./0000-0003-3442-877X FU Intramural NIH HHS [Z01 DA000485-03] NR 42 TC 36 Z9 36 U1 2 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD APR PY 2008 VL 10 IS 4 BP 643 EP 651 DI 10.1080/14622200801908174 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 294OY UT WOS:000255416600010 PM 18418787 ER PT J AU Ma, WJ Resnick, MA Gordenin, DA AF Ma, Wenjian Resnick, Michael A. Gordenin, Dmitry A. TI Apn1 and Apn2 endonucleases prevent accumulation of repair-associated DNA breaks in budding yeast as revealed by direct chromosomal analysis SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE EXCISION-REPAIR; DOUBLE-STRAND BREAKS; SACCHAROMYCES-CEREVISIAE; ABASIC SITES; ALKYLATION DAMAGE; SPONTANEOUS MUTAGENESIS; ESCHERICHIA-COLI; POLYMERASE; AGENTS; RECOMBINATION AB Base excision repair (BER) provides relief from many DNA lesions. While BER enzymes have been characterized biochemically, BER functions within cells are much less understood, in part because replication bypass and double-strand break (DSB) repair can also impact resistance to base damage. To investigate BER in vivo, we examined the repair of methyl methanesulfonate (MMS) induced DNA damage in haploid G1 yeast cells, so that replication bypass and recombinational DSB repair cannot occur. Based on the heat-lability of MMS-induced base damage, an assay was developed that monitors secondary breaks in full-length yeast chromosomes where closely spaced breaks yield DSBs that are observed by pulsed-field gel electrophoresis. The assay detects damaged bases and abasic (AP) sites as heat-dependent breaks as well as intermediate heat-independent breaks that arise during BER. Using a circular chromosome, lesion frequency and repair kinetics could be easily determined. Monitoring BER in single and multiple glycosylase and AP-endonuclease mutants confirmed that Mag1 is the major enzyme that removes MMS-damaged bases. This approach provided direct physical evidence that Apn1 and Apn2 not only repair cellular base damage but also prevent break accumulation that can result from AP sites being channeled into other BER pathway(s). C1 [Ma, Wenjian; Resnick, Michael A.; Gordenin, Dmitry A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Gordenin, DA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM gordenin@niehs.nih.gov RI Ma, Wenjian/C-1071-2012; OI Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural NIH HHS NR 45 TC 34 Z9 34 U1 0 U2 2 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 APR PY 2008 VL 36 IS 6 BP 1836 EP 1846 DI 10.1093/nar/gkm1148 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 284OC UT WOS:000254714700011 PM 18267974 ER PT J AU Plosky, BS Frank, EG Berry, DA Vennall, GP McDonald, JP Woodgate, R AF Plosky, Brian S. Frank, Ekaterina G. Berry, David A. Vennall, Graham P. McDonald, John P. Woodgate, Roger TI Eukaryotic Y-family polymerases bypass a 3-methyl-2 '-deoxyadenosine analog in vitro and methyl methanesulfonate-induced DNA damage in vivo SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE GENE; ESCHERICHIA-COLI DINB; THYMINE DIMER BYPASS; 3-METHYLADENINE DNA; ALKYLATING-AGENTS; ABASIC SITES; YEAST-CELLS; ERROR-PRONE; GLYCOSYLASE AB N3-methyl-adenine (3MeA) is the major cytotoxic lesion formed in DNA by S(N)2 methylating agents. The lesion presumably blocks progression of cellular replicases because the N3-methyl group hinders interactions between the polymerase and the minor groove of DNA. However, this hypothesis has yet to be rigorously proven, as 3MeA is intrinsically unstable and is converted to an abasic site, which itself is a blocking lesion. To circumvent these problems, we have chemically synthesized a 3-deaza analog of 3MeA (3dMeA) as a stable phosphoramidite and have incorporated the analog into synthetic oligonucleotides that have been used in vitro as templates for DNA replication. As expected, the 3dMeA lesion blocked both human DNA polymerases alpha and delta. In contrast, human polymerases eta, 1 and kappa, as well as Saccharomyces cerevisiae pol were able to bypass the lesion, albeit with varying efficiencies and accuracy. To confirm the physiological relevance of our findings, we show that in S. cerevisiae lacking Mag1-dependent 3MeA repair, pol eta (Rad30) contributes to the survival of cells exposed to methyl methanesulfonate (MMS) and in the absence of Mag1, Rad30 and Rev3, human polymerases eta, 1 and kappa are capable of restoring MMS-resistance to the normally MMS-sensitive strain. C1 [Plosky, Brian S.; Frank, Ekaterina G.; McDonald, John P.; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [Berry, David A.; Vennall, Graham P.] Berry & Associates Inc, Dexter, MI 48130 USA. RP Woodgate, R (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU Intramural NIH HHS NR 49 TC 39 Z9 40 U1 1 U2 3 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 APR PY 2008 VL 36 IS 7 BP 2152 EP 2162 DI 10.1093/nar/gkn058 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 290VZ UT WOS:000255152200011 PM 18281311 ER PT J AU Pursell, ZF McDonald, JT Mathews, CK Kunkel, TA AF Pursell, Zachary F. McDonald, J. Tyson Mathews, Christopher K. Kunkel, Thomas A. TI Trace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase gamma replication fidelity SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; P55 ACCESSORY SUBUNIT; POINT MUTATIONS; SACCHAROMYCES-CEREVISIAE; OXIDATIVE STRESS; NUCLEOTIDE POOL; PROTEIN; MOUSE; DISEASES; RESIDUE AB Replication of the mitochondrial genome by DNA polymerase gamma requires dNTP precursors that are subject to oxidation by reactive oxygen species generated by the mitochondrial respiratory chain. One such oxidation product is 8-oxo-dGTP, which can compete with dTTP for incorporation opposite template adenine to yield A-T to C-G transversions. Recent reports indicate that the ratio of undamaged dGTP to dTTP in mitochondrial dNTP pools from rodent tissues varies from similar to 1:1 to >100:1. Within this wide range, we report here the proportion of 8-oxo-dGTP in the dNTP pool that would be needed to reduce the replication fidelity of human DNA polymerase gamma. When various in vivo mitochondrial dNTP pools reported previously were used here in reactions performed in vitro, 8-oxo-dGTP was readily incorporated opposite template A and the resulting 8-oxo-G-A mismatch was not proofread efficiently by the intrinsic 3' exonuclease activity of pol gamma. At the dNTP ratios reported in rodent tissues, whether highly imbalanced or relatively balanced, the amount of 8-oxo-dGTP needed to reduce fidelity was <1% of dGTP. Moreover, direct measurements reveal that 8-oxo-dGTP is present at such concentrations in the mitochondrial dNTP pools of several rat tissues. The results suggest that oxidized dNTP precursors may contribute to mitochondrial mutagenesis in vivo, which could contribute to mitochondrial dysfunction and disease. C1 [Pursell, Zachary F.; McDonald, J. Tyson; Kunkel, Thomas A.] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Pursell, Zachary F.; McDonald, J. Tyson; Kunkel, Thomas A.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Mathews, Christopher K.] Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA. RP Kunkel, TA (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI McDonald, J. Tyson/0000-0003-1955-6052; Pursell, Zachary/0000-0001-5871-7192 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM073744, R01GM73744] NR 41 TC 39 Z9 39 U1 0 U2 3 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 APR PY 2008 VL 36 IS 7 BP 2174 EP 2181 DI 10.1093/nar/gkn062 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 290VZ UT WOS:000255152200013 PM 18276636 ER PT J AU Ueda, Y Kawakami, Y Kunii, D Okada, H Azuma, M Le, DSNT Yamamoto, S AF Ueda, Yakiko Kawakami, Yuko Kunii, Daisuke Okada, Hiroyuki Azuma, Masami Le, Duc Son N. T. Yamamoto, Shigeru TI Elevated concentrations of linoleic acid in erythrocyte membrane phospholipids in patients with inflammatory bowel disease SO NUTRITION RESEARCH LA English DT Article DE eicosanoids; erythrocyte membrane phospholipids; human; inflammatory bowel disease; n-6 and n-3 fatty acids; plasma phospholipids; polyunsaturated fatty acids ID POLYUNSATURATED FATTY-ACIDS; ARACHIDONIC-ACID; CROHNS-DISEASE; COLONIC MUCOSA; FISH-OIL; EPIDEMIOLOGY; METABOLISM; PLASMA; ALPHA; CELLS AB inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn disease (CD), is a disorder characterized by diffuse inflammation of the gastrointestinal tract. The immune response and inflammation are mediated by polyunsaturated fatty acids and influenced by dietary fats and lipid metabolism. This study examined the qualitative and quantitative fat intake of IBD patients and healthy controls on plasma phospholipid and erythrocyte membrane phospholipid (EMP) fatty acid content. Measurement of the fatty acid composition of plasma phospholipid and EMP were performed in 29 UC patients, 20 CD patients, and 31 healthy controls. Anthropometric characteristics and data on dietary intake were also collected. We observed significantly lower lipid intake in UC and CD patients vs controls. ne UC and CD patients had significantly higher levels of linoleic acid in their EMP than did controls. There were no significant differences in the levels of n-3 polyunsaturated fatty acids, but there were significantly higher levels of the n-6 in the EMP of UC and CD patients compared with controls. The significant differences persisted after the data were adjusted for potential confounders and lipid intake. Higher levels of linoleic acids and n-6 fatty acids, which are involved in production of proinflammatory mediators, were found in IBD patients compared with controls, thereby implicating n-6 fatty acids in the pathophysiology of the disease. (C) 2008 Elsevier Inc. All rights reserved. C1 [Ueda, Yakiko] Nara Womens Univ, Fac Human Life & Environm, Dept Food Sci & Nutr, Nara, Japan. [Okada, Hiroyuki] Okayama Univ, Grad Sch Med & Dent, Dept Med & Med Sci, Okayama 7008530, Japan. [Le, Duc Son N. T.] NIDDK, NIH, Bethesda, MD 20892 USA. [Yamamoto, Shigeru] Ochanomizu Univ, Grad Sch Humanities & Sci, Tokyo, Japan. RP Ueda, Y (reprint author), Nara Womens Univ, Fac Human Life & Environm, Dept Food Sci & Nutr, Kitauoyanishimachi, Nara, Japan. EM yueda@cc-nara-wu.ac.jp NR 38 TC 13 Z9 14 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0271-5317 J9 NUTR RES JI Nutr. Res. PD APR PY 2008 VL 28 IS 4 BP 239 EP 244 DI 10.1016/j.nutres.2008.02.005 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 295QQ UT WOS:000255489400004 PM 19083414 ER PT J AU Sumner, AE Sen, S Ricks, M Frempong, BA Sebring, NG Kushner, H AF Sumner, Anne E. Sen, Sabyasachi Ricks, Madia Frempong, Barbara A. Sebring, Nancy G. Kushner, Harvey TI Determining the waist circumference in African Americans which best predicts insulin resistance SO OBESITY LA English DT Article ID METABOLIC SYNDROME; TRIGLYCERIDE LEVELS; GLUCOSE-TOLERANCE; WEIGHT MANAGEMENT; UNITED-STATES; OBESITY; PREVALENCE; OVERWEIGHT; NUTRITION; CRITERIA AB Total body size and central fat distribution are important determinants of insulin resistance. The BMI and waist circumference ( WC) thresholds in African Americans that best predict insulin resistance are unknown. Our goal was to determine the BMI and WC values in African Americans, which optimally predict insulin resistance. The subjects were African Americans ( 68 men, 63 women), aged 35 +/- 8 years ( mean +/- s.d.), with a BMI of 30.9 +/- 7.5, in the range of 18.5-54.7 kg/m(2), and with a WC of 98 +/- 18, in the range of 69-173 cm. Insulin resistance was defined by the lowest tertile of the insulin sensitivity index ( S-I). The Youden index was calculated to determine the WC and BMI thresholds that predict insulin resistance with an optimal combination of sensitivity and specificity. In men the thresholds that optimally predicted insulin resistance were a BMI >= 30 kg/m(2) or a WC >= 102 cm. For women, insulin resistance was best predicted by a BMI >= 32 kg/ m(2) or a WC >= 98 cm. In African Americans, insulin resistance ( in men) was best predicted by a WC >= 102 cm, and in women by a WC >= 98 cm, or by a BMI value that fell in the obese category ( men: = 30 kg/ m(2), women: = 32 kg/ m(2)). C1 [Sumner, Anne E.; Sen, Sabyasachi; Ricks, Madia; Frempong, Barbara A.] NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Sebring, Nancy G.] NIH, Dept Nutr, Bethesda, MD 20892 USA. [Kushner, Harvey] BioMed Comp Inst, Philadelphia, PA USA. RP Sumner, AE (reprint author), NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov NR 26 TC 24 Z9 26 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD APR PY 2008 VL 16 IS 4 BP 841 EP 846 DI 10.1038/oby.2008.11 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 283ZG UT WOS:000254674400019 PM 18292752 ER PT J AU Myslobodsky, M AF Myslobodsky, Michael TI Ingenuity Pathway Analysis of Clozapine-Induced Obesity SO OBESITY FACTS LA English DT Article DE Weight regulation; Atypical neuroleptics; Microvasculature; Tissue edema ID INDUCED WEIGHT-GAIN; ACTIVATED PROTEIN-KINASE; EPIDERMAL-GROWTH-FACTOR; ADIPOSE-TISSUE; ANTIPSYCHOTIC-DRUGS; CHRONIC-SCHIZOPHRENIA; METABOLIC SYNDROME; DIABETES-MELLITUS; PROGENITOR CELLS; NEUROPEPTIDE-Y AB Background: Lipid accretion is one of the major side effects of clozapine pharmacotherapy of schizophrenia that made clozapine into an interesting obesity drug model. Method: Ingenuity Pathway Analysis (IPA) engine was used for core analysis and building the networks of weight regulation. Results: The examination of molecules that were selected into 'clozapine neighborhood' identified them as multifunctional signals that appear to orchestrate vascular and tissue functions plausibly implicated in adiposity side effect. Conclusions: It is hypothesized that clozapine unmasks the functional and morphological phenotype of microvascular deficit that facilitates shunting nutrients from utilization toward storage. C1 [Myslobodsky, Michael] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Myslobodsky, Michael] Howard Univ, Grad Sch, Washington, DC 20059 USA. RP Myslobodsky, M (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. EM myslobom@mail.nih.gov NR 86 TC 4 Z9 4 U1 2 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1662-4025 J9 OBESITY FACTS JI Obes. Facts PD APR PY 2008 VL 1 IS 2 BP 93 EP 102 DI 10.1159/000127278 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 431IY UT WOS:000265056200007 PM 20054168 ER PT J AU Castle, PE Cox, JT Jeronimo, J AF Castle, Philip E. Cox, J. Thomas Jeronimo, Jose TI An analysis of high-risk human papillomavirus DNA-negative cervical precancers in the ASCUS-LSIL triage study (ALTS) SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 24th International Papillomavirus Conference and Clinical Workshop CY NOV 03-09, 2007 CL Beijing, PEOPLES R CHINA ID ATYPICAL SQUAMOUS-CELLS; UNDETERMINED SIGNIFICANCE; LESION TRIAGE; MANAGEMENT STRATEGIES; CANCER; WOMEN; NEOPLASIA; HYBRID-CAPTURE-2; CLASSIFICATION; COLPOSCOPY AB To describe women diagnosed with cervical intraepithelial neoplasia-grade 3 (CIN-3) diagnosed over the 2-year duration of the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) Triage Study (ALTS) that tested negative for high-risk human papillomavirus (HPV) at enrollment. METHODS: Clinical center pathologists and quality control. pathology group reviewed all histology; any CIN-3 diagnosis on biopsy or loop electrosurgical excision procedure (n=621) by at least one pathology review over the duration of ALTS led to inclusion in this analysis. Enrollment cervical specimens were tested for high-risk HPV DNA by two HPV assays; results were combined to minimize simple testing errors. We compared the characteristics of baseline high-risk HPV-negative (n=33) to baseline high-risk HPV-positive (n=588) cumulative diagnosed CIN-3. RESULTS: High-risk HPV-negative CIN-3 cases were less likely to have a second, confirming diagnosis of CIN-3 (24% compared with 56%) by the other pathology group, were more likely to be diagnosed later in follow-up, and more likely to be referred into ALTS because of an ASCUS Pap test rather than an LSIL Pap. Upon review of case histories of the 33 baseline high-risk HPV-negative CIN-3 (5.3% of all cases), there was evidence that these cases were due to incident (new) cases (n=12, 1.9%), non-high-risk HPV (n=5, 0.8%), misclassified histology (n=8, 1.3%), and false-negative high-risk HPV (n=8, 1.3%). CONCLUSION: In any sizeable population, even among women with evidence of cytologic abnormalities, there will be a few cases of cervical precancer that will test high-risk HPV negative for one or more reasons. C1 [Castle, Philip E.] NCI, NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Castle, Philip E.; Cox, J. Thomas; Jeronimo, Jose] NCI, NIH, Div Canc Prevent, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Castle, Philip E.; Cox, J. Thomas; Jeronimo, Jose] Univ Calif Santa Barbara, Gynecol & Colposcopy Clin Student Hlth Serv, Santa Barbara, CA 93106 USA. [Castle, Philip E.; Cox, J. Thomas; Jeronimo, Jose] Univ New Mexico, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Sch Med, Albuquerque, NM 87131 USA. [Castle, Philip E.; Cox, J. Thomas; Jeronimo, Jose] Univ New Mexico, Hlth Sci Ctr, Dept Obstet & Gynecol, Sch Med, Albuquerque, NM 87131 USA. [Castle, Philip E.; Cox, J. Thomas; Jeronimo, Jose] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Castle, PE (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,Room 5004,EPS MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS NR 32 TC 34 Z9 35 U1 0 U2 2 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 APR PY 2008 VL 111 IS 4 BP 847 EP 856 DI 10.1097/AOG.0b013e318168460b PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 280NO UT WOS:000254433700007 PM 18378743 ER PT J AU Witkop, CT Zhang, J Sun, WY Troendle, J AF Witkop, Catherine Takacs Zhang, Jun Sun, Wenyu Troendle, James TI Natural history offetal position during pregnancy and risk of nonvertex delivery SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID EXTERNAL CEPHALIC VERSION; RANDOMIZED MULTICENTER TRIAL; BREECH PRESENTATION; BIOPHYSICAL ACTIVITIES; CIGARETTE-SMOKING; WEEKS GESTATION; TERM; MOVEMENTS; BIRTH AB OBJECTIVE: To examine the natural history of fetal position throughout pregnancy and the likelihood for nonvertex delivery. METHODS: We examined fetal positions at 15-22 weeks, at 31-35 weeks, and at delivery using data from the Routine Antenatal Diagnostic Imaging with Ultrasound trial. Characteristics of women with nonvertex and vertex presentation at delivery were compared, Multivariable logistic regression analysis was performed to determine risk factors for nonvertex presentation at delivery, and odds ratios were calculated for those risk factors found to be statistically significantly associated with nonvertex presentation. RESULTS: Data for 7,045 women who underwent routine prenatal ultrasound examinations were analyzed. We found no association between nonvertex presentation at 15-22 and at 31-35 weeks of gestation. A nonvertex fetus at 35 weeks had a 45% chance of spontaneous version by delivery. Multivariable logistic regression analysis found that multiparous women had half of the risk of nonvertex presentation as nulliparous Women. Smoking during pregnancy (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.10-1.96), low volume of amniotic fluid at 31-35 weeks (OR 3.74, 95% CI 1.85-7.53), and fundal position of the placenta at late ultrasound examination (OR 1.85, 95% CI 1.23-2.78) were all associated with significant increases in the risk of nonvertex position at delivery. CONCLUSION: Spontaneous version of a nonvertex fetus at 35 weeks of gestation is still likely. C1 [Witkop, Catherine Takacs; Zhang, Jun; Sun, Wenyu; Troendle, James] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Gen Prevent Med, Baltimore, MD 21205 USA. [Witkop, Catherine Takacs; Zhang, Jun; Sun, Wenyu; Troendle, James] NICHHD, NIH, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Witkop, CT (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Gen Prevent Med, 615 N Wolfe St,Room WB602, Baltimore, MD 21205 USA. EM katika@aya.yale.edu FU Intramural NIH HHS NR 21 TC 13 Z9 13 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 APR PY 2008 VL 111 IS 4 BP 875 EP 880 DI 10.1097/AOG.0b013e318168576d PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 280NO UT WOS:000254433700010 PM 18378746 ER PT J AU Subak, LL Brubaker, L Chai, TC Creasman, JM Diokno, AC Goode, PS Kraus, SR Kusek, JW Leng, WW Lukacz, ES Norton, P Tennstedt, S AF Subak, Leslee L. Brubaker, Linda Chai, Toby C. Creasman, Jennifer M. Diokno, Ananias C. Goode, Patricia S. Kraus, Stephen R. Kusek, John W. Leng, Wendy W. Lukacz, Emily S. Norton, Peggy Tennstedt, Sharon CA Urinary Incontinence Treatment Ne TI High costs of urinary incontinence among women electing surgery to treat stress incontinence SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID WILLINGNESS-TO-PAY; QUALITY-OF-LIFE; COMMUNITY; IMPACT; INSTRUMENT; DISEASE AB OBJECTIVE: To estimate costs for incontinence management, health-related quality of life, and willingness to pay for incontinence improvement in women electing surgery for stress urinary incontinence. METHODS: A total of 655 incontinent women enrolled in the Stress Incontinence Surgical Treatment Efficacy Trial, a randomized surgical trial. Baseline out-of-pocket costs for incontinence management were calculated by multiplying self-report of resources used (supplies, laundry, dry cleaning) by national resource costs ($2006). Health-related quality of life was estimated with the Health Utilities Index Mark 3. Participants estimated willingness to pay for 100% improvement in incontinence. Potential predictors of these outcomes were examined by using multivariable linear regression. RESULTS: Mean age was 52 +/- 10 years, and mean number of weekly incontinence episodes was 22 +/- 21. Mean and median (25%, 75% interquartile range) estimated personal costs for incontinence management among all women were $14 +/- $24 and $8 (interquartile range $3, $18) per week, and 617 (94%) women reported any cost. Costs increased significantly with incontinence frequency and mixed compared with stress incontinence. The mean and median Health Utilities Index Mark 3 scores were 0.73 +/- 0.25 and 0.84 (interquartile range 0.63, 0.92). Women were willing to pay a mean of $118 +/- $132 per month for complete resolution of incontinence, and willingness to pay increased significantly with greater expected incontinence improvement, household income, and incontinent episode frequency. CONCLUSION: Urinary incontinence is associated with substantial costs. Women spent nearly $750 per year out of pocket for incontinence management, had a significant decrement in quality of life, and were willing to pay nearly $1,400 per year for cure. C1 [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Loyola Univ, Dept Obstet Gynecol & Reprod Sci, Chicago, IL 60611 USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Maryland, Dept Urol, Baltimore, MD 21201 USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Alabama, Birmingham, AL USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Birmingham Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Birmingham, AL USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] NIDDK, Bethesda, MD USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Pittsburgh, Dept Urol, Pittsburgh, PA USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Calif San Diego, Dept Reprod Med, San Diego, CA 92103 USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Subak, Leslee L.; Brubaker, Linda; Chai, Toby C.; Creasman, Jennifer M.; Diokno, Ananias C.; Goode, Patricia S.; Kraus, Stephen R.; Kusek, John W.; Leng, Wendy W.; Lukacz, Emily S.; Norton, Peggy; Tennstedt, Sharon] New England Res Inst, Watertown, MA 02172 USA. RP Subak, LL (reprint author), UCSF, Mt Zions Womens Hlth Clin Res Ctr, 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM subakl@obgyn.ucsf.edu FU NIDDK NIH HHS [U01 DK058225, U01 DK058229, U01 DK058234, U01 DK58225, U01 DK58229, U01 DK58234, U01 DK60380, U01 DK058231, U01 DK060379, U01 DK060379-05, U01 DK060380, U01 DK060393, U01 DK060395, U01 DK060397, U01 DK060401, U01 DK58231, U01 DK60379, U01 DK60393, U01 DK60395, U01 DK60397]; PHS HHS [60401] NR 34 TC 36 Z9 37 U1 0 U2 4 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 APR PY 2008 VL 111 IS 4 BP 899 EP 907 DI 10.1097/AOG.0b013e31816a1e12 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 280NO UT WOS:000254433700013 PM 18378749 ER PT J AU Maraini, G Williams, SL Sperduto, RD Ferris, F Milton, RC Clemons, TE Rosinim, F Ferrigno, L AF Maraini, Giovanni Williams, Sally L. Sperduto, Robert D. Ferris, Frederick Milton, Roy C. Clemons, Traci E. Rosinim, Francesco Ferrigno, Luigina CA Clinical Trial Nutritional Supplem TI A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities SO OPHTHALMOLOGY LA English DT Article ID BLUE MOUNTAINS EYE; BEAVER DAM EYE; BETA-CAROTENE; VITAMIN SUPPLEMENTS; RISK-FACTORS; CATARACT; PREVALENCE; PROGRESSION; NUCLEAR; POPULATION AB Objective: To evaluate the effect of a multivitamin/mineral supplement on development or progression of age-related lens opacities. Design: Randomized, double-masked, single center, placebo-controlled clinical trial. Participants: One thousand twenty participants, 55 to 75 years old and with early or no cataract, were randomly assigned to a daily tablet of a multivitamin/mineral formulation or a placebo. Methods: Baseline and annual lens photographs were graded for severity of lens opacities according to a modification of the Age-Related Eye Disease Study system for classifying cataracts. Main Outcome Measures: The primary outcome was a prespecified increase from baseline in nuclear, cortical, or posterior subcapsular cataract (PSC) opacity grades or cataract surgery. Secondary outcomes included an increase in type-specific opacity grades, cataract surgery, and visual acuity (VA) loss from baseline 15 letters. Results: Participants were observed for an average of 9.0 +/- 2.4 years. There was a decrease in total lens events in participants assigned to the multivitamin/mineral formulation compared with those assigned to the placebo (hazard ratio [HR], 0.82; 95% confidence interval [Cl], 0.68-0.98; P = 0.03). Nuclear events were significantly less common (HR, 0.66; 95% Cl, 0.50-0.88; P = 0.004) and PSC events significantly more common (HR, 2.00; 95% Cl, 1.35-2.98; P < 0.001) in participants taking the multivitamin/mineral formulation than in those assigned to the placebo. No statistically significant treatment effects were seen for cortical opacities, moderate VA loss, or cataract surgery. Conclusions: Lens events were less common in participants who took the multivitamin/mineral formulation, but treatment had opposite effects on the development or progression of nuclear and PSC opacities, the 2 most visually important opacity subtypes. Ophthalmology 2008,115:599-607 (c) 2008 by the American Academy of Ophthalmology. C1 [Maraini, Giovanni; Williams, Sally L.] Univ Parma, I-43100 Parma, Italy. [Sperduto, Robert D.; Ferris, Frederick] NEI, Bethesda, MD 20892 USA. [Milton, Roy C.; Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Rosinim, Francesco; Ferrigno, Luigina] Ist Super Sanita, I-00161 Rome, Italy. RP Maraini, G (reprint author), Univ Parma, Via Gramsci 14, I-43100 Parma, Italy. NR 37 TC 43 Z9 44 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2008 VL 115 IS 4 BP 599 EP 607 DI 10.1016/j.ophtha.2008.01.005 PG 9 WC Ophthalmology SC Ophthalmology GA 281CU UT WOS:000254475100002 ER PT J AU Wang, JJ Ross, RJ Tuo, JS Burlutsky, G Tan, AG Chan, CC Favaloro, EJ Williams, A Mitchell, P AF Wang, Jie Jin Ross, Robert J. Tuo, Jingsheng Burlutsky, George Tan, Ava G. Chan, Chi-Chao Favaloro, Emmanuel J. Williams, Andrew Mitchell, Paul TI The LOC387715 polymorphism, inflammatory markers, smoking, and age-related macular degeneration - A population-based case-control study SO OPHTHALMOLOGY LA English DT Article ID COMPLEMENT FACTOR-H; C-REACTIVE PROTEIN; BLUE MOUNTAINS EYE; BODY-MASS INDEX; VISUAL IMPAIRMENT; ENVIRONMENTAL ASSOCIATIONS; MACULOPATHY; RISK; GENE; PREVALENCE AB Objective: To assess combined effects on the risk of age-related macular degeneration (AMD) by the LOC387715 polymorphism, smoking, and inflammatory or hemostatic factors. Design: Population-based case-control study. Participants: Two hundred seventy-eight AMD cases (224 early, 54 late) and 557 controls matched for age, gender, and smoking, drawn from the Blue Mountains Eye Study cohort. Methods: Subjects were genotyped for the LOC387715 Ala69Ser polymorphism (rs# 10490924). Smoking was self-reported. Serum high-sensitivity C-reactive protein (CRP), interleukin 6 (IL-6), soluble intercellular adhesion molecule 1 (slCAM-1), fibrinogen, homocysteine, plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor, and white cell count (WCC) were measured. Combined effects of this genetic variant plus any of these study factors on AMD risk were assessed using logistic regression models, adjusted for age and smoking. We defined interaction if the influence of 2 factors departed from the multiplicative scale, confirmed by a statistically significant interaction term. Otherwise, the combined effect was used. Main Outcome Measures: Age-related macular degeneration was graded using the Wisconsin grading system. Results: Combined effects on the likelihood of early or late AMD were demonstrated for the LOC387715 Ala69Ser G/T and T/T genotypes with the markers high-sensitivity CRP (odds ratios [ORs], 1.2 for the highest tertile alone, 1.6 for G/T and T/T genotypes alone, and 2.2 for both G/T and T/T genotypes plus the highest tertile, compared with the G/G genotype with the 2 lower tertiles), IL-6 (corresponding ORs, 1.1, 1.6, and 2.2), slCAM-1 (ORs, 1.0, 1.5, and 2.3, respectively), and PAI-1 (ORs, 1.3, 1.7, and 2.3, respectively), but not with WCC, fibrinogen, homocysteine, and von Willebrand factor. Findings were similar for early and late AMD separately. Current smokers with G/T and T/T genotypes had strong combined effects on late AMD risk compared with those who never smoked or past smokers with the G/G genotype (ORs, 1.2 for current smokers alone, 1.8 for G/T and T/T genotypes alone, and 6.1 for current smokers plus G/T and T/T genotypes). Conclusions: We found no significant interaction but combined effects for the LOC387715 genotypes with 3 inflammatory markers and PAW on the risk of early or late AMD, and with current smoking on the risk of late AMD. C1 [Wang, Jie Jin; Burlutsky, George; Tan, Ava G.; Mitchell, Paul] Univ Sydney, Westmead Hosp, Dept Ophthalmol, Ctr Vis Res, Westmead, NSW 2145, Australia. [Wang, Jie Jin; Burlutsky, George; Tan, Ava G.; Mitchell, Paul] Univ Sydney, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Ross, Robert J.; Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Favaloro, Emmanuel J.] Westmead Hosp, Dept Hematol, Inst Clin Pathol & Med Res, Sydney, NSW, Australia. [Williams, Andrew] Royal Prince Alfred Hosp, Dept Clin Immunol, Sydney, NSW, Australia. RP Wang, JJ (reprint author), Univ Sydney, Westmead Hosp, Dept Ophthalmol, Ctr Vis Res, Hawkesbury Rd, Westmead, NSW 2145, Australia. EM jiejin_wang@wmi.usyd.edu.au RI Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Tuo, Jingsheng/0000-0002-1372-7810 FU Intramural NIH HHS [Z01 EY000418-04] NR 51 TC 31 Z9 32 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2008 VL 115 IS 4 BP 693 EP 699 DI 10.1016/j.ophtha.2007.05.038 PG 7 WC Ophthalmology SC Ophthalmology GA 281CU UT WOS:000254475100016 PM 17675241 ER PT J AU Nelson, RG AF Nelson, R. G. TI Periodontal disease and diabetes SO ORAL DISEASES LA English DT Editorial Material ID STAGE RENAL-DISEASE; ADULTS 30 YEARS; UNITED-STATES; PIMA-INDIANS; TYPE-2; NEPHROPATHY; MORTALITY; MELLITUS; OLDER; AGE C1 NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. RP Nelson, RG (reprint author), NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM rgnelson@mail.nih.gov RI Nelson, Robert/B-1470-2012 NR 14 TC 7 Z9 8 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1354-523X J9 ORAL DIS JI Oral Dis. PD APR PY 2008 VL 14 IS 3 BP 204 EP 205 DI 10.1111/j.1601-0825.2008.01443.x PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 274DA UT WOS:000253980800002 PM 18336371 ER PT J AU Shirota, Y Illei, GG Nikolov, NP AF Shirota, Y. Illei, G. G. Nikolov, N. P. TI Biologic treatments for systemic rheumatic diseases SO ORAL DISEASES LA English DT Review DE autoimmunity; biologic therapies; monoclonal antibodies; rheumatic diseases; Sjogren's syndrome ID TUMOR-NECROSIS-FACTOR; PRIMARY SJOGRENS-SYNDROME; RECEIVING CONCOMITANT METHOTREXATE; INTERLEUKIN-1 RECEPTOR ANTAGONIST; CHIMERIC MONOCLONAL-ANTIBODY; PLACEBO-CONTROLLED TRIAL; HUMANIZED ANTI-CD22 ANTIBODY; B-LYMPHOCYTE STIMULATOR; PHASE-III TRIAL; FACTOR-ALPHA AB Many rheumatologic disorders, most notably Sjogren's syndrome, are associated with dental complications and in some cases oral diseases may trigger or drive connective tissue disease. During the past three decades the treatment in rheumatology was revolutionized by the introduction of disease-modifying anti-rheumatic drugs. Advances in our understanding of the pathogenesis of rheumatic diseases have led to the discovery of critical mechanisms of inflammation and autoimmunity and the invention of new target-specific biologic agents. In this review, we will summarize the current state of biologic therapies in rheumatology and discuss the implications of these on oral health and disease. C1 [Shirota, Y.; Illei, G. G.; Nikolov, N. P.] NIDCR, Sjogrens Syndrome Clin, MPTB, NIH, Bethesda, MD 20892 USA. RP Nikolov, NP (reprint author), NIDCR, Sjogrens Syndrome Clin, MPTB, NIH, Bldg 10,Room 1N-114, Bethesda, MD 20892 USA. EM nikolovn@mail.nih.gov FU Intramural NIH HHS [Z01 DE000704-06, Z01 DE000704-07, Z99 DE999999] NR 130 TC 8 Z9 8 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD APR PY 2008 VL 14 IS 3 BP 206 EP 216 DI 10.1111/j.1601-0825.2008.01440.x PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 274DA UT WOS:000253980800003 PM 18282173 ER PT J AU Martin, CL Reshmi, SC Ried, T Gottberg, W Wilson, JW Reddy, JK Khanna, P Johnson, JT Myers, EN Gollin, SM AF Martin, Christa Lese Reshmi, Shalini C. Ried, Thomas Gottberg, William Wilson, John W. Reddy, Jaya K. Khanna, Poornima Johnson, Jonas T. Myers, Eugene N. Gollin, Susanne M. TI Chromosomal imbalances in oral squamous cell carcinoma: Examination of 31 cell lines and review of the literature SO ORAL ONCOLOGY LA English DT Review DE head and neck cancer; gene amplification; cytogenetics; CGH; biomarker; 11q13 ID COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN BREAST-CANCER; NECK-CANCER; GENE AMPLIFICATION; CYCLIN D1; CYTOGENETIC ABNORMALITIES; TUMOR PROGRESSION; 11Q13 AMPLICON; SHORT ARM; FIELD CANCERIZATION AB Classical and molecular cytogenetic analysis, including fluorescence in situ hybridization (FISH) and chromosomal comparative genomic hybridization (CGH), were used to examine genetic changes involved in the development and/or progression of oral squamous cell carcinoma (OSCC). Of 31 OSCC cell tines studied, more than one-third expressed clonal structural. abnormalities involving chromosomes 3, 7, 8, 9, and 11. Eleven OSCC cell lines were evaluated using CGH to identify novel genome-wide gains, losses, or amplifications. By CGH, more than half of the cell tines showed loss of 3p, gain of 3q, 8q, and 20q. Further, molecular cytogenetic analyses by FISH of primary tumors showed that the karyotypes of cell lines derived from those tumors correlated with specific gains and Losses in the tumors from which they were derived. The most frequent nonrandom aberration identified by both karyotype and CGH analyses was amplification of chromosomal band 11q13 in the form of a homogeneously staining region. Our data suggest that loss of 9p and 11 q13 amplification may be of prognostic benefit in the management of OSCC, which is consistent with the literature. The results of this study validate the relationship between these OSCC cell lines and the tumors from which they were derived. The results also emphasize the usefulness of these cell lines as in vitro experimental models and provide important genetic information on these OSCC cell lines that were recently reported in this journal. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Martin, Christa Lese; Reshmi, Shalini C.; Khanna, Poornima; Gollin, Susanne M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Wilson, John W.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Wilson, John W.] Univ Pittsburgh, NSABP Biostat Ctr, Pittsburgh, PA 15261 USA. [Reddy, Jaya K.; Johnson, Jonas T.; Myers, Eugene N.; Gollin, Susanne M.] Univ Pittsburgh, Dept Otolaryngol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Khanna, Poornima; Johnson, Jonas T.; Myers, Eugene N.; Gollin, Susanne M.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15261 USA. [Martin, Christa Lese] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Ried, Thomas] NCI, NIH, Bethesda, MD 20892 USA. [Gottberg, William] Appl Imaging, Santa Clara, CA USA. RP Gollin, SM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, 130 DeSoto St, Pittsburgh, PA 15261 USA. EM sgollin@hgen.pitt.edu FU NCATS NIH HHS [UL1 TR000005]; NCI NIH HHS [P30 CA047904, P30 CA047904-109019, P30 CA047904-119019, P30 CA047904-11S29019, P30 CA047904-11S39019, P30 CA047904-129019, P30 CA047904-12S19019, P30 CA047904-12S29019, P30 CA047904-139019, P30 CA047904-149019, P30 CA047904-14S19019, P30 CA047904-159019, P30 CA047904-169019, P30CA47904, P50 CA097190, P50 CA097190-01A1, P50 CA097190-02, P50 CA097190-03, P50 CA097190-04]; NIDCR NIH HHS [R01 DE014729-03, P60 DE013059, P60 DE013059-010004, P60 DE013059-020004, P60 DE013059-030004, P60 DE013059-040004, P60DE13059, R01 DE010513-03, R01 DE014729, R01 DE014729-01, R01 DE014729-01S1, R01 DE014729-02, R01 DE014729-04, R01 DE014729-05, R01 DE016086, R01 DE016086-01, R01 DE016086-02, R01 DE016086-03, R01 DE016086-04, R01DE016086, R01DE10513, R01DE14729] NR 97 TC 43 Z9 44 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD APR PY 2008 VL 44 IS 4 BP 369 EP 382 DI 10.1016/j.oraloncology.2007.05.003 PG 14 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 293CT UT WOS:000255313100007 PM 17681875 ER PT J AU Merchant, SN McKenna, MJ Adams, JC Nadol, JB Fayad, J Gellibolian, R Linthicum, FH Tshiyama, A Lopez, I Ishiyama, G Baloh, R Platt, C AF Merchant, Saumil N. McKenna, Michael J. Adams, Joe C. Nadol, Joseph B., Jr. Fayad, Jose Gellibolian, Robert Linthicum, Fred H., Jr. Tshiyama, Akira Lopez, Ivan Ishiyama, Gail Baloh, Robert Platt, Christopher TI Human temporal bone consortium for research resource enhancement SO OTOLOGY & NEUROTOLOGY LA English DT Editorial Material ID 3-DIMENSIONAL VIRTUAL MODEL; INNER-EAR; VESTIBULAR DYSFUNCTION; COCHLEAR IMPLANTS; HISTOPATHOLOGY; DFNA9; PATHOLOGY; DEAFNESS; HEARING; PATIENT C1 [Merchant, Saumil N.; McKenna, Michael J.; Adams, Joe C.; Nadol, Joseph B., Jr.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. [Fayad, Jose; Gellibolian, Robert; Linthicum, Fred H., Jr.] House Ear Res Inst, Los Angeles, CA USA. [Tshiyama, Akira; Lopez, Ivan; Ishiyama, Gail; Baloh, Robert] Univ Calif Los Angeles, Los Angeles, CA USA. [Platt, Christopher] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RP Merchant, SN (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. OI Lopez, Ivan/0000-0001-5205-7293 FU NIDCD NIH HHS [U24 DC008559, U24 DC008559-02] NR 23 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD APR PY 2008 VL 29 IS 3 BP 271 EP 274 PG 4 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 288IW UT WOS:000254980800001 PM 18364572 ER PT J AU Houghton, PJ Morton, CL Kolb, EA Gorlick, R Lock, R Carol, H Reynolds, CP Maris, JM Keir, ST Billups, CA Smith, MA AF Houghton, Peter J. Morton, Christopher L. Kolb, E. Anders Gorlick, Richard Lock, Richard Carol, Hernan Reynolds, C. Patrick Maris, John M. Keir, Stephen T. Billups, Catherine A. Smith, Malcolm A. TI Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; preclinical testing; rapamycin ID IN-VIVO; MAMMALIAN TARGET; CANCER-THERAPY; PHASE-II; MODELS; CCI-779; ANGIOGENESIS; CHEMOTHERAPY; APOPTOSIS; AUTOPHAGY AB Background. Rapamycin is a highly specific inhibitor of mTOR, a serine/threonine kinase that controls cap-dependent translation. Here we report the activity of rapamycin against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Procedures. Rapamycin was tested against the in vitro panel at concentrations from 0.01 to 100 nM and was tested against the in vivo tumor panels by i.p. administration daily x 5 for 6 consecutive weeks at a dose of 5 mg/kg. Results. Rapamycin variably inhibited growth of the cell lines in the PPTP in vitro panel, with maximal inhibition values ranging from 19% to 85% (median 49%.) and a median EC50 of 0.7 nM. Ten of 23 cell lines achieved, at least 50% growth inhibition. Against the in vivo panels, rapamycin induced significant differences in EFS distribution in 27 of 36 solid tumor xenografts and in 5 of 8 ALL xenografts. Using the time to event activity measure, rapamycin had intermediate or high activity against 14 of 31 evaluable solid tumor xenografts and 5 of 8 ALL xenografts. Objective responses were observed in several panels, including: rhabdoid tumor (I PR), rhabdomyosarcoma (2PR), and osteosarcoma (I maintained CR). Two T-cell ALL xenografts had objective responses 0 PR, I maintained CR). Conclusions. Rapamycin demonstrated broad antitumor activity against the PPTP's in Vivo tumor panels, with particularly noteworthy activity for selected sarcoma and ALL xenografts. Future work will evaluate the molecular characteristics of responding models and the activity of combinations of rapamycin with other anticancer agents. C1 [Houghton, Peter J.; Morton, Christopher L.; Billups, Catherine A.] St Jude Childrens Res Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA. [Kolb, E. Anders; Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Reynolds, C. Patrick] Univ So Calif, Inst Pediat Clin Res, USC CHLA, Dept Therapeut Program, Los Angeles, CA USA. [Reynolds, C. Patrick] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Houghton, PJ (reprint author), St Jude Childrens Res Hosp, Dept Mol Pharmacol, 332 N Lauderdale, Memphis, TN 38105 USA. EM peter.houghton@stjude.org RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013 OI Carol, Hernan/0000-0002-9443-8032; FU NCI NIH HHS [N01-CM-42216, CA108786, CA21765] NR 27 TC 99 Z9 104 U1 0 U2 2 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2008 VL 50 IS 4 BP 799 EP 805 DI 10.1002/pbc.21296 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 269PK UT WOS:000253661200015 PM 17635004 ER PT J AU Buckingham, B Xing, DY Weinzimer, S Fiallo-Scharer, R Kollman, C Mauras, N Tsalikian, E Tamborlane, W Wysocki, T Ruedy, K Beck, R AF Buckingham, Bruce Xing, Dongyuan Weinzimer, Stu Fiallo-Scharer, Rosanna Kollman, Craig Mauras, Nelly Tsalikian, Eva Tamborlane, William Wysocki, Tim Ruedy, Katrina Beck, Roy CA Diabet Res Children Network TI Use of the DirecNet Applied Treatment Algorithm (DATA) for diabetes management with a real-time continuous glucose monitor (the FreeStyle Navigator) SO PEDIATRIC DIABETES LA English DT Article ID INTENSIVE INSULIN THERAPY; BLOOD-GLUCOSE; ADJUSTMENT; MORTALITY AB Background: There are no published guidelines for use of real-time continuous glucose monitoring data by a patient; we therefore developed the DirecNet Applied Treatment Algorithm (DATA). The DATA provides algorithms for making diabetes management decisions using glucose values: (i) in real time which include the direction and rate of change of glucose levels, and (ii) retrospectively based on downloaded sensor data. Objective: To evaluate the use and effectiveness of the DATA in children with diabetes using a real-time continuous glucose sensor (the FreeStyle Navigator). Subjects: Thirty children and adolescents (mean +/- standard deviation age = 11.2 +/- 4.1 yr) receiving insulin pump therapy. Methods: Subjects were instructed on use of the DATA and were asked to download their Navigator weekly to review glucose patterns. An Algorithm Satisfaction Questionnaire was completed at 3, 7, and 13 wk. Results: At 13 wk, all of the subjects and all but one parent thought that the DATA gave good, clear directions for insulin dosing, and thought the guidelines improved their postprandial glucose levels. In responding to alarms, 86% of patients used the DATA at least 50% of the time at 3 wk, and 59% reported doing so at 13 wk. Similar results were seen in using the DATA to adjust premeal bolus doses of insulin. Conclusions: These results show the feasibility of implementing the DATA when real-time continuous glucose monitoring is initiated and support its use in future clinical trials of real-time continuous glucose monitoring. C1 [Fiallo-Scharer, Rosanna] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Denver, CO 80202 USA. [Tsalikian, Eva] Univ Iowa, Carver Coll Med, Dept Pediat, Iowa City, IA USA. [Mauras, Nelly; Wysocki, Tim] Nemours Childrens Clin, Jacksonville, FL USA. [Buckingham, Bruce] Stanford Univ, Div Pediat Endocrinol & Diabetes, Stanford, CA 94305 USA. [Tamborlane, William] Yale Univ, Sch Med, Dept Pediat, New Haven, CT USA. [Xing, Dongyuan; Kollman, Craig; Ruedy, Katrina; Beck, Roy] Jaeb Ctr Hlth Res Tampa, Tampa, FL USA. Univ Minnesota, Cent Lab, Minneapolis, MN 55455 USA. Natl Inst Hlth, Bethesda, MD USA. RP Buckingham, B (reprint author), Jaeb Ctr Hlth Res, Direc Care of DirecNet Coordinating Ctr, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM direcnet@jaeb.org NR 11 TC 15 Z9 15 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD APR PY 2008 VL 9 IS 2 BP 142 EP 147 DI 10.1111/j.1399-5448.2007.00301.x PG 6 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 290NV UT WOS:000255130400011 ER PT J AU Jansson, LM Velez, ML Choo, R Shakleya, DM Huestis, MA Harrow, C Schroeder, JR AF Jansson, Lauren M. Velez, Martha L. Choo, Robin Shakleya, Diaa M. Huestis, Marilyn A. Harrow, Cheryl Schroeder, Jennifer R. TI Methadone maintenance and breastfeeding in the neonatal period - Reply SO PEDIATRICS LA English DT Letter C1 [Jansson, Lauren M.; Velez, Martha L.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21224 USA. [Choo, Robin; Shakleya, Diaa M.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Chem & Metab Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Harrow, Cheryl] Johns Hopkins Bayview Med Ctr, Div Neonatol, Baltimore, MD 21224 USA. [Schroeder, Jennifer R.] Natl Inst Drug Abuse, Off Clin Director, Intramural Res Program, Baltimore, MD 21224 USA. RP Jansson, LM (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21224 USA. NR 1 TC 0 Z9 0 U1 2 U2 3 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 APR PY 2008 VL 121 IS 4 BP 869 EP 870 DI 10.1542/peds.2008-0340 PG 8 WC Pediatrics SC Pediatrics GA 282OJ UT WOS:000254576800038 ER PT J AU Brown, SA Mcgue, M Maggs, J Schulenberg, J Hingson, R Swartzwelder, S Martin, C Chung, T Tapert, SF Sher, K Winters, KC Lowman, C Murphy, S AF Brown, Sandra A. McGue, Matthew Maggs, Jennifer Schulenberg, John Hingson, Ralph Swartzwelder, Scott Martin, Christopher Chung, Tammy Tapert, Susan F. Sher, Kenneth Winters, Ken C. Lowman, Cherry Murphy, Stacia TI A developmental perspective on alcohol and youths 16 to 20 years of age SO PEDIATRICS LA English DT Article DE alcohol; late adolescence; development ID SUBSTANCE-USE DISORDERS; INTERMITTENT ETHANOL EXPOSURE; VISUOSPATIAL WORKING-MEMORY; BINGE DRINKING TRAJECTORIES; VARIABLE-CENTERED ANALYSES; HEALTH-RISK BEHAVIORS; SCHOOL-BASED PROGRAMS; US COLLEGE-STUDENTS; ZERO TOLERANCE LAWS; DRUG-USE AB Late adolescence (ie, 16-20 years of age) is a period characterized by escalation of drinking and alcohol use problems for many and by the onset of an alcohol use disorder for some. This heightened period of vulnerability is a joint consequence of the continuity of risk from earlier developmental stages and the unique neurologic, cognitive, and social changes that occur in late adolescence. We review the normative neurologic, cognitive, and social changes that typically occur in late adolescence, and we discuss the evidence for the impact of these transitions on individual drinking trajectories. We also describe evidence linking alcohol abuse in late adolescence with neurologic damage and social impairments, and we discuss whether these are the bases for the association of adolescent drinking with increased risks of mental health, substance abuse, and social problems in adulthood. Finally, we discuss both the challenges and successes in the treatment and prevention of adolescent drinking problems. C1 [Brown, Sandra A.] Univ Calif San Diego, Dept Psychol, San Diego, CA 92103 USA. [Hingson, Ralph; Tapert, Susan F.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [McGue, Matthew] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Winters, Ken C.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Maggs, Jennifer] Penn State Univ, Dept Human Dev & Family Studies, University Pk, PA 16802 USA. [Schulenberg, John] Univ Michigan, Inst Social Res, Ann Arbor, MI 48109 USA. [Hingson, Ralph; Lowman, Cherry] Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD USA. [Swartzwelder, Scott] Duke Univ, Dept Psychol, Durham, NC 27706 USA. [Martin, Christopher; Chung, Tammy] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. [Sher, Kenneth] Univ Missouri, Dept Psychol Studies, Columbia, MO USA. [Murphy, Stacia] Natl Council Alcoholism & Drug Abuse, St Louis, MO USA. RP Brown, SA (reprint author), Univ Calif San Diego, Dept Psychol, 9500 Gilman Dr,MC0109, La Jolla, CA 92093 USA. EM sanbrown@ucsd.edu RI Schulenberg, John/A-2212-2008; Chung, Tammy/B-9712-2017 OI Schulenberg, John/0000-0003-2129-8486; Chung, Tammy/0000-0002-1527-2792 FU NIDA NIH HHS [K02 DA015347-05, K02 DA015347, R01 DA005104, R01 DA005104-07, R01 DA012995, R01 DA012995-05] NR 169 TC 215 Z9 215 U1 21 U2 98 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 APR PY 2008 VL 121 SU S BP S290 EP S310 DI 10.1542/peds.2007-2243D PG 21 WC Pediatrics SC Pediatrics GA 282OI UT WOS:000254576700006 PM 18381495 ER PT J AU Faden, VB Goldman, MS AF Faden, Vivian B. Goldman, Mark S. TI Editors' preface SO PEDIATRICS LA English DT Editorial Material C1 [Faden, Vivian B.] Natl Inst Alcohol Abuse & Alcoholism, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. [Goldman, Mark S.] Univ S Florida, Alcohol & Subst Use Res Inst, Tampa, FL 33620 USA. RP Faden, VB (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 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 APR PY 2008 VL 121 SU S BP S233 EP S234 DI 10.1542/peds.2007-22431 PG 2 WC Pediatrics SC Pediatrics GA 282OI UT WOS:000254576700002 PM 18381491 ER PT J AU Masten, AS Faden, VB Zucker, RA Spear, LP AF Masten, Ann S. Faden, Vivian B. Zucker, Robert A. Spear, Linda P. TI Underage drinking: A developmental framework SO PEDIATRICS LA English DT Article DE development; drinking; alcohol ID CHRONIC ETHANOL EXPOSURE; FETAL ALCOHOL SYNDROME; USE DISORDERS; ADULT RATS; HIPPOCAMPAL VOLUME; DNA METHYLATION; ADOLESCENT RATS; UNITED-STATES; SUBSTANCE USE; BRAIN-DAMAGE AB A developmental framework for understanding and addressing the problem of underage alcohol consumption is presented. The first section presents the rationale for a developmental approach, including striking age-related data on patterns of onset, prevalence, and course of alcohol use and disorders in young people. The second section examines the fundamental meaning of a developmental approach to conceptualizing underage drinking. The third section delineates contemporary principles of developmental psychopathology as a guide to future research and intervention efforts. Strategic, sensitive, and effective efforts to address the problem of underage drinking will require a developmentally informed approach to research, prevention, and treatment. C1 [Masten, Ann S.] Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. [Faden, Vivian B.] Natl Inst Alcohol Abuse & Alcoholism, Div Epidemiol & Prevent Res, Bethesda, MD USA. [Zucker, Robert A.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Zucker, Robert A.] Univ Michigan, Addict Res Ctr, Ann Arbor, MI 48109 USA. [Spear, Linda P.] SUNY Binghamton, Dept Psychol, Binghamton, NY USA. RP Masten, AS (reprint author), Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. EM amasten@umn.edu RI Masten, Ann/E-7091-2011; OI Masten, Ann/0000-0003-2871-7508 NR 112 TC 113 Z9 114 U1 3 U2 16 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 APR PY 2008 VL 121 SU S BP S235 EP S251 DI 10.1542/peds.2007-2243A PG 17 WC Pediatrics SC Pediatrics GA 282OI UT WOS:000254576700003 PM 18381492 ER PT J AU Windle, M Spear, LP Fuligni, AJ Angold, A Brown, JD Pine, D Smith, GT Giedd, J Dahl, RE AF Windle, Michael Spear, Linda P. Fuligni, Andrew J. Angold, Adrian Brown, Jane D. Pine, Daniel Smith, Greg T. Giedd, Jay Dahl, Ronald E. TI Transitions into underage and problem drinking: Developmental processes and mechanisms between 10 and 15 years of age SO PEDIATRICS LA English DT Article DE alcohol; development; adolescence ID ELEMENTARY-SCHOOL-CHILDREN; EARLY ALCOHOL-USE; ADULT RATS; ADOLESCENT DRINKING; ETHANOL-CONSUMPTION; DRUG-USE; SOCIAL FACILITATION; SEXUAL-MATURATION; BRAIN-DEVELOPMENT; SUBSTANCE-ABUSE AB Numerous developmental changes occur across levels of personal organization (eg, changes related to puberty, brain and cognitive-affective structures and functions, and family and peer relationships) in the age period of 10 to 15 years. Furthermore, the onset and escalation of alcohol use commonly occur during this period. This article uses both animal and human studies to characterize these multilevel developmental changes. The timing of and variations in developmental changes are related to individual differences in alcohol use. It is proposed that this integrated developmental perspective serve as the foundation for subsequent efforts to prevent and to treat the causes, problems, and consequences of alcohol consumption. C1 [Windle, Michael] Emory Univ, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. [Spear, Linda P.] SUNY Binghamton, Dept Psychol, Binghamton, NY USA. [Fuligni, Andrew J.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Angold, Adrian] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Brown, Jane D.] Univ N Carolina, Sch Journalism & Mass Commun, Chapel Hill, NC USA. [Pine, Daniel] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Giedd, Jay] NIMH, Unit Brain Imaging Child Psychiat Branch, Bethesda, MD 20892 USA. [Smith, Greg T.] Univ Kentucky, Dept Psychol, Lexington, KY 40506 USA. [Dahl, Ronald E.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Dahl, Ronald E.] Univ Pittsburgh, Dept Pediat, Pittsburgh, PA 15260 USA. RP Windle, M (reprint author), Emory Univ, Dept Behav Sci & Hlth Educ, 1518 Clifton Rd NE,Room 520, Atlanta, GA 30322 USA. EM mwindle@sph.emory.edu RI Giedd, Jay/A-3080-2008; Price, Katie/H-1931-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS [ZIA MH002794-08]; NIAAA NIH HHS [R01 AA007861] NR 143 TC 174 Z9 174 U1 9 U2 25 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 APR PY 2008 VL 121 SU S BP S273 EP S289 DI 10.1542/peds.2007-2243C PG 17 WC Pediatrics SC Pediatrics GA 282OI UT WOS:000254576700005 PM 18381494 ER PT J AU Zucker, RA Donovan, JE Masten, AS Mattson, ME Moss, HB AF Zucker, Robert A. Donovan, John E. Masten, Ann S. Mattson, Margaret E. Moss, Howard B. TI Early developmental processes and the continuity of risk for underage drinking and problem drinking SO PEDIATRICS LA English DT Article DE aggregation of risk; susceptibility; alcoholism; early childhood risk ID PRENATAL ALCOHOL EXPOSURE; ADOLESCENT SUBSTANCE USE; ILLICIT DRUG-USE; WORKING-MEMORY CAPACITY; AGE-OF-ONSET; USE DISORDERS; YOUNG ADULTHOOD; PROBLEM BEHAVIOR; LATE CHILDHOOD; FOLLOW-UP AB Developmental pathways to underage drinking emerge before the second decade of life. Many scientists, however, as well as the general public, continue to focus on proximal influences surrounding the initiation of drinking in adolescence, such as social, behavioral, and genetic variables related to availability and ease of acquisition of the drug, social reinforcement for its use, and individual differences in drug responses. In the past 20 years, a considerable body of evidence has accumulated on the early (often much earlier than the time of the first drink) predictors and pathways of youthful alcohol use and abuse. These early developmental influences involve numerous risk, vulnerability, promotive, and protective processes. Some of these factors are not related directly to alcohol use, whereas others involve learning and expectancies about later drug use that are shaped by social experience. The salience of these factors (identifiable in early childhood) for understanding the course and development of adult alcohol and other drug use disorders is evident from the large and growing body of findings on their ability to predict adult clinical outcomes. This review summarizes the evidence on early pathways toward and away from underage drinking, with a particular focus on the risk and protective factors and the mediators and moderators of risk for underage drinking that become evident during the preschool and early school years. It is guided by a developmental perspective on the aggregation of risk and protection and examines the contributions of biological, psychological, and social processes within the context of normal development. Implications of this evidence for policy, intervention, and future research are discussed. C1 [Zucker, Robert A.] Univ Michigan, Sch Med, Addict Res Ctr, Ann Arbor, MI 48109 USA. [Zucker, Robert A.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Donovan, John E.] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Masten, Ann S.] Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. [Mattson, Margaret E.; Moss, Howard B.] Natl Inst Alcohol Abuse & Alcoholism, Treatment & Recovery Res Branch, Bethesda, MD USA. RP Zucker, RA (reprint author), Univ Michigan, Sch Med, Addict Res Ctr, Rachel Upjohn Bldg,4250 Plymouth Rd, Ann Arbor, MI 48109 USA. EM zuckerra@umich.edu RI Masten, Ann/E-7091-2011; OI Masten, Ann/0000-0003-2871-7508 FU NIAAA NIH HHS [R37 AA007065, R01 AA012342, R37 AA007065-21] NR 173 TC 124 Z9 124 U1 8 U2 29 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD APR PY 2008 VL 121 SU S BP S252 EP S272 DI 10.1542/peds.2007-2243B PG 21 WC Pediatrics SC Pediatrics GA 282OI UT WOS:000254576700004 PM 18381493 ER PT J AU Bagby, RM Sellbom, M Costa, PT Widiger, TA AF Bagby, R. Michael Sellbom, Martin Costa, Paul T., Jr. Widiger, Thomas A. TI Predicting Diagnostic and Statistical Manual of Mental Disorders-IV personality disorders with the five-factor model of personality and the personality psychopathology five SO PERSONALITY AND MENTAL HEALTH LA English DT Article AB The five-factor model of personality (FFM), derived from personality trait psychology, is increasingly used to describe personality disorders (PDs). Critics have argued, however, that the personality traits of the FFM fail to capture adequately the full range of personality psychopathology. In this investigation, the personality domains of the personality psychopathology five (PSY-5), an alternative model designed specifically to assess pathological traits, were compared to the domain traits from the FFM in the prediction of the PD symptom counts. The personality traits from both dimensional models were assessed in a sample of 138 psychiatric patients with the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and the revised NEO personality inventory (NEO PI-R), respectively. Both instruments significantly predicted all 10 PD symptoms and contributed on average an additional 10% of the variance beyond that predicted by the other instrument. Whereas the MMPI-2 PSY-5 scales were comparatively better predictors of paranoid, schizotypal, narcissistic and antisocial PD symptom counts, the NEO PI-R domain scales outperformed the MMPI-2 PSY-5 scales in the prediction of borderline, avoidant and dependent PD symptom counts. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Bagby, R. Michael] Univ Toronto, Ctr Addict & Mental Hlth, Dept Clin Res, Toronto, ON M5T 1R8, Canada. [Bagby, R. Michael] Univ Toronto, Ctr Addict & Mental Hlth, Dept Psychiat, Toronto, ON M5T 1R8, Canada. [Sellbom, Martin] Kent State Univ, Dept Psychol, Kent, OH 44242 USA. [Costa, Paul T., Jr.] NIA, Personal Stress & Coping Sect, Lab Personal & Cognit, NIH, Bethesda, MD 20892 USA. [Widiger, Thomas A.] Univ Kentucky, Dept Psychol, Lexington, KY 40506 USA. RP Bagby, RM (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, Dept Clin Res, Coll St Site,250 Coll St, Toronto, ON M5T 1R8, Canada. EM michael_bagby@camh.net RI Sellbom, Martin/I-9302-2014 NR 69 TC 27 Z9 27 U1 4 U2 14 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1932-8621 J9 PERSONAL MENT HEALTH JI Personal. Ment. Health PD APR PY 2008 VL 2 IS 2 BP 55 EP 69 DI 10.1002/pmh.33 PG 15 WC Psychiatry; Psychology, Social SC Psychiatry; Psychology GA V13UT UT WOS:000207692400001 ER PT J AU Lane, R Feldman, HH Meyer, J He, Y Ferris, SH Nordberg, A Darreh-Shori, T Soininen, H Pirttila, T Farlow, MR Sfikas, N Ballard, C Greig, NH AF Lane, Roger Feldman, Howard H. Meyer, Joanne He, Yunsheng Ferris, Steven H. Nordberg, Agneta Darreh-Shori, Taher Soininen, Hilkka Pirttila, Tuula Farlow, Martin R. Sfikas, Nikolaos Ballard, Clive Greig, Nigel H. TI Synergistic effect of apolipoprotein E epsilon 4 and butyrylcholinesterase K-variant on progression from mild cognitive impairment to Alzheimer's disease SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE apolipoprotein E; butyrylcholinesterase; mild cognitive impairment ID AMYLOID-BETA-PROTEIN; APOE EPSILON-4; RISK-FACTORS; E GENOTYPE; DEMENTIA; GENES; ASSOCIATION; ACETYLCHOLINE; RIVASTIGMINE; THERAPY AB Objective To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon 4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). Methods This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. Results Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried >= 1 APOE epsilon 4 and >= 1 BCHE-K allele. The presence of APOE epsilon 4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon 4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon 4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon 4 allele. Conclusion In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon 4 alleles. Pharmacogenetics and Genomics 18:289-298 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Lane, Roger] Novartis Pharmaceut Corp, E Hanover, NJ 07936 USA. [Feldman, Howard H.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Meyer, Joanne; He, Yunsheng] Novartis Pharmaceut Corp, Clin Pharmacogenet, Cambridge, MA USA. [Ferris, Steven H.] NYU, Sch Med, Alzheimers Dis Ctr, New York, NY USA. [Nordberg, Agneta; Darreh-Shori, Taher] Karolinska Inst, Stockholm, Sweden. [Soininen, Hilkka; Pirttila, Tuula] Univ Kuopio, Dept Neurol, Kuopio, Finland. [Soininen, Hilkka; Pirttila, Tuula] Kuopio Univ Hosp, Kuopio, Finland. [Farlow, Martin R.] Indiana Univ, Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Sfikas, Nikolaos] Novartis Pharma AG, Basel, Switzerland. [Ballard, Clive] Kings Coll London, Dept Biomed Sci, London WC2R 2LS, England. [Greig, Nigel H.] NIA, Intramural Res Program, Drug Design & Dev Sect, Baltimore, MD 21224 USA. RP Lane, R (reprint author), Novartis Pharmaceut Corp, 59 Route 10, E Hanover, NJ 07936 USA. EM roger.lane@novartis.com NR 38 TC 27 Z9 29 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD APR PY 2008 VL 18 IS 4 BP 289 EP 298 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 281KR UT WOS:000254496300002 PM 18334913 ER PT J AU Gao, ZG Jacobson, KA AF Gao, Zhan-Guo Jacobson, Kenneth A. TI Translocation of arrestin induced by human A(3) adenosine receptor ligands in an engineered cell line: Comparison with G protein-dependent pathways SO PHARMACOLOGICAL RESEARCH LA English DT Article DE purines; G protein-coupled receptors; arrestin; adenosine; agonists; antagonists ID SELECTIVE ANTAGONISTS; RHEUMATOID-ARTHRITIS; COUPLED RECEPTORS; DRUG DISCOVERY; HIGHLY POTENT; CHO-CELLS; ACTIVATION; AGONISTS; DERIVATIVES; EFFICACY AB Structurally diverse ligands were studied in A(3) adenosine receptor (AR)-mediated beta-arrestin translocation in engineered CHO cells. The agonist potency and efficacy were similar, although not identical, to their G protein signaling. However, differences have also been found. MRS542, MRS1760, and other adenosine derivatives, A(3)AR antagonists in cyclic AMP assays, were partial agonists in beta-arrestin translocation, indicating possible biased agonism. The xanthine 7-riboside DBXRM, a full agonist, was only partially efficacious in beta-arrestin translocation. DBXRM was shown to induce a lesser extent of desensitization compared with IB-MECA. In kinetic studies, MRS3558, a potent and selective A(3)AR agonist, induced beta-arrestin translocation significantly faster than IB-MECA and Cl-IB-MECA. Non-nucleoside antagonists showed similar-inhibitory potencies as previously reported. PTX pretreatment completely abolished ERK1/2 activation, but not arrestin translocation. Thus, lead candidates for biased agonists at the A(3)AR have been identified with this arrestin-translocation assay, which promises to be an effective tool for ligand screening. Published by Elsevier Ltd. C1 [Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 40 TC 21 Z9 21 U1 0 U2 1 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 APR PY 2008 VL 57 IS 4 BP 303 EP 311 DI 10.1016/j.phrs.2008.02.008 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 305TX UT WOS:000256201800008 PM 18424164 ER PT J AU Parzynski, CS Jaszyna-Gasior, M Franken, FH Moolchan, ET AF Parzynski, Craig S. Jaszyna-Gasior, Maria Franken, Frederick H. Moolchan, Eric T. TI Measuring nicotine intake among highly-dependent adolescent smokers: Comparability of saliva and plasma cotinine concentrations SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE adolescents; nicotine dependence; cotinine; bioverification ID SELF-REPORTED SMOKING; HEALTHY-VOLUNTEERS; FLOW-RATE; METABOLISM; PATCH; VALIDITY AB Cotinine is the most common biomarker used to assess nicotine exposure and abstinence. It can be measured in various matrices including saliva, plasma, and urine. Previous research with adults has shown high correlations between saliva and plasma cotinine concentrations. However, the research has not examined this relationship in adolescents. Additionally, variability in saliva flow and metabolism across gender, ethnicity, and age may impact the relationship between saliva and plasma cotinine concentration. Our aim was to examine the relationship between saliva and plasma cotinine concentration in a group of nicotine-dependent adolescent smokers. Additionally, we examined these correlations across gender, ethnicity and age. The sample consisted of 66 adolescent smokers (age 15.1 +/- 1.3, 63.6% girls, 66.7% European American, CPD 18.3 +/- 8.5, FTND 7.1 +/- 13). Saliva and plasma specimens were collected before the treatment phase of a nicotine replacement therapy trial and analyzed. The relationship between saliva and plasma cotinine concentration was analyzed using Pearson's correlation coefficients. We performed a secondary analysis using multiple regressions to compare correlations across race, gender and age. Results indicated a positive correlation between saliva cotinine and plasma cotinine concentration (r=0.84, p<0.001). Differences in correlations across age were significant (t=3.03, p<0.01). Differences across ethnicity approached significance (t=-1.93, p=0.058). Future research should seek to further validate saliva-to-plasma cotinine concentration ratios in adolescents as well as characterize saliva-to-plasma concentration differences and their underlying mechanisms. Published by Elsevier Inc. C1 [Parzynski, Craig S.; Jaszyna-Gasior, Maria; Franken, Frederick H.; Moolchan, Eric T.] Natl Inst Drug Abuse, Intramural Res Program, Teen Tobacco Addict Treatment Res Clin, DHHS NIH NIDA IRP, Baltimore, MD 21224 USA. RP Moolchan, ET (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Teen Tobacco Addict Treatment Res Clin, DHHS NIH NIDA IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov FU Intramural NIH HHS [NIH0012919683, ]; PHS HHS [NIH0012919683] NR 35 TC 6 Z9 7 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2008 VL 89 IS 2 BP 145 EP 149 DI 10.1016/j.pbb.2007.12.003 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 275LZ UT WOS:000254074500003 PM 18199474 ER PT J AU White, DA Michaels, CC Holtzman, SG AF White, David A. Michaels, Clifford C. Holtzman, Stephen G. TI Periadolescent male but not female rats have higher motor activity in response to morphine than do adult rats SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE adolescence; drug abuse; opioid; behavior; elevated plus-maze; hot plate; tail-flick; sex difference; motor activity ID SEX-DIFFERENCES; GENDER-DIFFERENCES; OPIOID ANALGESIA; ADOLESCENT RATS; NICOTINE; SENSITIVITY; SENSITIZATION; REACTIVITY; TOLERANCE; BEHAVIOR AB Little has been done to investigate the effects of opioid exposure during adolescence. First we determined behavioral differences in response to acutely administered morphine between periadolescent and adult male and female rats. Second, we determined the impact of age of morphine exposure on sensitivity to morphine-induced locomotion later in life. For the acute morphine studies, antinociceptive responses were assessed using cumulative morphine dosing (0.5-12 mg/kg) followed by a time course after the last morphine injection (<= 4 hr), and dose-response curves for motor activity (2-h test) were determined following saline and morphine (0.1-3.0 mg/kg) administration. For the long-term study, periadolescent and adult rats were given saline or 1, 3, or 5 days of morphine (5.0 mg/kg, 2x/day). Changes in locomotor activity in response to saline or morphine (0.1-3.0 mg/kg) were determined 1 month later. A number of age- and sex-related behavioral differences were observed: basal differences in behavior were assay-dependent; however, male periadolescent rats were generally more sensitive to acute morphine-induced motor stimulation, while both male and female periadolescent rats tended to be less sensitive to morphine-induced antinociception. Lastly, following morphine exposure, activity was dependent on age of treatment and treatment regimen, with the greatest effects in 5-day periadolescent-treated animals. (C) 2007 Elsevier Inc. All rights reserved. C1 [White, David A.; Michaels, Clifford C.; Holtzman, Stephen G.] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. RP White, DA (reprint author), Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences, Drug Abuse Med Discovery & Toxicol Branch, 6001 Execut Blvd,Room 4123,MSC 9551, Bethesda, MD 20892 USA. EM whitedav@nida.nih.gov FU NIDA NIH HHS [K05 DA000008, K05 DA00008, R01 DA000541-29, Z01 DA000541, R01 DA014122-04, DA14122, R01 DA000541, R01 DA014122, R37 DA000541] NR 40 TC 21 Z9 22 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2008 VL 89 IS 2 BP 188 EP 199 DI 10.1016/j.pbb.2007.12.009 PG 12 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 275LZ UT WOS:000254074500008 PM 18206219 ER PT J AU Davis, MI AF Davis, Margaret I. TI Ethanol-BDNF interactions: Still more questions than answers SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE addiction; alcoholism; fetal alcohol spectrum disorders; TrkB; neurodegeneration ID NEUROTROPHIC FACTOR BDNF; NERVE GROWTH-FACTOR; ELEMENT-BINDING PROTEIN; CEREBELLAR GRANULE NEURONS; BINGE-EATING DISORDER; RAT CENTRAL AMYGDALA; TYROSINE KINASE-B; ACTIVITY-DEPENDENT SECRETION; DEVELOPING CEREBRAL-CORTEX; APOPTOSIS-RELATED PROTEINS AB Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulation of BDNF and associated signaling pathways in anxiety, addiction and homeostasis after ethanol exposure. Anxiety and depression are precipitating factors for substance abuse and these disorders also involve region-specific changes in BDNF in both pathogenesis and response to pharmacotherapy. Polymorphisms in the genes coding for BDNF and its receptor TrkB are linked to affective, substance abuse and appetitive disorders and therefore may play a role in the development of alcoholism. This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction. Many unresolved questions about region-specific changes in BDNF expression and the precise role of BDNF in neuropsychiatric disorders and addiction remain to be elucidated. Resolution of these questions will require significant integration of the literature on addiction and comorbid psychiatric disorders that contribute to the development of alcoholism. Published by Elsevier Inc. C1 NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Davis, MI (reprint author), NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, 5625 Fishers Lane MSC 9411, Bethesda, MD 20892 USA. EM midavis@mail.nih.gov RI Davis, Margaret/F-4165-2010; OI Davis, Margaret/0000-0002-0489-8351 FU Intramural NIH HHS [Z99 AA999999] NR 279 TC 65 Z9 68 U1 2 U2 6 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 APR PY 2008 VL 118 IS 1 BP 36 EP 57 DI 10.1016/j.pharmthera.2008.01.003 PG 22 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 306IG UT WOS:000256240900003 PM 18394710 ER PT J AU Glass, RS Berry, MJ Block, E Boakye, HT Carlson, BA Gailer, J George, GN Gladyshev, VN Hatfield, DL Jacobsen, NE Johnson, S Kahakachchi, C Kaminski, R Manley, SA Mix, H Pickering, IJ Prenner, EJ Saira, K Skowronska, A Tyson, JF Uden, PC Wu, Q Xu, XM Yamdagni, R Zhang, Y AF Glass, Richard S. Berry, Marla J. Block, Eric Boakye, Harriet T. Carlson, Bradley A. Gailer, Juergen George, Graham N. Gladyshev, Vadim N. Hatfield, Dolph L. Jacobsen, Neil E. Johnson, Sherida Kahakachchi, Chethaka Kaminski, Rafal Manley, Shawn A. Mix, Heiko Pickering, Ingrid J. Prenner, Elmar J. Saira, Kazima Skowronska, Aleksandra Tyson, Julian F. Uden, Peter C. Wu, Qiao Xu, Xue-Ming Yamdagni, Raghav Zhang, Yan TI Insights into the chemical biology of selenium SO PHOSPHORUS SULFUR AND SILICON AND THE RELATED ELEMENTS LA English DT Article; Proceedings Paper CT 10th International Conference on the Chemistry of Selenium and Tellurium CY JUN 22-27, 2007 CL Lodz, POLAND ID ORGANOSELENIUM COMPOUNDS; ARSINIUM ION; SELENOCYSTEINE; SPECTROSCOPY; GLUTATHIONE; EUKARYOTES; ARSENITE; SE-77; DONOR; GENE AB The long-sought pathway by which selenocysteyl-tRNA[Ser]Sec is synthesized in eukaryotes has been revealed. Seryl-tRNA[Ser]Sec is O-phosphorylated and SecS, a pyridoxal phosphate-dependent protein, catalyzes the reaction of O-phosphoseryl-tRNA[Ser]Sec with monoselenophosphate to give selenocysteyl-tRNA[Ser]Sec. H-1-{Se-77} HMQC-TOCSY NMR spectroscopy has been developed to detect the selenium-containing amino acids present in selenized yeast after protease XIV digestion. An archived selenized yeast sample is found to contain the novel amino acid S-(methylseleno)cysteine in addition to selenomethionine. Arsenite and selenite react with GSH to form (GS)(2)AsSe-. The structure of this compound has been determined by EXAFS, Se-77 NMR and Raman spectroscopic and chromatographic studies. Its formation under biological conditions has been demonstrated. C1 [Glass, Richard S.; Jacobsen, Neil E.] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. [Berry, Marla J.] Univ Hawaii, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Block, Eric; Johnson, Sherida] SUNY Albany, Dept Chem, Albany, NY 12222 USA. [Boakye, Harriet T.; Kahakachchi, Chethaka; Tyson, Julian F.; Uden, Peter C.] Univ Massachusetts, Dept Chem, Amherst, MA 01003 USA. [Carlson, Bradley A.; Xu, Xue-Ming] NCI, Ctr Canc Res, Lab Canc Prevent, Bethesda, MD 20892 USA. [Gailer, Juergen; Manley, Shawn A.; Mix, Heiko; Wu, Qiao; Xu, Xue-Ming; Yamdagni, Raghav] Univ Calgary, Dept Chem, Calgary, AB T2N 1N4, Canada. [George, Graham N.; Pickering, Ingrid J.] Univ Saskatchewan, Dept Geol Sci, Saskatoon, SK S7N 0W0, Canada. [Gladyshev, Vadim N.; Mix, Heiko; Saira, Kazima; Zhang, Yan] Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. [Hatfield, Dolph L.; Kaminski, Rafal; Skowronska, Aleksandra] Polish Acad Sci, Ctr Mol & Macromol Studies, Lodz, Poland. [Prenner, Elmar J.] Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada. RP Glass, RS (reprint author), Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. EM rglass@arizona.edu RI Prenner, Elmar/E-5549-2011; Gladyshev, Vadim/A-9894-2013; George, Graham/E-3290-2013; Pickering, Ingrid/A-4547-2013; Block, Eric/D-3989-2014; OI Pickering, Ingrid/0000-0002-0936-2994 NR 19 TC 5 Z9 5 U1 1 U2 16 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-6507 J9 PHOSPHORUS SULFUR JI Phosphorus Sulfur Silicon Relat. Elem. PD APR PY 2008 VL 183 IS 4 BP 924 EP 930 DI 10.1080/10426500801898366 PG 7 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 294WC UT WOS:000255436000010 ER PT J AU Franck, C Ip, W Bae, A Franck, N Bogart, E Le, TT AF Franck, Carl Ip, Wui Bae, Albert Franck, Nathan Bogart, Elijah Le, Thanhbinh Thi TI Contact-mediated cell-assisted cell proliferation in a model eukaryotic single-cell organism: An explanation for the lag phase in shaken cell culture SO PHYSICAL REVIEW E LA English DT Article ID DICTYOSTELIUM AB In cell culture, when cells are inoculated into fresh media, there can be a period of slow (or lag phase) growth followed by a transition to exponential growth. This period of slow growth is usually attributed to the cells' adaptation to a new environment. However, we argue that, based on observations of shaken suspension culture of Dictyostelium discoideum, a model single-cell eukaryote, this transition is due to a density effect. Attempts to demonstrate the existence of implicit cell signaling via long-range diffusible messengers (i.e., soluble growth factors) through cell-medium separation and microfluidic flow perturbation experiments produced negative results. This, in turn, led to the development of a signaling model based on direct cell-to-cell contacts. Employing a scaling argument for the collision rate due to fluid shear, we reasonably estimate the crossover density for the transition into the exponential phase and fit the observed growth kinetics. C1 [Franck, Carl; Ip, Wui; Bae, Albert; Franck, Nathan; Bogart, Elijah; Le, Thanhbinh Thi] Cornell Univ, Atom & Solid State Phys Lab, Ithaca, NY 14853 USA. RP Franck, C (reprint author), NIMH, Behav Genet Unit, Porter Neurosci Res Ctr, Bldg 35,Room 1C-1008,35 Convent Dr, Bethesda, MD 20892 USA. NR 28 TC 3 Z9 3 U1 0 U2 5 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD APR PY 2008 VL 77 IS 4 AR 041905 DI 10.1103/PhysRevE.77.041905 PN 1 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 295ED UT WOS:000255456900086 PM 18517654 ER PT J AU Krekelberg, WP Mittal, J Ganesan, V Truskett, TM AF Krekelberg, William P. Mittal, Jeetain Ganesan, Venkat Truskett, Thomas M. TI Structural anomalies of fluids: Origins in second and higher coordination shells SO PHYSICAL REVIEW E LA English DT Article ID FUNCTIONAL-GROUP CONTRIBUTIONS; UNIVERSAL SCALING LAW; RANDOM CLOSE PACKING; MOLECULAR-DYNAMICS; ATTRACTIVE COLLOIDS; HARD-SPHERES; LIQUID WATER; FREE-ENERGY; MODEL; ENTROPY AB Compressing or cooling a fluid typically enhances its static interparticle correlations. However, there are notable exceptions. Isothermal compression can reduce the translational order of fluids that exhibit anomalous waterlike trends in their thermodynamic and transport properties, while isochoric cooling (or strengthening of attractive interactions) can have a similar effect on fluids of particles with short-range attractions. Recent simulation studies by Yan [Phys. Rev. E 76, 051201 (2007)] on the former type of system and Krekelberg [J. Chem. Phys. 127, 044502 (2007)] on the latter provide examples where such structural anomalies can be related to specific changes in second and more distant coordination shells of the radial distribution function. Here, we confirm the generality of this microscopic picture through analysis, via molecular simulation and integral equation theory, of coordination shell contributions to the two-body excess entropy for several related model fluids which incorporate different levels of molecular resolution. The results suggest that integral equation theory can be an effective and computationally inexpensive tool for assessing, based on the pair potential alone, whether new model systems are good candidates for exhibiting structural (and hence thermodynamic and transport) anomalies. C1 [Krekelberg, William P.; Ganesan, Venkat; Truskett, Thomas M.] Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA. [Mittal, Jeetain] NIDDK, NIH, Lab Chem Phys, Bethesda, MD 20892 USA. [Ganesan, Venkat; Truskett, Thomas M.] Univ Texas Austin, Inst Theoret Chem, Austin, TX 78712 USA. RP Truskett, TM (reprint author), Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA. EM krekel@che.utexas.edu; jeetain@helix.nih.gov; venkat@che.utexas.edu; truskett@che.utexas.edu RI Truskett, Thomas/D-4624-2009; Ganesan, Venkat/B-9912-2011; Truskett, Thomas/C-4996-2014 OI Truskett, Thomas/0000-0002-6607-6468; NR 81 TC 33 Z9 33 U1 0 U2 10 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 EI 1550-2376 J9 PHYS REV E JI Phys. Rev. E PD APR PY 2008 VL 77 IS 4 AR 041201 DI 10.1103/PhysRevE.77.041201 PN 1 PG 10 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 295ED UT WOS:000255456900034 PM 18517602 ER PT J AU Murphy, E Steenbergen, C AF Murphy, Elizabeth Steenbergen, Charles TI Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury SO PHYSIOLOGICAL REVIEWS LA English DT Review ID MITOCHONDRIAL PERMEABILITY TRANSITION; PROTEIN-KINASE-C; MYOCARDIAL INFARCT SIZE; CYTOSOLIC FREE CALCIUM; PERFUSED RAT-HEART; CA-2&-INDUCED MEMBRANE TRANSITION; GLYCOGEN-SYNTHASE KINASE-3-BETA; K-ATP CHANNEL; OPIOID-INDUCED CARDIOPROTECTION; HUMAN SUPEROXIDE-DISMUTASE AB Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively depleted, ion pumps cannot function resulting in a rise in calcium (Ca2+), which further accelerates ATP depletion. The rise in Ca2+ during ischemia and reperfusion leads to mitochondrial Ca2+ accumulation, particularly during reperfusion when oxygen is reintroduced. Reintroduction of oxygen allows generation of ATP; however, damage to the electron transport chain results in increased mitochondrial generation of reactive oxygen species (ROS). Mitochondrial Ca2+ overload and increased ROS can result in opening of the mitochondrial permeability transition pore, which further compromises cellular energetics. The resultant low ATP and altered ion homeostasis result in rupture of the plasma membrane and cell death. Mitochondria have long been proposed as central players in cell death, since the mitochondria are central to synthesis of both ATP and ROS and since mitochondrial and cytosolic Ca2+ overload are key components of cell death. Many cardioprotective mechanisms converge on the mitochondria to reduce cell death. Reducing Ca2+ overload and reducing ROS have both been reported to reduce ischemic injury. Preconditioning activates a number of signaling pathways that reduce Ca2+ overload and reduce activation of the mitochondrial permeability transition pore. The mitochondrial targets of cardioprotective signals are discussed in detail. C1 NHLBI, Vasc Med Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Murphy, E (reprint author), Rm 7N112,Bldg 10,10 Ctr Dr, Bethesda, MD 20814 USA. EM murphy1@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL039752] NR 294 TC 601 Z9 637 U1 15 U2 101 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 J9 PHYSIOL REV JI Physiol. Rev. PD APR PY 2008 VL 88 IS 2 BP 581 EP 609 DI 10.1152/physrev.00024.2007 PG 29 WC Physiology SC Physiology GA 325NJ UT WOS:000257595300009 PM 18391174 ER PT J AU Murphy, E Steenbergen, C AF Murphy, Elizabeth Steenbergen, Charles TI Ion transport and energetics during cell death and protection SO PHYSIOLOGY LA English DT Review ID NUCLEAR-MAGNETIC-RESONANCE; CYTOSOLIC FREE CALCIUM; PERFUSED RAT-HEART; NA+-H+ EXCHANGE; ISCHEMIA-REPERFUSION INJURY; F-19 NMR-SPECTROSCOPY; TO-BEAT OSCILLATIONS; CA2+ OVERLOAD; ISCHEMIA/REPERFUSION INJURY; MITOCHONDRIAL CALCIUM AB During ischemia, ATP and phosphocreatine (PCr) decline, whereas intracellular hydrogen ion, intracellular sodium (Na+), calcium (Ca2+), and magnesium (Mg2+) concentrations all rise. If the ischemia is relatively short and there is little irreversible injury (cell death), PCr, pH, Na+, Mg2+, and Ca2+ all recovery quickly on reperfusion. ATP recovery can take up to 24 h because of loss of adenine base from the cell and the need for de novo synthesis. There are correlative data showing that a sustained rise in Ca2+ during ischemia and/or lack of recovery during reperfusion is associated with irreversible cell injury. Interventions that reduce the rise in Ca2+ during ischemia and reperfusion have been shown to reduce cell death. Therefore, a better understanding of the mechanisms responsible for the rise in Ca2+ during ischemia and early reperfusion could have important therapeutic implications. This review will discuss mechanisms involved in alterations in ions and high energy phosphate metabolites in perfused or intact heart during ischemia and reperfusion. C1 NHLBI, Dept Hlth & Human Serv, Natl Inst Hlth, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD USA. RP Murphy, E (reprint author), NHLBI, Dept Hlth & Human Serv, Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU Intramural NIH HHS [Z99 HL999999]; NHLBI NIH HHS [R01 HL039752] NR 71 TC 50 Z9 53 U1 1 U2 11 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1548-9213 J9 PHYSIOLOGY JI Physiology PD APR PY 2008 VL 23 IS 2 BP 115 EP 123 DI 10.1152/physiol.00044.2007 PG 9 WC Physiology SC Physiology GA 312QG UT WOS:000256685300007 PM 18400694 ER PT J AU Arnheiter, H Wang, X Bharti, K Debbache, J Skuntz, S Liu, WF Bismuth, K Hallsson, JH Steingrimson, E AF Arnheiter, Heinz Wang, Xin Bharti, Kapil Debbache, Julien Skuntz, Susan Liu, Wenfang Bismuth, Keren Hallsson, Jon H. Steingrimson, Eirikur TI The role of MITF isoforms during pigment cell development SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Arnheiter, Heinz; Wang, Xin; Bharti, Kapil; Debbache, Julien; Skuntz, Susan; Liu, Wenfang] NINDS, MDS, NIH, Bethesda, MD 20892 USA. [Bismuth, Keren] INSERM, UMR S 787, Mouse Mol Genet Grp, Paris, France. [Hallsson, Jon H.; Steingrimson, Eirikur] Univ Iceland, Fac Med, Reykjavik, Iceland. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 245 EP 245 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700027 ER PT J AU Ronai, Z AF Ronai, Ze'ev TI Re-wired signal transduction pathways in melanoma - a c-Jun/ATF2 prespective SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Ronai, Ze'ev] NCI, Ctr Canc, Signal Transduct Program, Burnham Inst Med Res, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 249 EP 250 PG 2 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700044 ER PT J AU Miyamura, Y Schlenz, K Blatt, T Batzer, J Choi, W Coelho, SG Vieira, WD Namiki, T Wolber, R Hearing, VJ AF Miyamura, Yoshinori Schlenz, Kathrin Blatt, Thomas Batzer, Jan Choi, Wonseon Coelho, Sergio G. Vieira, Wilfred D. Namiki, Takeshi Wolber, Rainer Hearing, Vincent J. TI The mechanism of melanin dispersion in human skin by ultraviolet (UV) radiation SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Miyamura, Yoshinori; Choi, Wonseon; Coelho, Sergio G.; Vieira, Wilfred D.; Namiki, Takeshi; Hearing, Vincent J.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Schlenz, Kathrin; Blatt, Thomas; Batzer, Jan; Wolber, Rainer] Beiersdorf AG, R&D, Skin Res Ctr, Hamburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 256 EP 256 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700066 ER PT J AU Hwang, HY Diwakar, G Jiang, S Michalowska, AM Zaidi, MR Merlino, G Hornyak, TJ AF Hwang, Ha-Young Diwakar, Ganesh Jiang, Shunlin Michalowska, Aleksandra M. Zaidi, Muhammad R. Merlino, Glenn Hornyak, Thomas J. TI Characterization of melanocyte label-retaining cells (LRCs) by microarray analysis SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Hwang, Ha-Young; Diwakar, Ganesh; Jiang, Shunlin; Hornyak, Thomas J.] Natl Canc Inst, Ctr Canc Res, Dermatol Branch, Bethesda, MD USA. [Michalowska, Aleksandra M.; Zaidi, Muhammad R.; Merlino, Glenn] Natl Canc Inst, Ctr Canc Res, Lab Canc Biol & Genet, Bethesda, MD USA. RI Zaidi, M. Raza/H-1386-2016 OI Zaidi, M. Raza/0000-0003-0480-3188 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 259 EP 259 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700075 ER PT J AU Pavan, WJ Matera, I Watkins-Chow, D Loftus, S Silver, LHD Baxter, L Pavan, W AF Pavan, William J. Matera, Ivana Watkins-Chow, Dawn Loftus, Stacie Silver, Ling Hou Debra Baxter, Laura Pavan, William TI A sensitized mutagenesis screen identifies modifiers of Sox10 neurocristopathies SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Pavan, William J.; Matera, Ivana; Watkins-Chow, Dawn; Loftus, Stacie; Silver, Ling Hou Debra; Baxter, Laura; Pavan, William] NHGRI, NIH, Genet Dis Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 260 EP 260 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700080 ER PT J AU Choi, W Wolber, R Gerwat, W Mann, T Hearing, VJ AF Choi, Wonseon Wolber, Rainer Gerwat, Wolfram Mann, Tobias Hearing, Vincent J. TI Characterization of the influence of fibroblasts on melanocyte function and pigmentation SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Choi, Wonseon; Hearing, Vincent J.] NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. [Wolber, Rainer; Gerwat, Wolfram; Mann, Tobias] Beiersdorf AG, Dept Skin Res, Hamburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 263 EP 263 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700089 ER PT J AU Gahl, WA Westbroek, W Huizing, M Gunay-Aygun, M Helip-Wooley, A Dorward, H Vincent, L Hess, R Fischer, R White, JG AF Gahl, William A. Westbroek, Wendy Huizing, Marjan Gunay-Aygun, Meral Helip-Wooley, Amanda Dorward, Heidi Vincent, Lisa Hess, Richard Fischer, Roxanne White, James G. TI Cyclic AMP signaling as a mediator of vasculogenic mimicry in aggressive human melanoma cells SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Gahl, William A.; Westbroek, Wendy; Huizing, Marjan; Gunay-Aygun, Meral; Helip-Wooley, Amanda; Dorward, Heidi; Vincent, Lisa; Hess, Richard; Fischer, Roxanne] NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. [White, James G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. [White, James G.] Univ Minnesota, Dept Pathol, Minneapolis, MN 55455 USA. [White, James G.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 264 EP 264 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700093 ER PT J AU Noonan, FP Bahn, J Poetschke-Klug, H Anver, M Wolnicka-Glubisz, A Merlino, G De Fabo, E AF Noonan, Frances P. Bahn, Jesse Poetschke-Klug, Heather Anver, Miriam Wolnicka-Glubisz, Agnieszka Merlino, Glenn De Fabo, Edward TI Mechanisms in UV-induced melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Noonan, Frances P.; Bahn, Jesse; Poetschke-Klug, Heather; Wolnicka-Glubisz, Agnieszka; De Fabo, Edward] George Washington Univ, SPHHS, Dept Environm & Occupat Hlth, Washington, DC USA. [Anver, Miriam] NCI, SAIC, Frederick, MD 21701 USA. [Merlino, Glenn] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 267 EP 267 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700103 ER PT J AU Merlino, G Ha, L Zaidi, R Sviderskaya, E Bennett, D Meltzer, P De Fabo, E Noonan, F AF Merlino, Glenn Ha, Linan Zaidi, Raza Sviderskaya, Elena Bennett, Dot Meltzer, Paul De Fabo, Ed Noonan, Frances TI Shedding on the dim beginnings of melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Merlino, Glenn; Ha, Linan; Zaidi, Raza] NCI, NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Sviderskaya, Elena; Bennett, Dot] Univ London, Div Basic Med Sci, London SW17 0RE, England. [Meltzer, Paul] NCI, Genet Branch, Bethesda, MD 20892 USA. [De Fabo, Ed; Noonan, Frances] George Washington Univ, Med Ctr, Washington, DC 20037 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 268 EP 268 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700107 ER PT J AU Steingrimsson, E Bergsteinsdottir, K Bauer, GL Christian, P Hallsson, JH Gisladottir, BK O'Sullivan, N Swing, D Copeland, NG Jenkins, NA AF Steingrimsson, Eirikur Bergsteinsdottir, Kristin Bauer, Georg L. Christian, Praetorius Hallsson, Jon H. Gisladottir, Bryndis K. O'Sullivan, Norene Swing, Debbie Copeland, Neal G. Jenkins, Nancy A. TI Signalling to the Mitf transcription factor in mouse melanocytes SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Steingrimsson, Eirikur; Bergsteinsdottir, Kristin; Bauer, Georg L.; Christian, Praetorius; Hallsson, Jon H.; Gisladottir, Bryndis K.] Univ Iceland, Fac Med, Reykjavik, Iceland. [O'Sullivan, Norene; Swing, Debbie] NCI, Frederick, MD 21702 USA. [Copeland, Neal G.; Jenkins, Nancy A.] Inst Mol & Cell Biol, Singapore 138673, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 269 EP 269 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700109 ER PT J AU Bismuth, KH Skuntz, S Hallsson, JH Steingrimsson, E Arnheiter, H AF Bismuth, Keren H. Skuntz, Susan Hallsson, Jon H. Steingrimsson, Eirikur Arnheiter, Heinz TI MITF and cell proliferation: the role of exon2B SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Bismuth, Keren H.; Skuntz, Susan; Arnheiter, Heinz] NINDS, NIH, Mammalian Dev Sect, Bethesda, MD 20892 USA. [Hallsson, Jon H.; Steingrimsson, Eirikur] Univ Iceland, Fac Med, Reykjavik, Iceland. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 270 EP 270 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700112 ER PT J AU Yamaguchi, Y Coelho, SG Zmudzka, BZ Takahashi, K Morita, A Beer, JZ Miller, SA Hearing, VJ AF Yamaguchi, Yuji Coelho, Sergio G. Zmudzka, Barbara Z. Takahashi, Kaoruko Morita, Akimichi Beer, Janusz Z. Miller, Sharon A. Hearing, Vincent J. TI Cyclobutane pyrimidine dimer formation and p53 production in human skin after repeated UV exposures SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Yamaguchi, Yuji; Morita, Akimichi] Nagoya City Univ, Grad Sch Med Sci, Dept Geriatr & Environm Dermatol, Nagoya, Aichi, Japan. [Coelho, Sergio G.; Takahashi, Kaoruko; Hearing, Vincent J.] NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. [Zmudzka, Barbara Z.; Beer, Janusz Z.; Miller, Sharon A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RI Yamaguchi, Yuji/B-9312-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 270 EP 271 PG 2 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700115 ER PT J AU Landi, MT AF Landi, Maria Teresa TI Role of heredity, the environment and somatic changes in melanoma etiology SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Landi, Maria Teresa] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 278 EP 278 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700142 ER PT J AU Namiki, T Valencia, JC Hearing, VJ AF Namiki, Takeshi Valencia, Julio C. Hearing, Vincent J. TI Characterization of the localization and function of MATP in melanocytes SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Namiki, Takeshi; Valencia, Julio C.; Hearing, Vincent J.] NCI, Natl Inst Hlth, Cell Biol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 302 EP 303 PG 2 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700223 ER PT J AU Hoashi, T Muller, J Tamaki, K Ohara, K Hearing, VJ AF Hoashi, Toshihiko Muller, Jacqueline Tamaki, Kunihiko Ohara, Kuniaki Hearing, Vincent J. TI The internal repeat domain of the melanosomal matrix protein PMEL17/GP100 is required for fibrillogenesis but not for intracellular trafficking SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Hoashi, Toshihiko; Tamaki, Kunihiko] Univ Tokyo, Fac Med, Dept Dermatol, Tokyo 113, Japan. [Hearing, Vincent J.] NCI, Natl Inst Hlth, Cell Biol Lab, Bethesda, MD 20892 USA. [Ohara, Kuniaki] Toranomon Gen Hosp, Dept Dermatol, Tokyo 1058470, Japan. [Muller, Jacqueline] US FDA, Div Viral Prod, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 303 EP 303 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700225 ER PT J AU Hou, L Watkins-Chow, D Rturo, I Rivas, C Pavan, WJ AF Hou, Ling Watkins-Chow, Dawn Rturo, Incao Rivas, Cecllia Pavan, William J. TI Identification of a novel modifier of Sox10 in melanocyte development SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Watkins-Chow, Dawn; Rturo, Incao; Rivas, Cecllia; Pavan, William J.] NHGRI, NIH, Genet Dis Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 309 EP 309 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700245 ER PT J AU Camilli, TC O'Connell, MP French, AA Taub, DD Indig, FE Franck, B Weeraratna, AT AF Camilli, Tura C. O'Connell, Michael P. French, Amanda A. Taub, Dennis D. Indig, Fred E. Franck, Brittany Weeraratna, Ashani T. TI P21waf1/Cip1 and Wnt5a cooperate to increase invasive phenotype in melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Camilli, Tura C.; O'Connell, Michael P.; French, Amanda A.; Taub, Dennis D.; Indig, Fred E.; Franck, Brittany; Weeraratna, Ashani T.] NIH, NIA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 315 EP 315 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700266 ER PT J AU Le Pape, E Wakamatsu, K Giubellino, A Valencia, JC Passeron, T Ito, S Wolber, R Hearing, VJ AF Le Pape, Elodie Wakamatsu, Kazumasa Giubellino, Alessio Valencia, Julio C. Passeron, Thierry Ito, Shosuke Wolber, Rainer Hearing, Vincent J. TI Regulation of melanocyte fate by an agonist inverse of MC1R, agouti protein SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Le Pape, Elodie; Valencia, Julio C.; Passeron, Thierry; Hearing, Vincent J.] NIH, NCI, Bethesda, MD 20892 USA. [Wakamatsu, Kazumasa; Ito, Shosuke] Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Aichi, Japan. [Giubellino, Alessio] NIH, UOB, NCI, Bethesda, MD 20892 USA. [Wolber, Rainer] Beiersdorf AG, Dept Skin Res, Hamburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 316 EP 316 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700268 ER PT J AU Coelho, SG Zhao, Y Bushar, HF Miller, SA Zmudzka, BZ Hearing, VJ Beer, JZ AF Coelho, Sergio G. Zhao, YanChun Bushar, Harry F. Miller, Sharon A. Zmudzka, Barbara Z. Hearing, Vincent J. Beer, Janusz Z. TI Insights into UV-induced long-lasting pigmentation in human skin SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Meeting Abstract C1 [Coelho, Sergio G.; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, YanChun; Bushar, Harry F.; Miller, Sharon A.; Zmudzka, Barbara Z.; Beer, Janusz Z.] Food & Drug Adm, Ctr Devices & Radiol Hlth, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2008 VL 21 IS 2 BP 322 EP 322 PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 289NR UT WOS:000255061700289 ER PT J AU Wilkinson, KA Gorelick, RJ Vasa, SM Guex, N Rein, A Mathews, DH Giddings, MC Weeks, KM AF Wilkinson, Kevin A. Gorelick, Robert J. Vasa, Suzy M. Guex, Nicolas Rein, Alan Mathews, David H. Giddings, Morgan C. Weeks, Kevin M. TI High-throughput SHAPE analysis reveals structures in HIV-1 genomic RNA strongly conserved across distinct biological states SO PLOS BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SELECTIVE 2'-HYDROXYL ACYLATION; SINGLE NUCLEOTIDE RESOLUTION; ACID-CHAPERONE ACTIVITY; PRIMER EXTENSION SHAPE; IN-VITRO EVIDENCE; NUCLEOCAPSID PROTEIN; SECONDARY STRUCTURE; REVERSE TRANSCRIPTION; PACKAGING SIGNAL AB Replication and pathogenesis of the human immunodeficiency virus (HIV) is tightly linked to the structure of its RNA genome, but genome structure in infectious virions is poorly understood. We invent high-throughput SHAPE ( selective 29-hydroxyl acylation analyzed by primer extension) technology, which uses many of the same tools as DNA sequencing, to quantify RNA backbone flexibility at single-nucleotide resolution and from which robust structural information can be immediately derived. We analyze the structure of HIV-1 genomic RNA in four biologically instructive states, including the authentic viral genome inside native particles. Remarkably, given the large number of plausible local structures, the first 10% of the HIV-1 genome exists in a single, predominant conformation in all four states. We also discover that noncoding regions functioning in a regulatory role have significantly lower ( p-value, 0.0001) SHAPE reactivities, and hence more structure, than do viral coding regions that function as the template for protein synthesis. By directly monitoring protein binding inside virions, we identify the RNA recognition motif for the viral nucleocapsid protein. Seven structurally homologous binding sites occur in a well-defined domain in the genome, consistent with a role in directing specific packaging of genomic RNA into nascent virions. In addition, we identify two distinct motifs that are targets for the duplex destabilizing activity of this same protein. The nucleocapsid protein destabilizes local HIV-1 RNA structure in ways likely to facilitate initial movement both of the retroviral reverse transcriptase from its tRNA primer and of the ribosome in coding regions. Each of the three nucleocapsid interaction motifs falls in a specific genome domain, indicating that local protein interactions can be organized by the long-range architecture of an RNA. High-throughput SHAPE reveals a comprehensive view of HIV-1 RNA genome structure, and further application of this technology will make possible newly informative analysis of any RNA in a cellular transcriptome. C1 [Wilkinson, Kevin A.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27515 USA. [Gorelick, Robert J.] Natl Canc Inst Fredrick, SAIC Frederick, AIDS Vaccine Program, Frederick, MD USA. [Vasa, Suzy M.; Giddings, Morgan C.] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC USA. [Guex, Nicolas] Swiss Inst Bioinformat, Lausanne, Switzerland. [Rein, Alan] Natl Canc Inst Fredrick, HIV Drug Resistance Program, Frederick, MD USA. [Mathews, David H.] Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. [Giddings, Morgan C.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Giddings, Morgan C.] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC USA. RP Weeks, KM (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27515 USA. EM weeks@unc.edu OI Wilkinson, Kevin/0000-0002-4560-0718 FU Intramural NIH HHS [Z01 BC010511-05, Z01 BC010512-05]; NCI NIH HHS [N01CO12400, N01-CO-12400]; NIAID NIH HHS [AI068462, P30 AI050410, P30 AI50410, R01 AI068462, R01 AI068462-01, R01 AI068462-03, R01 AI068462-03S1]; NIGMS NIH HHS [GM076485, R01 GM076485] NR 65 TC 48 Z9 48 U1 0 U2 8 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 APR PY 2008 VL 6 IS 4 BP 883 EP 899 DI 10.1371/journal.pbio.0060096 PG 17 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 293XL UT WOS:000255368600023 PM 18447581 ER PT J AU Finelli, LA Haney, S Bazhenov, M Stopfer, M Sejnowski, TJ AF Finelli, Luca A. Haney, Seth Bazhenov, Maxim Stopfer, Mark Sejnowski, Terrence J. TI Synaptic learning rules and sparse coding in a model sensory system SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID LOCUST ANTENNAL LOBE; OSCILLATING NEURAL ASSEMBLIES; LONG-TERM POTENTIATION; CAT VISUAL-CORTEX; MUSHROOM BODY; NETWORK OSCILLATIONS; OLFACTORY SYSTEM; ODOR REPRESENTATIONS; INSECT BRAIN; PLASTICITY AB Neural circuits exploit numerous strategies for encoding information. Although the functional significance of individual coding mechanisms has been investigated, ways in which multiple mechanisms interact and integrate are not well understood. The locust olfactory system, in which dense, transiently synchronized spike trains across ensembles of antenna lobe (AL) neurons are transformed into a sparse representation in the mushroom body (MB; a region associated with memory), provides a well-studied preparation for investigating the interaction of multiple coding mechanisms. Recordings made in vivo from the insect MB demonstrated highly specific responses to odors in Kenyon cells (KCs). Typically, only a few KCs from the recorded population of neurons responded reliably when a specific odor was presented. Different odors induced responses in different KCs. Here, we explored with a biologically plausible model the possibility that a form of plasticity may control and tune synaptic weights of inputs to the mushroom body to ensure the specificity of KCs' responses to familiar or meaningful odors. We found that plasticity at the synapses between the AL and the MB efficiently regulated the delicate tuning necessary to selectively filter the intense AL oscillatory output and condense it to a sparse representation in the MB. Activity-dependent plasticity drove the observed specificity, reliability, and expected persistence of odor representations, suggesting a role for plasticity in information processing and making a testable prediction about synaptic plasticity at AL-MB synapses. C1 [Finelli, Luca A.; Haney, Seth; Bazhenov, Maxim; Sejnowski, Terrence J.] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA. [Finelli, Luca A.; Haney, Seth; Bazhenov, Maxim; Sejnowski, Terrence J.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Stopfer, Mark] NICHD, Natl Inst Hlth, Bethesda, MD USA. [Sejnowski, Terrence J.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. RP Finelli, LA (reprint author), Salk Inst Biol Studies, Computat Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM lfinelli@salk.edu FU Intramural NIH HHS; NIDCD NIH HHS [R01 DC006306, R01 DC006306-01A1] NR 68 TC 31 Z9 31 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2008 VL 4 IS 4 AR e1000062 DI 10.1371/journal.pcbi.1000062 PG 18 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 294MY UT WOS:000255411400011 PM 18421373 ER PT J AU Turjanski, AG Gutkind, JS Best, RB Hummer, G AF Turjanski, Adrian Gustavo Gutkind, J. Silvio Best, Robert B. Hummer, Gerhard TI Binding-induced folding of a natively unstructured transcription factor SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; ACTIVATOR-COACTIVATOR COMPLEX; PROTEIN-PROTEIN ASSOCIATION; KIX DOMAIN; MOLECULAR-DYNAMICS; TRANSITION-STATE; STRUCTURAL BASIS; TRANSACTIVATION DOMAIN; CYCLIC-AMP; NONNATIVE INTERACTIONS AB Transcription factors are central components of the intracellular regulatory networks that control gene expression. An increasingly recognized phenomenon among human transcription factors is the formation of structure upon target binding. Here, we study the folding and binding of the pKID domain of CREB to the KIX domain of the co-activator CBP. Our simulations of a topology-based Go-type model predict a coupled folding and binding mechanism, and the existence of partially bound intermediates. From transition-path and Phi-value analyses, we find that the binding transition state resembles the unstructured state in solution, implying that CREB becomes structured only after committing to binding. A change of structure following binding is reminiscent of an induced-fit mechanism and contrasts with models in which binding occurs to pre-structured conformations that exist in the unbound state at equilibrium. Interestingly, increasing the amount of structure in the unbound pKID reduces the rate of binding, suggesting a "fly-casting''-like process. We find that the inclusion of attractive non-native interactions results in the formation of non-specific encounter complexes that enhance the on-rate of binding, but do not significantly change the binding mechanism. Our study helps explain how being unstructured can confer an advantage in protein target recognition. The simulations are in general agreement with the results of a recently reported nuclear magnetic resonance study, and aid in the interpretation of the experimental binding kinetics. C1 [Turjanski, Adrian Gustavo; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Natl Inst Hlth, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Best, Robert B.; Hummer, Gerhard] NIDDK, Natl Inst Hlth, Chem Phys Lab, Bethesda, MD USA. RP Turjanski, AG (reprint author), Natl Inst Dent & Craniofacial Res, Natl Inst Hlth, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 FU Intramural NIH HHS NR 71 TC 130 Z9 131 U1 3 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2008 VL 4 IS 4 AR e1000060 DI 10.1371/journal.pcbi.1000060 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 294MY UT WOS:000255411400017 PM 18404207 ER PT J AU Chang, WI Lin, ZS Kulessa, H Hebert, J Hogan, BLM Wu, DK AF Chang, Weise Lin, Zhengshi Kulessa, Holger Hebert, Jean Hogan, Brigid L. M. Wu, Doris K. TI Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements SO PLOS GENETICS LA English DT Article ID INNER-EAR DEVELOPMENT; BONE MORPHOGENETIC PROTEIN-4; SENSORY ORGAN GENERATION; PROSENSORY PATCHES; TOOTH DEVELOPMENT; HOMEOBOX GENES; HAIR-CELLS; EXPRESSION; CHICKEN; MOUSE AB Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-beta), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 ( Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification. C1 [Chang, Weise; Lin, Zhengshi; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD USA. [Hebert, Jean] Albert Einstein Coll Med, Dept Neurosci, New York, NY USA. [Hebert, Jean] Albert Einstein Coll Med, Dept Mol Genet, New York, NY USA. [Hogan, Brigid L. M.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Chang, WI (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD USA. EM wud@nidcd.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL71303, R01 HL071303, R37 HL071303] NR 69 TC 73 Z9 74 U1 4 U2 20 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 APR PY 2008 VL 4 IS 4 AR e1000050 DI 10.1371/journal.pgen.1000050 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 294LL UT WOS:000255407400014 PM 18404215 ER PT J AU Garcia-Closas, M Hall, P Nevanlinna, H Pooley, K Morrison, J Richesson, DA Bojesen, SE Nordestgaard, BG Axelsson, CK Arias, JI Milne, RL Ribas, G Gonzalez-Neira, A Benitez, J Zamora, P Brauch, H Justenhoven, C Hamann, U Ko, YD Bruening, T Haas, S Dork, T Schurmann, P Hillemanns, P Bogdanova, N Bremer, M Karstens, JH Fagerholm, R Aaltonen, K Aittomaki, K Von Smitten, K Blomqvist, C Mannermaa, A Uusitupa, M Eskelinen, M Tengstrom, M Kosma, VM Kataja, V Chenevix-Trench, G Spurdle, AB Beesley, J Chen, X Devilee, P Van Asperen, CJ Jacobi, CE Tollenaar, RAEM Huijts, PEA Klijn, JGM Chang-Claude, J Kropp, S Slanger, T Flesch-Janys, D Mutschelknauss, E Salazar, R Wang-Gohrke, S Couch, F Goode, EL Olson, JE Vachon, C Fredericksen, ZS Giles, GG Baglietto, L Severi, G Hopper, JL English, DR Southey, MC Haiman, CA Henderson, BE Kolonel, LN Le Marchand, L Stram, DO Hunter, DJ Hankinson, SE Cox, DG Tamimi, R Kraft, P Sherman, ME Chanock, SJ Lissowska, J Brinton, LA Peplonska, B Klijn, JGM Hooning, MJ Meijers-Heijboer, H Collee, JM Van den Ouweland, A Uitterlinden, AG Liu, J Lin, LY Yuqing, L Humphreys, K Czene, K Cox, A Balasubramanian, SP Cross, SS Reed, MWR Blows, F Driver, K Dunning, A Tyrer, J Ponder, BAJ Sangrajrang, S Brennan, P Mckay, J Odefrey, F Gabrieau, V Sigurdson, A Doody, M Struewing, JP Alexander, B Easton, DF Pharoah, PD AF Garcia-Closas, Montserrat Hall, Per Nevanlinna, Heli Pooley, Karen Morrison, Jonathan Richesson, Douglas A. Bojesen, Stig E. Nordestgaard, Borge G. Axelsson, Christen K. Arias, Jose I. Milne, Roger L. Ribas, Gloria Gonzalez-Neira, Anna Benitez, Javier Zamora, Pilar Brauch, Hiltrud Justenhoven, Christina Hamann, Ute Ko, Yon-Dschun Bruening, Thomas Haas, Susanne Doerk, Thilo Schuermann, Peter Hillemanns, Peter Bogdanova, Natalia Bremer, Michael Karstens, Johann Hinrich Fagerholm, Rainer Aaltonen, Kirsimari Aittomaki, Kristiina Von Smitten, Karl Blomqvist, Carl Mannermaa, Arto Uusitupa, Matti Eskelinen, Matti Tengstrom, Maria Kosma, Veli-Matti Kataja, Vesa Chenevix-Trench, Georgia Spurdle, Amanda B. Beesley, Jonathan Chen, Xiaoqing Devilee, Peter Van Asperen, Christi J. Jacobi, Catharina E. Tollenaar, Rob A. E. M. Huijts, Petra E. A. Klijn, Jan G. M. Chang-Claude, Jenny Kropp, Silke Slanger, Tracy Flesch-Janys, Dieter Mutschelknauss, Elke Salazar, Ramona Wang-Gohrke, Shan Couch, Fergus Goode, Ellen L. Olson, Janet E. Vachon, Celine Fredericksen, Zachary S. Giles, Graham G. Baglietto, Laura Severi, Gianluca Hopper, John L. English, Dallas R. Southey, Melissa C. Haiman, Christopher A. Henderson, Brian E. Kolonel, Laurence N. Le Marchand, Loic Stram, Daniel O. Hunter, David J. Hankinson, Susan E. Cox, David G. Tamimi, Rulla Kraft, Peter Sherman, Mark E. Chanock, Stephen J. Lissowska, Jolanta Brinton, Louise A. Peplonska, Beata Klijn, Jan G. M. Hooning, Maartje J. Meijers-Heijboer, Han Collee, J. Margriet Van den Ouweland, Ans Uitterlinden, Andre G. Liu, Jianjun Lin, Low Yen Yuqing, Li Humphreys, Keith Czene, Kamila Cox, Angela Balasubramanian, Sabapathy P. Cross, Simon S. Reed, Malcolm W. R. Blows, Fiona Driver, Kristy Dunning, Alison Tyrer, Jonathan Ponder, Bruce A. J. Sangrajrang, Suleeporn Brennan, Paul Mckay, James Odefrey, Fabrice Gabrieau, Valerie Sigurdson, Alice Doody, Michele Struewing, Jeffrey P. Alexander, Bruce Easton, Douglas F. Pharoah, Paul D. CA Australian Ovarian Kathleen Cuningham Fdn Consortium TI Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; KERATINOCYTE GROWTH-FACTOR; COLORECTAL-CANCER; PROSTATE-CANCER; EXPRESSION; RECEPTOR; RISK; FGFR2; APOPTOSIS; PATTERNS AB A three-stage genome-wide association study recently identified single nucleotide polymorphisms ( SNPs) in five loci ( fibroblast growth receptor 2 ( FGFR2), trinucleotide repeat containing 9 ( TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte- specific protein 1 ( LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER- positive ( per- allele OR ( 95%CI) = 1.31 (1.27-1.36)) than ER- negative (1.08 (1.03- 1.14)) disease ( P for heterogeneity = 10-(13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER- positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs ( rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER- negative disease, the strongest association being for rs3803662 in TNRC9 ( 1.14 ( 1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis ( per- allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER- positive and ER- negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment. C1 [Garcia-Closas, Montserrat; Collee, J. Margriet] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynaecol, Helsinki, Finland. [Pooley, Karen; Morrison, Jonathan] Univ Cambridge, Dept Oncol, Cambridge, England. [Bojesen, Stig E.] Univ Copenhagen, Dept Clin Biochem, Herlev & Bispebjerg Univ Hosp, DK-1168 Copenhagen, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Dept Bispebjerg Univ Hosp, DK-1168 Copenhagen, Denmark. [Axelsson, Christen K.] Univ Copenhagen, Herlev Univ Hosp, Dept Breast Surg, DK-1168 Copenhagen, Denmark. [Arias, Jose I.; Milne, Roger L.; Ribas, Gloria; Gonzalez-Neira, Anna; Benitez, Javier] Spanish Natl Canc Ctr, Madrid, Spain. [Arias, Jose I.] Montel Naraco Hosp, Oviedo, Spain. [Zamora, Pilar] Hosp La Paz, Madrid, Spain. [Brauch, Hiltrud; Justenhoven, Christina] Stuttgart & Univ Tubingen, Dr Margarete Fischer Bosch Inst Clin Pharmacol, Tubingen, Germany. [Hamann, Ute] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. [Ko, Yon-Dschun] Evangel Klin Bonn gGmhH Johanniter Krankenhaus, Bonn, Germany. [Bruening, Thomas] Ruhr Univ Bochum, Berufgenossenschaft Forsch Inst Arbeits Med, Bochum, Germany. [Haas, Susanne] Univ Bonn, Inst Pathol, D-5300 Bonn, Germany. [Doerk, Thilo; Schuermann, Peter; Hillemanns, Peter; Bogdanova, Natalia] Hannover Med Sch, Dept Gynecol & Obstet, D-3000 Hannover, Germany. [Bogdanova, Natalia; Bremer, Michael; Karstens, Johann Hinrich] Hannover Med Sch, Dept Radiat Oncol, D-3000 Hannover, Germany. [Aaltonen, Kirsimari] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Von Smitten, Karl] Univ Helsinki, Cent Hosp, Dept Surg, Helsinki, Finland. [Mannermaa, Arto] Univ Kuopio, Bioctr Kuopio, Inst Clin Med Pathol & Forens Med, FIN-70211 Kuopio, Finland. [Mannermaa, Arto] Kuopio Univ Hosp, Dept Pathol, SF-70210 Kuopio, Finland. [Uusitupa, Matti] Univ Kuopio, Bioctr Kuopio, Dept Publ Hlth & Clin Nutr, FIN-70211 Kuopio, Finland. [Eskelinen, Matti] Kuopio Univ Hosp, Dept Surg, SF-70210 Kuopio, Finland. [Tengstrom, Maria; Kataja, Vesa] Kuopio Univ Hosp, Dept Oncol, SF-70210 Kuopio, Finland. [Kataja, Vesa] Vaasa Cent Hosp, Dept Oncol, Vaasa, Finland. [Chenevix-Trench, Georgia; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Australian Ovarian] Royal Brisbane Hosp, Queensland Inst Med Res Post Off, Herston, Qld, Australia. [Kathleen Cuningham Fdn Consortium] Peter MacCallum Canc Inst, Melbourne, Vic, Australia. Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Jacobi, Catharina E.] Leiden Univ, Med Ctr, Dept Med Decis Making, Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg, Leiden, Netherlands. [Huijts, Petra E. A.; Klijn, Jan G. M.] Erasmus MC Daniel Hoed Canc Ctr, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Chang-Claude, Jenny; Kropp, Silke; Slanger, Tracy] German Canc Res Ctr, Div Canc Epidemol, D-6900 Heidelberg, Germany. [Flesch-Janys, Dieter; Mutschelknauss, Elke] Univ Clin Hamburg Eppendorf, Inst Med Biomet & Epidemol, Hamburg, Germany. [Salazar, Ramona] Bioglobe GmbH, Hamburg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Mol Biol Lab, Ulm, Germany. [Couch, Fergus; Goode, Ellen L.; Olson, Janet E.; Vachon, Celine; Fredericksen, Zachary S.] Mayo Clin, Coll Med, Rochester, MN USA. [Giles, Graham G.; Baglietto, Laura; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Hopper, John L.; English, Dallas R.] Univ Melbourne, Ctr MEGA Epidemol, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96822 USA. [Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Hunter, David J.; Hankinson, Susan E.; Cox, David G.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Hunter, David J.; Hankinson, Susan E.; Cox, David G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Cox, David G.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemol, Boston, MA 02115 USA. [Chanock, Stephen J.] Natl Canc Inst, Adv Technol Ctr, Gaithersburg, MD USA. [Lissowska, Jolanta] Ctr Canc, Dept Canc Epidemol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Peplonska, Beata] Nofer Inst Occupat Med, Lodz, Poland. [Klijn, Jan G. M.] Dr Daniel Den Hoed Canc Ctr, Erasmus Med Ctr, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands. [Meijers-Heijboer, Han; Collee, J. Margriet; Van den Ouweland, Ans] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Liu, Jianjun; Lin, Low Yen; Yuqing, Li] Genome Inst Singapore, Singapore, Singapore. [Cox, Angela] Univ Sheffield, Sch Med, Inst Canc Studies, Sheffield, S Yorkshire, England. [Balasubramanian, Sabapathy P.] Univ Sheffield, Sch Med, Acad Unit Surg Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Sch Med, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Ponder, Bruce A. J.] Canc Res UK, Cambridge Res Inst, Cambridge, England. [Sangrajrang, Suleeporn] Natl Canc Inst, Mol Epidemol Unit, Bangkok, Thailand. [Brennan, Paul; Mckay, James; Odefrey, Fabrice] Int Agcy Res Canc, F-69372 Lyon, France. [Struewing, Jeffrey P.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Alexander, Bruce] Univ Minnesota, Minneapolis, MN USA. RP Garcia-Closas, M (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. RI Peplonska, Beata/F-6004-2010; Cox, David/A-2023-2009; Spurdle, Amanda/A-4978-2011; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Struewing, Jeffery/I-7502-2013; Dork, Thilo/J-8620-2012; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; OI Cox, David/0000-0002-2152-9259; Spurdle, Amanda/0000-0003-1337-7897; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Struewing, Jeffery/0000-0002-4848-3334; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188 FU Cancer Research UK [, 10118, 10119, 10124, 11021]; Intramural NIH HHS; NCI NIH HHS [P50 CA116201, R01 CA122340] NR 30 TC 244 Z9 256 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD APR PY 2008 VL 4 IS 4 AR e1000054 DI 10.1371/journal.pgen.1000054 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 294LL UT WOS:000255407400004 PM 18437204 ER PT J AU Jin, YH Dunlap, PE McBride, SJ Al-Refai, H Bushel, PR Freedman, JH AF Jin, Yong Hwan Dunlap, Paul E. McBride, Sandra J. Al-Refai, Hanan Bushel, Pierre R. Freedman, Jonathan H. TI Global transcriptome and deletome profiles of yeast exposed to transition metals SO PLOS GENETICS LA English DT Article ID ACTIVATED PROTEIN-KINASES; RAS/CYCLIC AMP PATHWAY; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; ENVIRONMENTAL-CHANGES; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; DELETION STRAINS; DNA MICROARRAY; RIBOSOMAL-RNA AB A variety of pathologies are associated with exposure to supraphysiological concentrations of essential metals and to nonessential metals and metalloids. The molecular mechanisms linking metal exposure to human pathologies have not been clearly defined. To address these gaps in our understanding of the molecular biology of transition metals, the genomic effects of exposure to Group IB ( copper, silver), IIB ( zinc, cadmium, mercury), VIA ( chromium), and VB ( arsenic) elements on the yeast Saccharomyces cerevisiae were examined. Two comprehensive sets of metal-responsive genomic profiles were generated following exposure to equi-toxic concentrations of metal: one that provides information on the transcriptional changes associated with metal exposure (transcriptome), and a second that provides information on the relationship between the expression of similar to 4,700 non-essential genes and sensitivity to metal exposure (deletome). Approximately 22% of the genome was affected by exposure to at least one metal. Principal component and cluster analyses suggest that the chemical properties of the metal are major determinants in defining the expression profile. Furthermore, cells may have developed common or convergent regulatory mechanisms to accommodate metal exposure. The transcriptome and deletome had 22 genes in common, however, comparison between Gene Ontology biological processes for the two gene sets revealed that metal stress adaptation and detoxification categories were commonly enriched. Analysis of the transcriptome and deletome identified several evolutionarily conserved, signal transduction pathways that may be involved in regulating the responses to metal exposure. In this study, we identified genes and cognate signaling pathways that respond to exposure to essential and non-essential metals. In addition, genes that are essential for survival in the presence of these metals were identified. This information will contribute to our understanding of the molecular mechanism by which organisms respond to metal stress, and could lead to an understanding of the connection between environmental stress and signal transduction pathways. C1 [Jin, Yong Hwan; McBride, Sandra J.; Al-Refai, Hanan] Duke Univ, Nicholas Sch Environm & Earth Sci, Durham, NC 27706 USA. [Dunlap, Paul E.; Freedman, Jonathan H.] Natl Inst Environm Hlth Sci, Mol Toxicol Lab, NIH, Res Triangle Pk, NC USA. [Bushel, Pierre R.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Res Triangle Pk, NC USA. RP Jin, YH (reprint author), Duke Univ, Nicholas Sch Environm & Earth Sci, Durham, NC 27706 USA. EM freedma1@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [R01 ES009949, R01ES009949, U19 ES011375, U19ES011375] NR 81 TC 71 Z9 73 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD APR PY 2008 VL 4 IS 4 AR e1000053 DI 10.1371/journal.pgen.1000053 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 294LL UT WOS:000255407400003 PM 18437200 ER PT J AU Shattock, RJ Haynes, BF Pulendran, B Flores, J Esparza, J AF Shattock, Robin J. Haynes, Barton F. Pulendran, Bali Flores, Jorge Esparza, Jose CA Global HIV Vaccine Enterprise TI Improving defences at the portal of HIV entry: mucosal and innate immunity - A summary report from a global HIV vaccine enterprise working group SO PLOS MEDICINE LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; DENDRITIC CELLS; ANTIBODY-RESPONSES; HUMORAL IMMUNITY; IN-VIVO; INFECTION; RECEPTOR; TRANSMISSION; EXPRESSION C1 [Shattock, Robin J.] Univ London, London, England. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Durham, NC USA. [Pulendran, Bali] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Pulendran, Bali] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. [Flores, Jorge] NIH, Div AIDS, Bethesda, MD 20892 USA. [Esparza, Jose] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Shattock, RJ (reprint author), Univ London, London, England. EM Shattock@sgul.ac.uk NR 49 TC 47 Z9 47 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD APR PY 2008 VL 5 IS 4 BP 537 EP 541 AR e81 DI 10.1371/journal.pmed.0050081 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 293XX UT WOS:000255369800007 PM 18384232 ER PT J AU Rosas, IO Richards, TJ Konishi, K Zhang, Y Gibson, K Lokshin, AE Lindell, KO Cisneros, J MacDonald, SD Pardo, A Sciurba, F Dauber, J Selman, M Gochuico, BR Kaminski, N AF Rosas, Ivan O. Richards, Thomas J. Konishi, Kazuhisa Zhang, Yingze Gibson, Kevin Lokshin, Anna E. Lindell, Kathleen O. Cisneros, Jose MacDonald, Sandra D. Pardo, Annie Sciurba, Frank Dauber, James Selman, Moises Gochuico, Bernadette R. Kaminski, Naftali TI MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis SO PLOS MEDICINE LA English DT Article ID INTERSTITIAL LUNG-DISEASES; HYPERSENSITIVITY PNEUMONITIS; MATRIX METALLOPROTEINASE-7; PLASMA-CONCENTRATIONS; MATRILYSIN; CLASSIFICATION; SARCOIDOSIS; STATEMENT; GENES; SERUM AB Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression. Methods and Findings We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A-that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [ CI] 92.7%-100%) and specificity of 98.1% (95% CI 89.9%-100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%-100%) and specificity of 87.2% (95% CI 72.6%-95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%). Conclusions Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression. C1 [Cisneros, Jose; Selman, Moises] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. [Rosas, Ivan O.; Richards, Thomas J.; Konishi, Kazuhisa; Zhang, Yingze; Gibson, Kevin; Lindell, Kathleen O.; Sciurba, Frank; Dauber, James; Kaminski, Naftali] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Dorothy P & Richard P Simmons Ctr Interstitial Lu, Pittsburgh, PA USA. [Lokshin, Anna E.] Univ Pittsburgh, Sch Med, Div Hematol Oncol, Pittsburgh, PA USA. [Lokshin, Anna E.] Univ Pittsburgh, Sch Med, Univ Pittsburgh Canc Inst, Pittsburgh, PA USA. [MacDonald, Sandra D.; Gochuico, Bernadette R.] NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. [Pardo, Annie] Univ Nacl Autonoma Mexico, Fac Ciencias, Mexico City 04510, DF, Mexico. RP Selman, M (reprint author), Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. EM moiselman@salud.gob.mx; gochuicb@mail.nih.gov; kaminskin@upmc.edu OI Kaminski, Naftali/0000-0001-5917-4601 FU Intramural NIH HHS; NCATS NIH HHS [UL1 TR000005]; NHLBI NIH HHS [R01 HL073745, HL073745, HL0793941, HL0894932] NR 46 TC 144 Z9 153 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD APR PY 2008 VL 5 IS 4 BP 623 EP 633 AR e93 DI 10.1371/journal.pmed.0050093 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 293XX UT WOS:000255369800017 PM 18447576 ER PT J AU Sorich, MJ Pottier, N Pei, DQ Yang, W Kager, L Stocco, G Cheng, C Panetta, JC Pui, CH Relling, MV Cheok, MH Evans, WE AF Sorich, Michael J. Pottier, Nicolas Pei, Deqing Yang, Wenjian Kager, Leo Stocco, Gabriele Cheng, Cheng Panetta, John C. Pui, Ching-Hon Relling, Mary V. Cheok, Meyling H. Evans, William E. TI In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile SO PLOS MEDICINE LA English DT Article ID DIHYDROFOLATE-REDUCTASE; THYMIDYLATE SYNTHASE; RESISTANCE; CANCER; THERAPY; ACCUMULATION; TRANSPORT; MODEL; PHARMACOGENOMICS; POLYGLUTAMATES AB Background Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX. Methods and Findings We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial "up-front'' in vivo MTX treatment (1 g/m(2)) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1-18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02). Conclusions Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL. Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D). C1 [Sorich, Michael J.; Pottier, Nicolas; Yang, Wenjian; Kager, Leo; Stocco, Gabriele; Panetta, John C.; Relling, Mary V.; Cheok, Meyling H.; Evans, William E.] St Jude Childrens Hosp, Hematol Malignancies Program, Memphis, TN 38105 USA. [Sorich, Michael J.; Pottier, Nicolas; Yang, Wenjian; Kager, Leo; Stocco, Gabriele; Panetta, John C.; Relling, Mary V.; Cheok, Meyling H.; Evans, William E.] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Sorich, Michael J.] Univ S Australia, Sansom Inst, Adelaide, SA 5001, Australia. [Pottier, Nicolas] Fac Med Lille, EA2679, F-59045 Lille, France. [Pei, Deqing; Cheng, Cheng] St Jude Childrens Hosp, Dept Biostat, Memphis, TN 38105 USA. [Kager, Leo] St Anna Childrens Hosp, Dept Hematol Oncol, A-1090 Vienna, Austria. [Stocco, Gabriele] Inst Ricovero & Cura Carattere Sci, Trieste, Italy. [Stocco, Gabriele] Univ Trieste, Trieste, Italy. [Panetta, John C.; Pui, Ching-Hon; Relling, Mary V.; Cheok, Meyling H.; Evans, William E.] Univ Tennessee, Memphis, TN USA. [Pui, Ching-Hon] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [Relling, Mary V.; Evans, William E.] Natl Inst Hlth, Pharmacogenet Anticanc Agents Res Grp, Pharmacogenet Res Network, Memphis, TN USA. RP Evans, WE (reprint author), St Jude Childrens Hosp, Hematol Malignancies Program, 332 N Lauderdale St, Memphis, TN 38105 USA. EM william.evans@stjude.org RI Sorich, Michael/A-1210-2011; Kager, Leo/A-6398-2011; Cheok, Meyling/C-3822-2014; OI Sorich, Michael/0000-0003-1999-866X; Cheok, Meyling/0000-0002-7820-8026; pottier, nicolas/0000-0001-8913-6286; Stocco, Gabriele/0000-0003-0964-5879 FU NCI NIH HHS [R37 CA036401, R01 CA078224, R01 CA051001, P30 CA021765, R01 CA78224, R01 CA51001, R37 CA36401]; NIGMS NIH HHS [U01 GM61393, U01 GM061393] NR 48 TC 49 Z9 51 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD APR PY 2008 VL 5 IS 4 BP 646 EP 656 AR e83 DI 10.1371/journal.pmed.0050083 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 293XX UT WOS:000255369800019 PM 18416598 ER PT J AU Oliveira, F Lawyer, PG Kamhawi, S Valenzuela, JG AF Oliveira, Fabiano Lawyer, Phillip G. Kamhawi, Shaden Valenzuela, Jesus G. TI Immunity to Distinct Sand Fly Salivary Proteins Primes the Anti-Leishmania Immune Response towards Protection or Exacerbation of Disease SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID LUTZOMYIA-LONGIPALPIS SALIVA; NATURAL-KILLER-CELLS; VISCERAL LEISHMANIASIS; INTERLEUKIN-12 RECEPTOR; CUTANEOUS LEISHMANIASIS; VECTOR; TRANSMISSION; RESISTANCE; INFECTION; PREEXPOSURE AB Background: Leishmania parasites are transmitted in the presence of sand fly saliva. Together with the parasite, the sand fly injects biologically active salivary components that favorably change the environment at the feeding site. Exposure to bites or to salivary proteins results in immunity specific to these components. Mice immunized with Phlebotomus papatasi salivary gland homogenate (SGH) or pre-exposed to uninfected bites were protected against Leishmania major infection delivered by needle inoculation with SGH or by infected sand fly bites. Immunization with individual salivary proteins of two sand fly species protected mice from L. major infection. Here, we analyze the immune response to distinct salivary proteins from P. papatasi that produced contrasting outcomes of L. major infection. Methodology/Principal Findings: DNA immunization with distinct DTH-inducing salivary proteins from P. papatasi modulates L. major infection. PpSP15-immunized mice (PpSP15-mice) show lasting protection while PpSP44-immunized mice (PpSP44-mice) aggravate the infection, suggesting that immunization with these distinct molecules alters the course of anti-Leishmania immunity. Two weeks post-infection, 31.5% of CD4(+) T cells produced IFN-gamma in PpSP15-mice compared to 7.1% in PpSP44-mice. Moreover, IL-4-producing cells were 3-fold higher in PpSP44-mice. At an earlier time point of two hours after challenge with SGH and L. major, the expression profile of PpSP15-mice showed over 3-fold higher IFN-gamma and IL12-R beta 2 and 20-fold lower IL-4 expression relative to PpSP44-mice, suggesting that salivary proteins differentially prime anti-Leishmania immunity. This immune response is inducible by sand fly bites where PpSP15-mice showed a 3-fold higher IFN-gamma and a 5-fold lower IL-4 expression compared with PpSP44-mice. Conclusions/Significance: Immunization with two salivary proteins from P. papatasi, PpSP15 and PpSP44, produced distinct immune profiles that correlated with resistance or susceptibility to Leishmania infection. The demonstration for the first time that immunity to a defined salivary protein (PpSP44) results in disease enhancement stresses the importance of the proper selection of vector-based vaccine candidates. C1 [Oliveira, Fabiano; Kamhawi, Shaden; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Oliveira, Fabiano] Fiocruz MS, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Lawyer, Phillip G.] NIAID, Intracellular Parasite Biol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Oliveira, F (reprint author), NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM jvalenzuela@niaid.nih.gov RI Oliveira, Fabiano/B-4251-2009 OI Oliveira, Fabiano/0000-0002-7924-8038 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases FX The study was funded by the Division of Intramural Research, 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 28 TC 60 Z9 62 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2008 VL 2 IS 4 AR e226 DI 10.1371/journal.pntd.0000226 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 385IA UT WOS:000261806700009 PM 18414648 ER PT J AU Ilyushina, NA Govorkova, EA Gray, TE Bovin, NV Webster, RG AF Ilyushina, Natalia A. Govorkova, Elena A. Gray, Thomas E. Bovin, Nicolai V. Webster, Robert G. TI Human-like receptor specificity does not affect the neuraminidase-inhibitor susceptibility of H5N1 influenza viruses SO PLOS PATHOGENS LA English DT Article ID HUMAN AIRWAY EPITHELIUM; A VIRUS; IN-VITRO; HEMAGGLUTININ MUTATIONS; SIALIC-ACID; AMINO-ACID; B VIRUS; BINDING; ZANAMIVIR; HOST AB If highly pathogenic H5N1 influenza viruses acquire affinity for human rather than avian respiratory epithelium, will their susceptibility to neuraminidase (NA) inhibitors (the likely first line of defense against an influenza pandemic) change as well? Adequate pandemic preparedness requires that this question be answered. We generated and tested 31 recombinants of A/Vietnam/1203/04 (H5N1) influenza virus carrying single, double, or triple mutations located within or near the receptor binding site in the hemagglutinin (HA) glycoprotein that alter H5 HA binding affinity or specificity. To gain insight into how combinations of HA and NA mutations can affect the sensitivity of H5N1 virus to NA inhibitors, we also rescued viruses carrying the HA changes together with the H274Y NA substitution, which was reported to confer resistance to the NA inhibitor oseltamivir. Twenty viruses were genetically stable. The triple N158S/Q226L/N248D HA mutation (which eliminates a glycosylation site at position 158) caused a switch from avian to human receptor specificity. In cultures of differentiated human airway epithelial (NHBE) cells, which provide an ex vivo model that recapitulates the receptors in the human respiratory tract, none of the HA-mutant recombinants showed reduced susceptibility to antiviral drugs (oseltamivir or zanamivir). This finding was consistent with the results of NA enzyme inhibition assay, which appears to predict influenza virus susceptibility in vivo. Therefore, acquisition of human-like receptor specificity does not affect susceptibility to NA inhibitors. Sequence analysis of the NA gene alone, rather than analysis of both the NA and HA genes, and phenotypic assays in NHBE cells are likely to adequately identify drug-resistant H5N1 variants isolated from humans during an outbreak. C1 [Ilyushina, Natalia A.; Govorkova, Elena A.; Webster, Robert G.] St Jude Childrens Res Hosp, Dept Infect Dis, Div Virol, Memphis, TN 38101 USA. [Ilyushina, Natalia A.] DI Ivanovskii Virol Inst RAMS, Lab Virus Physiol, Moscow, Russia. [Gray, Thomas E.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Bovin, Nicolai V.] Shemyakin Inst Bioorgan Chem, Lab Carbohydrate Chem, Moscow, Russia. [Webster, Robert G.] Univ Tennessee, Hlth Sci Ctr, Dept Pathol, Memphis, TN USA. RP Ilyushina, NA (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, Div Virol, 332 N Lauderdale, Memphis, TN 38101 USA. EM robert.webster@stjude.org FU NIAID NIH HHS [HHSN266200700005C]; PHS HHS [A195357, A157570] NR 52 TC 35 Z9 36 U1 0 U2 1 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 APR PY 2008 VL 4 IS 4 AR e1000043 DI 10.1371/journal.ppat.1000043 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 294PU UT WOS:000255418800010 PM 18404209 ER PT J AU Jani, D Nagarkatti, R Beatty, W Angel, R Slebodnick, C Andersen, J Kumar, S Rathore, D AF Jani, Dewal Nagarkatti, Rana Beatty, Wandy Angel, Ross Slebodnick, Carla Andersen, John Kumar, Sanjai Rathore, Dharmendar TI HDP - A novel heme detoxification protein from the malaria parasite SO PLOS PATHOGENS LA English DT Article ID FALCIPARUM FOOD VACUOLE; PLASMODIUM-FALCIPARUM; BETA-HEMATIN; MOLECULAR-MECHANISM; HOST ERYTHROCYTE; GENOME SEQUENCE; POLYMERIZATION; IDENTIFICATION; CHLOROQUINE; SECRETION AB When malaria parasites infect host red blood cells (RBC) and proteolyze hemoglobin, a unique, albeit poorly understood parasite-specific mechanism, detoxifies released heme into hemozoin (Hz). Here, we report the identification and characterization of a novel Plasmodium Heme Detoxification Protein (HDP) that is extremely potent in converting heme into Hz. HDP is functionally conserved across Plasmodium genus and its gene locus could not be disrupted. Once expressed, the parasite utilizes a circuitous "Outbound-Inbound'' trafficking route by initially secreting HDP into the cytosol of infected RBC. A subsequent endocytosis of host cytosol ( and hemoglobin) delivers HDP to the food vacuole (FV), the site of Hz formation. As Hz formation is critical for survival, involvement of HDP in this process suggests that it could be a malaria drug target. C1 [Jani, Dewal; Nagarkatti, Rana; Rathore, Dharmendar] Virginia Tech, Virgina Bioinformat Inst, Blacksburg, VA USA. [Beatty, Wandy] Washington Univ, Sch Med, St Louis, MO USA. [Angel, Ross] Virginia Tech, Dept Geosci, Blacksburg, VA USA. [Slebodnick, Carla] Virginia Tech, Dept Chem, Blacksburg, VA USA. [Andersen, John] Natl Inst Hlth, Lab Malaria & Vector Res, Rockville, MD USA. [Kumar, Sanjai] US FDA, Bethesda, MD 20014 USA. RP Jani, D (reprint author), Virginia Tech, Virgina Bioinformat Inst, Blacksburg, VA USA. EM Rathore@vbi.vt.edu RI Angel, Ross/K-9924-2015 OI Angel, Ross/0000-0003-0861-398X NR 49 TC 73 Z9 74 U1 2 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 APR PY 2008 VL 4 IS 4 AR e1000053 DI 10.1371/journal.ppat.1000053 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 294PU UT WOS:000255418800003 PM 18437218 ER PT J AU Oh, S Perera, LP Terabe, M Ni, L Waldmann, TA Berzofsky, JA AF Oh, SangKon Perera, Liyanage P. Terabe, Masaki Ni, Ling Waldmann, Thomas A. Berzofsky, Jay A. TI IL-15 as a mediator of CD4(+) help for CD8(+) T cell longevity and avoidance of TRAIL-mediated apoptosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytotoxic T lymphocytes; T cell help ID RECOMBINANT VACCINIA VIRUS; HOMEOSTATIC PROLIFERATION; SECONDARY EXPANSION; CD8-T-CELL MEMORY; EXPRESSING IL-2; CD4-T-CELL HELP; RESPONSES; IL-15R-ALPHA; DEATH; DIFFERENTIATION AB CD4(+) helper T cells contribute to the induction and maintenance of antigen-specific CD8(+) T cells. Their absence results in short-lived antigen-specific CD8(+) T cells and defective secondary CD8(+) T cell responses because of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we show that IL-15 codelivered with vaccines can overcome CD4(+) T cell deficiency for promoting longevity of antigen-specific CD8(+) T cells and avoidance of TRAIL-mediated apoptosis. In both priming and secondary responses, IL-15 down-regulates proapoptotic Bax, an intermediate in TRAIL-mediated apoptosis, and increases anti-apoptotic Bcl-X-L in CD8(+) T cells. Thus, IL-15 is sufficient to mimic CD4(+) T cell help. Antigen-specific CD4(+) T cells induce dendritic cells (DCs) to produce IL-15. IL-15 is also necessary for optimal help, because helper cells do not deliver effective help through IL-15(-/-) DCs. Therefore, IL-15 codelivered with vaccines can overcome CD4(+) helper T cell deficiency for induction of functionally efficient CD8(+) T cells and maintenance of CD8(+) cytotoxic T lymphocytes (CTLs), and IL-15 is probably one of the natural mediators of help. These findings suggest new vaccine strategies against infections and cancers, especially in individuals with CD4-deficiency. C1 [Perera, Liyanage P.; Waldmann, Thomas A.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Oh, SangKon; Terabe, Masaki; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ni, Ling] Baylor Univ, Med Ctr, Baylor Inst Immunol Res, Dallas, TX 75204 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov; berzofsk@helix.nih.gov RI ni, ling/D-5594-2011 FU Intramural NIH HHS NR 36 TC 85 Z9 85 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 1 PY 2008 VL 105 IS 13 BP 5201 EP 5206 DI 10.1073/pnas.0801003105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284RO UT WOS:000254723700045 PM 18362335 ER PT J AU Barr, CS Schwandt, ML Lindell, SG Higley, JD Maestripieri, D Goldman, D Suomi, SJ Heilig, M AF Barr, Christina S. Schwandt, Melanie L. Lindell, Stephen G. Higley, J. Dee Maestripieri, Dario Goldman, David Suomi, Stephen J. Heilig, Markus TI Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetic; rhesus macaque; mother-infant bond; C77G; A118G ID SINGLE-NUCLEOTIDE POLYMORPHISM; ALCOHOL-USE DISORDERS; SEPARATION DISTRESS; RHESUS-MONKEYS; FUNCTIONAL POLYMORPHISM; A118G; MOTHER; SENSITIVITY; MACAQUES; ASSOCIATION AB in a variety of species, development of attachment to a caregiver is crucial for infant survival and partly mediated by the endogenous opioids. Functional mu-opioid receptor gene polymorphisms are present in humans (OPRM1 A118G) and rhesus macaques (OPRM1 C77G). We hypothesized that rhesus infants carrying a gain-of-function OPRM1 77G allele would experience increased reward during maternal contact and would, therefore, display increased measures of attachment. We collected behavioral data from rhesus macaques (n = 97) during early infancy and at 6 months of age, across four cycles of maternal separation (4 days) and reunion (3 days). Animals were genotyped for the OPRM1 C77G polymorphism, and the effects of this allele on attachment-related behaviors were analyzed. infants carrying the G allele exhibited higher levels of attachment behavior during early infancy. During prolonged periods of maternal separation, although infant macaques homozygous for the C allele exhibited decreases in their levels of distress vocalization with repeated separation, this response persisted in G allele carriers. The OPRM1 77G allele also affected social preference during reunion. C/G infants spent increasing amounts of time in social contact with their mothers as a function of repeated separation and were less likely to interact with other individuals in the social group, a pattern not observed among infants with the C/C genotype. These findings suggest a role for OPRM1 variation in the expression of attachment behavior in human subjects, especially as a function of separation from the caregiver. C1 [Barr, Christina S.; Schwandt, Melanie L.; Lindell, Stephen G.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Barr, Christina S.; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Higley, J. Dee] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Maestripieri, Dario] Univ Chicago, Dept Comparat Human Dev, Chicago, IL 60637 USA. [Suomi, Stephen J.] NICHHD, Lab Comparat Ecol, NIH, Poolesville, MD 20837 USA. RP Barr, CS (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM cbarr@mail.nih.gov RI Goldman, David/F-9772-2010; Schwandt, Melanie/L-9866-2016 OI Goldman, David/0000-0002-1724-5405; FU Intramural NIH HHS NR 41 TC 92 Z9 92 U1 0 U2 16 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 APR 1 PY 2008 VL 105 IS 13 BP 5277 EP 5281 DI 10.1073/pnas.0710225105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 284RO UT WOS:000254723700058 PM 18378897 ER PT J AU Cao, HP Lin, R AF Cao, Heping Lin, Rui TI Phosphorylation of recombinant tristetraprolin in vitro SO PROTEIN JOURNAL LA English DT Article; Proceedings Paper CT Experimental Biology 2006 Annual Meeting CY APR 01-05, 2006 CL San Francisco, CA SP Amer Assoc Anatomists, Amer Physiol Soc, Amer Soc Biochem & Mol Biol, Amer Soc Investigat Pathol, Amer Soc Nutr Sci, Amer Soc Pharmacol & Expt Therapeut DE glycogen synthase kinase 3b; inflammation phosphorylation; protein kinase; recombinant protein; tristetraprolin; zinc finger protein ID NECROSIS-FACTOR-ALPHA; ACTIVATED PROTEIN-KINASE; MESSENGER-RNA TURNOVER; ZINC-FINGER PROTEINS; RICH ELEMENT; SEQUENCE MOTIFS; BINDING-PROTEIN; WIDE PREDICTION; EXPRESSION; DEADENYLATION AB Tristetraprolin/zinc finger protein 36 (TTP/ ZFP36) binds and destabilizes some proinflammatory cytokine mRNAs. TTP-deficient mice develop a profound inflammatory syndrome due to excessive production of proinflammatory cytokines. TTP gene expression is induced by various factors including insulin, cinnamon, and green tea extracts. Previous studies have shown that TTP is highly phosphorylated in vivo and multiple phosphorylation sites are identified in human TTP. This study evaluated the potential protein kinases that could phosphorylate recombinant TTP in vitro. Motif scanning suggested that TTP was a potential substrate for various kinases. SDS-PAGE showed that in vitro phosphorylation of TTP with p42 and p38 MAP kinases resulted in visible electrophoretic mobility shift of TTP to higher molecular masses. Autoradiography showed that TTP was phosphorylated in vitro by GSK3b, PKA, PKB, PKC, but not Cdc2, in addition to p42, p38, and JNK. These results demonstrate that TTP is a substrate for a number of protein kinases in vitro. C1 [Cao, Heping] USDA ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. [Cao, Heping; Lin, Rui] NIEHS, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Cao, HP (reprint author), USDA ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, Bldg 307C,BARC E,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM Heping.Cao@ars.usda.gov FU Intramural NIH HHS [Z01 ES090080-10] NR 42 TC 13 Z9 14 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1572-3887 J9 PROTEIN J JI Protein J. PD APR PY 2008 VL 27 IS 3 BP 163 EP 169 DI 10.1007/s10930-007-9119-7 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302HB UT WOS:000255958300003 PM 18071886 ER PT J AU Wang, PS Patrick, AR Dormuth, CR Avorn, J Maclure, M Canning, CF Schneeweiss, S AF Wang, Philip S. Patrick, Amanda R. Dormuth, Colin R. Avorn, Jerry Maclure, Malcolm Canning, Claire F. Schneeweiss, Sebastian TI The impact of cost sharing on antidepressant use among older adults in British Columbia SO PSYCHIATRIC SERVICES LA English DT Article ID CONVERTING-ENZYME-INHIBITORS; LATE-LIFE DEPRESSION; HEALTH MAINTENANCE ORGANIZATION; PATIENTS AGED 65; PRIMARY-CARE; PRESCRIPTION DRUGS; RECEPTOR ANTAGONISTS; SERVICES; MEDICAID; HMO AB Objective: Antidepressant therapies are underused among older adults and could be further curtailed by patient cost- sharing requirements. The authors studied the effects of two sequential cost- sharing policies in a large, stable population of all British Columbia seniors: change from full prescription coverage to $ 10 -$ 25 copayments ( copay) in January 2002 and replacement with income- based deductibles and 25% coinsurance in May 2003. Methods: PharmaNet data were used to calculate monthly dispensing of antidepressants ( in imipramine- equivalent milligrams) among all British Columbia residents age 65 and older beginning January 1997 through December 2005. Monthly rates of starting and stopping antidepressants were calculated. Population- level patterns over time were plotted, and the effects of implementing cost- sharing policies on antidepressant use, initiation, and stopping were examined in segmented linear regression models. Results: Implementation of the copay policy was not associated with significant changes in level of antidepressant dispensing or the rate of dispensing growth. Subsequent implementation of the income- based deductible policy also did not lead to a significant change in dispensing level but led to a significant ( p=. 02) decrease in the rate of growth of antidepressant dispensing. The copay policy was associated with a significant ( p=. 01) drop in the frequency of antidepressant initiation among persons with depression. Income- based deductibles reduced the rate of increase in antidepressant initiation over time. Implementation of the copay and income- based deductible policies did not have significant effects on stopping rates. Conclusions: Introducing new forms of medication cost sharing appears to have the potential to reduce some use and initiation of antidepressant therapy by seniors. The clinical consequences of such reduced use need to be clarified. C1 [Wang, Philip S.] NIMH, Bethesda, MD 20892 USA. [Patrick, Amanda R.; Avorn, Jerry; Canning, Claire F.] Brigham & Womens Hosp, Div Pharmacoepidemiol, Boston, MA 02115 USA. [Dormuth, Colin R.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Maclure, Malcolm] Univ Victoria, Sch Hlth Informat Sci, Victoria, BC, Canada. RP Wang, PS (reprint author), NIMH, 6001 Execut Blvd,Rm 7141,MSC 9629, Bethesda, MD 20892 USA. EM wangphi@mail.nih.gov RI Schneeweiss, Sebastian/C-2125-2013 FU AHRQ HHS [5-R01-HS-010881-07, R01 HS010881]; NIA NIH HHS [R01 AG021950, R01 AG021950-04, R01-AG-021950]; NIMH NIH HHS [U01 MH069772, R01 MH069772, R01-MH-069772, U01 MH069772-04] NR 61 TC 9 Z9 11 U1 4 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD APR PY 2008 VL 59 IS 4 BP 377 EP 383 DI 10.1176/appi.ps.59.4.377 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 282OW UT WOS:000254578100009 PM 18378836 ER PT J AU Rinker, JA Busse, GD Roma, PG Chen, SA Barr, CS Riley, AL AF Rinker, Jennifer A. Busse, Gregory D. Roma, Peter G. Chen, Scott A. Barr, Christina S. Riley, Anthony L. TI The effects of nicotine on ethanol-induced conditioned taste aversions in Long-Evans rats SO PSYCHOPHARMACOLOGY LA English DT Article DE nicotine; ethanol; drug interactions; polydrug use; drug acceptability; conditioned taste aversion; hypothermia; blood alcohol; rats; female ID PLACE PREFERENCE; STIMULUS PROPERTIES; SACCHARIN AVERSIONS; RATTUS-NORVEGICUS; SEX-DIFFERENCES; RESISTANT RATS; ADULT RATS; ALCOHOL; COCAINE; MICE AB Rationale Overall drug acceptability is thought to be a function of the balance between its rewarding and aversive effects, the latter of which is reportedly affected by polydrug use. Objectives Given that nicotine and alcohol are commonly co-used, the present experiments sought to assess nicotine's impact on ethanol's aversive effects within a conditioned taste aversion design. Materials and methods Experiment 1 examined various doses of nicotine (0, 0.4, 0.8, 1.2 mg/kg) to determine a behaviorally active dose, and experiment 2 examined various doses of ethanol (0, 0.5, 1.0, 1.5 g/kg) to determine a dose that produced intermediate aversions. Experiment 3 then examined the aversive effects of nicotine (0.8 mg/kg) and ethanol (1.0 g/kg) alone and in combination. Additionally, nicotine's effects on blood alcohol concentrations (BAC) and ethanol-induced hypothermia were examined. Results Nicotine and ethanol combined produced aversions significantly greater than those produced by either drug alone or the summed aversive effects of the individual compounds. These effects were unrelated to changes in BAC, but nicotine and ethanol combined produced a prolonged hypothermic effect which may contribute to the increased aversions induced by the combination. Conclusions These data demonstrate that nicotine may interact with ethanol, increasing ethanol's aversive effects. Although the rewarding effects of concurrently administered nicotine and ethanol were not assessed, these data do indicate that the reported high incidence of nicotine and ethanol co-use is unlikely due to reductions in the aversiveness of ethanol with concurrently administered nicotine. It is more likely attributable to nicotine-related changes in ethanol's rewarding effects. C1 [Rinker, Jennifer A.; Busse, Gregory D.; Roma, Peter G.; Riley, Anthony L.] American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Chen, Scott A.; Barr, Christina S.] NIAAA, Sect Primate Studies, Lab Clin & Translat Studies, Poolesville, MD 20837 USA. RP Rinker, JA (reprint author), American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. EM jennifer.rinker@gmail.com OI Rinker, Jennifer/0000-0003-3738-3693 FU Intramural NIH HHS NR 71 TC 12 Z9 13 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2008 VL 197 IS 3 BP 409 EP 419 DI 10.1007/s00213-007-1050-2 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 277ZD UT WOS:000254252300007 PM 18204997 ER PT J AU Gehrke, BJ Chefer, VI Shippenberg, TS AF Gehrke, Brenda J. Chefer, Vladimir I. Shippenberg, Toni S. TI Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum SO PSYCHOPHARMACOLOGY LA English DT Article DE salvinorin A; dopamine; kappa-opioid receptor; dorsal striatum; no net flux microdialysis; rat ID KAPPA-OPIOID-RECEPTOR; NUCLEUS-ACCUMBENS; SALVIA-DIVINORUM; QUANTITATIVE MICRODIALYSIS; TRANSIENT CONDITIONS; AGONIST; COCAINE; BASAL; RELEASE; HALLUCINOGEN AB Rationale Acute systemic administration of salvinorin A, a naturally occurring kappa-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow. Objectives Conventional and quantitative microdialysis techniques were used to determine whether salvinorin A infusion into the dorsal striatum (DSTR) decreases DA overflow by altering DA uptake or release. The influence of repeated salvinorin A administration on basal DA dynamics and cocaine-evoked alterations in DA overflow and locomotion was also assessed. Materials and methods Salvinorin A was administered via the dialysis probe (0; 20-200 nM) or via intraperitoneal (i.p.) injection (1.0 or 3.2 mg/kg per dayx5 days). The effects of a challenge dose of cocaine were examined 48 h after repeated salvinorin treatment. Results Retrodialysis of salvinorin A produced a dose-related, KOPr antagonist reversible, decrease in DA levels. Extracellular DA levels were decreased whereas DA extraction fraction, which provides an estimate of DA uptake, was unaltered. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced. Conclusions These data demonstrate that acute, but not repeated, salvinorin A administration decreases mesostriatal neurotransmission and that activation of DSTR KOPr is sufficient for this effect. Differences in the interaction of salvinorin and synthetic KOPr agonists with cocaine suggest that the pharmacology of these agents may differ. C1 [Gehrke, Brenda J.; Chefer, Vladimir I.; Shippenberg, Toni S.] NIH, NIDA Intramural Res Program, Integrat Neurosci Sect, Baltimore, MD 21224 USA. RP Gehrke, BJ (reprint author), NIH, NIDA Intramural Res Program, Integrat Neurosci Sect, Baltimore, MD 21224 USA. EM gehrkeb@nida.nih.gov FU Intramural NIH HHS; NIDA NIH HHS [R01 DA018151, R01 DA018151-01A2] NR 38 TC 29 Z9 30 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2008 VL 197 IS 3 BP 509 EP 517 DI 10.1007/s00213-007-1067-6 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 277ZD UT WOS:000254252300017 PM 18246329 ER PT J AU Land, CE Zhumadilov, Z Gusev, BI Hartshorne, MH Wiest, PW Woodward, PW Crooks, LA Luckyanov, NK Fillmore, CM Carr, Z Abisheva, G Beck, HL Bouville, A Langer, J Weinstock, R Gordeev, KI Shinkarevi, S Simon, SL AF Land, C. E. Zhumadilov, Z. Gusev, B. I. Hartshorne, M. H. Wiest, P. W. Woodward, P. W. Crooks, L. A. Luckyanov, N. K. Fillmore, C. M. Carr, Z. Abisheva, G. Beck, H. L. Bouville, A. Langer, J. Weinstock, R. Gordeev, K. I. Shinkarevi, S. Simon, S. L. TI Ultrasound-detected thyroid nodule prevalence and radiation dose from fallout SO RADIATION RESEARCH LA English DT Article ID NEVADA TEST-SITE; CHERNOBYL CLEANUP WORKERS; HANFORD NUCLEAR SITE; RESPONSE RELATIONSHIPS; IONIZING-RADIATION; BRYANSK OBLAST; LOCAL FALLOUT; CANCER-RISKS; EXPOSURE; COHORT AB Settlements near the Semipalatinsk Test Site (SNTS) in northeastern Kazakhstan were exposed to radioactive fallout during 1949-1962. Thyroid disease prevalence among 2994 residents of eight villages was ascertained by ultrasound screening. Malignancy was determined by cytopathology. Individual thyroid doses from external and internal radiation sources were reconstructed from fallout deposition patterns, residential histories and diet, including childhood milk consumption. Point estimates of individual external and internal dose averaged 0.04 Gy (range 0-0.65) and 0.31 Gy (0-9.6), respectively, with a Pearson correlation coefficient of 0.46. Ultrasound-detected thyroid nodule prevalence was 18% and 39% among males and females, respectively. It was significantly and independently associated with both external and internal dose, the main study finding. The estimated relative biological effectiveness of internal compared to external radiation dose was 0.33, with 95% confidence bounds of 0.09-3.11. Prevalence of papillary cancer was 0.9% and was not significantly associated with radiation dose. In terms of excess relative risk per unit dose, our dose-response findings for nodule prevalence are comparable to those from populations exposed to medical X rays and to acute radiation from the Hiroshima and Nagasaki atomic bombings. (c) 2008 by Radiation Research Society. C1 [Land, C. E.; Luckyanov, N. K.; Fillmore, C. M.; Carr, Z.; Bouville, A.; Simon, S. L.] Natl Canc Inst, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Wiest, P. W.] Univ New Mexico, Sch Med, Dept Radiol, Albuquerque, NM 87131 USA. [Woodward, P. W.] Armed Forces Inst Pathol, Washington, DC 20306 USA. [Gordeev, K. I.; Shinkarevi, S.] Inst Biophys, Moscow, Russia. RP Land, CE (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Execut Plaza S,Rm 7046,6120 Execut Blvd, Bethesda, MD 20892 USA. EM landc@mail.nih.gov FU Intramural NIH HHS [ZIA CP010132-18] NR 57 TC 19 Z9 20 U1 1 U2 5 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 APR PY 2008 VL 169 IS 4 BP 373 EP 383 DI 10.1667/RR1063.1 PG 11 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 280SP UT WOS:000254446800001 PM 18363427 ER PT J AU Gharib, AM Ho, VB Rosing, DR Herzka, DA Stuber, M Arai, AE Pettigrew, RI AF Gharib, Ahmed M. Ho, Vincent B. Rosing, Douglas R. Herzka, Daniel A. Stuber, Matthias Arai, Andrew E. Pettigrew, Roderic I. TI Coronary artery anomalies and variants: Technical feasibility of assessment with coronary MR angiography at 3T SO RADIOLOGY LA English DT Article ID MAGNETIC-RESONANCE ANGIOGRAPHY; STATE-FREE-PRECESSION; GRADIENT-ECHO; SUDDEN-DEATH; DISEASE; ORIGIN; TIME; VISUALIZATION; ARTERIOGRAPHY; VALSALVA AB The purpose of this study was to prospectively use a whole-heart three-dimensional (3D) coronary magnetic resonance (MR) angiography technique specifically adapted for use at 3 T and a parallel imaging technique ( sensitivity encoding) to evaluate coronary arterial anomalies and variants (CAAV). This HIPAA-compliant study was approved by the local institutional review board, and informed consent was obtained from all participants. Twenty-two participants ( 11 men, 11 women; age range, 18-62 years) were included. Ten participants were healthy volunteers, whereas 12 participants were patients suspected of having CAAV. Coronary MR angiography was performed with a 3-T MR imager. A 3D free-breathing navigator-gated and vector electrocardiographically-gated segmented k-space gradient-echo sequence with adiabatic T2 preparation pulse and parallel imaging ( sensitivity encoding) was used. Whole-heart acquisitions ( repetition time msec/echo time msec, 4/ 1.35; 20 degrees flip angle; 1 x 1 x 2-mm acquired voxel size) lasted 10 - 12 minutes. Mean examination time was 41 minutes +/- 14 ( standard deviation). Findings included aneurysms, ectasia, arteriovenous fistulas, and anomalous origins. The 3D whole-heart acquisitions developed for use with 3 T are feasible for use in the assessment of CAAV.(C) RSNA, 2008. C1 [Gharib, Ahmed M.] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Gharib, Ahmed M.; Rosing, Douglas R.; Arai, Andrew E.] NHLBI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Pettigrew, Roderic I.] NIH, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Ho, Vincent B.] Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. [Herzka, Daniel A.] Philips Res N Amer, Clin Sites Res Program, Bethesda, MD USA. [Stuber, Matthias] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Stuber, Matthias] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Stuber, Matthias] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. RP Gharib, AM (reprint author), NIH, Dept Diagnost Radiol, Bldg 10,Room 3-5340,MSC 1263,10 Ctr Dr, Bethesda, MD 20892 USA. EM agharib@nhlbi.nih.gov RI Stuber, Matthias/B-2949-2010; Gharib, Ahmed/O-2629-2016 OI Stuber, Matthias/0000-0001-9843-2028; Gharib, Ahmed/0000-0002-2476-481X NR 42 TC 33 Z9 35 U1 2 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2008 VL 247 IS 1 BP 220 EP 227 DI 10.1148/radiol.2471070274 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 279MF UT WOS:000254358600027 PM 18372470 ER PT J AU Kissling, GE Portier, CJ Huff, J AF Kissling, Grace E. Portier, Christopher J. Huff, James TI MtBE and cancer in animals: Statistical issues with poly-3 survival adjustments for lifetime studies SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Letter ID CARCINOGENICITY; MORTALITY; BIOASSAY; PROGRAM C1 [Kissling, Grace E.; Portier, Christopher J.; Huff, James] NIEHS, Bethesda, MD USA. RP Kissling, GE (reprint author), NIEHS, Bethesda, MD USA. EM kissling@niehs.nih.gov RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 FU Intramural NIH HHS [Z99 ES999999] NR 9 TC 1 Z9 1 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD APR PY 2008 VL 50 IS 3 BP 428 EP 429 DI 10.1016/j.yrtph.2007.07.008 PG 2 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 302VA UT WOS:000255996700016 PM 17905498 ER PT J AU Vallee, M Aiba, K Piao, Y Palin, MF Ko, MSH Sirard, MA AF Vallee, Maud Aiba, Kazuhiro Piao, Yulan Palin, Marie-France Ko, Minoru S. H. Sirard, Marc-Andre TI Comparative analysis of oocyte transcript profiles reveals a high degree of conservation among species SO REPRODUCTION LA English DT Article ID SUPPRESSION SUBTRACTIVE HYBRIDIZATION; PREIMPLANTATION MOUSE DEVELOPMENT; GROWTH-DIFFERENTIATION FACTOR-9; DENSITY OLIGONUCLEOTIDE ARRAYS; GENE-EXPRESSION PATTERNS; MATCHED HUMAN HOMOLOGS; IN-VITRO MATURATION; BOVINE OOCYTES; MICROARRAY DATA; MESSENGER-RNA AB Cross-species comparison of gene expression is a powerful approach for discovering genes that have been conserved throughout evolution. Conserved genes are presumably very important in the mechanisms related to the unique molecular functions in oocytes. The objective of this study was to identify genes expressed in the oocyte and conserved across three diverse vertebrate species. We report the global gene expression profiles of Bos taurus and Xenopus laevis oocytes on an NIA mouse development microarray that consists of 60-mer oligonucleotide probes representing more than 20 000 mouse transcripts derived from stem cell, oocyte, and early embryo cDNA libraries. Analysis based on intensity values revealed that 9853 and 10 046 genes are expressed in bovine and Xenopus oocytes respectively. Furthermore, previously published microarray data on preimplantation development in the mouse were used for a comparative analysis of global oocyte gene expression profiles. Interestingly, a substantial proportion of the genes expressed in mouse oocytes is conserved between the three species (74%, 7275 genes). Moreover, functional annotation of these conserved oocyte-expressed genes confirmed that certain functions are conserved among the three species. RNA metabolism and cell cycle were among the over-represented Gene Ontology terms in the biological process category. Finally, a pattern-matching analysis identified 208 conserved maternally expressed genes. Results from these cross-species hybridizations allowed numerous genes expressed in oocytes and conserved between Mus musculus, B. taurus, and X. laevis to be identified. This comparative analysis of oocyte transcript profiles revealed a high degree of conservation among species. C1 [Vallee, Maud; Sirard, Marc-Andre] Univ Laval, CRBR, Dept Anim Sci, Quebec City, PQ G1K 7P4, Canada. [Aiba, Kazuhiro; Piao, Yulan; Ko, Minoru S. H.] NIA, Genet Lab, Dev Genom & Aging Sect, NIH, Baltimore, MD 21224 USA. [Palin, Marie-France] Agr & Agri Food Canada, Dairy & Swine Res & Dev Ctr, Lennoxville, PQ J1M 1Z3, Canada. RP Sirard, MA (reprint author), Univ Laval, CRBR, Dept Anim Sci, Quebec City, PQ G1K 7P4, Canada. EM marc-andre.sirard@crbr.ulaval.ca RI Sirard, Marc/A-9112-2011; Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS NR 72 TC 25 Z9 25 U1 0 U2 2 PU BIO SCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD APR PY 2008 VL 135 IS 4 BP 439 EP 448 DI 10.1530/REP-07-0342 PG 10 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 290DO UT WOS:000255103700003 PM 18367505 ER PT J AU Guittot, SM Verot, A Odet, F Chauvin, MA le Magueresse-Battistoni, B AF Guittot, Severine Mazaud Verot, Adelie Odet, Fanny Chauvin, Marie-Agnes le Magueresse-Battistoni, Brigitte TI A comprehensive survey of the laminins and collagens type IV expressed in mouse Leydig cells and their regulation by LH/hCG SO REPRODUCTION LA English DT Article ID RAT SERTOLI-CELLS; BASEMENT-MEMBRANE; EXTRACELLULAR-MATRIX; ANDROGEN RECEPTOR; GENE-EXPRESSION; GAMMA-3 CHAIN; DIFFERENTIAL EXPRESSION; TESTOSTERONE PRODUCTION; PLASMINOGEN ACTIVATION; SERINE PROTEASES AB Extracellular matrix (ECM) proteins have been shown to alter Leydig cell steroidogenesis in vitro, substantiating the hypothesis that Leydig cell steroidogenic activity and matrix environment are interdependent events. However, the nature of the ECM components synthesized by Leydig cells and their regulation by LH/human chorionic gonadotropin (hCG) remain unknown. Here, we examine the occurrence of the I I laminin subunits and the 6 alpha chains of collagen IV (COL4A1-6) by RT-PCR in Leydig cells cultured with or without LH/hCG. Leydig cells were a tumor Leydig cell line (mLTC-1) or 8-week-old mice Leydig cells. Based on PCR data, it is suggested that normal Leydig cells may synthesize a maximum of I I laminin heterotrimers and the 6 alpha chains of collagen IV. They also may synthesize various proteases and inhibitors of the metzincin family. The mLTC-1 cells have a limited repertoire as compared with normal Leydig cells. interestingly, none of the ten proteases and inhibitors monitored is under LH-hCG regulation whereas every protease and inhibitor of the serine protease family yet identified in Leydig cells is under gonadotropin regulation. In addition, a few laminin and collagen subunit genes are regulated by LH/hCG. These are laminins A and gamma 3 (Lama3 and Lamc3), Col4a3, and Col4a6, which are negatively regulated by LH/hCG in both Leydig cell types, and Col4a4, which was downregulated in primary cultures but not in mLTC-1 cells. Collectively, the present study suggests that Leydig cells modulate in a selective fashion their matrix environment in response to their trophic hormone. This may alter the steroidogenic outcome of Leydig cells. C1 [Guittot, Severine Mazaud; Verot, Adelie; le Magueresse-Battistoni, Brigitte] Hop Debrousse, INSERM, CNRS, INRA,UMR 1245,U418, F-69322 Lyon 05, France. [Odet, Fanny] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Chauvin, Marie-Agnes] INSERM, INRA, U870, U1235,Fac Med Lyon Sud, F-69600 Oullins, France. RP Guittot, SM (reprint author), Hop Debrousse, INSERM, CNRS, INRA,UMR 1245,U418, 29 Rue soeur Bouvier, F-69322 Lyon 05, France. EM severinemazaud@yahoo.fr; lemagueresse@lyon.inserm.fr RI Mazaud-Guittot, Severine/I-4694-2015 OI Mazaud-Guittot, Severine/0000-0003-0566-4124 NR 46 TC 10 Z9 10 U1 1 U2 10 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD APR PY 2008 VL 135 IS 4 BP 479 EP 488 DI 10.1530/REP-07-0561 PG 10 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 290DO UT WOS:000255103700007 ER PT J AU Newman, RG Kitchell, BE Wallig, MA Paria, B AF Newman, R. G. Kitchell, B. E. Wallig, M. A. Paria, B. TI The cloning and expression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase 2 in normal canine lymph nodes and in canine lymphoma SO RESEARCH IN VETERINARY SCIENCE LA English DT Article DE doe; canine; matrix metalloproteinase 2; lymphoma; TIMP2 ID NON-HODGKINS-LYMPHOMAS; MATRIX METALLOPROTEINASES; BASEMENT-MEMBRANE; IV COLLAGENASE; GELATINASE-A; PROGNOSTIC VALUE; MMP-9; BINDING; DOMAIN; CELLS AB Matrix metalloproteinase-2 (MMP-2) and its inhibitor, tissue inhibitor of matrix metalloproteinase 2 (TIMP2), are known to be important in cancer. The purposes of this study were to determine the cDNA sequence of canine MMP-2 and to investigate the expression patterns of MMP-2 and TIMP2 in normal canine lymph nodes and spontaneously arising canine lymphomas. We cloned and sequenced a PCR product containing most (1901 base pairs) of the coding sequence of canine MMP-2 that translates into a 623 amino acid protein. The cDNA and deduced amino acid sequences are highly homologous to those of other mammalian species. Canine MMP-2 and TIMP2 mRNAs were detectable in the majority of normal lymph node and lymphomatous samples evaluated. No statistical difference was identified when comparing the expression of either gene with regard to normal versus neoplastic nodes, nodal versus extranodal lymphoma, lymphoma grade, or B versus T cell immunophenotype. (c) 2007 Published by Elsevier Ltd. C1 [Newman, R. G.; Kitchell, B. E.] Michigan State Univ, Coll Vet Med, Dept Small Anim Clin Sci, Sect Oncol, E Lansing, MI 48824 USA. [Wallig, M. A.] Univ Illinois, Coll Vet Med, Vet Diagnost Lab, Urbana, IL 61802 USA. [Paria, B.] NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Kitchell, BE (reprint author), Michigan State Univ, Coll Vet Med, Dept Small Anim Clin Sci, Sect Oncol, E Lansing, MI 48824 USA. EM kitchell@cvm.msu.edu NR 24 TC 2 Z9 3 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0034-5288 J9 RES VET SCI JI Res. Vet. Sci. PD APR PY 2008 VL 84 IS 2 BP 206 EP 214 DI 10.1016/j.rvsc.2007.04.016 PG 9 WC Veterinary Sciences SC Veterinary Sciences GA 257NI UT WOS:000252805400008 PM 17604063 ER PT J AU Barr, RG Stemple, KJ Mesia-Vela, S Basner, RC Derk, SJ Henneberger, PK Milton, DK Taveras, B AF Barr, R. Graham Stemple, Kimberly J. Mesia-Vela, Sonia Basner, Robert C. Derk, Susan J. Henneberger, Paul K. Milton, Donald K. Taveras, Brenda TI Reproducibility and validity of a handheld spirometer SO RESPIRATORY CARE LA English DT Article CT 99th International Conference of the American-Thoracic-Society CY MAY 16-23, 2003 CL SEATTLE, WA SP Amer Thorac Soc DE spirometer; spirometry; forced vital capacity; FVC; forced expiratory volume; FEV(1) AB BACKGROUND: Handheld spirometers have several advantages over desktop spirometers, but worries persist regarding reproducibility and validity of data from handheld spirometers. We undertook an independent examination of the EasyOne handheld spirometer. METHODS: The laboratory testing included reproducibility and validity testing with a waveform generator. We used standard American Thoracic Society waveforms for in-line testing, calibration adaptor testing, and testing during compression of the mouthpiece. The clinical testing involved repeated tests with 24 spirometry-naive volunteers and comparison to spirometry results from laboratory (volume-sensing dry rolling seal) spirometer. RESULTS: The EasyOne exceeded standard thresholds for acceptability with the American Thoracic Society waveforms. In-line testing yielded valid results from the EasyOne. Between the EasyOne and the reference spirometer readings the mean +/- SD difference was 0.03 +/- 0.23 L for forced vital capacity (FVC) and -0.06 +/- 0.09 L for forced expiratory volume in the first second (FEV(1)). The calibration adaptor showed no appreciable problems. Extreme compression of the mouthpiece reduced the measured values. In clinical testing the coefficients of variation and limits of agreement were, respectively, 3.3% and 0.24 L for FVC, 2.6% and 0.18 L for FEV(1), and 1.9% and 0.05 for the FEV(1)/FVC ratio. The EasyOne readings were lower than those from the reference spirometer; the differences were: -0.12 L for FVC, -0.17 L for FEV(1), and -0.02 for FEV(1)/FVC. The limits of agreement were within criteria for FVC but not for the FEV(1), possibly due to a training effect. CONCLUSION: The EasyOne spirometer yielded generally reproducible results that were generally valid, compared to the values from the laboratory spirometer. The use of the EasyOne in clinical, occupational, and research settings seems justified. C1 [Barr, R. Graham; Mesia-Vela, Sonia; Basner, Robert C.; Taveras, Brenda] Columbia Univ, Dept Med, Med Ctr, New York, NY 10027 USA. [Stemple, Kimberly J.; Derk, Susan J.; Henneberger, Paul K.] NIOSH, Atlanta, GA USA. [Milton, Donald K.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Stemple, Kimberly J.] NIAID, Bethesda, MD USA. [Barr, R. Graham] Columbia Univ, Med Ctr, Dept Epidemiol, New York, NY USA. RP Barr, RG (reprint author), Columbia Univ, Dept Med, Med Ctr, New York, NY 10027 USA. RI Milton, Donald/G-3286-2010 OI Milton, Donald/0000-0002-0550-7834 FU NHLBI NIH HHS [HL 075476, HL 077612, R01 HL075476, R01 HL075476-01, R01 HL077612] NR 17 TC 17 Z9 17 U1 0 U2 2 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 J9 RESP CARE JI Respir. Care PD APR PY 2008 VL 53 IS 4 BP 433 EP 441 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 285DW UT WOS:000254758500003 PM 18364054 ER PT J AU Meyer, JM Davis, VG Goff, DC McEvoy, JP Nasrallah, HA Davis, SM Rosenheck, RA Daumit, GL Hsiao, J Swartz, MS Stroup, TS Lieberman, JA AF Meyer, Jonathan M. Davis, Vicki G. Goff, Donald C. McEvoy, Joseph P. Nasrallah, Henry A. Davis, Sonia M. Rosenheck, Robert A. Daumit, Gail L. Hsiao, John Swartz, Marvin S. Stroup, T. Scott Lieberman, Jeffrey A. TI Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: Prospective data from phase 1 SO SCHIZOPHRENIA RESEARCH LA English DT Article DE antipsychotic; schizophrenia; metabolic syndrome; lipids; HDL; triglycerides; waist circumference; central adiposity ID INTERNATIONAL-DIABETES-FEDERATION; TREATMENT PANEL-III; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; ATYPICAL ANTIPSYCHOTICS; FOLLOW-UP; RISK; GLUCOSE AB Background: The metabolic syndrome (MS) is associated with increased risk for diabetes mellitus and coronary heart disease, and is highly prevalent among schizophrenia patients. Given concerns over antipsychotic metabolic effects, this analysis explored MS status and outcomes in phase I of the CATIE Schizophrenia Trial. Methods: The change in proportion of subjects with MS and individual criteria was compared between antipsychotic treatment groups, along with mean changes for individual criteria. Primary analyses examined subjects with fasting laboratory assessments at baseline and 3 months. Other analyses examined 3-month changes in MS status, waist circumference (WC), HDL cholesterol and blood pressure in all subjects, metabolic changes at the end of phase I participation (EOP), and repeated measures changes in HDL, blood pressure (BP) and WC over phase 1. Results: At 3 months, there were no significant between-drug differences for the change in proportion of subjects meeting MS status or individual MS criteria in the smaller fasting cohort (n = 281) or for those meeting criteria for parameters not dependent on fasting status (BP, HDL, WC) among all subjects (n = 660). Among all subjects whose MS status could be determined at 3 months (n = 660), MS prevalence increased for olanzapine (from 34.8% to 43.9%), but decreased for ziprasidone (from 37.7% to 29.9%) (p = .001). Although effect sizes varied across subgroups, at 3 months olanzapine and quetiapine had the largest mean increase in waist circumference (0.7 in. for both) followed by risperidone (0.4 in.), compared to no change for ziprasidone (0.0 in.) and a decrease in waist circumference for perphenazine (-0.4 in.). Olanzapine also demonstrated significantly different changes in fasting triglycerides at 3 months (+21.5 mg/dl) compared to ziprasidone (-32.1 mg/dl). EOP exposure data was obtained, on average, nine months from baseline for all metabolic variables. Results from EOP and repeated measures analyses were consistent with those at 3 months for mean changes in WC and fasting triglycerides, but between group differences emerged for HDL and SBP. Conclusions: This large non-industry sponsored study confirms the differential metabolic effects between antipsychotics. Clinicians are advised to monitor all metabolic parameters, including WC, HDL and serum triglycerides, during antipsychotic treatment. (C) 2008 Elsevier B.V. All rights reserved. C1 [Meyer, Jonathan M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Meyer, Jonathan M.] VA San Diego Healthcare Syst, San Diego, CA USA. [Davis, Vicki G.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Bank Amer Ctr, Chapel Hill, NC 27514 USA. [Goff, Donald C.] Harvard Univ, Dept Psychiat, Cambridge, MA 02138 USA. [Goff, Donald C.] Massachusetts Gen Hosp, Schizophrenia Program, Freedom Trail Clin, Lindemann Mental Hlth Ctr, Boston, MA 02114 USA. [McEvoy, Joseph P.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [McEvoy, Joseph P.] John Umstead Hosp, Butner, NC 27509 USA. [Nasrallah, Henry A.] Univ Cincinnati, Cincinnati, OH 45267 USA. [Davis, Sonia M.] Quintiles Inc, Morrisville, NC 27560 USA. [Rosenheck, Robert A.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06520 USA. [Rosenheck, Robert A.] VA Connecticut Hlth Care Syst, NE Program Evaluat Ctr, West Haven, CT 06516 USA. [Daumit, Gail L.] Johns Hopkins Med Inst, Baltimore, MD 21287 USA. [Hsiao, John] NIMH, Adult Psychopharmacol Intervent Program, Bethesda, MD 20892 USA. [Swartz, Marvin S.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Stroup, T. Scott] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Lieberman, Jeffrey A.] Columbia Univ, Dept Psychiat, Inst Psychiat, New York, NY 10032 USA. RP Meyer, JM (reprint author), San Diego VAMC, 3350 La Jolla Village Dr 116A, San Diego, CA 92161 USA. EM jmmeyer@ucsd.edu; Vicki.Davis@mail.cscc.unc.edu; goff@psych.mgh.harvard.edu; jpmcevoy@duke.edu; NASRALHA@ucmail.uc.edu; sonia.davis@quintiles.com; robert.rosenheck@yale.edu; gdaumit@jhmi.edu; jh23f@nih.gov; swart001@mc.duke.edu; scott_stroup@med.unc.edu; JL2616@columbia.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NCRR NIH HHS [M01 RR000046-441041, M01 RR000046, M01 RR000046-451041]; NIMH NIH HHS [N01MH90001] NR 48 TC 134 Z9 137 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2008 VL 101 IS 1-3 BP 273 EP 286 DI 10.1016/j.schres.2007.12.487 PG 14 WC Psychiatry SC Psychiatry GA 305XX UT WOS:000256212200031 PM 18258416 ER PT J AU Buetow, K AF Buetow, Kenneth TI Heading for the BIG time SO SCIENTIST LA English DT Article AB Cancer is an immensely complex disease and in order to get a sense of the big picture, scientists need to combine observations from genornics, proteomics, pathology, imaging, and clinical trials. Encouraged by the support of National Cancer Institute, researchers spurred to the challenge by advisory boards, and set out to put a new set of tools into the hands of scientists, tools that would allow them to manage and understand the details of biomedical data becoming availableon online resource caBIG (Cancer Biomedical Informatics Grid). C1 Natl Canc Inst, Lab Populat Genet, Bethesda, MD USA. RP Buetow, K (reprint author), Natl Canc Inst, Lab Populat Genet, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD APR PY 2008 VL 22 IS 4 BP 60 EP 66 PG 7 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 279II UT WOS:000254348500022 ER PT J AU Pogue-Geile, K AF Pogue-Geile, Kay TI Defixation SO SCIENTIST LA English DT Editorial Material C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP Pogue-Geile, K (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD APR PY 2008 VL 22 IS 4 BP 83 EP 83 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 279II UT WOS:000254348500034 ER PT J AU Piatigorsky, J AF Piatigorsky, Joram TI Lens and cornea: The "refracton hypothesis" SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Editorial Material C1 NCI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NCI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM joramp@nei.nih.gov NR 0 TC 8 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD APR PY 2008 VL 19 IS 2 BP 69 EP 70 DI 10.1016/j.semcdb.2007.10.010 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 299BH UT WOS:000255730300001 PM 18054835 ER PT J AU Zelenka, PS Arpitha, P AF Zelenka, P. S. Arpitha, P. TI Coordinating cell proliferation and migration in the lens and cornea SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE lens; cornea; epithelial cells; migration; proliferation; wound healing; differentiation; signal transduction; growth factors; cytokines ID EPIDERMAL-GROWTH-FACTOR; PROTEIN-KINASE-C; METALLOPROTEINASE GELATINASE-B; PLATELET-ACTIVATING-FACTOR; EARLY GENE-PRODUCTS; EPITHELIAL-CELLS; MATRIX-METALLOPROTEINASE; FACTOR-BETA; FACTOR RECEPTOR; TGF-BETA AB Migration is a complex process for epithelial tissues, because the epithelium must move as an intact sheet to preserve its barrier function. The requirement for structural integrity is met by coupling cell-to-matrix and cell-to-cell adhesion at the cellular level, and by coordinating cell proliferation and cell migration in the tissue as a whole. Proliferation is suppressed at the migrating cell front, allowing cells in this region to remain tightly packed while advancing rapidly. At the same time, proliferation is enhanced in a region behind the advancing cell front to expand the epithelial cell sheet. This review considers the extracellular signals and intracellular signaling pathways that regulate these processes in the lens and corneal epithelium, with emphasis on the commonalities that link these tissues. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Zelenka, P. S.] NEI, NIH, Bethesda, MD 20892 USA. [Arpitha, P.] Aravind Med Res Fdn, Madurai, Tamil Nadu, India. RP Zelenka, PS (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM pz2b@nih.gov FU Intramural NIH HHS; NEI NIH HHS [Z01 EY 00238] NR 138 TC 29 Z9 29 U1 1 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD APR PY 2008 VL 19 IS 2 BP 113 EP 124 DI 10.1016/j.semcdb.2007.10.001 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 299BH UT WOS:000255730300006 PM 18035561 ER PT J AU Hejtmancik, JF AF Hejtmancik, J. Fielding TI Congenital cataracts and their molecular genetics SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE lens; cataract; molecular genetics; gene ID NANCE-HORAN-SYNDROME; GAMMA-D-CRYSTALLIN; AUTOSOMAL-DOMINANT CATARACT; ALPHA-B-CRYSTALLIN; ZONULAR PULVERULENT CATARACT; POSTERIOR POLAR CATARACT; MAJOR INTRINSIC PROTEIN; DESMIN-RELATED MYOPATHY; DNA-BINDING DOMAIN; ADULT I-PHENOTYPE AB Cataract can be defined as any opacity of the crystalline lens. Congenital cataract is particularly serious because it has the potential for inhibiting visual development, resulting in permanent blindness. Inherited cataracts represent a major contribution to congenital cataracts, especially in developed countries. While cataract represents a common end stage of mutations in a potentially large number of genes acting through varied mechanisms in practice most inherited cataracts have been associated with a subgroup of genes encoding proteins of particular importance for the maintenance of lens transparency and homeostasis. The increasing availability of more detailed information about these proteins and their functions and is making it possible to understand the pathophysiology of cataracts and the biology of the lens in general. Published by Elsevier Ltd. C1 NEI, MOGS, OGVFB, NIH, Bethesda, MD 20892 USA. RP Hejtmancik, JF (reprint author), NEI, MOGS, OGVFB, NIH, Bldg 10,Room 10B10,10 Ctr Dr,MSC 1860, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov FU Intramural NIH HHS [Z01 EY000272-17] NR 174 TC 176 Z9 185 U1 2 U2 17 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD APR PY 2008 VL 19 IS 2 BP 134 EP 149 DI 10.1016/j.semcdb.2007.10.003 PG 16 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 299BH UT WOS:000255730300008 PM 18035564 ER PT J AU Yoshinaga, K AF Yoshinaga, Koji TI Review of factors essential for blastocyst implantation for their modulating effects on the maternal immune system SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE implantation; immune system; cytokines; lymphocytes; BIEFs ID NATURAL-KILLER-CELLS; DECAY-ACCELERATING FACTOR; REGULATORY T-CELLS; LEUKEMIA INHIBITORY FACTOR; PLACENTAL LACTOGEN-II; METRIAL GLAND-CELLS; VIVO GENE-TRANSFER; DECIDUAL NK CELLS; MOUSE UTERUS; GROWTH-FACTOR AB Pituitary and ovarian hormones prepare the endometrium for successful blastocyst implantation and support its process directly or indirectly through the action of growth factors, cytokines and other molecules. Many of the blastocyst implantation essential factors (BIEFs) are modulators of the maternal immune system. Since little is known as to the action of these molecules on the uterine lymphocytes, its clarification is imperative to the understanding of the process of blastocyst implantation. Published by Elsevier Ltd. C1 NICHHD, Reprod Sci Branch, Populat Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. RP Yoshinaga, K (reprint author), NICHHD, Reprod Sci Branch, Populat Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. EM ky6a@nih.gov NR 106 TC 43 Z9 44 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD APR PY 2008 VL 19 IS 2 BP 161 EP 169 DI 10.1016/j.semcdb.2007.10.006 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 299BH UT WOS:000255730300011 PM 18054836 ER PT J AU Patel, M Chan, CC AF Patel, Mrinali Chan, Chi-Chao TI Immunopathological aspects of age-related macular degeneration SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE age-relatedmacular degeneration (AMD); inflammation; complement; macrophage; microglia ID COMPLEMENT FACTOR-H; CHLAMYDIA-PNEUMONIAE INFECTION; INDUCED CHOROIDAL NEOVASCULARIZATION; C-REACTIVE PROTEIN; RETINAL-PIGMENT EPITHELIUM; BEAVER DAM EYE; ALTERNATIVE PATHWAY; ENDOTHELIAL-CELLS; DRUSEN FORMATION; MURINE MODEL AB Age-related macular degeneration (AMD) represents a leading cause of blindness worldwide. While the clinical and histopathological aspects of AMD are well characterized, its etiology and pathogenesis remain unclear. Recent findings suggest a role for immunologic processes in AMD pathogenesis, including the age-related generation of extracellular deposits inside the Brusch membrane and beneath the retinal pigment epithelium, recruitment of macrophages for clearance of these deposits, complement activation, recruitment of tissue-destructive macrophages, microglial activation and accumulation, and proinflammatory effects of chronic inflammation by Chlamydia pneumoniae. This review discusses the evidence for the role of inflammation in human AMD and in animal models of AMD. C1 [Patel, Mrinali; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Patel, Mrinali] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,10-10N103,NIH NEI, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS [Z01 EY000418-04] NR 94 TC 101 Z9 104 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD APR PY 2008 VL 30 IS 2 BP 97 EP 110 DI 10.1007/s00281-008-0112-9 PG 14 WC Immunology; Pathology SC Immunology; Pathology GA 296CA UT WOS:000255519900004 PM 18299834 ER PT J AU Luger, D Caspi, RR AF Luger, Dror Caspi, Rachel R. TI New perspectives on effector mechanisms in uveitis SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE autoimmune disease; uveitis Th1; Th17; IL-23; IL-17; IFN-gamma ID EXPERIMENTAL AUTOIMMUNE UVEITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CD8 T-CELLS; IFN-GAMMA; INTERFERON-GAMMA; OCULAR AUTOIMMUNITY; CYTOKINE RECEPTOR; DEFICIENT MICE; INFLAMMATION; DISEASE AB Experimental autoimmune uveitis (EAU) in its several variants represents human autoimmune uveitis and has been instrumental in obtaining insights into the basic mechanisms of disease. Studies have uncovered that in addition to CD4+ Th1 cells, uveitis can be induced also by CD8+ T cells. Antibodies may have a secondary role after the blood-retinal barrier has been broken. The role in uveitis of a recently discovered IL-17-producing effector T cell type, Th17, is being intensively studied. Th17 cells elicit EAU, can be found in uveitic eyes along with Th1 cells, and are dominant in some types of EAU. In other types of EAU, Th1 cells have a dominant role. The dominant effector type is at least in part determined by conditions under which initial exposure to self-antigen occurs. These findings shed light on the heterogeneity of human disease and may ultimately help to develop better and more rational treatment strategies for human uveitis. C1 [Luger, Dror; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N222, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU Intramural NIH HHS [Z01 EY000184-25] NR 51 TC 50 Z9 56 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD APR PY 2008 VL 30 IS 2 BP 135 EP 143 DI 10.1007/s00281-008-0108-5 PG 9 WC Immunology; Pathology SC Immunology; Pathology GA 296CA UT WOS:000255519900008 PM 18317764 ER PT J AU Yeh, S Faia, LJ Nussenblatt, RB AF Yeh, Steven Faia, Lisa J. Nussenblatt, Robert B. TI Advances in the diagnosis and immunotherapy for ocular inflammatory disease SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE uveitis; biologics; immunosuppression; polymerase chain reaction; cytokine ID POLYMERASE-CHAIN-REACTION; OPTICAL COHERENCE TOMOGRAPHY; JUVENILE IDIOPATHIC ARTHRITIS; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; NECROSIS-FACTOR-ALPHA; TERM-FOLLOW-UP; INTERLEUKIN-1 RECEPTOR ANTAGONIST; ENDOTOXIN-INDUCED UVEITIS; PLACEBO-CONTROLLED TRIAL; KOYANAGI-HARADA-DISEASE AB Significant advances in the diagnosis and therapy for uveitis have been made to improve the quality of care for patients with ocular inflammatory diseases. While traditional ophthalmic examination techniques, fluorescein angiography, and optical coherence tomography continue to play a major role in the evaluation of patients with uveitis, the advent of spectral domain optical coherence tomography and fundus auto fluorescence into clinical practice provides additional information about disease processes. Polymerase chain reaction and cytokine diagnostics have also continued to play a greater role in the evaluation of patients with inflammatory diseases. The biologic agents, a group of medications that targets cytokines and other soluble mediators of inflammation, have demonstrated promise in targeted immunotherapy for specific uveitic entities. Their ophthalmic indications have continued to expand, improving the therapeutic armentarium of uveitis specialists. C1 [Yeh, Steven; Faia, Lisa J.; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,10S-219,10 Ctr Dr, Bethesda, MD 20892 USA. EM DrBob@nei.nih.gov NR 176 TC 18 Z9 21 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD APR PY 2008 VL 30 IS 2 BP 145 EP 164 DI 10.1007/s00281-008-0109-4 PG 20 WC Immunology; Pathology SC Immunology; Pathology GA 296CA UT WOS:000255519900009 PM 18320151 ER PT J AU Royal, RE Pingponk, JF AF Royal, Richard E. Pingponk, James F., Jr. TI Diagnosis and management of peritoneal carcinomatosis arising from adenocarcinoma of the colon and rectum SO SEMINARS IN ONCOLOGY LA English DT Review ID INTRAPERITONEAL CHEMOTHERAPY; PSEUDOMYXOMA-PERITONEI; COLORECTAL-CANCER; MALIGNANT ASCITES; GASTRIC-CANCER; CYTOREDUCTIVE SURGERY; OVARIAN-CANCER; MUCINOUS CARCINOMATOSIS; SYSTEMIC CHEMOTHERAPY; PROGNOSTIC FEATURES C1 [Royal, Richard E.; Pingponk, James F., Jr.] NCI, NIH, CRC, Surg Branch,Surg Metab Sect, Bethesda, MD 20892 USA. RP Pingponk, JF (reprint author), NCI, NIH, CRC, Surg Branch,Surg Metab Sect, Bldg 10,Room 4W-5932,10 Ctr Dr,MSC-1201, Bethesda, MD 20892 USA. EM James_Pingpank@nih.gov NR 54 TC 16 Z9 17 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2008 VL 35 IS 2 BP 183 EP 191 DI 10.1053/j.seminoncol.2007.12.007 PG 9 WC Oncology SC Oncology GA 294ZM UT WOS:000255444800012 PM 18396204 ER PT J AU Pyrgos, V Shoham, S Walsh, TJ AF Pyrgos, Vasilios Shoham, Shmuel Walsh, Thomas J. TI Pulmonary Zygomycosis SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE Zygomycosis; mucormycosis; fungal infection; pulmonary infection ID B LIPID COMPLEX; INVASIVE FUNGAL-INFECTIONS; RHINO-ORBITAL MUCORMYCOSIS; COLONY-STIMULATING FACTOR; LIPOSOMAL AMPHOTERICIN-B; CARE CANCER CENTER; RHINOCEREBRAL MUCORMYCOSIS; IN-VITRO; CUTANEOUS MUCORMYCOSIS; DEFEROXAMINE THERAPY AB Zygomycosis has emerged as an increasingly common infection in immunocompromised patients. Although the majority of these cases are community acquired, hospital outbreaks have been described, linked to the use of contaminated products. Risk factors for development of zygomycosis include uncontrolled diabetes mellitus, neutropenia, use of immunosuppressive medications, and iron overload states. Recent studies have shown the central role of iron in the pathogenesis of zygomycosis and the effect of disease states such as ketoacidosis and hyperglycernia on the availability of iron to the Zygomycetes. These organisms most commonly infect the sinuses, lungs, central nervous system, and skin and soft tissues. Diagnosis often involves invasive procedures, including deep tissue biopsy, because radiological studies are not specific for this disease, and other less invasive diagnostic modalities have not yet been proven to be sensitive or specific. Treatment may require a combined medical and surgical approach in these frequently frail patients; yet, even with such aggressive measures the mortality of zygomycosis remains high. C1 [Pyrgos, Vasilios; Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Shoham, Shmuel] Washington Hosp Ctr, Infect Dis Sect, Washington, DC 20010 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, CRC 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 106 TC 15 Z9 17 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD APR PY 2008 VL 29 IS 2 BP 111 EP 120 DI 10.1055/s-2008-1063850 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 280KR UT WOS:000254426200003 PM 18365993 ER PT J AU Zonios, DI Bennett, JE AF Zonios, Dimitrios I. Bennett, John E. TI Update on azole antifungals SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE azoles; triazoles; fluconazole; itraconazole; voriconazole; posaconazole; azole interactions ID STEADY-STATE PHARMACOKINETICS; BONE-MARROW-TRANSPLANTATION; INVASIVE FUNGAL-INFECTIONS; INCREASES PLASMA-CONCENTRATIONS; ACTIVE ANTIRETROVIRAL THERAPY; HIGH-DOSE FLUCONAZOLE; AMPHOTERICIN-B; RANDOMIZED-TRIAL; DRUG-INTERACTION; HEALTHY-VOLUNTEERS AB This is a comprehensive, clinically oriented review of the four commercially available triazoles: fluconazole, itraconazole, voriconazole, and posaconazole. Emphasis is placed in pharmacology, drug interactions, adverse events, antifungal activity, and the evolving perspective of their clinical use. Key clinical trials are briefly discussed, and specific drug indications summarized. Fluconazole remains a valuable low-cost choice for the treatment of various fiingal infections, including candidiasis and cryptococcosis. It has relatively few drug interactions and is safe but lacks activity against filamentous fungi. The use of itraconazole is historically plagued by erratic bioavailability of the oral capsule, improved with the oral solution. Drug interactions are numerous. Itraconazole exhibits significant activity against Aspergillus and the endemic fungi. Voriconazole has revolutionized the treatment of aspergillosis in severely immunocompromised patients, but its use is compromised by complicated pharmacokinetics, notable drug interactions, and relatively significant adverse events. Finally, posaconazole is the last addition to the azole armamentarium with extended antifungal spectrum, significant activity against the zygomycetes, and, apparently, optimal safety profile. Posaconazole has a significant role for the prophylaxis of invasive fungal infections in severely immunocompromised patients. Multiple daily dosing, a need for fatty foods for absorption, and absence of an intravenous formulation restrict its use to selected populations. C1 [Zonios, Dimitrios I.; Bennett, John E.] NIAID, Lab Clin Infect Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), 9000 Rockville Pike,Bldg 10-11N234, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov FU Intramural NIH HHS NR 129 TC 69 Z9 72 U1 0 U2 11 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD APR PY 2008 VL 29 IS 2 BP 198 EP 210 DI 10.1055/s-2008-1063858 PG 13 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 280KR UT WOS:000254426200011 PM 18366001 ER PT J AU Pasarica, M Mashtalir, N McAllister, EJ Kilroy, GE Koska, J Permana, P De Courten, B Yu, MH Ravussin, E Gimble, JM Dhurandhar, NV AF Pasarica, Magdalena Mashtalir, Nazar McAllister, Emily J. Kilroy, Gail E. Koska, Juraj Permana, Paska De Courten, Barbora Yu, Minghuan Ravussin, Eric Gimble, Jeffery M. Dhurandhar, Nikhil V. TI Adipogenic human adenovirus Ad-36 induces commitment, differentiation, and lipid accumulation in human adipose-derived stem cells SO STEM CELLS LA English DT Article DE obesity; adiposity; adipogenesis; infectobesity; lipogenesis; adipocyte progenitors ID CANINE-DISTEMPER VIRUS; LIPOPROTEIN-LIPASE; IN-VITRO; PREADIPOCYTE DIFFERENTIATION; COMMITTED PREADIPOCYTES; TEMPORAL-CHANGES; INDUCED OBESITY; STROMAL CELLS; PPAR-GAMMA; TISSUE AB Human adenovirus Ad-36 is causatively and correlatively linked with animal and human obesity, respectively. Ad-36 enhances differentiation of rodent preadipocytes, but its effect on adipogenesis in humans is unknown. To indirectly assess the role of Ad-36-induced adipogenesis in human obesity, the effect of the virus on commitment, differentiation, and lipid accumulation was investigated in vitro in primary human adipose-derived stem/stromal cells (hASC). Ad-36 infected hASC in a time- and dose-dependent manner. Even in the presence of osteogenic media, Ad-36-infected hASC showed significantly greater lipid accumulation, suggestive of their commitment to the adipocyte lineage. Even in the absence of adipogenic inducers, Ad-36 significantly increased hASC differentiation, as indicated by a time-dependent expression of genes within the adipogenic cascade-CCAAT/Enhancer binding protein-beta, peroxisome proliferator-activated receptor-gamma, and fatty acid-binding protein-and consequentially increased lipid accumulation in a time- and viral dose-dependent manner. Induction of hASC to the adipocyte state by Ad-36 was further supported by increased expression of lipoprotein lipase and the accumulation of its extracellular fraction. hASC from subjects harboring Ad-36 DNA in their adipose tissue due to natural infection had significantly greater ability to differentiate compared with Ad-36 DNA-negative counterparts, which offers a proof of concept. Thus, Ad-36 has the potential to induce adipogenesis in hASC, which may contribute to adiposity induced by the virus. C1 [Pasarica, Magdalena; Mashtalir, Nazar; McAllister, Emily J.; Kilroy, Gail E.; Ravussin, Eric; Gimble, Jeffery M.; Dhurandhar, Nikhil V.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Infect Obes Lab, Baton Rouge, LA 70808 USA. [Koska, Juraj; Permana, Paska; De Courten, Barbora] NIDDK, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ USA. [De Courten, Barbora] Baker Heart Res Inst, Melbourne, Vic, Australia. [Yu, Minghuan] Wayne State Univ, Detroit, MI USA. RP Dhurandhar, NV (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, Infect Obes Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM nikhil.dhurandhar@pbrc.edu OI de Courten, Barbora/0000-0001-8760-2511 FU NIDDK NIH HHS [1R01-DK066164, DK072476, P30 DK072476, P30 DK072476-04, R01 DK066164] NR 51 TC 59 Z9 63 U1 1 U2 11 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD APR PY 2008 VL 26 IS 4 BP 969 EP 978 DI 10.1634/stemcells.2007-0868 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 288QD UT WOS:000255000000014 PM 18203674 ER PT J AU Bera, TK Saint Fleur, A Ha, D Yamada, M Lee, Y Lee, B Hahn, Y Kaufman, DS Pera, M Pastan, I AF Bera, Tapan K. Saint Fleur, Ashley Ha, Duc Yamada, Masanori Lee, Yoomi Lee, Byungkook Hahn, Yoonsoo Kaufman, Dan S. Pera, Martin Pastan, Ira TI Selective POTE paralogs on chromosome 2 are expressed in human embryonic stem cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID HUMAN PROSTATE; HUMAN GENOME; CANCER; EVOLUTION; REGIONS; GENES; ANTIGENS; PROTEINS AB POTE is a primate-specific gene family that encodes cancer testis antigens that contain three domains, although the proteins vary greatly in size. The amino-terminal domain is novel and has three cysteine-rich domains of 37 amino acids. The second and third domains are rich in ankyrin repeats and spectrin-like helices respectively. In humans, 13 highly homologous paralogs are dispersed among eight chromosomes. Some members of the POTE gene family have an actin insertion at the carboxyl end of the protein. The expression of the POTE gene in normal adult tissues is restricted, but several POTE paralogs are frequently expressed in many cancers including breast, prostate, and lung cancers. We show here that POTE is expressed in several human embryonic stem (ES) cell lines. We found that UC06, WA01 and ES03 cell lines express mainly a POTE-2 gamma transcript but ES02 and ES04 cell lines predominantly express POTE-2 alpha. The WA09 cell line expressed both POTE-2 gamma and POTE-2 alpha. There is no detectable POTE gene expression in fetal tissues (ages 16 - 36 weeks). The POTE paralogs that are expressed in ES cells may have a specific function during lineage-specific differentiation of ES cells. C1 [Bera, Tapan K.; Saint Fleur, Ashley; Ha, Duc; Yamada, Masanori; Lee, Yoomi; Lee, Byungkook; Hahn, Yoonsoo; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kaufman, Dan S.] Univ Minnesota, Stem Cell Inst, Minneapolis, MN 55455 USA. [Kaufman, Dan S.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Pera, Martin] Monash Univ, Monash Inst Med Res, Clayton, Vic 3168, Australia. [Pera, Martin] Australian Stem Cell Ctr, Clayton, Vic, Australia. [Pera, Martin] Univ So Calif, Keck Sch Med, Ctr Stem Cell & Regenerat Med, Los Angeles, CA 90089 USA. [Hahn, Yoonsoo] Chung Ang Univ, Coll Nat Sci, Dept Life Sci, Seoul 156756, South Korea. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov RI PERA, MARTIN/A-9812-2012 OI PERA, MARTIN/0000-0001-6239-0428 FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL077923, R01 HL077923-02] NR 18 TC 7 Z9 9 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD APR PY 2008 VL 17 IS 2 BP 325 EP 332 DI 10.1089/scd.2007.0079 PG 8 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 297DK UT WOS:000255597100011 PM 18447647 ER PT J AU Ay, H Arsava, EM Vangel, M Oner, B Zhu, M Wu, O Singhal, A Koroshetz, WJ Sorensen, AG AF Ay, Hakan Arsava, E. Murat Vangel, Mark Oner, Banu Zhu, Mingwang Wu, Ona Singhal, Aneesh Koroshetz, Walter J. Sorensen, A. Gregory TI Interexaminer difference in infarct volume measurements on MRI - A source of variance in stroke research SO STROKE LA English DT Article DE acute stroke; diffusion-weighted imaging; MRI; neuroradiology ID CEREBRAL-BLOOD-FLOW; HIGH-RESOLUTION MEASUREMENT; TRACER BOLUS PASSAGES; HYPERACUTE STROKE; INTEROBSERVER AGREEMENT; INTERRATER RELIABILITY; DIFFUSION; PERFUSION; CLASSIFICATION; MISMATCH AB Background and Purpose - The measurement of ischemic lesion volume on diffusion- (DWI) and perfusion-weighted MRI (PWI) is examiner dependent. We sought to quantify the variance imposed by measurement error in DWI and PWI lesion volume measurements in ischemic stroke. Methods - Fifty-eight consecutive patients with DWI and PWI within 12 hours of symptom onset and follow-up MRI on >= day-5 were studied. Two radiologists blinded to each other measured lesion volumes by manual outlining on each image. Interexaminer reliability was evaluated by intraclass correlation coefficients (ICC) and relative paired difference or RPD (ratio of difference between 2 measurements to their mean). The ratio of between-examiner variability to between-subject variability (variance ratio) was calculated for each imaging parameter. Results - The correlation (ICC) between examiners ranged from 0.93 to 0.99. The median RPD was 10.0% for DWI, 14.1% for mean transit time, 18.9% for cerebral blood flow, 21.0% for cerebral blood volume, 16.8% for DWI/MTT mismatch, and 6.3% for chronic T2-weighted images. There was negative correlation between RPD and lesion volume in all but chronic T2-weighted images. The variance ratio ranged between 0.02 and 0.10. Conclusion - Despite high correlation between volume measurements of abnormal regions on DWI and PWI by different examiners, substantial differences in individual measurements can still occur. The magnitude of variance from measurement error is primarily determined by the type of imaging and lesion volume. Minimizing this source of variance will better enable imaging to deliver on its promise of smaller sample size. C1 [Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Stroke Serv, Boston, MA USA. [Ay, Hakan; Arsava, E. Murat; Vangel, Mark; Oner, Banu; Zhu, Mingwang; Wu, Ona; Sorensen, A. Gregory] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA USA. [Koroshetz, Walter J.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Ay, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013 OI Arsava, Ethem Murat/0000-0002-6527-4139 FU NCRR NIH HHS [P41-RR14075]; NINDS NIH HHS [NS38477, R01-NS38477-04] NR 28 TC 36 Z9 37 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2008 VL 39 IS 4 BP 1171 EP 1176 DI 10.1161/STROKEAHA.107.502104 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 283JQ UT WOS:000254632900020 PM 18292377 ER PT J AU McGinn, AP Kaplan, RC Verghese, J Rosenbaum, DM Psaty, BM Baird, AE Lynch, JK Wolf, PA Kooperberg, C Larson, JC Wassertheil-Smoller, S AF McGinn, Aileen P. Kaplan, Robert C. Verghese, Joe Rosenbaum, Daniel M. Psaty, Bruce M. Baird, Alison E. Lynch, John K. Wolf, Philip A. Kooperberg, Charles Larson, Joseph C. Wassertheil-Smoller, Sylvia TI Walking speed and risk of incident ischemic stroke among postmenopausal women SO STROKE LA English DT Article DE physical function; stroke; walking speed; women ID LOWER-EXTREMITY FUNCTION; CARDIOVASCULAR-HEALTH; OLDER-ADULTS; SUBSEQUENT DISABILITY; ELDERLY-PEOPLE; GAIT SPEED; FRAILTY; ABNORMALITIES; PREDICTORS; VALIDITY AB Background and Purpose - Walking speed is a simple, reliable, and valid measure of functional status that has been shown to be strongly correlated with age- related outcomes and may be an indicator of subclinical cerebrovascular disease. However, few studies have investigated the association of walking speed with risk of incident ischemic stroke. Methods - The present analyses included 13 048 postmenopausal women ( mean age 65 years) from the Women's Health Initiative free of stroke at baseline, 264 of whom had incident ischemic strokes on follow- up. Cox proportional hazards regression was used to obtain hazard ratios ( HRs) and 95% confidence intervals ( CIs) to assess the relationship between performance on a timed walk and risk of incident ischemic stroke. Multivariate adjustment included age, race/ ethnicity, body mass index, waist- hip ratio, depression, arthritis, hypertension, smoking, systolic blood pressure, treated diabetes, hormone use, NSAID use, aspirin use, self- reported general health, and history of coronary heart disease. Results - Slower walking speed was a significant predictor of incident ischemic stroke. After multivariate adjustment, the hazard for incident ischemic stroke was increased for the slowest walking speed tertile compared to the fastest walking speed tertile ( HR = 1.69, 95% CI: 1.21, 2.36). Additional adjustment for other physical function variables ( grip strength and chair stands) did not change the association significantly. Conclusions - Slow walking speed was found to be a strong predictor of increased risk of incident ischemic stroke among postmenopausal women independent of other established risk factors for stroke. C1 [McGinn, Aileen P.; Kaplan, Robert C.; Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Verghese, Joe; Rosenbaum, Daniel M.] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA. [Kooperberg, Charles; Larson, Joseph C.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA. [Baird, Alison E.] Boston Univ, Sch Med, Natl Inst Neurol Disorders & Storke, Stroke Neurosci Unit, Boston, MA 02118 USA. [Lynch, John K.] Boston Univ, Sch Med, Neuroepidemiol Branch, Boston, MA 02118 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP McGinn, AP (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave Belfer 1006A, Bronx, NY 10461 USA. EM amcginn@aecom.yu.edu RI Kaplan, Robert/A-2526-2011 NR 25 TC 29 Z9 29 U1 0 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 APR PY 2008 VL 39 IS 4 BP 1233 EP 1239 DI 10.1161/STROKEAHA.107.500850 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 283JQ UT WOS:000254632900029 PM 18292379 ER PT J AU Grotta, JC Jacobs, TP Koroshetz, WJ Moskowitz, MA AF Grotta, James C. Jacobs, Thomas P. Koroshetz, Walter J. Moskowitz, Michael A. TI Stroke program review group - An interim report SO STROKE LA English DT Article DE stroke; research; ischemia; hemorrhage AB The Stroke Program Review Group (SPRG) met for the first time in 2001 to identify and prioritize scientific needs and opportunities in stroke, and to consider strategies to address them. Out of this meeting came a set of scientific and resource recommendations (http://www.ninds.nih.gov/find_people/groups/stroke_prg/index.htm) including the recommendation to review progress after 5 years. In September 2006, the NINDS convened a second SPRG of prominent scientists, clinicians, industry leaders, and patient advocates to discuss progress since the first SPRG and to examine new opportunities in light of more recent advances. The report of the second SPRG meeting is found at http://www.ninds.nih.gov/find_people/groups/stroke_prg/09_2006_stroke_prg_report.htm. In this brief interim report, we list and summarize progress in each of the investigational domains outlined in the SPRG with an emphasis on those advances directly resulting from NINDS-funded research. Also listed are the top 2 or 3 research priorities for the next 5-year cycle for each investigational theme. What emerges from the first 2 reports is a clear set of priorities that have since been complemented by exciting advances that are likely to be the focus of a follow-up report from the next SPRG in 2010. C1 [Grotta, James C.] Univ Texas Houston, Sch Med, Dept Neurol, Houston, TX 77080 USA. [Jacobs, Thomas P.] NINDS, Ctr Neurosci, Extramural Res Program, NIH, Bethesda, MD 20892 USA. [Koroshetz, Walter J.] NINDS, Ctr Neurosci, NINDS Off Director, NIH, Bethesda, MD 20892 USA. [Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. RP Grotta, JC (reprint author), Univ Texas Houston, Sch Med, Dept Neurol, 6431 Fannin St, Houston, TX 77080 USA. EM james.c.grotta@uth.tmc.edu NR 0 TC 22 Z9 23 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 APR PY 2008 VL 39 IS 4 BP 1364 EP 1370 DI 10.1161/STROKEAHA.107.510776 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 283JQ UT WOS:000254632900053 PM 18309142 ER PT J AU Banerjee, HN Verma, M AF Banerjee, Hirendra N. Verma, Mukesh TI Application of nanotechnology in cancer SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE cancer diagnosis; gene expression; imaging; nanomedicine; nanotechnology ID GOLD NANORODS; NANOPARTICLES AB Nanotechnology refers broadly to a field of applied science and technology whose unifying theme is the control of matter on the molecular level in scales smaller than 1 micrometer, normally 1 to 100 nanometers, and the fabrication of devices within that size range. In the last five years this technology has been improved tremendously in disease diagnosis and prognosis and maximum research and clinical work has been completed in cancer. The use of various pharmaceutical nanocarriers has become one of the most important areas of nanomedicine. Novel nanotechnologies can complement and augment existing genomic and proteomic techniques to analyze variations across different tumor types, thus offering the potential to distinguish between normal and malignant cells. Sensitive biosensors constructed of nanoscale components (e.g., nanocantilevers, nanowires, and nanochannels) can recognize genetic and molecular events and have reporting capabilities, thereby offering the potential to detect rare molecular signals associated with malignancy. Such signals may then be collected for analysis by nanoscale harvesters that selectively isolate cancer-related molecules from tissues. The implication of nanotechnology in cancer is discussed in this article with an emphasis on biomarker detection, imaging studies for diagnosis, and its role in therapeutic intervention. C1 [Banerjee, Hirendra N.] Univ N Carolina, Dept Biol & Pharmaceut Sci, Elizabeth City State Univ, Elizabeth City, NC 27909 USA. [Verma, Mukesh] NCI, Methods & Technol Branch Epidemiol, Bethesda, MD 20892 USA. [Verma, Mukesh] NCI, Genet Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Banerjee, HN (reprint author), Univ N Carolina, Dept Biol & Pharmaceut Sci, Elizabeth City State Univ, Campus Box 930 1704 Weeksville Rd, Elizabeth City, NC 27909 USA. EM bhirendranath@mail.ecsu.edu NR 15 TC 10 Z9 10 U1 0 U2 8 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 1533-0346 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD APR PY 2008 VL 7 IS 2 BP 149 EP 154 PG 6 WC Oncology SC Oncology GA 288TT UT WOS:000255009400008 PM 18345704 ER PT J AU Sabik, LM Lie, RK AF Sabik, Lindsay M. Lie, Reidar K. TI Principles versus procedures in making health care coverage decisions: addressing inevitable conflicts SO THEORETICAL MEDICINE AND BIOETHICS LA English DT Article DE health care; priority setting; accountability for reasonableness; appeal process ID NICE; UNIT; ACCOUNTABILITY; MEDICINE; CRITERIA; ACCESS; REFORM; GOAL AB It has been suggested that focusing on procedures when setting priorities for health care avoids the conflicts that arise when attempting to agree on principles. A prominent example of this approach is "accountability for reasonableness." We will argue that the same problem arises with procedural accounts; reasonable people will disagree about central elements in the process. We consider the procedural condition of appeal process and three examples of conflicts over coverage decisions: a patients' rights law in Norway, health technologies coverage recommendations in the UK, and care withheld by HMOs in the US. In each case a process is at the center of controversy, illustrating the difficulties in establishing procedures that are widely accepted as legitimate. Further work must be done in developing procedural frameworks. C1 [Sabik, Lindsay M.; Lie, Reidar K.] Natl Inst Hlth, Dept Bioeth, Bethesda, MD 20892 USA. RP Lie, RK (reprint author), Natl Inst Hlth, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM rlie@cc.nih.gov OI Sabik, Lindsay/0000-0002-0613-4929 FU Intramural NIH HHS NR 37 TC 8 Z9 8 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-7415 J9 THEOR MED BIOETH JI Theor. Med. Bioeth. PD APR PY 2008 VL 29 IS 2 BP 73 EP 85 DI 10.1007/s11017-008-9062-4 PG 13 WC Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Social Issues; Biomedical Social Sciences GA 332CW UT WOS:000258060400001 PM 18535922 ER PT J AU Burns, DM Dybing, E Gray, N Hecht, S Anderson, C Sanner, T O'Connor, R Djordjevic, M Dresler, C Hainaut, P Jarvis, M Opperhuizen, A Straif, K AF Burns, D. M. Dybing, E. Gray, N. Hecht, S. Anderson, C. Sanner, T. O'Connor, R. Djordjevic, M. Dresler, C. Hainaut, P. Jarvis, M. Opperhuizen, A. Straif, K. TI Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal SO TOBACCO CONTROL LA English DT Article C1 [Burns, D. M.; Anderson, C.] UCSD Sch Med, San Diego, CA USA. [Dybing, E.] Norwegian Inst Publ Hlth, Div Environm Med, Oslo, Norway. [Gray, N.] Canc Council Victoria, Melbourne, Vic, Australia. [Hecht, S.] Univ Minnesota, Ctr Canc, Minneapolis, MN USA. [Sanner, T.] Norwegian Radium Hosp, Inst Canc Res, Dept Environm & Occupat Canc, Oslo, Norway. [O'Connor, R.] Roswell Pk Res Inst, Buffalo, NY USA. [Djordjevic, M.] NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. [Dresler, C.] Arkansas Dept Hlth, Little Rock, AR 72205 USA. [Hainaut, P.; Straif, K.] Int Agcy Res Canc, F-69372 Lyon, France. [Jarvis, M.] UCL Royal Free & Univ Coll Med Sch, London WC1E 6BT, England. RP Burns, DM (reprint author), 1120 Solana Dr, Del Mar, CA 92014 USA. EM dburns@ucsd.edu RI O'Connor, Richard/A-6961-2009 NR 16 TC 1 Z9 1 U1 2 U2 7 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 APR PY 2008 VL 17 IS 2 DI 10.1136/tc.2007.024158 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 280YH UT WOS:000254462200020 ER PT J AU Hard, GC Seely, JC Kissling, GE Betz, LJ AF Hard, Gordon C. Seely, John Curtis Kissling, Grace E. Betz, Laura J. TI Spontaneous Occurrence of a Distinctive Renal Tubule Tumor Phenotype in Rat Carcinogenicity Studies Conducted by the National Toxicology Program SO TOXICOLOGIC PATHOLOGY LA English DT Article DE rat; renal tubule tumors; spontaneous occurrence; amphophilic-vacuolar renal tumors; familial renal tumors ID CHRONIC PROGRESSIVE NEPHROPATHY; EKER RAT; NEOPLASTIC LESIONS; CONVENTIONAL RATS; 90-DAY TOXICITY; LABORATORY RAT; CELL CARCINOMA; TSC2 GENE; MODEL; CANCER AB The Toxicology Data Management System (TDMS) of the National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas, or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound. C1 [Seely, John Curtis] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Kissling, Grace E.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. [Betz, Laura J.] Constella Hlth Sci, Durham, NC USA. RP Hard, GC (reprint author), POB 86, Tairva 3544, New Zealand. EM gordonhard@msn.com FU Federal funds from the National Institute of Environmental Health Sciences (NIEHS),; NIH [N01-ES-95435] FX This work was supported by Federal funds from the National Institute of Environmental Health Sciences (NIEHS), NIH, under contract N01-ES-95435 to Experimental Pathology Laboratories (EPL) Inc, Research Triangle Park, NC, and, in part, by the Intramural Research Program of NIEHS, NIH. The authors are grateful to Drs. J. Hardisty and M. Hamlin of EPL, Research Triangle Park, NC, for their encouragement in this project. The authors are also indebted to Keith Connelly and Errol Parker of EPL Inc, who were responsible for accessing the slides from the Archives. Without their contribution, the survey would not have been achievable. In addition, we acknowledge Maureen Puccini and Emily Singletary of EPL Inc for assistance with photography. NR 27 TC 11 Z9 11 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 APR PY 2008 VL 36 IS 3 BP 388 EP 396 DI 10.1177/0192623308315829 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 463UO UT WOS:000267457900004 PM 18441261 ER PT J AU Dixon, D Herbert, RA Kissling, GE Brix, AE Miller, RA Maronpot, RR AF Dixon, Darlene Herbert, Ronald A. Kissling, Grace E. Brix, Amy E. Miller, Rodney A. Maronpot, Robert R. TI Summary of Chemically Induced Pulmonary Lesions in the National Toxicology Program (NTP) Toxicology and Carcinogenesis Studies SO TOXICOLOGIC PATHOLOGY LA English DT Article DE NTP; pathology; lung; pulmonary; lesions; chemicals; induced; rats; mice; lung neoplasms ID CLARA CELL ADENOMA; LUNG-CANCER HISTOLOGY; MOUSE LUNG; RATS; NEOPLASMS; ORIGIN; TUMORS; MICE; CLASSIFICATION; CIGARETTE AB The lung is the second most common target site of neoplasia of chemicals tested by the National Toxicology Program (NTP). Of all peer-reviewed NTP studies to date (N = 545), a total of sixty-four chemicals in sixty-six reports produced significant site-specific neoplasia in the lungs of rats and/or mice. Of the studies associated with lung tumor induction, approximately 35% were inhalation and 35% were gavage studies, with dosed-feed, dosed-water, topical, intraperitoneal, or in utero routes of chemical administration accounting for 18%, 6%, 3%, 1%, and 1% of the studies, respectively. The most commonly induced lung tumors were alveolar/bronchiolar (A/B) adenoma and/or carcinoma for both species. The most frequently observed nonneoplastic lesions included hyperplasia and inflammation in both species. The liver was the most common primary site of origin of metastatic lesions to the lungs of mice; however, skin was most often the primary site of origin of metastatic lesions to the lungs of rats. In summary, A/B adenoma and carcinoma were the most frequently diagnosed chemically induced tumors in the lungs of both rats and mice in the NTP toxicology and carcinogenesis bioassays, and hyperplasia and inflammation were the most common nonneoplastic changes observed. C1 [Dixon, Darlene; Herbert, Ronald A.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Brix, Amy E.; Miller, Rodney A.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. RP Dixon, D (reprint author), NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU National Institutes of Health (NIH); National Toxicology Program (NTP); National Institute of Environmental Health Sciences FX The authors thank Drs. John Peckham and Abraham Nyska for their critical review of this manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the National Toxicology Program (NTP), National Institute of Environmental Health Sciences. NR 19 TC 12 Z9 12 U1 0 U2 1 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 APR PY 2008 VL 36 IS 3 BP 428 EP 439 DI 10.1177/0192623308315360 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA 463UO UT WOS:000267457900008 PM 18441259 ER PT J AU Roberts, JE Wielgus, AR Boyes, WK Andley, U Chignell, CF AF Roberts, Joan E. Wielgus, Albert R. Boyes, William K. Andley, Usha Chignell, Colin F. TI Phototoxicity and cytotoxicity of fullerol in human lens epithelial cells SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE fullerenes; fullerol; ocular toxicology; phototoxicity; human lens epithelial cells; dynamic light scattering ID OCULAR PHOTOTOXICITY; ALPHA-CRYSTALLIN; STATE PROPERTIES; MALONIC-ACID; BOVINE LENS; C-60; DERIVATIVES; LIGHT; EYE; NANOPARTICLES AB The water-soluble, hydroxylated fullerene [fullerol, nano-C-60(OH)(22-26)] has several clinical applications including use as a drug carrier to bypass the blood ocular barriers. We have assessed fullerol's potential ocular toxicity by measuring its cytotoxicity and phototoxicity induced by UVA and visible light in vitro with human lens epithelial cells (HLE B-3). Accumulation of nano-C-60(OH)(22-26) in the cells was confirmed spectrephotometrically at 405 am and cell viability estimated using MTS and LDH assays. Fullerol was cytotoxic to HLE B-3 cells maintained in the dark at concentrations higher than 20 mu M. Exposure to either UVA or visible light in the presence of >5 mu M fullerol-induced phototoxic damage. When cells were pretreated with non-toxic antioxidants: 20 mu M lutein, 1 mM N-acetyl cysteine, or 1 mM L-ascorbic acid prior to irradiation, only the singlet oxygen quencher-lutein significantly protected against fullerol photodamage. Apoptosis was observed in lens cells treated with fullerol whether or not the cells were irradiated, in the order UVA>visible light>dark. Dynamic light scattering (DLS) showed that in the presence of the endogenous lens protein a-crystallin, large aggregates of fullerol were reduced. In conclusion, fullerol is both cytotoxic and phototoxic to human lens epithelial cells. Although the acute toxicity of water-soluble nano-C-60(OH)(22-26) is low, these compounds are retained in the body for long periods, raising concern for their chronic toxic effect. Before fullerols are used to deliver drugs to the eye, they should be tested for photo- and cytotoxicity in vivo. Published by Elsevier Inc. C1 [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. [Wielgus, Albert R.; Chignell, Colin F.] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Boyes, William K.] US EPA, Natl Hlth & Environm REs Lab, Div Neurotoxicol, Res Triangle Pk, NC 27711 USA. [Boyes, William K.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. RP Roberts, JE (reprint author), Fordham Univ, Dept Nat Sci, 113 W 60th St, New York, NY 10023 USA. EM jroberts@fordham.edu; wielgus@nichs.nih.gov; Boyes.William@epamail.epa.gov; andley@vision.wustl.edu; chignell@nichs.nih.gov FU Intramural NIH HHS [NIH0010085416, Z01 ES050046-29] NR 52 TC 67 Z9 69 U1 1 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD APR 1 PY 2008 VL 228 IS 1 BP 49 EP 58 DI 10.1016/j.taap.2007.12.010 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 282CD UT WOS:000254544300007 PM 18234258 ER PT J AU Shin, JW Jin, P Fan, Y Slezak, S David-Ocampo, V Khuu, HM Read, EJ Wang, E Marincola, FM Stroncek, DF AF Shin, Jeong Won Jin, Ping Fan, Yong Slezak, Stefanie David-Ocampo, Virginia Khuu, Hanh M. Read, Elizabeth J. Wang, Ena Marincola, Francesco M. Stroncek, David F. TI Evaluation of gene expression profiles of immature dendritic cells prepared from peripheral blood mononuclear cells SO TRANSFUSION LA English DT Article ID HUMAN MONOCYTES; CANCER-IMMUNOTHERAPY; MICROARRAY ANALYSIS; MATURATION; GENERATION; ANTIGEN; DIFFERENTIATION; IDENTIFICATION; SUBSETS; LINES AB BACKGROUND: Dendritic cells (DCs) generated ex vivo from peripheral blood monocytes or mobilized CD34+ cells and intended for clinical immunotherapy are typically characterized by morphologic, phenotypic, and functional assays. Assay results are highly dependent on conditions used to prepare the cells, so there is no standard assay battery for clinical DC products. This study evaluated gene expression profiling for characterization of immature DCs prepared from monocytes that had been elutriated from normal donor peripheral blood mononuclear cells (PBMNCs) immediately after collection or after storage at 4 degrees C for 48 hours. STUDY DESIGN AND METHODS: RNA was isolated from fresh and 48-hour-stored PBMNCs, elutriated monocytes, elutriated lymphocytes, and immature DCs from five healthy subjects and was analyzed with a cDNA gene expression microarray with 17,500 genes. RESULTS: Unsupervised hierarchical clustering separated the 40 products into four groups: one with all 10 immature DCs, one with all 10 elutriated lymphocytes, one with 7 PBMNCs, and one with 10 elutriated monocytes and 3 PBMNCs. Within each of the four groups, however, fresh and stored products, or products derived from fresh or stored products, clustered together. Comparison of genes differentially expressed by fresh versus stored products (paired t tests, p < 0.005) found 273 genes that differed between fresh and stored PBMCs, 429 between lymphocytes elutriated from fresh versus stored PBMNCs, 711 between monocytes elutriated from fresh versus stored PBMNCs, and 3 between immature DCs prepared from monocytes elutriated from fresh versus stored PBMCs. CONCLUSIONS: This study demonstrates the potential utility of gene expression profiling for characterization of cell therapy products. C1 Blood Syst Res Inst, San Francisco, CA USA. Soonchunhyang Univ Hosp, Dept Lab Med, Seoul, South Korea. NIH, NIH Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C711,10 Ctr Dr MSC 1184, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural NIH HHS [Z01 CL002095-11] NR 35 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD APR PY 2008 VL 48 IS 4 BP 647 EP 657 DI 10.1111/j.1537-2995.2007.01615.x PG 11 WC Hematology SC Hematology GA 278IC UT WOS:000254277500011 PM 18282241 ER PT J AU Estep, T Bucci, E Farmer, M Greenburg, G Harrington, J Kim, HW Klein, H Mitchell, P Nemo, G Olsen, K Palmer, A Valeri, CR Winslow, R AF Estep, Timothy Bucci, Enrico Farmer, Martha Greenburg, Gerson Harrington, John Kim, Hae Won Klein, Harvey Mitchell, Phyllis Nemo, George Olsen, Ken Palmer, Andre Valeri, C. Robert Winslow, Robert TI Basic science focus on blood substitutes: a summary of the NHLBI division of blood diseases and resources working group workshop, March 1, 2006 SO TRANSFUSION LA English DT Article ID HUMAN POLYMERIZED HEMOGLOBIN; RANDOMIZED-TRIAL; CARDIAC-SURGERY; ACUTE TRAUMA; TRANSFUSION AB In March 2006, a workshop sponsored by the National Heart, Lung, and Blood Institute was convened to identify the role of basic science research in clarifying issues that are impeding progress in the development of hemoglobin-based oxygen carrying (HBOC) solutions. These discussions resulted in a consensus that, although HBOCs have shown clinical promise, various side effects have inhibited further development and regulatory approval, with cardiovascular events being of particular concern. As a consequence, workshop participants focused on formulating research recommendations to better understand and mitigate these side effects. In addition, several important corollary issues were identified, including better understanding of the impact of HBOC infusion on human physiology; the need for rapid, noninvasive methods for the measurement of tissue oxygenation in human patients to better inform transfusion decisions; further investigation of routes and consequences of hemoglobin metabolism; optimization of clinical protocols for HBOC use; and assessment of the impact of HBOC formulation excipients. Also discussed was the possibility and desirability of developing new HBOCs with improved characteristics, such as prolonged functional intravascular persistence, greater stability, and a decreased propensity to generate reactive oxygen species. One practical limitation in this area is the consistent availability of pure, well-characterized HBOC solutions for the research community. This communication summarizes the opinion of workshop participants on these issues and concludes with a list of specific recommended areas of research that could positively impact the development of blood substitutes. C1 NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. Chart Biotech Consulting LLC, Erie, CO USA. Univ Maryland, Sch Med, Dept Biochem & Biol, Baltimore, MD 21201 USA. Harvard Univ, Sch Med, Dept Social Med, Boston, MA 02115 USA. Brown Univ, Dept Surg, Providence, RI 02912 USA. Biopure Corp, Cambridge, MA USA. SUNY Albany, Sch Sci & Engn, New Paltz, NY 12561 USA. NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. NHLBI, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. NHLBI, Blood Resources Program, Div Blood Dis & Resources, Bethesda, MD 20892 USA. Loyola Univ, Dept Chem, Chicago, IL 60626 USA. Ohio State Univ, Dept Chem & Biomol Engn, Columbus, OH 43210 USA. Naval Blood Res Lab, Plymouth, Devon, England. Sangart Inc, San Diego, CA USA. RP Mitchell, P (reprint author), NHLBI, Div Blood Dis & Resources, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM mitchelp@nhlbi.nih.gov NR 19 TC 25 Z9 26 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD APR PY 2008 VL 48 IS 4 BP 776 EP 782 DI 10.1111/j.1537-2995.2007.01604.x PG 7 WC Hematology SC Hematology GA 278IC UT WOS:000254277500028 PM 18194373 ER PT J AU Alter, HJ AF Alter, Harvey J. TI Pathogen reduction: A precautionary principle paradigm SO TRANSFUSION MEDICINE REVIEWS LA English DT Review ID WEST-NILE-VIRUS; BLOOD-TRANSFUSION; UNITED-STATES; INACTIVATION; HUMAN-HERPESVIRUS-8; TRANSMISSION; INFECTIONS; DONORS; RISKS AB Although remarkable advances have been made in the prevention of the major transfusion-transmitted diseases, long intervals have transpired between the first recognition of transfusion risk and the implementation of a preventive strategy. For hepatitis B virus, that interval was 30 years; for non-A, non-B/hepatitis C virus, 15 years; and for human immunodeficiency virus, West Nile virus, Trypanosoma cruzi, and bacteria, 3, 4, 5, and 18 years, respectively. In our existing reactive approach, there is a fundamental and inevitable delay before we can react; and thus, infections are destined to occur. The continued emergence or reemergence of transfusion-transmitted infections calls for a new paradigm of preemptive pathogen reduction (PR). Two PR systems, psoralen/UV-A and riboflavin/UV-A, have shown efficacy and safety for platelets and plasma; and psoralen/UV-A technology has been successfully implemented for platelets in Europe. Pathogen reduction can eliminate or reduce the risk for any nucleic acid containing agent, including bacteria, and thus will be effective for all but prion diseases. It is possible to introduce PR for platelets and plasma now and to concentrate resources on developing PR for red cells. This will require an intellectual and financial commitment from the National Institutes of Health, the Food and Drug Administration, industry, and the blood bank establishment, just as occurred for nucleic acid testing (NAT) technology. This can be done if there is sufficient will to do it. (C) 2008 Published by Elsevier Inc. C1 NIH, Infect Dis Sect, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Alter, HJ (reprint author), NIH, Infect Dis Sect, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov NR 16 TC 52 Z9 53 U1 0 U2 3 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 APR PY 2008 VL 22 IS 2 BP 97 EP 102 DI 10.1016/j.tmrv.2008.01.001 PG 6 WC Hematology SC Hematology GA 282AD UT WOS:000254539100001 PM 18353250 ER PT J AU Ofiviero, B Varchetta, S Donato, F Agnelli, F Rossi, G Berra, M Rigamonti, C Colombo, M Mavilio, D Mori, MU AF Ofiviero, B. Varchetta, S. Donato, F. Agnelli, F. Rossi, G. Berra, M. Rigamonti, C. Colombo, M. Mavilio, D. Mori, M. U. TI Prospective study of natural killer (NK) cell phenotype in recurring HCV infection following liver transplantation SO TRANSPLANT INTERNATIONAL LA English DT Meeting Abstract C1 Univ Pavia, I-27100 Pavia, Italy. IRCCS Fdn San Matteo, Pavia, Italy. IRCCS Fdn Policlin Mangiagalli Regina Elena, Gastroenterol & Liver Transplantat Unit, Milan, Italy. NIAID, NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0934-0874 J9 TRANSPL INT JI Transpl. Int. PD APR PY 2008 VL 21 SU 1 BP 1 EP 2 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 286II UT WOS:000254839200006 ER PT J AU Lavine, JS Poss, M Grenfell, BT AF Lavine, Jennie S. Poss, Mary Grenfell, Bryan T. TI Directly transmitted viral diseases: modeling the dynamics of transmission SO TRENDS IN MICROBIOLOGY LA English DT Review ID RESPIRATORY SYNCYTIAL VIRUS; INFECTIOUS-DISEASES; INDIVIDUAL VARIATION; POPULATION-DYNAMICS; UNITED-STATES; INFLUENZA; EVOLUTION; IMMUNITY; MEASLES; TUBERCULOSIS AB A key hurdle in understanding the spread and control of infectious diseases is to capture appropriately the dynamics of pathogen transmission. As people and goods travel increasingly rapidly around the world, so do pathogens; we must be prepared to understand their spread, in terms of the contact network between hosts, viral life history and within-host dynamics. This will require collaborative work that takes into account viral life history, strategy and evolution, and host genetics, demographics and immunodynamics. Mathematical models are a useful tool for integrating the data and analyses from diverse fields that contribute to our understanding of viral transmission dynamics in heterogeneous host populations. C1 [Lavine, Jennie S.; Poss, Mary; Grenfell, Bryan T.] Penn State Univ, Ctr Infect Dis Dynam, Mueller Lab 208, University Pk, PA 16803 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lavine, JS (reprint author), Penn State Univ, Ctr Infect Dis Dynam, Mueller Lab 208, University Pk, PA 16803 USA. EM js1236@psu.edu NR 52 TC 6 Z9 6 U1 0 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD APR PY 2008 VL 16 IS 4 BP 165 EP 172 DI 10.1016/j.tim.2008.01.007 PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 293PB UT WOS:000255346100006 PM 18356058 ER PT J AU Roberts, A Lamirande, EW Vogel, L Jackson, JP Paddock, CD Guarner, J Zaki, SR Sheahan, T Baric, R Subbarao, K AF Roberts, Anjeanette Lamirande, Elaine W. Vogel, Leatrice Jackson, Jadon P. Paddock, Christopher D. Guarner, Jeannette Zaki, Sherif R. Sheahan, Timothy Baric, Ralph Subbarao, Kanta TI Animal models and vaccines for SARS-CoV infection SO VIRUS RESEARCH LA English DT Article DE SARS coronavirus; BALB/c; C57BL/6; 129S6 mice; hamsters; ferrets; non-human primates; vaccines; FIPV; enhanced disease; urbani; HKU-39849; Frankfurt 1; GD03T0013 ID ACUTE-RESPIRATORY-SYNDROME; ANTIBODY-DEPENDENT ENHANCEMENT; SYNDROME-ASSOCIATED CORONAVIRUS; HUMAN MONOCLONAL-ANTIBODY; SYNCYTIAL VIRUS RSV; GOLDEN SYRIAN-HAMSTERS; PERITONITIS VIRUS; BALB/C MICE; NEUTRALIZING ANTIBODIES; SPIKE PROTEIN AB We summarize findings of SARS-CoV infections in several animal models each of which support viral replication in lungs accompanied by histopathological changes and/or clinical signs of illness to varying degrees. New findings are reported on SARS-CoV replication and associated pathology in two additional strains (C57BL/16 and 129S6) of aged mice. We also provide new comparative data on viral replication and associated pathology following infection of golden Syrian hamsters with various SARS-CoV strains and report the levels of neutralizing antibody titers following these infections and the cross-protective efficacy of infection with these strains in protecting against heterologous challenge. Finally, we summarize findings of a variety of vaccine approaches and discuss the available in vitro and in vivo data addressing the potential for disease enhancement following re-infection in animals previously vaccinated against or infected with SARS-CoV. Published by Elsevier B.V. C1 [Roberts, Anjeanette; Lamirande, Elaine W.; Vogel, Leatrice; Jackson, Jadon P.; Subbarao, Kanta] NIH, NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Paddock, Christopher D.; Guarner, Jeannette; Zaki, Sherif R.] Ctr Dis Control & Prevent, Infect Dis Pathol Activity, Atlanta, GA USA. [Sheahan, Timothy; Baric, Ralph] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Sheahan, Timothy; Baric, Ralph] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. RP Subbarao, K (reprint author), NIH, NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov RI Guarner, Jeannette/B-8273-2013 FU Intramural NIH HHS [Z01 AI000934-05] NR 78 TC 43 Z9 43 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD APR PY 2008 VL 133 IS 1 BP 20 EP 32 DI 10.1016/j.virusres.2007.03.025 PG 13 WC Virology SC Virology GA 290TP UT WOS:000255145400004 PM 17499378 ER PT J AU Nickel, JC Mullins, C Tripp, DA AF Nickel, J. Curtis Mullins, Chris Tripp, Dean A. TI Development of an evidence-based cognitive behavioral treatment program for men with chronic prostatitis/chronic pelvic pain syndrome SO WORLD JOURNAL OF UROLOGY LA English DT Article DE chronic prostatitis; chronic pelvic pain syndrome; biopsychosocial; cognitive-behavioral treatment ID PREDICTORS AB Objectives Psychosocial factors reported by patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) promote greater pain, disability, and ultimately poorer quality of life (QOL). We targeted those parameters in the development of a cognitive-behavioral (CB) program designed specifically for CP/CPPS. Methods and materials Five NIH sponsored biopsychosocial studies examined predictors of pain, disability, and QOL in CP/CPPS men. Pain, urinary symptoms, QOL, depressive symptoms, catastrophic thinking about pain, perceived control over pain, pain-contingent resting as a pain coping measure, social support and interaction, sexual functioning, and relationship issues were assessed. These data showed that CB intervention for pain catastrophizing, pain contingent rest, social support and depressive symptoms is warranted for men with CP/CPPS Results An evidence based 8-week CB program was developed. The content of the CB sessions are defined in an instructional patient workbook for each of the weekly 1-h sessions. The CB program guides patients in examining the relationship between their symptom-based distress, their thinking at such times and the emotions linked with those thoughts, and their behavioral responses to their particular thinking style (e.g., illness vs. wellness focused). Patients complete such analyses by using a Reaction Record format, which also delineates new thinking/behavioral responses. Conclusions The CB program developed for CP/CPPS is the first comprehensive attempt to target specific evidence supported biopsychosocial variables for both symptom and QOL improvement in CP/CPPS and is expected to provide a useful tool for the clinical management of this chronic condition. C1 [Nickel, J. Curtis; Tripp, Dean A.] Queens Univ, Dept Urol & Psychol, Kingston, ON K7L 2V7, Canada. [Mullins, Chris] NIDDK, NIH, Bethesda, MD USA. RP Nickel, JC (reprint author), Queens Univ, Dept Urol & Psychol, Kingston, ON K7L 2V7, Canada. EM jcn@queensu.ca FU NIDDK NIH HHS [DK065174 S2] NR 20 TC 20 Z9 22 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD APR PY 2008 VL 26 IS 2 BP 167 EP 172 DI 10.1007/s00345-008-0235-6 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 288DE UT WOS:000254965600009 PM 18293000 ER PT J AU Gohlke, JM Armant, O Parham, FM Smith, MV Zimmer, C Castro, DS Nguyen, L Parker, JS Gradwohl, G Portier, CJ Guillemot, F AF Gohlke, Julia M. Armant, Olivier Parham, Frederick M. Smith, Marjolein V. Zimmer, Celine Castro, Diogo S. Nguyen, Laurent Parker, Joel S. Gradwohl, Gerard Portier, Christopher J. Guillemot, Francois TI Characterization of the proneural gene regulatory network during mouse telencephalon development SO BMC BIOLOGY LA English DT Article ID NOTCH SIGNALING PATHWAY; BINDING PROTEIN HUD; TRANSCRIPTION FACTORS; NEURONAL DIFFERENTIATION; CELL-DIFFERENTIATION; SOMITE SEGMENTATION; EXPRESSION DATA; GROWTH-FACTOR; POU PROTEINS; FACTOR YY1 AB Background: The proneural proteins Mash1 and Ngn2 are key cell autonomous regulators of neurogenesis in the mammalian central nervous system, yet little is known about the molecular pathways regulated by these transcription factors. Results: Here we identify the downstream effectors of proneural genes in the telencephalon using a genomic approach to analyze the transcriptome of mice that are either lacking or overexpressing proneural genes. Novel targets of Ngn2 and/or Mash1 were identified, such as members of the Notch and Wnt pathways, and proteins involved in adhesion and signal transduction. Next, we searched the non-coding sequence surrounding the predicted proneural downstream effector genes for evolutionarily conserved transcription factor binding sites associated with newly defined consensus binding sites for Ngn2 and Mash1. This allowed us to identify potential novel co-factors and co-regulators for proneural proteins, including Creb, Tcf/Lef, Pou-domain containing transcription factors, Sox9, and Mef2a. Finally, a gene regulatory network was delineated using a novel Bayesian-based algorithm that can incorporate information from diverse datasets. Conclusion: Together, these data shed light on the molecular pathways regulated by proneural genes and demonstrate that the integration of experimentation with bioinformatics can guide both hypothesis testing and hypothesis generation. C1 [Armant, Olivier; Zimmer, Celine; Castro, Diogo S.; Nguyen, Laurent; Guillemot, Francois] Natl Inst Med Res, Div Mol Neurobiol, London NW7 1AA, England. [Gohlke, Julia M.; Parham, Frederick M.; Portier, Christopher J.] Natl Inst Environm Hlth Sci, Mol Toxicol Lab, Environm Syst Biol Grp, Res Triangle Pk, NC 27709 USA. [Smith, Marjolein V.; Parker, Joel S.] Constella Hlth Sci, Durham, NC 27713 USA. [Armant, Olivier; Gradwohl, Gerard] INSERM, U682, F-67200 Strasbourg, France. RP Guillemot, F (reprint author), Natl Inst Med Res, Div Mol Neurobiol, Mill Hill, London NW7 1AA, England. EM gohlkej@niehs.nih.gov; Olivier.Armant@itg.fzk.de; parham@niehs.nih.gov; msmith@constellagroup.com; czimmer@nimr.mrc.ac.uk; dcastro@nimr.mrc.ac.uk; lnguyen@ulg.ac.be; jparker@expressionanalysis.com; gerard.gradwohl@titus.u-strasbg.fr; portier@niehs.nih.gov; fguille@nimr.mrc.ac.uk RI Portier, Christopher/A-3160-2010; Gradwohl, Gerard/H-8543-2014; OI Portier, Christopher/0000-0002-0954-0279; Gradwohl, Gerard/0000-0002-6730-2615; Castro, Diogo/0000-0001-8178-9565; Gohlke, Julia/0000-0002-6984-2893; armant, olivier/0000-0001-7101-9209 FU Intramural NIH HHS; Medical Research Council [, MC_U117570528] NR 86 TC 64 Z9 65 U1 0 U2 6 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 MAR 31 PY 2008 VL 6 AR 15 DI 10.1186/1741-7007-6-15 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 303HZ UT WOS:000256032900001 PM 18377642 ER PT J AU Bago, AG Palkovits, M Usdin, TB Seress, L Dobolyi, A AF Bago, Attila G. Palkovits, Miklos Usdin, Ted B. Seress, Laszlo Dobolyi, Arpad TI Evidence for the expression of parathyroid hormone 2 receptor in the human brainstem SO IDEGGYOGYASZATI SZEMLE-CLINICAL NEUROSCIENCE LA English DT Article DE neuropeptide receptor; neuromodulation; nociceptive information processing; pain; visceral sensory transmission ID TUBEROINFUNDIBULAR PEPTIDE; 39 RESIDUES; NERVOUS-SYSTEM; PTH2 RECEPTOR; HYPOTHALAMUS AB Background and purpose - The parathyroid hormone 2 receptor (PTH2R) is a G protein coupled receptor. Pharmacological and anatomical evidence suggests that the recently identified tuberoinfundibular peptide of 39 residues is, and parathyroid hormone and parathyroid hormone-related peptide are not, its endogenous ligand. Initial functional studies suggest that the PTH2R is involved in the regulation of viscerosensory information processing. As a first step towards clinical applications, herein we describe the presence of the PTH2R in the human brainstem. Material and methods - Total RNA was isolated from postmortem human cortical and brainstem samples for RT-PCR. Good quality RNA, as assessed on formaldehyde gel, was reverse transcribed. The combined cDNA products were used as template in PCR reactions with primer pairs specific for the human PTH2R. In addition, PTH2R immunolabelling was performed on free floating sections of the human medulla oblongata using fluorescent amplification immunochemistry. Results - Specific bands in the RT-PCR experiments and sequencing of PCR products demonstrated the expression of PTH2R mRNA in the human brainstem. A high density of PTH2R-immunoreactive fibers was found in brain regions of the medulla oblongata including the nucleus of the solitary tract, the spinal trigeminal nucleus, and the dorsal reticular nucleus of the medulla. Conclusion - Independent demonstration of the presence of PTH2R mRNA and immunoreactivity supports the specific expression of the PTH2R in the human brainstem. The distribution of PTH2R-immunoreactive fibers in viscerosensory brain regions is similar to that reported in mouse and rat suggesting a similar role of the PTH2R in human as in rodents. This finding will have important implications when experimental data obtained on the function of the TIP39-PTH2R neuromodulator system in rodents are to be utilized in human. C1 [Dobolyi, Arpad] Semmelweis Univ, Dept Anat Histol & Embryol, Neuromorphol Lab, H-1094 Budapest, Hungary. [Bago, Attila G.; Palkovits, Miklos; Dobolyi, Arpad] Hungarian Acad Sci, Dept Anat Histol & Embryol, Neuromorphol & Neuroendocrine Res Lab, Budapest, Hungary. [Bago, Attila G.] Natl Inst Neurosurg, Budapest, Hungary. [Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. [Seress, Laszlo] Univ Pecs, Cent Electron Microscop Lab, Pecs, Hungary. RP Dobolyi, A (reprint author), Semmelweis Univ, Dept Anat Histol & Embryol, Neuromorphol Lab, Tuzolto 58, H-1094 Budapest, Hungary. EM dobolyi@ano.sote.hu RI Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 FU Intramural NIH HHS [Z01 MH002685-14] NR 11 TC 3 Z9 3 U1 0 U2 3 PU LITERATURA MEDICA PI BUDAPEST PA MARGIT KRT 31-33, BUDAPEST, 1024, HUNGARY SN 0019-1442 J9 IDEGGYOGY SZEMLE JI Ideggyogy. Szle. PD MAR 30 PY 2008 VL 61 IS 3-4 BP 123 EP 126 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 341CY UT WOS:000258693000007 PM 18459453 ER PT J AU Halim, ND Lipska, BK Hyde, TM Deep-Soboslay, A Saylor, EM Herman, MM Thakar, J Verma, A Kleinman, JE AF Halim, Nader D. Lipska, Barbara K. Hyde, Thomas M. Deep-Soboslay, Amy Saylor, E. Michael Herman, Mary M. Thakar, Jay Verma, Ajay Kleinman, Joel E. TI Increased lactate levels and reduced pH in postmortem brains of schizophrenics: Medication confounds SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE schizophrenia; postmortem; brain collection; pH; lactate ID GENE-EXPRESSION; ANTIPSYCHOTIC-DRUGS; OXIDATIVE STRESS; MESSENGER-RNA; METABOLISM; ABNORMALITIES; AMPHETAMINE; MONOAMINES; GLYCOGEN; LESSONS AB A number of postmortem studies have found decreased pH in brains of patients with schizophrenia. Insofar as lower pH has been associated with decreased mRNA expression in postmortem human brain, decreased pH in schizophrenia may represent an important potential confound in comparisons between patients and controls. We hypothesized that decreased pH may be related to increased concentration of lactic acid. However, in contrast to the previous notion that an increase in lactic acid represents evidence for primary metabolic abnormalities in schizophrenia, we hypothesized that this increase is secondary to prior antipsychotic treatment. We have tested this by first demonstrating that lactate levels in the cerebellum of patients with schizophrenia (n = 35) are increased relative to control subjects (n = 42) by 28%,p = 0.001. Second, we have shown that there is an excellent correlation between lactate levels in the cerebellum and pH. and that this correlation is particularly strong in patients (r = -0.78, p = 3E-6). Third. we have shown in rats that chronic haloperidol (0.8 mg/kg/day) and clozapine (5 mg/kg/day) increase lactic acid concentration in the frontal cortex relative to vehicle (by 31% and 22% respectively, p < 0.01). These data suggest that lactate increases in postmortem human brain of patients with schizophrenia are associated with decreased pH and that these changes are possibly related to antipsychotic treatment rather than a primary metabolic abnormality in the prefrontal cortex of patients with schizophrenia. Published by Elsevier B.V. C1 [Lipska, Barbara K.; Hyde, Thomas M.; Deep-Soboslay, Amy; Saylor, E. Michael; Herman, Mary M.; Kleinman, Joel E.] NIMH, Clin Brain Disorders Branch, Div Intramural Res Programs, Natl Inst Hlth, Bethesda, MD 20892 USA. [Halim, Nader D.] Grad Program Mol & Cell Biol, Bethesda, MD 20814 USA. [Halim, Nader D.; Thakar, Jay; Verma, Ajay] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Div Intramural Res Programs, Natl Inst Hlth, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lipskab@intra.nimh.nih.gov FU Intramural NIH HHS [Z01 MH002399-18, Z99 MH999999] NR 31 TC 31 Z9 32 U1 0 U2 0 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 MAR 30 PY 2008 VL 169 IS 1 BP 208 EP 213 DI 10.1016/j.jneumeth.2007.11.017 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 284BV UT WOS:000254681100025 PM 18177946 ER PT J AU Simonetti, A Gigli, A Capocaccia, R Mariotto, A AF Simonetti, Arianna Gigli, Anna Capocaccia, Riccardo Mariotto, Angela TI Estimating complete prevalence of cancers diagnosed in childhood SO STATISTICS IN MEDICINE LA English DT Article DE limited duration prevalence; completeness index; cancer registry ID POPULATION-BASED REGISTRIES; TUMOR-REGISTRY AB A method of estimating the complete prevalence of cancers diagnosed in childhood called CHILDPREV (CHILDhood PREValence), is presented. It is a semi-parametric method based on cancer registry data and on the completeness index method. It allows estimating prevalence even when no observation is available (typically older patients alive at the prevalence date may have been diagnosed with cancer before the introduction of the registry). The method was validated on Connecticut Tumor Registry data, which has 62 years of follow-up and provides complete prevalence, and compared with the fully parametric PIAMOD method. Results of complete childhood prevalence estimates based on SEER-9 cancer registries data for acute lymphocytic leukemia and all cancer sites combined are presented. Copyright (C) 2007 John Wiley & Sons, Ltd. C1 [Simonetti, Arianna; Capocaccia, Riccardo] Ist Super Sanita, Natl Ctr Epidemiol Surveillance & Hlth Promot, Dept Canc Epidemiol, I-00161 Rome, Italy. [Simonetti, Arianna] Univ Roma La Sapienza, Dept Stat Probabil & Appl Stat, Rome, Italy. [Simonetti, Arianna; Gigli, Anna] CNR, Inst Res Populat & Social Policies, Rome, Italy. [Mariotto, Angela] NCI, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. RP Simonetti, A (reprint author), Ist Super Sanita, Natl Ctr Epidemiol Surveillance & Hlth Promot, Dept Canc Epidemiol, Viale Regima Elena 299, I-00161 Rome, Italy. EM arianna.simonetti@iss.it OI Gigli, Anna/0000-0003-4929-505X FU PHS HHS [263 MQ 218967] NR 10 TC 9 Z9 9 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAR 30 PY 2008 VL 27 IS 7 BP 990 EP 1007 DI 10.1002/sim.3010 PG 18 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 284AZ UT WOS:000254678900004 PM 17724784 ER PT J AU Phogat, S Svehla, K Tang, M Spadaccini, A Muller, J Mascola, J Berkower, I Wyatt, R AF Phogat, S. Svehla, K. Tang, M. Spadaccini, A. Muller, J. Mascola, J. Berkower, I. Wyatt, R. TI Analysis of the human immunodeficiency virus type 1 gp41 membrane proximal external region arrayed on hepatitis B surface antigen particles SO VIROLOGY LA English DT Article DE HIV-1; neutralizing antibodies; envelope glycoproteins; gp41; particles ID ENVELOPE GLYCOPROTEINS; HIV-1 ENTRY; NEUTRALIZING EPITOPE; FALCIPARUM-MALARIA; ANTIBODY-RESPONSES; CELL RESPONSES; VACCINE; PROTEIN; FUSION; IMMUNOGENICITY AB Vaccine immunogens derived from the envelope glycoproteins of the human immunodeficiency virus type 1 (HIV-1) that elicit broad neutralizing antibodies remain an elusive goal. The highly conserved 30 amino-acid membrane proximal external region (MPER) of HIV gp41 contains the hydrophobic epitopes for two rare HIV-1 broad cross-reactive neutralizing antibodies, 2F5 and 4E10. Both these antibodies possess relatively hydrophobic HCDR3 loops and demonstrate enhanced binding to their epitopes in the context of the native gp160 precursor envelope glycoprotein by the intimate juxtaposition of a lipid membrane. The hepatitis B surface antigen (HBsAg) S1 protein forms nanoparticles that can be utilized both as an immunogenic array of the MPER and to provide the lipid environment needed for enhanced 2175 and 4E10 binding. We show that recombinant HBsAg particles with MPER (HBsAg-MPER) appended at the C-terminus of the S1 protein are recognized by 2F5 and 4E10 with high affinity compared to positioning the MPER at the N-terminus or the extracellular loop (ECL) of S1. Addition of C-terminal hydrophobic residues derived from the HIV-1 Env transmembrane region further enhances recognition of the MPER by both 2F5 and 4E10. Delipidation of the HBsAg-MPER particles decreases 2F5 and 4E10 binding and subsequent reconstitution with synthetic lipids restores optimal binding. Inoculation of the particles into small animals raised cross-reactive antibodies that recognize both the MPER and HIV-1 gp160 envelope glycoproteins expressed on the cell surface; however, no neutralizing activity could be detected. Prime:Boost immunization of the HBsAg-MPER particles in sequence with HIV envelope glycoprotein proteoliposomes (Env-PLs) did not raise neutralizing antibodies that could be mapped to the MPER region. However, the Env-PLs did raise anti-Env antibodies that had the ability to neutralize selected HIV-1 isolates. The first generation HBsAg-MPER particles represent a unique means to present HIV-1 envelope glycoprotein neutralizing determinants to the immune system. Published by Elsevier Inc. C1 [Phogat, S.; Svehla, K.; Tang, M.; Mascola, J.; Wyatt, R.] NIAID, Struct Virol Sect, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Spadaccini, A.; Muller, J.; Berkower, I.] US FDA, Ctr Biol, Bethesda, MD USA. RP Wyatt, R (reprint author), NIAID, Struct Virol Sect, NIH, Vaccine Res Ctr, 40 Covent Dr,Bldg 40,Room 4512, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 52 TC 48 Z9 48 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2008 VL 373 IS 1 BP 72 EP 84 DI 10.1016/j.virol.2007.11.005 PG 13 WC Virology SC Virology GA 279JA UT WOS:000254350300008 PM 18155743 ER PT J AU Okumura, A Alce, T Lubyova, B Ezelle, H Strebel, K Pitha, PM AF Okumura, Atsushi Alce, Tim Lubyova, Barbora Ezelle, Heather Strebel, Klaus Pitha, Paula M. TI HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation SO VIROLOGY LA English DT Article DE interferon; interferon regulatory factor 3 (IRT-3); HIV-1; Vpr; Vif; antiviral response ID INTERFERON REGULATORY FACTOR-3; DOUBLE-STRANDED-RNA; IMMUNODEFICIENCY-VIRUS; GENE-EXPRESSION; T-CELLS; TRANSCRIPTION FACTORS; DENDRITIC CELLS; INFECTED-CELLS; IN-VIVO; KAPPA-B AB The activation of IRF-3 during the early stages of viral infection is critical for the initiation of the antiviral response; however the activation of IRF-3 in HIV-1 infected cells has not yet been characterized. We demonstrate that the early steps of HIV-1 infection do not lead to the activation and nuclear translocation of IRF-3; instead, the relative levels of IRF-3 protein are decreased due to the ubiquitin-associated proteosome degradation. Addressing the molecular mechanism of this effect we show that the degradation is independent of HIV-1 replication and that virion-associated accessory proteins Vif and Vpr can independently degrade IRF-3. The null mutation of these two genes reduced the capacity of the HIV-1 virus to down modulate IRF-3 levels. The degradation was associated with Vif- and Vpr-mediated ubiquitination of IRF-3 and was independent of the activation of IRF-3. N-terminal lysine residues were shown to play a critical role in the Vif- and Vpr-mediated degradation of IRF-3. These data implicate Vif and Vpr in the disruption of the initial antiviral response and point to the need of HIV-1 to circumvent the antiviral response during the very early phase of replication. (C) 2007 Elsevier Inc. All rights reserved. C1 [Pitha, Paula M.] Johns Hopkins Univ, Dept Mol Biol & Genet, Baltimore, MD 21231 USA. [Okumura, Atsushi; Alce, Tim; Lubyova, Barbora; Pitha, Paula M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Pitha, Paula M.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21231 USA. [Ezelle, Heather] Univ Maryland, Sch Med, Baltimore, MD 21231 USA. [Strebel, Klaus] Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Pitha, PM (reprint author), Johns Hopkins Univ, Dept Mol Biol & Genet, Baltimore, MD 21231 USA. EM parowe@jhmi.edu RI Lubyova, Barbora/G-5921-2014; Okumura, Atsushi/E-8012-2015 OI Okumura, Atsushi/0000-0002-7779-3059 FU NIAID NIH HHS [R21 AI054537, AI054276-01A1, R21 AI054276, R21 AI054537-02] NR 59 TC 83 Z9 84 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 MAR 30 PY 2008 VL 373 IS 1 BP 85 EP 97 DI 10.1016/j.virol.2007.10.042 PG 13 WC Virology SC Virology GA 279JA UT WOS:000254350300009 PM 18082865 ER PT J AU Burke, RE AF Burke, Robert E. TI Local duty cycle and muscle spindle density SO BRAIN RESEARCH BULLETIN LA English DT Letter ID MEDIAL GASTROCNEMIUS; LOCOMOTION C1 [Burke, Robert E.] NINDS, Neural Control Lab, Bethesda, MD 20892 USA. RP Burke, RE (reprint author), POB 1722, El Prado, NM 87529 USA. EM reburke@taosnet.com NR 8 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 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD MAR 28 PY 2008 VL 75 IS 5 BP 501 EP 501 DI 10.1016/j.brainresbull.2007.10.002 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 293ED UT WOS:000255317100004 ER PT J AU Toscano, CD Ueda, Y Tomita, YA Vicini, S Bosetti, F AF Toscano, Christopher D. Ueda, Yumi Tomita, York A. Vicini, Stefano Bosetti, Francesca TI Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice SO BRAIN RESEARCH BULLETIN LA English DT Article DE fluoro-jade B; excitotoxicity; endocannabinoid; [H-3]-kainate autoradiography; racine seizure scale; GABA ID METHYL-D-ASPARTATE; CYCLOOXYGENASE-2 INHIBITOR ROFECOXIB; RECEPTOR-MEDIATED EXCITOTOXICITY; ELECTRICALLY INDUCED CONVULSIONS; CENTRAL-NERVOUS-SYSTEM; ACID-INDUCED SEIZURE; INDUCED CELL-DEATH; KAINIC ACID; RAT HIPPOCAMPUS; MOUSE-BRAIN AB Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatrie diseases. Metabolism of arachidonic acid (AA) through the phospholipase A(2) (PLA(2))/prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficientin either PTGS-1 (PTGS-1(-/-)) or PTGS-2 (PTGS-2(-/-)) to the prototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2(-/-), but not in PTGS-1(-/-), mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CBI endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2(-/-) mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2(-/-) mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE(2), a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2, but not PTGS-1, may increase the susceptibility to seizures. Published by Elsevier Inc. C1 [Toscano, Christopher D.; Bosetti, Francesca] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Ueda, Yumi; Tomita, York A.] Georgetown Univ, Lombardi Canc Ctr, Dept Oncol, Washington, DC 20057 USA. [Vicini, Stefano] Georgetown Univ, Dept Physiol & Biophys, Washington, DC 20057 USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9 Mem Dr,Room 1S126 MSC 0947, Bethesda, MD 20892 USA. EM frances@mail.nih.gov FU Intramural NIH HHS [NIH0011410670, Z01 AG000423-04, Z01 AG000427-01]; NIMH NIH HHS [MH 64797] NR 74 TC 20 Z9 20 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD MAR 28 PY 2008 VL 75 IS 5 BP 598 EP 609 DI 10.1016/j.brainresbull.2007.10.004 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 293ED UT WOS:000255317100018 PM 18355636 ER PT J AU Belova, GI Postnikov, YV Furusawa, T Birger, Y Bustin, M AF Belova, Galina I. Postnikov, Yuri V. Furusawa, Takashi Birger, Yehudit Bustin, Michael TI Chromosomal protein HMGN1 enhances the heat shock-induced remodeling of Hsp70 chromatin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOBILITY-GROUP PROTEINS; LINKER HISTONE H1; RNA-POLYMERASE-II; IN-VIVO; TRANSCRIPTION FACTOR; GENE-REGULATION; PHOSPHORYLATION; BINDING; EXPRESSION; ELONGATION AB The nucleosome-binding protein HMGN1 affects the structure and function of chromatin; however, its role in regulating specific gene expression in living cells is not fully understood. Here we use embryonic fibroblasts from Hmgn1(+/+) and Hmgn1(-/-) mice to examine the effect of HMGN1 on the heat shock-induced transcriptional activation of Hsp70, a well characterized gene known to undergo a rapid chromatin re-structuring during transcriptional activation. We find that loss of HMGN1 decreases the levels of Hsp70 transcripts at the early stages of heat shock. HMGN1 enhances the rate of heat shock-induced changes in the Hsp70 chromatin but does not affect the chromatin structure before induction, an indication that it does not predispose the gene to rapid activation. Heat shock elevates the levels of H3K14 acetylation in the Hsp70 chromatin of wild type cells more efficiently than in the chromatin of Hmgn1(+/+) cells, whereas treatment with histone deacetylase inhibitors abrogates the effects of HMGN1 on the heat shock response. We suggest that HMGN1 enhances the rate of heat shock-induced H3K14 acetylation in the Hsp70 promoter, thereby enhancing the rate of chromatin remodeling and the subsequent transcription during the early rounds of Hsp70 activation when the gene is still associated with histones in a nucleosomal conformation. C1 [Belova, Galina I.; Postnikov, Yuri V.; Furusawa, Takashi; Birger, Yehudit; Bustin, Michael] NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. [Birger, Yehudit] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Tel Hashomer, Israel. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, NIH, 37 Convent Dr,Rm 3122, Bethesda, MD 20892 USA. EM bustinm@mail.nih.gov RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [Z01 BC004496-30] NR 54 TC 20 Z9 20 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 MAR 28 PY 2008 VL 283 IS 13 BP 8080 EP 8088 DI 10.1074/jbc.M709782200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278LT UT WOS:000254288000004 PM 18218636 ER PT J AU Liu, BY Li, Z Mahesh, SP Pantanelli, S Hwang, FS Siu, WO Nussenblatt, RB AF Liu, Baoying Li, Zhuqing Mahesh, Sankaranarayana P. Pantanelli, Seth Hwang, Frank S. Siu, Willie O. Nussenblatt, Robert B. TI Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED TNF RECEPTOR; VERSUS-HOST-DISEASE; T-CELLS; CUTTING EDGE; ANTITUMOR IMMUNITY; SELF-TOLERANCE; PROTEIN GITR; FAMILY; LIGAND; SUPERFAMILY AB Glucocorticoid-induced tumor necrosis factor receptor (GITR), found constitutively expressed on human primary natural killer (NK) cells at low levels was up-regulated upon stimulation by either Toll-like receptor ligand or NK cell growth factor, interleukin (IL)-15. cDNA microarray analysis showed that engagement of GITR primarily suppressed the activation of NF-KB pathway of NK cells and up-regulated anti-inflammatory genes heme oxygenase- 1 and IL-10. Further analysis revealed that GITR activation suppressed NK cell proliferation in response to IL-15. GITR activation also suppressed proinflammatory cytokine secretion and increased NK cell apoptosis. GITR activation resulted in blocked phosphorylation of Stat5 and Akt, which may have contributed to the observed antiproliferative effect of GITR on NK cells. Increased apoptosis was independent of the Fas-FasL pathway, but Bcl-XL and phospho-Bad protein expressions were diminished, suggesting involvement of the mitochondrial apoptosis pathway. The results suggest that although GITR is an activation marker for NK cells similar to that for T cells, GITR serves as a negative regulator for NK cell activation. Our studies demonstrate a novel physiological role of GITR on NK cells. C1 [Liu, Baoying; Li, Zhuqing; Mahesh, Sankaranarayana P.; Pantanelli, Seth; Hwang, Frank S.; Siu, Willie O.; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov OI Pantanelli, Seth/0000-0003-4992-9606 FU Intramural NIH HHS NR 50 TC 34 Z9 35 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 28 PY 2008 VL 283 IS 13 BP 8202 EP 8210 DI 10.1074/jbc.M708944200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278LT UT WOS:000254288000017 PM 18230609 ER PT J AU Seabold, GK Wang, PY Chang, K Wang, CY Wang, YX Petralia, RS Wenthold, RJ AF Seabold, Gail K. Wang, Philip Y. Chang, Kai Wang, Chang-Yu Wang, Ya-Xian Petralia, Ronald S. Wenthold, Robert J. TI The SALM family of adhesion-like molecules forms heteromeric and homomeric complexes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEUCINE-RICH REPEAT; OLFACTORY-BULB AXONS; CELL-ADHESION; TRANSMEMBRANE PROTEINS; HIPPOCAMPAL-NEURONS; NEURITE OUTGROWTH; SYNAPSE FORMATION; NERVOUS-SYSTEM; SLIT PROTEINS; NMDA RECEPTOR AB Synaptic adhesion-like molecules (SALMs) are a newly discovered family of adhesion molecules that play roles in synapse formation and neurite outgrowth. The SALM family is comprised of five homologous molecules that are expressed largely in the central nervous system. SALMs 1 - 3 contain PDZ-binding domains, whereas SALMs 4 and 5 do not. We are interested in characterizing the interactions of the SALMs both among the individual members and with other binding partners. In the present study, we focused on the interactions formed by the five SALM members in rat brain and heterologous cells. In brain, we found that SALMs 1 -3 strongly co-immunoprecipitated with each other, whereas SALMs 4 and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes. In heterologous cells transfected with SALMs, co-immunoprecipitation studies showed that all five SALMs form heteromeric and homomeric complexes. We also determined if SALMs could form trans-cellular associations between transfected heterologous cells. Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. The ability of SALM4 to form trans interactions is due to its extracellular N terminus because chimeras of SALM4 N terminus and SALM2 C terminus can form trans interactions, whereas chimeras of SALM2 N terminus and SALM4 C terminus cannot. Co-culture experiments using HeLa cells and rat hippocampal neurons expressing the SALMs showed that SALM4 is recruited to points of contact between the cells. In neurons, these points of contact were seen in both axons and dendrites. C1 [Seabold, Gail K.; Wang, Philip Y.; Chang, Kai; Wang, Chang-Yu; Wang, Ya-Xian; Petralia, Ronald S.; Wenthold, Robert J.] NIDCD, NIH, Neurochem Lab, Bethesda, MD 20892 USA. RP Wenthold, RJ (reprint author), 50 S Dr,Bldg 50 Rm 4140, Bethesda, MD 20892 USA. EM wenthold@nidcd.nih.gov FU Intramural NIH HHS NR 64 TC 25 Z9 34 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 28 PY 2008 VL 283 IS 13 BP 8395 EP 8405 DI 10.1074/jbc.M709456200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278LT UT WOS:000254288000037 PM 18227064 ER PT J AU Takagi, Y Yang, Y Fujiwara, I Jacobs, D Cheney, RE Sellers, JR Kovacs, M AF Takagi, Yasuharu Yang, Yi Fujiwara, Ikuko Jacobs, Damon Cheney, Richard E. Sellers, James R. Kovacs, Mihaly TI Human myosin Vc is a low duty ratio, nonprocessive molecular motor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIN-BASED MOTOR; HAND-OVER-HAND; KINETIC CHARACTERIZATION; UNCONVENTIONAL MYOSIN; MUSCLE-CONTRACTION; REAL-TIME; VESICLE TRANSPORT; FLUORESCENT-PROBE; NECK LENGTH; MECHANISM AB Myosin Vc is the product of one of the three genes of the class V myosin found in vertebrates. It is widely found in secretory and glandular tissues, with a possible involvement in transferrin trafficking. Transient and steady-state kinetic studies of human myosin Vc were performed using a truncated, single-headed construct. Steady-state actin-activated ATPase measurements revealed a V(max) of 1.8 +/- 0.3 s(-1) and a K(ATPase) of 43 +/- 11 mu M. Unlike previously studied vertebrate myosin Vs, the rate-limiting step in the actomyosin Vc ATPase pathway is the release of inorganic phosphate (similar to 1.5 s(-1)), rather than the ADP release step (similar to 12.0-16.0 s(-1)). Nevertheless, the ADP affinity of actomyosin Vc (K(d) = 0.25 +/- 0.02 mu M) reflects a higher ADP affinity than seen in other myosin V isoforms. Using the measured kinetic rates, the calculated duty ratio of myosin Vc was similar to 10%, indicating that myosin Vc spends the majority of the actomyosin ATPase cycle in weak actin-binding states, unlike the other vertebrate myosin V isoforms. Consistent with this, a fluorescently labeled double-headed heavy meromyosin form showed no processive movements along actin filaments in a single molecule assay, but it did move actin filaments at a velocity of similar to 24 nm/s in ensemble assays. Kinetic simulations reveal that the high ADP affinity of actomyosin Vc may lead to elevations of the duty ratio of myosin Vc to as high as 64% under possible physiological ADP concentrations. This, in turn, may possibly imply a regulatory mechanism that may be sensitive to moderate changes in ADP concentration. C1 [Takagi, Yasuharu; Yang, Yi; Sellers, James R.] NHLBI, Lab Mol Physiol, Natl Inst Hlth, Bethesda, MD 20892 USA. [Fujiwara, Ikuko] NHLBI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Jacobs, Damon; Cheney, Richard E.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Kovacs, Mihaly] Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, Natl Inst Hlth, Bldg 50,Rm 3523, Bethesda, MD 20892 USA. EM sellersj@mail.nih.gov; stoci1@gmail.com RI Kovacs, Mihaly/A-6841-2011; Fujiwara, Ikuko/H-5717-2016 OI Fujiwara, Ikuko/0000-0002-9361-636X FU FIC NIH HHS [D43 TW 006230, 1 R01 TW 007241-01]; Howard Hughes Medical Institute; NIDCD NIH HHS [R01 DC003299] NR 71 TC 22 Z9 22 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 28 PY 2008 VL 283 IS 13 BP 8527 EP 8537 DI 10.1074/jbc.M709150200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278LT UT WOS:000254288000051 PM 18201966 ER PT J AU Zhang, DH Harry, GJ Blackshear, PJ Zeldin, DC AF Zhang, Donghui Harry, G. Jean Blackshear, Perry J. Zeldin, Darryl C. TI G-protein pathway suppressor 2 (GPS2) interacts with the regulatory factor X4 variant 3 (RFX4_v3) and functions as a transcriptional co-activator SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NECROSIS-FACTOR-ALPHA; EMBRYONIC STEM-CELLS; NERVOUS-SYSTEM; DNA-BINDING; EXPRESSION; BRAIN; IDENTIFICATION; FRACTALKINE; NUCLEUS; TRANSACTIVATION AB RFX4_v3 (regulatory factor X4 variant 3) is a brain-specific isoform of the transcription factor RFX4. Insertional mutagenesis in mice demonstrates that Rfx4_v3 is crucial for normal brain development. Many genes involved in critical processes during brain morphogenesis are dysregulated in Rfx4_v3 mutant brains. For example, Cx3cl1 is a CX3C-type chemokine that is abundant in brain and is a direct transcriptional target of RFX4_v3 through a specific promoter X-box (X-box 1), the responsive element for RFX proteins. To identify potential interacting partners for RFX4_v3, we performed yeast two-hybrid analysis. Nine candidate interactors were identified, including GPS2 (G-protein pathway suppressor 2). Indirect immunofluorescence demonstrated that GPS2 and RFX4_v3 co-localized to the nucleus. Both GPS2 and RFX4_v3 mRNAs were also present in most portions of the adult mouse brain as well as in brains at different ages, suggesting that the two proteins could bind to each other. Co-immunoprecipitation assays indicated that physical interactions between GPS2 and RFX4_v3 did indeed occur. Furthermore, GPS2 was recruited to the Cx3cl1 promoter by RFX4_v3 and potentiated RFX4_v3 transactivation on this promoter through X-box 1, suggesting that the protein-protein interaction was functionally relevant. GPS2 bound to both the carboxyl-terminal region (amino acids 575-735) and the middle region (amino acids 250-574) of the RFX4_v3 protein. RFX4_v3 amino acids 1-574 stimulated the Cx3cl1 promoter to a similar extent as the full-length RFX4_v3 protein; however, deletion of the carboxyl-terminal region of RFX4_v3 impaired the co-activating abilities of GPS2. Based on these data, we conclude that GPS2 interacts with RFX4_v3 to modulate transactivation of genes involved in brain morphogenesis, including Cx3Cl1. C1 [Zhang, Donghui; Zeldin, Darryl C.] NIEHS, Natl Inst Hlth, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Zhang, Donghui; Harry, G. Jean; Blackshear, Perry J.] NIEHS, Natl Inst Hlth, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.; Zeldin, Darryl C.] NIEHS, Natl Inst Hlth, Off Clin Res, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Zeldin, DC (reprint author), NIEHS, Natl Inst Hlth, Lab Resp Biol, 111 TW Alexander Dr,Bldg 101,Rm D236, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov FU Intramural NIH HHS [Z01 ES101583-05] NR 37 TC 16 Z9 18 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 MAR 28 PY 2008 VL 283 IS 13 BP 8580 EP 8590 DI 10.1074/jbc.M708209200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278LT UT WOS:000254288000057 PM 18218630 ER PT J AU Sun, P Tropea, JE Austin, BP Cherry, S Waugh, DS AF Sun, Ping Tropea, Joseph E. Austin, Brian P. Cherry, Scott Waugh, David S. TI Structural characterization of the Yersinia pestis type III secretion system needle protein YscF in complex with its heterodimeric chaperone YscE/YscG SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE type III secretion; plague; Yersinia; tetratricopeptide repeat; needle protein ID PSEUDOMONAS-AERUGINOSA; EUKARYOTIC CELLS; YOP SECRETION; PSEUDOTUBERCULOSIS; ENTEROCOLITICA; TRANSLOCATION; POLYPEPTIDE; REPEATS; BINDING; PSCF AB The plague-causing bacterium Yersinia pestis utilizes a type III secretion system to deliver effector proteins into mammalian cells where they interfere with signal transduction pathways that mediate phagocytosis and the inflammatory response. Effector proteins are injected through a hollow needle structure composed of the protein YscF. YscG and YscE act as "chaperones" to prevent premature polymerization of YscF in the cytosol of the bacterium prior to assembly of the needle. Here, we report the crystal structure of the YscEFG protein complex at 1.8 angstrom resolution. Overall, the structure is similar to that of the analogous PscEFG complex from the Pseudomonas aeruginosa type III secretion system, but there are noteworthy differences. The structure confirms that, like PscG, YscG is a member of the tetratricopeptide repeat family of proteins. YscG binds tightly to the C-terminal half of YscF, implying that it is this region of YscF that controls its polymerization into the needle structure. YscE interacts with the N-terminal tetratricopeptide repeat motif of YscG but makes very little direct contact with YscF. Its function may be to stabilize the structure of YscG and/or to participate in recruiting the complex to the secretion apparatus. No electron density could be observed for the 49 N-terminal residues of YscE This and additional evidence suggest that the N-terminus of YscF is disordered in the complex with YscE and YscG. As expected, conserved residues in the C-terminal half of YscF mediate important intra- and intermolecular interactions in the complex. Moreover, the phenotypes of some previously characterized mutations in the C-terminal half of YscF can be rationalized in terms of the structure of the heterotrimeric YscEFG complex. Published by Elsevier Ltd. C1 [Sun, Ping; Tropea, Joseph E.; Austin, Brian P.; Cherry, Scott; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD 21701 USA. EM waughd@ncifcrf.gov FU Intramural NIH HHS [Z01 BC010342-07] NR 44 TC 46 Z9 48 U1 1 U2 6 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 MAR 28 PY 2008 VL 377 IS 3 BP 819 EP 830 DI 10.1016/j.jmb.2007.12.067 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 293ZP UT WOS:000255374200021 PM 18281060 ER PT J AU Raghavan, B Balasubramanian, R Steele, JC Sackett, DL Fecik, RA AF Raghavan, Bhooma Balasubramanian, Ranganathan Steele, Jaeson C. Sackett, Dan L. Fecik, Robert A. TI Cytotoxic simplified tubulysin analogues SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BIOLOGICAL-PROPERTIES; PROTEASE INHIBITORS; AMINO-ACIDS; MYXOBACTERIA; POLYMERIZATION; PEPTIDE; TUBULIN; DESIGN AB An efficient route for the synthesis of the tubulysin family of antimitotic peptides was developed. Simplified tubulysin analogues were synthesized to define the minimum pharmacophore required for cytotoxicity. Simplified tubulysin analogues retain significant cytotoxicity and reveal important preliminary structure-activity relationships. C1 [Raghavan, Bhooma; Balasubramanian, Ranganathan; Steele, Jaeson C.; Fecik, Robert A.] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. [Sackett, Dan L.] NICHHD, NIH, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. RP Fecik, RA (reprint author), Univ Minnesota, Dept Med Chem, 8-101 Weaver Densford Hall,308 Harvard St SE, Minneapolis, MN 55455 USA. EM fecik001@umn.edu FU Intramural NIH HHS NR 21 TC 42 Z9 42 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 27 PY 2008 VL 51 IS 6 BP 1530 EP 1533 DI 10.1021/jm701321p PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 277JZ UT WOS:000254209800002 PM 18314944 ER PT J AU Ryu, EK Wu, Z Chen, K Lazarus, LH Marczak, ED Sasaki, Y Ambo, A Salvadori, S Ren, C Zhao, H Balboni, G Chen, XY AF Ryu, Eun Kyoung Wu, Zhanhong Chen, Kai Lazarus, Lawrence H. Marczak, Ewa D. Sasaki, Yusuke Ambo, Akihiro Salvadori, Severo Ren, Chuancheng Zhao, Heng Balboni, Gianfranco Chen, Xiaoyuan TI Synthesis of a potent and selective (18)F-Labeled delta-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY; RGD PEPTIDE; C-TERMINUS; IN-VIVO; AGONIST; PET; NALTRINDOLE; EXPRESSION; MICROPET; LIGANDS AB Identification and pharmacological characterization of two new selective delta-opioid receptor antagonists, derived from the Dmt-Tic pharmacophore, of potential utility in positron emission tomography (PET) imaging are described. On the basis of its high delta selectivity, H-Dmt-Tic-epsilon-Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of (18)F-labeled compounds prepared by the coupling of N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) with Boc-Dmt-Tic-epsilon-Lys(Z)-OH tinder slightly basic conditions at 37 degrees C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [(18)F]-1 was about 25-30% (n = 5) starting from [(18)F]SFB (n = 5) with an effective specific activity about 46 GBq/mu mol. In vitro autoradiography studies showed prominent uptake of [(18)F]-1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective d-opioid receptor antagonist), suggesting high specific binding of [(18)F]-1 to delta-opioid receptors. Noninvasive microPET imaging studies revealed the absence of [18F]-1 in rat brain, since it fails to cross the blood-brain barrier. This study demonstrates the suitability of [(18)F]-1 for imaging peripheral delta-opioid receptors. C1 [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. [Ryu, Eun Kyoung; Wu, Zhanhong; Chen, Kai; Chen, Xiaoyuan] Stanford Univ, Sch Med, MIPS, Dept Radiol, Stanford, CA 94305 USA. [Ryu, Eun Kyoung; Wu, Zhanhong; Chen, Kai; Chen, Xiaoyuan] Stanford Univ, Sch Med, Bio X Program, Stanford, CA 94305 USA. [Ryu, Eun Kyoung] Chuncheon Ctr, Korea Basic Sci Inst, Chunchon, South Korea. [Lazarus, Lawrence H.; Marczak, Ewa D.] NIEHS, Med Chem Grp, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Sasaki, Yusuke; Ambo, Akihiro] Tohoku Pharmaceut Univ, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Salvadori, Severo; Balboni, Gianfranco] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [Salvadori, Severo; Balboni, Gianfranco] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. [Ren, Chuancheng; Zhao, Heng] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. RP Balboni, G (reprint author), Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. EM gbalboni@unica.it FU Intramural NIH HHS [Z01 ES100472-06, Z99 ES999999, Z01 ES090053-20]; NCI NIH HHS [P50 CA 114747, P50 CA114747, R01 CA 119053, R01 CA119053, R21 CA 102123, R21 CA 121842, R21 CA102123, R21 CA121842] NR 36 TC 3 Z9 3 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 27 PY 2008 VL 51 IS 6 BP 1817 EP 1823 DI 10.1021/jm7014765 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 277JZ UT WOS:000254209800030 PM 18311909 ER PT J AU Velazquez, CA Chen, QH Citro, ML Keefer, LK Knaus, EE AF Velazquez, Carlos A. Chen, Qiao-Hong Citro, Michael L. Keefer, Larry K. Knaus, Edward E. TI Second-generation aspirin and indomethacin prodrugs possessing an O(2)-(Acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl)diazenium-1,2-diolate nitric oxide donor moiety: Design, synthesis, biological evaluation, and nitric oxide release studies SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NITRATE TOLERANCE; NITROSAMINO ACIDS; SODIUM-NITRITE; AMINO-ACIDS; RATS; DIAZENIUMDIOLATE; NSAIDS; NO; GASTROPATHY AB The carboxylic acid group of the anti-inflammatory (AI) drugs aspirin and indomethacin was covalently linked to the 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate ion via a one-carbon methylene spacer to obtain two new hybrid prodrugs. The aspirin prodrug (23) was a 2.2-fold more potent AI agent than aspirin, whereas the indomethacin prodrug (26) was about 1.6-fold less potent than indomethacin. Prodrugs 23 and 26 slowly released nitric oxide (NO) upon dissolution in phosphate buffer at pH 7.4 (1.1 mol of NO/mol of compound after 43 h), but the rate and the extent of NO release were higher (1.9 mol of NO/mol of compound in 3 min or less) when the compounds were incubated in the presence of porcine liver esterase.. In vivo ulcer index (UI) studies showed that the aspirin prodrug 23 (UI = 0.7) and indomethacin prodrug 26 (UI = 0) were substantially less ulcerogenic than the parent drugs aspirin (UI = 51) and indomethacin (UI = 64). C1 [Chen, Qiao-Hong; Knaus, Edward E.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. [Velazquez, Carlos A.; Keefer, Larry K.] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Citro, Michael L.] NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Knaus, EE (reprint author), Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. EM eknaus@pharmacy.ualberta.ca RI Velazquez, Carlos/C-4224-2008; Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS; NCI NIH HHS [N01 CO 12400] NR 49 TC 41 Z9 42 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 27 PY 2008 VL 51 IS 6 BP 1954 EP 1961 DI 10.1021/jm701450q PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 277JZ UT WOS:000254209800043 PM 18314945 ER PT J AU Michishita, E McCord, RA Berber, E Kioi, M Padilla-Nash, H Damian, M Cheung, P Kusumoto, R Kawahara, TLA Barrett, JC Chang, HY Bohr, VA Ried, T Gozani, O Chua, KF AF Michishita, Eriko McCord, Ronald A. Berber, Elisabeth Kioi, Mitomu Padilla-Nash, Hesed Damian, Mara Cheung, Peggie Kusumoto, Rika Kawahara, Tiara L. A. Barrett, J. Carl Chang, Howard Y. Bohr, Vilhelm A. Ried, Thomas Gozani, Or Chua, Katrin F. TI SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin SO NATURE LA English DT Article ID PROTECTS HUMAN TELOMERES; WERNER-SYNDROME CELLS; S-PHASE; DYSFUNCTIONAL TELOMERES; SYNDROME FIBROBLASTS; GENOMIC INSTABILITY; MAMMALIAN TELOMERES; DNA-DAMAGE; SENESCENCE; TRF2 AB The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomycescerevisiae(1,2). In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing- like phenotype(3). However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin- associated protein(3), but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD(+)-dependent, histone H3 lysine 9 ( H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end- to- end chromosomal fusions and premature cellular senescence. Moreover, SIRT6- depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder(4,5). At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome(4,5). We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome. C1 [Michishita, Eriko; McCord, Ronald A.; Berber, Elisabeth; Damian, Mara; Chua, Katrin F.] Stanford Univ, Dept Med, Div Endocrinol Gerontol & Metab, Sch Med, Stanford, CA 94305 USA. [Kioi, Mitomu] Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA. [Cheung, Peggie; Gozani, Or] Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. [Kawahara, Tiara L. A.; Chang, Howard Y.] Stanford Univ, Program Epithelial Biol, Sch Med, Stanford, CA 94305 USA. [Michishita, Eriko; McCord, Ronald A.; Berber, Elisabeth; Damian, Mara; Chua, Katrin F.] VA Palo Alto Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Palo Alto, CA 94304 USA. [Padilla-Nash, Hesed; Ried, Thomas] NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Barrett, J. Carl] NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Kusumoto, Rika; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Chua, KF (reprint author), Stanford Univ, Dept Med, Div Endocrinol Gerontol & Metab, Sch Med, Stanford, CA 94305 USA. EM kfchua@stanford.edu OI Kioi, Mitomu/0000-0002-7981-3340 FU NIA NIH HHS [K08 AG028961-03, K08 AG028961, R01 AG028867, R01 AG028867-03]; NIGMS NIH HHS [R01 GM079641, R01 GM079641-02] NR 32 TC 428 Z9 454 U1 1 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 27 PY 2008 VL 452 IS 7186 BP 492 EP U16 DI 10.1038/nature06736 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 279FU UT WOS:000254341300036 PM 18337721 ER PT J AU Crawley, JN AF Crawley, Jacqueline N. TI Behavioral phenotyping strategies for mutant mice SO NEURON LA English DT Review ID INBRED MOUSE STRAINS; AMYOTROPHIC-LATERAL-SCLEROSIS; ELEVATED PLUS-MAZE; ANXIETY-RELATED BEHAVIORS; SPATIAL WORKING-MEMORY; MORRIS WATER MAZE; TRANSGENIC MICE; KNOCKOUT MICE; HUNTINGTONS-DISEASE; ALZHEIMERS-DISEASE AB Comprehensive behavioral analyses of transgenic and knockout mice have successfully identified the functional roles of many genes in the brain. Over the past 10 years, strategies for mouse behavioral phenotyping have evolved to maximize the scope and replicability of findings from a cohort of mutant mice, minimize the interpretation of procedural artifacts, and provide robust translational tools to test hypotheses and develop treatments. This Primer addresses experimental design issues and offers examples of high-throughput batteries, learning and memory tasks, and anxiety-related tests. C1 NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. RP Crawley, JN (reprint author), NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. EM crawleyj@intra.nimh.nih.gov FU Intramural NIH HHS NR 131 TC 188 Z9 194 U1 2 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 27 PY 2008 VL 57 IS 6 BP 809 EP 818 DI 10.1016/j.neuron.2008.03.001 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 281LV UT WOS:000254500000005 PM 18367082 ER PT J AU Cho, RW Park, JM Wolff, SBE Xu, D Hopf, C Kim, JA Reddy, RC Petralia, RS Perin, MS Linden, DJ Worley, PF AF Cho, Richard W. Park, Joo Min Wolff, Steffen B. E. Xu, Desheng Hopf, Carsten Kim, Jin-ah Reddy, Radhika C. Petralia, Ronald S. Perin, Mark S. Linden, David J. Worley, Paul F. TI mGluR1/5-Dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE SO NEURON LA English DT Article ID DHPG-INDUCED LTD; IONOTROPIC GLUTAMATE RECEPTORS; SYNAPSE-ASSOCIATED PROTEIN-97; CEREBELLAR PURKINJE NEURONS; ALPHA CONVERTING-ENZYME; KINASE-C INHIBITOR; GYRUS IN-VITRO; AMPA RECEPTORS; CA1 REGION; ACTIVATION CAUSES AB Matrix metalloproteases (MMPs) play a role in remodeling the extracellular matrix during brain development and have been implicated in synaptic plasticity. Here, we report that a member of the neuronal pentraxin (NP) family, neuronal pentraxin receptor (NPR), undergoes regulated cleavage by the MMP tumor necrosis factor-a converting enzyme (TACE). NPR is enriched at excitatory synapses where it associates with AMPA-type glutamate receptors (AMPAR) and enhances synaptogenesis. However, in response to activation of group 1 mGluRs (mGluR1/5), TACE cleaves NPR and releases the pentraxin domain from its N-terminal transmembrane domain. Cleaved NPR rapidly accumulates in endosomes where it colocalizes with AMPAR. This process is necessary for mGluR1/5-dependent LTD in hippocampal and cerebellar synapses. These observations suggest that cleaved NPR functions to "capture" AMPAR for endocytosis and reveal a bifunctional role of NPs in both synapse strengthening and weakening. C1 [Cho, Richard W.; Park, Joo Min; Wolff, Steffen B. E.; Xu, Desheng; Hopf, Carsten; Kim, Jin-ah; Reddy, Radhika C.; Linden, David J.; Worley, Paul F.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Worley, Paul F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Petralia, Ronald S.] Natl Inst Deafness & Other Communicat Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Perin, Mark S.] Cleveland Clin Fdn, Dept Neurosci, Cleveland, OH 44195 USA. RP Worley, PF (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. EM pworley@jhmi.edu FU Intramural NIH HHS; NINDS NIH HHS [5R01NS039156-08, R01 NS039156, R01 NS039156-08]; PHS HHS [R37MM51106] NR 62 TC 57 Z9 57 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 27 PY 2008 VL 57 IS 6 BP 858 EP 871 DI 10.1016/j.neuron.2008.01.010 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 281LV UT WOS:000254500000010 PM 18367087 ER PT J AU Terashima, A Pelkey, KA Rah, JC Suh, YH Roche, KW Collingridge, GL McBain, CJ Isaac, JTR AF Terashima, Akira Pelkey, Kenneth A. Rah, Jong-Cheol Suh, Young Ho Roche, Katherine W. Collingridge, Graham L. McBain, Chris J. Isaac, John T. R. TI An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity SO NEURON LA English DT Article ID LONG-TERM DEPRESSION; CA2+-PERMEABLE AMPA RECEPTORS; DOMAIN-CONTAINING PROTEINS; KINASE-C-ALPHA; DENDRITIC SPINES; BINDING-PROTEIN; CA1 SYNAPSES; PKC PHOSPHORYLATION; SUBUNIT COMPOSITION; PDZ DOMAINS AB PICK1 is a calcium-sensing, PDZ domain-containing protein that interacts with GluR2 and GluR3 AMPA receptor (AMPAR) subunits and regulates their trafficking. Although PICK1 has been principally implicated in long-term depression (LTD), PICK1 overexpression in CA1 pyramidal neurons causes a CaMK- and PKC-dependent potentiation of AMPAR-mediated transmission and an increase in synaptic GluR2-lacking AMPARs, mechanisms associated with NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here, we directly tested whether PICK1 participates in both hippocampal NMDAR-dependent LTP and LTD. We show that the PICK1 potentiation of AMPAR-mediated transmission is NMDAR dependent and fully occludes LTP. Conversely, blockade of PICK1 PDZ interactions or lack of PICK1 prevents LTP. These observations demonstrate an important role for PICK1 in LTP. In addition, deletion of PICK1 or blockade of PICK1 PDZ binding prevented NMDAR-dependent LTD. Thus, PICK1 plays a critical role in bidirectional NMDAR-dependent long-term synaptic plasticity in the hippocampus. C1 [Terashima, Akira; Rah, Jong-Cheol; Isaac, John T. R.] Natl Inst Neurol Disorders & Stroke, Dev Synapt Plast Sect, NIH, Bethesda, MD 20892 USA. [Terashima, Akira; Collingridge, Graham L.; Isaac, John T. R.] Univ Bristol, Sch Med Sci, Dept Anat, MRC Ctr Synspt Plat, Bristol BS8 1TD, Avon, England. [Pelkey, Kenneth A.; McBain, Chris J.] NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. [Suh, Young Ho; Roche, Katherine W.] Natl Inst Neurol Disorders & Stroke, Receptor Biol Unit, NIH, Bethesda, MD 20892 USA. RP Isaac, JTR (reprint author), Natl Inst Neurol Disorders & Stroke, Dev Synapt Plast Sect, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM isaacj@ninds.nih.gov RI Collingridge, Graham/C-4605-2015; OI Collingridge, Graham/0000-0002-9572-5359; Roche, Katherine/0000-0001-7282-6539 FU Intramural NIH HHS [Z01 NS003011-03]; Medical Research Council [, G0601813]; Wellcome Trust NR 73 TC 92 Z9 95 U1 4 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 27 PY 2008 VL 57 IS 6 BP 872 EP 882 DI 10.1016/j.neuron.2008.01.028 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 281LV UT WOS:000254500000011 PM 18367088 ER PT J AU Pistell, PJ Zhu, M Ingram, DK AF Pistell, P. J. Zhu, M. Ingram, D. K. TI Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer's disease SO NEUROSCIENCE LA English DT Article DE Alzheimer's disease; learning; transgenic mice; conditioned taste aversion ID TRANSGENIC MICE; A-BETA; MEMORY DEFICITS; BRAIN; DEPOSITION; TAU; LESIONS; APP; PROTEINS; ESTROGEN AB Research into the underlying mechanisms of cognitive dysfunction in Alzheimer's disease (AD) has relied traditionally on tasks such as the water maze which evaluate spatial learning and memory. Since non-spatial forms of memory are also disrupted by AD, it is critical to establish other paradigms capable of investigating these deficits. Utilizing a non-spatial learning task, acquisition of conditioned taste aversion (CTA) was evaluated in a mouse model of AD. This line of transgenic mice encode a mutated allele of the human amyloid precursor protein (APP) and presenilin 1 (PS1) genes and exhibit extensive amyloid plaque deposition in the brain by 6-7 mo of age. Compared with wild-type mice, 10-17 month old APP/PS1 mice failed to acquire CTA to saccharin. Mice that only possessed one of the two mutations were able to acquire CTA to the saccharin. In 2-5 month old APP/PS1 mice acquisition of CTA was disrupted despite the lack of extensive plaque deposition. However, further analysis indicated a potential gender difference in both the CTA deficit and onset of plaque deposition with females showing greater conditioned aversion. Published by Elsevier Ltd on behalf of IBRO. C1 [Pistell, P. J.; Ingram, D. K.] Pennington Biomed Res Ctr, Natl Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. [Pistell, P. J.; Zhu, M.; Ingram, D. K.] NIA, Behav Neurosci Sect, Lab Expt Gerontol, Natl Inst Hlth,Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Pistell, PJ (reprint author), Pennington Biomed Res Ctr, Natl Neurosci & Aging Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Paul.Pistell@pbrc.edu FU Intramural NIH HHS; NCRR NIH HHS [P20 RR021945-01, 1P20RR02-1945, P20 RR021945]; NIDDK NIH HHS [1P30 DK072476, P30 DK072476, P30 DK072476-01] NR 37 TC 25 Z9 25 U1 0 U2 0 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 MAR 27 PY 2008 VL 152 IS 3 BP 594 EP 600 DI 10.1016/j.neuroscience.2008.01.025 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 286BI UT WOS:000254819900003 PM 18304749 ER PT J AU Baumann, MH Clark, RD Franken, FH Rutter, JJ Rothman, RB AF Baumann, M. H. Clark, R. D. Franken, F. H. Rutter, J. J. Rothman, R. B. TI Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges SO NEUROSCIENCE LA English DT Article DE ecstasy; 5-HT; dopamine; transporter; neuroendocrine; microdialysis ID SEROTONERGIC-DOPAMINERGIC MEDIATION; MDMA NEUROTOXICITY; RHESUS-MONKEYS; IN-VIVO; (+/-)3,4-METHYLENE-DIOXYMETHAMPHETAMINE ECSTASY; METHYLENEDIOXYMETHAMPHETAMINE MDMA; EXTRACELLULAR SEROTONIN; AMPHETAMINE DERIVATIVES; NUCLEUS-ACCUMBENS; CROSS-TOLERANCE AB 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) stimulates the transporter-mediated release of monoamines, including 5-HT. High-dose exposure to MDMA causes persistent 5-HT deficits (e.g. depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-Induced 5-HT depletions in rats. Male rats received binges of three i.p. injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kgx3, low dose) or at a fivefold higher amount (7.5 mg/kgx3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute i.v. challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by i.v. MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting similar to 50% loss of forebrain 5-HT 2 weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of i.v. MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with i.v. MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation. Published by Elsevier Ltd on behalf of IBRO. C1 [Baumann, M. H.; Rothman, R. B.] Natl Inst Drug Abuse, Clin Psychopharmacol Sect, Intramural Res Program, Natl Inst Hlth,DHHS, Baltimore, MD 21224 USA. [Clark, R. D.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Franken, F. H.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Rutter, J. J.] Truman Univ, Dept Biol Sci, Kirksville, MO 63501 USA. RP Baumann, MH (reprint author), Natl Inst Drug Abuse, Clin Psychopharmacol Sect, Intramural Res Program, Natl Inst Hlth,DHHS, 333 Cassell Dr,Suite 4500, Baltimore, MD 21224 USA. EM mbaumann@mail.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 69 TC 40 Z9 40 U1 1 U2 3 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 MAR 27 PY 2008 VL 152 IS 3 BP 773 EP 784 DI 10.1016/j.neuroscience.2008.01.007 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 286BI UT WOS:000254819900019 PM 18313226 ER PT J AU Detrano, R Guerci, AD Carr, JJ Bild, DE Burke, G Folsom, AR Liu, K Shea, S Szklo, M Bluemke, DA O'Leary, DH Tracy, R Watson, K Wong, ND Kronmal, RA AF Detrano, Robert Guerci, Alan D. Carr, J. Jeffrey Bild, Diane E. Burke, Gregory Folsom, Aaron R. Liu, Kiang Shea, Steven Szklo, Moyses Bluemke, David A. O'Leary, Daniel H. Tracy, Russell Watson, Karol Wong, Nathan D. Kronmal, Richard A. TI Coronary calcium as a predictor of coronary events in four racial or ethnic groups SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BEAM COMPUTED-TOMOGRAPHY; HEART-DISEASE EVENTS; ARTERY CALCIUM; RISK-FACTORS; ATHEROSCLEROSIS MESA; PROGNOSTIC VALUE; CALCIFICATION; ADULTS; PREVALENCE; CHOLESTEROL AB Background: In white populations, computed tomographic measurements of coronary-artery calcium predict coronary heart disease independently of traditional coronary risk factors. However, it is not known whether coronary-artery calcium predicts coronary heart disease in other racial or ethnic groups. Methods: We collected data on risk factors and performed scanning for coronary calcium in a population-based sample of 6722 men and women, of whom 38.6% were white, 27.6% were black, 21.9% were Hispanic, and 11.9% were Chinese. The study subjects had no clinical cardiovascular disease at entry and were followed for a median of 3.8 years. Results: There were 162 coronary events, of which 89 were major events (myocardial infarction or death from coronary heart disease). In comparison with participants with no coronary calcium, the adjusted risk of a coronary event was increased by a factor of 7.73 among participants with coronary calcium scores between 101 and 300 and by a factor of 9.67 among participants with scores above 300 (P<0.001 for both comparisons). Among the four racial and ethnic groups, a doubling of the calcium score increased the risk of a major coronary event by 15 to 35% and the risk of any coronary event by 18 to 39%. The areas under the receiver-operating-characteristic curves for the prediction of both major coronary events and any coronary event were higher when the calcium score was added to the standard risk factors. Conclusions: The coronary calcium score is a strong predictor of incident coronary heart disease and provides predictive information beyond that provided by standard risk factors in four major racial and ethnic groups in the United States. No major differences among racial and ethnic groups in the predictive value of calcium scores were detected. C1 [Detrano, Robert; Wong, Nathan D.] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92697 USA. [Guerci, Alan D.] St Francis Hosp, Roslyn, NY USA. [Carr, J. Jeffrey; Burke, Gregory] Wake Forest Baptist Med Ctr, Winston Salem, NC USA. [Bild, Diane E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Folsom, Aaron R.] Univ Minnesota, Minneapolis, MN USA. [Liu, Kiang] Northwestern Univ, Chicago, IL 60611 USA. [Shea, Steven] Columbia Univ, New York, NY USA. [Szklo, Moyses; Bluemke, David A.] Johns Hopkins Univ, Baltimore, MD USA. [O'Leary, Daniel H.] Caritas Carney Hosp, Dorchester, MA USA. [Tracy, Russell] Univ Vermont, Burlington, VT USA. [Watson, Karol] Univ Calif Los Angeles, Los Angeles, CA USA. [Kronmal, Richard A.] Univ Washington, Seattle, WA 98195 USA. RP Detrano, R (reprint author), Univ Calif Irvine, Dept Radiol Sci, Med Sci Bldg, Irvine, CA 92697 USA. EM robert@chinacal.org RI Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Bluemke, David/0000-0002-8323-8086 FU NHLBI NIH HHS [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95169] NR 30 TC 1073 Z9 1107 U1 3 U2 30 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 MAR 27 PY 2008 VL 358 IS 13 BP 1336 EP 1345 DI 10.1056/NEJMoa072100 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 278TE UT WOS:000254308400004 PM 18367736 ER PT J AU Guimaraes, KS Przytycka, TM AF Guimaraes, Katia S. Przytycka, Teresa M. TI Interrogating domain-domain interactions with parsimony based approaches SO BMC BIOINFORMATICS LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; SACCHAROMYCES-CEREVISIAE; RB PROTEIN; COMPLEXES; DATABASE; E2F; TRANSCRIPTION; EVOLUTION; GENOMICS; NETWORK AB Background: The identification and characterization of interacting domain pairs is an important step towards understanding protein interactions. In the last few years, several methods to predict domain interactions have been proposed. Understanding the power and the limitations of these methods is key to the development of improved approaches and better understanding of the nature of these interactions. Results: Building on the previously published Parsimonious Explanation method (PE) to predict domain-domain interactions, we introduced a new Generalized Parsimonious Explanation (GPE) method, which (i) adjusts the granularity of the domain definition to the granularity of the input data set and (ii) permits domain interactions to have different costs. This allowed for preferential selection of the so-called "co-occurring domains" as possible mediators of interactions between proteins. The performance of both variants of the parsimony method are competitive to the performance of the top algorithms for this problem even though parsimony methods use less information than some of the other methods. We also examined possible enrichment of co-occurring domains and homo-domains among domain interactions mediating the interaction of proteins in the network. The corresponding study was performed by surveying domain interactions predicted by the GPE method as well as by using a combinatorial counting approach independent of any prediction method. Our findings indicate that, while there is a considerable propensity towards these special domain pairs among predicted domain interactions, this overrepresentation is significantly lower than in the iPfam dataset. Conclusion: The Generalized Parsimonious Explanation approach provides a new means to predict and study domain-domain interactions. We showed that, under the assumption that all protein interactions in the network are mediated by domain interactions, there exists a significant deviation of the properties of domain interactions mediating interactions in the network from that of iPfam data. C1 [Guimaraes, Katia S.; Przytycka, Teresa M.] NIH, Natl Biotechnol Ctr, Natl Lib Med, Bethesda, MD 20894 USA. [Guimaraes, Katia S.] Univ Fed Pernambuco, Ctr Informat, BR-50732 Recife, PE, Brazil. RP Przytycka, TM (reprint author), NIH, Natl Biotechnol Ctr, Natl Lib Med, Bethesda, MD 20894 USA. EM katiaguim@gmail.com; przytyck@mail.nih.gov RI Guimaraes, Katia/C-5577-2008 FU Intramural NIH HHS NR 44 TC 16 Z9 18 U1 0 U2 3 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 MAR 26 PY 2008 VL 9 AR 171 DI 10.1186/1471-2105-9-171 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 303IX UT WOS:000256035300002 PM 18366803 ER PT J AU Wang, LZ Xie, CS Greggio, E Parisiadou, L Shim, H Sun, LX Chandran, J Lin, X Lai, C Yang, WJ Moore, DJ Dawson, TM Dawson, VL Chiosis, G Cookson, MR Cai, HB AF Wang, Lizhen Xie, Chengsong Greggio, Elisa Parisiadou, Loukia Shim, Hoon Sun, Lixin Chandran, Jayanth Lin, Xian Lai, Chen Yang, Wan-Jou Moore, Darren J. Dawson, Ted M. Dawson, Valina L. Chiosis, Gabriela Cookson, Mark R. Cai, Huaibin TI The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2 SO JOURNAL OF NEUROSCIENCE LA English DT Article DE HSP90; LRRK2; G2019S; Parkinson's disease; protein degradation; chaperone ID HSP90 MOLECULAR CHAPERONE; PARKINSONS-DISEASE; KINASE-ACTIVITY; NEURONAL TOXICITY; LRRK2 MUTATION; PROTEIN; CANCER; DEGENERATION; SUPPRESSION; EXPRESSION AB Parkinson's disease (PD), a progressive neurodegenerative disease characterized by bradykinesia, rigidity, and resting tremor, is the most common neurodegenerative movement disorder. Although the majority of PD cases are sporadic, some are inherited, including those caused by leucine-rich repeat kinase 2 (LRRK2) mutations. The substitution of serine for glycine at position 2019 (G2019S) in the kinase domain of LRRK2 represents the most prevalent genetic mutation in both familial and apparently sporadic cases of PD. Because mutations in LRRK2 are likely associated with a toxic gain of function, destabilization of LRRK2 may be a novel way to limit its detrimental effects. Here we show that LRRK2 forms a complex with heat shock protein 90 (Hsp90) in vivo and that inhibition of Hsp90 disrupts the association of Hsp90 with LRRK2 and leads to proteasomal degradation of LRRK2. Hsp90 inhibitors may therefore limit the mutant LRRK2-elicited toxicity to neurons. As a proof of principle, we show that Hsp90 inhibitors rescue the axon growth retardation caused by overexpression of the LRRK2 G2019S mutation in neurons. Therefore, inhibition of LRRK2 kinase activity can be achieved by blocking Hsp90-mediated chaperone activity and Hsp90 inhibitors may serve as potential anti-PD drugs. C1 [Wang, Lizhen; Xie, Chengsong; Parisiadou, Loukia; Shim, Hoon; Sun, Lixin; Chandran, Jayanth; Lin, Xian; Lai, Chen; Yang, Wan-Jou; Cai, Huaibin] NIA, NIH, Neurogenet Lab, Unit Transgeneis, Bethesda, MD 20892 USA. [Greggio, Elisa; Cookson, Mark R.] NIA, Unit Cell Biol & Gene Express, Neurogenet Lab, Bethesda, MD 20892 USA. [Moore, Darren J.; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21025 USA. [Moore, Darren J.; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21025 USA. [Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21025 USA. [Chiosis, Gabriela] Mem Sloan Kettering Canc Ctr, Dept Med, Program Mol Pharmacol & Chem, New York, NY 10021 USA. RP Cai, HB (reprint author), NIA, NIH, Neurogenet Lab, Unit Transgeneis, Bldg 35,1A116,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. EM caih@mail.nih.gov RI Cai, Huaibin/H-3359-2013; Greggio, Elisa/H-6119-2013; OI Cai, Huaibin/0000-0002-8596-6108; Greggio, Elisa/0000-0002-8172-3598; Dawson, Valina/0000-0002-2915-3970 FU Intramural NIH HHS [Z01 AG000959-04, Z99 AG999999]; NIA NIH HHS [1R21AG028811, R21 AG028811]; NINDS NIH HHS [P50 NS038377] NR 42 TC 120 Z9 122 U1 0 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 MAR 26 PY 2008 VL 28 IS 13 BP 3384 EP 3391 DI 10.1523/JNEUROSCI.0185-08.2008 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 279WT UT WOS:000254386600014 PM 18367605 ER PT J AU Horak, M Chang, K Wenthold, RJ AF Horak, Martin Chang, Kai Wenthold, Robert J. TI Masking of the endoplasmic reticulum retention signals during assembly of the NMDA receptor SO JOURNAL OF NEUROSCIENCE LA English DT Article DE glutamate receptors; ion channel assembly; subunit interaction; ER retention; masking; intracellular trafficking ID CELL-SURFACE EXPRESSION; FUNCTIONAL EXPRESSION; SUBUNITS; TRAFFICKING; PROTEIN; DOMAIN; PHOSPHORYLATION; STOICHIOMETRY; REGION; EXPORT AB NMDA receptors are glutamate-gated ion channels that play important roles in synaptic transmission and excitotoxicity. The functional NMDA receptor is thought to be a heterotetramer composed mainly of two NR1 and two NR2 subunits. Although it is generally accepted that only correctly assembled NMDA receptors can pass the ER quality control, the mechanism underlying this process is not well understood. Using truncated and chimeric NMDA receptor subunits expressed in heterologous cells and cortical neurons, we found that the third membrane domains (M3) of both NR1 and NR2B contain signals that cause the unassembled subunits to be retained in the ER. M3of both NR1 and NR2B and, M4 of NR1, are necessary for masking ER retention signals found in M3. Thus, our data reveal a critical role of the membrane domains in the assembly of functional NMDA receptors. C1 [Horak, Martin; Chang, Kai; Wenthold, Robert J.] Natl Inst Def & Other Commun Disorders, NIH, Neurochem Lab, Bethesda, MD 20892 USA. RP Horak, M (reprint author), Natl Inst Def & Other Commun Disorders, NIH, Neurochem Lab, 50 S Dr,Room 4146, Bethesda, MD 20892 USA. EM horakm@nidcd.nih.gov RI Horak, Martin/F-9819-2010; Horak, Martin/A-7297-2010 FU Intramural NIH HHS NR 30 TC 30 Z9 30 U1 3 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 26 PY 2008 VL 28 IS 13 BP 3500 EP 3509 DI 10.1523/JNEUROSCI.5239-07.2008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 279WT UT WOS:000254386600025 PM 18367616 ER PT J AU Best, RB Hummer, G AF Best, Robert B. Hummer, Gerhard TI Protein folding kinetics under force from molecular simulation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID DYNAMICS SIMULATIONS; SINGLE PROTEIN; SPECTROSCOPY; MICROSCOPY; HAIRPINS; MODELS AB Despite a large number of studies on the mechanical unfolding of proteins, there are still relatively few successful attempts to refold proteins in the presence of a stretching force. We explore refolding kinetics under force using simulations of a coarse-grained model of ubiquitin. The effects of force on the folding kinetics can be fitted by a one-dimensional Kramers theory of diffusive barrier crossing, resulting in physically meaningful parameters for the height and location of the folding activation barrier. By comparing parameters obtained from pulling in different directions, we find that the unfolded state plays a dominant role in the refolding kinetics. Our findings explain why refolding becomes very slow at even moderate pulling forces and suggest how it could be practically observed in experiments at higher C1 [Best, Robert B.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 FU Intramural NIH HHS NR 24 TC 25 Z9 26 U1 0 U2 11 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 MAR 26 PY 2008 VL 130 IS 12 BP 3706 EP + DI 10.1021/ja0762691 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 276WE UT WOS:000254173600001 PM 18307341 ER PT J AU Tang, C Ghirlando, R Clore, GM AF Tang, Chun Ghirlando, Rodolfo Clore, G. Marius TI Visualization of transient ultra-weak protein self-association in solution using paramagnetic relaxation enhancement SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HISTIDINE-CONTAINING PROTEIN; PHOSPHORYL TRANSFER COMPLEX; MOLECULAR-DYNAMICS SIMULATIONS; ESCHERICHIA-COLI; PHOSPHOTRANSFERASE SYSTEM; ALPHA-SYNUCLEIN; ANALYTICAL ULTRACENTRIFUGATION; STRUCTURAL-CHARACTERIZATION; RESOLUTION STRUCTURE; ENCOUNTER COMPLEXES AB Ultra-weak macromolecular self-association is exceptionally difficult to both detect and visualize using conventional biophysical techniques owing to the very low population of the associated species, yet such weak intermolecular interactions coupled with nucleation events play an important role in driving spontaneous self-assembly to form higher-order architectures (such as crystals, viral capsids, and amyloid fibrils). In this article, we detect and characterize transient, ultra-weak self-association (K-D >= 15 mM) involving the histidine-containing protein HPr by means of paramagnetic relaxation enhancement (PRE), using EDTA-Mn2+ conjugated at three separate sites (E5C, E25C, and E32C, one at a time). Large intermolecular PRE effects, above the background observed with hydroxylamine-EDTA-Mn2+ as a control, are observed for two of the three paramagnetically labeled sites, E5C and E32C. The extent of self-association can be modulated (significantly reduced) by increasing the ionic strength or by the introduction of a negative charge (S46D mutation) within a positively charged surface patch, and abolished upon the addition of the N-terminal domain of enzyme I (EIN) to form a specific EIN-HPr complex. The PRE profiles observed for E5C and E32C can be fitted simultaneously and accounted for quantitatively using conjoined rigid body/torsion angle dynamics-simulated annealing with an ensemble of states to represent the distribution of one molecule of HPr relative to its partner. C1 [Tang, Chun; Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS NR 42 TC 54 Z9 56 U1 2 U2 18 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 MAR 26 PY 2008 VL 130 IS 12 BP 4048 EP 4056 DI 10.1021/ja710493m PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 276WE UT WOS:000254173600068 PM 18314985 ER PT J AU Lal, A Kim, HH Abdelmohsen, K Kuwano, Y Pullmann, R Srikantan, S Subrahmanyam, R Martindale, JL Yang, XL Ahmed, F Navarro, F Dykxhoorn, D Lieberman, J Gorospe, M AF Lal, Ashish Kim, Hyeon Ho Abdelmohsen, Kotb Kuwano, Yuki Pullmann, Rudolf Srikantan, Subramanya Subrahmanyam, Ramesh Martindale, Jennifer L. Yang, Xiaoling Ahmed, Fariyal Navarro, Francisco Dykxhoorn, Derek Lieberman, Judy Gorospe, Myriam TI p16(INK4a) Translation Suppressed by miR-24 SO PLOS ONE LA English DT Article AB Background: Expression of the tumor suppressor p16(INK4a) increases during aging and replicative senescence. Methodology/Principal Findings: Here, we report that the microRNA miR-24 suppresses p16 expression in human diploid fibroblasts and cervical carcinoma cells. Increased p16 expression with replicative senescence was associated with decreased levels of miR-24, a microRNA that was predicted to associate with the p16 mRNA coding and 3'-untranslated regions. Ectopic miR-24 overexpression reduced p16 protein but not p16 mRNA levels. Conversely, introduction of antisense (AS)-miR-24 blocked miR-24 expression and markedly enhanced p16 protein levels, p16 translation, and the production of EGFP-p16 reporter bearing the miR-24 target recognition sites. Conclusions/Significance: Together, our results suggest that miR-24 represses the initiation and elongation phases of p16 translation. C1 [Lal, Ashish; Kim, Hyeon Ho; Abdelmohsen, Kotb; Kuwano, Yuki; Pullmann, Rudolf; Srikantan, Subramanya; Subrahmanyam, Ramesh; Martindale, Jennifer L.; Yang, Xiaoling; Gorospe, Myriam] NIA, IRP, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Lal, Ashish; Ahmed, Fariyal; Navarro, Francisco; Dykxhoorn, Derek; Lieberman, Judy] Harvard Med Sch, CBR Inst Biomed Res, Dept Pediat, Boston, MA USA. RP Lal, A (reprint author), NIA, IRP, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. EM alal@cbrinstitute.org; myriam-gorospe@nih.gov RI Subrahmanyam, Ramesh/K-5503-2012; Lieberman, Judy/A-2717-2015; Dykxhoorn, Derek/D-1357-2015; OI srikantan, subramanya/0000-0003-1810-6519; abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging - Intramural Research Program FX National Institute on Aging - Intramural Research Program NR 40 TC 148 Z9 157 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 26 PY 2008 VL 3 IS 3 AR e1864 DI 10.1371/journal.pone.0001864 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 370KZ UT WOS:000260762400023 PM 18365017 ER PT J AU Polman, CH Reingold, SC Barkhof, F Calabresi, PA Clanet, M Cohen, JA Cutter, GR Freedman, MS Kappos, L Lublin, FD McFarland, HF Metz, LM Miller, AE Montalban, X O'Connor, PW Panitch, H Richert, JR Petkau, J Schwid, SR Sormani, MP Thompson, AJ Weinshenker, BG Wolinsky, JS AF Polman, C. H. Reingold, S. C. Barkhof, F. Calabresi, P. A. Clanet, M. Cohen, J. A. Cutter, G. R. Freedman, M. S. Kappos, L. Lublin, F. D. McFarland, H. F. Metz, L. M. Miller, A. E. Montalban, X. O'Connor, P. W. Panitch, H. Richert, J. R. Petkau, J. Schwid, S. R. Sormani, M. P. Thompson, A. J. Weinshenker, B. G. Wolinsky, J. S. TI Ethics of placebo-controlled clinical trials in multiple sclerosis - A reassessment SO NEUROLOGY LA English DT Article ID INTERFERON BETA-1B TREATMENT; DOUBLE-BLIND; INFORMED-CONSENT; ISSUES; MS; MULTICENTER; NATALIZUMAB; HELSINKI; DECLARATION; DISABILITY AB The increasing number of established effective therapies for relapsing multiple sclerosis ( MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons ( e. g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes. C1 [Polman, C. H.; Barkhof, F.] Free Univ Amsterdam, Ctr Med, Dept Neurol, NL-1007 MB Amsterdam, Netherlands. [Reingold, S. C.] Netherlands Sci & Clin Review Associates LLC, New York, NY USA. [Reingold, S. C.; Richert, J. R.] Natl Multiple Sclerosis Soc, Res & Clin Programs Dept, New York, NY USA. [Calabresi, P. A.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Clanet, M.] CHU Hop Purpan, Federat Neurol, Toulouse, France. [Cohen, J. A.] Cleveland Clin Fdn, Mellen Ctr MS Treatment & Res, Cleveland, OH USA. [Cutter, G. R.] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. [Freedman, M. S.] Ottawa Gen Hosp, Div Neurol, Ottawa, ON K1H 8L6, Canada. [Kappos, L.] Univ Basel, Dept Neurol, CH-4003 Basel, Switzerland. [Lublin, F. D.; Miller, A. E.] Mt Sinai Sch Med, Corinne Goldsmith Dickinson Ctr MS, New York, NY USA. [McFarland, H. F.] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Metz, L. M.] Calgary Hlth Reg, MS Clin, Calgary, AB, Canada. Univ Calgary, Calgary, AB T2N 1N4, Canada. [Montalban, X.] Hosp Univ Vall Hebron, Unitat Neuroimmunol Clin, Barcelona, Spain. [O'Connor, P. W.] St Michaels Hosp, Div Neurol, Toronto, ON M5B 1W8, Canada. [Panitch, H.] Univ Vermont, Coll Med, Dept Neurol, Burlington, VT USA. [Petkau, J.] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1W5, Canada. [Schwid, S. R.] Univ Rochester, Ctr Med, Dept Neurol, New York, NY USA. [Sormani, M. P.] Univ Genoa, Biostat Unit, I-16126 Genoa, Italy. [Sormani, M. P.] Ist Sci San Raffaele, Dept Neurol, Neuroimaging Res Unit, I-20132 Milan, Italy. Univ Osped San Raffaele, Milan, Italy. [Thompson, A. J.] Natl Hosp Neurol & Neurosurg, Dept Clin Neurol, London WC1N 3BG, England. [Weinshenker, B. G.] Mayo Clin, Coll Med, Dept Neurol, Rochester, MN USA. [Wolinsky, J. S.] Univ Texas Houston, Ctr Hlth Sci, Dept Neurol, Houston, TX USA. RP Polman, CH (reprint author), Free Univ Amsterdam, Ctr Med, Dept Neurol, POB 4075, NL-1007 MB Amsterdam, Netherlands. EM ch.polman@vumc.nl RI Thompson, Alan/C-2654-2008 OI Thompson, Alan/0000-0002-4333-8496 NR 45 TC 33 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 25 PY 2008 VL 70 IS 13 BP 1134 EP 1140 PN 2 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 278PB UT WOS:000254297700019 PM 18362273 ER PT J AU Shen, Y Lange, O Delaglio, F Rossi, P Aramini, JM Liu, GH Eletsky, A Wu, YB Singarapu, KK Lemak, A Ignatchenko, A Arrowsmith, CH Szyperski, T Montelione, GT Baker, D Bax, A AF Shen, Yang Lange, Oliver Delaglio, Frank Rossi, Paolo Aramini, James M. Liu, Gaohua Eletsky, Alexander Wu, Yibing Singarapu, Kiran K. Lemak, Alexander Ignatchenko, Alexandr Arrowsmith, Cheryl H. Szyperski, Thomas Montelione, Gaetano T. Baker, David Bax, Ad TI Consistent blind protein structure generation from NMR chemical shift data SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE molecular fragment replacement; protein structure prediction; ROSETTA; structural genomics ID MOLECULAR FRAGMENT REPLACEMENT; STRUCTURE PREDICTION; SEQUENCE HOMOLOGY; DATA-COLLECTION; INFORMATION; QUALITY; MODELS; CHAIN; ANGLE; N-15 AB Protein NMR chemical shifts are highly sensitive,to local structure. A robust protocol is described that exploits this relation for de novo protein structure generation, using as input experimental parameters the C-13(alpha), C-13(beta), C-13', N-15, H-1(alpha) and H-1(N) NMR chemical shifts. These shifts are generally available at the early stage of the traditional NMR structure determination process, before the collection and analysis of structural restraints. The chemical shift based structure determination protocol uses an empirically optimized procedure to select protein fragments from the Protein Data Bank, in conjunction with the standard ROSETTA Monte Carlo assembly and relaxation methods. Evaluation of 16 proteins, varying in size from 56 to 129 residues, yielded full-atom models that have 0.7-1.8 angstrom root mean square deviations for the backbone atoms relative to the experimentally determined x-ray or NMR structures. The strategy also has been successfully applied in a blind manner to nine protein targets with molecular masses up to 15.4 kDa, whose conventional NMR structure determination was conducted in parallel by the Northeast Structural Genomics Consortium. This protocol potentially provides a new direction for high-throughput NMR structure determination. C1 [Lange, Oliver] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Lange, Oliver] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Shen, Yang; Delaglio, Frank; Bax, Ad] NIDDK, Chem Phys Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Rossi, Paolo; Aramini, James M.; Liu, Gaohua; Montelione, Gaetano T.] Univ Med & Dent New Jersey, Ctr Adv Biotechnol & Med, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Rossi, Paolo; Aramini, James M.; Liu, Gaohua; Montelione, Gaetano T.] Univ Med & Dent New Jersey, NE Struct Genom Consortium Rutgers, Piscataway, NJ 08854 USA. [Eletsky, Alexander; Wu, Yibing; Singarapu, Kiran K.; Szyperski, Thomas] SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA. [Eletsky, Alexander; Wu, Yibing; Singarapu, Kiran K.; Szyperski, Thomas] SUNY Buffalo, Dept Biol Struct, Buffalo, NY 14260 USA. [Lemak, Alexander; Ignatchenko, Alexandr; Arrowsmith, Cheryl H.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L5, Canada. RP Baker, D (reprint author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA. EM dabaker@u.washington.edu; bax@nih.gov RI Shen, Yang/C-3064-2008; Lange, Oliver/B-2861-2009; Lange, Oliver/G-1366-2010; Lange, Oliver/K-5749-2012; Baker, David/K-8941-2012; OI Shen, Yang/0000-0003-1408-8034; Lange, Oliver/0000-0002-4018-7020; Baker, David/0000-0001-7896-6217; Ignatchenko, Alexandr/0000-0002-6083-941X FU Howard Hughes Medical Institute; Intramural NIH HHS; NIGMS NIH HHS [U54-GM074958, U54 GM074958] NR 32 TC 465 Z9 470 U1 5 U2 51 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 MAR 25 PY 2008 VL 105 IS 12 BP 4685 EP 4690 DI 10.1073/pnas.0800256105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 285JI UT WOS:000254772700029 PM 18326625 ER PT J AU Jadhao, SJ Achenbach, J Swayne, DE Donis, R Cox, N Matsuoka, Y AF Jadhao, Samadhan J. Achenbach, Jenna Swayne, David E. Donis, Ruben Cox, Nancy Matsuoka, Yumiko TI Development of Eurasian H7N7/PR8 high growth reassortant virus for clinical evaluation as an inactivated pandemic influenza vaccine SO VACCINE LA English DT Article DE influenza; pandemic; H7N7/PR8 vaccine ID AVIAN INFLUENZA; A VIRUS; BRITISH-COLUMBIA; COMMERCIAL POULTRY; HUMAN ILLNESS; H5N1 VIRUSES; MOUSE MODEL; IMMUNOGENICITY; HEMAGGLUTININ; OUTBREAK AB Avian-to-human transmission of the high pathogenicity (HP) H7N7 subtype avian influenza viruses in the Netherlands during 2003 caused zoonotic infections in 89 people, including a case of acute fatal respiratory distress syndrome. Public health emergency preparedness against H7N7 avian influenza viruses with pandemic potential. includes the development of vaccine candidate viruses. In order to develop a high growth reassortant vaccine candidate virus, tow pathogenicity (LP) A/mallard/Netherlands/12/2000 (H7N3) and A/mattard/Netherlands/2/2000 (H10N7) strains were selected as donors of the H7 haemagglutinin and N7 neuraminidase genes, respectively. The donor viruses exhibited high amino acid sequence homology with the surface glycoproteins of A/Netherlands/219/03 H7N7 virus (NL219), an isolate recovered from the fatal human case. Adhering to the seasonal influenza vaccine licensure regulations, we generated a H7N7/PR8 reassortant containing desired surface glycoprotein genes from the mallard viruses and internal genes of A/Puerto Rico/8/34 human vaccine strain (H1N1). Antigenic analysis revealed that the vaccine candidate virus confers broad antigenic cross-reactivity against contemporary Eurasian and the North American H7 subtype human isotates. Mice immunized with formalin inactivated (FI) H7N7/PR8 whole virus vaccine with or without aluminum hydroxide adjuvant conferred clinical protection from mortality and reduced pulmonary replication of the NL219 challenge virus. The A H7N7/PR8 whole virus vaccine also afforded cross-protection in mice at the pulmonary level against antigenically distinct North American LP A/Canada/444/04 (H7N3) human isolate. The vaccine candidate virus satisfied the agricultural safety requirements for chickens, proved safe in mice, and has entered in phase-I human clinical trial in the United States. Published by Elsevier Ltd. C1 [Jadhao, Samadhan J.; Achenbach, Jenna; Donis, Ruben; Cox, Nancy; Matsuoka, Yumiko] Ctr Dis Control, Influenza Div, Atlanta, GA 30333 USA. [Swayne, David E.] USDA ARS, SE Poultry Res Lab, Athens, GA 30605 USA. RP Matsuoka, Y (reprint author), NIAID, NIH, Infect Dis Lab, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM Samadhan.Jadhao@ars.usda.gov; MatsuokaY@niaid.nih.gov NR 37 TC 21 Z9 22 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 25 PY 2008 VL 26 IS 14 BP 1742 EP 1750 DI 10.1016/j.vaccine.2008.01.036 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 283RV UT WOS:000254655100005 PM 18336962 ER PT J AU Fox, CS Pencina, MJ D'Agostino, RB Murabito, JM Seely, EW Pearce, EN Vasan, RS AF Fox, Caroline S. Pencina, Michael J. D'Agostino, Ralph B. Murabito, Joanne M. Seely, Ellen W. Pearce, Elizabeth N. Vasan, Ramachandran S. TI Relations of thyroid function to body weight SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RISK FACTOR; MASS INDEX; US ADULTS; SERUM TSH; SUBCLINICAL HYPOTHYROIDISM; ENERGY-EXPENDITURE; NATIONAL-HEALTH; UNITED-STATES; PIMA-INDIANS; OBESITY AB Background: Overt hypothyroidism and hyperthyroidism maybe associated with weight gain and loss. We assessed whether variations in thyroid function within the reference (physiologic) range are associated with body weight. Methods: Framingham Offspring Study participants (n=2407) who attended 2 consecutive routine examinations, were not receiving thyroid hormone therapy, and had baseline serum thyrotropin (TSH) concentrations of 0.5 to 5.0 mIU/L and follow-up concentrations of 0.5 to 10.0 mIU/L were included in this study. Baseline TSH concentrations were related to body weight and body weight change during 3.5 years of follow-up. Results: At baseline, adjusted mean weight increased progressively from 64.5 to 70.2 kg in the lowest to highest TSH concentration quartiles in women (P < .001 for trend), and from 82.8 (lowest quartile) to 85.6 kg (highest quartile) in men (P=.007 for trend). During 3.5 years of follow-up, mean (SD) body weight increased by 1.5 (5.6) kg in women and 1.0 (5.0) kg in men. Baseline TSH concentrations were not associated with weight change during follow-up. However, an increase in TSH concentration at follow-up. was positively associated with weight gain in women (0.5-2.3 kg across increasing quartiles of TSH concentration change; P < .00 I for trend) and men (0.4-1.3 kg across quartiles of TSH concentration change; P=.007 for trend). Conclusions: Thyroid function (as assessed by serum TSH concentration) within the reference range is associated with body weight in both sexes. Our findings raise the possibility that modest increases in serum TSH concentrations within the reference range may be associated with weight gain. C1 [Fox, Caroline S.; Pencina, Michael J.; D'Agostino, Ralph B.; Murabito, Joanne M.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Fox, Caroline S.] NHLBI, Bethesda, MD 20892 USA. [Fox, Caroline S.; Seely, Ellen W.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Endocrinol Hypertens & Diabet, Boston, MA 02115 USA. [Pencina, Michael J.; D'Agostino, Ralph B.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Sect Gen Internal Med, Boston, MA 02215 USA. [Pearce, Elizabeth N.] Boston Univ, Sch Med, Dept Endocrinol, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Prevent Med, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU NHLBI NIH HHS [N01-HC-25195, 2K24 HL04334]; NIDDK NIH HHS [5K23 DK64611] NR 37 TC 103 Z9 104 U1 1 U2 11 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 MAR 24 PY 2008 VL 168 IS 6 BP 587 EP 592 DI 10.1001/archinte.168.6.587 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 277UY UT WOS:000254241400006 PM 18362250 ER PT J AU Newsome, BB Warnock, DG McClellan, WM Herzog, CA Kiefe, CI Eggers, PW Allison, JJ AF Newsome, Britt B. Warnock, David G. McClellan, William M. Herzog, Charles A. Kiefe, Catarina I. Eggers, Paul W. Allison, Jeroan J. TI Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Nephrology CY OCT 31-NOV 05, 2007 CL San Francisco, CA SP Amer Soc Nephrol ID ACUTE KIDNEY INJURY; COOPERATIVE CARDIOVASCULAR PROJECT; QUALITY-OF-CARE; REPLACEMENT THERAPY; MEDICARE PATIENTS; INTENSIVE-CARE; HEART-FAILURE; OUTCOMES; POPULATION; PROGNOSIS AB Background: Although small changes in creatinine level during hospitalization have been associated with risk of short-term mortality, associations with posthospitalization end-stage renal disease (ESRD) and long-term mortality are unknown. We assessed the relationship between change in serum creatinine levels up to 3.0 mg/dL and death and ESRD among elderly survivors of hospitalization for acute myocardial infarction. Methods: Retrospective cohort study of a nationally representative sample of Medicare beneficiaries admitted with acute myocardial infarction to nonfederal US hospitals between February 1994 and July 1995. Outcomes were mortality and ESRD through June 2004. Results: The 87 094 eligible patients admitted to 4473 hospitals had a mean age of 77.1 years; for the 43.2% with some creatinine increase, quartiles of increase were 0.1, 0.2, 0.3 to 0.5, and 0.6 to 3.0 mg/dL. Incidence of ESRD and mortality ranged from 2.3 and 139.1 cases per 1000 person-years, respectively, among patients with no increase to 20.0 and 274.9 cases per 1000 person-years in the highest quartile of creatinine increase. Compared with patients without creatinine increase, adjusted hazard ratios by quartile of increase were 1.45, 1.97, 2.36, and 3.26 for ESRD and 1.14, 1.16, 1.26, and 1.39 for mortality, with no 95% confidence intervals overlapping 1.0 for,either end point. Conclusion: In a nationally representative sample of elderly patients discharged after hospitalization for acute myocardial infarction, small changes in serum creatinine level during hospitalization were associated with an independent higher risk of ESRD and death. C1 [Newsome, Britt B.; Warnock, David G.] Univ Alabama, Div Nephrol, Birmingham, AL 35294 USA. [Newsome, Britt B.; Kiefe, Catarina I.; Allison, Jeroan J.] Univ Alabama, Div Prevent Med, Birmingham, AL 35294 USA. [Allison, Jeroan J.] Univ Alabama, Div Gen Internal Med, Birmingham, AL 35294 USA. [Newsome, Britt B.; Kiefe, Catarina I.; Allison, Jeroan J.] Univ Alabama, Ctr Nephrol Res & Training, Dept Med, Birmingham, AL 35294 USA. [Kiefe, Catarina I.] Univ Alabama, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [McClellan, William M.] Emory Univ, Sch Med, Dept Med, Div Renal, Atlanta, GA 30322 USA. [Herzog, Charles A.] US Renal Data Syst, Cardiovasc Special Studies Ctr, Minneapolis, MN USA. [Eggers, Paul W.] NIDDKD, Bethesda, MD 20892 USA. RP Newsome, BB (reprint author), Univ Alabama, Div Nephrol, 1530 3rd Ave,S Room 524, Birmingham, AL 35294 USA. OI Allison, Jeroan/0000-0003-4472-2112 NR 59 TC 150 Z9 156 U1 0 U2 3 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 MAR 24 PY 2008 VL 168 IS 6 BP 609 EP 616 DI 10.1001/archinte.168.6.609 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 277UY UT WOS:000254241400009 PM 18362253 ER PT J AU Karev, GP Novozhilov, AS Berezovskaya, FS AF Karev, Georgy P. Novozhilov, Artem S. Berezovskaya, Faina S. TI Modeling the dynamics of inhomogeneous natural rotifer populations under toxicant exposure SO ECOLOGICAL MODELLING LA English DT Article; Proceedings Paper CT 5th European Conference on Ecological Modelling CY SEP 19-23, 2005 CL Pushchino, RUSSIA DE heterogeneous populations; natural rotifer population model; bifurcation diagram AB Most population models assume that individuals within a given population are identical, that is, the fundamental role of variation is ignored. Here we develop a general approach to modeling heterogeneous populations with discrete evolutionary time step. The theory is applied to models of natural rotifer population dynamics. We show that under particular conditions the behavior of the inhomogeneous model possesses complex transition regimes, which depends both on the mean and the variance of the initial parameter distribution; the final state of the population depends on the least possible value from the domain of the parameter. The question of population persistence is discussed. Published by Elsevier B.V. C1 [Karev, Georgy P.; Novozhilov, Artem S.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Berezovskaya, Faina S.] Howard Univ, Dept Math, Washington, DC 20059 USA. RP Karev, GP (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM karev@ncbi.nlm.nih.gov RI Novozhilov, Artem/D-7544-2012; Novozhilov, Artem/C-9248-2013 OI Novozhilov, Artem/0000-0001-5469-2557 NR 13 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3800 J9 ECOL MODEL JI Ecol. Model. PD MAR 24 PY 2008 VL 212 IS 1-2 BP 80 EP 85 DI 10.1016/j.ecolmodel.2007.10.011 PG 6 WC Ecology SC Environmental Sciences & Ecology GA 277PM UT WOS:000254227100010 ER PT J AU Venteicher, AS Meng, ZJ Mason, PJ Veenstra, TD Artandi, SE AF Venteicher, Andrew S. Meng, Zhaojing Mason, Philip J. Veenstra, Timothy D. Artandi, Steven E. TI Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly SO CELL LA English DT Article ID DOMINANT DYSKERATOSIS-CONGENITA; CHROMATIN REMODELING COMPLEX; SMALL NUCLEOLAR RNPS; REVERSE-TRANSCRIPTASE; RNA COMPONENT; LENGTH; CELLS; PROTEINS; RIBONUCLEOPROTEINS; PURIFICATION AB Telomerase is a multisubunit ribonucleoprotein (RNP) complex that adds telomere repeats to the ends of chromosomes. Three essential telomerase components have been identified thus far: the telomerase reverse transcriptase (TERT), the telomerase RNA component (TERC), and the TERC-binding protein dyskerin. Few other proteins are known to be required for human telomerase function, limiting our understanding of both telomerase regulation and mechanisms of telomerase action. Here, we identify the ATPases pontin and reptin as telomerase components through affinity purification of TERT from human cells. Pontin interacts directly with both TERT and dyskerin, and the amount of TERT bound to pontin and reptin peaks in S phase, evidence for cell-cycle-dependent regulation of TERT. Depletion of pontin and reptin markedly impairs telomerase RNP accumulation, indicating an essential role in telomerase assembly. These findings reveal an unanticipated requirement for additional enzymes in telomerase biogenesis and suggest alternative approaches for inhibiting telomerase in cancer. C1 [Venteicher, Andrew S.; Artandi, Steven E.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Venteicher, Andrew S.; Artandi, Steven E.] Stanford Univ, Sch Med, Program Biophys, Stanford, CA 94305 USA. [Artandi, Steven E.] Stanford Univ, Sch Med, Program Canc Biol, Stanford, CA 94305 USA. [Meng, Zhaojing; Veenstra, Timothy D.] NCI, Lab Proteom & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Mason, Philip J.] Washington Univ, Sch Med, Dept Internal Med, Div Hematol, St Louis, MO 63110 USA. RP Artandi, SE (reprint author), Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. EM sartandi@stanford.edu RI Mason, Philip/B-1087-2008 FU NCI NIH HHS [CA111691, CA125453, N01-CO-12400, N01CO12400, R01 CA106995, R01 CA111691, R01 CA111691-03, R01 CA125453, R01 CA125453-02]; NIGMS NIH HHS [GM07365, T32 GM007365] NR 45 TC 162 Z9 168 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 21 PY 2008 VL 132 IS 6 BP 945 EP 957 DI 10.1016/j.cell.2008.01.019 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 278GR UT WOS:000254273600014 PM 18358808 ER PT J AU Burg, MB Ferraris, JD AF Burg, Maurice B. Ferraris, Joan D. TI Intracellular organic osmolytes: Function and regulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID STRESS; PROTEINS; YEAST; OSMOREGULATION; STABILITY; EVOLUTION; PRESSURE; PLANTS AB Cells of almost all organisms accumulate organic osmolytes when exposed to hyperosmolality, most often in the form of high salt or urea. In this review, we discuss 1) how the organic osmolytes protect; 2) the identity of osmolytes in Archaea, bacteria, yeast, plants, marine animals, and mammals; 3) the mechanisms by which they are accumulated; 4) sensors of osmolality; 5) the signaling pathways involved; and 6) mutual counteraction by urea and methylamines. C1 [Burg, Maurice B.; Ferraris, Joan D.] NIH, NHLBI, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Burg, MB (reprint author), NIH, NHLBI, Dept Hlth & Human Serv, Bldg 10,Rm 6N260,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Maurice_Burg@nih.gov FU Intramural NIH HHS NR 24 TC 176 Z9 180 U1 10 U2 57 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 MAR 21 PY 2008 VL 283 IS 12 BP 7309 EP 7313 DI 10.1074/jbc.R700042200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 274JP UT WOS:000253997900003 PM 18256030 ER PT J AU Wang, QY Li, LY Ye, YH AF Wang, Qiuyan Li, Lianyun Ye, Yihong TI Inhibition of p97-dependent protein degradation by Eeyarestatin I SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ER-ASSOCIATED DEGRADATION; TRANSMEMBRANE CONDUCTANCE REGULATOR; RETICULUM-ASSOCIATED DEGRADATION; UBIQUITIN-PROTEASOME SYSTEM; CELL ANTIGEN RECEPTOR; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; MEMBRANE-PROTEIN; MISFOLDED GLYCOPROTEINS; AAA-ATPASE AB Elimination of misfolded proteins from the endoplasmic reticulum ( ER) by ER-associated degradation involves substrate retro-translocation from the ER lumen into the cytosol for degradation by the proteasome. For many substrates, retrotranslocation requires the action of ubiquitinating enzymes, which polyubiquitinate substrates emerging from the ER lumen, and of the p97-Ufd1-Npl4 ATPase complex, which hydrolyzes ATP to dislocate polyubiquitinated substrates into the cytosol. Polypeptides extracted by p97 are eventually transferred to the proteasome for destruction. In mammalian cells, ERAD can be blocked by a chemical inhibitor termed Eeyarestatin I, but the mechanism of EerI action is unclear. Here we report that EerI can associate with a p97 complex to inhibit ERAD. The interaction of EerI with the p97 complex appears to negatively influence a deubiquitinating process that is mediated by p97-associated deubiquitinating enzymes. We further show that ataxin-3, a p97-associated deubiquitinating enzyme previously implicated in ER-associated degradation, is among those affected. Interestingly, p97-associated deubiquitination is also involved in degradation of a soluble substrate. Our analyses establish a role for a novel deubiquitinating process in proteasome-dependent protein turnover. C1 [Wang, Qiuyan; Li, Lianyun; Ye, Yihong] NIDDK, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, Natl Inst Hlth, 5 Ctr Dr, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU Intramural NIH HHS NR 60 TC 90 Z9 91 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 21 PY 2008 VL 283 IS 12 BP 7445 EP 7454 DI 10.1074/jbc.M708347200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 274JP UT WOS:000253997900019 PM 18199748 ER PT J AU Truscott, SM Wang, X Lybarger, L Biddison, WE McBerry, C Martinko, JM Connolly, JM Linette, GP Fremont, DH Hansen, TH Carreno, BM AF Truscott, Steven M. Wang, Xiaoli Lybarger, Lonnie Biddison, William E. McBerry, Cortez Martinko, John M. Connolly, Janet M. Linette, Gerald P. Fremont, Daved H. Hansen, Ted H. Carreno, Beatriz M. TI Human major histocompatibility complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; SINGLE-CHAIN TRIMERS; CELL-RECEPTOR; MONOCLONAL-ANTIBODIES; DENDRITIC CELLS; DNA VACCINES; EPITOPE; HLA-A2; RECOGNITION; HLA-B27 AB The ongoing discovery of disease-associated epitopes detected by CD8 T cells greatly facilitates peptide-based vaccine approaches and the construction of multimeric soluble recombinant proteins ( e. g. tetramers) for isolation and enumeration of antigen-specific CD8 T cells. Related to these outcomes of epitope discovery is the recent demonstration that MHC class I/peptide complexes can be expressed as single chain trimers ( SCTs) with peptide, beta(2)m and heavy chain connected by linkers to form a single polypeptide chain. Studies using clinically relevant mouse models of human disease have shown that SCTs expressed by DNA vaccination are potent stimulators of cytotoxic T lymphocytes. Their vaccine efficacy has been attributed to the fact that SCTs contain a preprocessed and preloaded peptide that is stably displayed on the cell surface. Although SCTs of HLA class I/ peptide complexes have been previously reported, they have not been characterized for biochemical stability or susceptibility to exogenous peptide binding. Here we demonstrate that human SCTs remain almost exclusively intact when expressed in cells and can incorporate a disulfide trap that dramatically excludes the binding of exogenous peptides. The mechanistic and practical applications of these findings for vaccine development and T cell isolation/ enumeration are discussed. C1 [Truscott, Steven M.; Wang, Xiaoli; Connolly, Janet M.; Fremont, Daved H.; Hansen, Ted H.] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Truscott, Steven M.; Wang, Xiaoli; Connolly, Janet M.; Fremont, Daved H.; Hansen, Ted H.] Washington Univ, Sch Med, Dept Immunol, St Louis, MO 63110 USA. [Linette, Gerald P.; Carreno, Beatriz M.] Washington Univ, Sch Med, Dept Internal Med, Div Oncol, St Louis, MO 63110 USA. [Biddison, William E.] Natl Inst Hlth, NINDS, Mol Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Lybarger, Lonnie] Univ Arizona, Arizona Hlth Sci Ctr, Dept Cell Biol & Anat, Tucson, AZ 85724 USA. [McBerry, Cortez; Martinko, John M.] So Illinois Univ, Dept Microbiol, Carbondale, IL 62901 USA. RP Hansen, TH (reprint author), Washington Univ, Sch Med, Dept Pathol, Box 8118,660 S Euclid Ave, St Louis, MO 63110 USA. EM hansen@pathology.wustl.edu FU NIAID NIH HHS [AI027568, AI055849, U54-AI057160] NR 56 TC 12 Z9 13 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 21 PY 2008 VL 283 IS 12 BP 7480 EP 7490 DI 10.1074/jbc.M709935200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 274JP UT WOS:000253997900023 PM 18195006 ER PT J AU Lenz, G Davis, RE Ngo, VN Lam, L George, TC Wright, GW Dave, SS Zhao, H Xu, WH Rosenwald, A Ott, G Muller-Hermelink, HK Gascoyne, RD Connors, JM Rimsza, LM Campo, E Jaffe, ES Delabie, J Smeland, EB Fisher, RI Chan, WC Staudt, LM AF Lenz, Georg Davis, R. Eric Ngo, Vu N. Lam, Lloyd George, Thaddeus C. Wright, George W. Dave, Sandeep S. Zhao, Hong Xu, Weihong Rosenwald, Andreas Ott, German Muller-Hermelink, Hans Konrad Gascoyne, Randy D. Connors, Joseph M. Rimsza, Lisa M. Campo, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Fisher, Richard I. Chan, Wing C. Staudt, Louis M. TI Oncogenic CARD11 mutations in human diffuse large B cell lymphoma SO SCIENCE LA English DT Article ID HODGKIN LYMPHOMA; ACTIVATION; CARMA1; PHOSPHORYLATION; PROLIFERATION; CHEMOTHERAPY; REQUIREMENT; SURVIVAL AB The ability to select a better option from multiple acceptable ones is important for animals to optimize their resources. The mechanisms that underlie such decision- making processes are not well understood. We found that selection of egg- laying site in Drosophila melanogaster is a suitable system to probe the neural circuit that governs simple decision- making processes. First, Drosophila females pursue active probing of the environment before depositing each egg, apparently to evaluate site quality for every egg. Second, Drosophila females can either accept or reject a sucrose- containing medium, depending on the context. Last, communication of the "acceptability" of the sucrose- containing medium as an egg- laying option to the reproductive system depends on the function of a group of insulin- like peptide 7 ( ILP7)- producing neurons. These findings suggest that selection of egg- laying site involves a simple decision- making process and provide an entry point toward a systematic dissection of this process. C1 [Lenz, Georg; Davis, R. Eric; Ngo, Vu N.; Lam, Lloyd; Dave, Sandeep S.; Zhao, Hong; Xu, Weihong; Staudt, Louis M.] NCI, Metab Branch, Div Canc Treatment & Diag, Canc Res Ctr, Bethesda, MD 20892 USA. [George, Thaddeus C.] Amnis Corp, Seattle, WA 98121 USA. [Wright, George W.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Canc Res Ctr, Bethesda, MD 20892 USA. [Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, D-70376 Stuttgart, Germany. [Gascoyne, Randy D.; Connors, Joseph M.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. [Campo, Elias] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain. [Jaffe, Elaine S.] NCI, Pathol Lab, Div Canc Treatment & Diag, Canc Res Ctr, Bethesda, MD 20892 USA. [Delabie, Jan] Rikshosp Radiumhosp Med Ctr, Dept Immunol, N-0310 Oslo, Norway. [Smeland, Erlend B.] Rikshosp Univ Hosp, Inst Canc Res, N-0310 Oslo, Norway. [Smeland, Erlend B.] Norwegian Radium Hosp, Ctr Canc Biomed, Fac Div, N-0310 Oslo, Norway. [Fisher, Richard I.] SW Oncol Grp, Ann Arbor, MI 48106 USA. [Fisher, Richard I.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. [Chan, Wing C.] Univ Nebraska, Med Ctr, Dept Pathol, Omaha, NE 68198 USA. [Chan, Wing C.] Univ Nebraska, Med Ctr, Dept Microbiol, Omaha, NE 68198 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Div Canc Treatment & Diag, Canc Res Ctr, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov RI Lenz, Georg/I-6844-2012; OI Delabie, Jan/0000-0001-5023-0689; Campo, elias/0000-0001-9850-9793 FU Intramural NIH HHS; NCI NIH HHS [UO1-CA84967] NR 23 TC 379 Z9 396 U1 3 U2 27 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 MAR 21 PY 2008 VL 319 IS 5870 BP 1676 EP 1679 DI 10.1126/science.1153629 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276VR UT WOS:000254172300044 PM 18323416 ER PT J AU Lopez, JE Beare, PA Heinzen, RA Norimine, J Lahmers, KK Palmer, GH Brown, WC AF Lopez, Job E. Beare, Paul A. Heinzen, Robert A. Norimine, Junzo Lahmers, Kevin K. Palmer, Guy H. Brown, Wendy C. TI High-throughput identification of T-lymphocyte antigens from Anaplasma marginale expressed using in vitro transcription and translation SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Anaplasma marginale; in vitro transcription and translation; IVTT; T-lymphocyte antigens; high-throughput screening ID OUTER-MEMBRANE PROTEINS; MAJOR SURFACE PROTEIN-2; BABESIA-BOVIS; CELL LINES; VACCINE; CATTLE; CHALLENGE; INFECTION; DISCOVERY; RESPONSES AB The ability to rapidly screen a complex pathogen proteome for proteins that elicit recall T-lymphocyte responses from immune individuals would accelerate vaccine development. An outer membrane fraction of the rickettsia] pathogen Anaplasma marginale induces protective immunity against infection and disease in cattle. We have used this immunization model to evaluate high-throughput screening of proteins expressed by in vitro transcription and translation (IVTT) for recognition by memory CD4(+) T-lymphocytes. Fifty selected vaccine candidate antigens identified from the A. marginale genome were expressed from transcriptionally active PCR products using an Escherichia coli-based IVTT system, and bead-affinity purified using antibodies to His and FLAG epitope tags. IVTT-expressed bead-bound antigens were processed and presented by antigen presenting cells to T-lymphocytes from outer membrane immunized animals and evaluated for immunogenicity in proliferation assays. Antigens that consistently stimulated responses were known T-cell antigens major surface protein (MSP)2, MSP3, VirB9, and VirB10 and newly identified T-cell antigens outer membrane protein (OMP)4, OMP9, elongation factor-Tu, Ana29, and OMA87. Specific T-cell stimulation was achieved even at low antigen concentration, and was highly sensitive when compared with unbound IVTT reaction products. This method allows rapid expression and identification of T-lymphocyte antigens for any pathogen for which the genome sequence is available. (C) 2008 Elsevier B.V. All rights reserved. C1 [Lopez, Job E.; Norimine, Junzo; Lahmers, Kevin K.; Palmer, Guy H.; Brown, Wendy C.] Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. [Beare, Paul A.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Brown, WC (reprint author), Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. EM wbrown@vetmed.wsu.edu OI Lahmers, Kevin/0000-0002-5290-3426 FU Intramural NIH HHS; NIAID NIH HHS [AI-053692, R01 AI053692] NR 21 TC 30 Z9 31 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAR 20 PY 2008 VL 332 IS 1-2 BP 129 EP 141 DI 10.1016/j.jim.2007.12.018 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 292ZK UT WOS:000255304400014 PM 18243240 ER PT J AU Koenigs, M Young, L Adolphs, R Tranel, D Cushman, F Hauser, M Damasio, A AF Koenigs, M. Young, L. Adolphs, R. Tranel, D. Cushman, F. Hauser, M. Damasio, A. TI Do abnormal responses show utilitarian bias? Reply SO NATURE LA English DT Letter ID MORAL JUDGMENT C1 [Koenigs, M.; Adolphs, R.; Tranel, D.; Damasio, A.] Univ Iowa Hosp & Clin, Dept Neurol, Iowa City, IA 52242 USA. [Young, L.; Cushman, F.; Hauser, M.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Adolphs, R.] CALTECH, Div Humanities & Social Sci, Pasadena, CA 91125 USA. [Adolphs, R.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Damasio, A.] Univ So Calif, Brain & Creativ Inst, Los Angeles, CA 90089 USA. [Damasio, A.] Univ So Calif, Dornsife Ctr Cognit Neuroimaging, Los Angeles, CA 90089 USA. RP Koenigs, M (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. EM radolphs@hss.caltech.edu OI Koenigs, Michael/0000-0002-5799-4881 NR 8 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 20 PY 2008 VL 452 IS 7185 BP E5 EP E6 DI 10.1038/nature06804 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276BX UT WOS:000254117400036 ER PT J AU Rothenberg, ME Klion, AD Roufosse, FE Kahn, JE Weller, PF Simon, HU Schwartz, LB Rosenwasser, LJ Ring, J Griffin, EF Haig, AE Frewer, PIH Parkin, JM Gleich, GJ AF Rothenberg, Marc E. Klion, Amy D. Roufosse, Florence E. Kahn, Jean Emmanuel Weller, Peter F. Simon, Hans-Uwe Schwartz, Lawrence B. Rosenwasser, Lanny J. Ring, Johannes Griffin, Elaine F. Haig, Ann E. Frewer, Paul I. H. Parkin, Jacqueline M. Gleich, Gerald J. CA Mepolizumab HES Study Grp TI Treatment of patients with the hypereosinophilic syndrome with mepolizumab SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMANIZED MONOCLONAL-ANTIBODY; ANTI-INTERLEUKIN-5 ANTIBODY; HUMAN INTERLEUKIN-5; ATOPIC-DERMATITIS; EOSINOPHILS; ANTI-IL-5; THERAPY; GLUCOCORTICOIDS; EFFICACY; IMATINIB AB Background: The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity. Methods: We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti-interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1-PDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a blood eosinophil count of less than 1000 per microliter. Patients received either intravenous mepolizumab or placebo while the prednisone dose was tapered. The primary end point was the reduction of the prednisone dose to 10 mg or less per day for 8 or more consecutive weeks. Results: The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no increase in clinical activity of the hypereosinophilic syndrome. A blood eosinophil count of less than 600 per microliter for 8 or more consecutive weeks was achieved in 95% of patients receiving mepolizumab, as compared with 45% of patients receiving placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P<0.001). Serious adverse events occurred in seven patients receiving mepolizumab (14 events, including one death; mean [+/-SD] duration of exposure, 6.7+/-1.9 months) and in five patients receiving placebo (7 events; mean duration of exposure, 4.3+/-2.6 months). Conclusions: Our study shows that treatment with mepolizumab, an agent designed to target eosinophils, can result in corticosteroid-sparing for patients negative for FIP1L1-PDGFRA who have the hypereosinophilic syndrome. (ClinicalTrials.gov number, NCT00086658.). C1 [Rothenberg, Marc E.] Univ Cincinnati, Childrens Hosp & Med Ctr, Div Allergy & Immunol, Dept Pediat, Cincinnati, OH 45229 USA. [Klion, Amy D.] NIAID, Bethesda, MD 20892 USA. [Roufosse, Florence E.] Univ Libre Bruxelles, Serv Med Interne, Hop Erasme, Gosselies, Belgium. [Roufosse, Florence E.] Inst Med Immunol, Gosselies, Belgium. [Kahn, Jean Emmanuel] Hop Foch, Serv Med Interne, Suresnes, France. [Weller, Peter F.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Simon, Hans-Uwe] Univ Bern, Bern, Switzerland. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Richmond, VA USA. [Rosenwasser, Lanny J.] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Ring, Johannes] Tech Univ Munich, Munich, Germany. [Griffin, Elaine F.] Envis Pharma, Horsham, W Sussex, England. [Haig, Ann E.] GlaxoSmithKline Inc, King Of Prussia, PA USA. [Frewer, Paul I. H.; Parkin, Jacqueline M.] GlaxoSmithKline Inc, Middlesex, England. [Gleich, Gerald J.] Univ Utah, Sch Med, Salt Lake City, UT USA. RP Rothenberg, ME (reprint author), Univ Cincinnati, Childrens Hosp & Med Ctr, Div Allergy & Immunol, Dept Pediat, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM rothenberg@cchmc.org OI Simon, Hans-Uwe/0000-0002-9404-7736; Klion, Amy/0000-0002-4986-5326 FU Intramural NIH HHS; NCRR NIH HHS [MO1 RR001032, M01 RR00064, M01 RR 08084]; NIAID NIH HHS [AI61097] NR 30 TC 250 Z9 260 U1 1 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 20 PY 2008 VL 358 IS 12 BP 1215 EP 1228 DI 10.1056/NEJMoa070812 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 275TL UT WOS:000254094400003 PM 18344568 ER PT J AU Flegal, KM Graubard, BI Williamson, DF Gail, MH AF Flegal, Katherine M. Graubard, Barry I. Williamson, David F. Gail, Mitchell H. TI Cardiovascular risk factors, mortality, and overweight - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Flegal, Katherine M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Graubard, Barry I.; Gail, Mitchell H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Williamson, David F.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. EM kmf2@cdc.gov RI Flegal, Katherine/A-4608-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR 19 PY 2008 VL 299 IS 11 BP 1261 EP 1261 DI 10.1001/jama.299.11.1261-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 275NO UT WOS:000254079100016 ER PT J AU Masciari, S Van den Abbeele, AD Diller, LR Rastarhuyeva, I Yap, J Schneider, K Digianni, L Li, FP Fraumeni, JF Syngal, S Garber, JE AF Masciari, Serena Van den Abbeele, Annick D. Diller, Lisa R. Rastarhuyeva, Iryna Yap, Jeffrey Schneider, Katherine Digianni, Lisa Li, Frederick P. Fraumeni, Joseph F., Jr. Syngal, Sapna Garber, Judy E. TI F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SOFT-TISSUE SARCOMA; P53 MUTATIONS; F-18 FLUORODEOXYGLUCOSE; FDG-PET; COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; COLORECTAL-CANCER; FAMILIAL SYNDROME; RATIONAL APPROACH; DOSE REDUCTION AB Context Individuals with Li-Fraumeni syndrome ( LFS) have an inherited cancer predisposition to a diverse array of malignancies beginning early in life; survivors of one cancer have a markedly elevated risk of additional primary tumors. The underlying genetic defect in the majority of the families is a germline mutation in the TP53 tumor suppressor gene. The diversity of tumors and rarity of families have contributed to the difficulty in devising effective screening recommendations for members of LFS kindreds. Objective To gather preliminary data with which to evaluate F18- fluorodeoxyglucose positron emission tomography/ computed tomography ( FDG- PET/ CT) imaging as a potential surveillance modality to detect early malignancies in asymptomatic members of LFS kindreds. Design, Setting, and Participants Members of LFS families with documented germline TP53 mutations or obligate carrier status, no history of cancer within 5 years of enrollment, and no symptoms of cancer or ill- health were offered FDG-PET/ CT scanning as a screening test in a comprehensive US cancer center from 2006 to 2007. Scans were initially reviewed clinically, then centrally reviewed by an expert radiologist. Main OutcomeMeasure The primary outcome was the detection of new primary cancers using FDG- PET/ CT scanning. Results Of 15 individuals, baseline FDG- PET/ CT scan identified asymptomatic cancers in 3 ( 20%). Two individuals had papillary thyroid cancers ( stage II and stage III) and one individual had stage II esophageal adenocarcinoma. Conclusions These preliminary data provide the first evidence for a potential cancer surveillance strategy that may be worthy of further investigation for patients with LFS. Concerns about radiation exposure and other challenges inherent in screening high-risk patients will require further consideration. C1 [Masciari, Serena; Schneider, Katherine; Digianni, Lisa; Li, Frederick P.; Syngal, Sapna; Garber, Judy E.] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Van den Abbeele, Annick D.; Rastarhuyeva, Iryna; Yap, Jeffrey] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Diller, Lisa R.] Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. [Fraumeni, Joseph F., Jr.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Syngal, Sapna] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. RP Garber, JE (reprint author), Dana Farber Canc Inst, Div Populat Sci, 44 Binney St,SM 209, Boston, MA 02115 USA. EM judy_garber@dfci.harvard.edu NR 35 TC 49 Z9 51 U1 0 U2 1 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 MAR 19 PY 2008 VL 299 IS 11 BP 1315 EP 1319 DI 10.1001/jama.299.11.1315 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 275NO UT WOS:000254079100022 PM 18349092 ER PT J AU Pearson, TA Manolio, TA AF Pearson, Thomas A. Manolio, Teri A. TI How to interpret a genome-wide association study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID FALSE DISCOVERY RATE; POPULATION STRATIFICATION; CROHN-DISEASE; BREAST-CANCER; SUSCEPTIBILITY VARIANT; CONFER SUSCEPTIBILITY; MACULAR DEGENERATION; COLORECTAL-CANCER; COMMON DISEASES; HAPLOTYPE MAP AB Genome- wide association ( GWA) studies use high- throughput genotyping technologies to assay hundreds of thousands of single- nucleotide polymorphisms ( SNPs) and relate them to clinical conditions and measurable traits. Since 2005, nearly 100 loci for as many as 40 common diseases and traits have been identified and replicated in GWA studies, many in genes not previously suspected of having a role in the disease under study, and some in genomic regions containing no known genes. GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false- positive and false- negative results and for biases related to selection of study participants and genotyping errors. Although these studies are clearly many steps removed from actual clinical use, and specific applications of GWA findings in prevention and treatment are actively being pursued, at present these studies mainly represent a valuable discovery tool for examining genomic function and clarifying pathophysiologic mechanisms. This article describes the design, interpretation, application, and limitations of GWA studies for clinicians and scientists for whom this evolving science may have great relevance. C1 [Pearson, Thomas A.; Manolio, Teri A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Pearson, Thomas A.] Univ Rochester, Med Ctr, Clin & Translat Sci Inst, Rochester, NY 14642 USA. RP Manolio, TA (reprint author), NHGRI, Off Populat Genom, NIH, 31 Ctr Dr,Room 4B-09,MSC 2154, Bethesda, MD 20892 USA. EM manolio@nih.gov FU NCRR NIH HHS [RR024160, UL1 RR024160] NR 73 TC 404 Z9 431 U1 7 U2 51 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 MAR 19 PY 2008 VL 299 IS 11 BP 1335 EP 1344 DI 10.1001/jama.299.11.1335 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 275NO UT WOS:000254079100024 PM 18349094 ER PT J AU Feero, WG Guttmacher, AE Collins, FS AF Feero, W. Gregory Guttmacher, Alan E. Collins, Francis S. TI The genome gets personal - Almost SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID WIDE ASSOCIATION C1 [Feero, W. Gregory; Guttmacher, Alan E.; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Feero, WG (reprint author), NHGRI, NIH, Bldg 31,Room 4B09,31 Ctr Dr, Bethesda, MD 20892 USA. EM feerow@mail.nih.gov NR 15 TC 107 Z9 109 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 MAR 19 PY 2008 VL 299 IS 11 BP 1351 EP 1352 DI 10.1001/jama.299.11.1351 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 275NO UT WOS:000254079100026 PM 18349096 ER PT J AU Uhlmann, WR Guttmacher, AE AF Uhlmann, Wendy R. Guttmacher, Alan E. TI Key Internet genetics resources for the clinician SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Uhlmann, Wendy R.] Univ Michigan, Med Genet Clin, Dept Internal Med, Ann Arbor, MI 48109 USA. [Uhlmann, Wendy R.] Univ Michigan, Med Genet Clin, Dept Human Genet, Ann Arbor, MI 48109 USA. [Guttmacher, Alan E.] NHGRI, Bethesda, MD 20892 USA. RP Uhlmann, WR (reprint author), Univ Michigan, Med Genet Clin, Dept Internal Med, 300 N Ingalls,NI3 A03,SPC 5419, Ann Arbor, MI 48109 USA. EM wuhlmann@umich.edu NR 20 TC 12 Z9 12 U1 0 U2 1 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 MAR 19 PY 2008 VL 299 IS 11 BP 1356 EP 1358 DI 10.1001/jama.299.11.1356 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 275NO UT WOS:000254079100028 PM 18349098 ER PT J AU Sostaric, JZ AF Sostaric, Joe Z. TI A chemical sensor that can detect the frequency of ultrasound SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID GAS/SOLUTION INTERFACE; CAVITATION BUBBLES; AQUEOUS-SOLUTIONS; SURFACE-TENSION; ADSORPTION; SONOCHEMISTRY; OH AB Herein is described a chemical sensor that can detect the frequency of ultrasound. Exposure of aqueous n-alkyl sulfate or sulfonate surfactant solutions to high-intensity ultrasound results in the formation of secondary carbon-centered radicals. The yield of these radicals reaches a maximum plateau, the magnitude of which is limited by the dynamic ability of the surfactant to accumulate at the rapidly oscillating gas/solution interface of cavitation bubbles. For this reason, the maximum plateau yield observed following sonolysis of sodium butane sulfonate solutions compared to that of sodium dodecyl sulfate solutions (i.e., CH(SBso),/CH(SDS)) Was greater than 1. Interestingly, it was found that the CH(SBSo)/CH(SDS) ratio had a linear dependence on ultrasound frequency. Since it is known from earlier studies that the CH(SBSs)/CH(SDS) ratio is independent of ultrasound intensity and of the geometry of flat plate exposure systems, a plot of the CH(SBSo)/CH(SDS) ratio against ultrasound frequency yields a calibration curve. With this calibration curve, the CH(SBSo)/CH(SDS) ratio can be used to detect the frequency of ultrasound in flat plate transducer systems. The effect can best be described in terms of the dynamic surface tension of surfactants in relation to the influence of ultrasound frequency on the lifetime of the gas/solution interface of sonochemically active cavitation bubbles. C1 [Sostaric, Joe Z.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Sostaric, JZ (reprint author), Ohio State Univ, Ctr Biomed EPR Sepct & Imaging, DHLRI, Columbus, OH 43210 USA. EM sostaric.2@osu.edu RI Sostaric, Joe/A-6033-2008 FU Intramural NIH HHS NR 26 TC 6 Z9 6 U1 1 U2 3 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 MAR 19 PY 2008 VL 130 IS 11 BP 3248 EP + DI 10.1021/ja077311v PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 273SL UT WOS:000253951900008 PM 18302375 ER PT J AU Zuo, XB Wang, JB Foster, TR Schwieters, CD Tiede, DM Butcher, SE Wang, YX AF Zuo, Xiaobing Wang, Jingbu Foster, Trenton R. Schwieters, Charles D. Tiede, David M. Butcher, Samuel E. Wang, Yun-Xing TI Global molecular structure and interfaces: Refining an RNA : RNA complex structure using solution X-ray scattering data SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TETRALOOP-RECEPTOR COMPLEX; DIPOLAR COUPLINGS; RELATIVE ORIENTATION; PROTEIN STRUCTURES; NMR; REFINEMENT; DIMER; FIELD AB Determining the global architecture of multicomponent systems is a central problem in understanding biomacromolecular machines. Defining interfaces among components and the global structure of multicomponent systems is a central problem in understanding the biological interactions on a molecular level. We demonstrate that solution X-ray scattering data can be used to precisely determine intermolecular interfaces from just the subunit structures, in the complete absence of intermolecular NMR restraints using an example of a 30 kDa RNA-RNA complex. The backbone root-mean-square deviation (rmsd) between structures that are determined using the scattering data and using intermolecular distance restraints is about 0.4 angstrom. Further, we refined the global structure of the complex using scattering data as a global restraint. The rmsd in backbone structures that are determined with and without the scattering data refinement is about 3.2 angstrom, suggesting the impact of the refinement to the overall structure. Information about the "global correctness" of solution RNA structures could not be practically obtained otherwise, due to the molecular nature of the RNA molecules, but could only be defined by the scattering data together by residual dipolar couplings. This method provides a powerful new approach for refining global structures of macromolecular complexes whose subunits are elongated. C1 [Foster, Trenton R.; Butcher, Samuel E.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Zuo, Xiaobing; Wang, Jingbu; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Tiede, David M.] Argonne Natl Lab, Chem Sci & Engn Div, Argonne, IL 60439 USA. RP Butcher, SE (reprint author), Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. EM butcher@.biochem.wisc.edu; wangyu@ncifcrf.gov RI Zuo, Xiaobing/F-1469-2010; ID, BioCAT/D-2459-2012; OI Zuo, Xiaobing/0000-0002-0134-4804 FU Intramural NIH HHS NR 18 TC 44 Z9 44 U1 0 U2 4 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 MAR 19 PY 2008 VL 130 IS 11 BP 3292 EP + DI 10.1021/ja7114508 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 273SL UT WOS:000253951900030 PM 18302388 ER PT J AU Preston, DL Cullings, H Suyama, A Funamoto, S Nishi, N Soda, M Mabuchi, K Kodama, K Kasagi, F Shore, RE AF Preston, Dale L. Cullings, Harry Suyama, Akihiko Funamoto, Sachiyo Nishi, Nobuo Soda, Midori Mabuchi, Kiyohiko Kodama, Kazunori Kasagi, Fumiyoshi Shore, Roy E. TI Solid cancer incidence in atomic bomb survivors exposed in utero or as young children SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID IONIZING-RADIATION; CHILDHOOD-CANCER; DOSE-ESTIMATION; MORTALITY; TUMORS; MICE; IRRADIATION; INDUCTION; RISK; FETAL AB Background In utero exposure to radiation is known to increase risks of childhood cancers, and childhood exposure is associated with increased risks of adult-onset cancers. However, little is known about whether in utero exposure to radiation increases risks of adult-onset cancers. Methods Solid cancer incidence rates were examined among survivors of the atomic bombings of Hiroshima and Nagasaki who were in utero (n = 2452) or younger than 6 years (n = 15388) at the time of the bombings. Poisson regression was used to estimate and compare the levels and temporal patterns of the radiation-associated excess risks of first primary solid cancers among these survivors at ages 12-55. All statistical tests were two-sided. Results There were 94 eligible cancers in the in utero group and 649 in the early childhood group. The excess relative risk (ERR) increased with dose for both in utero (age 50, ERR = 1.0 per Sv, 95% confidence interval [Cl] = 0.2 to 2.3 per Sv) and early childhood (age 50, ERR = 1.7 per Sv, 95% Cl = 1.1 to 2.5 Sv) exposures. The ERR declined (P=.046) with increasing attained age in the combined cohort. Excess absolute rates (EARs) increased markedly with attained age among those exposed in early childhood but exhibited little change in the in utero group. At age 50, the estimated EARs per 10000 person-years per Sv were 6.8 (95% Cl <0 to 49) for those exposed in utero and 56 (95% Cl = 36 to 79) for those exposed as young children. Conclusions Both the in utero and early childhood groups exhibited statistically significant dose-related increases in incidence rates of solid cancers. The apparent difference in EARs between the two groups suggests that lifetime risks following in utero exposure may be considerably lower than for early childhood exposure, but further follow-up is needed. C1 [Preston, Dale L.] Hirosoft Int Corp, Eureka, CA 95501 USA. [Nishi, Nobuo; Kodama, Kazunori; Kasagi, Fumiyoshi; Shore, Roy E.] Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima, Japan. [Cullings, Harry; Funamoto, Sachiyo] Radiat Effects Res Fdn, Dept Stat, Hiroshima, Japan. [Mabuchi, Kiyohiko] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Suyama, Akihiko; Soda, Midori] Radiat Effects Res Fdn, Dept Epidemiol, Nagasaki, Japan. RP Preston, DL (reprint author), Hirosoft Int Corp, 1335 H St, Eureka, CA 95501 USA. EM preston@hirosoft.net FU Intramural NIH HHS; NCI NIH HHS [N01-CP31012] NR 48 TC 129 Z9 135 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 MAR 19 PY 2008 VL 100 IS 6 BP 428 EP 436 DI 10.1093/jnci/djn045 PG 9 WC Oncology SC Oncology GA 278OT UT WOS:000254296900014 PM 18334707 ER PT J AU Chiara, F Castellaro, D Marin, O Petronilli, V Brusilow, WS Juhaszova, M Sollott, SJ Forte, M Bernardi, P Rasola, A AF Chiara, Federica Castellaro, Diego Marin, Oriano Petronilli, Valeria Brusilow, William S. Juhaszova, Magdalena Sollott, Steven J. Forte, Michael Bernardi, Paolo Rasola, Andrea TI Hexokinase II Detachment from Mitochondria Triggers Apoptosis through the Permeability Transition Pore Independent of Voltage-Dependent Anion Channels SO PLOS ONE LA English DT Article AB Type II hexokinase is overexpressed in most neoplastic cells, and it mainly localizes on the outer mitochondrial membrane. Hexokinase II dissociation from mitochondria triggers apoptosis. The prevailing model postulates that hexokinase II release from its mitochondrial interactor, the voltage-dependent anion channel, prompts outer mitochondrial membrane permeabilization and the ensuing release of apoptogenic proteins, and that these events are inhibited by growth factor signalling. Here we show that a hexokinase II N-terminal peptide selectively detaches hexokinase II from mitochondria and activates apoptosis. These events are abrogated by inhibiting two established permeability transition pore modulators, the adenine nucleotide translocator or cyclophilin D, or in cyclophilin D knock-out cells. Conversely, insulin stimulation or genetic ablation of the voltage-dependent anion channel do not affect cell death induction by the hexokinase II peptide. Therefore, hexokinase II detachment from mitochondria transduces a permeability transition pore opening signal that results in cell death and does not require the voltage-dependent anion channel. These findings have profound implications for our understanding of the pathways of outer mitochondrial membrane permeabilization and their inactivation in tumors. C1 [Chiara, Federica; Castellaro, Diego; Petronilli, Valeria; Bernardi, Paolo; Rasola, Andrea] Univ Padua, CNR, Inst Neurosci, Dept Biomed Sci, Padua, Italy. [Marin, Oriano] Univ Padua, Venetian Inst Mol Med, Dept Biol Chem, Padua, Italy. [Brusilow, William S.] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI USA. [Juhaszova, Magdalena; Sollott, Steven J.] NIH, Natl Inst Aging, Gerontol Res Ctr, Lab Cardiovascul Sci, Baltimore, MD USA. [Forte, Michael] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR USA. RP Chiara, F (reprint author), Univ Padua, CNR, Inst Neurosci, Dept Biomed Sci, Padua, Italy. EM bernardi@bio.unipd.it; rasola@bio.unipd.it RI Bernardi, Paolo/C-3656-2008; Petronilli, Valeria/C-3558-2015; OI Bernardi, Paolo/0000-0001-9187-3736; Petronilli, Valeria/0000-0003-4026-6404; Rasola, Andrea/0000-0003-4522-3008 FU Progetti di Ricerca di Interesse Nazionale del Ministero dell Universita e della Ricerca; USA NIH-PHS [GM69883]; Intramural Research Program, National Institute on Aging, NIH; AIRC; Progetti di Ateneo dell Universita di Padova FX This work was made possible by grants from the Progetti di Ricerca di Interesse Nazionale del Ministero dell Universita e della Ricerca (MIUR-PRIN, to P.B.), from the USA NIH-PHS (Grant GM69883 to M.F and P.B.), from the Intramural Research Program, National Institute on Aging, NIH (to M.J. and S.J.S.), from AIRC (to P.B.), and from Progetti di Ateneo dell Universita di Padova (to A.R.). NR 42 TC 130 Z9 136 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 19 PY 2008 VL 3 IS 3 AR e1852 DI 10.1371/journal.pone.0001852 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 370KY UT WOS:000260762300041 PM 18350175 ER PT J AU Laiyemo, AO Murphy, G Albert, PS Wang, Z Cross, AJ Marcus, PM Caan, B Marshall, JR Lance, P Paskett, ED Weissfeld, J Slattery, ML Burt, R Iber, F Shike, M Kikendall, JW Lanza, E Schatzkin, A AF Laiyemo, Adeyinka O. Murphy, Gwen Albert, Paul S. Wang, Zhuoqiao Cross, Amanda J. Marcus, Pamela M. Caan, Bette Marshall, James R. Lance, Peter Paskett, Electra D. Weissfeld, Joel Slattery, Martha L. Burt, Randall Iber, Frank Shike, Moshe Kikendall, J. Walter Lanza, Elaine Schatzkin, Arthur TI Postpolypectomy colonoscopy surveillance guidelines: Predictive accuracy for advanced adenorna at 4 years SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CLINICAL-PRACTICE GUIDELINES; AMERICAN-CANCER-SOCIETY; PRIMARY-CARE PHYSICIANS; COLORECTAL-CANCER; NATIONAL-SURVEY; SCREENING COLONOSCOPY; ADENOMATOUS POLYPS; FOLLOW-UP; RECURRENCE; POLYPECTOMY AB Background: Lack of confidence in postpolypectomy surveillance guidelines may be a factor in the observed low adherence rates among providers. Objective: To assess the 2006 postpolypectomy colonoscopy surveillance guidelines, which recommend 3-year follow-up colonoscopy for individuals with high-risk adenomas (defined as >= 3 adenomas or any advanced adenomas) and 5- to 10-year follow-up for patients with 2 or fewer nonadvanced adenomas, who are considered to be at low risk. Design: Analysis of prospective data from the Polyp Prevention Trial. Setting: United States. Participants: 1905 patients who had colorectal adenomas removed at baseline screening or diagnostic colonoscopy and completed the trial. Measurements: Baseline adenoma characteristics, risk-stratified according to definitions used in the guidelines, were examined as predictors for advanced adenoma recurrence. Results: 125 patients (6.6%) had advanced and 629 (33.0%) had nonadvanced adenoma recurrence; 1151 (60.4%) had no recurrence within 4 years of follow-up. The probability of advanced adenoma recurrence was 0.09 (95% Cl, 0.07 to 0.11) among patients with high-risk adenomas at baseline and 0.05 (Cl, 0.04 to 0.06) among those with low-risk adenomas at baseline. The relative risk for advanced adenoma recurrence for patients with high-risk adenomas versus those with low-risk adenomas at baseline was 1.68 (Cl, 1.19 to 2.38) when advanced adenoma recurrence was compared with no advanced adenoma recurrence and 1.76 (Cl, 1.26 to 2.46) when advanced adenoma recurrence was compared with no adenoma recurrence. The c-statistics for these 2 comparisons were 0.68 and 0.72, respectively. Limitation: Participants were self-selected and had restrictions on the degree of obesity. Conclusion: Although the risk for recurrence of advanced adenoma within 4 years is greater for patients with high-risk adenomas at baseline than for those with low-risk adenomas, the discrimination of this risk stratification scheme is relatively low. C1 NIH, Natl Canc Inst, Bethesda, MD 20892 USA. Informat Management Serv Inc, Rockville, MD USA. Kaiser Fdn Res Inst, Oakland, CA USA. Roswell Pk Canc Inst, Buffalo, NY USA. Arizona Canc Ctr, Tucson, AZ USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Utah, Salt Lake City, UT USA. Edward Hines Jr Hosp Vet Affairs Med Ctr, Hines, IL USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Laiyemo, AO (reprint author), NCI, Div Canc Prevent, Biometry Res Grp, Canc Prevent Fellowship Program, 6130 Execut Blvd,Suite 3121, Bethesda, MD 20892 USA. EM laiyemoa@mail.nih.gov RI Murphy, Gwen/G-7443-2015 FU Intramural NIH HHS NR 35 TC 60 Z9 61 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAR 18 PY 2008 VL 148 IS 6 BP 419 EP 426 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 279KT UT WOS:000254354800002 PM 18347350 ER PT J AU Cook, NR Obarzanek, E Cutler, JA Buring, JE Rexrode, KM Kumanyika, SK Appel, LJ Whelton, PK AF Cook, Nancy R. Obarzanek, Eva Cutler, Jeffrey A. Buring, Julie E. Rexrode, Kathryn M. Kumanyika, Shiriki K. Appel, Lawrence J. Whelton, Paul K. CA Trials Hypertens Prevent Collabrat TI Joint effects of sodium and potassium intake on subsequent cardiovascular disease: The trials of hypertension prevention follow-up study SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Cook, Nancy R.; Buring, Julie E.; Rexrode, Kathryn M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Obarzanek, Eva; Cutler, Jeffrey A.] NHLBI, Washington, DC USA. [Kumanyika, Shiriki K.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Appel, Lawrence J.] Johns Hopkins Univ, Baltimore, MD USA. [Whelton, Paul K.] Loyola Univ Hlth Syst, Maywood, IL USA. NR 0 TC 0 Z9 0 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 MAR 18 PY 2008 VL 117 IS 11 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200042 ER PT J AU Furtado, J Campos, H Sumner, AE Miller, EE Appel, LJ Carey, V Sacks, FM AF Furtado, Jeremy Campos, Hanna Sumner, Anne E. Miller, Edgar E. Appel, Lawrence J. Carey, Vincent Sacks, Frank M. TI The paradox of low triglycerides and high CVD risk in blacks: Steps toward a resolution through nutritional interventions, ApoC-III and ApoE SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Furtado, Jeremy; Campos, Hanna; Sacks, Frank M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Sumner, Anne E.] NIH, Bethesda, MD 20892 USA. [Miller, Edgar E.; Appel, Lawrence J.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Carey, Vincent] Harvard Univ, Sch Med, Boston, MA USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 18 PY 2008 VL 117 IS 11 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200037 ER PT J AU Ix, JH Wassel-Fyr, C Kanaya, A Vittinghoff, E Johnson, KC Koster, A Cauley, JA Harris, TB Cummings, SR Shlipak, MG AF Ix, Joachim H. Wassel-Fyr, Christina Kanaya, Alka Vittinghoff, Eric Johnson, Karen C. Koster, Annemarie Cauley, Jane A. Harris, Tamara B. Cummings, Steven R. Shlipak, Michael G. TI Fetuin-A and risk of incident diabetes mellitus in elderly persons: The health aging and body composition (health ABC) study SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Ix, Joachim H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Wassel-Fyr, Christina; Kanaya, Alka; Vittinghoff, Eric; Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Koster, Annemarie; Harris, Tamara B.] NIH, Bethesda, MD 20892 USA. [Cauley, Jane A.] Univ Pittsburgh, Pittsburgh, PA USA. [Cummings, Steven R.] Calif Pacific Med Ctr, San Francisco, CA USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 18 PY 2008 VL 117 IS 11 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200056 ER PT J AU Kottgen, A Hwang, SJ Rampersaud, E Coresh, J North, KE Pankow, JS Meigs, JB Levy, D Boerwinkle, E Shuldiner, AR Fox, CS Kao, LW AF Kottgen, Anna Hwang, Shih-Jen Rampersaud, Evadnie Coresh, Josef North, Kari E. Pankow, James S. Meigs, James B. Levy, Daniel Boerwinkle, Eric Shuldiner, Alan R. Fox, Caroline S. Kao, Linda W. TI Variants in the transcription factor 7-like 2 gene region are associated with incident kidney disease and markers of kidney function in the atherosclerosis risk in communities study, the framingham heart study offspring cohort, and the heredity and phenotype intervention (HAPI) heart study SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Kottgen, Anna; Coresh, Josef; Kao, Linda W.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hwang, Shih-Jen; Levy, Daniel; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rampersaud, Evadnie; Shuldiner, Alan R.] Univ Maryland, Baltimore, MD 21201 USA. [North, Kari E.] Univ N Carolina, Chapel Hill, NC USA. [Pankow, James S.] Univ Minnesota, Minneapolis, MN USA. [Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Boerwinkle, Eric] Univ Texas Houston, Houston, TX USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 18 PY 2008 VL 117 IS 11 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200041 ER PT J AU Liu, J Joshi, D Sempos, CT AF Liu, Jian Joshi, Divya Sempos, Christopher T. TI Non-high-density-lipoprotein cholesterol and cardiovascular risk factors among adolescents with and without impaired fasting glucose SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Liu, Jian; Joshi, Divya] Brock Univ, St Catharines, ON L2S 3A1, Canada. [Sempos, Christopher T.] NIH, Bethesda, MD 20892 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 18 PY 2008 VL 117 IS 11 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200028 ER PT J AU Molenaar, EA Massaro, JM Jacques, PF Pou, KM Ellison, RC Hoffmann, U Pencina, K Vasan, RS O'Donnell, CJ Fox, CS AF Molenaar, Esther A. Massaro, Joseph M. Jacques, Paul F. Pou, Karla M. Ellison, R. C. Hoffmann, Udo Pencina, Karol Vasan, Ramachandran S. O'Donnell, Christopher J. Fox, Caroline S. TI Lifestyle factors with subcutaneous and visceral adiposity: The Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Molenaar, Esther A.] Univ Med Ctr Utrecht, Julius Cntr Hlth Sci & Primary Care, Utrecht, Netherlands. [Molenaar, Esther A.] Municipal Hlth Serv Utrecht, Utrecht, Netherlands. [Massaro, Joseph M.; Pencina, Karol] Boston Sch Publ Hlth, Boston, MA USA. [Jacques, Paul F.] Tufts Univ, Boston, MA 02111 USA. [Pou, Karla M.; Fox, Caroline S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ellison, R. C.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hoffmann, Udo; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Inst Framingham Heart Study, Boston, MA USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 18 PY 2008 VL 117 IS 11 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200093 ER PT J AU Preis, SR Hwang, SJ Coady, S D'Agostino, R Pencina, MJ Savage, P Levy, D Fox, CS AF Preis, Sarah R. Hwang, Shih-Jen Coady, Sean D'Agostino, Ralph, Sr. Pencina, Michael J. Savage, Peter Levy, Daniel Fox, Caroline S. TI Trends in mortality among women and men with and without diabetes in the Framingham heart study - Abstracts SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Preis, Sarah R.; Hwang, Shih-Jen; Levy, Daniel; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Coady, Sean; Savage, Peter] NHLBI, NIH, Bethesda, MD 20892 USA. [D'Agostino, Ralph, Sr.; Pencina, Michael J.] Boston Univ, Boston, MA 02215 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 18 PY 2008 VL 117 IS 11 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200025 ER PT J AU Svetkey, LP Stevens, VJ Brantley, PJ Appel, LJ Hollis, JF Loria, CM Vollmer, WM Gullion, CM Funk, K AF Svetkey, Laura P. Stevens, Victor J. Brantley, Phillip J. Appel, Lawrence J. Hollis, Jack F. Loria, Catherine M. Vollmer, William M. Gullion, Christina M. Funk, Kristine CA Weight Loss Maintenance Collaborat TI Strategies for sustaining weight loss: Findings from the weight loss maintenance trial SO CIRCULATION LA English DT Meeting Abstract CT 48th Annal Scientific Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 13-15, 2008 CL Colorado Springs, CO C1 [Svetkey, Laura P.] Duke Univ, Med Ctr, Durham, NC USA. [Stevens, Victor J.; Hollis, Jack F.; Vollmer, William M.; Gullion, Christina M.; Funk, Kristine] Cntr Hlth Rsch, Portland, OR USA. [Brantley, Phillip J.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Appel, Lawrence J.] Johns Hopkins Med Cntr, Baltimore, MD USA. [Loria, Catherine M.] NHLBI, NIH, Bethesda, MD 20892 USA. RI Kattelmann, Kendra/E-8225-2013 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 18 PY 2008 VL 117 IS 11 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 275IN UT WOS:000254065200054 ER PT J AU Qin, LY He, J Hanes, RN Pluzarev, O Hong, JS Crews, FT AF Qin, Liya He, Jun Hanes, Richard N. Pluzarev, Olivera Hong, Jau-Shyong Crews, Fulton T. TI Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID TUMOR-NECROSIS-FACTOR; ALCOHOLIC LIVER-DISEASE; PARKINSONS-DISEASE; GENE-EXPRESSION; FACTOR-ALPHA; RATS; MICE; NEUROGENESIS; NEURODEGENERATION; SECRETION AB Background: Cytokines and alcohol share a common modulation of inflammation and hormones as well as being implicated in multiple diseases, but the mechanisms are poorly understood. The purpose of this study was to investigate the interaction of liver, serum and brain cytokines as well as whether ethanol would potentiate endotoxin (Lipopolysaccharide, LPS) responses once ethanol had cleared. Methods: Male C57BL/6J mice were treated intragastrically with water (control) or ethanol (5 g/kg, i.g., 25% ethanol, w/v), with volumes matched, for 1 day or daily for 10 days. Mice were then injected intraperitoneally with saline (control) or LPS (3 mg/kg, i.p.) in saline 24 hrs after the last dose of ethanol. Gene expression and protein synthesis of proinflammatory cytokines and anti-inflammatory cytokine, oxidative enzymes, microglial activation and inhibition of neurogenesis were examined using real-time PCR, ELISA, and immunohistochemistry. Results: LPS increased proinflammatory cytokines (TNF alpha, MCP-1, IL-1 beta) several fold in liver, brain and serum at 1 hr. Ethanol is known to increase liver cytokines and alter the risk of multiple chronic diseases. Ten daily doses of ethanol increased brain and liver TNFa, and pretreatment with ethanol potentiated LPS-induced increases in TNF alpha, MCP-1, IL-1 beta in liver, serum and brain. Proinflammatory cytokine levels in liver and serum returned to basal levels within a day, whereas brain proinflammatory cytokines remained elevated for long periods. IL-10, an anti-inflammatory cytokine, is reduced in brain by ethanol and LPS, while brain proinflammatory cytokines remain increased, whereas liver IL-10 is increased when proinflammatory cytokines have returned to control levels. Activation of brain microglia indicated by morphological changes, reduced neurogenesis and increased brain expression of COX-2 and gp9I(phox) NADPH oxidase subunit mRNA were found in the 10 daily doses of ethanol-pretreated LPS group. Conclusion: Acute increases in serum cytokines induce long lasting increases in brain proinflammatory cytokines. Ten daily doses of ethanol exposure results in persistent alterations of cytokines and significantly increases the magnitude and duration of central and peripheral proinflammatory cytokines and microglial activation. Ethanol induced differential anti-inflammatory cytokine IL-10 responses in liver and brain could cause long lasting disruption of cytokine cascades that could contribute to protection or increased risk of multiple chronic diseases. C1 [Qin, Liya; He, Jun; Hanes, Richard N.; Pluzarev, Olivera; Crews, Fulton T.] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. RP Crews, FT (reprint author), Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, CB 7178, Chapel Hill, NC 27599 USA. EM liya_qin@med.unc.edu; jun_he@med.unc.edu; rhanes@med.unc.edu; olivera@med.unc.edu; hong3@niehs.nih.gov; ftcrews@med.unc.edu NR 35 TC 160 Z9 162 U1 3 U2 10 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 MAR 18 PY 2008 VL 5 AR 10 DI 10.1186/1742-2094-5-10 PG 17 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 296QM UT WOS:000255560900001 PM 18348728 ER PT J AU Benko, WS Hruska, KS Nagan, N Goker-Alpan, O Hart, PS Schiffmann, R Sidransky, E AF Benko, W. S. Hruska, K. S. Nagan, N. Goker-Alpan, O. Hart, P. S. Schiffmann, R. Sidransky, E. TI Uniparental disomy of chromosome 1 causing concurrent Charcot-Marie-Tooth and Gaucher disease type 3 SO NEUROLOGY LA English DT Editorial Material ID NEUROPATHIES; MUTATIONS C1 [Sidransky, E.] NHGRI, NIH, Med Genet Branch, Sect Mol Neurogenet, Bethesda, MD 20892 USA. [Benko, W. S.; Schiffmann, R.] NINDS, Metab Neurol Branch, Bethesda, MD 20892 USA. [Benko, W. S.; Goker-Alpan, O.; Hart, P. S.] NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. [Nagan, N.] Athena Diagnost Inc, Worcester, MA USA. RP Sidransky, E (reprint author), NHGRI, NIH, Med Genet Branch, Sect Mol Neurogenet, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 5 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 18 PY 2008 VL 70 IS 12 BP 976 EP 978 DI 10.1212/01.wnl.0000305963.37449.32 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 275IQ UT WOS:000254065500015 PM 18347322 ER PT J AU Gold, B Kirchhoff, T Stefanov, S Lautenberger, J Viale, A Garber, J Friedman, E Narod, S Olshen, AB Gregersen, P Kosarin, K Olsh, A Bergeron, J Ellis, NA Klein, RJ Clark, AG Norton, L Dean, M Boyd, J Offit, K AF Gold, Bert Kirchhoff, Tomas Stefanov, Stefan Lautenberger, James Viale, Agnes Garber, Judy Friedman, Eitan Narod, Steven Olshen, Adam B. Gregersen, Peter Kosarin, Kristi Olsh, Adam Bergeron, Julie Ellis, Nathan A. Klein, Robert J. Clark, Andrew G. Norton, Larry Dean, Michael Boyd, Jeff Offit, Kenneth TI Genome-wide association study provides evidence for a breast cancer risk locus at 6q22-33 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genomics; mapping; disease; predisposition; SNP ID SUSCEPTIBILITY GENE; CHROMOSOME 8P12-P22; LINKAGE ANALYSIS; FAMILY HISTORY; POLYMORPHISMS; INHIBITION; APOPTOSIS; CELLS AB We performed a three-phase genome-wide association study (GWAS) using cases and controls from a genetically isolated population, Ashkenazi Jews (AJ), to identify loci associated with breast cancer risk. In the first phase, we compared allele frequencies of 150,080 SNPs in 249 high-risk, BRCA1/2 mutation-negative AJ familial cases and 299 cancer-free AJ controls using chi(2) and the Cochran-Armitage trend tests. In the second phase, we genotyped 343 SNPs from 123 regions most significantly associated from stage 1, including 4 SNPs from the FGFR2 region, in 950 consecutive AJ breast cancer cases and 979 age-matched AJ controls. We replicated major associations in a third independent set of 243 AJ cases and 187 controls. We obtained a significant allele P value of association with AJ breast cancer in the FGFR2 region (P = 1.5 x 10(-5), odds ratio (OR) 1.26, 95% confidence interval (CI) 1.13-1.40 at rs1078806 for all phases combined). In addition, we found a risk locus in a region of chromosome 6q22.33 (P = 2.9 x 10(-8), OR 1.41, 95% Cl 1.25-1.59 at rs2180341). Using several SNPs at each implicated locus, we were able to verify associations and impute haplotypes. The major haplotype at the 6q22.33 locus conferred protection from disease, whereas the minor haplotype conferred risk. Candidate genes in the 6q22.33 region include ECHDC1, which encodes a protein involved in mitochondrial fatty acid oxidation, and also RNF146, which encodes a ubiquitin protein ligase, both known pathways in breast cancer pathogenesis. C1 [Kirchhoff, Tomas; Kosarin, Kristi; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, New York, NY 10065 USA. [Gold, Bert; Stefanov, Stefan; Lautenberger, James; Olsh, Adam; Dean, Michael] NCI, Human Genet Sect, Lab Genom Divers, Frederick, MD 21702 USA. [Viale, Agnes] Mem Sloan Kettering Canc Ctr, Genome Core Lab, New York, NY 10065 USA. [Norton, Larry] Mem Sloan Kettering Canc Ctr, Breast Med Serv, New York, NY 10065 USA. [Olshen, Adam B.] Mem Sloan Kettering Canc Ctr, Dept Biostat & Epidemiol, New York, NY 10065 USA. [Klein, Robert J.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Program, Boston, MA 02115 USA. [Friedman, Eitan] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Narod, Steven] Ctr Res Womens Hlth, Toronto, ON M5G 1N8, Canada. [Gregersen, Peter] N Shore Long Isl Jewish Res Inst, Ctr Genom & Human Genet, Manhasset, NY 11030 USA. [Bergeron, Julie] SAIC Frederick Inc, Human Genet Sect, Lab Genom Divers, Frederick, MD 21702 USA. [Ellis, Nathan A.] Univ Chicago, Dept Med, Div Gastroenterol, Chicago, IL 60637 USA. [Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Boyd, Jeff] Mem Hlth Univ Med Ctr, Anderson Canc Inst, Savannah, GA 31404 USA. RP Offit, K (reprint author), Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, 1275 York Ave, New York, NY 10065 USA. EM offitk@mskcc.org RI Dean, Michael/G-8172-2012; Klein, Robert/K-1888-2013; OI Dean, Michael/0000-0003-2234-0631; Klein, Robert/0000-0003-3539-5391; Norton, Larry/0000-0003-3701-9250; Kirchhoff, Tomas/0000-0002-9055-2364 NR 31 TC 213 Z9 224 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 MAR 18 PY 2008 VL 105 IS 11 BP 4340 EP 4345 DI 10.1073/pnas.0800441105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278DH UT WOS:000254263300049 PM 18326623 ER PT J AU Russell, RS Meunier, JC Takikawa, S Faulk, K Engle, RE Bukh, J Purcell, RH Emerson, SU AF Russell, Rodney S. Meunier, Jean-Christophe Takikawa, Shingo Faulk, Kristina Engle, Ronald E. Bukh, Jens Purcell, Robert H. Emerson, Suzanne U. TI Advantages of a single-crystal production assay to study cell culture-adaptive mutations of hepatitis C virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE single-cycle growth; CD81-dependent ID ENVELOPE GLYCOPROTEIN E2; INFECTION IN-VITRO; CD81 BINDING; ION-CHANNEL; P7 PROTEIN; RESIDUES; IDENTIFICATION; REPLICATION; PARTICLES; VIABILITY AB The JFH1 strain of hepatitis C virus (HCV) is unique among HCV isolates, in that the wild-type virus can traverse the entire replication cycle in cultured cells. However, without adaptive mutations, only low levels of infectious virus are produced. In the present study, the effects of five mutations that were selected during serial passage in Huh-7.5 cells were studied. Recombinant genomes containing all five mutations produced 3-4 logs more infectious virions than did wild type. Neither a coding mutation in NS5A nor a silent mutation in E2 was adaptive, whereas coding mutations in E2, p7, and NS2 all increased virus production. A single-cycle replication assay in CD81-deficient cells was developed to study more precisely the effect of the adaptive mutations. The E2 mutation had minimal effect on the amount of infectious virus released but probably enhanced entry into cells. In contrast, both the p7 and NS2 mutations independently increased the amount of virus released. C1 [Russell, Rodney S.; Meunier, Jean-Christophe; Takikawa, Shingo; Faulk, Kristina; Engle, Ronald E.; Bukh, Jens; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Emerson, Suzanne U.] NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Bukh, Jens] Copenhagen Univ Hosp, Dept Infect Dis, DK-2650 Hvidovre, Denmark. [Bukh, Jens] Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, DK-1448 Copenhagen, Denmark. RP Purcell, RH (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM rpurcell@niaid.nih.gov FU Intramural NIH HHS NR 32 TC 105 Z9 107 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 18 PY 2008 VL 105 IS 11 BP 4370 EP 4375 DI 10.1073/pnas.0800422105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278DH UT WOS:000254263300054 PM 18334634 ER PT J AU Chen, XB Winters, C Azzam, R Li, X Galbraith, JA Leapman, RD Reese, TS AF Chen, Xiaobing Winters, Christine Azzam, Rita Li, Xiang Galbraith, James A. Leapman, Richard D. Reese, Thomas S. TI Organization of the core structure of the postsynaptic density SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EM tomography; high-pressure freezing; hippocampal neuron; PSD-95 ID NMDA RECEPTOR SUBUNITS; GLUTAMATE RECEPTORS; AMPA RECEPTORS; DENDRITIC SPINES; PROTEIN PSD-95; SYNAPTIC CLEFT; FAMILY; COMPLEX; DOMAIN; STARGAZIN AB Much is known about the composition and function of the postsynaptic density (PSD), but less is known about its molecular organization. We use EM tomography to delineate the organization of PSDs at glutamatergic synapses in rat hippocampal cultures. The core of the PSD is dominated by vertically oriented filaments, and ImmunoGold labeling shows that PSD-95 is a component of these filaments. Vertical filaments contact two types of transmembrane structures whose sizes and positions match those of glutamate receptors and intermesh with two types of horizontally oriented filaments lying 10-20 nm from the postsynaptic membrane. The longer horizontal filaments link adjacent NMDAR-type structures, whereas the smaller filaments link both NMDA- and AMPAR-type structures. The orthogonal, interlinked scaffold of filaments at the core of the PSD provides a structural basis for understanding dynamic aspects of postsynaptic function. C1 [Chen, Xiaobing; Winters, Christine; Galbraith, James A.; Reese, Thomas S.] NINCDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Leapman, Richard D.] Natl Inst Biomed Imaging & BioEngn, Lab Bioengn & Physical Sci, NIH, Bethesda, MD 20892 USA. [Li, Xiang] Columbia Univ, Dept Physiol & Cell Biophys, New York, NY 10032 USA. RP Reese, TS (reprint author), NINCDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM treese@mbl.edu FU Intramural NIH HHS NR 47 TC 118 Z9 127 U1 1 U2 13 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 MAR 18 PY 2008 VL 105 IS 11 BP 4453 EP 4458 DI 10.1073/pnas.0800897105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278DH UT WOS:000254263300068 PM 18326622 ER PT J AU He, TX Tao, XC Wu, XY Cai, LS Pike, VW AF He, Tianxiong Tao, Xiaochun Wu, Xinyan Cai, Lisheng Pike, Victor W. TI Acetylation of N-heteroaryl bromides via PdCl(2)/(o-tolyl)(3)P catalyzed Heck reactions SO SYNTHESIS-STUTTGART LA English DT Article DE acetylation; butyl vinyl ether; isopropanol; N-heteroaryl bromides ID ELECTRON-RICH OLEFINS; HYDROGEN SUBSTITUTION-REACTIONS; COUPLING REACTIONS; ARYL HALIDES; PALLADIUM; COMPLEXES; OXIDATION; POTENT; DERIVATIVES; INHIBITORS AB A new user-friendly and convenient method for the acetylation of N-heteroaryl bromides is described. This process is based on the palladium-catalyzed olefination of an N-heteroaryl bromide with butyl vinyl ether, followed by acid hydrolysis of the intermediate heteroaryl vinyl ether in situ. Isopropanol at 85 degrees C, in the presence of K(3)PO(4)center dot 3H(2)O (2 equiv), PdCl(2) (2 mol%) and (o-tolyl)(3)P (4 mol%), provided the best conditions, giving yields of N-heteroaryl bromides up to 75%. C1 [He, Tianxiong; Tao, Xiaochun; Wu, Xinyan] E China Univ Sci & Technol, Organomet Chem Lab, Shanghai 200237, Peoples R China. [Cai, Lisheng; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Tao, XC (reprint author), E China Univ Sci & Technol, Organomet Chem Lab, Shanghai 200237, Peoples R China. EM xctao@ecust.edu.cn; LishengCai@mail.nih.gov NR 33 TC 9 Z9 9 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD MAR 18 PY 2008 IS 6 BP 887 EP 890 DI 10.1055/s-2008-1032193 PG 4 WC Chemistry, Organic SC Chemistry GA 286JA UT WOS:000254841000008 ER PT J AU Moy, SS Nadler, JJ Poe, MD Nonneman, RJ Young, NB Koller, BH Crawley, JN Duncan, GE Bodfish, JW AF Moy, Sheryl S. Nadler, Jessica J. Poe, Michele D. Nonneman, Randal J. Young, Nancy B. Koller, Beverly H. Crawley, Jacqueline N. Duncan, Gaxy E. Bodfish, James W. TI Development of a mouse test for repetitive, restricted behaviors: Relevance to autism SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE autism; exploration; olfaction; restricted interests; social preference; stereotypy ID NMDA RECEPTOR FUNCTION; FREE-EXPLORATORY PARADIGM; X MENTAL-RETARDATION; MODIFIED HOLE-BOARD; CORPUS-CALLOSUM; ANIMAL-MODEL; STEREOTYPED BEHAVIOR; SYNAPTIC PLASTICITY; INBRED STRAINS; GENETIC MODEL AB Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T(+)tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1(neo/neo) mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a Whole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T(+)tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T(+)f/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1(neo/neo) mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1(neo/neo), mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently demonstrated for one particular olfactory stimulus. Further work is required to determine the characteristics of optimal mouse social stimuli in the olfactory hole-board test. (C) 2007 Elsevier B.V. All rights reserved. C1 [Moy, Sheryl S.; Nadler, Jessica J.; Poe, Michele D.; Nonneman, Randal J.; Young, Nancy B.; Crawley, Jacqueline N.; Duncan, Gaxy E.; Bodfish, James W.] Univ N Carolina, Sch Med, Neurodev Disorders Res Ctr, Chapel Hill, NC 27599 USA. [Moy, Sheryl S.; Crawley, Jacqueline N.; Duncan, Gaxy E.; Bodfish, James W.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. [Nadler, Jessica J.; Koller, Beverly H.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA. [Nadler, Jessica J.; Koller, Beverly H.] NIMH, Intramural Res Program, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Moy, SS (reprint author), Univ N Carolina, Sch Med, Neurodev Disorders Res Ctr, CB 7146, Chapel Hill, NC 27599 USA. EM ssmoy@med.unc.edu RI Poe, Michele/K-6615-2012 OI Poe, Michele/0000-0001-9693-3638 FU NICHD NIH HHS [P30 HD003110, P30 HD003110-40, P30 HD03110]; NIMH NIH HHS [MH063398, R01 MH063398, R01 MH063398-05, R01 MH073402, R01 MH073402-04, R01 MH73402, U54 MH066418, U54 MH066418-05, U54 MH66418] NR 85 TC 96 Z9 96 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 17 PY 2008 VL 188 IS 1 BP 178 EP 194 DI 10.1016/j.bbr.2007.10.029 PG 17 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 266PK UT WOS:000253448200018 PM 18068825 ER PT J AU Iyer, LM Abhiman, S Aravind, L AF Iyer, Lakshminarayan M. Abhiman, Saraswathi Aravind, L. TI MutL homologs in restriction-modification systems and the origin of eukaryotic MORC ATPases SO BIOLOGY DIRECT LA English DT Article ID MISMATCH REPAIR; ESCHERICHIA-COLI; STRUCTURAL BASIS; DOMAIN; IDENTIFICATION; PROTEINS; FAMILY; MOUSE; SPERMATOGENESIS; ENDONUCLEASES AB The provenance and biochemical roles of eukaryotic MORC proteins have remained poorly understood since the discovery of their prototype MORCI, which is required for meiotic nuclear division in animals. The MORC family contains a combination of a gyrase, histidine kinase, and MutL (GHKL) and S5 domains that together constitute a catalytically active ATPase module. We identify the prokaryotic MORCs and establish that the MORC family belongs to a larger radiation of several families of GHKL proteins (paraMORCs) in prokaryotes. Using contextual information from conserved gene neighborhoods we show that these proteins primarily function in restriction-modification systems, in conjunction with diverse superfamily II DNA helicases and endonucleases. The common ancestor of these GHKL proteins, MutL and topoisomerase ATPase modules appears to have catalyzed structural reorganization of protein complexes and concomitant DNA-superstructure manipulations along with fused or standalone nuclease domains. Furthermore, contextual associations of the prokaryotic MORCs and their relatives suggest that their eukaryotic counterparts are likely to carry out chromatin remodeling by DNA superstructure manipulation in response to epigenetic signals such as histone and DNA methylation. Reviewers: This article was reviewed by Arcady Mushegian and Gaspar Jekely. C1 [Iyer, Lakshminarayan M.; Abhiman, Saraswathi; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM lakshmin@mail.nih.gov; sarawaa@mail.nih.gov; aravind@mail.nih.gov OI SARASWATHI, ABHIMAN/0000-0003-4761-4176 FU Intramural NIH HHS NR 22 TC 50 Z9 50 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAR 17 PY 2008 VL 3 AR 8 DI 10.1186/1745-6150-3-8 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 286RI UT WOS:000254863300002 PM 18346280 ER PT J AU Rogozin, IB Thomson, K Csueroes, M Carmel, L Koonin, EV AF Rogozin, Igor B. Thomson, Karen Csueroes, Miklos Carmel, Liran Koonin, Eugene V. TI Homoplasy in genome-wide analysis of rare amino acid replacements: the molecular-evolutionary basis for Vavilov's law of homologous series SO BIOLOGY DIRECT LA English DT Article ID NEMATODE-ARTHROPOD CLADE; LONG-BRANCH ATTRACTION; PHYLOGENETIC ANALYSIS; ANIMAL PHYLOGENY; MODEL ORGANISMS; EUKARYOTE TREE; ECDYSOZOA; COELOMATA; GENE; RECONSTRUCTION AB Background: Rare genomic changes (RGCs) that are thought to comprise derived shared characters of individual clades are becoming an increasingly important class of markers in genome-wide phylogenetic studies. Recently, we proposed a new type of RGCs designated RGC_CAMs (after Conserved Amino acids-Multiple substitutions) that were inferred using genome-wide identification of amino acid replacements that were: i) located in unambiguously aligned regions of orthologous genes, ii) shared by two or more taxa in positions that contain a different, conserved amino acid in a much broader range of taxa, and iii) require two or three nucleotide substitutions. When applied to animal phylogeny, the RGC_CAM approach supported the coelomate clade that unites deuterostomes with arthropods as opposed to the ecdysozoan (molting animals) clade. However, a non-negligible level of homoplasy was detected. Results: We provide a direct estimate of the level of homoplasy caused by parallel changes and reversals among the RGC_CAMs using 462 alignments of orthologous genes from 19 eukaryotic species. It is shown that the impact of parallel changes and reversals on the results of phylogenetic inference using RGC_CAMs cannot explain the observed support for the Coelomata clade. In contrast, the evidence in support of the Ecdysozoa clade, in large part, can be attributed to parallel changes. It is demonstrated that parallel changes are significantly more common in internal branches of different subtrees that are separated from the respective common ancestor by relatively short times than in terminal branches separated by longer time intervals. A similar but much weaker trend was detected for reversals. The observed evolutionary trend of parallel changes is explained in terms of the covarion model of molecular evolution. As the overlap between the covarion sets in orthologous genes from different lineages decreases with time after divergence, the likelihood of parallel changes decreases as well. Conclusion: The level of homoplasy observed here appears to be low enough to justify the utility of RGC_CAMs and other types of RGCs for resolution of hard problems in phylogeny. Parallel changes, one of the major classes of events leading to homoplasy, occur much more often in relatively recently diverged lineages than in those separated from their last common ancestor by longer time intervals of time. This pattern seems to provide the molecular-evolutionary underpinning of Vavilov's law of homologous series and is readily interpreted within the framework of the covarion model of molecular evolution. Reviewers: This article was reviewed by Alex Kondrashov, Nicolas Galtier, and Maximilian Telford and Robert Lanfear ( nominated by Laurence Hurst). C1 [Rogozin, Igor B.; Carmel, Liran; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. [Thomson, Karen] Univ New Orleans, Dept Comp Sci, New Orleans, LA 70148 USA. [Csueroes, Miklos] Univ Montreal, Dept Comp Sci & Operat Res, Montreal, PQ H3C 3J7, Canada. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM rogozin@ncbi.nlm.nih.gov; driftwood_999@yahoo.com; csuros@iro.umontreal.ca; carmel@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 63 TC 23 Z9 24 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAR 17 PY 2008 VL 3 AR 7 DI 10.1186/1745-6150-3-7 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 286RI UT WOS:000254863300001 PM 18346278 ER PT J AU Jackson, SN Singhal, SK Woods, AS Morales, M Shippenberg, T Zhang, L Oz, M AF Jackson, Shelley N. Singhal, Sachin K. Woods, Arnina S. Morales, Marisela Shippenberg, Toni Zhang, Li Oz, Murat TI Volatile anesthetics and endogenous cannabinoid anandamide have additive and independent inhibitory effects on alpha(7)-nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE anandamide; volatile anesthetic; nicotinic receptor; Xenopus oocyte ID T-TUBULE MEMBRANES; DEPENDENT CALCIUM FLUXES; ION CHANNELS; GENERAL-ANESTHETICS; GLYCINE RECEPTORS; K+ CHANNELS; FATTY-ACIDS; SYNTHETIC CANNABINOIDS; POTASSIUM CHANNELS; LAEVIS OOCYTES AB In earlier studies, the volatile anesthetics and the endogenous cannabinoid anandamide have been shown to inhibit the function of alpha(7)-nicotinic acetylcholine receptors. In the present study, interactions between the effects of volatile anesthetics and anandamide on the function of alpha(7)-nicotinic acetylcholine receptors expressed in Xenopus oocytes were investigated using the two-electrode voltage-clamp technique. Anandamide and volatile anesthetics isoflurane and halothane inhibited currents evoked with acetylcholine (100 mu M) in a reversible and concentration-dependent manner. Coapplication of anandamide and volatile anesthetics caused a significantly greater inhibition of alpha(7)-nicotinic acetylcholine receptor function than anandamide or volatile anesthetics alone. Analyses of oocytes by matrix-assisted laser desorption/ionization mass spectroscopy indicated that volatile anesthetics did not alter the lipid profile of oocytes. Results of studies with chimeric alpha(7)-nicotinic acetylcholine-5-HT3 receptors comprised of the N-terminal domain of the alpha(7)-nicotinic acetylcholine receptor and the transmembrane and carboxyl-terminal domains of 5-HT3 receptors suggest that while isoflurane inhibition of the alpha(7)-nicotinic acetylcholine receptor is likely to involve the N-terminal region of the receptor, the site of action for anandamide involves transmembrane and carboxyl-terminal domains of the receptors. These data indicate that endocannabinoids and isoflurane have additive inhibitory effects on alpha(7)-nicotinic acetylcholine receptor function through allosteric binding sites located on the distinct regions of the receptor. Published by Elsevier B.V. C1 [Shippenberg, Toni; Oz, Murat] NIDA, NIH, DHHS, Intramural Res Program,Integrat Neurosci Sect,Cel, Baltimore, MD 21224 USA. [Singhal, Sachin K.; Zhang, Li] NIAAA, NIH, DHHS, Lab Integrat Neurosci, Rockville, MD 20852 USA. RP Oz, M (reprint author), NIDA, NIH, DHHS, Intramural Res Program,Integrat Neurosci Sect,Cel, 5500 Nanthan Shock Dr, Baltimore, MD 21224 USA. EM moz@intra.nida.nih.gov RI Oz, Murat/E-2148-2012 FU Intramural NIH HHS [NIH0011080950, Z01 DA000503-01] NR 61 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAR 17 PY 2008 VL 582 IS 1-3 BP 42 EP 51 DI 10.1016/j.ejphar.2007.12.023 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 272RP UT WOS:000253877700006 PM 18242598 ER PT J AU Tripathi, BK Stepp, MA Gao, CY Zelenka, PS AF Tripathi, Brajendra K. Stepp, Mary A. Gao, Chun Y. Zelenka, Peggy S. TI The Cdk5 inhibitor olomoucine promotes corneal debridement wound closure in vivo SO MOLECULAR VISION LA English DT Article ID EPITHELIAL-CELLS; EXPRESSION; SRC; LOCALIZATION; ACTIVATION; MIGRATION; ONCOGENE; INTEGRIN; REPAIR; ROLES AB Purpose: To investigate the effect of the Cdk5 inhibitor olomoucine on corneal debridement wound healing in vivo. Methods: Corneal debridement wounds of 1.5 mm were made on the ocular surface of CD-1 mice. A 20 mu l drop of 15 mu M olomoucine in 1% DMSO was applied to the wound area immediately after wounding and again after 6 h. Control mice received identical applications of 1% DMSO. Mice were euthanized after 18 h, two weeks, and three weeks for evaluation of wound healing and restratification. Corneas were stained with Richardson's dye, photographed, and processed for histology and immunofluorescence as whole mounts or paraffin sections. The remaining wound area at 18 h was measured by image analysis. Scratch wounded cultures of human corneal-limbal epithelial cells (HCLE) were used to examine the effect of olomoucine on matrix metalloproteinase (MMP) expression in vitro. MMP-2 and MMP-9 were detected by immunofluorescence and immunoblotting. Results: Olomoucine treatment significantly enhanced corneal wound closure without increasing inflammation or infiltration of polymorphonuclear leukocytes 18 h after wounding (p < 0.05). The increased localization of MMP-9 within epithelial cells at the wound edge was further enhanced by olomoucine while the expression of MMP-2 was reduced. Olomoucine treatment of scratch wounded HCLE cells produced similar changes in MMP-9 and MMP-2 expression. The examination of treated corneas two and three weeks after wounding showed normal epithelial restratification with no evidence of inflammation or stromal disorganization. Conclusions: Topical application of olomoucine in 1% DMSO significantly enhances closure of small epithelial debridement wounds without increasing inflammation or impairing reepithelialization. C1 [Tripathi, Brajendra K.; Gao, Chun Y.; Zelenka, Peggy S.] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Stepp, Mary A.] George Washington Univ, Med Ctr, Dept Anat, Washington, DC 20037 USA. RP Zelenka, PS (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bldg 7,Room 102,MSC 0704, Bethesda, MD 20892 USA. EM zelenkap@nei.nih.gov OI Stepp, Mary Ann/0000-0001-5623-2538 FU Intramural NIH HHS; NEI NIH HHS [R01 EY008512, Z01 EY000238, R01-EY-008512-17] NR 23 TC 5 Z9 7 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAR 17 PY 2008 VL 14 IS 65-67 BP 542 EP 548 PG 7 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 312IH UT WOS:000256662400002 PM 18385789 ER PT J AU Strohsnitter, WC Hatch, EE Hyer, M Troisi, R Kaufman, RH Robboy, SJ Palmer, JR Titus-Ernstoff, L Anderson, D Hoover, RN Noller, KL AF Strohsnitter, William C. Hatch, Elizabeth E. Hyer, Marianne Troisi, Rebecca Kaufman, Raymond H. Robboy, Stanley J. Palmer, Julie R. Titus-Ernstoff, Linda Anderson, Diane Hoover, Robert N. Noller, Kenneth L. TI The association between in utero cigarette smoke exposure and age at menopause SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; diethylstilbestrol; menopause; prenatal exposure delayed effects; smoke; smoking ID NATURAL MENOPAUSE; ALPHA-FETOPROTEIN; WOMEN; ESTRIOL; WEIGHT; ONSET; MODEL; TWIN; HCG AB Menopause onset, on average, occurs earlier among women who smoke cigarettes than among women who do not smoke. Prenatal smoke exposure may also influence age at menopause through possible effects on follicle production in utero. Smoking information was obtained from the mothers of 4,025 participants in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, a US study begun in 1975 to examine the health effects of prenatal diethylstilbestrol exposure. Between 1994 and 2001, participants provided information on menopausal status. Cox proportional hazards modeling compared the probability of menopause among participants who were and were not prenatally exposed to maternal cigarette smoke. Participants prenatally exposed to maternal cigarette smoke were more likely than those unexposed to be postmenopause (hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). The association was present among only those participants who themselves had never smoked cigarettes (hazard ratio = 1.38, 95% confidence interval: 1.10, 1.74) and was absent among active smokers (hazard ratio = 1.03, 95% confidence interval: 0.81, 1.31). In this cohort of participants predominantly exposed to diethylstilbestrol, results suggest that prenatal exposure to maternal cigarette smoke may play a role in programming age at menopause. The possibility that active cigarette smoking modifies this effect is also suggested. C1 [Strohsnitter, William C.; Noller, Kenneth L.] Tufts Univ, New England Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. [Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hyer, Marianne] Informat Management Serv Inc, Rockville, MD USA. [Troisi, Rebecca; Titus-Ernstoff, Linda] Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Lebanon, NH 03766 USA. [Troisi, Rebecca; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kaufman, Raymond H.] Methodist Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Robboy, Stanley J.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Robboy, Stanley J.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Palmer, Julie R.] Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Slone Epidemiol Unit, Brookline, MA USA. [Anderson, Diane] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. RP Strohsnitter, WC (reprint author), Tufts Univ, New England Med Ctr, Dept Obstet & Gynecol, 750 Washington St, Boston, MA 02111 USA. EM Wstrohsnitter@tufts-nemc.org OI Palmer, Julie/0000-0002-6534-335X; Hatch, Elizabeth/0000-0001-7901-3928 FU NCI NIH HHS [N01 CP001012, N01-CP-01012-21, N01-CP-01288, N01-CP-01289, N01-CP-01290] NR 24 TC 21 Z9 21 U1 1 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 MAR 15 PY 2008 VL 167 IS 6 BP 727 EP 733 DI 10.1093/aje/kwm351 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 278NI UT WOS:000254293200013 PM 18192675 ER PT J AU Weisskopf, MG O'Reilly, E Chen, H Schwarzschild, MA Ascherio, A AF Weisskopf, M. G. O'Reilly, E. Chen, H. Schwarzschild, M. A. Ascherio, A. TI Re: "Plasma urate and risk of Parkinson's disease" - The authors reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [Weisskopf, M. G.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Weisskopf, M. G.; Ascherio, A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [O'Reilly, E.; Ascherio, A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chen, H.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Schwarzschild, M. A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Weisskopf, MG (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. EM mweissko@hsph.harvard.edu NR 3 TC 0 Z9 0 U1 0 U2 1 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 MAR 15 PY 2008 VL 167 IS 6 BP 753 EP U4 DI 10.1093/aje/kwn009 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 278NI UT WOS:000254293200019 ER PT J AU Hube, AM Lachenbruch, PA Dugan, EM Miller, FW Rider, LG AF Hube, Adam M. Lachenbruch, Peter A. Dugan, Elizabeth M. Miller, Frederick W. Rider, Lisa G. CA Juvenile Dermatomyositis Dis Activ TI Alternative scoring of the cutaneous assessment tool in juvenile dermatomyositis: Results using abbreviated formats SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; VALIDATED DISEASE-ACTIVITY; MYOSITIS ASSESSMENT SCALE; MUSCLE FUNCTION; DAMAGE INDEXES; RELIABILITY AB Objective. The Cutaneous Assessment Tool (CAT) is a comprehensive, semiquantitative tool for the assessment of skin disease in juvenile dermatomyositis (DM). The goal of this study was to determine whether alternative scoring methods would shorten the CAT without compromising its measurement characteristics. Methods. A total of 113 children with juvenile DM were assessed at baseline; 94 were assessed again 7-9 months later. Interrater reliability, internal consistency, construct validity, and responsiveness were obtained using the original scoring method and 2 alternative methods: the maximum and binary scoring methods. Results. Spearman's correlations of the maximum and binary methods with the original were both 0.98 (P < 0.0001) for the CAT activity score, and 0.96 and 0.98, respectively (P < 0.0001), for the CAT damage score. Values obtained for interrater reliability, internal consistency, construct validity, and responsiveness were similar for all 3 scoring methods. Although there was a trend toward the maximum method having higher interrater reliability and the binary method having higher responsiveness, the confidence intervals were overlapping and no statistically significant differences were observed. Correlation coefficients for the 3 scoring methods with other measures of myositis disease activity and damage were very similar. Conclusion. The maximum and binary methods of scoring the CAT have measurement characteristics similar to the original method. Adoption of one of these abbreviated scoring methods should increase its acceptability to clinicians and researchers. C1 [Hube, Adam M.] IWK Hlth Ctr, Div Pediat Rheumatol, Halifax, NS B3K 6R8, Canada. [Hube, Adam M.] Dalhousie Univ, Halifax, NS B3K 6R8, Canada. [Lachenbruch, Peter A.] US FDA, Dept Hlth & Human Serv, Rockville, MD USA. [Dugan, Elizabeth M.] Washington Hosp Ctr, Washington, DC 20010 USA. [Miller, Frederick W.; Rider, Lisa G.] NIH, Natl Inst Environm Hlth Sci, Dept Hlth & Human Serv, Bethesda, MD USA. RP Hube, AM (reprint author), IWK Hlth Ctr, Div Pediat Rheumatol, 5850 Univ Ave, Halifax, NS B3K 6R8, Canada. EM adam.huber@iwk.nshealth.ca OI Miller, Frederick/0000-0003-2831-9593; Rider, Lisa/0000-0002-6912-2458 FU Intramural NIH HHS [Z01 ES101081-06, Z99 ES999999] NR 12 TC 13 Z9 15 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD MAR 15 PY 2008 VL 59 IS 3 BP 352 EP 356 DI 10.1002/art.23313 PG 5 WC Rheumatology SC Rheumatology GA 272IA UT WOS:000253851900009 PM 18311761 ER PT J AU Robey, RW Shukla, S Finley, EM Oldham, RK Barnett, D Ambudkar, SV Fojo, T Bates, SE AF Robey, Robert W. Shukla, Suneet Finley, Elizabeth M. Oldham, Robert K. Barnett, Daryl Ambudkar, Suresh V. Fojo, Tito Bates, Susan E. TI Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)-mediated transport by the orally administered inhibitor, CBT-1 (R) SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE P-glycoprotem; MRP1; ABCG2; CBT-1 (R); drug resistance; inhibitor ID ACUTE-MYELOID-LEUKEMIA; HUMAN LUNG-CANCER; PHASE-I; BREAST-CANCER; CYCLOSPORINE-A; CELL-LINES; MRP; COMBINATION; EXPRESSION; BIRICODAR AB Cellular expression of ATP-binding cassette (ABC) transport proteins, such as P-glycoprotein (Pgp), multidrug resistance- associated protein (MRP1), or ABCG2, is known to confer a drug-resistant phenotype. Thus, the development of effective transporter inhibitors could be of value to cancer treatment. CBT-1 (R) is a bisbenzylisoquinoline plant alkyloid currently in development as a Pgp inhibitor. We characterized its interactions with the three major ABC transporters associated with drug resistance - Pgp, MRP1 and ABCG2 - and compared it to other known inhibitors. CBT-1 (R) completely inhibited rhodamine 123 transport from Pgp-overexpressing cells at a concentration of 1 mu M. Additionally, 1 mu M completely reversed Pgp-mediated resistance to vinblastine, paclitaxel and depsipeptide in SW620 Ad20 cells. CBT-1 (R), was found to compete [I-125]-IAPP labeling of Pgp with an IC50 of 0.14 mu M, and low concentrations of CBT-1 (R) (<1 mu M) stimulated Pgp-mediated ATP hydrolysis. in MRP1-overexpressing cells, 10 mu M CBT-1 (R) was found to completely inhibit MRPI-mediated calcein transport. CBT-1 (R) at 25 mu M did not have a significant effect on ABCG2-mediated pheophorbide a transport. Serum levels of CBT-1 (R) in samples obtained from eight patients receiving CBT-1 (R) increased intracellular rhodamine 123 levels in CD56+ cells 2.1- to 5.7-fold in an ex vivo assay. CBT-1 (R) is able to inhibit the ABC transporters Pgp and MRPI, making it an attractive candidate for clinical trials in cancers where Pgp and/or MRP1 might be overexpressed. Further clinical studies with CBT-1 (R) are warranted. (c) 2007 Elsevier Inc. All rights reserved. C1 [Robey, Robert W.; Finley, Elizabeth M.; Fojo, Tito; Bates, Susan E.] NIH, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Shukla, Suneet; Ambudkar, Suresh V.] NIH, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. [Barnett, Daryl] CBA Res Inc, Lexington, KY 40517 USA. RP Robey, RW (reprint author), 9000 Rockville Pike,Bldg 10,Room 12C217, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov RI Ambudkar, Suresh/B-5964-2008; shukla, suneet/B-4626-2012 FU Intramural NIH HHS [Z99 CA999999] NR 43 TC 70 Z9 73 U1 0 U2 9 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 MAR 15 PY 2008 VL 75 IS 6 BP 1302 EP 1312 DI 10.1016/j.bcp.2007.12.001 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 284EC UT WOS:000254687800006 PM 18234154 ER PT J AU Gao, ZG Hechler, B Besada, P Gachet, C Jacobson, KA AF Gao, Zhan-Guo Hechler, Beatrice Besada, Pedro Gachet, Christian Jacobson, Kenneth A. TI Caged agonist of P2Y(1) and P2Y(12) receptors for light-directed facilitation of platelet aggregation SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE aggregation; nucleotides; G-protein-coupled receptors; phospholipase C; calcium ID ATP; DESENSITIZATION; PHOTOLYSIS; POTENT; ANALOG; BLOOD AB We have prepared a caged form (MRS2703) of a potent dual agonist of the P2Y(1) and P2Y(12) nucleotide receptors, 2-MeSADP, by blocking the p-phosphate group with a 1-(3,4-dimethyloxyphenyl)eth-1-yl phosphoester. Although MRS2703 is itself inactive at human P2Y(1) and P2Y(12) receptors expressed heterologously in 1321N1 astrocytoma cells or in washed human platelets, this derivative readily regenerates the parent agonist upon mild irradiation with long-wave UV light (360 nm). The functional effect of the regenerated agonist was demonstrated by a rise in intracellular calcium mediated by either P2Y(1) or P2Y(12) receptors in transfected cells. Washed human platelets exposed to a solution of MRS2703 were induced to aggregate upon UV irradiation. At 1.0 mu M MRS2703, full aggregation was achieved within 1 min of irradiation. Thus, this caged nucleotide promises to be a useful probe for potent P2Y receptor activation with light-directed spatial and temporal control. Published by Elsevier Inc. C1 [Gao, Zhan-Guo; Besada, Pedro; Jacobson, Kenneth A.] NIDDKD, NIH, Bioorgan Chem Lab, Mol Recognit Sect, Bethesda, MD 20892 USA. [Hechler, Beatrice; Gachet, Christian] EFS Alsace, Strasbourg, France. [Hechler, Beatrice; Gachet, Christian] Univ Strasbourg 1, Strasbourg, France. RP Jacobson, KA (reprint author), NIDDKD, NIH, Bioorgan Chem Lab, Mol Recognit Sect, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Besada Pereira, Pedro/E-6051-2012; Jacobson, Kenneth/A-1530-2009; Hechler, Beatrice/D-4227-2017 OI Besada Pereira, Pedro/0000-0002-9985-9063; Jacobson, Kenneth/0000-0001-8104-1493; FU Intramural NIH HHS [Z01 DK031116-20] NR 26 TC 6 Z9 6 U1 0 U2 2 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 MAR 15 PY 2008 VL 75 IS 6 BP 1341 EP 1347 DI 10.1016/j.bcp.2007.10.037 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 284EC UT WOS:000254687800010 PM 18199424 ER PT J AU Krain, AL Gotimer, K Hefton, S Ernst, M Castellanos, FX Pine, DS Milham, MP AF Krain, Amy L. Gotimer, Kristin Hefton, Sara Ernst, Monique Castellanos, F. Xavier Pine, Daniel S. Milham, Michael P. TI A functional magnetic resonance imaging investigation of uncertainty in adolescents with anxiety disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE adolescence; anxiety; fMRI; uncertainty; decision-making ID COGNITIVE-BEHAVIORAL TREATMENT; DECISION-MAKING; AMYGDALA ACTIVATION; SOCIAL ANXIETY; FEARFUL FACES; BRAIN IMAGES; WORRY; CHILDHOOD; FMRI; OPTIMIZATION AB Background: Pediatric anxiety disorders, although highly prevalent, are understudied with little known about their pathophysiology. intolerance of uncertainty (IU) is a trait associated with worry, a key characteristic of these disorders. Neural responses to uncertainty in healthy subjects involve the same frontal-limbic circuits that are hyper-responsive in pediatric anxiety. As such,the present study examines the relationship between IU and neural responses to uncertainty in anxious adolescents. Methods: Sixteen adolescents (ages 13-17) diagnosed with generalized anxiety disorder and/or social phobia (ANX) and 13 non-anxious control subjects completed a decision-making task while functional magnetic resonance imaging scans were acquired. Results: The ANX group endorsed greater task-related anxiety and less certainty than control subjects on a post-task questionnaire. Compared with control subjects, the ANX group did not demonstrate hyper-responsivity of brain regions as hypothesized. Across groups, IU was positively correlated with activity in several frontal and limbic regions. Further analyses identified subgroups within the ANX group: those with high IU activated frontal/limbic regions, whereas those with low IU and less anxiety during the task deactivated the same regions in response to uncertainty. Conclusions: Results substantiate the hypothesized link between IU and neural responses to uncertainty in some adolescents with anxiety disorders. Our findings, if replicated, suggest that trait measures, such as IU, can significantly improve our understanding of the neurobiological basis of pediatric anxiety disorders. C1 [Krain, Amy L.; Gotimer, Kristin; Hefton, Sara; Castellanos, F. Xavier; Milham, Michael P.] NYU, Ctr Child Study, Sch Med, New York, NY 10016 USA. [Castellanos, F. Xavier] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Ernst, Monique; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Krain, AL (reprint author), NYU, Ctr Child Study, Sch Med, 215 Lexington Ave,13th Floor, New York, NY 10016 USA. EM amy.krain@med.nyu.edu RI Roy, Amy/J-7613-2013; Milham, Michael/K-9501-2014; OI Castellanos, Francisco/0000-0001-9192-9437 FU NIMH NIH HHS [K23MH074821] NR 38 TC 51 Z9 53 U1 2 U2 21 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 MAR 15 PY 2008 VL 63 IS 6 BP 563 EP 568 DI 10.1016/j.biopsych.2007.06.011 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 268ZD UT WOS:000253618300006 PM 17719566 ER PT J AU Salvadori, S Fiorini, S Trapella, C Porreca, F Davis, P Sasaki, Y Arnbo, A Marczak, ED Lazarus, LH Balboni, G AF Salvadori, Severo Fiorini, Stella Trapella, Claudio Porreca, Frank Davis, Peg Sasaki, Yusuke Arnbo, Akihiro Marczak, Ewa D. Lazarus, Lawrence H. Balboni, Gianfranco TI Role of benzimidazole (Bid) in the delta-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502) SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Dmt-Tic pharmacophore; delta-opioid receptors; opioid peptides; UFP-502 ID DMT-TIC PHARMACOPHORE; RECEPTOR AGONISTS; C-TERMINUS; ANTAGONISTS; SELECTIVITY; AFFINITY; DERIVATIVES; PEPTIDES; ANALOGS; ACIDS AB H-Dmt-Tic-NH-CH2-Bid (UFP-502) was the first delta-opioid agonist prepared from the Dmt-Tic pharmacophore. It showed interesting pharmacological properties, such as stimulation of mRNA BDNF expression and antidepression. To evaluate the importance of 1H-benzimidazol-2-yl (Bid) in the induction of delta-agonism, it was substituted by similar heterocycles: The substitution of NH(1) by O or S transforms the reference delta-agonist into delta-antagonists. Phenyl ring of benzimidazole is not important for delta-agonism; in fact 1H-imidazole-2-yl retains delta-agonist activity. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. [Salvadori, Severo; Fiorini, Stella; Trapella, Claudio; Balboni, Gianfranco] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [Salvadori, Severo; Fiorini, Stella; Trapella, Claudio; Balboni, Gianfranco] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. [Porreca, Frank; Davis, Peg] Univ Arizona, Dept Pharmacol, Tucson, AZ 85721 USA. [Sasaki, Yusuke; Arnbo, Akihiro] Tohoku Pharmaceut Univ, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Marczak, Ewa D.; Lazarus, Lawrence H.] NIEHS, Med Chem Grp, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Balboni, G (reprint author), Univ Cagliari, Dept Toxicol, Via Osped 72, I-09124 Cagliari, Italy. EM gbalboni@unica.it RI Trapella, Claudio/I-2128-2012; OI Trapella, Claudio/0000-0002-6666-143X; SALVADORI, Severo/0000-0002-8224-2358 FU Intramural NIH HHS [Z01 ES090053-20, Z01 ES100472-06, Z99 ES999999] NR 26 TC 8 Z9 9 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 15 PY 2008 VL 16 IS 6 BP 3032 EP 3038 DI 10.1016/j.bmc.2007.12.032 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 290MU UT WOS:000255127700030 PM 18178091 ER PT J AU Kitada, S Kress, CL Krajewska, M Jia, L Pellecchia, M Reed, JC AF Kitada, Shinichi Kress, Christina L. Krajewska, Maryla Jia, Lee Pellecchia, Maurizio Reed, John C. TI Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048) SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; LYMPHOCYTIC-LEUKEMIA; ANTITUMOR-ACTIVITY; TRANSGENIC MICE; APOPTOSIS; EXPRESSION; DIAGNOSIS; SURVIVAL; FAMILY; CELLS AB Altered expression of Bcl-2 family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product gossypol and its semisynthetic derivative apogossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family proteins. Daily oral dosing studies showed that mice tolerate doses of apogossypol 2- to 4-times higher than gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of gossypol, with apogossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is overexpressed in B cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2-expressing B cells from transgenic mice were more sensitive to cytotoxicity induced by apogossypol than gossypol, with LD50 values of 3 to 5 mu M and 7.5 to 10 mu M, respectively. In vivo, using the maximum tolerated dose of gossypol for sequential daily dosing, apogossypol displayed superior activity to gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2-transgenic mice. Taken together, these studies indicate that apogossypol is superior to parent compound gossypol with respect to toxicology and efficacy, suggesting that further development of this compound for cancer therapy is warranted. C1 [Kitada, Shinichi; Kress, Christina L.; Krajewska, Maryla; Pellecchia, Maurizio; Reed, John C.] Burnham Inst Med Res, Canc Res Ctr, La Jolla, CA 92037 USA. [Kitada, Shinichi; Reed, John C.] CLL Res Consortium, San Diego, CA USA. [Jia, Lee] NCI, NIH, DCTD, Dev Therapeut Program, Rockville, MD USA. RP Reed, JC (reprint author), Burnham Inst Med Res, Canc Res Ctr, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM reedoffice@burnham.org FU NCI NIH HHS [CA-113318, N01-CM-07110, N01-CM-52205, N01CM52205, P01 CA081534, P01-CA081534, U19 CA113318] NR 29 TC 62 Z9 72 U1 3 U2 21 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 MAR 15 PY 2008 VL 111 IS 6 BP 3211 EP 3219 DI 10.1182/blood-2007-09-113647 PG 9 WC Hematology SC Hematology GA 274OC UT WOS:000254009600036 PM 18202226 ER PT J AU Dang, DT Chun, SY Burkitt, K Abe, M Chen, S Havre, P Mabjeesh, NJ Heath, EI Vogelzang, NJ Cruz-Correa, M Blayney, DW Ensminger, WD Croix, BS Dang, NH Dang, LH AF Dang, Duyen T. Chun, Sang Y. Burkitt, Kyunghee Abe, Masako Chen, Shaowei Havre, Pamela Mabjeesh, Nicola J. Heath, Elisabeth I. Vogelzang, Nicholas J. Cruz-Correa, Marcia Blayney, Douglas W. Ensminger, William D. Croix, Brad St. Dang, Nam H. Dang, Long H. TI Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition SO CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; CANCER-THERAPY; LUNG-CANCER; VEGF; EXPRESSION; HIF-1; BEVACIZUMAB; XENOGRAFTS; LETHALITY; SUNITINIB AB Antiangiogenic therapy improves survival in patients with advanced stage cancers. Currently, there are no reliable predictors or markers for tumor vessel response to antiangiogenic therapy. To model effective antiangiogenic therapy, we disrupted the VEGF gene in three representative cancer cell lines. HCT116 xenografts had low proportions of endothelial tubes covered by pericytes that stained with alpha-smooth muscle actin (SMA) antibody. Upon disruption of VEGF, HCT116(VEGF-/-) xenografts had significantly decreased tumor microvessel perfusion compared with their parental counterparts. Furthermore, HCT116(VEGF-/-) xenografts mounted a tumor-reactive response to hypoxia, characterized by the induction of hypoxia-inducible factor-1 (HIF-1) target genes. One highly induced protein was DPP4, a measurable serum protein that has well-described roles in cancer progression. In contrast, LS174T and MKN45 tumor xenografts had high proportion of endothelial tubes that were covered by SMA+ pericytes. Upon disruption of VEGF, LS174T(VEGF-/-) and MKN45(VEGF-/-) xenografts maintained tumor microvessel perfusion. As such, there were no changes in intratumoral hypoxia or HIF-1 alpha induction. Together, these data show that the extent of tumor vessel response to angiogenic inhibition could be correlated with (a) the preexisting coverage of tumor endothelial tubes with SMA+ pericytes and (b) differential tumor induction of HIF-1 target genes. The data further show that DPP4 is a novel marker of HIF-1 induction. Altogether, these preclinical findings suggest novel clinical trials for predicting and monitoring tumor vessel responses to antiangiogenic therapy. C1 [Chun, Sang Y.; Burkitt, Kyunghee; Chen, Shaowei; Blayney, Douglas W.; Ensminger, William D.; Dang, Long H.] Univ Michigan, Med Ctr, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Dang, Duyen T.] Univ Michigan, Med Ctr, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Dang, Duyen T.; Blayney, Douglas W.; Ensminger, William D.; Dang, Long H.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Abe, Masako; Havre, Pamela; Vogelzang, Nicholas J.; Dang, Nam H.] Nevada Canc Inst, Las Vegas, NV USA. [Mabjeesh, Nicola J.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Urol, Prostate Canc Res Lab, IL-69978 Tel Aviv, Israel. [Heath, Elisabeth I.] Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [Cruz-Correa, Marcia] Univ Puerto Rico, Ctr Canc, San Juan, PR 00936 USA. [Croix, Brad St.] NCI, Frederick, MD 21701 USA. RP Dang, LH (reprint author), Univ Michigan, Med Ctr, Dept Internal Med, Div Hematol Oncol, 1150 W Med Ctr Dr,MSRB I 6514, Ann Arbor, MI 48109 USA. EM lhdang@umich.edu FU NCI NIH HHS [K22CA111897, P30 CA46592]; NIDDK NIH HHS [P30 DK34933] NR 36 TC 44 Z9 48 U1 0 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 MAR 15 PY 2008 VL 68 IS 6 BP 1872 EP 1880 DI 10.1158/0008-5472.CAN-07-1589 PG 9 WC Oncology SC Oncology GA 274TO UT WOS:000254024400032 PM 18339868 ER PT J AU Williams, CK Segarra, M Sierra, MDLL Sainson, RCA Tosato, G Harris, AL AF Williams, Cassin Kimmel Segarra, Marta Sierra, Maria De La Luz Sainson, Richard C. A. Tosato, Giovanna Harris, Adrian L. TI Regulation of CXCR4 by the notch ligand delta-like 4 in endothelial cells SO CANCER RESEARCH LA English DT Article ID INHIBITS TUMOR-GROWTH; VASCULAR DEVELOPMENT; UP-REGULATION; FACTOR-I; ANGIOGENESIS; EXPRESSION; DLL4; ARTERIAL; MECHANISM; BLOCKADE AB Gene-targeting studies have shown that Delta-like 4 (Dll4) is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are not well defined. We generated primary human umbilical vascular endothelial cells that express Dll4 protein to study Dll4 function and previously showed that Dll4 down-regulates vascular endothelial growth factor (VEGF) receptor 2 and NRP1 expression and inhibits VEGF function. We now report that expression of Dll4 in endothelial cells inhibited attachment and migration to stromal-derived growth factor 1 (SDF1) chemokine. Cell surface, total protein, and mRNA levels of CXCR4, principal signaling receptor for SDF1, were significantly decreased in Dll4-transduced endothelial cells, attributable to a significant reduction of CXCR4 promoter activity. An immobilized recombinant extracellular portion of Dll4 (rhDLL4) was sufficient to down-regulate CXCR4 mRNA and protein, whereas protein levels of SDF1, VEGF, and RDC1 were unchanged. The gamma-secretase inhibitor L-685,458 significantly reconstituted CXCR4 mRNA in rhDLL4-stimulated endothelial cells. CXCR4 mRNA levels were significantly reduced in mouse xenografts of Dll4-transduced human gliomas compared with control gliomas, and vascular CXCR4 was not detected by immunohistochemistry in the enlarged vessels within the Dll4 gliomas. Thus, Dll4 may contribute to vascular differentiation and inhibition of the angiogenic response by regulating multiple receptor pathways. C1 [Williams, Cassin Kimmel; Sainson, Richard C. A.; Harris, Adrian L.] NCI, Ctr Canc Res, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Williams, Cassin Kimmel; Segarra, Marta; Sierra, Maria De La Luz; Tosato, Giovanna] Univ Oxford, John Radcliffe Hosp, Weather Inst Mol Med, Mol Oncol Labs, Oxford OX3 9DU, England. RP Tosato, G (reprint author), NCI, Ctr Canc Res, Cellular Oncol Lab, Bldg 37,Room 4124, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov OI Harris, Adrian/0000-0003-1376-8409 FU Intramural NIH HHS NR 25 TC 37 Z9 38 U1 0 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 MAR 15 PY 2008 VL 68 IS 6 BP 1889 EP 1895 DI 10.1158/0008-5472.CAN-07-2181 PG 7 WC Oncology SC Oncology GA 274TO UT WOS:000254024400034 PM 18339870 ER PT J AU Park, JM Terabe, M Steel, JC Forni, G Sakai, Y Morris, JC Berzofsky, JA AF Park, Jong Myun Terabe, Masaki Steel, Jason C. Forni, Guido Sakai, Yoshio Morris, John C. Berzofsky, Jay A. TI Therapy of advanced established murine breast cancer with a recombinant adenoviral ErbB-2/neu vaccine SO CANCER RESEARCH LA English DT Article ID TRANSGENIC BALB/C MICE; MAMMARY CARCINOGENESIS; MONOCLONAL-ANTIBODY; METASTATIC BREAST; DNA VACCINATION; OVARIAN-CANCER; NEU ONCOGENE; PHASE-II; T-CELL; CARCINOMAS AB ErbB-2 (HER-2/neu) is a transforming oncogene expressed by a substantial fraction of breast cancers, and monoclonal antibody therapy directed toward this antigen is an established treatment modality. However, not all tumors respond, and with a monoclonal antibody directed to a single epitope, there is always the risk of tumor escape. Furthermore, passive antibody therapy requires continual treatment. Whereas cancer vaccines have prevented the growth of tumors, it has been far more difficult to treat large established tumors. Here, we show that vaccination with a recombinant adenovirus expressing a truncated ErbB-2 antigen can cure large established subcutaneous ErbB-2-expressing breast cancers in mice, and can also cure extensive established lung metastatic disease. We also show that the mechanism of protection involves antibody-mediated blockade of ErbB-2 function, independent of Fie receptors. We conclude that a vaccine inducing antibodies to a functional oncogenic receptor could have tremendous therapeutic potential against cancers overexpressing such molecules. C1 [Park, Jong Myun; Terabe, Masaki; Berzofsky, Jay A.] NIH, Natl Canc Inst, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steel, Jason C.; Sakai, Yoshio; Morris, John C.] NIH, Natl Canc Inst, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Forni, Guido] Univ Turin, Ctr Mol Biotechnol, Turin, Italy. RP Terabe, M (reprint author), NIH, Natl Canc Inst, Vaccine Branch, Ctr Canc Res, Bldg 10,Room 6B-12, Bethesda, MD 20892 USA. EM terabe@mail.nih.gov RI Steel, Jason/D-1805-2013 OI Steel, Jason/0000-0003-3608-7542 FU Intramural NIH HHS NR 25 TC 22 Z9 24 U1 0 U2 0 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 MAR 15 PY 2008 VL 68 IS 6 BP 1979 EP 1987 DI 10.1158/0008-5472.CAN-07-5688 PG 9 WC Oncology SC Oncology GA 274TO UT WOS:000254024400044 PM 18339880 ER PT J AU Alfano, RW Leppla, SH Liu, SH Bugge, TH Duesbery, NS Frankel, AE AF Alfano, Randall W. Leppla, Stephen H. Liu, Shihui Bugge, Thomas H. Duesbery, Nicholas S. Frankel, Arthur E. TI Potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin - Implications for broad anti-tumor efficacy SO CELL CYCLE LA English DT Review DE angiogenesis; anthrax lethal toxin; B-RAF; lethal factor; matrix metalloproteinase; protective antigen ID ENDOTHELIAL GROWTH-FACTOR; PROTEIN-KINASE KINASE; MELANOMA-CELLS; PROTECTIVE ANTIGEN; MESSENGER-RNA; MAP-KINASES; NUDE-MICE; CANCER; RAS; INACTIVATION AB Angiogenesis is a critical step in solid tumor progression. The mitogen-activated protein kinase ( MAPK) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. Anthrax Lethal Toxin ( LeTx), secreted from the gram positive Bacillus anthracis, demonstrates potent MAPK pathway inhibition. In vivo efficacy studies revealed that LeTx has broad anti-tumor efficacy via the targeting of angiogenesis. However, specificity in animal models was limited due to the presence of receptors on many normal tissues and the ubiquitous expression of furin in tissues. Further, half-life of LeTx was short due to circulating furin-like proteases. Gelatinases are expressed on tumor angiogenic sprouts and only to a limited extent in normal tissues or blood. In order to circumvent nonspecific LeTx activation, enhance tumor vascular targeting, and improve plasma half-life, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. The MMP-activated LeTx showed potent angiogenic inhibition in vivo in the absence of systemic toxicity. Based on these studies, this attenuated toxin has clinical potential as a broad anti-tumor agent. C1 [Alfano, Randall W.; Frankel, Arthur E.] Scott & White Mem Hosp & Clin, Inst Canc Res, Temple, TX 76502 USA. [Leppla, Stephen H.; Liu, Shihui] NIAID, Lab Bacterial Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. [Bugge, Thomas H.] Natl Inst Dental & Craniofacial Res, Oral & Pharyngeal Canc Branch, Natl Inst Hlth, Bethesda, MD USA. [Duesbery, Nicholas S.] Van Andel Res Inst, Lab Canc & Dev Cell Biol, Grand Rapids, MI USA. RP Frankel, AE (reprint author), Scott & White Mem Hosp & Clin, Inst Canc Res, 5701 S Airport Rd, Temple, TX 76502 USA. EM afrankel@swmail.sw.org OI DUESBERY, NICK/0000-0002-4258-5655 NR 57 TC 18 Z9 18 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2008 VL 7 IS 6 BP 745 EP 749 PG 5 WC Cell Biology SC Cell Biology GA 285IV UT WOS:000254771400011 PM 18245947 ER PT J AU Saikkonen, B Pareek, TK Agarwal, N Molinolo, A Kriete, M Kulkarni, AB AF Saikkonen, Brenda Pareek, Tej Kumar Agarwal, Nitin Molinolo, Alfredo Kriete, Martin Kulkarni, Ashok B. TI Conditional deletion of cyclin-dependent kinase 5 in primary sensory neurons leads to atypical skin lesions SO CELL CYCLE LA English DT Article DE Cdk5; nociception; skin; wound-healing; psoriasis ID ULCERATIVE DERMATITIS; CDK5; MICE AB The key role of Cyclin-dependent kinase 5 ( Cdk5) in neuronal function has been well established but understanding of its importance in sensory pathways is in its infancy. Recently we described the important role of Cdk5 in pain signaling. Our studies indicated that conditional deletion of Cdk5 in small sensory neurons causes hypoalgesia. In current study, we identified development of atypical non-healing skin lesions in these mutant mice during the general colony maintenance. Detailed examination of these lesions clearly distinguishes them from ulcerative dermatitis. Here we hypothesize that these skin lesions are due to general sensation loss in these mice as evident from deep skin scratches that turn into unhealed wounds. C1 [Saikkonen, Brenda; Molinolo, Alfredo; Kriete, Martin; Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, LCDB, NIH, Bethesda, MD 20892 USA. [Pareek, Tej Kumar] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Agarwal, Nitin] Univ Heidelberg, Inst Pharmacol, D-6900 Heidelberg, Germany. RP Kulkarni, AB (reprint author), NIDCR, Funct Genom Sect, LCDB, NIH, 30 Convent Dr,Bldg 30,Room 130,MSC 4395, Bethesda, MD 20892 USA. EM ak4Om@nih.gov OI Pareek, Tej/0000-0001-5134-1647 NR 6 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2008 VL 7 IS 6 BP 750 EP 753 PG 4 WC Cell Biology SC Cell Biology GA 285IV UT WOS:000254771400012 PM 18239462 ER PT J AU Steadman, K Stein, WD Litman, T Yang, SX Abu-Asab, M Dutcher, SK Bates, S AF Steadman, Kenneth Stein, Wilfred D. Litman, Thomas Yang, Sherry X. Abu-Asab, Mones Dutcher, Sarah K. Bates, Susan TI PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors SO CELL CYCLE LA English DT Article DE spheroids; drug resistance; cell adhesion; intractable cancers; microarrays; confluence ID CELL LUNG-CANCER; ANCHORAGE-INDEPENDENT GROWTH; TRANSPORTER P-GLYCOPROTEIN; EXTRACELLULAR-MATRIX; IN-VITRO; BREAST-CANCER; MULTICELLULAR RESISTANCE; CHEMOTHERAPEUTIC DRUGS; CARCINOMA CELLS; ADHESION AB Cancers arising in pancreas, lung, liver and stomach are difficult to treat successfully. Wanting to understand the basis for such intractability, we previously performed comparative analyses of publicly available gene expression data from tumor biopsies. Expression of many cell adhesion genes correlated significantly with intractability of cancers, our surrogate of intractability being the SEER five-year survivals of patients with disseminated tumors. To model resistance mediated by cell adhesion, we evaluated HCT 116 cells grown in two modes differing in cell adhesion status: ( i) as monolayers attached to plastic culture dishes, ( ii) cells attached to one another in spheroids. We determined gene expression profiles of cells grown in these two modes, for three or six days, using the human genome U133A microarray ( Affymetrix, Inc.). There was a striking overlap between ( a) the genes expressed differentially between early monolayers and early spheroids and ( b) those expressed differentially between early and confluent monolayers. However, there was no similarity between these overlaps and the genes that were differentially expressed in intractable, as opposed to more tractable, tumors. We hypothesize that the cytotoxicity resistance for polyHEMA spheroids and for confluent cells have a similar basis, one that differs from the resistance found in intractable solid tumors in patients. Cytotoxicity, cell cycle and immunohistochemistry assays on early and on confluent monolayers, and on spheroids, showed similarities between these latter two conditions. We conclude that while spheroids ( and confluent monolayer cells) show drug resistance, the mechanisms underlying this resistance diverge from those conferring resistance to intractable cancers. C1 [Steadman, Kenneth; Stein, Wilfred D.; Dutcher, Sarah K.; Bates, Susan] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Stein, Wilfred D.] Hebrew Univ Jerusalem, Jerusalem, Israel. [Litman, Thomas] Exiqon, Vedbaek, Denmark. [Yang, Sherry X.] Natl Clin Target Validat Lab, Bethesda, MD USA. [Abu-Asab, Mones] NCI, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Stein, WD (reprint author), NCI, Med Oncol Branch, NIH, Rm 12c208 Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM wdstein@gmail.com; sebates@helix.nih.gov RI Steadman, Kenneth/J-3883-2013; OI Abu-Asab, Mones/0000-0002-4047-1232 NR 48 TC 5 Z9 5 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2008 VL 7 IS 6 BP 818 EP 829 PG 12 WC Cell Biology SC Cell Biology GA 285IV UT WOS:000254771400020 PM 18239467 ER PT J AU Strevel, EL Chau, NG Pond, GR Murgo, AJ Ivy, PS Siu, LL AF Strevel, Elizabeth L. Chau, Nicole G. Pond, Gregory R. Murgo, Anthony J. Ivy, Percy S. Siu, Lillian L. TI Improving the quality of abstract reporting for phase I cancer trials SO CLINICAL CANCER RESEARCH LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; CONSORT STATEMENT; CLINICAL-TRIALS; AMERICAN-SOCIETY; RECOMMENDATIONS; PUBLICATION AB Purpose: Conference abstracts of phase I trials (P1T) communicate important anticancer drug development information. Our objectives were to determine elements essential for good P1T abstract reporting, to assess the quality of P1T abstracts submitted to American Society of Clinical Oncology (ASCO) meetings, and to propose reporting guidelines. Experimental Design: A survey of developmental therapeutics experts established elements of P1T reporting quality, and a scoring system was generated. All P1T abstracts published in ASCO Annual Proceedings from 1997 to 2006 were reviewed, and the scoring system was applied. Results: A survey was distributed twice to 69 experts, with a response rate of 39% (27 of 69). Experts rated 37 elements using a five-point scale, and elements with mean ratings over 3.75 were included in the final scoring system. One thousand six hundred and eighty three P1T abstracts were reviewed. A positive and linear association was observed between average expert rating of the elements and the proportion of P1T abstracts including those elements (Spearman correlation coefficient, p = 0.60, P < 0.001). The median for all 1,683 abstracts was 62.5% (range, 25-95%; SD, 12.3%). Year of presentation was found to be significantly associated with higher quality scores (p = 0.20, P < 0.001), with later years possessing better quality scores. The quality score was statistically significant as a predictor of type of presentation (odds ratio, 1.10; 95% confidence interval, 1.02-1.19 per 10% increase; P = 0.014), with oral presentations having the highest scores. Conclusions: The quality of FIT abstract reporting at ASCO has improved over time, although there is room for optimization. The quality of P1T abstract reporting may be enhanced using guidelines derived from our expert consensus. C1 [Strevel, Elizabeth L.; Chau, Nicole G.; Pond, Gregory R.; Siu, Lillian L.] Univ Toronto, Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M5G 2M9, Canada. [Murgo, Anthony J.; Ivy, Percy S.] NCI, Bethesda, MD 20892 USA. RP Siu, LL (reprint author), Univ Toronto, Princess Margaret Hosp, Div Med Oncol & Hematol, 610 Univ Ave,Suite 5-718, Toronto, ON M5G 2M9, Canada. EM lillian.siu@uhn.on.ca NR 27 TC 6 Z9 6 U1 0 U2 1 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 MAR 15 PY 2008 VL 14 IS 6 BP 1782 EP 1787 DI 10.1158/1078-0432.CCR-07-4886 PG 6 WC Oncology SC Oncology GA 275LL UT WOS:000254072900025 PM 18347180 ER PT J AU Bennett, J AF Bennett, John TI Is real-time polymerase chain reaction ready for real use in detecting candidemia? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID AMPHOTERICIN-B; FLUCONAZOLE; INFECTIONS; SYSTEM; TRIAL C1 NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Bennett, J (reprint author), NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov NR 11 TC 5 Z9 6 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2008 VL 46 IS 6 BP 897 EP 898 DI 10.1086/528692 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 266RD UT WOS:000253453800018 PM 18260754 ER PT J AU Mannheimer, SB Wold, N Gardner, EM Telzak, EE Hullsiek, KH Chesney, M Wu, AW MacArthur, RD Matts, J Friedland, G AF Mannheimer, Sharon B. Wold, Nicholas Gardner, Edward M. Telzak, Edward E. Hullsiek, Katherine Huppler Chesney, Margaret Wu, Albert W. MacArthur, Rodger D. Matts, John Friedland, Gerald CA Terry Beirn Community Programs Cli TI Mild-to-moderate symptoms during the first year of antiretroviral therapy worsen quality of life in HIV-infected individuals SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID HEALTH-STATUS QUESTIONNAIRE; SERVICES UTILIZATION; CLINICAL IMPORTANCE; TRIAL; DISEASE; PREVALENCE; VALIDITY; EVENTS; RELIABILITY; OUTCOMES AB Symptoms and quality of life were assessed among human immunodeficiency virus (HIV)-infected individuals initiating their first course of antiretroviral therapy. Symptoms, which were mostly mild or moderate, were common in the first year and significantly affected the patients' quality of life. Quality of life was inversely related to the number of symptoms and in the change in the number of symptoms from baseline. C1 [Mannheimer, Sharon B.] Columbia Univ, Coll Phys & Surg, Harlem Hosp Ctr, Div Infect Dis, New York, NY USA. [Mannheimer, Sharon B.] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. [Telzak, Edward E.] Albert Einstein Coll Med, Bronx Lebanon Hosp Ctr, AIDS Program, New York, NY USA. [Telzak, Edward E.] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Telzak, Edward E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Wold, Nicholas; Hullsiek, Katherine Huppler; Matts, John] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Gardner, Edward M.] Univ Colorado, Div Infect Dis, Denver, CO 80202 USA. [Gardner, Edward M.] Hlth Sci Ctr, Denver, CO USA. [Chesney, Margaret] NIH, Natl Ctr Complementary & Alternat Med, Div Extramural Res & Training, Bethesda, MD 20892 USA. [Wu, Albert W.] Johns Hopkins Univ, John Hopkins Bloomberg Sch Publ Hlth, Dept Med, Baltimore, MD USA. [Wu, Albert W.] Johns Hopkins Univ, Sch Med, Dept Hlth & Policy Management, Baltimore, MD USA. [Wu, Albert W.] Johns Hopkins Univ, Sch Med, Dept Epidemiol, Baltimore, MD USA. [Wu, Albert W.] Johns Hopkins Univ, Sch Med, Dept Int Hlth, Baltimore, MD USA. [MacArthur, Rodger D.] Wayne State Univ, Div Infect Dis, Detroit, MI USA. [Friedland, Gerald] Yale Univ, Yale New Haven Hosp, Sch Med, AIDS Program, New Haven, CT USA. RP Mannheimer, SB (reprint author), 506 Lenox Ave,Rm 3101-A, New York, NY 10037 USA. EM sbm20@columbia.edu FU NIAID NIH HHS [5U01AI042170-10, 5U01AI046362-03] NR 33 TC 14 Z9 14 U1 2 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2008 VL 46 IS 6 BP 941 EP 945 DI 10.1086/528859 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 266RD UT WOS:000253453800027 PM 18279044 ER PT J AU Ng, HKT Filardo, G Zheng, G AF Ng, Hon Keung Tony Filardo, Giovanni Zheng, Gang TI Confidence interval estimating procedures for standardized incidence rates SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article ID EXPECTATION AB Performances of some common confidence interval construction procedures for direct standardized incidence or mortality rate were compared. The asymptotic method, the method based on matching moments, the method based on gamma distribution and the method based on beta distribution were investigated through Monte Carlo simulations based on data from an epidemiologic study of cardiovascular disease and randomly generated scenarios. These interval estimation procedures, as well as some mixed procedures developed for the present study, were evaluated in terms of their coverage probability and expected length. (c) 2007 Elsevier B.V. All rights reserved. C1 [Ng, Hon Keung Tony; Filardo, Giovanni] So Methodist Univ, Dept Stat Sci, Dallas, TX 75275 USA. [Filardo, Giovanni] Baylor Res Inst, Inst Hlth Care Res & Improvement, Dallas, TX 75206 USA. [Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Ng, HKT (reprint author), So Methodist Univ, Dept Stat Sci, Dallas, TX 75275 USA. EM ngh@mail.smu.edu NR 21 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 EI 1872-7352 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD MAR 15 PY 2008 VL 52 IS 7 BP 3501 EP 3516 DI 10.1016/j.csda.2007.11.004 PG 16 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 290TU UT WOS:000255145900016 ER PT J AU Bharti, K Liu, W Csermely, T Bertuzzi, S Arnheiter, H AF Bharti, Kapil Liu, Wenfang Csermely, Tamas Bertuzzi, Stefano Arnheiter, Heinz TI Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF SO DEVELOPMENT LA English DT Article DE retina; Retinal pigment epithelium; Mitf red-eyed white; Mitf black-eyed white; Chx10-ocular retardation; internal start codons ID RETINAL PIGMENTED EPITHELIUM; MOUSE MICROPHTHALMIA LOCUS; AUG INITIATOR CODON; OCULAR RETARDATION; GENOME-WIDE; GENE CHX10; MUTATIONS; MELANOCYTES; CELLS; IDENTIFICATION AB During vertebrate eye development, the transcription factor MITF plays central roles in neuroepithelial domain specification and differentiation of the retinal pigment epithelium. MITF is not a single protein but represents a family of isoforms generated from a common gene by alternative promoter/exon use. To address the question of the role and regulation of these isoforms, we first determined their expression patterns in developing mouse eyes and analyzed the role of some of them in genetic models. We found that two isoforms, A- and J-Mitf, are present throughout development in both retina and pigment epithelium, whereas H-Mitf is detected preferentially and D-Mitf exclusively in the pigment epithelium. We further found that a genomic deletion encompassing the promoter/exon regions of H-, D- and B-Mitf leads to novel mRNA isoforms and proteins translated from internal start sites. These novel proteins lack the normal, isoform-specific N-terminal sequences and are unable to support the development of the pigment epithelium, but are capable of inducing pigmentation in the ciliary margin and the iris. Moreover, in mutants of the retinal Mitf regulator Chx10 (Vsx2), reduced cell proliferation and abnormal pigmentation of the retina are associated with a preferential upregulation of H- and D-Mitf. This retinal phenotype is corrected when H- and D- Mitf are missing in double Mitf/Chx10 mutants. The results suggest that Mitf regulation in the developing eye is isoform-selective, both temporally and spatially, and that some isoforms, including H- and D-Mitf, are more crucial than others in effecting normal retina and pigment epithelium development. C1 [Bharti, Kapil; Liu, Wenfang; Csermely, Tamas; Bertuzzi, Stefano; Arnheiter, Heinz] NIH, NINDS, Mammalian Dev Sect, Bethesda, MD 20892 USA. RP Arnheiter, H (reprint author), NIH, NINDS, Mammalian Dev Sect, Bethesda, MD 20892 USA. EM ha3p@nih.gov FU Intramural NIH HHS [Z01 NS002790-19]; Telethon [TCP99018] NR 35 TC 66 Z9 67 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 EI 1477-9129 J9 DEVELOPMENT JI Development PD MAR 15 PY 2008 VL 135 IS 6 BP 1169 EP 1178 DI 10.1242/dev.014142 PG 10 WC Developmental Biology SC Developmental Biology GA 266HY UT WOS:000253426300018 PM 18272592 ER PT J AU Pacher, P AF Pacher, Pal TI Poly(ADP-ribose) polymerase inhibition as a novel therapeutic approach against intraepidermal nerve fiber loss and neuropathic pain associated with advanced diabetic neuropathy: A commentary on "PARP Inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy" SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Editorial Material ID ENDOTHELIAL DYSFUNCTION; COMPLICATIONS; PEROXYNITRITE; PATHOGENESIS; ACTIVATION; STRESS; DAMAGE C1 NIAAA, Sect Oxidat Stress Tissue Injuiry, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Pacher, P (reprint author), NIAAA, Sect Oxidat Stress Tissue Injuiry, Lab Physiol Studies, NIH, 5625 Fishers Lane,Room 2-N17,MSC 9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS [Z01 AA000375-02, Z99 AA999999] NR 19 TC 4 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR 15 PY 2008 VL 44 IS 6 BP 969 EP 971 DI 10.1016/j.freeradbiomed.2007.12.020 PG 3 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278HH UT WOS:000254275300005 PM 18194675 ER PT J AU Hennighausen, L Robinson, GW AF Hennighausen, Lothar Robinson, Gertraud W. TI Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B SO GENES & DEVELOPMENT LA English DT Review DE mammary epithelium; hepatocytes; immunoregulation; body growth; cytokine ID MAMMARY-GLAND DEVELOPMENT; REGULATORY T-CELLS; GROWTH-FACTOR-I; POSTNATAL BODY GROWTH; GLUCOCORTICOID-RECEPTOR; GENE-EXPRESSION; DNA-BINDING; INDUCED TRANSFORMATION; LYMPHOID DEVELOPMENT; EPITHELIAL-CELLS AB Transcription factors from the family of Signal Transducers and Activators of Transcription (STAT) are activated by numerous cytokines. Two members of this family, STAT5A and STAT5B (collectively called STAT5), have gained prominence in that they are activated by a wide variety of cytokines such as interleukins, erythropoietin, growth hormone, and prolactin. Furthermore, constitutive STAT5 activation is observed in the majority of leukemias and many solid tumors. Inactivation studies in mice as well as human mutations have provided insight into many of STAT5's functions. Disruption of cytokine signaling through STAT5 results in a variety of cell-specific effects, ranging from a defective immune system and impaired erythropoiesis, the complete absence of mammary development during pregnancy, to aberrant liver function. On a molecular level, STAT5 has been linked to cell specification, proliferation, differentiation, and survival. Evidence is growing that the diverse outcomes of STAT5 signaling are not only determined by the expression of specific receptors but also by the interaction of STAT5 with cofactors and the cell-specific activity of members of the SOCS family, which negatively regulate STAT function. In this review, we focus on emerging concepts and challenges in the field of Janus kinase (JAK)-STAT5 signaling. First, we discuss unique functions of STAT5 in three distinct systems: mammary epithelial cells, hepatocytes, and regulatory T cells. Second, we present an example of how STAT5 can achieve cell specificity in hepatocytes through a physical and functional interaction with the glucocorticoid receptor. Third, we focus on the relevance of STAT5 in the development and progression of leukemia. Next, we discuss lessons derived from human mutations and disease. Finally, we address an emerging issue that the interpretation of experiments from STAT5-deficient mice and cells might be compromised as these cells might reroute and reprogram cytokine signals to the "wrong" STATs and thus acquire inappropriate cues. We propose that mice with mutations in various components of the JAK-STAT signaling pathway are living laboratories, which will provide insight into the versatility of signaling hardware and the adaptability of the software. C1 [Hennighausen, Lothar; Robinson, Gertraud W.] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM hennighausen@nih.gov RI Robinson, Gertraud/I-2136-2012 FU Intramural NIH HHS [Z99 DK999999] NR 81 TC 175 Z9 186 U1 4 U2 19 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAR 15 PY 2008 VL 22 IS 6 BP 711 EP 721 DI 10.1101/gad.1643908 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 275PF UT WOS:000254083400004 PM 18347089 ER PT J AU Hwang, CH Wu, DK AF Hwang, Chan-Ho Wu, Doris K. TI Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans SO HUMAN MOLECULAR GENETICS LA English DT Article ID BONE MORPHOGENETIC PROTEINS; GENE-ENCODING NOGGIN; STAPES ANKYLOSIS; MIDDLE-EAR; MUTATIONS; MOUSE; EXPRESSION; CARTILAGE; SKELETOGENESIS; DIFFERENTIATION AB Conductive hearing loss occurs when sound waves are not relayed efficiently to the inner ear. Mutations of the NOGGIN (NOG) gene in humans are associated with several autosomal dominant disorders such as proximal symphalangism and multiple synostoses. These syndromes are characterized by skeletal defects and synostoses, which include conductive hearing loss. Noggin is an antagonist of bone morphogenetic proteins (BMPs), and balanced levels of BMPs and Noggin are required for proper skeletal formation. Depending on the genetic background, some of the Nog(+/-) mice display mild hearing loss, that is, conductive in nature. Since Noggin is a single exon gene, this data strongly suggest that the autosomal dominant disorders associated with NOG mutations are due to haploinsufficiency of NOGGIN. The conductive hearing loss in Nog(+/-) mice is caused by an ectopic bone bridge located between the stapes and the posterior wall of the tympanum, which affects the normal mobility of the ossicle. Our analyses suggest that the ectopic bone formation is caused by a failure of the stapes and styloid process to separate completely during development. This failure of bone separation in the Nog(+/-) mice reveals another consequence of chondrocyte hyperplasia due to unopposed Bmp activities in these mutants such as Bmp4 and Bmp14 (Gdf5). More importantly, these results establish Nog(+/-) mice as the first animal model for the study of conductive rather than neurosensory hearing loss that has direct relevance to human genetic disorders. C1 [Hwang, Chan-Ho; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, Rockville, MD 20850 USA. RP Wu, DK (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, 5 Res Court,Rm 2B34, Rockville, MD 20850 USA. EM wud@nidcd.nih.gov FU Intramural NIH HHS NR 42 TC 25 Z9 26 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 15 PY 2008 VL 17 IS 6 BP 844 EP 853 DI 10.1093/hmg/ddm356 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 272BN UT WOS:000253832700008 PM 18096605 ER PT J AU Lung, HL Lo, CC Wong, CCL Cheung, AKL Cheong, KF Wong, N Kwong, FM Chan, KC Law, EWL Tsao, SW Chua, D Sham, JS Cheng, Y Stanbridge, EJ Robertson, GP Lung, ML AF Lung, Hong Lok Lo, Cathy Carfield Wong, Carmen Chak Lui Cheung, Arthur Kwok Leung Cheong, Ka Fu Wong, Nathalie Kwong, Fung Mei Chan, Kinf Chi Law, Evan Wai Lok Tsao, Sai Wah Chua, Daniel Sham, Jonathan Shuntong Cheng, Yue Stanbridge, Eric J. Robertson, Gavin P. Lung, Maria Li TI Identification of tumor suppressive activity by irradiation microcell-mediated chromosome transfer and involvement of alpha B-crystallin in nasopharyngeal carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE chromosome 11q; alpha B-crystallin (CRYAB); nasopharyngeal carcinoma; irradiation microcell-mediated chromosome transfer; microcell hybrid ID COMPARATIVE GENOMIC HYBRIDIZATION; GENE AMPLIFICATION; EPITHELIAL-CELLS; EXPRESSION; CANCER; HETEROZYGOSITY; STRESS; 3P21.3; REGION; 11Q13 AB In previous studies, we successfully refined nasopharyngeal carcinoma (NPC) critical regions (CRs) mapping to chromosome 11q13 and 11q22-23. The chromosome 11 fragment containing the 1.8 Mb NPC CR at 11q13 (CRI), the CR at 11q22.3 mapped near D11S2000 (CR2), part of the CR at 11q23.1-11q23.2 overlap in with DIIS1300 and DlIS1391 (CR3), and the CR at cell adhesion molecule 1 (CADM1) locus (CR4), was chosen as the chromosome 11 donor cell line for the present study. Gamma irradiation was applied to cleave this truncated chromosome into smaller fragments and a new panel of donor cells containing further deleted fragments was produced. Subdones XMCH3.2 and XMCH3.4 were chosen for subsequent transfer to HONE1 cells; each contains a single copy of deleted chromosome 11 fragment with or without CR2 and the THY1 locus, previously shown to be involved in NPC. Both resultant chromosome 11 fragments in XMCH3.2 and XMCH3.4 caused tumor suppression. The association of alpha B-crystallin (CRYAB), a gene identified as being differentially expressed by gene profiling of NPC and an immortalized nasopharyngeal epithelial cell line, and which is located near CR3, was found to be associated with tumor suppression in all the tumor-suppressive hybrids. In addition, the expression level of this gene was down-regulated in the 7 NPC cell lines and in 5 out of 14 normal/tumor tissue pairs in the present study. Both promoter hypermethylation and allelic loss may be involved in the inactivation of this gene, suggesting its possible role in NPC development. (C) 2007 Wiley-Liss, Inc. C1 [Lung, Hong Lok; Lo, Cathy Carfield; Wong, Carmen Chak Lui; Cheung, Arthur Kwok Leung; Cheong, Ka Fu; Kwong, Fung Mei; Chan, Kinf Chi; Law, Evan Wai Lok; Cheng, Yue; Lung, Maria Li] Hong Kong Univ Sci & Technol, Dept Biol, Kowloon, Hong Kong, Peoples R China. [Lung, Hong Lok; Lo, Cathy Carfield; Wong, Carmen Chak Lui; Cheung, Arthur Kwok Leung; Cheong, Ka Fu; Kwong, Fung Mei; Chan, Kinf Chi; Law, Evan Wai Lok; Cheng, Yue; Lung, Maria Li] Hong Kong Univ Sci & Technol, Ctr Canc Res, Kowloon, Hong Kong, Peoples R China. [Wong, Nathalie] Chinese Univ Hong Kong, Dept Anat & Cellular Pathol, Shatin, Hong Kong, Peoples R China. [Tsao, Sai Wah] Univ Hong Kong, Dept Anat, Hong Kong, Hong Kong, Peoples R China. [Chua, Daniel; Sham, Jonathan Shuntong] Univ Hong Kong, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. [Cheng, Yue] Natl Naval Med Ctr, Natl Canc Inst, Genet Branch, Bethesda, MD USA. [Stanbridge, Eric J.] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. [Robertson, Gavin P.] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA. RP Lung, ML (reprint author), Hong Kong Univ Sci & Technol, Dept Biol, Clear Water Bay, Kowloon, Hong Kong, Peoples R China. EM bomaria@ust.hk RI Lung, Hong Lok/C-4494-2009; Cheng, Yue/E-9853-2010; Cheung, Arthur Kwok Leung/H-8940-2013; OI Cheng, Yue/0000-0002-2472-1879; Robertson, Gavin P./0000-0003-0152-2997 NR 29 TC 12 Z9 12 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2008 VL 122 IS 6 BP 1288 EP 1296 DI 10.1002/ijc.23259 PG 9 WC Oncology SC Oncology GA 264QE UT WOS:000253302800012 PM 18027848 ER PT J AU Carpenter, LM Newton, R Casabonne, D Ziegler, J Mbulaiteye, S Mbidde, E Wabinga, H Jaffe, H Beral, V AF Carpenter, Lucy M. Newton, Robert Casabonne, Delphine Ziegler, John Mbulaiteye, Sam Mbidde, Edward Wabinga, Henry Jaffe, Harold Beral, Valerie TI Antibodies against malaria and Epstein-Barr virus in childhood Burkitt lymphoma: A case-control study in Uganda SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Burkitt lymphoma; malaria antibodies; Epstein-Barr virus; Uganda ID AFRICAN CHILDREN; MALIGNANT LYMPHOMA; INFECTION; CANCER AB Burkitt lymphoma, a childhood tumor common in parts of sub-Saharan Africa, has been directly associated with Epstein-Barr virus (EBV) and indirectly with prevalence of malaria. We studied antibodies to both EBV and malaria in children diagnosed with this cancer in Uganda. We performed a case-control study of HIV-seronegative children (<= 15 years) admitted to hospital. Cases were diagnosed with Burkitt lymphoma and controls with nonmalignant conditions or non-lymphatic cancers. Interviews were conducted and serological samples collected and, when possible, tested for both EBV and malaria. Adjusted odds ratios (ORs) for Burkitt lymphoma were estimated using unconditional logistic regression adjusting for sex, age, residential district, household income and tribe. The mean age of cases was 7 years and 61% were male. Compared to controls, cases were more likely to be reported having received more frequent treatment for malaria in the past year (OR = 2.0; p = 0.001) and less likely to be living in a home where insecticides were used (OR = 0.2; p < 0.0001). Odds ratios for Burkitt lymphoma in children increased with increasing antibody levels against EBV (p < 0.0001) and malaria (p = 0.05). Findings were similar for children residing in districts close to the capital city and in remote areas. Cases were 5 times more likely than controls to have raised levels of both EBV and malaria antibodies (OR = 5.0; p = 0.003). Our findings suggest that EBV and malaria may act synergistically in the pathogenesis of childhood Burkitt lymphoma. Malaria prevention measures may also prevent this childhood cancer. (C) 2007 Wiley-Liss, Inc. C1 [Carpenter, Lucy M.; Jaffe, Harold] Univ Oxford, Dept Publ Hlth, Oxford OX3 7LF, England. [Newton, Robert] Univ York, Dept Hlth Sci, Epidemiol & Genet Unit, York YO10 5DD, N Yorkshire, England. [Casabonne, Delphine; Beral, Valerie] Univ Oxford, Canc Epidemiol Unit, Oxford OX3 7LF, England. [Ziegler, John; Mbidde, Edward; Wabinga, Henry] Uganda Canc Inst, Kampala, Uganda. [Ziegler, John; Mbidde, Edward; Wabinga, Henry] Makerere Univ, Sch Med, Kampala, Uganda. [Mbulaiteye, Sam] NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, Bethesda, MD USA. RP Carpenter, LM (reprint author), Univ Oxford, Dept Publ Hlth, Old Rd Campus, Oxford OX3 7LF, England. EM lucy.carpenter@dphpc.ox.ac.uk RI Beral, Valerie/B-2979-2013; Casabonne, Delphine/H-6425-2014 NR 27 TC 39 Z9 39 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2008 VL 122 IS 6 BP 1319 EP 1323 DI 10.1002/ijc.23254 PG 5 WC Oncology SC Oncology GA 264QE UT WOS:000253302800016 PM 18000823 ER PT J AU Boersma, BJ Reimers, M Yi, M Ludwig, JA Luke, BT Stephens, RM Yfantis, HG Lee, DH Weinstein, JN Ambs, S AF Boersma, Brenda J. Reimers, Mark Yi, Ming Ludwig, Joseph A. Luke, Brain T. Stephens, Robert M. Yfantis, Harry G. Lee, Dong H. Weinstein, John N. Ambs, Stefan TI A stromal gene signature associated with inflammatory breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE inflammatory breast cancer; stroma; gene signature; prediction ID EXPRESSION SIGNATURE; MICROARRAY ANALYSIS; TUMOR-SUPPRESSOR; POOR-PROGNOSIS; CARCINOMAS; PROTEIN; PROGRESSION; RECEPTOR; SURVIVAL; PHENOTYPE AB The factors that determine whether a breast carcinoma will develop into inflammatory breast cancer (IBC) remain poorly understood. Recent evidence indicates that the tumor stroma influences cancer phenotypes. We tested the hypotheses that the gene expression signature of the tumor stroma is a distinctive feature of IBC. We used laser capture microdissection to obtain enriched populations of tumor epithelial cells and adjacent stromal cells from 15 patients with IBC and 35 patients with invasive, noninflammatory breast cancer (non-IBC). Their mRNA expression profiles were assessed using Affymetrix GeneChips(TM). In addition, a previously established classifier for IBC was evaluated for the resulting data sets. The gene expression profile of the tumor stroma distinguished IBC from non-IBC, and a previously established IBC prediction signature performed better in classifying IBC using the gene expression profile of the tumor stroma than it did using the profile of the tumor epithelium. In a pathway analysis, the genes differentially expressed between IBC and non-IBC tumors clustered in distinct pathways. We identified multiple pathways related to the endoplasmic stress response that could be functionally significant in IBC. Our findings suggest that the gene expression in the tumor stroma may play a role in determining the IBC phenotype. (C) 2007 Wiley-Liss, Inc. C1 [Boersma, Brenda J.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Natl Inst Hlth, Ctr Canc Res, Bethesda, MD 20892 USA. [Reimers, Mark; Ludwig, Joseph A.; Weinstein, John N.] NCI, Natl Inst Hlth, Ctr Canc Res,Lab Mol Pharmacol, Genom & Bioinformat Grp, Bethesda, MD 20892 USA. [Yi, Ming; Luke, Brain T.; Stephens, Robert M.] NCI Frederick SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD USA. [Ludwig, Joseph A.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX USA. [Yfantis, Harry G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Natl Inst Hlth, Ctr Canc Res, Bldg 37-Room 3050B, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Boersma, Brenda/A-9270-2009 OI Boersma, Brenda/0000-0002-8992-2735 FU Intramural NIH HHS NR 56 TC 90 Z9 92 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2008 VL 122 IS 6 BP 1324 EP 1332 DI 10.1002/ijc.23237 PG 9 WC Oncology SC Oncology GA 264QE UT WOS:000253302800017 PM 17999412 ER PT J AU Surazynski, A Donald, SP Cooper, SK Whiteside, MA Salnikow, K Liu, YM Phang, JM AF Surazynski, Arkadiusz Donald, Steven P. Cooper, Sandra K. Whiteside, Martin A. Salnikow, Konstantin Liu, Yongmin Phang, James M. TI Extracellular matrix and HIF-1 signaling: The role of prolidase SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE proline; hypoxia; invasion; extracellular matrix; matrix metalloproteinase ID PROLINE OXIDASE; BREAST-CANCER; METALLOPROTEINASES; TISSUE; NICKEL AB Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis. ECM is predominantly collagen, and the imino acids (Pro and HyPro) comprise 25% of collagen residues. The final step in collagen degradation is catalyzed by prolidase, the obligate peptidase for imidodipeptides with Pro and HyPro in the carboxyl terminus. Defective wound healing in patients with inherited prolidase deficiency is associated with histologic features of angiopathy suggesting that prolidase may play a role in angiogenesis. Because HIF-1 alpha is central to angiogenesis, we considered that prolidase may modulate this pathway. To test this hypothesis, we made expression constructs of human prolidase and obtained stable transfectants in colorectal cancer cells (RKO). Overexpression of prolidase resulted in increased nuclear hypoxia inducible factor (HIF-1 alpha) levels and elevated expression of HIF-1-dependent gene products, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). The activation of HIF-1-dependent transcription was shown by prolidase-dependent activation of hypoxia response element (HRE)-luciferase expression. We used an oxygen-dependent degradation domain (ODD)-luciferase reporter construct as a surrogate for HIF-1 alpha as an in situ prolyl-hydroxylase assay. Since this reporter is degraded by VHL-dependent mechanisms, the increased levels of luciferase observed with prolidase expression reflected the decreased HIF-1 alpha prolyl hydroxylase activity. Additionally, the differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1 alpha levels. These findings show that metabolism of imidodipeptides by prolidase plays a previously unrecognized role in angiogenic signaling. (C) 2007 Wiley-Liss, Inc. C1 [Surazynski, Arkadiusz; Donald, Steven P.; Whiteside, Martin A.; Phang, James M.] NCI, Comparat Carcinogenesis Lab, Metab & Canc Susceptibil Sect, Frederick, MD 21702 USA. [Surazynski, Arkadiusz] Med Univ Bialylstok, Dept Med Chem, Bialystok, Poland. [Cooper, Sandra K.; Liu, Yongmin] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Salnikow, Konstantin] NCI, Comparat Carcinogenesis Lab, Met Sect, Frederick, MD 21702 USA. RP Liu, YM (reprint author), NCI, Comparat Carcinogenesis Lab, Metab & Canc Susceptibil Sect, Bldg 538,Room 144, Frederick, MD 21702 USA. EM liuy@ncifcrf.gov; phang@mail.ncifcrf.gov FU PHS HHS [N01-C0-12400] NR 23 TC 43 Z9 44 U1 3 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2008 VL 122 IS 6 BP 1435 EP 1440 DI 10.1002/ije.23263 PG 6 WC Oncology SC Oncology GA 264QE UT WOS:000253302800032 PM 17999410 ER PT J AU Barlesi, F Giaccone, G Gallegos-Ruiz, MI Span, SW Lefesvre, P Kruyt, FAE Rodriguez, JA AF Barlesi, Fabrice Giaccone, Giuseppe Gallegos-Ruiz, Marielle I. Span, Simone W. Lefesvre, Pierre Kruyt, Frank A. E. Rodriguez, Jose Antonio TI Genotype analysis of the VNTR polymorphism in the SMYD3 histone methyltransferase gene: Lack of correlation with the level of histone H3 methylation in NSCLC tissues or with the risk of NSCLC SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID TANDEM REPEATS POLYMORPHISM; VARIABLE NUMBER; CANCER; REGION C1 [Giaccone, Giuseppe] NCI, NIH, CCR, Med Oncol Branch, Bethesda, MD 20817 USA. [Barlesi, Fabrice; Gallegos-Ruiz, Marielle I.; Span, Simone W.; Kruyt, Frank A. E.; Rodriguez, Jose Antonio] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Barlesi, Fabrice] Univ Aix Marseille 2, Assistance Publ Hop Marseille, Marseille, France. [Lefesvre, Pierre] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Rodriguez, Jose Antonio] Univ Basque Country, Dept Genet Phys Anthropol & Anim Physiol, Leioa, Spain. RP Giaccone, G (reprint author), NCI, NIH, CCR, Med Oncol Branch, Bethesda, MD 20817 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 7 TC 2 Z9 3 U1 1 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2008 VL 122 IS 6 BP 1441 EP 1442 DI 10.1002/ije.23227 PG 2 WC Oncology SC Oncology GA 264QE UT WOS:000253302800033 PM 18027872 ER PT J AU Deutsch, M Land, S Begovic, M Sharif, S AF Deutsch, Melvin Land, Stephanie Begovic, Mirsada Sharif, Saima TI The incidence of arm edema in women with breast cancer randomized on the national surgical adjuvant breast and bowel project study B-04 to radical mastectomy versus total mastectomy and radiotherapy versus total mastectomy alone SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY OCT 17-20, 2004 CL Atlanta, GA SP Amer Soc Therapeut Radiol & Oncol DE arm edema; radical mastectomy; total mastectomy; radiotherapy; breast cancer ID AXILLARY DISSECTION; LYMPHEDEMA; CARCINOMA; COMPLICATIONS; IRRADIATION; MANAGEMENT; SURGERY; SURVIVORS; SHOULDER; THERAPY AB Purpose: To determine the incidence and factors associated with the development of arm edema in women who participated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study B-04. Methods and Materials: Between 1971 and 1974, the NSABP protocol B-04 randomized 1,665 eligible patients with resectable breast cancer to either (1) the Halstead-type radical mastectomy; (2) total mastectomy and radiotherapy to the chest wall, axilla, supraclavicular region, and internal mammary nodes if by clinical examination axillary nodes were involved by tumor; and (3) for patients with a clinically uninvolved axilla, a third arm, total mastectomy alone. Measurements of the ipsilateral and contralateral arm circumferences were to be performed every 3 months. Results: There was at least one recorded measurement of arm circumferences for 1,457 patients (87.5% of eligible patients). There were 674 women (46.3%) who experienced arm edema at some point during the period of follow-up until February 1976. For radical mastectomy patients, total mastectomy and radiotherapy patients, and total mastectomy patients alone, arm edema was recorded at least once in 58.1%,38.2%, and 39.1% of patients, respectively (p<.001) and at last recorded measurement in 30.7%,14.8%, and 15.5%, respectively (p = <.001). Increasing body mass index (BMI) also showed a statistically significant correlation with arm edema at any time (p =.001) and at last assessment (p =.005). Conclusions: Patients who undergo mastectomy, including those whose treatment plans do not include axillary dissection or postoperative radiotherapy, suffer an appreciable incidence of arm edema. (C) 2008 Elsevier Inc. C1 [Deutsch, Melvin] UPMC Presbyterian, Dept Radiat Oncol, Pittsburgh, PA USA. [Deutsch, Melvin; Land, Stephanie; Begovic, Mirsada; Sharif, Saima] Natl Surg Adjuvant Breast & Bowel Project, Operat Ctr, Pittsburgh, PA USA. [Deutsch, Melvin; Land, Stephanie; Begovic, Mirsada; Sharif, Saima] Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. RP Deutsch, M (reprint author), UPMC Presbyterian, Dept Radiat Oncol, 200 Lothrop St,B Wing,3rd Floor, Pittsburgh, PA USA. EM deutschm@upmc.edu FU NCI NIH HHS [U10-CA-12027, U10-CA-37377, U10-CA-69651, U10-CA-69974] NR 24 TC 33 Z9 37 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2008 VL 70 IS 4 BP 1020 EP 1024 DI 10.1016/j.ijrobp.2007.07-2376 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 273PB UT WOS:000253942900008 PM 18029105 ER PT J AU Smyth, JT DeHaven, WI Bird, GS Putney, JW AF Smyth, Jeremy T. DeHaven, Wayne I. Bird, Gary S. Putney, James W., Jr. TI Ca2+-store-dependent and -independent reversal of Stim1 localization and function SO JOURNAL OF CELL SCIENCE LA English DT Article DE Stim1; ML-9; inhibitors; store-operated channels ID LIGHT-CHAIN KINASE; OPERATED CA2+ ENTRY; EMBRYONIC KIDNEY-CELLS; PLASMA-MEMBRANE; CALCIUM-ENTRY; ENDOPLASMIC-RETICULUM; ENDOTHELIAL-CELLS; CHANNEL FUNCTION; SMOOTH-MUSCLE; CRAC CHANNELS AB Stim1 responds to depletion of ER Ca2+ stores by rearranging from tubular structures throughout the ER into punctate structures near the plasma membrane, where it activates Orai store-operated Ca2+ entry (SOCE) channels. However, the mechanism and structural determinants of the localization and reversal of Stim1 puncta formation are poorly understood. Using HEK293 cells expressing Stim1 tagged with enhanced yellow fluorescent protein (EYFP-Stim1), we show that the basis for SOCE termination is the reversal of the punctate Stim1 localization, which absolutely depends on SOCE-dependent store refilling. We also describe rapid, store-independent reversal of EYFP-Stim1 punctae by the ML-9 inhibitor of myosin-light-chain kinase (MLCK). ML-9 similarly inhibited SOCE and the Ca2+- release-activated Ca2+ (CRAC) current. Reversal by ML-9 resulted in full re-establishment of the tubular EYFP-Stim1 localization. A constitutively active EF-hand mutant of EYFP-Stim1 was also reversed by ML-9, regardless of the Ca2+ store content. Inhibition by ML-9 was not due to MLCK inhibition as other inhibitors of MLCK had no effect. Finally, we provide evidence that EYFP-Stim1 punctae form in specific predetermined cellular loci. We conclude that SOCE is tightly coupled to formation of Stim1 puncta, and both SOCE and puncta formation involve a dynamic, reversible signaling complex that probably consists of components in addition to Stim1 and Orai channels. C1 [Smyth, Jeremy T.; DeHaven, Wayne I.; Bird, Gary S.; Putney, James W., Jr.] NIH, Dept Hlth & Human Serv, NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIH, Dept Hlth & Human Serv, NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov FU Intramural NIH HHS [Z01 ES090087-11, Z99 ES999999] NR 29 TC 96 Z9 96 U1 1 U2 1 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 MAR 15 PY 2008 VL 121 IS 6 BP 762 EP 772 DI 10.1242/jcs.023903 PG 11 WC Cell Biology SC Cell Biology GA 283TU UT WOS:000254660200005 PM 18285445 ER PT J AU Berzofsky, JA Terabe, M AF Berzofsky, Jay A. Terabe, Masaki TI NKT cells in tumor immunity: Opposing subsets define a new immunoregulatory axis SO JOURNAL OF IMMUNOLOGY LA English DT Review ID KILLER-T-CELLS; NONOBESE DIABETIC MICE; GROWTH-FACTOR-BETA; HEPATITIS-B-VIRUS; NATURAL-KILLER; ALPHA-GALACTOSYLCERAMIDE; DENDRITIC CELLS; IN-VIVO; CUTTING EDGE; ANTITUMOR IMMUNITY AB NKTcells are true Ag-specific T cells that also have innate properties and form a bridge between the innate and adaptive immune systems. Distinct NKT cell subsets play positive and negative regulatory roles and define a new immunoregulatory axis with broad implications for tumor immunity and other immunological and disease settings. C1 [Berzofsky, Jay A.; Terabe, Masaki] NCI, Vaccine Branch, Bethesda, MD 20892 USA. RP Terabe, M (reprint author), NCI, Vaccine Branch, Bldg 10,Room 6B-12, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov; terabe@mail.nih.gov FU Intramural NIH HHS NR 126 TC 76 Z9 82 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 MAR 15 PY 2008 VL 180 IS 6 BP 3627 EP 3635 PG 9 WC Immunology SC Immunology GA 324GS UT WOS:000257506600003 PM 18322166 ER PT J AU Yang, YH An, J Weng, NP AF Yang, Yinhua An, Jie Weng, Nan-Ping TI Telomerase is involved in IL-7-mediated differential survival of naive and memory CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID STRESS-INDUCED APOPTOSIS; LIFE-SPAN; LYMPHOCYTE DEVELOPMENT; GENE-EXPRESSION; IL-7 PROMOTES; ACTIVATION; PROLIFERATION; HTERT; INTERLEUKIN-7; LENGTH AB IL-7 plays an essential role in T cell maintenance and survival. The survival effect of IL-7 is thought to be mediated through regulation of Bcl2 family proteins. After a comparative analysis of IL-7-induced growth and cell death of human naive and memory CD4(+) T cells, we observed that more memory CD4(+) T cells underwent cell division and proceeded to apoptosis than naive cells in response to IL-7. However, IL-7-induced expressions of Bcl2 family members (Bcl2, Bcl-xL, Bax, and Bad) were similar between naive and memory cells. Instead, we found that IL-7 induced higher levels of telomerase activity in naive cells than in memory cells, and the levels of IL-7-induced telomerase activity had a significant inverse correlation with cell death in CD4(+) T cells. Furthermore, we showed that reducing expression of telomerase reverse transcriptase and telomerase activity significantly increased cell death of IL-7-cultured CD4(+) T cells. Together, these findings demonstrate that telomerase is involved in IL-7-mediated differential survival of naive and memory CD4(+) T cells. C1 [Yang, Yinhua; An, Jie; Weng, Nan-Ping] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Weng, NP (reprint author), NIA, Immunol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Wengn@mail.nih.gov FU Intramural NIH HHS [Z01 AG000756-10] NR 36 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2008 VL 180 IS 6 BP 3775 EP 3781 PG 7 WC Immunology SC Immunology GA 324GS UT WOS:000257506600021 PM 18322183 ER PT J AU Hooks, JJ Nagineni, CN Hooper, LC Hayashi, K Detrick, B AF Hooks, John J. Nagineni, Chandrasekharam N. Hooper, Laura C. Hayashi, Kozaburo Detrick, Barbara TI IFN-beta provides immuno-protection in the retina by inhibiting ICAM-1 and CXCL9 in retinal pigment epithelial cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL CORONAVIRUS RETINOPATHY; INTERCELLULAR-ADHESION MOLECULE-1; TOXOPLASMA-GONDII INFECTION; VIRUS-INFECTION; GENE-EXPRESSION; CYTOMEGALOVIRUS REPLICATION; MACULAR DEGENERATION; INNATE IMMUNITY; INTERFERON; GAMMA AB The retinal pigment epithelial (RPE) cell is a potent regulatory cell that facilitates normal physiologic processes and plays a critical role in a variety of retinal diseases. We evaluated IFN-beta production in human RPE cells through TLR signaling and investigated the effects of IFN-beta on RPE cells. RPE cells treated with poly(1:Q or infected with an RNA virus produce IFN-beta. Kinetic studies revealed that IFN-beta levels continue to increase over a 48-h period and this was associated with the up-regulation of IRF-7 gene expression, a known positive feedback molecule for IFN-beta production. Microarray analysis revealed that in IFN-beta treated cells, 480 genes of 22,283 genes were up or down-regulated by > 2-fold. We hypothesize that IFN-beta induction during TLR signaling in the retina is an immunosuppressive factor produced to limit immunopathologic damage. Cytokine activation of RPE cells results in the production of the chemokines, CXCL9 and CXCL10, and the adhesion molecule, ICAM-1. Pretreatment of RPE cells with IFN-beta resulted in inhibition of ICAM-1 production and elimination of CXCL9 production. This treatment did not alter CXCL10 production. Anti-IFN-beta Ab blocked the inhibitory action of IFN-beta. Real time PCR analysis revealed that IFN-beta treatment inhibited gene expression of sICAM-1 and CXCL9. The results indicate a critical role for RPE cell derived IFN-beta in the downregulation of CXCL9 and ICAM-I expression in the retina and suggest that the inhibition of CXCL9 is an immuno-suppressive mechanism that protects the retina from excessive inflammation. C1 [Hooks, John J.; Nagineni, Chandrasekharam N.; Hooper, Laura C.; Hayashi, Kozaburo] NEI, Immunol Lab, Immunol & Virol Sect, NIH, Bethesda, MD 20892 USA. [Detrick, Barbara] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. RP Hooks, JJ (reprint author), NEI, Immunol Lab, Immunol & Virol Sect, NIH, Bldg 10,room 10N248, Bethesda, MD 20892 USA. EM hooksj@nei.nih.gov FU Intramural NIH HHS NR 57 TC 20 Z9 20 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2008 VL 180 IS 6 BP 3789 EP 3796 PG 8 WC Immunology SC Immunology GA 324GS UT WOS:000257506600023 PM 18322185 ER PT J AU Tarasenko, T Kole, HK Bolland, S AF Tarasenko, Tatyana Kole, Hemanta K. Bolland, Silvia TI A lupus-suppressor BALB/c locus restricts IgG2 autoantibodies without altering intrinsic B cell-tolerance mechanisms SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-GAMMA-RIIB; SYSTEMIC-LUPUS; SPONTANEOUS AUTOIMMUNITY; DEFICIENT MICE; MOUSE STRAINS; C57BL/6 MICE; BXSB MICE; ERYTHEMATOSUS; DISEASE; SUSCEPTIBILITY AB Fc gamma R2B-deficient mice develop autoantibodies and glomerulonephritis with a pathology closely resembling human lupus when on the C57BL/6 (B6) background. The same mutation on the BALB/c background does not lead to spontaneous disease, suggesting differences in lupus susceptibility between the BALB/c and B6 strains. An F2 genetic analysis from a B6/BALB cross identified regions from the B6 chromosomes 12 and 17 with positive linkage for IgG autoantibodies. We have generated a congenic strain that contains the suppressor allele from the BALB/c chromosome 12 centromeric region (sbb2(a)) in an otherwise B6.Fc gamma R2B(-/-) background. None of the B6.Fc gamma R2B(-/-)sbb2(a/a) mice tested have developed IgG autoantibodies in the serum or autoimmune pathology. Mixed bone marrow reconstitution experiments indicate that sbb2(a) is expressed in non-B bone marrow-derived cells and acts in trans. sbb2(a) does not alter L chain editing frequencies of DNA Abs in the 3H9H/56R H chain transgenic mice, but the level of IgG2a anti-DNA Abs in the serum is reduced. Thus, sbb2(a) provides an example of a non-MHC lupus-suppressor locus that protects from disease by restricting the production of pathogenic IgG isotypes even in backgrounds with inefficient Ab editing checkpoints. C1 [Tarasenko, Tatyana; Kole, Hemanta K.; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM sbolland@nih.gov FU Intramural NIH HHS NR 38 TC 12 Z9 12 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2008 VL 180 IS 6 BP 3807 EP 3814 PG 8 WC Immunology SC Immunology GA 324GS UT WOS:000257506600025 PM 18322187 ER PT J AU Anderson, CF Lira, R Kamhawi, S Belkaid, Y Wynn, TA Sacks, D AF Anderson, Charles F. Lira, Rosalia Kamhawi, Shaden Belkaid, Yasmine Wynn, Thomas A. Sacks, David TI IL-10 and TGF-beta control the establishment of persistent and transmissible infections produced by Leishmania tropica in C57BL/6 mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTHROPONOTIC CUTANEOUS LEISHMANIASIS; EXPERIMENTAL VISCERAL LEISHMANIASIS; METACYCLIC PROMASTIGOTES; DENDRITIC CELLS; MAJOR INFECTION; DESERT-STORM; BALB/C MICE; CYTOKINES; REFUGEE; MOUSE AB Leishmania tropica is the causative agent of Old World anthroponotic cutaneous leishmaniasis, which is characterized by lesions that take an extended period of time to heal, often resulting in disfiguring scars, and are more refractory to treatment than leishmaniasis caused by Leishmania major. Immunologic studies involving experimental animal models of L. tropica infection are virtually nonexistent. In the current study, infectious-stage L. tropica were used to establish dermal infections in C57BL/6 and BALB/c mice. In both strains, the lesions were slow to develop and showed minimal pathology. They nonetheless contained a stable number of between 10(4) and 10(5) parasites for over 1 year, which were efficiently picked up by a natural sand fly vector, Phlebotomus sergenti. Control of parasite growth depended on the development of a Th1 response, as C57BL/6 mice genetically deficient in Th1 cytokines and BALB/c mice treated with Abs to IFN-gamma harbored significantly more parasites. By contrast, IL-10-deficient mice harbored significantly fewer parasites throughout the infection. To further study the immunologic mechanisms that may prevent efficient clearance of the parasites, IL-10 and TGF-beta signaling were abrogated during the chronic phase of infection in wild-type C57BL/6 mice. Distinct from chronic L. major infection, IL-10 blockade alone had no effect on L. tropica, but required simultaneous treatment with anti-TGF-beta Abs to promote efficient parasite clearance from the infection site. Thus, chronic infection with L. tropica appears to be established via multiple suppressive factors, which together maintain the host as a long-term reservoir of infection for vector sand flies. C1 [Anderson, Charles F.; Lira, Rosalia; Kamhawi, Shaden; Belkaid, Yasmine; Wynn, Thomas A.; Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 26 TC 35 Z9 39 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 MAR 15 PY 2008 VL 180 IS 6 BP 4090 EP 4097 PG 8 WC Immunology SC Immunology GA 324GS UT WOS:000257506600057 PM 18322219 ER PT J AU Pazdrak, K Young, TW Stafford, S Olszewska-Pazdrak, B Straub, C Starosta, V Brasier, A Kurosky, A AF Pazdrak, Konrad Young, Travis W. Stafford, Susan Olszewska-Pazdrak, Barbara Straub, Christof Starosta, Vitaliy Brasier, Allan Kurosky, Alexander TI Cross-talk between ICAM-1 and granulocyte-macrophage colony-stimulating factor receptor signaling modulates eosinophil survival and activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; GM-CSF RECEPTOR; TYROSINE-PHOSPHATASE; DECREASED EXPRESSION; AIRWAY EOSINOPHILS; BETA-CHAIN; HLA-DR; IL-5; CELL; DEGRANULATION AB Reversal of eosinophilic inflammation has been an elusive therapeutic goal in the management of asthma pathogenesis. In this regard, GM-CSF is a primary candidate cytokine regulating eosinophil activation and survival in the lung; however, its molecular mechanism of propagation and maintenance of stimulated eosinophil activation is not well understood. In this study, we elucidate those late interactions occurring between the GM-CSF receptor and activated eosinophil signaling molecules. Using coimmunoprecipitation with GM-CSF-stimulated eosinophils, we have identified that the GM-CSF receptor beta-chain (GMR beta) interacted with ICAM-1 and Shp2 phosphatase, as well as Slp76 and ADAP adaptor proteins. Separate experiments using affinity binding with a tyrosine-phosphorylated peptide containing an ITIM (ICAM-1 residues 480-488) showed binding to Shp2 phosphatase and GMR beta. However, the interaction of GMR beta with the phosphorylated ICAM-1-derived peptide was observed only with stimulated eosinophil lysates, suggesting that the interaction of GMR beta with ICAM-1 required phosphorylated Shp2 and/or phosphorylated GMR beta. Importantly, we found that inhibition of ICAM-1 in activated eosinophils blocked GM-CSF-induced expression of c-fos, c-myc, IL-8, and TNF-alpha. Moreover, inhibition of ICAM-1 expression with either antisense oligonucleotide or an ICAM-1-blocking Ab effectively inhibited ERK activation and eosinophil survival. We concluded that the interaction between ICAM-1 and the GM-CSF receptor was essential for GM-CSF-induced eosinophil activation and survival. Taken together, these results provide novel mechanistic insights defining the interaction between ICAM-1 and the GM-CSF receptor and highlight the importance of targeting ICAM-1 and GM-CSF/IL-5/IL-3 receptor systems as a therapeutic strategy to counter eosinophilia in asthma. C1 [Pazdrak, Konrad; Young, Travis W.; Stafford, Susan; Olszewska-Pazdrak, Barbara; Straub, Christof; Starosta, Vitaliy; Brasier, Allan; Kurosky, Alexander] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Pazdrak, Konrad; Brasier, Allan; Kurosky, Alexander] Univ Texas Med Branch, Sealy Ctr Mol Med, Galveston, TX 77555 USA. [Pazdrak, Konrad; Young, Travis W.; Stafford, Susan; Straub, Christof; Starosta, Vitaliy; Brasier, Allan; Kurosky, Alexander] Univ Texas Med Branch, NHLBI, Proteom Ctr, Galveston, TX 77555 USA. RP Kurosky, A (reprint author), Univ Texas Med Branch, Dept Biochem & Mol Biol, 301 Univ Blvd, Galveston, TX 77555 USA. EM akurosky@utmb.edu FU NCI NIH HHS [R24 CA088317, 1R24 CA88317]; NHLBI NIH HHS [HHSN268201000037C, N01 HV028184, N01 HV028184-13, N01HV-28184, N01HV28184]; NIAID NIH HHS [P01 AI062885] NR 49 TC 20 Z9 20 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2008 VL 180 IS 6 BP 4182 EP 4190 PG 9 WC Immunology SC Immunology GA 324GS UT WOS:000257506600068 PM 18322230 ER PT J AU Levin, MJ Oxman, MN Zhang, JH Johnson, GR Stanley, H Hayward, AR Caulfield, MJ Irwin, MR Smith, JG Clair, J Chan, ISF Williams, H Harbecke, R Marchese, R Straus, SE Gershon, A Weinberg, A AF Levin, M. J. Oxman, M. N. Zhang, J. H. Johnson, G. R. Stanley, H. Hayward, A. R. Caulfield, M. J. Irwin, M. R. Smith, J. G. Clair, J. Chan, I. S. F. Williams, H. Harbecke, R. Marchese, R. Straus, S. E. Gershon, A. Weinberg, A. CA Vet Affairs Cooperative Studies TI Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT 12-15, 2006 CL Toronto, CANADA SP Infect Dis Soc Amer ID OLDER-ADULTS; ANTIGENS; COMPLICATIONS; VALIDATION; FREQUENCY; DECLINE; ASSAY; RISK; AGE AB Background. A double-blind, placebo-controlled trial that involved 38,546 subjects >= 60 years old demonstrated efficacy of a high-potency live-attenuated Oka/ Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome. Methods. The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA. Results. VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects >= 70 years old. Conclusions. The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia. C1 [Levin, M. J.; Hayward, A. R.; Weinberg, A.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Oxman, M. N.; Stanley, H.; Williams, H.; Harbecke, R.] Dept Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Oxman, M. N.; Stanley, H.; Williams, H.; Harbecke, R.] Univ Calif San Diego, San Diego, CA 92103 USA. [Irwin, M. R.] Univ Calif Los Angeles, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA USA. [Zhang, J. H.] Vet Affairs Cooperat Studies, Program Coordinating Ctr, West Haven, CT USA. [Caulfield, M. J.; Smith, J. G.; Clair, J.; Chan, I. S. F.; Marchese, R.] Merck & Co Inc, Merck Res Labs, West Point, PA USA. [Straus, S. E.] NIAID, Natl Inst Hlth, Bethesda, MD 20892 USA. [Weinberg, A.] Columbia Univ, New York, NY USA. RP Levin, MJ (reprint author), C227,4200 E,9tj Ave, Denver, CO 80262 USA. EM myron.levin@uchsc.edu RI Irwin, Michael/H-4870-2013 OI Irwin, Michael/0000-0002-1502-8431 FU NCI NIH HHS [R01 CA10014152]; NCRR NIH HHS [M01 RR000865, M01-RR00865]; NHLBI NIH HHS [R01 HL079955]; NIA NIH HHS [P60 AG010415, P60 AG10415, R01 AG026006, R01 AG026006-01, R01 AG026364]; NIAID NIH HHS [U01 AI068632]; NIAMS NIH HHS [R01 AR049840]; NICHD NIH HHS [N01-HD-3-3345]; NIMH NIH HHS [R01 MH055253, R01 MH55253, T32 MH019925, T32MH19925]; NINR NIH HHS [R01 NR009228]; PHS HHS [H12HA00070] NR 38 TC 136 Z9 142 U1 2 U2 11 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 MAR 15 PY 2008 VL 197 IS 6 BP 825 EP 835 DI 10.1086/528696 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 271FI UT WOS:000253773900008 PM 18419349 ER PT J AU Zhu, Z Bossart, KN Bishop, KA Crameri, G Dimitrov, AS McEachern, JA Feng, Y Middleton, D Wang, LF Broder, CC Dimitrov, DS AF Zhu, Zhongyu Bossart, Katharine N. Bishop, Kimberly A. Crameri, Gary Dimitrov, Antony S. McEachern, Jennifer A. Feng, Yang Middleton, Deborah Wang, Lin-Fa Broder, Christopher C. Dimitrov, Dimiter S. TI Exceptionally potent cross-reactive neutralization of Nipah and Hendra viruses by a human monoclonal antibody SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RECEPTOR-BINDING; G-GLYCOPROTEIN AB We have previously identified neutralizing human monoclonal antibodies against Nipah virus (NiV) and Hendra virus (HeV) by panning a large nonimmune antibody library against a soluble form of the HeV attachment-envelope glycoprotein G (sG(HeV)). One of these antibodies, m102, which exhibited the highest level of crossreactive neutralization of both NiV and HeVG, was affinity maturated by light-chain shuffling combined with random mutagenesis of its heavy-chain variable domain and panning against sGHeV. One of the selected antibody Fab clones, m102.4, had affinity of binding to sGHeV that was equal to or higher than that of the other Fabs; it was converted to IgG1 and tested against infectious NiV and HeV. It exhibited exceptionally potent and crossreactive inhibitory activity with 50% inhibitory concentrations below 0.04 and 0.6 mu g/ mL, respectively. The virus-neutralizing activity correlated with the binding affinity of the antibody to sG(HeV) and sG(NiV). m102.4 bound a soluble form of NiV G (sG(NiV)) better than it bound sG(HeV), and it neutralized NiV better than HeV, despite being originally selected against sGHeV. These results suggest that m102.4 has potential as a therapeutic agent for the treatment of diseases caused by henipaviruses. It could be also used for prophylaxis and diagnosis, and as a research reagent. C1 [Zhu, Zhongyu; Feng, Yang; Dimitrov, Dimiter S.] NCI, CCRNP, Prot Interact Grp, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Zhu, Zhongyu] NCI, Sci Applicat Int Corp Frederick, Basic Res Program, Frederick, MD 21701 USA. [Bishop, Kimberly A.; Dimitrov, Antony S.; Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Bossart, Katharine N.; Crameri, Gary; McEachern, Jennifer A.; Middleton, Deborah; Wang, Lin-Fa] Commonwealth Sci & Ind Res Org Livestock Ind, Australian Anim Hlth Lab, Geelong, Vic, Australia. [Bossart, Katharine N.; Crameri, Gary; McEachern, Jennifer A.; Middleton, Deborah; Wang, Lin-Fa] Australian Biosecur Cooperat Res Ctr Emerging Inf, Geelong, Vic, Australia. RP Zhu, Z (reprint author), NCI, CCRNP, Prot Interact Grp, Ctr Canc Res,NIH, Bldg469,Rm 150B,POB Miller Dr, Frederick, MD 21702 USA. EM zhongyuzhu@ncifcrf.gov RI Crameri, Gary/H-8441-2013; Barr, Jennifer/H-9254-2013; OI Bossart, Katharine/0000-0001-6886-6896 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [AI054715, AI057168] NR 18 TC 57 Z9 65 U1 0 U2 4 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 MAR 15 PY 2008 VL 197 IS 6 BP 846 EP 853 DI 10.1086/528801 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 271FI UT WOS:000253773900010 PM 18271743 ER PT J AU Donohue, SR Halldin, C Schou, M Hong, J Phebus, L Chernet, E Hitchcock, SA Gardinier, KM Ruley, KM Krushinski, JH Schaus, J Pike, VW AF Donohue, Sean R. Halldin, Christer Schou, Magnus Hong, Jinsoo Phebus, Lee Chernet, Eyassu Hitchcock, Stephen A. Gardinier, Kevin M. Ruley, Kevin M. Krushinski, Joseph H. Schaus, John Pike, Victor W. TI Radiolabeling of a high potency cannabinoid subtype-1 receptor ligand, N-(4-fluoro-benzyl)-4-(3-(piperidin-1-yl)-indole-1-sulfonyl)benzamide (PipISB), with carbon-11 or fluorine-18 SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE CB(1) receptor; PET; carbon-11; fluorine-18; arylsulfonyl-substituted indole; PipISB ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; PET; ANTAGONIST; BRAIN; RADIOLIGANDS; SR141716A; MONOXIDE; BROMIDES; RODENTS AB PipISB [N-(4-fluoro-benzyl)-4-(3-(piperidin-1-yl)-indole-1-sulfonyl)benzamide, 9] was identified as a selective high potency CB, receptor ligand. Here we describe the labeling of 9 with positron-emitters to provide candidate radioligands for imaging brain CB(1) receptors with positron emission tomography (PET). The radiolabeling of 9 was achieved by two methods, method A with carbon-11 and method B with fluorine-18. In method A, [(11)C]9 was prepared in one step from [(11)C]carbon monoxide, itself prepared from cyclotron-produced [(11)C]carbon dioxide. In method B, [(18)F]9 was prepared from cyclotron-produced [(18)F]fluoride ion in a two-stage, four-step synthesis with [18F]4-fluoro-benzyl bromide as a labeling agent. The radiosynthesis time for method A was 44 min; decay-corrected radiochemical yields (RCYs) from [(11)C]carbon monoxide ranged from 3.1 to 11.6% and specific radioactivities ranged from 21 to 67 GBq/mu mol. The radiosynthesis time for method B was 115 min; RCYs from [(18)F]fluoride ion ranged from 1.5 to 5.6% and specific radioactivities ranged from 200 to 348 GBq/mu mol. With these methods, [(11)C]9 and [(18)F]9 may be prepared in adequate activity and quality for future evaluation as PET radioligands. C1 [Donohue, Sean R.; Hong, Jinsoo; Pike, Victor W.] NIMH, Natl Inst Hlth, Mol Imaging Branch, Bethesda, MD 20892 USA. [Donohue, Sean R.; Halldin, Christer; Schou, Magnus] Karolinska Hosp, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. [Phebus, Lee; Chernet, Eyassu; Hitchcock, Stephen A.; Gardinier, Kevin M.; Ruley, Kevin M.; Krushinski, Joseph H.; Schaus, John] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Donohue, SR (reprint author), NIMH, Natl Inst Hlth, Mol Imaging Branch, Bldg 10,Rm B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM donohues@intra.nimh.nih.gov NR 33 TC 17 Z9 17 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAR 15 PY 2008 VL 51 IS 3-4 BP 146 EP 152 DI 10.1002/jlcr.1491 PG 7 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 299BI UT WOS:000255730400004 ER PT J AU Kiesewetter, DO Knudson, K Collins, M Srinivasula, S Lim, E Di Mascio, M AF Kiesewetter, Dale O. Knudson, Kathleen Collins, Matt Srinivasula, Sharat Lim, Esther Di Mascio, Michele TI Enantiomeric radiochemical synthesis of R and S (1-(6-amino-9H-purin-9-yl)-3-fluoropropan-2-yloxy)methylphosphonic acid (FPMPA) SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article; Proceedings Paper CT 17th International Symposium on Radiopharmaceutical Sciences CY APR 30-MAY 04, 2007 CL Aachen, GERMANY DE fluorine-18; Tenofovir; antiretroviral drugs; HAART ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACYCLIC NUCLEOSIDE PHOSPHONATES; ANTIRETROVIRAL AGENTS; DRUG-RESISTANCE; INFECTION; DERIVATIVES; INVITRO; PHARMACOKINETICS; THERAPY; INVIVO AB Therapy for human immunodeficiency virus (HIV)-infected patients requires chronic multidrug administration. The eventual failure of therapy in some patients has brought into question the tissue concentration of the drugs. With an appropriately radiolabeled compound, we could utilize positron emission tomography to provide quantitative time-activity curves for various tissues. We have developed a fluorine-18 labeled analog of Tenofovir, the active metabolite of Tenofovir DF, a commonly prescribed component of multidrug therapy. Because (1-(6-amino-9H-purin-9-yl)-3-fluoropropan-2-yloxy)methylphosphonic acid (FPMPA) has a chiral center, we prepared both enantiomers and confirmed that the S-isomer exhibited significantly higher antiviral activity than the R-Isomer. In viral replication inhibition assays in human MT4 cells infected with SHIV(DJ12R), S-FPMPA had an IC(50) of 1.85 mu M (95% CI 0.8-5.53), while the R-isomer was inactive. An appropriate chiral precursor was prepared to allow the incorporation of fluorine-18. The [(18)F]FPMPA in racemic, R, or S form was prepared in a 50 min synthesis in 38 +/- 5% yield (n = 23, corrected for decay). The product was of high radiochemical and enantiomeric purity. The specific activity of the final product was 4.0 +/- 1.8 Ci/mu mol at EOB (end of bombardment). This product may provide information about drug tissue distribution in animal models under chronic drug treatment. C1 [Kiesewetter, Dale O.; Knudson, Kathleen] NIBIB, NIH, PRG, Positron Emiss Tomog Radiochem Grp, Bethesda, MD 20892 USA. [Collins, Matt] Bioqual, Rockville, MD USA. [Srinivasula, Sharat] NCI Frederick, SAIC Frederick, Biostat Res Branch, Ft Detrick, MD 21702 USA. [Lim, Esther] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Di Mascio, Michele] NIAID, NIH, Biostat Res Branch, Bethesda, MD 20892 USA. RP Kiesewetter, DO (reprint author), NIBIB, NIH, PRG, Positron Emiss Tomog Radiochem Grp, 10 Ctr Dr MSC 1180,10-1C401, Bethesda, MD 20892 USA. EM dk7k@nih.gov FU Intramural NIH HHS [Z01 EB000001-03]; NCI NIH HHS [N01CO12400] NR 32 TC 3 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAR 15 PY 2008 VL 51 IS 3-4 BP 187 EP 194 DI 10.1002/jlcr.1505 PG 8 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 299BI UT WOS:000255730400011 PM 19724660 ER PT J AU McBain, CJ AF McBain, Chris J. TI New directions in synaptic and network plasticity - a move away from NMDA receptor mediated plasticity SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material C1 NIH, Program Dev Neurobiol, NICHD, Porter Neurosci Ctr, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), NIH, Program Dev Neurobiol, NICHD, Porter Neurosci Ctr, Rm 3C903,35 Convent Dr, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov NR 6 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2008 VL 586 IS 6 BP 1473 EP 1474 DI 10.1113/jphysiol.2008.151183 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 278IA UT WOS:000254277300006 PM 18344227 ER PT J AU Pelkey, KA McBain, CJ AF Pelkey, Kenneth A. McBain, Chris J. TI Target-cell-dependent plasticity within the mossy fibre-CA3 circuit reveals compartmentalized regulation of presynaptic function at divergent release sites SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article; Proceedings Paper CT Symposium on Synaptic Plasticity CY NOV 02, 2007 CL San Diego, CA ID LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; INTERNEURON SYNAPSES; METABOTROPIC GLUTAMATE-RECEPTOR-7; ENDOCANNABINOID RELEASE; FEEDFORWARD INHIBITION; RECEPTOR SUBTYPES; CALCIUM-CHANNELS; RAT HIPPOCAMPUS; IN-VIVO AB Individual axons of central neurons innervate a large number of distinct postsynaptic targets belonging to divergent functional categories such as glutamatergic principal cells and inhibitory interneurons. While each bouton along a common axon should experience the same activity pattern in response to action potential firing within the parent presynaptic neuron, accumulating evidence suggests that neighbouring boutons contacting functionally distinct postsynaptic targets regulate their release properties independently, despite being separated by only a few microns. This target-cell-specific autonomy of presynaptic function can greatly expand the computational prowess of central axons to allow for precise coordination of large neuronal ensembles within a given circuit. An excellent example of target-cell-specific presynaptic mechanisms occurs in the CA3 hippocampus where mossy fibre (MF) axons of dentate gyrus granule cells target both principal cells and local circuit inhibitory interneurons via both anatomically and functionally specialized terminals. Of particular interest, mechanisms of both short- and long-term plasticity remain autonomous at these divergent release sites due to an anatomical and biochemical segregation of discrete molecular signalling cascades. Here we review roughly a decades worth of research on the MF-CA3 pathway to showcase the target-cell dependence of presynaptically expressed NMDA receptor-independent synaptic plasticity. C1 [Pelkey, Kenneth A.; McBain, Chris J.] NIH, Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. RP Pelkey, KA (reprint author), NICHD LCSN, Lab Cellular & Synapt Neurophysiol, Bldg 35,Rm 3C705, Bethesda, MD 20892 USA. EM pelkeyk2@mail.nih.gov FU Intramural NIH HHS NR 66 TC 34 Z9 34 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2008 VL 586 IS 6 BP 1495 EP 1502 DI 10.1113/jphysiol.2007.148635 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 278IA UT WOS:000254277300010 PM 18079156 ER PT J AU Hwang, ST Janik, JE Jaffe, ES Wilson, WH AF Hwang, Sam T. Janik, John E. Jaffe, Elaine S. Wilson, Wyndham H. TI Mycosis fungoides and Sezary syndrome SO LANCET LA English DT Review ID CUTANEOUS-T-CELL; ELEVATED SERUM CTACK/CCL27; SKIN-ASSOCIATED CHEMOKINE; POLYMERASE-CHAIN-REACTION; TREATMENT-OF-CANCER; LONG-TERM SURVIVAL; PHASE-II TRIAL; DENDRITIC CELLS; IMMUNE-RESPONSES; HTLV-I AB Mycosis fungoides and Sezary syndrome are the most common of the cutaneous T-cell lymphomas, which are a heterogeneous group of neoplasms that affect the skin as a primary site. Although the aetiologies of mycosis fungoides and Sezary syndrome are unknown, important insights have been gained in the immunological and genetic perturbations that are associated with these diseases. Unlike some B-cell lymphomas, cutaneous T-cell lymphomas as a group are rarely if ever curable and hence need chronic-disease management. New approaches to treatments are being investigated and include biological and cytotoxic drugs, phototherapy, and monoclonal antibodies that are directed towards novel molecular targets. New molecular technologies such as complementary-DNA microarray have the potential to increase the accuracy of diagnosis and provide important prognostic information. Treatments can be combined to greatly improve clinical outcome without substantially increasing toxic effects in advanced disease that is otherwise difficult to treat. Although present treatment strategies are generally not curative, there is hope that experimental treatments, particularly immunotherapy, might eventually reverse or suppress the abnormalities of mycosis fungoides and Sezary syndrome to the point at which they become non-life-threatening, chronic diseases. C1 [Hwang, Sam T.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Janik, John E.; Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hwang, ST (reprint author), Bldg 10,Room 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangs@mail.nih.gov NR 159 TC 107 Z9 114 U1 0 U2 4 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 MAR 15 PY 2008 VL 371 IS 9616 BP 945 EP 957 DI 10.1016/S0140-6736(08)60420-1 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 275FH UT WOS:000254056800031 PM 18342689 ER PT J AU Clarimon, J Pagonabarraga, J Paisan-Ruiz, C Campolongo, A Pascual-Sedano, B Marti-Masso, JF Singleton, AB Kulisevsky, J AF Clarimon, Jordi Pagonabarraga, Javier Paisan-Ruiz, Coro Campolongo, Antonia Pascual-Sedano, Berta Marti-Masso, Jose-Felix Singleton, Andrew B. Kulisevsky, Jaime TI Tremor dominant parkinsonism: Clinical description and LRRK2 mutation screening SO MOVEMENT DISORDERS LA English DT Article DE tremor dominant parkinsonism; Parkinson; tremor; LRRK2 ID OLFACTORY DYSFUNCTION; DISEASE; FAMILIES; DISORDER; G2019S; PREVALENCE; FREQUENCY; RELATIVES; COHORT; STAGE AB Tremor dominant parkinsonism (TDP) is characterized by initial prominent resting and action tremor, mild parkinsonism, unpredictable response to medication, and a better prognosis than idiopathic Parkinson's disease (PD). We report on clinical features and longitudinal course of 26 patients suffering! from TDP. Mean disease duration was 6.5 +/- 3 years, 61.5% of patients had a positive family history of tremor, 73% did not need drug treatment, performance of 123I-Ioflupane SPECT showed reduced striatal tracer uptake in 65.4% of patients, and odor identification testing was pathologic in all the patients tested (n = 22). Co-occurrence of action and testing tremor were the most annoying and disabling symptoms in all the patients, whereas rigidity and/or bradykinesia were clinically irrelevant in most of them. We also sequenced the full coding region of the Leucine-rich repeat kinase 2 gene (LRRK2) in all patients. We found a novel Val2390Met mutation that was not found in 864 chromosomes. Our results suggest a broader clinical heterogeneity related to LRRK2 mutations and points towards TDP as a subtype within the spectrum of PD, in which disabling tremor but otherwise mild parkinsonian signs and a better prognosis are the main characteristics. (C) 2007 Movement Disorder Society. C1 [Clarimon, Jordi; Pagonabarraga, Javier; Campolongo, Antonia; Pascual-Sedano, Berta; Kulisevsky, Jaime] St Pau Hosp, Ctr Invest Biomed Red, Movement Disorders Unit, Dept Neurol, Barcelona 16708025, Spain. [Clarimon, Jordi] Alzheimers Lab, Memory Unit, Barcelona 16708025, Spain. [Paisan-Ruiz, Coro; Singleton, Andrew B.] NIA, NIH, Mol Genet Unit, Bethesda, MD USA. [Marti-Masso, Jose-Felix] Hosp Donostia, Serv Neurol, San Sebastian, Spain. RP Kulisevsky, J (reprint author), St Pau Hosp, Ctr Invest Biomed Red, Movement Disorders Unit, Dept Neurol, St Antoni M Claret, Barcelona 16708025, Spain. EM jkulisevsky@santpau.es RI Paisan-Ruiz, Coro/C-2912-2009; Singleton, Andrew/C-3010-2009; Marti Masso, Jose Felix/D-8619-2013; OI Marti Masso, Jose Felix/0000-0001-8428-4386; Pascual Sedano, Berta Maria/0000-0002-9298-8241; Clarimon, Jordi/0000-0002-6824-6942; Campolongo, Antonia/0000-0002-7962-3264 NR 40 TC 26 Z9 26 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 MAR 15 PY 2008 VL 23 IS 4 BP 518 EP 523 DI 10.1002/mds.21771 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 285WX UT WOS:000254808000007 PM 18098275 ER PT J AU Tamura, Y Matsuhashi, M Lin, P Ou, B Vorbach, S Kakigi, R Hallett, M AF Tamura, Yohei Matsuhashi, Masao Lin, Peter Ou, Bai Vorbach, Sherry Kakigi, Ryusuke Hallett, Mark TI Impaired intracortical inhibition in the primary somatosensory cortex in focal hand dystonia SO MOVEMENT DISORDERS LA English DT Article DE somesthetic temporal discrimination; focal hand dystonia; somatosensory-evoked potential; surround inhibition ID SHORT-LATENCY COMPONENTS; TEMPORAL DISCRIMINATION; EVOKED-POTENTIALS; RECOVERY FUNCTION; MEDIAN NERVE; GENERALIZED DYSTONIA; THALAMIC AFFERENTS; CEREBRAL-CORTEX; STIMULI; RESPONSES AB Somesthetic temporal discrimination (STD) is impaired in focal hand dystonia (FHD). We explored the electro-physiological correlate of the STD deficit to assess whether this is due to dysfunction of temporal inhibition in the somatosensory inhibitory pathway or due to dysfunction in structures responsible for nonmodality-specific timing integration. Eleven FHD patients and 11 healthy volunteers were studied. STD threshold was investigated as the time interval required for perceiving a pair of stimuli as two separate stimuli in time. We also examined the somatosensory-evoked potential (SEP) in a paired-pulse paradigm. We compared STD threshold and recovery function of SEP between the groups. STD thresholds were significantly greater in FHD than in healthy volunteers. The amount of P27 suppression in the 5 ms-ISI condition was significantly less in FHD. It was also found that the STD threshold and P27 suppression were significantly correlated: the greater the STD threshold, the less the P27 suppression. Significantly less suppression of P27 with a lack of significant change in N20 indicates that the impairment of somatosensory information processing in the time domain is due to dysfunction within the primary somatosensory cortex, suggesting that that the STD deficit in FHD is more attributable to dysfunction in the somatosensory pathway. (C) 2007 Movement Disorder Society. C1 [Tamura, Yohei; Matsuhashi, Masao; Lin, Peter; Ou, Bai; Vorbach, Sherry; Hallett, Mark] NINDS, NIH, Human Mortor Control Sect, Med Neurol Branch, Bethesda, MD 20892 USA. [Tamura, Yohei; Kakigi, Ryusuke] Natl Inst Physiol Sci, Dept Integrat Physiol, Okazaki, Aichi, Japan. [Tamura, Yohei] Jikei Univ, Sch Med, Dept Neurol, Tokyo, Japan. RP Hallett, M (reprint author), NINDS, NIH, Human Mortor Control Sect, Med Neurol Branch, Bldg 10,Rm 5N226, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU Intramural NIH HHS NR 31 TC 42 Z9 42 U1 1 U2 3 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 MAR 15 PY 2008 VL 23 IS 4 BP 558 EP 565 DI 10.1002/mds.21870 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 285WX UT WOS:000254808000013 PM 18074393 ER PT J AU Gao, X Chen, H Schwarzschild, MA Logroscino, G Ascherio, A AF Gao, Xiang Chen, Honglei Schwarzschild, Michael A. Logroscino, Giancarlo Ascherio, Alberto TI Perceived imbalance and risk of Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE perceived imbalance; Parkinson's disease; prospective study ID PHYSICAL-ACTIVITY QUESTIONNAIRE; MALE HEALTH-PROFESSIONALS; REPRODUCIBILITY; VALIDITY; FREQUENCY AB We prospectively examined associations between perceived imbalance and Parkinson's disease (PD) risk in the Health Professional Follow-up Study (HPFS), and Nurses' Health Study (NHS). We included 39,087 men and 82,299 women free of PD at baseline (1990) in the current analyses. We documented 449 incident PD cases during 12 years followup. Subjects who reported difficulty with balance before 1990 (baseline) were 1.8 more times likely to develop PD, relative to those who reported no balance difficulty (pooled multivariate RR = 1.8; 95% CI: 1.3, 2.5; P < 0.0001). When we further examined associations between perceived imbalance at baseline and PD onset during different time periods, we found a significant elevation of PD risk only during the first 4 years of follow-up. This result suggests that the imbalance may in some cases be an early sign of PD, and may represent the onset of motor symptoms although they have not been clinically recognized. (C) 2008 Movement Disorder Society. C1 [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, 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. [Logroscino, Giancarlo; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. RP Gao, X (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM xgao@hsph.harvard.edu RI LOGROSCINO, GIANCARLO/K-5148-2016; OI LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Chen, Honglei/0000-0003-3446-7779 FU Intramural NIH HHS [Z01 ES101986-02]; NINDS NIH HHS [R01 NS048517-01A2, R01 NS048517] NR 14 TC 11 Z9 11 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 MAR 15 PY 2008 VL 23 IS 4 BP 613 EP 616 DI 10.1002/mds.21919 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 285WX UT WOS:000254808000024 PM 18181208 ER PT J AU Proschan, M Follmann, D AF Proschan, Michael Follmann, Dean TI Cluster without fluster: The effect of correlated outcomes on inference in randomized clinical trials SO STATISTICS IN MEDICINE LA English DT Article DE clinical trials; clusters; conditional inference; correlated outcomes; permutation; randomization ID DESIGN AB Inference for randomized clinical trials is generally based on the assumption that outcomes are independently and identically distributed under the null hypothesis. In some trials, particularly in infectious disease, outcomes may be correlated. This may be known in advance (e.g. allowing randomization of family members) or completely unplanned (e.g. sexual sharing among randomized participants). There is particular concern when the form of the correlation is essentially unknowable, in which case we cannot take advantage of the correlation to construct a more efficient test. Instead, we can only investigate the impact of potential correlation on the independent-samples test statistic. Randomization tends to balance out treatment and control assignments within clusters, so it is logical that performance of tests averaged over all possible randomization assignments would be essentially unaffected by arbitrary correlation. We confirm this intuition by showing that a permutation test controls the type 1 error rate in a certain average sense whenever the clustering is independent of treatment assignment. It is nonetheless possible to obtain a 'bad' randomization such that members of a cluster tend to be assigned to the same treatment. Conditioned on such a bad randomization, the type I error rate is increased. Published in 2007 by John Wiley & Sons, Ltd. C1 [Proschan, Michael; Follmann, Dean] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Proschan, M (reprint author), NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM proscham@mail.nih.gov NR 10 TC 6 Z9 6 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAR 15 PY 2008 VL 27 IS 6 BP 795 EP 809 DI 10.1002/sim.2977 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 271IR UT WOS:000253782600002 PM 17594680 ER PT J AU Wyatt, LS Belyakov, IM Earl, PL Berzofsky, JA Moss, B AF Wyatt, Linda S. Belyakov, Igor M. Earl, Patricia L. Berzofsky, Jay A. Moss, Bernard TI Enhanced cell surface expression, immunogenicity and genetic stability resulting from a spontaneous truncation of HIV Env expressed by a recombinant MVA SO VIROLOGY LA English DT Article DE truncated HIV Env; recombinant modified vaccinia virus Ankara; mucosal immunity ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; CYTOTOXIC T-LYMPHOCYTES; VACCINIA VIRUS; ENVELOPE GLYCOPROTEIN; CYTOPLASMIC DOMAIN; PROTECTIVE IMMUNITY; RHESUS-MONKEYS; HOST-RANGE; GAG-POL AB During propagation of modified vaccinia virus Ankara (MVA) encoding HIV 89.6 Env, a few viral foci stained very prominently. Virus cloned from such foci replicated to higher titers than the parent and displayed enhanced genetic stability on passage. Sequence analysis showed a single nucleotide deletion in the 89.6 env gene of the mutant that caused a frame shift and truncation of 115 amino acids from the cytoplasmic domain. The truncated Env was more highly expressed on the cell surface, induced higher antibody responses than the full-length Env, reacted with HIV neutralizing monoclonal antibodies and mediated CD4/co-receptor-dependent fusion. Intramuscular (IM), intradermal (ID) needleless, and intrarectal (IR) catheter inoculations gave comparable serum IgG responses. However, intraoral (10) needleless injector route gave the highest IgA in lung washings and IR gave the highest IgA and IgG responses in fecal extracts. Induction of CTL responses in the spleens of individual mice as assayed by intracellular cytokine staining was similar with both the full-length and truncated Env constructs. Induction of acute and memory CTL in the spleens of mice immunized with the truncated Env construct by ID, IO, and IR routes was comparable and higher than by the IM route, but only the IR route induced CTL in the gut-associated lymphoid tissue. Thus, truncation of Env enhanced genetic stability as well as serum and mucosal antibody responses, suggesting the desirability of a similar modification in MVA-based candidate HIV vaccines. Published by Elsevier Inc. C1 [Wyatt, Linda S.; Earl, Patricia L.; Moss, Bernard] NIAID, NIH, Viral Dis Lab, MSC 310, Bethesda, MD 20892 USA. [Belyakov, Igor M.; Berzofsky, Jay A.] NCI, NIH, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wyatt, LS (reprint author), NIAID, NIH, Viral Dis Lab, MSC 310, 33 North Dr, Bethesda, MD 20892 USA. EM lwyatt@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000416-24] NR 65 TC 27 Z9 28 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 MAR 15 PY 2008 VL 372 IS 2 BP 260 EP 272 DI 10.1016/j.virol.2007.10.033 PG 13 WC Virology SC Virology GA 271JI UT WOS:000253784300004 PM 18048074 ER PT J AU Zheng, YF Ourmanov, N Hirsch, VM AF Zheng, Yanfang Ourmanov, Nour Hirsch, Vanessa M. TI Persistent transcription of a nonintegrating mutant of simian immunodeficiency virus in rhesus macrophages SO VIROLOGY LA English DT Article DE simian immunodeficiency virus; nonintegrating mutant; transcription; macrophage ID ACTIVE ANTIRETROVIRAL THERAPY; RAPID PROGRESSOR MACAQUES; CIRCULAR VIRAL-DNA; TYPE-1 INTEGRASE; NUCLEAR IMPORT; INFECTION; HIV; EXPRESSION; RESERVOIRS; MUTATIONS AB A nonintegrating mutant, SIVsmD116N, was derived from the infectious pathogenic SIVsmE543 -3 clone by introducing an Asp (D) to Asn (N) mutation into the catalytic domain of integrase. Although SIVsmD116N generated all viral proteins following transfection, cell-free virus did not productively infect CEMx174 cells, macaque peripheral blood mononuclear cells (PBMCs) or monocyte-derived macrophages (MDM). Viral DNA and transcripts were observed transiently in SIVsmD116N-infected CEMx174 cells and macaque PBMC but persisted in MDM for as long as 20 days. Circular forms of viral DNA were detected but there was no evidence of integration detected by Alu PCR. We found that SIV D116N mutant remained transcriptionally active and expressed low levels of viral proteins persistently in MDM. These data are consistent with a role for macrophages as a persistent latent reservoir for AIDS viruses. The capacity of nonintegrating SIV to persistently generate viral products in macrophages suggests that nonintegrating lentiviral vectors could be engineered to efficiently and safely express proteins for vaccine purposes. (c) 2007 Elsevier Inc. All rights reserved. C1 [Zheng, Yanfang; Ourmanov, Nour; Hirsch, Vanessa M.] NIAID, NIH, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Hirsch, VM (reprint author), 4 Ctr Dr,Rm B1-41, Bethesda, MD 20892 USA. EM vhirsch@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000686-15] NR 29 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 MAR 15 PY 2008 VL 372 IS 2 BP 291 EP 299 DI 10.1016/j.virol.2007.11.002 PG 9 WC Virology SC Virology GA 271JI UT WOS:000253784300006 PM 18054062 ER PT J AU Kelly, J Beddall, MH Yu, DY Iyer, SR Marsh, JW Wu, YT AF Kelly, Jeremy Beddall, Margaret H. Yu, Dongyang Iyer, Subashini R. Marsh, Jon W. Wu, Yuntao TI Human macrophages support persistent transcription from unintegrated HIV-1 DNA SO VIROLOGY LA English DT Article DE HIV-1; transcription; unintegrated HIV DNA; 1-LTR circle; 2-LTR circle; macrophage; nef; chemokine ID IMMUNODEFICIENCY-VIRUS TYPE-1; MONOCYTE-DERIVED MACROPHAGES; CENTRAL-NERVOUS-SYSTEM; MURINE LEUKEMIA-VIRUS; CD4(+) T-CELLS; NECROSIS-FACTOR-ALPHA; GENE-EXPRESSION; VIRAL-DNA; IN-VITRO; RESIDENT MICROGLIA AB Retroviruses require integration of their RNA genomes for both stability and productive viral replication. In HIV infection of non-dividing, resting CD4 T cells, where integration is greatly impeded, the reverse transcribed HIV DNA has limited biological activity and a short half-life. In metabolically active and proliferating T cells, unintegrated DNA rapidly diminishes with cell division. HIV also infects the non-dividing but metabolically active macrophage population. In an in vitro examination of HIV infection of macrophages, we find that unintegrated viral DNA not only has an unusual stability, but also maintains biological activity. The unintegrated linear DNA, 1-LTR, and 2-LTR circles are stable for at least 30 days. Additionally, there is persistent viral gene transcription, which is selective and skewed towards viral early genes such as nef and tat with highly diminished rev and vif. One viral early gene product Nef was measurably synthesized. We also find that independent of integration, the HIV infection process in macrophages leads to generation of numerous chemokines. (c) 2007 Elsevier Inc. All rights reserved. C1 [Kelly, Jeremy; Yu, Dongyang; Iyer, Subashini R.; Wu, Yuntao] George Mason Univ, Dept Mol & Microbiol, Manassas, VA USA. [Beddall, Margaret H.; Marsh, Jon W.; Wu, Yuntao] NIMH, Sect Mol Virol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Wu, YT (reprint author), George Mason Univ, Dept Mol & Microbiol, 1000 Univ Blvd,MS 4E3, Manassas, VA USA. EM ywu8@gmu.edu FU Intramural NIH HHS; NIAID NIH HHS [AI069981, R21 AI069981, R21 AI069981-01A2]; NINDS NIH HHS [NS051130, R21 NS051130, R21 NS051130-01A1, R21 NS051130-02] NR 86 TC 73 Z9 75 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2008 VL 372 IS 2 BP 300 EP 312 DI 10.1016/j.virol.2007.11.007 PG 13 WC Virology SC Virology GA 271JI UT WOS:000253784300007 PM 18054979 ER PT J AU Bossart, KN Tachedjian, M McEachern, JA Crameri, G Zhu, ZY Dimitrov, DS Broder, CC Wang, LF AF Bossart, Katharine N. Tachedjian, Mary McEachern, Jennifer A. Crameri, Gary Zhu, Zhongyu Dimitrov, Dimiter S. Broder, Christopher C. Wang, Lin-Fa TI Functional studies of host-specific ephrin-B ligands as Henipavirus receptors SO VIROLOGY LA English DT Article DE Henipavirus; ephrin-B2; ephrin-B3; multi-species tropism; ephrin receptors; therapeutics ID NIPAH-VIRUS-INFECTION; HENDRA-VIRUS; G-GLYCOPROTEIN; PTEROPID BATS; NEUTRALIZATION; ANTIBODIES; OUTBREAK; MALAYSIA; BINDING; PROTEIN AB Hendra virus (HeV) and Nipah virus (NiV) are closely related paramyxoviruses that infect and cause disease in a wide range of mammalian hosts. To determine whether host receptor molecules play a role in species-specific and/or virus-specific infection we have cloned and characterized ephrin-B2 and ephrin-B3 ligands from a range of species, including human, horse, pig, cat, dog, bats (Pteropus alecto and Pteropus vampyrus) and mouse. HeV and NiV were both able to infect cells expressing any of the ephrin-B2 and ephrin-B3 molecules. There did not appear to be significant differences in receptor function from different species or receptor usage by HeV and NiV Soluble ephrin ligands, their receptors and G-specific human monoclonal antibodies differentially blocked henipavirus infections suggesting different receptor affinities, overlapping receptor binding domains of the henipavirus attachment glycoprotein (G) and that the functional domains of the ephrin ligands may be important for henipavirus binding. (c) 2007 Elsevier Inc. All rights reserved. C1 [Bossart, Katharine N.; Tachedjian, Mary; McEachern, Jennifer A.; Wang, Lin-Fa] CSIRO, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. [Zhu, Zhongyu] NCI, SAIC Frederick Inc, BRP, Frederick, MD 21702 USA. [Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, CCR, CCRNP, Prot Interact Grp, Frederick, MD 21702 USA. [Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Bossart, KN (reprint author), CSIRO, Australian Anim Hlth Lab, 5 Portarlington Rd, Geelong, Vic 3220, Australia. EM Katharine.Bossart@csiro.au; Mary.Tachedjian@csiro.au; Jennifer.McEachem@csiro.au; Gary.Crameri@csiro.au; zhongyuzhu@ncifcrf.gov; dimitrov@ncifcrf.gov; cbroder@usuhs.mil; Linfa.Wang@csiro.au RI Crameri, Gary/H-8441-2013; Barr, Jennifer/H-9254-2013; OI Bossart, Katharine/0000-0001-6886-6896 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [AI057168] NR 32 TC 41 Z9 44 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 MAR 15 PY 2008 VL 372 IS 2 BP 357 EP 371 DI 10.1016/j.virol.2007.11.011 PG 15 WC Virology SC Virology GA 271JI UT WOS:000253784300012 PM 18054977 ER PT J AU Minang, JT Barsov, EV Yuan, F Trivett, MT Piatak, M Lifson, JD Ott, DE Ohlen, C AF Minang, Jacob T. Barsov, Eugene V. Yuan, Fang Trivett, Matthew T. Piatak, Michael, Jr. Lifson, Jeffirey D. Ott, David E. Ohlen, Claes TI Efficient inhibition of SIV replication in rhesus CD4(+) T-cell clones by autologous immortalized SIV-specific CD8(+) T-cell clones SO VIROLOGY LA English DT Article DE AIDS; human telomerase reverse transcriptase; immortalized CD8(+) T-cell clones; SIV ID SIMIAN IMMUNODEFICIENCY VIRUS; TELOMERASE REVERSE-TRANSCRIPTASE; TOXIC LYMPHOCYTES-T; IN-VIVO PERSISTENCE; VIRAL LOAD; NONCYTOLYTIC MECHANISMS; EXPRESSION KINETICS; ANTIVIRAL ACTIVITY; LIFE-SPAN; INFECTION AB CD8(+) cytotoxic T lymphocyte (CTL) responses play an important role in controlling the replication of primate lentiviruses. Induction of these responses is a key objective for most current AIDS vaccine approaches. Despite a variety of approaches for measuring properties and activities of CTL, the functions responsible for controlling viral replication in vivo have not been clearly identified. Assays measuring CTL-mediated suppression of viral replication in vitro are beginning to be used as possible correlates of in vivo virus suppressive activity, but the utility and interpretive value of these assays are typically limited by properties of the cells that have been used. We investigated the capacity of SIV-specific CTL clones (effectors), immortalized by transduction with human telomerase reverse transcriptase (hTERT), to suppress SIV replication in autologous hTERT immortalized CD4(+) T-cell clones (targets). Immortalized and non- immortalized SIV-specific effector cells showed IFN-gamma production and degranulation in response to viral antigen specific stimulation and significantly inhibited SIV(mac)239 replication (2 to 4 log decrease in viral RNA or cell-associated proviral DNA) (p<0.0005). Our in vitro assays of inhibition of viral replication, using T-cell clones as effectors and targets, provide a well-defined approach for evaluating possible mechanisms of CTL-mediated control of viral production which may involve direct killing of infected target cells and/or release of proinflammatory cytokines such as IFN-gamma and TNF-alpha. The use of hTERT immortalized effector and target cells for such assays preserves relevant functional properties while providing a convenient, reproducible means of conducting studies over time. Published by Elsevier Inc. C1 [Minang, Jacob T.; Barsov, Eugene V.; Yuan, Fang; Trivett, Matthew T.; Piatak, Michael, Jr.; Lifson, Jeffirey D.; Ott, David E.; Ohlen, Claes] NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Ohlen, C (reprint author), NCI, SAIC Frederick Inc, AIDS Vaccine Program, POB B, Frederick, MD 21702 USA. EM cohlen@ncifcrf.gov FU NCI NIH HHS [N01 CO012400, N01-CO-012400] NR 49 TC 13 Z9 13 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 MAR 15 PY 2008 VL 372 IS 2 BP 430 EP 441 DI 10.1016/j.virol.2007.11.013 PG 12 WC Virology SC Virology GA 271JI UT WOS:000253784300018 PM 18068748 ER PT J AU Ungvari, Z Parrado-Fernandez, C Csiszar, A de Cabo, R AF Ungvari, Zoltan Parrado-Fernandez, Cristina Csiszar, Anna de Cabo, Rafael TI Mechanisms underlying caloric restriction and lifespan regulation - implications for vascular aging SO CIRCULATION RESEARCH LA English DT Review DE aging; antioxidants; caloric restriction; nuclear receptors; redox ID GROWTH-FACTOR-I; MEMBRANE ELECTRON-TRANSPORT; RANDOMIZED CONTROLLED-TRIAL; ARTERIAL ENDOTHELIAL-CELLS; NICOTINAMIDE ADENINE-DINUCLEOTIDE; SKELETAL-MUSCLE MITOCHONDRIA; LIVER PLASMA-MEMBRANE; OXIDATIVE DNA-DAMAGE; LOWERS BLOOD-GLUCOSE; DISEASE RISK-FACTORS AB This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species and inhibition of inflammatory pathways play a central role in the antiaging cardiovascular effects of caloric restriction. Particular emphasis is placed on the potential role of the plasma membrane redox system in caloric restriction-induced pathways responsible for sensing oxidative stress and increasing cellular oxidative stress resistance. We propose that caloric restriction increases bioavailability of NO, decreases vascular reactive oxygen species generation, activates the Nrf2/antioxidant response element pathway, inducing reactive oxygen species detoxification systems, exerts antiinflammatory effects, and, thereby, suppresses initiation/progression of vascular disease that accompany aging. C1 [Parrado-Fernandez, Cristina; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Ungvari, Zoltan; Csiszar, Anna] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Parrado-Fernandez, Cristina] Univ Cordoba, Lab Biol Celular, E-14071 Cordoba, Spain. RP de Cabo, R (reprint author), NIA, Lab Expt Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS [Z01 AG000368-03]; NHLBI NIH HHS [HL077256, HL43023, P01 HL043023, R01 HL077256] NR 168 TC 105 Z9 107 U1 4 U2 9 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 MAR 14 PY 2008 VL 102 IS 5 BP 519 EP 528 DI 10.1161/CIRCRESAHA.107.168369 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 274GJ UT WOS:000253989500005 PM 18340017 ER PT J AU Taylor, K Clarke, DJ McCullough, B Chin, W Seo, E Yang, D Oppenheim, J Uhrin, D Govan, JRW Campopiano, DJ MacMillan, D Barran, P Dorin, JR AF Taylor, Karen Clarke, David J. McCullough, Bryan Chin, Wutharath Seo, Emily Yang, De Oppenheim, Joost Uhrin, Dusan Govan, John R. W. Campopiano, Dominic J. MacMillan, Derek Barran, Perdita Dorin, Julia R. TI Analysis and separation of residues important for the chemoattractant and antimicrobial activities of beta-defensin 3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN BETA-DEFENSINS; IMMATURE DENDRITIC CELLS; INDUCIBLE PEPTIDE; HOST-DEFENSE; CHEMOKINE; CCR6; IDENTIFICATION; RECEPTOR; INNATE; IMMUNITY AB beta-Defensins are important in mammalian immunity displaying both antimicrobial and chemoattractant activities. Three canonical disulfide intramolecular bonds are believed to be dispensable for antimicrobial activity but essential for chemoattractant ability. However, here we show that HBD3 ( human beta-defensin 3) alkylated with iodoactemide and devoid of any disulfide bonds is still a potent chemoattractant. Furthermore, when the canonical six cysteine residues are replaced with alanine, the peptide is no longer active as a chemoattractant. These findings are replicated by the murine ortholog Defb14. We restore the chemoattractant activity of Defb14 and HBD3 by introduction of a single cysteine in the fifth position (Cys(V)) of the beta-defensin six cysteine motif. In contrast, a peptide with a single cysteine at the first position (Cys(I)) is inactive. Moreover, a range of overlapping linear fragments of Defb14 do not act as chemoattractants, suggesting that the chemotactic activity of this peptide is not dependent solely on an epitope surrounding Cys(V). Full-length peptides either with alkylated cysteine residues or with cysteine residues replaced with alanine are still strongly antimicrobial. Defb14 peptide fragments were also tested for antimicrobial activity, and peptides derived from the N-terminal region display potent antimicrobial activity. Thus, the chemoattractant and antimicrobial activities of beta-defensins can be separated, and both of these functions are independent of intramolecular disulfide bonds. These findings are important for further understanding of the mechanism of action of defensins and for therapeutic design. C1 [Taylor, Karen; Dorin, Julia R.] Western Gen Hosp, MRC, Human Res Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Clarke, David J.; McCullough, Bryan; Chin, Wutharath; Seo, Emily; Uhrin, Dusan; Campopiano, Dominic J.; Barran, Perdita] Univ Edinburgh, Sch Chem, Edinburgh EH9 3JJ, Midlothian, Scotland. [Yang, De; Oppenheim, Joost] NCI Frederick, NIH, Sci Applicat & Int Cooperat Inc, Ctr Canc Res,Lab Mol Immunoregulat, Frederick, MD 21702 USA. [Govan, John R. W.] Univ Edinburgh, Cyst Fibrosis Lab, Edinburgh EH16 4SB, Midlothian, Scotland. [MacMillan, Derek] UCL, Christopher Ingold Labs, Dept Chem, London WC1H 0AJ, England. RP Dorin, JR (reprint author), Western Gen Hosp, MRC, Human Res Unit, Edinburgh EH4 2XU, Midlothian, Scotland. EM julia.dorin@hgu.mrc.ac.uk FU Medical Research Council [MC_U127527201] NR 41 TC 61 Z9 64 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 MAR 14 PY 2008 VL 283 IS 11 BP 6631 EP 6639 DI 10.1074/jbc.M709238200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 271HN UT WOS:000253779600004 PM 18180295 ER PT J AU Hu, P Kinyamu, HK Wang, LL Martin, J Archer, TK Teng, C AF Hu, Peng Kinyamu, H. Karimi Wang, Liangli Martin, Jessica Archer, Trevor K. Teng, Christina TI Estrogen induces estrogen-related receptor alpha gene expression and chromatin structural changes in estrogen receptor (ER)-positive and ER-negative breast cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; PROTEIN-COUPLED RECEPTOR; INDEPENDENT TRANSCRIPTIONAL ACTIVATION; HORMONE RESPONSE ELEMENT; HUMAN LACTOFERRIN GENE; GROWTH-FACTOR RECEPTOR; LIGAND-BINDING DOMAIN; NUCLEAR RECEPTORS; ORPHAN RECEPTOR; COACTIVATOR-1-ALPHA PGC-1-ALPHA AB Estrogen-related receptor alpha(ERR alpha), a member of the nuclear receptor superfamily, is closely related to the estrogen receptors (ER alpha and ER beta). The ERR alpha gene is estrogen-responsive in several mouse tissues and cell lines, and a multiple hormone-response element (MHRE) in the promoter is an important regulatory region for estrogen- induced ERR alpha gene expression. ERR alpha was recently shown to be a negative prognostic factor for breast cancer survival, with its expression being highest in cancer cells lacking functional ER alpha. The contribution of ERR alpha in breast cancer progression remains unknown but may have important clinical implications. In this study, we investigated ERR alpha gene expression and chromatin structural changes under the influence of 17 beta- estradiol in both ER-positive MCF-7 and ER-negative SKBR3 breast cancer cells. We mapped the nucleosome positions of the ERR alpha promoter around the MHRE region and found that the MHRE resides within a single nucleosome. Local chromatin structure of the MHRE exhibited increased restriction enzyme hypersensitivity and enhanced histone H3 and H4 acetylation upon estrogen treatment. Interestingly, estrogen- induced chromatin structural changes could be repressed by estrogen antagonist ICI 182 780 in MCF-7 cells yet were enhanced in SKBR3 cells. We demonstrated, using chromatin immunoprecipitation assays, that 17 beta- estradiol induces ERR alpha gene expression in MCF-7 cells through active recruitment of co-activators and release of co-repressors when ERR alpha and AP1 bind and ER alpha is tethered to the MHRE. We also found that this estrogen effect requires the MAPK signaling pathway in both cell lines. C1 [Hu, Peng; Wang, Liangli; Martin, Jessica; Teng, Christina] NIEHS, NIH, Reprod & Dev Toxicol Lab, Gene Regulat Sect, Res Triangle Pk, NC 27709 USA. [Hu, Peng; Wang, Liangli; Martin, Jessica; Teng, Christina] NIEHS, NIH, Chromatin & Gene Express Sect, Res Triangle Pk, NC 27709 USA. [Kinyamu, H. Karimi; Archer, Trevor K.] NIEHS, NIH, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Teng, C (reprint author), NIEHS, NIH, Reprod & Dev Toxicol Lab, Gene Regulat Sect, 111 Alexander Dr,POB 12233,MD E2-01, Res Triangle Pk, NC 27709 USA. EM teng1@niehs.nih.gov FU Intramural NIH HHS NR 83 TC 13 Z9 15 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 MAR 14 PY 2008 VL 283 IS 11 BP 6752 EP 6763 DI 10.1074/jbc.M705937200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 271HN UT WOS:000253779600017 PM 18174157 ER PT J AU Bortner, CD Sifre, MI Cidlowski, JA AF Bortner, Carl D. Sifre, Maria I. Cidlowski, John A. TI Cationic gradient reversal and cytoskeleton-independent volume regulatory pathways define an early stage of apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMA-MEMBRANE DEPOLARIZATION; FAS-INDUCED APOPTOSIS; CELL-VOLUME; ACTIN CYTOSKELETON; MEDIATED APOPTOSIS; ACTIVATION; SHRINKAGE; DEATH; K+; MECHANISMS AB Cell shrinkage, or apoptotic volume decrease ( AVD), is a ubiquitous characteristic of programmed cell death that is independent of the death stimulus and occurs in all examples of apoptosis. Here we distinguished two specific stages of AVD based on cell size and a unique early reversal of intracellular ions that occurs in response to activation of both intrinsic and extrinsic cell death signal pathways. The primary stage of AVD is characterized by an early exchange of the normal intracellular ion distribution for sodium from 12 to 113.6 mM and potassium from 139.5 to 30 mM. This early ionic reversal is associated with a 20 - 40% decrease in cell volume, externalization of phosphatidylserine, loss of mitochondrial membrane potential, and caspase activation and activity along with nuclear condensation that occurs independent of actin cytoskeleton disruption. Disruption of the actin cytoskeleton, however, prevents a secondary stage of AVD in apoptotic cells, characterized by a loss of both potassium and sodium that results in an 80 - 85% loss in cell volume, DNA degradation, and apoptotic body formation. Together these studies demonstrate that AVD occurs in two distinct stages with the earliest stage reflecting a cellular cationic gradient reversal. C1 [Bortner, Carl D.; Sifre, Maria I.; Cidlowski, John A.] NIEHS, NIH, Dept Hlth & Human Serv, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Bortner, CD (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM bortner@niehs.nih.gov FU Intramural NIH HHS [Z01 ES090079-12] NR 33 TC 35 Z9 35 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 MAR 14 PY 2008 VL 283 IS 11 BP 7219 EP 7229 DI 10.1074/jbc.M707809200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 271HN UT WOS:000253779600067 PM 18187415 ER PT J AU He, N Jahchan, NS Hong, E Li, Q Bayfield, MA Maraia, RJ Luo, K Zhou, Q AF He, Nanhai Jahchan, Nadine S. Hong, Eunmee Li, Qiang Bayfield, Mark A. Maraia, Richard J. Luo, Kunxin Zhou, Qiang TI A la-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis SO MOLECULAR CELL LA English DT Article ID POLYMERASE-II TRANSCRIPTION; BASEMENT-MEMBRANE CULTURES; TRANSFER-RNA MATURATION; POSITIVE TRANSCRIPTION; FACTOR-B; HEXIM1; COMPLEXES; KINASE; DIFFERENTIATION; MORPHOGENESIS AB The general transcription factor P-TEFb stimulates RNA polymerase 11 elongation and cotranscriptional processing of pre-mRNA. Contributing to a functional equilibrium important for growth control, a reservoir of P-TEFb is maintained in an inactive snRNP where 7SK snRNA is a central scaffold. Here, we identify PIP7S as a La-related protein stably associated with and required for 7SK snRNP integrity. PIP7S binds and stabilizes nearly all the nuclear 7SK via 3'-UUU-OH, leading to the sequestration and inactivation of P-TEFb. This function requires its La domain and intact C terminus. The latter is frequently deleted in human tumors due to microsatellite instability-associated mutations. Consistent with the tumor suppressor role of a Drosophila homolog of PIP7S, loss of PIP7S function shifts the P-TEFb equilibrium toward the active state, disrupts epithelial differentiation, and causes P-TEFb-dependent malignant transformation. Through PIP7S modulation of P-TEFb, our data thus link a general elongation factor to growth control and tumorigenesis. C1 [He, Nanhai; Jahchan, Nadine S.; Hong, Eunmee; Li, Qiang; Luo, Kunxin; Zhou, Qiang] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Bayfield, Mark A.; Maraia, Richard J.] Natl Inst Hlth, Inst Child Hlth & Human Dev, Intramural Res Program, Bethesda, MD 20892 USA. RP Zhou, Q (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM qzhou@berkeley.edu FU NIAID NIH HHS [AI41757] NR 35 TC 115 Z9 119 U1 1 U2 2 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 MAR 14 PY 2008 VL 29 IS 5 BP 588 EP 599 DI 10.1016/j.molcel.2008.01.003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 275VM UT WOS:000254100200009 PM 18249148 ER PT J AU John, S Sabo, PJ Johnson, TA Sung, MH Biddie, SC Lightman, SL Voss, TC Davis, SR Meltzer, PS Stamatoyannopoulos, JA Hager, GL AF John, Sam Sabo, Peter J. Johnson, Thomas A. Sung, Myong-Hee Biddie, Simon C. Lightman, Stafford L. Voss, Ty C. Davis, Sean R. Meltzer, Paul S. Stamatoyannopoulos, John A. Hager, Gordon L. TI Interaction of the glucocorticoid receptor with the chromatin landscape SO MOLECULAR CELL LA English DT Article ID LIGAND-SPECIFIC DYNAMICS; HISTONE VARIANT H2A.Z; NUCLEAR RECEPTOR; IN-VIVO; LIVING CELLS; REMODELING COMPLEX; STEROID-RECEPTORS; SWI/SNF COMPLEX; CROSS-TALK; KAPPA-B AB The generality and spectrum of chromatin-remodeling requirements for nuclear receptor function are unknown. We have characterized glucocorticoid receptor(GR) binding events and chromatin structural transitions across GR-induced or -repressed genes. This analysis reveals that GR binding invariably occurs at nuclease-accessible sites (DHS). A remarkable diversity of mechanisms, however, render these sites available for GR binding. Accessibility of the GR binding sites is either constitutive or hormone inducible. Within each category, some DHS sites require the Brg1-containing Swi/Snf complex, but others are Brg1 independent, implicating a different remodeling complex. The H2A.Z histone variant is highly enriched at both inducible and constitutive DHS sites and is subject to exchange during hormone activation. The DHS profile is highly cell specific, implicating cell-selective organization of the chromatin landscape as a critical determinant of tissue-selective receptor function. Furthermore, the widespread requirement for chromatin remodeling supports the recent hypothesis that the rapid exchange of receptor proteins occurs during nucleosome reorganization. C1 [Sabo, Peter J.; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Sabo, Peter J.; Stamatoyannopoulos, John A.] Univ Washington, Dept Comp Sci & Engn, Seattle, WA 98195 USA. [John, Sam; Johnson, Thomas A.; Sung, Myong-Hee; Biddie, Simon C.; Voss, Ty C.; Hager, Gordon L.] NCI, NIH, Ctr Canc Res, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. [Davis, Sean R.; Meltzer, Paul S.] NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Biddie, Simon C.; Lightman, Stafford L.] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. RP Stamatoyannopoulos, JA (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM jstam@u.washington.edu; hagerg@exchange.nih.gov OI Davis, Sean/0000-0002-8991-6458 FU Intramural NIH HHS NR 44 TC 192 Z9 194 U1 3 U2 10 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 MAR 14 PY 2008 VL 29 IS 5 BP 611 EP 624 DI 10.1016/j.moicel.2008.02.010 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 275VM UT WOS:000254100200011 PM 18342607 ER PT J AU George, DT Gilman, J Hersh, J Thorsell, A Herion, D Geyer, C Peng, X Kielbasa, W Rawlings, R Brandt, JE Gehlert, DR Tauscher, JT Hunt, SP Hommer, D Heilig, M AF George, David T. Gilman, Jodi Hersh, Jacqueline Thorsell, Annika Herion, David Geyer, Christopher Peng, Xiaomei Kielbasa, William Rawlings, Robert Brandt, John E. Gehlert, Donald R. Tauscher, Johannes T. Hunt, Stephen P. Hommer, Daniel Heilig, Markus TI Neurokinin 1 receptor antagonism as a possible therapy for alcoholism SO SCIENCE LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; MICE LACKING; SUBSTANCE-P; DEPENDENCE; STRESS; DRUG; REINSTATEMENT; MECHANISMS; RELAPSE; SEEKING AB Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor ( NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist ( LY686017; n = 25) or placebo ( n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well- being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism. C1 [George, David T.; Gilman, Jodi; Hersh, Jacqueline; Thorsell, Annika; Herion, David; Rawlings, Robert; Hommer, Daniel; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Geyer, Christopher] NIH, Dept Nursing, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Peng, Xiaomei; Kielbasa, William; Brandt, John E.; Gehlert, Donald R.; Tauscher, Johannes T.] Eli Lilly & Co, Lilly Res Lab, Indianapolis, IN 46285 USA. [Hunt, Stephen P.] UCL, Dept Anat & Dev Biol, London WC1E 6BT, England. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI HUNT, STEPHEN/C-1646-2008; Tauscher, Johannes/M-5976-2016; OI Thorsell, Annika/0000-0003-3535-3845 FU Intramural NIH HHS NR 25 TC 127 Z9 129 U1 3 U2 9 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 MAR 14 PY 2008 VL 319 IS 5869 BP 1536 EP 1539 DI 10.1126/science.1153813 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273PI UT WOS:000253943800042 PM 18276852 ER PT J AU Baumann, C Schmidtmann, A Muegge, K De La Fuente, R AF Baumann, Claudia Schmidtmann, Anja Muegge, Kathrin De La Fuente, Rabindranath TI Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia SO BMC MOLECULAR BIOLOGY LA English DT Article ID DNA METHYLTRANSFERASE EXPRESSION; PATERNAL METHYLATION IMPRINT; HISTONE H3 METHYLTRANSFERASE; GERM-CELL DEVELOPMENT; DE-NOVO METHYLATION; CONSTITUTIVE HETEROCHROMATIN; LYSINE-9 METHYLATION; SNF2 FAMILY; SYNAPTONEMAL COMPLEXES; CHROMATIN-STRUCTURE AB Background: Establishment of chromosomal cytosine methylation and histone methylation patterns are critical epigenetic modifications required for heterochromatin formation in the mammalian genome. However, the nature of the primary signal( s) targeting DNA methylation at specific genomic regions is not clear. Notably, whether histone methylation and/ or chromatin remodeling proteins play a role in the establishment of DNA methylation during gametogenesis is not known. The chromosomes of mouse neonatal spermatogonia display a unique pattern of 5-methyl cytosine staining whereby centromeric heterochromatin is hypo-methylated whereas chromatids are strongly methylated. Thus, in order to gain some insight into the relationship between global DNA and histone methylation in the germ line we have used neonatal spermatogonia as a model to determine whether these unique chromosomal DNA methylation patterns are also reflected by concomitant changes in histone methylation. Results: Our results demonstrate that histone H3 tri-methylated at lysine 9 (H3K9(me3)), a hallmark of constitutive heterochromatin, as well as the chromatin remodeling protein ATRX remained associated with pericentric heterochromatin regions in spite of their extensive hypo-methylation. This suggests that in neonatal spermatogonia, chromosomal 5-methyl cytosine patterns are regulated independently of changes in histone methylation, potentially reflecting a crucial mechanism to maintain pericentric heterochromatin silencing. Furthermore, chromatin immunoprecipitation and fluorescence in situ hybridization, revealed that ATRX as well as H3K9me3 associate with Y chromosome- specific DNA sequences and decorate both arms of the Y chromosome, suggesting a possible role in heterochromatinization and the predominant transcriptional quiescence of this chromosome during spermatogenesis. Conclusion: These results are consistent with a role for histone modifications and chromatin remodeling proteins such as ATRX in maintaining transcriptional repression at constitutive heterochromatin domains in the absence of 5-methyl cytosine and provide evidence suggesting that the establishment and/ or maintenance of repressive histone and chromatin modifications at pericentric heterochromatin following genome- wide epigenetic reprogramming in the germ line may precede the establishment of chromosomal 5-methyl cytosine patterns as a genomic silencing strategy in neonatal spermatogonia. C1 [Baumann, Claudia; De La Fuente, Rabindranath] Univ Penn, New Bolton Ctr,Female Germ Cell Biol Grp, Sch Vet Med,Dept Clin Studies, Ctr Anim Transgenesis & Germ Cell Res, Kennett Sq, PA 19348 USA. [Schmidtmann, Anja; Muegge, Kathrin] NCI, Lab Canc Prevent, SAIC Basic Res Program, Frederick, MD 21701 USA. RP De La Fuente, R (reprint author), Univ Penn, New Bolton Ctr,Female Germ Cell Biol Grp, Sch Vet Med,Dept Clin Studies, Ctr Anim Transgenesis & Germ Cell Res, 382 W St Rd,Kennett Sq, Kennett Sq, PA 19348 USA. EM cbaumann@vet.upenn.edu; aschmidtmann@ncifcrf.gov; muegge@ncifcrf.gov; rfuente@vet.upenn.edu FU NCI NIH HHS [N01CO12400, N01-CO-12400]; NICHD NIH HHS [HD042740, R01 HD042740] NR 78 TC 17 Z9 17 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2199 J9 BMC MOL BIOL JI BMC Mol. Biol. PD MAR 13 PY 2008 VL 9 AR 29 DI 10.1186/1471-2199-9-29 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 279PI UT WOS:000254366700001 PM 18366812 ER PT J AU Romagnoli, R Baraldi, PG Sarkar, T Carrion, MD Cara, CL Cruz-Lopez, O Preti, D Tabrizi, MA Tolomeo, M Grimaudo, S Di Cristina, A Zonta, N Balzarini, J Brancale, A Hsieh, HP Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Sarkar, Taradas Carrion, Maria Dora Cara, Carlota Lopez Cruz-Lopez, Olga Preti, Delia Tabrizi, Mojgan Aghazadeh Tolomeo, Manlio Grimaudo, Stefania Di Cristina, Antonella Zonta, Nicola Balzarini, Jan Brancale, Andrea Hsieh, Hsing-Pang Hamel, Ernest TI Synthesis and biological evaluation of 1-methyl-2-(3 ',4 ',5 '-trimethoxybenzoyl)-3-aminoindoles as a new class of antimitotic agents and tubulin inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID VASCULAR DISRUPTING AGENTS; ANTINEOPLASTIC AGENTS; MEDICINAL CHEMISTRY; ANTITUBULIN AGENTS; POLYMERIZATION; DERIVATIVES; COLCHICINE; COMBRETASTATIN-A-4; ANALOGS; GROWTH AB The 2-(3,4,5-trimethoxybenzoyl)-2-aminoindole nucleus was used as the fundamental structure for the synthesis of compounds modified with respect to positions C-4 to C-7 with different moieties (chloro, methyl, or methoxy). Additional structural variations concerned the indole nitrogen, which was alkylated with small alkyl groups such as methyl or ethyl. We have identified 1-methyl-2-(3,4,5-trimethoxybenzoyl)-3-amino-7-methoxyindole as a new highly potent anti proliferative agent that targets tubulin at the colchicine binding site and leads to apoptotic cell death. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Carrion, Maria Dora; Cara, Carlota Lopez; Cruz-Lopez, Olga; Preti, Delia; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Tolomeo, Manlio; Grimaudo, Stefania; Di Cristina, Antonella] Univ Palermo, Dipartimento Oncol, Policlin P Giaccone, Div Ematol & Serv AIDS, Palermo, Italy. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Zonta, Nicola; Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3XF, S Glam, Wales. [Hsieh, Hsing-Pang] Natl Hlth Res Inst, Div Biotechnol & Pharmaceut Res, Miaoli, Taiwan. [Sarkar, Taradas; Hamel, Ernest] NCI Frederick, Div Canc Treatment & Diag, NIH, Dev Therapeut Program,Toxicol & Pharmacol Branch, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI Hsieh, Hsing-Pang/B-2649-2010; antonietta, di cristina/I-9251-2012; Aghazadeh Tabrizi, Mojgan/I-9169-2014; Brancale, Andrea/N-9445-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017; Carrion, M. Dora/G-8638-2015; preti, delia/G-9916-2015; Romagnoli, Romeo/G-9887-2015 OI Brancale, Andrea/0000-0002-9728-3419; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Grimaudo, Stefania/0000-0003-3225-4112; Carrion, M. Dora/0000-0002-6794-3949; preti, delia/0000-0002-1075-3781; NR 21 TC 59 Z9 61 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 13 PY 2008 VL 51 IS 5 BP 1464 EP 1468 DI 10.1021/jm7011547 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 271JO UT WOS:000253784900040 PM 18260616 ER PT J AU Chen, SN Turner, A Jaki, BU Nikolic, D van Breemen, RB Friesen, JB Pauli, GF AF Chen, Shao-Nong Turner, Allison Jaki, Birgit U. Nikolic, Dejan van Breemen, Richard B. Friesen, J. Brent Pauli, Guido F. TI An experimental implementation of chemical subtraction SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE chemical subtraction; selective removal; countercurrent chromatography (CCC); Vaccinium rnacrocarpon Ait.; bacterial adhesion ID COUNTER-CURRENT CHROMATOGRAPHY; FIMBRIATED ESCHERICHIA-COLI; CRANBERRY JUICE; HIGH-SPEED; INHIBIT ADHERENCE; NATURAL-PRODUCTS; URINARY; PROANTHOCYANIDINS AB A preparative analytical method was developed to selectively remove ("chemically subtract") a single compound from a complex mixture, such as a natural extract or fraction, in a single step. The proof of concept is demonstrated by the removal of pure benzoic acid (BA) from cranberry (Vaccinium macrocarpon Ait.) juice fractions that exhibit anti-adhesive effects versus uropathogenic Escherichia coli. Chemical subtraction of BA, representing a major constituent of the fractions, eliminates the potential in vitro interference of the bacteriostatic effect of BA on the E. coli antiadherence action measured in bioassays. Upon BA removal, the anti-adherent activity of the fraction was fully retained, 36% inhibition of adherence in the parent fraction at 100 mu g/mL increased to 58% in the BA-free active fraction. The method employs countercurrent chromatography (CCC) and operates loss-free for both the subtracted and the retained portions as only liquid-liquid partitioning is involved. While the high purity (97.47% by quantitative H-1 NMR) of the subtracted BA confirms the selectivity of the method, one minor impurity was determined to be scopoletin by HR-ESI-MS and (q)HNMR and represents the first coumarin reported from cranberries. A general concept for the selective removal of phytoconstituents by CCC is presented, which has potential broad applicability in the biological evaluation of medicinal plant extracts and complex pharmaceutical preparations. (C) 2007 Elsevier B.V. All rights reserved. C1 [Chen, Shao-Nong; Turner, Allison; Nikolic, Dejan; van Breemen, Richard B.; Friesen, J. Brent; Pauli, Guido F.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. [Chen, Shao-Nong; Turner, Allison; Nikolic, Dejan; van Breemen, Richard B.; Friesen, J. Brent; Pauli, Guido F.] Univ Illinois, Coll Pharm, PCRPS, Chicago, IL 60612 USA. [Jaki, Birgit U.; Friesen, J. Brent; Pauli, Guido F.] Univ Illinois, Coll Pharm, Inst TB Res, Chicago, IL 60612 USA. [Friesen, J. Brent] Dominican Univ, Rosary Coll Arts & Sci, River Forest, IL 60305 USA. RP Pauli, GF (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res, M-C 971, Chicago, IL 60612 USA. EM gfp@uic.edu OI Pauli, Guido/0000-0003-1022-4326 FU NCCIH NIH HHS [F AT00623, F31 AT000623, F31 AT000623-04, P50 AT000155, P50 AT000155-08, P50 AT00155] NR 39 TC 10 Z9 10 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD MAR 13 PY 2008 VL 46 IS 4 BP 692 EP 698 DI 10.1016/j.jpba.2007.12.014 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 276KI UT WOS:000254139400011 PM 18234463 ER PT J AU Eremina, V Jefferson, JA Kowalewska, J Hochster, H Haas, M Weisstuch, J Richardson, C Kopp, JB Kabir, MG Backx, PH Gerber, HP Ferrara, N Barisoni, L Alpers, CE Quaggin, SE AF Eremina, Vera Jefferson, J. Ashley Kowalewska, Jolanta Hochster, Howard Haas, Mark Weisstuch, Joseph Richardson, Catherine Kopp, Jeffrey B. Kabir, M. Golam Backx, Peter H. Gerber, Hans-Peter Ferrara, Napoleone Barisoni, Laura Alpers, Charles E. Quaggin, Susan E. TI VEGF inhibition and renal thrombotic microangiopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PREECLAMPSIA; PROTEINURIA; HYPERTENSION; ANTIBODIES; RISK AB The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy. C1 [Eremina, Vera; Quaggin, Susan E.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Eremina, Vera; Quaggin, Susan E.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Quaggin, Susan E.] Univ Toronto, St Michaels Hosp, Div Nephrol, Toronto, ON M5B 1W8, Canada. [Jefferson, J. Ashley] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Jefferson, J. Ashley; Alpers, Charles E.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Hochster, Howard] NYU, Inst Canc, New York, NY USA. [Haas, Mark] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Weisstuch, Joseph; Barisoni, Laura] NYU, Sch Med, New York, NY USA. [Richardson, Catherine] Pacific Nephrol Assoc, Tacoma, WA USA. [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, Bethesda, MD 20892 USA. [Kabir, M. Golam; Backx, Peter H.] Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON, Canada. [Kabir, M. Golam; Backx, Peter H.] Toronto Gen Hosp, Res Inst, Toronto, ON, Canada. [Gerber, Hans-Peter] Seattle Genet, Bothell, WA USA. [Ferrara, Napoleone] Genentech Inc, San Francisco, CA 94080 USA. RP Quaggin, SE (reprint author), Mt Sinai Hosp, Samuel Lunenfeld Res Inst, 600 Univ Ave, Toronto, ON M5G 1X5, Canada. EM quaggin@mshri.on.ca OI Kopp, Jeffrey/0000-0001-9052-186X FU Canadian Institutes of Health Research [105268, 36494, 44289, 62931] NR 19 TC 617 Z9 644 U1 2 U2 24 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 MAR 13 PY 2008 VL 358 IS 11 BP 1129 EP 1136 DI 10.1056/NEJMoa0707330 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 272RK UT WOS:000253877200006 PM 18337603 ER PT J AU Svetkey, LP Stevens, VJ Brantley, PJ Appel, LJ Hollis, JF Loria, CM Vollmer, WM Gullion, CM Funk, K Smith, P Samuel-Hodge, C Myers, V Lien, LF Laferriere, D Kennedy, B Jerome, GJ Heinith, F Harsha, DW Evans, P Erlinger, TP Dalcin, AT Coughlin, J Charleston, J Champagne, CM Bauck, A Ard, JD Aicher, K AF Svetkey, Laura P. Stevens, Victor J. Brantley, Phillip J. Appel, Lawrence J. Hollis, Jack F. Loria, Catherine M. Vollmer, William M. Gullion, Christina M. Funk, Kristine Smith, Patti Samuel-Hodge, Carmen Myers, Valerie Lien, Lillian F. Laferriere, Daniel Kennedy, Betty Jerome, Gerald J. Heinith, Fran Harsha, David W. Evans, Pamela Erlinger, Thomas P. Dalcin, Arline T. Coughlin, Janelle Charleston, Jeanne Champagne, Catherine M. Bauck, Alan Ard, Jamy D. Aicher, Kathleen CA Weight Loss Maintenance Collaborat TI Comparison of strategies for sustaining weight loss - The weight loss maintenance randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LIFE-STYLE INTERVENTION; BLOOD-PRESSURE; DIETARY PATTERNS; CLINICAL-TRIAL; CONTROL REGISTRY; MISSING DATA; HYPERTENSION; OBESITY; OVERWEIGHT; REDUCTION AB Context Behavioral weight loss interventions achieve short- term success, but regain is common. Objective To compare 2 weight loss maintenance interventions with a self- directed control group. Design, Setting, and Participants Two- phase trial in which 1032 overweight or obese adults ( 38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6- month weight loss program ( phase 1) were randomized to a weight- loss maintenance intervention ( phase 2). Enrollment at 4 academic centers occurred August 2003- July 2004 and randomization, February-December 2004. Data collection was completed in June 2007. Interventions After the phase 1 weight- loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology - based intervention, or self- directed control. Main Outcome Changes in weight from randomization. Results Mean entry weight was 96.7 kg. During the initial 6- month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal- contact group regained less weight ( 4.0 kg) than those in the self- directed group ( 5.5 kg; mean difference at 30 months, - 1.5 kg; 95% confidence interval [ CI], - 2.4 to - 0.6 kg; P=. 001). At 30 months, weight regain did not differ between the interactive technology - based ( 5.2 kg) and self- directed groups ( 5.5 kg; mean difference - 0.3 kg; 95% CI, - 1.2 to 0.6 kg; P=. 51); however, weight regain was lower in the interactive technology - based than in the self- directed group at 18 months ( mean difference, - 1.1 kg; 95% CI, - 1.9 to - 0.4 kg; P=. 003) and at 24 months ( mean difference, - 0.9 kg; 95% CI, - 1.7 to - 0.02 kg; P=. 04). At 30 months, the difference between the personal-contact and interactive technology - based group was - 1.2 kg ( 95% CI - 2.1 to - 0.3; P=. 008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight. Conclusions The majority of individuals who successfully completed an initial behavioral weight loss program maintained a weight below their initial level. Monthly brief personal contact provided modest benefit in sustaining weight loss, whereas an interactive techonology - based intervention provided early but transient benefit. Trial Registration clinicaltrials. gov Identifier: NCT00054925. C1 [Svetkey, Laura P.; Aicher, Kathleen] Duke Univ, Med Ctr, Duke Hypertens Ctr, Div Nephrol,Dept Med, Durham, NC 27710 USA. [Lien, Lillian F.] Duke Univ, Med Ctr, Duke Hypertens Ctr, Div Endocrinol,Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27710 USA. [Stevens, Victor J.; Hollis, Jack F.; Vollmer, William M.; Gullion, Christina M.; Funk, Kristine; Laferriere, Daniel; Heinith, Fran; Evans, Pamela; Bauck, Alan] Kaiser Permanente NW, Hlth Sci Programs, Ctr Hlth Res, Portland, OR USA. [Brantley, Phillip J.; Smith, Patti; Myers, Valerie] Louisiana State Univ, Pennington Biomed Res Ctr, Behav Med Lab, Baton Rouge, LA 70808 USA. [Appel, Lawrence J.; Jerome, Gerald J.; Dalcin, Arline T.; Coughlin, Janelle; Charleston, Jeanne] Johns Hopkins Univ, Prohlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Loria, Catherine M.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Samuel-Hodge, Carmen] Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. [Samuel-Hodge, Carmen] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Erlinger, Thomas P.] Univ Texas Austin, Med Branch, Dept Med, Austin, TX 78712 USA. [Ard, Jamy D.] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. RP Svetkey, LP (reprint author), Duke Univ, Med Ctr, Duke Hypertens Ctr, Div Nephrol,Dept Med, Box 3075, Durham, NC 27710 USA. EM Svetk001@mc.duke.edu RI Kattelmann, Kendra/E-8225-2013; OI Jerome, Gerald/0000-0003-0612-2626 FU NHLBI NIH HHS [-HL68955, 5-U01 HL68734, 5-U01 HL68790, 5-U01 HL68920, 5-U01 HL68676] NR 53 TC 330 Z9 333 U1 4 U2 32 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 MAR 12 PY 2008 VL 299 IS 10 BP 1139 EP 1148 DI 10.1001/jama.299.10.1139 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 272CE UT WOS:000253835000017 PM 18334689 ER PT J AU Moon, Y Il Kim, J Yang, H Eling, TE AF Moon, Yuseok Il Kim, Jeung Yang, Hyun Eling, Thomas E. TI Growth compensatory role of sulindac sulfide-induced thrombospondin-1 linked with ERK1/2 and RhoA GTPase signaling pathways SO LIFE SCIENCES LA English DT Article DE thrombospondin-1; ERK1/2; RhoA ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ACTIVATED PROTEIN-KINASES; COLON-CARCINOMA CELLS; SMOOTH-MUSCLE-CELLS; TUMOR-GROWTH; CYCLOOXYGENASE INHIBITORS; UP-REGULATION; INDUCTION; EGR-1; EXPRESSION AB Previously, we reported that non-steroidal anti-inflammatory drugs (NSAIDs) suppress cellular invasion which was mediated by thrombospondin-1 (TSP-1). As the extending study of the previous observation, we investigated the effect of NSAID-induced TSP-1 on the cellular growth and its related signaling transduction of the TSP-1 production. Among diverse NSAIDs, sulindac sulfide was most potent of inducing the human TSP-1 protein expression. Functionally, induced TSP-1 expression was associated with the growth-compensatory action of NSAID. TSP-1 expression was also elevated by mitogenic signals of ERK1/2 and RhoA GTPase pathway which had also growth-promotive capability after sulindac sulfide treatment. These findings suggest the possible mechanism through which tumor cells can survive the chemopreventive action of NSAIDs or the normal epithelium can reconstitute after NSAID-mediated ulceration in a compensatory way. (C) 2007 Elsevier Inc. All rights reserved. C1 [Moon, Yuseok; Yang, Hyun] Pusan Natl Univ, Sch Med, Dept Microbiol & Immunol, Pusan 602739, South Korea. [Moon, Yuseok; Il Kim, Jeung; Yang, Hyun] Pusan Natl Univ, Sch Med, Med Res Inst, Pusan 602739, South Korea. [Il Kim, Jeung] Pusan Natl Univ, Sch Med, Dept Orthoped, Pusan, South Korea. [Eling, Thomas E.] NIH, NIEHS, Res Triangle Pk, NC 27709 USA. RP Moon, Y (reprint author), Pusan Natl Univ, Sch Med, Dept Microbiol & Immunol, Pusan 602739, South Korea. EM moon@pusan.ac.kr FU Intramural NIH HHS [Z01 ES010016-09] NR 36 TC 3 Z9 5 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAR 12 PY 2008 VL 82 IS 11-12 BP 591 EP 599 DI 10.1016/j.lfs.2007.11.030 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 276CC UT WOS:000254117900006 PM 18261746 ER PT J AU Wheaton, LA Bohlhalter, S Nolte, G Shibasaki, H Hattori, N Fridman, E Vorbach, S Grafman, J Hallett, M AF Wheaton, Lewis A. Bohlhalter, Stephan Nolte, Guido Shibasaki, Hiroshi Hattori, Noriaki Fridman, Esteban Vorbach, Sherry Grafman, Jordan Hallett, Mark TI Cortico-cortical networks in patients with ideomotor apraxia as revealed by EEG coherence analysis SO NEUROSCIENCE LETTERS LA English DT Article DE parietal; coherence; stroke; ideomotor apraxia; plasticity ID POSTERIOR PARIETAL CORTEX; BRAIN ACTIVATION; PREMOTOR AREAS; RHESUS-MONKEY; STROKE; PRAXIS; HEMISPHERE; MOVEMENTS; RECOVERY AB We sought to determine whether coherent networks which circumvent lesioned cortex are seen in patients with ideomotor apraxia (IMA) while performing tool-use pantomimes. Five normal subjects and five patients with IMA (three patients with corticobasal degeneration and two with left hemisphere stroke) underwent 64-channel EEG recording while performing three tool-use pantomimes with their left hand in a self-paced manner. Beta band (20-22 Hz) coherence indicates that normal subjects have a dominant left hemisphere network responsible for praxis preparation, which was absent in patients. Corticobasal degeneration patients showed significant coherence increase between left parietal-right premotor areas. Left hemisphere stroke patients showed significant coherence increases in a right parietofrontal network. The right hemisphere appears to store useable praxis representations in IMA patients with left hemisphere damage. Published by Elsevier Ireland Ltd. C1 [Wheaton, Lewis A.; Bohlhalter, Stephan; Nolte, Guido; Shibasaki, Hiroshi; Hattori, Noriaki; Vorbach, Sherry; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Wheaton, Lewis A.] Baltimore Vet Affairs Hosp, Baltimore, MD USA. [Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Wheaton, Lewis /B-4482-2009; OI Wheaton, Lewis /0000-0003-0771-0294; Grafman, Jordan H./0000-0001-8645-4457; Fridman, Esteban/0000-0001-7879-8874 FU Intramural NIH HHS [Z01 NS002669-23] NR 24 TC 18 Z9 18 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 12 PY 2008 VL 433 IS 2 BP 87 EP 92 DI 10.1016/j.neulet.2007.12.065 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 280PZ UT WOS:000254440000003 PM 18249498 ER PT J AU Kola, B Farkas, I Christ-Crain, M Wittmann, G Lolli, F Amin, F Harvey-White, J Liposits, Z Kunos, G Grossman, AB Fekete, C Korbonits, M AF Kola, Blerina Farkas, Imre Christ-Crain, Mirjam Wittmann, Gabor Lolli, Francesca Amin, Faisal Harvey-White, Judith Liposits, Zsolt Kunos, George Grossman, Ashley B. Fekete, Csaba Korbonits, Marta TI The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System SO PLOS ONE LA English DT Article AB Introduction: Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction. Methods: The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors. Results and Conclusions: Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons. C1 [Farkas, Imre; Wittmann, Gabor; Liposits, Zsolt; Fekete, Csaba] Hungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, Budapest, Hungary. [Kola, Blerina; Christ-Crain, Mirjam; Lolli, Francesca; Amin, Faisal; Grossman, Ashley B.; Korbonits, Marta] Univ London, Barts & London Sch Med & Dentist, Dept Endocrinol, London, England. [Harvey-White, Judith; Kunos, George] NIH, NIAAA, Lab Physiol Stud, Bethesda, MD USA. [Fekete, Csaba] Tufts-New England Med Ctr, Dept Med, Tupper Res Inst, Div Endocrinol, Diabetes, Metabol & Mol Med, Boston, MA USA. RP Fekete, C (reprint author), Hungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, Budapest, Hungary. EM Feketecs@koki.hu; m.korbonits@qmul.ac.uk OI Fekete, Csaba/0000-0002-8206-562X; Korbonits, Marta/0000-0002-4101-9432 FU Wellcome Trust [319/2006]; ETT; Sixth EU Research Framework Programme [LSHM-CT-2003-503041] FX This study was supported by a Wellcome Trust Project Grant, by ETT (319/2006) and the Sixth EU Research Framework Programme (contact LSHM-CT-2003-503041). The funders did not have a role in this manuscript. NR 34 TC 143 Z9 146 U1 3 U2 11 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 MAR 12 PY 2008 VL 3 IS 3 AR e1797 DI 10.1371/journal.pone.0001797 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 369VW UT WOS:000260723000045 PM 18335063 ER PT J AU Santos, AFA Lengruber, RB Soares, EA Jere, A Sprinz, E Martinez, AMB Silveira, J Sion, FS Pathak, VK Soares, MA AF Santos, Andre F. A. Lengruber, Renan B. Soares, Esmeralda A. Jere, Abhay Sprinz, Eduardo Martinez, Ana M. B. Silveira, Jussara Sion, Fernando S. Pathak, Vinay K. Soares, Marcelo A. TI Conservation Patterns of HIV-1 RT Connection and RNase H Domains: Identification of New Mutations in NRTI-Treated Patients SO PLOS ONE LA English DT Article AB Background: Although extensive HIV drug resistance information is available for the first 400 amino acids of its reverse transcriptase, the impact of antiretroviral treatment in C-terminal domains of Pol (thumb, connection and RNase H) is poorly understood. Methods and Findings: We wanted to characterize conserved regions in RT C-terminal domains among HIV-1 group M subtypes and CRF. Additionally, we wished to identify NRTI-related mutations in HIV-1 RT C-terminal domains. We sequenced 118 RNase H domains from clinical viral isolates in Brazil, and analyzed 510 thumb and connection domain and 450 RNase H domain sequences collected from public HIV sequence databases, together with their treatment status and histories. Drug-naive and NRTI-treated datasets were compared for intra- and inter-group conservation, and differences were determined using Fisher's exact tests. One third of RT C-terminal residues were found to be conserved among group M variants. Three mutations were found exclusively in NRTI-treated isolates. Nine mutations in the connection and 6 mutations in the RNase H were associated with NRTI treatment in subtype B. Some of them lay in or close to amino acid residues which contact nucleic acid or near the RNase H active site. Several of the residues pointed out herein have been recently associated to NRTI exposure or increase drug resistance to NRTI. Conclusions: This is the first comprehensive genotypic analysis of a large sequence dataset that describes NRTI-related mutations in HIV-1 RT C-terminal domains in vivo. The findings into the conservation of RT C-terminal domains may pave the way to more rational drug design initiatives targeting those regions. C1 [Santos, Andre F. A.; Lengruber, Renan B.; Soares, Esmeralda A.; Soares, Marcelo A.] Univ Fed Rio de Janeiro, Dept Genet, Lab Virol Humana, Rio De Janeiro, Brazil. [Jere, Abhay; Pathak, Vinay K.] Natl Canc Inst Frederick, HIV Drug Resistance Program, Frederick, MD USA. [Sprinz, Eduardo] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Martinez, Ana M. B.; Silveira, Jussara] Fundacao Univ Rio Grande, Rio Grande, Brazil. [Sion, Fernando S.] Hosp Univ Gaffree Guinle, Rio De Janeiro, Brazil. [Soares, Marcelo A.] Inst Nacl Canc, Unidade Genet, Rio De Janeiro, Brazil. RP Santos, AFA (reprint author), Univ Fed Rio de Janeiro, Dept Genet, Lab Virol Humana, Rio De Janeiro, Brazil. EM masoares@biologia.ufrj.br RI Santos, Andre/I-5734-2016 FU Brazilian Ministry of Science and Technology [403589/2004-5]; Rio de Janeiro State Science Foundation [E-26/171.337/2002]; Brazilian Ministry of Health [322/2005] FX Financial support for this study was from the Brazilian Ministry of Science and Technology (CNPq) grant no. 403589/2004-5, Rio de Janeiro State Science Foundation (FAPERJ) grant no. E-26/171.337/2002 and the Brazilian Ministry of Health (PN-DST/AIDS) grant no. 322/2005. The sponsors had no role in any step of the study design, data analysis or manuscript preparation. NR 32 TC 39 Z9 39 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 12 PY 2008 VL 3 IS 3 AR e1781 DI 10.1371/journal.pone.0001781 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 369VW UT WOS:000260723000033 PM 18335052 ER PT J AU Parsons, LM Grishaev, A Bax, A AF Parsons, Lisa M. Grishaev, Alexander Bax, Ad TI The periplasmic domain of To1R from haemophilus influenzae forms a dimer with a large hydrophobic groove: NMR solution structure and comparison to SAXS data SO BIOCHEMISTRY LA English DT Article ID C-TERMINAL DOMAIN; ESCHERICHIA-COLI; OUTER-MEMBRANE; PROTEIN STRUCTURES; DIPOLAR COUPLINGS; X-RAY; EVOLUTIONARY RELATIONSHIP; CYTOPLASMIC MEMBRANE; TOLR PROTEINS; KEY RESIDUES AB To1R is a part of the Pal/Tol system which forms a five-member, membrane-spanning, multiprotein complex that is conserved in Gram-negative bacteria. The Pal/Tol system helps to maintain the integrity of the outer membrane and has been proposed to be involved in several other cellular processes including cell division. Obtaining the structure of To1R is of interest not only to help explain the many proposed functions of the Pal/Tol system but also to gain an understanding of the To1R homologues ExbD and MotB and to provide more targets for antibacterial treatments. In addition, the structure may provide insights into how colicins and bacteriophages are able to enter the cell. Here we report the solution structure of the homodimeric periplasmic domain of To1R from Haemophilus influenzae, determined with conventional, NOE-based NMR spectroscopy, supplemented by extensive residual dipolar coupling measurements. A novel method for assembling the dimer from small-angle X-ray scattering data confirms the NMR-derived structure. To facilitate NMR spectral analysis, a To1R construct containing residues 59-1.30 of the 139-residue protein was created. The periplasmic domain of To1R forms a C-2-symmetric dimer consisting of a strongly curved eight-stranded beta-sheet, generating a large deep groove on one side, while four helices cover the other face of the sheet. The structure of the To1R dimer together with data from the literature suggests how the periplasmic domain of To1R is most likely oriented relative to the cytoplasmic membrane and how it may interact with other components of the Pal/Tol system, particularly To1Q. C1 [Parsons, Lisa M.; Grishaev, Alexander; Bax, Ad] NIDDKD, NIH, Phys Chem Lab, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, NIH, Phys Chem Lab, 5 Mem Dr, Bethesda, MD 20892 USA. EM bax@nih.gov FU Intramural NIH HHS NR 54 TC 23 Z9 23 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 11 PY 2008 VL 47 IS 10 BP 3131 EP 3142 DI 10.1021/bi702283x PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270NG UT WOS:000253726900007 PM 18269247 ER PT J AU Westermann, D Mersmann, J Melchior, A Freudenberger, T Petrik, C Schaefer, L Lullmann-Rauch, R Lettau, O Jacoby, C Schrader, J Brand-Herrmann, SM Young, MF Schultheiss, HP Levkau, B Baba, HA Unger, T Zacharowski, K Tschope, C Fischer, JW AF Westermann, D. Mersmann, J. Melchior, A. Freudenberger, T. Petrik, C. Schaefer, L. Luellmann-Rauch, R. Lettau, O. Jacoby, C. Schrader, J. Brand-Herrmann, S. -M. Young, M. F. Schultheiss, H. P. Levkau, B. Baba, H. A. Unger, T. Zacharowski, K. Tschoepe, C. Fischer, J. W. TI Biglycan is required for adaptive remodeling after myocardial infarction SO CIRCULATION LA English DT Article DE collagen; myocardial infarction; extracellular matrix; fibrosis; proteoglycans ID TARGETED DISRUPTION; COLLAGEN FIBRILS; HEART-FAILURE; I COLLAGEN; DECORIN; MICE; EXPRESSION; FIBRILLOGENESIS; INHIBITION; RUPTURE AB Background-After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI. Methods and Results-Experimental MI was induced in wild-type (WT) and bgn(-/0) mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn(-/0) mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn(-/0) mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn(-/0) mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn(-/0) mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn(-/0), 111 +/- 4.2 mu L versus WT, 96 +/- 4.4 mu L; P < 0.05) and LV end-diastolic pressure (bgn(-/0), 24 +/- 2.7 versus WT, 18 +/- 1.8 mm Hg; P < 0.05) and severely impaired LV function (EF, bgn(-/0), 12 +/- 2% versus WT, 21 +/- 4%; P < 0.05) 21 days after MI. Conclusion-Biglycan is required for stable collagen matrix formation of infarct scars and for preservation of cardiac hemodynamic function. C1 [Westermann, D.; Lettau, O.; Schultheiss, H. P.; Tschoepe, C.] Charite Univ Klin Berlin, Abt Kardiol & Pneumol, Berlin, Germany. [Mersmann, J.] Univ Klin Duesseldorf, Mol Cadioprotect & Inflammat Grp, Anasthesiol Klin, Dusseldorf, Germany. [Melchior, A.; Freudenberger, T.; Fischer, J. W.] Univ Klin Duesseldorf, Inst Pharmakol & Klin Pharmakol, Klin Mol Pharmacol, Dusseldorf, Germany. [Petrik, C.; Unger, T.] Charite Univ Med Berlin, Inst Pharmakol & Toxikol, Cardiovasc Res Ctr, Berlin, Germany. [Schaefer, L.] Univ Frankfurt, Nephropharmakol Allgemeine Pharmakol & Toxikol Kl, Frankfurt, Germany. [Luellmann-Rauch, R.] Univ Kiel, Inst Atom, Kiel, Germany. [Jacoby, C.; Schrader, J.] Univ Dusseldorf, Inst Herzkreislauf Physiol, Dusseldorf, Germany. [Brand-Herrmann, S. -M.] Univ Munster, Dept Mol Genet Cardiovasc Dis, Leibniz Inst Arteriosclerosis Res, Munster, Germany. [Young, M. F.] Natl Inst Dent & Cranofac Res, Craniofac & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Baba, H. A.] Univ Klinikum Essen, Inst Pathol, Essen, Germany. [Levkau, B.] Univ Klinikum Essen, Inst Pathophysiol, Essen, Germany. [Zacharowski, K.] Univ Hosp Bristol, Dept Anaesthesia, Mol Cardioprotect & Inflammat Grp, Bristol, Avon, England. RP Fischer, JW (reprint author), Univ Dusseldorf, Inst Pharmakol & Klin Pharmakol, Moorenstr 5, D-40225 Dusseldorf, Germany. EM jens.fischer@uni-duesseldorf.de NR 30 TC 64 Z9 64 U1 1 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 MAR 11 PY 2008 VL 117 IS 10 BP 1269 EP 1276 DI 10.1161/CIRCULATIONAHA.107.714147 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 272KU UT WOS:000253859100005 PM 18299507 ER PT J AU Groszer, M Keays, DA Deacon, RMJ De Bono, JP Prasad-Mulcare, S Gaub, S Baum, MG French, CA Nicod, J Coventry, JA Enard, W Fray, M Brown, SDM Nolan, PM Paeaebo, S Channon, KM Costa, RM Eilers, J Ehret, G Nicholas, J Rawlins, P Fisher, SE AF Groszer, Matthias Keays, David A. Deacon, Robert M. J. de Bono, Joseph P. Prasad-Mulcare, Shweta Gaub, Simone Baum, Muriel G. French, Catherine A. Nicod, Jrme Coventry, Julie A. Enard, Wolfgang Fray, Martin Brown, Steve D. M. Nolan, Patrick M. Paeaebo, Svante Channon, Keith M. Costa, Rui M. Eilers, Jens Ehret, Guenter Nicholas, J. Rawlins, P. Fisher, Simon E. TI Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits SO CURRENT BIOLOGY LA English DT Article ID LONG-TERM DEPRESSION; LANGUAGE DISORDER; INHERITED SPEECH; BASAL GANGLIA; FOXP2 GENE; STRIATUM; BRAIN; IDENTIFICATION; ABNORMALITIES; ULTRASOUNDS AB The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene [1]. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language [2]. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning [3, 4]. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits. C1 [Groszer, Matthias; Keays, David A.; French, Catherine A.; Nicod, Jrme; Coventry, Julie A.; Fisher, Simon E.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Deacon, Robert M. J.; Nicholas, J.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [de Bono, Joseph P.; Channon, Keith M.] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Prasad-Mulcare, Shweta; Costa, Rui M.] NIAAA, Lab Integrat Neurosci, Natl Inst Hlth, Rockville, MD 20852 USA. [Gaub, Simone; Ehret, Guenter] Univ Ulm, Inst Neurobiol, D-89069 Ulm, Germany. [Baum, Muriel G.; Eilers, Jens] Univ Leipzig, Carl Ludwig Inst Physiol, D-04103 Leipzig, Germany. [Enard, Wolfgang; Paeaebo, Svante] Max Planck Inst Evolutionary Anthropol, D-04103 Leipzig, Germany. [Fray, Martin; Brown, Steve D. M.] MRC, Mammalian Genet Unit, Didcot OX11 0RD, Oxon, England. RP Fisher, SE (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. EM simon.fisher@wellii.ox.ac.uk RI Fisher, Simon/E-9130-2012; Eilers, Jens/E-6251-2012; Enard, Wolfgang/K-3483-2014; OI Fisher, Simon/0000-0002-3132-1996; Eilers, Jens/0000-0003-0497-5625; French, Catherine/0000-0003-2072-8413; Costa, Rui/0000-0003-0495-8374; Nolan, Patrick/0000-0001-5550-0334 FU British Heart Foundation; Medical Research Council [G0200482, MC_U142684172, MC_U142684173, MC_U142684175]; Wellcome Trust [, 073334, 080971] NR 39 TC 142 Z9 143 U1 0 U2 32 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 MAR 11 PY 2008 VL 18 IS 5 BP 354 EP 362 DI 10.1016/j.cub.2008.01.060 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 273LL UT WOS:000253932000027 PM 18328704 ER PT J AU Blum, A Costello, R Zalos, G Quan, M Csako, G Cannon, RO AF Blum, Arnon Costello, Rene Zalos, Gloria Quan, Mylinh Csako, Gyorgy Cannon, Richard O., III TI Variability in levels of C-reactive protein over brief intervals in patients with coronary artery disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 [Blum, Arnon; Costello, Rene; Zalos, Gloria; Quan, Mylinh; Csako, Gyorgy; Cannon, Richard O., III] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A364 EP A364 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997102467 ER PT J AU Cao, JJ Bandettini, P Pang, J Arai, A AF Cao, Jie J. Bandettini, Patricia Pang, Johnny Arai, Andrew TI Myocardial scar identified by contrast enhanced cardiac MRI independently predicts all-cause mortality SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 [Cao, Jie J.; Bandettini, Patricia; Pang, Johnny; Arai, Andrew] Natl Inst Hlth, Bethesda, MD USA. RI Bandettini, Peter/F-5871-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A157 EP A157 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997101130 ER PT J AU Chantler, PD AF Chantler, Paul D. TI Normal individuals who do not increase arterial load during exercise have a higher long term mortality SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 [Chantler, Paul D.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A174 EP A175 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997101206 ER PT J AU Desai, A Lippincott, M Blum, A De Jesus, J Zalos, G Smith, K Carlow, A Rodrigo, M Cannon, RO AF Desai, Aditi Lippincott, Margaret Blum, Arnon De Jesus, Janet Zalos, Gloria Smith, Kevin Carlow, Andrea Rodrigo, Maria Cannon, Richard O., III TI Brief periods of daily exercise at the workplace along with lifestyle and nutritional guidance improve cardiovascular profile of sedentary employees SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 [Desai, Aditi; Lippincott, Margaret; Blum, Arnon; De Jesus, Janet; Zalos, Gloria; Smith, Kevin; Carlow, Andrea; Rodrigo, Maria; Cannon, Richard O., III] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 MAR 11 PY 2008 VL 51 IS 10 SU A BP A365 EP A365 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997102470 ER PT J AU Gardin, JM Leifer, E Whellan, D Flog, J Kokkinos, P LeBlanc, MH Wolfel, G Kitzman, D AF Gardin, Julius M. Leifer, Eric Whellan, David Flog, Jerome Kokkinos, Peter LeBlanc, Marie-Helene Wolfel, Gene Kitzman, Dalane TI Relationship of Doppler-echo left ventricular diastolic function to aerobic exercise capacity in systolic heart failure: The HF-ACTION study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 St Johns Hosp, Detroit, MI USA. Wayne State Univ, Med Ctr, Detroit, MI 48202 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A176 EP A176 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997101214 ER PT J AU Hsia, J Rossouw, J Pettinger, M Greenland, P Kooperberg, C Robinson, J Lloyd-Jones, DM Hendrix, SL Bray, P Cushman, M AF Hsia, Judith Rossouw, Jacques Pettinger, Mary Greenland, Philip Kooperberg, Charles Robinson, Jennifer Lloyd-Jones, Donald M. Hendrix, Susan L. Bray, Paul Cushman, Mary TI Value of biomarkers to identify women at risk for coronary events with postmenopausal hormones SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 George Washington Univ, Washington, DC USA. NHLBI, Bethesda, MD 20892 USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A323 EP A323 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997102301 ER PT J AU Koh, KK Quon, MJ Han, SH Chung, WJ Oh, BC Shin, EK AF Koh, Kwang K. Quon, Michael J. Han, Seung H. Chung, Wook-Jin Oh, Byung C. Shin, Eak K. TI Simvastatin improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients independent of doses SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 Gachon Univ, Gil Med Ctr, Inchon, South Korea. NIH, Diabet Unit, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A281 EP A281 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997102112 ER PT J AU Patibandla, S Carlow, A Rodrigo, M Zalos, G Smith, K Cannon, RO AF Patibandla, Sushmitha Carlow, Andrea Rodrigo, Maria Zalos, Gloria Smith, Kevin Cannon, Richard O., III TI Cardiac rehabilitation effects on lipids in coronary artery disease patients on lipid-lowering therapies SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 [Patibandla, Sushmitha; Carlow, Andrea; Rodrigo, Maria; Zalos, Gloria; Smith, Kevin; Cannon, Richard O., III] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A364 EP A365 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997102468 ER PT J AU Windham, BG Ferrucci, L Griswold, ME Farasat, SM Egan, J Carlson, O Najjar, SS AF Windham, B. Gwen Ferrucci, Luigi Griswold, Michael E. Farasat, S. Morteza Egan, Josephine Carlson, Olga Najjar, Samer S. TI Adipocytokines in the relationship between adiposity and arterial stiffness SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 NIA, Baltimore, MD 21224 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A302 EP A302 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997102205 ER PT J AU Zhou, YF Billings, EM Wang, S Yu, ZX Hunter, T Kozlov, S Horvath, KA AF Zhou, Yifu Billings, Eric M. Wang, Suna Yu, Zuxi Hunter, Timothy Kozlov, Shawn Horvath, Keith A. TI Hypoxia up-regulated cholesterol synthesis and angiogenesis-related genes in porcine mesenchymal stem cells SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 [Zhou, Yifu; Billings, Eric M.; Wang, Suna; Yu, Zuxi; Hunter, Timothy; Kozlov, Shawn; Horvath, Keith A.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU A BP A293 EP A293 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JH UT WOS:000253997102166 ER PT J AU Kim, JH Kocaturk, O Raman, VK Sonmez, M Sampath, S Yucetas, A Ozturk, C Derbyshire, JA Guttman, MA Kim, AH Berry, C McVeigh, ER Lederman, RJ AF Kim, June-Hong Kocaturk, Ozgur Raman, Venkatesh K. Sonmez, Merdim Sampath, Smita Yucetas, Akin Ozturk, Cenglzhan Derbyshire, John A. Guttman, Michael A. Kim, Ann H. Berry, Colin McVeigh, Elliot R. Lederman, Robert J. TI Novel transcatheter mitral valve cerclage annuloplasty (MVCA) attenuates mitral regurgitation and preserves entrapped coronary arteries SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 57th Annual Scientific Session of the American-College-of-Cardiology CY MAR 29-APR 01, 2008 CL Chicago, IL SP Amer Coll Cardiol C1 [Kim, June-Hong; Kocaturk, Ozgur; Raman, Venkatesh K.; Sonmez, Merdim; Sampath, Smita; Yucetas, Akin; Ozturk, Cenglzhan; Derbyshire, John A.; Guttman, Michael A.; Kim, Ann H.; Berry, Colin; McVeigh, Elliot R.; Lederman, Robert J.] NHLBI, Bethesda, MD 20892 USA. RI Kocaturk, Ozgur/A-1419-2016; Ozturk, Cengizhan/A-6177-2016 OI Ozturk, Cengizhan/0000-0002-6966-0774 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2008 VL 51 IS 10 SU B BP B22 EP B22 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 274JI UT WOS:000253997200084 ER PT J AU Ayala, YM Misteli, T Baralle, FE AF Ayala, Youhna M. Misteli, Tom Baralle, Francisco E. TI TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NUCLEAR FACTOR TDP-43; FRONTOTEMPORAL LOBAR DEGENERATION; CELL-CYCLE; CFTR EXON-9; MUSCLE REGENERATION; BINDING-PROPERTIES; MYOD PATHWAYS; DNA; CDK6; TRANSCRIPTION AB TDP-43 (for TAR DNA binding protein) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in specific pre-mRNA splicing and transcription events. TDP-43 recently has been identified as the main component of cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), two neurodegenerative disorders. The cellular role of this protein remains to be identified. Here, we show that loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis. Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. The control of Cdk6 expression mediated by TDP-43 involves GT repeats in the target gene sequence. Cdk6 up-regulation in TDP-43-depleted cells is accompanied by an increase in phosphorylation of two of its major targets, the retinoblastoma protein pRb and pRb-related protein pRb2/p130. TDP-43 silencing also is followed by changes in the expression levels of several factors that control cell proliferation. Morphological nuclear defects and increased apoptosis upon TDP-43 loss are mediated via the pRb pathway because pRb-negative cells (Saos-2) do not undergo programmed cell death or nuclear shape deformation upon TDP-43 removal. Our results identify a regulatory target of TDP-43 and show that TDP-43 depletion has important consequences in essential metabolic processes in human cells. C1 [Ayala, Youhna M.; Baralle, Francisco E.] Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy. [Misteli, Tom] NCI, Natl Inst Hlth, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. RP Baralle, FE (reprint author), Int Ctr Genet Engn & Biotechnol, Padriciano 99, I-34012 Trieste, Italy. EM baralle@icgeb.org FU Intramural NIH HHS; Telethon [GGP06147] NR 42 TC 137 Z9 142 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 11 PY 2008 VL 105 IS 10 BP 3785 EP 3789 DI 10.1073/pnas.0800546105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273KZ UT WOS:000253930600024 PM 18305152 ER PT J AU Khan, SN Witsch, EJ Goodman, NG Panigrahi, AK Chen, C Jiang, YF Cline, AM Erikson, J Weigert, M Prak, ETL Radic, M AF Khan, Salar N. Witsch, Esther J. Goodman, Noah G. Panigrahi, Anil K. Chen, Ching Jiang, Yufei Cline, Amy M. Erikson, Jan Weigert, Martin Prak, Eline T. Luning Radic, Marko TI Editing and escape-from editing in anti-DNA B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoantibodies; B cell development; receptor editing ID ALLELIC INCLUSION; CHAIN REARRANGEMENT; MARGINAL ZONE; SELF-ANTIGEN; SELECTION; ANTIBODIES; RECEPTORS; MICE; TOLERANCE; AUTOANTIGENS AB Tolerance to dsDNA is achieved through editing of Ig receptors that react with dsDNA. Nevertheless, some B cells with anti-dsDNA receptors escape editing and migrate to the spleen. Certain anti-dsDNA B cells that are recovered as hybridomas from the spleens of anti-dsDNA H chain transgenic mice also bind an additional, Golgi-associated antigen. B cells that bind this antigen accumulate intracellular IgM. The intracellular accumulation of IgM is incomplete, because IgM clusters are observed at the cell surface. In the spleen, B cells that express the heavy and light chains encoding this IgM are surface IgM-bright and acquire the CD21-high/CD23-low phenotype of marginal zone B cells. Our data imply that expression of an Ig that binds dsDNA and an additional antigen expressed in the secretory compartment renders B cells resistant to central tolerance. In the periphery, these B cells may be sequestered in the splenic marginal zone. C1 [Witsch, Esther J.; Weigert, Martin] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Khan, Salar N.; Cline, Amy M.; Radic, Marko] Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA. [Witsch, Esther J.; Weigert, Martin] Univ Chicago, Gwen Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. [Goodman, Noah G.; Panigrahi, Anil K.; Prak, Eline T. Luning] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Chen, Ching] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Jiang, Yufei] NCI, Vaccine Branch, Natl Naval Med Res Ctr, NIH, Bethesda, MD 20889 USA. [Erikson, Jan] Wistar Inst Anat & Biol, Program Immunol, Philadelphia, PA 19104 USA. RP Weigert, M (reprint author), Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. EM mweigert@bsd.uchicago.edu RI Khan, Salar/N-2444-2013 OI Khan, Salar/0000-0002-9531-6918 NR 39 TC 16 Z9 16 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 11 PY 2008 VL 105 IS 10 BP 3861 EP 3866 DI 10.1073/pnas.0800025105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273KZ UT WOS:000253930600038 PM 18310318 ER PT J AU Palmer, S Malclarelli, F Wiegand, A Bernstein, B Hanna, GJ Brun, SC Kempf, DJ Mellors, JW Coffin, JM King, MS AF Palmer, Sarah Malclarelli, Frank Wiegand, Ann Bernstein, Barry Hanna, George J. Brun, Scott C. Kempf, Dale J. Mellors, John W. Coffin, John M. King, Martin S. TI Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV persistence; HIV therapy; HIV viremia ID CD4(+) T-CELLS; DYNAMICS IN-VIVO; VIRUS TYPE-1 RNA; COMBINATION THERAPY; LATENT RESERVOIR; HIV-1 INFECTION; FOLLOW-UP; PLASMA; REPLICATION; TIME AB Residual viremia can be detected in most HIV-1-infected patients on antiretroviral therapy despite suppression of plasma RNA to <50 copies per ml, but the source and duration of this viremia is currently unknown. Therefore, we analyzed longitudinal plasma samples from 40 patients enrolled in the Abbott M97-720 trial at baseline (pretherapy) and weeks 60 to 384 by using an HIV-1 RNA assay with single-copy sensitivity. All patients were on therapy (lopinavir/ritonavir, stavudine, and lamivudine) with plasma HIV RNA <50 copies per ml by week 96 of the study and thereafter. Single-copy assay results revealed that 77% of the patient samples had detectable low-level viremia (>= 1 copy per ml), and all patients had at least one sample with detectable viremia. A nonlinear mixed effects model revealed a biphasic decline in plasma RNA levels occurring over weeks 60 to 384: an initial phase of decay with a half-life of 39 weeks and a subsequent phase with no perceptible decay. The level of pretherapy viremia extrapolated for each phase of decay was significantly correlated with total baseline viremia for each patient (R-2 = 0.27, P = 0.001 and R-2 = 0.19, P < 0.005, respectively), supporting a biological link between the extent of overall baseline viral infection and the infection of long-lived reservoirs. These data suggest that low-level persistent viremia appears to arise from at least two cell compartments, one in which viral production decays over time and a second in which viral production remains stable for at least 7 years. C1 [Palmer, Sarah; Malclarelli, Frank; Wiegand, Ann] Natl Canc Inst, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Bernstein, Barry; Hanna, George J.; Brun, Scott C.; Kempf, Dale J.; King, Martin S.] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA. [Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Coffin, John M.] Tufts Univ, Boston, MA 02111 USA. RP Palmer, S (reprint author), Natl Canc Inst, HIV Drug Resistance Program, NIH, 1050 Boyles St,Bldg 535,Room 109, Frederick, MD 21702 USA. EM spalmer@ncifcrf.gov; john.coffin@tufts.edu FU Intramural NIH HHS [Z01 BC010818-01]; PHS HHS [25XS119] NR 28 TC 343 Z9 346 U1 2 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 MAR 11 PY 2008 VL 105 IS 10 BP 3879 EP 3884 DI 10.1073/pnas.0800050105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 273KZ UT WOS:000253930600041 PM 18332425 ER PT J AU Larsson, SC Virtanen, MJ Mars, M Mannisto, S Pietinen, P Albanes, D Virtamo, J AF Larsson, Susanna C. Virtanen, Mikko J. Mars, Monica Mannisto, Satu Pietinen, Pirjo Albanes, Demetrius Virtamo, Jarmo TI Magnesium, calcium, potassium, and sodium intakes and risk of stroke in male smokers SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID OLDER US WOMEN; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; DIETARY MAGNESIUM; NUTRITIONAL FACTORS; JAPANESE MEN; HYPERTENSION; MORTALITY; METAANALYSIS; FINLAND AB Background: A high intake of magnesium, calcium, and potassium and a low intake of sodium have been hypothesized to reduce the risk of stroke. However, prospective data relating intake of these minerals to risk of stroke are inconsistent. Methods: We examined the relationship of dietary magnesium, calcium, potassium, and sodium intake with risk of stroke in a cohort of 26 556 Finnish male smokers, aged 50 to 69 years, who were free from stroke at baseline. Dietary intake was assessed at baseline using a detailed and validated food frequency questionnaire. During a mean follow-up of 13.6 years (1985-2004), 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were identified in the national registries. Results: After adjustment for age and cardiovascular risk factors, a high magnesium intake was associated with a statistically significant lower risk of cerebral infarction but not with intracerebral or subarachnoid hemorrhages. The multivariate relative risk of cerebral infarction was 0.85 (95% confidence interval, 0.76-0.97; P for trend = .004) for men in the highest quintile of magnesium intake compared with those in the lowest quintile. The inverse association between magnesium intake and cerebral infarction was stronger in men younger than 60 years (relative risk, 0.76; 95% confidence interval, 0.64-0.89; P for interaction = .02). Calcium, potassium, and sodium intake was not significantly associated with risk of any subtype of stroke (P for trend > .05). Conclusion: These findings in male smokers suggest that a high magnesium intake may play a role in the primary prevention of cerebral infarction. C1 [Larsson, Susanna C.] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden. [Virtanen, Mikko J.; Mannisto, Satu; Pietinen, Pirjo; Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Mars, Monica] Univ Wageningen & Res Ctr, Div Human Nutr, Wageningen, Netherlands. [Albanes, Demetrius] NCI, NIH, Bethesda, MD 20892 USA. RP Larsson, SC (reprint author), Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Box 210, SE-17177 Stockholm, Sweden. EM Susanna.Larsson@ki.se RI Mars, Monica/O-4423-2014; Albanes, Demetrius/B-9749-2015; Larsson, Susanna/F-6065-2015 OI Mars, Monica/0000-0003-2010-1039; Larsson, Susanna/0000-0003-0118-0341 FU CCR NIH HHS [N01-RC45035, N01-RC-37004]; NCI NIH HHS [N01-CN-45165] NR 42 TC 69 Z9 70 U1 0 U2 2 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 MAR 10 PY 2008 VL 168 IS 5 BP 459 EP 465 DI 10.1001/archinte.168.5.459 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 272SZ UT WOS:000253881400003 PM 18332289 ER PT J AU Malone, JH Michalak, P AF Malone, John H. Michalak, Pawel TI Gene expression analysis of the ovary of hybrid females of Xenopus laevis and X-muelleri SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID NERVE GROWTH-FACTOR; GERM PLASM COMPONENT; DNA MICROARRAYS; RAT OVARY; RNA; LOCALIZATION; OOCYTE; DROSOPHILA; CELLS; TRANSITION AB Background: Interspecific hybrids of frogs of the genus Xenopus result in sterile hybrid males and fertile hybrid females. Previous work has demonstrated a dramatic asymmetrical pattern of misexpression in hybrid males compared to the two parental species with relatively few genes misexpressed in comparisons of hybrids and the maternal species (X. laevis) and dramatically more genes misexpressed in hybrids compared to the paternal species (X. muelleri). In this work, we examine the gene expression pattern in hybrid females of X. laevis x X. muelleri to determine if this asymmetrical pattern of expression also occurs in hybrid females. Results: We find a similar pattern of asymmetry in expression compared to males in that there were more genes differentially expressed between hybrids and X. muelleri compared to hybrids and X. laevis. We also found a dramatic increase in the number of misexpressed genes with hybrid females having about 20 times more genes misexpressed in ovaries compared to testes of hybrid males and therefore the match between phenotype and expression pattern is not supported. Conclusion: We discuss these intriguing findings in the context of reproductive isolation and suggest that divergence in female expression may be involved in sterility of hybrid males due to the inherent sensitivity of spermatogenesis as defined by the faster male evolution hypothesis for Haldane's rule. C1 [Malone, John H.] Univ Texas Arlington, Dept Biol, Arlington, TX 76010 USA. [Malone, John H.; Michalak, Pawel] NIDDKD, Cellular & Dev Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Malone, JH (reprint author), Univ Texas Arlington, Dept Biol, Box 19498, Arlington, TX 76010 USA. EM malonej@niddk.nih.gov; michalak@uta.edu NR 48 TC 10 Z9 10 U1 0 U2 4 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 MAR 10 PY 2008 VL 8 AR 82 DI 10.1186/1471-2148-8-82 PG 11 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 298UF UT WOS:000255711900001 PM 18331635 ER PT J AU Bock, NA Paiva, FF Nascimento, GC Newman, JD Silva, AC AF Bock, Nicholas A. Paiva, Fernando F. Nascimento, George C. Newman, John D. Silva, Afonso C. TI Cerebrospinal fluid to brain transport of manganese in a non-human primate revealed by MRI SO BRAIN RESEARCH LA English DT Article DE manganese; brain; rat; marmoset; magnetic resonance imaging ID IN-VIVO; ENHANCED MRI; MOUSE-BRAIN; NEUROTOXICITY; EXPOSURE; RATS; INHALATION; MONKEYS; BARRIER; ACCUMULATION AB Manganese overexposure in non-human primates and humans causes a neurodegenerative disorder called manganism thought to be related to an accumulation of the metal in the basal ganglia. Here, we assess changes in the concentration of manganese in regions of the brain of a non-human primate (the common marmoset, Callithrix jacchus) following four systemic injections of 30 mg/kg MnCl2 H2O in the tail vein using T-1-weighted magnetic resonance imaging (MRI) and compare these to changes in the rat following the same exposure route and dose. The doses were spaced 48 h apart and we imaged the animals 48 h after the final dose. We find that marmosets have significantly larger T-1-weighted image enhancements in regions of the brain compared to rats, notably in the basal ganglia and the visual cortex. To confirm this difference across species reflects actual differences in manganese concentrations and not variations in the MRI properties of manganese, we measured the longitudinal relaxivity of manganese (chi(1)) in the in vivo brain and found no significant species' difference. The high manganese uptake in the marmoset basal ganglia and visual cortex can be explained by CSF-brain transport from the large lateral ventricles and we confirm this route of uptake with time-course MRI during a tail-vein infusion of manganese. There is also high uptake in the substructures of the hippocampus that are adjacent to the ventricles. The large manganese accumulation in these structures on overexposure may be common to all primates, including humans. Published by Elsevier B.V. C1 [Bock, Nicholas A.; Paiva, Fernando F.; Nascimento, George C.; Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, Natl Inst Hlth, Bethesda, MD 20892 USA. [Newman, John D.] NICHHD, Dev Neuroethol Unit, Comparat Ethol Lab, Natl Inst Hlth,NIH Anim Ctr, Poolesville, MD 20837 USA. RP Bock, NA (reprint author), NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, Natl Inst Hlth, 10 Ctr Dr,Bldg 10,Room BD109, Bethesda, MD 20892 USA. EM bockn@mail.nih.gov RI Silva, Afonso/A-7129-2009; Paiva, Fernando/C-1429-2012 OI Paiva, Fernando/0000-0002-8989-9707 FU Intramural NIH HHS [Z99 NS999999] NR 49 TC 44 Z9 47 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAR 10 PY 2008 VL 1198 BP 160 EP 170 DI 10.1016/j.brainres.2007.12.065 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 275XU UT WOS:000254106400018 PM 18243167 ER PT J AU Greenberg, CC Connelly, PS Daniels, MP Horowits, R AF Greenberg, Cynthia C. Connelly, Patricia S. Daniels, Mathew P. Horowits, Robert TI Krp1 (Sarcosin) promotes lateral fusion of myofibril assembly intermediates in cultured mouse cardiomyocytes SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE kelch; heart; myofibrillogenesis; alpha-actinin; actin; myosin ID KELCH-REPEAT SUPERFAMILY; N-RAP; CHICK CARDIOMYOCYTES; SARCOPLASMIC-RETICULUM; CARDIAC MYOCYTES; STRIATED-MUSCLE; SKELETAL-MUSCLE; PROTEIN; OBSCURIN; EXPRESSION AB Krp1, also called sarcosin, is a cardiac and skeletal muscle kelch repeat protein hypothesized to promote the assembly of myofibrils, the contractile organelles of striated muscles, through interaction with N-RAP and actin. To elucidate its role, endogenous Krp1 was studied in primary embryonic mouse cardiomyocytes. While immunofluorescence showed punctate Krp1 distribution throughout the cell, detergent extraction revealed a significant pool of Krp1 associated with cytoskeletal elements. Reduction of Krp1 expression with siRNA resulted in specific inhibition of myofibril accumulation with no effect on cell spreading. Immunostaining analysis and electron microscopy revealed that cardiomyocytes lacking Krp1 contained sarcomeric proteins with longitudinal periodicities similar to mature myofibrils, but fibrils remained thin and separated. These thin myofibrils were degraded by a scission mechanism distinct from the myofibril disassembly pathway observed during cell division in the developing heart. The data are consistent with a model in which Krp1 promotes lateral fusion of adjacent thin fibrils into mature, wide myofibrils and contribute insight into mechanisms of myofibrillogenesis and disassembly. Published by Elsevier Inc. C1 [Greenberg, Cynthia C.; Horowits, Robert] NIAMSD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Connelly, Patricia S.; Daniels, Mathew P.] NHLBI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Horowits, R (reprint author), NIAMSD, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1154,MSC 8024, Bethesda, MD 20892 USA. EM horowits@helix.nih.gov FU Intramural NIH HHS [Z01 AR027014-16] NR 45 TC 20 Z9 21 U1 0 U2 5 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAR 10 PY 2008 VL 314 IS 5 BP 1177 EP 1191 DI 10.1016/j.yexcr.2007.12.009 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 270XA UT WOS:000253752300023 PM 18178185 ER PT J AU Galabova-Kovacs, G Catalanotti, F Matzen, D Reyes, GX Zezula, J Herbst, R Silva, A Walter, I Baccarini, M AF Galabova-Kovacs, Gergana Catalanotti, Federica Matzen, Dana Reyes, Gloria X. Zezula, Juergen Herbst, Ruth Silva, Alcino Walter, Ingrid Baccarini, Manuela TI Essential role of B-Raf in oligodendrocyte maturation and myelination during postnatal central nervous system development SO JOURNAL OF CELL BIOLOGY LA English DT Article ID GROWTH-FACTOR; KINASE ACTIVATION; DEFICIENT MICE; MAPK CASCADE; AXON GROWTH; IN-VIVO; DIFFERENTIATION; GENE; PATHWAY; PROTEIN AB Mutations in the extracellular signal-regulated kinase (ERK) pathway, particularly in the mitogen-activated protein kinase/ERK kinase (MEK) activator B-Raf, are associated with human tumorigenesis and genetic disorders. Hence, B-Raf is a prime target for molecule-based therapies, and understanding its essential biological functions is crucial for their success. B-Raf is expressed preferentially in cells of neuronal origin. Here, we show that in mice, conditional ablation of B-Raf in neuronal precursors leads to severe dysmyelination, defective oligodendrocyte differentiation, and reduced ERK activation in brain. Both B-Raf ablation and chemical inhibition of MEK impair oligodendrocyte differentiation in vitro. In glial cell cultures, we find B-Raf in a complex with MEK, Raf-1, and kinase suppressor of Ras. In B-Raf-deficient cells, more Raf-1 is recruited to MEK, yet MEK/ERK phosphorylation is impaired. These data de. ne B-Raf as the rate-limiting MEK/ERK activator in oligodendrocyte differentiation and myelination and have implications for the design and use of Raf inhibitors. C1 [Galabova-Kovacs, Gergana; Catalanotti, Federica; Matzen, Dana; Reyes, Gloria X.; Baccarini, Manuela] Univ Vienna, Max F Perutz Labs, A-1030 Vienna, Austria. [Silva, Alcino] NIMH, Bethesda, MD 20892 USA. [Walter, Ingrid] Univ Vet Med, Dept Histol & Embryol, A-1210 Vienna, Austria. [Herbst, Ruth] Med Univ Vienna, Ctr Brain Res, A-1090 Vienna, Austria. [Zezula, Juergen] Med Univ Vienna, Ctr Biomol Med & Pharmacol, Inst Pharmacol, A-1090 Vienna, Austria. RP Baccarini, M (reprint author), Univ Vienna, Max F Perutz Labs, Waehringer Guertel 18, A-1030 Vienna, Austria. EM manuela.baccarini@univie.ac.at RI Baccarini, Manuela/B-6481-2014 OI Baccarini, Manuela/0000-0002-3033-391X FU Austrian Science Fund FWF [P 18712] NR 51 TC 50 Z9 51 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAR 10 PY 2008 VL 180 IS 5 BP 947 EP 955 DI 10.1083/jcb.200709069 PG 9 WC Cell Biology SC Cell Biology GA 275OI UT WOS:000254081100011 PM 18332218 ER PT J AU Yao, JC Phan, A Hoff, PM Chen, HX Charnsangavej, C Yeung, SCJ Hess, K Ng, C Abbruzzese, JL Ajani, JA AF Yao, James C. Phan, Alexandria Hoff, Paulo M. Chen, Helen X. Charnsangavej, Chusilp Yeung, Sai-Ching J. Hess, Kenneth Ng, Chaan Abbruzzese, James L. Ajani, Jaffer A. TI Targeting vascular endothelial growth factor in advanced carcinoid tumor: A random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alfa-2b SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 9th International Symposium on Anti-Angiogenic Agents CY FEB 01-03, 2007 CL San Diego, CA ID GASTROENTEROPANCREATIC TUMORS; NEUROENDOCRINE TUMORS; ALPHA-INTERFERON; SOMATOSTATIN; ANGIOGENESIS; COMBINATION; EXPRESSION; THERAPY; PROLIFERATION; RECEPTORS AB Purpose Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alfa-2b was evaluated among patients with metastatic or unresectable carcinoid tumors. Patients and Methods Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alfa-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow. Results In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P < .01) and 28% (P < .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alfa-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P < .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed. Conclusion Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment. C1 [Yao, James C.] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Unit 426, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Diagnost Imaging, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Gen Internal Med, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Ambulatory Treatment & Emergency Care, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Biostat & Appl Math, Houston, TX 77030 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Yao, JC (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Unit 426, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM jyao@mdanderson.org FU NCI NIH HHS [N01-CM-17003]; PHS HHS [22XSO94A] NR 33 TC 229 Z9 243 U1 0 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2008 VL 26 IS 8 BP 1316 EP 1323 DI 10.1200/JCO.2007.13.6374 PG 8 WC Oncology SC Oncology GA 276XZ UT WOS:000254178300022 PM 18323556 ER PT J AU Daugherty, CK Ratain, MJ Emanuel, EJ Farrell, AT Schilsky, RL AF Daugherty, Christopher K. Ratain, Mark J. Emanuel, Ezekiel J. Farrell, Ann T. Schilsky, Richard L. TI Ethical, scientific, and regulatory perspectives regarding the use of placebos in cancer clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID CELL LUNG-CANCER; PHASE-III TRIAL; ADVANCED PANCREATIC-CANCER; RANDOMIZED DISCONTINUATION TRIAL; REFRACTORY PROSTATE-CANCER; COOPERATIVE-ONCOLOGY-GROUP; CISPLATIN-INDUCED NAUSEA; ACTIVE-CONTROL TRIALS; DOUBLE-BLIND; 1ST-LINE CHEMOTHERAPY AB Purpose To examine the ethical, scientific, and regulatory issues in the design and conduct of placebo-controlled cancer clinical trials. Methods Several content experts contributed to this article. Results Specific criteria can be applied to determine the appropriate use of placebos in oncology drug development. Placebo controls may be justified to prove efficacy of a new treatment in diseases with high placebo response rates; in conditions that wax and wane in severity, have spontaneous remissions, or have an uncertain and unpredictable course; when existing therapies are minimally effective or have serious adverse effects; or in the absence of effective therapy. Use of placebos may also be justified to assure blinding of physicians and patients regarding treatment assignment so as to minimize bias in assessment of study end points. If a trial meets these methodologic criteria, it must then fulfill additional criteria to be considered ethical. These criteria include full disclosure to patients and an assurance that participants randomly assigned to placebo are not substantially more likely than those in active treatment group(s) to die; suffer irreversible morbidity, disability, or other substantial harms; suffer reversible but serious harm; or suffer severe discomfort. Conclusion We conclude that placebo-controlled oncology trials are scientifically feasible, ethically justifiable, and may be necessary or desirable to meet regulatory standards for drug approval. Using cross-over or randomized withdrawal trial designs, requiring inclusion of state-of-the-art palliative care, and developing valid and acceptable surrogates for survival are critical strategies to address some of the ethical dilemmas associated with placebo-controlled trials. C1 Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. US FDA, Rockville, MD 20857 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Schilsky, RL (reprint author), Univ Chicago, Pritzker Sch Med, 5841 S Maryland Ave,MC 2115, Chicago, IL 60637 USA. EM rschilsk@medicine.bsd.uchicago.edu NR 57 TC 25 Z9 25 U1 2 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 MAR 10 PY 2008 VL 26 IS 8 BP 1371 EP 1378 DI 10.1200/JCO.2007.13.5335 PG 8 WC Oncology SC Oncology GA 276XZ UT WOS:000254178300029 PM 18227527 ER PT J AU Vikram, B AF Vikram, Bhadrasain TI Does postoperative radiation therapy benefit patients with prostate cancer? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 Natl Canc Inst, Rockville, MD USA. RP Vikram, B (reprint author), Natl Canc Inst, Rockville, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2008 VL 26 IS 8 BP 1392 EP 1392 DI 10.1200/JCO.2007.15.4302 PG 1 WC Oncology SC Oncology GA 276XZ UT WOS:000254178300040 PM 18323568 ER PT J AU Zech, LA Hoeg, JM AF Zech, Loren A., Jr. Hoeg, Jeffery M. TI Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia SO LIPIDS IN HEALTH AND DISEASE LA English DT Article ID CORONARY-ARTERY-DISEASE; LOW-DENSITY LIPOPROTEIN; ULTRAFAST COMPUTED-TOMOGRAPHY; CARDIOVASCULAR RISK-FACTORS; HEART-DISEASE; CALCIFIC ATHEROSCLEROSIS; II HYPERLIPOPROTEINEMIA; LIPID DEPOSITION; SERUM-LIPIDS; FOAM CELLS AB Background: A relationship between corneal arcus and atherosclerosis has long been suspected but is controversial. The homozygous familial hypercholesterolemia patients in this study present a unique opportunity to assess this issue. They have both advanced atherosclerosis and corneal arcus. Methods: This is a cross-sectional study of 17 patients homozygous for familial hypercholesterolemia presenting to the Clinical Center of the National Institutes of Health. Plasma lipoproteins, circumferential extent of arcus, thoracic aorta and coronary calcific atherosclerosis score, and Achilles tendon width were measured at the National Institutes of Health. Results: Patients with corneal arcus had higher scores for calcific atherosclerosis (mean 2865 compared to 412), cholesterol-year score (mean 11830 mg-yr/dl compared to 5707 mg-yr/ dl), and Achilles tendon width (mean 2.54 cm compared to 1.41 cm) than those without. Corneal arcus and Achilles tendon width were strongly correlated and predictive of each other. Although corneal arcus was correlated with calcific atherosclerosis (r = 0.67; p = 0.004), it was not as highly correlated as was the Achilles tendon width (r = 0.855; p < 0.001). Conclusion: Corneal arcus reflects widespread tissue lipid deposition and is correlated with both calcific atherosclerosis and xanthomatosis in these patients. Patients with more severe arcus tend to have more severe calcific atherosclerosis. Corneal arcus is not as good an indicator of calcific atherosclerosis as Achilles tendon thickness, but its presence suggests increased atherosclerosis in these hypercholesterolemic patients. C1 [Zech, Loren A., Jr.] Univ Illinois, Coll Med, Urbana, IL 61801 USA. [Zech, Loren A., Jr.; Hoeg, Jeffery M.] NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Zech, LA (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10-Room 7N115,10 Ctr Dr MSC 1666, Bethesda, MD 20892 USA. EM lzech@uiuc.edu; lzech@uiuc.edu NR 68 TC 13 Z9 13 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD MAR 10 PY 2008 VL 7 AR 7 DI 10.1186/1476-511X-7-7 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 282GJ UT WOS:000254555400001 PM 18331643 ER PT J AU Frolov, VA Zimmerberg, J AF Frolov, Vadim A. Zimmerberg, Joshua TI Flexible scaffolding made of rigid BARs SO CELL LA English DT Editorial Material ID MEMBRANE CURVATURE; DOMAIN; MECHANISMS; PROTEINS AB Crescent-shaped BAR domains are generic actors in the creation of membrane curvature. In this issue, Frost et al. (2008) reveal how collective twisting of rigid F-BAR domains on a soft membrane surface may lead to different membrane curvatures. C1 [Frolov, Vadim A.; Zimmerberg, Joshua] NICHHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM joshz@mail.nih.gov OI Frolov, Vadim/0000-0002-0653-5669 NR 10 TC 4 Z9 4 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 7 PY 2008 VL 132 IS 5 BP 727 EP 729 DI 10.1016/j.cell.2008.02.025 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 271VY UT WOS:000253818000008 PM 18329357 ER PT J AU Schones, DE Cui, KR Cuddapah, S Roh, TY Barski, A Wang, ZB Wei, G Zhao, KJ AF Schones, Dustin E. Cui, Kairong Cuddapah, Suresh Roh, Tae-Young Barski, Artem Wang, Zhibin Wei, Gang Zhao, Keji TI Dynamic regulation of nucleosome positioning in the human genome SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; HISTONE H2A VARIANT; RNA-POLYMERASE; DEVELOPMENTAL REGULATORS; SACCHAROMYCES-CEREVISIAE; STRUCTURAL-ANALYSIS; CHROMATIN-STRUCTURE; SWI/SNF COMPLEX; IN-VIVO; WIDE AB The positioning of nucleosomes with respect to DNA plays an important role in regulating transcription. However, nucleosome mapping has been performed for only limited genomic regions in humans. We have generated genome-wide maps of nucleosome positions in both resting and activated human CD4(+) T cells by direct sequencing of nucleosome ends using the Solexa high-throughput sequencing technique. We find that nucleosome phasing relative to the transcription start sites is directly correlated to RNA polymerase II (Pol II) binding. Furthermore, the first nucleosome downstream of a start site exhibits differential positioning in active and silent genes. TCR signaling induces extensive nucleosome reorganization in promoters and enhancers to allow transcriptional activation or repression. Our results suggest that H2A.Z-containing and modified nucleosomes are preferentially lost from the -1 nucleosome position. Our data provide a comprehensive view of the nucleosome landscape and its dynamic regulation in the human genome. C1 [Schones, Dustin E.; Cui, Kairong; Cuddapah, Suresh; Roh, Tae-Young; Barski, Artem; Wang, Zhibin; Wei, Gang; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Zhao, KJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov RI Wei, Gang/A-3291-2011; OI Barski, Artem/0000-0002-1861-5316 FU Intramural NIH HHS NR 66 TC 708 Z9 729 U1 3 U2 51 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 7 PY 2008 VL 132 IS 5 BP 887 EP 898 DI 10.1016/j.cell.2008.02.022 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 271VY UT WOS:000253818000024 PM 18329373 ER PT J AU Wyatt, K Gao, C Tsai, JY Fariss, RN Ray, S Wistow, G AF Wyatt, Keith Gao, Chun Tsai, Jen-Yue Fariss, Robert N. Ray, Sugata Wistow, Graeme TI A role for lengsin, a recruited enzyme, in terminal differentiation in the vertebrate lens SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FIBER CELL-DIFFERENTIATION; FIBRILLARY ACIDIC PROTEIN; EYE LENS; GENE-EXPRESSION; NEIBANK PROJECT; VIMENTIN; FILENSIN; MOUSE; CYTOSKELETON; TRANSITION AB Lengsin is an eye lens-specific member of the glutamine synthetase (GS) superfamily. Lengsin has no GS activity, suggesting that it has a structural rather than catalytic role in lens. In situ hybridization and immunofluorescence showed that lengsin is expressed in terminally differentiating secondary lens fiber cells. Yeast two-hybrid (Y2H) and recombinant protein experiments showed that full-length lengsin can bind the 2B filament region of vimentin. In affinity chromatography, lengsin also bound the equivalent region of CP49 (BFSP2; phakinin), a related intermediate filament protein specific to the lens. Both the vimentin and CP49 2B fragments bound lengsin in surface plasmon resonance spectroscopy with fast association and slow dissociation kinetics. Lengsin expression correlates with a transition zone in maturing lens fiber cells in which cytoskeleton is reorganized. Lengsin and lens intermediate filament proteins co-localize at the plasma membrane in maturing fiber cells. This suggests that lengsin may act as a component of the cytoskeleton itself or as a chaperone for the reorganization of intermediate filament proteins during terminal differentiation in the lens. C1 [Wyatt, Keith; Gao, Chun; Tsai, Jen-Yue; Fariss, Robert N.; Ray, Sugata; Wistow, Graeme] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct Genom, NIH, Bldg 7,Rm 201, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov FU Intramural NIH HHS [Z01 EY000433-04] NR 36 TC 17 Z9 20 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 7 PY 2008 VL 283 IS 10 BP 6607 EP 6615 DI 10.1074/jbc.M709144200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 271HM UT WOS:000253779500066 PM 18178558 ER PT J AU Ghirlando, R Felsenfeld, G AF Ghirlando, Rodolfo Felsenfeld, Gary TI Hydrodynamic studies on defined heterochromatin fragments support a 30-nm fiber having six nucleosomes per turn SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE chromatin; structure; hydrodynamics; heterochromatin ID HIGHER-ORDER STRUCTURE; CHICKEN ERYTHROCYTE CHROMATIN; BETA-GLOBIN GENE; HISTONE; REGION; SUPERSTRUCTURE; ORGANIZATION; SOLUBILITY; SCATTERING; FILAMENT AB We have compared the physical properties of a 15.51-kb constitutive heterochromatin segment and a 16.17-kb facultative heterochromatin segment that form part of the chicken beta-globin locus. These segments were excised from an avian erythroleukemia cell line by restriction enzyme digestion and released from the nucleus, thus allowing measurement of the sedimentation coefficients by use of calibrated sucrose gradients. A determination of the buoyant density of the cross-linked particle in CsCl led to the total mass of the particles and their frictional coefficients, f. Despite the slight differences in nucleosome density, the measured value of f for both fragments was consistent with a rodlike particle having a diameter of 33-45 nm and a length corresponding to approximately six to seven nucleosomes per 11-mn turn. At higher ionic strengths we found no evidence of any abrupt conformational change, demonstrating that these chromatin fragments released from the nucleus did not assume the more compact conformations recently described for some reconstituted structures. Published by Elsevier Ltd. C1 [Ghirlando, Rodolfo; Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov RI Ghirlando, Rodolfo/A-8880-2009 FU Intramural NIH HHS [Z01 DK036151-01] NR 37 TC 48 Z9 48 U1 0 U2 5 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 MAR 7 PY 2008 VL 376 IS 5 BP 1417 EP 1425 DI 10.1016/j.jmb.2007.12.051 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 282RW UT WOS:000254585900016 PM 18234217 ER PT J AU Barinka, C Hlouchova, K Rovenska, M Majer, P Dauter, M Hin, N Ko, YS Tsukamoto, T Slusher, BS Konvalinka, J Lubkowski, J AF Barinka, Cyril Hlouchova, Klara Rovenska, Miroslava Majer, Pavel Dauter, Miroslawa Hin, Niyada Ko, Yao-Sen Tsukamoto, Takashi Slusher, Barbara S. Konvalinka, Jan Lubkowski, Jacek TI Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE prostate-specific membrane antigen; metallopeptidase; folate hydrolase; NAALADase; phosphapeptide ID LINKED ACIDIC DIPEPTIDASE; ELECTRON-DENSITY MAPS; UREA-BASED INHIBITORS; MEMBRANE ANTIGEN; POTENT INHIBITORS; GAMMA-GLUTAMATE; PROSTATE-CANCER; EXPRESSION; NAALADASE; NAAG AB Human glutamate carboxypeptidase II (GCPII) is involved in neuronal signal transduction. and intestinal folate absorption by means of the hydrolysis of its two natural substrates, N-acetyl-aspartyl-glutamate and folyl-poly-gamma-glutamates, respectively. During the past years, tremendous efforts have been made toward the structural analysis of GCPII. Crystal structures of GCPII in complex with various ligands have provided insight into the binding of these ligands, particularly to the S1' site of the enzyme. In this article, we have extended structural characterization of GCPII to its S1 site by using dipeptide-based inhibitors that interact with both S1 and S1' sites of the enzyme. To this end, we have determined crystal structures of human GCPII in complex with phosphapeptide analogs of folyl-gamma-glutamate, aspartyl-glutamate, and gamma-glutamyl-glutamate, refined at 1.50, 1.60, and 1.67 angstrom resolution, respectively. The S1 pocket of GCPII could be accurately defined and analyzed for the first time, and the data indicate the importance of Asn519, Arg463, Arg534, and Arg536 for recognition of the penultimate (i.e., P1) substrate residues. Direct interactions between the positively charged guanidinium groups of Arg534 and Arg536 and a P1 moiety of a substrate/inhibitor provide mechanistic explanation of GCPII preference for acidic dipeptides. Additionally, observed conformational flexibility of the Arg463 and Arg536 side chains likely regulates GCPII affinity toward different inhibitors and modulates GCPII substrate specificity. The biochemical experiments assessing the hydrolysis of several GCPII substrate derivatives modified at the P1 position, also included in this report, further complement and extend conclusions derived from the structural analysis. The data described here form an a solid foundation for the structurally aided design of novel low-molecular-weight GCPII inhibitors and imaging agents. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Barinka, Cyril; Lubkowski, Jacek] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Hlouchova, Klara; Rovenska, Miroslava; Konvalinka, Jan] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Gilead Sci & IOCB Res Ctr, Prague 6, Czech Republic. [Hlouchova, Klara; Rovenska, Miroslava; Konvalinka, Jan] Charles Univ Prague, Fac Nat Sci, Dept Biochem, Prague 2, Czech Republic. [Majer, Pavel; Hin, Niyada; Ko, Yao-Sen; Tsukamoto, Takashi; Slusher, Barbara S.] MGI Pharma Inc, Baltimore, MD USA. [Dauter, Miroslawa] SAIC Frederick Inc, Basic Res Program, Argonne Natl Lab, Argonne, IL USA. RP Barinka, C (reprint author), NCI, Ctr Canc Res, Frederick, MD 21701 USA. EM cyril@ncifcrf.gov RI Konvalinka, Jan/G-7518-2014; Barinka, Cyril/G-9803-2014; OI Konvalinka, Jan/0000-0003-0695-9266; Hlouchova, Klara/0000-0002-5651-4874 FU Intramural NIH HHS [NIH0012079625, Z01 BC010760-01] NR 42 TC 36 Z9 37 U1 0 U2 6 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 MAR 7 PY 2008 VL 376 IS 5 BP 1438 EP 1450 DI 10.1016/j.jmb.2007.12.066 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 282RW UT WOS:000254585900018 PM 18234225 ER PT J AU Chowell, G Bettencourt, LMA Johnson, N Alonso, WJ Viboud, C AF Chowell, Gerardo Bettencourt, Luis M. A. Johnson, Niall Alonso, Wladimir J. Viboud, Cecile TI The 1918-1919 influenza pandemic in England and Wales: spatial patterns in transmissibility and mortality impact SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE influenza; Spanish flu pandemic; reproduction number; demographics; scaling laws; England and Wales ID EPIDEMIC; DYNAMICS; INTERVENTIONS; INFECTIONS; DISEASE; AGENTS; RATES; CITY AB Spatial variations in disease patterns of the 1918-1919 influenza pandemic remain poorly studied. We explored the association between influenza death rates, transmissibility and several geographical and demographic indicators for the autumn and winter waves of the 1918-1919 pandemic in cities, towns and rural areas of England and Wales. Average measures of transmissibility, estimated by the reproduction number, ranged between 1.3 and 1.9, depending on model assumptions and pandemic wave and showed little spatial variation. Death rates varied markedly with urbanization, with 30-40% higher rates in cities and towns compared with rural areas. In addition, death rates varied with population size across rural settings, where low population areas fared worse. By contrast, we found no association between transmissibility, death rates and indicators of population density and residential crowding. Further studies of the geographical mortality patterns associated with the 1918-1919 influenza pandemic may be useful for pandemic planning. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, Gerardo; Bettencourt, Luis M. A.] Los Alamos Natl Lab, Div Theoret, Ctr Nonlinear Studies & Math Modeing & Anal MS B2, Los Alamos, NM 87545 USA. [Bettencourt, Luis M. A.] Santa Fe Inst, Santa Fe, NM 87501 USA. [Johnson, Niall] Australian Commiss Safety & Quality Hlth Care, Sydney, NSW 2001, Australia. [Alonso, Wladimir J.; Viboud, Cecile] NCI, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, POB 872402, Tempe, AZ 85287 USA. EM gchowell82@asu.edu RI Chowell, Gerardo/A-4397-2008; Chowell, Gerardo/F-5038-2012 OI Chowell, Gerardo/0000-0003-2194-2251 NR 42 TC 55 Z9 56 U1 2 U2 18 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD MAR 7 PY 2008 VL 275 IS 1634 BP 501 EP 509 DI 10.1098/rspb.2007.1477 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 256YC UT WOS:000252764800004 PM 18156123 ER PT J AU Zarin, DA Tse, T AF Zarin, Deborah A. Tse, Tony TI Medicine - Moving toward transparency of clinical trials SO SCIENCE LA English DT Editorial Material ID PUBLICATION BIAS; MYOCARDIAL-INFARCTION; REGISTRATION; RISK; ROSIGLITAZONE; FDA; LESSONS C1 [Zarin, Deborah A.; Tse, Tony] NIH, Natl Lib Med, US Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Zarin, DA (reprint author), NIH, Natl Lib Med, US Dept Hlth & Human Serv, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 46 TC 89 Z9 89 U1 1 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 MAR 7 PY 2008 VL 319 IS 5868 BP 1340 EP 1342 DI 10.1126/science.1153632 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 270HW UT WOS:000253712900025 PM 18323436 ER PT J AU Mechanic, LE Luke, BT Goodman, JE Chanock, SJ Harris, CC AF Mechanic, Leah E. Luke, Brian T. Goodman, Julie E. Chanock, Stephen J. Harris, Curtis C. TI Polymorphism Interaction Analysis (PIA): A method for investigating complex gene-gene interactions SO BMC BIOINFORMATICS LA English DT Article ID MULTIFACTOR-DIMENSIONALITY REDUCTION; ENVIRONMENT INTERACTIONS; DNA-REPAIR; CANCER; SUSCEPTIBILITY; ASSOCIATION; DISEASE; VALIDATION; EPISTASIS; RISK AB Background: The risk of common diseases is likely determined by the complex interplay between environmental and genetic factors, including single nucleotide polymorphisms (SNPs). Traditional methods of data analysis are poorly suited for detecting complex interactions due to sparseness of data in high dimensions, which often occurs when data are available for a large number of SNPs for a relatively small number of samples. Validation of associations observed using multiple methods should be implemented to minimize likelihood of false-positive associations. Moreover, high-throughput genotyping methods allow investigators to genotype thousands of SNPs at one time. Investigating associations for each individual SNP or interactions between SNPs using traditional approaches is inefficient and prone to false positives. Results: We developed the Polymorphism Interaction Analysis tool (PIA version 2.0) to include different approaches for ranking and scoring SNP combinations, to account for imbalances between case and control ratios, stratify on particular factors, and examine associations of user-defined pathways (based on SNP or gene) with case status. PIA v. 2.0 detected 2-SNP interactions as the highest ranking model 77% of the time, using simulated data sets of genetic models of interaction (minor allele frequency = 0.2; heritability = 0.01; N = 1600) generated previously [Velez DR, White BC, Motsinger AA, Bush WS, Ritchie MD, Williams SM, Moore JH: A balanced accuracy function for epistasis modeling in imbalanced datasets using multifactor dimensionality reduction. Genet Epidemiol 2007, 31: 306-315.]. Interacting SNPs were detected in both balanced (20 SNPs) and imbalanced data (case: control 1: 2 and 1: 4, 10 SNPs) in the context of non-interacting SNPs. Conclusion: PIA v. 2.0 is a useful tool for exploring gene*gene or gene*environment interactions and identifying a small number of putative associations which may be investigated further using other statistical methods and in replication study populations. C1 [Mechanic, Leah E.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Luke, Brian T.] NCI, SAIC Frederick, Adv Biomed Comp Ctr, NIH, Frederick, MD 21701 USA. [Goodman, Julie E.] Gradient Inc, Boston, MA USA. [Chanock, Stephen J.] NCI, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mechanil@mail.nih.gov; lukeb@ncifcrf.gov; jgoodman@gradientcorp.com; chanocks@mail.nih.gov; harrisc@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 24 TC 31 Z9 33 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 6 PY 2008 VL 9 AR 146 DI 10.1186/1471-2105-9-146 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 286QY UT WOS:000254862300001 PM 18325117 ER PT J AU Shurin, SB Nabel, EG AF Shurin, Susan B. Nabel, Elizabeth G. TI Pharmacogenomics - Ready for prime time? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID WARFARIN C1 [Shurin, Susan B.; Nabel, Elizabeth G.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Shurin, SB (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 45 Z9 50 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 6 PY 2008 VL 358 IS 10 BP 1061 EP 1063 DI 10.1056/NEJMe0800801 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 269JG UT WOS:000253644700011 PM 18322288 ER PT J AU Hardy, J Low, N Singleton, A AF Hardy, John Low, Nancy Singleton, Andrew TI Whole genome association studies: Deciding when persistence becomes perseveration SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Editorial Material ID NATIONAL-COMORBIDITY-SURVEY; DISORDERS; GENETICS; SCHIZOPHRENIA; DISEASES; PREVALENCE; LIFETIME; ANXIETY; MOOD C1 [Hardy, John; Singleton, Andrew] Neurogenet Lab, Bethesda, MD 20892 USA. [Hardy, John] Inst Neurol UCL, Reta Lila Weston Lab, London, England. [Low, Nancy] Inst Neurol UCL, Dept Mol Neurosci, London, England. [Low, Nancy] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Low, Nancy] NIMH, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), Neurogenet Lab, Porter Neurosci Bldg,MSC3707 NIH Main Campus, Bethesda, MD 20892 USA. EM j.hardy@ion.ucl.ac.uk RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 FU Medical Research Council [G0701075] NR 23 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR 5 PY 2008 VL 147B IS 2 BP 131 EP 133 DI 10.1002/ajmg.b.30568 PG 3 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 271OS UT WOS:000253798700001 PM 17541974 ER PT J AU Scattoni, ML McFarlane, HG Zhodzishsky, V Caldwell, HK Young, WS Ricceri, L Crawley, JN AF Scattoni, M. L. McFarlane, H. G. Zhodzishsky, V. Caldwell, H. K. Young, W. S. Ricceri, L. Crawley, J. N. TI Reduced ultrasonic vocalizations in vasopressin 1b knockout mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE social recognition; female-female mouse interactions; maternal potentiation; nest odor orientation; autistic spectrum disorders; mouse models ID V-1B RECEPTOR ANTAGONIST; RAT PUPS; SOCIAL RECOGNITION; AGGRESSIVE-BEHAVIOR; MATERNAL POTENTIATION; MUS-MUSCULUS; OXYTOCIN; AUTISM; MOUSE; SSR149415 AB The neuropeptides oxytocin and vasopressin have been implicated in rodent social and affiliative behaviors, including social bonding, parental care, social recognition, social memory, vocalizations, territoriality, and aggression, as well as components of human social behaviors and the etiology of autism. Previous investigations of mice with various manipulations of the oxytocin and vasopressin systems reported unusual levels of ultrasonic vocalizations in social settings. We employed a vasopressin 1b receptor (Avpr1b) knockout mouse to evaluate the role of the vasopressin 1b receptor subtype in the emission of ultrasonic vocalizations in adult and infant mice. Avpr1b null mutant female mice emitted fewer ultrasonic vocalizations, and their vocalizations were generally at lower frequencies, during a resident-intruder test. Avpr1b null mutant pups emitted ultrasonic vocalizations similar to heterozygote and wildtype littermates when separated from the nest on postnatal days 3, 6, 9, and 12. However, maternal potentiation of ultrasonic vocalizations in Avpr1b null and heterozygote mutants was absent, when tested at postnatal day 9. These results indicate that Avpr1b null mutant mice are impaired in the modulation of ultrasonic vocalizations within different social contexts at infant and adult ages. Published by Elsevier B.V. C1 [Scattoni, M. L.; McFarlane, H. G.; Zhodzishsky, V.; Crawley, J. N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Scattoni, M. L.; Ricceri, L.] Ist Super Sanita, Behav Neurosci Sect, Dept Cell Biol & Neurosci, I-00161 Rome, Italy. [McFarlane, H. G.] Kenyon Coll, Dept Psychol, Gambier, OH 43022 USA. [Caldwell, H. K.; Young, W. S.] NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. RP Scattoni, ML (reprint author), NIMH, Lab Behav Neurosci, Bldg 35 Room 1C-909, Bethesda, MD 20892 USA. EM scattonim@mail.nih.gov RI Young, W Scott/A-9333-2009; Scattoni, Maria Luisa/K-4116-2016; OI Young, W Scott/0000-0001-6614-5112; Scattoni, Maria Luisa/0000-0002-6659-0280; Ricceri, Laura/0000-0001-9850-2284 FU Intramural NIH HHS [NIH0012343496, Z01 MH002179-22]; NIMH NIH HHS [Z01 MH002179] NR 58 TC 64 Z9 64 U1 3 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 5 PY 2008 VL 187 IS 2 BP 371 EP 378 DI 10.1016/j.bbr.2007.09.034 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 259BX UT WOS:000252915200019 PM 18005969 ER PT J AU Kanfi, Y Shalman, R Peshti, V Pilosof, SN Gozlan, YM Pearson, KJ Lerrer, B Moazed, D Marine, JC de Cabo, R Cohen, HY AF Kanfi, Yariv Shalman, Ronnie Peshti, Victoria Pilosof, Shmuel N. Gozlan, Yosi M. Pearson, Kevin J. Lerrer, Batya Moazed, Danesh Marine, Jean-Christophe de Cabo, Rafael Cohen, Haim Y. TI Regulation of SIRT6 protein levels by nutrient availability SO FEBS LETTERS LA English DT Article DE SIRT6; sirtuin; calorie restriction; nutrient availability ID CALORIC RESTRICTION; SACCHAROMYCES-CEREVISIAE; CELL-SURVIVAL; LIFE-SPAN; SIR2; PRIMATES; PATHWAY AB Sirtuins have been shown to regulate life-span in response to nutritional availability. We show here that levels of the mammalian sirtuin, SIRT6, increased upon nutrient deprivation in cultured cells, in mice after fasting, and in rats fed a calorie-restricted diet. The increase in SIRT6 levels is due to stabilization of SIRT6 protein, and not via an increase in SIRT6 transcription. In addition, p53 positively regulates SIRT6 protein levels under standard growth conditions but has no role in the nutrient-dependent regulation of SIRT6. These observations imply that at least two sirtuins are involved in regulation of life-span by nutrient availability. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Kanfi, Yariv; Shalman, Ronnie; Peshti, Victoria; Pilosof, Shmuel N.; Gozlan, Yosi M.; Lerrer, Batya; Cohen, Haim Y.] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Pearson, Kevin J.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Moazed, Danesh] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Marine, Jean-Christophe] Univ Ghent VIB, B-9000 Ghent, Belgium. RP Cohen, HY (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. EM cohenh6@mail.biu.ac.il RI de Cabo, Rafael/E-7996-2010; Marine, Jean Christophe/J-2237-2015; de Cabo, Rafael/J-5230-2016; Marine, Jean-Christophe/K-3292-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Marine, Jean-Christophe/0000-0003-2433-9837; , rafael/0000-0003-2830-5693 FU Howard Hughes Medical Institute; NIGMS NIH HHS [R01 GM061641, R01 GM061641-10] NR 18 TC 97 Z9 99 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAR 5 PY 2008 VL 582 IS 5 BP 543 EP 548 DI 10.1016/j.febslet.2008.01.019 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 326OZ UT WOS:000257670100002 PM 18242175 ER PT J AU Chowdhury, B Zhang, ZJ Mukherjee, AB AF Chowdhury, Bhabadeb Zhang, Zhongjian Mukherjee, Anil B. TI Uteroglobin interacts with the heparin-binding site of fibronectin and prevents fibronectin-IgA complex formation found in IgA-nephropathy SO FEBS LETTERS LA English DT Article DE uteroglobin; Clara cell 10 kDa protein; fibronectin; IgA-nephropathy ID PROTEIN; CD44; FRAGMENT; MATRIX; DOMAIN; MICE AB Immunoglobulin A (IgA)-nephropathy (IgAN) is the most common primary renal glomerular disease in the world that has no effective treatment. High levels of circulating IgA-fibronectin (Fn) complexes, characteristically found in IgAN patients, are suggested to cause abnormal deposition of IgA and Fn in the renal glomeruli of these patients causing renal failure. We previously reported that binding of Fn to uteroglobin (UG), a multifunctional anti-inflammatory protein, inhibits Fn-IgA heteromerization. However, the specific site of Fn-UG interaction until now remained unidentified. We report here that UG interacts with the heparin-binding site of Fn and propose that small molecules competing for interaction with this site may reduce the level of circulating Fn-IgA complexes in IgAN. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Chowdhury, Bhabadeb; Zhang, Zhongjian; Mukherjee, Anil B.] NICHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NICHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Intramural NIH HHS [Z99 HD999999, Z01 HD000910-28] NR 21 TC 2 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAR 5 PY 2008 VL 582 IS 5 BP 611 EP 615 DI 10.1016/j.febslet.2008.01.025 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 326OZ UT WOS:000257670100012 PM 18243143 ER PT J AU Runkoa, AP Griswold, AJ Min, KT AF Runkoa, Alexander P. Griswold, Anthony J. Min, Kyung-Tai TI Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila SO FEBS LETTERS LA English DT Article DE frataxin; Friedreich's ataxia; oxidative stress; Drosophila ID FRIEDREICH ATAXIA; SUPEROXIDE-DISMUTASE; IRON ACCUMULATION; MUTANT MICE; GENE; HOMOLOG; CYTOTOXICITY; MELANOGASTER; LETHALITY; LONGEVITY AB In Friedreich's ataxia, reduction of the mitochondria protein frataxin results in the accumulation of iron and reactive oxygen species, which leads to oxidative damage, neurodegeneration and a diminished lifespan. Recent studies propose that frataxin might play a role in the antioxidative process. Here we show that overexpression of Drosophila frataxin in the mitochondria of female transgenic animals increases antioxidant capability, resistance to oxidative stress insults, and longevity. This suggests that Drosophila frataxin may function to protect the mitochondria from oxidative stresses and the ensuing cellular damage. (c) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Griswold, Anthony J.; Min, Kyung-Tai] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Runkoa, Alexander P.] NINDS, Porter Neurosci Res Ctr, MSC 3705, NIH, Bethesda, MD 20892 USA. RP Min, KT (reprint author), Indiana Univ, Dept Biol, 1001 E 3rd St, Bloomington, IN 47405 USA. EM kyumin@indiana.edu RI Griswold, Anthony/B-7507-2012; OI min, kyung-tai/0000-0003-0983-4258 FU Intramural NIH HHS NR 28 TC 37 Z9 40 U1 1 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 MAR 5 PY 2008 VL 582 IS 5 BP 715 EP 719 DI 10.1016/j.febslet.2008.01.046 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 326OZ UT WOS:000257670100029 PM 18258192 ER PT J AU Heiss, G Wallace, R Anderson, GL Aragaki, A Beresford, SAA Brzyski, R Chlebowski, RT Gass, M LaCroix, A Manson, JE Prentice, RL Rossouw, J Stefanick, ML AF Heiss, Gerardo Wallace, Robert Anderson, Garnet L. Aragaki, Aaron Beresford, Shirley A. A. Brzyski, Robert Chlebowski, Rowan T. Gass, Margery LaCroix, Andrea Manson, Joann E. Prentice, Ross L. Rossouw, Jacques Stefanick, Marcia L. CA WHI Investigators TI Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID POSTMENOPAUSAL HORMONE-THERAPY; PLUS PROGESTIN; LUNG-CANCER; CLINICAL-TRIAL; WOMEN; SURVIVAL; DISEASE; BREAST; MAMMOGRAPHY; REPLACEMENT AB Context The Women's Health Initiative ( WHI) trial of estrogen plus progestin vs placebo was stopped early, after a mean 5.6 years of follow- up, because the overall health risks of hormone therapy exceeded its benefits. Objective To report health outcomes at 3 years ( mean 2.4 years of follow- up) after the intervention was stopped. Design, Setting, and Participants The intervention phase was a double- blind, placebo- controlled, randomized trial of conjugated equine estrogens ( CEE) 0.625 mg daily plus medroxyprogesterone acetate ( MPA) 2.5 mg daily, in 16 608 women aged 50 through 79 years, recruited by 40 centers from 1993 to 1998. The postintervention phase commenced July 8, 2002, and included 15 730 women. Main Outcome Measures Semi- annual monitoring and outcomes ascertainment continued per trial protocol. The primary end points were coronary heart disease and invasive breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. Results The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% ( annualized rate) in the CEE plus MPA ( 343 events) and 1.91% in the placebo group ( 323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group ( 1.56% [ n= 281] vs 1.26% [ n= 218]; hazard ratio [ HR], 1.24; 95% confidence interval [ CI], 1.04- 1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo ( 0.42% [ n= 79] vs 0.33% [ n= 60]; HR, 1.27; 95% CI, 0.91- 1.78) with a modest trend toward a lower HR during the follow- up after the intervention. All- cause mortality was somewhat higher in the CEE plus MPA than in the placebo group ( 1.20% [ n= 233] vs 1.06% [ n= 196]; HR, 1.15; 95% CI, 0.95- 1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 ( HR, 1.12; 95% CI, 1.03- 1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention. Conclusions The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention. A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12% higher in women randomly assigned to receive CEE plus MPA compared with placebo. Trial Registration clinicaltrials. gov Identifier: NCT00000611. C1 [Heiss, Gerardo] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Wallace, Robert] Univ Iowa, Iowa City, IA USA. [Anderson, Garnet L.; Aragaki, Aaron; Beresford, Shirley A. A.; LaCroix, Andrea; Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Brzyski, Robert] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Gass, Margery] Univ Cincinnati, Cincinnati, OH USA. [Manson, Joann E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Rossouw, Jacques] NHLBI, Bethesda, MD 20892 USA. [Stefanick, Marcia L.] Stanford Prevent Res Ctr, Stanford, CA USA. RP Heiss, G (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, 137 E Franklin St,Ste 306, Chapel Hill, NC 27514 USA. EM gerardo_heiss@unc.edu NR 26 TC 201 Z9 207 U1 1 U2 9 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 MAR 5 PY 2008 VL 299 IS 9 BP 1036 EP 1045 DI 10.1001/jama.299.9.1036 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 269JH UT WOS:000253644800021 PM 18319414 ER PT J AU Emanuel, EJ Fuchs, VR AF Emanuel, Ezekiel J. Fuchs, Victor R. TI Who really pays for health care? The myth of "shared responsibility" SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID BENEFITS C1 [Emanuel, Ezekiel J.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Fuchs, Victor R.] Stanford Univ, Dept Econ, Stanford, CA 94305 USA. RP Emanuel, EJ (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov NR 18 TC 37 Z9 37 U1 0 U2 1 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 MAR 5 PY 2008 VL 299 IS 9 BP 1057 EP 1059 DI 10.1001/jama.299.9.1057 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 269JH UT WOS:000253644800024 PM 18319416 ER PT J AU Koizumi, H Wilson, CG Wong, S Yamanishi, T Koshiya, N Smith, JC AF Koizumi, Hidehiko Wilson, Christopher G. Wong, Stephen Yamanishi, Tadashi Koshiya, Naohiro Smith, Jeffrey C. TI Functional imaging, spatial reconstruction, and biophysical analysis of a respiratory motor circuit isolated in vitro SO JOURNAL OF NEUROSCIENCE LA English DT Article DE breathing; brainstem; calcium imaging; rhythm; pre-Botzinger complex; premotoneurons ID PRE-BOTZINGER COMPLEX; PERSISTENT SODIUM CURRENT; RHYTHM GENERATION; HYPOGLOSSAL MOTONEURONS; PACEMAKER NEURONS; PREBOTZINGER COMPLEX; SPINAL-CORD; RAT; NETWORK; MODELS AB We combined real-time calcium-based neural activity imaging with whole-cell patch-clamp recording techniques to map the spatial organization and analyze electrophysiological properties of respiratory neurons forming the circuit transmitting rhythmic drive from the pre-Botzinger complex (pre-BotC) through premotoneurons to hypoglossal (XII) motoneurons. Inspiratory pre-BotC neurons, XII premotoneurons (preMNs), and XII motoneurons (MNs) were retrogradely labeled with Ca2+-sensitive dye in neonatal rat in vitro brainstem slices. PreMN cell bodies were arrayed dorsomedially to pre-BotC neurons with little spatial overlap; axonal projections to MNs were ipsilateral. Inspiratory MNs were distributed in dorsal and ventral subnuclei of XII. Voltage-clamp recordings revealed that two currents, persistent sodium current (NaP) and K+-dominated leak current (Leak), primarily contribute to preMN/MN subthreshold current-voltage relationships. NaP or Leak conductance densities in preMNs and MNs were not significantly different. We quantified preMN and MN action potential time course and spike frequency-current (f-I) relationships and found no significant differences in repetitive spiking dynamics, steady-state f-I gains, and afterpolarizing potentials. Rhythmic synaptic drive current densities were similar in preMNs and MNs. Our results indicate that, despite topographic and morphological differences, preMNs and MNs have some common intrinsic membrane, synaptic integration, and spiking properties that we postulate ensure fidelity of inspiratory drive transmission and conversion of synaptic drive into (pre) motor output. There also appears to be a common architectonic organization for some respiratory drive transmission circuits whereby many preMNs are spatially segregated from pre-BotC rhythm-generating neurons, which we hypothesize may facilitate downstream integration of convergent inputs for premotor pattern formation. C1 [Koizumi, Hidehiko; Wilson, Christopher G.; Wong, Stephen; Yamanishi, Tadashi; Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Koizumi, Hidehiko] Osaka Univ, Grad Sch Dent, Suita, Osaka 5650871, Japan. [Wilson, Christopher G.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Wilson, Christopher G.] Case Western Reserve Univ, Dept Neurosci, Cleveland, OH 44106 USA. [Wong, Stephen] Howard Hughes Med Inst, Bethesda, MD 20814 USA. [Koshiya, Naohiro] Johns Hopkins Campus, Blanchette Rockefeller Neurosci Inst, Rockville, MD 20850 USA. RP Smith, JC (reprint author), NINDS, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 3C-917,35 Convent Dr, Bethesda, MD 20892 USA. EM jsmith@helix.nih.gov FU Intramural NIH HHS NR 40 TC 68 Z9 69 U1 0 U2 5 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 MAR 5 PY 2008 VL 28 IS 10 BP 2353 EP 2365 DI 10.1523/JNEUROSCI.3553-07.2008 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 271WG UT WOS:000253818800007 PM 18322082 ER PT J AU Leng, Y Liang, MH Ren, M Marinova, Z Leeds, P Chuang, DM AF Leng, Yan Liang, Min-Huei Ren, Ming Marinova, Zoya Leeds, Peter Chuang, De-Maw TI Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: Roles of glycogen synthase kinase-3 inhibition SO JOURNAL OF NEUROSCIENCE LA English DT Article DE lithium; valproic acid; HDAC inhibitors; neuroprotection; GSK-3; bipolar disorder ID FOCAL CEREBRAL-ISCHEMIA; REDUCES BRAIN-DAMAGE; BIPOLAR DISORDER; MOOD STABILIZERS; GLUTAMATE EXCITOTOXICITY; ALZHEIMERS-DISEASE; SIGNALING PATHWAY; TRANSCRIPTIONAL ACTIVATION; CELLULAR PLASTICITY; MOLECULAR-MECHANISM AB Lithium and valproic acid (VPA) are two primary drugs used to treat bipolar mood disorder and have frequently been used in combination to treat bipolar patients resistant to monotherapy with either drug. Lithium, a glycogen synthase kinase-3 (GSK-3) inhibitor, and VPA, a histone deacetylase ( HDAC) inhibitor, have neuroprotective effects. The present study was undertaken to demonstrate synergistic neuroprotective effects when both drugs were coadministered. Pretreatment of aging cerebellar granule cells with lithium or VPA alone provided little or no neuroprotection against glutamate-induced cell death. However, copresence of both drugs resulted in complete blockade of glutamate excitotoxicity. Combined treatment with lithium and VPA potentiated serine phosphorylation of GSK-3 alpha and beta isoforms and inhibition of GSK-3 enzyme activity. Transfection with GSK-3 alpha small interfering RNA ( siRNA) and/or GSK-3 beta siRNA mimicked the ability of lithium to induce synergistic protection with VPA. HDAC1 siRNA or other HDAC inhibitors ( phenylbutyrate, sodium butyrate or trichostatin A) also caused synergistic neuroprotection together with lithium. Moreover, combination of lithium and HDAC inhibitors potentiated beta-catenin-dependent, Lef/Tcf-mediated transcriptional activity. An additive increase in GSK-3 serine phosphorylation was also observed in mice chronically treated with lithium and VPA. Together, for the first time, our results demonstrate synergistic neuroprotective effects of lithium and HDAC inhibitors and suggest that GSK-3 inhibition is a likely molecular target for the synergistic neuroprotection. Our results may have implications for the combined use of lithium and VPA in treating bipolar disorder. Additionally, combined use of both drugs may be warranted for clinical trials to treat glutamate-related neurodegenerative diseases. C1 [Leng, Yan; Liang, Min-Huei; Ren, Ming; Marinova, Zoya; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bldg 10,Room 3D-38,10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU Intramural NIH HHS [, Z99 MH999999] NR 66 TC 135 Z9 136 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 5 PY 2008 VL 28 IS 10 BP 2576 EP 2588 DI 10.1523/JNEUROSCI.5467-07.2008 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 271WG UT WOS:000253818800026 PM 18322101 ER PT J AU del Junco, DJ Vernon, SW Coan, SP Tiro, JA Bastian, LA Savas, LS Perz, CA Lairson, DR Chan, W Warrick, C McQueen, A Rakowski, W AF del Junco, Deborah J. Vernon, Sally W. Coan, Sharon P. Tiro, Jasmin A. Bastian, Lori A. Savas, Lara S. Perz, Catherine A. Lairson, David R. Chan, Wen Warrick, Cynthia McQueen, Amy Rakowski, William TI Promoting regular mammography screening I. A systematic assessment of validity in a randomized trial SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HEALTH-INSURANCE PORTABILITY; BREAST-CANCER; TAILORED INTERVENTIONS; BEHAVIORAL MEDICINE; ACCOUNTABILITY ACT; REPEAT MAMMOGRAPHY; WOMEN VETERANS; RESPONSE RATES; CARE; INFORMATION AB Background Most health promotion trials in cancer screening offer limited evidence of external validity. We assessed internal and external validity in a nationwide, population-based trial of an intervention to promote regular mammography screening. Methods Beginning in September 2000, study candidates age 52 years and older (n = 23 000) were randomly selected from the National Registry of Women Veterans and sent an eligibility survey. Consistent with intention-to-treat principles for effectiveness trials, we randomly assigned eligible respondents and nonrespondents to one of five groups. We mailed baseline surveys to groups 1-3 followed by intervention materials of varying personalization to groups 1 and 2. We delayed mailing baseline surveys to two additional control groups to coincide with the mailing of postintervention follow-up surveys to groups 1-3 at year 1 (group 4) and year 2 (group 5). Mammography rates were determined from self-report and Veterans Health Administration records. To assess internal validity, we compared groups on participation and factors associated with mammography screening at each stage. To assess external validity, we compared groups 3, 4, and 5 on mammography rates at the most recent follow-up to detect any cueing effects of prior surveys and at the respective baselines to uncover any secular trends. We also compared nonparticipants with participants on factors associated with mammography screening at the trial's end. Results We established study eligibility for 21 340 (92.8%) of the study candidates. Groups 1-3 were similar throughout the trial in participation and correlates of mammography screening. No statistically significant survey cueing effects or differences between nonparticipants and participants across groups were observed. Mammography screening rates over the 30 months preceding the respective baselines were lower in group 5 (82.3% by self-report) than in groups 1-4 (85.1%, P = .024, group 5 vs groups 1-4 combined), suggesting a decline over time similar to that reported for US women in general. Conclusion This systematic assessment provides evidence of the trial's internal and external validity and illustrates an approach to evaluating validity that is readily adaptable to future trials of behavioral interventions. C1 [del Junco, Deborah J.] Univ Texas Houston, Hlth Sci Ctr, Ctr Clin & Translat Sci, Houston, TX 77030 USA. [Vernon, Sally W.; Coan, Sharon P.; Lairson, David R.; Chan, Wen; McQueen, Amy] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Tiro, Jasmin A.] NCI, Div Canc Control & Populat Sci, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. [Bastian, Lori A.] Durham VA Duke Univ, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Savas, Lara S.] Baylor Coll Med, Dept Med, Sect Gen Med, Houston, TX 77030 USA. [Perz, Catherine A.] Univ Houston, Dept Psychol, Victoria, TX USA. [Warrick, Cynthia] Elizabeth City State Univ, Sch Math Sci & Technol, Elizabeth City, NC USA. [Rakowski, William] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. RP del Junco, DJ (reprint author), Univ Texas Houston, Hlth Sci Ctr, Ctr Clin & Translat Sci, 6410 Fannin St,LL 125, Houston, TX 77030 USA. EM deborah.j.deljunco@uth.tmc.edu OI Tiro, Jasmin/0000-0001-8300-0441 FU NCI NIH HHS [R01 CA076330-04, R01 CA076330, R01 CA076330-01A2, R01 CA076330-02, R01 CA076330-02S1, R01 CA076330-03, R01 CA076330-03S1, R01 CA076330-04S1, R01 CA076330-05, R01 CA076330-05S1, R01 CA076330-05S2, R01 CA76330, R03 CA 103512, R03 CA103512, R03 CA103512-01A2, R03 CA103512-02] NR 73 TC 14 Z9 14 U1 0 U2 2 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 MAR 5 PY 2008 VL 100 IS 5 BP 333 EP 346 DI 10.1093/jnci/djn027 PG 14 WC Oncology SC Oncology GA 271OD UT WOS:000253796800010 PM 18314473 ER PT J AU Vernon, SW del Junco, DJ Tiro, JA Coan, SP Perz, CA Bastian, LA Rakowski, W Chan, W Lairson, DR McQueen, A Fernandez, ME Warrick, C Halder, A DiClemente, C AF Vernon, Sally W. del Junco, Deborah J. Tiro, Jasmin A. Coan, Sharon P. Perz, Catherine A. Bastian, Lori A. Rakowski, William Chan, Wen Lairson, David R. McQueen, Amy Fernandez, Maria E. Warrick, Cynthia Halder, Arada DiClemente, Carlo TI Promoting regular mammography screening II. Results from a Randomized controlled trial in US women veterans SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID FECAL OCCULT BLOOD; INCREASE MAMMOGRAPHY; TAILORED INTERVENTION; REPEAT MAMMOGRAPHY; COLORECTAL-CANCER; DECISION-MAKING; METAANALYSIS; HEALTH; POPULATION; MODEL AB Background Few health promotion trials have evaluated strategies to increase regular mammography screening. We conducted a randomized controlled trial of two theory-based interventions in a population-based, nationally representative sample of women veterans. Methods Study candidates 52 years and older were randomly sampled from the National Registry of Women Veterans and randomly assigned to three groups. Groups 1 and 2 received interventions that varied in the extent of personalization (tailored and targeted vs targeted-only, respectively); group 3 was a survey-only control group. Postintervention follow-up surveys were mailed to all women after 1 and 2 years. Outcome measures were self-reported mammography coverage (completion of one postintervention mammogram) and compliance (completion of two postintervention mammograms). In decreasingly conservative analyses (intention-to-treat [ITT], modified intention-to-treat [MITT], and per-protocol [PP]), we examined crude coverage and compliance estimates and adjusted for covariates and variable follow-up time across study groups using Cox proportional hazards regression. For the PP analyses, we also used logistic regression. Results None of the among-group differences in the crude incidence estimates for mammography coverage was statistically significant in ITT, MITT, or PP analyses. Crude estimates of compliance differed at statistically significant levels in the PP analyses and at levels approaching statistical significance in the ITT and MITT analyses. Absolute differences favoring the intervention over the control groups were 1%-3% for ITT analysis, 1%-5% for MITT analysis, and 2%-6% for the PP analysis. Results from Cox modeling showed no statistically significant effect of the interventions on coverage or compliance in the ITT, MITT, or PP analyses, although hazard rate ratios (HRRs) for coverage were consistently slightly higher in the intervention groups than the control group (range for HRRs = 1.05-1.09). A PP analysis using logistic regression produced odds ratios (ORs) that were consistently higher than the corresponding hazard rate ratios for both coverage and compliance (range for ORs = 1.15-1.29). Conclusions In none of our primary analyses did the tailored and targeted intervention result in higher mammography rates than the targeted-only intervention, and there was limited support for either intervention being more effective than the baseline survey alone. We found that adjustment for variable follow-up time produced more conservative (less favorable) intervention effect estimates. C1 [Vernon, Sally W.; Coan, Sharon P.; Chan, Wen; Lairson, David R.; McQueen, Amy; Fernandez, Maria E.; Halder, Arada] Univ Texas Houston, Sch Publ Hlth, Div Hlth Promot & Behav Sci, Houston, TX 77030 USA. [del Junco, Deborah J.] Univ Texas Houston, Hlth Sci Ctr, Ctr Clin & Translat Sci, Houston, TX USA. [Tiro, Jasmin A.] NCI, Div Canc Prevent, Off Prevent Oncol, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Perz, Catherine A.] Univ Houston, Victoria, TX USA. [Bastian, Lori A.] Duke Univ, Durham Vet Hlth Adm, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Rakowski, William] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Warrick, Cynthia] Elizabeth City State Univ, Sch Math Sci & Technol, Elizabeth City, NC USA. [DiClemente, Carlo] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. RP Vernon, SW (reprint author), Univ Texas Houston, Sch Publ Hlth, Div Hlth Promot & Behav Sci, 7000 Fannin,Ste 2560, Houston, TX 77030 USA. EM sally.w.vernon@uth.tmc.edu OI Tiro, Jasmin/0000-0001-8300-0441 FU NCI NIH HHS [R01 CA076330-02, R01 CA076330-03S1, R01 CA076330-05, R01 CA076330-05S2, R03 CA 103512, R03 CA103512, R03 CA103512-02, R01 CA076330-04S1, R01 CA076330-03, R03 CA103512-01A2, R01 CA76330, R01 CA076330-05S1, R01 CA076330-04, R01 CA076330-02S1, R01 CA076330-01A2, R01 CA076330, KO7 CA79759, R25 CA057712] NR 79 TC 22 Z9 22 U1 1 U2 6 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 MAR 5 PY 2008 VL 100 IS 5 BP 347 EP 358 DI 10.1093/jnci/djn026 PG 12 WC Oncology SC Oncology GA 271OD UT WOS:000253796800011 PM 18314474 ER PT J AU Oleksyk, TK Zhao, K De La Vega, FM Gilbert, DA O'Brien, SJ Smith, MW AF Oleksyk, Taras K. Zhao, Kai De La Vega, Francisco M. Gilbert, Dennis A. O'Brien, Stephen J. Smith, Michael W. TI Identifying Selected Regions from Heterozygosity and Divergence Using a Light-Coverage Genomic Dataset from Two Human Populations SO PLOS ONE LA English DT Article ID RECENT POSITIVE SELECTION; BLOOD-GROUP LOCUS; NATURAL-SELECTION; LINKAGE DISEQUILIBRIUM; HUMAN-EVOLUTION; HAPLOTYPE MAP; SIGNATURES; GENE; DISEASE; DIVERSITY AB When a selective sweep occurs in the chromosomal region around a target gene in two populations that have recently separated, it produces three dramatic genomic consequences: 1) decreased multi-locus heterozygosity in the region; 2) elevated or diminished genetic divergence (F-ST) of multiple polymorphic variants adjacent to the selected locus between the divergent populations, due to the alternative fixation of alleles; and 3) a consequent regional increase in the variance of FST ((SFST)-F-2) for the same clustered variants, due to the increased alternative fixation of alleles in the loci surrounding the selection target. In the first part of our study, to search for potential targets of directional selection, we developed and validated a resampling-based computational approach; we then scanned an array of 31 different-sized moving windows of SNP variants (5-65 SNPs) across the human genome in a set of European and African American population samples with 183,997 SNP loci after correcting for the recombination rate variation. The analysis revealed 180 regions of recent selection with very strong evidence in either population or both. In the second part of our study, we compared the newly discovered putative regions to those sites previously postulated in the literature, using methods based on inspecting patterns of linkage disequilibrium, population divergence and other methodologies. The newly found regions were cross-validated with those found in nine other studies that have searched for selection signals. Our study was replicated especially well in those regions confirmed by three or more studies. These validated regions were independently verified, using a combination of different methods and different databases in other studies, and should include fewer false positives. The main strength of our analysis method compared to others is that it does not require dense genotyping and therefore can be used with data from population-based genome SNP scans from smaller studies of humans or other species. C1 [Oleksyk, Taras K.; Zhao, Kai; O'Brien, Stephen J.; Smith, Michael W.] NCI, Lab Genom Div, Frederick, MD 21701 USA. [Oleksyk, Taras K.; Smith, Michael W.] NCI, SAIC Frederick, Inc, Basic Res Prog, Frederick, MD USA. [De La Vega, Francisco M.; Gilbert, Dennis A.] Appl Biosyst Inc, Foster City, CA USA. RP Oleksyk, TK (reprint author), NCI, Lab Genom Div, Frederick, MD 21701 USA. EM oleksyk@ncifcrf.gov RI De La Vega, Francisco/H-3832-2011; Smith, Michael/B-5341-2012; Taras, Oleksyk/J-8805-2013 OI Taras, Oleksyk/0000-0002-8148-3918 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. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 45 TC 31 Z9 32 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 5 PY 2008 VL 3 IS 3 AR e1712 DI 10.1371/journal.pone.0001712 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367XT UT WOS:000260586600008 PM 18320033 ER PT J AU Ruiz, MIG Floor, K Roepman, P Rodriguez, JA Meijer, GA Mooi, WJ Jassem, E Niklinski, J Muley, T van Zandwijk, N Smit, EF Beebe, K Neckers, L Ylstra, B Giaccone, G AF Ruiz, Marielle I. Gallegos Floor, Karijn Roepman, Paul Rodriguez, Jose A. Meijer, Gerrit A. Mooi, Wolter J. Jassem, Ewa Niklinski, Jacek Muley, Thomas van Zandwijk, Nico Smit, Egbert F. Beebe, Kristin Neckers, Len Ylstra, Bauke Giaccone, Giuseppe TI Integration of Gene Dosage and Gene Expression in Non-Small Cell Lung Cancer, Identification of HSP90 as Potential Target SO PLOS ONE LA English DT Article AB Background: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease. Methodology and Principal Findings: In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%), which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008), survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04). Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. Conclusions: We suggest that targeting HSP90 will have clinical impact for NSCLC patients. C1 [Ruiz, Marielle I. Gallegos; Floor, Karijn; Rodriguez, Jose A.; Giaccone, Giuseppe] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Roepman, Paul] Agendia BV, Amsterdam, Netherlands. [Meijer, Gerrit A.; Mooi, Wolter J.; Ylstra, Bauke] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Jassem, Ewa] Univ Gdansk, Gdansk, Poland. [Niklinski, Jacek] Univ Bialystok, Bialystok, Poland. [Muley, Thomas] Univ Heidelberg, Thoraxklinik Heidelberg, Heidelberg, Germany. [van Zandwijk, Nico] Netherlands Canc Inst, Amsterdam, Netherlands. [Smit, Egbert F.] Vrije Univ Amsterdam, Med Ctr, Dept Pulmonary Dis, Amsterdam, Netherlands. [Beebe, Kristin; Neckers, Len] NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD USA. RP Ruiz, MIG (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. EM giacconeg@mail.nih.gov RI van Zandwijk, Nico/E-4177-2012; Ylstra, Bauke/D-2906-2012; Giaccone, Giuseppe/E-8297-2017 OI van Zandwijk, Nico/0000-0002-8405-9688; Ylstra, Bauke/0000-0001-9479-3010; Giaccone, Giuseppe/0000-0002-5023-7562 NR 36 TC 54 Z9 55 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 MAR 5 PY 2008 VL 3 IS 3 AR e0001722 DI 10.1371/journal.pone.0001722 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367XT UT WOS:000260586600018 ER PT J AU Li, JH Hamdan, FF Kim, SK Jacobson, KA Zhang, XH Han, SJ Wess, J AF Li, Jian Hua Hamdan, Fadi F. Kim, Soo-Kyung Jacobson, Kenneth A. Zhang, Xiaohong Han, Sung-Jun Wess, Juergen TI Ligand-specific changes in M-3 muscarinic acetylcholine receptor structure detected by a disulfide scanning strategy SO BIOCHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; BETA(2) ADRENERGIC-RECEPTOR; CROSS-LINKING STRATEGY; CONFORMATIONAL-CHANGES; INVERSE AGONISM; MOLECULAR-BASIS; CONSTITUTIVE ACTIVATION; RHODOPSIN STRUCTURE; RANDOM MUTAGENESIS; MECHANISMS AB G protein-coupled receptor (GPCR) function can be modulated by different classes of ligands including full and inverse agonists. At present, little is known about the conformational changes that agonist ligands induce in their target GPCRs. In this study, we employed an in situ disulfide cross-linking strategy to monitor ligand-induced structural changes in a series of cysteine (Cys)-substituted mutant M-3 muscarinic acetylcholine receptors. One of our goals was to study whether the cytoplasmic end of transmembrane domain V (TM V), a region known to be critically involved in receptor/G protein coupling, undergoes a major conformational change, similar to the adjacent region of TM VI. Another goal was to determine and compare the disulfide cross-linking patterns observed after treatment of the different mutant receptors with full versus inverse muscarinic agonists. Specifically, we generated 20 double Cys mutant M-3 receptors harboring one Cys substitution within the cytoplasmic end of TM V (L249-1253) and a second one within the cytoplasmic end of TM VI (A489-L492). These receptors were transiently expressed in COS-7 cells and subsequently characterized in pharmacological and disulfide cross-linking studies. Our cross-linking data, in conjunction with a three-dimensional model of the M-3 muscarinic receptor, indicate that M-3 receptor activation does not trigger major structural disturbances within the cytoplasmic segment of TM V, in contrast to the pronounced structural changes predicted to occur at the cytoplasmic end of TM VI. We also demonstrated that full and inverse muscarinic agonists had distinct effects on the efficiency of disulfide bond formation in specific double Cys mutant M3 receptors. The present study provides novel information about the dynamic changes that accompany M-3 receptor activation and how the receptor conformations induced (or stabilized) by full versus inverse muscarinic agonists differ from each other at the molecular level. Because all class I GPCRs are predicted to share a similar transmembrane topology, the conclusions drawn from the present study should be of broad general relevance. C1 [Li, Jian Hua; Hamdan, Fadi F.; Zhang, Xiaohong; Han, Sung-Jun; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Kim, Soo-Kyung; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A 05,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Li, Jianhua/B-7671-2011; Han, Sung-Jun/B-9547-2012; Jacobson, Kenneth/A-1530-2009 OI Li, Jianhua/0000-0002-5744-3182; Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS NR 51 TC 14 Z9 15 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 4 PY 2008 VL 47 IS 9 BP 2776 EP 2788 DI 10.1021/bi7019113 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266TX UT WOS:000253461000009 PM 18247581 ER PT J AU Sibmooh, N Piknova, B Rizzatti, F Schechter, AN AF Sibmooh, Nathawut Piknova, Barbora Rizzatti, Fabiola Schechter, Alan N. TI Oxidation of iron-nitrosyl-hemoglobin by dehydroascorbic acid releases nitric oxide to form nitrite in human erythrocytes SO BIOCHEMISTRY LA English DT Article ID RED-BLOOD-CELLS; ASCORBIC-ACID; VITAMIN-C; HEMODIALYSIS-PATIENTS; BIOLOGICAL TISSUES; IN-VIVO; NO; PLASMA; TRANSPORT; SYNTHASE AB The reaction of deoxyhemoglobin with nitric oxide (NO) or nitrite ions (NO2-) produces iron-nitrosyl-hemoglobin (HbNO) in contrast to the reaction with oxyhemoglobin, which produces methemoglobin and nitrate (NO3-). HbNO has not been associated with the known bioactivities of NO. We hypothesized that HbNO in erythrocytes could be an important source of bioactive NO/nitrite if its oxidation was coupled to the ascorbic acid (ASC) cycle. Studied by absorption and electron paramagnetic resonance (EPR) spectroscopy, DHA oxidized HbNO to methemoglobin and liberated NO from HbNO as determined by chemiluminescence. Both DHA and ascorbate free radical (AFR), the intermediate between ASC and DHA, enhanced NO oxidation to nitrite, but not nitrate; nor did either oxidize nitrite to nitrate. DHA increased the basal levels of nitrite in erythrocytes, while the reactions of nitrite with hemoglobin are slow. In erythrocytes loaded with HbNO, HbNO disappeared after DHA addition, and the AFR signal was detected by EPR. We suggest that the ASC-AFR-DHA cycle may be coupled to that of HbNO-nitrite and provide a mechanism for the endocrine transport of NO via hemoglobin within erythrocytes, resulting in the production of intracellular nitrite. Additionally, intracellular nitrite and nitrate seem to be largely generated by independent pathways within the erythrocyte. These data provide a physiologically robust mechanism for erythrocytic transport of NO bioactivity allowing for hormone-like properties. C1 [Sibmooh, Nathawut; Piknova, Barbora; Rizzatti, Fabiola; Schechter, Alan N.] NIDDK, NIH, Mol Med Branch, Bethesda, MD 20892 USA. [Sibmooh, Nathawut] Mahidol Univ, Fac Sci, Dept Pharmacol, Bangkok 10400, Thailand. RP Schechter, AN (reprint author), NIDDK, NIH, Mol Med Branch, 10 Ctr Dr,Bldg 10,Room 9N314, Bethesda, MD 20892 USA. EM aschecht@helix.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural NIH HHS; NIBIB NIH HHS [P41 EB001980] NR 48 TC 14 Z9 15 U1 4 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 4 PY 2008 VL 47 IS 9 BP 2989 EP 2996 DI 10.1021/bi702158d PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266TX UT WOS:000253461000033 PM 18225862 ER PT J AU da Fonseca, RR Johnson, WE O'Brien, SJ Ramos, MJ Antunes, A AF da Fonseca, Rute R. Johnson, Warren E. O'Brien, Stephen J. Ramos, Maria Joao Antunes, Agostinho TI The adaptive evolution of the mammalian mitochondrial genome SO BMC GENOMICS LA English DT Article ID CYTOCHROME-C-OXIDASE; TRANSMEMBRANE PROTEIN TOPOLOGY; NADH-QUINONE OXIDOREDUCTASE; COMPLEX-I; EXERCISE INTOLERANCE; METABOLIC-RATE; B GENE; OXIDATIVE-PHOSPHORYLATION; SACCHAROMYCES-CEREVISIAE; NONSENSE MUTATION AB Background: The mitochondria produce up to 95% of a eukaryotic cell's energy through oxidative phosphorylation. The proteins involved in this vital process are under high functional constraints. However, metabolic requirements vary across species, potentially modifying selective pressures. We evaluate the adaptive evolution of 12 protein-coding mitochondrial genes in 41 placental mammalian species by assessing amino acid sequence variation and exploring the functional implications of observed variation in secondary and tertiary protein structures. Results: Wide variation in the properties of amino acids were observed at functionally important regions of cytochrome b in species with more-specialized metabolic requirements (such as adaptation to low energy diet or large body size, such as in elephant, dugong, sloth, and pangolin, and adaptation to unusual oxygen requirements, for example diving in cetaceans, flying in bats, and living at high altitudes in alpacas). Signatures of adaptive variation in the NADH dehydrogenase complex were restricted to the loop regions of the transmembrane units which likely function as protons pumps. Evidence of adaptive variation in the cytochrome c oxidase complex was observed mostly at the interface between the mitochondrial and nuclear-encoded subunits, perhaps evidence of co-evolution. The ATP8 subunit, which has an important role in the assembly of F-0, exhibited the highest signal of adaptive variation. ATP6, which has an essential role in rotor performance, showed a high adaptive variation in predicted loop areas. Conclusion: Our study provides insight into the adaptive evolution of the mtDNA genome in mammals and its implications for the molecular mechanism of oxidative phosphorylation. We present a framework for future experimental characterization of the impact of specific mutations in the function, physiology, and interactions of the mtDNA encoded proteins involved in oxidative phosphorylation. C1 [da Fonseca, Rute R.; Ramos, Maria Joao; Antunes, Agostinho] Univ Porto, REQUIMTE, Dept Quim, Fac Ciencias, P-4169007 Oporto, Portugal. [da Fonseca, Rute R.] Univ Copenhagen, Inst Biol, DK-2100 Copenhagen O, Denmark. [Johnson, Warren E.; O'Brien, Stephen J.; Antunes, Agostinho] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [da Fonseca, Rute R.; Antunes, Agostinho] Univ Porto, CIMAR CIIMAR, Ctr Interdisciplinar Invest Marinha & Ambiental, P-4050123 Oporto, Portugal. RP Antunes, A (reprint author), Univ Porto, REQUIMTE, Dept Quim, Fac Ciencias, Rua Campo Alegre 687, P-4169007 Oporto, Portugal. EM rute.r.da.fonseca@gmail.com; johnsonw@ncifcrf.gov; obrien@ncifcrf.gov; mjramos@fc.up.pt; aantunes@ncifcrf.gov RI da Fonseca, Rute/F-9143-2013; REQUIMTE, AL/H-9106-2013; Chaves, Pedro/K-1288-2013; REQUIMTE, TCB/M-6190-2013; REQUIMTE, UCIBIO/N-9846-2013; Scientific output, CIIMAR/E-5122-2012; Ramos, Maria/D-6183-2013; Johnson, Warren/D-4149-2016; OI da Fonseca, Rute/0000-0002-2805-4698; Scientific output, CIIMAR/0000-0001-6270-2153; Ramos, Maria/0000-0002-7554-8324; Johnson, Warren/0000-0002-5954-186X; Antunes, Agostinho/0000-0002-1328-1732 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 87 TC 97 Z9 98 U1 4 U2 42 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAR 4 PY 2008 VL 9 AR 119 DI 10.1186/1471-2164-9-119 PG 22 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 298RP UT WOS:000255705100001 PM 18318906 ER PT J AU Shimizu, Y Kinoshita, I Kikuchi, J Yamazaki, K Nishimura, M Birrer, MJ Dosaka-Akita, H AF Shimizu, Y. Kinoshita, I. Kikuchi, J. Yamazaki, K. Nishimura, M. Birrer, M. J. Dosaka-Akita, H. TI Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant-negative mutant SO BRITISH JOURNAL OF CANCER LA English DT Article DE cJun; AP-1; non-small cell lung cancer; dominant-negative mutant ID ANCHORAGE-INDEPENDENT GROWTH; SIGNAL-TRANSDUCTION PATHWAYS; TRANSCRIPTION FACTOR AP-1; C-JUN; CYCLIN-A; KINASE-ACTIVITY; RAT1A CELLS; UP-REGULATION; RAT-1A CELLS; TARGET GENE AB cJun, a major constituent of AP-1 transcription factor transducing multiple mitogen growth signals, is frequently overexpressed in non-small cell lung cancers (NSCLCs). The purpose of this study is to determine the effects of AP-1 blockade on the growth of NSCLC cells using a cJun dominant-negative mutant, TAM67. Transiently transfected TAM67 inhibited AP-1 transcriptional activity in NSCLC cell lines, NCI-H1299 (H1299), A549 and NCI-H520 (H520). The colony-forming efficiency of H1299 and A549 was reduced by TAM67, while that of H520 was not. To elucidate the effects of TAM67 on the growth of H1299, we established H1299 clone cells that expressed TAM67 under the control of a doxycycline-inducible promoter. In the H1299 clone cells, the induced TAM67 inhibited anchorage-dependent growth by promoting G1 cell-cycle block, but not by apoptosis. The induced TAM67 decreased the expression of a cell-cycle regulatory protein, cyclin A. TAM67 also inhibited anchorage-independent growth of these cells. Furthermore, TAM67 reduced growth of established xenograft tumours from these cells in nude mice. These results suggest that AP-1 plays an essential role in the growth of at least some of NSCLC cells. C1 [Shimizu, Y.; Kinoshita, I.; Dosaka-Akita, H.] Hokkaido Univ, Grad Sch Med, Dept Med Oncol, Kita Ku, Sapporo, Hokkaido 0608638, Japan. [Kinoshita, I.; Kikuchi, J.] Hokkaido Univ, Sch Med, Dept Med 1, Sapporo, Hokkaido 0608638, Japan. [Birrer, M. J.] NCI, Ctr Canc Res, Cell & Canc Biol Dept, Rockville, MD 20850 USA. RP Kinoshita, I (reprint author), Hokkaido Univ, Grad Sch Med, Dept Med Oncol, Kita Ku, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. EM kinoshii@med.hokudai.ac.jp RI Shimizu, Yasushi/D-8057-2012; Akita, Hirotoshi/E-1356-2012; Nishimura, Masaharu/A-4062-2012 NR 39 TC 18 Z9 18 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 MAR 4 PY 2008 VL 98 IS 5 BP 915 EP 922 DI 10.1038/sj.bjc.6604267 PG 8 WC Oncology SC Oncology GA 281WG UT WOS:000254529000010 PM 18283312 ER PT J AU Serra, A Liao, K Martinez-Conde, S Optican, LM Leigh, RJ AF Serra, A. Liao, K. Martinez-Conde, S. Optican, L. M. Leigh, R. J. TI Suppression of saccadic intrusions in hereditary ataxia by memantine SO NEUROLOGY LA English DT Editorial Material C1 [Serra, A.; Liao, K.; Leigh, R. J.] Case Western Reserve Univ, Vet Affairs Med Ctr, Cleveland, OH 44106 USA. [Serra, A.] Univ Sassari, Inst Clin Neurol, I-07100 Sassari, Italy. [Martinez-Conde, S.] Barrow Neurol Inst, Dept Neurobiol, Phoenix, AZ 85013 USA. [Optican, L. M.] DHHS, Sensorimotor Res Lab, NEI, NIH, Bethesda, MD USA. RP Leigh, RJ (reprint author), Univ Hosp, Dept Neurol, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM rjl4@po.cwru.edu RI liao, ke/B-1453-2010 FU Intramural NIH HHS [Z01 EY000302-13]; NEI NIH HHS [EY06717, R01 EY006717] NR 7 TC 23 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 4 PY 2008 VL 70 IS 10 BP 810 EP 812 DI 10.1212/01.wnl.0000286952.01476.eb PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 271GE UT WOS:000253776100011 PM 18316692 ER PT J AU Uddin, M Goodman, M Erez, O Romero, R Liu, G Islam, M Opazo, JC Sherwood, CC Grossman, LI Wildman, DE AF Uddin, Monica Goodman, Morris Erez, Offer Romero, Roberto Liu, Guozhen Islam, Munirul Opazo, Juan C. Sherwood, Chet C. Grossman, Lawrence I. Wildman, Derek E. TI Distinct genomic signatures of adaptation in pre- and postnatal environments during human evolution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fetal; human disease; mitochondria; placenta; thyroid ID CYTOCHROME-C-OXIDASE; THYROID-HORMONE; PHYLOGENETIC ANALYSIS; POSITIVE SELECTION; BRAIN-DEVELOPMENT; GENE-EXPRESSION; HUMAN PLACENTA; PROTEIN; TRANSCRIPTION; MIGRATION AB The human genome evolution project seeks to reveal the genetic underpinnings of key phenotypic features that are distinctive of humans, such as a greatly enlarged cerebral cortex, slow development, and long life spans. This project has focused predominantly on genotypic changes during the 6-million-year descent from the last common ancestor (LCA) of humans and chimpanzees. Here, we argue that adaptive genotypic changes during earlier periods of evolutionary history also helped shape the distinctive human phenotype. Using comparative genome sequence data from 10 vertebrate species, we find a signature of human ancestry-specific adaptive evolution in 1,240 genes during their descent from the LCA with rodents. We also find that the signature of adaptive evolution is significantly different for highly expressed genes in human fetal and adult-stage tissues. Functional annotation clustering shows that on the ape stem lineage, an especially evident adaptively evolved biological pathway contains genes that function in mitochondria, are crucially involved in aerobic energy production, and are highly expressed in two energy-demanding tissues, heart and brain. Also, on this ape stem lineage, there was adaptive evolution among genes associated with human autoimmune and aging-related diseases. During more recent human descent, the adaptively evolving, highly expressed genes in fetal brain are involved in mediating neuronal connectivity. Comparing adaptively evolving genes from pre- and postnatal-stage tissues suggests that different selective pressures act on the development vs. the maintenance of the human phenotype. C1 [Uddin, Monica; Goodman, Morris; Liu, Guozhen; Opazo, Juan C.; Grossman, Lawrence I.; Wildman, Derek E.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Goodman, Morris; Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Erez, Offer; Romero, Roberto; Wildman, Derek E.] NICHHD, NIH, Perinatol Res Branch, Bethesda, MD 20892 USA. [Islam, Munirul] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Sherwood, Chet C.] George Washington Univ, Dept Anthropol, Washington, DC 20052 USA. [Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Wildman, Derek E.] Hutzel Womens Hosp, Detroit, MI 48201 USA. RP Goodman, M (reprint author), Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. EM mgoodwayne@aol.com; dwildman@med.wayne.edu RI Opazo, Juan/A-9363-2009; OI Opazo, Juan/0000-0001-7938-4083 FU Intramural NIH HHS; NINDS NIH HHS [NS-42867, R01 NS042867] NR 56 TC 30 Z9 31 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 4 PY 2008 VL 105 IS 9 BP 3215 EP 3220 DI 10.1073/pnas.0712400105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 272FY UT WOS:000253846500010 PM 18305157 ER PT J AU Contreras, JE Srikumar, D Holmgren, M AF Contreras, Jorge E. Srikumar, Deepa Holmgren, Miguel TI Gating at the selectivity filter in cyclic nucleotide-gated channels SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SHAKER POTASSIUM CHANNELS; RECTIFIER K+ CHANNELS; QUATERNARY AMMONIUM; ROD PHOTORECEPTORS; ACTIVATION GATE; ION CHANNELS; CONFORMATIONAL-CHANGE; CA2+ BLOCKAGE; GIANT AXONS; PORE REGION AB By opening and closing the permeation pathway (gating) in response to cGMP binding, cyclic nucleotide-gated (CNG) channels serve key roles in the transduction of visual and olfactory signals. Compiling evidence suggests that the activation gate in CNG channels is not located at the intracellular end of pore, as it has been established for voltage-activated potassium (K-v) channels. Here, we show that ion permeation in CNG channels is tightly regulated at the selectivity filter. By scanning the entire selectivity filter using small cysteine reagents, like cadmium and silver, we observed a state-dependent accessibility pattern consistent with gated access at the middle of the selectivity filter, likely at the corresponding position known to regulate structural changes in KcsA channels in response to low concentrations of permeant ions. C1 [Contreras, Jorge E.; Srikumar, Deepa; Holmgren, Miguel] NINDS, Porter Neurosci Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Holmgren, M (reprint author), NINDS, Porter Neurosci Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. EM holmgren@ninds.nih.gov FU Intramural NIH HHS NR 61 TC 47 Z9 47 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 4 PY 2008 VL 105 IS 9 BP 3310 EP 3314 DI 10.1073/pnas.0709809105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 272FY UT WOS:000253846500026 PM 18287006 ER PT J AU Padilla, PI Uhart, M Pacheco-Rodriguez, G Peculis, BA Moss, J Vaughan, M AF Padilla, Philip Ian Uhart, Marina Pacheco-Rodriguez, Gustavo Peculis, Brenda A. Moss, Joel Vaughan, Martha TI Association of guanine nucleotide-exchange protein BIG1 in HepG2 cell nuclei with nucleolin, U3 snoRNA, and fibrillarin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ADP-RIBOSYLATION FACTORS; RIBOSOMAL-RNA; KINASE-A; ARF; U8; LOCALIZATION; BIOGENESIS; MATURATION; DYNAMICS; COMPLEX AB BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein, activates class I ADP-ribosylation factors (ARF1-3) by catalyzing the replacement of bound GDP by GTP, an action critical for the regulation of protein transport in eukaryotic cells. Our earlier report [Padilla PI, Pancheco-Rodriguez G, Moss J, Vaughan M (2004) Proc Natl Acad Sci USA 101:2752-2757] that BIG 1 concentrated in nucleoli of serum-starved HepG2 cells prompted us to identify molecules associated with BIG1 in dynamic nucleolar structures. Antibodies against BIG1 or nucleolin coprecipitated both proteins from nuclei, which was abolished by the incubation of nuclei with RNase A or DNase, indicating that the interaction depended on nucleic acids. P-32 labeling of RNAs immunoprecipitated with BIG1 or nucleolin from nuclei revealed bands of approximate to 210 bases that also hybridized with U3 small nucleolar (sno)RNA-specific oligonucleotides. Clones of U3 snoRNA cDNAs from the material precipitated by antibodies against BIG1 or nucleolin yielded identical nucleotide sequences that also were found in genomic DNA. Later analyses revealed the presence of fibrillarin, nucleoporin p62, and La in BIG1 and nucleolin immunoprecipitates. Our data demonstrate that BIG1, nucleolin, U3, the U3-binding protein fibrillarin, and the RNA-binding protein La may exist together in nuclear complexes, consistent with a potential role for BIG1 in nucleolar processes. Evidence that BIG1 and nucleolin, but not fibrillarin, can be present with p62 at the nuclear envelope confirms the presence of BIG1 and nucleolin in dynamic molecular complexes that change in composition while moving through nuclei. Nuclear functions of BIG1 remain to be determined. C1 [Padilla, Philip Ian; Uhart, Marina; Pacheco-Rodriguez, Gustavo; Moss, Joel; Vaughan, Martha] NHLBI, Translat Med Brach, Natl Inst Hlth, Bethesda, MD 20892 USA. [Peculis, Brenda A.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. RP Vaughan, M (reprint author), NHLBI, Translat Med Brach, Natl Inst Hlth, Bethesda, MD 20892 USA. EM vaughanm@nhlbi.nih.gov FU Intramural NIH HHS NR 35 TC 11 Z9 12 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 4 PY 2008 VL 105 IS 9 BP 3357 EP 3361 DI 10.1073/pnas.0712387105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 272FY UT WOS:000253846500034 PM 18292223 ER PT J AU Lee, IH Cao, L Mostoslavsky, R Lombard, DB Liu, J Bruns, NE Tsokos, M Alt, FW Finkel, T AF Lee, In Hye Cao, Liu Mostoslavsky, Raul Lombard, David B. Liu, Jie Bruns, Nicholas E. Tsokos, Maria Alt, Frederick W. Finkel, Toren TI A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LIFE-SPAN EXTENSION; CALORIE RESTRICTION; CELL-SURVIVAL; C-ELEGANS; MICE; DISEASE; PGC-1-ALPHA; P53; NEURODEGENERATION; SIRTUINS AB We demonstrate a role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. In particular, transient increased expression of Sirt1 is sufficient to stimulate basal rates of autophagy. In addition, we show that Sirt1(-/-) mouse embryonic fibroblasts do not fully activate autophagy under starved conditions. Reconstitution with wild-type but not a deacetylase-inactive mutant of Sirt1 restores autophagy in these cells. We further demonstrate that Sirt1 can form a molecular complex with several essential components of the autophagy machinery, including autophagy genes (Atg)5, Atg7, and Atg8. In vitro, Sirt1 can, in an NAD-dependent fashion, directly deacetylate these components. The absence of Sirt1 leads to markedly elevated acetylation of proteins known to be required for autophagy in both cultured cells and in embryonic and neonatal tissues. Finally, we show that Sirt1-/- mice partially resemble Atg5(-/-) mice, including the accumulation of damaged organelles, disruption of energy homeostasis, and early perinatal mortality. Furthermore, the in utero delivery of the metabolic substrate pyruvate extends the survival of Sirt1-/- pups. These results suggest that the Sirt1 deacetylase is an important in vivo regulator of autophagy and provide a link between sirtuin function and the overall cellular response to limited nutrients. C1 [Mostoslavsky, Raul; Lombard, David B.; Alt, Frederick W.] Harvard Univ, Sch Med, CBR Inst Biomed Res, Childrens Hosp,Howard Hughes Med Inst, Boston, MA 02115 USA. [Lee, In Hye; Liu, Jie; Bruns, Nicholas E.; Finkel, Toren] NHLBI, Translat Med Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Canc Res Ctr, Boston, MA 02114 USA. [Lombard, David B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Tsokos, Maria] Natl Canc Inst, Pathol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, CBR Inst Biomed Res, Childrens Hosp,Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; tf35d@nih.gov FU Intramural NIH HHS NR 37 TC 514 Z9 542 U1 8 U2 55 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 MAR 4 PY 2008 VL 105 IS 9 BP 3374 EP 3379 DI 10.1073/pnas.0712145105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 272FY UT WOS:000253846500037 PM 18296641 ER PT J AU Li, SW Takeuchi, F Wang, JA Fan, QY Komurasaki, T Billings, EM Pacheco-Rodriguez, G Moss, J Darling, TN AF Li, Shaowei Takeuchi, Fumiko Wang, Ji-an Fan, Qingyuan Komurasaki, Toshi Billings, Eric M. Pacheco-Rodriguez, Gustavo Moss, Joel Darling, Thomas N. TI Mesenchymal-epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE angiofibromas; paracrine; periungual fibromas TSC1; TSC2 ID EPIDERMAL-GROWTH-FACTOR; SIGNALING PATHWAYS; ADENOMA SEBACEUM; FACTOR FAMILY; SKIN-LESIONS; IN-VITRO; EXPRESSION; CELLS; GENE; PATHOGENESIS AB Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the. existence or location of cells with biallelic mutations ("two-hit" cells) was unclear. We compared TSC skin hamartomas (angiofibromas and periungual fibromas) with normal-appearing skin of the same patient, and we observed more proliferation and mTOR activation in hamartoma epidermis. Two-hit cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal-epithelia l interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed with real-time PCR, and increased amounts of epiregulin protein were demonstrated with immunoprecipitation. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by two-hit cells in the dermis and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin. C1 [Li, Shaowei; Takeuchi, Fumiko; Wang, Ji-an; Fan, Qingyuan; Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Komurasaki, Toshi] Taisho Pharmaceut Co Ltd, Mol & Pharmacol Labs, Mol Biol Lab, Saitama, Saitama 3319530, Japan. [Billings, Eric M.; Pacheco-Rodriguez, Gustavo; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Darling, TN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM tdarling@usuhs.mil OI Darling, Thomas/0000-0002-5161-1974 FU Intramural NIH HHS; NCI NIH HHS [1 R01 CA100907, R01 CA100907] NR 43 TC 26 Z9 27 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 4 PY 2008 VL 105 IS 9 BP 3539 EP 3544 DI 10.1073/pnas.0712397105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 272FY UT WOS:000253846500065 PM 18292222 ER PT J AU Tootell, RBH Devaney, KJ Young, JC Postelnicu, G Rajimehr, R Ungerleider, LG AF Tootell, Roger B. H. Devaney, Kathryn J. Young, Jeremy C. Postelnicu, Gheorghe Rajimehr, Reza Ungerleider, Leslie G. TI fMRI mapping of a morphed continuum of 3D shapes within inferior temporal cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE category; continuous; single-stimulus ID MONKEY INFEROTEMPORAL CORTEX; SURFACE-BASED ANALYSIS; FUSIFORM FACE AREA; VISUAL PROPERTIES; FUNCTIONAL-ORGANIZATION; NONHUMAN-PRIMATES; SELECTIVE CELLS; MACAQUE; OBJECTS; NEURONS AB Here, we mapped fMRI responses to incrementally changing shapes along a continuous 3D morph, ranging from a head ("face") to a house ("place"). The response to each shape was mapped independently by using single-stimulus imaging, and stimulus shapes were equated for lower-level visual cues. We measured activity in 2-mm samples across human inferior temporal cortex from the fusiform face area (FFA) (apparently selective for faces) to the parahippocampal place area (PPA) (apparently selective for places), testing for (i) incremental changes in the topography of FFA and PPA (predicted by the continuous-mapping model) or (ii) little or no response to the intermediate morphed shapes (predicted by the category model). Neither result occurred; instead, we found approximately linearly graded changes in the response amplitudes to graded-shape changes, without changes in topography-similar to visual responses in different lower-tier cortical areas. C1 [Tootell, Roger B. H.; Devaney, Kathryn J.; Young, Jeremy C.; Postelnicu, Gheorghe; Rajimehr, Reza] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Tootell, Roger B. H.] NIMH, Lab Brain Cognit, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Tootell, RBH (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM tootell@nmr.mgh.harvard.edu FU Intramural NIH HHS; NCRR NIH HHS [P41 RR014075, P41 RR14075]; NEI NIH HHS [R01 EY017081, R01 EY017081-01A1, R01 EY017081-02, R01 EY017081-03]; NIMH NIH HHS [R01 MH67529, R01 MH067529] NR 40 TC 18 Z9 18 U1 0 U2 0 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 MAR 4 PY 2008 VL 105 IS 9 BP 3605 EP 3609 DI 10.1073/pnas.0712274105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 272FY UT WOS:000253846500076 PM 18287004 ER PT J AU Nielsen, J Hoffer, JD Knepper, MA Agre, P Nielsen, S Fenton, RA AF Nielsen, Jakob Hoffer, Jason D. Knepper, Mark A. Agre, Peter Nielsen, Soren Fenton, Robert A. TI Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: Mechanisms for aquaporin 2 down-regulation and cellular proliferation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE differential gel electrophoresis (DIGE); kidney; GSK3 beta; Akt kinase ID GLYCOGEN-SYNTHASE KINASE-3-BETA; MEDULLARY COLLECTING DUCT; INDUCED NDI; ALTERED EXPRESSION; KIDNEY; RATS; CELLS; TRANSPORTERS; MEDICINE AB Lithium is a commonly prescribed mood-stabilizing drug. However, chronic treatment with lithium induces numerous kidney-related side effects, such as dramatically reduced aquaporin 2 (AQP2) abundance, altered renal function, and structural changes. As a model system, inner medullary collecting ducts (IMCD) isolated from rats treated with lithium for either 1 or 2 weeks were subjected to differential 2D gel electrophoresis combined with mass spectrometry and bioinformatics analysis to identify (i) signaling pathways affected by lithium and (ii) unique candidate proteins for AQP2 regulation. After 1 or 2 weeks of lithium treatment, we identified 6 and 74 proteins with altered abundance compared with controls, respectively. We randomly selected 17 proteins with altered abundance caused by lithium treatment for validation by immunoblotting. Bioinformatics analysis of the data indicated that proteins involved in cell death, apoptosis, cell proliferation, and morphology are highly affected by lithium. We demonstrate that members of several signaling pathways are activated by lithium treatment, including the PKB/Akt-kinase and the mitogen-activated protein kinases (MAPK), such as extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38. Lithium treatment increased the intracellular accumulation of beta-catenin in association with increased levels of phosphorylated glycogen synthase kinase type 3 beta (GSK3 beta). This study provides a comprehensive analysis of the proteins affected by lithium treatment in the IMCD and, as such, provides clues to potential lithium targets in the brain. C1 [Agre, Peter] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Nielsen, Jakob; Nielsen, Soren; Fenton, Robert A.] Aarhus Univ, Water & Salt Res Ctr, DK-8000 Aarhus, Denmark. [Nielsen, Jakob; Nielsen, Soren; Fenton, Robert A.] Aarhus Univ, Inst Anat, DK-8000 Aarhus, Denmark. [Hoffer, Jason D.; Knepper, Mark A.] NHLBI, Natl Inst Hlth, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Agre, P (reprint author), Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. EM pagre@cellbio.duke.edu; rofe@ana.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01 HL001285] NR 26 TC 57 Z9 59 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 MAR 4 PY 2008 VL 105 IS 9 BP 3634 EP 3639 DI 10.1073/pnas.0800001105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 272FY UT WOS:000253846500081 PM 18296634 ER PT J AU Rothenburg, S Deigendesch, N Dey, M Dever, TE Tazi, L AF Rothenburg, Stefan Deigendesch, Nikolaus Dey, Madhusudan Dever, Thomas E. Tazi, Loubna TI Double-stranded RNA-activated protein kinase PKR of fishes and amphibians: Varying the number of double-stranded RNA binding domains and lineage-specific duplications SO BMC BIOLOGY LA English DT Article ID Z-DNA-BINDING; EDITING ENZYME ADAR1; INITIATION FACTOR-II; Z-ALPHA DOMAIN; HANDED Z-DNA; ADENOSINE-DEAMINASE; EUKARYOTIC INITIATION-FACTOR-2-ALPHA; INTRACELLULAR-LOCALIZATION; SUBSTRATE RECOGNITION; TRANSLATIONAL CONTROL AB Background: Double-stranded (ds) RNA, generated during viral infection, binds and activates the mammalian anti-viral protein kinase PKR, which phosphorylates the translation initiation factor eIF2 alpha leading to the general inhibition of protein synthesis. Although PKR-like activity has been described in fish cells, the responsible enzymes eluded molecular characterization until the recent discovery of goldfish and zebrafish PKZ, which contain Z-DNA-binding domains instead of dsRNA-binding domains ( dsRBDs). Fish and amphibian PKR genes have not been described so far. Results: Here we report the cloning and identification of 13 PKR genes from 8 teleost fish and amphibian species, including zebrafish, demonstrating the coexistence of PKR and PKZ in this latter species. Analyses of their genomic organization revealed up to three tandemly arrayed PKR genes, which are arranged in head-to-tail orientation. At least five duplications occurred independently in fish and amphibian lineages. Phylogenetic analyses reveal that the kinase domains of fish PKR genes are more closely related to those of fish PKZ than to the PKR kinase domains of other vertebrate species. The duplication leading to fish PKR and PKZ genes occurred early during teleost fish evolution after the divergence of the tetrapod lineage. While two dsRBDs are found in mammalian and amphibian PKR, one, two or three dsRBDs are present in fish PKR. In zebrafish, both PKR and PKZ were strongly upregulated after immunostimulation with some tissue-specific expression differences. Using genetic and biochemical assays we demonstrate that both zebrafish PKR and PKZ can phosphorylate eIF2a in yeast. Conclusion: Considering the important role for PKR in host defense against viruses, the independent duplication and fixation of PKR genes in different lineages probably provided selective advantages by leading to the recognition of an extended spectrum of viral nucleic acid structures, including both dsRNA and Z-DNA/RNA, and perhaps by altering sensitivity to viral PKR inhibitors. Further implications of our findings for the evolution of the PKR family and for studying PKR/PKZ interactions with viral gene products and their roles in viral infections are discussed. C1 [Rothenburg, Stefan; Dey, Madhusudan; Dever, Thomas E.] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Rothenburg, Stefan; Deigendesch, Nikolaus] Univ Hosp Eppendorf, Inst Immunol, D-20246 Hamburg, Germany. [Tazi, Loubna] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. RP Rothenburg, S (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM rothenst@mail.nih.gov; ndeigend@uke.uni-hamburg.de; deym@MAIL.NIH.GOV; tdever@box-t.nih.gov; lt247@byu.edu RI Rothenburg, Stefan/A-8340-2008; OI Dever, Thomas/0000-0001-7120-9678 FU Intramural NIH HHS NR 69 TC 42 Z9 44 U1 1 U2 7 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 MAR 3 PY 2008 VL 6 AR 12 DI 10.1186/1741-7007-6-12 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 286VZ UT WOS:000254875400001 PM 18312693 ER PT J AU Morales, M Hein, K Vogel, Z AF Morales, M. Hein, K. Vogel, Z. TI Hippocampal interneurons co-express transcripts encoding the alpha 7 nicotinic receptor subunit and the cannabinoid receptor 1 SO NEUROSCIENCE LA English DT Article DE CB1; 5-HT3 receptors; 5-HT; CCK; Alzheimer's disease; schizophrenia ID NICOTINIC ACETYLCHOLINE-RECEPTOR; ALPHA-BUNGAROTOXIN-BINDING; DISTINCT NEURONAL SUBPOPULATIONS; CENTRAL-NERVOUS-SYSTEM; ADULT-MOUSE FOREBRAIN; RAT HIPPOCAMPUS; ENDOGENOUS CANNABINOIDS; ACH RECEPTORS; CB1 RECEPTORS; GABAERGIC TRANSMISSION AB The notion of functional interactions between the alpha 7 nicotinic acetylcholine (alpha 7 nACh) and the cannabinoid systems is emerging from recent in vitro and in vivo studies. Both the alpha 7 nACh receptor and the cannabinoid receptor 1 (CB1) are highly expressed in the hippocampus. To begin addressing possible anatomical interactions between the alpha 7 nACh and the cannabinoid systems in the rat hippocampus, we investigated the distribution of neurons expressing alpha 7 nACh mRNA in relation to those containing CB1 mRNA. By in situ hybridization we found that the alpha 7 nACh mRNA is diffusely expressed in principal neurons and is highly expressed in a subset of interneurons. We observed that the pattern of distribution of hippocampal interneurons co-expressing transcripts encoding alpha 7 nACh and glutamate decarboxylase (GAD; synthesizing enzyme of GABA) closely resembles the one displayed by interneurons expressing CB1 mRNA. By double in situ hybridization we established that the majority of hippocampal interneurons expressing alpha 7 nACh mRNA have high levels of CB1 mRNA. As CB1 interneurons contain cholecystolkinin (CCK), we investigated the degree of cellular co-expression of alpha 7 nACh mRNA and CCK, and found that the cellular co-existence of alpha 7 nACh and CCK varies within the different layers of the hippocampus. In summary, we established that most of the hippocampal alpha 7 nACh expressing interneurons are endowed with CB1 mRNA. We found that these alpha 7 nACh/CB1 interneurons are the major subpopulation of hippocampal interneurons expressing CB1 mRNA. The alpha 7 nACh expressing interneurons represent half of the detected population of CCK containing neurons in the hippocampus. Since it is well established that the vast majority of hippocampal interneurons expressing CB1 mRNA have 5-HT type 3 (5-HT,) receptors, we conclude that these hippocampal alpha 7 nACh/5HT(3)/CB1/CCK interneurons correspond to those previously postulated to relay inputs from diverse cortical and subcortical regions about emotional, motivational, and physiological states. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Morales, M.; Hein, K.; Vogel, Z.] Natl Inst Drug Abuse, Intramural Res Program, Cellular Neurophysiol Sect, Baltimore, MD 21224 USA. RP Morales, M (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Cellular Neurophysiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000449-02, NIH0012231544] NR 55 TC 19 Z9 19 U1 0 U2 3 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 MAR 3 PY 2008 VL 152 IS 1 BP 70 EP 81 DI 10.1016/j.neuroscience.2007.12.019 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 273JZ UT WOS:000253927600009 PM 18222041 ER PT J AU Lao, ZQ Shen, DG Liu, DF Jawad, AF Melhern, ER Launer, LJ Bryan, RN Davatzikos, C AF Lao, Zhiqiang Shen, Dinggang Liu, Dengfeng Jawad, Abbas F. Melhern, Elias R. Launer, Lenore J. Bryan, R. Nick Davatzikos, Christos TI Computer-assisted segmentation of white matter lesions in 3D MR images using support vector machine SO ACADEMIC RADIOLOGY LA English DT Article DE white matter lesion segmentation; support vector machine; machine learning ID ATTENUATED INVERSION-RECOVERY; MULTIPLE-SCLEROSIS LESIONS; SPIN-ECHO SEQUENCES; AUTOMATED SEGMENTATION; COGNITIVE FUNCTION; DIABETES-MELLITUS; ALZHEIMER-DISEASE; PROBABILISTIC SEGMENTATION; CARDIOVASCULAR HEALTH; CEREBRAL INFARCTIONS AB Rationale and Objectives. Brain lesions, especially white matter lesions (WMLs), are associated with cardiac and vascular disease, but also with normal aging. Quantitative analysis of WML in large clinical trials is becoming more and more important. Materials and Methods. In this article, we present a computer-assisted WML segmentation method, based on local features extracted from multiparametric magnetic resonance imaging (MRI) sequences (ie, T1-weighted, T2-weighted, proton density-weighted, and fluid attenuation inversion recovery MRI scans). A support vector machine classifier is first trained on expert-defined WMLs, and is then used to classify new scans. Results. Postprocessing analysis further reduces false positives by using anatomic knowledge and measures of distance from the training set. Conclusions. Cross-validation on a population of 35 patients from three different imaging sites with WMLs of varying sizes, shapes, and locations tests the robustness and accuracy of the proposed segmentation method, compared with the manual segmentation results from two experienced neuroradiologists. C1 [Lao, Zhiqiang; Shen, Dinggang; Jawad, Abbas F.; Melhern, Elias R.; Bryan, R. Nick; Davatzikos, Christos] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Jawad, Abbas F.] Childrens Hosp Philadelphia, Dept Biostat, Philadelphia, PA 19104 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Liu, Dengfeng] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Natl Inst Hlth, Bethesda, MD USA. RP Lao, ZQ (reprint author), Univ Penn, Dept Radiol, 3600 Market St,Suite 380, Philadelphia, PA 19104 USA. EM Zhiqiang.Lao@uphs.upenn.edu RI Melhem, Elias/E-5205-2013 FU Intramural NIH HHS; NHLBI NIH HHS [N01 HC095178, N01-HC-95178, N01HC95178]; NIA NIH HHS [R01 AG014971, R01 AG014971-05, R01-AG-1497]; NICHD NIH HHS [P01 HD024448-100006] NR 62 TC 104 Z9 104 U1 3 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD MAR PY 2008 VL 15 IS 3 BP 300 EP 313 DI 10.1016/j.acra.2007.10.012 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 271LD UT WOS:000253789000005 PM 18280928 ER PT J AU Liang, HY Park, S Gallas, BD Myers, KJ Badano, A AF Liang, Hongye Park, Subok Gallas, Brandon D. Myers, Kyle J. Badano, Aldo TI Image browsing in slow medical liquid crystal displays SO ACADEMIC RADIOLOGY LA English DT Article DE model observer; display quality; contrast sensitivity; temporal response ID HUMAN-OBSERVER; LUMPY BACKGROUNDS; CT SCANS; NOISE; PACS; MODEL AB Rationale and Objectives. Statistics show that radiologists are reading more studies than ever before, creating the challenge of interpreting an increasing number of images without compromising diagnostic performance. Stack-mode image display has the potential to allow radiologists to browse large three-dimensional (3D) datasets at refresh rates as high as 30 images/second. In this framework, the slow temporal response of liquid crystal displays (LCDs) can compromise the image quality when the images are browsed in a fast sequence. Materials and Methods. In this article, we report on the effect of the LCD response time at different image browsing speeds based on the performance of a contrast-sensitive channelized-hoteling observer. A stack of simulated 3D clustered lumpy background images with a designer nodule to be detected is used. The effect of different browsing speeds is calculated with LCD temporal response measurements from our previous work. The image set is then analyzed by the model observer, which has been shown to predict human detection performance in Gaussian and non-Gaussian lumpy backgrounds. This methodology allows us to quantify the effect of slow temporal response of medical liquid crystal displays on the performance of the anthropomorphic observers. Results. We find that the slow temporal response of the display device greatly affects lesion contrast and observer performance. A detectability decrease of more than 40% could be caused by the slow response of the display. Conclusions. After validation with human observers, this methodology can be applied to more realistic background data with the goal of providing recommendations for the browsing speed of large volumetric image datasets (from computed tomography, magnetic resonance, or tomosynthesis) when read in stack-mode. C1 [Liang, Hongye; Park, Subok; Gallas, Brandon D.; Myers, Kyle J.; Badano, Aldo] US FDA, CDRH NIBIB Lab Assessment Med Imaging Syst, Div Imaging & Appl Math, Off Sci & Engn Labs,Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Badano, A (reprint author), US FDA, CDRH NIBIB Lab Assessment Med Imaging Syst, Div Imaging & Appl Math, Off Sci & Engn Labs,Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 3113, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov OI Gallas, Brandon/0000-0001-7332-1620; badano, aldo/0000-0003-3712-6670 NR 21 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD MAR PY 2008 VL 15 IS 3 BP 370 EP 382 DI 10.1016/j.acra.2007.10.017 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 271LD UT WOS:000253789000012 PM 18280935 ER PT J AU Barinka, C Prahl, A Lubkowski, J AF Barinka, Cyril Prahl, Adam Lubkowski, Jacek TI Structure of human monocyte chemoattractant protein 4 (MCP-4/CCL13) SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID CC-CHEMOKINE; GLYCOSAMINOGLYCAN BINDING; CHEMOTACTIC PROTEIN-2; MOLECULAR REPLACEMENT; ELECTRON-DENSITY; IN-VIVO; MCP-1; RECEPTOR; IDENTIFICATION; INFLAMMATION AB Monocyte chemoattractant proteins (MCPs) belong to the CC chemokine family and are involved in many (patho)physiological processes characterized by mononuclear cell infiltration, including tissue remodeling, atherosclerosis and cancer metastasis. Here, the crystal structure of human monocyte chemoattractant protein 4 (MCP-4) refined at 1.70 angstrom resolution is reported with crystallographic values R = 0.180 and R-free = 0.212. The overall MCP-4 fold reveals the typical tertiary features of the CC chemokine family. A central three-stranded antiparallel beta-sheet is C-terminally flanked by an overlaying alpha-helix, while the N-terminal part of the molecule forms an extended loop that is anchored to the rest of the molecule via two disulfide bridges, Cys11-Cys35 and Cys12-Cys51. The crystal packing suggests the existence of MCP-4 dimers with a dimerization interface similar to those previously reported for the X-ray structures of MCP-1 and MCP-2. C1 [Barinka, Cyril; Prahl, Adam; Lubkowski, Jacek] NCI, Canc Res Ctr, Frederick, MD 21702 USA. RP Lubkowski, J (reprint author), NCI, Canc Res Ctr, Frederick, MD 21702 USA. EM jacek@ncifcrf.gov RI Prahl, Adam/H-7654-2014; Barinka, Cyril/G-9803-2014 FU Intramural NIH HHS NR 35 TC 11 Z9 13 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAR PY 2008 VL 64 BP 273 EP 278 DI 10.1107/S0907444907066164 PN 3 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 266IG UT WOS:000253427100006 PM 18323622 ER PT J AU Fulciniti, F Frangella, C Staiano, M La Vecchia, F Botti, G Demuru, A Magliulo, G Boon, ME AF Fulciniti, Franco Frangella, Carmela Staiano, Maria La Vecchia, Franca Botti, Gerardo Demuru, Antonio Magliulo, Gabriella Boon, Mathilde E. TI Air-dried smears for optimal diagnostic immunocytochemistry SO ACTA CYTOLOGICA LA English DT Article; Proceedings Paper CT 32nd European Congress of Cytology CY OCT 01-04, 2006 CL Venice, ITALY DE cytopathology techniques; immunocytochemistry; smears; air-dried ID ULTRAFAST PAPANICOLAOU STAIN; FINE-NEEDLE ASPIRATION; CYTOLOGY; ANTIGEN; RECEPTOR; CANCER AB Objective To exploit formalin-postfixed, air-dried smears for diagnostic immunocytochemistry (ICC). Study Design A series of 144 cases of diagnostic fine needle cytology samples in which air-dried, supplementary smears were available was used to exploit postfixation in the process of antigenic stabilization and rescue for immunocytochemical staining. Results Postfixation with formalin and with a formalin/ethanol solution gave comparable results as far as recovery and immunocytochemical detection of most monoclonal and polyclonal antibodies. The visualization of the antibody reactions was often superior to that obtained with wet-fixed slides, probably due to the interaction of slow cell dehydration with their consequent optimal flattening observed with formalin postfixation after short rehydration in physiologic saline. Conclusion Although wet fixation of cytopathologic slides in 95% ethanol represents a common standard for ICC, the usage of formalin-postfixed air-dried smears proved reliable and efficient for antigenic rescue and may enter routine usage in cytopathology laboratories. Moreover, in some instances, the visual evaluation of results was easier in the larger, well-flattened cells obtained in air-dried cells. C1 [Fulciniti, Franco; Staiano, Maria; La Vecchia, Franca] NCI, Dept Pathol, Cytopathol Serv, Bethesda, MD 20892 USA. [Frangella, Carmela] Univ Naples Federico 2, Dept Pathol, Cytopathol Serv, Naples, Italy. [Boon, Mathilde E.] Leiden Cytol & Pathol Lab, NL-2301 GB Leiden, Netherlands. RP Fulciniti, F (reprint author), Fdn G Pascale, Ist Nazl Diagnosi & Cura Tumori, Settore Citodiagnost, Via Mariano Semmola 1, I-80131 Naples, Italy. EM franco.fulciniti@mail.com NR 16 TC 4 Z9 5 U1 0 U2 4 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0001-5547 J9 ACTA CYTOL JI Acta Cytol. PD MAR-APR PY 2008 VL 52 IS 2 BP 178 EP 186 DI 10.1159/000325476 PG 9 WC Pathology SC Pathology GA 280XT UT WOS:000254460800009 PM 18499990 ER PT J AU Rimondini, R Sommer, WH Dall'Olio, R Heilig, M AF Rimondini, Roberto Sommer, Wolfang H. Dall'Olio, Rossella Heilig, Markus TI Long-lasting tolerance to alcohol following a history of dependence SO ADDICTION BIOLOGY LA English DT Article DE alcohol; alcoholism; animal model; loss of righting reflex; rat; tolerance ID CORTICOTROPIN-RELEASING-FACTOR; CHRONIC INTERMITTENT ETHANOL; ANIMAL-MODELS; UCHB RATS; SENSITIVITY; DRINKING; SENSITIZATION; CONSUMPTION; PLASTICITY; ALLOSTASIS AB Tolerance to alcohol effects is one of the defining features of clinical alcohol dependence. Here, we hypothesized that the post-dependent state may include tolerance to sedative-hypnotic alcohol actions. To address this question, we used a recently developed animal model in which repeated cycles of alcohol intoxication and withdrawal trigger long-lasting behavioral plasticity. This animal model shares important features with the clinical condition. Animals were exposed to 7 weeks of intermittent alcohol vapor, allowed to recover for 3 weeks, and tested in protracted abstinence to exclude contributions from acute withdrawal. Post-dependent and control rats were injected with a hypnotic dose of alcohol (3 g/kg), and the loss of righting reflex (LORR) was recorded, blood alcohol levels were monitored, and the elimination rate was calculated. Post-dependent animals showed a decrease in LORR. Alcohol metabolism and elimination kinetics did not differ between groups. In conclusion, a history of alcohol dependence induces long-lasting hypnotic tolerance. This process may play an important role in maintaining the dependent state. C1 [Rimondini, Roberto; Dall'Olio, Rossella] Univ Bologna, Dept Pharmacol, I-40128 Bologna, Italy. [Sommer, Wolfang H.; Heilig, Markus] NIAAA, NIH, Lab Clin & Translat Studies, Bethesda, MD USA. RP Rimondini, R (reprint author), Univ Bologna, Dept Pharmacol, Via Irnerio 48, I-40128 Bologna, Italy. EM roberto.rimondini@unibo.it RI Rimondini, Roberto/B-2500-2010; OI Rimondini, Roberto/0000-0003-4099-513X; Heilig, Markus/0000-0003-2706-2482 NR 28 TC 22 Z9 22 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2008 VL 13 IS 1 BP 26 EP 30 DI 10.1111/j.1369-1600.2007.00079.x PG 5 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 259GN UT WOS:000252927900003 PM 17850416 ER PT J AU Huang, J Young, B Pletcher, MT Heilig, M Wahlestedt, C AF Huang, Jia Young, Brandon Pletcher, Mathew T. Heilig, Markus Wahlestedt, Claes TI Association between the nociceptin receptor gene (OPRL1) single nucleotide polymorphisms and alcohol dependence SO ADDICTION BIOLOGY LA English DT Article DE alcohol dependence; association; OPRL1; polymorphism; nociceptin receptor; Scandinavian population ID ORPHANIN-FQ; OPIOID RECEPTOR; PREFERRING RATS; MALE TWINS; PEPTIDE; ABUSE; BEHAVIOR; MORPHINE; BLOCKS; SAMPLE AB OPRL1 encodes the nociceptin receptor, which has been shown to be involved in alcohol dependence in previous studies. In the present study, we investigated the association between genetic polymorphisms of OPRL1 and alcohol dependence in a Scandinavian population. We genotyped 15 single nucleotide polymorphisms (SNPs) spanning the OPRL1 locus and found that SNP rs6010718 was significantly associated with both Type I and Type II alcoholics (P < 0.05). Linkage disequilibrium and haplotype analysis identified two haplotype blocks in this region. Furthermore, two haplotypes composed of five tag SNPs showed significant association with alcohol dependence. These findings suggest that genetic variants of the OPRL1 gene play a role in alcohol dependence in the Scandinavian population, warranting further investigation at the OPRL1 locus. C1 [Huang, Jia; Wahlestedt, Claes] Scripps Res Inst, Mol & Integrat Neurosci Dept, Jupiter, FL USA. [Young, Brandon; Pletcher, Mathew T.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL USA. [Heilig, Markus] NIAAA, NIH, Lab Clin & Translat Studies, Bethesda, MD USA. RP Wahlestedt, C (reprint author), Scripps Res Inst, 5353 Parkside Dr, Jupiter, FL 33458 USA. EM clawah@scripps.edu RI Wahlestedt, Claes/A-7039-2009; OI Heilig, Markus/0000-0003-2706-2482 NR 26 TC 25 Z9 25 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2008 VL 13 IS 1 BP 88 EP 94 DI 10.1111/j.1369-1600.2007.00089.x PG 7 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 259GN UT WOS:000252927900011 PM 18269382 ER PT J AU Lehrmann, E Afanador, ZR Deep-Soboslay, A Gallegos, G Darwin, WD Lowe, RH Barnes, AJ Huestis, MA Cadet, JL Herman, MM Hyde, TM Kleinman, JE Freed, WJ AF Lehrmann, Elin Afanador, Zoan R. Deep-Soboslay, Amy Gallegos, Gloria Darwin, William D. Lowe, Ross H. Barnes, Allan J. Huestis, Marilyn A. Cadet, Jean L. Herman, Mary M. Hyde, Thomas M. Kleinman, Joel E. Freed, William J. TI Postmortem diagnosis and toxicological validation of illicit substance use SO ADDICTION BIOLOGY LA English DT Article DE addiction; biological matrix; drug abuse; hair toxicology; Postmortem Substance Abuse Assessment Questionnaire; substance use disorders ID NATIONAL EPIDEMIOLOGIC SURVEY; HAIR ANALYSIS; DSM-IV; PSYCHIATRIC-DISORDERS; ANXIETY DISORDERS; COCAINE USE; DRUG-USE; ABUSE; ALCOHOL; BRAIN AB The present study examines the diagnostic challenges of identifying ante-mortem illicit substance use in human postmortem cases. Substance use, assessed by clinical case history reviews, structured next-of-kin interviews, by general toxicology of blood, urine and/or brain, and by scalp hair testing, identified 33 cocaine, 29 cannabis, 10 phencyclidine and nine opioid cases. Case history identified 42% cocaine, 76% cannabis, 10% phencyclidine and 33% opioid cases. Next-of-kin interviews identified almost twice as many cocaine and cannabis cases as Medical Examiner (ME) case histories, and were crucial in establishing a detailed lifetime substance use history. Toxicology identified 91% cocaine, 68% cannabis, 80% phencyclidine and 100% opioid cases, with hair testing increasing detection for all drug classes. A cocaine or cannabis use history was corroborated by general toxicology with 50% and 32% sensitivity, respectively, and with 82% and 64% sensitivity by hair testing. Hair testing corroborated a positive general toxicology for cocaine and cannabis with 91% and 100% sensitivity, respectively. Case history corroborated hair toxicology with 38% sensitivity for cocaine and 79% sensitivity for cannabis, suggesting that both case history and general toxicology underestimated cocaine use. Identifying ante-mortem substance use in human postmortem cases are key considerations in case diagnosis and for characterization of disorder-specific changes in neurobiology. The sensitivity and specificity of substance use assessments increased when ME case history was supplemented with structured next-of-kin interviews to establish a detailed lifetime substance use history, while comprehensive toxicology, and hair testing in particular, increased detection of recent illicit substance use. C1 [Lehrmann, Elin; Afanador, Zoan R.; Gallegos, Gloria; Freed, William J.] NIDA, NIH, IRP, Cellular Neurobiol Res Branch, Baltimore, MD 21224 USA. [Darwin, William D.; Lowe, Ross H.; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, NIH, IRP, Chem & Drug Metab Sect, Baltimore, MD 21224 USA. [Cadet, Jean L.] NIDA, NIH, IRP, Mol Neuropsychiat Branch, Baltimore, MD 21224 USA. [Deep-Soboslay, Amy; Herman, Mary M.; Hyde, Thomas M.; Kleinman, Joel E.] NIMH, Natl Inst Drug Abuse, Clin Brain Disorders Branch, GCAP,IRP, Baltimore, MD USA. NIH, Dept Hlth & Human Serv, Baltimore, MD USA. RP Lehrmann, E (reprint author), NIDA, NIH, IRP, DHHS,Dev & Plastic Sect,Cellular Neurobiol Res B, 333 Cassell Dr, Baltimore, MD 21224 USA. EM elehrman@intra.nida.nih.gov OI Lehrmann, Elin/0000-0002-9869-9475 FU Intramural NIH HHS [Z99 AG999999] NR 35 TC 6 Z9 7 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2008 VL 13 IS 1 BP 105 EP 117 DI 10.1111/j.1369-1600.2007.00085.x PG 13 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 259GN UT WOS:000252927900013 PM 18201295 ER PT J AU Backinger, CL Fagan, P O'Connell, ME Grana, R Lawrence, D Bishop, JA Gibson, JT AF Backinger, Cathy L. Fagan, Pebbles O'Connell, Mary E. Grana, Rachel Lawrence, Deirdre Bishop, Jennifer Anne Gibson, James Todd TI Use of other tobacco products among US adult cigarette smokers: Prevalence, trends and correlates SO ADDICTIVE BEHAVIORS LA English DT Article DE cigarette smokers; multiple tobacco use cigar; pipe; snuff; chewing tobacco; trends ID YOUNG-ADULTS AB This paper examines the trends in concurrent use of cigarettes and other tobacco and sociodemographic variables associated with concurrent use among adult cigarette smokers in the United States. Data from the 1995/96, 1998, 2000, and 2001/02 Tobacco Use Supplements to the Current Population Survey were used to estimate concurrent use of tobacco among cigarette smokers among adults ages 18 years and older (n for all 4 survey groups = 552,804). Concurrent use of tobacco fluctuated over the survey periods for current smokers and ranged from 3.7% in 1995/96 to 7.9% in 1998. Results from the multivariate logistic regression indicate that male current, daily, and intermittent smokers had substantially higher odds of concurrent use (OR = 12.9, 11.7, 17.2, respectively) than their female counterparts. Age, race/ethnicity, geographic region, income, and survey years were significantly associated with concurrent use among current and daily smokers; for intermittent smokers, these variables and occupation were significantly associated with concurrent use. The strongest correlates for multiple tobacco use among cigarettes smokers were being male and Non-Hispanic White. These factors should. be considered when planning tobacco prevention and control efforts. In addition, surveillance efforts should continue to monitor changes in concurrent use and further investigate the increased risk of cancer among smokers who also use other forms of tobacco. Published by Elsevier Ltd. C1 [Backinger, Cathy L.; Fagan, Pebbles; Lawrence, Deirdre] NCI, Tobacco Control Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [O'Connell, Mary E.] NCI, SAIC Fredrick Inc, Frederick, MD 21701 USA. RP Backinger, CL (reprint author), NCI, Tobacco Control Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. EM backingc@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 22 TC 42 Z9 43 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD MAR PY 2008 VL 33 IS 3 BP 472 EP 489 DI 10.1016/j.addbeh.2007.10.009 PG 18 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 267AJ UT WOS:000253480000007 PM 18053653 ER PT J AU Chambers, D AF Chambers, David TI Introduction: Advancing implementation research in mental health SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Editorial Material C1 NIMH, Bethesda, MD 20892 USA. RP Chambers, D (reprint author), NIMH, Bethesda, MD 20892 USA. EM dchamber@mail.nih.gov NR 2 TC 6 Z9 6 U1 0 U2 0 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0894-587X J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD MAR PY 2008 VL 35 IS 1-2 BP 1 EP 2 DI 10.1007/s10488-007-0161-8 PG 2 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 245WI UT WOS:000251969100001 ER PT J AU Chambers, DA AF Chambers, David A. TI Advancing the science of implementation: A workshop summary SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Editorial Material DE implementation science; evidence-based practices ID MENTAL-HEALTH AB While much has been written about reducing the gap between science and practice, relatively little progress has been made to develop a sound knowledge base underlying implementation of effective interventions. To respond to these challenges, the National Institute of Mental Health organized a workshop entitled, "Advancing the Science of Implementation: Improving the Fit between Mental Health Intervention Development and Service Systems." Over the 2-day workshop, a multi-disciplinary group of intervention and services researchers, implementers, methodologists, organizational theorists, and clinicians was brought together in an "engaged scholarship" * format composed of small and large-group settings to discuss the development of a sound knowledge base on the implementation of evidence-based practices. Using three specific intervention categories, participants identified constructs seen to be important to the implementation of the model in real-world systems. Following each breakout session, attendees reconvened for a full group discussion and brief presentations were conducted to highlight interventions in the areas of organizational measures, social network analysis and field opportunities. This summary describes some of the constructs relevant to implementation research and presents research questions that, if studied, will lay a solid foundation for implementation research. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Chambers, DA (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,RM 7133 MSC 9631, Bethesda, MD 20892 USA. EM dchamber@mail.nih.gov NR 22 TC 19 Z9 19 U1 0 U2 2 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0894-587X J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD MAR PY 2008 VL 35 IS 1-2 BP 3 EP 10 DI 10.1007/s10488-007-0146-7 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 245WI UT WOS:000251969100002 PM 18040772 ER PT J AU Mendel, P Meredith, LS Schoenbaum, M Sherbourne, CD Wells, KB AF Mendel, Peter Meredith, Lisa S. Schoenbaum, Michael Sherbourne, Cathy D. Wells, Kenneth B. TI Interventions in organizational and community context: A framework for building evidence on dissemination and implementation in health services research SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article; Proceedings Paper CT Workshop on Advancing the Science of Implementation - Improving the Fit Between Mental Health Intervention Development and Service Systems CY OCT 28-29, 2004 CL Bethesda, MD SP Natl Inst Mental Hlth DE dissemination; diffusion; implementation; organizational context; community-based research; evidence-based interventions ID RANDOMIZED CONTROLLED-TRIAL; QUALITY IMPROVEMENT COLLABORATIVES; SEVERE MENTAL-ILLNESS; MANAGED PRIMARY-CARE; SOCIAL-MOVEMENTS; TREATING DEPRESSION; OPINION LEADERS; UNITED-STATES; DIFFUSION; NETWORK AB The effective dissemination and implementation of evidence-based health interventions within community settings is an important cornerstone to expanding the availability of quality health and mental health services. Yet it has proven a challenging task for both research and community stakeholders. This paper presents the current framework developed by the UCLA/RAND NIMH Center to address this research-to-practice gap by: (1) providing a theoretically-grounded understanding of the multi-layered nature of community and healthcare contexts and the mechanisms by which new practices and programs diffuse within these settings; (2) distinguishing among key components of the diffusion process-including contextual factors, adoption, implementation, and sustainment of interventions-showing how evaluation of each is necessary to explain the course of dissemination and outcomes for individual and organizational stakeholders; (3) facilitating the identification of new strategies for adapting, disseminating, and implementing relatively complex, evidence-based healthcare and improvement interventions, particularly using a community-based, participatory approach; and (4) enhancing the ability to meaningfully generalize findings across varied interventions and settings to build an evidence base on successful dissemination and implementation strategies. C1 [Mendel, Peter; Meredith, Lisa S.; Schoenbaum, Michael; Sherbourne, Cathy D.; Wells, Kenneth B.] RAND Corp, Santa Monica, CA 90407 USA. [Wells, Kenneth B.] Univ Calif Los Angeles, Semel Inst, Hlth Serv Res Ctr, Los Angeles, CA 90095 USA. [Schoenbaum, Michael] NIMH, Div Res & Intervent Res, Bethesda, MD 20892 USA. RP Mendel, P (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90407 USA. EM mendel@rand.org; lisa_meredith@rand.org; schoenbaumm@mail.nih.gov; cathy_sherbourne@rand.org; kwells@ucla.edu FU NIMH NIH HHS [P30 MH068639, P50 MH054623]; NIMHD NIH HHS [1P20MD00182-01, P20 MD000182] NR 124 TC 122 Z9 124 U1 3 U2 39 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD MAR PY 2008 VL 35 IS 1-2 BP 21 EP 37 DI 10.1007/s10488-007-0144-9 PG 17 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 245WI UT WOS:000251969100004 PM 17990095 ER PT J AU Morrow, KM Ruiz, MS AF Morrow, Kathleen M. Ruiz, Monica S. TI Assessing microbicide acceptability: A comprehensive and integrated approach SO AIDS AND BEHAVIOR LA English DT Article; Proceedings Paper CT Microbicides 2006 Conference CY APR 23-26, 2006 CL Cape Town, SOUTH AFRICA DE microbicides; acceptability; measurement; clinical trials; preclinical development ID VAGINAL GEL FORMULATIONS; WOMEN; HIV; SAFETY; TRIAL; FLOWS AB A safe, effective, and acceptable microbicide is needed in order to decisively impact the global AIDS pandemic. As such, microbicide acceptability research is of paramount importance. In order to best utilize limited financial resources and save precious development time, acceptability studies should be fully integrated into preclinical and clinical trial contexts where candidate products are being developed and tested. An integrated approach for examining theoretically valid and relevant variables is needed so that data across studies and products can more effectively advance the field. We propose an approach for measuring factors related to microbicide acceptability in each phase of product development, and dependent on what product-specific knowledge is already established in the field. We discuss the roles that behavioral and social science methodologies should play in all phases of microbicide development, as well as the challenges faced when conducting acceptability research in the context of preclinical and clinical trial settings. C1 [Morrow, Kathleen M.] Brown Univ, Warren Alpert Med Sch, Miriam Hosp, Ctr Behav & Prevent Med,Dept Psychiat & Human Beh, Providence, RI 02912 USA. [Ruiz, Monica S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morrow, KM (reprint author), Brown Univ, Warren Alpert Med Sch, Miriam Hosp, Ctr Behav & Prevent Med,Dept Psychiat & Human Beh, Coro W,Suite 500,1 Hoppin St, Providence, RI 02912 USA. EM kmorrow@lifespan.org FU NIAID NIH HHS [U01 AI048040, P30 AI042853, P30 AI42853, N01-AI-35176, U01 AI48040, N01 AI045200]; NIDA NIH HHS [1R01DA10871]; NIMH NIH HHS [R21 MH080591, R01 MH064455-01S1, R01 MH064455-03, R01 MH064455-02, R21 MH080591-01, R01 MH064455-05, R01 MH064455, R01 MH064455-04, R01 MH064455-01] NR 32 TC 48 Z9 48 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD MAR PY 2008 VL 12 IS 2 BP 272 EP 283 DI 10.1007/s10461-007-9266-z PG 12 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 267QH UT WOS:000253523800011 PM 17592763 ER PT J AU Ceriotto, M Harris, DR Duarte, G Gonin, R Aguiar, RP Warley, EM Madi, JM Zala, CA Read, JS AF Ceriotto, Mariana Harris, D. Robert Duarte, Geraldo Gonin, Rene Aguiar, Regina P. Warley, Eduardo M. Madi, Jose M. Zala, Carlos A. Read, Jennifer S. CA NISDI Pernatal Study Grp TI Laboratory abnormalities among HIV-1-infected pregnant women receiving antiretrovirals in Latin America and the Caribbean SO AIDS PATIENT CARE AND STDS LA English DT Letter ID MATERNAL TOXICITY; NEVIRAPINE; THERAPY C1 [Ceriotto, Mariana] Hosp Cecilia Grierson, Buenos Aires, DF, Argentina. [Harris, D. Robert; Gonin, Rene] WESTAT Corp, Rockville, MD 20850 USA. [Duarte, Geraldo] Univ Sao Paulo, Sch Med, BR-14049 Ribeirao Preto, Brazil. [Warley, Eduardo M.] Hosp Diego Paroissien, Buenos Aires, DF, Argentina. [Aguiar, Regina P.] Univ Fed Minas Gerais, Sch Med, Belo Horizonte, MG, Brazil. [Madi, Jose M.] Univ Caxias do Sul, Caxias do Sul, Brazil. [Zala, Carlos A.] Hosp Juan Fernandez, Buenos Aires, DF, Argentina. [Read, Jennifer S.] NICHD, CRMC, DHHS, Pediat Adolescent & Mat AIDS Branch, Bethesda, MD USA. RP Ceriotto, M (reprint author), Hosp Cecilia Grierson, Buenos Aires, DF, Argentina. RI Mussi-Pinhata, Marisa/G-6568-2012; Duarte, Geraldo/J-7906-2012 FU NICHD NIH HHS [N01-HD-3-3345] NR 11 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD MAR PY 2008 VL 22 IS 3 BP 167 EP 171 DI 10.1089/apc.2007.0080 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 283QJ UT WOS:000254651300001 PM 18338942 ER PT J AU Chang, LW Kagaayi, J Nakigozi, G Packer, AH Serwadda, D Quinn, TC Gray, RH Bollinger, RC Reynolds, SJ AF Chang, Larry W. Kagaayi, Joseph Nakigozi, Gertrude Packer, Arnold H. Serwadda, David Quinn, Thomas C. Gray, Ronald H. Bollinger, Robert C. Reynolds, Steven J. TI Responding to the human resource crisis: Peer health workers, mobile phones, and HIV care in Rakai, Uganda SO AIDS PATIENT CARE AND STDS LA English DT Letter C1 [Chang, Larry W.; Quinn, Thomas C.; Bollinger, Robert C.; Reynolds, Steven J.] Johns Hopkins Med Inst, Div Infect Dis, Baltimore, MD 21205 USA. [Kagaayi, Joseph; Nakigozi, Gertrude; Serwadda, David] Rakai Hlth Sci Program, Rakai Dist, Uganda. [Packer, Arnold H.] Johns Hopkins Univ, Baltimore, MD USA. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, NIH, Bethesda, MD USA. [Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Chang, LW (reprint author), 1830 E Monument St,Room 401, Baltimore, MD 21287 USA. EM larrywillchang@gmail.com FU Intramural NIH HHS [Z99 AI999999] NR 6 TC 38 Z9 40 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD MAR PY 2008 VL 22 IS 3 BP 173 EP 174 DI 10.1089/apc.2007.0234 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 283QJ UT WOS:000254651300002 PM 18290750 ER PT J AU Borkowsky, W Yogev, R Muresan, P McFarland, E Frenkel, L Fenton, T Capparelli, E Moye, J Harding, P Ellis, N Heckman, B Kraimer, J AF Borkowsky, William Yogev, Ram Muresan, Petronella McFarland, Elizabeth Frenkel, Lisa Fenton, Terry Capparelli, Edmund Moye, Jack Harding, Paul Ellis, Nina Heckman, Barbara Kraimer, Joyce TI Planned multiple exposures to autologous virus in HIV type 1-infected pediatric Populations increases HIV-Specific immunity and reduces HIV viremia SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID STRUCTURED TREATMENT INTERRUPTION; CHRONICALLY HIV-1-INFECTED PATIENTS; DENDRITIC-CELL VACCINE; THERAPEUTIC IMMUNIZATION; T-CELLS; ANTIRETROVIRAL THERAPY; RECOMBINANT GP160; VIRAL LOAD; INFECTION; RESPONSES AB We tested to determine if planned multiple exposures to autologous HIV in pediatric patients with HIV-1 infection will induce cellular immunity that controls viremia. A prospective multicenter study of aviremic pediatric patients on highly active antiretroviral therapy who underwent progressively longer antiretroviral treatment interruptions in cycles starting with 3 days, increasing by 2 days in length each consecutive cycle, was conducted. Eight individuals became viremic and reached Cycle 13 or greater with an "off-therapy" interval of >= 27 days. HIV-specific interferon- gamma ( IFN-gamma) production to inactivated HIV and vaccinia vectors expressing gag, env, nef, and pol increased ( > 10-fold) from baseline in six of eight subjects. The HIV-specific lymphoproliferative response as measured by the median stimulation index ( SI) increased in the treatment group from 1 at baseline to 16, 12, 4, and 3 at Cycles 7, 10, 13, and 17, respectively. Median plasma RNA levels peaked at Cycle 7 (4.45 log) and declined to levels < 10(4) cp/ml after Cycle 10 ( 4.1, 3.5, and 3.4 at Cycles 10, 13, and 17). In a subset of five patients who reached Cycle 17, HIV-specific IFN-gamma frequencies were 4- to 30-fold higher and median RNA levels were 0.32-2.10 ( median 1.3) log lower than at comparable days off treatment at Cycle 8 ( 17 days off therapy). A second group of children, not undergoing drug interruption, did not develop significant increases in either HIV-specific IFN-gamma production or SI. Increased HIV-specific immune responses and decreased HIV RNA were seen in those children who have had > 10 cycles of antiretroviral discontinuations of increasing durations acting as autologous virus vaccinations. Other studies may have failed due to an insufficient number of exposures to HIV; most of the studies had fewer than six drug interruptions. C1 [Borkowsky, William] NYU, Sch Med, New York, NY 10016 USA. [Yogev, Ram] Chicago Childrens Mem Hosp, Chicago, IL 60614 USA. [Muresan, Petronella; Fenton, Terry] Harvard Univ, Sch Publ Hlth, FSTRF, Boston, MA 02115 USA. [McFarland, Elizabeth; Harding, Paul] Univ Colorado, Hlth Sci Ctr, Denver, CO 80045 USA. [Frenkel, Lisa; Ellis, Nina] Univ Washington, Seattle, WA 98103 USA. [Capparelli, Edmund] Univ Calif San Diego, La Jolla, CA 92093 USA. [Moye, Jack] NICHD, NIH, Bethesda, MD 20892 USA. [Heckman, Barbara] Frontier Sci & Technol Res Fdn Inc, Data Management Ctr, Amherst, NY 14226 USA. [Kraimer, Joyce] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. RP Borkowsky, W (reprint author), NYU, Sch Med, 550 1st Ave, New York, NY 10016 USA. EM borkow01@gcrc.med.nyu.edu OI moye, john/0000-0001-9976-8586 FU NCRR NIH HHS [M01 RR00069, RR00096]; NIAID NIH HHS [AI-27559] NR 35 TC 7 Z9 7 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2008 VL 24 IS 3 BP 401 EP 411 DI 10.1089/aid.2007.0110 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 284VP UT WOS:000254735200009 PM 18327977 ER PT J AU Biancotto, A Iglehart, SJ Lisco, A Vanpouille, C Grivel, JC Lurain, NS Reichelderfer, PS Margolis, LB AF Biancotto, Angelique Iglehart, Sarah J. Lisco, Andrea Vanpouille, Christophe Grivel, Jean-Charles Lurain, Nell S. Reichelderfer, Patricia S. Margolis, Leonid B. TI Upregulation of human cytomegalovirus by HIV type 1 in human lymphoid tissue ex Vivo SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID MYELOID CELLS; T-CELLS; INFECTION; VIRUS; EXPRESSION; LATENT; HUMAN-HERPESVIRUS-6; SUSCEPTIBILITY; HISTOCULTURES; REPLICATION AB HIV-1 copathogens are believed to play a critical role in progression to AIDS. Human cytomegalovirus ( HCMV) has a high prevalence in the general population and is a common copathogen in HIV-1-infected individuals. Important events in copathogen interactions with HIV-1 take place in lymphoid tissue where critical events in HIV-1 disease occur. Here, we used an experimental system of human lymphoid tissue ex vivo to investigate interactions of HCMV with HIV-1. We inoculated ex vivo blocks of human lymphoid tissue with a recombinant strain of HCMV, expressing the green fluorescent protein, and HIV-1 and monitored viral replication and the phenotype of productively infected cells. HCMV readily replicated in tissue blocks as revealed by the release of HCMV viral DNA and an increasing number of viral-positive cells. Immunophenotyping of HCMV-infected cells showed a preferential infection of activated lymphocytes. The number of these cells significantly increased in HIV-1-coinfected tissues. Accordingly, HCMV replication was enhanced 2- to-3 fold. This upregulation occurred in tissues infected with either CXCR4- or CCR5-utilizing HIV-1. Thus, HIV-1 creates new targets for HCMV, which may explain the strong association of HCMV with HIV-1 infection in vivo. Ex vivo-infected human lymphoid tissue constitutes a model to study the mechanisms of HCMV tissue pathogenesis and its interactions with HIV-1 and this model may provide new targets for anti-HIV-1 therapy. C1 [Biancotto, Angelique; Iglehart, Sarah J.; Lisco, Andrea; Vanpouille, Christophe; Grivel, Jean-Charles; Reichelderfer, Patricia S.; Margolis, Leonid B.] NICHHD, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. [Lurain, Nell S.] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. RP Biancotto, A (reprint author), NICHD, LCMB, NIH, Bldg 10,Room 9D51,10 Ctr Dr, Bethesda, MD 20892 USA. EM biancoa@mail.nih.gov FU Intramural NIH HHS NR 37 TC 8 Z9 8 U1 1 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2008 VL 24 IS 3 BP 453 EP 462 DI 10.1089/aid.2007.0155 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 284VP UT WOS:000254735200015 PM 18327985 ER PT J AU Breslow, RA Graubard, BI AF Breslow, Rosalind A. Graubard, Barry I. TI Prospective study of alcohol consumption in the United States: Quantity, frequency, and cause-specific mortality SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol consumption; drinking patterns; cohort study; longitudinal study; mortality; all-cause mortality; cancer mortality; cardiovascular mortality; National Health Interview Survey ID NUTRITION EXAMINATION SURVEY; CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; DRINKING PATTERNS; NATIONAL-HEALTH; BREAST-CANCER; MODERATE DRINKING; AVERAGE VOLUME; RISK; MEN AB Background: Alcohol average volume (quantity multiplied by frequency) has been associated with mortality in drinkers. However, average volume may mask associations due to quantity or frequency alone. Methods: We prospectively assessed relationships between alcohol quantity and frequency, and mortality from all-causes, cardiovascular disease, cancer, and other-causes in a cohort created by linking the 1988 National Health Interview Survey (response rate 87%) to the National Death Index through 2002. Participants were 20,765 current drinkers age >= 18 years. At 14-year follow-up 2,547 had died. Results: For quantity, among men who consumed >= 5 drinks (compared to 1 drink) on drinking days, adjusted relative risks (RR) of mortality were: for cardiovascular disease, 1.30 [95% confidence interval (CI) 0.96-1.75; p for linear trend (p-trend) = 0.0295], for cancer, 1.53 (95% CI 1.11-2.09; p-trend = 0.0026), and for other-causes, 1.42 (95% CI 1.08-1.87; p-trend = 0.0029); among women for other-causes, 2.88 (95% CI 1.61-5.12; p-trend = 0.0010). For frequency, among men in the highest frequency quartile (compared to the lowest), RR were: for cardiovascular disease, 0.79 (95% CI 0.63-0.99; p-trend = 0.0330), for cancer, 1.23 (95% CI 0.95-1.59; p-trend = 0.0461), and for other-causes, 1.30 (95% CI 1.01-1.67; p-trend = 0.0070); among women, for cancer, 1.65 (95% CI 1.12-2.45, p-trend = 0.0031). Average volume obscured effects of quantity alone and frequency alone, particularly for cardiovascular disease in men where quantity and frequency trended in opposite directions. Conclusions: Alcohol quantity and frequency were independently associated with cause-specific mortality. Accumulating evidence of their differential effects may, in the future, be useful for clinical and public health recommendations. C1 [Breslow, Rosalind A.] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Natl Inst Hlth, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. RP Breslow, RA (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2081, Bethesda, MD 20892 USA. EM rbreslow@mail.nih.gov NR 29 TC 38 Z9 39 U1 2 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2008 VL 32 IS 3 BP 513 EP 521 DI 10.1111/j.1530-0277.2007.00595.x PG 9 WC Substance Abuse SC Substance Abuse GA 267II UT WOS:000253502300018 PM 18215212 ER PT J AU Trojanowski, JQ Duff, K Fillit, H Koroshetz, W Kuret, J Murdhy, D Refolo, L AF Trojanowski, John Q. Duff, Karen Fillit, Howard Koroshetz, Walter Kuret, Jeff Murdhy, Diane Refolo, Larrv TI New directions for frontotemporal dementia drug discovery SO ALZHEIMERS & DEMENTIA LA English DT Article DE tau; TDP-43; neurodegeneration; frontotemporal dementia; therapy; prevention ID TAU HYPERPHOSPHORYLATION; LOBAR DEGENERATION; TAUOPATHY; GLYCOGEN-SYNTHASE-KINASE-3; TANGLES; DISEASE; TARGET; MODEL; MICE AB This report summarizes the recommendations of the Frontotemporal Dementia (FTD) Working Group on FTD Drug Discovery that was part of an international FTD Workshop held on January 18 and 19, 2007, in Miami, Florida. The workshop was sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) of the National Institutes of Health (NlH) and the Association for Frontotemporal Dementia (AFTD) with the express purpose of defining opportunities to improve the diagnosis and treatment of patients affected by a neurodegenerative disorder classified as one of the many variants of FTD. The recognition that almost all forms of FTD are due to TDP-43 proteinopathies and tauopathies creates new opportunities for FTD drug discovery targeting pathways of TDP-43 and tau-mediated neurodegeneration. (c) 2008 The Alzheimer's Association. All rights reserved. C1 [Trojanowski, John Q.] Univ Penn, Sch Med, Inst Aging, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Trojanowski, John Q.] Univ Penn, Sch Med, Dept Pathol & Lab, Philadelphia, PA 19104 USA. [Duff, Karen] Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. [Fillit, Howard] Inst Study Aging, New York, NY USA. [Kuret, Jeff] Ohio State Univ, Columbus, OH 43210 USA. [Duff, Karen; Koroshetz, Walter; Murdhy, Diane; Refolo, Larrv] NINDS, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Trojanowski, JQ (reprint author), Univ Penn, Sch Med, Inst Aging, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. EM trojanow@mail.med.upenn.edu FU NIA NIH HHS [P01 AG017586, P30 AG010124, P30 AG010124-17S2] NR 19 TC 20 Z9 22 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2008 VL 4 IS 2 BP 89 EP 93 DI 10.1016/j.jalz.2007.06.001 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 279JX UT WOS:000254352600003 PM 18631953 ER PT J AU Bardy, GH Lee, KL Mark, DB Poole, JE Toff, WD Tonkin, AM Smith, W Dorian, P Yallop, JJ Packer, DL White, RD Longstreth, W Anderson, J Johnson, G Bischoff, E Munkers, CD Brown, A McNulty, S Ray, LD Clapp-Channing, NE Rosenberg, Y Salive, M Schron, EB AF Bardy, Gust H. Lee, Kerry L. Mark, Daniel B. Poole, Jeanne E. Toff, William D. Tonkin, Andrew M. Smith, Warren Dorian, Paul Yallop, Julie J. Packer, Douglas L. White, Roger D. Longstreth, Will Anderson, Jill Johnson, George Bischoff, Eric Munkers, Crystal D. Brown, Amanda McNulty, Steven Ray, Linda Davidson Clapp-Channing, Nancy E. Rosenberg, Yves Salive, Marcel Schron, Eleanor B. CA HAT Investigators TI Rationale and design of the home automatic external defibrillator trial (HAT) SO AMERICAN HEART JOURNAL LA English DT Article ID HOSPITAL CARDIAC-ARREST; AMERICAN-HEART-ASSOCIATION; CARDIOPULMONARY-RESUSCITATION; VENTRICULAR-FIBRILLATION; MYOCARDIAL-INFARCTION; IMPROVING SURVIVAL; CLINICAL-TRIALS; LIFE-SUPPORT; CARE; PROFESSIONALS AB Most cardiac arrests occur in the home, where emergency medical services (EMS) systems are challenged to provide timely care. Because a large proportion of sudden cardiac arrests (SCAs) are due to ventricular tachycardia or ventricular fibrillation, home use of an automated external defibrillator (AED) might offer an opportunity to decrease mortality in those at risk. Predicting who will have a cardiac arrest in the general population is difficult. Individuals at high risk are usually easily identified and may become candidates for implantable cardioverter defibrillators. It is within the population at lower risk where home AEDs may be most useful. The purpose of the Home Automatic External Defibrillator Trial (HAT) is to test whether providing home access to an AED can improve survival in patients at modest risk of SCA, such as those surviving an anterior myocardial infarction but in whom implantable cardioverter defibrillator therapy is not deemed necessary. Between January 23, 2003, and October 20, 2005, 7001 patients were enrolled, with completion of follow-up scheduled for September 30, 2007. Randomization was conducted in a I : I fashion between control therapy, comprising the standard lay response to SCA (calling the EMS and performing cardiopulmonary resuscitation), and the use of an AED first, followed by calling the EMS and performing cardiopulmonary resuscitation. The primary end point is all-cause mortality. Secondary outcomes include survival from SCA (witnessed and unwitnessed, in home and out of home), incremental cost-effectiveness, and quality of life measures for both the patient and the spouse/companion. The results of the trial should be available in mid 2008. C1 [Bardy, Gust H.; Poole, Jeanne E.; Anderson, Jill; Johnson, George; Bischoff, Eric; Munkers, Crystal D.; Brown, Amanda] Seattle Inst Cardiac Res, Seattle, WA 98103 USA. [Lee, Kerry L.; Mark, Daniel B.; McNulty, Steven; Ray, Linda Davidson; Clapp-Channing, Nancy E.] Duke Univ, Clin Res Inst, Durham, NC USA. [Rosenberg, Yves; Salive, Marcel; Schron, Eleanor B.] NHLBI, US NIH, Bethesda, MD 20892 USA. [Poole, Jeanne E.; Longstreth, Will] Univ Washington, Seattle, WA 98195 USA. [Packer, Douglas L.; White, Roger D.] Mayo Clin, Rochester, MN USA. [Tonkin, Andrew M.; Yallop, Julie J.] Monash Univ, Clayton, Vic 3168, Australia. [Smith, Warren; Yallop, Julie J.] Auckland Gen Hosp, Auckland, New Zealand. [Toff, William D.] Univ Leicester, Leicester, Leics, England. [Dorian, Paul] Univ Toronto, Toronto, ON, Canada. RP Bardy, GH (reprint author), Seattle Inst Cardiac Res, 7900 E Green Lake Dr N,302, Seattle, WA 98103 USA. EM gbordy@sicr.org OI Toff, William/0000-0001-5631-4496; Mark, Daniel/0000-0001-6340-8087 FU NHLBI NIH HHS [1 U01 HL67972-01A1] NR 39 TC 10 Z9 10 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAR PY 2008 VL 155 IS 3 BP 445 EP 454 DI 10.1016/j.ahj.2007.12.008 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 271OO UT WOS:000253798100006 PM 18294476 ER PT J AU Goldberger, JJ Bonow, RO Cuffe, M Dyer, A Greenland, P Rosenberg, Y O'Rourke, R Shah, PK Smith, S AF Goldberger, Jeffrey J. Bonow, Robert O. Cuffe, Michael Dyer, Alan Greenland, Philip Rosenberg, Yves O'Rourke, Robert Shah, Prediman K. Smith, Sidney TI Post-myocardial infarction beta-blocker therapy: The bradycardia conundrum. Rationale and design for the Pacemaker, & beta-blocker therapy post-MI (PACE-MI) trial SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CONVERTING ENZYME-INHIBITORS; LEFT-VENTRICULAR DYSFUNCTION; IDIOPATHIC DILATED CARDIOMYOPATHY; DRUG SURVEILLANCE PROGRAM; ASSOCIATION TASK-FORCE; CHRONIC HEART-FAILURE; RANDOMIZED TRIAL; ELDERLY-PATIENTS; NORWEGIAN MULTICENTER AB Multiple clinical trials have demonstrated beta-blockers improving survival after myocardial infarction (MI). Patients with "bradycardia-related" contraindications to beta-blockers, such as those with asymptomatic bradycardia or AV conduction abnormalities, have been excluded from clinical trials of beta-blockers and continue to be excluded from post-MI beta-blocker therapy in routine clinical practice. These patients tend to be elderly and have a high 1-year mortality. If beta-blockers provide benefit to the post-MI patient independent of their heart rate-lowering effect, then these patients could benefit substantially from initiation of beta-blocker therapy. However, in this particular group of patients, beta-blockers can be safely initiated only if more severe or significant bradycardia can be prevented by pacemaker implantation. It is unclear whether adverse effects related to pacemaker implantation could also negate some or all of the hypothesized benefit of beta-blocker therapy. Although beta-blockers are particularly effective in the elderly, the benefit of beta-blocker therapy in patients with bradycardia-related contraindications to beta-blockers has not been established. The PACE-MI trial is a randomized controlled trial that will address whether beta-blocker therapy enabled by pacemaker implantation is superior to no beta-blocker and no pacemaker therapy after MI in patients with rhythm contra indications to beta-blockers or in those who have developed symptomatic bradycardia due to beta-blockers. The trial will randomize 1124 patients to standard therapy (not to include beta-blockers as patients must have a contra indication to be enrolled) or standard therapy plus pacemaker implantation and beta-blocker. The primary end point is the composite end point of total mortality plus nonfatal reinfarction. C1 [Goldberger, Jeffrey J.; Bonow, Robert O.] Northwestern Univ, Feinberg Sch Med, Div Cardiac Electrophysiol, Bluhm Cardiovasc Ctr, Chicago, IL 60611 USA. [Goldberger, Jeffrey J.; Bonow, Robert O.] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. [Cuffe, Michael] Duke Univ Hlth Syst, Durham, NC USA. [Rosenberg, Yves] NHLBI, Bethesda, MD 20892 USA. [O'Rourke, Robert] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Shah, Prediman K.] Cedars Sinai Heart Ctr, Los Angeles, CA USA. [Smith, Sidney] Univ N Carolina, Ctr Cardiovasc Sci & Med, Chapel Hill, NC USA. RP Goldberger, JJ (reprint author), Northwestern Univ, Feinberg Sch Med, Div Cardiac Electrophysiol, Bluhm Cardiovasc Ctr, 251 E Huron,Feinberg Pavil Suite 8-542, Chicago, IL 60611 USA. EM j-goldberger@northwestern.edu FU NHLBI NIH HHS [5U01HL080416] NR 82 TC 9 Z9 9 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAR PY 2008 VL 155 IS 3 BP 455 EP 464 DI 10.1016/j.ahj.2007.10.041 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 271OO UT WOS:000253798100007 PM 18294477 ER PT J AU Lopez-Jimenez, F Wu, CO Tian, X O'Connor, C Rich, MW Burg, MM Sheps, D Raczynski, J Somers, VK Jaffe, AS AF Lopez-Jimenez, Francisco Wu, Colin O. Tian, Xin O'Connor, Chris Rich, Michael W. Burg, Matthew M. Sheps, David Raczynski, James Somers, Virend K. Jaffe, Allan S. TI Weight change after myocardial infarction - the enhancing recovery in coronary heart disease patients (ENRICHD) experience SO AMERICAN HEART JOURNAL LA English DT Article ID BODY-MASS INDEX; CREATININE CLEARANCE; PROGNOSTIC IMPORTANCE; OBESITY PARADOX; ARTERY-DISEASE; MORTALITY; RISK; INTERVENTION; IMPACT; DEATH AB Background The relationship of changes in weight to outcomes in patients after myocardial infarction (MI) is controversial. Methods From the ENRICHD trial data, we assessed weight change, and the associations of baseline weight and change at follow-up with outcomes and interactions between psychosocial factors. Results At baseline, 73.6% of patients (n = 1706) were overweight or obese; 134 patients had body mass index of >= 40. Underweight patients were more likely to die or have nonfatal recurrent MI. After controlling for covariates, overweight and obese patients had similar outcomes to normal-weight patients. Eighteen percent of patients gained >5%, 27% lost >5%, and 55% had <= 5% change in weight. Compared with weight loss of <= 55%, the risk of death (adjusted hazard ratio 1.74, P = .01) and cardiovascular death (hazard ratio 1.79, P = .04) increased with weight, loss of >5%. After propensity matching, weight loss of >5% remained as a significant risk factor for death and cardiovascular death. There was no interaction between weight change and depression and/or social support at baseline or follow-up. Weight change was not associated with recurrent MI or cardiovascular hospitalizations. Conclusions A large proportion of patients lose or gain >5% of body weight after an MI. The association between obesity and lower mortality is modulated by comorbidities. Weight loss after MI is associated with worse outcomes and is not related to depression or social support. C1 [Lopez-Jimenez, Francisco; Somers, Virend K.; Jaffe, Allan S.] Mayo Clin Coll Med & Mayo Clin Fdn, Div Cardiovasc Dis, Rochester, MN USA. [Jaffe, Allan S.] Mayo Clin Coll Med & Mayo Clin Fdn, Dept Lab Med & Pathol, Rochester, MN USA. [Wu, Colin O.; Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [O'Connor, Chris] Duke Univ, Sch Med, Durham, NC USA. [Rich, Michael W.] Washington Univ, Sch Med, St Louis, MO USA. [Burg, Matthew M.] Yale Univ, Sch Med, New Haven, CT USA. [Sheps, David] Univ Florida, Sch Med, Gainesville, FL USA. [Raczynski, James] Univ Alabama, Sch Med, Birmingham, AL USA. RP Lopez-Jimenez, F (reprint author), 200 1st St SW, Rochester, MN 55905 USA. EM lopez@mayo.edu FU NHLBI NIH HHS [N01 HC055146, N01 HC055141, R01 HL073211, N01 HC055142, R01 HL065176-07, N01 HC055143, N01 HC055145, N01 HC055148, N01 HC055147, R01 HL073211-05, N01 HC055140, N01 HC055144, R01 HL065176] NR 30 TC 20 Z9 20 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAR PY 2008 VL 155 IS 3 BP 478 EP 484 DI 10.1016/j.ahj.2007.10.026 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 271OO UT WOS:000253798100010 PM 18294480 ER PT J AU Jordan, PN Hall, KD AF Jordan, Peter N. Hall, Kevin D. TI Dynamic coordination of macronutrient balance during infant growth: insights from a mathematical model SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE macronutrients; infant growth; body composition; oxidation rates; mathematical model; doubly labeled water ID BIRTH-WEIGHT INFANTS; ENERGY-EXPENDITURE; INDIRECT CALORIMETRY; BODY-COMPOSITION; SUBSTRATE UTILIZATION; PRETERM INFANTS; (H2O)-H-2-O-18 METHOD; RESPIRATORY QUOTIENT; WEIR EQUATION; NUTRITION AB Background: Complex dynamic changes in body composition, dietary intake, energy expenditure, and macronutrient oxidation occur during infant growth. Although previous investigators have focused on energy requirements for normal growth, little is known about the dynamic coordination of macronutrient balance. Objective: Our objective was to develop a mathematical model of the dynamic relations between diet, macronutrient oxidation, and energy expenditure during normal infant growth. Design: We developed a mathematical model that integrates longitudinal data on changes of body composition and carbon dioxide production determined with the doubly labeled water method to calculate both energy intake requirements and macronutrient oxidation rates during normal infant growth. Results: The calculated fat oxidation rate was initially < 20 kcal . kg(-1) . d(-1), despite the consumption of > 60 kcal . kg(-1) . d(-1) of dietary fat. This discrepancy was maintained until approximate to 6 mo, after which fat intake was only slightly greater than fat oxidation. Nonfat oxidation closely followed nonfat dietary intake for the duration of the period studied. Model calculations of the energy intake requirements for normal growth were slightly lower than previous estimates. The calculations were robust to variations of body weight, body composition, and diet composition input data, but depended sensitively on variations of carbon dioxide production data. Conclusions: Our model presents a dynamic picture of how macronutrient oxidation adapts in concert with dietary changes and energy expenditure to give rise to normal tissue deposition. The model integrates a variety of data in a self-consistent way, simulating the complex metabolic adaptations occurring during normal growth while extracting important physiologic information from the data that would otherwise be unavailable. C1 [Jordan, Peter N.; Hall, Kevin D.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, Lab Biol Modeling, NIH, 12 South Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Hall, Kevin/F-2383-2010 FU Intramural NIH HHS [Z01 DK013036-01] NR 29 TC 16 Z9 16 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2008 VL 87 IS 3 BP 692 EP 703 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 273KA UT WOS:000253927700023 PM 18326609 ER PT J AU Boccia, S Hung, R Ricciardi, G Gianfagna, F Ebert, MPA Fang, JY Gao, CM Gotze, T Graziano, F Lacasana-Navarro, M Lin, DX Lopez-Carrillo, L Qiao, YL Shen, HB Stolzenberg-Solomon, R Takezaki, T Weng, YR Zhang, FF van Duijn, CM Boffetta, P Taioli, E AF Boccia, Stefania Hung, Rayjean Ricciardi, Gualtiero Gianfagna, Francesco Ebert, Matthias P. A. Fang, Jing-Yuan Gao, Chang-Ming Goetze, Tobias Graziano, Francesco Lacasana-Navarro, Marina Lin, Dongxin Lopez-Carrillo, Lizbeth Qiao, You-Lin Shen, Hongbing Stolzenberg-Solomon, Rachael Takezaki, Toshiro Weng, Yu-Rong Zhang, Fang Fang van Duijn, Cornelia M. Boffetta, Paolo Taioli, Emanuela TI Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: A Huge-GSEC review SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE epidemiology; folic acid; genetic predisposition to disease; meta-analysis; MTHFR; stomach neoplasms ID GENOMIC DNA HYPOMETHYLATION; CORONARY-HEART-DISEASE; CELL FOLATE LEVELS; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; FOLIC-ACID; GENETIC SUSCEPTIBILITY; COMMON MUTATION; STOMACH-CANCER; MTHFR POLYMORPHISMS; PLASMA HOMOCYSTEINE AB Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate, whose role in gastric carcinogenesis is controversial. The authors performed a meta-analysis and individual data pooled analysis of case-control studies that examined the association between C677T and A1298C polymorphisms (the former being associated with low folate serum levels) and gastric cancer (meta-analyses: 16 studies, 2,727 cases and 4,640 controls for C677T and seven studies, 1,223 cases and 2,015 controls for A1298C; pooled analyses: nine studies, 1,540 cases and 2,577 controls for C677T and five studies, 1,146 cases and 1,549 controls for A1298C). An increased risk was found for MTHFR 677 TT in the meta-analysis (odds ratio (OR) 1.52, 95% confidence interval (CI): 1.31, 1.77) and pooled analysis (OR = 1.49, 95% CI: 1.14, 1.95). No association resulted for MTHFR 1298 CC (meta-OR = 0.94, 95% CI: 0.65, 1.35; pooled OR = 0.90, 95% CI: 0.69, 1.34). Results from the pooled analysis of four studies on C677T stratified according to folate levels showed an increased risk for individuals with low (OR 2.05, 95% CI: 1.13, 3.72) versus high (OR = 0.95, 95% CI: 0.54, 1.67) folate levels. Overall, these findings support the hypothesis that folate plays a role in gastric carcinogenesis. C1 [Boccia, Stefania; Ricciardi, Gualtiero; Gianfagna, Francesco] Univ Cattolica Sacro Cuore, Inst Hyg, Genet Epidemiol & Mol Biol Unit, I-00168 Rome, Italy. [Hung, Rayjean; Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon, France. [Ebert, Matthias P. A.; Goetze, Tobias] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 2, D-8000 Munich, Germany. [Fang, Jing-Yuan; Weng, Yu-Rong] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Digest Dis, Shanghai 200030, Peoples R China. [Gao, Chang-Ming; Takezaki, Toshiro] Jiangsu Prov Inst Canc Res, Dept Epidemiol, Nanjing, Peoples R China. [Gianfagna, Francesco] Azienda Osped San Salvatore, Div Med Oncol, Pesaro, Italy. [Lacasana-Navarro, Marina] Andalusian Sch Publ Hlth, Granada, Spain. [Lin, Dongxin] Chinese Acad Med Sci, Inst Canc, Dept Etiol & Carcinogenesis, Beijing 100037, Peoples R China. [Lin, Dongxin] Peking Union Med Coll, Beijing, Peoples R China. [Lopez-Carrillo, Lizbeth] Mexico Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Dept Epidemiol, Beijing 100037, Peoples R China. [Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Stat, Nanjing, Peoples R China. [Stolzenberg-Solomon, Rachael] Natl Canc Inst, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD USA. [Zhang, Fang Fang] UNT Hlth Sci Ctr, Dept Epidemiol, Ft Worth, TX USA. [van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol & Biostat, Rotterdam, Netherlands. [Taioli, Emanuela] Univ Pittsburgh, Sch Publ Hlth, Inst Canc, Pittsburgh, PA 15260 USA. RP Boccia, S (reprint author), Univ Cattolica Sacro Cuore, Inst Hyg, Genet Epidemiol & Mol Biol Unit, L Go Vito 1, I-00168 Rome, Italy. EM sboccia@rm.unicatt.it RI Hung, Rayjean/A-7439-2013; Qiao, You-Lin/B-4139-2012; Lacasana, Marina/N-2614-2015; Gianfagna, Francesco/K-4561-2016 OI Qiao, You-Lin/0000-0001-6380-0871; Gianfagna, Francesco/0000-0003-4615-0816 FU NCI NIH HHS [P30CA047904-19S1] NR 82 TC 62 Z9 68 U1 0 U2 8 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 MAR 1 PY 2008 VL 167 IS 5 BP 505 EP 516 DI 10.1093/aje/kwm344 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 270UQ UT WOS:000253746100001 PM 18162478 ER PT J AU Kan, HD Stevens, J Heiss, G Rose, KM London, SJ AF Kan, Haidong Stevens, June Heiss, Gerardo Rose, Kathryn M. London, Stephanie J. TI Dietary fiber, lung function, and chronic obstructive pulmonary disease in the atherosclerosis risk in communities study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE dietary fiber; forced expiratory volume; pulmonary disease; chronic obstructive; respiratory function tests; vital capacity ID C-REACTIVE PROTEIN; FRESH FRUIT CONSUMPTION; FIRST NATIONAL-HEALTH; SURVEY NHANES-I; EPIDEMIOLOGIC EVIDENCE; VENTILATORY FUNCTION; GENERAL-POPULATION; BRITISH ADULTS; WHOLE GRAINS; CANCER RISK AB Recent data suggest beneficial effects of fiber intake on chronic respiratory symptoms in adults that are independent of antioxidant vitamin intake, but little is known about fiber consumption in relation to lung function and chronic obstructive pulmonary disease (COPD). The authors investigated the association of fiber intake with lung function and COPD in 11,897 US men and women from the Atherosclerosis Risk in Communities study (1987-1989). After control for potential confounders, positive associations were found between lung function and fiber intake from all sources as well as from cereal or fruit alone. Compared with those in the lowest quintile, participants in the highest quintile of total fiber intake had a 60.2-ml higher forced expiratory volume in 1 second (FEV1) (p for trend < 0.001), 55.2-ml higher forced vital capacity (FVC) (p = 0.001), 0.4% higher FEV1/FVC ratio (p = 0.040), 1.8% higher percent predicted FEV1 (p < 0.001), and 1.4% higher percent predicted FVC (p = 0.001). Adjusted odds ratios of COPD for the highest versus lowest quintiles of intake were 0.85 (p = 0.044) for total fiber, 0.83 (p = 0.021) for cereal fiber, and 0.72 (p = 0.005) for fruit fiber. This study provides the first known evidence that dietary fiber is independently associated with better lung function and reduced prevalence of COPD. C1 [Kan, Haidong; London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Stevens, June] Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27515 USA. [Stevens, June; Heiss, Gerardo; Rose, Kathryn M.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA. RP London, SJ (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM london2@niehs.nih.gov OI London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS [Z01 ES043012-09]; NHLBI NIH HHS [N01HC55020, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055022, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55021, N01HC55022]; NIEHS NIH HHS [Z01 ES043012] NR 59 TC 20 Z9 20 U1 1 U2 8 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 MAR 1 PY 2008 VL 167 IS 5 BP 570 EP 578 DI 10.1093/aje/kwm343 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 270UQ UT WOS:000253746100010 PM 18063592 ER PT J AU Peters, TM Ekelund, U Leitzmann, M Easton, D Warren, R Luben, R Bingham, S Khaw, KT Wareham, NJ AF Peters, Tricia M. Ekelund, Ulf Leitzmann, Michael Easton, Douglas Warren, Ruth Luben, Robert Bingham, Sheila Khaw, Kay-Tee Wareham, Nicholas J. TI Physical activity and mammographic breast density in the EPIC-Norfolk cohort study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast; breast neoplasms; exercise; mammography; motor activity ID POSTMENOPAUSAL WOMEN; CANCER-RISK; PARENCHYMAL PATTERNS; PREMENOPAUSAL WOMEN; SEX-HORMONES; ESTROGEN METABOLISM; ADIPOSE-TISSUE; UNITED-STATES; BODY-SIZE; ASSOCIATION AB Physical inactivity and high mammographic breast density have both been associated with increased breast cancer risk. However, the association between physical activity and mammographic breast density remains inconsistent. In the European Prospective Investigation of Cancer (EPIC)-Norfolk population-based cohort study (United Kingdom), the authors investigated the cross-sectional association between physical activity level at baseline during 1993-1997 and breast density among 1,394 postmenopausal, cancer-free women. Usual physical activity was assessed by a brief, validated questionnaire. Percentage breast density was determined visually from mammograms by three trained radiologists using the Boyd six-category scale. The association between physical activity level and breast density risk category was examined. No statistically significant association between physical activity and percentage breast density was observed in the unadjusted or adjusted regression models. A suggested increase in breast density for the most active women in the unadjusted regression analysis (odds ratio = 1.13, 95% confidence interval: 0.71, 1.80) was reversed after inclusion of body mass index and reproductive and lifestyle variables (odds ratio = 0.78, 95% confidence interval: 0.45, 1.34). The lack of an association between physical activity and percentage breast density suggests that an association between physical activity and breast cancer risk is unlikely to be mediated through an effect on mammographic breast density. C1 [Peters, Tricia M.; Ekelund, Ulf; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England. [Peters, Tricia M.; Leitzmann, Michael] NIH, NCI, Bethesda, MD 20892 USA. [Easton, Douglas] Univ Cambridge, Strangeways Res Lab, Canc Res UK, Genet Epidemiol Grp, Cambridge CB2 1TN, England. [Warren, Ruth] Addenbrookes Hosp, Dept Radiol, Cambridge CB2 2QQ, England. [Luben, Robert] Univ Cambridge, Sch Clin Med, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Bingham, Sheila] Dunn Human Nutr Unit, MRC, Cambridge, England. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Clin Gerontol Unit, Cambridge CB2 1TN, England. RP Ekelund, U (reprint author), Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Box 285,Hills Rd, Cambridge CB2 0QQ, England. EM ulf.ekelund@mrc-epid.cam.ac.uk OI Luben, Robert/0000-0002-5088-6343 FU Cancer Research UK [10118]; Medical Research Council [MC_U106179471, MC_U106179473]; NIGMS NIH HHS [T32 GM008444] NR 48 TC 11 Z9 11 U1 1 U2 3 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 MAR 1 PY 2008 VL 167 IS 5 BP 579 EP 585 DI 10.1093/aje/kwm350 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 270UQ UT WOS:000253746100011 PM 18162477 ER PT J AU Stolzenberg-Solomon, RZ Adams, K Leitzmann, M Schairer, C Michaud, DS Hollenbeck, A Schatzkin, A Silverman, DT AF Stolzenberg-Solomon, Rachael Z. Adams, Kenneth Leitzmann, Michael Schairer, Catherine Michaud, Dominique S. Hollenbeck, Albert Schatzkin, Arthur Silverman, Debra T. TI Adiposity, physical activity, and pancreatic cancer in the National Institutes of Health-AARP Diet and Health Cohort SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adenocarcinoma; adiposity; body mass index; cohort studies; exercise; pancreatic neoplasms; smoking; waist-hip ratio ID BODY-MASS INDEX; FOOD FREQUENCY QUESTIONNAIRES; CIGARETTE-SMOKING; RISK-FACTORS; GLUCOSE-METABOLISM; ANTHROPOMETRIC FACTORS; ORIGINAL WHITEHALL; INSULIN-RESISTANCE; MEDICAL CONDITIONS; EXOGENOUS INSULIN AB Obesity and lack of physical activity have been inconsistently associated with pancreatic cancer. Using data from a self-administered baseline questionnaire (1995-1996), the authors investigated the association between adiposity and physical activity and pancreatic cancer in 495,035 participants of the National Institutes of Health-AARP Diet and Health Study who were aged 50-71 years. To avoid the influence of subclinical disease, follow-up time started 1 year after baseline, and subjects with a body mass index (BMI) of < 18.5 kg/m(2) were excluded. A subcohort (n = 302,060) completed a second questionnaire with information about physical activity and waist and hip circumference. During follow-up though 2000, 654 pancreatic cancer cases were identified. The authors used Cox proportional hazard models to generate adjusted hazard ratios and 95% confidence intervals. Compared with those with a BMI of 18.5-<25, those with a BMI of >= 35 had a 45% greater pancreatic cancer risk (95% confidence interval (CI): 1.04, 2.02; p(trend) = 0.02). Significant positive associations for BMI were observed among nonsmokers (for BMI >= 35: hazard ratio = 1.70, 95% CI: 1.14, 2.53; p(trend) = 0.004) but not recent smokers (p(interaction) = 0.08). Waist circumference was positively associated with pancreatic cancer (fourth vs. first quartile: hazard ratio 2.53, 95% CI: 1.13, 5.65; p(trend) = 0.04) in women but not men. The authors observed no association with physical activity. Their results suggest a positive association between adiposity and pancreatic cancer. C1 [Stolzenberg-Solomon, Rachael Z.; Adams, Kenneth; Leitzmann, Michael; Schatzkin, Arthur] NIH, NCI, Dept Hlth & Human Serv, Nutr Epidemiol Branch,Div Canc Epidemiol & Genet, Rockville, MD USA. [Schairer, Catherine] NIH, NCI, Dept Hlth & Human Serv, Biostat Branch,Div Canc Epidemiol & Genet, Rockville, MD USA. [Michaud, Dominique S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hollenbeck, Albert] AARP, Environm Anal Dept, Washington, DC USA. [Silverman, Debra T.] NIH, NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, Rockville, MD USA. RP Stolzenberg-Solomon, RZ (reprint author), 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM rs221z@nih.gov RI Michaud, Dominique/I-5231-2014 FU Intramural NIH HHS NR 67 TC 59 Z9 60 U1 0 U2 0 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 MAR 1 PY 2008 VL 167 IS 5 BP 586 EP 597 DI 10.1093/aje/kwm361 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 270UQ UT WOS:000253746100012 PM 18270373 ER PT J AU Trochim, WM Marcus, SE Masse, LC Moser, RP Weld, PC AF Trochim, William M. Marcus, Stephen E. Masse, Louise C. Moser, Richard P. Weld, Patrick C. TI The evaluation of large research initiatives - A participatory integrative mixed-methods approach SO AMERICAN JOURNAL OF EVALUATION LA English DT Article DE center grants; concept mapping; evaluating research; federal evaluation; logic models ID CITATION ANALYSIS; RESEARCH IMPACT; COCITATION ANALYSIS; BIBLIOMETRICS; SCIENCE; CONCEPTUALIZATION; SCIENTOMETRICS; JOURNALS AB Over the past few decades there has been a rise in the number of federally funded large scientific research initiatives, with increased calls to evaluate their processes and outcomes. This article describes efforts to evaluate such initiatives in one agency within the U.S. federal government. The authors introduce the Evaluation of Large Initiatives (ELI) project, a preliminary effort to explore how to accomplish such evaluation. They describe a pilot effort of this project to evaluate the Transdisciplinary Tobacco Use Research Center (TTURC) initiative of the National Cancer Institute. They present a summary of this pilot evaluation including the methods used (concept mapping, logic modeling, a detailed researcher survey, content. analysis and systematic peer-evaluation of progress reports, bibliometric analysis and peer evaluation of publications and citations, and financial expenditures analysis) and a brief overview of results. Finally, they discuss several important lessons and recommendations that emerged from this work. C1 [Trochim, William M.] Cornell Univ, Ithaca, NY 14853 USA. [Marcus, Stephen E.; Weld, Patrick C.] Natl Canc Inst, Bethesda, MD USA. [Masse, Louise C.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Trochim, WM (reprint author), Cornell Univ, 249 MVR Hall, Ithaca, NY 14853 USA. EM wmt1@cornell.edu NR 56 TC 55 Z9 55 U1 3 U2 33 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1098-2140 J9 AM J EVAL JI Am. J. Eval. PD MAR PY 2008 VL 29 IS 1 BP 8 EP 28 DI 10.1177/1098214007309280 PG 21 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA 263FO UT WOS:000253203200001 ER PT J AU Arean, P Alexopoulos, G Reynolds, C Niederehe, G AF Arean, Patricia Alexopoulos, George Reynolds, Charles Niederehe, George TI RESULTS FROM THE NIMH WORKSHOP ON PSYCHOSOCIAL INTERVENTIONS IN LATE LIFE MENTAL ILLNESS SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Arean, Patricia] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Alexopoulos, George] Cornell Univ, Weill Med Coll, White Plains, NY USA. [Reynolds, Charles] Univ Pittsburg, Sch Med, Pittsburgh, PA USA. [Niederehe, George] NIMH, Bethesda, MD 20892 USA. 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 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2008 VL 16 IS 3 SU 1 BP A29 EP A30 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YV UT WOS:000207905800047 ER PT J AU Evans, J Palmer, B Eyler, L Kaschow, J AF Evans, Jovier Palmer, Barton Eyler, Lisa Kaschow, John TI LATE LIFE SCHIZOPHRENIA RESEARCH: CLINICAL, ETHICAL, AND TRANSLATIONAL APPROACHES SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Evans, Jovier] NIMH, NIH, Bethesda, MD 20892 USA. [Palmer, Barton; Eyler, Lisa] Univ Calif San Diego, La Jolla, CA 92093 USA. [Kaschow, John] Western Psychiat Inst & Clin, VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. 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 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2008 VL 16 IS 3 SU 1 BP A15 EP A15 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YV UT WOS:000207905800011 ER PT J AU Shanahan, B Lebowitz, BD Bartels, SJ Bruce, ML Halpain, M Light, E Reynolds, CF Smith, G Streim, JE Unutzer, J AF Shanahan, Brian Lebowitz, Barry D. Bartels, Stephen J. Bruce, Martha L. Halpain, Maureen Light, Enid Reynolds, Charles F. Smith, Gwenn Streim, Joel E. Unuetzer, Juergen TI A Web-Based Response to Addressing the Current NIMH Funding Climate for Geriatric Mental Health Researchers SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Shanahan, Brian] MediSpin Inc, New York, NY USA. [Lebowitz, Barry D.; Halpain, Maureen] Univ Calif San Diego, San Diego, CA 92103 USA. [Bartels, Stephen J.] New Hampshire Dartmouth Psychiat Res Ctr, Lebanon, NH USA. [Bruce, Martha L.] Cornell Univ, Weill Med Coll, White Plains, NY USA. [Light, Enid] NIMH, Bethesda, MD 20892 USA. [Reynolds, Charles F.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Smith, Gwenn] Univ Toronto, Toronto, ON, Canada. [Streim, Joel E.; Unuetzer, Juergen] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. 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 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2008 VL 16 IS 3 SU 1 BP A115 EP A116 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YV UT WOS:000207905800187 ER PT J AU Unutzer, J Taylor, J Schoenbaum, M Katon, W Pincus, H Hogan, D AF Unuetzer, Juergen Taylor, Jennifer Schoenbaum, Michael Katon, Wayne Pincus, Harold Hogan, Diane TI Depression in Green Ribbon Health's Medicare Health Support Program SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Katon, Wayne] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Taylor, Jennifer; Hogan, Diane] Green Ribbon Hlth, Tampa, FL USA. [Schoenbaum, Michael] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Pincus, Harold] Columbia Univ, Dept Psychiat, New York, NY USA. [Pincus, Harold] Qual & Outcomes Res New York Presb, New York, NY USA. 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 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2008 VL 16 IS 3 SU 1 BP A92 EP A92 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YV UT WOS:000207905800145 ER PT J AU Baird, DD AF Baird, D. D. TI Endocrine events of early pregnancy SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 [Baird, D. D.] NIH, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2008 VL 20 IS 2 BP 214 EP 214 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 266YJ UT WOS:000253473800020 ER PT J AU Hediger, ML Schisterman, EF Wactawski-Wende, J Hovey, K AF Hediger, M. L. Schisterman, E. F. Wactawski-Wende, J. Hovey, K. TI Linear proportions, cardiovascular and reproductive risk in adult women: The BioCycle Study SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 [Hediger, M. L.; Schisterman, E. F.] DHHS, NIH, NICHD, DESPR, Bethesda, MD USA. [Wactawski-Wende, J.; Hovey, K.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1042-0533 EI 1520-6300 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2008 VL 20 IS 2 BP 223 EP 223 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 266YJ UT WOS:000253473800050 ER PT J AU Kulkarni, A Wilson, DM AF Kulkarni, Avanti Wilson, David M., III TI The involvement of DNA-damage and -repair defects in neurological dysfunction SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Review ID STRAND-BREAK REPAIR; BASE EXCISION-REPAIR; AMYOTROPHIC-LATERAL-SCLEROSIS; RNA-POLYMERASE-II; XERODERMA-PIGMENTOSUM PATIENTS; TRANSCRIPTION-COUPLED REPAIR; TELANGIECTASIA-LIKE DISORDER; HISTIDINE TRIAD SUPERFAMILY; HUMAN POLYNUCLEOTIDE KINASE; ATAXIA-OCULOMOTOR APRAXIA AB A genetic link between defects in DNA repair and neurological abnormalities has been well established through studies of inherited disorders such as ataxia telangiectasia and xeroderma pigmentosum. In this review, we present a comprehensive summary of the major types of DNA damage, the molecular pathways that function in their repair, and the connection between defective DNA-repair responses and specific neurological disease. Particular attention is given to describing the nature of the repair defect and its relationship to the manifestation of the associated neurological dysfunction. Finally, the review touches upon the role of oxidative stress, a leading precursor to DNA damage, in the development of certain neurodegenerative pathologies, such as Alzheimer's and Parkinson's. C1 [Kulkarni, Avanti; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM wilsonda@grc.nia.nih.gov FU Intramural NIH HHS NR 291 TC 37 Z9 37 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2008 VL 82 IS 3 BP 539 EP 566 DI 10.1016/j.ajhg.2008.01.009 PG 28 WC Genetics & Heredity SC Genetics & Heredity GA 275JN UT WOS:000254067800001 PM 18319069 ER PT J AU Mochel, F Knight, MA Tong, WH Hernandez, D Ayyad, K Taivassalo, T Andersen, PM Singleton, A Rouault, TA Fischbeck, KH Haller, RG AF Mochel, Fanny Knight, Melanie A. Tong, Wing-Hang Hernandez, Dena Ayyad, Karen Taivassalo, Tanja Andersen, Peter M. Singleton, Andrew Rouault, Tracey A. Fischbeck, Kenneth H. Hallers, Ronald G. TI Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SUCCINATE-DEHYDROGENASE; PAROXYSMAL MYOGLOBINURIA; ACONITASE DEFICIENCY; HEREDITARY MYOPATHY; FRIEDREICH ATAXIA; 4FE-4S CLUSTERS; FRATAXIN; HOMEOSTASIS; DISEASE; BIOGENESIS AB A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis. C1 [Mochel, Fanny] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. [Knight, Melanie A.; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Tong, Wing-Hang; Rouault, Tracey A.] NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. [Hernandez, Dena; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ayyad, Karen; Hallers, Ronald G.] VA N Texas Med Ctr, Dallas, TX 75216 USA. [Taivassalo, Tanja] McGill Univ, Dept Kinesiol, Montreal, PQ H2W 1S4, Canada. [Andersen, Peter M.] Umea Univ Hosp, Inst Clin Neurosci, S-90185 Umea, Sweden. [Hallers, Ronald G.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Hallers, Ronald G.] Presbyterian Med Ctr, Inst Exercise & Environm Med, Neuromuscular Ctr, Dallas, TX 75231 USA. RP Mochel, F (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. EM mochelf@ninds.nih.gov RI Singleton, Andrew/C-3010-2009 FU Intramural NIH HHS; NIAMS NIH HHS [R01 AR050597] NR 30 TC 108 Z9 112 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2008 VL 82 IS 3 BP 652 EP 660 DI 10.1016/j.ajhg.2007.12.012 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 275JN UT WOS:000254067800010 PM 18304497 ER PT J AU Zaykin, DV Shibata, K AF Zaykin, Dmitri V. Shibata, Kyoko TI Genetic flip-flop without an accompanying change in linkage disequilibrium SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID PATTERNS C1 [Zaykin, Dmitri V.; Shibata, Kyoko] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. RP Zaykin, DV (reprint author), Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. EM zaykind@niehs.nih.gov FU Intramural NIH HHS NR 8 TC 39 Z9 39 U1 0 U2 1 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 MAR PY 2008 VL 82 IS 3 BP 794 EP 796 DI 10.1016/j.ajhg.2008.02.001 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 275JN UT WOS:000254067800025 PM 18319078 ER PT J AU Xu, JQ Lee, ET Devereux, RB Umans, JG Bella, JN Shara, NM Yeh, JL Fabsitz, RR Howard, BV AF Xu, Jiaqiong Lee, Elisa T. Devereux, Richard B. Umans, Jason G. Bella, Jonathan N. Shara, Nawar M. Yeh, Jeunliang Fabsitz, Richard R. Howard, Barbara V. TI A longitudinal study of risk factors for incident albuminuria in diabetic American Indians: The Strong Heart Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE longitudinal analysis; risk factors; incidence; albuminuria; American Indians ID ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE; NONDIABETIC INDIVIDUALS; FOLLOW-UP; MICROALBUMINURIA; NEPHROPATHY; MELLITUS; PROTEINURIA; POPULATION; EXCRETION AB Background: There have been no studies that use longitudinal data with more than 2 measurements and methods of longitudinal data analysis to identify risk factors for incident albuminuria over time more effectively. Study Design: Longitudinal study. Settings & Participants: A subgroup of participants in the Strong Heart Study, a population-based sample of American Indians, in central Arizona, Oklahoma, and North and South Dakota. Participants with diabetes without albuminuria were followed up for a mean of 4 years. Predictors: Age, sex, study center, high-density lipoprotein and low-density lipoprotein cholesterol levels, triglyceride level, body mass index, systolic blood pressure, use of antihypertensive medication, smoking, hemoglobin A(1c) level, fasting glucose level, type of diabetes therapy, diabetes duration, plasma creatinine level, and urinary albumin-creatinine ratio (UACR). Outcomes & Measurements: Albuminuria was defined as UACR of 30 mg/g or greater. Urine creatinine and albumin were measured by using the picric acid method and a sensitive nephelometric technique, respectively. Results: Of 750 and 568 participants with diabetes without albuminuria and with normal plasma creatinine levels at the first and second examinations, 246 and 132 developed albuminuria by the second and third examinations, respectively. Incident albuminuria was predicted by baseline UACR, fasting glucose level, systolic blood pressure, plasma creatinine level, study center, current smoking, and use of angiotensin-converting enzyme inhibitors and antidiabetic medications. UACR of 10 to 30 mg/g increased the odds of developing albuminuria 2.7-fold compared with UACR less than 5 mg/g. Limitations: Single random morning urine specimen. Conclusions: Many risk factors identified for incident albuminuria can be modified. Control of blood pressure and glucose level, smoking cessation, and use of angiotensin-converting enzyme inhibitors may reduce the incidence of albuminuria. C1 [Xu, Jiaqiong; Lee, Elisa T.; Yeh, Jeunliang] Methodist Hosp, Res Inst, Ctr Biostat, Houston, TX USA. [Xu, Jiaqiong; Lee, Elisa T.; Yeh, Jeunliang] Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Devereux, Richard B.] Weill Cornell Med Coll, New York, NY USA. [Umans, Jason G.; Shara, Nawar M.; Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD USA. [Bella, Jonathan N.] Bronx Lebanon Hosp Ctr, Bronx, NY USA. [Bella, Jonathan N.] Albert Einstein Coll Med, Bronx, NY USA. [Fabsitz, Richard R.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Xu, JQ (reprint author), Methodist Hosp, Res Inst, Ctr Biostat, 6565 Fannin St MGJ6, Houston, TX USA. EM sxu@tmhs.org FU Intramural NIH HHS; NHLBI NIH HHS [U01 HL041642, U01 HL041652, U01 HL041654, U01 HL041654-12, U01 HL041654-13, U01 HL041654-14, U01-HL-41642, U01-HL-41652, UL01-HL-41654] NR 41 TC 17 Z9 17 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2008 VL 51 IS 3 BP 415 EP 424 DI 10.1053/j.ajkd.2007.11.010 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 285TU UT WOS:000254799900012 PM 18295057 ER PT J AU Balk, K Biesecker, LG AF Balk, Katherine Biesecker, Leshe G. TI The clinical atlas of Greig cephalopolysyndactyly syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE polydactyly; cutaneous syndactyly; macrocephaly; hypertelorism; hydrocephalus; seizures ID POLYDACTYLY TYPE-A; GLI3 MUTATIONS; ACROCALLOSAL SYNDROME; PHENOTYPE PREDICTION; GENE; SPECTRUM; FAMILIES; POSITION AB Greig cephalopolysyndactyly syndrome (GCPS) is a rare multiple congenital anomaly syndrome that is inherited in an autosomal dominant pattern and is caused by haploin-sufficiency of the GLI3 gene. The syndrome typically includes preaxial or mixed pre- and postaxial polydactyly and cutaneous syndactyly, ocular hypertelorism, and macrocephaly in its typical forms, but sometimes includes hydrocephalus, seizures, mental retardation, and developmental delay in more severe cases. Patients with milder forms of GCPS can have Subtle craniofacial dysmorphic features that are difficult to distinguish from normal variation. This article presents the spectrum of dysmorphic findings in GCPS highlighting some of its key presenting features to familiarize clinicians with the variable expressivity of the condition. Published 2008 Wiley-Liss, Inc. C1 [Balk, Katherine] NINR, NIH, Bethesda, MD 20892 USA. [Biesecker, Leshe G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), 49 Convent Dr,Room4A56, Bethesda, MD 20892 USA. EM lesheb@helix.nih.gov FU Intramural NIH HHS NR 20 TC 17 Z9 17 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR 1 PY 2008 VL 146A IS 5 BP 548 EP 557 DI 10.1002/ajmg.a.32167 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 269LJ UT WOS:000253650200003 PM 18241058 ER PT J AU Roberson, R Toso, L Abebe, D Spong, CY AF Roberson, Robin Toso, Laura Abebe, Daniel Spong, Catherine Y. TI Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med DE Down syndrome; KIF17; NR2B; synaptic plasticity; Ts65Dn ID LONG-TERM POTENTIATION; SUPERFAMILY PROTEINS; TS65DN MOUSE; TRANSPORT; DYNAMICS; MEMORY; MICE AB OBJECTIVE: Down syndrome (DS), a major cause of mental retardation, affects 1 of 800 newborns. Mouse models for Down syndrome have been studied and found to have developmental and learning deficits, including the Ts65Dn (DS) mouse model. N-methyl-D-aspartate receptor NR2B subunit enhances synaptic plasticity. The up-regulation of KIF17, a motor protein that transports NR2B to the synaptic region parallels up-regulation of synaptic NR2B. Down regulation of reflects up-regulation of less plastic NR2A subunit. We evaluated NR2B, NR2A, and KIF17 in Ts65Dn and control mice. STUDY DESIGN: Ts65Dn (4) and control (4) adult brains were collected; NR2A, NR2B, and KIF17 were measured by Western blot and quantified using National Institutes of Health Image software. Comparisons were made using analysis of variance, <.05 was considered significant. RESULTS: There was a significant decrease in KIF17 (P=.04) level in Ts65Dn mice as compared with the control animals, but there were no significant differences in the levels of NR2A (P=.79) and NR2B (P=.96). CONCLUSION: The significant decrease of KIF17 in Ts65Dn animals may in part mediate cognitive defects in DS. C1 [Roberson, Robin] NICHHD, NIH, Unit Perinatal & Dev Neurobiol, Bethesda, MD 20895 USA. NIAAA, Bethesda, MD USA. RP Roberson, R (reprint author), NICHHD, NIH, Unit Perinatal & Dev Neurobiol, 9000 Rockville Pike, Bethesda, MD 20895 USA. EM robersor@mail.nih.gov NR 24 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2008 VL 198 IS 3 AR 313.e1 DI 10.1016/j.ajog.2008.01.033 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 270OL UT WOS:000253730000028 ER PT J AU Sperduto, RD Clemons, TE Lindblad, AS Ferris, FL AF Sperduto, Robert D. Clemons, Traci E. Lindblad, Anne S. Ferris, Frederick L., III CA Age-Related Eye Dis Study Res Grp TI Cataract classification using serial examinations in the Age-Related Eye Disease Study: Age-Related Eye Disease Study report no. 24 SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID HIGH-DOSE SUPPLEMENTATION; LENS OPACITIES; CLINICAL-TRIAL; BETA-CAROTENE; VISION LOSS; MAJOR GENE; VITAMIN-C; AREDS; SYSTEM; PHOTOGRAPHS AB PURPOSE: To describe use of serial lens examinations to assign cataract phenotype in the Age-Related Eye Disease Study (AREDS). DESIGN: Cohort study. METHODS: Lens photographs were graded annually using the AREDS system for classifying cataracts. Nuclear grades (0.9 to 6.1) were assigned using standard photographs. Percentage of pupillary involvement was used to assign cortical and posterior subcapsular grades. Cutpoints were established for the presence or absence of each type of opacity (absent <4.0 for nuclear, <10% for cortical, and <5% of central 5 mm for posterior subcapsular). An algorithm weighted for grades at the last three examinations was used to assign cataract phenotype. Separately, cataract phenotype was assigned as grade predicted at final visit by linear regression of serial grades. Results from the two approaches were compared and final person phenotypes were established. These person cataract phenotype assignments were compared with phenotype assignments based on the last serial grade alone. RESULTS: Four thousand six hundred and twenty-eight AREDS participants aged 55 to 80 years at baseline had median follow,up of 10.6 years. Person phenotype assignments agreed for the two approaches in 4,557 (98.5%) participants after some algorithmic adjudication. Phenotypes were no cataract (n = 1,418), nuclear (n = 1,287), cortical (n = 1,396), posterior subcapsular (n = 541), cataract surgery and no specific opacity type (n = 335), and questionable (n = 426). Phenotype assignments based on serial grades and on last examination alone were in good agreement. CONCLUSIONS: Serial lens photographs obtained over a 10-year period were used to provide a robust assignment of cataract phenotype. Well-characterized cataract phenotypes are of importance as genetic studies of the AREDS cohort are considered. C1 [Clemons, Traci E.; Lindblad, Anne S.] EMMES Corp, Rockville, MD 20850 USA. [Sperduto, Robert D.; Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. RP Clemons, TE (reprint author), EMMES Corp, 401 N Washington St,Suite 700, Rockville, MD 20850 USA. EM telemons@emmes.com NR 12 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2008 VL 145 IS 3 BP 504 EP 508 DI 10.1016/j.ajo.2007.10.024 PG 5 WC Ophthalmology SC Ophthalmology GA 272EE UT WOS:000253841900019 PM 18201681 ER PT J AU Sun, JP Chen, H Chen, C Whitsett, JA Mishina, Y Bringas, P Ma, JC Warburton, D Shi, W AF Sun, Jianping Chen, Hui Chen, Cheng Whitsett, Jeffrey A. Mishina, Yuji Bringas, Pablo, Jr. Ma, Jeffrey C. Warburton, David Shi, Wei TI Prenatal lung epithelial cell-specific abrogation of Alk3-bone morphogenetic protein signaling causes neonatal respiratory distress by disrupting distal airway formation SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; BRANCHING MORPHOGENESIS; MOUSE EMBRYOGENESIS; EXPRESSION; RECEPTOR; CATENIN; LIMB; ALVEOLARIZATION; PROLIFERATION; GASTRULATION AB Bone morphogenetic proteins (BMPs) play important roles in regulating lung development and function although the endogenous regulatory effects of BMP signaling are still controversial. We found that BMP type I receptor Alk3 is expressed predominantly in airway epithelial cells during development. The function of Alk3 in lung development was determined using an inducible knockout mouse model by crossing epithelial cell-specific Cre transgenic mice SPC-rtTA/TetO-Cre and floxed-Alk3 mice. Abrogation of Alk3 in mouse lung epithelia from either early lung organogenesis or late gestation resulted in similar neonatal respiratory distress phenotypes accompanied by collapsed lungs. Early-induction of Alk3 knockout in lung epithelial cells caused retardation of early lung branching morphogenesis, reduced cell proliferation, and differentiation. However, late gestation induction of the knockout caused changes in cell proliferation and survival, as shown by altered cell biology, reduced expression of peripheral epithelial markers (Clara cell-specific protein, surfactant protein C, and aquaporin-5), and lack of surfactant secretion. Furthermore, canonical Wnt signaling was perturbed, possibly through reduced Writ inhibitory factor-1 expression in Alk3-knockout lungs. Therefore, our data suggest that deficiency of appropriate BMP signaling in lung epithelial cells results in prenatal lung malformation, neonatal atelectasis, and respiratory failure. C1 [Sun, Jianping; Chen, Hui; Ma, Jeffrey C.; Warburton, David; Shi, Wei] Childrens Hosp Los Angeles, Dept Surg, Dev Biol Program, Los Angeles, CA 90027 USA. [Bringas, Pablo, Jr.; Shi, Wei] Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90089 USA. [Whitsett, Jeffrey A.] Cincinnati Childrens Hosp, Med Ctr, Div Pulm Biol, Dept Pediat, Cincinnati, OH USA. [Whitsett, Jeffrey A.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Mishina, Yuji] NIH, Reprod & Dev Toxicol Lab, Mol Dev Biol Grp, Res Triangle Pk, NC USA. [Chen, Cheng] China Med Univ, Dept Dev Biol, Shenyang, Peoples R China. RP Shi, W (reprint author), Childrens Hosp Los Angeles, Dept Surg, Dev Biol Program, 4650 Sunset Blvd,MS 35, Los Angeles, CA 90027 USA. EM wshi@chla.usc.edu FU NHLBI NIH HHS [HL44060, HL60231, R01 HL044977, R01 HL068597, R01 HL068597-07, R01 HL075773, R01 HL044060, P01 HL060231, HL75773, HL68597, HL44977] NR 42 TC 35 Z9 35 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2008 VL 172 IS 3 BP 571 EP 582 DI 10.2353/ajpath.2008.070286 PG 12 WC Pathology SC Pathology GA 268YM UT WOS:000253616400003 PM 18258849 ER PT J AU Nagaraju, K Rawat, R Veszelovszky, E Thapliyal, R Kesari, A Sparks, S Raben, N Plotz, P Hoffman, EP AF Nagaraju, Kanneboyina Rawat, Rashmi Veszelovszky, Edina Thapliyal, Rachana Kesari, Akanchha Sparks, Susan Raben, Nina Plotz, Paul Hoffman, Eric P. TI Dysferlin deficiency enhances monocyte phagocytosis - A model for the inflammatory onset of limb-girdle muscular dystrophy 2B SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; DEFECTIVE MEMBRANE REPAIR; MHC CLASS-I; MIYOSHI MYOPATHY; RHO-GTPASES; T-CELLS; BINDING PROTEINS; UP-REGULATION; TNF RECEPTOR; MUSCLE-CELLS AB Dysferlin deficiency causes limb-girdle muscular dystrophy type 2B (LGMD2B; proximal weakness) and Miyoshi myopathy (distal weakness). Muscle inflammation is often present in dysferlin deficiency, and patients are frequently misdiagnosed as having polymyositis. Because monocytes normally express dysferlin, we hypothesized that monocyte/macrophage dysfunction in dysferlin-deficient patients might contribute to disease onset and progression. We therefore examined phagocytic activity, in the presence and absence of cytokines, in freshly isolated peripheral blood monocytes from LGMD2B patients and in the SJL dysferlin-deficient mouse model. Dysferlin-deflcient monocytes showed increased phagocytic activity compared with control cells. siRNA-mediated inhibition of dysferlin expression in the J774 macrophage cell line resulted in significantly enhanced phagocytosis, both at baseline and in response to tumor necrosis factor-a. Immunohistochemical analysis revealed positive staining for several mononuclear cell activation markers in LGMD2B human muscle and SJL mouse muscle. SJL muscle showed strong up-regulation of endocytic proteins CIMPR, clathrin, and adaptin-a, and LGMD2B muscle exhibited decreased expression of decay accelerating factor, which was not dysferlin-specific. We further showed that expression levels of small Rho family GTPases RhoA, Rac1, and Cdc 42 were increased in dysferlin-deficient murine immune cells compared with control cells. Therefore, hypothesize that mild myofiber damage in dysferlin-deficient muscle stimulates an inflammatory cascade that may initiate, exacerbate, and possibly perpetuate the underlying myofiber-specific dystrophic process. C1 [Nagaraju, Kanneboyina; Rawat, Rashmi; Veszelovszky, Edina; Kesari, Akanchha; Sparks, Susan; Hoffman, Eric P.] George Washington Univ, Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. [Thapliyal, Rachana] Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21205 USA. [Raben, Nina; Plotz, Paul] NIAMSD, NIH, Arthrit Rheumatism Branch, Bethesda, MD 20892 USA. RP Nagaraju, K (reprint author), George Washington Univ, Childrens Natl Med Ctr, Res Ctr Genet Med, 111 Michigan Ave, Washington, DC 20010 USA. EM knagaraju@cnmcresearch.org FU Intramural NIH HHS; NCRR NIH HHS [M01 RR020359, M01-RR020359]; NIAMS NIH HHS [R01 AR050478, R01-AR050478] NR 52 TC 71 Z9 72 U1 1 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2008 VL 172 IS 3 BP 774 EP 785 DI 10.2353/ajpath.2008.070327 PG 12 WC Pathology SC Pathology GA 268YM UT WOS:000253616400021 PM 18276788 ER PT J AU Goodwin, TM Poursharif, B Korst, LM MacGibbon, KW Romero, R Fejzo, MS AF Goodwin, T. Murphy Poursharif, Borzouyeh Korst, Lisa M. MacGibbon, Kimber W. Romero, Roberto Fejzo, Marlena S. TI Secular trends in the treatment of hyperemesis gravidarum SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE hyperemesis gravidarum; nausea; vomiting; pregnancy ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; UNITED-STATES; DOUBLE-BLIND; PREGNANCY; NAUSEA; GINGER; MANAGEMENT; THERAPY AB The purpose of this study was to describe the treatment of women with hyperemesis gravidarum (HG). Women with HG pregnancies of at least 27 weeks duration occurring between 1985 and 2004 described their treatment on an HG website from 2003 to 2005. The usage and effectiveness of > 20 treatment options were reported by 765 women for 1193 pregnancies. The women who used intravenous (IV) hydration, serotonin inhibitors, and parenteral nutrition (PN) reported the highest rates of effectiveness, with 84%, 83%, and 79% reporting that these respective treatments may have contributed to decreased nausea/vomiting. The use of conventional treatments increased from 20 to 30% to > 60% between 1985 and 1989 and 2000 and 2004; serotonin inhibitor use increased to 55% after its introduction in the 1990s. Over the past 20 years, multiple treatments have been used for women with HG, with a trend toward treatment with reportedly more effective modalities, such as IV hydration and serotonin inhibitors. C1 [Goodwin, T. Murphy; Poursharif, Borzouyeh; Korst, Lisa M.; Fejzo, Marlena S.] Univ So Calif, Keck Sch Med, LAC USC Womens & Childrens Hosp, Dept Obstet & Gynecol,Div Maternal Fetal Med, Los Angeles, CA 90033 USA. [MacGibbon, Kimber W.] Hyperemesis Educ & Res Fdn, Leesburg, VA USA. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. RP Korst, LM (reprint author), Univ So Calif, Keck Sch Med, LAC USC Womens & Childrens Hosp, Dept Obstet & Gynecol,Div Maternal Fetal Med, 1240 N Miss Rd,5K40, Los Angeles, CA 90033 USA. OI MacGibbon, Kimber/0000-0002-6534-3114 FU Intramural NIH HHS NR 30 TC 16 Z9 16 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD MAR PY 2008 VL 25 IS 3 BP 141 EP 147 DI 10.1055/s-2008-1040344 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 276LL UT WOS:000254143000002 PM 18260047 ER PT J AU Jain, S Zharikova, OL Ravindran, S Nanovskya, TN Mattison, DR Hankins, GDV Ahmed, MS AF Jain, Sangeeta Zharikova, Olga L. Ravindran, Selvan Nanovskya, Tatiana N. Mattison, Donald R. Hankins, Gary D. V. Ahmed, Mahmoud S. TI Glyburide metabolism by placentas of healthy and gestational diabetics SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE gestational diabetes; glyburide; placental metabolism; diabetic diet ID TRANSPLACENTAL TRANSFER; GROWTH-FACTOR; HUMAN SERUM; MICROSOMES; TROPHOBLAST; PREGNANCY; METHADONE; KINETICS; HUMANS AB The aim of this investigation was to determine the metabolism of glyburide (GL) by microsomes prepared from placentas obtained from uncomplicated pregnancies (UP), women with gestational diabetics (GD) on a diabetic diet, and those on a diet and GL. Term placentas were obtained from UP and GD. Crude microsomal. fractions were prepared by differential centrifugation and stored at -80 degrees C. The activity of the microsomes in metabolizing glyburide to the trans-4-hydroxycyclohexyl glyburide (THCGL) and cis-3-hydroxycyclohexyl glyburide (CHCGL) was determined and quantified using high-performance liquid chromatography-mass spectrometer (HPLC-MS). The activity of the placental microsomes varied widely between individual placentas in each group. The median values (pmol.mg(-1) P.min(-1)) for the rates of THCGL formation were 0.34, 0.3, and 0.23 for placentas of UP, GD on diet, and GD on GL and a diet, respectively. The median values for CHCGL formation were 0.13 for UP, 0.11 for GD on a diet, and 0.10 (pmol.mg(-1) P.min(-1)) for GD on GL and a diet. A pool of individual microsomal fractions from each group was prepared and its activity revealed the following: greater formation of THCGL in the UP (0.36 +/- 0.10) than GD (0.22 +/- 0.03) (p = 0.058 for GD on a diet, 0.04 for GD on GL). There was greater formation of CHCGL in UP (0.26 +/- 0.04) than GD (0.12 +/- 0.003) (p < 0.006). There was no difference in GD on a diet and GD on GL plus diet. We concluded that the apparent differences in the formation of metabolites may be statistically significant, but it is unlikely to be of physiological importance, given the sample size and other experimental factors. Therefore, a more comprehensive investigation is underway. C1 [Jain, Sangeeta; Zharikova, Olga L.; Ravindran, Selvan; Nanovskya, Tatiana N.; Hankins, Gary D. V.; Ahmed, Mahmoud S.] Univ Texas Galveston, Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Mattison, Donald R.] NICHHD, Obstet & Pediat Pharmacol Branch, Rockville, MD USA. RP Ahmed, MS (reprint author), Univ Texas Galveston, Med Branch, Dept Obstet & Gynecol, 301 Univ Blvd, Galveston, TX 77555 USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 23 TC 5 Z9 5 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD MAR PY 2008 VL 25 IS 3 BP 169 EP 174 DI 10.1055/s-2008-1061503 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 276LL UT WOS:000254143000008 PM 18300189 ER PT J AU Carper, MJ Cade, WT Cam, M Zhang, S Shalev, A Yarasheski, KE Ramanadham, S AF Carper, Michael J. Cade, W. Todd Cam, Margaret Zhang, Sheng Shalev, Anath Yarasheski, Kevin E. Ramanadham, Sasanka TI HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE metabolic syndrome; insulin-signaling pathways; human immunodeficiency virus ID NECROSIS-FACTOR-ALPHA; GLUCOSE-TRANSPORT; ADIPOSE-TISSUE; ANTIRETROVIRAL THERAPY; 3T3-L1 ADIPOCYTES; LIPID-METABOLISM; CELL FUNCTION; NEGATIVE MEN; RECEPTOR; LIPOLYSIS AB Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60-80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty (fa/ fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-alpha and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/ hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs. C1 [Carper, Michael J.; Cade, W. Todd; Zhang, Sheng; Yarasheski, Kevin E.; Ramanadham, Sasanka] Washington Univ, Sch Med, Dept Internal Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA. [Cade, W. Todd] Washington Univ, Sch Med, Program Phys Therapy, St Louis, MO 63110 USA. [Cam, Margaret] NIDDK, NIH, Bethesda, MD USA. [Shalev, Anath] Univ Wisconsin, Dept Med, Madison, WI USA. RP Ramanadham, S (reprint author), Washington Univ, Sch Med, Dept Internal Med, Div Endocrinol Metab & Lipid Res, Southwest Towet,Room 846A,Campus Box 8127,660 S E, St Louis, MO 63110 USA. EM sramanad@im.wustl.edu RI Yarasheski, Kevin/A-3025-2008; OI Yarasheski, Kevin/0000-0001-5436-2451 FU NCRR NIH HHS [P41-RR00954, P41 RR000954]; NIDDK NIH HHS [T32 DK007296, T32-DK-007296-27, DK-059531, DK-074345, P30 DK056341-08, P60 DK020579, P60-DK-020579, R01 DK049393, R01 DK049393-12, R01 DK059531-07, R21 DK074345, R01 DK049393-11, R21 DK074345-02, R01-DK-69455, R01 DK059531-09, R01 DK059531-06, R01 DK049393-09A1, P30-DK-056431, P30 DK056341-07, P30 DK056341, DK-049393, R01 DK069455, R21 DK074345-01, DK-074343, K01 DK074343, R56 DK049393, R01 DK049393-10, R01 DK059531, R01 DK059531-08] NR 49 TC 24 Z9 24 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2008 VL 294 IS 3 BP E558 EP E567 DI 10.1152/ajpendo.00167.2007 PG 10 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 271VE UT WOS:000253816000010 PM 18171911 ER PT J AU Pacher, P Ungvari, Z AF Pacher, Pal Ungvari, Zoltan TI Pleiotropic effects of the CB2 cannabinoid receptor activation on human monocyte migration: implications for atherosclerosis and inflammatory diseases SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Editorial Material ID HEPATIC ISCHEMIA/REPERFUSION INJURY; MYOCARDIAL-ISCHEMIA; SYSTEM; ENDOCANNABINOIDS; APOPTOSIS; PROTECTS; STRESS; DRUGS; MICE C1 [Ungvari, Zoltan] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress & Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Ungvari, Z (reprint author), New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. EM pacher@mail.nih.gov; zoltan_ungvari@nymc.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS [Z01 AA000375-02]; NHLBI NIH HHS [HL-077256, HL-43023, P01 HL043023, R01 HL077256, R01 HL077256-01A2] NR 28 TC 9 Z9 10 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD MAR PY 2008 VL 294 IS 3 BP H1133 EP H1134 DI 10.1152/ajpheart.00020.2008 PG 2 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 271WH UT WOS:000253818900004 PM 18203843 ER PT J AU Rieg, T Pothula, K Schroth, J Satriano, J Osswald, H Schnermann, J Insel, PA Bundey, RA Vallon, V AF Rieg, Timo Pothula, Kanishka Schroth, Jana Satriano, Joseph Osswald, Hartmut Schnermann, Juergen Insel, Paul A. Bundey, Richard A. Vallon, Volker TI Vasopressin regulation of inner medullary collecting ducts and compensatory changes in mice lacking adenosine A(1) receptors SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE arginine vasopressin; aquaporin-2; cyclooxygenase ID THICK ASCENDING LIMB; TUBULOGLOMERULAR FEEDBACK; MESSENGER-RNA; ADENYLYL-CYCLASE; GENE-EXPRESSION; STIMULATED CAMP; BLOOD-PRESSURE; P2Y2 RECEPTOR; RENIN RELEASE; RAT-KIDNEY AB Activation of adenosine A(1) receptors (A(1)R) can inhibit arginine vasopressin (AVP)-induced cAMP formation in isolated cortical and medullary collecting ducts. To assess the in vivo consequences of the absence of A(1)R, we performed experiments in mice lacking A(1)R (A(1)R(.-/-)) We assessed the effects of the vasopressin V-2 receptor (V2R) agonist 1-desamino-8-D-arginine vasopressin (dDAVP) on cAMP formation in isolated inner medullary collecting ducts (IMCD) and on water excretion in conscious water-loaded mice. dDAVP-induced cAMP formation in isolated IMCD was significantly greater (similar to 2-fold) in A(1)R(-/-) compared with wild-type mice (WT) and, in contrast to WT, was not inhibited by the A1R agonist N6-cyclohexyladenosine. A(1)R(-/-) and WT had similar basal urinary excretion of vasopressin, expression of aquaporin-2 protein in renal cortex and medulla, and acute increases in urinary flow rate and electrolyte-free water clearance in response to the V2R antagonist SR121463 or acute water loading; the latter increased inner medullary A(1)R expression in WT. Dose dependence of dDAVP-induced antidiuresis after acute water loading was not different between the genotypes. However, A(1)R(-/-) had greater inner medullary expression of cyclooxygenase-1 under basal conditions and of the P2Y(2) and EP3 receptor in response to water loading compared with WT mice. Thus vasopressin-induced cAMP formation is enhanced in isolated IMCD of mice lacking A(1)R, but the adenosine-A(1)R/V2R interaction demonstrated in vitro is likely compensated in vivo by multiple mechanisms, a number of which can be "uncovered" by water loading. C1 [Rieg, Timo; Satriano, Joseph; Insel, Paul A.; Vallon, Volker] Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, La Jolla, CA 92161 USA. [Pothula, Kanishka; Insel, Paul A.; Bundey, Richard A.; Vallon, Volker] Univ Calif San Diego, Div Nephrol & Hypertens, Dept Pharmacol, La Jolla, CA 92161 USA. [Rieg, Timo; Schroth, Jana; Satriano, Joseph; Vallon, Volker] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Schnermann, Juergen] NIDDK, NIH, Bethesda, MD USA. [Rieg, Timo; Osswald, Hartmut] Univ Tubingen, Fac Med, Inst Pharmacol & Toxicol, Tubingen, Germany. RP Vallon, V (reprint author), Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, 3350 La Jolla Village Dr 9151, La Jolla, CA 92161 USA. EM vvallon@ucsd.edu FU NIDDK NIH HHS [DK-56248, R01 DK056248, DK-28602]; NIGMS NIH HHS [GM-66232] NR 55 TC 12 Z9 12 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2008 VL 294 IS 3 BP F638 EP F644 DI 10.1152/ajprenal.00344.2007 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 268IW UT WOS:000253574500022 PM 18199602 ER PT J AU Webber, LS Catellier, DJ Lytle, LA Murray, DM Pratt, CA Young, DR Elder, JP Lohman, TG Stevens, J Jobe, JB Pate, RR AF Webber, Larry S. Catellier, Diane J. Lytle, Leslie A. Murray, David M. Pratt, Charlotte A. Young, Deborah R. Elder, John P. Lohman, Timothy G. Stevens, June Jobe, Jared B. Pate, Russell R. TI Promoting physical activity in middle school girls - Trial of activity for adolescent girls SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HEALTH PROMOTION; FORMATIVE RESEARCH; UNITED-STATES; INTERVENTION; PREVENTION; PROGRAM; TAAG; OVERWEIGHT; EDUCATION AB Background: Physical activity is important for weight control and good health; however, activity levels decline in the adolescent years, particularly in girls. Design: Group randomized controlled trial. Setting/participants: Middle school girls with English-speaking skills and no conditions to prevent participation in physical activity in 36 schools in six geographically diverse areas of the United States. Random, cross-sectional samples were drawn within schools: 6th graders in 2003 (n=1721) and 8th graders in 2005 (n=3504) and 2006 (n=3502). Intervention: A 2-year study-directed intervention (fall 2003 to spring 2005) targeted schools, community agencies, and girls to increase opportunities, support, and incentives for increased physical activity. Components included programs linking schools and community agencies, physical education, health education, and social marketing. A third-year intervention used school and community personnel to direct intervention activities. Main outcome measures: The primary outcome, daily MET-weighted minutes of moderate-to-vigorous physical activity (MET-weighted MVPA), was assessed using accelerometry. Percent body fat was assessed using anthropometry. Results: After the staff-directed intervention (pre-stated primary outcome), there were no differences (mean=-0.4, 95% CI=-8.2 to 7.4) in adjusted MET-weighted MVPA between 8th-grade girls in schools assigned to intervention or control. Following the Program Champion-directed intervention, girls in intervention schools were more physically active than girls in control schools (mean difference 10.9 MET-weighted minutes of MVPA, 95% CI=0.52-21.2). This difference is about 1.6 minutes of daily MVPA or 80 kcal per week. There were no differences in fitness or percent body fat at either 8th-grade timepoint. Conclusion: A school-based, community-linked intervention modestly improved physical activity in girls. Trial Registration: NCT00006409. C1 [Webber, Larry S.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Biostat, New Orleans, LA 70112 USA. [Catellier, Diane J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Stevens, June] Univ N Carolina, Dept Nutr & Epidemiol, Chapel Hill, NC USA. [Lytle, Leslie A.] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. [Murray, David M.] Ohio State Univ, Div Epidemiol, Columbus, OH 43210 USA. [Pratt, Charlotte A.; Jobe, Jared B.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Young, Deborah R.] Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. [Elder, John P.] Univ San Diego, Grad Sch Publ Hlth, San Diego, CA 92110 USA. [Lohman, Timothy G.] Univ Arizona, Dept Physiol, Tucson, AZ USA. [Pate, Russell R.] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. RP Webber, LS (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Biostat, SL18,1440 Canal St, New Orleans, LA 70112 USA. EM lwebber@tulane.edtr OI Baranowski, Tom/0000-0002-0653-2222 FU NHLBI NIH HHS [U01 HL066845, U01 HL066845-06, U01 HL066852, U01 HL066852-06, U01 HL066853, U01 HL066853-07, U01 HL066855, U01 HL066855-01, U01 HL066855-02, U01 HL066855-03, U01 HL066855-04, U01 HL066855-05, U01 HL066855-06, U01 HL066856, U01 HL066856-06, U01 HL066857, U01 HL066857-07, U01 HL066858, U01 HL066858-06, U01HL066845, U01HL066852, U01HL066853, U01HL066856, U01HL066857, U01HL066858] NR 57 TC 153 Z9 153 U1 1 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2008 VL 34 IS 3 BP 173 EP 184 DI 10.1016/j.amepre.2007.11.018 PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 265ET UT WOS:000253342600001 PM 18312804 ER PT J AU Lillie, SE AF Lillie, Sarah E. TI Diffusion of innovation in the age of YouTube SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Letter C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Lillie, SE (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM lillies@mail.nih.gov NR 7 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2008 VL 34 IS 3 BP 267 EP 267 DI 10.1016/j.amepre.2007.11.009 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 265ET UT WOS:000253342600015 PM 18312819 ER PT J AU Vitiello, B Pearson, JL AF Vitiello, Benedetto Pearson, Jane L. TI A depressed adolescent at high risk of suicidal behavior SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; FOLLOW-UP; THERAPY; TADS; IDEATION; SSRIS; ANTIDEPRESSANTS; PSYCHOTHERAPY; INTERVENTION; METAANALYSIS C1 [Vitiello, Benedetto; Pearson, Jane L.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Vitiello, B (reprint author), NIMH, Div Serv & Intervent Res, Rm 7147,6001 Execut Blvd, Bethesda, MD 20892 USA. EM bvitiell@mail.nih.gov NR 35 TC 7 Z9 7 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2008 VL 165 IS 3 BP 323 EP 328 DI 10.1176/appi.ajp.2007.07101549 PG 6 WC Psychiatry SC Psychiatry GA 271HL UT WOS:000253779400010 PM 18316430 ER PT J AU Brotman, MA Guyer, AE Lawson, ES Horsey, SE Rich, BA Dickstein, DP Pine, DS Leibenluft, E AF Brotman, Melissa A. Guyer, Amanda E. Lawson, Evin S. Horsey, Sarah E. Rich, Brendan A. Dickstein, Daniel P. Pine, Daniel S. Leibenluft, Ellen TI Facial emotion labeling deficits in children and adolescents at risk for bipolar disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT Meeting of the Career-Development-Institute-for-Bipolar-Disorder CY MAY 01, 2006 CL Boca Raton, FL SP Career Dev Inst Bipolar Disorder ID RATING-SCALE; RELIABILITY; VALIDITY; FLEXIBILITY; PHENOTYPES; ACCURACY; MANIA AB Objective: Research has revealed facial emotion labeling deficits in children and adolescents with bipolar disorder. To assess whether such impairments may be an endophenotype for bipolar disorder, the authors examined facial emotion identification proficiency in children who were at risk for bipolar disorder because they had a first-degree relative with the illness. Method: The facial expressions subtests of the Diagnostic Analysis of Nonverbal Accuracy scale were administered to 52 patients with bipolar disorder, 24 at-risk youths, and 78 control subjects, all 4-18 years of age. Results: Compared with the control group, both the bipolar and at-risk groups made more errors identifying facial emotions. The number of errors did not differ significantly between the bipolar and at-risk groups. Conclusions: Deficits in facial emotion labeling may be a risk marker for bipolar disorder. Further study is needed to determine the neural mechanisms involved, as well as to explore other emotional processing impairments in youths at risk for bipolar disorder and to identify genetic associations. C1 NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Brotman, MA (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, 15K N Dr,Room 208, Bethesda, MD 20892 USA. EM brotmanm@mail.nih.gov RI Brotman, Melissa/H-7409-2013; Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU Intramural NIH HHS; NIMH NIH HHS [MH 060952] NR 27 TC 89 Z9 90 U1 1 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2008 VL 165 IS 3 BP 385 EP 389 DI 10.1176/appi.ajp.2007.06122050 PG 5 WC Psychiatry SC Psychiatry GA 271HL UT WOS:000253779400019 PM 18245180 ER PT J AU Ryskulova, A Turczyn, K Makuc, DM Cotch, MF Klein, RJ Janiszewski, R AF Ryskulova, Asel Turczyn, Kathleen Makuc, Diane M. Cotch, Mary Frances Klein, Richard J. Janiszewski, Rosemary TI Self-reported age-related eye diseases and visual impairment in the United States: Results of the 2002 National Health Interview Survey SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID NUTRITION EXAMINATION SURVEY; OPEN-ANGLE GLAUCOMA; DIABETIC-RETINOPATHY; PREVALENCE; ADULTS; POPULATION; BLINDNESS; US; AMERICANS; MORTALITY AB Objectives. We sought to establish national data on the prevalence of visual impairment, blindness, and selected eye conditions (cataract, diabetic retinopathy, glaucoma, and macular degeneration) and to characterize these conditions within sociodemographic subgroups. Methods. Information on self-reported visual impairment and diagnosed eye diseases was collected from 31044 adults. We calculated weighted prevalence estimates and odds ratios with logistic regression using SUDAAN. Results. Among noninstitutionalized US adults 18 years and older, the estimated prevalence for visual impairment was 9.3% (19.1 million Americans), including 0.3% (0.7 million) with blindness. Lifetime prevalence of diagnosed diseases was as follows: cataract, 8.6% (17 million); glaucoma, 2.0% (4 million); macular degeneration, 1.1% (2 million); and diabetic retinopathy, 0.7% (1.3 million). The prevalence of diabetic retinopathy among persons with diagnosed diabetes was 9.9%. Conclusions. We present the most recently available national data on self-reported visual impairment and selected eye diseases in the United States. The results of this study provide a baseline for future public health initiatives relating to visual impairment. C1 [Ryskulova, Asel; Turczyn, Kathleen; Makuc, Diane M.; Klein, Richard J.] CDC, Natl Ctr Hlth Stat, Off Anal & Epidemiol, Hyattsville, MD 20782 USA. [Cotch, Mary Frances; Janiszewski, Rosemary] NEI, NIH, Bethesda, MD 20892 USA. RP Ryskulova, A (reprint author), CDC, Natl Ctr Hlth Stat, Off Anal & Epidemiol, 3311 Toledo Rd,Room 6309, Hyattsville, MD 20782 USA. EM aryskulova@cdc.gov OI Cotch, Mary Frances/0000-0002-2046-4350 FU Intramural NIH HHS [Z01 EY000402-07, Z01 EY000402-06, Z99 EY999999, ZIA EY000402-09, ZIA EY000402-10, ZIA EY000402-12, ZIA EY000402-08] NR 44 TC 53 Z9 55 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2008 VL 98 IS 3 BP 454 EP 461 DI 10.2105/AJPH.2006.098202 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 270TG UT WOS:000253742500016 PM 18235074 ER PT J AU Augustson, EM Wanke, KL Rogers, S Bergen, AW Chatterjee, N Synder, K Albanes, D Taylor, PR Caporaso, NE AF Augustson, Erik M. Wanke, Kay L. Rogers, Scott Bergen, Andrew W. Chatterjee, Nilanjan Synder, Kirk Albanes, Demetrius Taylor, Phil R. Caporaso, Neil E. TI Predictors of sustained smoking cessation: A prospective analysis of chronic smokers from the alpha-tocopherol beta-carotene cancer prevention study SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID NICOTINE DEPENDENCE TREATMENT; PSYCHIATRIC-DISORDERS; ALCOHOL DEPENDENCE; LUNG-CANCER; TOBACCO USE; PREVALENCE; ABSTINENCE; RECOMMENDATIONS; DEPRESSION; HISTORY AB Objectives. Because US smoking rates have not declined during the past decade, there is a renewed need to identify factors associated with smoking cessation. Using a nested case-control design, we explored the association between ability to sustain cessation over an extended period and demographic, smoking, medical, and behavioral variables. Methods. We selected a sample of 1379 sustained quitters (abstinent from smoking for at least 40 months) and 1388 relapsers (abstinent for more than 8 months before relapse) from participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, a nutritional intervention study involving Finnish men aged 50 to 69 years at baseline. Contingency table and multiple regression analyses were used to evaluate potential differences between the 2 groups on baseline variables. Results. Compared with sustained quitters, relapsers were more likely to report symptoms of emotional distress and higher levels of nicotine dependence, to drink more alcohol, and to report more medical conditions. Conclusions. Factors associated with both tobacco use and comorbid conditions impact an individual's ability to maintain long-term smoking cessation. Understanding the underlying mechanisms of action and potential common pathways among these factors may help to improve smoking cessation therapies. C1 [Augustson, Erik M.] NCI, DCCPS, TCRB, Bethesda, MD 20892 USA. [Augustson, Erik M.] Sci Applicat Int Corp, Frederick, MD USA. [Wanke, Kay L.; Bergen, Andrew W.; Taylor, Phil R.; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Rogers, Scott] NCI, Div Canc Control & Populat Sci, Epidemiol & Genet Res Program, Bethesda, MD 20892 USA. [Rogers, Scott] US Dept Treasury, Bethesda, MD USA. [Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Synder, Kirk] Informat Management Serv Inc, Bethesda, MD USA. [Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. RP Augustson, EM (reprint author), NCI, DCCPS, TCRB, EPN-4039B,6130 Execut Blvd,MSC 7337, Bethesda, MD 20892 USA. EM augustse@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Bergen, Andrew/0000-0002-1237-7644 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 41 TC 45 Z9 45 U1 0 U2 6 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2008 VL 98 IS 3 BP 549 EP 555 DI 10.2105/AJPH.2005.084137 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 270TG UT WOS:000253742500029 PM 17600267 ER PT J AU Frazee, LA Bourguet, CC Gutierrez, W Elder-Arrington, J Elackattu, AEP Haller, NA AF Frazee, Lawrence A. Bourguet, Claire C. Gutierrez, Wilson Elder-Arrington, Jacinta Elackattu, Alphi E. P. Haller, Nairmeen Awad TI Retrospective evaluation of a method to predict fresh-frozen plasma dosage in anticoagulated patients SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Article DE fresh-frozen plasma; warfarin; anticoagulation reversal; dose prediction ID PROTHROMBIN COMPLEX CONCENTRATE; URGENT REVERSAL; FACTOR VIIA; WARFARIN; THERAPY; TRANSFUSION; HEMOSTASIS; EFFICACY AB In the United States, fresh-frozen plasma (FFP) is commonly used for urgent reversal of warfarin; however, dosage recommendations are difficult to find. If validated, a proposed method that uses a nonlinear relationship between international normalized ratio (INR) and clotting factor activity (CFa) would be useful. This study retrospectively evaluated a proposed equation with adult medical inpatients who received FFP for warfarin reversal. For each patient the equation was used to predict the dose of FFP required to achieve the observed change in INR, which was then compared to the actual dose. The equation was considered successful if the predicted dose was within +/-20% of the actual dose. Subgroup analyses included subjects who received concomitant vitamin K; subjects with supratherapeutic INRs (>3); and subjects with significantly elevated INRs (>5). Of the 209 patients screened, 91 met criteria for inclusion in the study. Use of the equation to calculate the predicted dose of FFP was successful in 11 patients (12.1%) with use of actual body weight for prediction and in 23 patients (25.3%) with use of ideal body weight (P = 0.02). The equation performed similarly in all subgroups analyzed. The mean predicted FFP dose was significantly greater than the actual dose in all patients when actual body weight was used (925.2 mL vs. 620.6 mL; P < 0.001). Least-squares regression modeling of repeat INR (converted to CFa) produced a model that accounted for 57% of the variance in repeat INR. The value predicted from the model was closer to the actual CFa than was the value predicted from the published equation in every comparison, but it was statistically different only when actual body weight was used. This study revealed that a published equation for calculation of FFP dose to reverse oral anticoagulation resulted in doses that were significantly higher than the actual dose. Use of ideal body weight improved accuracy but was still not successful for the majority of patients. Until trials are able to prospectively demonstrate the accuracy of a dose-prediction model for FFP, dosing will remain largely empiric. C1 [Frazee, Lawrence A.] Akron Gen Med Ctr, Dept Pharm, Akron, OH 44307 USA. [Frazee, Lawrence A.; Bourguet, Claire C.; Elackattu, Alphi E. P.; Haller, Nairmeen Awad] NE Ohio Univ, Coll Med, Rootstown, OH 44272 USA. [Gutierrez, Wilson; Haller, Nairmeen Awad] Akron Gen Med Ctr, Dept Med, Akron, OH USA. [Elder-Arrington, Jacinta] NHLBI, NIH, Bethesda, MD 20892 USA. RP Frazee, LA (reprint author), Akron Gen Med Ctr, Dept Pharm, 400 Wabash Ave, Akron, OH 44307 USA. EM lfrazec@agmc.org NR 17 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1075-2765 J9 AM J THER JI Am. J. Ther. PD MAR-APR PY 2008 VL 15 IS 2 BP 111 EP 118 DI 10.1097/MJT.0b013e3180ed4345 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 306WD UT WOS:000256277700005 PM 18356630 ER PT J AU Girlanda, R Kleiner, DE Duan, Z Ford, EAS Wright, EC Mannon, RB Kirk, AD AF Girlanda, R. Kleiner, D. E. Duan, Z. Ford, E. A. S. Wright, E. C. Mannon, R. B. Kirk, A. D. TI Monocyte infiltration and kidney allograft dysfunction during acute rejection SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Acute rejection; histopathology; kidney transplantation; monocytes; T cells ID HUMAN RENAL-ALLOGRAFTS; STIMULATING FACTOR EXPRESSION; MONOCLONAL-ANTIBODIES; TRANSPLANT REJECTION; BIOPSIES; MACROPHAGE; CELL; RECIPIENTS; TOLERANCE; RNA AB Multiple cell types infiltrate acutely rejecting renal allografts. Typically, monocytes and T cells predominate. Although T cells are known to be required for acute rejection, the degree to which monocytes influence this process remains incompletely defined. Specifically, it has not been established to what degree monocytes impact the clinical phenotype of rejection or how their influence compares to that of T cells. We therefore investigated the relative impact of T cells and monocytes by correlating their presence as measured by immunohistochemical staining with the magnitude of the acute change in renal function at the time of biopsy in 78 consecutive patients with histological acute rejection. We found that functional impairment was strongly associated with the degree of overall cellular infiltration as scored using Banff criteria. However, when cell types were considered, monocyte infiltration was quantitatively associated with renal dysfunction while T-cell infiltration was not. Similarly, renal tubular stress, as indicated by HLA-DR expression, increased with monocyte but not T-cell infiltration. These data suggest that acute allograft dysfunction is most closely related to monocyte infiltration and that isolated T-cell infiltration has less acute functional impact. This relationship may be useful in assigning acute clinical relevance to biopsy findings. C1 [Ford, E. A. S.; Mannon, R. B.; Kirk, A. D.] NIDDK, Transplant Branch, NIH, Bethesda, MD 20892 USA. [Girlanda, R.] Georgetown Univ Hosp, Transplant Inst, Washington, DC 20007 USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Duan, Z.; Wright, E. C.] NIDDK, Off Director, NIH, Bethesda, MD USA. [Kirk, A. D.] Emory Transplant Ctr, Atlanta, GA USA. RP Kirk, AD (reprint author), NIDDK, Transplant Branch, NIH, Bethesda, MD 20892 USA. EM adkirk@emory.edu RI Kirk, Allan/B-6905-2012; OI Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS [Z01 DK062007-06] NR 32 TC 54 Z9 58 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2008 VL 8 IS 3 BP 600 EP 607 DI 10.1111/j.1600-6143.2007.02109.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 267IV UT WOS:000253503600020 PM 18294156 ER PT J AU Lin, CJ Katongole-Mbidde, E Byekwaso, T Orem, J Rabkin, CS Mbulaiteye, SM AF Lin, Cynthia J. Katongole-Mbidde, Edward Byekwaso, Tadeos Orem, Jackson Rabkin, Charles S. Mbulaiteye, Sam M. TI Short report: Intestinal parasites in Kaposi sarcoma patients in Uganda: Indication of shared risk factors or etiologic association SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID IMMUNODEFICIENCY-VIRUS HIV; HUMAN-HERPESVIRUS-8 INFECTION; NEMATODE INFECTIONS; CANCER; ADULTS; PREVALENCE; AIDS; HELMINTHS; DIARRHEA; CHILDREN AB Kaposi sarcoma (KS) is endemic in Uganda and shares several risk factors with intestinal parasite infestation, including rural residence, contact with surface water, and walking barefoot, however, the significance of these ecologic relationships is unknown. We investigated these relationships among 1,985 Ugandan patients with cancer. Odds ratios (OR) were calculated using logistic regression. KS patients had higher carriage of Strongyloides stercoralis larvae (OR 2.1, 95% CI 1.2-3.7) and lower carriage of hookworm ova (0.6, 0.4-1.0) and Entamoeba coli cysts (0.7, 0.5-1.0), after adjusting for region of residence, age, gender, and diagnosis. While our findings may be due to confounding, they are compatible with shared risk factors or etiological association between parasites and KS, and warrant well-designed follow up studies. C1 [Katongole-Mbidde, Edward; Byekwaso, Tadeos; Orem, Jackson] Mulago Hosp, Uganda Canc Inst, Kampala, Uganda. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Execut Plaza S Room 7080, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N02-CO-12400] NR 25 TC 6 Z9 8 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAR PY 2008 VL 78 IS 3 BP 409 EP 412 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 273KE UT WOS:000253928100013 PM 18337336 ER PT J AU Urv, TK Zigman, WB Silverman, W AF Urv, Tiina K. Zigman, Warren B. Silverman, Wayne TI Maladaptive behaviors related to dementia status in adults with down syndrome SO AMERICAN JOURNAL ON MENTAL RETARDATION LA English DT Article ID MILD COGNITIVE IMPAIRMENT; MENTAL-RETARDATION; ADAPTIVE-BEHAVIOR; ALZHEIMERS-DISEASE; INTELLECTUAL DISABILITY; NEUROPSYCHIATRIC SYMPTOMS; PSYCHIATRIC-SYMPTOMS; OLDER-PEOPLE; AGE; DECLINE AB Changes in maladaptive behaviors related to specific stages of dementia were investigated in 251 adults 45 years of age and older with Down syndrome. Findings indicate clear differences in maladaptive behaviors at various stages of dementia. Generally, individuals with no signs or symptoms of dementia displayed fewer and less severe maladaptive behaviors than individuals in the early and mid-stages of dementia. Individuals transitioning into the early stages of dementia from no dementia displayed increased aggression, fearfulness, sadness, sleep problems, social inadequacy, stealing, and general regressive behavior. Thus, new concerns regarding these types of behaviors could be particularly useful in clarifying the dementia status of adults with Down syndrome and developing individualized plans for support. C1 [Urv, Tiina K.] Univ Massachusetts, Sch Med, Eunice Kennedy Shriver Ctr, Amherst, MA 01003 USA. [Zigman, Warren B.] New York State Inst Basic Res Dev Disabil, New York, NY USA. [Silverman, Wayne] Kennedy Krieger Inst, Baltimore, MD USA. [Silverman, Wayne] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Urv, TK (reprint author), NICHD, 6100 Execut Blvd,Rm 4B09D,MSC 7510, Bethesda, MD 20892 USA. EM urvtiin@mail.nih.gov FU NIA NIH HHS [R01 AG14763]; NICHD NIH HHS [P01 HD37425, P01 HD35897] NR 64 TC 24 Z9 24 U1 6 U2 14 PU AMER ASSOC MENTAL RETARDATION PI WASHINGTON PA 444 N CAPITOL ST, NW, STE 846, WASHINGTON, DC 20001-1512 USA SN 0895-8017 J9 AM J MENT RETARD JI Am. J. Ment. Retard. PD MAR PY 2008 VL 113 IS 2 BP 73 EP 86 DI 10.1352/0895-8017(2008)113[73:MBRTDS]2.0.CO;2 PG 14 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 265WP UT WOS:000253392800002 PM 18240877 ER PT J AU Nikolovska-Coleska, Z Meagher, JL Jiang, S Kawamoto, SA Gao, W Yi, H Qin, DG Roller, PP Stuckey, JA Wang, SM AF Nikolovska-Coleska, Zaneta Meagher, Jennifer L. Jiang, Sheng Kawamoto, Steven A. Gao, Wei Yi, Han Qin, Dongguang Roller, Peter P. Stuckey, Jeanne A. Wang, Shaomeng TI Design and characterization of bivalent Smac-based peptides as antagonists of XIAP and development and validation of a fluorescence polarization assay for XIAP containing both BIR2 and BIR3 domains SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE bivalent Smac mimetics; XIAP; fluorescence polarization binding assay; apoptosis ID APOPTOSIS PROTEIN XIAP; IAP PROTEINS; INHIBITOR; BINDING; CANCER; SMAC/DIABLO; ACTIVATION; CASPASES; POTENT AB XIAP (X-chromosome-linked inhibitor of apoptosis protein) is an inhibitor of apoptosis by binding to and inhibition of caspase-3 and caspase-7 through its BIR2 domain and caspase-9 through its BIR3 domain. Smac (second mitochondria-derived activator of caspases) protein is an endogenous antagonist of XIAP. Smac forms a dimer and concurrently binds both the BIR2 and BIR3 domains in XIAP, functioning as a highly efficient and potent cellular inhibitor of XIAP. In this article, we have designed and synthesized a bivalent Smac-based ligand (Smac-1) and its fluorescent labeled analogue (Smac-1F) and characterized their interaction with different constructs of XIAP. Our study demonstrates that bivalent Smac-based ligands bind concurrently to both the BIR2 and BIR3 domains of XIAP and are more than 500 times more potent than the corresponding monovalent Smac-based ligands. Bivalent Smac-based ligands also function as much more potent antagonists of XIAP than do the corresponding monovalent Smac-based ligands in cell-free functional assays. Using Smac-IF and XIAP containing both BIR2 and BIR3 domains, we also developed and validated a new fluorescence polarization-based assay. Hence, our designed bivalent Smac-based peptides mimic the mode of dimeric Smac protein in their interaction with XIAP containing both BIR2 and BIR3 domains and achieve extremely high potency in binding and functional assays. Our study provides new insights into the mode of action of bivalent Smac ligands targeting XIAP and a basis for the design and development of cell-permeable, bivalent Smac mimetics. (c) 2008 Published by Elsevier Inc. C1 [Nikolovska-Coleska, Zaneta; Kawamoto, Steven A.; Gao, Wei; Yi, Han; Qin, Dongguang; Wang, Shaomeng] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Nikolovska-Coleska, Zaneta; Kawamoto, Steven A.; Gao, Wei; Yi, Han; Qin, Dongguang; Wang, Shaomeng] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Nikolovska-Coleska, Zaneta; Kawamoto, Steven A.; Gao, Wei; Yi, Han; Qin, Dongguang; Wang, Shaomeng] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. [Nikolovska-Coleska, Zaneta; Kawamoto, Steven A.; Gao, Wei; Yi, Han; Qin, Dongguang; Wang, Shaomeng] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Meagher, Jennifer L.; Stuckey, Jeanne A.] Univ Michigan, Div Biophys Res, Inst Life Sci, Ann Arbor, MI 48109 USA. [Jiang, Sheng; Roller, Peter P.] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. [Stuckey, Jeanne A.] Univ Michigan, Dept Biol Chem, Div Biophys Res, Ann Arbor, MI 48109 USA. RP Wang, SM (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu RI Wang, Shaomeng/E-9686-2010 FU NCI NIH HHS [R01CA109025] NR 23 TC 29 Z9 29 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 1 PY 2008 VL 374 IS 1 BP 87 EP 98 DI 10.1016/j.ab.2007.10.032 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 260KV UT WOS:000253010100012 PM 18023397 ER PT J AU Sandstrom, DJ AF Sandstrom, David J. TI Isoflurane reduces excitability of Drosophila larval motoneurons by activating a hyperpolarizing leak conductance SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Society-for-Neuroscience CY NOV 12-16, 2005 CL Washington, DC SP Soc Neurosci ID SODIUM-CHANNEL GENE; NEUROHYPOPHYSEAL NERVE-TERMINALS; SENSITIVE PARALYTIC MUTANTS; DOMAIN K+ CHANNELS; VOLATILE ANESTHETICS; NEUROMUSCULAR SYNAPSES; INHALATION ANESTHETICS; TRANSMITTER RELEASE; POTASSIUM CHANNELS; DELAYED RECTIFIER AB Background: Mechanisms of anesthetic-mediated presynaptic inhibition are incompletely understood. lsoflurane reduces presynaptic excitability at the larvalDrosophila neuromuscular junction, slowing conduction velocity and depressing glutamate release. Mutations in the Para voltage-gated Na+ channel enhance anesthetic sensitivity of adult flies. Here, the author examines the role of para in anesthetic sensitivity and seeks to identify the conductance underlying presynaptic inhibition at this synapse. Methods: Neuromuscular transmission was studied using a two-electrode voltage clamp, with isoflurane applied in physiologic saline. The relation between ionic conductances and presynaptic function was modeled in the Neuron Simulation Environment. Motoneuron ionic currents were monitored via whole cell recordings. Results: Presynaptic inhibition by isoflurane was enhanced significantly in para mutants. Computer simulations of presynaptic actions of anesthetics indicated that each candidate target conductance would have diagnostic effects on the relation between latency and amplitude of synaptic currents. The experimental latency-amplitude relation for isoflurane most closely resembled activation of a simulated hyperpolarizing leak. Simulations indicated that increased isoflurane potency in para axons resulted from reduced excitability of mutant axons. In whole cell recordings, isoflurane activated a hyperpolarizing leak current. The effects of isoflurane at the neuromuscular junction were insensitive to low pH. Conclusions: The effects of isoflurane on presynaptic excitability are mediated via an acid-insensitive inhibitory leak conductance. para mutations enhance the sensitivity of this anesthetic-modulated neural pathway by reducing axonal excitability. This work provides a link between anesthetic-sensitive leak currents and presynaptic function and has generated new tools for analysis of the function of this synapse. C1 NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sandstrom, DJ (reprint author), NIMH, Mol Biol Lab, NIH, MSC 3736, Bethesda, MD 20892 USA. EM sandstrd@mail.nih.gov FU Intramural NIH HHS NR 71 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2008 VL 108 IS 3 BP 434 EP 446 PG 13 WC Anesthesiology SC Anesthesiology GA 265XS UT WOS:000253395800015 PM 18292681 ER PT J AU Korelitz, JJ Zito, JM Gavin, NI Masters, MN McNally, D Irwin, DE Kelleher, K Bethel, J Xu, YL Rubin, J Mattison, DR AF Korelitz, James J. Zito, Julie M. Gavin, Norma I. Masters, Mary N. McNally, Diane Irwin, Debra E. Kelleher, Kelly Bethel, James Xu, Yiling Rubin, Judith Mattison, Donald R. TI Asthma-related medication use among children in the United States SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID CONTROLLER MEDICATIONS; PEDIATRIC ASTHMA; HOSPITALIZATION; PREVALENCE; EMERGENCY; BURDEN; TRENDS; IMPACT; RISK AB Background: Asthma is one of the most common chronic conditions in children and has a major impact on health care use and quality of life. The Best Pharmaceuticals for Children Act mandates the federal government to sponsor pediatric studies of drugs approved for use in the United States but lacking evaluation in the pediatric population and lacking interest of commercial sponsors. As input into the drug selection and prioritization process, information is needed on the percentage of children who receive asthma-related medications. Objective: To estimate the percentage of children who receive asthma-related medications. Methods: Retrospective analysis of outpatient medical and drug claims from members of commercial health care insurance plans enrolled any time from January 1, 2004, through December 31, 2005. The study population included 4,259,103 children throughout the United States aged birth through 17 years. Results: Fifteen percent of all children were dispensed an asthma-related medication. Among 218,943 children with an asthma diagnosis. 188.286 (86%) had a dispensed asthma-related medication at any time during the 2-year study period. Among children without any asthma diagnoses, 398,880 (10%) had a dispensed medication. Fifty-nine percent of children with an asthma diagnosis were dispensed an anti-inflammatory medication within 90 days after a claim with a diagnosis of asthma. Conclusions: Asthma-related medications are dispensed to a large percentage of the pediatric population, including many who do not have claims with asthma diagnoses listed. Data on the pharmacokinetics and safety of these drugs in children are largely unknown and difficult to obtain. Clinical studies that use new tools and approaches are needed to resolve this information gap. C1 [Korelitz, James J.; Masters, Mary N.; Bethel, James; Xu, Yiling] WESTAT Corp, Rockville, MD 20850 USA. [Zito, Julie M.; McNally, Diane; Rubin, Judith] Univ Maryland, Baltimore, MD 21201 USA. [Gavin, Norma I.] RTI Int, Res Triangle Pk, NC USA. [Irwin, Debra E.] Univ N Carolina, Chapel Hill, NC USA. [Kelleher, Kelly] Columbus Childrens Res Inst, Columbus, OH USA. [Mattison, Donald R.] NICHHD, Rockville, MD USA. RP Korelitz, JJ (reprint author), WESTAT Corp, 1650 Res Blvd, Rockville, MD 20850 USA. EM JamesKorelitz@Westat.com RI Mattison, Donald/C-2015-2009; Kelleher, Kelly/E-3361-2011; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 FU PHS HHS [GS-23F-8144H] NR 31 TC 7 Z9 8 U1 0 U2 0 PU AMER COLL ALLERGY ASTHMA IMMUNOLOGY PI ARLINGTON HTS PA 85 WEST ALGONQUIN RD SUITE 550, ARLINGTON HTS, IL 60005 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD MAR PY 2008 VL 100 IS 3 BP 222 EP 229 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 274JT UT WOS:000253998300009 PM 18426141 ER PT J AU Qin, L Gilbert, PB Follmann, D Li, DF AF Qin, Li Gilbert, Peter B. Follmann, Dean Li, Dongfeng TI ASSESSING SURROGATE ENDPOINTS IN VACCINE TRIALS WITH CASE-COHORT SAMPLING AND THE COX MODEL SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Clinical trial; discrete failure time model; missing data; potential outcomes; principal stratification; surrogate marker ID FAILURE TIME REGRESSION; PROPORTIONAL HAZARDS MODEL; CAUSAL INFERENCE; CLINICAL-TRIALS; COVARIATE DATA; IMMUNOGENICITY; DESIGNS AB Assessing immune responses to study vaccines as surrogates of protection plays a central role in vaccine clinical trials. Motivated by three ongoing or pending HIV vaccine efficacy trials. we consider such surrogate endpoint assessment in a randomized placebo-controlled trial with case-cohort sampling of immune responses mid a time to event endpoint. Based on the principal surrogate definition under the principal stratification framework proposed by Frangakis and Rubin [Biometrics 58 (2002) 21-29] and adapted by Gilbert and Hudgens (2006), we introduce estimands that measure the value of an immune response as a surrogate of protection in the context of the Cox proportional hazards model. The estimands are not identified because the immune response to vaccine is not measured in placebo recipients. We formulate the problem as a Cox model with missing covariates, and employ novel trial designs for predicting the missing immune responses and thereby identifying, the estimands. The first design utilizes information from baseline predictors of the immune response, and bridges their relationship in the vaccine recipients to the placebo recipients. The second design provides a validation set for the unmeasured immune responses of uninfected placebo recipients by immunizing them with the study vaccine after trial closeout. A maximum estimated likelihood approach is proposed for estimation of the parameters. Simulated data examples are given to evaluate the proposed designs Mid Study their properties. C1 [Qin, Li; Gilbert, Peter B.] Univ Washington, Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Dept Biostat, Seattle, WA 98109 USA. [Follmann, Dean] NIAID, Bethesda, MD 20892 USA. [Li, Dongfeng] Peking Univ, Sch Math Sci, Beijing 100871, Peoples R China. RP Qin, L (reprint author), Univ Washington, Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Dept Biostat, 1100 Fairview Ave N,LE-400, Seattle, WA 98109 USA. EM lqin@scharp.org; pgilbert@scharp.org; dfollmann@niaid.nih.gov; ldf@math.pku.edu.cn FU US NIH-NIAID [2 RO1 AI054165-04]; NIH [R37 AI29168] FX Supported by US NIH-NIAID Grant 2 RO1 AI054165-04 and NIH Grant R37 AI29168. NR 34 TC 15 Z9 15 U1 1 U2 6 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD MAR PY 2008 VL 2 IS 1 BP 386 EP 407 DI 10.1214/07-AOAS132 PG 22 WC Statistics & Probability SC Mathematics GA 374QB UT WOS:000261057700023 PM 19079758 ER PT J AU Beckjord, EB Rutten, LJF Arora, NK Hesse, BW AF Beckjord, Ellen B. Rutten, Lila J. Finney Arora, Neeraj K. Hesse, Bradford W. TI Breast cancer risk perceptions and self-efficacy: An analysis of the risk perception attitude framework SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Beckjord, Ellen B.] RAND Corp, Pittsburgh, PA USA. [Rutten, Lila J. Finney; Arora, Neeraj K.; Hesse, Bradford W.] NCI, Bethesda, MD 20892 USA. EM ebeckjor@rand.org NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S69 EP S69 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500265 ER PT J AU Beckjord, EB Rutten, LJF Arora, NK Bradford, HW AF Beckjord, Ellen B. Rutten, Lila J. Finney Arora, Neeraj K. Bradford, Hesse W. TI Supporting the "activated patient:" a population-level analysis of the risk perception attitude framework SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Beckjord, Ellen B.] RAND Corp, Pittsburgh, PA USA. [Rutten, Lila J. Finney; Arora, Neeraj K.; Bradford, Hesse W.] NCI, Bethesda, MD 20892 USA. EM ebeckjor@rand.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S69 EP S69 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500264 ER PT J AU Breslau, ES AF Breslau, Erica S. TI Implementation, integration and systems: Learning from the past and moving to the future in behavioral medicine SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Breslau, Erica S.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM breslaue@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S92 EP S92 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500357 ER PT J AU Chen, LS Kaphingst, KA AF Chen, Lei-Shih Kaphingst, Kimberly A. TI Does individuals' perception of personal risk of lung cancer affect their attitudes toward protective health behavior? SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Chen, Lei-Shih] Univ N Florida, Jacksonville, FL USA. [Kaphingst, Kimberly A.] NHGRI, Bethesda, MD 20892 USA. EM l.chen@unf.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S71 EP S71 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500275 ER PT J AU Croyle, R AF Croyle, Robert TI Needed by behavioral scientists: Big science and proactive outreach SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Croyle, Robert] NCI, Bethesda, MD 20892 USA. EM croyler@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S96 EP S96 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500372 ER PT J AU Czajkowski, SM Otto, MW Smits, JA Murray, HW McHugh, RK Zvolensky, MJ Resnicow, K Belue, R Kaufmann, PG AF Czajkowski, Susan M. Otto, Michael W. Smits, Jasper A. Murray, Heather W. McHugh, R. Kathryn Zvolensky, Michael J. Resnicow, Ken Belue, Rhonda Kaufmann, Peter G. TI The promise of translational behavioral science: Using basic science findings, innovative methodologies and new theoretical perspectives to build better health behavior interventions SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Czajkowski, Susan M.] NHLBI, Clin Applicat & Prevent Branch, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Otto, Michael W.; Murray, Heather W.; McHugh, R. Kathryn] Boston Univ, Boston, MA 02215 USA. [Smits, Jasper A.] So Methodist Univ, Dallas, TX 75275 USA. [Zvolensky, Michael J.] Univ Vermont, Burlington, VT USA. [Resnicow, Ken] Univ Michigan, Ann Arbor, MI 48109 USA. [Belue, Rhonda] Penn State Univ, University Pk, PA 16802 USA. EM Czajkows@mail.nih.gov RI Smits, Jasper/A-4350-2008 OI Smits, Jasper/0000-0001-7128-9807 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S12 EP S12 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500045 ER PT J AU Dunton, GF AF Dunton, Genevieve F. TI Determinants of physical activity adoption versus maintenance among middle-aged adults: Disentangling the roles of internal and external motivation SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Dunton, Genevieve F.] NCI, Hlth Promot Res Branch, Bethesda, MD 20892 USA. EM duntong@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S214 EP S214 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500837 ER PT J AU Dunton, GF Tscherne, J Rodriguez, D AF Dunton, Genevieve F. Tscherne, James Rodriguez, Daniel TI Examining psychosocial factors that predict changes in adolescent physical activity between 10th and 11th grade using structural equation modeling SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Dunton, Genevieve F.] NCI, Hlth Promot Res Branch, Bethesda, MD 20892 USA. [Tscherne, James; Rodriguez, Daniel] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. EM duntong@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S212 EP S212 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500827 ER PT J AU Evers, K Kerner, JF AF Evers, Kerry Kerner, Jon F. TI Disseminating & implementing Computerized Tailored Interventions: Industry and government perspectives SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Evers, Kerry] Pro Change Behav Syst Inc, W Kingston, RI USA. [Kerner, Jon F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM kevers@prochange.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S226 EP S226 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500882 ER PT J AU Gorin, A Niemeier, H Hogan, P Coday, M DiLillo, V Gluck, M Wadden, T West, D Williamson, D Yanovski, S AF Gorin, A. Niemeier, H. Hogan, P. Coday, M. DiLillo, V. Gluck, M. Wadden, T. West, D. Williamson, D. Yanovski, S. TI Binge eating and weight loss outcomes in overweight individuals with type 2 diabetes: Results from the look ahead clinical trial SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Gorin, A.] Univ Connecticut, Storrs, CT 06269 USA. [Niemeier, H.] Brown Univ, Sch Med, Providence, RI 02912 USA. [Hogan, P.] Wake Forest Univ, Wake Forest, NC USA. [Coday, M.] Univ Tennessee, Memphis, TN USA. [DiLillo, V.] Ohio Wesleyan Univ, Delaware, OH 43015 USA. [Gluck, M.] NIDDK, Phoenix, AZ USA. [Wadden, T.] Univ Penn, Philadelphia, PA 19104 USA. [West, D.] Univ Arkansas, Sch Med, Little Rock, AR 72204 USA. [Williamson, D.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Yanovski, S.] NIDDK, Bethesda, MD USA. EM agorin@lifespan.org NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S33 EP S33 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500122 ER PT J AU Hall, KL Kreuter, M Strecher, V Evers, K Kerner, J AF Hall, Kara L. Kreuter, Matthew Strecher, Victor Evers, Kerry Kerner, Jon TI Disseminating & implementing Computerized Tailored Interventions now and in the future: Who's reached and who's not SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Hall, Kara L.; Kerner, Jon] NCI, Bethesda, MD 20892 USA. [Evers, Kerry] Pro Change Behavior Syst, Kingston, RI USA. [Kreuter, Matthew] St Louis Univ, Sch Publ Hlth, St Louis, MO 63103 USA. [Strecher, Victor] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. EM hallka@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S225 EP S225 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500879 ER PT J AU Hall, KL Rossi, JS AF Hall, Kara L. Rossi, Joseph S. TI Meta-analytic examination of the strong and weak principles across 48 health behaviors SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Hall, Kara L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rossi, Joseph S.] Univ Rhode Isl, Canc Prevent Res Ctr, Kingston, RI 02881 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S6 EP S6 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500019 ER PT J AU Kaufman, A Augustson, E AF Kaufman, Annette Augustson, Erik TI Investigating depression and body image as predictors of female adolescent smoking SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufman, Annette; Augustson, Erik] US Natl Canc Inst, Bethesda, MD USA. [Kaufman, Annette] George Washington Univ, Washington, DC USA. EM kaufmana@mail.hah.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S65 EP S65 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500249 ER PT J AU Kaufman, A Parascandola, M Augustson, E AF Kaufman, Annette Parascandola, Mark Augustson, Erik TI Adolescent smokeless tobacco and cigarette use: Factors that predict transition SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufman, Annette; Parascandola, Mark; Augustson, Erik] US Natl Canc Inst, Bethesda, MD USA. [Kaufman, Annette] George Washington Univ, Washington, DC USA. EM kaufmana@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S65 EP S65 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500248 ER PT J AU Kim, KH Bursac, Z DiLillo, V White, D West, D AF Kim, Karen H. Bursac, Zoran DiLillo, Vicki White, Della West, Delia TI Stress, race, and body weight SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kim, Karen H.; Bursac, Zoran; West, Delia] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [DiLillo, Vicki] Ohio Wesleyan Univ, Delaware, OH 43015 USA. [White, Della] NHGRI, NIH, Bethesda, MD 20892 USA. EM khk@uams.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S165 EP S165 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500642 ER PT J AU Kobrin, S Rothman, A Aiken, L AF Kobrin, Sarah Rothman, Alex Aiken, Leona TI Understanding why and when intervention strategies work: How mediation and moderation analyses can link psychosocial models and behavioral interventions SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kobrin, Sarah] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Rothman, Alex] Univ Minnesota, Minneapolis, MN USA. EM kobrins@mail.nih.gov NR 0 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S2 EP S2 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500007 ER PT J AU Koehly, LM Hadley, DW AF Koehly, Laura M. Hadley, Donald W. TI Understanding the association between "encouragement to screen" relations and the adoption of recommended screening behaviors and the moderating effect of family context in families with Lynch syndrome SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Koehly, Laura M.; Hadley, Donald W.] NHGRI, SBRB, NIH, Bethesda, MD 20892 USA. EM koehlyl@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S9 EP S9 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500032 ER PT J AU Lipkus, IM Bollen, MJ Gierisch, JM O'Neill, SC Rimer, BK AF Lipkus, Isaac M. Bollen, Michael J. Gierisch, Jennifer M. O'Neill, Suzanne C. Rimer, Barbara K. TI When ambivalence predicts repeat mammography screening: It's the amount of thought that counts SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Lipkus, Isaac M.] Duke Univ, Med Ctr, Durham, NC 27701 USA. [Lipkus, Isaac M.; Bollen, Michael J.; Gierisch, Jennifer M.; Rimer, Barbara K.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [O'Neill, Suzanne C.] NHGRI, Bethesda, MD 20892 USA. EM lipku001@mc.duke.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S162 EP S162 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500631 ER PT J AU Masse, LC Valente, M Yaroch, A Agurs-Collins, T Atienza, A Blanck, H Weber, D AF Masse, Louise C. Valente, Maria Yaroch, Amy Agurs-Collins, Tanya Atienza, Audie Blanck, Heidi Weber, Deanne TI Home and school influences on US children's diet, physical activity and sedentary behaviors SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Masse, Louise C.; Valente, Maria] Univ British Columbia, Vancouver, BC V6H 3V4, Canada. [Yaroch, Amy; Agurs-Collins, Tanya; Atienza, Audie] NCI, Bethesda, MD 20892 USA. [Blanck, Heidi] CDC, Atlanta, GA 30333 USA. [Weber, Deanne] Porter Novelli, Washington, DC USA. EM lmasse@cw.bc.ca NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S178 EP S178 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500691 ER PT J AU McDonald, P Irwin, M Ancoli-Israel, S Bower, J Ahles, T Miller, G AF McDonald, Paige Irwin, Michael Ancoli-Israel, Sonia Bower, Julienne Ahles, Tim Miller, Gregory TI Behavioral consequences of cancer and its treatment: Mechanisms of the sixth vital sign SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [McDonald, Paige] NCI, Basic & Biobehav Res Branch, Bethesda, MD 20892 USA. [Irwin, Michael; Bower, Julienne] Univ Calif Los Angeles, Los Angeles, CA USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, San Diego, CA 92103 USA. [Ahles, Tim] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Miller, Gregory] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. EM pm252v@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S4 EP S4 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500012 ER PT J AU Micklin, M Mann, L Kitt, C Guadagno, MA AF Micklin, Michael Mann, Lee Kitt, Cheryl Guadagno, Mary Ann TI Nih peer review: Continuity and change SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Micklin, Michael; Mann, Lee; Kitt, Cheryl; Guadagno, Mary Ann] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. EM micklinm@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S2 EP S2 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500005 ER PT J AU Morgan, G Augustson, E O'Connell, ME AF Morgan, Glen Augustson, Erik O'Connell, Mary E. TI Low income smoking: 20 years of data, NHIS 1983-2006 SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Morgan, Glen; Augustson, Erik; O'Connell, Mary E.] NCI, Bethesda, MD 20892 USA. EM oconnellm@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S174 EP S174 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500675 ER PT J AU Morgan, GD Bartlett, SJ Goldstein, MG AF Morgan, Glen D. Bartlett, Susan J. Goldstein, Michael G. TI Enhancing core competencies for supporting self management and promoting health risk behavior change SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Morgan, Glen D.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Bartlett, Susan J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Goldstein, Michael G.] Inst Healthcare Commun, New Haven, CT USA. EM gmorgan@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S2 EP S2 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500008 ER PT J AU Moser, RP Rutten, LF Yaroch, AL Augustson, E Sullivan, H AF Moser, Richard P. Rutten, Lila Finney Yaroch, Amy L. Augustson, Erik Sullivan, Helen TI Secondary data analysis of national and state health survey data: Access, analysis and funding SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Moser, Richard P.; Rutten, Lila Finney; Yaroch, Amy L.; Augustson, Erik; Sullivan, Helen] NCI, Bethesda, MD 20892 USA. EM moserr@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S1 EP S1 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500002 ER PT J AU Niemeier, H Gorin, A Hogan, P Coday, M DiLillo, V Gluck, M Wadden, T West, D Williamson, D Yanovski, S AF Niemeier, H. Gorin, A. Hogan, P. Coday, M. DiLillo, V. Gluck, M. Wadden, T. West, D. Williamson, D. Yanovski, S. TI Binge eating in overweight individuals with type 2 diabetes seeking weight loss treatment SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Niemeier, H.] Brown Univ, Warren Alpert Med Sch, Weight Control & Diabet Res Ctr, Providence, RI 02903 USA. [Gorin, A.] Univ Connecticut, Storrs, CT USA. [Hogan, P.] Wake Forest Univ, Wake Forest, NC USA. [Coday, M.] Univ Tennessee, Memphis, TN USA. [DiLillo, V.] Ohio Wesleyan Univ, Delaware, OH 43015 USA. [Gluck, M.] NIDDK, Phoenix, AZ USA. [Wadden, T.] Univ Penn, Philadelphia, PA 19104 USA. [West, D.] Univ Arkansas, Sch Med, Little Rock, AR 72204 USA. [Williamson, D.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Yanovski, S.] NIDDK, Bethesda, MD USA. EM Heather_Niemeier@Brown.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S209 EP S209 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500818 ER PT J AU Nigg, CR Prochaska, J Noar, SM Hall, KL Allegrante, JP Prochaska, JO AF Nigg, Claudio R. Prochaska, Jodi Noar, Seth M. Hall, Kara L. Allegrante, John P. Prochaska, James O. TI Conceptualizing multiple health behavior change SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Nigg, Claudio R.] Univ Hawaii, Honolulu, HI 96822 USA. [Prochaska, Jodi] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Prochaska, James O.] Univ Rhode Isl, Canc Prevent Res Ctr, Kingston, RI 02881 USA. [Noar, Seth M.] Univ Kentucky, Lexington, KY USA. [Hall, Kara L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Allegrante, John P.] Columbia Univ, Teachers Coll, Hlth & Behav Studies, New York, NY 10027 USA. EM cnigg@hawaii.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S5 EP S5 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500017 ER PT J AU O'Neill, S Rini, C Goldsmith, R Valdimarsdottir, H Cohen, L Schwartz, M AF O'Neill, Suzanne Rini, Christine Goldsmith, Rachel Valdimarsdottir, Heiddis Cohen, Lawrence Schwartz, Marc TI Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [O'Neill, Suzanne] NHGRI, SBRB, NIH, Bethesda, MD 20892 USA. [Rini, Christine; Goldsmith, Rachel; Valdimarsdottir, Heiddis] Mt Sinai Sch Med, New York, NY USA. [Schwartz, Marc] Georgetown Univ, Washington, DC USA. [Cohen, Lawrence] Univ Delaware, Newark, DE USA. EM oneills@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S20 EP S20 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500076 ER PT J AU O'Neill, S Peshkin, BN Abraham, A Walker, L Luta, G Tercyak, KP AF O'Neill, Suzanne Peshkin, Beth N. Abraham, Anisha Walker, Leslie Luta, George Tercyak, Kenneth P. TI Adolescent medical providers' recommendations for predictive genetic testing for smoking behavior and lung cancer risk SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [O'Neill, Suzanne] NHGRI, SBRB, NIH, Bethesda, MD 20892 USA. [Peshkin, Beth N.; Abraham, Anisha; Luta, George; Tercyak, Kenneth P.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Walker, Leslie] Childrens Hosp & Reg Med Ctr, Seattle, WA USA. [Peshkin, Beth N.; Luta, George; Tercyak, Kenneth P.] Lombardi Comprehens Canc Ctr, Washington, DC USA. EM oneills@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S20 EP S20 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500075 ER PT J AU Ramirez, A Chu, K Kaur, JS Partridge, EE Chen, MS AF Ramirez, Amelie Chu, Kenneth Kaur, Judith S. Partridge, Edward E. Chen, Moon S. TI The current and future state of cancer disparities SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Ramirez, Amelie] Univ Texas Hlth Sci Ctr San Antonio, UT SPH, San Antonio, TX 78230 USA. [Chu, Kenneth] Natl Canc Inst, Ctr Reduce Canc Hlth Dispar, Rockville, MD USA. [Chen, Moon S.] Calif State Univ Sacramento, Davis Canc Ctr, Sacramento, CA 95819 USA. [Kaur, Judith S.] Mayor Clin Coll Med, Rochester, MN USA. [Partridge, Edward E.] Univ Alabama, Birmingham, AL USA. [Chen, Moon S.] CNP Asian Amer Network Canc Awareness, Sacramento, CA USA. [Ramirez, Amelie] CNP Redes Accion, San Antonio, TX USA. [Kaur, Judith S.] CNP Amer Indian Alaska Native Initiat Canc, Rochester, MN USA. [Partridge, Edward E.] CNP Deep S Network Canc Control, Birmingham, AL USA. EM ramirezag@uthscsa.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S223 EP S223 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500873 ER PT J AU Robertson, TP Dunton, GF AF Robertson, Trina P. Dunton, Genevieve F. TI Results of a tailored internet plus email intervention to increase physical activity in women: "Women's Fitness Planner" SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Robertson, Trina P.] Dairy Council Calif, Irvine, CA 92612 USA. [Dunton, Genevieve F.] NCI, Off Prevent Oncol, NIH, Bethesda, MD USA. EM trinar@dairycouncilofca.org NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S167 EP S167 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500650 ER PT J AU Rodriguez, D Dunton, GF AF Rodriguez, Daniel Dunton, Genevieve Fridlund TI Type of physical activity and depression symptoms in adolescents: A latent class analysis SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Rodriguez, Daniel] Univ Penn, Philadelphia, PA 19104 USA. [Dunton, Genevieve Fridlund] NCI, NIH, Bethesda, MD 20892 USA. EM drodrig2@mail.med.upenn.edu NR 0 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S205 EP S205 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500799 ER PT J AU Rodriguez, D Dunton, GF AF Rodriguez, Daniel Dunton, Genevieve Fridulund TI Adolescent physical activity and smoking: A moderated-mediation analysis of gender differences via sport competence beliefs and depressive symptoms SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Rodriguez, Daniel] Univ Penn, Philadelphia, PA 18938 USA. [Dunton, Genevieve Fridulund] NCI, NIH, Bethesda, MD 20892 USA. EM drodrig2@mail.med.upenn.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S193 EP S193 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500751 ER PT J AU Rutten, LJ Moser, RP Beckjord, EB Hesse, BW Augustson, EM AF Rutten, Lila J. Moser, Richard P. Beckjord, Ellen B. Hesse, Bradford W. Augustson, Erik M. TI Smoking knowledge and behavior in the US: Sociodemographic, smoking status, and geographic patterns SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Rutten, Lila J.; Moser, Richard P.; Hesse, Bradford W.; Augustson, Erik M.] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Beckjord, Ellen B.] RAND Corp, Rand Hlth, Pittsburgh, PA USA. EM finneyl@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S192 EP S192 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500748 ER PT J AU Sanderson, SC O'Neill, SC White, DB McBride, CM AF Sanderson, Saskia C. O'Neill, Suzanne C. White, Della B. McBride, Colleen M. TI Association and predictors of congruence between interest in hypothetical and uptake of actual genetic testing SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Sanderson, Saskia C.; O'Neill, Suzanne C.; White, Della B.; McBride, Colleen M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. EM sanderson@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S20 EP S20 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500074 ER PT J AU Shaikh, AR Yaroch, A Li, TD Moser, R Colon-Ramos, U McNutt, S Weber, D Nebeling, L Atienza, A Resnicow, K AF Shaikh, Abdul R. Yaroch, Amy Li, Tiandong Moser, Rick Colon-Ramos, Uriyoan McNutt, Suzanne Weber, Deanne Nebeling, Linda Atienza, Audie Resnicow, Ken TI Correlates of fruit and vegetable consumption in the National Cancer Institute's food attitudes and behaviors survey SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Shaikh, Abdul R.; Yaroch, Amy; Moser, Rick; Colon-Ramos, Uriyoan; Nebeling, Linda; Atienza, Audie] NCI, Bethesda, MD 20892 USA. [Li, Tiandong; McNutt, Suzanne] Westat Corp, Rockville, MD USA. [Weber, Deanne] Porter Novelli, Washington, DC USA. [Resnicow, Ken] Univ Michigan, Ann Arbor, MI 48109 USA. EM shaikhab@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S77 EP S77 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500296 ER PT J AU Spring, B Pagoto, SL Ramirez, AG Salllis, JF Kerner, JF AF Spring, Bonnie Pagoto, Sherry L. Ramirez, Amelie G. Salllis, James F. Kerner, Jon F. TI Evidence-based practice in obesity: From the individual to the population SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Spring, Bonnie] Northwestern Univ, Chicago, IL 60610 USA. [Pagoto, Sherry L.] Univ Massachusetts, Worcester, MA 01605 USA. [Ramirez, Amelie G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Kerner, Jon F.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. EM bspring@northwestern.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S7 EP S7 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500025 ER PT J AU Stefanek, M Jacobsen, P Croyle, R AF Stefanek, Michael Jacobsen, Paul Croyle, Robert TI Mapping the future: A "big picture" view for behavioral oncology SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Stefanek, Michael] Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30303 USA. [Croyle, Robert] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jacobsen, Paul] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. EM michael.stefanek@cancer.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S96 EP S96 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500371 ER PT J AU Stirratt, MJ Malitz, F AF Stirratt, Michael J. Malitz, Faye TI Toward a comprehensive understanding of HIV treatment adherence: Addressing engagement and retention in medical care SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Stirratt, Michael J.] NIMH, Div Aids & Hlth & Behav Res, Bethesda, MD 20892 USA. [Malitz, Faye] HRSA, HIV AIDS Bur, Rockville, MD USA. EM stirrattm@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S231 EP S231 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500903 ER PT J AU Svetkey, LP Stevens, VJ Brantley, PJ Appel, LJ Hollis, JF Loria, CM Vollmer, WM Gullion, CM Funk, K AF Svetkey, Laura P. Stevens, Victor J. Brantley, Phillip J. Appel, Lawrence J. Hollis, Jack F. Loria, Catherine M. Vollmer, William M. Gullion, Christina M. Funk, Kristine TI Predictors of weight loss maintenance in the weight loss maintenance trial SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Svetkey, Laura P.] Duke Univ, Med Ctr, Durham, NC USA. [Stevens, Victor J.; Hollis, Jack F.; Vollmer, William M.; Gullion, Christina M.; Funk, Kristine] Ctr Hlth Res, Portland, OR USA. [Brantley, Phillip J.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Appel, Lawrence J.] Johns Hopkins Med Ctr, Baltimore, MD USA. [Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. EM svetk001@mc.duke.edu RI Kattelmann, Kendra/E-8225-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S109 EP S109 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500422 ER PT J AU Tamers, SL Agurs-Collins, T Dodd, K Nebeling, L AF Tamers, Sara L. Agurs-Collins, Tanya Dodd, Kevin Nebeling, Linda TI US and France fruit and vegetable consumption patterns in adolescents: An international comparison SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Tamers, Sara L.; Agurs-Collins, Tanya; Nebeling, Linda] NCI, NIH, DCCPS BRP HPRB, Rockville, MD USA. [Dodd, Kevin] NCI, NIH, DCP BRG, Rockville, MD USA. EM saratamers@hotmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S199 EP S199 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500778 ER PT J AU Wade, CH McBride, CM Alford, SH Baxevanis, AD Reid, R Larson, EB Brody, LC AF Wade, Christopher H. McBride, Colleen M. Alford, Sharon Hensley Baxevanis, Andreas D. Reid, Robert Larson, Eric B. Brody, Lawrence C. TI When genetic susceptibility testing is offered for multiple common health conditions, who is interested? SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Wade, Christopher H.; McBride, Colleen M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Wade, Christopher H.; Baxevanis, Andreas D.; Brody, Lawrence C.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Alford, Sharon Hensley] Henry Ford Health Syst, Josephine Ford Canc Ctr, Detroit, MI USA. [Reid, Robert; Larson, Eric B.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. EM wadee@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S19 EP S19 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500073 ER PT J AU Weaver, K Rauscher, G Campbell, R Warnecke, R AF Weaver, Kathryn Rauscher, Garth Campbell, Richard Warnecke, Richard TI Does path to detection mediate ethnic minority disparities in stage at breast cancer diagnosis? SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Weaver, Kathryn] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Weaver, Kathryn; Rauscher, Garth; Campbell, Richard] Univ Illinois, Sch Publ Hlth, Chicago, IL USA. [Warnecke, Richard] Univ Illinois, Ctr Populat Hlth & Hlth Dispar, Chicago, IL USA. EM weaverk@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S48 EP S48 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500181 ER PT J AU Wolf, RL Lepore, SJ Basch, CE Yaroch, AL AF Wolf, Randi L. Lepore, Stephen J. Basch, Charles E. Yaroch, Amy L. TI Tailored telephone counseling to promote fruit and vegetable consumption among urban and predominantly immigrant black men SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Wolf, Randi L.; Basch, Charles E.] Columbia U, Teachers Coll, New York, NY USA. [Lepore, Stephen J.] Temple U, Philadelphia, PA USA. [Yaroch, Amy L.] NCI, NIH, Rockville, MD USA. EM wolf@tc.columbia.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 SU 1 BP S170 EP S170 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500662 ER PT J AU Yaroch, AL Tooze, J Ramos, UC Shaikh, A Thompson, F McNutt, S Moshfegh, A Nebeling, L AF Yaroch, Amy L. Tooze, Janet Ramos, Uriyoan Colon Shaikh, Abdul Thompson, Frances McNutt, Suzanne Moshfegh, Alanna Nebeling, Linda TI Is bigger better? Validity of three screeners to assess fruit and vegetable intake SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Yaroch, Amy L.; Ramos, Uriyoan Colon; Shaikh, Abdul; Thompson, Frances; Nebeling, Linda] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Tooze, Janet] Wake Forest Univ, Winston Salem, NC 27109 USA. [McNutt, Suzanne] Westat Corp, Rockville, MD USA. [Moshfegh, Alanna] USDA ARS, Beltsville, MD USA. EM yarocha@mail.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2008 VL 35 BP S185 EP S185 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 348YH UT WOS:000259245500721 ER EF