FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Tsuji, Y Yoshimura, N Aoki, H Sharov, AA Ko, MSH Motohashi, T Kunisada, T AF Tsuji, Yukiiko Yoshimura, Naoko Aoki, Hitomi Sharov, Alexei A. Ko, Minoru S. H. Motohashi, Tsutomu Kunisada, Takahiro TI Maintenance of undifferentiated mouse embryonic stem cells in suspension by the serum- and feeder-free defined culture condition SO DEVELOPMENTAL DYNAMICS LA English DT Article DE embryonic stem cell; suspension culture; serum-free; feeder-free; cell adhesion molecules ID HUMAN ES CELLS; SELF-RENEWAL; FREE GROWTH; PLURIPOTENCY; STAT3; DIFFERENTIATION; ACTIVATION; EXPRESSION; NANOG; SUPPRESSION AB The proven pluripotency of ES cells is expected to allow their therapeutic use for regenerative medicine. We present here a novel suspension culture method that facilitates the proliferation of pluripotent ES cells without feeder cells. The culture medium contains polyvinyl alcohol (PVA), free of either animal-derived or synthetic serum, and contains very low amounts of peptidic or proteinaceous materials, which are favorable for therapeutic use. ES cells showed sustained proliferation in the suspension culture, and their undifferentiated state and pluripotency were experimentally verified. DNA microarray analyses showed a close relationship between the elevated expression of genes related to cell adhesions. We suggest that this suspension culture condition provides a better alternative to the conventional attached cell culture condition, especially for possible therapeutic use, by limiting the exposure of ES cells to feeder cells and animal products. C1 [Tsuji, Yukiiko; Yoshimura, Naoko; Aoki, Hitomi; Motohashi, Tsutomu; Kunisada, Takahiro] Gifu Univ, Grad Sch Med, Dept Tissue & Organ Dev Regenerat & Adv Med Sci, Gifu 5011194, Japan. [Sharov, Alexei A.; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, Baltimore, MD 21224 USA. RP Kunisada, T (reprint author), Gifu Univ, Sch Med, Gifu 5011194, Japan. EM tkunisad@gifu-u.ac.jp RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS [Z01 AG000662-07] NR 44 TC 15 Z9 15 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD AUG PY 2008 VL 237 IS 8 BP 2129 EP 2138 DI 10.1002/dvdy.21617 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 338CJ UT WOS:000258482300020 PM 18624284 ER PT J AU Bell, M Wang, H Chen, H McLenithan, JC Gong, DW Yang, RZ Yu, DZ Fried, SK Quon, MJ Londos, C Sztalryd, C AF Bell, Ming Wang, Hong Chen, Hui McLenithan, John C. Gong, Da-Wei Yang, Rong-Zee Yu, Daozhan Fried, Susan K. Quon, Michael J. Londos, Constantine Sztalryd, Carole TI Consequences of lipid droplet coat protein downregulation in liver cells: abnormal lipid droplet metabolism and induction of insulin resistance SO DIABETES LA English DT Article ID DIFFERENTIATION-RELATED PROTEIN; ADIPOSE TRIGLYCERIDE LIPASE; CHANARIN-DORFMAN-SYNDROME; PERILIPIN-A; MEDIATED LIPOLYSIS; 3T3-L1 ADIPOCYTES; FATTY-ACIDS; ACYL-COA; CGI-58; MICE AB OBJECTIVE-Accumulation of intracellular lipid droplets (LDs) in non-adipose tissues is recognized as a strong prognostic factor for the development of insulin resistance in obesity. LDs are coated with perilipin, adipose differentiation-related protein, tail interacting protein of 47 kd (PAT) proteins that are thought to regulate LD turnover by modulating lipolysis. Our hypothesis is that PAT proteins modulate LD metabolism and therefore insulin resistance. RESEARCH DESIGN AND METHODS-We used a cell culture model (murine AML12 loaded with oleic acid) and small interfering RNA to directly assess the impact of PAT proteins on LD accumulation, lipid metabolism, and insulin action. PAT proteins associated with excess fat deposited in livers of diet-induced obese (DIO) mice were also measured. RESULTS-Cells lacking PAT proteins exhibited a dramatic increase in LD size and a decrease in LD number. Further, the lipolytic rate increased by similar to 2- to 2.5-fold in association with increased adipose triglyceride lipase (ATGL) at the LD surface. Downregulation of PAT proteins also produced insulin resistance, as indicated by decreased insulin stimulation of Akt phosphorylation (P < 0.001). Phosphoinositide-dependent kinase-1 and phosphoinositide 3-kinase decreased, and insulin receptor substrate-1 307 phosphorylation increased. Increased lipids in DIO mice livers were accompanied by changes in PAT composition but also increased ATGL, suggesting a relative PAT deficiency. CONCLUSIONS-These data establish an important role for PAT proteins as surfactant at the LD surface, packaging lipids in smaller units and restricting access of lipases and thus preventing insulin resistance. We suggest that a deficiency of PAT proteins relative to the quantity of ectopic fat could contribute to cellular dysfunction in obesity and type 2 diabetes. C1 [Bell, Ming; Wang, Hong; Sztalryd, Carole] Univ Maryland, Sch Med, Baltimore Vet Affairs Hlth Care Ctr, Educ & Clin Ctr,Div Gerontol,Dept Med, Baltimore, MD 21201 USA. [Chen, Hui; Quon, Michael J.] Natl Ctr Complementary & Alternat Med, Diabet Unit, NIH, Bethesda, MD USA. [McLenithan, John C.; Gong, Da-Wei; Yang, Rong-Zee; Yu, Daozhan; Fried, Susan K.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol, Baltimore, MD 21201 USA. [Londos, Constantine] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sztalryd, C (reprint author), Univ Maryland, Sch Med, Baltimore Vet Affairs Hlth Care Ctr, Educ & Clin Ctr,Div Gerontol,Dept Med, Baltimore, MD 21201 USA. EM csztalry@greec.umaryland.edu RI Yu, Daozhan/K-5285-2012; OI Fried, Susan/0000-0003-1101-9332; Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS; NIDDK NIH HHS [R01 DK075017, 1R01 DK 075017-01A2, DK072488, P30 DK072488, R01 DK075017-02, R01 DK075017-02S1] NR 48 TC 89 Z9 91 U1 1 U2 16 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2008 VL 57 IS 8 BP 2037 EP 2045 DI 10.2337/db07-1383 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 333EB UT WOS:000258134200005 PM 18487449 ER PT J AU Fox, CS Pencina, MJ Wilson, PWF Paynter, NP Vasan, RS D'agostino, RB AF Fox, Caroline S. Pencina, Michaei J. Wilson, Peter W. F. Paynter, Nina P. Vasan, Ramachandran S. D'agostino, Ralph B. TI Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham Heart Study SO DIABETES CARE LA English DT Article ID BURDEN; MELLITUS; BMI; US AB OBJECTIVE - We assessed the lifetime risk of cardiovascular disease (CVD) among individuals with and without obesity and diabetes. RESEARCH DESIGN AND METHODS - Participants were drawn from the original and offspring cohorts of the Framingham Heart Study. Lifetime (30-year) risk of CVD was assessed using a modified Kaplan-Meier approach adjusting for the competing risk of death, beginning from age 50 years. RESULTS - Over 30 years, the lifetime risk of CVD among women With diabetes was 54.8% among normal-weight women and 78.8% among obese women. Among normal-weight men with diabetes, the lifetime risk of CVD was 78.6%, whereas it was 86.9% among obese men. CONCLUSIONS - The lifetime risk of CVD among individuals with diabetes is high, and this relationship is further accentuated with increasing adiposity. C1 [Fox, Caroline S.; Pencina, Michaei J.; Paynter, Nina P.; Vasan, Ramachandran S.; D'agostino, Ralph B.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Bethesda, MD 20892 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Hypertens, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Pencina, Michaei J.; Paynter, Nina P.; D'agostino, Ralph B.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Wilson, Peter W. F.] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; R.S.V. [K24 HL04334] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (grant N01-HC-25195). R.S.V. was supported in part by grant K24 HL04334. NR 10 TC 79 Z9 82 U1 1 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2008 VL 31 IS 8 BP 1582 EP 1584 DI 10.2337/dc08-0025 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 338CH UT WOS:000258482000023 PM 18458146 ER PT J AU Kandula, NR Diez-Roux, AV Chan, CL Daviglus, ML Jackson, SA Ni, HY Schreiner, PJ AF Kandula, Namratha R. Diez-Roux, Ana V. Chan, Cheeling Daviglus, Martha L. Jackson, Sharon A. Ni, Hanyu Schreiner, Pamela J. TI Association of acculturation levels and prevalence of diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) SO DIABETES CARE LA English DT Article; Proceedings Paper CT 79th Annual Scientific Session of the American-Heart-Association CY NOV 12-15, 2006 CL Chicago, IL SP Amer Heart Assoc ID CARDIOVASCULAR-DISEASE RISK; SOCIOECONOMIC-STATUS; MEXICAN-AMERICANS; PHYSICAL-ACTIVITY; ASIAN-AMERICANS; ADULTS; US; POPULATION; OBESITY; IMMIGRANTS AB OBJECTIVE - The prevalence of type 2 diabetes among Hispanic and Asian Americans is increasing. These,groups are largely comprised of immigrants who may be undergoing behavioral and lifestyle changes associated with development of diabetes. We studied the association between acculturation and diabetes in a population sample of 708 Mexican-origin Hispanics 547 non-Mexican-origin Hispanics, and 737 Chinese participants in the multi-Ethnic Study 4 Atherosclerosis (MESA). RESEARCH DESIGN AND METHODS - Diabetes was defined as fasting glucose >= 126 mg/dl and/or use of antidiabetic medications. An acculturation score was calculated for all participants using nativity,),cars living in the U.S., and language spoken at home. The score ranged from 0 to 5 (0 = least acculturated and 5 = most acculturated). Relative risk regression was used to estimate the association between acculturation and diabetes. RESULTS - For non-Mexican-origin Hispanics, the Prevalence of diabetes was positively associated with acculturation score, after adjustment for sociodemographics. The prevalence of diabetes was significantly higher among the most acculturated versus the least acculturated non-Mexican-origin Hispanics (prevalence ratio 2.49 [95% CI 1.14-5.44]); the higher the (P for trend 0.059). This relationship acculturation score is, the higher the prevalence of diabetes between acculturation and diabetes was partly attenuated after adjustment for BMI or diet. Diabetes prevalence was not related to acculturation among Chinese or Mexican-origin Hispanics. CONCLUSIONS - Among non-Mexican-origin Hispanics in MESA, greater acculturation is associated With higher diabetes prevalence. The relation is atleast partly mediated by BMI and diet. Acculturation is a factor that should be considered when predictors of diabetes in racial/ethnic groups are examined. C1 [Kandula, Namratha R.] Northwestern Univ, Div Gen Internal Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Diez-Roux, Ana V.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Chan, Cheeling; Daviglus, Martha L.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Jackson, Sharon A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Ni, Hanyu] NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Schreiner, Pamela J.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Kandula, NR (reprint author), Northwestern Univ, Div Gen Internal Med, Feinberg Sch Med, Chicago, IL 60611 USA. EM n-kandula@northwestern.edu NR 25 TC 91 Z9 91 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2008 VL 31 IS 8 BP 1621 EP 1628 DI 10.2337/dc07-2182 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 338CH UT WOS:000258482000032 PM 18458142 ER PT J AU Zolnik, BS Stern, ST Kaiser, JM Heakal, Y Clogston, JD Kester, M McNeil, SE AF Zolnik, Banu S. Stern, Stephan T. Kaiser, James M. Heakal, Yasser Clogston, Jeffrey D. Kester, Mark McNeil, Scott E. TI Rapid distribution of liposomal short-chain ceramide in vitro and in vivo SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CANCER; DELIVERY; SPHINGOLIPIDS; PATHOGENESIS; DOXORUBICIN; RETENTION; TOLERANCE; APOPTOSIS; THERAPY; PLASMA AB Ceramide, an endogenous sphingolipid, has demonstrated antineoplastic activity in vitro and in vivo. However, the chemotherapeutic utility of ceramide is limited because of its insolubility. To increase the solubility of ceramide, liposomal delivery systems have been used. The objective of the present study was to characterize the pharmacokinetics and tissue distribution of C6-ceramide and control (non-C6-ceramide) nanoliposomes in rats, using [(14)C] C6-ceramide and [(3)H] distearylphosphatidylcholine (DSPC) as tracers of the ceramide and liposome components, respectively. Ceramide liposomes were administered at 50 mg of liposomes/kg by jugular vein to female Sprague-Dawley rats. The apparent volume of distribution (V(d)) of [(3)H] DSPC was approximately 50 ml/ kg, suggesting that the liposomes were confined to the systemic circulation. In contrast, the V(d) of [(14)C] C6-ceramide was 20-fold greater than that of liposomes, indicating extensive tissue distribution. This high V(d) of [ (14)C] C6-ceramide in relation to that of [(3)H] DSPC suggests that ceramide and liposomes distribute independently of each other. This disparate disposition was confirmed by tissue distribution studies, in which [(14)C] C6-ceramide exhibited rapid tissue accumulation compared with to [3H] DSPC. Examination of ceramide liposome blood compartmentalization in vitro also demonstrated divergent partitioning, with liposomes being confined to the plasma fraction and ceramide rapidly equilibrating between red blood cell and plasma fractions. A bilayer exchange mechanism for ceramide transfer is proposed to explain the results of the present study, as well as give insight into the documented antineoplastic efficacy of short-chain ceramide liposomes. Our studies suggest that this nanoscale PEGylated drug delivery system for short-chain ceramide offers rapid tissue distribution without adverse effects for a neoplastic-selective, insoluble agent. C1 [Zolnik, Banu S.; Stern, Stephan T.; Clogston, Jeffrey D.; McNeil, Scott E.] NCI, SAIC Frederick Inc, Adv Technol Program, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. [Kaiser, James M.; Heakal, Yasser; Kester, Mark] Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA USA. RP Stern, ST (reprint author), NCI, SAIC Frederick Inc, Adv Technol Program, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. EM sternstephan@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU NCI NIH HHS [N01-CO-12400] NR 28 TC 46 Z9 47 U1 1 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD AUG PY 2008 VL 36 IS 8 BP 1709 EP 1715 DI 10.1124/dmd.107.019679 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 328WW UT WOS:000257829900031 PM 18490436 ER PT J AU Salvadore, G Drevets, WC Henter, ID Zarate, CA Manji, HK AF Salvadore, Giacomo Drevets, Wayne C. Henter, Ioline D. Zarate, Carlos A. Manji, Husseini K. TI Early intervention in bipolar disorder, part I: clinical and imaging findings SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Review DE bipolar disorder; early intervention; first episode; high risk; imaging ID WHITE-MATTER HYPERINTENSITIES; MAJOR DEPRESSIVE DISORDER; DORSOLATERAL PREFRONTAL CORTEX; STRUCTURAL BRAIN ABNORMALITIES; COMORBIDITY SURVEY REPLICATION; SUSTAINED ATTENTION-DEFICIT; RANDOMIZED CONTROLLED-TRIAL; ANTERIOR CINGULATE CORTEX; WEEKLY SYMPTOMATIC STATUS; MOOD DISORDERS AB The concept of prevention is not new to psychiatry and has long been recognized in general medicine. Recent evidence has highlighted that early pharmacological and psychosocial treatment dramatically ameliorates poor prognosis and outcome for individuals with psychotic disorders, reducing conversion rates to full-blown illness and decreasing symptom severity. Nevertheless, despite the many recent advances in our thinking about early intervention, the need for early intervention in bipolar disorder (BPD) is an area that has been relatively neglected. This review attempts to synthesize what is currently known about early intervention in BPD. We discuss methodological issues pertaining to this topic, review clinical studies that focus on high-risk subjects as well as first-episode patients and review findings from brain imaging studies in the offspring of individuals with BPD as well as in first-episode patients. A companion paper discusses the cellular and molecular mechanisms of action of agents with neurotrophic and neuroplastic properties, with a particular emphasis on lithium and valproate. C1 [Salvadore, Giacomo; Drevets, Wayne C.; Henter, Ioline D.; Zarate, Carlos A.; Manji, Husseini K.] NIMH, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mood & Anxiety Disorders Res Program, NIH, Bldg 35,1C912, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health FX The authors would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Health. NR 132 TC 15 Z9 15 U1 4 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1751-7885 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD AUG PY 2008 VL 2 IS 3 BP 122 EP 135 DI 10.1111/j.1751-7893.2008.00071.x PG 14 WC Psychiatry SC Psychiatry GA 449PA UT WOS:000266341300002 PM 19649152 ER PT J AU Salvadore, G Drevets, WC Henter, ID Zarate, CA Manji, HK AF Salvadore, Giacomo Drevets, Wayne C. Henter, Ioline D. Zarate, Carlos A. Manji, Husseini K. TI Early intervention in bipolar disorder, part II: therapeutics SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Review DE bipolar disorder; early intervention; lithium; neurotrophic effect; valproate ID RANDOMIZED CONTROLLED-TRIAL; TRANSCRANIAL MAGNETIC STIMULATION; AMYOTROPHIC-LATERAL-SCLEROSIS; COGNITIVE-BEHAVIORAL THERAPY; GLYCOGEN-SYNTHASE KINASE-3; RESISTANT MAJOR DEPRESSION; MICE OVEREXPRESSING BCL-2; WEEKLY SYMPTOMATIC STATUS; MOOD-STABILIZING AGENTS; ATTENUATES BRAIN-DAMAGE AB Recent evidence has shown that early pharmacological and psychosocial treatment dramatically ameliorates poor prognosis and outcome for individuals with psychotic disorders, reducing conversion rates to full-blown illness and decreasing symptom severity. In a companion paper, we discussed methodological issues pertaining to early intervention in bipolar disorder (BPD), reviewed clinical studies that focus on high-risk subjects as well as first-episode patients, and reviewed findings from brain imaging studies in the offspring of individuals with BPD as well as in first-episode patients. In this paper, we discuss how drugs that modulate cellular and neural plasticity cascades are likely to benefit patients in the very early stages of BPD, because they target some of the core pathophysiological mechanisms of this devastating illness. Cellular and molecular mechanisms of action of agents with neurotrophic and neuroplastic properties are discussed, with a particular emphasis on lithium and valproate. We also discuss their potential use as early intervention strategies for improving symptoms and functioning in patients in the earliest stages of BPD, as well as high-risk individuals. C1 [Salvadore, Giacomo; Drevets, Wayne C.; Henter, Ioline D.; Zarate, Carlos A.; Manji, Husseini K.] NIMH, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mood & Anxiety Disorders Res Program, NIH, Bldg 35,1C912, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov FU National Institute of Mental Health FX We would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Health. NR 119 TC 14 Z9 14 U1 2 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1751-7885 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD AUG PY 2008 VL 2 IS 3 BP 136 EP 146 DI 10.1111/j.1751-7893.2008.00072.x PG 11 WC Psychiatry SC Psychiatry GA 449PA UT WOS:000266341300003 PM 19649153 ER PT J AU Guzman, NA Blanc, T Phillips, TM AF Guzman, Norberto A. Blanc, Timothy Phillips, Terry M. TI Immunoaffinity capillary electrophoresis as a powerful strategy for the quantification of low-abundance biomarkers drugs and metabolites in biological matrices SO ELECTROPHORESIS LA English DT Review DE affinity capillary electrophoresis; analyte concentrator; biomarkers; immunoaffinity; capillary electrophoresis; proteomics; solid-phase extraction ID LASER-INDUCED FLUORESCENCE; ELECTROSPRAY-MASS-SPECTROMETRY; SOLID-PHASE EXTRACTION; PERFORMANCE LIQUID-CHROMATOGRAPHY; ONLINE SAMPLE PRECONCENTRATION; ON-A-CHIP; AFFINITY-CHROMATOGRAPHY; ZONE-ELECTROPHORESIS; MOLECULAR RECOGNITION; PROTEIN DIGESTION AB In the last few years, there has been a greater appreciation by the scientific community of how separation science has contributed to the advancement of biomedical research. Despite past contributions in facilitating several biomedical breakthroughs, separation sciences still urgently need the development of improved methods for the separation and detection of biological and chemical substances. In particular, the challenging task of quantifying small molecules and biomolecules, found in low abundance in complex matrices (e.g., serum), is a particular area in need of new high-efficiency techniques. The tandem or on-line coupling of highly selective antibody capture agents with the high-resolving power of CE is being recognized as a powerful analytical tool for the enrichment and quantification of ultra-low abundance analytes in complex matrices. This development will have a significant impact on the identification and characterization of many putative biornarkers and on biomedical research in general. Immunoaffinity CE (IACE) technology is rapidly emerging as the most promising method for the analysis of low-abundance biomarkers; its power comes from a three-step procedure: (i) bioselective adsorption and (ii) subsequent recovery of compounds from an immobilized affinity ligand followed by (iii) separation of the enriched compounds. This technology is highly suited to automation and can be engineered to as a multiplex instrument capable of routinely performing hundreds of assays per day. Furthermore, a significant enhancement in sensitivity can be achieved for the purified and enriched affinity targeted analytes. Thus, a compound that exists in a complex biological matrix at a concentration far below its LOD is easily brought to well within its range of quantification. The present review summarizes several applications of IACE, as well as a chronological description of the improvements made in the fabrication of the analyte concentrator-microreactor device leading to the development of a multidimensional biomarker analyzer. C1 [Guzman, Norberto A.; Blanc, Timothy] Princeton Biochem Inc, Biomarker Lab, Princeton, NJ 08543 USA. [Phillips, Terry M.] Natl Inst Biomed Imaging & Bioeng, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. RP Blanc, T (reprint author), Princeton Biochem Inc, Biomarker Lab, POB 7102, Princeton, NJ 08543 USA. EM guzman@affinityce.com FU Intramural NIH HHS [NIH0010602809]; PHS HHS [NIH0010602809] NR 200 TC 71 Z9 72 U1 2 U2 32 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD AUG PY 2008 VL 29 IS 16 BP 3259 EP 3278 DI 10.1002/elps.200800058 PG 20 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 343MC UT WOS:000258856900002 PM 18646282 ER PT J AU Wellner, EF Kalish, H AF Wellner, Edward F. Kalish, Heather TI A chip-based immunoaffinity capillary electrophoresis assay for assessing hormones in human biological fluids SO ELECTROPHORESIS LA English DT Article DE body fluids; chip-based immunoaffinity capillary electrophoresis; hormones; miniaturization ID MICROCHIP; CYTOKINES; BLOOD; CHROMATOGRAPHY; MARKERS; SALIVA; CE AB A chip-based capillary electrophoresis system has been designed for assessing the concentrations of four hormones in whole human blood, saliva, and urine. The desired analytes were isolated by immunoextraction using a panel of four analyte-specific antibodies immobilized onto a glass fiber insert within the injection port of the chip. Following extraction, the captured analytes were labeled prior to electro-elution into the chip separation channel, where they were resolved into four individual peaks in circa 2 min. Quantification of each peak was achieved by on-line LIF detection and integration of the area under each peak. Comparison to commercial high-sensitivity immunoassays demonstrated that the chip-based assay provided fast, accurate, and precise measurements for the analytes under investigation. As the availability of commercially available antibodies rapidly expands, the application of this system will greatly increase. Chip-based CE separations of multiple analytes from a single sample also provide a significant advantage in the analysis of small samples. C1 [Wellner, Edward F.; Kalish, Heather] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Kalish, H (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, 13-E42,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kalishh@mail.nih.gov FU Intramural NIH HHS [Z99 EB999999] NR 27 TC 13 Z9 13 U1 2 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD AUG PY 2008 VL 29 IS 16 BP 3477 EP 3483 DI 10.1002/elps.200700785 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 343MC UT WOS:000258856900024 PM 18651671 ER PT J AU Patel, MM Widdowson, MA Glass, RI Akazawa, K Vinje, J Parashar, UD AF Patel, Manish M. Widdowson, Marc-Alain Glass, Roger I. Akazawa, Kenichiro Vinje, Jan Parashar, Umesh D. TI Systematic literature review of role of noroviruses in sporadic gastroenteritis SO EMERGING INFECTIOUS DISEASES LA English DT Article ID HUMAN CALICIVIRUSES; MOLECULAR EPIDEMIOLOGY; HOSPITALIZED CHILDREN; GENETIC DIVERSITY; CHIANG-MAI; ROTAVIRUS; PREVALENCE; INFECTIONS; DIARRHEA; INFANTS AB We conducted a systematic review of studies that used reverse transcription-PCR to diagnose norovirus (NoV) infections in patients with mild or moderate (outpatient) and severe (hospitalized) diarrhea. NoVs accounted for 12% (95% confidence interval [CI] 10%-15%) of severe gastroenteritis cases among children < 5 years of age and 12% (95% Cl 9%-15%) of mild and moderate diarrhea cases among persons of all ages. Of 19 studies among children < 5 years of age, 7 were in developing countries where pooled prevalence of severe NoV disease (12%) was comparable to that for industrialized countries (12%). We estimate that each year NoVs cause 64,000 episodes of diarrhea requiring hospitalization and 900,000 clinic visits among children in industrialized countries, and up to 200,000 deaths of children < 5 years of age in developing countries. Future efforts should focus on developing targeted strategies, possibly even vaccines, for preventing NoV disease and better documenting their impact among children living in developing countries, where > 95% of the deaths from diarrhea occur. C1 [Patel, Manish M.; Widdowson, Marc-Alain; Glass, Roger I.; Vinje, Jan; Parashar, Umesh D.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Glass, Roger I.] NIH, Bethesda, MD 20892 USA. [Akazawa, Kenichiro] Chigasaki Tokushukai Med Ctr, Kanagawa, Japan. RP Patel, MM (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop A47, Atlanta, GA 30333 USA. EM aul3@cdc.gov OI Widdowson, Marc-Alain/0000-0002-0682-6933; Vinje, Jan/0000-0002-1530-3675 NR 41 TC 487 Z9 520 U1 3 U2 68 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2008 VL 14 IS 8 BP 1224 EP 1231 DI 10.3201/eid1408.071114 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 334JA UT WOS:000258216900006 PM 18680645 ER PT J AU Brooks, PJ Cheng, TF Gnatt, A AF Brooks, P. J. Cheng, T.-F. Gnatt, A. TI DNA adducts as mediators of human disease and structural probes of transcription mechanism SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Brooks, P. J.; Cheng, T.-F.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Gnatt, A.] Univ Maryland, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 518 EP 518 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800011 ER PT J AU Smith, MT McHale, CM Zhang, L Porter, K Hubbard, AE Rappaport, SM Skibola, CF Vermeule, R Li, G Yin, S Rothman, N Lan, Q AF Smith, M. T. McHale, C. M. Zhang, L. Porter, K. Hubbard, A. E. Rappaport, S. M. Skibola, C. F. Vermeule, R. Li, G. Yin, S. Rothman, N. Lan, Q. TI Toxicogenomics studies in humans using a systems biology approach: Benzene as an example SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Smith, M. T.; McHale, C. M.; Zhang, L.; Porter, K.; Hubbard, A. E.; Rappaport, S. M.; Skibola, C. F.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Vermeule, R.] Univ Utrecht, Utrecht, Netherlands. [Li, G.; Yin, S.] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Rothman, N.; Lan, Q.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 519 EP 519 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800016 ER PT J AU Copeland, WC AF Copeland, W. C. TI Mitochondrial DNA mutagenesis in mitochondrial diseases due to defects in DNA Polymerase Gamma SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Copeland, W. C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 521 EP 521 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800025 ER PT J AU Van Houten, B Haugen, AJ Di Prospero, N Parker, J Fanin, R Chou, J Meyer, J Halweg, C Collins, J Durr, A Fischbeck, K AF Van Houten, B. Haugen, A. Di Prospero, N. Parker, J. Fanin, R. Chou, J. Meyer, J. Halweg, C. Collins, J. Durr, A. Fischbeck, K. TI Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Van Houten, B.] Univ Pittsburgh, Pittsburgh, PA USA. [Haugen, A.; Fanin, R.; Chou, J.; Halweg, C.; Collins, J.] NIEHS, NIH, Res Triangle Pk, NC USA. [Di Prospero, N.; Fischbeck, K.] NINDS, NIH, Bethesda, MD 20892 USA. [Meyer, J.] Duke Univ, Durham, NC USA. [Parker, J.] Express Anal, Durham, NC USA. [Durr, A.] Hop La Pitie Salpetriere, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 522 EP 522 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800027 ER PT J AU Olivero, OA AF Olivero, O. A. TI Centrosome amplification: A new endpoint? SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Olivero, O. A.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 525 EP 525 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800041 ER PT J AU Freeman, L Blair, A Stewart, P Lubin, JH Hayes, R Hoover, RN Hauptmann, M AF Freeman, L. Blair, A. Stewart, P. Lubin, J. H. Hayes, R. Hoover, R. N. Hauptmann, M. TI Epidemiology of formaldehyde and leukemia SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Freeman, L.; Blair, A.; Stewart, P.; Lubin, J. H.; Hayes, R.; Hoover, R. N.; Hauptmann, M.] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 527 EP 527 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800047 ER PT J AU Vitiello, B AF Vitiello, B. TI attention deficit/hyperactivity disorder (ADHD) and its treatment SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Vitiello, B.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 528 EP 528 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800051 ER PT J AU Witt, KL Shelby, MD Itchon-Ramos, N Faircloth, M Kissling, GE Chrisman, AK Ravi, H Murli, H Mattison, DR Kollins, SH AF Witt, K. L. Shelby, M. D. Itchon-Ramos, N. Faircloth, M. Kissling, G. E. Chrisman, A. K. Ravi, H. Murli, H. Mattison, D. R. Kollins, S. H. TI Chromosomal aberrations, sister chromatid exchanges, and micronuclei in lymphocytes of pediatric ADHD patients treated with stimulant drugs SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Witt, K. L.; Shelby, M. D.; Kissling, G. E.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Itchon-Ramos, N.; Faircloth, M.; Chrisman, A. K.; Ravi, H.; Kollins, S. H.] Duke Univ, Med Ctr, Dept Psychiat, Duke ADHD Program, Durham, NC 27710 USA. [Murli, H.] Covance Labs, Vienna, VA USA. [Mattison, D. R.] NICHHD, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009; Kollins, Scott/G-2965-2012; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 528 EP 528 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800052 ER PT J AU Manqanatha, MG Shelton, SD Dobrovolsky, VN Shaddock, JG McGarrity, LY Lin, CJ Chen, JJ Mattison, DR Morris, SM AF Manqanatha, M. G. Shelton, S. D. Dobrovolsky, V. N. Shaddock, J. G. McGarrity, L. Y. Lin, C. J. Chen, J. J. Mattison, D. R. Morris, S. M. TI Genotoxicity of methylphenidate hydrochloride in big blue mice SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Manqanatha, M. G.; Shelton, S. D.; Dobrovolsky, V. N.; Shaddock, J. G.; McGarrity, L. Y.; Morris, S. M.] US FDA, Natl Ctr Toxicol Res, Genet & Reprod Toxicol Div, Jefferson, AR 72079 USA. [Lin, C. J.; Chen, J. J.] US FDA, NCTR, Personalized Med & Nutr Div, Jefferson, AR USA. [Mattison, D. R.] NICHHD, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 529 EP 529 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800054 ER PT J AU Morris, SM Hotchkiss, CE Bishop, ME Dobrovolsky, V Doerge, D Twaddle, N Chen, JJ Lin, CJ Paule, M Slikker, W Petibone, DM Tucker, JD Manjanatha, MG Mattison, DR AF Morris, S. M. Hotchkiss, C. E. Bishop, M. E. Dobrovolsky, V Doerge, D. Twaddle, N. Chen, J. J. Lin, C. J. Paule, M. Slikker, W. Petibone, D. M. Tucker, J. D. Manjanatha, M. G. Mattison, D. R. TI The genetic toxicology of methiphenidate hydrochloride in non-human primates SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Morris, S. M.; Bishop, M. E.; Dobrovolsky, V; Manjanatha, M. G.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chen, J. J.; Lin, C. J.] WANPRC, Seattle, WA USA. [Doerge, D.; Twaddle, N.] Wayne State Univ, Detroit, MI USA. [Manjanatha, M. G.] NICHD, CRMC, NIH, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 529 EP 529 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800053 ER PT J AU Slikker, W Mattison, DR Patterson, TA Paule, MG Li, M Doerge, D Twaddle, N Hotchkiss, CE Chen, JJ Morris, SM AF Slikker, W. Mattison, D. R. Patterson, T. A. Paule, M. G. Li, M. Doerge, D. Twaddle, N. Hotchkiss, C. E. Chen, J. J. Morris, S. M. TI Pharmacological effects of methylphenidate in the developing primate SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Slikker, W.; Patterson, T. A.; Paule, M. G.; Li, M.; Doerge, D.; Twaddle, N.; Chen, J. J.; Morris, S. M.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Mattison, D. R.] NICHD, NIH, Bethesda, MD USA. [Hotchkiss, C. E.] Washington Natl Primate Res Ctr, Seattle, WA USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 529 EP 529 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800056 ER PT J AU Cantor, KP AF Cantor, K. P. TI Epidemiologic studies of cancer and disinfection byproducts (DBP) SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Cantor, K. P.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 531 EP 531 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800062 ER PT J AU Wilson, DM AF Wilson, I. I. I. D. M. TI Base excision repair in cancer susceptibility and neurodegeneration SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Wilson, I. I. I. D. M.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 531 EP 531 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800061 ER PT J AU Anderson, LM Ge, X Spurrier, JM McCann, SD Wang, C Crawford, EB Fields, JR Leighty, RM Quinones, OA Alvord, WG Shiao, YH AF Anderson, L. M. Ge, X. Spurrier, J. M. McCann, S. D. Wang, C. Crawford, E. B. Fields, J. R. Leighty, R. M. Quinones, O. A. Alvord, W. G. Shiao, Y. H. TI Chemical stressors in fathers alter allele-associated DNA methylation of the 45S rRNA in propeny SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Anderson, L. M.; Ge, X.; Spurrier, J. M.; McCann, S. D.; Wang, C.; Crawford, E. B.; Fields, J. R.; Shiao, Y. H.] NCI, Frederick, MD 21701 USA. [Leighty, R. M.; Quinones, O. A.; Alvord, W. G.] DMS Inc, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 545 EP 545 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800114 ER PT J AU Yu, M Olivero, OA Poirier, MC AF Yu, M. Olivero, O. A. Poirier, M. C. TI Centrosomal amplification, a genotoxic mechanism common to nucleoside analogs, could be inhibited by the antioxidant WR 1065 SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Yu, M.; Olivero, O. A.; Poirier, M. C.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 548 EP 548 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800124 ER PT J AU Hunter, SE Collins, L Van Houten, B AF Hunter, S. E. Collins, L. Van Houten, B. TI Double strand break repair in human mitochondrial extracts SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Hunter, S. E.; Collins, L.; Van Houten, B.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 549 EP 549 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800127 ER PT J AU Abraham, J Brooks, P AF Abraham, J. Brooks, P. TI The oxidative DNA lesions, 8,5'-cyclo-2'-deoxyadenosine and 8-oxo-7,8 dihydro-2'-deoxyadenosine, differentially alter the binding of HSF1 and CREB transcription factors to target DNA sequences SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Abraham, J.; Brooks, P.] NIAAA, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 551 EP 551 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800136 ER PT J AU French, JE Parron, VI AF French, J. E. Parron, V., I TI Susceptibility to ionizing radiation induced tumors and DNA strand break repair in p53 deficient and wildtype mouse hematopoietic: Stem cells (HSC) in vivo and in vitro SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [French, J. E.; Parron, V., I] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 551 EP 551 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800138 ER PT J AU Torres, SM Walker, DM Seilkop, SK Copeland, WC Walker, VE AF Torres, S. M. Walker, D. M. Seilkop, S. K. Copeland, W. C. Walker, V. E. TI DGGE-based detection of mitochondrial tRNA gene and flanking region mutations in umbilical cord tissue from HIV-1 uninfected infants receiving perinatal AZT-based therapies SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Torres, S. M.; Walker, V. E.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Torres, S. M.] Univ New Mexico, Albuquerque, NM 87131 USA. [Walker, D. M.; Walker, V. E.] BioMosaics Inc, Burlington, VT USA. [Seilkop, S. K.] SKS Consulting Srvs, Silver City, NC USA. [Copeland, W. C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 556 EP 556 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800157 ER PT J AU John, K Singh, PB Pratt, MM Ragavan, N Cole, KC Matanhelia, SS Phillips, DH Martin, FL AF John, K. Singh, P. B. Pratt, M. M. Ragavan, N. Cole, K. C. Matanhelia, S. S. Phillips, D. H. Martin, F. L. TI Gene expression of phase I and phase II metabolizing enzymes and PAH-DNA adduct formation in human prostate as risk factors in prostate cancer etiology SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [John, K.; Pratt, M. M.] NCI, NIH, Bethesda, MD 20892 USA. [Singh, P. B.; Ragavan, N.; Martin, F. L.] Univ Lancaster, Lancaster, England. [Cole, K. C.; Matanhelia, S. S.; Phillips, D. H.] Inst Canc Res, Surrey, England. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 557 EP 557 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800161 ER PT J AU Einem, TL Divi, RL Shockley, ME Keshava, C Weston, A Poirier, MC AF Einem, T. L. Divi, R. L. Shockley, M. E. Keshava, C. Weston, A. Poirier, M. C. TI Abundant expression of CYP1A1 is positively, while CYP1B1 and NQ01 are negatively, associated with benzo(a)pyrene (BP)-DNA adduct formation in normal human mammary epithelial cells (NHMECs) SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Einem, T. L.; Divi, R. L.; Shockley, M. E.; Poirier, M. C.] NCI, NIH, Bethesda, MD 20892 USA. [Keshava, C.] US EPA, Res Triangle Pk, NC 27711 USA. [Weston, A.] NIOSH, CDC, Morgantown, WV USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 559 EP 559 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800167 ER PT J AU Shelton, SD Manjanatha, MG Mattison, DR Morris, SM AF Shelton, S. D. Manjanatha, M. G. Mattison, D. R. Morris, S. M. TI Evaluation of cll mutations in Big Blue mice fed methylphenidate hydrochloride for up to 24 weeks SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Shelton, S. D.; Manjanatha, M. G.; Morris, S. M.] US FDA, Natl Ctr Toxicol Res, DGRT, Jefferson, AR 72079 USA. [Mattison, D. R.] NICHHD, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 561 EP 561 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800176 ER PT J AU Bishop, ME Hotchkiss, CE Lin, CJ Chen, JJ Mattison, DR Morris, SM AF Bishop, M. E. Hotchkiss, C. E. Lin, C.-J. Chen, J. J. Mattison, D. R. Morris, S. M. TI Flow cytometric determination of the micronucleus frequency in juvenile rhesus monkeys chronically exposed to methylphenidate hydrochloride SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Bishop, M. E.; Morris, S. M.] US FDA, DGRT, NCTR, Jefferson, AR USA. [Lin, C.-J.; Chen, J. J.] US FDA, DPMN, NCTR, Jefferson, AR USA. [Hotchkiss, C. E.] WANPRC UWashington, Seattle, WA USA. [Mattison, D. R.] NICHD, OPP, NIH, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 564 EP 564 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800188 ER PT J AU Dobrovolsky, VN Shaddock, JG Manjanatha, MG Miura, D Mattison, DR Morris, SM AF Dobrovolsky, V. N. Shaddock, J. G. Manjanatha, M. G. Miura, D. Mattison, D. R. Morris, S. M. TI Genotoxicity of methylphenidate hydrochloride in the rhesus monkey SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Dobrovolsky, V. N.; Shaddock, J. G.; Manjanatha, M. G.; Miura, D.; Morris, S. M.] NCTR, Jefferson, AR USA. [Mattison, D. R.] NICHD, Bethesda, MD USA. [Miura, D.] Teijin, Tokyo, Japan. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 565 EP 565 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800191 ER PT J AU Witt, KL Recio, L Shepard, K Green, A Baldetti, C Winters, J Davis, J Caspary, W Hobbs, CA AF Witt, K. L. Recio, L. Shepard, K. Green, A. Baldetti, C. Winters, J. Davis, J. Caspary, W. Hobbs, C. A. TI Evaluation of micronucleus frequencies and DNA damage in male rats administered methylphenidate hydrochloride (ritalin) for 28 days SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Witt, K. L.; Caspary, W.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Recio, L.; Shepard, K.; Green, A.; Baldetti, C.; Winters, J.; Hobbs, C. A.] ILS Inc, Div Genet Toxicol, Res Triangle Pk, NC USA. [Davis, J.] ILS Inc, Integrat Toxicol Div, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 567 EP 567 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800198 ER PT J AU Hobbs, CA Recio, L Shepard, K Winters, J Green, A Baldetti, C Streicker, M Davis, J Caspary, W Witt, KL AF Hobbs, C. A. Recio, L. Shepard, K. Winters, J. Green, A. Baldetti, C. Streicker, M. Davis, J. Caspary, W. Witt, K. L. TI Time course of chemical-induced in vivo genotoxicity evaluated using a combined protocol for micronucleus and comet analyses SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Hobbs, C. A.; Recio, L.; Shepard, K.; Winters, J.; Green, A.; Baldetti, C.; Streicker, M.; Davis, J.] Integrated Syst Lab, Res Triangle Pk, NC USA. [Caspary, W.; Witt, K. L.] NIEHS, Toxicol Branch, Res Triangle Pk, NC 27709 USA. [Caspary, W.; Witt, K. L.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 570 EP 570 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800212 ER PT J AU Recio, L Hobbs-Riter, C Shepard, K Baldetti, C Streicker, M Winters, J Caspary, W Witt, KL AF Recio, L. Hobbs-Riter, C. Shepard, K. Baldetti, C. Streicker, M. Winters, J. Caspary, W. Witt, K. L. TI Combined protocol for simultaneous measurement of micronucleated erythrocyte frequencies and DNA damage in rodents SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 39th Annual Meeting of the Environment-Mutagen-Society CY OCT 18-22, 2008 CL PR SP Environm Mutagen Soc C1 [Recio, L.; Hobbs-Riter, C.; Shepard, K.; Baldetti, C.; Streicker, M.; Winters, J.] ILS, Res Triangle Pk, NC USA. [Caspary, W.; Witt, K. L.] NIEHS, NTP, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2008 VL 49 IS 7 BP 574 EP 574 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 341PG UT WOS:000258725800227 ER PT J AU Galperin, MY AF Galperin, Michael Y. TI New feel for new phyla SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID CANDIDATUS PHYTOPLASMA AUSTRALIENSE; PACHNODA-EPHIPPIATA COLEOPTERA; HUMUS-FEEDING LARVA; GENOME SEQUENCE; SP-NOV.; MYCOBACTERIUM-TUBERCULOSIS; AKKERMANSIA-MUCINIPHILA; PHYLOGENETIC DIVERSITY; METHANE OXIDATION; VERRUCOMICROBIA C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS [Z99 LM999999] NR 46 TC 3 Z9 3 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD AUG PY 2008 VL 10 IS 8 BP 1927 EP 1933 DI 10.1111/j.1462-2920.2008.01699.x PG 7 WC Microbiology SC Microbiology GA 327FR UT WOS:000257715500001 PM 18665943 ER PT J AU Sartorius, A Ruf, M Kief, C Demirakca, T Bailer, J Ende, G Henn, FA Meyer-Lindenberg, A Dressing, H AF Sartorius, Alexander Ruf, Matthias Kief, Christine Demirakca, Traute Bailer, Josef Ende, Gabriele Henn, Fritz A. Meyer-Lindenberg, Andreas Dressing, Harald TI Abnormal amygdala activation profile in pedophilia SO EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE LA English DT Article DE fMRI; pedophilia; striato-limbic pathway; amygdala ID VISUAL SEXUAL STIMULI; BRAIN; PARAPHILIAS; SEROTONIN; MEMORY; FMRI; MEN; DISORDERS; OFFENDERS; SYSTEM AB Despite considerable public interest research in neurobiological correlates of pedophilia is scarce. Since amygdala activation is central for emotional valuation, arousal, and salience, we investigated the activation profile of this structure in 10 male subjects with pedophilia (exclusively attracted to boys), all convicted sex-offenders and sentenced to forensic psychiatric treatment along with ten male heterosexual matched controls. We used a sexually non-explicit functional Magnetic Resonance Imaging (fMRI) paradigm with images of men, women, boys or girls randomly embedded in neutral target/non-target geometrical symbols. We applied statistical parametric mapping (SPM2) and SPSS 14 for image processing and analysis. While controls activated significantly less to pictures of children compared to adults, the activation profile was reversed in subjects with pedophilia, who exhibited significantly more activation to children than adults. The highest activation was observed for boys in the patient group, and for women in control participants. Our data show enhanced activation to children's pictures even in an incidental context and suggest the provocative hypothesis that a normally present mechanism for reduced emotional arousal for children relative to adults is reversed in pedophilia, suggesting a neural substrate associated with deviant sexual preference in this condition. More extensive research in this field would be of benefit for both the victims and the offenders. C1 [Sartorius, Alexander; Ruf, Matthias; Kief, Christine; Demirakca, Traute; Bailer, Josef; Ende, Gabriele; Henn, Fritz A.; Meyer-Lindenberg, Andreas; Dressing, Harald] Cent Inst Mental Hlth, D-68159 Mannheim, Germany. [Meyer-Lindenberg, Andreas] NIMH, Unit Syst Neurosci Psychiat, Clin Brain Disorders Branch, New York, NY USA. [Henn, Fritz A.] Brookhaven Natl Lab, Life Sci Directorate, Upton, NY 11973 USA. RP Dressing, H (reprint author), Cent Inst Mental Hlth, J5, D-68159 Mannheim, Germany. EM harald.dressing@zi-mannheim.de RI Ende, Gabriele/B-7012-2009; Sartorius, Alexander/E-3061-2012; Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Rhineland-Palatine FX This study was funded by a grant from the Rhineland-Palatine ministry of labour and social affairs. Pedophile patients are treated in forensic security hospitals of Landeck (Director M. Noetzel, M. D.) and Andernach (Director W. Schuhmacher-Wandersleb M. D.). NR 44 TC 32 Z9 32 U1 7 U2 22 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0940-1334 J9 EUR ARCH PSY CLIN N JI Eur. Arch. Psych. Clin. Neurosci. PD AUG PY 2008 VL 258 IS 5 BP 271 EP 277 DI 10.1007/s00406-008-0782-2 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 339UI UT WOS:000258602400002 PM 18504635 ER PT J AU Siltanen, S Syrjaekoski, K Fagerholm, R Ikonen, T Lipman, P Mallott, J Holli, K Tammela, TLJ Jarvinen, HJ Mecklin, JP Aittomaki, K Blomqvist, C Bailey-Wilson, JE Nevanlinna, H Aaltonen, LA Schleutker, J Vahteristo, P AF Siltanen, Sanna Syrjaekoski, Kirsi Fagerholm, Rainer Ikonen, Tarja Lipman, Peter Mallott, Jacob Holli, Kaija Tammela, Teuvo L. J. Jarvinen, Heikki J. Mecklin, Jukka-Pekka Aittomaki, Kristiina Blomqvist, Carl Bailey-Wilson, Joan E. Nevanlinna, Heli Aaltonen, Lauri A. Schleutker, Johanna Vahteristo, Pia TI ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE ARLTS1; ARL11; prostate cancer; breast cancer; colorectal cancer ID CYS148ARG VARIANT; BRCA2 MUTATIONS; OVARIAN-CANCER; FAMILIES; GENE; POLYMORPHISMS; ASSOCIATION; FINLAND AB Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases versus sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5-1.2%) in all patient subgroups versus 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (odds ratio (OR), 1.48; 95% confidence interval (CI), 1.16-1.87; P = 0.001) and prostate cancer patients (OR, 1.50; 95% CI, 1.13-1.99; P = 0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8 of 164, 4.9%) than in controls (13 of 809, 1.6%; OR, 3.14; 95% CI, 1.28-7.70, P = 0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data. C1 [Aaltonen, Lauri A.; Vahteristo, Pia] Univ Helsinki, Dept Med Genet, FIN-00014 Helsinki, Finland. [Siltanen, Sanna; Syrjaekoski, Kirsi; Ikonen, Tarja; Schleutker, Johanna] Univ Tampere, Canc Genet Lab, Inst Med Technol, FIN-33101 Tampere, Finland. [Siltanen, Sanna; Syrjaekoski, Kirsi; Ikonen, Tarja; Schleutker, Johanna] Tampere Univ Hosp, Canc Genet Lab, Inst Med Technol, Tampere, Finland. [Fagerholm, Rainer; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynaecol, Cent Hosp, Helsinki, Finland. [Lipman, Peter; Mallott, Jacob; Bailey-Wilson, Joan E.] Natl Human Genome Res Inst, Inherited Dis Res Branch, Natl Inst Hlth, Baltimore, MD USA. [Holli, Kaija] Univ Tampere, Dept Oncol, FIN-33101 Tampere, Finland. [Holli, Kaija] Tampere Univ Hosp, Dept Oncol, Tampere, Finland. [Tammela, Teuvo L. J.] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, Tampere, Finland. [Jarvinen, Heikki J.] Univ Helsinki, Cent Hosp, Dept Surg 2, Helsinki, Finland. [Mecklin, Jukka-Pekka] Jyvaskyla Cent Hosp, Dept Surg, Jyvaskyla, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. RP Vahteristo, P (reprint author), Univ Helsinki, Dept Med Genet, POB 63, FIN-00014 Helsinki, Finland. EM pia.vahteristo@helsinki.fi RI Aaltonen, Lauri/A-5375-2010; OI Aaltonen, Lauri/0000-0001-6839-4286; Bailey-Wilson, Joan/0000-0002-9153-2920; Nevanlinna, Heli/0000-0002-0916-2976 FU Intramural NIH HHS [Z01 HG200331-04] NR 28 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD AUG PY 2008 VL 16 IS 8 BP 983 EP 991 DI 10.1038/ejhg.2008.43 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 329SY UT WOS:000257892100016 PM 18337727 ER PT J AU Ali, M Atula, SA Bath, PMW Grotta, J Lyden, P Marler, JR Sacco, RL Lees, KR AF Ali, M. Atula, S. A. Bath, P. M. W. Grotta, J. Lyden, P. Marler, J. R. Sacco, R. L. Lees, K. R. TI Stroke outcome in clinical trial patients in different countries SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 12th Congress of the European-Federation-of-Neurological-Societies CY AUG 23-26, 2008 CL Madrid, SPAIN SP European Federat Neurol Soc C1 [Ali, M.; Atula, S. A.; Lees, K. R.] Univ Glasgow, Western Infirm, Gardiner Inst, Dept Med & Therapeut, Glasgow G11 6NT, Lanark, Scotland. [Bath, P. M. W.] Univ Nottingham, Div Stroke Med, Nottingham NG7 2RD, England. [Grotta, J.] Univ Texas Houston, Houston Med Sch, Dept Neurol, Houston, TX USA. [Lyden, P.] Univ San Diego, San Diego, CA 92110 USA. [Marler, J. R.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20824 USA. [Sacco, R. L.] Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD AUG PY 2008 VL 15 SU 3 BP 55 EP 56 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 336QF UT WOS:000258379000182 ER PT J AU Hughes, R Bril, V Dalakas, MC Deng, C Donofrio, P Hanna, K Hartung, HP Latov, N Merkies, I van Doorn, P AF Hughes, R. Bril, V. Dalakas, M. C. Deng, C. Donofrio, P. Hanna, K. Hartung, H. P. Latov, N. Merkies, I. van Doorn, P. TI Long-term safety profile (up to 48 weeks) of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C; Gamunex (R)) therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 12th Congress of the European-Federation-of-Neurological-Societies CY AUG 23-26, 2008 CL Madrid, SPAIN SP European Federat Neurol Soc C1 [Hughes, R.] Kings Coll London, Guys Hosp, Dept Clin Neurosci, London WC2R 2LS, England. [Bril, V.] Univ Hlth Network, Toronto, ON, Canada. [Dalakas, M. C.] NIH, Neuromuscular Dis Sect, Bethesda, MD 20892 USA. [Deng, C.; Hanna, K.] Talecris Biotherapeut Inc, Res Triangle Pk, NC USA. [Donofrio, P.] Vanderbilt Univ, Dept Neurol, Nashville, TN USA. [Hartung, H. P.] Univ Dusseldorf, Dept Neurol, D-4000 Dusseldorf, Germany. [Latov, N.] Cornell Univ, Peripheral Neuropathy Ctr, New York, NY 10021 USA. [Merkies, I.; van Doorn, P.] Erasmus Mc, Dept Neurol, Rotterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD AUG PY 2008 VL 15 SU 3 BP 162 EP 162 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 336QF UT WOS:000258379000541 ER PT J AU Conforto, AB Ferreiro, KN dos Santos, RL Moreira, VL Scaff, M Cohen, LG AF Conforto, A. B. Ferreiro, K. N. dos Santos, R. L. Moreira, V. L. Scaff, M. Cohen, L. G. TI Corticomotor excitability in subacute ischemic stroke correlates with arm motor function and lesion location SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 12th Congress of the European-Federation-of-Neurological-Societies CY AUG 23-26, 2008 CL Madrid, SPAIN SP European Federat Neurol Soc C1 [Conforto, A. B.; Ferreiro, K. N.; dos Santos, R. L.; Moreira, V. L.; Scaff, M.] Univ Sao Paulo, Hosp Clin, Dept Neurol, Sao Paulo, Brazil. [Conforto, A. B.] Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo, Brazil. [Cohen, L. G.] NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD AUG PY 2008 VL 15 SU 3 BP 373 EP 373 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 336QF UT WOS:000258379001233 ER PT J AU Farias, SN Cohen, LG Yamamoto, FI Marchiori, PE Scaff, M Conforto, AB AF Farias, S. N. Cohen, L. G. Yamamoto, F. I. Marchiori, P. E. Scaff, M. Conforto, A. B. TI Corticomotor excitability in chronic cerebellar infarcts SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 12th Congress of the European-Federation-of-Neurological-Societies CY AUG 23-26, 2008 CL Madrid, SPAIN SP European Federat Neurol Soc C1 [Farias, S. N.; Yamamoto, F. I.; Marchiori, P. E.; Scaff, M.; Conforto, A. B.] Univ Sao Paulo, Hosp Clin, Dept Neurol, Sao Paulo, Brazil. [Cohen, L. G.] NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. [Conforto, A. B.] Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo, Brazil. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD AUG PY 2008 VL 15 SU 3 BP 373 EP 373 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 336QF UT WOS:000258379001232 ER PT J AU Wolf, RC Sambataro, F Vasic, N Schoenfeldt-Lecuona, C Ecker, D Landwehrmeyer, GB AF Wolf, R. C. Sambataro, F. Vasic, N. Schoenfeldt-Lecuona, C. Ecker, D. Landwehrmeyer, G. B. TI Functional dysconnectivity of multiple prefrontal networks in premanifest Huntington's disease SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 12th Congress of the European-Federation-of-Neurological-Societies CY AUG 23-26, 2008 CL Madrid, SPAIN SP European Federat Neurol Soc C1 [Wolf, R. C.; Vasic, N.; Schoenfeldt-Lecuona, C.] Univ Ulm, Dept Psychiat 3, D-89069 Ulm, Germany. [Ecker, D.; Landwehrmeyer, G. B.] Univ Ulm, Dept Neurol, D-7900 Ulm, Germany. [Sambataro, F.] Univ Bari, Dept Psychiat, I-70121 Bari, Italy. [Sambataro, F.] NIMH, NIH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD AUG PY 2008 VL 15 SU 3 BP 411 EP 411 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 336QF UT WOS:000258379001362 ER PT J AU Mazzola, C Panlilio, LV Goldberg, SR Yasar, S Drago, F AF Mazzola, C. Panlilio, L. V. Goldberg, S. R. Yasar, S. Drago, F. TI Peroxisome proliferator-activated receptors (PPARs): new target for attention and memory function SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 21st Congress of the European-College-of-Neuropsychopharmacology CY AUG 30-SEP 03, 2008 CL Barcelona, SPAIN SP European Coll Neuropsychopharmacol C1 [Mazzola, C.; Drago, F.] Univ Catania, Dept Exp Clin Pharmacol, Sch Med, Catania, Italy. [Panlilio, L. V.; Goldberg, S. R.] NIDA, NIH, Pharmacol Sect, Behav Neurosci Res Branch,Intramural Res Program, Baltimore, MD USA. [Yasar, S.] Johns Hopkins Med Sch, Div Geriatr Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD AUG PY 2008 VL 18 SU 4 BP S235 EP S235 DI 10.1016/S0924-977X(08)70291-8 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 353UK UT WOS:000259593800182 ER PT J AU Nocon, A Wittchen, HU Beesdo, K Pine, DS Hofler, M Lieb, R Gloster, AT AF Nocon, A. Wittchen, H. U. Beesdo, K. Pine, D. S. Hoefler, M. Lieb, R. Gloster, A. T. TI Relationship of panic and agoraphobia: rethinking of a diagnostic concept? SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 21st Congress of the European-College-of-Neuropsychopharmacology CY AUG 30-SEP 03, 2008 CL Barcelona, SPAIN SP European Coll Neuropsychopharmacol C1 [Nocon, A.] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Wittchen, H. U.; Beesdo, K.; Hoefler, M.] Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, Dresden, Germany. [Pine, D. S.] NIMH, Div Intramural Res Programs, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Lieb, R.] Univ Basel, Basel, Switzerland. [Gloster, A. T.] Univ Dresden, Inst Clin Psychol & Psychotherapy, Dresden, Germany. RI Beesdo-Baum, Katja/A-5793-2012; Wittchen, Hans-Ulrich/A-8507-2014 NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD AUG PY 2008 VL 18 SU 4 BP S491 EP S492 DI 10.1016/S0924-977X(08)70735-1 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 353UK UT WOS:000259593801293 ER PT J AU Soehnlein, O Oehmcke, S Ma, X Rothfuchs, AG Frithiof, R van Rooijen, N Morgelin, M Herwald, H Lindbom, L AF Soehnlein, O. Oehmcke, S. Ma, X. Rothfuchs, A. G. Frithiof, R. van Rooijen, N. Morgelin, M. Herwald, H. Lindbom, L. TI Neutrophil degranulation mediates severe lung damage triggered by streptococcal M1 protein SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE lung injury; M1 protein; neutrophil granule proteins; Streptococcus pyogenes ID EPITHELIAL-CELLS; N-TERMINUS; MONOCYTES; PATHOGENESIS; INFLAMMATION; MACROPHAGES; ACTIVATION; EXPRESSION; FIBRINOGEN; LEUKOCYTES AB Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome commonly associated with acute lung injury. The aim of the present study was to investigate the role of neutrophils and their secretion products in M1 protein-induced lung damage. The degranulation of neutrophills by M1 protein was studied in whole blood using marker analysis for individual granule subsets. In mice, M1 protein was injected intravenously and the lung damage was assessed by histology, electron microscopy, cell count in bronchoalveolar lavage fluid and analysis of lung vascular permeability. Comparisons were made in mice with intact white blood count, neutropenic mice and neutropenic mice injected with the secretion of activated neutrophils. In whole blood, M1 protein forms complexes with fibrinogen that bind to beta(2)-integrins on the neutrophil surface, resulting in degranulation of all four subsets of neutrophil granules. Intravenous injection of M1 protein into mice induced neutrophil accumulation in the lung, increase in vascular permeability and acute lung damage. Depletion of neutrophils from the circulation completely abrogated lung injury and vascular leakage. Interestingly, the lung damage was restored by injecting neutrophil secretion. The present data suggest that neutrophil granule proteins are directly responsible for lung damage induced by the streptococcal M1 protein. C1 [Soehnlein, O.; Ma, X.; Frithiof, R.; Lindbom, L.] Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden. [Oehmcke, S.; Morgelin, M.; Herwald, H.] Lund Univ, Dept Clin Sci, Lund, Sweden. [Rothfuchs, A. G.] NIAID, Parasit Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [van Rooijen, N.] Virje Univ, Dept Mol Cell Biol, Amsterdam, Netherlands. RP Soehnlein, O (reprint author), Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden. EM Oliver.Sohnlein@ki.se RI Rothfuchs, Antonio/F-5981-2013; OI Rothfuchs, Antonio/0000-0001-6001-7240; Lindbom, Lennart/0000-0001-9243-257X; Herwald, Heiko/0000-0002-8111-2842 NR 31 TC 63 Z9 63 U1 0 U2 3 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD AUG PY 2008 VL 32 IS 2 BP 405 EP 412 DI 10.1183/09031936.00173207 PG 8 WC Respiratory System SC Respiratory System GA 337DZ UT WOS:000258417000023 PM 18321926 ER PT J AU Dreisbach, AW Lertora, JJL AF Dreisbach, Albert W. Lertora, Juan J. L. TI The effect of chronic renal failure on drug metabolism and transport SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE chronic renal failure; CYP; cytochrome P450; drug transport; efflux transporters; hepatic clearance; P-glycoprotein; uremic toxins ID PROTEIN-BINDING; DOWN-REGULATION; CLINICAL PHARMACOKINETICS; HEPATIC CYTOCHROME-P450; ANEPHRIC PATIENTS; GENE-EXPRESSION; KIDNEY-DISEASE; P-GLYCOPROTEIN; SERUM-ALBUMIN; L-PROPRANOLOL AB Background: Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine. Objectives: The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport. Methods: A search of the National Library of Medicine PubMed was done with terms such as chronic renal failure, cytochrome P450 [CYP], liver metabolism, efflux drug transport and uptake transport, including relevant articles back to 1969. Results: Animal studies in CRF have shown a significant downregulation (40-85%) of hepatic and intestinal CYP metabolism. High levels of parathyroid hormone, cytokines and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein and organic anion transporting polypeptide are also affected. Conclusion: CRF alters intestinal, renal and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions. C1 [Dreisbach, Albert W.] Univ Mississippi, Med Ctr, Dept Med, Div Nephrol, Jackson, MS 39216 USA. [Lertora, Juan J. L.] NIH, Ctr Clin, Clin Pharmacol Program, Bethesda, MD 20892 USA. RP Dreisbach, AW (reprint author), Univ Mississippi, Med Ctr, Dept Med, Div Nephrol, 2500 N State St, Jackson, MS 39216 USA. EM adreisbach@umsmed.edu FU Intramural NIH HHS [Z99 CL999999] NR 93 TC 81 Z9 81 U1 2 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1742-5255 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD AUG PY 2008 VL 4 IS 8 BP 1065 EP 1074 DI 10.1517/17425250802273527 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 342UJ UT WOS:000258808800004 PM 18680441 ER PT J AU Giubellino, A Burke, TR Bottaro, DP AF Giubellino, Alessio Burke, Terrence R., Jr. Bottaro, Donald P. TI Grb2 signaling in cell motility and cancer SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE cell migration; Grb2; tumor metastasis ID GROWTH-FACTOR RECEPTOR; FOCAL-ADHESION KINASE; WISKOTT-ALDRICH-SYNDROME; ACTIVATED PROTEIN-KINASE; SH2 DOMAIN-BINDING; CHRONIC MYELOGENOUS LEUKEMIA; STRUCTURE-BASED DESIGN; ACTIN-BASED MOTILITY; ADAPTER PROTEIN; HIGH-AFFINITY AB Background: Metastasis is the primary cause of death in most human cancers, and understanding the molecular mechanisms underpinning this multistep process is fundamental to identifying novel molecular targets and developing more effective therapies. Objective/methods: Here we review the role of growth factor receptor-bound protein 2 (Grb2) in cancer and specifically in metastasis-related processes, and summarize the development of anticancer therapeutics selectively targeting this adapter protein. Results/conclusion: Grb2 is a key molecule in intracellular signal transduction, linking activated cell surface receptors to downstream targets by binding to specific phosphotyrosine-containing and proline-rich sequence motifs. Grb2 signaling is critical for cell cycle progression and actin-based cell motility, and, consequently, more complex processes such as epithelial morphogenesis, angiogenesis and vasculogenesis. These functions make Grb2 a therapeutic target for strategies designed to prevent the spread of solid tumors through local invasion and metastasis. C1 [Giubellino, Alessio; Bottaro, Donald P.] NCI, Urol Oncol Branch, CCR, Bethesda, MD 20892 USA. [Burke, Terrence R., Jr.] NCI, Med Chem Lab, Frederick, MD 21701 USA. RP Giubellino, A (reprint author), NCI, Urol Oncol Branch, CCR, Bldg 10 CRC 1 W Room 3961,10 Ctr Dr MSC 1107, Bethesda, MD 20892 USA. EM giubella@mail.nih.gov RI Bottaro, Donald/F-8550-2010; Burke, Terrence/N-2601-2014; OI Bottaro, Donald/0000-0002-5057-5334; Giubellino, Alessio/0000-0002-5352-0662 FU Intramural NIH HHS [Z01 SC006659-25, Z99 CA999999, Z99 HD999999] NR 125 TC 67 Z9 70 U1 0 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD AUG PY 2008 VL 12 IS 8 BP 1021 EP 1033 DI 10.1517/14728222.12.8.1021 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 330CL UT WOS:000257916900009 PM 18620523 ER PT J AU Gude, DR Alvarez, SE Paugh, SW Mitra, P Yu, JD Griffiths, R Barbour, SE Milstien, S Spiegel, S AF Gude, David R. Alvarez, Sergio E. Paugh, Steven W. Mitra, Poulami Yu, JiaDe Griffiths, Rachael Barbour, Suzanne E. Milstien, Sheldon Spiegel, Sarah TI Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal SO FASEB JOURNAL LA English DT Article DE chemotaxis; leukemia cells; monocytes; secretion ID MYELOID-LEUKEMIA CELLS; DEPENDENT MECHANISM; GROWTH-FACTOR; 1-PHOSPHATE; FTY720; MIGRATION; RECEPTOR; N,N-DIMETHYLSPHINGOSINE; PROTEASE; PHOSPHORYLATION AB Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates myriad important cellular processes, including growth, survival, cytoskeleton rearrangements, motility, and immunity. Here we report that treatment of Jurkat and U937 leukemia cells with the pan-sphingosine kinase (SphK) inhibitor N,N-dimethylsphingosine to block S1P formation surprisingly caused a large increase in expression of SphK1 concomitant with induction of apoptosis. Another SphK inhibitor, D, L-threo-dihydrosphingosine, also induced apoptosis and produced dramatic increases in SphK1 expression. However, up-regulation of SphK1 was not a specific effect of its inhibition but rather was a consequence of apoptotic stress. The chemotherapeutic drug doxorubicin, a potent inducer of apoptosis in these cells, also stimulated SphK1 expression and activity and promoted S1P secretion. The caspase inhibitor ZVAD reduced not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of S1P. Apoptotic cells secrete chemotactic factors to attract phagocytic cells, and we found that S1P potently stimulated chemotaxis of monocytic THP-1 and U937 cells and primary monocytes and macrophages. Collectively, our data suggest that apoptotic cells may upregulate SphK1 to produce and secrete S1P that serves as a "come-and-get-me" signal for scavenger cells to engulf them in order to prevent necrosis. C1 [Gude, David R.; Alvarez, Sergio E.; Paugh, Steven W.; Mitra, Poulami; Yu, JiaDe; Griffiths, Rachael; Barbour, Suzanne E.; Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Gude, David R.; Alvarez, Sergio E.; Paugh, Steven W.; Mitra, Poulami; Yu, JiaDe; Griffiths, Rachael; Barbour, Suzanne E.; Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23298 USA. [Milstien, Sheldon] NIMH, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, 1101 E Marshall St,2011 Sanger Hall, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Paugh, Steven/A-7739-2008 OI Paugh, Steven/0000-0001-5697-9228 FU Intramural NIH HHS; NCI NIH HHS [R01 CA061774, R01 CA61774]; NIGMS NIH HHS [R37 GM043880] NR 56 TC 121 Z9 125 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2008 VL 22 IS 8 BP 2629 EP 2638 DI 10.1096/fj.08-107169 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 332NI UT WOS:000258089300004 PM 18362204 ER PT J AU Hartz, AMS Bauer, B Block, ML Hong, JS Miller, DS AF Hartz, Anika M. S. Bauer, Bjoern Block, Michelle L. Hong, Jau-Shyong Miller, David S. TI Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier SO FASEB JOURNAL LA English DT Article DE NADPH oxidase; reactive oxygen species; TNF-alpha; TNF-receptor 1; JNK ID NECROSIS-FACTOR-ALPHA; AIR-POLLUTION; EFFLUX TRANSPORTERS; DRUG-THERAPY; IN-VIVO; KAPPA-B; ACTIVATION; MACROPHAGE; EXPRESSION; PATHOLOGY AB Here, we report that diesel exhaust particles (DEPs), a major constituent of urban air pollution, affect blood-brain barrier function at the tissue, cellular, and molecular levels. Isolated rat brain capillaries exposed to DEPs showed increased expression and transport activity of the key drug efflux transporter, P-glycoprotein (6 h EC(50) was similar to 5 mu g/ml). Upregulation of P-glycoprotein was abolished by blocking transcription or protein synthesis. Inhibition of NADPH oxidase or pretreatment of capillaries with radical scavengers ameliorated DEP-induced P-glycoprotein up-regulation, indicating a role for reactive oxygen species in signaling. DEP exposure also increased brain capillary tumor necrosis factor-alpha (TNF-alpha) levels. DEP-induced P-glycoprotein up-regulation was abolished when TNF-receptor 1 (TNF-R1) was blocked and was not evident in experiments with capillaries from TNF-R1 knockout mice. Inhibition of JNK, but not NF-kappa B, blocked DEP-induced P-glycoprotein up-regulation, indicating a role for AP-1 in the signaling pathway. Consistent with this, DEPs increased phosphorylation of c-jun. Together, our results show for the first time that a component of air pollution, DEPs, alters blood-brain barrier function through oxidative stress and proinflammatory cytokine production. These experiments disclose a novel blood-brain barrier signaling pathway, with clear implications for environmental toxicology, CNS pathology, and the pharmacotherapy of CNS disorders. C1 [Hartz, Anika M. S.; Bauer, Bjoern; Block, Michelle L.; Hong, Jau-Shyong; Miller, David S.] NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. [Hartz, Anika M. S.] Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. [Bauer, Bjoern] Univ Minnesota, Coll Pharm, Dept Pharmaceut Sci, Duluth, MN 55812 USA. [Block, Michelle L.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [R00 ES015409, R00 ES015409-02, R00ES015409] NR 46 TC 101 Z9 104 U1 0 U2 11 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2008 VL 22 IS 8 BP 2723 EP 2733 DI 10.1096/fj.08-106997 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 332NI UT WOS:000258089300012 PM 18474546 ER PT J AU Kleinau, G Jaeschke, H Mueller, S Raaka, BM Neumann, S Paschke, R Krause, G AF Kleinau, Gunnar Jaeschke, Holger Mueller, Sandra Raaka, Bruce M. Neumann, Susanne Paschke, Ralf Krause, Gerd TI Evidence for cooperative signal triggering at the extracellular loops of the TSH receptor SO FASEB JOURNAL LA English DT Article DE glycoprotein hormone receptors; activation mechanism; signal transduction; endocrinology ID GLYCOPROTEIN HORMONE-RECEPTORS; THYROID-STIMULATING HORMONE; PROTEIN-COUPLED RECEPTOR; LEUCINE-RICH REPEATS; SITE-DIRECTED MUTAGENESIS; VIRUS TYPE-1 ENTRY; THYROTROPIN RECEPTOR; CONSTITUTIVE ACTIVITY; CRYSTAL-STRUCTURE; GONADOTROPIN RECEPTORS AB The mechanisms governing transition of the thyroid stimulating hormone (TSH) receptor (TSHR) from basal to active conformations are poorly understood. Considering that constitutively activating mutations (CAMs) and inactivating mutations in each of the extracellular loops (ECLs) trigger only partial TSHR activation or inactivation, respectively, we hypothesized that full signaling occurs via multiple extracellular signal propagation events. Therefore, individual CAMs in the extracellular region were combined to create double and triple mutants. In support of our hypothesis, combinations of mutants in the ECLs are in some cases additive, while in others they are even synergistic, with triple mutant I486A/I568V/V656F exhibiting a 70-fold increase in TSH-independent signaling. The proximity but likely different spatial orientation of the residues of activating and inactivating mutations in each ECL supports a dual functionality to facilitate signal induction and conduction, respectively. This is the first report for G-protein coupled receptors, suggesting that multiple and cooperative signal propagating events at all three ECLs are required for full receptor activation. Our findings provide new insights concerning molecular signal transmission from extracellular domains toward the transmembrane helix bundle of the glycoprotein hormone receptors. C1 [Kleinau, Gunnar; Krause, Gerd] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany. [Jaeschke, Holger; Mueller, Sandra; Paschke, Ralf] Univ Klinikum Leipzig, Dept Med, Leipzig, Germany. [Raaka, Bruce M.; Neumann, Susanne] NIDDK, NIH, Clin Endocrinol Branch, Bethesda, MD USA. RP Krause, G (reprint author), Leibniz Inst Mol Pharmacol, Robert Rossle Str 10, D-13125 Berlin, Germany. EM gkrause@fmp-berlin.de RI Horstmann, Britta/C-2154-2008 FU Intramural NIH HHS NR 65 TC 30 Z9 31 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2008 VL 22 IS 8 BP 2798 EP 2808 DI 10.1096/fj.07-104711 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 332NI UT WOS:000258089300020 PM 18381815 ER PT J AU Lee, JY Yang, ST Lee, SK Jung, HH Shin, SY Hahm, KS Kim, JI AF Lee, Ju Y. Yang, Sung-Tae Lee, Seung K. Jung, Hyun H. Shin, Song Y. Hahm, Kyung-Soo Kim, Jae I. TI Salt-resistant homodimeric bactenecin, a cathelicidin-derived antimicrobial peptide SO FEBS JOURNAL LA English DT Article DE antimicrobial peptides; bactenecin; dimerization; peptide-membrane interaction; salt resistance ID ANTIBACTERIAL ACTIVITY; BACTERICIDAL ACTIVITY; CATIONIC PEPTIDE; SELF-ASSOCIATION; INNATE IMMUNITY; MEMBRANE; PURIFICATION; DIMERIZATION; NEUTROPHILS; FAMILY AB The cathelicidin antimicrobial peptide bactenecin is a beta-hairpin molecule with a single disulfide bond and broad antimicrobial activity. The proform of bactenecin exists as a dimer, however, and it has been proposed that bactenecin is released as a dimer in vivo, although there has been little study of the dimeric form of bactenecin. To investigate the effect of bactenecin dimerization on its biological activity, we characterized the dimer's effect on phospholipid membranes, the kinetics of its bactericidal activity, and its salt sensitivity. We initially synthesized two bactenecin dimers (antiparallel and parallel) and two monomers (beta-hairpin and linear). Under oxidative folding conditions, reduced linear bactenecin preferentially folded into a dimer forming a ladder-like structure via intermolecular disulfide bonding. As compared to the monomer, the dimer had a greater ability to induce lysis of lipid bilayers and was more rapidly bactericidal. Interestingly, the dimer retained antimicrobial activity at physiological salt concentrations (150 mM NaCl), although the monomer was inactivated. This salt resistance was also seen with bactenecin dimer containing one intermolecular disulfide bond, and the bactenecin dimer appears to undergo multimeric oligomerization at high salt concentrations. Overall, dimeric bactenecin shows potent and rapid antimicrobial activity, and resists salt-induced inactivation under physiological conditions through condensation and oligomerization. These characteristics shed light on the features that a peptide would need to serve as an effective therapeutic agent. C1 [Lee, Ju Y.; Yang, Sung-Tae; Lee, Seung K.; Jung, Hyun H.; Kim, Jae I.] Gwangju Inst Sci & Technol, Dept Life Sci, Bioimaging Res Ctr, Kwangju 500712, South Korea. [Shin, Song Y.; Hahm, Kyung-Soo] Chosun Univ, Grad Sch & Res Ctr Proteineous Mat, Dept Biomat, Kwangju, South Korea. [Yang, Sung-Tae] NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, Natl Inst Hlth, Bethesda, MD USA. RP Kim, JI (reprint author), Gwangju Inst Sci & Technol, Dept Life Sci, Bioimaging Res Ctr, Kwangju 500712, South Korea. EM jikim@gist.ac.kr NR 30 TC 27 Z9 27 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD AUG PY 2008 VL 275 IS 15 BP 3911 EP 3920 DI 10.1111/j.1742-4658.2008.06536.x PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 324WT UT WOS:000257550800016 PM 18616463 ER PT J AU Moses-Kolko, EL Wisner, KL Price, JC Berga, SL Drevets, WC Meltzer, CC AF Moses-Kolko, Eydie L. Wisner, Katherine L. Price, Julie C. Berga, Sarah L. Drevets, Wayne C. Meltzer, Carolyn C. TI The complexities of receptor binding - Reply SO FERTILITY AND STERILITY LA English DT Letter ID DEPRESSION; WOMEN C1 [Moses-Kolko, Eydie L.; Wisner, Katherine L.; Drevets, Wayne C.; Meltzer, Carolyn C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Wisner, Katherine L.] Univ Pittsburgh, Sch Med, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Price, Julie C.] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA USA. [Meltzer, Carolyn C.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Berga, Sarah L.] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA USA. [Meltzer, Carolyn C.] Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. [Meltzer, Carolyn C.] Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. [Berga, Sarah L.; Meltzer, Carolyn C.] Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. [Berga, Sarah L.; Meltzer, Carolyn C.] Emory Univ, Sch Med, Dept Behav Sci, Atlanta, GA USA. [Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Bethesda, MD 20892 USA. RP Moses-Kolko, EL (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. NR 5 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2008 VL 90 IS 2 BP 465 EP 466 DI 10.1016/j.fertnstert.2008.06.025 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 338CW UT WOS:000258483800050 ER PT J AU Bhagwat, AA Bhagwat, M AF Bhagwat, Arvind A. Bhagwat, Medha TI Methods and tools for comparative genomics of foodborne pathogens SO FOODBORNE PATHOGENS AND DISEASE LA English DT Review ID ENTEROHEMORRHAGIC ESCHERICHIA-COLI; DEPENDENT ACID-RESISTANCE; SHIGELLA-FLEXNERI; STRAINS; SURVIVAL; SALMONELLOSIS; TYPHIMURIUM; VIRULENCE; DISEASE; SYSTEMS AB A comparison of genome sequences and of encoded proteins with the database of existing annotated sequences is a useful approach to understand the information at the genome level. Here we demonstrate the utility of several DNA and protein sequence comparison tools to interpret the information obtained from several genome projects, Comparisons are presented between closely related strains of Esherichia coli commensal isolates, different isolates or O157:H7, and Shigella spp. It is expected that comparative genome analysis will generate a wealth of data to compare pathogenic isolates with varying levels of pathogenicity, which in turn may reveal mechanisms by which the pathogen may adapt to a particular nutrient supply in certain foods. These genome sequence analysis tools will strengthen foodborne pathogen surveillance and subsequent risk assessment to enhance the safety of the food supply. C1 [Bhagwat, Arvind A.] ARS, Produce Qual & Safety Lab, Henry A Wallace Beltsville Agr Res Ctr, USDA, Beltsville, MD 20705 USA. [Bhagwat, Medha] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Bhagwat, AA (reprint author), ARS, Produce Qual & Safety Lab, Henry A Wallace Beltsville Agr Res Ctr, USDA, Bldg 002,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM arvind.bhagwat@ars.usda.gov FU Intramural Research Program of the NIH; National Library of Medicine FX This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. NR 33 TC 11 Z9 12 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD AUG PY 2008 VL 5 IS 4 BP 487 EP 497 DI 10.1089/fpd.08.0117 PG 11 WC Food Science & Technology SC Food Science & Technology GA 340ZT UT WOS:000258684200011 PM 18713064 ER PT J AU Rasooly, A Herold, KE AF Rasooly, Avraham Herold, Keith E. TI Food microbial pathogen detection and analysis using DNA microarray technologies SO FOODBORNE PATHOGENS AND DISEASE LA English DT Review ID WHOLE-GENOME AMPLIFICATION; ANTIMICROBIAL RESISTANCE GENES; HIGH-DENSITY MICROARRAY; OLIGONUCLEOTIDE MICROARRAY; ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; RIBOSOMAL DNA; BACILLUS-ANTHRACIS; POINT MUTATIONS; FLOW-CYTOMETRY AB Culture-based methods used for microbial detection and identification are simple to use, relatively inexpensive, and sensitive. However, culture-based methods are too time-consuming for high-throughput testing and too tedious for analysis of samples with multiple organisms and provide little clinical information methods, such as polymerase chain reaction (PCR), overcome some these limitations since they are generally faster and can provide more information than culture-based methods. One limitation of traditional PCR-based methods is that they are normally limited to the analysis of a single pathogen, a small group of related pathogens, or a small number of relevant genes. Microarray technology enables a significant expansion of the capability of DNA-based methods in terms of the number of DNA sequences that can be analyzed simultaneously, enabling molecular identification and characterization of multiple pathogens and many genes in a single array assay. Microarray analysis of microbial pathogens has potential uses in research, food safety, medical, agricultural, regulatory, public health, and industrial settings. In this article, we describe the main technical elements of microarray technology and the application and potential use of DNA microarrays for food microbial analysis. C1 [Rasooly, Avraham] NCI, NIH, Rockville, MD 20852 USA. [Herold, Keith E.] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Rasooly, A (reprint author), NCI, NIH, 6130 Execut Blvd EPN,Room 6035A, Rockville, MD 20852 USA. EM rasoolya@mail.nih.gov NR 100 TC 41 Z9 46 U1 2 U2 19 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD AUG PY 2008 VL 5 IS 4 BP 531 EP 550 DI 10.1089/fpd.2008.0119 PG 20 WC Food Science & Technology SC Food Science & Technology GA 340ZT UT WOS:000258684200015 PM 18673074 ER PT J AU Fox, MA Stein, AR French, HT Murphy, DL AF Fox, M. A. Stein, A. R. French, H. T. Murphy, D. L. TI Head twitches in serotonin transporter (SERT)-deficient mice: 5-HT(1A) and 5-HT(2A) receptor interactions SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Meeting Abstract C1 [Fox, M. A.; Stein, A. R.; French, H. T.; Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0767-3981 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD AUG PY 2008 VL 22 SU 2 BP 91 EP 91 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 324WW UT WOS:000257551100351 ER PT J AU Murphy, D AF Murphy, D. TI How the serotonin story is being rewritten by new gene-based discoveries SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Meeting Abstract C1 [Murphy, D.] NIMH, Clin Sci Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0767-3981 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD AUG PY 2008 VL 22 SU 2 BP 107 EP 107 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 324WW UT WOS:000257551100400 ER PT J AU Holmes, A AF Holmes, A. TI Corticolimbic abnormalities and executive functions following SERT gene loss in mice SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Meeting Abstract C1 [Holmes, A.] NIAAA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0767-3981 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD AUG PY 2008 VL 22 SU 2 BP 118 EP 118 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 324WW UT WOS:000257551100457 ER PT J AU Fox, MA Jensen, CL Murphy, DL AF Fox, M. A. Jensen, C. L. Murphy, D. L. TI Altered analgesic and serotonin syndrome behavioral effects of traditional and non-traditional opioids in serotonin transporter (SERT)-deficient mice SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Meeting Abstract C1 [Fox, M. A.; Jensen, C. L.; Murphy, D. L.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0767-3981 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD AUG PY 2008 VL 22 SU 2 BP 129 EP 129 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 324WW UT WOS:000257551100515 ER PT J AU Bressler, A Chrzanowski, T Lewis, A Belegundu, S Beikmann, B Tessarrollo, L Luellen, B Blizard, D Andrews, A AF Bressler, A. Chrzanowski, T. Lewis, A. Belegundu, S. Beikmann, B. Tessarrollo, L. Luellen, B. Blizard, D. Andrews, A. TI Improved route learning in aging mice with constitutive reductions in brain-derived neurotrophic factor SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Meeting Abstract C1 [Bressler, A.; Chrzanowski, T.; Lewis, A.; Belegundu, S.; Beikmann, B.; Luellen, B.; Blizard, D.; Andrews, A.] Penn State Univ, University Pk, PA 16802 USA. [Tessarrollo, L.] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0767-3981 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD AUG PY 2008 VL 22 SU 2 BP 130 EP 130 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 324WW UT WOS:000257551100520 ER PT J AU Schotta, G Sengupta, R Kubicek, S Malin, S Kauer, M Callen, E Celeste, A Pagani, M Opravil, S De La Rosa-Velazquez, IA Espejo, A Bedford, MT Nussenzweig, A Busslinger, M Jenuwein, T AF Schotta, Gunnar Sengupta, Roopsha Kubicek, Stefan Malin, Stephen Kauer, Monika Callen, Elsa Celeste, Arkady Pagani, Michaela Opravil, Susanne De La Rosa-Velazquez, Inti A. Espejo, Alexsandra Bedford, Mark T. Nussenzweig, Andre Busslinger, Meinrad Jenuwein, Thomas TI A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse SO GENES & DEVELOPMENT LA English DT Article DE H4K20 methylation; Suv4-20h enzymes; DNA repair; genome integrity; B-cell differentiation; class-switch recombination ID CLASS-SWITCH RECOMBINATION; DOUBLE-STRAND BREAKS; HISTONE LYSINE METHYLATION; S-PHASE; MAMMALIAN CHROMATIN; DAMAGE-RESPONSE; 53BP1; METHYLTRANSFERASE; GENE; H4 AB H4K20 methylation is a broad chromatin modification that has been linked with diverse epigenetic functions. Several enzymes target H4K20 methylation, consistent with distinct mono-, di-, and trimethylation states controlling different biological outputs. To analyze the roles of H4K20 methylation states, we generated conditional null alleles for the two Suv4-20h histone methyltransferase (HMTase) genes in the mouse. Suv4-20h-double-null (dn) mice are perinatally lethal and have lost nearly all H4K20me3 and H4K20me2 states. The genome-wide transition to an H4K20me1 state results in increased sensitivity to damaging stress, since Suv4-20h-dn chromatin is less efficient for DNA double-strand break (DSB) repair and prone to chromosomal aberrations. Notably, Suv4-20h-dn B cells are defective in immunoglobulin class-switch recombination, and Suv4-20h-dn deficiency impairs the stem cell pool of lymphoid progenitors. Thus, conversion to an H4K20me1 state results in compromised chromatin that is insufficient to protect genome integrity and to process a DNA-rearranging differentiation program in the mouse. C1 [Schotta, Gunnar; Sengupta, Roopsha; Kubicek, Stefan; Malin, Stephen; Kauer, Monika; Pagani, Michaela; Opravil, Susanne; De La Rosa-Velazquez, Inti A.; Busslinger, Meinrad; Jenuwein, Thomas] Vienna Bioctr, Res Inst Mol Pathol, A-1030 Vienna, Austria. [Callen, Elsa; Celeste, Arkady; Nussenzweig, Andre] NCI, Expt Immunol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Espejo, Alexsandra; Bedford, Mark T.] Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 79857 USA. RP Schotta, G (reprint author), Univ Munich, Munich Ctr Integrated Prot Sci CiPSM, Adolf Butenandt Inst, Schillerstr 44, D-80336 Munich, Germany. EM Gunnar.Schotta@med.uni-muenchen.de; jenuwein@imp.univie.ac.at RI Busslinger, Meinrad/J-1249-2016; Kubicek, Stefan/C-2089-2017; OI Busslinger, Meinrad/0000-0002-9111-9351; Kubicek, Stefan/0000-0003-0855-8343; Schotta, Gunnar/0000-0003-4940-6135; Espejo, Alexsandra/0000-0002-8841-7219 FU NIDDK NIH HHS [DK62248, R01 DK062248, R56 DK062248] NR 56 TC 177 Z9 181 U1 7 U2 17 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 AUG 1 PY 2008 VL 22 IS 15 BP 2048 EP 2061 DI 10.1101/gad.476008 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 332XX UT WOS:000258117500006 PM 18676810 ER PT J AU Gowher, H Stuhlmann, H Felsenfeld, G AF Gowher, Humaira Stuhlmann, Heidi Felsenfeld, Gary TI Vezf1 regulates genomic DNA methylation through its effects on expression of DNA methyltransferase Dnmt3b SO GENES & DEVELOPMENT LA English DT Article DE DNA methylation; BGP1; Vezf1; Dnmt3b ID DE-NOVO METHYLATION; CPG-BINDING-PROTEIN; ICF SYNDROME; TRANSCRIPTION FACTOR; IMMUNODEFICIENCY SYNDROME; MAMMALIAN DEVELOPMENT; HYPOMETHYLATION; GENE; PROMOTER; CELLS AB The zinc finger protein vascular endothelial zinc finger 1 (Vezf1) has been implicated in the development of the blood vascular and lymphatic system in mice, and has been characterized as a transcriptional activator in some systems. The chicken homolog, BGP1, has binding sites in the beta- globin locus, including the upstream insulator element. We report that in a mouse embryonic stem cell line deletion of both copies of Vezf1 results in loss of DNA methylation at widespread sites in the genome, including Line1 elements and minor satellite repeats, some imprinted genes, and several CpG islands. Loss of methylation appears to arise from a substantial decrease in the abundance of the de novo DNA methyltransferase, Dnmt3b. These results suggest that naturally occurring mutations in Vezf1/BGP1 might have widespread effects on DNA methylation patterns and therefore on epigenetic regulation of gene expression. C1 [Gowher, Humaira; Felsenfeld, Gary] NIDDKD, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Stuhlmann, Heidi] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10021 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL 068648, R01 HL068648] NR 55 TC 26 Z9 26 U1 1 U2 1 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 AUG 1 PY 2008 VL 22 IS 15 BP 2075 EP 2084 DI 10.1101/gad.1658408 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 332XX UT WOS:000258117500008 PM 18676812 ER PT J AU Inagaki, M Komatsu, Y Scott, G Yamada, G Ray, M Ninomiya-Tsuji, J Mishina, Y AF Inagaki, Maiko Komatsu, Yoshihiro Scott, Greg Yamada, Gen Ray, Manas Ninomiya-Tsuji, Jun Mishina, Yuji TI Generation of a conditional mutant allele for Tab1 in mouse SO GENESIS LA English DT Article DE conditional gene knockout; MAP kinase; BMP; Tab1; TGF-beta ID BETA SIGNAL-TRANSDUCTION; KAPPA-B ACTIVATION; TAK1 MAPKKK; KINASE TAK1; IN-VIVO; PATHWAY; PROTEIN; BMP; IL-1; MEDIATOR AB TAK1 binding protein 1 (TAB1) binds and induces autophosphorylation of TGF-beta activating kinase (TAK1). TAK1, a mitogen-activated kinase kinase kinase, is involved in several distinct signaling pathways including non-Smad pathways for TGF-beta superfamily members and inflammatory responses caused by cytokines. Conventional disruption of the murine Tab1 gene results in late gestational lethality showing intraventricular septum defects and underdeveloped lung alveoli. To gain a better understanding of the roles of TAB1 in different tissues, at different stages of development, and in pathological conditions, we generated Tab1 floxed mice in which the loxP sites flank Exons 9 and 10 to remove the C-terminal region of TAB1 protein necessary for activation of TAK1. We demonstrate that Cre-mediated recombination using Sox2-Cre, a Cre line expressed in the epiblast during early embryogenesis, results in deletion of the gene and protein. These homozygous Cre-recombined null embryos display an identical phenotype to conventional null embryos. This animal model will be useful in revealing distinct roles of TAB1 in different tissues at different stages. C1 [Komatsu, Yoshihiro; Mishina, Yuji] NIEHS, NIH, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Inagaki, Maiko; Ninomiya-Tsuji, Jun] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. [Yamada, Gen] Kumamoto Univ, Ctr Anim Resources & Dev, Grad Sch Mol & Genom Pharm, Kumamoto, Japan. RP Mishina, Y (reprint author), NIEHS, NIH, Reprod & Dev Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM mishina@niehs.nih.gov FU NIEHS, NIH (Intramural Research Progam); NIH; Japan Society for the Promotion of Science FX Contract grant sponsor: NIEHS, NIH (Intramural Research Progam); Contract grant sponsor: NIH; Contract grant sponsor: Japan Society for the Promotion of Science NR 40 TC 13 Z9 14 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1526-954X J9 GENESIS JI Genesis PD AUG PY 2008 VL 46 IS 8 BP 431 EP 439 DI 10.1002/dvg.20418 PG 9 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 343XP UT WOS:000258889900007 PM 18693278 ER PT J AU Lebet, T Chiles, R Hsu, AP Mansfield, ES Warrington, JA Puck, JM AF Lebet, Tonya Chiles, Richard Hsu, Amy P. Mansfield, Elaine S. Warrington, Janet A. Puck, Jennifer M. TI Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray SO GENETICS IN MEDICINE LA English DT Article DE severe combined immunodeficiency; mutation detection; microarray; resequencing; sequencing; hot-spot; point mutation; indel; IL2RG; IL7R; JAK3; DCLR1C ID IL2RG; DATABASE; DEFECTS; UPDATE AB Purpose: Mutation diagnosis of severe combined immunodeficiency is challenging because of the multiplicity of disease genes and large number of disease-causing mutations, including unique ones that continue to be found. A resequencing microarray could facilitate mutation detection, increasing the chance of diagnosing infants early for optimal rescue by hematopoietic stem cell transplantation. Methods: After analyzing cumulative mutations, We developed a custom Affymetrix GeneChip (R) microarray including probes representing exons and flanking regions of severe combined immunodeficiency disease genes. DNA samples were analyzed by array versus standard dideoxy genomic sequencing. We tested males and their mothers with X-linked IL2RG variants and patients and carriers with autosomal variants in IL7R, JAK3, and DCLRE1C. Results: New, unique severe combined immunodeficiency mutations are frequent. Resequencing array call rates of 95-98% exceeded GeneChip product specifications, and all of 47 point mutations in known samples were detected, as were the sites of 12 of 22 disease-causing insertions and deletions. Each gene had particular nucleotides that were often not called correctly and had to be excluded from analysis; exclusion rates ranged from 0.4% (hemizygous IL2RG) to 9.2% (heterozygous JAK3). Conclusion: Microarray resequencing is a promising technology for severe combined immunodeficiency mutation diagnosis that can detect both known and new mutations. Future customization of probe sequences and analysis algorithms Could increase the number of accurately called nucleotides. C1 [Lebet, Tonya; Puck, Jennifer M.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Chiles, Richard] Signal Demand, San Francisco, CA USA. [Hsu, Amy P.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Mansfield, Elaine S.; Warrington, Janet A.] Affymetrix Inc, Santa Clara, CA USA. RP Puck, JM (reprint author), Univ Calif San Francisco, Sch Med, Dept Pediat, Box 0519,513 Parnassus Ave,HSE 301A, San Francisco, CA 94143 USA. EM puckj@peds.ucsf.edu FU Jeffrey Model Foundation; Affymetrix, Inc; NIAID; NIH [USIDNIFT, AI-30070] FX A portion of the research referred to in this publication was carried out under a research program initiated, developed, and funded in part by the Jeffrey Model Foundation (www.info4PI. org). Additional funding provided by Affymetrix, Inc. is gratefully acknowledged. JMP is supported in part by an NIAID, NIH, award to USIDNIFT, AI-30070. The authors thank Charles Haines for IL7R analysis, the immunologists (especially Mort Cowan and Zheng Xiao) and geneticists who referred cases, and the families with SCID who participated in our research. NR 31 TC 22 Z9 22 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD AUG PY 2008 VL 10 IS 8 BP 575 EP 585 DI 10.1097/GIM.0b013e31818063bc PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 341SW UT WOS:000258736200003 PM 18641513 ER PT J AU Petrykowska, HM Vockley, CM Elnitski, L AF Petrykowska, Hanna M. Vockley, Christopher M. Elnitski, Laura TI Detection and characterization of silencers and enhancer-blockers in the greater CFTR locus SO GENOME RESEARCH LA English DT Article ID BETA-GLOBIN INSULATOR; HUMAN GENOME; BLOCKING ACTIVITY; CONTROL REGION; BINDING-SITES; FUNCTIONAL ELEMENTS; PROTEIN CTCF; CHROMATIN; SEQUENCES; 1-PERCENT AB Silencers and enhancer-blockers (EBs) are cis-acting, negative regulatory elements (NREs) that control interactions between promoters and enhancers. Although relatively uncharacterized in terms of biological mechanisms, these elements are likely to be abundant in the genome. We developed an experimental strategy to identify silencers and EBs using transient transfection assays. A known insulator and EB from the chicken beta-globin locus, cHS4, served as a control element for these assays. We examined 47 sequences from a 1.8-Mb region of human chromosome 7 for silencer and EB activities. The majority of functional elements displayed directional and promoter-specific activities. A limited number of sequences acted in a dual manner, as both silencers and EBs. We examined genomic data, epigenetic modifications, and sequence motifs within these regions. Strong silencer elements contained a novel CT-rich motif, often in multiple copies. Deletion of the motif from three regions caused a measurable loss of silencing ability in these sequences. Moreover, five duplicate occurrences of this motif were identified in the cHS4 insulator. These motifs provided an explanation for an uncharacterized silencing activity we measured in the insulator element. Overall, we identified 15 novel NREs, which contribute new insights into the prevalence and composition of sequences that negatively regulate gene expression. C1 [Petrykowska, Hanna M.; Vockley, Christopher M.; Elnitski, Laura] NHGRI, Genome Technol Branch, NIH, Rockville, MD 20852 USA. RP Elnitski, L (reprint author), NHGRI, Genome Technol Branch, NIH, Rockville, MD 20852 USA. EM elnitski@mail.nih.gov FU Intramural NIH HHS NR 27 TC 22 Z9 24 U1 0 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 2008 VL 18 IS 8 BP 1238 EP 1246 DI 10.1101/gr.073817.107 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 332XJ UT WOS:000258116100005 PM 18436892 ER PT J AU Wong, HL Koh, WP Probst-Hensch, NM Van den Berg, D Yu, MC Ingles, SA AF Wong, H-L Koh, W-P Probst-Hensch, N. M. Van den Berg, D. Yu, M. C. Ingles, S. A. TI Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach SO GUT LA English DT Article ID GROWTH-FACTOR-I; SINGAPORE CHINESE HEALTH; IGF-BINDING PROTEIN-3; COLON-CANCER; FACTOR (IGF)-I; FACTOR BINDING-PROTEIN-3; CIRCULATING LEVELS; BREAST-CANCER; FACTOR SYSTEM; FACTOR-ALPHA AB Rationale: Insulin-like growth factor-1 (IGF1) has been proposed to mediate the obesity-related carcinogenic effects of "Western lifestyle''. While genetic factors explain at least half of inter-individual IGF1 variation, the IGF1 polymorphisms hypothesised to underlie the variation in cancer incidence rates remain ill-defined. Methods: We used a comparative genomics approach to identify putative regulatory polymorphisms in the IGF1 promoter region within a rapidly westernising population, the Singapore Chinese. Association of IGF1 genotype with colorectal cancer risk was assessed among 298 colorectal cancer cases and 1142 controls nested within the Singapore Chinese Health Study. Results: We identified a common (minor allele frequency = 0.36) single-nucleotide polymorphism (SNP), IGF1-2995 C/A, within a consensus domain for an octamer binding factor (Oct1/Oct2) transcription factor binding site. Possession of one or two copies of the minor allele (genotypes AA and CA) conferred an approximate 40% decrease in risk in comparison to genotype CC (odds ratio, 0.59; 95% confidence interval, 0.45 to 0.77). This association was stronger for colon cancer than for rectal cancer (p(heterogeneity) < 0.001) and for those who were physically active versus inactive (p(interaction) = 0.05). Models including other previously identified promoter polymorphisms did not provide a better prediction of colorectal cancer risk. Conclusions: Our results support the hypotheses that IGF1 plays a role in colonic carcinogenesis and that genetically inherited variation in IGF1 expression influences risk of colorectal cancer. C1 [Van den Berg, D.; Ingles, S. A.] Univ So Calif, Keck Sch Med, USC Norris Canc Ctr, Los Angeles, CA 90033 USA. [Wong, H-L] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DDHS, Rockville, MD USA. [Koh, W-P] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Community Occupat & Family Med, Singapore 117595, Singapore. [Probst-Hensch, N. M.] Univ Zurich, Dept Pathol, Inst Social & Prevent Med, Mol Epidemiol Canc Registry, CH-8006 Zurich, Switzerland. [Yu, M. C.] Univ Minnesota, Ctr Canc, Minneapolis, MN USA. RP Ingles, SA (reprint author), Univ So Calif, Keck Sch Med, USC Norris Canc Ctr, 1441 Eastlake Ave,Room 6419, Los Angeles, CA 90033 USA. EM ingles@usc.edu FU NCI NIH HHS [R01 CA080205, R01 CA055069, R01 CA080205-09, R01 CA098497, R01 CA098497-01A2, R01 CA098497-02, R01 CA098497-03, R01 CA098497-04, R01 CA098497-05, R01 CA80205, R01 CA98497, R35 CA053890] NR 59 TC 25 Z9 25 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD AUG PY 2008 VL 57 IS 8 BP 1090 EP 1096 DI 10.1136/gut.2007.140855 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 326GI UT WOS:000257646200017 PM 18308828 ER PT J AU Di Rocco, M Giona, F Carubbi, F Linari, S Minichilli, F Brady, RO Marian, G Cappellini, MD AF Di Rocco, Maja Giona, Fiorina Carubbi, Francesca Linari, Silvia Minichilli, Fabrizio Brady, Roscoe O. Marian, Giuliano Cappellini, Maria Domenica TI A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE Gaucher disease; severity score index ID ENZYME REPLACEMENT THERAPY; BONE-MARROW INVOLVEMENT; GLUCOCEREBROSIDASE GENE; FUNCTION ABNORMALITIES; PARKINSON-DISEASE; TREATED PATIENTS; MIGLUSTAT; LIVER; DEFICIENCY; BIOMARKERS AB Background Gaucher disease is the first lysosomal storage disease for which specific therapy became available. Over 4800 patients have been treated with enzyme replacement therapy. Analysis of Gaucher disease registry data has outlined the clinical heterogeneity of the disease and the different responses to treatment from patient to patient, and for different organs. This variability in clinical response justifies the development of a severity score index to assess disease activity, stage and prognosis, and to quantify the effects of treatment. Design and Methods The new scoring system proposed here, the "Gaucher Disease Severity Score Index - Type I" (GauSSI-1), is based on the clinical experience of the authors and an extensive literature review, including data from the International Gaucher Registry. In particular for skeletal disease, all the available scoring systems have been reviewed and compared in order to provide a skeletal scoring system that allows use of any of the different methods on an equivalent basis. Results The new scoring system, GauSSI-I, was developed. Six specific domains, in which different items were scored according to their impact on morbidity, were characterized. GauSSI-I was evaluated in 53 type I Gaucher patients treated with imiglucerase, and it was compared to the Zimran score, the only severity index score so far available. Conclusions The GauSSI-I is a reliable method for staging the severity of adult type I Gaucher disease, and it is more sensitive than the Zimran score for monitoring the response to treatment. C1 [Di Rocco, Maja] Gaslini Inst, Div Pediat 2, Rare Dis Unit, Genoa, Italy. [Giona, Fiorina] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, Rome, Italy. [Carubbi, Francesca] Univ Modena & Reggio Emilia, Dept Med Endocrinol Metab & Geriatr, Modena, Italy. [Linari, Silvia] Careggi Univ Hosp, Ctr Inherited Bleeding Disorders, Agcy Hemophilia & Reg Reference, Florence, Italy. [Minichilli, Fabrizio] CNR, Inst Clin Physiol, Sect Epidemiol & Stat, I-56100 Pisa, Italy. [Brady, Roscoe O.] NINDS, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. [Marian, Giuliano] Univ Pisa, Reg Ctr Nucl Med, Pisa, Italy. [Cappellini, Maria Domenica] Univ Milan, Fdn IRCCS, Policlin Mangiagalli Regina Elena, Dept Internal Med, Milan, Italy. RP Di Rocco, M (reprint author), Gaslini Inst Largo, Div Pediat 2, Rare Dis Unit, Gerolamo Gaslini 5, I-16147 Genoa, Italy. EM majadirocco@ospedale-gaslini.ge.it RI Carubbi, Francesca/P-3973-2015; OI Carubbi, Francesca/0000-0001-7504-6407; CAPPELLINI, MARIA DOMENICA/0000-0001-8676-6864 NR 38 TC 31 Z9 31 U1 0 U2 4 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD AUG PY 2008 VL 93 IS 8 BP 1211 EP 1218 DI 10.3324/haematol.12379 PG 8 WC Hematology SC Hematology GA 330PC UT WOS:000257954300014 PM 18603565 ER PT J AU Yabroff, KR Mariotto, AB Feuer, E Brown, ML AF Yabroff, K. Robin Mariotto, Angela B. Feuer, Eric Brown, Martin L. TI Projections of the costs associated with colorectal cancer care in the United States, 2000-2020 SO HEALTH ECONOMICS LA English DT Article DE colorectal neoplasms; cost of illness; costs and cost analysis; SEER Program; Medicare; prevalence ID SEER-MEDICARE DATA; US; INTERVENTIONS; POPULATION; PATTERNS; SERVICES; RISK AB Because of aging trends in the US, the number of prevalent colorectal cancer patients is expected to increase. We projected economic burden to the Medicare program and its beneficiaries through the year 2020. Burden was estimated for the initial phase of care, the period following diagnosis, the last year of life, and the continuing phase. Projected burden was evaluated with varying assumptions about incidence, survival, and costs of care. Estimated costs of care in 2000 in the initial, continuing, and last year of life phases of care were approximately $3.18 billion, $1.68 billion, and $2.63 billion, respectively. By the year 2020 under the 'fixed' current incidence, survival, and cost scenario, projected costs for the initial, continuing, and last year of life phases were $4.75 billion, $2.63 billion, and $4.05 billion. Under the current trends scenario (decreasing incidence, improving survival, and increasing costs), costs were $5.19 billion, $3.57 billion, and $5.27 billion. By the year 2020, estimated costs of colorectal cancer care among individuals aged 65 and older increased by 53% in the fixed scenario and by 89% in the current trends scenario. The future economic burden of colorectal cancer to the Medicare program and its beneficiaries in the US will be substantial. Published in 2007 by John Wiley & Sons, Ltd. C1 [Yabroff, K. Robin; Mariotto, Angela B.; Feuer, Eric; Brown, Martin L.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Pl N,Room 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 21 TC 38 Z9 38 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9230 J9 HEALTH ECON JI Health Econ. PD AUG PY 2008 VL 17 IS 8 BP 947 EP 959 DI 10.1002/hec.1307 PG 13 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 344QK UT WOS:000258942200004 PM 17910108 ER PT J AU Nansel, TR Weaver, NL Jacobsen, HA Glasheen, C Kreuter, MW AF Nansel, Tonja R. Weaver, Nancy L. Jacobsen, Heather A. Glasheen, Cristie Kreuter, Matthew W. TI Preventing unintentional pediatric injuries: a tailored intervention for parents and providers SO HEALTH EDUCATION RESEARCH LA English DT Article ID PRIMARY-CARE; ANTICIPATORY GUIDANCE; NUTRITION EDUCATION; SMOKING-CESSATION; SAFETY; CHILDHOOD; INFORMATION; TRIAL; COMMUNICATION; EPIDEMIOLOGY AB The purpose of this study was to determine the efficacy of providing (i) tailored injury prevention information (T-IPI) to parents and (ii) concurrent T-IPI to parents and providers to promote parent adoption of safety practices. During well-child visits, parents of children ages 4 and younger completed a computer assessment and were randomized to receive generic injury prevention information, T-IPI or T-IPI supplemented with a tailored summary for providers. Follow-up assessments were completed by telephone 1 month later. Parents receiving T-IPI alone or with supplementary provider information were more likely to report adopting a new injury prevention behavior than those receiving generic information (49 and 45%, respectively, compared with 32%; odds ratio = 2.0 and 1.9, respectively), and these effects were greatest among the least educated parents. In addition, more complicated behavior changes were reported by those receiving tailored information. Provider receipt of feedback did not result in significantly different provider-parent communication or change in parents' safety practices. Providing parents with individually tailored pediatric injury prevention information may be an effective method for delivering injury prevention anticipatory guidance. Tailoring may have particular utility for more complicated behaviors and for communication with less educated parents. C1 [Nansel, Tonja R.] NICHHD, NIH, Dept Hlth & Human Serv, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Weaver, Nancy L.; Jacobsen, Heather A.; Glasheen, Cristie; Kreuter, Matthew W.] St Louis Univ, Sch Publ Hlth, Hlth Commun Res Lab, St Louis, MO 63140 USA. RP Nansel, TR (reprint author), NICHHD, NIH, Dept Hlth & Human Serv, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595 FU Intramural NIH HHS [Z01 HD002402-09] NR 47 TC 27 Z9 27 U1 4 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 EI 1465-3648 J9 HEALTH EDUC RES JI Health Educ. Res. PD AUG PY 2008 VL 23 IS 4 BP 656 EP 669 DI 10.1093/her/cym041 PG 14 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 325GJ UT WOS:000257576700008 PM 17906313 ER PT J AU O'Brien, C Joshi, S Feld, JJ Guindi, M Dienes, HP Heathcote, EJ AF O'Brien, Conor Joshi, Supriya Feld, Jordan J. Guindi, Maha Dienes, Hans P. Heathcote, E. Jenny TI Long-term follow-up of antimitochondrial antibody - Positive autoimmune hepatitis SO HEPATOLOGY LA English DT Article ID PRIMARY BILIARY-CIRRHOSIS; OVERLAP SYNDROME; URSODEOXYCHOLIC ACID; FREQUENCY; TRIAL; BUDESONIDE; DIAGNOSIS; FEATURES; THERAPY; FORM AB Antimitochondrial antibodies (AMAs) are the serological hallmark for primary biliary cirrhosis (PBC). When AMAs are detected in patients with chronic hepatitis, they negatively impact on the autoimmune hepatitis (AIH) scoring system. The purpose of this study was to determine if AMAs detected in the sera of patients with overt AIH have clinical or pathological significance. All patients with a clinicopathologic diagnosis of AIH from one center were reviewed. Only those meeting the criteria for probable or definite AIH according to the International Autoimmune Hepatitis Group were included. Patients found to be consistently AMA-positive via enzyme-linked immunosorbent assay (ELISA) for pyruvate dehydrogenase complex E2 subunit were reviewed in detail. Fifteen of 126 patients with typical features of AIH (pretreatment AIH score > 10) had detectable AMAs in serum. None had any histologic features suggestive of PBC. None had detectable anti-liver-kidney microsomal antibodies. Of these 15 patients, all have remained persistently AMA-positive via ELISA. All 15 patients have been followed long-term, and their clinical course remained typical for AIH. No bile duct damage typical of PBC was seen on initial or follow-up liver biopsies. Conclusion: Patients with overt AIH who test positive for AMAs at initial presentation and are treated with corticosteroid therapy have shown no clinical or histologic evidence of PBC despite the continued detection of AMAs over a follow-up of up to 27 years. C1 [O'Brien, Conor; Joshi, Supriya; Heathcote, E. Jenny] Univ Toronto, Toronto Western Hosp, Univ Hlth Network, Dept Med, Toronto, ON M5T 2S8, Canada. [Feld, Jordan J.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Guindi, Maha] Univ Toronto, Toronto Western Hosp, Univ Hlth Network, Dept Pathol, Toronto, ON M5T 2S8, Canada. [Dienes, Hans P.] Univ Cologne, Inst Pathol, Cologne, Germany. RP Heathcote, EJ (reprint author), Univ Toronto, Toronto Western Hosp, Univ Hlth Network, Dept Med, 399 Bathurst St,6B Fell Pavil 154, Toronto, ON M5T 2S8, Canada. EM jenny.heathcote@utoronto.ca NR 30 TC 59 Z9 59 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2008 VL 48 IS 2 BP 550 EP 556 DI 10.1002/hep.22380 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 334UT UT WOS:000258247400021 PM 18666262 ER PT J AU Wu, YP Mizugishi, K Bektas, M Sandhoff, R Proia, RL AF Wu, Yun-Ping Mizugishi, Kiyomi Bektas, Meryem Sandhoff, Roger Proia, Richard L. TI Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROTEIN-COUPLED-RECEPTOR; SPHINGOSINE-1-PHOSPHATE RECEPTORS; ASTROCYTE PROLIFERATION; VASCULAR MATURATION; MULTIPLE-SCLEROSIS; CELL-PROLIFERATION; NERVOUS-SYSTEM; FTY720; ACTIVATION; PHOSPHORYLATION AB Sphingosine-1-phosphate (S1P) is a lipid-signaling molecule produced by sphingosine kinase in response to a wide number of stimuli. By acting through a family of widely expressed G protein-coupled receptors, S1P regulates diverse physiological processes. Here we examined the role of S1P signaling in neurodegeneration using a mouse model of Sandhoff disease, a prototypical neuronopathic lysosomal storage disorder. When sphingosine kinase 1 (Sphk1) was deleted in Sandhoff disease mice, a milder disease course occurred, with decreased proliferation of glial cells and less-pronounced astrogliosis. A similar result of milder disease course and reduced astroglial proliferation was obtained by deletion of the gene for the S1P(3) receptor, a G protein-coupled receptor enriched in astrocytes. Our studies demonstrate a functional role of S1P synthesis and receptor expression in astrocyte proliferation leading to astrogliosis during the terminal stages of neurodegeneration in Sandhoff disease mice. Because astrocyte responses are involved in many types of neurodegeneration, the Sphk1/S1P receptor signaling axis may be generally important during the pathogenesis of neurodegenerative diseases. C1 [Wu, Yun-Ping; Mizugishi, Kiyomi; Bektas, Meryem; Proia, Richard L.] NIDDKD, Genet Dev & Dis Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sandhoff, Roger] German Canc Res Ctr, INF 280, D-69120 Heidelberg, Germany. RP Proia, RL (reprint author), NIDDKD, Genet Dev & Dis Branch, Natl Inst Hlth, Bldg 10,Room 9D-06,10 Ctr DR MSC 1821, Bethesda, MD 20892 USA. EM proia@nih.gov RI Proia, Richard/A-7908-2012 FU Intramural NIH HHS NR 45 TC 55 Z9 56 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2008 VL 17 IS 15 BP 2257 EP 2264 DI 10.1093/hmg/ddn126 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 328HF UT WOS:000257788300001 PM 18424450 ER PT J AU Li, KY Besse, EK Ha, D Kovtunovych, G Rouault, TA AF Li, Kuanyu Besse, Edward K. Ha, Dung Kovtunovych, Gennadiy Rouault, Tracey A. TI Iron-dependent regulation of frataxin expression: implications for treatment of Friedreich ataxia SO HUMAN MOLECULAR GENETICS LA English DT Article ID MITOCHONDRIAL PROCESSING PEPTIDASE; SULFUR CLUSTER BIOGENESIS; RESPONSIVE PROTEINS; MOLECULAR CONTROL; HUMAN-CELLS; HOMEOSTASIS; DEFICIENCY; CHELATORS; CARDIOMYOPATHY; TRANSCRIPTION AB Friedreich ataxia (FA) is a progressive neurodegenerative disease caused by expansion of a trinucleotide repeat within the first intron of the gene that encodes frataxin. In our study, we investigated the regulation of frataxin expression by iron and demonstrated that frataxin mRNA levels decrease significantly in multiple human cell lines treated with the iron chelator, desferal (DFO). In addition, frataxin mRNA and protein levels decrease in fibroblast and lymphoblast cells derived from both normal controls and from patients with FA when treated with DFO. Lymphoblasts and fibroblasts of FA patients have evidence of cytosolic iron depletion, as indicated by increased levels of iron regulatory protein 2 (IRP2) and/or increased IRE-binding activity of IRP1. We postulate that this inferred cytosolic iron depletion occurs as frataxin-deficient cells overload their mitochondria with iron, a downstream regulatory effect that has been observed previously when mitochondrial iron-sulfur cluster assembly is disrupted. The mitochondrial iron overload and presumed cytosolic iron depletion potentially further compromise function in frataxin-deficient cells by decreasing frataxin expression. Thus, our results imply that therapeutic efforts should focus on an approach that combines iron removal from mitochondria with a treatment that increases cytosolic iron levels to maximize residual frataxin expression in FA patients. C1 [Li, Kuanyu; Besse, Edward K.; Ha, Dung; Kovtunovych, Gennadiy; Rouault, Tracey A.] NICHHD, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Program Mol Med, Bethesda, MD 20892 USA. EM trou@helix.nih.gov FU Intramural NIH HHS NR 43 TC 74 Z9 77 U1 0 U2 5 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 AUG 1 PY 2008 VL 17 IS 15 BP 2265 EP 2273 DI 10.1093/hmg/ddn127 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 328HF UT WOS:000257788300002 PM 18424449 ER PT J AU Weickert, CS Miranda-Angulo, AL Wong, J Perlman, WR Ward, SE Radhakrishna, V Straub, RE Weinberger, DR Kleinman, JE AF Weickert, Cynthia Shannon Miranda-Angulo, Ana L. Wong, Jenny Perlman, William R. Ward, Sarah E. Radhakrishna, Vakkalanka Straub, Richard E. Weinberger, Daniel R. Kleinman, Joel E. TI Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSCRIPTION FACTOR-1 MYT1; FEMALE RHESUS-MONKEYS; MAJOR MENTAL-ILLNESS; PREFRONTAL CORTEX; GENDER-DIFFERENCES; MENSTRUAL-CYCLE; HUMAN BRAIN; ER-ALPHA; SUSCEPTIBILITY LOCUS; BIPOLAR DISORDER AB Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small case-control genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P = 0.01-0.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P = 0.01-0.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the 'at risk' PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3' haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing. C1 [Weickert, Cynthia Shannon; Wong, Jenny] UNSW, Prince Wales Med Res Inst, Maquarie Grp Fdn Chair,Schizophrenia Res Lab, Dept Psychiat,Schizophrenia Res Inst, Randwick, NSW 2031, Australia. [Weickert, Cynthia Shannon; Miranda-Angulo, Ana L.; Perlman, William R.; Ward, Sarah E.] NIMH, MiNDS Unit, Sect Neuropathol, NIH, Bethesda, MD 20892 USA. [Kleinman, Joel E.] NIMH, Sect Neuropathol, CBDB, NIH, Bethesda, MD 20892 USA. [Radhakrishna, Vakkalanka; Straub, Richard E.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, GCAP, NIH, Bethesda, MD 20892 USA. RP Weickert, CS (reprint author), UNSW, Prince Wales Med Res Inst, Maquarie Grp Fdn Chair,Schizophrenia Res Lab, Dept Psychiat,Schizophrenia Res Inst, Corner Barker & Easy St, Randwick, NSW 2031, Australia. EM cyndi@powmri.edu.au RI Shannon Weickert, Cynthia/G-3171-2011 FU Intramural NIH HHS NR 75 TC 92 Z9 95 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2008 VL 17 IS 15 BP 2293 EP 2309 DI 10.1093/hmg/ddn130 PG 17 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 328HF UT WOS:000257788300005 PM 18424448 ER PT J AU Di, X Yu, L Moore, AB Castro, L Zheng, X Hermon, T Dixon, D AF Di, X. Yu, L. Moore, A. B. Castro, L. Zheng, X. Hermon, T. Dixon, D. TI A low concentration of genistein induces estrogen receptor-alpha and insulin-like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells SO HUMAN REPRODUCTION LA English DT Article DE genistein; LM cells; SMC; ER alpha; IGF-IR ID SMOOTH-MUSCLE CELLS; CANCER MCF-7 CELLS; ER-ALPHA; SIGNALING PATHWAYS; IGF-I; ENVIRONMENTAL ESTROGENS; DEVELOPMENTAL EXPOSURE; BETA EXPRESSION; BINDING-PROTEIN; GENE-EXPRESSION AB BACKGROUND: Previously, we found that genistein at low concentrations stimulates the growth of human uterine leiomyoma (LM) cells, but not uterine smooth muscle (myometrial) cells (SMC). The aim of this study was to understand the molecular mechanism whereby genistein causes hyperproliferation of LM cells. METHODS: The effects of genistein at 1 mu g/ml on LM cells and SMC were evaluated using estrogen response element gene reporter, real-time RT-PCR, western blot, immunoprecipitation and cell proliferation assays. RESULTS: Elevated estrogen receptor (ER) transactivation, increased mRNA expression of early estrogen-responsive genes, progesterone receptor and insulin-like growth factor-I (IGF-I), and decreased protein levels of ER-alpha (ER alpha) were found in genistein-treated LM cells, but not SMC. Additionally, extracellular regulated kinase (ERK), Src homology/collagen (Shc) and ER alpha were transiently activated, and interactions between ER alpha and IGF-I receptor (IGF-IR) were rapidly induced by genistein in LM cells. Using ER antagonist ICI 182,780 and MAPK/ERK kinase (MEK) inhibitor PD98059, we found that these early events were inhibited and the proliferative effect of genistein on LM cells was abrogated. CONCLUSIONS: ER alpha is involved in the transient activation of ERK/mitogen activated protein kinase (MAPK) by genistein via its early association with IGF-IR, leading to hyper-responsiveness of LM cells and confirming that ER signaling is enhanced by activation of ERK/MAPK in LM cells. C1 [Di, X.; Yu, L.; Moore, A. B.; Castro, L.; Zheng, X.; Hermon, T.; Dixon, D.] NIEHS, Comparat Pathobiol Grp, Cellular & Mol Pathol Branch, DHHS,NIH, Res Triangle Pk, NC 27709 USA. RP Dixon, D (reprint author), NIEHS, Comparat Pathobiol Grp, Cellular & Mol Pathol Branch, DHHS,NIH, POB 12233,MDC2-09, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU Intramural NIH HHS NR 63 TC 39 Z9 43 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD AUG PY 2008 VL 23 IS 8 BP 1873 EP 1883 DI 10.1093/humrep/den087 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 328HH UT WOS:000257788500026 PM 18492705 ER PT J AU Lieb, W Pencina, MJ Wang, TJ Larson, MG Lanier, KJ Benjamin, EJ Levy, D Tofler, GH Meigs, JB Newton-Cheh, C Vasan, RS AF Lieb, Wolfgang Pencina, Michael J. Wang, Thomas J. Larson, Martin G. Lanier, Katherine J. Benjamin, Emelia J. Levy, Daniel Tofler, Geoffrey H. Meigs, James B. Newton-Cheh, Christopher Vasan, Ramachandran S. TI Association of parental hypertension with concentrations of select biomarkers in nonhypertensive offspring SO HYPERTENSION LA English DT Article DE hypertension; offspring; biomarkers; C-reactive protein ID C-REACTIVE PROTEIN; AORTIC ENDOTHELIAL-CELLS; PLASMINOGEN-ACTIVATOR INHIBITOR-1; CORONARY HEART-DISEASE; BLOOD-PRESSURE; ALBUMIN EXCRETION; RISK; MICROALBUMINURIA; ALDOSTERONE; POPULATION AB Children of parents with hypertension are at increased risk of developing high blood pressure. We hypothesize that circulating concentrations of putative biomarkers ( that may play a role in development of high blood pressure) are higher in nonhypertensive offspring of parents with hypertension. We compared concentrations of 4 different biomarkers ( urinary albumin: creatinine ratio, circulating C-reactive protein, aldosterone: renin ratio, and plasminogen activator inhibitor-1) in nonhypertensive Framingham offspring study participants with none ( n = 233), 1 ( n = 474), or both ( n = 322) parents with hypertension. Parental hypertension was defined as onset before age 60 years, based on longitudinal observations of the original Framingham cohort. Serum C-reactive protein concentrations were higher in nonhypertensive offspring with 1 ( median: 1.7; Q1 to Q3: 0.8 to 3.6 mg/L) or both parents with hypertension ( median: 1.8; Q1 to Q3: 0.7 to 3.6 mg/L) compared with offspring without parental hypertension ( median: 1.4; Q1 to Q3: 0.7 to 3.2 mg/L). In multivariable analyses, parental hypertension was associated with higher serum C-reactive protein concentration in offspring (15% increase per parent with hypertension; P = 0.004). Prospectively, the relation of parental hypertension to longitudinal changes in blood pressure in the nonhypertensive offspring was attenuated on adjustment for C-reactive protein ( P = 0.04 for attenuation). The levels of the other biomarkers evaluated did not significantly differ in offspring according to parental hypertension status. In conclusion, serum C-reactive protein concentrations are higher in nonhypertensive offspring of parents with hypertension. These data suggest that inflammation may partly mediate the familial influences on hypertension risk. C1 [Lieb, Wolfgang; Pencina, Michael J.; Wang, Thomas J.; Larson, Martin G.; Benjamin, Emelia J.; Levy, Daniel; Newton-Cheh, Christopher; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Pencina, Michael J.; Larson, Martin G.; Lanier, Katherine J.] Boston Univ, Sch Med, Dept Math, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Wang, Thomas J.; Newton-Cheh, Christopher] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. [Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Gen Med, Boston, MA USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. [Tofler, Geoffrey H.] Royal N Shore Hosp, Sydney, NSW, Australia. [Newton-Cheh, Christopher] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Newton-Cheh, Christopher] MIT, Cambridge, MA 02139 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM vasan@bu.edu RI Lieb, Wolfgang/C-1990-2012; OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [2K24 HL04334, HL080025, K23 HL074077, K23 HL080025, K23-HL-074077, K24 HL004334, N01-HC-25195, N01HC25195]; NIA NIH HHS [R01 AG028321]; NIDDK NIH HHS [K24 DK080140-01, K24 DK080140] NR 41 TC 14 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 2008 VL 52 IS 2 BP 381 EP 386 DI 10.1161/HYPERTENSIONAHA.108.113589 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 329QA UT WOS:000257882300036 PM 18574071 ER PT J AU Koh, KK Quon, MJ AF Koh, Kwang Kon Quon, Michael J. TI Combination therapy for treatment or prevention of atherosclerosis SO HYPERTENSION LA English DT Letter ID ANGIOTENSIN-II; CANDESARTAN C1 [Koh, Kwang Kon] Gachon Univ, Div Cardiol, Gil Med Ctr, Inchon, South Korea. [Quon, Michael J.] Natl Ctr Complementary & Alternat Med, Diabet Unit, Clin Invest Lab, Natl Inst Hlth, Bethesda, MD USA. RP Koh, KK (reprint author), Gachon Univ, Div Cardiol, Gil Med Ctr, Inchon, South Korea. NR 6 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 2008 VL 52 IS 2 BP E18 EP E18 DI 10.1161/HYPERTENSIONAHA.108.115840 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 329QA UT WOS:000257882300052 PM 18574065 ER PT J AU Wen, H Bennett, EE Hegedus, MA Carroll, SC AF Wen, Han Bennett, Eric E. Hegedus, Monica A. Carroll, Stefanie C. TI Spatial harmonic imaging of X-ray scattering initial results SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE diffraction; imaging; scatter; X-ray ID RADIOGRAPHY AB Coherent X-ray scattering is related to the electron density distribution by a Fourier transform, and therefore a window into the microscopic structures of biological samples. Current techniques of scattering rely on small-angle measurements from highly collimated X-ray beams produced from synchrotron light sources. Imaging of the distribution of scattering provides a new contrast mechanism which is different from absorption radiography, but is a lengthy process of raster or line scans of the beam over the object. Here, we describe an imaging technique in the spatial frequency domain capable of acquiring both the scattering and absorption distributions in a single exposure. We present first results obtained with conventional X-ray equipment. This method interposes a grid between the X-ray source and the imaged object, so that the grid-modulated image contains a primary image and a grid harmonic image. The ratio between the harmonic and primary images is shown to be a pure scattering image. It is the auto-correlation of the electron density distribution at a specific distance. We tested a number of samples at 60-200 nm autocorrelation distance, and found the scattering images to be distinct from the absorption images and reveal new features. This technique is simple to implement, and should help broaden the imaging applications of X-ray scattering. C1 [Wen, Han; Bennett, Eric E.; Hegedus, Monica A.; Carroll, Stefanie C.] NHLBI, NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NHLBI, NIH, Cardiac Energet Lab, Bldg 10, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [ZIA HL004606-13] NR 9 TC 53 Z9 53 U1 1 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD AUG PY 2008 VL 27 IS 8 BP 997 EP 1002 DI 10.1109/TMI.2007.912393 PG 6 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 334ZG UT WOS:000258260000001 PM 18672418 ER PT J AU Chen, T Babb, J Kellman, P Axel, L Kim, D AF Chen, Ting Babb, James Kellman, Peter Axel, Leon Kim, Daniel TI Semiautomated segmentation of myocardial contours for fast strain analysis in cine displacement-encoded MRI SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE energy minimization; magnetic resonance imaging (MRI); segmentation; strain ID LEVEL SET APPROACH; IMAGE SEGMENTATION; STIMULATED ECHOES; DENSE; TRACKING; PROPAGATION; SNAKES AB The purposes of this study were to develop a semiautomated cardiac contour segmentation method for use with cine displacement-encoded MRI and evaluate its accuracy against manual segmentation. This segmentation model was designed with two distinct phases: preparation and evolution. During the model preparation phase, after manual image cropping and then image intensity standardization, the myocardium is separated from the background based on the difference in their intensity distributions, and the endo- and epi-cardial contours are initialized automatically as zeros of an underlying level set function. During the model evolution phase, the model deformation is driven by the minimization of an energy function consisting of five terms: model intensity, edge attraction, shape prior, contours interaction, and contour smoothness. The energy function is minimized iteratively by adaptively weighting the five terms in the energy function using an annealing algorithm. The validation experiments were performed on a pool of cine data sets of five volunteers. The difference between the semiautomated segmentation and manual segmentation was sufficiently small as to be considered clinically irrelevant. This relatively accurate semiautomated segmentation method can be used to significantly increase the throughput of strain analysis of cine displacement-encoded MR images for clinical applications. C1 [Chen, Ting; Babb, James; Axel, Leon; Kim, Daniel] NYU, Dept Radiol, New York, NY 10016 USA. [Kellman, Peter] NHLBI, NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Chen, T (reprint author), NYU, Dept Radiol, 560 1St Ave, New York, NY 10016 USA. EM ting.chen@med.nyu.edu; babbj01@endeavor.med.nyu.edu; kellmanp@nhlbi.nih.gov; leon.axel@nyumc.org; kimd10@endeavor.med.nyu.edu OI Axel, Leon/0000-0003-0608-4690 NR 39 TC 29 Z9 29 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD AUG PY 2008 VL 27 IS 8 BP 1084 EP 1094 DI 10.1109/TMI.2008.918327 PG 11 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 334ZG UT WOS:000258260000009 PM 18672426 ER PT J AU Long, EO AF Long, Eric O. TI Negative signaling by inhibitory receptors: the NK cell paradigm SO IMMUNOLOGICAL REVIEWS LA English DT Review DE inhibition; innate immunity; natural killer cell; signaling; tyrosine phosphatase ID PROTEIN-TYROSINE-PHOSPHATASE; NATURAL-KILLER-CELLS; COMPLEX CLASS-I; MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTOR; FC-GAMMA-RIIB; TERMINAL SRC KINASE; T-CELL; CUTTING EDGE; PIR-B AB Receptors carrying immunoreceptor tyrosine-based inhibition motifs (ITIMs) in their cytoplasmic tail control a vast array of cellular responses, ranging from autoimmunity, allergy, phagocytosis of red blood cells, graft versus host disease, to even neuronal plasticity in the brain. The inhibitory function of many receptors has been deduced on the basis of cytoplasmic ITIM sequences. Tight regulation of natural killer (NK) cell cytotoxicity and cytokine production by inhibitory receptors specific for major histocompatibility complex class I molecules has served as a model system to study the negative signaling pathway triggered by an ITIM-containing receptor in the physiological context of NK-target cell interactions. Advances in our understanding of the molecular details of inhibitory signaling in NK cells have provided a conceptual framework to address how ITIM-mediated regulation controls cellular reactivity in diverse cell types. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM eLong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 FU Intramural NIH HHS [Z01 AI000525-20, Z01 AI000842-09] NR 162 TC 162 Z9 168 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2008 VL 224 BP 70 EP 84 DI 10.1111/j.1600-065X.2008.00660.x PG 15 WC Immunology SC Immunology GA 334GW UT WOS:000258211300007 PM 18759921 ER PT J AU Dutta, S Joglekar, N Joshi, S Steven, JR AF Dutta, Soma Joglekar, Neelam Joshi, Smita Steven, J. Reynolds TI Experience of conducting a phase I safety & acceptability clinical trial of a candidate vaginal microbicide & lessons learned SO INDIAN JOURNAL OF MEDICAL RESEARCH LA English DT Letter ID WOMEN; PREVENTION C1 [Dutta, Soma; Joglekar, Neelam; Joshi, Smita] Natl AIDS Res Inst, Pune 411026, Maharashtra, India. [Steven, J. Reynolds] NIAID, NIH, Bethesda, MD 20892 USA. [Steven, J. Reynolds] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Dutta, S (reprint author), Natl AIDS Res Inst, G-73,MIDC,Post Box 1895, Pune 411026, Maharashtra, India. EM seeksoma@rediffmail.com NR 10 TC 4 Z9 4 U1 0 U2 0 PU INDIAN COUNCIL MEDICAL RES PI NEW DELHI PA PO BOX 4911 ANSARI NAGAR, NEW DELHI 110029, INDIA SN 0971-5916 J9 INDIAN J MED RES JI Indian J. Med. Res. PD AUG PY 2008 VL 128 IS 2 BP 212 EP 213 PG 2 WC Immunology; Medicine, General & Internal; Medicine, Research & Experimental SC Immunology; General & Internal Medicine; Research & Experimental Medicine GA 365SB UT WOS:000260427000021 PM 19001688 ER PT J AU Selleri, S Palazzo, M Deola, S Wang, E Balsari, A Marincola, FM Rumio, C AF Selleri, Silvia Palazzo, Marco Deola, Sara Wang, Ena Balsari, Andrea Marincola, Francesco M. Rumio, Cristiano TI Induction of pro-inflammatory programs in enteroendocrine cells by the Toll-like receptor agonists flagellin and bacterial LPS SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE enteroendocrine cells; inflammation; intestine; TLR ID FOOD-INTAKE; DENDRITIC CELLS; ENDOCRINE CELL; CHOLECYSTOKININ; GUT; LIPOPOLYSACCHARIDE; MACROPHAGES; EXPRESSION; DISEASE; LYMPHOCYTES AB Enteroendocrine cells are hormone-secreting cells spread along the intestinal epithelium. Their principal function is to promote the digestion of food. However, little is known about other functions that these cells may play, since they are difficult to study as a whole endocrine organ due to their diffuse localization. It is known that the intestinal epithelial barrier is actively involved in the host defense against pathogen invasion. Here we applied gene expression profiling to characterize the response of the human LCC-18 enteroendocrine cell line to physiological and pathological stimuli mimicked by fatty acids (FAs), flagellin and LPS exposure. We observed that these cells participate in an innate immune reaction to pathogens through the expression of pro-inflammatory factors (i.e. CXCL1 and 3 and IL-32) that we could validate by molecular and proteomic approach. Interestingly, IL-32 has been recently found over-expressed in the inflamed mucosa of patients affected by inflammatory bowel disease. This is very important because modifications of enteroendocrine cells during intestinal inflammation have been so far considered as secondary effects of the inflammatory status rather than due to direct pathogen/enteroendocrine cell interaction. As expected, FAs exposure up-regulates pro-differentiative genes and the production of cholecystokinin but it does not enhance the expression of pro-inflammatory genes. The present observations enlighten a new aspect of the cross talk between immune and endocrine system and suggest enteroendocrine cells as important contributors of inflammatory processes occurring in the gut in response to pathogen exposure and direct enhancers of the inflammatory status associated with human inflammatory bowel disease. C1 [Selleri, Silvia; Palazzo, Marco; Rumio, Cristiano] Univ Milan, Dept Human Morphol, Mucosal Immun Lab, I-20133 Milan, Italy. [Selleri, Silvia; Deola, Sara; Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Bethesda, MD 20892 USA. [Balsari, Andrea] Univ Milan, Ist Nazl Tumori, Mol Targeting Unit, I-20133 Milan, Italy. [Balsari, Andrea] Univ Milan, Inst Pathol, I-20133 Milan, Italy. RP Rumio, C (reprint author), Univ Milan, Dept Human Morphol, Mucosal Immun Lab, Via Mangiagalli 31, I-20133 Milan, Italy. EM cristiano.rumio@unimi.it RI balsari, andrea/M-5657-2016 OI balsari, andrea/0000-0002-3250-2668 FU Associazione Italiana per la Ricerca sul Cancro NR 33 TC 22 Z9 22 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 2008 VL 20 IS 8 BP 961 EP 970 DI 10.1093/intimm/dxn055 PG 10 WC Immunology SC Immunology GA 330SS UT WOS:000257963700002 PM 18544573 ER PT J AU Meng, XL Yang, JY Chen, GL Zhang, LJ Wang, LH Li, J Wang, JM Wu, CF AF Meng, Xue Lian Yang, Jin Yu Chen, Guo Liang Zhang, Li Jia Wang, Li Hui Li, Jie Wang, Ji Ming Wu, Chun Fu TI RV09, a novel resveratrol analogue, inhibits NO and TNF-alpha production by LPS-activated microglia SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE RV09; resveratrol; microglia; NO; TNF-alpha ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; PROSTAGLANDIN E-2 PRODUCTION; NEURONAL CELL-DEATH; NITRIC-OXIDE; REACTIVE OXYGEN; INFLAMMATORY MECHANISMS; ALZHEIMERS-DISEASE; GENE-EXPRESSION; IMMUNE-SYSTEM AB Excessive activation of microglial cells has been implicated in various neurodegenerative diseases. Resveratrol, a polyphenotic compound found in grapes and wine, has been reported to reduce the activation of microglia. In the present study, 5-[2-(4-bromothiophen-2-yl)vinyl] benzene-1,3-diol (RV09), a novel resveratrol analogue, was found to suppress NO production by LPS-activated N9 microglial cell Line and/or cultured rat cortical microglia. RV09 appeared to have a slight NO-scavenging activity in sodium nitroprusside (SNP) solution. The inhibition of iNOS was also observed, suggesting the blockage of transcriptional Levels. Moreover, RV09 attenuated the expression of mRNA and protein of tumor necrosis factor-alpha (TNF-alpha) in a concentration-dependent manner. Further studies revealed that RV09 blocked I kappa B alpha phosphorylation and degradation, as well as reactive oxygen species (ROS) production in N9 microglial cells. It was also found that RV09 is a effective scavenger for 2,2-diphenyl-1-picrylhydrazyl (DPPH) used as a general free radical model. In the summary, these data suggest that, by blocking I kappa B alpha phosphorylation and degradation, RV09 acts to suppress the LPS-induced NO and TNF-alpha production in microglia, and this effect was mediated, at Least in part, by inhibiting the generation of ROS. Our results suggested that RV09 is a novel anti-inflammatory agent which can inhibit proinflammatory responses of microglia. (C) 2008 Elsevier B.V. All rights reserved. C1 [Meng, Xue Lian; Yang, Jin Yu; Zhang, Li Jia; Wang, Li Hui; Wu, Chun Fu] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China. [Chen, Guo Liang; Li, Jie] Shenyang Pharmaceut Univ, Dept Pharmaceut Engn, Shenyang 110016, Peoples R China. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Wu, CF (reprint author), Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China. EM wucf@syphu.edu.cn NR 58 TC 40 Z9 44 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 EI 1878-1705 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD AUG PY 2008 VL 8 IS 8 BP 1074 EP 1082 DI 10.1016/j.intimp.2008.03.011 PG 9 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 325GM UT WOS:000257577000002 PM 18550010 ER PT J AU Talwar, GP Dar, SA Rai, MK Reddy, KVR Mitra, D Kulkarni, SV Doncel, GF Buck, CB Schiller, JT Muralidhar, S Bala, M Agrawal, SS Bansal, K Verma, JK AF Talwar, G. P. Dar, Sajad A. Rai, Mahendra K. Reddy, K. V. R. Mitra, Debashis Kulkarni, Sujata V. Doncel, Gustavo F. Buck, Christopher B. Schiller, John T. Muralidhar, Sumathi Bala, Manju Agrawal, S. S. Bansal, Kavita Verma, Jitendra K. TI A novel polyherbal microbicide with inhibitory effect on bacterial, fungal and viral genital pathogens SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Article DE Basant; Neisseria gonorrhoeae; Candida; HIV; HPV ID AGENT AB A polyherbal cream (Basant) has been formulated using diferuloylmethane (curcumin), purified extracts of Emblica officinalis (Amla), purified saponins from Sapindus mukorossi, Aloe vera and rose water along with pharmacopoeially approved excipients and preservatives. Basant inhibits the growth of WHO strains and clinical isolates of Neisseria gonorrhoeae, including those resistant to penicillin, tetracycline, nalidixic acid and ciprofloxacin. It has pronounced inhibitory action against Candida glabrata, Candida albicans and Candida tropicalis isolated from women with vulvovaginal candidiasis, including three isolates resistant to azole drugs and amphotericin B. Basant displayed a high virucidal action against human immunodeficiency virus HIV-1NL4.3 in CEM-GFP reporter T and P4 (Hela-CD4-LTR-beta Gal) cell lines with a 50% effective concentration (EC50) of. 1:20000 dilution and nearly complete (98-99%) inhibition at 1:1000 dilution. It also prevented the entry of HIV-1 (IIIB) virus into P4-CCR5 cells (EC50 similar to 1:2492). Two ingredients, Aloe and Amla, inhibited the transduction of human papillomavirus type 16 (HPV-16) pseudovirus in HeLa cells at concentrations far below those that are cytotoxic and those used in the formulation. Basant was found to be totally safe according to pre-clinical toxicology carried out on rabbit vagina after application for 7 consecutive days or twice daily for 3 weeks. Basant has the potential of regressing vulvovaginal candidiasis and preventing N. gonorrhoeae, HIV and HPV infections. (C) 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. C1 [Talwar, G. P.; Dar, Sajad A.; Rai, Mahendra K.; Bansal, Kavita; Verma, Jitendra K.] Talwar Res Fdn, New Delhi 110068, India. [Rai, Mahendra K.; Agrawal, S. S.] Univ Delhi, Delhi Inst Pharmaceut Sci & Res, New Delhi, India. [Reddy, K. V. R.] Natl Inst Res Reprod Hlth ICMR, Bombay, Maharashtra, India. [Mitra, Debashis; Kulkarni, Sujata V.] Natl Ctr Cell Sci, Pune, Maharashtra, India. [Doncel, Gustavo F.] Eastern Virginia Med Sch, CONRAD, Arlington, VA USA. [Buck, Christopher B.; Schiller, John T.] NCI, NIH, Bethesda, MD 20892 USA. [Muralidhar, Sumathi; Bala, Manju] Safdarjang Hosp, Reg STD Teaching Training & Res Ctr, New Delhi, India. RP Talwar, GP (reprint author), Talwar Res Fdn, E-8 Neb Valley, New Delhi 110068, India. EM gptalwar@gmail.com OI Buck, Christopher/0000-0003-3165-8094 NR 16 TC 26 Z9 27 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD AUG PY 2008 VL 32 IS 2 BP 180 EP 185 DI 10.1016/j.ijantimicag.2008.03.004 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 334JC UT WOS:000258217100012 PM 18571386 ER PT J AU Lim, MA Stack, CM Cuasay, K Stone, MM McFarlane, HG Waschek, JA Hill, JM AF Lim, Maria A. Stack, Conor M. Cuasay, Katrina Stone, Madeleine M. McFarlane, Hewlet G. Waschek, James A. Hill, Joanna M. TI Regardless of genotype, offspring of VIP-deficient female mice exhibit developmental delays and deficits in social behavior SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE vasoactive intestinal peptide; developmental milestones; developmental delays; social behavior; neurodevelopmental disorders; autism; neuropeptide; maternal attachment; play behavior ID VASOACTIVE-INTESTINAL-PEPTIDE; DEPENDENT NEUROTROPHIC FACTOR; CYCLASE-ACTIVATING POLYPEPTIDE; EMBRYONIC GROWTH; NEURITE OUTGROWTH; ENVELOPE PROTEIN; GENE-EXPRESSION; IGF-I; MOUSE; ANTAGONIST AB Pharmacological studies indicate that vasoactive intestinal peptide (VIP) may be necessary for normal embryonic development in the mouse. For example, VIP antagonist treatment before embryonic day I I resulted in developmental delays, growth restriction, modified adult brain chemistry and reduced social behavior. Here, developmental milestones, growth, and social behaviors of neonates of VIP-deficient mothers (VIP +/-) mated to VIP +/- males were compared with the offspring of wild type mothers (VIP +/+) mated to VIP +/+ and +/- males, to assess the contributions of both maternal and offspring VIP genotype. Regardless of their own genotype, all offsprings of VIP-deficient mothers exhibited developmental delays. No delays were seen in the offspring of wild type mothers, regardless of their own genotype. Body weights were significantly reduced in offspring of VIP-deficient mothers, with VIP null (-/-) the most affected. Regardless of genotype, all offspring of VIP-deficient mothers expressed reduced maternal affiliation compared with wild type offspring of wild type mothers; +/- offspring of wild type mothers did not differ in maternal affiliation from their wild type littermates. Play behavior was significantly reduced in all offsprings of VIP-deficient mothers. Maternal behavior did not differ between wild type and VIP-deficient mothers, and cross-fostering of litters did not change offspring development, indicating that offspring deficits were induced prenatally. This study illustrated that the VIP status of a pregnant mouse had a greater influence on the growth, development and behavior of her offspring than the VIP genotype of the offspring themselves. Deficiencies were apparent in +/+, +/- and -/- offspring born to VIP-deficient mothers; no deficiencies were apparent in +/- offspring born to normal mothers. These results underscore the significant contribution of the uterine environment to normal development and indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders with social behavior deficits such as autism. Published by Elsevier Ltd on behalf of ISDN. C1 [Lim, Maria A.; Stack, Conor M.; Cuasay, Katrina; Stone, Madeleine M.; McFarlane, Hewlet G.; Hill, Joanna M.] NIMH, Behav Sci Lab, NIH, Bethesda, MD 20892 USA. [McFarlane, Hewlet G.] Kenyon Coll, Dept Psychol, Gambier, OH 43022 USA. [Waschek, James A.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RP Hill, JM (reprint author), NIMH, Behav Sci Lab, NIH, Bldg 35,Room 1C903,35 Convent Dr, Bethesda, MD 20892 USA. EM hilljoa@mail.nih.gov FU Intramural NIH HHS [, NIH0010150863]; PHS HHS [NIH0010150863] NR 61 TC 13 Z9 13 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD AUG PY 2008 VL 26 IS 5 BP 423 EP 434 DI 10.1016/j.ijdevneu.2008.03.002 PG 12 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 312EC UT WOS:000256650900006 PM 18423945 ER PT J AU Mrozek, K Carroll, AJ Maharry, K Rao, KW Patil, SR Pettenati, MJ Watson, MS Arthur, DC Tantravahi, R Heerema, NA Koduru, PRK Block, AW Qumsiyeh, MB Edwards, CG Sterling, LJ Holland, KB Bloomfield, CD AF Mrozek, Krzysztof Carroll, Andrew J. Maharry, Kati Rao, Kathleen W. Patil, Shivanand R. Pettenati, Mark J. Watson, Michael S. Arthur, Diane C. Tantravahi, Ramana Heerema, Nyla A. Koduru, Prasad R. K. Block, Annemarie W. Qumsiyeh, Mazin B. Edwards, Colin G. Sterling, Lisa J. Holland, Kels B. Bloomfield, Clara D. TI Central review of cytogenetics is necessary for cooperative group correlative and clinical studies of adult acute leukemia: The Cancer and Leukemia Group B experience SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Review DE karyotyping; chromosome aberrations; human; correlative studies; acute leukemia ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; INTERNAL TANDEM DUPLICATION; GENE-EXPRESSION SIGNATURE; DISEASE-FREE SURVIVAL; DE-NOVO; YOUNGER ADULTS; PROGNOSTIC-SIGNIFICANCE; POSTREMISSION THERAPY; FAVORABLE PROGNOSIS AB The Cancer and Leukemia Group B has performed central review of karyotypes submitted by institutional cytogenetics laboratories from patients with acute myeloid (AML) and acute lymphoblastic (ALL) leukemia since 1986. We assessed the role of central karyotype review in maintaining accurate, high quality cytogenetic data for clinical and translational studies using two criteria: the proportion of karyotypes rejected (i.e. inadequate), and, among accepted (i.e. adequate) cases, the proportion of karyotypes whose interpretation was changed on central karyotype review. We compared the first four years during which central karyotype review was performed with a recent 4-year period and found that the proportion of rejected samples decreased significantly for both AML and ALL. However, during the latter period, central karyotype reviews still found 8% of AML and 16% of ALL karyotypes inadequate. Among adequate cases, the karyotype was revised in 26% of both AML and ALL samples. Some revisions resulted in changing the patients' assignment to particular World Health Organization diagnostic categories and/or moving patients from one prognostic group to another. Overall, when both data on rejection rates and data on karyotype revisions made in accepted cases were considered together, 32% of AML and 38% of ALL samples submitted were either rejected or revised on central karyotype review during the recent 4-year period. These data underscore the necessity of continued central karyotype review in multi-institutional cooperative group studies. C1 [Mrozek, Krzysztof; Maharry, Kati; Edwards, Colin G.; Sterling, Lisa J.; Holland, Kels B.; Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Hematol & Oncol, Columbus, OH 43210 USA. [Carroll, Andrew J.] Univ Alabama, Birmingham, AL USA. [Maharry, Kati; Holland, Kels B.] Duke Univ, Med Ctr, CALGB Stat Ctr, Durham, NC 27706 USA. [Rao, Kathleen W.] Univ N Carolina, Chapel Hill, NC USA. [Patil, Shivanand R.] Univ Iowa, Iowa City, IA USA. [Pettenati, Mark J.] Wake Forest Univ, Med Ctr, Winston Salem, NC USA. [Watson, Michael S.] Amer Coll Med Genet, Bethesda, MD USA. [Arthur, Diane C.] NCI, Bethesda, MD 20892 USA. [Tantravahi, Ramana] Dana Farber Canc Inst, Boston, MA 02115 USA. [Heerema, Nyla A.] Ohio State Univ, Ctr Comprehens Canc, Dept Pathol, Columbus, OH 43210 USA. [Koduru, Prasad R. K.] N Shore Univ Hosp, Manhasset, NY USA. [Block, Annemarie W.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RP Mrozek, K (reprint author), Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Hematol & Oncol, Room 1248B, 300 W 10th Ave, Columbus, OH 43210 USA. EM Icrzysztof.mrozek@osumc.edu RI Mrozek, Krzysztof/A-3142-2008 FU NCI NIH HHS [U10 CA032291-27, CA02599, CA101140, CA16058, CA16450, CA31946, CA32291, CA35279, CA47545, CA47559, CA47577, CA47642, CA77440, CA77658, P30 CA016058, P30 CA016058-34, U10 CA016450-28, U10 CA031946, U10 CA031946-28, U10 CA032291, U10 CA035279, U10 CA047559, U10 CA047577, U10 CA047577-22, U10 CA047642, U10 CA047642-19, U10 CA077440, U10 CA077658, U10 CA077658-12, U10 CA101140, U10 CA101140-06] NR 55 TC 36 Z9 37 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD AUG PY 2008 VL 33 IS 2 BP 239 EP 244 DI 10.3892/ijo_00000002 PG 6 WC Oncology SC Oncology GA 338CB UT WOS:000258481400002 PM 18636143 ER PT J AU Shibui, T Higo, Y Tsutsui, TW Uchida, M Oshimura, M Barrett, JC Tsutsui, T AF Shibui, Takeo Higo, Yukari Tsutsui, Takeo W. Uchida, Minoru Oshimura, Mitsuo Barrett, J. Carl Tsutsui, Takeki TI Changes in expression of imprinted genes following treatment of human cancer cell lines with non-mutagenic or mutagenic carcinogens SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE epigenetic modification; imprinted genes; chemical carcinogens; human cells ID PRADER-WILLI-SYNDROME; HISTONE H3 LYSINE-9; DNA METHYLATION; EPIGENETIC MECHANISMS; ASSOCIATION; IMMORTALIZATION; ACETYLATION; FIBROBLASTS; CHROMATIN; HYPOMETHYLATION AB It remains possible that chemicals that act by mutagenic mechanisms as well as chemicals that do not induce gene mutations may affect epigenetic gene expression. To test the possibility, we investigated the ability of both types of chemicals to alter the expression of five imprinted genes, PEG3, SNRPN, NDN, ZAC and H19, using two human colon cancer cell lines and a human breast cancer cell line. The expression of imprinted genes was changed by some non-mutagenic and mutagenic carcinogens independent of their mutagenic activity. The genes most commonly exhibiting the changes in expression were SNRPN and PEG3. Alterations of the expression of NDN and ZAC were also observed in some conditions. Methylation-specific PCR and chromatin immunoprecipitation assays suggest the possibility that changes in the expression of SNRPN may be associated with DNA hypomethylation and historic acetylation of the promoters and euchromatinization of the heterochromatic domains of the promoters. Changes in expression of the imprinted genes, PEG3 and NDN, were also observed in cells immortalized by treatment of normal human fibroblasts with 4-nitroquinoline 1-oxide or aflatoxin B-1 We previously demonstrated that expression of the cancer-related gene, INK4a, in these immortal cells was lost via epigenetic mechanisms. The results prove that, in cancer cells, some mutagenic or non-mutagenic carcinogens can epigenetically influence the transcription levels of imprinted genes and also suggest the possibility that some chemical carcinogens may have epigenetic carcinogenic effects in human cells. C1 [Tsutsui, Takeki] Nippon Dent Univ Tokyo, Sch Life Dent, Dept Pharmacol, Chiyoda Ku, Tokyo 1028159, Japan. [Shibui, Takeo; Uchida, Minoru] Nippon Dent Univ Hosp Tokyo, Tokyo 1028158, Japan. [Oshimura, Mitsuo] Tottori Univ, Sch Life Sci, Dept Mol & Cellular Genet, Tottori 6800022, Japan. [Barrett, J. Carl] NCI, Lab Biosyst & Cancer, NIH, Bethesda, MD 20892 USA. RP Tsutsui, T (reprint author), Nippon Dent Univ Tokyo, Sch Life Dent, Dept Pharmacol, Chiyoda Ku, 1-9-20 Fujimi, Tokyo 1028159, Japan. EM takeki@tokyo.ndu.ac.jp NR 43 TC 5 Z9 8 U1 2 U2 3 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD AUG PY 2008 VL 33 IS 2 BP 351 EP 360 DI 10.3892/ijo_00000015 PG 10 WC Oncology SC Oncology GA 338CB UT WOS:000258481400015 PM 18636156 ER PT J AU Raju, TNK AF Raju, Tonse N. K. TI Ischemic perinatal stroke: challenge and opportunities SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article ID FACTOR-V-LEIDEN; ARTERIAL STROKE; RISK-FACTORS; ANTIPHOSPHOLIPID ANTIBODIES; SINOVENOUS THROMBOSIS; CEREBRAL INFARCTION; CHILDREN; DISORDERS; INFANT; FETAL AB The second highest risk group for developing a cerebral stroke is the perinatal period, generally defined as 20 weeks of gestation through 28th postnatal day of age. In this commentary, a brief overview of ischemic perinatal strokes is presented. Ischemic perinatal stroke (IPS) occurs at a rate of 1:2300 to 1:5000 births, accounting for 30% of children with hemiplegic cerebral palsy (CP). Thus, IPS is the most common known cause for CP [1-3]. Although they occur frequently, much remains to be studied about perinatal strokes in general and the ischemic variety in particular. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Raju, TNK (reprint author), NICHHD, NIH, 6100 Execut Blvd,Room 4B03, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 28 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1747-4930 J9 INT J STROKE JI Int. J. Stroke PD AUG PY 2008 VL 3 IS 3 BP 169 EP 172 DI 10.1111/j.1747-4949.2008.00205.x PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 333RI UT WOS:000258169600005 PM 18705894 ER PT J AU Swamynathan, SK Davis, J Piatigorsky, J AF Swamynathan, Shivalingappa K. Davis, Janine Piatigorsky, Joram TI Identification of candidate klf4 target genes reveals the molecular basis of the diverse regulatory roles of klf4 in the mouse cornea SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID METALLOPROTEINASE GELATINASE B; TRANSCRIPTION FACTORS; IN-VIVO; EPITHELIAL-CELLS; OCULAR SURFACE; EXPRESSION PATTERNS; MICROARRAY ANALYSIS; BARRIER FUNCTION; GOBLET CELLS; KAPPA-B AB PURPOSE. Kruppel-like factor 4 (Klf4) plays a crucial role in the development and maintenance of the mouse cornea. In the current study, wild-type (WT) and Klf4-conditional null (Klf4CN) corneal gene expression patterns were examined, to gain understanding of the molecular basis of the Klf4CN corneal phenotype. METHODS. Expression of more than 22,000 genes in 10 WT and Klf4CN corneas was compared by microarrays, analyzed using BRB ArrayTools (National Cancer Institute, Bethesda, MD) and validated by Q-RT-PCR. Transient cotransfections were used to test whether Klf4 activates the aquaporin-3, Aldh3a1, and TKT promoters. RESULTS. Scatterplot analysis identified 740 and 529 genes up-and downregulated by more than twofold, respectively, in the Klf4CN corneas. Cell cycle activators were upregulated, whereas the inhibitors were downregulated, consistent with the increased Klf4CN corneal epithelial cell proliferation. Desmosomal components were downregulated, consistent with the Klf4CN corneal epithelial fragility. Downregulation of aquaporin-3, detected by microarray, was confirmed by immunoblot and immunohistochemistry. Aquaporin-3 promoter activity was stimulated 7- to 10-fold by cotransfection with pCI-Klf4. The corneal crystallins Aldh3A1 and TKT were downregulated in the Klf4CN cornea, and their respective promoter activities were upregulated 16- and 9-fold by pCI-Klf4 in cotransfections. The expression of epidermal keratinocyte differentiation markers was affected in the Klf4CN cornea. Although the cornea-specific keratin-12 was downregulated, most other keratins were upregulated, suggesting hyperkeratosis. CONCLUSIONS. Functionally diverse candidate Klf4 target genes were identified, revealing the molecular basis of the diverse aspects of the Klf4CN corneal phenotype. These results establish Klf4 as an important node in the genetic network of transcription factors regulating the corneal hyperkeratosis. C1 [Swamynathan, Shivalingappa K.] Univ Pittsburgh, Sch Med, Inst Eye & Ear, Dept Ophthalmol, Pittsburgh, PA 15213 USA. [Swamynathan, Shivalingappa K.; Davis, Janine; Piatigorsky, Joram] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Swamynathan, SK (reprint author), Univ Pittsburgh, Sch Med, Inst Eye & Ear, Dept Ophthalmol, 203 Lothrop St,Room 1025, Pittsburgh, PA 15213 USA. EM swamynathansk@upmc.edu OI Swamynathan, Shivalingappa/0000-0002-9158-1511 FU NEI NIH HHS [1 K22 EY016875-01, 5P30 EY08098-19, K22 EY016875, K22 EY016875-01, P30 EY008098] NR 80 TC 29 Z9 31 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2008 VL 49 IS 8 BP 3360 EP 3370 DI 10.1167/iovs.08-1811 PG 11 WC Ophthalmology SC Ophthalmology GA 330NW UT WOS:000257951100015 PM 18469187 ER PT J AU Takada, Y Vijayasarathy, C Zeng, Y Kjellstrom, S Bush, RA Sieving, PA AF Takada, Yuichiro Vijayasarathy, Camasamudram Zeng, Yong Kjellstrom, Sten Bush, Ronald A. Sieving, Paul A. TI Synaptic pathology in retinoschisis knockout (Rs1(-/y)) mouse retina and modification by rAAV-Rs1 gene delivery SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID X-LINKED RETINOSCHISIS; FIBRILLARY ACIDIC PROTEIN; OUTER PLEXIFORM LAYER; JUVENILE RETINOSCHISIS; PHOTORECEPTOR DEGENERATION; BIPOLAR CELLS; CHOROIDAL NEOVASCULARIZATION; TRANSGENIC RAT; DETACHMENT; ABNORMALITIES AB PURPOSE. At an early age, the retinoschisin knockout (Rs1-KO) mouse retina has progressive photoreceptor degeneration with severe disruption of the outer plexiform layer (OPL) that decreases at older ages. The electroretinogram (ERG) undergoes parallel changes. The b-wave amplitude from bipolar cells is reduced disproportionately to the photoreceptor a-wave at young but not at older ages. The protein expression and morphology of the OPL in Rs1-KO mice was investigated at different ages, to explore the role of the synaptic layer in these ERG changes. METHODS. Retinas of wild-type (Wt) and Rs1-KO mice from postnatal day (P) 7 to 12 months were evaluated by light and electron microscopy (EM) and biochemistry. PSD95 (postsynaptic density protein), mGluR6 (metabotropic glutamate receptor subtype 6), retinoschisin (Rs1), the Muller cell proteins glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS), the bipolar cell marker protein kinase C alpha (PKC alpha), and the horizontal cell marker calbindin were localized by immunofluorescence and immuno-EM. Levels of PSD95 and mGluR6 were determined by quantitative Western blot. Rs1-KO mice treated by intravitreous injection of rAAV(2/2)-CMV-Rs1 in one eye at P14 were evaluated at 8 months by full-field scotopic ERG responses and retinal immunohistochemistry. RESULTS. Rs1 was associated with the outer surface of synaptic membranes in wild-type (Wt) retinas. PSD95 and mGluR6 were juxtaposed in the OPL of the Rs1-KO retinas by P14, implying that synaptic structures are formed. Light microscopic retinal morphology was similar in Wt and Rs1-KO at P14, but by P21, the OPL was disrupted in Rs1-KO, and some PSD95 and mGluR6 was mislocalized in the outer nuclear layer (ONL). GFAP expression spanned all retinal layers. EM showed synaptic structures adjacent to photoreceptor nuclei. PSD95 and mGluR6 levels were normal at 1 month on Western blot but declined to 59% (P < 0.001) and 55% (P < 0.05) of Wt, respectively, by 4 months. Levels thereafter showed no further reduction out to 12 months. Eyes injected with AAV-Rs1 were studied at 8 months by immunohistochemistry and had higher expression of PSD95 and mGluR6 and less GFAP expression compared with fellow untreated eyes. CONCLUSIONS. In the Rs1-KO mouse, retinal layer formation and synaptic protein expression in the OPL is normal up to P14, implying normal development of synaptic connections. Aberrant localization of synaptic proteins by P21 indicates that displacement of developing and/or mature synapses contributes to the b-wave reduction at young ages, when photoreceptor numbers and synaptic protein levels are normal. The subsequent decline in PSD95 and mGluR6 between 1 and 12 months in Rs1-KO retina mirrors the course of b-wave change and provides evidence of causal relationship between the ERG and OPL changes. These findings and the improved structural integrity of the OPL and b-wave amplitude after Rs1 gene transfer therapy provide a cellular and molecular basis for interpreting the changes in retinal signaling in this model. C1 [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. [Takada, Yuichiro; Vijayasarathy, Camasamudram; Zeng, Yong; Kjellstrom, Sten; Bush, Ronald A.; Sieving, Paul A.] NIDCD, Sect Translat Res Retinal & Macular Degenerat, NIH, Bethesda, MD USA. RP Sieving, PA (reprint author), NEI, NIH, 31 Ctr Dr,Bldg 31,Room 6A03,MSC 2510, Bethesda, MD 20892 USA. EM paulsieving@nei.nih.gov FU Intramural NIH HHS [Z01 DC000065-06] NR 47 TC 49 Z9 49 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2008 VL 49 IS 8 BP 3677 EP 3686 DI 10.1167/iovs.07-1071 PG 10 WC Ophthalmology SC Ophthalmology GA 330NW UT WOS:000257951100056 PM 18660429 ER PT J AU Vachot, L Williams, VG Bess, JW Lifson, JD Robbiani, M AF Vachot, Laurence Williams, Vennansha G. Bess, Julian W., Jr. Lifson, Jeffrey D. Robbiani, Melissa TI Candida albicans - Induced DC activation partially restricts HIV amplification in DCs and increases DC to T-cell spread of HIV SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT Conference on Initative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living with HIV/AIDS CY JUN 28-30, 2007 CL Chicago, IL DE dendritic cells; HIV pathogenesis; AIDS; opportunistic infections; Candida albicans ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMACYTOID DENDRITIC CELLS; OROPHARYNGEAL CANDIDIASIS; LANGERHANS CELLS; INFECTION; MATURE; STIMULATION; MATURATION; IMMUNITY; SIGN AB Dendritic cells (DCs) are central to the innate and adaptive responses needed to control pathogens, yet HIV exploits DCs to promote infection. The influence of other pathogens on DC-HIV interplay has not been extensively studied. We used Candida albicans (Candida) as a model pathogen which elicits innate DC responses that are likely important in controlling Candida by healthy immune systems. HIV did not impede Candida-specific DC activation. Candida-induced CD80 and CD83 upregulation was greater in DCs that had captured HIV coinciding with increased amplification in presence of T cells and reduced but persistent low-level DC infection. In contrast, HIV-infected DCs matured normally in response to Candida, but this did not shut down HIV replication in DCs, and again Candida augmented HIV amplification in DC T-cell mixtures. HIV-infected DCs secreted more IL-10 and IL-1 beta earlier than uninfected DCs and initially induced a higher frequency of CD4(+)CD25(+)FoxP3(+) T-regulatory cells in response to Candida. Elevated early IL-10 production in cocultures was evident only when azidothymidine (AZT) was included to limit T-regulatory cell infection and destruction. Therefore, HIV manipulates the DCs innate and adaptive responses to Candida to further augment HIV spread, ultimately destroying the cells needed to limit candidiasis. C1 [Vachot, Laurence; Williams, Vennansha G.; Robbiani, Melissa] Populat Council, Ctr Biomed Res, New York, NY 10065 USA. [Bess, Julian W., Jr.; Lifson, Jeffrey D.] Natl Canc Inst, Sci Applicat Int Corp, AIDS Vaccine Program, Frederick, MA USA. RP Robbiani, M (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10065 USA. EM mrobbiani@popcouncil.org FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [AI065412, AI065413]; NICHD NIH HHS [HD041752]; NIDCR NIH HHS [DE015512]; PHS HHS [A1040877] NR 65 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2008 VL 48 IS 4 BP 398 EP 407 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 328OQ UT WOS:000257808100004 PM 18614931 ER PT J AU Bardeguez, AD Lindsey, JC Shannon, M Tuomala, RE Cohn, SE Smith, E Stek, A Buschur, S Cotter, A Bettica, L Read, JS AF Bardeguez, Arlene D. Lindsey, Jane C. Shannon, Maureen Tuomala, Ruth E. Cohn, Susan E. Smith, Elizabeth Stek, Alice Buschur, Shelly Cotter, Amanda Bettica, Linda Read, Jennifer S. CA PACTG 1025 Protocol Team TI Adherence to antiretrovirals among US women during and after pregnancy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT Conference on Initative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living with HIV/AIDS CY JUN 28-30, 2007 CL Chicago, IL DE pregnancy; adherence; HIV-1 infection; substance use; depression; viral suppression ID IMMUNODEFICIENCY-VIRUS-INFECTION; DRUG-RESISTANCE; ZIDOVUDINE ADHERENCE; MEDICATION ADHERENCE; PROTEASE INHIBITORS; REPORTED ADHERENCE; HIV; THERAPY; OUTCOMES; TRANSMISSION AB Background: Antiretrovirals (ARVs) are recommended for maternal health and to reduce HIV-1 mother-to-child transmission, but suboptimal adherence can counteract its benefits. Objectives: To describe antepartum and postpartum adherence to ARV regimens and factors associated with adherence. Methods: We assessed adherence rates among subjects enrolled in Pediatric AIDS Clinical Trials Group Protocol 1025 from August 2002 to July 2005 on tablet formulations with at least one self-report adherence assessment. Perfectly adherent subjects reported no missed doses 4 days before their studs visit. Generalized estimating equations were used to compare antepartum with postpartum adherence rates and to identify factors associated with perfect adherence. Results: Of 519 eligible subjects, 334/445 (75%) reported perfect adherence during pregnancy. This rate significantly decreased 6, 24, and 48 weeks postpartum [185/284 (65%), 76/118 (64%), and 42/64 (66%), respectively (P < 0.01)]. Pregnant subjects with perfect adherence had lower viral loads. The odds of perfect adherence were significantly higher for women who initiated ARVs during pregnancy (P < 0.01), did not have AIDS (P = 0.02), never missed prenatal vitamins (P < 0.01), never used marijuana (P = 0.05), or felt happy all or most of the time (P < 0.01). Conclusions: Perfect adherence to ARVs was better antepartum, but overall rates were low. Interventions to improve adherence during pregnancy are needed. C1 [Bardeguez, Arlene D.; Bettica, Linda] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Obstet Gynecol & Womens Hlth, Newark, NJ 07103 USA. [Lindsey, Jane C.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Tuomala, Ruth E.] Univ Hawaii, Dept Nursing, Honolulu, HI 96822 USA. [Tuomala, Ruth E.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Cohn, Susan E.] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. [Smith, Elizabeth] NIAID, NIH, Bethesda, MD 20892 USA. [Smith, Elizabeth; Read, Jennifer S.] Dept Hlth & Human Serv, Bethesda, MD USA. [Stek, Alice] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. [Buschur, Shelly] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Cotter, Amanda] Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. [Read, Jennifer S.] NICHHD, NIH, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. RP Bardeguez, AD (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Obstet Gynecol & Womens Hlth, 185 S Orange Ave MSB E-506, Newark, NJ 07103 USA. EM bardegad@umdnj.edu FU NCRR NIH HHS [M01 RR000069, MO1 RR00069]; NIAID NIH HHS [U01 AI041110, AI27658, U01 AI027658, U01 AI068632-03, U01 AI41110, UM1 AI069477]; NICHD NIH HHS [HD-3-3345] NR 33 TC 59 Z9 60 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2008 VL 48 IS 4 BP 408 EP 417 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 328OQ UT WOS:000257808100005 PM 18614923 ER PT J AU Chantry, CJ Hughes, MD Alvero, C Cervia, JS Hodge, J Borum, P Moye, J AF Chantry, Caroline J. Hughes, Michael D. Alvero, Carmelita Cervia, Joseph S. Hodge, Janice Borum, Peggy Moye, Jack, Jr. CA PACTG 1010 Team TI Insulin-like growth factor-1 and lean body mass in HIV-infected children SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT Conference on Initative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living with HIV/AIDS CY JUN 28-30, 2007 CL Chicago, IL DE HIV; insulin-like growth factor-1; growth; body composition; lean body mass; children; binding proteins; IGF-1-binding protein-1; IGF-1-binding protein-3 ID HUMAN-IMMUNODEFICIENCY-VIRUS; FACTOR BINDING PROTEIN-1; PLACEBO-CONTROLLED TRIAL; THERAPY; HORMONE; BORN; INTERLEUKIN-6; MORTALITY; CELLS; WOMEN AB Objectives: To describe insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1-binding protein-1 (IGFBP-1) and IGFBP-3 in HIV+ children before and after initiating or changing antiretroviral therapy and to evaluate association of growth and body composition to growth factors at baseline and over time. Methods: Ninety-seven prepubertal HIV+ children aged I month to younger than 13 years were observed over 48 weeks after beginning or changing antiretroviral therapy. Serum IGF-1, IGFBP-1, and IGFBP-3 were measured and compared with age- and sex-specific norms. Anthropometric measures were compared as follows: subjects vs matched children from (a) the National Health and Nutrition Examination Survey to generate z scores and (b) HIV-exposed, uninfected children from Women and Infants Transmission Study; and subjects with normal vs abnormal IGF-1 and IGFBP concentrations at baseline. Anthropometric changes were compared for children whose IGF-1 level normalized vs remaining subjects. Multivariate analysis adjusting for sex, race, and baseline age evaluated associations between anthropometry and IGF-1 and IGFBP concentrations. Results: In multivariate analysis, lower baseline IGF-1 and IGFBP-3 were associated with lower mean weight, height, mid-arm muscle circumference, and mid-thigh circumference z scores. Twenty-four percent of children had a low IGF-1 level at baseline, 50% of whom normalized IGF-1 on study. Children whose IGF-1 normalized had greater increases in mean mid-arm muscle circumference z score (1.00 vs -0.03, P = 0.029), but a trend toward lesser mean height increase (P = 0.082) than remaining subjects. Likewise, in comparison to controls from Women and Infants Transmission Study, mean mid-arm muscle circumference also increased more in children whose IGF-1 normalized (P = 0.024) but mean height changed less (P = 0.003). Fifty-five percent of children had elevated IGFBP-1 at baseline, 69% of whom normalized. Conclusions: IGF-1 increases and IGFBP-1 decreases in HIV-infected children upon initiation or change in antiretroviral therapy. Improved muscle mass, but not linear growth, is associated with normalized IGF-1 concentration. These findings suggest that IGF-1 may merit evaluation as a potential therapeutic strategy to improve lean body mass in HIV-infected children. C1 [Chantry, Caroline J.] Univ Calif Davis, Med Ctr, Dept Pediat, Sacramento, CA 95817 USA. [Hughes, Michael D.; Alvero, Carmelita] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Cervia, Joseph S.] Albert Einstein Coll Med, Dept Internal Med & Pediat, Bronx, NY 10467 USA. [Hodge, Janice] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Borum, Peggy] Univ Florida, Dept Food Sci & Human Nutr, Gainesville, FL 32611 USA. [Borum, Peggy] Univ Florida, Dept Pediat, Gainesville, FL 32611 USA. [Moye, Jack, Jr.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Chantry, CJ (reprint author), Univ Calif Davis, Med Ctr, Dept Pediat, 2516 Stockton Blvd, Sacramento, CA 95817 USA. EM caroline.chantry@ucdmc.ucdavis.edu OI moye, john/0000-0001-9976-8586 NR 28 TC 7 Z9 8 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2008 VL 48 IS 4 BP 437 EP 443 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 328OQ UT WOS:000257808100008 PM 18614924 ER PT J AU Cohen, SG AF Cohen, Sheldon G. TI Asthma and athletics SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material C1 [Cohen, Sheldon G.] NIAID, Bethesda, MD 20892 USA. [Cohen, Sheldon G.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, 8600 Rockville Pike,Bldg 38,Room 1E21, Bethesda, MD 20892 USA. EM scohen@niaid.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2008 VL 122 IS 2 BP 435 EP 439 DI 10.1016/j.jaci.2008.05.046 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 337HO UT WOS:000258426300045 PM 18678347 ER PT J AU Brindle, TJ Miller, JL Lebiedowska, MK Stanhope, SJ AF Brindle, Timothy J. Miller, Jeri L. Lebiedowska, Maria K. Stanhope, Steven J. TI Gastrocnemius Fascicle Length Changes With Two-Joint Passive Movements SO JOURNAL OF APPLIED BIOMECHANICS LA English DT Article DE ultrasound; muscle; kinematics ID MUSCLE-TENDON UNIT; IN-VIVO; MECHANICAL-PROPERTIES; HUMAN WALKING; LEG MUSCLES; MOMENT ARM; ANKLE; JOINT; KNEE; CONTRACTION AB Predicting muscle fascicle length changes during passive movements may lead to a better understanding of muscle function. The purpose of this study was to experimentally compare fascicle length changes in the gastrocnemius during two-joint passive movements with a previously derived kinematic model based on anatomical measures from a cadaver. The ratio of passive ankle to knee motion was manipulated to generate medial gastrocnemius fascicle elongation and lateral gastrocnemius fascicle shortening. Ultrasound images from both heads of the gastrocnemius fascicles were acquired at 10 degrees knee flexion increments and compared with this kinematic model. Our results suggest that the two-joint kinematic model from which we originally based our knee and ankle movements did not adequately reflect fascicle length changes during any of the movement conditions in this study. From our data, we propose that for every degree of ankle motion the medial and lateral gastrocnemius changes 0.42 mm and 0.96 mm, respectively, whereas changes of 0.14 mm and 0.22 mm are observed for the medial and lateral gastrocnemius, respectively, during knee movements. C1 [Brindle, Timothy J.; Miller, Jeri L.; Lebiedowska, Maria K.; Stanhope, Steven J.] Natl Inst Hlth, Biomech Lab, Bethesda, MD 20892 USA. RP Brindle, TJ (reprint author), Natl Inst Hlth, Biomech Lab, Bethesda, MD 20892 USA. NR 27 TC 4 Z9 4 U1 0 U2 6 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1065-8483 J9 J APPL BIOMECH JI J. Appl. Biomech. PD AUG PY 2008 VL 24 IS 3 BP 252 EP 261 PG 10 WC Engineering, Biomedical; Sport Sciences SC Engineering; Sport Sciences GA 366MD UT WOS:000260484800007 PM 18843155 ER PT J AU Chenoweth, MR Wickner, S AF Chenoweth, Matthew R. Wickner, Sue TI Complex regulation of the DnaJ homolog CbpA by the global regulators sigma(S) and Lrp, by the specific inhibitor CbpM, and by the proteolytic degradation of CbpM SO JOURNAL OF BACTERIOLOGY LA English DT Article ID P-BAD PROMOTER; ESCHERICHIA-COLI; STATIONARY-PHASE; MOLECULAR CHAPERONE; SMALL RNA; EXPRESSION; REPLICATION; GENES; MODULATION; STARVATION AB CbpA is a DnaJ homolog that functions as a DnaK cochaperone. Several cellular processes, including growth at low and high temperatures and septum formation during cell division, require either CbpA or DnaJ. CbpA is encoded in an operon with the gene for CbpM, which is a specific in vivo and in vitro inhibitor of CbpA. Here, we have cooverexpressed CbpA with CbpM in a Delta cbpAM Delta dnaJ strain and examined the resulting phenotypes. Under these conditions, sufficient free CbpA activity was present to support growth at low temperatures, but not at high temperatures. Defects in cell division and in lambda replication were also partially complemented by CbpA when cooverexpressed with CbpM. Utilizing reporter fusions, we demonstrated that the cbpAM operon was maximally transcribed at the transition from exponential growth to stationary phase. Transcription was controlled by the sigma(S) and Lrp global regulators, and both leucine availability and growth temperature influenced transcription. CbpA and CbpM accumulated to similar levels in stationary phase, similar to 2,300 monomers per cell. When not bound to CbpA, CbpM was unstable and was degraded by the Lon and ClpAP proteases. These data demonstrate that CbpA activity is controlled at multiple levels. C1 [Chenoweth, Matthew R.; Wickner, Sue] Natl Canc Inst, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), Natl Canc Inst, Mol Biol Lab, NIH, 37 Convent Dr,Rm 5144, Bethesda, MD 20892 USA. EM WicknerS@mail.nih.gov FU Intramural NIH HHS NR 31 TC 11 Z9 11 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2008 VL 190 IS 15 BP 5153 EP 5161 DI 10.1128/JB.00437-08 PG 9 WC Microbiology SC Microbiology GA 332VV UT WOS:000258112100002 PM 18502857 ER PT J AU Rajabi, M de Leeuw, E Pazgier, M Li, J Lubkowski, J Lu, W AF Rajabi, Mohsen de Leeuw, Erik Pazgier, Marzena Li, Jing Lubkowski, Jacek Lu, Wuyuan TI The conserved salt bridge in human alpha-defensin 5 is required for its precursor processing and proteolytic stability SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN ALPHA-DEFENSINS; HUMAN BETA-DEFENSINS; ANTIMICROBIAL PEPTIDES; HOST-DEFENSE; MAMMALIAN DEFENSINS; NEUTROPHIL DEFENSIN; CHEMICAL LIGATION; MOUSE CRYPTDIN-4; PANETH CELLS; PROTEINS AB Mammalian alpha-defensins, expressed primarily in leukocytes and epithelia, play important roles in innate and adaptive immune responses to microbial infection. Six invariant cysteine residues forming three indispensable disulfide bonds and one Gly residue required structurally for an atypical beta-bulge are totally conserved in the otherwise diverse sequences of all known mammalian alpha-defensins. In addition, a pair of oppositely charged residues (Arg/Glu), forming a salt bridge across a protruding loop in the molecule, is highly conserved. To investigate the structural and functional roles of the conserved Arg(6)-Glu(14) salt bridge in human alpha-defensin 5 (HD5), we chemically prepared HD5 and its precursor proHD5 as well as their corresponding salt bridge-destabilizing analogs E14Q-HD5 and E57Q-proHD5. The Glu-to-Gln mutation, whereas significantly reducing the oxidative folding efficiency of HD5, had no effect on the folding of proHD5. Bovine trypsin productively and correctly processed proHD5 in vitro but spontaneously degraded E57Q-proHD5. Significantly, HD5 was resistant to trypsin treatment, whereas E14Q-HD5 was highly susceptible. Further, degradation of E14Q-HD5 by trypsin was initiated by the cleavage of the Arg(13)-Gln(14) peptide bond in the loop region, a catastrophic proteolytic event resulting directly in quick digestion of the whole defensin molecule. The E14Q mutation did not alter the bactericidal activity of HD5 against Staphylococcus aureus but substantially enhanced the killing of Escherichia coli. By contrast, proHD5 and E57Q-proHD5 were largely inactive against both strains at the concentrations tested. Our results confirm that the primary function of the conserved salt bridge in HD5 is to ensure correct processing of proHD5 and subsequent stabilization of mature alpha-defensin in vivo. C1 [Rajabi, Mohsen; de Leeuw, Erik; Li, Jing; Lu, Wuyuan] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Rajabi, Mohsen; de Leeuw, Erik; Li, Jing; Lu, Wuyuan] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Pazgier, Marzena; Lubkowski, Jacek] NCI, Macromol Assembly Struct & Cell Signaling Sect, Natl Inst Hlth, Frederick, MD 21702 USA. RP Lu, W (reprint author), Univ Maryland, Sch Med, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM wlu@ihv.umaryland.edu RI Lu, Wuyuan/B-2268-2010; Pazgier, Marzena/B-7295-2012 FU NIAID NIH HHS [AI 056264, AI 061482] NR 53 TC 33 Z9 34 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 1 PY 2008 VL 283 IS 31 BP 21509 EP 21518 DI 10.1074/jbc.M801851200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 329VN UT WOS:000257898800024 PM 18499668 ER PT J AU Ramaswamy, S Gurkan, L Sharma, B Cascio, B Fishbein, KW Spencer, RG AF Ramaswamy, Sharan Gurkan, Liksen Sharma, Blanka Cascio, Brett Fishbein, Kenneth W. Spencer, Richard G. TI Assessment of tissue repair in full thickness chondral defects in the rabbit using magnetic resonance imaging transverse relaxation measurements SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE articular cartilage; histomorphometry; hydrogel; measurement/assessment; tissue engineering ID ARTICULAR-CARTILAGE; OSTEOCHONDRAL REPAIR; MRI; IMPLANTATION; CHONDROCYTES; GRAFTS; MODEL; KNEE AB The purpose of this study was to determine if the noninvasive and nondestructive technique of magnetic resonance imaging could be used to quantify the amount of repair tissue that fills surgically-induced chondral defects in the rabbit. Sixteen 4-mm diameter full-thickness chondral defects were created. A photopolymerizable hydrogel was used to seal the defects as a treatment modality. At 5 weeks, the animals were sacrificed and the distal femur was subjected to MRI analyses at high field (9.4 T). The transverse relaxation time (T-2) in each defect was measured. Histology and histomorphometric analysis were used to quantify the amount of repair tissue that filled each defect. The relationship between T-2 and percent tissue fill was found to fit well to a negatively sloped, linear model. The linear (Pearson's product-moment) correlation coefficient was found to be r = -0.82 and the associated coefficient of determination was r(2) = 0.67. This correlation suggests that the MRI parameter T-2 can be used to track changes in the amount of repair tissue that fills cartilage defects. This would be especially useful in in vivo cartilage tissue engineering studies that attempt to determine optimal biomaterials for scaffold design. (c) 2007 Wiley Periodicals, Inc. C1 [Ramaswamy, Sharan; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Gurkan, Liksen; Cascio, Brett] Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, Baltimore, MD 21287 USA. [Sharma, Blanka] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. RP Spencer, RG (reprint author), NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Room 4D-08,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU Intramural NIH HHS NR 27 TC 12 Z9 13 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4973 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD AUG PY 2008 VL 86B IS 2 BP 375 EP 380 DI 10.1002/jbm.b.31030 PG 6 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 330GT UT WOS:000257929400010 PM 18161814 ER PT J AU Amyot, F Small, A Boukari, H Sackett, D Elliott, J McDaniel, D Plant, A Gandjbakhche, A AF Amyot, Franck Small, Alex Boukari, Hacene Sackett, Dan Elliott, John McDaniel, Dennis Plant, Anne Gandjbakhche, Amir TI Thin films of oriented collagen fibrils for cell motility studies SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE thin collagen film; endothelial cell motility; morphology; assay ID EXTRACELLULAR-MATRIX; CONTACT GUIDANCE; MIGRATION; FIBROBLASTS; ORIENTATION; MORPHOLOGY; PROTRUSION; COMPLEXES; CUES; GELS AB Collagen films with oriented fibrils mimic tissues that have been remodeled by fibroblasts, which naturally tend to orient collagen fibrils in vivo. We have prepared thin films of ordered fibrils of collagen I, a major component of the extracellular matrix. The films were prepared by modifying a technique previously used to produce collagen I films for studies of cell morphology and intracellular signaling. By modifying the drying step, we were able to produce thin monolayers of collagen fibrils with consistent orientations over macroscopic (> 100 mu m) distances. We quantified the degree of orientation of the collagen fibrils using Fourier analysis of optical microscopy images. We also conducted experiments with vascular endothelial cells, and found that cell orientation and migration are well-correlated with fibril orientation. Using polarized cells, we showed oriented thin collagen Him induces natural migration along the fibrils without using any sort of attractor. Taken together, these results demonstrate additional functionality and physiological relevance for a class of films being successfully applied in a variety of cell biology experiments. (c) 2008 Wiley Periodicals, Inc. C1 [Amyot, Franck; Small, Alex; Gandjbakhche, Amir] NICHHD, Lab Integrat & Med Biophys, Sect Biomed Stochast Phys, NIH, Bethesda, MD 20892 USA. [Boukari, Hacene; Sackett, Dan] NICHHD, Lab Integrat & Med Biophys, Sect Cell Biophys, NIH, Bethesda, MD 20892 USA. [Elliott, John; McDaniel, Dennis; Plant, Anne] Natl Inst Stand & Technol, Div Biotechnol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Amyot, F (reprint author), NICHHD, Lab Integrat & Med Biophys, Sect Biomed Stochast Phys, NIH, 9 South Dr, Bethesda, MD 20892 USA. EM amyotf@mail.nih.gov NR 27 TC 7 Z9 7 U1 1 U2 12 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4973 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD AUG PY 2008 VL 86B IS 2 BP 438 EP 443 DI 10.1002/jbm.b.31039 PG 6 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 330GT UT WOS:000257929400018 PM 18286591 ER PT J AU Kuszewski, JJ Thottungal, RA Clore, GM Schwieters, CD AF Kuszewski, John J. Thottungal, Robin Augustine Clore, G. Marius Schwieters, Charles D. TI Automated error-tolerant macromolecular structure determination from multidimensional nuclear Overhauser enhancement spectra and chemical shift assignments: improved robustness and performance of the PASD algorithm SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE automated structure determination; automated NOE assignment; Xplor-NIH ID PROTEIN-STRUCTURE DETERMINATION; RESTRAINED MOLECULAR-DYNAMICS; NMR STRUCTURE DETERMINATION; POTATO CARBOXYPEPTIDASE INHIBITOR; MAGNETIC-RESONANCE SPECTROSCOPY; X-RAY-SCATTERING; 3-DIMENSIONAL STRUCTURES; DISTANCE GEOMETRY; DIPOLAR COUPLINGS; HIGH-RESOLUTION AB We report substantial improvements to the previously introduced automated NOE assignment and structure determination protocol known as PASD (Kuszewski et al. (2004) J Am Chem Soc 26:6258-6273). The improved protocol includes extensive analysis of input spectral data to create a low-resolution contact map of residues expected to be close in space. This map is used to obtain reasonable initial guesses of NOE assignment likelihoods which are refined during subsequent structure calculations. Information in the contact map about which residues are predicted to not be close in space is applied via conservative repulsive distance restraints which are used in early phases of the structure calculations. In comparison with the previous protocol, the new protocol requires significantly less computation time. We show results of running the new PASD protocol on six proteins and demonstrate that useful assignment and structural information is extracted on proteins of more than 220 residues. We show that useful assignment information can be obtained even in the case in which a unique structure cannot be determined. C1 [Kuszewski, John J.; Thottungal, Robin Augustine; Schwieters, Charles D.] Natl Inst Hlth, Ctr Informat Technol, Imaging Sci Lab, Bethesda, MD 20892 USA. [Clore, G. Marius] NIDDK, Natl Inst Hlth, Chem Phys Lab, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), Natl Inst Hlth, Ctr Informat Technol, Imaging Sci Lab, Bldg 12A, Bethesda, MD 20892 USA. EM Charles.Schwieters@nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS [Z01 CT000090-27, Z01 DK029023-17, Z99 CT999999] NR 50 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD AUG PY 2008 VL 41 IS 4 BP 221 EP 239 DI 10.1007/s10858-008-9255-1 PG 19 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 339XR UT WOS:000258611100004 PM 18668206 ER PT J AU Titus, SA Xiao, L Southall, N Lu, JM Inglese, J Brasch, M Austin, CP Zheng, W AF Titus, Steven A. Xiao, Li Southall, Noel Lu, Jianming Inglese, James Brasch, Michael Austin, Christopher P. Zheng, Wei TI Cell-based PDE4 assay in 1536-well plate format for high-throughput screening SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE phosphodiesterase; PDE4; cyclic nucleotide gated ion channels; cell-based assay; high-throughout screening ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; SELECTIVE INHIBITORS; DRUG DEVELOPMENT; THYROTROPIN; RECEPTOR; POTENT; EXPRESSION; SUBTYPE; TARGETS; CLONING AB The cyclic nucleotide phosphodiesterases (PDEs) are intracellur enzymes that catalyze the hydrolysis of 3,'5'-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their sorresponding 5'-nuceotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases, including asthma, cardiovascular disease, attention-deficit hyperactivity disorder. Parkinson's disease, and Alzheimer's disease. Although biochemical assays would provide a better assessment of compund activity in a more physiological context. The authors report the development and validation of a new cell-based PDE4 assay using a constitutively active G-protein-coupled receptor as a driving force for cAMP production and a cyclic nucleotide-gated cation channel as a biosensor in 1536-well plates. C1 [Titus, Steven A.; Southall, Noel; Inglese, James; Austin, Christopher P.; Zheng, Wei] NIH, Chem Genom Ctr, NHGRI, Bethesda, MD 20892 USA. [Xiao, Li; Lu, Jianming; Brasch, Michael] BD Biosci, Rockville, MD USA. RP Zheng, W (reprint author), NIH, Chem Genom Ctr, NHGRI, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU National Human Genome Research Institute; National Institutes of Health FX We thank Paul Shinn and Adam Yasgar for the compound management and Sam Michael. Carleen Klumpp, and Dick Jones for technical assistance with instrumentation. This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 37 TC 10 Z9 10 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD AUG PY 2008 VL 13 IS 7 BP 609 EP 618 DI 10.1177/1087057108319977 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 340VN UT WOS:000258673200004 PM 18591513 ER PT J AU Austin, C AF Austin, Christopher TI HTS & chemical genomics in academia: Opportunity and challenge SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Meeting Abstract C1 [Austin, Christopher] Natl Inst Hlth, Chem Genom Ctr NCGC, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD AUG PY 2008 VL 13 IS 7 BP 702 EP 702 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 340VN UT WOS:000258673200036 ER PT J AU Ahmet, I Lakatta, EG Talan, MI AF Ahmet, Ismayil Lakatta, Edward G. Talan, Mark I. TI Combination of beta 1AR blocker and beta 2AR agonist vs. combination of beta 1AR blocker and ACEI in the treatment of chronic heart failure: Comparison of therapeutic effectiveness SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 [Ahmet, Ismayil; Lakatta, Edward G.; Talan, Mark I.] NIH, NIA, Cardiovasc Sci Lab, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 233 BP S74 EP S74 DI 10.1016/j.cardfail.2008.06.417 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100234 ER PT J AU Carson, P Gottleib, S Anand, I Plehn, J Silver, M Lindenfeld, J Chris, O Miller, A White, M Fiuzat, M Liggett, SB Davis, G Robertson, AD Bristow, MR AF Carson, Peter Gottleib, Stephen Anand, Inder Plehn, Johnathan Silver, Marc Lindenfeld, JoAnn Chris, O'Connor Miller, Alan White, Michel Fiuzat, Mona Liggett, Stephen B. Davis, Gordon Robertson, A. Douglas Bristow, Michael R. TI Determination of hospitalization type by investigator case report form or adjudication committee in a large heart failure clinical trial (BEST) SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 [Lindenfeld, JoAnn; Robertson, A. Douglas; Bristow, Michael R.] Univ CO HSC, Denver, CO USA. [Fiuzat, Mona; Davis, Gordon; Bristow, Michael R.] ARCA Biopharma Inc, Denver, CO USA. [Miller, Alan] Univ FL Jacksonville, Jacksonville, FL USA. [Anand, Inder] Univ Minnesota, Minneapolis, MN USA. [Carson, Peter] VAMC, Washington, DC USA. [White, Michel] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Plehn, Johnathan] NHLBI, Bethesda, MD 20892 USA. [Gottleib, Stephen; Liggett, Stephen B.] Univ MD, Med Ctr, Baltimore, MD USA. Duke Univ, Durham, NC USA. [Silver, Marc] Advocate Christ Hosp, Chicago, IL USA. RI bristow, michael/G-7850-2011; liggett, stephen/E-7453-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 302 BP S93 EP S93 DI 10.1016/j.cardfail.2008.06.258 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100302 ER PT J AU Lindenfeld, J Liggett, SB Plehn, J Port, JD Fiuzat, M Budhathoki, C Bristow, MR AF Lindenfeld, Joann Liggett, Stephen B. Plehn, Johnathan Port, J. David Fiuzat, Mona Budhathoki, Chakra Bristow, Michael R. TI Ischemic cardiomyopathy response to bucindolol may be differentially Influenced by b(1) 389 Arg/Gly and b(2) Genotypes SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 [Lindenfeld, Joann; Port, J. David; Budhathoki, Chakra; Bristow, Michael R.] Univ CO, HSC, Denver, CO USA. [Liggett, Stephen B.] Univ MD Med Ctr, Baltimore, MD USA. [Port, J. David; Fiuzat, Mona; Bristow, Michael R.] ARCA Biopharma Inc, Denver, CO USA. [Plehn, Johnathan] NHLBI, Bethesda, MD 20892 USA. RI bristow, michael/G-7850-2011; liggett, stephen/E-7453-2012 NR 0 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 247 BP S77 EP S78 DI 10.1016/j.cardfail.2008.06.431 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100248 ER PT J AU Lindenfeld, J Plehn, J Liggett, SB Port, JD Fiuzat, M Robertson, AD Budhathoki, C Bristow, MR AF Lindenfeld, JoAnn Plehn, Johnathan Liggett, Stephen B. Port, J. David Fiuzat, Mona Robertson, A. Douglas Budhathoki, Chakra Bristow, Michael R. TI Different patterns of LVEF/remodeling and clinical endpoint effects for bucindolol in b(1)-AR 389 Arg/Gly genotypes SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 [Lindenfeld, JoAnn; Port, J. David; Robertson, A. Douglas; Budhathoki, Chakra; Bristow, Michael R.] Univ Colorado, HSC, Denver, CO 80202 USA. [Fiuzat, Mona; Bristow, Michael R.] ARCA Biopharma Inc, Denver, CO USA. [Plehn, Johnathan] NHLBI, Bethesda, MD 20892 USA. [Liggett, Stephen B.] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. RI bristow, michael/G-7850-2011; liggett, stephen/E-7453-2012 NR 0 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 127 BP S40 EP S41 DI 10.1016/j.cardfail.2008.06.287 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100128 ER PT J AU O'Connor, C Anand, I Fiuzat, M Plehn, J Goulieb, S Silver, M Lindenfeld, J Miller, A White, M Robertson, A Bristow, M Carson, P AF O'Connor, C. Anand, I. Fiuzat, M. Plehn, J. Goulieb, S. Silver, M. Lindenfeld, J. Miller, A. White, M. Robertson, A. Bristow, M. Carson, P. TI Additive effects of beta(1) 389 Arg/Gly alpha(2c) 322-325 Wt/Del genotype combinations on adjudicated hospitalizations and death in the beta-blocker evaluation of survival trial (BEST) SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 NHLBI, Bethesda, MD 20892 USA. MHI, Arlington, VA 22201 USA. RI bristow, michael/G-7850-2011 NR 0 TC 7 Z9 7 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 216 BP S69 EP S69 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100217 ER PT J AU Kirk, MJ Hayward, RM Sproull, M Scott, T Smith, S Cooley-Zgela, T Crouse, NS Citrin, DE Camphausen, K AF Kirk, M. J. Hayward, R. M. Sproull, M. Scott, T. Smith, S. Cooley-Zgela, T. Crouse, N. S. Citrin, D. E. Camphausen, K. TI Non-patient related variables affecting levels of vascular endothelial growth factor in urine biospecimens SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE angiogenesis; VEGF; tumour markers; urine; biospecimens ID METASTATIC COLORECTAL-CANCER; CLINICAL-SIGNIFICANCE; BREAST-CANCER; ANGIOGENESIS; BEVACIZUMAB; FLUOROURACIL; COMBINATION; LEUCOVORIN; KINETICS; MARKERS AB Vascular endothelial growth factor (VEGF) is an angiogenic protein proposed to be an important biomarker for the prediction of tumour growth and disease progression. Recent studies suggest that VEGF measurements in biospecimens, including urine, may have predictive value across a range of cancers. However, the reproducibility and reliability of urinary VEGF measurements have not been determined. We collected urine samples from patients receiving radiation treatment for glioblastoma multiforme (GBM) and examined the effects of five variables on measured VEGF levels using an ELISA assay. To quantify the factors affecting the precision of the assay, two variables were examined: the variation between ELISA kits with different lot numbers and the variation between different technicians. Three variables were tested for their effects on measured VEGF concentration: the time the specimen spent at room temperature prior to assay, the addition of protease inhibitors prior to specimen storage and the alteration of urinary pH. This study found that VEGF levels were consistent across three different ELISA kit lot numbers. However, significant variation was observed between results obtained by different technicians. VEGF concentrations were dependent on time at room temperature before measurement, with higher values observed 3-7 hrs after removal from the freezer. No significant difference was observed in VEGF levels with the addition of protease inhibitors, and alteration of urinary pH did not significantly affect VEGF measurements. In conclusion, this determination of the conditions necessary to reliably measure urinary VEGF levels will be useful for future studies related to protein biomarkers and disease progression. C1 [Kirk, M. J.; Hayward, R. M.; Sproull, M.; Scott, T.; Smith, S.; Cooley-Zgela, T.; Crouse, N. S.; Citrin, D. E.; Camphausen, K.] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room B2-3561,10 Ctr Dr, Bethesda, MD 20892 USA. EM Camphauk@mail.nih.gov FU Intramural NIH HHS NR 21 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD AUG PY 2008 VL 12 IS 4 BP 1250 EP 1255 DI 10.1111/j.1582-4934.2007.00182.x PG 6 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 336IU UT WOS:000258358300022 PM 18782189 ER PT J AU Kim, JS Romero, R Tarca, AL LaJeunesse, C Han, YM Kim, MJ Suh, YL Draghici, S Mittal, P Gotsch, F Kusanovic, JP Hassan, S Kim, CJ AF Kim, Jung-Sun Romero, Roberto Tarca, Adi Laurentiu LaJeunesse, Christopher Han, Yu Mi Kim, Mi Jeong Suh, Yeon Lim Draghici, Sorin Mittal, Pooja Gotsch, Francesca Kusanovic, Juan Pedro Hassan, Sonia Kim, Chong Jai TI Gene expression profiling demonstrates a novel role for foetal fibrocytes and the umbilical vessels in human fetoplacental development SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE umbilical vein; umbilical artery; placenta; funisitis; chorioamnionitis; intrauterine growth restriction; transcriptome; microarray ID INFLAMMATORY RESPONSE SYNDROME; CIRCULATING FIBROCYTES; PERIPHERAL-BLOOD; STEM-CELLS; BRONCHOPULMONARY DYSPLASIA; INFECTION; CORD; BIOLOGY; ARTERY; DIFFERENTIATION AB There is a difference in the susceptibility to inflammation between the umbilical vein (UV) and the umbilical arteries (UAs). This led us to hypothesize that there is an intrinsic difference in the pro-inflammatory response between UA and UV. Real-time quantitative RT-PCR and microarray analysis revealed higher expression of interleukin (IL)-1 beta and IL-8 mRNA in the UV and differential expression of 567 genes between the UA and UV associated with distinct biological processes, including the immune response. Differential expression of human leukocyte antigen (HLA)-DRA mRNA between the UA and UV was due to unexpected HLA-DR(+) cells migrating via the umbilical vessels into Wharton's jelly, more frequently in the UV. A significant proportion of these cells co-expressed CD45 and type I pro-collagen, and acquired CD163 or alpha-smooth muscle actin immunoreactivity in Wharton's jelly. Migrating cells were also found in the chorionic and stem villous vessels. Furthermore, the extent of migration increased with progression of gestation, but diminished in intrauterine growth restriction (IUGR). The observations herein strongly suggest that circulating foetal fibrocytes, routing via umbilical and placental vessels, are a reservoir for key cellular subsets in the placenta. This study reports fibrocytes in the human umbilical cord and placenta for the first time, and a novel role for both circulating foetal cells and the umbilical vessels in placental development, which is deranged in IUGR. C1 [Kim, Jung-Sun; Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Kim, Jung-Sun; Mittal, Pooja; Hassan, Sonia] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Tarca, Adi Laurentiu; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Suh, Yeon Lim] Sungkyunkwan Univ, Sch Med, Dept Pathol, Seoul, South Korea. RP Kim, CJ (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM cjkim@med.wayne.edu RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 FU Intramural NIH HHS [Z01 HD002400-17] NR 45 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD AUG PY 2008 VL 12 IS 4 BP 1317 EP 1330 DI 10.1111/j.1582-4934.2008.00284.x PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 336IU UT WOS:000258358300028 PM 18298660 ER PT J AU Inkson, CA Ono, M Kuznetsov, SA Fisher, LW Robey, PG Young, MF AF Inkson, Colette A. Ono, Mitsuaki Kuznetsov, Sergei A. Fisher, Larry W. Robey, Pamela Gehron Young, Marian F. TI TGF-beta 1 and WISP-1/CCN-4 can regulate each other's activity to cooperatively control osteoblast function SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE WISP-1; CCN; TGF-beta 1; BMP; wnt; osteoblast; proliferation; differentiation; smad-2; VWF-IIc; chordin ID TISSUE GROWTH-FACTOR; MESENCHYMAL STEM-CELLS; PROGRESSIVE PSEUDORHEUMATOID DYSPLASIA; IMMEDIATE-EARLY GENE; FACTOR CTGF; IN-VITRO; TGF-BETA; AXIAL SKELETON; WNT PATHWAYS; CCN FAMILY AB Wnt-induced secreted protein-1 (WISP-1), likeother members of the CCN family, is expressed in skeletal tissues. Its mechanism of action remains unknown. Expression of WISP-1 was analyzed in human bone marrow stroma cells (hBMSC) by RT-PCR. We identified two major transcripts corresponding to those Of full-length WISP-1, and of the splice variant WISP-1va which lacks a putative BMP/TGF-beta binding site. To investigate the function Of WISP-1 in bone, hBMSC cultures were treated with recombinant human (rh)WISP-1 and analyzed for proliferation and osteogenic differentiation. WISP-1 treatment increased both BrdU incorporation and alkaline phosphatase (AP) activity. Considering the known functional synergy found between the TGF-beta super-family and members of the CCN family, we next tested the effect of WISP-1 on TGF-beta 1 activity. We found that rhWISP-1 could reduce rhTGF-beta 1 induced BrdU incorporation. Similarly, rhTGF-beta 1 inhibited rhWISP-1 induction of AP activity. To explore functional differences between the WISP-1 variants, WISP-1 or WISP-1va were transfected into hBMSC. Both variants could strongly induce BrdU incorporation. However, there were no effects of either variant on AP activity without an additional osteogenic Stimulus Such as TGF-beta 1. Taken together Our results suggest a functional relationship between WISP-1 and TGF-beta 1. To further define this relationship we analyzed the effect of WISP-1 on TGF-beta signaling. rhWISP-1 significantly reduced TGF-beta 1 induced phosphorylation of Smad-2. Our data indicates that full-length WISP-1 and its variant WISP-1va are modulators of proliferation and osteogenic differentiation, and may be novel regulators of TGF-beta 1 signaling in osteoblast-like cells. C1 [Inkson, Colette A.; Ono, Mitsuaki; Kuznetsov, Sergei A.; Fisher, Larry W.; Robey, Pamela Gehron; Young, Marian F.] NIDR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Young, MF (reprint author), NIDR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. EM myoung@dir.nidcr.nih.gov RI Robey, Pamela/H-1429-2011; OI Robey, Pamela/0000-0002-5316-5576; Inkson, Colette/0000-0003-1215-312X FU Intramural NIH HHS [Z01 DE000379-24] NR 55 TC 31 Z9 35 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD AUG 1 PY 2008 VL 104 IS 5 BP 1865 EP 1878 DI 10.1002/jcb.21754 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 334SD UT WOS:000258240600031 PM 18404666 ER PT J AU Kumar, A Jeang, KT AF Kumar, Ajit Jeang, Kuan-Teh TI Insights into cellular microRNAs and human immunodeficiency virus type 1 (HIV-1) SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID SMALL INTERFERING RNAS; DOUBLE-STRANDED-RNA; ENDOGENOUS RETROVIRUSES; ANTIVIRAL DEFENSE; SILENCING PATHWAY; MAMMALIAN-CELLS; BINDING PROTEIN; NONCODING RNAS; TAR ELEMENT; DICER AB Recent findings suggest that mammalian microRNAs (miRNAs) may influence viral replication in host cells. Studies on HIV-1 infection have contributed in part to the development of this notion. Herein, we review, in brief, some of the evidence supportive of an interplay between human miRNAs and HIV-1 in cells. Several cellular miRNAs potentially act to restrict HIV-1 replication, and the virus has countermeasures to evade such restriction. C1 [Kumar, Ajit] George Washington Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC USA. [Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20889 USA. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20889 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU Intramural NIH HHS NR 79 TC 16 Z9 16 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 2008 VL 216 IS 2 BP 327 EP 331 DI 10.1002/jcp.21488 PG 5 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 322CJ UT WOS:000257352500007 PM 18452151 ER PT J AU Duverger, O Morasso, MI AF Duverger, Olivier Morasso, Maria I. TI Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID NAIL-PATELLA-SYNDROME; RESTRICTED HOMEODOMAIN PROTEIN; HAIR FOLLICLE DEVELOPMENT; EARLY TOOTH DEVELOPMENT; GLAND DEVELOPMENT; MURINE DENTITION; EXPRESSION PATTERNS; STEM-CELLS; CRANIOFACIAL DEVELOPMENT; ODONTOGENIC MESENCHYME AB Homeobox genes are an evolutionarily conserved class of transcription factors that are key regulators during developmental processes such as regional specification, patterning, and differentiation. In this review, we summarize the expression pattern, loss- and/or gain-of-function mouse models, and naturally occurring mouse and human mutations of known homeobox genes required for the development of ectodermal appendages. C1 [Duverger, Olivier; Morasso, Maria I.] NIAMSD, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. RP Morasso, MI (reprint author), NIAMSD, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. EM morassom@mail.nih.gov FU Intramural NIH HHS [Z01 AR041124-08] NR 114 TC 34 Z9 35 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 2008 VL 216 IS 2 BP 337 EP 346 DI 10.1002/jcp.21491 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 322CJ UT WOS:000257352500009 PM 18459147 ER PT J AU Bishu, S Schmidt, KC Burlin, T Channing, M Conant, S Huang, TJ Liu, ZH Qin, M Unterman, A Xia, ZY Zametkin, A Herscovitch, P Smith, CB AF Bishu, Shrinivas Schmidt, Kathleen C. Burlin, Thomas Channing, Michael Conant, Shielah Huang, Tianjiang Liu, Zhong-hua Qin, Mei Unterman, Aaron Xia, Zengyan Zametkin, Alan Herscovitch, Peter Smith, Carolyn B. TI Regional rates of cerebral protein synthesis measured with L-[1-C-11]leucine and PET in conscious, young adult men: normal values, variability, and reproducibility SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-of-Nuclear-Medicine CY JUN 02-06, 2007 CL Washington, DC SP Soc Nucl Med DE brain; leucine; positron emission tomography-human; protein synthesis ID POSITRON-EMISSION-TOMOGRAPHY; TISSUE AMINO-ACIDS; GLUCOSE-UTILIZATION; PRECURSOR POOL; KINETIC-MODELS; BRAIN TISSUE; LOCAL-RATES; INVIVO; TRACER; MOUSE AB We report regional rates of cerebral protein synthesis ( rCPS) measured with the fully quantitative L-[ 1- C-11] leucine positron emission tomography ( PET) method. The method accounts for the fraction (lambda) of unlabeled amino acids in the precursor pool for protein synthesis derived from arterial plasma; the remainder ( 1 - lambda) comes from tissue proteolysis. We determined rCPS and k in 18 regions and whole brain in 10 healthy men ( 21 to 24 years). Subjects underwent two 90- min dynamic PET studies with arterial blood sampling at least 2 weeks apart. Rates of cerebral protein synthesis varied regionally and ranged from 0.97 +/- 0.70 to 2.25 +/- 0.20nmol/ g per min. Values of rCPS were in good agreement between the two PET studies. Mean differences in rCPS between studies ranged from 9% in cortical regions to 15% in white matter. The k value was comparatively more uniform across regions, ranging from 0.63 +/- 0.03 to 0.79 +/- 0.02. Mean differences in k between studies were 2% to 8%. Intersubject variability in rCPS was on average 6% in cortical areas, 9% in subcortical regions, and 12% in white matter; intersubject variability in k was 2% to 8%. Our data indicate that in human subjects low variance and highly reproducible measures of rCPS can be made with the L-[ 1-C-11] leucine PET method. C1 [Bishu, Shrinivas; Schmidt, Kathleen C.; Burlin, Thomas; Huang, Tianjiang; Liu, Zhong-hua; Qin, Mei; Unterman, Aaron; Xia, Zengyan; Smith, Carolyn B.] Natl Inst Mental Hlth, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. [Channing, Michael; Conant, Shielah] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Zametkin, Alan] Natl Inst Mental Hlth, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Bishu, S (reprint author), Natl Inst Mental Hlth, Sect Neuroadaptat & Prot Metab, NIH, Bldg 10,Room 2D54,10 Ctr Dr, Bethesda, MD 20892 USA. EM bishus@mail.nih.gov FU Intramural NIH HHS [Z01 MH000889-28, NIH0012783015] NR 41 TC 17 Z9 17 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2008 VL 28 IS 8 BP 1502 EP 1513 DI 10.1038/jcbfm.2008.43 PG 12 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 329TB UT WOS:000257892400010 PM 18493259 ER PT J AU Bandelin, PB Moreno, AJ LeMar, HJ Stratakis, CA Oliver, TG AF Bandelin, Paul Byron Moreno, Albert J. LeMar, Homer Jess Stratakis, Constantine A. Oliver, Thomas George TI The use of positron emission tomography-computed tomography scan in the evaluation of a patient with Carney complex SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID DISEASE C1 [LeMar, Homer Jess; Oliver, Thomas George] William Beaumont Army Med Ctr, Endocrine Serv, El Paso, TX 79920 USA. [Bandelin, Paul Byron] William Beaumont Army Med Ctr, Dept Med, El Paso, TX 79920 USA. [Moreno, Albert J.] William Beaumont Army Med Ctr, Nucl Med Serv, El Paso, TX 79920 USA. [Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Oliver, TG (reprint author), William Beaumont Army Med Ctr, Endocrine Serv, 5005 N Piedras St, El Paso, TX 79920 USA. EM Thomas.george.oliver@us.army.mil NR 5 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 2946 EP 2947 DI 10.1210/jc.2008-0313 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500002 PM 18685116 ER PT J AU Panicker, V Cluett, C Shields, B Murray, A Parnell, KS Perry, JRB Weedon, MN Singleton, A Hernandez, D Evans, J Durant, C Ferrucci, L Melzer, D Saravanan, P Visser, TJ Ceresini, G Hattersley, AT Vaidya, B Dayan, CM Frayling, TM AF Panicker, Vijay Cluett, Christie Shields, Beverley Murray, Anna Parnell, Kirstie S. Perry, John R. B. Weedon, Michael N. Singleton, Andrew Hernandez, Dena Evans, Jonathan Durant, Claire Ferrucci, Luigi Melzer, David Saravanan, Ponnusamy Visser, Theo J. Ceresini, Graziano Hattersley, Andrew T. Vaidya, Bijay Dayan, Colin M. Frayling, Timothy M. TI A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID THYROID-HORMONE PARAMETERS; GENOME-WIDE ASSOCIATION; INSULIN-RESISTANCE; SUBCLINICAL HYPOTHYROIDISM; TARGETED DISRUPTION; CONTROLLED-TRIAL; IODOTHYRONINE; POLYMORPHISM; THERAPY; TSH AB Introduction: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. Methods: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation. Results: A SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. Conclusions: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters. C1 [Panicker, Vijay; Saravanan, Ponnusamy; Dayan, Colin M.] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. [Evans, Jonathan; Durant, Claire] Univ Bristol, Acad Unit Psychiat, Bristol BS1 3NY, Avon, England. [Panicker, Vijay] Univ Western Australia, Fac Med Dent & Hlth Sci, Perth, WA 6009, Australia. [Panicker, Vijay; Cluett, Christie; Shields, Beverley; Murray, Anna; Parnell, Kirstie S.; Perry, John R. B.; Weedon, Michael N.; Hernandez, Dena; Hattersley, Andrew T.; Frayling, Timothy M.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England. [Singleton, Andrew; Hernandez, Dena] NIA, Mol Genet Unit, NIH, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Saravanan, Ponnusamy] Univ Warwick, Clin Sci Res Unit, Warwick CV2 2DX, England. [Visser, Theo J.] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3015 GD Rotterdam, Netherlands. [Ceresini, Graziano] Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Vaidya, Bijay] Royal Devon & Exeter Hosp, Dept Endocrinol, Exeter EX2 5DW, Devon, England. RP Dayan, CM (reprint author), Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England. EM Colin.Dayan@bristol.ac.uk RI Singleton, Andrew/C-3010-2009; Saravanan, Ponnusamy/M-6142-2016; OI Saravanan, Ponnusamy/0000-0002-9566-2626; Panicker, Vijay/0000-0003-1551-8411; Dayan, Colin/0000-0002-6557-3462; Murray, Anna/0000-0002-2351-2522; Evans, Jonathan/0000-0003-3171-640X; Vaidya, Bijay/0000-0002-2223-0494; Melzer, David/0000-0002-0170-3838 FU Intramural NIH HHS; NIA NIH HHS [R01 AG24233-01, Z01 AG000965-02, Z01 AG000965, R01 AG024233] NR 29 TC 49 Z9 51 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 3075 EP 3081 DI 10.1210/jc.2008-0397 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500021 PM 18492748 ER PT J AU Smith, EP Specker, B Bachrach, BE Kimbro, KS Li, XJ Young, MF Fedarko, NS Abuzzahab, MJ Frank, GR Cohen, RM Lubahn, DB Korach, KS AF Smith, Eric P. Specker, Bonny Bachrach, Bert E. Kimbro, K. S. Li, X. J. Young, Marian F. Fedarko, Neal S. Abuzzahab, M. J. Frank, Graeme R. Cohen, Robert M. Lubahn, Dennis B. Korach, Kenneth S. TI Impact on bone of an estrogen receptor-alpha gene loss of function mutation SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CONGENITAL AROMATASE DEFICIENCY; POSTMENOPAUSAL WOMEN; CORTICAL BONE; SEX STEROIDS; HISTOMORPHOMETRY; TESTOSTERONE; MEN; MASS; ANDROGENS; OSTEOPOROSIS AB Context: The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor ( ER)-alpha. Objective: Our objective was to assess the impact of a loss of function mutation in the ER-alpha gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-alpha heterozygosity on spine density and adult height in an extended pedigree. Design and Participants: A longitudinal follow-up of the propositus with homozygous loss of function mutation of ER-alpha and single contact evaluation of the kindred were performed. Main Outcome Measures: Iliac crest bone biopsy and peripheral quantitative computed tomography of propositus with serial measures of areal spine bone mineral density (aBMD) by dual-energy x-ray absorptiometry and bone age were performed. Members of pedigree were evaluated for ER-alpha mutation carrier status and spine aBMD. Results: Bone biopsy revealed marked osteopenia (cortex: 641 mu m), low trabecular volume (10.6%), decreased thickness (76.2 mu m), normal trabecular number, and low activation frequency (0.099/yr). Radial periosteal circumference was similar, endosteal circumference larger, and trabecular and cortical volumetric bone mineral density markedly lower (158 and 1092 mg/cm(3), respectively) than controls. Spine aBMD at age 28.5 yr (0.745 g/cm(2)) decreased to 0.684 g/cm(2) (Z score - 3.85) in 3.5 yr. Bone age advanced from 15-17.5 yr. Kindred analysis revealed that gene carriers had spine aBMD Z scores less than zero (P = 0.003), but carriers and nonmutant members were similar (-0.84 +/- 0.26 vs. -0.64 +/- 0.16). Conclusion: Homozygous ER-alpha disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER-alpha heterozygosity appears to not impair spine aBMD. C1 [Smith, Eric P.; Cohen, Robert M.] Univ Cincinnati, Coll Med, Dept Internal Med, Div Endocrinol Diabet & Metab, Cincinnati, OH 45267 USA. [Specker, Bonny] S Dakota State Univ, Ethel Austin Martin Program Human Nutr, Brookings, SD 57007 USA. [Bachrach, Bert E.; Abuzzahab, M. J.] Univ Cincinnati, Coll Med, Div Endocrinol, Childrens Hosp Res Fdn, Cincinnati, OH 45229 USA. [Kimbro, K. S.; Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Kimbro, K. S.] Emory Univ, Sch Med, Dept Hematol & Oncol, Atlanta, GA 30322 USA. [Li, X. J.] Wyeth Ayerst Res, Womens Hlth & Musculoskeletal Biol, Cambridge, MA 02140 USA. [Young, Marian F.] Natl Inst Dent Craniofacial Res, Bethesda, MD 20892 USA. [Fedarko, Neal S.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. [Frank, Graeme R.] Long Isl Jewish Med Ctr, Schneider Childrens Hosp, Div Pediat Endocrinol, New Hyde Pk, NY 11042 USA. [Lubahn, Dennis B.] Univ Missouri, Dept Biochem & Child Hlth, Columbia, MO 65211 USA. RP Smith, EP (reprint author), Univ Cincinnati, Coll Med, Dept Med, Div Endocrinol Diabet & Metab,Vontz Ctr Mol Studi, 3125 Eden Ave, Cincinnati, OH 45267 USA. EM smithep@email.uc.edu OI Korach, Kenneth/0000-0002-7765-418X NR 40 TC 39 Z9 42 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 3088 EP 3096 DI 10.1210/jc.2007-2397 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500023 PM 18505767 ER PT J AU Hivert, MF Sullivan, LM Fox, CS Nathan, DM Sr, RBD Wilson, PWF Meigs, JB AF Hivert, Marie-France Sullivan, Lisa M. Fox, Caroline S. Nathan, David M. Sr, Ralph B. D'Agostino Wilson, Peter W. F. Meigs, James B. TI Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TYPE-2 DIABETES-MELLITUS; C-REACTIVE PROTEIN; ADIPOSE-TISSUE; SERUM RESISTIN; METABOLIC SYNDROME; PLASMA ADIPONECTIN; OBESITY; SENSITIVITY; POPULATION; MACROPHAGES AB Context: Adipose tissue-derived adipokines may contribute to insulin resistance. Objective: We tested the hypothesis that adipokines are associated with insulin resistance in a community-based cohort and that associations are maintained in people with and without the metabolic syndrome ( high vs. low risk of diabetes). Design, Setting, and Participants: We studied a cross-sectional sample of 2356 individuals attending the seventh examination (1998-2001) of the Framingham Offspring Study. We measured levels of glucose, insulin, adiponectin, resistin, and TNF alpha in fasting blood samples and defined metabolic syndrome by updated National Cholesterol Education Program criteria. We used ANOVA to test associations of adipokines with insulin resistance and multivariable logistic regression models to assess joint associations of adipokines and metabolic syndrome with insulin resistance. Main Outcome Measure: Homeostasis model (HOMA-IR), with insulin resistance defined by HOMA-IR greater than the 75th percentile, was measured. Results: Age- and sex-adjusted HOMA-IR levels were inversely related to adiponectin (r = -0.40, P < 0.0001) and positively related to resistin (r = 0.13, P < 0.0001) and TNF alpha (r = 0.12, P < 0.0001). The prevalence of insulin resistance increased with decreasing tertiles of adiponectin (from 10.9% in the third to 42.5% in the first tertile; P < 0.0001) and increasing tertiles of resistin ( from 19.3 to 30.9%; P < 0.0001) and TNF alpha (from 18.8 to 32.0%; P < 0.0001). Results were similar after adjustment for body mass index. These associations were present in individuals with or without the metabolic syndrome. In multivariable regression models, metabolic syndrome and adipokines individually and jointly were significantly associated with insulin resistance. Conclusion: Adverse levels of adipokines are associated with insulin resistance in individuals at low or high diabetes risk. C1 Massachusetts Gen Hosp, Div Gen Med, Dept Med, Ctr Diabet, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Div Gen Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Endocrinol & Metab, NHLBI,Framingham Heart Study, Cambridge, MA 02138 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Math & Stat, Consulting Unit, Boston, MA USA. Emory Univ, Sch Med, Div Cardiol, Dept Med, Atlanta, GA 30306 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, Ctr Diabet, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM hjmeigs@partners.org OI Sullivan, Lisa/0000-0003-0726-7149 FU NCRR NIH HHS [M01 RR001066, M01-RR-01066]; NHLBI NIH HHS [N01-HC-25195, N01HC25195]; NIDDK NIH HHS [K24 DK080140, K24 DK080140-01]; PHS HHS [K24 DZK080140] NR 39 TC 134 Z9 148 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 3165 EP 3172 DI 10.1210/jc.2008-0425 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500033 PM 18492747 ER PT J AU Castle, PE Solomon, D Wheeler, CM Gravitt, PE Wacholder, S Schiffman, M AF Castle, Philip E. Solomon, Diane Wheeler, Cosette M. Gravitt, Patti E. Wacholder, Sholom Schiffman, Mark TI Human papillomavirus genotype specificity of Hybrid Capture 2 SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HYBRID CAPTURE 2; CERVICAL INTRAEPITHELIAL NEOPLASIA; RANDOMIZED CONTROLLED-TRIAL; 2006 CONSENSUS GUIDELINES; ATYPICAL SQUAMOUS-CELLS; LIQUID-BASED CYTOLOGY; HIGH-RISK; UNDETERMINED SIGNIFICANCE; COSTA-RICA; SCREENING-TESTS AB Hybrid Capture 2 (hc2), a clinical test for carcinogenic human papillomavirus (HPV) DNA, has proven to be a sensitive but only modestly specific predictor of cervical precancer and cancer risk. Some of its nonspecificity for clinical end points can be ascribed to cross-reactivity with noncarcinogenic HPV genotypes. However, the reference genotyping tests that have been used for these comparisons are also imperfect. We therefore sought to describe further the HPV genotype specificity of hc2 by comparing the hc2 results to paired results from two related PGMY09/11 L1 primer-based HPV genotyping assays: Linear Array (LA) and its prototype predecessor, the line blot assay (LBA). LA and LBA results were considered separately and combined (detection by either assay or both assays) for 37 individual HPV genotypes and HPV risk group categories (carcinogenic HPV > noncarcinogenic HPV > negative). Baseline specimens from 3,179 of 3,488 (91.5%) women referred to ALTS (a clinical trial to evaluate the management strategies for women with atypical squamous cells of undetermined significance [ ASCUS] or low-grade squamous intraepithelial lesions) because of an ASCUS Papanicolaou smear were tested by all three assays. Among single-genotype infections with genotypes targeted by hc2 as detected by either PCR assay, HPV genotype 35 (HPV35) (86.4%), HPV56 (84.2%), and HPV58 (76.9%) were the most likely to test positive by hc2. Among single-genotype infections with genotypes not targeted by hc2 as detected by either assay, HPV82 (80.0%), HPV66 (60.0%) (recently classified as carcinogenic), HPV70 (59.1%), and HPV67 (56.3%) were the most likely to test positive by hc2. Among women who tested negative for carcinogenic HPV by both PCR tests and were positive for noncarcinogenic HPV by either test, 28% of women were hc2 positive. Conversely, 7.8% of all hc2-positive results in this population were due to cross-reactivity of hc2 with untargeted, noncarcinogenic HPV genotypes. In conclusion, hc2 cross-reacts with certain untargeted, noncarcinogenic HPV genotypes that are phylogenetically related to the targeted genotypes, but the degree of cross-reactivity may be less than previously reported. C1 [Castle, Philip E.; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, DHHS, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,Room 5030,EPS MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU National Cancer Institute; National Institutes of Health; Department of Health and Human Services [CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105]; NIH FX ALTS was supported by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services contracts CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105. This work was also supported in part by intramural research program of the NIH, National Cancer Institute. Some of the equipment and supplies used in these studies were donated or provided at reduced cost by Digene Corporation, Gaithersburg, MD; Cytyc Corporation, Boxborough, MA; National Testing Laboratories, Fenton, MO; DenVu, Tucson, AZ; TriPath Imaging, Inc., Burlington, NC; and Roche Molecular Systems Inc., Alameda, CA.; We thank the ALTS Group Investigators for their help in planning and conducting the trial. We thank Information Management Services, Inc., Rockville, MD for data management and programming support. We thank Meera Sangaramoorthy, Manu Sharma, and Kennita Riddick for the Roche Linear Array testing. NR 49 TC 103 Z9 107 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2008 VL 46 IS 8 BP 2595 EP 2604 DI 10.1128/JCM.00824-08 PG 10 WC Microbiology SC Microbiology GA 344EI UT WOS:000258908700016 PM 18579716 ER PT J AU Pfaller, MA Diekema, DJ Ostrosky-Zeichner, L Rex, JH Alexander, BD Andes, D Brown, SD Chaturvedi, V Ghannoum, MA Knapp, CC Sheehan, DJ Walsh, TJ AF Pfaller, M. A. Diekema, D. J. Ostrosky-Zeichner, L. Rex, J. H. Alexander, B. D. Andes, D. Brown, S. D. Chaturvedi, V. Ghannoum, M. A. Knapp, C. C. Sheehan, D. J. Walsh, T. J. TI Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: Analysis and proposal for interpretive MIC breakpoints SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID IN-VITRO SUSCEPTIBILITY; LIPOSOMAL AMPHOTERICIN-B; INVASIVE CANDIDIASIS; DOUBLE-BLIND; ESOPHAGEAL CANDIDIASIS; REDUCED SUSCEPTIBILITY; ECHINOCANDIN SUSCEPTIBILITY; GLOBAL SURVEILLANCE; ANTIFUNGAL THERAPY; RESISTANT CANDIDA AB The CLSI Antifungal Subcommittee followed the M23-A2 "blueprint" to develop interpretive MIC breakpoints for anidulafungin, caspofungin, and micafungin against Candida species. MICs of <= 2 mu g/ml for all three echinocandins encompass 98.8 to 100% of all clinical isolates of Candida spp. without bisecting any species group and represent a concentration that is easily maintained throughout the dosing period. Data from phase III clinical trials demonstrate that the standard dosing regimens for each of these agents may be used to treat infections due to Candida spp. for which MICs are as high as 2 mu g/ml. An MIC predictive of resistance to these agents cannot be defined based on the data from clinical trials due to the paucity of isolates for which MICs exceed 2 mu g/ml. The clinical data set included only three isolates from patients treated with an echinocandin (caspofungin) for which the MICs were > 2 mu g/ml (two C. parapsilosis isolates at 4 mu g/ml and one C. rugosa isolate at 8 mu g/ml). Based on these data, the CLSI subcommittee has decided to recommend a "susceptible only" breakpoint MIC of <= 2 mu g/ml due to the lack of echinocandin resistance in the population of Candida isolates thus far. Isolates for which MICs exceed 2 mu g/ml should be designated "nonsusceptible" (NS). For strains yielding results suggestive of an NS category, the organism identification and antimicrobial-susceptibility test results should be confirmed. Subsequently, the isolates should be submitted to a reference laboratory that will confirm the results by using a CLSI reference dilution method. C1 [Pfaller, M. A.] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. [Ostrosky-Zeichner, L.] Univ Texas Houston, Houston, TX USA. [Rex, J. H.] AstraZenica, Macclesfield, Cheshire, England. [Alexander, B. D.] Duke Univ, Durham, NC USA. [Andes, D.] Univ Wisconsin, Madison, WI USA. [Brown, S. D.] Inst Clin Microbiol, Wilsonville, OR USA. [Chaturvedi, V.] New York State Dept Hlth, Albany, NY USA. [Ghannoum, M. A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Knapp, C. C.] Trek Diagnost Syst, Cleveland, OH USA. [Sheehan, D. J.] Pfizer Inc, New York, NY USA. [Walsh, T. J.] NCI, Bethesda, MD 20892 USA. RP Pfaller, MA (reprint author), Univ Iowa, Dept Pathol, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM michael-pfaller@uiowa.edu OI Diekema, Daniel/0000-0003-1273-0724 FU Astellas; Merck; Pfizer FX Beverly Ringenberg provided excellent support in the preparation of the manuscript.; This work was supported in part by grants from Astellas, Merck, and Pfizer. NR 65 TC 153 Z9 156 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2008 VL 46 IS 8 BP 2620 EP 2629 DI 10.1128/JCM.00566-08 PG 10 WC Microbiology SC Microbiology GA 344EI UT WOS:000258908700019 PM 18579718 ER PT J AU Flamand, L Gravel, A Boutolleau, D Alvarez-Lafuente, R Jacobson, S Malnati, MS Kohn, D Tang, YW Yoshikawa, T Ablashi, D AF Flamand, Louis Gravel, Annie Boutolleau, David Alvarez-Lafuente, Roberto Jacobson, Steve Malnati, Mauro S. Kohn, Debra Tang, Yi-Wei Yoshikawa, Tetsushi Ablashi, Dharam TI Multicenter comparison of PCR assays for detection of human herpesvirus 6 DNA in serum SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HUMAN HERPESVIRUS-6 INFECTION; STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; REAL-TIME PCR; MEDIATED ISOTHERMAL AMPLIFICATION; POLYMERASE-CHAIN-REACTION; MULTIPLE-SCLEROSIS; EXANTHEM-SUBITUM; HHV-6 DNA; RENAL-TRANSPLANTATION AB Human herpesvirus 6 (HHV-6) is a ubiquitous virus with which infections have been associated with pathologies ranging from delayed bone marrow engraftment to a variety of neurological diseases. The lack of a standardized assay that can be used to detect and estimate HHV-6 DNA contents in various clinical specimens can lead and has led to discordant results among investigators and on the potential association of HHV-6 to diseases. To identify the most reliable and sensitive assays, an identical set of 11 coded serum samples spiked with various quantities of the HHV-6A variant (range, 4 to 400,000 genome copies/ml) was sent to eight independent laboratories around the world. Each laboratory was asked to estimate the HHV-6 DNA content by use of its own protocols and assays. Among the various assays, three TaqMan-based real-time PCR assays yielded quantities that were closest to the quantity of HHV-6 that had been spiked. To provide better homogeneity between the results from the different laboratories working on HHV-6, we propose that investigators interested in quantifying HHV-6 in clinical samples adopt one of these assays. C1 [Flamand, Louis; Gravel, Annie] Univ Laval, Rheumatol & Immunol Res Ctr, CHUL Res Ctr, Quebec City, PQ G1V 4G2, Canada. [Flamand, Louis] Univ Laval, Dept Anat & Physiol, Fac Med, Quebec City, PQ G1V 4G2, Canada. [Boutolleau, David] Univ Paris 06, Dept Virol, EA2387, Grp Hosp Pitie Salpetriere, Paris, France. [Alvarez-Lafuente, Roberto] Hosp Clin San Carlos, Serv Neurol, Madrid 28040, Spain. [Jacobson, Steve] NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. [Malnati, Mauro S.] Ist Sci San Raffaele, Unit Human Virol, DIBIT, I-20132 Milan, Italy. [Kohn, Debra] Cleveland Clin, Dept Clin Pathol, Cleveland, OH 44195 USA. [Tang, Yi-Wei] Vanderbilt Univ, Med Ctr, Mol Infect Dis Lab, Nashville, TN 37232 USA. [Yoshikawa, Tetsushi] Fujita Hlth Univ Coll, Dept Med Informat Technol, Aichi, Japan. [Ablashi, Dharam] HHV6 Fdn, Santa Barbara, CA 93108 USA. RP Flamand, L (reprint author), Univ Laval, Rheumatol & Immunol Res Ctr, CHUL Res Ctr, Room T1-49,2705 Laurier Blvd, Quebec City, PQ G1V 4G2, Canada. EM louis.flamand@crcul.ulaval.ca RI Boutolleau, David/D-9610-2014 OI Boutolleau, David/0000-0001-9401-4662 NR 59 TC 33 Z9 33 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2008 VL 46 IS 8 BP 2700 EP 2706 DI 10.1128/JCM.00370-08 PG 7 WC Microbiology SC Microbiology GA 344EI UT WOS:000258908700031 PM 18550745 ER PT J AU Jeronimo, J Wentzensen, N Long, R Schiffman, M Dunn, ST Allen, RA Walker, JL Gold, MA Zuna, RE Sherman, ME Wacholder, S Wang, SS AF Jeronimo, J. Wentzensen, N. Long, R. Schiffman, M. Dunn, S. T. Allen, R. A. Walker, J. L. Gold, M. A. Zuna, R. E. Sherman, M. E. Wacholder, S. Wang, S. S. TI Evaluation of linear array human papillomavirus genotyping using automatic optical imaging software SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID SQUAMOUS INTRAEPITHELIAL LESION; CERVICAL-CANCER; UNDETERMINED SIGNIFICANCE; DIAGNOSIS; NEOPLASIA; TRIAGE AB Variations in biological behavior suggest that each carcinogenic human papillomavirus (HPV) type should be considered individually in etiologic studies. HPV genotyping assays might have clinical applications if they are approved for use by the FDA. A widely used genotyping assay is the Roche Linear Array HPV genotyping test (LA). We used LA to genotype the HPV isolates from cervical specimens from women with the full spectrum of cervical disease: cervical cancer, cervical intraepithelial neoplasia (CIN), and HPV infections. To explore the feasibility and value of the automated reading of the LA results, we custom-designed novel, optical imaging software that provides optical density measurements of LA bands. We compared unmagnified visual examination with the automated measurements. The two measurements were highly associated. By either method, the threshold between a negative and a positive result was fairly sharp, with a clear bimodal distribution. Visually, most positive results were judged to be strong or medium, with fewer equivocal results categorized as weak (9.5% of positive samples), very weak (6.5% of positive samples), or extremely weak (7.7% of positive samples). The automated measurements of the intensities were significantly associated with the strength of the visual categories (P < 0.001). At the extremes of the automated signal intensities (<= 20 units or >= 120 units), the bands were almost always categorized visually as negative and positive, respectively. In the equivocal zone (20 to 119 units), specimens were more increasingly likely to be judged to be visually positive as the number of other, definite infections on the same strip increased (P for trend < 0.001). Multiple, concurrent infections comprise >= 25% of HPV infections; thus, any systematic visual tendency that influences their evaluation when the result is equivocal should be minimized. Therefore, automated reading is probably worth development if easy-to-calibrate hardware and software can be optimized. C1 [Jeronimo, J.; Wentzensen, N.; Schiffman, M.; Sherman, M. E.; Wacholder, S.; Wang, S. S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Long, R.] Natl Lib Med, Commun Engn Branch, Bethesda, MD USA. [Dunn, S. T.; Allen, R. A.; Zuna, R. E.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Walker, J. L.; Gold, M. A.] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. RP Jeronimo, J (reprint author), PATH, 1455 NW Leary Way, Seattle, WA 98107 USA. EM jjeronimo@path.org NR 12 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2008 VL 46 IS 8 BP 2759 EP 2765 DI 10.1128/JCM.00188-08 PG 7 WC Microbiology SC Microbiology GA 344EI UT WOS:000258908700039 PM 18550741 ER PT J AU Azad, NS Posadas, EM Kwitkowski, VE Steinberg, SM Jain, L Annunziata, CM Minasian, L Sarosy, G Kotz, HL Premkumar, A Cao, L McNally, D Chow, C Chen, HX Wright, JJ Kohn, EC AF Azad, Nilofer S. Posadas, Edwin M. Kwitkowski, Virginia E. Steinberg, Seth M. Jain, Lokesh Annunziata, Christina M. Minasian, Lori Sarosy, Gisele Kotz, Herbert L. Premkumar, Ahalya Cao, Liang McNally, Deborah Chow, Catherine Chen, Helen X. Wright, John J. Kohn, Elise C. TI Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity 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 REFRACTORY SOLID TUMORS; RENAL-CELL CARCINOMA; COLORECTAL-CANCER; TYROSINE KINASE; OVARIAN-CANCER; LUNG-CANCER; PHASE-II; BAY-43-9006; SAFETY; TRIAL AB Purpose Sorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects. Patients and Methods Patients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD). Results Thirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22 + months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization >= 4 months (median, 6 months; range, 4 to 22 + months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles). Conclusion Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored. C1 Ctr Canc Res, Med Oncol Branch, Biostat & Data Management Sect, Bethesda, MD USA. [Kohn, Elise C.] NCI, Pathol Lab, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), NCI, Pathol Lab, Canc Therapy Evaluat Program, 10 Ctr Dr,MSC1500, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov RI Annunziata, Christina/L-3219-2016; Figg Sr, William/M-2411-2016 OI Annunziata, Christina/0000-0003-2033-6532; FU Intramural NIH HHS NR 28 TC 210 Z9 216 U1 1 U2 14 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 AUG 1 PY 2008 VL 26 IS 22 BP 3709 EP 3714 DI 10.1200/JCO.2007.10.8332 PG 6 WC Oncology SC Oncology GA 331ZV UT WOS:000258052100011 PM 18669456 ER PT J AU Dodd, LE Korn, EL Freidlin, B Jaffe, CC Rubinstein, LV Dancey, J Mooney, MM AF Dodd, Lori E. Korn, Edward L. Freidlin, Boris Jaffe, C. Carl Rubinstein, Lawrence V. Dancey, Janet Mooney, Margaret M. TI Blinded independent central review of progression-free survival in phase III clinical trials: Important design element or unnecessary expense? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC BREAST-CANCER; RENAL-CELL CARCINOMA; PLUS CAPECITABINE; END-POINTS; BEVACIZUMAB; ANTHRACYCLINE; SORAFENIB; TAXANE; CARE AB Progression-free survival is an important end point in advanced disease settings. Blinded independent central review (BICR) of progression in randomized clinical trials has been advocated to control bias that might result from errors in progression assessments. However, although BICR lessens some potential biases, it does not remove all biases from evaluations of treatment effectiveness. In fact, as typically conducted, BICRs may introduce bias because of informative censoring, which results from having to censor unconfirmed locally determined progressions. In this article, we discuss the rationale for BICR and different ways of implementing independent review. We discuss the limitations of these approaches and review published trials that report implementing BICR. We demonstrate the existence of informative censoring using data from a randomized phase II trial. We conclude that double-blinded trials with consistent application of measurement criteria are the best means of ensuring unbiased trial results. When such designs are not practical, BICR is not recommended as a general strategy for reducing bias. However, BICR may be useful as an auditing tool to assess the reliability of marginally positive results. C1 [Dodd, Lori E.] NCI, Branch Biometr Res, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Branch Invest Drug, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Branch Canc Invest, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Branch Diagnost Imaging, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Dodd, LE (reprint author), NCI, Branch Biometr Res, Div Canc Treatment & Diag, 6130 Execut Blvd,MSC 743,EPN Rm 8140, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov NR 22 TC 77 Z9 77 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2008 VL 26 IS 22 BP 3791 EP 3796 DI 10.1200/JCO.2008.16.1711 PG 6 WC Oncology SC Oncology GA 331ZV UT WOS:000258052100023 PM 18669467 ER PT J AU Kingman, A Susin, C Albandar, JM AF Kingman, Albert Susin, Cristiano Albandar, Jasim M. TI Effect of partial recording protocols on severity estimates of periodontal disease SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE bias; mean periodontal probing pockets and attachment level; partial recording; periodontal diseases/diagnosis ID UNITED-STATES; ADULT-POPULATION; ATTACHMENT LOSS; RAMFJORD-TEETH; PREVALENCE; EXTENT; INDEX; RISK; ORGANIZATION; INDICATORS AB Objectives: The study aim was to assess bias magnitudes of periodontal disease severity estimates for specific partial recording protocols (PRPs) in epidemiological studies. Material and Methods: Estimates of mean clinical attachment loss (MCAL) and mean probing pocket depth (MPPD) were derived for 20 different PRPs using full-mouth periodontal data from 1437 dentate Brazilian subjects 14-103 years old having at least four teeth. Biases, relative biases and intra-class correlations for all PRPs were evaluated. Graphical methods were used to assess how well the PRP-based estimates agreed with full-mouth scores across levels of disease. Results: Slightly higher levels of disease were evidenced on lingual than on buccal sites. Seven multi-site PRPs and the Ramfjord PRP produced small biases in MPPD (-0.17 to 0.04 mm) and MCAL with relative biases under 8% and 4% in absolute value for MPPD and MCAL, respectively. Biases for full- and random half-mouth-based PRPs were similar. The three-site random half-mouth MB-B-DL and the Ramfjord PRPs produced the smallest biases, with relative biases < 3% in absolute value for MPPD and MCAL. Conclusions: Bias for MPPD or MCAL estimates varies by site type, number of sites per tooth and number of quadrants included in the PRP. C1 [Kingman, Albert] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Susin, Cristiano] Univ Fed Rio Grande do Sul, Fac Dent Periodontol, Porto Alegre, RS, Brazil. [Albandar, Jasim M.] Temple Univ, Sch Dent, Dept Periodontol, Periodontal Diagnost Res Lab, Philadelphia, PA USA. RP Kingman, A (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RI Susin, Cristiano/B-9822-2008; OI Albandar, Jasim M./0000-0001-7801-3811 NR 27 TC 59 Z9 63 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD AUG PY 2008 VL 35 IS 8 BP 659 EP 667 DI 10.1111/j.1600-051X.2008.01243.x PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 332IB UT WOS:000258075600001 PM 18513337 ER PT J AU Machado-Vieira, R Soares, JC Lara, DR Luckenbaugh, DA Busnello, JV Marca, G Cunha, A Souza, DO Zarate, CA Kapczinski, F AF Machado-Vieira, Rodrigo Soares, Jair C. Lara, Diogo R. Luckenbaugh, David A. Busnello, Joao V. Marca, Getulio Cunha, Angelo Souza, Diogo O. Zarate, Carlos A., Jr. Kapczinski, Flavio TI A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID URIC-ACID METABOLISM; ADD-ON THERAPY; CONTROLLED TRIAL; XANTHINE-OXIDASE; DISORDER; SCHIZOPHRENIA; ADENOSINE; DYSFUNCTION; MANAGEMENT; EPILEPSY AB Objective: The therapeutics for bipolar disorders are still far from adequate, and new options with improved effectiveness, safety, and tolerability in a wide range of patients are necessary. Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders. This study aimed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania. Method: A randomized, placebo-controlled, double-blind study was performed in adult inpatients (N = 180) with a DSM-IV-TR diagnosis of bipolar I disorder, current episode manic with or without psychotic features (rapid cyclers and mixed episodes were not included). No antipsychotic agent was used during the study. Subjects were given fixed oral doses of either allopurinol 600 mg/day (N = 60), dipyridamole 200 mg/day (N = 60), or placebo (N = 60) added to lithium for 4 weeks. Subjects were rated at baseline and days 7, 14, 2 1, and 28 using the Young Mania Rating Scale (YMRS) as the primary efficacy measure. The study was conducted between September 2003 and September 2006. Results: Allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (p < .001) and day 28 (p = .003) compared with placebo using a linear model analysis (d = 0.32, 95% Cl = 0.07 to 0.57). Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo (p = .008). Lithium showed a significant antimanic efficacy even in the placebo group. Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group (p < .001). Conclusion: Allopurinol is clinically effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania, especially for those presenting tolerability and safety issues with antipsychotics. The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder. Further placebo-controlled studies with allopurinol compared with standard mood stabilizers in mania and maintenance are warranted. Trial Registration: clinicaltrials.gov Identifier: NCT00560079. C1 [Machado-Vieira, Rodrigo] NIMH, Mood & Anxiety Disorders Program, Natl Inst Hlth, Bethesda, MD 20892 USA. [Machado-Vieira, Rodrigo; Busnello, Joao V.; Marca, Getulio] Espirita Hosp Porto Alegre, Bipolar Disorder Res Program, Porto Alegre, RS, Brazil. [Lara, Diogo R.] Pontificia Univ Catolica Rio de Janeiro, Fac Biociencias, Porto Alegre, RS, Brazil. [Souza, Diogo O.; Kapczinski, Flavio] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Soares, Jair C.] Univ N Carolina, Mood Disorders Program, Chapel Hill, NC USA. New Hampshire Dept Hlth & Human Serv, Bethesda, MD USA. [Cunha, Angelo] Univ Fed Santa Maria, Rio Grande Do Sul, Brazil. RP Machado-Vieira, R (reprint author), NIMH, Mood & Anxiety Disorders Program, Natl Inst Hlth, 35 Convent Dr, Bethesda, MD 20892 USA. EM machadovieirar@terra.com.br RI Kapczinski, Flavio/D-3175-2013; Kapczinski, Flavio/J-5803-2014; Souza, Diogo/J-8894-2014; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Souza, Diogo/0000-0002-4322-0404; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural NIH HHS [Z99 MH999999] NR 35 TC 55 Z9 56 U1 0 U2 2 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2008 VL 69 IS 8 BP 1237 EP 1245 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 339VF UT WOS:000258604700006 PM 18681754 ER PT J AU Kolbrich, EA Goodwin, RS Gorelick, DA Hayes, RJ Stein, EA Huestis, MA AF Kolbrich, Erin A. Goodwin, Robert S. Gorelick, David A. Hayes, Robert J. Stein, Elliot A. Huestis, Marilyn A. TI Physiological and subjective responses to controlled oral 3,4-methylenedioxymethamphetamine administration SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID PSYCHOMOTOR PERFORMANCE; HEALTHY-VOLUNTEERS; HUMAN PHARMACOLOGY; DESIGNER DRUGS; ECSTASY MDMA; HUMANS; PHARMACOKINETICS; PLASMA; QUANTIFICATION; TOXICOKINETICS AB A randomized, within-subject, double-blind, inpatient study of the physiological and subjective effects of oral 3,4-methylenedioxymethamphetamine (MDMA) was conducted in human volunteers with previous MDMA experience. Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were administered in a controlled inpatient setting at least 7 days apart to 6 African American (4 male, 2 female) and 2 white (both male) volunteers (mean [SE] age, 21.1 [0.8] years; weight, 77.2 [7.7] kg). 3,4-Methylenedioxymethamphetamine doses were 46 to 150 mg, in the range of typical recreational doses. Participants completed all sessions without clinically significant adverse events. 3,4-Methylenedioxymethamphetamine produced significant dose-dependent increases in heart rate (highest, 132 bpm), systolic (highest, 171 mm Hg) and diastolic (highest, 102 mm Hg) blood pressure, and subjective responses for energy level, closeness to others, mind racing, heightened senses, and high (evaluated by visual analog scales). Peak effects occurred 1 to 2 hours after dose, with no secondary peak. There were no significant effects on body temperature (measured at tympanic membrane), respiratory rate, or blood oxygen saturation (by pulse oximetry). Although most physiological and subjective parameters were significantly correlated with MDMA plasma concentrations, correlation coefficients were low and clinically insignificant, eliminating the ability to predict effects from single plasma concentrations. These findings suggest that oral MDMA in typical recreational doses produces short-term effects on cardiovascular function and subjective state but that temperature effects may result from interaction with environmental and subject factors. C1 [Hayes, Robert J.; Stein, Elliot A.; Huestis, Marilyn A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 5A72, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000468-04, NIH0011996773] NR 38 TC 34 Z9 35 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2008 VL 28 IS 4 BP 432 EP 440 DI 10.1097/JCP.0b013e31817ef470 PG 9 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 328AD UT WOS:000257768700011 PM 18626271 ER PT J AU Ross, J Ostlund, EN Cao, DJ Tatsumi, M Hoshino, Y AF Ross, Jerri Ostlund, Eileen N. Cao, Dianjun Tatsumi, Masatoshi Hoshino, Yasutaka TI Acrylamide concentration affects the relative position of VP7 gene of serotype G2 strains as determined by polyacrylamide gel electrophoresis SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE rotavirus; PAGE; electropherotype; diarrhea; VP7 gene ID HUMAN ROTAVIRUS SEROTYPES; VACCINE CANDIDATES; NEUTRALIZATION; REASSORTANTS; BOVINE; ANTIBODIES; GENOME; ACID; RNA AB Background: During the course of development and characterization of various rotavirus reassortants. we found that the relative position of the gene encoding neutralization and protective antigen VP7 of certain rotavirus strains in a PAGE gel was influenced by the concentration of acrylamide. Objectives: We investigated systematically various factors that affected the relative position of the rotavirus VP7 gene in a PAGE gel. Study design: We analyzed dsRNAs of selected rotavirus strains hearing G1, G2, G3 or G9 specificity by PAGE at varying concentrations of acrylamide. Results: We demonstrated that the relative position of the VP7 gene of three G2 strains varied depending upon the concentration of acrylamide in a PAGE gel, which occurred not only in a homologous G2 virus gene background but also in a heterologous G3 virus gene background; and the VP7 gene bearing G1, G3, G4 or G9 specificity did not display this phenomenon when the PAGE running conditions were varied. Conclusions: The concentration of acrylamide in a PAGE gel was the major factor that influenced the relative position of the VP7 gene of G2 rotavirus strains (i.e., VP7 gene coding assignment by PAGE). Published by Elsevier B.V. C1 [Ross, Jerri; Ostlund, Eileen N.; Cao, Dianjun; Tatsumi, Masatoshi; Hoshino, Yasutaka] NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bldg 50,Room 6308,50 S Dr,MSC 8026, Bethesda, MD 20892 USA. EM thoshino@niaid.nih.aov FU Intramural NIH HHS [Z01 AI000339-26, Z01 AI000340-26] NR 27 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 J9 J CLIN VIROL JI J. Clin. Virol. PD AUG PY 2008 VL 42 IS 4 BP 374 EP 380 DI 10.1016/j.jcv.2008.03.019 PG 7 WC Virology SC Virology GA 334RV UT WOS:000258239800009 PM 18457989 ER PT J AU Vladimirski, BB Tabak, J O'Donovan, MJ Rinzel, J AF Vladimirski, Boris B. Tabak, Joel O'Donovan, Michael J. Rinzel, John TI Episodic activity in a heterogeneous excitatory network, from spiking neurons to mean field SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE spontaneous rhythmic activity; spiking network; mean field; heterogeneity; dynamic range ID SPINAL-CORD; NEURAL-NETWORKS; CHICK-EMBRYO; MECHANISMS; EXPRESSION; DEPRESSION; CIRCUITS; MODELS; SYNCHRONIZATION; OSCILLATIONS AB Many developing neural systems exhibit spontaneous activity (O'Donovan, Curr Opin Neurobiol 9:94-104, 1999; Feller, Neuron 22:653-656, 1999) characterized by episodes of discharge (active phases) when many cells are firing, separated by silent phases during which few cells fire. Various models exhibit features of episodic behavior by means of recurrent excitation for supporting an episode and slow activity-dependent depression for terminating one. The basic mechanism has been analyzed using mean-field, firing-rate models. Firing-rate models are typically formulated ad hoc, not derived from a spiking network description, and the effects of substantial heterogeneity amongst the units are not usually considered. Here we develop an excitatory network of spiking neurons (N-cell model) with slow synaptic depression to model episodic rhythmogenesis. This N-cell model displays episodic behavior over a range of heterogeneity in bias currents. Important features of the episodic behavior include orderly recruitment of individual cells during silent phases and existence of a dynamical process whereby a small critical subpopulation of intermediate excitability conveys synaptic drive from active to silent cells. We also derive a general self-consistency equation for synaptic drive that includes cell heterogeneity explicitly. We use this mean-field description to expose the dynamical bistability that underlies episodic behavior in the heterogeneous network. In a systematic numerical study we find that the robustness of the episodic behavior improves with increasing heterogeneity. Furthermore, the heterogeneity of depression variables (imparted by the heterogeneity in cellular firing thresholds) plays an important role in this improvement: it renders the network episodic behavior more robust to variations in excitability than if depression is uniformized. We also investigate the effects of noise vs. heterogeneity on the robustness of episodic behavior, especially important for the developing nervous system. We demonstrate that noise-induced episodes are very fragile, whereas heterogeneity-produced episodic rhythm is robust. C1 [Vladimirski, Boris B.; Rinzel, John] NYU, Courant Inst Math Sci, New York, NY 10012 USA. [Rinzel, John] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Tabak, Joel] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [O'Donovan, Michael J.] NIH, NINDS, Dev Neurobiol Sect, Bethesda, MD 20892 USA. RP Vladimirski, BB (reprint author), Univ Bern, Dept Physiol, Buhlpl 5, CH-3012 Bern, Switzerland. EM bbv20l@nyu.edu RI tabak, joel/K-1549-2013; o'donovan, michael/A-2357-2015; OI o'donovan, michael/0000-0003-2487-7547; Tabak, Joel/0000-0002-0588-957X FU Intramural NIH HHS; NIMH NIH HHS [MH62595-01] NR 34 TC 26 Z9 26 U1 3 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD AUG PY 2008 VL 25 IS 1 BP 39 EP 63 DI 10.1007/s10827-007-0064-4 PG 25 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 314QS UT WOS:000256824500003 PM 18322788 ER PT J AU Rogers, CG Linehan, WM Pinto, PA AF Rogers, Craig G. Linehan, W. Marston Pinto, Peter A. TI Robotic nephrectomy for kidney cancer in a horseshoe kidney with renal vein tumor thrombus: Novel technique for thrombectomy SO JOURNAL OF ENDOUROLOGY LA English DT Article C1 [Rogers, Craig G.] Henry Ford Hosp, Vittikuti Urol Inst, Detroit, MI 48202 USA. [Rogers, Craig G.; Linehan, W. Marston; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Rogers, CG (reprint author), Henry Ford Hosp, Vittikuti Urol Inst, 2799 W Grand Blvd, Detroit, MI 48202 USA. EM Crogers2@hfhs.org FU Intramural NIH HHS [Z01 SC006659-25] NR 3 TC 9 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD AUG PY 2008 VL 22 IS 8 BP 1561 EP 1563 DI 10.1089/end.2008.0043 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 345YP UT WOS:000259034700002 PM 18721039 ER PT J AU Pennington, J Stumbo, P AF Pennington, Jean Stumbo, Phyllis TI US National Nutrient Databank Conference - A look to the past and the future SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE National Nutrient Databank Conference; NNDC; Databank conference; food composition; dietary assessment software; database management AB The United States (US) National Nutrient Databank Conference (NNDC) has been held annually since 1976 to provide a venue for the presentation and exchange of information about food composition data and databases and dietary assessment software. NNDCs have been held in 19 US states, Washington DC, and Canada. The yearly Conference is guided by a Steering Committee with elected officers. The Steering Committee identifies potential hosting organizations, and annual meetings are organized by Program and Arrangement Committees. The NNDC began gathering information about available databases at its second meeting and subsequently produced a Nutrient Databank Directory that went through nine editions under the leadership of a Database Committee. The directory is currently available on-line as the 2006 International Nutrient Databank Directory. The NNDC website (http://www.nal.usda.gov/fnic/foodcomp/conf/) provides a link to the Directory as well as information about prior and future NNDCs. Many of the individuals who were instrumental in conceptualizing, organizing, and developing this Conference have retired or are nearing retirement, and younger professionals are moving in to continue to nurture and guide the group. This brief history of the NNDC is provided to preserve the past of this organization and to encourage newer attendees to contribute to its future. (C) 2008 Elsevier Inc. All rights reserved. C1 [Pennington, Jean] NIH, Bethesda, MD 20892 USA. [Stumbo, Phyllis] Univ Iowa, Med Res Facil, Gen Clin Res Ctr, Iowa City, IA 52242 USA. RP Pennington, J (reprint author), NIH, 6707 Democracy Blvd,Room 629, Bethesda, MD 20892 USA. EM jp157d@nih.gov NR 38 TC 2 Z9 2 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 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD AUG PY 2008 VL 21 IS 5 BP 435 EP 443 DI 10.1016/j.jfca.2008.03.001 PG 9 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 323YO UT WOS:000257484700012 ER PT J AU Robinson, JM Shavers, V AF Robinson, JaMuir M. Shavers, Vickie TI The role of health insurance coverage in cancer screening utilization SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE cancer screening; race; ethnicity; health insurance; underinsurance; health services ID UNITED-STATES; CARE NEEDS; DISPARITIES; ADHERENCE; WOMEN AB Introduction. Although previous studies have shown a correlation between health insurance coverage and cancer screening, underinsurance and cancer screening among racial/ethnic minorities has not been examined. Methods. Data from the 2000 and 2003 National Health Interview Surveys are used in this analysis. Cross-tabulations, age, and racial/ethnic group stratified regression analyses are used to examine associations between health insurance status and receipt of mammography, Pap testing, prostate specific antigen tests, fecal occult blood test (FOBT) and colorectal endoscopy. Results. In overall models, uninsurance was associated with lower receipt of all tests except FOBT among participants ages 65-85 years. Underinsurance was associated with lower receipt of mammography among women under 65 years only. Conclusion. These findings show age variation in the association between cancer screening and health insurance coverage. In addition, health insurance appears to act similarly across racial/ethnic groups. Further examination of underinsurance in cancer screening utilization and other health behaviors is needed. C1 [Robinson, JaMuir M.] NCI, Canc Prevent & Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Robinson, JaMuir M.] NCI, Off Educ & Special Initiat, Bethesda, MD 20892 USA. [Shavers, Vickie] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Robinson, JM (reprint author), 6116 Execut Blvd,Ste 202, Bethesda, MD 20892 USA. EM robinjam@mail.nih.gov NR 25 TC 30 Z9 31 U1 1 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2008 VL 19 IS 3 BP 842 EP 856 PG 15 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 336FW UT WOS:000258350700015 PM 18677074 ER PT J AU Su, XW Yee, LJ Im, K Rhodes, SL Tang, YM Tong, XM Howell, C Raincharran, D Rosen, HR Taylor, MW Liang, TJ Yang, HY AF Su, Xiaowen Yee, Leland J. Im, KyungAh Rhodes, Shannon L. Tang, YongMing Tong, Xiaomei Howell, Charles Raincharran, Darmendra Rosen, Hugo R. Taylor, Milton W. Liang, T. Jake Yang, Huiying CA Virahep-C Study Grp TI Association of single nucleotide polymorphisms in interferon signaling pathway genes and interferon-stimulated genes with the response to interferon therapy for chronic hepatitis C SO JOURNAL OF HEPATOLOGY LA English DT Article DE pharmacogenetics; hepatitis C; interferon therapy; interferon signaling pathway genes; interferon-stimulated genes; genetics; race; therapy; interferon ID VIRUS-INFECTION; OLIGOADENYLATE SYNTHETASE; RIBAVIRIN TREATMENT; VIRAL-INFECTION; EXPRESSION; MXA; PROMOTER; PEGINTERFERON; HAPLOTYPES; ENHANCERS AB Background/Aims: Interferon signaling pathway genes (IPGs) and interferon-stimulated genes (ISGs) are associated with the host response to hepatitis C virus (HCV) infection. We studied single nucleotide polymorphisms (SNPs) in IPGs and ISGs for their associations with response to pegylated interferon alpha-2a (Peg-IFN-alpha) plus ribavirin therapy in HCV genotype-1 infected patients. Methods: A two-stage study design was used. First, out of 118 SNPs selected, 91 SNPs from 5 IPGs and 12 ISGs were genotyped in a cohort of 374 treatment-native HCV patients and assessed for association with sustained virologic response (SVR). Next, 14 potentially functional SNPs from the OASL gene were studied in this cohort. Results: Three OASL SNPs (rs3213545 and rs1169279 from stage I, and rs2859398 from stage II), were significantly associated with SVR [rs3213545: p = 0.03, RR = 1.27 (1.03-1.58); rs.1169279: p = 0.02, RR = 1.32 (1.05-1.65) p = 0.02; rs2859398: p = 0.02, RR = 1.29 (1.04-1.61)] after adjusting for other covariates. Further analysis showed that these three SNPs independently associated with SVR. Additionally, a similar trend towards the associations of these three SNPs with SVR was observed in a smaller, independent HCV cohort consisting of subjects from a number of clinical practice settings. Conclusions: Our study suggests that OASL variants are involved in the host response to IFN-based therapy in HCV patients. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Yee, Leland J.; Im, KyungAh; Raincharran, Darmendra] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15232 USA. [Su, Xiaowen; Rhodes, Shannon L.; Tang, YongMing; Tong, Xiaomei; Yang, Huiying] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Yee, Leland J.] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA USA. [Im, KyungAh] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15232 USA. [Howell, Charles] Univ Maryland, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Baltimore, MD 21201 USA. [Rosen, Hugo R.] Univ Colorado, Integrated Program Immunol & Hepatitis Res Ctr C, Div Gastroenterol & Hepatol, Denver, CO 80202 USA. [Taylor, Milton W.] Indiana Univ, Dept Biol, Bloomington, IN USA. [Liang, T. Jake] NIDDK, Div Digest Dis, NIH, Bethesda, MD USA. RP Yee, LJ (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, A511 Crabtree Hall,130 DeSoto St, Pittsburgh, PA 15232 USA. EM YeeL@edc.pitt.edu FU Intramural NIH HHS; NCRR NIH HHS [1KL2RR024154-01, KL2 RR024154, M01 RR000042, M01 RR000046, M01 RR000079, M01 RR00046, M01 RR000645, M01 RR00645, M01 RR016500, M01 RR16500, M02 RR000079]; NIDDK NIH HHS [U01 DK060335, K24 DK066144, U01 DK060309, U01 DK060324, U01 DK060327, U01 DK060329, U01 DK060340, U01 DK060341, U01 DK060341-05, U01 DK060342, U01 DK060344, U01 DK060345, U01 DK060346, U01 DK060349, U01 DK060352, U01 DK60309, U01 DK60324, U01 DK60327, U01 DK60329, U01 DK60335, U01 DK60340, U01 DK60341, U01 DK60342, U01 DK60344, U01 DK60345, U01 DK60346, U01 DK60349, U01 DK60352] NR 29 TC 28 Z9 28 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2008 VL 49 IS 2 BP 184 EP 191 DI 10.1016/j.jhep.2008.04.011 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 337JR UT WOS:000258432900006 PM 18571276 ER PT J AU Song, BJ Moon, KH Olsson, NU Salem, N AF Song, Byoung-Joon Moon, Kwan-Hoon Olsson, Nils U. Salem, Norman, Jr. TI Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain poly unsaturated fatty acids SO JOURNAL OF HEPATOLOGY LA English DT Article DE alcoholic fatty liver; polyunsaturated fatty acids; Long-Evans rat; oxidative/nitrosative stress; protein oxidation; beta-oxidation of fatty acids; mitochondrial dysfunction ID DIETARY SATURATED FAT; NITRIC-OXIDE; DEPENDENT HEPATOTOXICITY; ETHANOL-CONSUMPTION; LIPID-PEROXIDATION; METABOLISM; MICE; INDUCTION; DISEASE; INJURY AB Background/Aims: We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6,omega-6) and docosahexaenoic (DHA,22:6n3,omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet prevents alcohol-induced fatty liver. Methods: Male Long-Evans rats were fed an ethanol or control liquid-diet with or without DHA/AA for 9 weeks. Plasma transaminase levels, liver histology, oxidative/nitrosative stress markers, and activities of oxidatively-modified mitochondrial proteins were evaluated. Results: Chronic alcohol administration increased the degree of fatty liver but fatty liver decreased significantly in rats fed the alcohol-DHA/AA-supplemented diet. Alcohol exposure increased oxidative/nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. However, these increments were normalized in rats fed the alcohol-DHA/AA-supplemented diet. The number of oxidatively-modified mitochondrial proteins was markedly increased following alcohol exposure but significantly reduced in rats fed the alcohol-DHA/AA-supplemented diet. The suppressed activities of mitochondrial aldehyde dehydrogenase, ATP synthase, and 3-ketoacyl-CoA thiolase in ethanol-exposed rats were also recovered in animals fed the ethanol-DHA/AA-supplemented diet. Conclusions: Addition of DHA/AA prevents alcohol-induced fatty liver and mitochondrial dysfunction in an animal model by protecting various mitochondrial enzymes most likely through reducing oxidative/nitrosative stress. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Song, Byoung-Joon; Moon, Kwan-Hoon; Olsson, Nils U.; Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, Natl Inst Hlth, 5625 Fishers Lane,Rm 2S-30, Bethesda, MD 20892 USA. EM bjs@mail.nih.gov FU Intramural Program of National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the Intramural Program of National Institute on Alcohol Abuse and Alcoholism. The skillful technical assistance of Chris Tahan and the staff of the NIAAA's animal facility (Dr. Lee Chedester, Ms. Toni Calzone and Dr. Raouf Kechrid) is gratefully acknowledged. We are also grateful to Dr. Miriam Anver at NCI-SAIC, Inc. for blind reading and scoring of the histological slides. We are also thankful to Dr. Nancy E. Braverman (Johns Hopkins University Medical School, Baltimore, MD, USA) for providing the specific antibody to 3-ketoacyl-CoA thiolase. NR 45 TC 54 Z9 55 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2008 VL 49 IS 2 BP 262 EP 273 DI 10.1016/j.jhep.2008.04.023 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 337JR UT WOS:000258432900015 PM 18571270 ER PT J AU Elenkov, IJ Kvetnansky, R Hashiramoto, A Bakalov, VK Link, AA Zachman, K Crane, M Jezova, D Rovensky, J Dimitrov, MA Gold, PW Bonini, S Fleisher, T Chrousos, GP Wilder, RL AF Elenkov, Ilia J. Kvetnansky, Richard Hashiramoto, Akira Bakalov, Vladimir K. Link, Amrey A. Zachman, Keith Crane, Marianna Jezova, Daniela Rovensky, Jozef Dimitrov, Mariana A. Gold, Philip W. Bonini, Sergio Fleisher, Thomas Chrousos, George P. Wilder, Ronald L. TI Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: Presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans? SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BETA(2)-ADRENERGIC AGONIST SALBUTAMOL; SINGLE NUCLEOTIDE POLYMORPHISMS; IL-10 PRODUCTION; INTERINDIVIDUAL DIFFERENCES; INDUCED ARTHRITIS; CELL CLONES; T-CELLS; CATECHOLAMINES; SYSTEM; RATS AB Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual's neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary "defect" related to specific neurohormonal immune phenotype(s). We report that in a large subpopulation of healthy humans the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS ex vivo. In alternative settings, we found low baseline levels and profoundly blunted stress-induced epinephrine responses but high TNF-alpha levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a beta adrenoreceptor agonist suppressed LPS-induced TNF-alpha production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the beta(2) adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-a and IL-12, but stimulated IL-10 production. The order of potency for hormones able to inhibit IL-12 production ex vivo was: epinephrine > norepinephrine > = 1,25-(OH)(2) vitamin D(3) > hydrocortisone. This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles. Since Lewis and Fischer rats have opposite susceptibility to experimental immunological diseases, this suggests that the parallel human phenotypes could be linked to differing responsiveness and susceptibility to infections and immune/inflammatory-related conditions. C1 [Elenkov, Ilia J.; Bonini, Sergio] Italian Natl Res Council, Inst Neurobiol & Mol Med, I-00133 Rome, Italy. [Elenkov, Ilia J.; Hashiramoto, Akira; Crane, Marianna; Wilder, Ronald L.] NIAMSD, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. [Link, Amrey A.; Zachman, Keith; Chrousos, George P.] NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. [Bakalov, Vladimir K.] NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. [Crane, Marianna] Lister Hill Ctr Biomed Commun, Bethesda, MD 20892 USA. [Gold, Philip W.] NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. [Fleisher, Thomas] NIH, Dept Lab Med, Serv Immunol, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Kvetnansky, Richard; Rovensky, Jozef] Slovak Acad Sci, Inst Expt Endocrinol, Bratislava, Slovakia. RP Elenkov, IJ (reprint author), Italian Natl Res Council, Inst Neurobiol & Mol Med, Via Fosso Cavaliere 100, I-00133 Rome, Italy. EM ilia.elenkov@tiscali.it OI Bonini, Sergio/0000-0003-0079-3031 NR 47 TC 31 Z9 33 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 AUG 1 PY 2008 VL 181 IS 3 BP 1737 EP 1745 PG 9 WC Immunology SC Immunology GA 329VG UT WOS:000257898100019 PM 18641310 ER PT J AU Richard, K Pierce, SK Song, WX AF Richard, Katharina Pierce, Susan K. Song, Wenxia TI The agonists of TLR4 and 9 are sufficient to activate memory B cells to differentiate into plasma cells in vitro but not in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; GERMINAL-CENTERS; BONE-MARROW; ANTIGEN; IMMUNOGLOBULIN; RESPONSES; IMMUNITY; PERSISTENCE; EXPRESSION; ABSENCE AB Memory B cells can persist for a lifetime and be reactivated to yield high affinity, isotype switched plasma cells. The generation of memory B cells by Ag immunization requires adjuvants that generally contain TLR agonists. However, requirements for memory B cell activation and the role of TLRs in this activation are not well understood. In this study, we analyzed the response of memory B cells from immunized mice to TLR9 and 4 agonists CpG oligodeoxynucleotides (ODN) and LPS. Mouse memory B cells express both TLR9 and 4, and respond to both CpG ODN and LPS in vitro by differentiating into high affinity IgG secreting plasma cells. In contrast, neither CpG ODN nor LPS alone is sufficient to activate memory B cells in vivo. Ag is required for the clonal expansion of Ag-specific memory B cells, the differentiation of memory B cells to high affinity IgG secreting plasma cells, and the recall of high affinity Ab responses. The Ag-specific B cells that have not yet undergone isotype switching showed a relatively higher expression of TLR4 than memory B cells, which was reflected in a heightened response to LPS, but in both cases yielded mostly low affinity IgM secreting plasma cells. Thus, although memory B cells are sensitive to TLR agonists in vitro, TLR agonists alone appear to have little affect on B cell memory in vivo. C1 [Richard, Katharina; Song, Wenxia] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Song, WX (reprint author), Univ Maryland, Dept Mol Genet & Cell Biol, 1133 Microbiol Bldg, College Pk, MD 20742 USA. EM wenxsong@umd.edu FU Intramural NIH HHS [Z01 AI000899-07]; NIAID NIH HHS [R01 AI059617, AI059617, R01 AI059617-03] NR 34 TC 34 Z9 34 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2008 VL 181 IS 3 BP 1746 EP 1752 PG 7 WC Immunology SC Immunology GA 329VG UT WOS:000257898100020 PM 18641311 ER PT J AU Lages, CS Suffia, I Velilla, PA Huang, B Warshaw, G Hildeman, DA Belkaid, Y Chougnet, C AF Lages, Celine S. Suffia, Isabelle Velilla, Paula A. Huang, Bin Warshaw, Gregg Hildeman, David A. Belkaid, Yasmin Chougnet, Claire TI Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation SO JOURNAL OF IMMUNOLOGY LA English DT Review ID IMMUNOLOGICAL SELF-TOLERANCE; LEISHMANIA-MAJOR INFECTION; PERIPHERAL-BLOOD; DENDRITIC CELLS; RETINOIC-ACID; SUPPRESSIVE ACTIVITY; CYTOKINE PRODUCTION; REG-CELLS; TGF-BETA; LYMPHOCYTE SUBSETS AB Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (T-regs), a CD4(+) T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all T-regs, especially in aged hosts, we characterized T-regs by the expression of FOXP3, a transcription factor crucial for T-reg differentiation and function. The proportion of FOXP3(+)CD4(+) T-reg increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3(+) T-regs from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral T-regs from elderly humans improves effector T cell responses in most subjects. Importantly, T-regs from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young T-regs. The increased proportion of T-regs in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old T-regs efficiently suppressed the production of IFN-gamma by effector T cells. Finally, in vivo depletion of T-regs in old mice attenuated disease severity. Accumulation of functional T-regs in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of T-reg numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population. C1 [Warshaw, Gregg] Univ Cincinnati, Off Geriatr Med, Cincinnati, OH 45267 USA. [Suffia, Isabelle; Belkaid, Yasmin] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Hildeman, David A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. [Hildeman, David A.] Cincinnati Childrens Hosp, Res Fdn, Div Immunobiol, Cincinnati, OH 45229 USA. [Lages, Celine S.; Velilla, Paula A.; Chougnet, Claire] Cincinnati Childrens Hosp, Res Fdn, Div Mol Immunol, Cincinnati, OH 45229 USA. [Huang, Bin] Childrens Hosp, Med Ctr, Ctr Biostat & Epidemiol, Cincinnati, OH 45229 USA. RP Chougnet, C (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Mol Immunol ML 7021, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM Claire.Chougnet@cchnic.org RI Hildeman, David/I-4884-2015; Huang, bin/G-2468-2014 OI Hildeman, David/0000-0002-0421-8483; FU Intramural NIH HHS; NIA NIH HHS [AG025149, R21 AG025149, R21 AG025149-01A1]; NIAID NIH HHS [R01 AI057753] NR 102 TC 152 Z9 158 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 AUG 1 PY 2008 VL 181 IS 3 BP 1835 EP 1848 PG 14 WC Immunology SC Immunology GA 329VG UT WOS:000257898100030 PM 18641321 ER PT J AU Stummvoll, GH DiPaolo, RJ Huter, EN Davidson, TS Glass, D Ward, JM Shevach, EM AF Stummvoll, Georg H. DiPaolo, Richard J. Huter, Eva N. Davidson, Todd S. Glass, Deborah Ward, Jerrold M. Shevach, Ethan M. TI Th1, Th2, and Th17 effector T cell-induced autoimmune gastritis differs in pathological pattern and in susceptibility to suppression by regulatory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PERNICIOUS-ANEMIA; DENDRITIC CELLS; DISEASE; ANTIGEN; ENCEPHALOMYELITIS; RESPONSES; IL-17; MICE; AUTOANTIGEN; PREVENT AB Th cells can be subdivided into IFN-gamma-secreting Th1, IL-4/IL-5-secreting Th2, and IL-17-secreting Th17 cells. We have evaluated the capacity of fully differentiated Th1, Th2, and Th17 cells derived from a mouse bearing a transgenic TCR specific for the gastric parietal cell antigen, H(+)K(+)-ATPase, to induce autoimmune gastritis after transfer to immunodeficient recipients. We have also 14 determined the susceptibility of the disease induced by each of the effector T cell types to suppression by polyclonal regulatory T cells (Treg) in vivo. Each type of effector cell induced autoimmune gastritis with distinct histological patterns. Th17 cells induced the most destructive disease with cellular infiltrates composed primarily of eosinophils accompanied by high levels of serum IgE. Polyclonal Treg could suppress the capacity of Th1 cells, could moderately suppress Th2 cells, but could suppress Th17-induced disease only at early time points. The major effect of the Treg was to inhibit the expansion of the effector T cells. However, effector cells isolated from protected animals were not anergic and were fully competent to proliferate and produce effector cytokines ex vivo. The strong inhibitory effect of polyclonal Treg on the capacity of some types of differentiated effector cells to induce disease provides an experimental basis for the clinical use of polyclonal Treg in the treatment of autoimmune disease in humans. C1 [Stummvoll, Georg H.; DiPaolo, Richard J.; Huter, Eva N.; Davidson, Todd S.; Glass, Deborah; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Cellular Immunol Sect, Bethesda, MD 20892 USA. [Ward, Jerrold M.] NIAID, Comparat Med Branch, Infect Dis Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Cellular Immunol Sect, Bldg 10 Room 11N315, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000224-26] NR 37 TC 102 Z9 113 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2008 VL 181 IS 3 BP 1908 EP 1916 PG 9 WC Immunology SC Immunology GA 329VG UT WOS:000257898100037 PM 18641328 ER PT J AU Cannon, G Yi, YJ Ni, HP Stoddard, E Scales, DA Van Ryk, DI Chaiken, I Malamud, D Weissman, D AF Cannon, Georgetta Yi, Yanjie Ni, Houping Stoddard, Earl Scales, David A. Van Ryk, Donald I. Chaiken, Irwin Malamud, Daniel Weissman, Drew TI HIV envelope binding by macrophage-expressed gp340 promotes HIV-1 infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCYTE-DERIVED MACROPHAGES; SURFACTANT PROTEIN-D; C-TYPE LECTIN; DC-SIGN; CELL-SURFACE; SALIVARY AGGLUTININ; HEPARAN-SULFATE; DENDRITIC CELLS; STREPTOCOCCUS-MUTANS AB The scavenger receptor cysteine-rich protein gp340 functions as part of the host innate immune defense system at mucosal surfaces. In the genital tract, its expression by cervical and vaginal epithelial cells promotes HIV trans-infection and may play a role in sexual transmission. Gp340 is an alternatively spliced product of the deleted in malignant brain tumors 1 (DMBT1) gene. In addition to its innate immune system activity, DMBT1 demonstrates instability in multiple types of cancer and plays a role in epithelial cell differentiation. We demonstrate that monocyte-derived macrophages express gp340 and that HIV-1 infection is decreased when envelope cannot bind it. Inhibition of infection occurred at the level of fusion of M-, T-, and dual-tropic envelopes. Additional HIV-1 envelope binding molecules, such as dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), mannose-binding lectin, and heparan sulfate, enhance the efficiency of infection of the cells that express them by increasing the local concentration of infectious virus. Our data suggest that gp340, which is expressed by macrophages in vivo, may function to enhance infection in much the same manner. Its expression on tissue macrophages and epithelial cells suggests important new opportunities for HIV-1 pathogenesis investigation and therapy. C1 [Cannon, Georgetta; Ni, Houping; Stoddard, Earl; Scales, David A.; Weissman, Drew] Univ Penn, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Yi, Yanjie] Univ Penn, Dept Med, Div Pulm & Crit Care Med, Philadelphia, PA 19104 USA. [Van Ryk, Donald I.] NIAID, NIH, Bethesda, MD 20892 USA. [Chaiken, Irwin] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USA. [Malamud, Daniel] NYU, Coll Dent, Dept Basic Sci, New York, NY 10010 USA. RP Weissman, D (reprint author), Univ Penn, Dept Med, Div Infect Dis, 522B Johnson Pavil, Philadelphia, PA 19104 USA. EM dreww@mail.med.upenn.edu OI Malamud, Daniel/0000-0002-9094-4122 FU NHLBI NIH HHS [HL620600]; NIAID NIH HHS [R01 AI060505, R01 AI060505-01A1, R01 AI060505-03, R01 AI060505-05, R01 AI060505-04, R01 AI060505-02]; NIDCR NIH HHS [DE12930, R01 DE012930-02, R01 DE012930-03, R01 DE012930-01] NR 49 TC 19 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 AUG 1 PY 2008 VL 181 IS 3 BP 2065 EP 2070 PG 6 WC Immunology SC Immunology GA 329VG UT WOS:000257898100053 PM 18641344 ER PT J AU Londono, D Marques, A Hornung, RL Cadavid, D AF Londono, Diana Marques, Adriana Hornung, Ronald L. Cadavid, Diego TI IL-10 helps control pathogen load during high-level bacteremia SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RELAPSING FEVER BORRELIOSIS; TUMOR-NECROSIS-FACTOR; SEPTIC SHOCK; INTERLEUKIN-10-DEFICIENT MICE; LISTERIA-MONOCYTOGENES; MENINGOCOCCAL DISEASE; PERSISTENT INFECTION; TRYPANOSOMA-CRUZI; LYME-BORRELIOSIS; SEVERE SEPSIS AB During relapsing fever borreliosis, a high pathogen load in the blood occurs at times of peak bacteremia. Specific IgM Abs are responsible for spirochetal clearance so in absence of B cells there is persistent high-level bacteremia. Previously, we showed that B cell-deficient mice persistently infected with Borrelia turicatae produce high levels of IL-10 and that exogenous IL-10 reduces bacteremia. This suggested that IL-10 helps reduce bacteremia at times of high pathogen load by a B cell-independent mechanism, most likely involving innate immunity. To investigate this possibility, we compared B. turicatae infection in RAG2/IL-10(-/-) and RAG2(-/-) mice. The results showed that IL-10 deficiency resulted in significantly higher bacteremia, higher TNF levels, and early mortality. Examination of the spleen and peripheral blood showed markedly increased apoptosis of immune cells in infected RAG2/IL-10(-/-) mice. Neutralization of TNF reduced apoptosis of leukocytes and splenocytes, increased production of IFN-gamma by NK cells, increased phagocytosis in the spleen, decreased spirochetemia, and rescued mice from early death. Our results indicate that at times of high pathogen load, as during peak bacteremia in relapsing fever borreliosis, IL-10 protects innate immune cells from apoptosis via inhibition of TNF resulting in improved pathogen control. C1 [Londono, Diana; Cadavid, Diego] Univ Med & Dent New Jersey, Dept Neurol & Neurosci, Newark, NJ 07103 USA. [Londono, Diana; Cadavid, Diego] Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Emerging Pathogens, Newark, NJ 07103 USA. [Marques, Adriana] NIAID, Clin Studies Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hornung, Ronald L.] Natl Canc Inst, Clin Serv Program, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. RP Cadavid, D (reprint author), Bingen Idec, Expt Neurol Grp, 14 Cambridge Ctr,,Bldg 6A,6th Floor, Cambridge, MA 02142 USA. EM diego.cadavid@biogenidec.com FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01-CO-12400]; NINDS NIH HHS [R21 NS053997-02, R21NS053997-01, R21 NS053997-01, R21 NS053997] NR 51 TC 19 Z9 22 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 AUG 1 PY 2008 VL 181 IS 3 BP 2076 EP 2083 PG 8 WC Immunology SC Immunology GA 329VG UT WOS:000257898100055 PM 18641346 ER PT J AU Abraham, J Bhat, SG AF Abraham, Jessy Bhat, S. G. TI Permeabilization of baker's yeast with N-lauroyl sarcosine SO JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY LA English DT Article DE permeabilization; N-Lauroyl sarcosine; baker's yeast; saccharomyces cerevisiae; catalase ID SACCHAROMYCES-CEREVISIAE CELLS; CATALASE; ACID; IMMOBILIZATION; ENZYMES; SOLUBILIZATION; DETERGENTS; BILAYERS; BROMIDE; OXIDASE AB N-Lauroyl sarcosine (LS), a cationic, non-toxic and biodegradable detergent readily permeabilized whole cells of baker's yeast (Saccharomyces cerevisiae). Permeabilization was carried out to increase assayable cellular catalase activity, an enzyme of great physiological and industrial importance, and to release 5'-nucleotides which find food/nutritional applications. The event of permeabilization was concentration, time and temperature dependent. Maximum permeabilization of yeast cells were observed when 1 g wet weight (0.2 g dry wt) of cells were permeabilized with 1.0 ml of 2% LS at 45 degrees C for 15 min. LS-permeabilized cells showed 350-fold increase in catalase activity and the supernatant obtained after permeabilization was rich in 5'-nucleotides. LS-permeabilized baker's yeast cells can be used as a source of biocatalyst and to isolate valuable by-products. C1 [Abraham, Jessy] NIAAA, Mol Neurobiol Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Abraham, Jessy; Bhat, S. G.] Cent Food Technol Res Inst, Dept Biochem & Nutr, Mysore 570013, Karnataka, India. RP Abraham, J (reprint author), NIAAA, Mol Neurobiol Sect, Neurogenet Lab, 5625 Fishers Lane,Room 3S-32,MSC 9412, Bethesda, MD 20892 USA. EM jessy1994@yahoo.com NR 34 TC 11 Z9 12 U1 0 U2 10 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1367-5435 J9 J IND MICROBIOL BIOT JI J. Ind. Microbiol. Biotechnol. PD AUG PY 2008 VL 35 IS 8 BP 799 EP 804 DI 10.1007/s10295-008-0350-9 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 330MK UT WOS:000257945700002 PM 18415131 ER PT J AU Miller, MA Viboud, C Olson, DR Grais, RF Rabaa, MA Simonsen, L AF Miller, Mark A. Viboud, Cecile Olson, Donald R. Grais, Rebecca F. Rabaa, Maia A. Simonsen, Lone TI Prioritization of influenza pandemic vaccination to minimize years of life lost SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 9th Annual Conference on Vaccine Research CY MAY 08-10, 2006 CL Baltimore, MD ID PUBLIC-HEALTH; UNITED-STATES; AGE DISTRIBUTION; COST-EFFECTIVENESS; MORTALITY; DISEASE; BURDEN; STRATEGIES; IMPACT; ETHICS AB Background. How to allocate limited vaccine supplies in the event of an influenza pandemic is currently under debate. Conventional vaccination strategies focus on those at highest risk for severe outcomes, including seniors, but do not consider (1) the signature pandemic pattern in which mortality risk is shifted to younger ages, (2) likely reduced vaccine response in seniors, and (3) differences in remaining years of life with age. Methods. We integrated these factors to project the age-specific years of life lost (YLL) and saved in a future pandemic, on the basis of mortality patterns from 3 historical pandemics, age-specific vaccine efficacy, and the 2000 US population structure. Results. For a 1918-like scenario, the absolute mortality risk is highest in people < 45 years old; in contrast, seniors (those >= 65 years old) have the highest mortality risk in the 1957 and 1968 scenarios. The greatest YLL savings would be achieved by targeting different age groups in each scenario; people < 45 years old in the 1918 scenario, people 45-64 years old in the 1968 scenario, and people < 45 years old in the 1957 scenario. Conclusions. Our findings shift the focus of pandemic vaccination strategies onto younger populations and illustrate the need for real-time surveillance of mortality patterns in a future pandemic. Flexible setting of vaccination priority is essential to minimize mortality. C1 [Miller, Mark A.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Olson, Donald R.] New York City Dept Hlth & Mental Hyg, New York, NY USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. RP Miller, MA (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM millemar@mail.nih.gov OI Rabaa, Maia/0000-0003-0529-2228; Simonsen, Lone/0000-0003-1535-8526 NR 50 TC 35 Z9 36 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 1 PY 2008 VL 198 IS 3 BP 305 EP 311 DI 10.1086/589716 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 326KU UT WOS:000257658500003 PM 18558871 ER PT J AU Hoover, SE Kawada, J Wilson, W Cohen, JI AF Hoover, Susan E. Kawada, Junichi Wilson, Wyndham Cohen, Jeffrey I. TI Oropharyngeal shedding of Epstein-Barr virus in the absence of circulating B cells SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ASYMPTOMATIC CARRIERS; INFECTION; REACTIVATION; PHARMACODYNAMICS; RITUXIMAB; EBV AB Infection with Epstein-Barr virus (EBV) results in lifelong infection of B cells in the peripheral blood and in episodic shedding of virus from the oropharynx. We monitored patients treated with rituximab (anti-CD20 monoclonal antibody) and found that several had both no detectable B cells and no EBV in the blood but shed EBV from the throat. Although some models postulate that EBV traffics from the B cells in the blood to the throat, where it is subsequently shed, our findings indicate that circulating EBV in B cells is not necessary for the virus to persist in, and to be shed from, the oropharynx. C1 [Hoover, Susan E.; Kawada, Junichi; Cohen, Jeffrey I.] NIH, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Wilson, Wyndham] NCI, Lymphoma Therapeut Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Lab Clin Infect Dis, Bldg 10,Rm 11N234,10 Ctr Dr,MSC 1888, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov RI Hoover, Susan/F-8580-2015; Kawada, Jun-ichi/I-7322-2014 FU Intramural NIH HHS [Z01 AI000913-06] NR 15 TC 10 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 1 PY 2008 VL 198 IS 3 BP 318 EP 323 DI 10.1086/589714 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 326KU UT WOS:000257658500005 PM 18544038 ER PT J AU Ramanathan, R Burbelo, PD Groot, S Iadarola, MJ Neva, FA Nutman, TB AF Ramanathan, Roshan Burbelo, Peter D. Groot, Sandra Iadarola, Michael J. Neva, Franklin A. Nutman, Thomas B. TI A luciferase immunoprecipitation systems assay enhances the sensitivity and specificity of diagnosis of Strongyloides stercoralis infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 56th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY NOV 04-08, 2007 CL Philadelphia, PA SP Amer Soc Trop Med & Hyg ID IMMUNODIAGNOSIS; RESPONSES AB Background. We investigated whether luciferase immunoprecipitation systems (LIPS) can be the basis for a more rapid, specific, and standardized assay for the diagnosis of Strongyloides stercoralis infection. Methods. A LIPS assay was developed based on immunoglobulin (Ig) G or IgG4 antibody to a recombinant Strongyloides antigen (NIE) and was compared with an NIE enzyme-linked immunosorbent assay (ELISA). A second antigen, S. stercoralis immunoreactive antigen (SsIR), was tested alone and in combination with NIE. The assays were tested using serum samples from patients with parasitologically proven S. stercoralis or filarial infections and from healthy, uninfected control subjects. Results. The NIE LIPS assay based on IgG antibody easily differentiated between S. stercoralis-infected and uninfected patients (P < .0001) and demonstrated improved specificity compared with the NIE ELISA (100% vs. 95%). Serum from filaria-infected patients did not cross-react when tested with the NIE LIPS assay. When SsIR was used in combination with NIE in the LIPS format, sensitivity and specificity improved to 100%, with a 7-fold difference between positive and negative values. No advantage was found in using a LIPS assay based on IgG4. At post-treatment follow-up, a significant decline in antibody titers was detected using the NIE ELISA (P < .0017) and the NIE LIPS assay (P < .0001). Conclusions. LIPS addresses several limitations of current ELISAs and represents a major advance in the diagnosis of S. stercoralis infection. C1 [Ramanathan, Roshan; Neva, Franklin A.; Nutman, Thomas B.] NIAID, Clin Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Burbelo, Peter D.; Groot, Sandra; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. RP Ramanathan, R (reprint author), NIAID, Clin Parasitol Unit, Parasit Dis Lab, NIH, 4 Ctr Dr,Bldg 4,Room B1-05, Bethesda, MD 20892 USA. EM ramanathanr@niaid.nih.gov FU Intramural NIH HHS [Z01 DE000724-01] NR 16 TC 67 Z9 68 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 1 PY 2008 VL 198 IS 3 BP 444 EP 451 DI 10.1086/589718 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 326KU UT WOS:000257658500021 PM 18558872 ER PT J AU Guillard, M Verrijp, K Voermans, N Huizing, M Morava, E Van Bokhoven, H Van Engelen, B Wevers, RA Lammens, M Lefeber, DJ AF Guillard, M. Verrijp, K. Voermans, N. Huizing, M. Morava, E. Van Bokhoven, H. Van Engelen, B. Wevers, R. A. Lammens, M. Lefeber, D. J. TI Biochemical tools in the diagnosis of glycosylation related myopathies SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Guillard, M.; Wevers, R. A.; Lefeber, D. J.] Radboud UMC, Lab Ped & Neurol, Nijmegen, Netherlands. [Verrijp, K.; Lammens, M.] Radboud UMC, Dept Pathol, Nijmegen, Netherlands. [Voermans, N.; Van Engelen, B.] Radboud UMC, Dept Neurol, Nijmegen, Netherlands. [Huizing, M.] NIH, Med Genet Branch, Bethesda, MD 20892 USA. [Morava, E.] Radboud UMC, Dept Pediat, Nijmegen, Netherlands. RI van Engelen, Baziel/D-3475-2009; Engelen, B.G.M./H-8027-2014; Wevers, Ron/H-8116-2014; Bokhoven, J.H.L.M./H-8015-2014; Morava, E./L-4529-2015; Voermans, N.C./L-4724-2015 OI Wevers, Ron/0000-0003-2278-9746; NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD AUG PY 2008 VL 31 SU 1 MA 195P BP 50 EP 50 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 340PB UT WOS:000258656400196 ER PT J AU Udey, MC Rosenberg, AS AF Udey, Mark C. Rosenberg, Amy S. TI Langerhans cell dogma: Another round of rejections SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID LANGERIN(+) DENDRITIC CELLS; T-CELLS; CONTACT HYPERSENSITIVITY; SKIN; DEVELOP AB Mice that are deficient in epidermal Langerhans cells allow the functions of these cells in vivo to be rigorously assessed. Experiments that have been carried out with these animals have yielded surprising results, leading to major changes in existing paradigms. In this issue, Obhrai and coworkers explore the involvement of Langerhans cells in skin graft rejection and describe fascinating results. C1 [Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rosenberg, Amy S.] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20014 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM udey@helix.nih.gov NR 14 TC 2 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 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2008 VL 128 IS 8 BP 1881 EP 1883 DI 10.1038/jid.2008.167 PG 3 WC Dermatology SC Dermatology GA 331SA UT WOS:000258031700003 PM 18626480 ER PT J AU Inui, H Oh, KS Nadem, C Ueda, T Khan, SC Metin, A Gozukara, E Emmert, S Slor, H Busch, DB Baker, CC DiGiovanna, JJ Tamura, D Seitz, CS Gratchev, A Wu, WH Chung, KY Chung, HJ Azizi, E Woodgate, R Schneider, TD Kraemer, KH AF Inui, Hiroki Oh, Kyu-Seon Nadem, Carine Ueda, Takahiro Khan, Sikandar C. Metin, Ahmet Gozukara, Engm Emmert, Steffen Slor, Hanoch Busch, David B. Baker, Carl C. DiGiovanna, John J. Tamura, Deborah Seitz, Cornelia S. Gratchev, Alexei Wu, Wen Hao Chung, Kee Yang Chung, Hye Jin Azizi, Esther Woodgate, Roger Schneider, Thomas D. Kraemer, Kenneth H. TI Xeroderma pigmentosum-variant patients from America, Europe, and Asia SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID DNA-POLYMERASE-ETA; MESSENGER-RNA LEVELS; TRANSLESION SYNTHESIS; ULTRAVIOLET-LIGHT; THYMINE DIMER; REPAIR GENE; HUMAN-CELLS; Y-FAMILY; COCKAYNE-SYNDROME; SKIN-CANCER AB Xeroderma pigmentosum-variant (XP-V) patients have sun sensitivity and increased skin cancer risk. Their cells have normal nucleotide excision repair, but have defects in the POLH gene encoding an error-prone polymerase, DNA polymerase eta (pol eta). To survey the molecular basis of XP-V worldwide, we measured pol eta protein in skin fibroblasts from putative XP-V patients (aged 8-66 years) from 10 families in North America, Turkey, Israel, Germany, and Korea. Pol eta was undetectable in cells from patients in eight families, whereas two showed faint bands. DNA sequencing identified 10 different POLH mutations. There were two splicing, one nonsense, five frameshift (3 deletion and 2 insertion), and two missense mutations. Nine of these mutations involved the catalytic domain. Although affected siblings had similar clinical features, the relation between the clinical features and the mutations was not clear. POLH mRNA levels were normal or reduced by 50% in three cell strains with undetectable levels of pol eta protein, indicating that nonsense-mediated message decay was limited. We found a wide spectrum of mutations in the POLH gene among XP-V patients in different countries, suggesting that many of these mutations arose independently. C1 [Inui, Hiroki; Oh, Kyu-Seon; Nadem, Carine; Ueda, Takahiro; Khan, Sikandar C.; DiGiovanna, John J.; Tamura, Deborah; Kraemer, Kenneth H.] NCI, DNA Repair Sect, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Metin, Ahmet] Ankara Ataturk Res & Training Hosp, Dermatol Clin, Ankara, Turkey. [Gozukara, Engm] Yeditepe Univ, Sch Med, Dept Med Biol & Genet, Istanbul, Turkey. [Emmert, Steffen] Univ Gottingen, Dept Dermatol, Gottingen, Germany. [Slor, Hanoch] Tel Aviv Univ, Sch Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. [Busch, David B.] Armed Forces Inst Pathol, Washington, DC 20306 USA. [Baker, Carl C.] NIAMS Extramural Program, Bethesda, MD USA. [DiGiovanna, John J.] Brown Univ, Warren Alpert Sch Med, Dept Dermatol, Div Dematopharmacol, Providence, RI 02912 USA. [Seitz, Cornelia S.] Univ Wurzburg, Dept Dermatol, D-8700 Wurzburg, Germany. [Gratchev, Alexei] Univ Heidelberg, Univ Med Ctr Mannheim, Dept Dermatol, D-6800 Mannheim, Germany. [Wu, Wen Hao; Chung, Kee Yang; Chung, Hye Jin] Yonsei Univ, Coll Med, Cutaneous Biol Res Inst, Dept Dermatol, Seoul, South Korea. [Azizi, Esther] Tel Aviv Univ, Sch Med, Dept Dermatol, IL-69978 Tel Aviv, Israel. [Woodgate, Roger] NICHHD, Lab Genom Integr, Bethesda, MD 20892 USA. [Schneider, Thomas D.] NCI, Nanobiol Program, Canc Res Ctr, Frederick, MD 21701 USA. RP Kraemer, KH (reprint author), NCI, DNA Repair Sect, Basic Res Lab, Ctr Canc Res, Bldg 37,Room 4002,MSC 4258, Bethesda, MD 20892 USA. EM kraemerk@nih.gov RI Gratchev, Alexei/J-3170-2013; OI Schneider, Thomas/0000-0002-9841-1531; Gratchev, Alexei/0000-0003-2137-1866 FU Intramural NIH HHS [Z01 HD001500-25, Z01 BC008396-18] NR 76 TC 40 Z9 42 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2008 VL 128 IS 8 BP 2055 EP 2068 DI 10.1038/jid.2008.48 PG 14 WC Dermatology SC Dermatology GA 331SA UT WOS:000258031700027 PM 18368133 ER PT J AU Green, KA Almholt, K Ploug, M Rono, B Castellino, FJ Johnsen, M Bugge, TH Romer, J Lund, LR AF Green, Kirsty A. Almholt, Kasper Ploug, Michael Rono, Birgitte Castellino, Francis J. Johnsen, Morten Bugge, Thomas H. Romer, John Lund, Leif R. TI Profibrinolytic effects of metalloproteinases during skin wound healing in the absence of plasminogen SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID MATRIX METALLOPROTEINASES; UROKINASE-TYPE; DEFICIENT MICE; LIGNEOUS CONJUNCTIVITIS; FUNCTIONAL OVERLAP; FIBRINOGEN; CANCER; KERATINOCYTES; ACTIVATOR; MMPS AB Genetic ablation of plasminogen (Pig) and pharmacological inhibition of metalloproteinase activity by galardin delay skin wound healing in mice, whereas the combined inhibition of these two enzyme systems completely prevents healing. In this study, the impact of plasmin and metalloproteinases as profibrinolytic enzymes has been investigated by comparing skin wound healing in the absence and presence of fibrin. Pig deficiency impairs skin wound healing kinetics, but this delay is only partially restored in the absence of fibrin. This suggests that plasmin-mediated fibrinolysis is the primary, but not the exclusive, requirement for healing of wounds in these mice. In addition, we observe that lack of fibrin reduces Pig activation significantly during wound healing. The profibrinolytic role of metalloproteinases is revealed by the finding that lack of fibrin partially restores the otherwise arrested healing of PIg-deficient wounds after metalloproteinase inhibition. In conclusion, the residual impairment of skin wound healing in the absence of fibrin suggests the existence of a fibrin-independent substrate(s) for plasmin and metalloproteinases. Furthermore, these in vivo data reveal that galardin-sensitive metalloproteinases mediate compensatory fibrinolysis to facilitate wound healing in the absence of plasmin. C1 [Green, Kirsty A.; Almholt, Kasper; Ploug, Michael; Rono, Birgitte; Romer, John; Lund, Leif R.] Rigshosp, Finsen Lab, Copenhagen Bioctr, DK-2200 Copenhagen, Denmark. [Castellino, Francis J.] Univ Notre Dame, WM Keck Ctr Transgene Res, Notre Dame, IN 46556 USA. [Johnsen, Morten] Univ Copenhagen, Inst Mol Biol, Copenhagen Bioctr, DK-1168 Copenhagen, Denmark. [Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Natl Inst Hlth, Bethesda, MD USA. RP Lund, LR (reprint author), Rigshosp, Finsen Lab, Copenhagen Bioctr, Bldg 3-3,Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. EM lund@inet.uni2.dk RI Almholt, Kasper/D-6133-2013; Johnsen, Morten/L-8016-2014; OI Johnsen, Morten/0000-0003-3763-2362; Almholt, Kasper/0000-0002-9250-514X FU NHLBI NIH HHS [HL013143] NR 40 TC 19 Z9 19 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2008 VL 128 IS 8 BP 2092 EP 2101 DI 10.1038/jid.2008.54 PG 10 WC Dermatology SC Dermatology GA 331SA UT WOS:000258031700031 PM 18337830 ER PT J AU Leonard, WJ Zeng, R Spolski, R AF Leonard, Warren J. Zeng, Rong Spolski, Rosanne TI Interleukin 21: a cytokine/cytokine receptor system that has come of age SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article ID COMMON GAMMA-CHAIN; T-CELLS; IL-21 RECEPTOR; NK CELLS; B-CELLS; IN-VIVO; METASTATIC MELANOMA; ALTERNATIVE PATHWAY; CYTOKINE RECEPTOR; ADAPTIVE IMMUNITY AB Interleukin-21 (IL-21) and its receptor represent the sixth cytokine system whose actions were recognized to require the common cytokine receptor gamma chain. IL-21 is produced by activated CD4(+) T cells, natural killer T cells, and follicular T helper cells and has actions on a range of lympho-hematopoietic lineages. Among its many effects, IL-21 serves a critical role for immunoglobulin production and terminal B cell differentiation, acts as a T cell comitogen and can drive the expansion of CD8(+) T cells, can negatively regulate dendritic cell function and plays an essential role in the differentiation of Th17 cells. Importantly, IL-21 is implicated in the pathogenesis of autoimmunity and exhibits potent actions as an antitumor agent. The ability to regulate and manipulate the actions of IL-21, therefore, has important implications for immunoregulation and the therapy of human disease. C1 [Leonard, Warren J.; Zeng, Rong; Spolski, Rosanne] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Rm 7B05, Bethesda, MD 20892 USA. EM wil@helix.nih.gov FU Intramural NIH HHS NR 62 TC 71 Z9 76 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP 348 EP 356 DI 10.1189/jlb.0308149 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600104 PM 18467657 ER PT J AU Rosenberg, HF AF Rosenberg, Helene F. TI The many faces of IgE: an interview with Dr. Toshiaki Kawakami SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material ID MAST-CELL SURVIVAL; ACTIVATION; MIGRATION; ANTIGEN; GENE C1 NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, NIH, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP 368 EP 370 DI 10.1189/jlb.1307841 PG 3 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600106 ER PT J AU Hernandez-Novoa, B Bishop, L Logun, C Munson, PJ Elnekave, E Rangel, ZG Barb, J Danner, RL Kovacs, JA AF Hernandez-Novoa, Beatriz Bishop, Lisa Logun, Carolea Munson, Peter J. Elnekave, Eldad Rangel, Zoila G. Barb, Jennifer Danner, Robert L. Kovacs, Joseph A. TI Immune responses to Pneumocystis murina are robust in healthy mice but largely absent in CD40 ligand-deficient mice SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE immunodeficiency diseases; rodent; lung ID NK CELL ACTIVATION; HYPER-IGM SYNDROME; CD8(+) T-CELLS; CARINII-PNEUMONIA; MEDIATED CYTOTOXICITY; MUCUS OVERPRODUCTION; GAMMA-INTERFERON; DENDRITIC CELLS; HOST IMMUNE; IFN-GAMMA AB Pneumocystis is a pathogen of immuno-compromised hosts but can also infect healthy hosts, in whom infection is rapidly controlled and cleared. Microarray methods were used to examine differential gene expression in the lungs of C57BL/6 and CD40 ligand knockout (CD40L-KO) mice over time following exposure to Pneumocystis murina. Immunocompetent C57BL/6 mice, which control and clear infection efficiently, showed a robust response to infection characterized by the up-regulation of 349 primarily immune response-associated genes. Temporal changes in the expression of these genes identified an early (Week 2), primarily innate response, which waned before the infection was controlled; this was followed by primarily adaptive immune responses that peaked at Week 5, which coincided with clearance of the infection. In conjunction with the latter, there was an increased expression of B cell-associated (Ig) genes at Week 6 that persisted through 11 weeks. In contrast, CD40L-KO mice, which are highly susceptible to developing severe Pneumocystis pneumonia, showed essentially no up-regulation of immune response-associated genes at Days 35-75. Immunohistochemical staining supported these observations by demonstrating an increase in CD4+, CD68+, and CD19+ cells in C57BL/6 but not CD40L-KO mice. Thus, the healthy host demonstrates a robust, biphasic response to infection by Pneumocystis; CD40L is an essential upstream regulator of the adaptive immune responses that efficiently control infection and prevent development of progressive pneumonia. C1 [Hernandez-Novoa, Beatriz; Bishop, Lisa; Logun, Carolea; Danner, Robert L.; Kovacs, Joseph A.] NIAID, NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Munson, Peter J.; Rangel, Zoila G.; Barb, Jennifer] NIAID, NIH, Ctr Informat Technol, Div Computat Biosci,Math & Stat Comp Lab, Bethesda, MD 20892 USA. [Elnekave, Eldad] NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), NIAID, NIH, Ctr Clin, Dept Crit Care Med, Bldg 10,Room 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@nih.gov FU Intramural NIH HHS NR 68 TC 18 Z9 18 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP 420 EP 430 DI 10.1189/jlb.1207816 PG 11 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600112 PM 18467653 ER PT J AU Brinster, C Shevach, EM AF Brinster, Carine Shevach, Ethan M. TI Costimulatory effects of IL-1 on the expansion/differentiation of CD4(+) CD25(+) Foxp3(+) and CD4(+) CD25(+) Foxp3(-) T cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE rodent; dendritic cells; costimulation; cell proliferation ID DENDRITIC CELLS; IN-VITRO; INTERLEUKIN-1; EXPANSION; ARTHRITIS; ACTIVATION; INDUCTION; RECEPTOR; TOLERANCE; MICE AB CD4(+)CD25(+) forkhead box p3 (Foxp3)(+) regulatory T cells (Treg) control peripheral tolerance. Although Treg are anergic when stimulated through the TCR, mature bone marrow-derived, but not splenic, dendritic cells (DC) can induce their proliferation after TCR stimulation in the absence of IL-2. One possibility is that the DC produce proinflammatory cytokines such as IL-1 or IL-6 that function as growth factors for Treg. We have analyzed the costimulatory effects of IL-1 on the expansion of Foxp3(+) Treg in vitro. When CD4(+)CD25(+) T cells were cultured in the presence of splenic DC and IL-1, marked expansion of the Foxp3(+) T cells was observed. The effects of IL-1 were mediated on CD4(+)CD25(+) Foxp3(-) T cells present in the starting population rather than on the DC or on the CD4(+)CD25(+) Foxp3(-) T cells. In contrast, stimulation of CD4(+)CD25(+) T cells with plate- bound anti-CD3 and IL-1 in the absence of DC resulted in the outgrowth of a CD4(+)CD25(+) Foxp3 - T cell population composed of NKT cells and non-NKT, IL-17producing cells. Foxp3(+) Treg purified from mice expressing the reporter gene enhanced GFP in the Foxp3 locus failed to proliferate when costimulated with IL-1. These findings have important implications for the design of protocols for the expansion of CD4(+)CD25(+) T cells for cellular biotherapy. C1 [Brinster, Carine; Shevach, Ethan M.] NIAID, NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, NIH, Immunol Lab, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Intramural NIH HHS NR 23 TC 19 Z9 20 U1 1 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP 480 EP 487 DI 10.1189/jlb.0208085 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600119 PM 18477692 ER PT J AU Cortes, LM Avichezer, D Silver, PB Luger, D Mattapallil, MJ Chan, CC Caspi, RR AF Cortes, Lizette M. Avichezer, Dody Silver, Phyllis B. Luger, Dror Mattapallil, Mary J. Chan, Chi-Chao Caspi, Rachel R. TI Inhibitory peptide analogs derived from a major uveitogenic epitope protect from antiretinal autoimmunity by inducing type 2 and regulatory T cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE experimental autoimmune uveitis; tolerance ID MULTIPLE-SCLEROSIS; RETINAL ANTIGENS; MICE; UVEITIS; LIGAND; UVEORETINITIS; IMMUNOMODULATION; IMMUNOTHERAPY; MECHANISMS; INDUCTION AB We identified inhibitory peptide analogs (IPAs), capable of immunomodulating experimental autoimmune uveitis (EAU), induced in B10. RIII mice by immunization with the retinal antigen interphotoreceptor-binding protein in CFA. Alanine-substituted peptides of the major pathogenic epitope, residues 161 - 180, were synthesized. They were tested for immunogenicity, cross-reactivity with the native 161 - 180 epitope, pathogenicity, and ability to prevent EAU when given in IFA before EAU challenge with native murine ( m) 161 - 180. Two peptides, 169A and 171A, were unable to elicit disease but cross-reacted with m161 - 180 by lymphocyte proliferation. Mice pretreated with either of the substituted peptides failed to develop EAU after challenge with the native epitope, m161 - 180, and had reduced cellular responses by lymphocyte proliferation and by delayed hypersensitivity. Their cytokine response profile to m161 - 180 showed reduced antigenspecific IFN-gamma and IL-17, whereas IL-4, IL-5, IL-10, and IL-13 from IPA-protected mice were increased, and serum antibody titers to m161 - 180 revealed reduced IgG2a and elevated IgG1 isotypes, suggesting a Th2 shift in the response. Protection was transferable with lymphoid cells from protected donors to naive recipients, who were subsequently immunized for EAU. Thus, IPA pretreatment prevents induction of EAU by skewing the response to a subsequent uveitogenic challenge with the native peptide to a nonpathogenic phenotype, as well as by eliciting transferable regulatory cells. C1 [Cortes, Lizette M.; Avichezer, Dody; Silver, Phyllis B.; Luger, Dror; Mattapallil, Mary J.; Caspi, Rachel R.] NEI, Immunoregulat Lab, NIH, Bethesda, MD 20893 USA. [Chan, Chi-Chao] NEI, Lab Retinal Immunol, NIH, Bethesda, MD 20893 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,10-10N222, Bethesda, MD 20893 USA. EM rcaspi@helix.nih OI Caspi, Rachel/0000-0002-7140-7671 NR 26 TC 8 Z9 9 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP 577 EP 585 DI 10.1189/jlb.0308189 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600128 PM 18495789 ER PT J AU Chaturvedi, A Pierce, S AF Chaturvedi, Akanksha Pierce, Susan TI Synergistic engagement of TLR9 and the B-cell receptor SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Meeting Abstract CT 3rd International Damage Associated Molecular Pattern Molecules (DAMPs) and Alarmins Symposium CY AUG 30-SEP 02, 2008 CL Pittsburgh, PA C1 [Chaturvedi, Akanksha; Pierce, Susan] NIAID, NIH, Bethesda, MD 20892 USA. EM Achaturvedi@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP A10 EP A10 PG 1 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600030 ER PT J AU Chou, D Egen, JG Germain, RN Belkaid, Y AF Chou, David Egen, Jackson G. Germain, Ronald N. Belkaid, Yasmine TI Live imaging of natural regulatory T cells during leishmania major infection SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Meeting Abstract CT 3rd International Damage Associated Molecular Pattern Molecules (DAMPs) and Alarmins Symposium CY AUG 30-SEP 02, 2008 CL Pittsburgh, PA C1 [Chou, David; Belkaid, Yasmine] NIAID, Mucosal Immun Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Egen, Jackson G.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Immunol Lab, Bethesda, MD 20892 USA. EM chou.david@medstudent.pitt.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP A23 EP A23 PG 1 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600062 ER PT J AU Krensky, AM AF Krensky, Alan M. TI Granulysin release in the immune response SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Meeting Abstract CT 3rd International Damage Associated Molecular Pattern Molecules (DAMPs) and Alarmins Symposium CY AUG 30-SEP 02, 2008 CL Pittsburgh, PA C1 [Krensky, Alan M.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. EM krenskya@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP A8 EP A9 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600026 ER PT J AU Oppenheim, JJ Tewary, P de la Rosa, G Yang, D AF Oppenheim, Joost J. Tewary, Poonam de la Rosa, Gonzalo Yang, De TI Degranulation and cell injury rapidly releases alarmins to galvanize immunity SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Meeting Abstract CT 3rd International Damage Associated Molecular Pattern Molecules (DAMPs) and Alarmins Symposium CY AUG 30-SEP 02, 2008 CL Pittsburgh, PA C1 [Oppenheim, Joost J.; Tewary, Poonam; de la Rosa, Gonzalo] NCI Frederick, CCR, CIP, Mol Immunoregulat Lab, Frederick, MD USA. [Yang, De] SAIC Frederick Inc, BRP, Frederick, MD USA. EM oppenhei@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP A6 EP A6 PG 1 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600019 ER PT J AU Van Houten, B Haugen, A Di Prospero, N Parker, J Fannin, R Chou, J Halweg, C Meyer, J Durr, A Fischbeck, K AF Van Houten, Bennett Haugen, Astrid Di Prospero, Nicholas Parker, Joel Fannin, Rick Chou, Jeff Halweg, Christopher Meyer, Joel Durr, Alexander Fischbeck, Kenneth TI Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Meeting Abstract CT 3rd International Damage Associated Molecular Pattern Molecules (DAMPs) and Alarmins Symposium CY AUG 30-SEP 02, 2008 CL Pittsburgh, PA C1 [Van Houten, Bennett; Haugen, Astrid; Halweg, Christopher] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC USA. [Di Prospero, Nicholas; Fischbeck, Kenneth] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Fannin, Rick; Chou, Jeff] NIEHS, Lab Toxicogenom, Res Triangle Pk, NC USA. [Parker, Joel] Express Anal, Durham, NC USA. [Meyer, Joel] Duke Univ, Nicholas Sch Environm & Earth Sci, Durham, NC USA. [Durr, Alexander] Hop La Pitie Salpetriere, Dept Genet, Paris, France. EM vanhout1@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG 1 PY 2008 VL 84 IS 2 BP A35 EP A35 PG 1 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 332OF UT WOS:000258091600093 ER PT J AU Igarashi, M Ma, KZ Chang, L Bell, JM Rapoport, SI AF Igarashi, Miki Ma, Kaizong Chang, Lisa Bell, Jane M. Rapoport, Stanley I. TI Rat heart cannot synthesize docosahexaenoic acid from circulating alpha-linolenic acid because it lacks elongase-2 SO JOURNAL OF LIPID RESEARCH LA English DT Article DE diet; heart; deprivation; elongation; synthesis; n-3 polyunsaturated fatty acids ID POLYUNSATURATED FATTY-ACIDS; THIN-LAYER CHROMATOGRAPHY; N-3 PUFA DEPRIVATION; FISH-OIL; BRAIN PHOSPHOLIPIDS; IN-VIVO; DESATURASE EXPRESSION; LIVER CONVERSION; GENE-EXPRESSION; ISCHEMIC-HEART AB The extent to which the heart can convert alpha-linolenic acid (alpha-LNA, 18:3n-3) to longer chain n-3 PUFAs is not known. Conversion rates can be measured in vivo using radiolabeled alpha-LNA and a kinetic fatty acid model. [1-C-14]alpha-LNA was infused intravenously for 5 min in unanesthetized rats that had been fed an n-3 PUFA-adequate [4.6% alpha-LNA, no docosahexaenoic acid (DHA, 22:6n-3)] or n-3 PUFA-deficient diet (0.2% alpha-LNA, nor DHA) for 15 weeks after weaning. Arterial plasma was sampled, as was the heart after high-energy microwaving. Rates of conversion of alpha-LNA to longer chain n-3 PUFAs were low, and DHA was not synthesized at all in the heart. Most alpha-LNA within the heart had been beta-oxidized. In deprived compared with adequate rats, DHA concentrations in plasma and heart were both reduced by >90%, whereas heart and plasma levels of docosapentaenoic acid (DPAn-6, 22:5n-6) were elevated. Dietary deprivation did not affect cardiac mRNA levels of elongase-5 or desaturases Delta 6 and Delta 5, but elongase-2 mRNA could not be detected. In summary, the rat heart does not synthesize DHA from alpha-LNA, owing to the absence of elongase-2, but must obtain its DHA entirely from plasma. Dietary n-3 PUFA deprivation markedly reduces heart DHA and increases heart DPAn-6, which may make the heart vulnerable to different insults. C1 [Igarashi, Miki; Ma, Kaizong; Chang, Lisa; Bell, Jane M.; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sec, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Igarashi, M (reprint author), NIA, Brain Physiol & Metab Sec, Natl Inst Hlth, Bethesda, MD 20892 USA. EM mikii@mail.nih.gov FU Intramural NIH HHS NR 63 TC 37 Z9 38 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD AUG PY 2008 VL 49 IS 8 BP 1735 EP 1745 DI 10.1194/jlr.M800093-JLR200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CS UT WOS:000257566400015 PM 18456640 ER PT J AU Guttman, MA Raval, AN Lederman, RJ McVeigh, ER AF Guttman, Michael A. Raval, Amish N. Lederman, Robert J. McVeigh, Elliot R. TI Real-time catheter-directed MRA with effective background suppression and persistent rendering SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE real-time; angiography; interventional; cardiovascular ID DIGITAL-SUBTRACTION-ANGIOGRAPHY; CONTRAST AGENT; ARTERIES AB Purpose: To develop an imaging and visualization technique for real-time magnetic resonance angiography (rtMRA) fully integrated with a real-time interactive imaging environment on a clinical MR scanner. Materials and Methods: Intraarterial injections of contrast agent and imaging processing techniques were employed for rapid catheter-directed assessment of vessel patency and regional tissue perfusion. Operators can image multiple thin slices to maximize anatomic detail or use thick slice or projection imaging to maximize vessel coverage. Techniques in both pulse sequence and image processing were employed to ensure background suppression. Accumulation of maximum pixel values allows persistent display of bolus signal as it passes through the vessels and into tissues. Automatic brightness adjustment was used to ensure visibility at all stages of bolus passage. Results: Experimental intraarterial rtMRA of coronary. renal, and carotid arteries show that vessel trajectories and perfusion territories are well visualized in swine. Switching between standard real-time imaging and rtMRA imaging after contrast injection was easy to perform during a procedure without stopping the scanner. Conclusion: The proposed technique facilitates visualization of intraarterial contrast injections using real-time MRI. Although designed for rapid deployment during rtMRI-guided interventional procedures, the technique may also be useful to supplement the study of vessel anatomy, flow, or perfusion. C1 [Guttman, Michael A.; McVeigh, Elliot R.] NHLBI, NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. [Raval, Amish N.; Lederman, Robert J.] NHLBI, NIH, Cardiovasc Branch, Bethesda, MD 20892 USA. RP Guttman, MA (reprint author), NHLBI, NIH, Cardiac Energet Lab, 10 Ctr Dr,Bldg 10 Rm B1D416, Bethesda, MD 20892 USA. EM mguttman@nih.gov OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL004609-04, Z01 HL005062-05] NR 11 TC 4 Z9 4 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD AUG PY 2008 VL 28 IS 2 BP 538 EP 542 DI 10.1002/jmri.21409 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 336TK UT WOS:000258387300037 PM 18666149 ER PT J AU Yamaguchi, K Sugiyama, T Kato, S Kondo, Y Ageyama, N Kanekiyo, M Iwata, M Koyanagi, Y Yamamoto, N Honda, M AF Yamaguchi, Koushi Sugiyama, Takahiro Kato, Shinji Kondo, Yoichi Ageyama, Naohide Kanekiyo, Masaru Iwata, Misao Koyanagi, Yoshio Yamamoto, Naoki Honda, Mitsuo TI A novel CD4-conjugated ultraviolet light-activated photocatalyst inactivates HIV-1 and SIV efficiently SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE ultraviolet light; photocatalyst; CD4-conjugated TiO2; HIV; SIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; BACILLUS-CALMETTE-GUERIN; PRIMING-BOOSTING VACCINATION; CANDIDATE VACCINE; TYPE-1; INFECTION; NEUTRALIZATION; ANTIBODY; AIDS; MACAQUES AB In this study, we found that the electric potential derived from the redox reaction of ultraviolet (UV)-illuminated CD4-conjugated titanium dioxide (TiO2) inactivated a wide range of high-titered primary HIV-1 isolates, regardless of virus co-receptor usage or genetic clade. In vitro incubation of HIV-1 isolates with CD4-conjugated TiO2 (CD4-TiO2) followed by UV illumination led to inhibition of viral infectivity in both H9 cells and peripheral blood mononuclear cells as well as to the complete inactivation of plasma virions from HIV-1-infected individuals. Treatment with a newly established extra-corporeal circulation system with the photocatalyst in rhesus macaques completely inactivated plasma virus in the system and effectively, reduced the infectious plasma viral load. Furthermore, plasma viremia and infectious viral loads were controlled following a second therapeutic photocatalyst treatment during primary SIVmac239 infection of macaques. Our findings suggest that this therapeutic immunophysical strategy may help control human immunodeficiency viral infection in vivo. C1 [Yamaguchi, Koushi] Natl Ctr Child Hlth & Dev, Div Mat Med, Dept Perinatol, Setagaya Ku, Tokyo 1578535, Japan. [Yamaguchi, Koushi; Sugiyama, Takahiro; Kanekiyo, Masaru; Yamamoto, Naoki] Natl Inst Infect Dis, AIDS Res Ctr, Shinjuku Ku, Tokyo, Japan. [Sugiyama, Takahiro; Kato, Shinji; Kondo, Yoichi; Iwata, Misao] Noritake Co, Ctr Res & Dev, Nishi Ku, Nagoya, Aichi, Japan. [Ageyama, Naohide] Natl Inst Biomed Innovat, Tsukuba Primate Res Ctr, Tsukuba, Ibaraki, Japan. [Koyanagi, Yoshio] Kyoto Univ, Inst Virus Res, Sakyo Ku, Kyoto 606, Japan. [Honda, Mitsuo] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Yamaguchi, K (reprint author), Natl Ctr Child Hlth & Dev, Div Mat Med, Dept Perinatol, Setagaya Ku, Okura 2-10-1, Tokyo 1578535, Japan. EM yamaguchi-k@ncchd.go.jp NR 31 TC 7 Z9 7 U1 1 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD AUG PY 2008 VL 80 IS 8 BP 1322 EP 1331 DI 10.1002/jmv.21235 PG 10 WC Virology SC Virology GA 319NN UT WOS:000257170800002 PM 18551617 ER PT J AU Sayers, T AF Sayers, Thomas TI Productively combining proteasome inhibition with the immunotherapy of cancer SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Editorial Material ID APOPTOSIS-INDUCING LIGAND; TUMOR-CELLS; BORTEZOMIB; EXPOSURE; VACCINES; THERAPY; DEATH C1 Natl Canc Inst, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Sayers, T (reprint author), Natl Canc Inst, SAIC Frederick Inc, Bld 560 Rm 31-67, Frederick, MD 21702 USA. EM sayerst@mail.nih.gov FU NCI NIH HHS [N01CO12400, N01 CO012400, N01-CO-12400] NR 17 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 J9 J MOL MED-JMM JI J. Mol. Med. PD AUG PY 2008 VL 86 IS 8 BP 857 EP 860 DI 10.1007/s00109-008-0384-5 PG 4 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 330ML UT WOS:000257945800001 PM 18612622 ER PT J AU Puhl, HL Ikeda, SR AF Puhl, Henry L., III Ikeda, Stephen R. TI Identification of the sensory neuron specific regulatory region for the mouse gene encoding the voltage-gated sodium channel Na(V)1.8 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE pain; promoter; sensory neuron; tetrodotoxin-resistant sodium channel ID NERVE GROWTH-FACTOR; RESTRICTIVE SILENCER FACTOR; ROOT GANGLION NEURONS; PAINFUL DIABETIC-NEUROPATHY; ALPHA-SUBUNIT; RECEPTOR GENE; NA+ CHANNELS; RAT-BRAIN; INITIAL-CHARACTERIZATION; MOLECULAR-MECHANISMS AB Voltage-gated sodium channels (VGSC) are critical membrane components that participate in the electrical activity of excitable cells. The type one VGSC family includes the tetrodotoxin insensitive sodium channel, Na(V)1.8, encoded by the Scn10a gene. Na(V)1.8 expression is restricted to small and medium diameter nociceptive sensory neurons of the dorsal root ganglia and cranial sensory ganglia. To understand the stringent transcriptional regulation of the Scn10a gene, the sensory neuron specific promoter was functionally identified. While identifying the mRNA 5'-end, alternative splicing within the 5'-UTR was observed to create heterogeneity in the RNA transcript. Four kilobases of upstream genomic DNA was cloned and the presence of tissue specific promoter activity was tested by microinjection and adenoviral infection of fluorescent protein reporter constructs into primary mouse and rat neurons, and cell lines. The region contained many putative transcription factor-binding sites and strong homology with the predicted rat ortholog. Homology to the predicted human ortholog was limited to the proximal end and several conserved cis elements were noted. Two regulatory modules were identified by microinjection of reporter constructs into dorsal root ganglia and superior cervical ganglia neurons: a neuron specific proximal promoter region between -1.6 and -0.2 kb of the transcription start site cluster, and a distal sensory neuron switch region beyond -1.6 kb that restricted fluorescent protein expression to a subset of primary sensory neurons. C1 [Puhl, Henry L., III] NIAAA, Lab Mol Physiol, NIH, DICBR,LMP, Bethesda, MD 20892 USA. RP Puhl, HL (reprint author), NIAAA, Lab Mol Physiol, NIH, DICBR,LMP, 5625 Fishers Lane,Room TS-06, Bethesda, MD 20892 USA. EM puhlh@mail.nih.gov OI Ikeda, Stephen/0000-0002-4088-9508; Puhl, Henry/0000-0003-3095-7201 FU Intramural NIH HHS [Z99 AA999999] NR 80 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2008 VL 106 IS 3 BP 1209 EP 1224 DI 10.1111/j.1471-4159.2008.05466.x PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 327CV UT WOS:000257708100020 PM 18466327 ER PT J AU Blair, J AF Blair, J. TI Cognitive neuroscience of psychopathy SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract CT 21st Annual Meeting of the British-Neuropsychiatry-Association CY FEB 07-08, 2008 CL Inst Child Health, London, ENGLAND SP British Neuropsychiat Assoc HO Inst Child Health C1 [Blair, J.] NIMH, Unit Affect Cognit Neurosci, Mood & Anxiety Disorders Programme, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD AUG PY 2008 VL 79 IS 8 MA 01 BP 968 EP 968 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 328KF UT WOS:000257796600031 ER PT J AU Sidman, RL Taksir, T Fidler, J Zhao, M Dodge, JC Passini, MA Raben, N Thurberg, BL Cheng, SH Shihabuddin, LS AF Sidman, Richard L. Taksir, Tatyana Fidler, Jonathan Zhao, Michael Dodge, James C. Passini, Marco A. Raben, Nina Thurberg, Beth L. Cheng, Seng H. Shihabuddin, Lamya S. TI Temporal neuropathologic and behavioral phenotype of 6(neo)/6(neo) Pompe disease mice SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE axon terminal degeneration; genetic disease; glycogen storage in CNS; lysosomal storage diseases; neurobiology ID GLYCOGEN-STORAGE-DISEASE; ACID ALPHA-GLUCOSIDASE; ENZYME REPLACEMENT THERAPY; CUPRIC-SILVER TECHNIQUE; KNOCKOUT MOUSE MODEL; NEURAL STEM-CELLS; FLUORO-JADE-C; MALTASE DEFICIENCY; GENERALIZED GLYCOGENOSIS; DEGENERATING NEURONS AB Pompe disease (glycogen storage disease 11) is caused by mutations in the acid a-glucosidase gene. The most common form is rapidly progressive with glycogen storage, particularly in muscle, which leads to profound weakness, cardiac failure, and death by the age of 2 years. Although usually considered a muscle disease, glycogen storage also occurs in the CNS. We evaluated the progression of neuropathologic and behavioral abnormalities in a Pompe disease mouse model (6(neo)/6(neo)) that displays many features of the human disease. Homozygous mutant mice store excess glycogen within large neurons of hindbrain, spinal cord, and sensory ganglia by the age of I month, accumulations then spread progressively within many CNS cell types. "Silver degeneration" and Fluoro-Jade C stains revealed severe degeneration in axon terminals of primary sensory neurons at 3 to 9 months. These abnormalities were accompanied by progressive behavioral impairment on rotorod, wire hanging, and foot fault tests. The extensive neuropathologic alterations in this model suggest that therapy of skeletal and cardiac muscle disorders by systemic enzyme replacement therapy may not be sufficient to reverse functional deficits due to CNS glycogen storage, particularly early-onset, rapidly progressive disease. A better understanding of the basis for clinical manifestations is needed to correlate CNS pathology with Pompe disease manifestations. C1 [Sidman, Richard L.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Taksir, Tatyana; Fidler, Jonathan; Zhao, Michael; Dodge, James C.; Passini, Marco A.; Thurberg, Beth L.; Cheng, Seng H.; Shihabuddin, Lamya S.] Harvard Univ, Sch Med, Boston, MA USA. Genzyme Corp, Framingham, MA 01701 USA. [Raben, Nina] NIAMS, NIH, Bethesda, MD USA. RP Sidman, RL (reprint author), Harvard Inst Med, 855A,77 Ave, Boston, MA 02115 USA. EM richard-sidman@hms.harvard.edu FU Intramural NIH HHS [Z99 AR999999] NR 61 TC 36 Z9 36 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD AUG PY 2008 VL 67 IS 8 BP 803 EP 818 PG 16 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 333QU UT WOS:000258168200008 PM 18648322 ER PT J AU Masri, R Bezdudnaya, T Trageser, JC Keller, A AF Masri, Radi Bezdudnaya, Tatiana Trageser, Jason C. Keller, Asaf TI Encoding of stimulus frequency and sensor motion in the posterior medial thalamic nucleus SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID ROSTRAL SECTOR; RAT THALAMUS; GROUP POM; WHISKING; RESPONSES; CORTEX; SYSTEM; INFORMATION; NEURONS; ANESTHESIA AB In all sensory systems, information is processed along several parallel streams. In the vibrissa-to-barrel cortex system, these include the lemniscal system and the lesser-known paralemniscal system. The posterior medial nucleus (POm) is the thalamic structure associated with the latter pathway. Previous studies suggested that POm response latencies are positively correlated with stimulation frequency and negatively correlated with response duration, providing a basis for a phase locked loop-temporal decoding of stimulus frequency. We tested this hypothesis by analyzing response latencies of POm neurons, in both awake and anesthetized rats, to vibrissae deflections at frequencies between 0.3 and 11 Hz. We found no significant, systematic correlation between stimulation frequency and the latency or duration of POm responses. We obtained similar findings from recording in awake rats, in rats under different anesthetics, and in anesthetized rats in which the reticular activating system was stimulated. These findings suggest that stimulus frequency is not reliably reflected in response latency of POm neurons. We also tested the hypothesis that POm neurons respond preferentially to sensor motion, that is, they respond to whisking in air, without contacts. We recorded from awake, head-restrained rats while monitoring vibrissae movements. All POm neurons responded to passive whisker deflections, but none responded to noncontact whisking. Thus like their counterparts in the trigeminal ganglion, POm neurons may not reliably encode whisking kinematics. These observations suggest that POm neurons might not faithfully encode vibrissae inputs to provide reliable information on vibrissae movements or contacts. C1 [Masri, Radi; Bezdudnaya, Tatiana; Keller, Asaf] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Masri, Radi; Bezdudnaya, Tatiana; Keller, Asaf] Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. [Trageser, Jason C.] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Keller, A (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, 20 Penn St, Baltimore, MD 21201 USA. EM akeller@umaryland.edu FU NINDS NIH HHS [R01 NS035360-12, F31 NS-046123, NS-31078, R01 NS051799, R01 NS051799-04, R01 NS035360, NS-051799] NR 42 TC 27 Z9 27 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2008 VL 100 IS 2 BP 681 EP 689 DI 10.1152/jn.01322.2007 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 336WC UT WOS:000258394500014 PM 18234976 ER PT J AU Sheinin, A Talani, G Davis, MI Lovinger, DM AF Sheinin, Anton Talani, Giuseppe Davis, Margaret I. Lovinger, David M. TI Endocannabinoid- and mGluR5-dependent short-term synaptic depression in an isolated neuron/bouton preparation from the hippocampal CA1 region SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID DEPOLARIZATION-INDUCED SUPPRESSION; METABOTROPIC GLUTAMATE RECEPTORS; ENDOGENOUS CANNABINOIDS; ANANDAMIDE TRANSPORTER; VANILLOID RECEPTORS; BOUTON PREPARATION; PYRAMIDAL CELLS; TRPV1 CHANNELS; NEURONS; INHIBITION AB Endocannabinoids released from the postsynaptic neuronal membrane can activate presynaptic CB 1 receptors and inhibit neurotransmitter release. In hippocampal slices, depolarization of the CA1 pyramidal neurons elicits an endocannabinoid-mediated inhibition of gamma-aminobutyric acid release known as depolarization-induced suppression of inhibition (DSI). Using the highly reduced neuron/synaptic bouton preparation from the CA1 region of hippocampus, we have begun to examine endocannabinoid-dependent short-term depression (STD) of inhibitory synaptic transmission under well-controlled physiological and pharmacological conditions in an environment free of other cells. Application of the CB 1 synthetic agonist WIN55212-2 and endogenous cannabinoids 2-AG and anandamide produced a decrease in spontaneous inhibitory postsynaptic current (sIPSC) frequency and amplitude, indicating the presence of CB 1 receptors at synapses in this preparation. Endocannabinoid-dependent STD is different from DSI found in hippocampal slices and the neuron/bouton preparation from basolateral amygdala (BLA) since depolarization alone was not sufficient to induce suppression of sIPSCs. However, concurrent application of the metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) and postsynaptic depolarization resulted in a transient (30-50 s) decrease in sIPSC frequency and amplitude. Application of DHPG alone had no effect on sIPSCs. The depolarization/DHPG-induced STD was blocked by the CB 1 antagonist SR141716A and the mGluR5 antagonist MPEP and was sensitive to intracellular calcium concentration. Comparing the present findings with earlier work in hippocampal slices and BLA, it appears that endocannabinoid release is less robust in isolated hippocampal neurons. C1 [Sheinin, Anton; Talani, Giuseppe; Davis, Margaret I.; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Fishers TS-13, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov RI Davis, Margaret/F-4165-2010; OI Davis, Margaret/0000-0002-0489-8351 FU Intramural NIH HHS; NIDA NIH HHS [DA-11322] NR 37 TC 12 Z9 12 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2008 VL 100 IS 2 BP 1041 EP 1052 DI 10.1152/jn.90226.2008 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 336WC UT WOS:000258394500044 PM 18497350 ER PT J AU Guo, J Williams, DJ Ikeda, SR AF Guo, Juan Williams, Damian J. Ikeda, Stephen R. TI N-arachidonoyl L-serine, a putative endocannabinoid, alters the activation of N-type Ca2+ channels in sympathetic neurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CALCIUM-CHANNELS; MAMMALIAN NEURONS; INHIBITION; ANANDAMIDE; RECEPTOR; ACID; CURRENTS AB The effect of N-arachidonoyl L-serine (ARA-S), a recently discovered lipoamino acid found in the CNS, on N-type Ca2+ channels of rat sympathetic ganglion neurons was determined using whole cell patch clamp. Application of ARA-S produced a rapid and reversible augmentation of Ca2+ current that was voltage dependent and resulted from a hyperpolarizing shift in the activation curve. ARA-S did not influence G protein modulation of Ca2+ channels and appeared to act independently of G-protein-coupled receptors. These findings provide a foundation for investigating possible roles for ARA-S in nervous system function. C1 [Guo, Juan; Williams, Damian J.; Ikeda, Stephen R.] NIAAA, Sect Transmitter Signaling, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Ikeda, SR (reprint author), NIAAA, Sect Transmitter Signaling, Lab Mol Physiol, NIH, 5625 Fishers Ln,MSC 9411, Bethesda, MD 20892 USA. EM sikeda@mail.nih.gov OI Ikeda, Stephen/0000-0002-4088-9508 FU Intramural NIH HHS NR 24 TC 12 Z9 12 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2008 VL 100 IS 2 BP 1147 EP 1151 DI 10.1152/jn.01204.2007 PG 5 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 336WC UT WOS:000258394500053 PM 18234973 ER PT J AU Masri, R Bezdudnaya, T Trageser, JC Keller, A AF Masri, R. Bezdudnaya, T. Trageser, J. C. Keller, A. TI Latency coding in POm: Importance of parametric regimes - Reply SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Letter ID RAT C1 [Keller, A.] Univ Maryland, Program Neurosci, Sch Med, Baltimore, MD 21201 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Keller, A (reprint author), Univ Maryland, Program Neurosci, Sch Med, Baltimore, MD 21201 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2008 VL 100 IS 2 BP 1155 EP 1157 DI 10.1152/jn.90633.2008 PG 3 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 336WC UT WOS:000258394500055 ER PT J AU Baggenstos, M Chew, E Butman, JA Oldfield, EH Lonser, RR AF Baggenstos, Martin Chew, Emily Butman, John A. Oldfield, Edward H. Lonser, Russell R. TI Progressive peritumoral edema defining the optic fibers and resulting in reversible visual loss - Case report SO JOURNAL OF NEUROSURGERY LA English DT Article DE edema; hemangioblastoma; optic nerve; tumor; von Hippel-Lindau disease ID VONHIPPEL-LINDAU DISEASE; CENTRAL-NERVOUS-SYSTEM; DIFFUSION-TENSOR; HEMANGIOBLASTOMA; DELIVERY; TUMORS AB Hemangioblastomas are frequently associated with peritumoral edema caused by extravasation of plasma ultrafiltrate through permeable neoplastic vessels. The authors report the clinical and imaging findings in a 62-year-old man with von Hippel-Lindau disease who presented with rapid (within 24 hours) loss of color vision and near-complete loss of left eye vision (acuity too poor to test). Serial MR imaging demonstrated a stable vascular tumor in the medioinferior aspect of the left optic nerve, associated with progressive edema extending from the nerve through to the bilateral optic radiations. Complete resection of the lesion was performed via an extended transsphenoidal approach, and histological examination confirmed the lesion was a hemangioblastoma. Postoperatively, the patient recovered color vision and had improvement in visual acuity (20/320). Serial imaging in this unique case captured the progressive extravasation of peritumoral edema that tracked and defined the parallel white matter tracts of first- and second-order neurons of the optic system, causing vision loss. Tumor resection led to resolution of the edema and improvement in visual function. C1 [Baggenstos, Martin; Oldfield, Edward H.; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Chew, Emily] NEI, Clin Trials Branch, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 FU Intramural NIH HHS [Z01 NS003053-01] NR 23 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD AUG PY 2008 VL 109 IS 2 BP 313 EP 317 DI 10.3171/JNS/2008/109/8/0313 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 330QR UT WOS:000257958400022 PM 18671645 ER PT J AU Yao, XH Ping, YF Chen, JH Xu, CP Chen, DL Zhang, R Wang, JM Bian, XW AF Yao, X-H Ping, Y-F Chen, J-H Xu, C-P Chen, D-L Zhang, R. Wang, J. M. Bian, X-W TI Glioblastoma stem cells produce vascular endothelial growth factor by activation of a G-protein coupled formylpeptide receptor FPR SO JOURNAL OF PATHOLOGY LA English DT Article DE cancer stem cells; glioma; angiogenesis; formylpeptide receptor; fMLF; VEGF ID ACUTE MYELOID-LEUKEMIA; FORMYL-PEPTIDE RECEPTORS; MALIGNANT HUMAN GLIOMAS; SCID MICE; ANGIOGENESIS; EXPRESSION; IDENTIFICATION; HIERARCHY; TUMORS AB Glioma stem cells (GSCs), or stem cell-like glioma cells, isolated from malignant glioma cell lines, were capable of producing vascular endothelial growth factor (VEGF). However, the exact role of such tumour cells in angiogenesis remains unknown. In this study, we isolated a small proportion of CD133(+) GSCs from the human glioblastoma cell line U87 and found that these GSCs possessed multipotent differentiation potential and released high levels of VEGF as compared with CD133(-) tumour cells. The CD133(+) GSCs also formed larger xenograft tumours that contained higher VEGF immunoreactivity and denser microvessels. Moreover, GSCs expressed a functional G protein-coupled formylpeptide receptor FPR, which was activated by a chemotactic peptide ligand, N-formylmethionyl-leucyl-phenylaianine (fMLF), to mediate calcium flux and the production of VEGF by GSCs. Our results indicate that FPR expressed by human GSCs may play an important role in glioma angiogenesis. Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Yao, X-H; Ping, Y-F; Chen, J-H; Xu, C-P; Chen, D-L; Zhang, R.; Bian, X-W] Third Mil Med Univ, SW Hosp, Inst Pathol, Chongqing 400038, Peoples R China. [Chen, J-H] Third Mil Med Univ, SW Hosp, Dept Pharm, Chongqing 400038, Peoples R China. [Wang, J. M.] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Bian, XW (reprint author), Third Mil Med Univ, SW Hosp, Inst Pathol, Chongqing 400038, Peoples R China. EM bianxiuwu@263.net RI Bian, Xiuwu/F-1569-2011; Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 FU National Basic Research Programme of China [2006CB708503]; National Natural Science Foundation of China [30670804] FX The authors thank Mrs Wei Sun and Miss Li-Ting Wang (Central Laboratory, Third Military Medical University, Chongqing, People's Republic of China) for technical assistance in laser confocal scanning microscopy. This project was supported by grants from the National Basic Research Programme of China (973 Project, No. 2006CB708503) and the National Natural Science Foundation of China (NSFC, No. 30670804). NR 28 TC 51 Z9 58 U1 2 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD AUG PY 2008 VL 215 IS 4 BP 369 EP 376 DI 10.1002/path.2356 PG 8 WC Oncology; Pathology SC Oncology; Pathology GA 339OA UT WOS:000258585700003 PM 18523971 ER PT J AU Ning, C Green-Golan, L Stratakis, CA Leschek, E Sinaii, N Schroth, E Ernst, M Merke, DP AF Ning, Cong Green-Golan, Liza Stratakis, Constantine A. Leschek, Ellen Sinaii, Ninet Schroth, Elizabeth Ernst, Monique Merke, Deborah P. TI Body image in adolescents with disorders of steroidogenesis SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE body image; precocious puberty; congenital adrenal hyperplasia; familial male precocious puberty; Cushing's syndrome ID CONGENITAL ADRENAL-HYPERPLASIA; QUALITY-OF-LIFE; IDIOPATHIC SHORT STATURE; ADULT FEMALE-PATIENTS; SELF-ASSESSMENT; PRECOCIOUS PUBERTY; SEXUAL-MATURATION; CHILDREN; GIRLS; ADJUSTMENT AB Aim: Little is known about body image in children with endocrine conditions. We evaluated body image in children with congenital adrenal hyperplasia (CAH), familial male precocious puberty (FMPP), and Cushing's syndrome (CS). Study design: We compared 67 patients (41 CAH, 12 FMPP, 14 CS) age 8-18 years with 55 age-matched controls. Results: Patients expressed more weight unhappiness than controls (females: p < 0.001; males: p = 0.01). This difference remained for females after adjusting for body mass index (BMI) (p = 0.03), but not for males (p = 0.12). Unhappiness with height and age of appearance was similar between groups. In female patients, higher BMI was a significant predictor of weight unhappiness (p = 0.01). Conclusion: Adolescents with CAH, FMPP, and CS are at risk for negative body image regarding weight, but not height or age of appearance. Weight unhappiness is partially related to greater weight, but factors unrelated to physical findings seem to contribute to negative body image in female patients. C1 [Green-Golan, Liza; Sinaii, Ninet; Merke, Deborah P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Ning, Cong; Stratakis, Constantine A.] NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. [Merke, Deborah P.] NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. [Leschek, Ellen] NIDDK, Bethesda, MD 20892 USA. [Schroth, Elizabeth; Ernst, Monique] NIMH, Mood & Anxiety Disorders Program, Emot Dev & Affect Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Merke, DP (reprint author), NIH, Ctr Clin, Bldg 10-CRC,Room 1-2740, Bethesda, MD 20892 USA. EM dmerke@mail.nih.gov FU National Institutes of Health; Congenital Adrenal hyperplasia Research, Education and Support (CARES) Foundation FX This research was supported in part by the Intramural Research Program of the National Institutes of Health and in part by the Congenital Adrenal hyperplasia Research, Education and Support (CARES) Foundation.; The authors thank Dr. Robert Wesley for assistance with data analysis. NR 42 TC 1 Z9 1 U1 0 U2 3 PU FREUND PUBLISHING HOUSE LTD PI TEL AVIV PA PO BOX 35010, TEL AVIV 61350, ISRAEL SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD AUG PY 2008 VL 21 IS 8 BP 771 EP 780 PG 10 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 350IO UT WOS:000259346200009 PM 18825877 ER PT J AU Mussai, FJ Cunningham, LC Rezvani, G Stratakis, CA Reynolds, JC Nesterova, G Henshaw, RM Levine, JE Helman, LJ Arthur, DC Kim, SY AF Mussai, Francis J. Cunningham, Lea C. Rezvani, Geoffrey Stratakis, Constantine A. Reynolds, James C. Nesterova, Galina Henshaw, Robert M. Levine, Jason E. Helman, Lee J. Arthur, Diane C. Kim, Su Young TI Hypocalcemia in a patient with osteosarcoma and 22q11.2 deletion syndrome SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE hypocalcemia; osteosarcoma; 2q11.2 deletion syndrome ID STUDY-GROUP PROTOCOLS; MULTIFOCAL OSTEOSARCOMA AB Hypocalcemia is a rare complication of ostcosarcoma, having been described in only 4 reports. We present the case of a 16-year-old male with metastatic osteosarcoma of the right humerus who was found to have severe asymptomatic hypocalcemia. Cytogenetic analysis of peripheral blood revealed a microdeletion in band 22q11.2. Following amputation of the tumor-bearing extremity, the patient's calcium levels increased, but did not normalize. These findings suggested that the etiology of his hypocalcemia was osteoblastic utilization of calcium by the tumor, exacerbated by 22q11.2 deletion syndrome. C1 [Mussai, Francis J.; Cunningham, Lea C.; Kim, Su Young] Natl Canc Inst, Pediat Oncol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Arthur, Diane C.] Natl Canc Inst, Pathol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. NICHHD, Pediat Endocrinol Training Program, Natl Inst Hlth, Bethesda, MD 20892 USA. [Reynolds, James C.] NHGRI, Dept Nucl Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Nesterova, Galina] NHGRI, Med Genet Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Henshaw, Robert M.] Georgetown Univ, Sch Med, Washington Canc Inst, Dept Orthoped, Washington, DC USA. RP Kim, SY (reprint author), Natl Canc Inst, Pediat Oncol Branch, Natl Inst Hlth, 10 Ctr Dr,Bldg 10,CRC 1-3816, Bethesda, MD 20892 USA. EM kimsuyou@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 13 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD AUG PY 2008 VL 30 IS 8 BP 612 EP 617 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 335AK UT WOS:000258263000010 PM 18799940 ER PT J AU Bryant, S Balboni, G Guerrini, R Salvadori, S Marczak, E Lazarus, LH AF Bryant, Sharon Balboni, Gianfranco Guerrini, Remo Salvadori, Severo Marczak, Ewa Lazarus, L. H. TI 3D-pharmaeophore based virtual screening: discovery of opioid GPCR lead compounds SO JOURNAL OF PEPTIDE SCIENCE LA English DT Meeting Abstract C1 [Bryant, Sharon; Marczak, Ewa; Lazarus, L. H.] NIEHS, Res Triangle Pk, NC 27709 USA. [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. [Guerrini, Remo; Salvadori, Severo] Univ Ferrara, Dept Pharm Sci, I-44100 Ferrara, Italy. [Guerrini, Remo; Salvadori, Severo] Univ Ferrara, Biotech Ctr, I-44100 Ferrara, Italy. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1075-2617 J9 J PEPT SCI JI J. Pept. Sci. PD AUG PY 2008 VL 14 IS 8 SU S BP 25 EP 25 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 345VZ UT WOS:000259026900056 ER PT J AU McCrae, RR Yamagata, S Jang, KL Riemann, R Ando, J Ono, Y Angleitner, A Spinath, FM AF McCrae, Robert R. Yamagata, Shinji Jang, Kerry L. Riemann, Rainer Ando, Juko Ono, Yutaka Angleitner, Alois Spinath, Frank M. TI Substance and artifact in the higher-order factors of the Big Five SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article; Proceedings Paper CT 13th Biennial Conference of the International-Society-for-the-Study-of-Individual-Differences CY JUL, 2007 CL Giessen, GERMANY SP Int Soc Study Individual Differences DE Big Five; five-factor model; behavior genetics; cross-observer; cross-cultural ID CROSS-CULTURAL TWIN; 5-FACTOR MODEL; DISCRIMINANT VALIDITY; BEHAVIORAL-GENETICS; PERSONALITY; TRAITS; EXTROVERSION; REACTIVITY; OBSERVER; SCALES AB J. M. Digman (1997) proposed that the Big Five personality traits showed a higher-order structure with 2 factors he labeled alpha and beta. These factors have been alternatively interpreted as heritable components of personality or as artifacts of evaluative bias. Using structural equation modeling, the authors reanalyzed data from a cross-national twin study and from American cross-observer studies and analyzed new multimethod data from a German twin study. In all analyses, artifact models outperformed substance models by root-mean-square error of approximation criteria, but models combining both artifact and substance were slightly better. These findings suggest that the search for the biological basis of personality traits may be more profitably focused on the 5 factors themselves and their specific facets, especially in monomethod studies. C1 [McCrae, Robert R.] NIA, Gerontol Res Ctr, Lab Personal & Cognit, Baltimore, MD 21224 USA. [Yamagata, Shinji] Univ Tokyo, Grad Sch Arts & Sci, Dept Cognit & Behav Sci, Tokyo, Japan. [Jang, Kerry L.] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Riemann, Rainer] Univ Jena, Dept Psychol, Jena, Germany. [Ando, Juko] Keio Univ, Fac Letters, Dept Educ, Tokyo, Japan. [Ono, Yutaka] Keio Univ, Ctr Hlth, Tokyo, Japan. [Angleitner, Alois] Univ Bielefeld, Dept Psychol, Bielefeld, Germany. [Spinath, Frank M.] Univ Saarland, Dept Psychol, Saarland, Germany. RP McCrae, RR (reprint author), NIA, Gerontol Res Ctr, Lab Personal & Cognit, Baltimore, MD 21224 USA. EM mccraej@grc.nia.nih.gov FU Intramural NIH HHS NR 55 TC 65 Z9 67 U1 1 U2 11 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-3514 J9 J PERS SOC PSYCHOL JI J. Pers. Soc. Psychol. PD AUG PY 2008 VL 95 IS 2 BP 442 EP 455 DI 10.1037/0022-3514.95.2.442 PG 14 WC Psychology, Social SC Psychology GA 329CW UT WOS:000257845500013 PM 18665712 ER PT J AU Pulay, AJ Dawson, DA Ruan, WJ Pickering, RP Huang, BJ Chou, SP Grant, BF AF Pulay, Attila J. Dawson, Deborah A. Ruan, W. June Pickering, Roger P. Huang, Boji Chou, S. Patricia Grant, Bridget F. TI The relationship of impairment to personality disorder severity among individuals with specific Axis I disorders: Results from the national epidemiologic survey on alcohol and related conditions SO JOURNAL OF PERSONALITY DISORDERS LA English DT Article ID INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; UNITED-STATES; DSM-III; DRUG MODULES; PANIC DISORDER; RELIABILITY; VALIDITY; COOCCURRENCE; DISABILITIES AB The present study examined one dimensional approach to personality disorders (PDs) in a large (n = 43,093), nationally representative sample of the U.S. population. Respondents were classified in four personality severity categories (no PD, subthreshold PD, simple PD, complex PD). Linear regression analyses were conducted to examine mental disability by PD severity for major DSM-IV substance use, mood and anxiety disorders. Significant increases in disability were observed between no PD and simple PD and between simple PD and complex PD for each Axis I disorder except drug dependence, but few differences in disability were found between no PD and subthreshold PD. This study found support for the clinical utility of the dimensional classification of PD severity with regard to the distinction between simple and complex PD and for a combined no PD-subthreshold PD level of severity. Future planned analyses will address the clinical utility of the classification prospectively, with a full battery of all Axis II PDs. C1 [Pulay, Attila J.; Dawson, Deborah A.; Ruan, W. June; Pickering, Roger P.; Huang, Boji; Chou, S. Patricia; Grant, Bridget F.] Dept Hlth & Human Serv, Bethesda, MD USA. RP Pulay, AJ (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Room 3080,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM pulaya@mail.nih.gov RI Pulay, Attila/B-6155-2011 FU Intramural NIH HHS [NIH0012690046]; PHS HHS [NIH0012690046] NR 61 TC 12 Z9 12 U1 0 U2 0 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0885-579X J9 J PERS DISORD JI J. Pers. Disord. PD AUG PY 2008 VL 22 IS 4 BP 405 EP 417 DI 10.1521/pedi.2008.22.4.405 PG 13 WC Psychiatry SC Psychiatry GA 332UV UT WOS:000258109500006 PM 18684052 ER PT J AU Liu, J Lu, YF Wu, Q Goyer, RA Waalkes, MP AF Liu, Jie Lu, Yuanfu Wu, Qin Goyer, Robert A. Waalkes, Michael P. TI Mineral arsenicals in traditional medicines: Orpiment, realgar, and arsenolite SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; TRIOXIDE AS2O3; HEAVY-METALS; IN-VITRO; CANCER; PHARMACOKINETICS; NANOPARTICLES; METABOLISM; MECHANISMS; THERAPY AB Mineral arsenicals have long been used in traditional medicines for various diseases, yet arsenic can be highly toxic and carcinogenic. Arsenic in traditional medicines typically comes from deliberate addition for therapeutic purposes, mainly in the form of mineral arsenicals, including orpiment (As2S3), realgar (As4S4), and arsenolite (contains arsenic trioxide, As2O3). Inorganic arsenic is now accepted in Western medicine as a first line chemotherapeutic agent against certain hematopoietic cancers. This perspective analyzes the pharmacology and toxicology of these arsenicals used in traditional medicines. Orpiment and realgar are less soluble and poorly absorbed from the gastrointestinal tract, whereas the bioavailability of arsenic trioxide is similar to inorganic arsenic salts such as sodium arsenite. Pharmacological studies show that arsenic trioxide and realgar are effective against certain malignancies. Orpiment and realgar are used externally for various skin diseases. Realgar is frequently included as an ingredient in oral traditional remedies for its antipyretic, anti-inflammatory, antiulcer, anti-convulsive, and anti-schistosomiasis actions, but the pharmacological basis for this inclusion still remains to be fully justified. Toxicological studies show that cardiovascular toxicity is the major concern for arsenic trioxide and that the gastrointestinal and dermal adverse effects may occur after prolonged use of mineral arsenicals. Little is known regarding the possible secondary cancers resulting from the long-term use of any of these arsenicals. Similar to the safety evaluation of seafood arsenicals, total arsenic content alone appears to be insufficient for mineral arsenical safety evaluation. Arsenic speciation, bioavailability, and toxicity/benefit should be considered in evaluation of mineral arsenical-containing traditional medicines. C1 [Liu, Jie; Goyer, Robert A.; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Ctr Canc Res,NCI, Res Triangle Pk, NC 27709 USA. RP Liu, J (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Ctr Canc Res,NCI, Mail Drop F0-09, Res Triangle Pk, NC 27709 USA. EM liu6@niehs.nih.gov FU Intramural NIH HHS [Z01 BC005488-22] NR 41 TC 84 Z9 99 U1 0 U2 21 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2008 VL 326 IS 2 BP 363 EP 368 DI 10.1124/jpet.108.139543 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 327VC UT WOS:000257755600001 PM 18463319 ER PT J AU Hyodo, F Soule, BP Matsumoto, KI Matusmoto, S Cook, JA Hyodo, E Sowers, AL Krishna, MC Mitchell, JB AF Hyodo, Fuminori Soule, Benjamin P. Matsumoto, Ken-Ichiro Matusmoto, Shingo Cook, John A. Hyodo, Emi Sowers, Anastasia L. Krishna, Murali C. Mitchell, James B. TI Assessment of tissue redox status using metabolic responsive contrast agents and magnetic resonance imaging SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; NITROXIDE SPIN LABELS; FREE-RADICALS; MURINE TUMOR; EPR OXIMETRY; SOD MIMICS; MRI; REDUCTION; RADIATION; TEMPOL AB Regulation of tissue redox status is important to maintain normal physiological conditions in the living body. Disruption of redox homoeostasis may lead to oxidative stress and can induce many pathological conditions such as cancer, neurological disorders and ageing. Therefore, imaging of tissue redox status could have clinical applications. Redox imaging employing magnetic resonance imaging (MRI) with nitroxides as cell-permeable redox-sensitive contrast agents has been used for non-invasive monitoring of tissue redox status in animal models. The redox imaging applications of nitroxide electron paramagnetic resonance imaging (EPRI) and MRI are reviewed here, with a focus on application of tumour redox status monitoring. While particular emphasis has been placed on differences in the redox status in turnours compared to selected normal tissues, the technique possesses the potential to have broad applications to the study of other disease states, inflammatory processes and other circumstances where oxidative stress is implicated. C1 [Hyodo, Fuminori; Soule, Benjamin P.; Matsumoto, Ken-Ichiro; Matusmoto, Shingo; Cook, John A.; Hyodo, Emi; Sowers, Anastasia L.; Krishna, Murali C.; Mitchell, James B.] NIH, Radiat Biol Branch, Ctr Canc Res, Natl Canc Inst, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NIH, Radiat Biol Branch, Ctr Canc Res, Natl Canc Inst, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM jbm@HELIX.NIH.GOV FU Intramural NIH HHS [Z01 BC010787-01] NR 59 TC 40 Z9 40 U1 0 U2 11 PU PHARMACEUTICAL PRESS-ROYAL PHARMACEUTICAL SOC GREAT BRITIAN PI LONDON PA 1 LAMBETH HIGH ST, LONDON SE1 7JN, ENGLAND SN 0022-3573 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD AUG PY 2008 VL 60 IS 8 BP 1049 EP 1060 DI 10.1211/jpp.60.8.0011 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 328YT UT WOS:000257834800011 PM 18644197 ER PT J AU Alves, G Wu, WW Wang, GH Shen, RF Yu, YK AF Alves, Gelio Wu, Wells W. Wang, Guanghui Shen, Rong-Fong Yu, Yi-Kuo TI Enhancing peptide identification confidence by combining search methods SO JOURNAL OF PROTEOME RESEARCH LA English DT Article ID MASS-SPECTRAL DATA; DATABASE SEARCHES; P-VALUES; TANDEM; MS/MS; ALGORITHM; ACCURACY AB Confident peptide identification is one of the most important components in mass-spectrometry-based proteomics. We propose a method to properly combine the results from different database search methods to enhance the accuracy of peptide identifications. The database search methods included in our analysis are SEQUEST (v27 rev12), ProblD (v1.0), InsPecT (v20060505), Mascot (v2.1), X! Tandem v2007.07.01.2), OMSSA (v2.0) and RAId_DbS. Using two data sets, one collected in profile mode and one collected in centroid mode, we tested the search performance of all 21 combinations of two search methods as well as all 35 possible combinations of three search methods. The results obtained from our study suggest that properly combining search methods does improve retrieval accuracy. In addition to performance results, we also describe the theoretical framework which in principle allows one to combine many independent scoring methods including de novo sequencing and spectral library searches. The correlations among different methods are also investigated in terms of common true positives, common false positives, and a global analysis. We find that the average correlation strength, between any pairwise combination of the seven methods studied, is usually smaller than the associated standard error. This indicates only weak correlation may be present among different methods and validates our approach in combining the search results. The usefulness of our approach is further confirmed by showing that the average cumulative number of false positive peptides agrees reasonably well with the combined E-value. The data related to this study are freely available upon request. C1 [Alves, Gelio; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Wu, Wells W.; Wang, Guanghui; Shen, Rong-Fong] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 19 TC 44 Z9 44 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD AUG PY 2008 VL 7 IS 8 BP 3102 EP 3113 DI 10.1021/pr700798h PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 334CR UT WOS:000258200400005 PM 18558733 ER PT J AU Woods, AS Moyer, SC Jackson, SN AF Woods, Amina S. Moyer, Susan C. Jackson, Shelley N. TI Amazing stability of phosphate-quaternary amine interactions SO JOURNAL OF PROTEOME RESEARCH LA English DT Article ID TRAP MASS-SPECTROMETRY; ELECTROSTATIC INTERACTION; FRAGMENTATION; ARGININE; RECEPTOR; CHLORISONDAMINE AB We have previously used MALDI mass spectrometry to highlight ammonium- or guaniclinium-aromatic interactions via cation-pi bonding and ammonium- or guanidinium-phosphate interactions through salt bridge formation. In the present work, the gas-phase stability and dissociation pathways of the interaction between phosphorylated peptides and compounds containing quaternary amines are demonstrated using electrospray ionization mass spectrometry. The presence of one quaternary amine in a compound is enough to form a noncovalent complex with a phosphorylated residue. However, if two quaternary amines are present in one molecule, the electrostatic interactions of the quaternary amines with the phosphate results in a "covalent-like" stability, and these bonds can withstand fragmentation by collision-induced dissociation at energies similar to those that fragment covalent bonds. Such interactions are important in accounting for physiological, pathophysiological, and pharmacological effects of many therapeutic compounds and small molecules containing quaternary amines or phosphates. C1 [Woods, Amina S.; Jackson, Shelley N.] NIDA, IRP, NIH, Baltimore, MD 21224 USA. [Moyer, Susan C.] Agilent Technol, Wilmington, DE USA. RP Woods, AS (reprint author), NIDA, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 15 TC 19 Z9 19 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD AUG PY 2008 VL 7 IS 8 BP 3423 EP 3427 DI 10.1021/pr8001595 PG 5 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 334CR UT WOS:000258200400032 PM 18578519 ER PT J AU Woods, AS Marcellino, D Jackson, SN Franco, R Ferre, S Agnati, LF Fuxe, K AF Woods, Amina S. Marcellino, Daniel Jackson, Shelley N. Franco, Rafael Ferre, Sergi Agnati, Luigi F. Fuxe, Kjell TI How calmodulin interacts with the adenosine A(2A) and the doparnine D-2 receptors SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE calmodulin; dopamine D-2 receptor; adenosine A(2A) receptor; receptor heteromers; mass spectrometry ID PROTEIN COUPLED RECEPTORS; ELECTROSTATIC INTERACTIONS; MASS-SPECTROMETRY; BINDING; PHOSPHATE; PEPTIDES; ACTIVATION; ARGININE; HETEROMERIZATION; LOOP AB Receptor heteromerization is a mechanism used by G protein-coupled receptors to diversify their properties and function. We previously demonstrated that these interactions occur through salt bridge formation between epitopes of the involved receptors. Recent studies claim that calmodulin (CaM) binds to an Arg-rich epitope located in the amino-terminus of the dopamine D-2 receptor third intracellular loop. This is the same epitope involved in adenosine A(2A)-D-2 receptor heteromerization, through Coulombic interaction between the Arg residues and a phosphorylated serine (pS) located in the medial segment of the C-terminus of the A(2A) receptor. Mass spectrometric analysis indicates that an electrostatic interaction involving the D, receptor Arg-rich epitope and several CaM acidic epitopes are mainly responsible for the D-2 receptor-CaM binding. CaM could also form multiple noncovalent complexes by means of electrostatic interactions with an epitope localized in the proximal segment of the C-terminus of the A(2A) receptor. Ca2+ disrupted the binding of CaM to the D-2 but not to the A(2A) receptor epitope, and CaM disrupted the electrostatic interactions between the D-2 receptor epitope and the more distal A(2A) receptor epitope. A model is introduced with the possible functional implications of A(2A)(-) D-2-CaM interactions. These in vitro findings imply a possible regulatory role for CaM in receptor heteromers formation. C1 [Woods, Amina S.; Jackson, Shelley N.; Ferre, Sergi] NIDA, IRP, NIH, DHHS, Baltimore, MD 21224 USA. [Marcellino, Daniel; Fuxe, Kjell] Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. [Agnati, Luigi F.] Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. [Franco, Rafael] Univ Barcelona, Dept Biochem, Barcelona, Catalunya, Spain. RP Woods, AS (reprint author), NIDA, IRP, NIH, DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015 OI Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919 FU Intramural NIH HHS [Z99 DA999999] NR 29 TC 26 Z9 26 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD AUG PY 2008 VL 7 IS 8 BP 3428 EP 3434 DI 10.1021/pr8001782 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 334CR UT WOS:000258200400033 PM 18590318 ER PT J AU Sutin, AR AF Sutin, Angelina R. TI Autobiographical memory as a dynamic process: Autobiographical memory mediates basic tendencies and characteristic adaptations SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE autobiographical memory; personality; emotion; phenomenology; mediation ID ACADEMIC-PERFORMANCE; PERSONALITY; PHENOMENOLOGY; VALIDATION; MOTIVATION AB Two studies tested whether autobiographical memory content and phenomenology mediate two consistent findings in the personality literature: Neuroticism and subjective health and Conscientiousness and achievement striving. In Study 1, participants (N = 162) retrieved and rated four memories and completed measures of Neuroticism and subjective health. In Study 2, participants (N= 345) retrieved and rated two memories and completed measures of Conscientiousness and achievement goals and study strategies. In both studies, memory content and phenomenology mediated the relations between personality and health and achievement in expected ways. For example, participants high in Neuroticism reported more somatic complaints because their memories were saturated with negative affective content. Discussion focuses on the utility of integrating trait and social-cognitive approaches to personality. (C) 2007 Elsevier Inc. All rights reserved. C1 [Sutin, Angelina R.] Univ Calif Davis, Dept Psychol, Davis, CA 95616 USA. RP Sutin, AR (reprint author), NIA, Bethesda, MD 20892 USA. EM arsutin@ucdavis.edu NR 20 TC 11 Z9 12 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD AUG PY 2008 VL 42 IS 4 BP 1060 EP 1066 DI 10.1016/j.jrp.2007.10.002 PG 7 WC Psychology, Social SC Psychology GA 318ZK UT WOS:000257131100019 ER PT J AU Potter, J Odutola, J Gonzales, CA Ward, MM AF Potter, Jeffrey Odutola, Jennifer Gonzales, Christian Amurrio Ward, Michael M. TI Validation of English and Spanish-language versions of a screening questionnaire for rheumatoid arthritis in an underserved community SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE rheumatoid arthritis; screening; Spanish language ID SELF-REPORTED DIAGNOSIS; UNITED-STATES; POPULATION; DISORDERS; CLASSIFICATION; PREVALENCE; HEALTH; WOMEN; OLDER; CAGE AB Objective. Questionnaires to screen for rheumatoid arthritis (RA) have been tested in groups that were primarily well educated and Caucasian. We sought to validate the RA questions of the Connective Tissue Disease Screening Questionnaire (CSQ) in ethnic minorities in an underserved community, and to test a Spanish-language version. Methods. The Spanish-language version was developed by 2 native speakers. Consecutive English-speaking or Spanish-speaking patients in a community-based rheumatology practice completed the questionnaire. Diagnoses were confirmed by medical record review. Sensitivity and specificity of the questionnaire for a diagnosis of RA were computed for each language version, using 2 groups as controls: patients with noninflammatory conditions, and participants recruited from the Community. Results. The English-language version was tested in 53 patients with RA (79% ethnic minorities; mean education level 11.3 yrs), 85 rheumatology controls with noninflammatory conditions, and 82 community controls. Using 3 positive responses as indicating a positive screening test, the sensitivity of the questionnaire was 0.77, the specificity based on rheumatology controls was 0.45, and the specificity based on community controls was 0.94. The Spanish-language version was tested in 55 patients with RA (mean education level 7.8 yrs), 149 rheumatology controls, and 88 Community controls. The sensitivity of the Spanish-language version was 0.87, with specificities of 0.60 and 0.97 using the rheumatology controls and community controls, respectively. Conclusion. The sensitivity of the English-language version of the RA questions of the CSQ was lower in this study than in other cohorts, reflecting differences in the performance of the questions in different ethnic or socioeconomic groups. The Spanish-language version demonstrated good sensitivity, and both had excellent specificity when tested in community controls. C1 [Potter, Jeffrey; Odutola, Jennifer; Gonzales, Christian Amurrio; Ward, Michael M.] NIH NIAMS IRP, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIH NIAMS IRP, Bldg 10 CRC,Room 4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [Z01 AR041153-03] NR 17 TC 4 Z9 4 U1 1 U2 1 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2008 VL 35 IS 8 BP 1545 EP 1549 PG 5 WC Rheumatology SC Rheumatology GA 332UL UT WOS:000258108500015 PM 18597406 ER PT J AU Wolf, RL Lepore, SJ Vandergirift, JL Wetmore-Arkader, L McGinty, E Pietrzak, G Yaroch, AL AF Wolf, Randi L. Lepore, Stephen J. Vandergirift, Jonathan L. Wetmore-Arkader, Lindsay McGinty, Elizabeth Pietrzak, Gabriel Yaroch, Amy L. TI Knowledge, barriers, and stage of change as correlates of fruit and vegetable consumption among urban and mostly immigrant black men SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CORONARY HEART-DISEASE; PSYCHOSOCIAL FACTORS; DIETARY CHANGE; DIABETES-MELLITUS; BLOOD-PRESSURE; UNITED-STATES; US ADULTS; HEALTH; TRIAL; RISK AB Background Daily fruit and vegetable consumption in black men is low and has remained relatively unchanged during the past 20 years. Objective To examine awareness of fruit and vegetable recommendations promoted by federal agencies and correlates of fruit and vegetable consumption among an urban and mostly immigrant population of adult black men. Design A cross-sectional study analyzing baseline data (n=490) from a randomized controlled trial. Setting A large health care worker's union. Main outcome measures Knowledge, perceived benefits, stage of readiness, perceived barriers, and daily servings of fruit and vegetable intake. Statistical analyses performed One-way analysis of variance and t tests were used to compare fruit and vegetable intake across main study variables. Regression analysis was used to identify independent predictors of fruit and vegetable intake. Results Fruit and vegetable intake was low (mean was three servings/day). Ninety-four percent were not aware that men should consume at least nine servings of fruits and vegetables daily and 59.8% were not aware that eating a colorful variety is important. In contrast, over half (54.7%) were aware that a single serving is equal to about a handful; 94.1% correctly reported fruit and vegetables as an important source of fiber; 79.6% correctly reported vitamin pills were not a substitute for eating fruits and vegetables; and 94.5% recognized that there are health benefits to eating fruits and vegetables, although identification of specific benefits was minimal. In regression analysis, a greater level of fruit and vegetable consumption was significantly associated with greater knowledge of fruit and vegetable recommendations, lower perceived barriers, and a more advanced stage of change (action vs contemplation/preparation). Perceived health benefits were not associated with fruit and vegetable consumption. Conclusions There is a lack of awareness of the current fruit and vegetable recommendations. In addition, men reported fruit and vegetable intakes that were far below national recommendations. Greater efforts are needed to help urban and primarily immigrant black men realize the importance of and recommendations for fruit and vegetable consumption. C1 [Wolf, Randi L.; Wetmore-Arkader, Lindsay; McGinty, Elizabeth; Pietrzak, Gabriel] Columbia Univ, Teachers Coll, Dept Hlth & Behav Studies, New York, NY 10027 USA. [Lepore, Stephen J.] Temple Univ, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Yaroch, Amy L.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Wolf, RL (reprint author), Columbia Univ, Teachers Coll, Dept Hlth & Behav Studies, 525 W 120th St,Box 137, New York, NY 10027 USA. EM wolf@tc.columbia.edu FU NCI NIH HHS [CA 104223, R01 CA104223, R01 CA104223-01A1] NR 64 TC 31 Z9 31 U1 3 U2 12 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 2008 VL 108 IS 8 BP 1315 EP 1322 DI 10.1016/j.jada.2008.05.011 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 335KZ UT WOS:000258290800010 PM 18656571 ER PT J AU Rivera, JA Fried, LP Weiss, CO Simonsick, EM AF Rivera, Josette A. Fried, Linda P. Weiss, Carlos O. Simonsick, Eleanor M. TI At the tipping point: Predicting severe mobility difficulty in vulnerable older women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; mobility difficulty; clinical assessment ID AGING-STUDY-II; MUSCULOSKELETAL PAIN; PHYSICAL PERFORMANCE; EMOTIONAL VITALITY; BODY-COMPOSITION; DISABLED WOMEN; RISK-FACTORS; DISABILITY; HEALTH; DECLINE AB OBJECTIVES: To identify clinical measures that aid detection of impending severe mobility difficulty in older women. DESIGN: Cross-sectional and longitudinal cohort study. SETTING: Urban community in Baltimore, Maryland. PARTICIPANTS: One thousand two community-dwelling, moderate to severely disabled women aged 65 and older in the Women's Health and Aging Study I. MEASUREMENTS: Self-report and performance measures representing six domains necessary for mobility: central and peripheral nervous systems, muscles, bones and joints, perception, and energy. Severe mobility difficulty was defined as usual gait of 0.5m/s or less, and reported difficulty walking across a small room, or dependence on a walking aid during a 4-m walking test. RESULTS: Four hundred sixty-seven out of 984 (47%) had severe mobility difficulty at baseline, and 104/474 (22%) developed it within 12 months. Baseline mobility difficulty was correlated with poor vision, knee pain, feelings of helplessness, inability to stand with feet side by side for 10 seconds, difficulty keeping balance while dressing or walking, inability to rise from a chair five times, and cognitive impairment. Of these, knee pain (odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.05-2.89), helplessness (OR = 1.87, 95% CI = 1.10-3.24), poor vision (OR = 2.03, 95% CI = 1.06-3.89), inability to rise from a chair five times (OR 2.50, 95% CI = 1.15-5.41), and cognitive impairment (OR = 4.75, 95% CI = 1.67-.13.48) predicted incident severe mobility difficulty within 12 months, independent of age. CONCLUSION: Five simple measures may aid identification of disabled older women at high risk of severe mobility difficulty. Further Studies should determine generalizability to men and higher-functioning individuals. C1 [Simonsick, Eleanor M.] NIA, St Harbor Hosp, Clin Res Branch, Baltimore, MD 21225 USA. [Rivera, Josette A.; Fried, Linda P.; Weiss, Carlos O.; Simonsick, Eleanor M.] Johns Hopkins Med Inst, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. [Rivera, Josette A.; Fried, Linda P.; Weiss, Carlos O.; Simonsick, Eleanor M.] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. RP Simonsick, EM (reprint author), NIA, St Harbor Hosp, Clin Res Branch, 3001 S Hanover,5th Floor, Baltimore, MD 21225 USA. EM SimonsickEl@grc.nia.nih.gov FU Intramural NIH HHS; NCRR NIH HHS [M01 RR000052, M01-RR00052]; NIA NIH HHS [N01AG12112, N01 AG012112, P30 AG021334, P30 AG021334-04, T32 AG000120] NR 43 TC 27 Z9 28 U1 2 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2008 VL 56 IS 8 BP 1417 EP 1423 DI 10.1111/j.1532-5415.2008.01819.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 340AD UT WOS:000258617500005 PM 18808598 ER PT J AU McDermott, MM Liu, K Ferrucci, L Tian, L Guralnik, JM Green, D Tan, J Liao, YH Pearce, WH Schneider, JR Mccue, K Ridker, P Rifai, N Criqui, MH AF McDermott, Mary M. Liu, Kiang Ferrucci, Luigi Tian, Lu Guralnik, Jack M. Green, David Tan, Jin Liao, Yihua Pearce, William H. Schneider, Joseph R. McCue, Kimberly Ridker, Paul Rifai, Nader Criqui, Michael H. TI Circulating blood markers and functional impairment in peripheral arterial disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE intermittent claudication; peripheral vascular disease; physical functioning; inflammation ID ANKLE BRACHIAL INDEX; C-REACTIVE PROTEIN; D-DIMER; MUSCLE CHARACTERISTICS; PHYSICAL-ACTIVITY; RISK-FACTORS; HOMOCYSTEINE; ATHEROSCLEROSIS; INFLAMMATION; PREDICTORS AB OBJECTIVES: To determine whether higher levels of inflammatory blood markers, D-dimer, and homocysteine were associated with greater impairment in lower extremity functioning in persons with peripheral arterial disease (PAD). DESIGN: Cross-sectional. SETTING: Three Chicago-area medical centers. PARTICIPANTS: Four hundred twenty-three persons with PAD (ankle-brachial index (ABI) < 0.90). MEASUREMENTS: Lower extremity performance was assessed using the 6-minute walk and with usual- and fast-paced 4-m walking speed. Blood markers were D-dimer, C-reactive protein (CRP), interleukin-6 (IL-6), Soluble vascular cellular adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), and homocysteine. Calf muscle area was measured using computed tomography. RESULTS: Adjusting for confounders, higher levels of D-dimer (P < .001), IL-6 (P < .001), sVCAM-1. (P = .006), CRP (P = .01), homocysteine (P = .004), and sICAM-1 (P = .046) were associated with poorer 6-minute walk performance. Higher levels of D-dimer (P < .001), IL-6 (P = .003), sVCAM-1 (P = .001), and homocysteine (P = .005) were associated with slower usual-paced 4-m walking speed. Higher levels of D-dimer, sVCAM-1, sICAM-1, IL-6, and homocysteine were associated with slower fast-paced walking speed. Results were attenuated after additional adjustment for calf muscle area. CONCLUSION: Higher levels of inflammation and D-dimer were associated with poorer lower extremity performance in participants with PAD, independent of confounders including ABI. C1 [McDermott, Mary M.; Green, David; McCue, Kimberly] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang; Tian, Lu; Tan, Jin; Liao, Yihua] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Pearce, William H.; Schneider, Joseph R.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Ferrucci, Luigi] NIA, Lab Clin Epidemiol, Baltimore, MD 21224 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Schneider, Joseph R.] Northwestern Hosp, Dept Surg, Div Vasc Surg, Evanston, IL USA. [Ridker, Paul] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rifai, Nader] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung, and Blood Institute; National Heart, Lung, and Blood Institute [R01-HL58099, R01-HL64739, R01-HL71223, R01-HL076298]; National Center for Research Resources [RR-00048]; National Institutes of Health (NIH); National Institute on Aging FX Mary McDermott receives salary support from the National Heart, Lung, and Blood Institute and honoraria for educational activities from Bristol Meyers Squibb Sanofi Aventis. Kiang Liu, Lu Tian, David Green, Jin Tan, Yihua Liao, Kimberly McCue, William H. Pearce, Paul M. Ridker, Nader Rifai, and Michael H. Criqui receive salary support from the National Heart, Lung, and Blood Institute. Paul Ridker is a co-inventor of the assay used for analyzing C-reactive protein. Supported by grants R01-HL58099, R01-HL64739, R01-HL71223, and R01-HL076298 from the National Heart, Lung, and Blood Institute and by grant #RR-00048 from the National Center for Research Resources, National Institutes of Health (NIH). Supported in part by the Intramural Research Program, National Institute on Aging, NIH. NR 29 TC 30 Z9 30 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2008 VL 56 IS 8 BP 1504 EP 1510 DI 10.1111/j.1532-5415.2008.01797.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 340AD UT WOS:000258617500017 PM 18662216 ER PT J AU Darbari, DS Castro, O Taylor, JG Fasano, R Rehm, J Gordeuk, VR Minniti, CP AF Darbari, Deepika S. Castro, Oswaldo Taylor, James G. Fasano, Ross Rehm, Jeffrey Gordeuk, Victor R. Minniti, Caterina P. TI Severe vaso-occlusive episodes associated with use of systemic corticosteroids in patients with sickle cell disease SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE sickle cell anemia; corticosteroids; adverse events; vaso-occlusion bone ID FAT-EMBOLISM SYNDROME; ACUTE CHEST SYNDROME; CHILDREN; CRISIS AB Patients with sickle cell disease (SCD) are occasionally prescribed systemic corticosteroids to treat steroid-responsive conditions. Additionally, use of systemic corticosteroids for sickle cell pain episodes and acute chest syndrome is under investigation. We report 4 patients with SCID who developed severe vaso-occlusive events following the administration of systemic steroids. We also review similar cases from the literature and suggest measures for reducing the potential risk associated with use of systemic corticosteroids in this group of patients. We conclude that corticosteroids should be used with caution in patients with SCD. C1 [Darbari, Deepika S.; Fasano, Ross; Minniti, Caterina P.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Castro, Oswaldo; Gordeuk, Victor R.] Howard Univ, Coll Med, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Taylor, James G.] NHLBI, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Rehm, Jeffrey] Pulm Associates Fredericksburg, Fredericksburg, VA USA. RP Darbari, DS (reprint author), 600 N Wolfe St,CMSC-800, Baltimore, MD 21287 USA. EM darbaris@yahoo.com OI Taylor, James/0000-0002-4421-1809 FU National Center for Research Resources [K12RR17613, 2MOIRR10284-10]; National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD [R25 HL003679-08, 1 R01 HL079912-02] FX This work was supported in part by contract grants #K12RR17613 and #2MOIRR10284-10 from National Center for Research Resources and #2 R25 HL003679-08 and #1 R01 HL079912-02 from National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD, and by the intramural research program of NIH. NR 10 TC 23 Z9 23 U1 0 U2 0 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD AUG PY 2008 VL 100 IS 8 BP 948 EP 951 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 338CM UT WOS:000258482600010 PM 18717146 ER PT J AU Ratcliffe, MB Howard, C Mann, M del Nido, P AF Ratcliffe, Mark B. Howard, Cheryl Mann, Michael del Nido, Pedro TI National Institutes of Health funding for cardiothoracic surgical research SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID SURGERY AB Objective: Our objective was determine the status of National Institutes of Health (NIH) funding for cardiothoracic surgery research. Summary Background Data: (1) Funding from the NIH is critical if new procedures and devices are to be developed. (2) The success rate for NIH applications coming from cardiothoracic surgery faculty is thought to be inferior. (3) Per capita numbers of surgical NIH application and awards and application success fate have recently been found to be below the average for the NIH. Methods: Application and award data for full-time academic cardiothoracic surgeons were obtained by matching records in the NIH IMPAC 11 database with membership rosters of The Society of Thoracic Surgeons and The American Association for Thoracic Surgery. Manpower data were obtained from 1999, 2003, and 2005 reports of the STS/AATS Workforce committee. Society membership was used as a surrogate for investigator experience. Results: The number of NIH applications has increased steeply in the past 7 years; however, the number of awards has remained constant. This pattern was observed for surgery and cardiothoracic surgery as well. Until 2003, the cardiothoracic surgery application success rate was actually higher than that of surgery and the NIH as a whole (between 25% and 40%). Since then, however, the cardiothoracic surgery application success rate has declined steeply and is now only 14%. NIH applications and awards per 100 cardiothoracic surgeons, although similar to those of surgery, are very much less than the NIH as a whole. Conclusion: Per capita NIH funding of cardiothoracic surgeons is very much less than that of the NIH as a whole. The primary cause is the low per capita number of applications submitted by cardiothoracic surgeons. Junior cardiothoracic faculty should be encouraged to apply for career development awards. However, since the ability to shift cost from clinical to academic faculty is declining, affirmative action from the NIH may be necessary. C1 [Ratcliffe, Mark B.] San Francisco VA Med Ctr, Surg Serv 112, San Francisco, CA 94121 USA. [Ratcliffe, Mark B.; Mann, Michael] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Howard, Cheryl] NHLBI, Div Sci Program Operat, Bethesda, MD 20892 USA. [del Nido, Pedro] Childrens Hosp, Boston, MA 02115 USA. RP Ratcliffe, MB (reprint author), San Francisco VA Med Ctr, Surg Serv 112, 4150 Clement St, San Francisco, CA 94121 USA. EM mark.ratcliffe@rned.va.gov NR 14 TC 16 Z9 16 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD AUG PY 2008 VL 136 IS 2 BP 392 EP 397 DI 10.1016/j.jtcvs.2008.04.009 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 338UQ UT WOS:000258535300021 PM 18692647 ER PT J AU Sokoll, LJ Wang, YH Feng, ZD Kagan, J Partin, AW Sanda, MG Thompson, IM Chan, DW AF Sokoll, Lori J. Wang, Yinghui Feng, Ziding Kagan, Jacob Partin, Alan W. Sanda, Martin G. Thompson, Ian M. Chan, Daniel W. TI [-2]proenzyme prostate specific antigen for prostate cancer detection: A National Cancer Institute Early Detection Research Network validation study SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; prostate-specific antigen; tumor markers; biological; early diagnosis ID MULTICENTER CLINICAL-TRIAL; TRANSITION ZONE; SERUM; NG/ML; MEN; IMPROVE; RANGE; FORMS; PSA AB Purpose: This study evaluated the [-2]proenzyme prostate specific antigen serum marker using a blinded reference specimen set from 3 National Cancer Institute Early Detection Research Network centers from men with an indication for prostate biopsy. Materials and Methods: Serum was collected before biopsy from 123 men with no prior biopsy or prostate cancer history. Specimens (cancer cases 51%, noncancer controls 49%) were selected equally from the 3 sites, and analyzed for prostate specific antigen, free prostate specific antigen, [-2]proenzyme prostate specific antigen, benign prostate specific antigen and testosterone (Beckman Coulter ACCESS (R) analyzer). Results: There was no difference in total prostate specific antigen concentrations (noncancer 6.80 +/- 5.20 ng/ml, cancer 6.94 +/- 5.12 ng/ml) among the groups. Overall %[-2]proenzyme prostate specific antigen had the greatest area under the curve (AUC 0.69) followed by percent free prostate specific antigen (AUC 0.61). For %[-2]proenzyme prostate specific antigen maximal sensitivity was 60% and specificity was 70%. A logistic regression model combining prostate specific antigen, benign prostate specific antigen, percent free prostate specific antigen, %[-2]proenzyme prostate specific antigen, [-2]proenzyme prostate specific antigen/benign prostate specific antigen and testosterone had an AUC of 0.73. In the 2 to 10 ng/ml prostate specific antigen range %[-2]proenzyme prostate specific antigen and the model had the largest AUC (0.73). The AUC for percent free prostate specific antigen was 0.53. Specificities for %[-2]proenzyme prostate specific antigen, the logistic regression model and percent free prostate specific antigen at 90% sensitivity were 41%, 32% and 18%, and at 95% sensitivity were 31%, 26% and 16%, respectively. Conclusions: %[-2]proenzyme prostate specific antigen was the best predictor of prostate cancer detection compared to percent free prostate specific antigen, particularly in the 2 to 10 ng/ml total prostate specific antigen range. These findings provide a rationale for broader validation studies to determine whether % [-2]proenzyme prostate specific antigen alone can replace other molecular prostate specific antigen assays (such as percent free prostate specific antigen) for improving the accuracy of prostate cancer early detection. These findings also support the usefulness of well characterized, carefully collected reference sets to evaluate new biomarkers. C1 [Sokoll, Lori J.; Partin, Alan W.; Chan, Daniel W.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. [Sokoll, Lori J.; Partin, Alan W.; Chan, Daniel W.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21287 USA. [Kagan, Jacob] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Wang, Yinghui; Feng, Ziding] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Sanda, Martin G.] Beth Israel Deaconess Med Ctr, Div Urol, Boston, MA 02215 USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. RP Sokoll, LJ (reprint author), Johns Hopkins Med Inst, Dept Pathol, 600 N Wolfe St,Meyer B-125, Baltimore, MD 21287 USA. EM lsokoll@jhmi.edu RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015 FU NCI NIH HHS [U01 CA086323, U01 CA086368, U01 CA086402, U01 CA11391, U01 CA86323, U01 CA86368, U01 CA86402, U24 CA115102, U24 CA115102-03] NR 20 TC 62 Z9 67 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2008 VL 180 IS 2 BP 539 EP 543 DI 10.1016/j.juro.2008.04.015 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 325LE UT WOS:000257589600035 PM 18550118 ER PT J AU Thompson, IM Tangen, CM Ankerst, DP Chi, C Lucia, MS Goodman, P Parnes, H Coltman, CA AF Thompson, Ian M. Tangen, Catherine M. Ankerst, Donna P. Chi, Chen Lucia, M. Scott Goodman, Phyllis Parnes, Howard Coltman, Charles A., Jr. TI The performance of prostate specific antigen for predicting prostate cancer is maintained after a prior negative prostate biopsy SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; prostate-specific antigen; mass screening; sensitivity and specificity ID UNITED-STATES; MEN; PREVENTION; NG/ML AB Purpose: It has been suggested that prostate specific antigen has no predictive value for prostate cancer after a first negative biopsy. has been performed. We compared the performance operating characteristics of prostate specific antigen for prostate cancer between a first and subsequent prostate biopsy in a group of men with complete verification of cancer status. Materials and Methods: From the 18,882 participants in the Prostate Cancer Prevention Trial we examined men in the placebo group who had only a first biopsy or a first and second prostate biopsy with a prostate specific antigen and digital rectal examination within 1 year before each biopsy. The receiver operating characteristic curve was estimated for prostate specific antigen for detection of prostate cancer on the first biopsy compared to the second, and the C-statistics were compared. Results: Of this group 5,608 men had a first biopsy and 687 of those with a negative first biopsy underwent a second biopsy. The C-statistic was 0.650 (95% CI 0.632, 0.668) for the first biopsy and 0.664 (95% CI 0.607, 0.721) for the second biopsy. The C-statistic for the second biopsy was statistically significantly greater than 0.5 (p <0.001) and overlapped with that from the first biopsy. Conclusions: Prostate specific antigen does not lose predictive value for the detection of prostate cancer even after a first biopsy shows no evidence of cancer, and its performance characteristics are only slightly decreased. C1 [Thompson, Ian M.; Ankerst, Donna P.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Coltman, Charles A., Jr.] SW Oncol Grp, San Antonio, TX USA. [Tangen, Catherine M.; Chi, Chen; Goodman, Phyllis] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Lucia, M. Scott] Univ Colorado, Denver, CO 80202 USA. [Parnes, Howard] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Thompson, IM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. EM thompsoni@uthscsa.edu NR 14 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2008 VL 180 IS 2 BP 544 EP 547 DI 10.1016/j.juro.2008.04.014 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 325LE UT WOS:000257589600037 PM 18550097 ER PT J AU Hall, SA Link, CL Pulliam, SJ Hanno, PM Eggers, PW Kusek, JW McKinlay, JB AF Hall, Susan A. Link, Carol L. Pulliam, Samantha J. Hanno, Philip M. Eggers, Paul W. Kusek, John W. McKinlay, John B. TI The relationship of common medical conditions and medication use with symptoms of painful bladder syndrome: Results from the Boston Area Community Health Survey SO JOURNAL OF UROLOGY LA English DT Article DE cystitis; interstitial; epidemiology; comorbidity ID URINARY-TRACT SYMPTOMS; INTERSTITIAL CYSTITIS; LIFE; MEN AB Purpose: The etiology of painful bladder syndrome is currently unknown. We investigated the relationship between medical factors and symptoms suggestive of painful bladder syndrome in a population based random sample. Materials and Methods: Data were collected from the Boston Area Community Health Survey, an epidemiological study conducted from 2002 to 2005 in a racially and ethnically diverse population (30 to 79 years old) from Boston, Massachusetts. The operational definition of painful bladder syndrome was symptom based. Those reporting pain increasing as the bladder fills and/or pain relieved by urination (fairly often/usually/almost always) for 3+ months were considered to have symptoms suggestive of painful bladder syndrome. We used multivariate logistic regression to estimate odds ratios and 95% confidence intervals (adjusted for demographics, anthropometric and other factors) for the association of comorbidities, surgery and medication use with painful bladder syndrome symptoms. Results: The prevalence of painful bladder syndrome symptoms was 1.3% in men and 2.6% in women. In men only depression was associated in a multivariate model (OR 4.96; 95% CI 1.65, 14.92). In women associations were observed for depression (OR 3.35; 95% CI 1.93, 5.81), history of urinary tract infections (OR 2.17; 95% CI 1.49, 4.96), chronic yeast infections (OR 3.11; 95% CI -1.29, 7.51), hysterectomy (OR 2.82; 95% CI 1.20, 6.62), calcium channel blockers (OR 4.59; 95% CI 2.71, 9.72) and cardiac glycosides (OR 10.28; 95% CI 1.46, 72.35), while thyroid medications and statins were inversely associated (OR 0.13; 95% CI 0.03, 0.47 and OR 0.24; 95% CI 0.08, 0.76; respectively). Conclusions: Gynecologic factors and certain medications may be associated with the painful bladder syndrome in women. Our results for medications suggest potentially modifiable risk factors. C1 [Hall, Susan A.; Link, Carol L.; McKinlay, John B.] New England Res Inst, Watertown, MA 02472 USA. [Pulliam, Samantha J.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. [Hanno, Philip M.] Univ Penn, Dept Urol, Philadelphia, PA 19104 USA. [Eggers, Paul W.; Kusek, John W.] NIDDK, Bethesda, MD USA. RP Hall, SA (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. EM shall@nerisicience.com FU NIDDK NIH HHS [U01 DK056842, DK 56842] NR 20 TC 15 Z9 15 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 AUG PY 2008 VL 180 IS 2 BP 593 EP 598 DI 10.1016/j.juro.2008.04.002 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 325LE UT WOS:000257589600056 PM 18554659 ER PT J AU Link, CL Pulliam, SJ Hanno, PM Hall, SA Eggers, PW Kusek, JW McKinlay, JB AF Link, Carol L. Pulliam, Samantha J. Hanno, Philip M. Hall, Susan A. Eggers, Paul W. Kusek, John W. McKinlay, John B. TI Prevalence and psychosocial correlates of symptoms suggestive of painful bladder syndrome: Results from the Boston Area Community Health Survey SO JOURNAL OF UROLOGY LA English DT Article DE cystitis; interstitial; anxiety; social class; urology ID INTERSTITIAL CYSTITIS SYMPTOMS; LOWER URINARY-TRACT; CONTINENCE SOCIETY; BACH SURVEY; WOMEN; POPULATION; DISORDERS; MEN AB Purpose: We estimated the prevalence of symptoms suggestive of painful bladder syndrome defined as pain increasing as the bladder fills and/or pain relieved by urination for at least 3 months, and its association with sociodemographics (gender, age, race/ethnicity and socioeconomic status), lifestyle (smoking, alcohol consumption, physical activity) and psychosocial variables (sexual, physical, emotional abuse experienced as a child or as an adult, worry, trouble paying for basics, depression). Materials and Methods: The data used come from the Boston Area Community Health Survey, an epidemiological study of 5,506 randomly selected adults 30 to 79 years old of 3 race/ethnic groups (black, Hispanic, white). Results: The overall prevalence of symptoms suggestive of painful bladder syndrome was 2% (1.3% in men and 2.6% in women) with increased prevalence in middle-aged adults and those of lower socioeconomic status. Symptoms suggestive of painful bladder syndrome were more common in those who experienced abuse, in those who were worried about someone close to them and in those who were having trouble paying for basics. This pattern held even after adjusting for depression. Conclusions: Painful bladder syndrome is associated with a number of lifestyle and psychosocial correlates. This suggests that the treatment of patients with painful bladder syndrome (physical symptoms) may benefit from a multifaceted approach of combining medical, psychological and cognitive treatment. C1 [Link, Carol L.; Hall, Susan A.; McKinlay, John B.] New England Res Inst, Watertown, MA 02472 USA. [Pulliam, Samantha J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hanno, Philip M.] Univ Penn Hlth Syst, Philadelphia, PA USA. [Eggers, Paul W.; Kusek, John W.] NIDDK, Bethesda, MD USA. RP Link, CL (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. EM clink@neriscience.com FU NIDDK NIH HHS [U01 DK056842-05, U01 DK056842, U01 DK56842] NR 24 TC 24 Z9 24 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2008 VL 180 IS 2 BP 599 EP 606 DI 10.1016/j.juro.2008.04.009 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 325LE UT WOS:000257589600057 PM 18554658 ER PT J AU LaMere, BJ Howell, R Fetterman, B Shieh, J Castle, PE AF LaMere, Brandon J. Howell, Renee Fetterman, Barbara Shieh, Jen Castle, Philip E. CA Pap Cohort Study Grp TI Impact of 6-month frozen storage of cervical specimens in alkaline buffer conditions on human papillomavirus genotyping SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE human papillomavirus (HPV); HPV genotypes; PCR ID PERSISTENCE AB The impact of 6-month storage of cervical specimens under alkaline conditions that occurs as the result of Hybrid Capture 2 testing on human papillomavirus (HPV) genotyping is not well documented. To examine this issue, 143 frozen hc2-positive specimens in specimen transport medium were selected at random from each of the following groups: specimens stored for 6 months, 4 months, and 2.5 months under alkaline pH (pH 12-13) and specimens stored 1 month at neutral pH (pH 6-7) as controls. Specimens were tested in a masked fashion for 20 HPV genotypes (HPV6, 11, 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82) using a prototype, research-use-only GP5+/6+ L1 consensus PCR method and multiplex hybridization using Luminex (R) xMAP (R) for detection of specific HPV genotypes One control specimen had missing test results. There were no statistical differences in the number of HPV genotypes detected, number of carcinogenic HPV genotypes detected, or in the signal strength among HPV-positive results across groups. Six-month frozen storage of cervical specimens at alkaline pH had little impact on testing for HPV genotypes among hc2-positive women using this HPV genotyping method. Published by Elsevier B.V. C1 [Castle, Philip E.] NCI, Div Canc Epidemiol, NIH, DHHS, Bethesda, MD 20892 USA. [LaMere, Brandon J.; Fetterman, Barbara; Shieh, Jen] Kaiser Permanente No Calif, Reg Lab, Berkeley, CA USA. [Howell, Renee] Qiagen, Gaithersburg, MD USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5030,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS [Z01 CP010124-12] NR 5 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD AUG PY 2008 VL 151 IS 2 BP 298 EP 300 DI 10.1016/j.jviromet.2008.05.017 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 335RH UT WOS:000258307200021 PM 18571737 ER PT J AU Cardenas-Mora, J Spindler, JE Jang, MK McBride, AA AF Cardenas-Mora, Juan Spindler, Jonathan E. Jang, Moon Kyoo McBride, Alison A. TI Dimerization of the papillomavirus E2 protein is required for efficient mitotic chromosome association and Brd4 binding SO JOURNAL OF VIROLOGY LA English DT Article ID BROMODOMAIN PROTEIN; CRYSTAL-STRUCTURE; TRANSCRIPTIONAL ACTIVATION; TRANSACTIVATION DOMAIN; ORIGIN-BINDING; DNA; CHROMATIN; RECOGNITION; DIMERS AB The E2 proteins of several papillomaviruses link the viral genome to mitotic chromosomes to ensure retention and the efficient partitioning of genomes into daughter cells following cell division. Bovine papillomavirus type I E2 binds to chromosomes in a complex with Brd4, a cellular bromodomain protein. Interaction with Brd4 is also important for E2-mediated transcriptional regulation. The transactivation domain of E2 is crucial for interaction with the Brd4 protein; proteins lacking or mutated in this domain do not interact with Brd4. However, we found that the C-terminal DNA binding/dimerization domain of E2 is also required for efficient binding to Brd4. Mutations that eliminated the DNA binding function of E2 had no effect on the ability of E2 to interact with Brd4, but an E2 protein with a mutation that disrupted C-terminal dimerization bound Brd4 with greatly reduced efficiency. Furthermore, E2 proteins in which the C-terminal domains were replaced with the dimeric DNA binding domain of EBNA-1 or GaN bound efficiently to the Brd4 protein, but the replacement of the E2 C-terminal domain with a monomeric red fluorescent protein did not rescue efficient Brd4 binding. Thus, E2 bound to Brd4 most efficiently as a dimer. To prove this finding further, the E2 DNA binding domain was replaced with an FKBP12-derived domain in which dimerization was regulated by a bivalent ligand. This fusion protein bound Brd4 efficiently only in the presence of the ligand, confirming that a dimer of E2 was required. Correspondingly, E2 proteins that could dimerize were able to bind to mitotic chromosomes much more efficiently than monomeric E2 polypeptides. C1 [Cardenas-Mora, Juan; Spindler, Jonathan E.; Jang, Moon Kyoo; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM amcbride@nih.gov FU Intramural NIH HHS NR 35 TC 21 Z9 21 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 15 BP 7298 EP 7305 DI 10.1128/JVI.00772-08 PG 8 WC Virology SC Virology GA 328AV UT WOS:000257770500005 PM 18495759 ER PT J AU Smith, MZ Asher, TE Venturi, V Davenport, MP Douek, DC Price, DA Kent, SJ AF Smith, Miranda Z. Asher, Tedi E. Venturi, Vanessa Davenport, Miles P. Douek, Daniel C. Price, David A. Kent, Stephen J. TI Limited maintenance of vaccine-induced simian immunodeficiency virus-specific CD8 T-cell receptor clonotypes after virus challenge SO JOURNAL OF VIROLOGY LA English DT Article ID MHC CLASS-I; VIRAL ESCAPE; IMMUNE ESCAPE; MUTATIONAL ESCAPE; RHESUS-MONKEYS; EPITOPE; LYMPHOCYTES; REPERTOIRE; REPLICATION; RECOGNITION AB T-cell receptors (TCRs) govern the specificity, efficacy, and cross-reactivity of CD8 T cells. Here, we studied CD8 T-cell clonotypes from Mane-A*10(+) pigtail macaques responding to the simian immunodeficiency virus (SIV) Gag KP9 epitope in a setting of vaccination and subsequent viral challenge. We observed a diverse TCR repertoire after DNA, recombinant poxvirus, and live attenuated virus vaccination, with none of 59 vaccine-induced KP9-specific TCRs being identical between macaques. The KP9-specific TCR repertoires remained diverse after SIV or simian-human immunodeficiency virus challenge but, remarkably, exhibited substantially different clonotypic compositions compared to the corresponding populations prechallenge. Within serial samples from individual pigtail macaques, only a small subset (33.9%) of TCRs induced by vaccination were maintained or expanded after challenge. Most (66.1%) of the TCRs induced by vaccination were not detectable after challenge. Our results suggest that some CD8 T cells induced by vaccination are more efficient than others at responding to a viral challenge. These findings have implications for future AIDS virus vaccine studies, which should consider the "fitness" of vaccine-induced T cells in order to generate robust responses in the face of virus exposure. C1 [Smith, Miranda Z.; Kent, Stephen J.] Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic 3010, Australia. [Asher, Tedi E.; Douek, Daniel C.; Price, David A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Venturi, Vanessa; Davenport, Miles P.] UNSW, Ctr Vasc Res, Sydney, NSW, Australia. [Price, David A.] Cardiff Univ, Dept Med Biochem & Immunol, Sch Med, Cardiff, Wales. RP Kent, SJ (reprint author), Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic 3010, Australia. EM skent@unimelb.edu.au RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Kent, Stephen/0000-0002-8539-4891; Smith, Miranda/0000-0002-6404-9204 FU Intramural NIH HHS; Medical Research Council [G0501963] NR 43 TC 13 Z9 13 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 15 BP 7357 EP 7368 DI 10.1128/JVI.00607-08 PG 12 WC Virology SC Virology GA 328AV UT WOS:000257770500011 PM 18508897 ER PT J AU Lamirande, EW DeDiego, ML Roberts, A Jackson, JP Alvarez, E Sheahan, T Shieh, WJ Zaki, SR Baric, R Enjuanes, L Subbarao, K AF Lamirande, Elaine W. DeDiego, Marta L. Roberts, Anjeanette Jackson, Jadon P. Alvarez, Enrique Sheahan, Tim Shieh, Wun-Ju Zaki, Sherif R. Baric, Ralph Enjuanes, Luis Subbarao, Kanta TI A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in Golden Syrian hamsters SO JOURNAL OF VIROLOGY LA English DT Article ID SARS CORONAVIRUS; INFECTION; VACCINES; BATS AB The immunogenicity and protective efficacy of a live attenuated vaccine consisting of a recombinant severe acute respiratory syndrome (SARS) coronavirus lacking the E gene (rSARS-CoV-Delta E) were studied using hamsters. Hamsters immunized with rSARS-CoV-Delta E developed high serum-neutralizing antibody titers and were protected from replication of homologous (SARS-CoV Urbani) and heterologous (GD03) SARS-CoV in the upper and lower respiratory tract. rSARS-CoV-Delta E-immunized hamsters remained active following wildtype virus challenge, while mock-immunized hamsters displayed decreased activity. Despite being attenuated in replication in the respiratory tract, rSARS-CoV-Delta E is an immunogenic and efficacious vaccine in hamsters. C1 [Lamirande, Elaine W.; Roberts, Anjeanette; Jackson, Jadon P.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [DeDiego, Marta L.; Alvarez, Enrique; Enjuanes, Luis] Campus Univ Autonoma, Nacl Biotecnol CSIC, Ctr Nacl Biotecnol, Dept Mol & Cell Biol, Madrid 28049, Spain. [Sheahan, Tim; Baric, Ralph] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Shieh, Wun-Ju; Zaki, Sherif R.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov RI DeDiego, Marta L./B-2307-2017; OI DeDiego, Marta L./0000-0002-7888-7372; Enjuanes, Luis/0000-0002-0854-0226 FU Intramural NIH HHS; NIAID NIH HHS [AI059136, R01 AI059136] NR 11 TC 34 Z9 34 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 15 BP 7721 EP 7724 DI 10.1128/JVI.00304-08 PG 4 WC Virology SC Virology GA 328AV UT WOS:000257770500045 PM 18463152 ER PT J AU Mitchell, RS Chaudhuri, R Lindwasser, OW Tanaka, KA Lau, D Murillo, R Bonifacino, JS Guatelli, JC AF Mitchell, Richard S. Chaudhuri, Rittik Lindwasser, O. Wolf Tanaka, Kristie A. Lau, David Murillo, Rudy Bonifacino, Juan S. Guatelli, John C. TI Competition model for upregulation of the major histocompatibility complex class II-associated invariant chain by human immunodeficiency virus type I Nef SO JOURNAL OF VIROLOGY LA English DT Article ID MHC CLASS-II; ADAPTER PROTEIN COMPLEXES; AP2 CLATHRIN ADAPTER; CD4 DOWN-REGULATION; HIV-1 NEF; CYTOPLASMIC TAIL; SORTING SIGNALS; ENDOCYTIC PATHWAY; CELL-SURFACE; RAPID INTERNALIZATION AB The human immunodeficiency virus type 1 (HIV-1) Nef protein upregulates the expression of the invariant chain (li)/major histocompatibility complex class II (MHC-II) complex at the cell surface. This complex appears to reach the antigen-loading endosomal compartment at least in part via an indirect pathway in which it is internalized from the cell surface via the adaptor protein 2 (AP-2) complex. Here we provide evidence for a competition model to explain how Nef upregulates the expression of Ii at the cell surface. In this model, Nef and Ii compete for binding to AP-2. In support of this model, Nef decreased the rate of internalization of Ii from the cell surface. The AP-binding dileucine motif in Nef, ENTSLL165, was necessary and sufficient for the upregulation of Ii. In addition, two leucine-based AP-binding motifs in the Ii cytoplasmic tail, DDQRDLI(8) and EQLPML(17), were critical for the efficient upregulation of Ii by Nef. Experiments using Nef variants in which the native dileucine-based sorting motif was replaced with similar motifs from cellular transmembrane proteins allowed modulation of AP-binding specificity. Analysis of these variants suggested that the binding of Nef to AP-2 is sufficient to upregulate Ii at the plasma membrane. Finally, interference with the expression of AP-2 caused an upregulation of li at the plasma membrane, and this decreased the effect of Nef. These data indicate that Nef usurps AP-2 complexes to dysregulate Ii trafficking and potentially interfere with antigen presentation in the context of MHC-II. C1 [Mitchell, Richard S.; Tanaka, Kristie A.; Murillo, Rudy; Guatelli, John C.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Lau, David] Univ Calif San Diego, Div Biol, La Jolla, CA 92093 USA. [Chaudhuri, Rittik; Lindwasser, O. Wolf; Bonifacino, Juan S.] NICHHD, Cell Biol & Metab Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Guatelli, John C.] San Diego Vet Afairs Healthcare Syst, San Diego, CA 92121 USA. RP Mitchell, RS (reprint author), Univ Calif San Diego, Dept Med, 9500 Gilman Dr,SCRB Rm 303, La Jolla, CA 92093 USA. EM rsmitchell@ucsd.edu FU Intramural NIH HHS; NIAID NIH HHS [AI 36214, R01 AI038201, P30 AI036214, T32 AI007384, R21 AI038201, AI07384, AI38201, AI36214] NR 49 TC 12 Z9 13 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 AUG PY 2008 VL 82 IS 16 BP 7758 EP 7767 DI 10.1128/JVI.02668-07 PG 10 WC Virology SC Virology GA 333QF UT WOS:000258166500001 PM 18524831 ER PT J AU Bitko, V Musiyenko, A Bayfield, MA Maraia, RJ Barik, S AF Bitko, Vira Musiyenko, Alla Bayfield, Mark A. Maraia, Richard J. Barik, Sailen TI Cellular la protein shields nonsegmented negative-strand RNA viral leader RNA from RIG-I and enhances virus growth by diverse mechanisms SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; VESICULAR STOMATITIS-VIRUS; ANTIVIRAL INNATE IMMUNITY; SITE-MEDIATED TRANSLATION; INDUCIBLE GENE-I; MESSENGER-RNA; SENDAI-VIRUS; NUCLEOTIDE-SEQUENCE; INTERFERON SYSTEM; EPITHELIAL-CELLS AB The La antigen (SS-B) associates with a wide variety of cellular and viral RNAs to affect gene expression in multiple systems. We show that La is the major cellular protein found to be associated with the abundant 44-nucleotide viral leader RNA (leRNA) early after infection with respiratory syncytial virus (RSV), a nonsegmented negative-strand RNA virus. Consistent with this, La redistributes from the nucleus to the cytoplasm in RSV-infected cells. Upon RNA interference knockdown of La, leRNA is redirected to associate with the RNA-binding protein RIG-1, a known activator of interferon (IFN) gene expression, and this is accompanied by the early induction of IFN mRNA. These results suggest that La shields leRNA from RIG-1, abrogating the early viral activation of type I IFN. We mapped the leRNA binding function to RNA recognition motif I of La and showed that while wild-type La greatly enhanced RSV growth, a La mutant defective in RSV leRNA binding also did not support RSV growth. Comparative studies of RSV and Sendai virus and the use of IFN-negative Vero cells indicated that La supports the growth of nonsegmented negative-strand RNA viruses by both IFN suppression and a potentially novel IFN-independent mechanism. C1 [Bitko, Vira; Musiyenko, Alla; Barik, Sailen] Univ S Alabama, Dept Biochem & Mol Biol, Coll Med, Mobile, AL 36688 USA. [Bayfield, Mark A.; Maraia, Richard J.] NICHHD, Intramural Res Program Genet Differentiat, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Barik, S (reprint author), Univ S Alabama, Dept Biochem & Mol Biol, Coll Med, 307 Univ Blvd, Mobile, AL 36688 USA. EM sbarik@jaguar1.usouthal.edu FU Intramural NIH HHS; NIAID NIH HHS [R01 AI059267, AI059267] NR 73 TC 30 Z9 31 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 16 BP 7977 EP 7987 DI 10.1128/JVI.02762-07 PG 11 WC Virology SC Virology GA 333QF UT WOS:000258166500022 PM 18550659 ER PT J AU Fogg, CN Arnerico, JL Earl, PL Resch, W Aldaz-Carroll, L Eisenberg, RJ Cohen, GH Moss, B AF Fogg, Christiana N. Arnerico, Jeffrey L. Earl, Patricia L. Resch, Wolfgang Aldaz-Carroll, Lydia Eisenberg, Roselyn J. Cohen, Gary H. Moss, Bernard TI Disparity between levels of in vitro neutralization of vaccinia virus by antibody to the A27 protein and protection of mice against intranasal challenge SO JOURNAL OF VIROLOGY LA English DT Article ID 2 INFECTIOUS FORMS; ATTENUATED SMALLPOX VACCINE; OUTER-MEMBRANE PROTEINS; TO-CELL SPREAD; ENVELOPE PROTEIN; MONOCLONAL-ANTIBODIES; POXVIRUS INFECTION; ESCHERICHIA-COLI; NONHUMAN-PRIMATES; FUSION PROTEIN AB Immunization with recombinant proteins may provide a safer alternative to live vaccinia virus for prophylaxis of poxvirus infections. Although antibody protects against vaccinia virus infection, the mechanism is not understood and the selection of immunogens is daunting as there are dozens of surface proteins and two infectious forms known as the mature virion (MV) and the enveloped virion (EV). Our previous studies showed that mice immunized with soluble forms of EV membrane proteins A33 and B5 and MV membrane protein L1 or passively immunized with antibodies to these proteins survived an intranasal challenge with vaccinia virus. The present study compared MV protein A27, which has a role in virus attachment to glycosaminoglycans on the cell surface, to L1 with respect to immunogenicity and protection. Although mice developed similar levels of neutralizing antibody after immunizations with A27 or L1, A27-immunized mice exhibited more severe disease upon an intranasal challenge with vaccinia virus. In addition, mice immunized with A27 and A33 were not as well protected as mice receiving L1 and A33. Polyclonal rabbit anti-A27 and anti-L1 IgG had equivalent W-neutralizing activities when measured by the prevention of infection of human or mouse cells or cells deficient in glycosaminoglycans or by adding antibody prior to or after virus adsorption. Nevertheless, the passive administration of antibody to A27 was poorly protective compared to the antibody to L1. These studies raise questions regarding the basis for antibody protection against poxvirus disease and highlight the importance of animal models for the early evaluation of vaccine candidates. C1 [Fogg, Christiana N.; Arnerico, Jeffrey L.; Earl, Patricia L.; Resch, Wolfgang; Moss, Bernard] NIAID, NIH, Viral Dis Lab, Bethesda, MD 20892 USA. [Aldaz-Carroll, Lydia; Eisenberg, Roselyn J.; Cohen, Gary H.] Univ Maryland, Sch Dent, Philadelphia, PA USA. [Aldaz-Carroll, Lydia; Eisenberg, Roselyn J.; Cohen, Gary H.] Univ Maryland, Sch Vet Med, Philadelphia, PA USA. RP Moss, B (reprint author), NIAID, NIH, Viral Dis Lab, 33 N Dr MSC3210,Bldg 33,Room 1E13C1, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS; NIAID NIH HHS [AI53044, U54 AI057168] NR 72 TC 17 Z9 20 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 16 BP 8022 EP 8029 DI 10.1128/JVI.00568-08 PG 8 WC Virology SC Virology GA 333QF UT WOS:000258166500026 PM 18524827 ER PT J AU Bartlett, EJ Hennessey, M Skiadopoulos, MH Schmidt, AC Collins, PL Murphy, BR Pickles, RJ AF Bartlett, Emmalene J. Hennessey, Margaret Skiadopoulos, Mario H. Schmidt, Alexander C. Collins, Peter L. Murphy, Brian R. Pickles, Raymond J. TI Role of interferon in the replication of human parainfluenza virus type 1 wild type and mutant viruses in human ciliated airway epithelium SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; ACUTE OTITIS-MEDIA; INFLUENZA-A VIRUS; NF-KAPPA-B; VACCINE CANDIDATES; C-PROTEINS; ANTIVIRAL RESPONSES; REVERSE GENETICS; V-PROTEIN; ATTENUATING MUTATIONS AB Human parainfluenza virus type 1 (HPIV1) is a significant cause of pediatric respiratory disease in the upper and lower airways. An in vitro model of human ciliated airway epithelium (HAE), a useful tool for studying respiratory virus-host interactions, was used in this study to show that HPIV1 selectively infects ciliated cells within the HAE and that progeny virus is released from the apical surface with little apparent gross cytopathology. In HAE, type I interferon (IFN) is induced following infection with an HPIV1 mutant expressing defective C proteins with an F170S amino acid substitution, rHPIV1-C-F170S, but not following infection with wild-type HPIV1. IFN induction coincided with a 100- to 1,000-fold reduction in virus titer, supporting the hypothesis that the HPIV1 C proteins are critical for the inhibition of the innate immune response. Two recently characterized live attenuated HPIV1 vaccine candidates expressing mutant C proteins were also evaluated in HAE. The vaccine candidates, rHPIV1-(CHNLY942A)-H-R84G/Delta 170-L-T553A and rHPIV1-(CHNL Delta 1710-11)-H-R84G/Delta 170-L-T553A, which contain temperature-sensitive (ts) attenuating (att) and non-ts att mutations, were highly restricted in growth in HAE at permissive (32 degrees C) and restrictive (37 degrees C) temperatures. The viruses grew slightly better at 37 degrees C than at 32 degrees C, and rHPIV1-(CHNLY942A)-H-R84G/Delta 170-L-T553A was less attenuated than rHPIV1-(CHNL Delta 1710-11)-H-R84G/Delta 170-L-T553A. The level of replication in HAE correlated with that previously observed for African green monkeys, suggesting that the HAE model has potential as a tool for the preclinical evaluation of HPIV1 vaccines, although how these in vitro data will correlate with vaccine virus replication in seronegative human subjects remains to be seen. C1 [Pickles, Raymond J.] Univ N Carolina, UNC Sch Med, Cyst Fibrosis Pulm Res & Treatment Lab, Chapel Hill, NC 27599 USA. [Bartlett, Emmalene J.; Skiadopoulos, Mario H.; Schmidt, Alexander C.; Collins, Peter L.; Murphy, Brian R.] NIAID, Infect Dis Lab, NIH, Resp Viruses Sect,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hennessey, Margaret; Pickles, Raymond J.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. RP Pickles, RJ (reprint author), Univ N Carolina, UNC Sch Med, Cyst Fibrosis Pulm Res & Treatment Lab, 7023 Thurston Bowles, Chapel Hill, NC 27599 USA. EM branston@med.unc.edu FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL77844-1, R01 HL077844] NR 67 TC 20 Z9 20 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 16 BP 8059 EP 8070 DI 10.1128/JVI.02263-07 PG 12 WC Virology SC Virology GA 333QF UT WOS:000258166500030 PM 18524813 ER PT J AU Yang, YP McKerlie, C Lu, Z Wang, L Buchwald, M AF Yang, Yongping McKerlie, Colin Lu, Zhan Wang, Lena Buchwald, Manuel TI In vivo potential effects of adenovirus type 5 E1A and E1B on lung carcinogenesis and lymphoproliferative inflammation SO JOURNAL OF VIROLOGY LA English DT Article ID PRIMARY RAT-CELLS; TRANSFORMATION; INFECTION; PROTEIN; P53; EXPRESSION; PROLIFERATION; PATHOGENESIS; ONCOGENES; ABSENCE AB Triggering uncontrolled cellular proliferation, chronic inflammation, and/or disruption of p53 activity is critical for tumorigenesis initiated by latent viral oncogenes. The adenovirus type 5 (Ad5) early genes E1A and E1B can maintain lifelong latency in the lungs of patients with chronic pulmonary diseases. To determine the in vivo effects of the latent Ad5 E1A and E1B oncogenes, we have examined the influence of Ad5 E1A and E1B gene products on mouse lung carcinogenesis and inflammation by generation and characterization of lungspecific transgenic mouse models. Here, we show that either the Ad5 E1A 243-amino-acid (aa) protein or the E1B 58-kDa protein was dominantly expressed in the transgenic lung. Preferential expression of Ad5 E1A 243-aa protein alone was not sufficient to induce lung carcinogenesis but resulted in low-grade cellular proliferation and high-grade lymphoproliferative inflammation in the lung. The presence of Ad5 E1B dramatically enhanced the expression of the E1A 243-aa protein, in addition to impairing p53 and apoptosis response, resulting in uncontrolled cellular proliferation, lymphoproliferative inflammation, and metastatic carcinomas in the lung after a period of latency. Our studies may provide clues to understanding the potential in vivo biological effects of Ad5 E1A and E1B latent in the lung and a new scope for assessing in vivo functions of viral genes latent in the infection target tissue. C1 [Yang, Yongping; Lu, Zhan; Buchwald, Manuel] Univ Toronto, Hosp Sick Children, Genet & Genom Biolog Programs, Toronto, ON M5G 1X8, Canada. [McKerlie, Colin] Univ Toronto, Canc Biol Program, Sunnybrook & Womens Coll Hlth Sci Ctr, Toronto, ON, Canada. [McKerlie, Colin] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [McKerlie, Colin] Univ Toronto, Dept Pathobiol, Toronto, ON, Canada. [Buchwald, Manuel] Univ Toronto, Dept Mol & Med Genet, Toronto, ON, Canada. RP Yang, YP (reprint author), NCI, Ctr Canc Res, Biopharmaceut Dev Program, Frederick, MD 21702 USA. EM yongpiny@mail.nih.gov NR 25 TC 4 Z9 4 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 AUG PY 2008 VL 82 IS 16 BP 8105 EP 8111 DI 10.1128/JVI.00536-08 PG 7 WC Virology SC Virology GA 333QF UT WOS:000258166500034 PM 18524829 ER PT J AU Bukh, J Thimme, R Meunier, JC Faulk, K Spangenberg, HC Chang, KM Satterfield, W Chisari, FV Purcell, RH AF Bukh, Jens Thimme, Robert Meunier, Jean-Christophe Faulk, Kristina Spangenberg, Hans Christian Chang, Kyong-Mi Satterfield, William Chisari, Francis V. Purcell, Robert H. TI Previously infected chimpanzees are not consistently protected against reinfection or persistent infection after reexposure to the identical hepatitis C virus strain SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL RESPONSES; NEUTRALIZING ANTIBODY; IN-VIVO; RECOVERED CHIMPANZEES; MOLECULAR CLONE; CDNA-CLONE; IMMUNITY; CHALLENGE; VACCINE; HCV AB Protective immunity after resolved hepatitis C virus (HCV) infection has been reported. However, the breadth of this immunity has remained controversial, and the role of neutralizing antibodies has not been well-defined. In the present study, two chimpanzees (CH96A008 and CH1494) with resolved monoclonal H77C (genotype 1a) infection were rechallenged with low-dose homologous H77C virus about 12 months after viral clearance; CH96A008 became persistently infected, and CH1494 had transient viremia lasting 2 weeks. CH1494 was subsequently either partially or completely protected following five homologous rechallenges with monoclonal H77C or polyclonal H77 and after six heterologous rechallenges with HC-J4 (genotype 1b) or HC-J6 (genotype 2a) viruses. Subsequently, a final challenge with H77C resulted in persistent HCV infection. In both chimpanzees, serum neutralizing antibodies against retroviral pseudoparticles bearing the H77C envelope proteins were not detected during the initial infection or during rechallenge. However, anamnestic cellular immune responses developed during the initial homologous rechallenge, in particular in CH96A008, which developed a persistent infection. Polyprotein sequences of viruses recovered from CH1494 after the two homologous rechallenges that resulted in transient viremia were identical with the H77C virus. In contrast, the polyprotein sequences of viruses recovered from both chimpanzees after homologous rechallenge resulting in persistent infection had numerous changes. These findings have important implications for our understanding of immunity against HCV; even in the best-case scenario with autologous rechallenge, low-level viral persistence was seen in the presence of primed T-cell responses. C1 [Bukh, Jens; Meunier, Jean-Christophe; Faulk, Kristina; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Bukh, Jens] Univ Copenhagen Hosp, Dept Infect Dis, Copenhagen Hepatitis Program C, DK-2650 Hvidovre, Denmark. [Bukh, Jens] Univ Copenhagen Hosp, Clin Res Ctr, DK-2650 Hvidovre, Denmark. [Bukh, Jens] Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, DK-2200 Copenhagen N, Denmark. [Thimme, Robert; Spangenberg, Hans Christian; Chang, Kyong-Mi; Chisari, Francis V.] Scripps Res Inst, Dept Mol & Expt Med, Div Expt Pathol, La Jolla, CA 92037 USA. [Satterfield, William] MD Anderson Canc Ctr, Michale E Keeling Ctr Comparat Med & Res, Dept Vet Sci, Bastrop, TX 78602 USA. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bldg 50,Room 6531,50 S Dr,MSC 8009, Bethesda, MD 20892 USA. EM jbukh@niaid.nih.gov RI Chisari, Francis/A-3086-2008; OI Chisari, Francis/0000-0002-4832-1044 FU Intramural NIH HHS; NIAID NIH HHS [N01-AO-062713, N01AO62713] NR 36 TC 56 Z9 57 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 16 BP 8183 EP 8195 DI 10.1128/JVI.00142-08 PG 13 WC Virology SC Virology GA 333QF UT WOS:000258166500041 PM 18550671 ER PT J AU Simonsick, EM Newman, AB Visser, M Goodpaster, B Kritchevsky, SB Rubin, S Nevitt, MC Harris, TB AF Simonsick, Eleanor M. Newman, Anne B. Visser, Marjolein Goodpaster, Bret Kritchevsky, Stephen B. Rubin, Susan Nevitt, Michael C. Harris, Tamara B. CA Hlth Aging Body Composition Study TI Mobility limitation in self-described well-functioning older adults: Importance of endurance walk testing SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE mobility; walking; limitation; endurance; performance; testing ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE BATTERY; DISTANCE CORRIDOR WALK; BODY-COMPOSITION; SUBSEQUENT DISABILITY; HEALTH ABC; GAIT SPEED; WOMEN; ASSOCIATION; EXERCISE AB Background. Mobility limitations are prevalent, potentially reversible precursors to mobility loss that may go undetected in older adults. This study evaluates standardized administration of an endurance walk test for identifying unrecognized and impending mobility limitation in community elders. Methods. Men and women (1480 and 1576, respectively) aged 70-79 years with no reported mobility limitation participating in the Health, Aging and Body Composition study were administered the Long Distance Corridor Walk. Walk performance was examined to determine unrecognized mobility deficits at baseline and predict new self-recognition of mobility limitation within 2 years. Results. On testing, 23% and 36% of men and women evidenced mobility deficits defined as a contraindication to exertion, meeting stopping criteria or exceeding 7 minutes to walk 400 in. Unrecognized deficits increased with age and were more prevalent in blacks, smokers, obese individuals, and infrequent walkers. Within 2 years, 21% and 34% of men and women developed newly recognized mobility limitation; those with baseline unrecognized deficits had higher rates, 40% and 54% (p < .001), respectively. For each additional 30 seconds over 5 minutes needed to walk 400 m, likelihood of newly recognized mobility limitation increased by 65% and 37% in men and women independent of age, race, obesity, smoking status, habitual walking, reported walking ease, and usual gait speed. Conclusions. A sizable proportion of elders who report no walking difficulty have observable deficits in walking performance that precede and predict their recognition of mobility limitation. Endurance walk testing can help identify these deficits and provide the basis for treatment to delay progression of mobility loss. C1 [Rubin, Susan; Nevitt, Michael C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Visser, Marjolein] Vrije Univ Amsterdam, Inst Res Extramural Med, Amsterdam, Netherlands. [Newman, Anne B.; Goodpaster, Bret] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Newman, Anne B.; Goodpaster, Bret] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Simonsick, Eleanor M.] Johns Hopkins Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Simonsick, Eleanor M.; Harris, Tamara B.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.; Harris, Tamara B.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Simonsick, EM (reprint author), Harbor Hosp, Clin Res Branch, NIA, NIA ASTRA Unit, 3001 S Hanover St, Baltimore, MD 21225 USA. EM simonsickel@mail.nih.gov RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institutes of Health; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA) and NIA contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. NR 35 TC 46 Z9 47 U1 0 U2 1 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 AUG PY 2008 VL 63 IS 8 BP 841 EP 847 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 352RT UT WOS:000259515800009 PM 18772472 ER PT J AU Saczynski, JS Jonsdottir, MK Sigurdsson, S Eiriksdottir, G Jonsson, PV Garcia, ME Kjartansson, O van Buchem, MA Gudnason, V Launer, LJ AF Saczynski, Jane S. Jonsdottir, Maria K. Sigurdsson, Sigurdur Eiriksdottir, Gudny Jonsson, Palmi V. Garcia, Melisa E. Kjartansson, Olafur van Buchem, Mark A. Gudnason, Vlimundur Launer, Lenore J. TI White matter lesions and cognitive performance: The role of cognitively complex leisure activity SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE epidemiology; cognition; white matter lesions; leisure activity ID RAT VISUAL-CORTEX; ENRICHED ENVIRONMENT; DEPRESSIVE SYMPTOMS; DISEASE; HIPPOCAMPAL; BRAIN; IMPAIRMENT; REYKJAVIK; SAMPLE; ADULTS AB Background. Among persons with white matter lesions (WMLs), there is a range of cognitive function. We examine whether participation in leisure activities modifies the effect of WML load on cognitive function. Methods. Data are from 2300 men and women (aged 66-92 years) participating in the population-based Age Gene/Environment Susceptibility-Reykjavik Study. Subcortical WML load was calculated as a weighted sum, based on size of lesions in the four lobes. Periventricular WML load was calculated as the sum of lesion scores. based on size, for the frontal caps, occipitoparietal caps and bands. The upper quartile of lesion load in either area was compared to the lower three quartiles. Composite scores of memory (MEM), speed of processing (SP), and executive function (EF) were constructed from a battery of neuropsychological tests. Frequency of participation in nine cognitively stimulating leisure activities was assessed via questionnaire; the upper quartile was compared to the lower three quartiles. Multiple regression, controlling for demographic and health factors and brain infarcts, was used to test the main effects and interaction of WMLs and leisure activity on cognitive function. Results. High leisure activity was associated with higher performance in all three cognitive abilities: MEM beta = 0.20, 95% confidence interval [CI], 0.11-0.29: SP beta = 0.37, 95% CI, 0.29-0.45; and EF beta = 0.23, 95% CI, 0.15-0.29. High WML load was associated with significantly lower performance in SP (P = -0.06. 95% CI, -0.13 to -0.01). The effect of WMLs on SP performance was modified by high leisure activity (p for interaction < .05). Conclusion. Participation in cognitively stimulating leisure activity may attenuate the effect of WML pathology on cognitive performance. C1 [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA 01605 USA. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Worcester, MA 01605 USA. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Jonsdottir, Maria K.; Sigurdsson, Sigurdur; Eiriksdottir, Gudny; Jonsson, Palmi V.; Kjartansson, Olafur; Gudnason, Vlimundur] Iceland Heart Assoc, Kopavogur, Iceland. [Saczynski, Jane S.; Garcia, Melisa E.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Saczynski, JS (reprint author), Univ Massachusetts, Sch Med, Div Geriatr Med, Biotech 4,Suite 315,377 Plantat St, Worcester, MA 01605 USA. EM jane.saczynski@umassmed.edu RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program; Icelandic Heart Association; Icelandic Parliament; National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute FX This study was funded by National Institutes of Health contract N01-AG-12100, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Components of the study were also supported by the National Eye Institute, the National Institute on Deafness and Other Communication Disorders, and the National Heart, Lung, and Blood Institute. NR 42 TC 30 Z9 30 U1 0 U2 3 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 AUG PY 2008 VL 63 IS 8 BP 848 EP 854 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 352RT UT WOS:000259515800010 PM 18772473 ER PT J AU Chen, S Wassenhove-McCarthy, DJ Yamaguchi, Y Holzman, LB van Kuppevelt, TH Jenniskens, GJ Wijnhoven, TJ Woods, AC McCarthy, KJ AF Chen, Shoujun Wassenhove-McCarthy, Deborah J. Yamaguchi, Yu Holzman, Lawrence B. van Kuppevelt, Toin H. Jenniskens, Guido J. Wijnhoven, Tessa J. Woods, Ann C. McCarthy, Kevin J. TI Loss of heparan sulfate glycosaminoglycan assembly in podocytes does not lead to proteinuria SO KIDNEY INTERNATIONAL LA English DT Article DE Ext1; heparan; proteoglycan; glycosaminoglycan; podocyte; glomerulus ID GLOMERULAR-BASEMENT-MEMBRANE; KIDNEY; PROTEOGLYCANS; MORPHOGENESIS; LOCALIZATION; PERMEABILITY; EXPRESSION; SYNDECANS; FERRITIN; PERLECAN AB Podocytes synthesize the majority of the glomerular basement membrane components with some contribution from the glomerular capillary endothelial cells. The anionic charge of heparan sulfate proteoglycans is conferred by covalently attached heparan sulfate glycosaminoglycans and these are thought to provide critical charge selectivity to the glomerular basement membrane for ultrafiltration. One key component in herparan sulfate glycosaminoglycan assembly is the Ext1 gene product encoding a subunit of heparan sulfate co-polymerase. Here we knocked out Ext1 gene expression in podocytes halting polymerization of heparin sulfate glycosaminoglycans on the proteoglycan core proteins secreted by podocytes. Glomerular development occurred normally in these knockout animals but changes in podocyte morphology, such as foot process effacement, were seen as early as 1 month after birth. Immunohistochemical analysis showed a significant decrease in heparan sulfate glycosaminoglycans confirmed by ultrastructural studies using polyethyleneimine staining. Despite podocyte abnormalities and loss of heparan sulfate glycosaminoglycans, severe albuminuria did not develop in the knockout mice. We show that the presence of podocyte-secreted heparan sulfate glycosaminoglycans is not absolutely necessary to limit albuminuria suggesting the existence of other mechanisms that limit albuminuria. Heparan sulfate glycosaminoglycans appear to have functions that control podocyte behavior rather than be primarily an ultrafiltration barrier. C1 [Wassenhove-McCarthy, Deborah J.; McCarthy, Kevin J.] Louisiana State Univ, Hlth Sci Ctr, Dept Pathol, Shreveport, LA 71106 USA. [Chen, Shoujun; McCarthy, Kevin J.] Louisiana State Univ, Hlth Sci Ctr, Dept Cell Biol & Anat, Shreveport, LA 71106 USA. [Yamaguchi, Yu] NCI Canc Ctr, Burnham Inst Med Res, Tumor Microenvironm Program, La Jolla, CA USA. [Holzman, Lawrence B.] Univ Michigan, Sch Med, Dept Med, Ann Arbor, MI 48104 USA. [van Kuppevelt, Toin H.; Jenniskens, Guido J.; Wijnhoven, Tessa J.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Biochem, NL-6525 ED Nijmegen, Netherlands. [Wijnhoven, Tessa J.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Pediat Nephrol, NL-6525 ED Nijmegen, Netherlands. [Woods, Ann C.] Univ Alabama, Sch Med, Dept Cell Biol, Birmingham, AL USA. RP McCarthy, KJ (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Pathol, 1501 Kings Highway, Shreveport, LA 71106 USA. EM kmccar2@lsuhsc.edu RI Kuppevelt, A.H.M.S.M./L-4463-2015; OI McCarthy, Kevin/0000-0001-9317-5624 FU NIDDK NIH HHS [1-RO1-DK48055, R01 DK048055, R01 DK077860] NR 35 TC 48 Z9 49 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2008 VL 74 IS 3 BP 289 EP 299 DI 10.1038/ki.2008.159 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 325XU UT WOS:000257622900007 PM 18480751 ER PT J AU Schnermann, J Briggs, JP AF Schnermann, Jurgen Briggs, Josephine P. TI Tubuloglomerular feedback: mechanistic insights from gene-manipulated mice SO KIDNEY INTERNATIONAL LA English DT Review DE NaCl transport; macula densa; Na,K-ATPase; adenosine; ATP; angiotensin II ID MACULA DENSA CELLS; NITRIC-OXIDE SYNTHASE; RECEPTOR-DEFICIENT MICE; THICK ASCENDING LIMB; ANGIOTENSIN-CONVERTING ENZYME; GLOMERULAR-FILTRATION RATE; K-CL COTRANSPORTER; IMMUNOCYTOCHEMICAL LOCALIZATION; ADENOSINE RECEPTORS; NEPHRON FUNCTION AB Tubuloglomerular feedback (TGF) describes a causal and direct relationship between tubular NaCl concentration at the end of the ascending limb of the loop of Henle and afferent arteriolar tone. The use of genetically altered mice has led to an expansion of our understanding of the mechanisms underlying the functional coupling of epithelial, mesangial, and vascular cells in TGF. Studies in mice with deletions of the A or B isoform of NKCC2 (Na,K,2Cl cotransporter) and of ROMK indicate that NaCl uptake is required for response initiation. A role for transcellular salt transport is suggested by the inhibitory effect of ouabain in mutant mice with an ouabain-sensitive alpha 1 Na,K-ATPase. No effect on TGF was observed in NHE2- and H/K-ATPase-deficient mice. TGF responses are abolished in A1 adenosine receptor-deficient mice, and studies in mice with null mutations in NTPDase1 or ecto-5'-nucleotidase indicate that adenosine involved in TGF is mainly derived from dephosphorylation of released ATP. Angiotensin II is a required cofactor for the elicitation of TGF responses, as AT1 receptor or angiotensin-converting enzyme deficiencies reduce TGF responses, mostly by reducing adenosine effectiveness. Overall, the evidence from these studies in genetically altered mice indicates that transcellular NaCl transport induces the generation of adenosine that, in conjunction with angiotensin II, elicits afferent arteriolar constriction. C1 [Schnermann, Jurgen] NIDDK, NIH, Bethesda, MD 20892 USA. [Briggs, Josephine P.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Schnermann, J (reprint author), NIDDK, NIH, 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 FU Howard Hughes Medical Institute; Intramural NIH HHS [Z01 DK043408-08] NR 82 TC 52 Z9 52 U1 0 U2 5 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 AUG PY 2008 VL 74 IS 4 BP 418 EP 426 DI 10.1038/ki.2008.145 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 332ED UT WOS:000258064100008 PM 18418352 ER PT J AU Kataoka, TR Nishizawa, Y AF Kataoka, Tatsuki R. Nishizawa, Yasuko TI Stat4 suppresses the proliferation of connective tissue-type mast cells SO LABORATORY INVESTIGATION LA English DT Article DE IL-6; mast cell; Stat3; Stat4 ID C-KIT; T-CELLS; EXPRESSION; MICE; IL-4; HOMEOSTASIS; INHIBITION; MATURATION; P27(KIP1); RESPONSES AB Mast cells are the progeny of hematopoietic stem cells, and murine mast cells are usually divided into two distinct populations, mucosal mast cells (MMCs) and connective tissue-type mast cells (CTMCs). We previously reported that CTMCs expressed signal transducer and activator of transcription (Stat) 4, but MMCs did not. Stat4 is also expressed in T cells and plays important roles in their homeostasis. In the present study, we show that Stat4 is involved in the homeostasis of CTMCs. The number of skin CTMCs increased in Stat4-deficient Balb/c mice, but that of gastric MMCs did not, when compared to those in control Balb/c(+/+) mice. The comparison between cultured Stat4-deficient CTMCs and cultured Balb/c(+/+) CTMCs revealed that cell cycle progression and cyclin D3 expression in the cultured Stat4-deficient CTMCs were enhanced in a Stat3 activation-dependent manner. This phenotype was explained by upregulation of KitL-induced interleukin (IL)-6 acting in an autocrine manner in cultured Stat4-deficient CTMCs. These results show that Stat4 suppresses the proliferation of CTMCs by controlling IL-6 via an autocrine mechanism. C1 [Kataoka, Tatsuki R.] Osaka Univ, Sch Med, Dept Pathol, Grad Sch Frontier Biosci, Osaka 530, Japan. [Kataoka, Tatsuki R.; Nishizawa, Yasuko] Osaka Med Ctr Canc & Cardiovasc Dis, Res Inst, Dept Pathol, Osaka, Japan. [Nishizawa, Yasuko] Osaka Univ, Grad Sch Pharmaceut Sci, Lab Clin & Expt Pathophysiol, Osaka, Japan. RP Kataoka, TR (reprint author), NIAID, NIH, LAD, Bldg 10,Room 11C206,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM kataokat@niaid.nih.gov NR 33 TC 9 Z9 9 U1 0 U2 0 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 AUG PY 2008 VL 88 IS 8 BP 856 EP 864 DI 10.1038/labinvest.2008.51 PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 329TA UT WOS:000257892300006 PM 18521064 ER PT J AU Bhatti, P Sigurdson, AJ Mabuchi, K AF Bhatti, Parveen Sigurdson, Alice J. Mabuchi, Kiyohiko TI Can low-dose radiation increase risk of cardiovascular disease? SO LANCET LA English DT Editorial Material ID INDUCED GENOMIC INSTABILITY; IONIZING-RADIATION; RADIOTHERAPY; MORTALITY; EXPOSURE; WORKERS C1 [Bhatti, Parveen; Sigurdson, Alice J.; Mabuchi, Kiyohiko] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Mabuchi, K (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM mabuchik@mail.nih.gov NR 10 TC 11 Z9 13 U1 0 U2 1 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 AUG-SEP PY 2008 VL 372 IS 9640 BP 697 EP 699 DI 10.1016/S0140-6736(08)61285-4 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 344YZ UT WOS:000258964500008 PM 18761208 ER PT J AU Simonsen, L Taylor, RJ Viboud, C Miller, MA Jackson, LA AF Simonsen, Lone Taylor, Robert J. Viboud, Cecile Miller, Mark A. Jackson, Lisa A. TI Mortality benefits of influenza vaccination in elderly people - Reply SO LANCET INFECTIOUS DISEASES LA English DT Letter ID RESPONSES; SAFETY C1 [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC 20052 USA. [Taylor, Robert J.] SAGE Analyt LLC, Bethesda, MD USA. [Viboud, Cecile; Miller, Mark A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Jackson, Lisa A.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. RP Simonsen, L (reprint author), George Washington Univ, Dept Global Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC 20052 USA. EM lone@gwu.edu OI Simonsen, Lone/0000-0003-1535-8526 NR 8 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD AUG PY 2008 VL 8 IS 8 BP 463 EP 465 DI 10.1016/S1473-3099(08)70164-6 PG 3 WC Infectious Diseases SC Infectious Diseases GA 331PO UT WOS:000258024800007 ER PT J AU Patel, AK Alexander, TH Andalibi, A Ryan, AF Doherty, JK AF Patel, Andrew K. Alexander, Thomas H. Andalibi, Ali Ryan, Allen F. Doherty, Joni K. TI Vestibular Schwannoma Quantitative Polymerase Chain Reaction Expression of Estrogen and Progesterone Receptors SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT Annual Meeting of the Western Section of the Triological-Society CY JAN 31-FEB 02, 2008 CL Rancho Mirage, CA SP Triol Soc, Western Sect DE Vestibular schwannoma; neurofibromatosis 2; estrogen receptor; progesterone receptor; acoustic-neuroma; pregnancy; ErbB receptor family ID ACOUSTIC NEUROMA; INTRACRANIAL TUMORS; HORMONE RECEPTORS; STEROID-RECEPTORS; PREGNANCY; BRAIN; NEURILEMMOMAS; NEURINOMAS; ERBB AB Objectives/Hypothesis: Determine the role of estrogen receptor (ER) and progesterone receptor (PR) expression in sporadic and neurofibromatosis 2 (NF2)-related vestibular schwannomas (VS). Growth and proliferation signaling in. human VS tumorigenesis may play a key role in molecular therapeutic targeting. VS carry mutations of the NF2 gene encoding the tumor suppressor, merlin, which interacts with ErbB2 in Schwann cells, implicating ErbB receptors in VS tumorigenesis. ErbB receptor family members are over-expressed or constitutively activated in many human tumors, and are effective therapeutic targets in some human cancers. VS occur more frequently in women and are larger, more vascular, and demonstrate increased growth rates during pregnancy. ER and PR may play a role in ErbB pathway activation and VS progression. Study Design: Quantitative real-time polymerase chain reaction (qRT-PCR) for ER and PR messenger RNA was performed using greater auricular and vestibular nerve controls (n = 8), sporadic VS (n = 23), and NF2-related VS (n = 16) tissues. Methods: The qRT-PCR data were normalized with standardization to a single constitutively expressed control gene, human cyclophylin. Results: Reverse transcription of messenger RNA from control and tumor specimens followed by RT Q-PCR demonstrated differences in ER and PR gene expression between sporadic and NF2-related VS. Conclusions: ER and PR expression in VS might have implications for development of a VS-specific drug delivery system using antihormone and ErbB pathway small molecule inhibitors, due to crosstalk between these receptors. These signals may be critical for re-establishing ErbB-mediated cell density dependent growth inhibition. C1 [Patel, Andrew K.; Alexander, Thomas H.; Ryan, Allen F.; Doherty, Joni K.] Univ Calif San Diego, Dept Surg, Div Otolaryngol Head & Neck Surg, Sch Med, La Jolla, CA 92093 USA. [Patel, Andrew K.; Alexander, Thomas H.; Ryan, Allen F.; Doherty, Joni K.] Vet Affairs Med Ctr, La Jolla, CA USA. [Andalibi, Ali] House Ear Res Inst, Los Angeles, CA USA. [Andalibi, Ali] NCI, Washington, DC USA. RP Doherty, JK (reprint author), 200 W Arbor Dr,Mail Code 8895, San Diego, CA 92103 USA. EM jkdoherty@ucsd.edu RI Alexander, Thomas/E-5836-2015 OI Alexander, Thomas/0000-0001-7994-7755 FU BLRD VA [I01 BX001205]; NIDCD NIH HHS [T32 DC000028] NR 32 TC 9 Z9 9 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2008 VL 118 IS 8 BP 1458 EP 1463 DI 10.1097/MLG.0b013e318177e20b PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 368ZP UT WOS:000260662600023 PM 18670322 ER PT J AU Turchi, J Buffalari, D Mishkin, M AF Turchi, Janita Buffalari, Deanne Mishkin, Mortimer TI Double dissociation of pharmacologically induced deficits in visual recognition and visual discrimination learning SO LEARNING & MEMORY LA English DT Article ID STRIATAL CHOLINERGIC INTERNEURONS; SUBSTANTIA-NIGRA; PERIRHINAL CORTEX; DOPAMINE RELEASE; RHINAL CORTEX; MONKEYS; MEMORY; MODULATION; NEURONS; LESIONS AB Monkeys trained in either one-trial recognition at 8- to 10-min delays or multi-trial discrimination habits with 24-h intertrial intervals received systemic cholinergic and dopaminergic antagonists, scopolamine and haloperidol, respectively, in separate sessions. Recognition memory was impaired markedly by scopolamine but not at all by haloperidol, whereas habit formation was impaired markedly by haloperidol but only minimally by scopolamine. These differential drug effects point to differences in synaptic modification induced by the two neuromodulators that parallel the contrasting properties of the two types of learning, namely, fast acquisition but weak retention of memories versus slow acquisition but durable retention of habits. C1 [Turchi, Janita; Mishkin, Mortimer] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Buffalari, Deanne] Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. RP Turchi, J (reprint author), NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. EM turchij@mail.nih.gov FU Intramural NIH HHS NR 29 TC 9 Z9 9 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD AUG PY 2008 VL 15 IS 8 BP 565 EP 568 DI 10.1101/lm.966208 PG 4 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 334VD UT WOS:000258248400002 PM 18685146 ER PT J AU Shearer, J Coenen, KR Pencek, RR Swift, LL Wasserman, DH Rottman, JN AF Shearer, Jane Coenen, Kimberly R. Pencek, R. Richard Swift, Larry L. Wasserman, David H. Rottman, Jeffrey N. TI Long chain fatty acid uptake in vivo: Comparison of [I-125]-BMIPP and [H-3]-bromopalmitate SO LIPIDS LA English DT Article DE tracer; kinetics; thin layer chromatography; uptake; clearance ID GLUCOSE-UPTAKE; BMIPP UPTAKE; MYOCARDIUM; METABOLISM; MUSCLE; CARDIOMYOPATHY; INHIBITION; ISCHEMIA; TRACERS; TISSUES AB Insulin resistance is characterized by increased metabolic uptake of fatty acids. Accordingly, techniques to examine in vivo shifts in fatty acid metabolism are of value in both clinical and experimental settings. Partially metabolizable long chain fatty acid (LCFA) tracers have been recently developed and employed for this purpose: [9,10-H-3]-(R)-2-bromopalmitate ([H-3]-BROMO) and [I-125]-15-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid ([I-125]-BMIPP). These analogues are taken up like native fatty acids, but once inside the cell do not directly enter beta-oxidation. Rather, they become trapped in the slower processes of omega and alpha-oxidation. Study aims were to (1) simultaneously assess and compare [H-3]-BROMO and [I-125]-BMIPP and (2) determine if tracer breakdown is affected by elevated metabolic demands. Catheters were implanted in a carotid artery and jugular vein of Sprague-Dawley rats. Following 5 days recovery, fasted animals (5 h) underwent a rest (n = 8) or exercise (n = 8) (0.6 mi/h) protocol. An instantaneous bolus containing both [H-3]-BROMO and [I-125]-BMIPP was administered to determine LCFA uptake. No significant difference between [I-125]-BMIPP and [H-3]-BROMO uptake was found in cardiac or skeletal muscle during rest or exercise. In liver, rates of uptake were more than doubled with [H-3]-BROMO compared to [I-125]-BMIPP. Analysis of tracer conversion by TLC demonstrated no difference at rest. Exercise resulted in greater metabolism and excretion of tracers with similar to 37% and similar to 53% of [I-125]-BMIPP and [H-3]-BROMO present in conversion products at 40 min. In conclusion, [H-3]-BROMO and [I-125]-BMIPP are indistinguishable for the determination of tissue kinetics at rest in skeletal and cardiac muscle. Exercise preferentially exacerbates the breakdown of [H-3]-BROMO, making [I-125]-BMIPP the analogue of choice for prolonged (> 30 min) experimental protocols with elevated metabolic demands. C1 [Shearer, Jane] Univ Calgary, Dept Kinesiol, Calgary, AB T2N 1N4, Canada. [Shearer, Jane] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB T2N 1N4, Canada. [Shearer, Jane; Coenen, Kimberly R.; Pencek, R. Richard; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Swift, Larry L.] Vanderbilt Univ, Dept Pathol, Nashville, TN 37232 USA. [Rottman, Jeffrey N.] Vanderbilt Univ, Dept Cardiol, Nashville, TN 37232 USA. [Wasserman, David H.; Rottman, Jeffrey N.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. RP Shearer, J (reprint author), Univ Calgary, Dept Kinesiol, 2500 Univ Dr NW, Calgary, AB T2N 1N4, Canada. EM jshearer@ucalgary.ca FU NIDDK NIH HHS [R01 DK054902, U24-DK-59637, DK-54902, U24 DK059637] NR 24 TC 8 Z9 8 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD AUG PY 2008 VL 43 IS 8 BP 703 EP 711 DI 10.1007/s11745-008-3183-4 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 330MR UT WOS:000257946900003 PM 18481132 ER PT J AU Elinoff, J Talmor, D Subramaniam, B Karmpaliotis, D Goldberger, AL Malhotra, A AF Elinoff, Jason Talmor, Daniel Subramaniam, Balachundhar Karmpaliotis, Dimitrios Goldberger, Ary L. Malhotra, Atul TI Effects of mechanical ventilation on the electrocardiogram in adults SO LUNG LA English DT Article DE electrocardiography; positive pressure ventilation; lung; airway; heart ID PULMONARY-DISEASE; P-WAVE; LUNG DISEASE; AXIS; HALOTHANE AB The effects of mechanical ventilation on the surface electrocardiogram (ECG) have not been systematically investigated and the anticipated changes such as rightward P and QRS axes shifts, reduced QRS voltage, and slow R-wave progression are not supported by definitive data. We sought to determine the effects of mechanical ventilation on the surface ECG in hemodynamically stable adults without active cardiopulmonary disease. Seventeen patients in good overall health who were undergoing elective outpatient surgery had serial ECGs done preoperatively, intraoperatively, and postoperatively. No clinically significant changes in QRS or P-wave axis were detected. R-wave progression was not altered and there were no significant differences in the QRS amplitudes pre-, intra-, or postoperatively in either the precordial or limb leads. The present study shows that hemodynamically stable patients without active cardiopulmonary disease undergoing elective surgery demonstrate relatively minor ECG changes from baseline despite the addition of positive pressure ventilation. Clinicians should not assume that substantial changes in P wave or QRS axis or amplitude in patients undergoing mechanical ventilation are due to the effects of positive pressure ventilation alone. C1 [Malhotra, Atul] Brigham & Womens Hosp, Dept Internal Med, Div Pulm, Div Crit Care, Boston, MA 02115 USA. [Malhotra, Atul] Brigham & Womens Hosp, Dept Internal Med, Sleep Div, Boston, MA 02115 USA. [Talmor, Daniel; Subramaniam, Balachundhar; Goldberger, Ary L.; Malhotra, Atul] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Elinoff, Jason] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Talmor, Daniel; Subramaniam, Balachundhar] Beth Israel Deaconess Med Ctr, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02215 USA. [Karmpaliotis, Dimitrios] Piedmont Hosp, Fuqua Heart Ctr, Cardiol Georgia, Atlanta, GA 30309 USA. [Goldberger, Ary L.] Beth Israel Deaconess Med Ctr, Dept Internal Med, Div Cardiol, Boston, MA 02215 USA. [Goldberger, Ary L.] Beth Israel Deaconess Med Ctr, Dept Internal Med, Div Interdisciplinary Med Biotechnol, Boston, MA 02215 USA. RP Malhotra, A (reprint author), Brigham & Womens Hosp, Dept Internal Med, Div Pulm, Div Crit Care, 75 Francis St, Boston, MA 02115 USA. EM elinoffj@cc.nih.gov; dtalmor@bidmc.harvard.edu; bsubrama@bidmc.harvard.edu; dkarmpaliotis@cardioga.com; agoldber@caregroup.harvard.edu; amalhotra1@partners.org FU NHLBI NIH HHS [K24 HL093218, HL060292, R01-HL73146-01, R01 HL085188, R01 HL090897, R01 HL073146, P50 HL060292]; NIA NIH HHS [K23 AG024837, AG024837-01] NR 20 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2040 J9 LUNG JI Lung PD AUG PY 2008 VL 186 IS 4 BP 219 EP 223 DI 10.1007/s00408-008-9094-6 PG 5 WC Respiratory System SC Respiratory System GA 327KB UT WOS:000257726900004 PM 18478291 ER PT J AU Shapiro, EM Koretsky, AP AF Shapiro, Erik M. Koretsky, Alan P. TI Convertible manganese contrast for molecular and cellular MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; manganese; cells; contrast agents; brain ID GENE-EXPRESSION; T-1 CONTRAST; PARTICLES; NANOPARTICLES; MELANIN; BRAIN; AGENT AB We describe here the use of inorganic manganese based particles as convertible MRI agents. As has been demonstrated with iron oxide particles, manganese oxide and manganese carbonate particles can be internalized within phagocytotic cells, being subsequently shuttled to endosomes and/or lysosomes. As intact particles, only susceptibility-induced MRI contrast is exhibited, most often seen as dark contrast in susceptibility-weighted images. Modulation of MRI contrast is accomplished by the selective degradation of these particles within the endosomal and lysosomal compartments of cells. Upon particle deconstruction in the endosomes and lysosomes, the dissolved Mn2+ acts as a T-1 agent, eliciting bright contrast in T-1-weighted images. This modulation of MRI contrast is demonstrated both in vitro in cells in culture, and also in vivo, in rat brain. These particles are the potential building blocks for an entire class of new environmentally responsive MRI contrast agents. C1 [Shapiro, Erik M.] Yale Univ, Magnet Resonance Res Ctr, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Shapiro, EM (reprint author), Yale Univ, Magnet Resonance Res Ctr, Sch Med, Dept Diagnost Radiol, TAC N129,300 Cedar St,POB 208043, New Haven, CT 06510 USA. EM erik.shapiro@yale.edu RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS003047-01]; NINDS NIH HHS [P30 NS052519, P30 NS-52519] NR 17 TC 39 Z9 40 U1 2 U2 19 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 AUG PY 2008 VL 60 IS 2 BP 265 EP 269 DI 10.1002/mrm.21631 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 332TK UT WOS:000258105800004 PM 18666118 ER PT J AU Sarlls, JE Pierpaoli, C AF Sarlls, Joelle E. Pierpaoli, Carlo TI Diffusion-weighted radial fast spin-echo for high-resolution diffusion tensor imaging at 3T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE DTI; FSE; RARE; CPMG; MRI; human; brain ID HUMAN BRAIN; MRI; TISSUES; MOTION; EPI AB There is a need for an imaging sequence that can provide high-resolution diffusion tensor images at 3T near air-tissue interfaces. By employing a radial fast spin-echo (FSE) collection in conjunction with magnitude filtered back-projection reconstruction, high-resolution diffusion-weighted images can be produced without susceptibility artifacts. However, violation of the Carr-Purcell-Melboom-Gill (CPMG) condition of diffusion prepared magnetization is a prominent problem for FSE trains that is magnified at higher fields. The unique aspect of violating the CPMG condition in trajectories that oversample the center of k-space and the implications for choosing the solution are examined. For collecting diffusion-weighted radial-FSE data at 3T we propose mixed-CPMG phase cycling of RF refocusing pulses combined with a 300% wider refocusing than excitation slice. It is shown that this approach produces accurate diffusion values in a phantom, and can be used to collect undistorted, high-resolution diffusion tensor images of the human brain. C1 [Sarlls, Joelle E.; Pierpaoli, Carlo] NICHHD, NIH, Bethesda, MD 20892 USA. RP Sarlls, JE (reprint author), NICHHD, NIH, Bldg 13,Room 3W16,13 S Dr, Bethesda, MD 20892 USA. EM sarllsjo@mail.nih.gov RI Pierpaoli, Carlo/E-1672-2011 FU Intramural NIH HHS [Z99 NS999999] NR 26 TC 8 Z9 8 U1 1 U2 3 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 AUG PY 2008 VL 60 IS 2 BP 270 EP 276 DI 10.1002/mrm.21639 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 332TK UT WOS:000258105800005 PM 18666119 ER PT J AU Lin, AL Fox, PT Yang, YH Lu, HZ Tan, LH Gao, JH AF Lin, Ai-Ling Fox, Peter T. Yang, Yihong Lu, Hanzhang Tan, Li-Hai Gao, Jia-Hong TI Evaluation of MRI models in the measurement of CMRO2 and its relationship with CBF SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; PET; cerebral metabolism; cerebral blood flow ID CEREBRAL-BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; CALIBRATED FUNCTIONAL MRI; VASCULAR-SPACE-OCCUPANCY; HUMAN VISUAL-CORTEX; QUANTITATIVE ASSESSMENT; OXIDATIVE-METABOLISM; OXYGEN-METABOLISM; BRAIN ACTIVATION; NEURAL ACTIVITY AB The aim of this study was to investigate the various MRI biophysical models in the measurements of local cerebral metabolic rate of oxygen (CMRO2) and the corresponding relationship with cerebral blood flow (CBF) during brain activation. This aim was addressed by simultaneously measuring the relative changes in CBF, cerebral blood volume (CBV), and blood oxygen level dependent (BOLD) MRI signals in the human visual cortex during visual stimulation. A radial checkerboard delivered flash stimulation at five different frequencies. Two MRI models, the single-compartment model (SCM) and the multi-compartment model (MCM), were used to determine the relative changes in CMRO2 using three methods: [1] SCM with parameters identical to those used in a prior MRI study (M = 0.22; alpha = 0.38); [2] SCM with directly measured parameters (M from hypercapnia and alpha from measured delta CBV and delta CBF); and [3] MCM. The magnitude of relative changes in CMRO2 and the nonlinear relationship between CBF and CMRO2 obtained with Methods [2] and [3] were not in agreement with those obtained using Method [1]. However, the results of Methods [2] and [3] were aligned with positron emission tomography findings from the literature. Our results indicate that if appropriate parameters are used, the SCM and MCM models are equivalent for quantifying the values of CMRO2 and determining the flow-metabolism relationship. C1 [Lin, Ai-Ling; Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, San Antonio, TX 78229 USA. [Yang, Yihong] Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, Baltimore, MD USA. [Lu, Hanzhang] Univ Texas SW Med Ctr Dallas, Adv Imaging Res Ctr, Dallas, TX 75390 USA. [Tan, Li-Hai] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China. [Gao, Jia-Hong] Univ Chicago, Brain Res Imaging Ctr, Chicago, IL 60637 USA. [Gao, Jia-Hong] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. RP Gao, JH (reprint author), Univ Chicago, Dept Radiol, 5841 S Maryland,MC 2026, Chicago, IL 60637 USA. EM jgao@uchicago.edu RI Lin, Ai-Ling/F-3972-2010; Fox, Peter/B-4725-2010 OI Fox, Peter/0000-0002-0465-2028 FU Intramural NIH HHS [Z99 DA999999]; NCRR NIH HHS [S10-RR17198]; NIBIB NIH HHS [R01 EB004753] NR 40 TC 43 Z9 43 U1 0 U2 9 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 AUG PY 2008 VL 60 IS 2 BP 380 EP 389 DI 10.1002/mrm.21655 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 332TK UT WOS:000258105800018 PM 18666102 ER PT J AU Chang, LC Koay, CG Basser, PJ Pierpaoli, C AF Chang, Lin-Ching Koay, Cheng Guan Basser, Peter J. Pierpaoli, Carlo TI Linear least-squares method for unbiased estimation of T-1 from SPGR signals SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T-1 estimation; linear model; accuracy; uncertainties; SPGR signals ID HIGH-RESOLUTION T-1; RELAXATION-TIMES; SPIN-LATTICE; FLIP ANGLES; T1; BRAIN; QUANTIFICATION; ACCURATE; NMR; T2 AB The longitudinal relaxation time, T-1, can be estimated from two or more spoiled gradient recalled echo images (SPGR) acquired with different flip angles and/or repetition times (TRs). The function relating signal intensity to flip angle and TR is nonlinear; however, a linear form proposed 30 years ago is currently widely used. Here we show that this linear method provides T-1 estimates that have similar precision but lower accuracy than those obtained with a nonlinear method. We also show that T-1 estimated by the linear method is biased due to improper accounting for noise in the fitting. This bias can be significant for clinical SPGR images; for example, T-1 estimated in brain tissue (800 ms < T-1 < 1600 ms) can be overestimated by 10% to 20%. We propose a weighting scheme that correctly accounts for the noise contribution in the fitting procedure. Monte Carlo simulations of SPGR experiments are used to evaluate the accuracy of the estimated T-1 from the widely-used linear, the proposed weighted-uncertainty linear, and the nonlinear methods. We show that the linear method with weighted uncertainties reduces the bias of the linear method, providing T-1 estimates comparable in precision and accuracy to those of the nonlinear method while reducing computation time significantly. C1 [Chang, Lin-Ching] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. [Chang, Lin-Ching; Koay, Cheng Guan; Basser, Peter J.; Pierpaoli, Carlo] NICHHD, NIH, Bethesda, MD 20892 USA. RP Chang, LC (reprint author), Catholic Univ Amer, Dept Elect Engn & Comp Sci, 620 Michigan Ave NE, Washington, DC 20064 USA. EM changl@cua.edu RI Pierpaoli, Carlo/E-1672-2011; Basser, Peter/H-5477-2011 FU Intramural NIH HHS [ZIA HD000267-13] NR 26 TC 20 Z9 20 U1 0 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 AUG PY 2008 VL 60 IS 2 BP 496 EP 501 DI 10.1002/mrm.21669 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 332TK UT WOS:000258105800034 PM 18666108 ER PT J AU Linguraru, MG Vasilyev, NV Marx, GR Tworetzky, W Del Nido, PJ Howe, RD AF Linguraru, Marius George Vasilyev, Nikolay V. Marx, Gerald R. Tworetzky, Wayne Del Nido, Pedro J. Howe, Robert D. TI Fast block flow tracking of atrial septal defects in 4D echocardiography SO MEDICAL IMAGE ANALYSIS LA English DT Article DE real-time ultrasound; echocardiography; atrial septal defect; tracking; mutual information; block matching; optical flow; block flow ID BEATING-HEART-SURGERY; ULTRASOUND IMAGES; CARDIOPULMONARY BYPASS; SPECKLE TRACKING; MOTION TRACKING; SEGMENTATION; CLOSURE; REGISTRATION; VELOCITY; MODEL AB We are working to develop beating-heart atrial septal defect (ASD) closure techniques using real-time 3D ultrasound guidance. The major image processing challenges are the low-image quality and the processing of information at high-frame rate. This paper presents comparative results for ASD tracking in time sequences of 3D volumes of cardiac ultrasound. We introduce a block flow technique, which combines the velocity computation from optical flow for an entire block with template matching. Enforcing adapted similarity constraints to both the previous and first frames ensures optimal and unique solutions. We compare the performance of the proposed A algorithm with that of block matching and region-based optical flow on eight in vivo 4D datasets acquired from porcine beating-heart procedures. Results show that our technique is more stable and has higher sensitivity than both optical flow and block matching in tracking ASDs. Computing velocity at the block level, our technique tracks ASD motion at 2 frames/s, much faster than optical flow and comparable in computation cost to block matching, and shows promise for real-time (30 frames/s). We report consistent results on clinical intra-operative images and retrieve the cardiac cycle (in ungated images) from error analysis. Quantitative results are evaluated on synthetic data with maximum tracking errors of 1 voxel. (C) 2008 Elsevier B.V. All rights reserved. C1 [Linguraru, Marius George; Howe, Robert D.] Harvard Univ, Div Engn & Appl Sci, Cambridge, MA 02138 USA. [Vasilyev, Nikolay V.; Del Nido, Pedro J.] Harvard Univ, Sch Med, Dept Cardiac Surg, Boston, MA USA. [Marx, Gerald R.; Tworetzky, Wayne] Harvard Univ, Sch Med, Childrens Hosp, Dept Cardiol, Boston, MA USA. RP Linguraru, MG (reprint author), NIH, Dept Diagnost Radiol, Bldg 10, Bethesda, MD 20892 USA. EM lingurarum@mail.nih.gov FU NHLBI NIH HHS [R01 HL073647, R01 HL073647-01] NR 38 TC 13 Z9 14 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD AUG PY 2008 VL 12 IS 4 BP 397 EP 412 DI 10.1016/j.media.2007.12.005 PG 16 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 336CX UT WOS:000258343000002 PM 18282783 ER PT J AU Hendee, W Cleary, K Ehman, R Fullerton, G Grundfest, W Haller, J Kelley, C Meyer, A Murphy, RF Phillips, W Torchilin, V AF Hendee, William Cleary, Kevin Ehman, Richard Fullerton, Gary Grundfest, Warren Haller, John Kelley, Christine Meyer, Anne Murphy, Robert F. Phillips, William Torchilin, Vladimir TI Bioengineering and Imaging Research Opportunities Workshop V: A white paper on imaging and characterizing structure and function in native and engineered tissues SO MEDICAL PHYSICS LA English DT Article DE tissue engineering; functional; molecular and structural imaging; imaging of engineered tissues; targeted cell; gene and drug delivery; single-cell measurements; emerging imaging technologies ID MAGNETIC-RESONANCE ELASTOGRAPHY; CANCER-THERAPY; MICROSCOPY; RECOMMENDATIONS; VISUALIZATION; SYSTEMS AB The fifth Bioengineering and Image Research Opportunities Workshop (BIROW V) was held on January 18-19, 2008. As with previous BIROW meetings, the purpose of BIROW V was to identify and characterize research and engineering opportunities in biomedical engineering and imaging. The topic of this BIROW meeting was Imaging and Characterizing Structure and Function in Native and Engineered Tissues. Under this topic, four areas were explored in depth: (1) Heterogeneous single-cell measurements and their integration into tissue and organism models; (2) Functional, molecular and structural imaging of engineered tissue in vitro and in vivo; (3) New technologies for characterizing cells and tissues in situ; (4) Imaging for targeted cell, gene and drug delivery. (c) 2008 American Association of Physicists in Medicine. C1 [Hendee, William] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Cleary, Kevin] Georgetown Univ, Washington, DC 20007 USA. [Ehman, Richard] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA. [Fullerton, Gary] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Grundfest, Warren] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Haller, John] NIBIB, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kelley, Christine] NIBIB, Div Discovery Sci & Technol, NIH, DHHS, Bethesda, MD 20892 USA. [Meyer, Anne] SUNY Buffalo, Buffalo, NY 14214 USA. [Murphy, Robert F.] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Phillips, William] Univ Texas San Antonio, Med Ctr, Dept Radiol, Res Div MSC 7800, San Antonio, TX 78229 USA. [Torchilin, Vladimir] Northeastern Univ, Dept Pharm & Sci, Boston, MA 02115 USA. RP Hendee, W (reprint author), Med Coll Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM whendee@mcw.edu RI Phillips, William/E-8427-2010 OI Phillips, William/0000-0001-8248-7817 NR 26 TC 1 Z9 1 U1 0 U2 2 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 AUG PY 2008 VL 35 IS 8 BP 3428 EP 3435 DI 10.1118/1.2948317 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 331UU UT WOS:000258038900003 PM 18777902 ER PT J AU Li, J Van Uitert, R Yao, JH Petrick, N Franaszek, M Huang, A Summers, RM AF Li, Jiang Van Uitert, Robert Yao, Jianhua Petrick, Nicholas Franaszek, Marek Huang, Adam Summers, Ronald M. TI Wavelet method for CT colonography computer-aided polyp detection SO MEDICAL PHYSICS LA English DT Article; Proceedings Paper CT 3rd IEEE International Symposium on Biomedical Imaging CY APR 06-09, 2006 CL Arlington, VA SP IEEE DE CT colonography; CAD; false positive reduction; wavelet; SVM committee ID TOMOGRAPHIC VIRTUAL COLONOSCOPY; COLONIC POLYPS; FALSE POSITIVES; CLASSIFICATION; NETWORK; REDUCTION; ALGORITHM; DIAGNOSIS; SELECTION; SEGMENTATION AB Computed tomographic colonography (CTC) computer aided detection (CAD) is a new method to detect colon polyps. Colonic polyps are abnormal growths that may become cancerous. Detection and removal of colonic polyps, particularly larger ones, has been shown to reduce the incidence of colorectal cancer. While high sensitivities and low false positive rates are consistently achieved for the detection of polyps sized 1 cm or larger, lower sensitivities and higher false positive rates occur when the goal of CAD is to identify "medium"-sized polyps, 6-9 mm in diameter. Such medium-sized polyps may be important for clinical patient management. We have developed a wavelet-based postprocessor to reduce false positives for this polyp size range. We applied the wavelet-based postprocessor to CTC CAD findings from 44 patients in whom 45 polyps with sizes of 6-9 mm were found at segmentally unblinded optical colonoscopy and visible on retrospective review of the CT colonography images. Prior to the application of the wavelet-based postprocessor, the CTC CAD system detected 33 of the polyps (sensitivity 73.33%) with 12.4 false positives per patient, a sensitivity comparable to that of expert radiologists. Fourfold cross validation with 5000 bootstraps showed that the wavelet-based postprocessor could reduce the false positives by 56.61% (p < 0.001), to 5.38 per patient (95% confidence interval [4.41, 6.34]), without significant sensitivity degradation (32/45, 71.11%, 95% confidence interval [66.39%, 75.74%], p=0.1713). We conclude that this wavelet-based postprocessor can substantially reduce the false positive rate of our CTC CAD for this important polyp size range. C1 [Li, Jiang; Van Uitert, Robert; Yao, Jianhua; Franaszek, Marek; Huang, Adam; Summers, Ronald M.] Natl Inst Hlth, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Petrick, Nicholas] NIBIB, Ctr Devices & Radiol Hlth, Joint Lab Assessment Med Imaging Syst, US FDA, Silver Spring, MD 20993 USA. RP Li, J (reprint author), Natl Inst Hlth, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. EM lijiang_ts@yahoo.com FU Intramural NIH HHS NR 58 TC 13 Z9 14 U1 1 U2 3 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 AUG PY 2008 VL 35 IS 8 BP 3527 EP 3538 DI 10.1118/1.2938517 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 331UU UT WOS:000258038900014 PM 18777913 ER PT J AU Wagner, EMA Jen, KLC Artiss, JD Remaley, AT AF Wagner, Elke Mani A. Jen, Kai-Lin Cathenine Artiss, Joseph Donald Remaley, Alan Thomas TI Dietary alpha-cyclodextrin lowers low-density lipoprotein cholesterol and alters plasma fatty acid profile in low-density lipoprotein receptor knockout mice on a high-fat diet SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID AORTIC ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; TRANSGENIC MICE; LDL RECEPTOR; HYPERCHOLESTEROLEMIA; INFLAMMATION; METAANALYSIS; EXCRETION; OBESITY; LIPIDS AB High dietary intake of saturated fat and cholesterol, and elevated low-density lipoprotein cholesterol levels are some of the modifiable risk factors for cardiovascular disease. alpha-Cyclodextrin (a-CD) when given orally has been shown in rats to increase fecal saturated fat excretion and to reduce blood total cholesterol levels in obese hypertriglyceridemic subjects with type 2 diabetes mellitus. In this study, the effects of dietary a-CD on lipid metabolism in low-density lipoprotein receptor knockout mice were investigated. Low-density lipoprotein receptor knockout mice were fed a "Western diet" (21% milk fat) with or without 2.1% of a-CD (10% of dietary fat content) for 14 weeks. At sacrifice. there was no difference in body weight; but significant decreases were observed in plasma cholesterol (15.3%), free cholesterol (20%), cholesterol esters (14%), and phospholipid (17.5%) levels in mice treated with alpha-CD compared with control mice. The decrease in total cholesterol was primarily in the proatherogenic apolipoprotein B-containing lipoprotein fractions, with no significant change in the high-density lipoprotein fraction. Furthermore, alpha-CD improved the blood fatty acid profile, reducing the saturated fatty acids (4.5%) and trans-isomers (11%) while increasing (2.5%) unsaturated fatty acids. In summary, the addition of alpha-CD improved the lipid profile by lowering proatherogenic lipoproteins and trans-fatty acids and by decreasing the ratio of saturated and trans-fatty acids to polyunsaturated fatty acids (-5.8%), thus suggesting that it may be useful as a dietary supplement for reducing cardiovascular disease. Published by Elsevier Inc. C1 [Remaley, Alan Thomas] NHLBI, NIH, Lipid Metab Sect, Dept Lab Med, Bethesda, MD 20892 USA. [Jen, Kai-Lin Cathenine; Artiss, Joseph Donald] ArtJen Complexus Holdings Corp, Windsor, ON N9A 6V, Canada. [Jen, Kai-Lin Cathenine] Wayne State Univ, Dept Nutr & Food Sci, Detroit, MI 48202 USA. [Artiss, Joseph Donald] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. RP Remaley, AT (reprint author), NHLBI, NIH, Lipid Metab Sect, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. EM aremaley@nih.gov FU Intramural NIH HHS [Z01 HL002058-12] NR 28 TC 14 Z9 14 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2008 VL 57 IS 8 BP 1046 EP 1051 DI 10.1016/j.metabol.2008.02.020 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334BC UT WOS:000258196300005 PM 18640380 ER PT J AU Jacobowitz, DM Jozwik, C Fukuda, T Pollard, HB AF Jacobowitz, David M. Jozwik, Catherine Fukuda, Takemi Pollard, Harvey B. TI Immunohistochemical localization of Phosphoglycerate mutase in capillary endothelium of the brain and periphery SO MICROVASCULAR RESEARCH LA English DT Article DE phosphoglycerate mutase; capillaries; endothelium; immunocytochemistry ID POLYACRYLAMIDE GELS; RAT-BRAIN; 2,3-BISPHOSPHOGLYCERATE PHOSPHATASE; ENOLASE ACTIVITY; CREATINE-KINASE; PROTEINS; CARCINOMA; ISOENZYMES; ELECTROPHORESIS; IDENTIFICATION AB To elucidate the cellular localization of Phosphoglycerate mutase (PGAM1) type B in the brain and periphery, immunocytochemical studies were performed. The purified antigen used to generate the antiserum to PGAM1 was run on an SDS-PAGE gel, stained with coomassie blue, which yielded one sharp band at 29 kDa. Immunocytochemistry of formalin perfused rats revealed distinct localization of PGAM1 in the endothelium of the capillaries and arteries of the brain, liver and kidneys. Since enhanced glycogenesis is a well-known characteristic of cancer cells, it is of interest that sustained angiogenesis is a hallmark that distinguishes cancer cells from their normal counterparts. In view of the fact that PGAM1 increases in a variety of tumors, we suggest that PGAM1 may have a pathological role of vascular invasion into cancerous tissue. Published by Elsevier Inc. C1 [Jacobowitz, David M.; Jozwik, Catherine; Pollard, Harvey B.] Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Jacobowitz, David M.; Fukuda, Takemi] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Jacobowitz, DM (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM djacobowitz@usuhs.mil FU National Institute of Mental Health [Z0-1-MH-00388-31]; National Institutes of Health [N01-HV28187] FX This work was supported by the National Institute of Mental Health [Grant Z0-1-MH-00388-31 (to DMJ) and National Institutes of Health Grant N01-HV28187 (to HBP)]. NR 25 TC 6 Z9 6 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 0026-2862 EI 1095-9319 J9 MICROVASC RES JI Microvasc. Res. PD AUG PY 2008 VL 76 IS 2 BP 89 EP 93 DI 10.1016/j.mvr.2008.04.001 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 347JC UT WOS:000259135500003 PM 18533197 ER PT J AU Keiser, PB Coulibaly, Y Kubofcik, J Diallo, AA Klion, AD Traore, SF Nutman, TB AF Keiser, Paul B. Coulibaly, Yaya Kubofcik, Joseph Diallo, Abdallah A. Klion, Amy D. Traore, Sekou F. Nutman, Thomas B. TI Molecular identification of Wolbachia from the filarial nematode Mansonella perstans SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Wolbachia; endosymbiont; Mansonella; ribosomal ID MULTIPLE SEQUENCE ALIGNMENT; WUCHERERIA-BANCROFTI; ONCHOCERCA-VOLVULUS; POSTTREATMENT REACTIONS; DOUBLE-BLIND; PATHOGENESIS; DOXYCYCLINE; BACTERIA; ENDOSYMBIONTS; ENDOBACTERIA AB Wolbachiae are bacterial endosymbionts of insects and many filarial nematodes whose products trigger inflammation in filarial infections. The dependence of the parasites on their endosymbionts has also led to the use of antibiotics directed against the Wolbachiae, therapy that has been demonstrated to have a profound salutary effect on filarial infections. The identification of Wolbachiae in Mansonella species has been conclusively shown for Mansonella ozzardi (Mo), but not for Mansonella perstans (Mp). Using primers known to amplify the 16S ribosomal DNA of other filarial Wolbachiae, an identical 1393 bp band was found in all samples tested. Sequence analysis of these samples demonstrated a single consensus sequence for Mp Wolbachia 16S rDNA that was most similar to Wolbachia sequences from other filarial nematodes. When aligned with the only other Mansonella Wolbachia sequence (Mo) there were only 8 nucleotide differences in the 1369 bp overlapping sequence. Phylogenetic dendrograms, examining the relationship of the Mp Wolbachia to other Wolbachia 16S rDNA, showed that the Wolbachia tracked almost identically to the 5S rRNA of their parasite host. Wolbachia surface protein (WSP) was also demonstrated in protein extracted from Mp-containing whole blood. In advance of a treatment trial of Mp, a method for the quantitation of Mp Wolbachia was developed and used to demonstrate not only a relationship between microfilarial numbers and Wolbachia copy numbers, but also to demonstrate the effect of antibiotic on ridding Mp of Wolbachia. Published by Elsevier B.V. C1 [Keiser, Paul B.; Kubofcik, Joseph; Klion, Amy D.; Nutman, Thomas B.] NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Coulibaly, Yaya; Diallo, Abdallah A.; Traore, Sekou F.] Univ Bamako, Fac Med Pharm & Dent, Entomol Unit, Bamako, Mali. RP Nutman, TB (reprint author), NIAID, NIH, Parasit Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Intramural NIH HHS [Z01 AI000512-20] NR 30 TC 23 Z9 24 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD AUG PY 2008 VL 160 IS 2 BP 123 EP 128 DI 10.1016/j.molbiopara.2008.04.012 PG 6 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 329ES UT WOS:000257850300007 PM 18538871 ER PT J AU Ellwanger, K Saito, H Clement-Lacroix, P Maltry, N Niedermeyer, J Lee, WK Baron, R Rawadi, G Westphal, H Niehrs, C AF Ellwanger, Kristina Saito, Hiroaki Clement-Lacroix, Philippe Maltry, Nicole Niedermeyer, Joachim Lee, Woon Kyu Baron, Roland Rawadi, Georges Westphal, Heiner Niehrs, Christof TI Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID APICAL ECTODERMAL RIDGE; RECEPTOR-RELATED PROTEIN-5; WNT/BETA-CATENIN; SIGNALING PATHWAY; MOUSE; LRP6; EXPRESSION; MASS; DKK1; MUTANT AB Kremen1 and Kremen2 (Krm1 and Krm2) are transmembrane coreceptors for Dickkopf1 (Dkk1), an antagonist of Wnt/beta-catenin signaling. The physiological relevance of Kremen proteins in mammals as Writ modulators is unresolved. We generated and characterized Krm mutant mice and found that double mutants show enhanced Wnt signaling accompanied by ectopic postaxial forelimb digits and expanded apical ectodermal ridges. Triple mutant Krm1(-/-) Krm2(-1-) Dkk1(-/-) mice show enhanced growth of ectopic digits, indicating that Dkk1 and Krm genes genetically interact during limb development. Wnt/beta-catenin signaling also plays a critical role in bone formation. Single Krm mutants show normal bone formation and bone mass, while double mutants show increased bone volume and bone formation parameters. Our study provides the first genetic evidence for a functional interaction of Kremen proteins with Dkk1 as negative regulators of Wnt/beta-catenin signaling and reveals that Kremen proteins are not universally required for Dkk1 function. C1 [Ellwanger, Kristina; Maltry, Nicole; Niedermeyer, Joachim; Niehrs, Christof] Deutsch Krebsforschungszentrum, Div Mol Embryol, DKFZ ZMBH Alliance, D-69120 Heidelberg, Germany. [Saito, Hiroaki; Baron, Roland] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Saito, Hiroaki; Baron, Roland] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Clement-Lacroix, Philippe; Rawadi, Georges] Galapagos Co, Romainville, France. [Lee, Woon Kyu; Westphal, Heiner] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Niehrs, C (reprint author), Deutsch Krebsforschungszentrum, Div Mol Embryol, DKFZ ZMBH Alliance, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM niehrs@dkfz.de FU Intramural NIH HHS NR 50 TC 63 Z9 66 U1 0 U2 4 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 AUG PY 2008 VL 28 IS 15 BP 4875 EP 4882 DI 10.1128/MCB.00222-08 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 336GP UT WOS:000258352600020 PM 18505822 ER PT J AU Liu, P Qian, L Sung, JS de Souza-Pinto, NC Zheng, L Bogenhagen, DF Bohr, VA Wilson, DM Shen, B Dernple, B AF Liu, Pingfang Qian, Limin Sung, Jung-Suk de Souza-Pinto, Nadja C. Zheng, Li Bogenhagen, Daniel F. Bohr, Vilhelm A. Wilson, David M., III Shen, Binghui Dernple, Bruce TI Removal of oxidative DNA damage via FEN1-dependent long-patch base excision repair in human cell mitochondria SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POLYMERASE-GAMMA; MAMMALIAN MITOCHONDRIA; HUMAN BRAIN; REPLICATION; 2-DEOXYRIBONOLACTONE; ENDONUCLEASE; MUTATIONS; DISEASE; MICE; FEN1 AB Repair of oxidative DNA damage in mitochondria was thought limited to short-patch base excision repair (SP-BER) replacing a single nucleotide. However, certain oxidative lesions cannot be processed by SP-BER. Here we report that 2-deoxyribonolactone (dL), a major type of oxidized abasic site, inhibits replication by mitochondrial DNA (mtDNA) polymerase gamma and interferes with SP-BER by covalently trapping polymerase gamma during attempted dL excision. However, repair of dL was detected in human mitochondrial extracts, and we show that this repair is via long-patch BER (LP-BER) dependent on flap endonuclease I (FEN1), not previously known to be present in mitochondria. FEN1 was retained in protease-treated mitochondria and detected in mitochondriall nucleoids that contain known mitochondrial replication and transcription proteins. Results of immunofluorescence and subcellullar fractionation studies were also consistent with the presence of FEN1 in the mitochondria of intact cells. Immunodepletion experiments showed that the LP-BER activity of mitochondriall extracts was strongly diminished in parallel with the removal of FEN1, although some activity remained, suggesting the presence of an additional flap-removing enzyme. Biological evidence for a FEN1 role in repairing mitochondrial oxidative DNA damage was provided by RNA interference experiments, with the extent of damage greater and the recovery slower in FEN1-depleted cells than in control cells. The mitochondrial LP-BER pathway likely plays important roles in repairing dL lesions and other oxidative lesions and perhaps in normal mtDNA replication. C1 [Qian, Limin; Zheng, Li; Shen, Binghui] City Hope Natl Med Ctr, Dept Radiat Biol, Duarte, CA 91010 USA. [Qian, Limin; Zheng, Li; Shen, Binghui] Beckman Res Inst, Duarte, CA 91010 USA. [Liu, Pingfang; Dernple, Bruce] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Sung, Jung-Suk] Dongguk Univ, Dept Biol, Seoul 100715, South Korea. [de Souza-Pinto, Nadja C.; Bohr, Vilhelm A.; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Bogenhagen, Daniel F.] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. RP Shen, B (reprint author), City Hope Natl Med Ctr, Dept Radiat Biol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM bshen@coh.org; bdemple@hsph.harvard.edu RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X FU Intramural NIH HHS; NCI NIH HHS [R01 CA073764, R01CA073764, T32 CA009078, T32 CA09078]; NIGMS NIH HHS [R01 GM029681, R01 GM040000, R01GM029681, R01GM040000]; PHS HHS [5U19-A1067751-2] NR 62 TC 116 Z9 119 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2008 VL 28 IS 16 BP 4975 EP 4987 DI 10.1128/MCB.00457-08 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 334AR UT WOS:000258195200006 PM 18541666 ER PT J AU Galimov, AR Kruglov, AA Bolsheva, NL Yurkevich, OY Liepinsh, DJ Mufazalov, IA Kuprash, DV Nedospasov, SA AF Galimov, A. R. Kruglov, A. A. Bolsheva, N. L. Yurkevich, O. Yu. Liepinsh, D. Ja. Mufazalov, I. A. Kuprash, D. V. Nedospasov, S. A. TI Chromosomal localization and molecular organization of the human genomic fragment containing the TNF/LT locus in transgenic mice SO MOLECULAR BIOLOGY LA English DT Article DE TNF; LT alpha; human transgene ID TUMOR-NECROSIS-FACTOR; MAJOR HISTOCOMPATIBILITY COMPLEX; RHEUMATOID-ARTHRITIS; LYMPHOTOXIN-BETA; FACTOR-ALPHA; GENES; MOUSE; SERUM; LIPOPOLYSACCHARIDE; APOPTOSIS AB The molecular organization, copy number, and chromosome location of the human TNF/LT transgenes were studied in the genomes of two transgenic mouse strains. One strain proved to carry two transgene copies arranged head-to-tail and detected on chromosome 8 by karyotyping. The other strain had one transgene copy observed on chromosome 5. The strains provide a model for studying the physiological functions of the tumor necrosis factor and lymphotoxin. C1 [Galimov, A. R.; Kruglov, A. A.; Bolsheva, N. L.; Yurkevich, O. Yu.; Mufazalov, I. A.; Kuprash, D. V.; Nedospasov, S. A.] Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia. [Galimov, A. R.; Kruglov, A. A.; Mufazalov, I. A.] Moscow MV Lomonosov State Univ, Fac Bioengn & Bioinformat, Moscow 119899, Russia. [Liepinsh, D. Ja.] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Nedospasov, S. A.] Moscow MV Lomonosov State Univ, Belozersky Inst Physicochem Biol, Moscow 199992, Russia. RP Galimov, AR (reprint author), Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia. EM urrsus@gmail.com RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016 OI Kuprash, Dmitry/0000-0002-1488-4148; FU Presidium of the Russian Academy of Sciences; Howard Hughes Medical Institute; Russian Foundation for Basic Research [07-04-12208-ofi, 08-0800391] FX We are grateful to T. Spies for cosmid 031A and to D. Pen'kov and R. Kazaryan for help in experiments. This work was supported by the program "Molecular and Cell Biology" of the Presidium of the Russian Academy of Sciences, the Howard Hughes Medical Institute, and the Russian Foundation for Basic Research (project nos. 07-04-12208-ofi and 08-0800391). NR 30 TC 0 Z9 0 U1 0 U2 0 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 J9 MOL BIOL+ JI Mol. Biol. PD AUG PY 2008 VL 42 IS 4 BP 558 EP 566 DI 10.1134/S0026893308040110 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337AQ UT WOS:000258408300011 ER PT J AU Chae, JI Ju, SK Lee, MK Park, JH Shim, JH Lee, KK Lee, DS AF Chae, J. I. Ju, S. K. Lee, M. K. Park, J. H. Shim, J. H. Lee, K. K. Lee, D. S. TI Cloning of rat TARC cDNA and analysis of tissue-specific mRNA expression SO MOLECULAR BIOLOGY LA English DT Article DE chemokine; TARC; CCR4; immunological regulation; molecular immunoligy ID ACTIVATION-REGULATED CHEMOKINE; MOLECULAR-CLONING; T-CELLS; ATOPIC-DERMATITIS; RECEPTOR CCR4; CUTTING EDGE; THYMUS AB Thymus-and activation-regulated chemokine (TARC) is one that selectively controls the migration of type 2-helper T lymphocytes into inflammatory lesions. TARC is a CC chemokine and plays an essential role in recruiting CC chemokine receptor 4-positive Th2 cells to allergic lesions. We cloned TARC cDNA from rat thymus using RT-PCR. The rat TARC clone contained a full-length open reading frame encoding 93 amino acids that showed 83 and 66% homology with mouse and human homologs, respectively. The expression of TARC mRNA was mainly in the lymphoid organs, for example, the thymus, spleen, and lymph node. The recombinant TARC was expressed in Escherichia coli and purified in an active form. In addition, the purified rat TARC with S-tagged specifically binds to human CCR4 in CD4/CCR4-transfected HOS cells by cell-binding assay using flow cytometry. The TARC cDNA clones obtained in this study will be valuable for future studies on allergic diseases in rats. C1 [Chae, J. I.; Lee, K. K.] Korea Res Inst Biosci & Biotechnol, Ctr Regenerat Med, Taejon 305333, South Korea. [Ju, S. K.; Lee, M. K.] Korea Res Inst Biosci & Biotechnol, Omics & Integrat Res Ctr, Taejon 305333, South Korea. [Park, J. H.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Shim, J. H.] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lee, D. S.] Kangwon Natl Univ, Coll Anim Resource Sci, Chunchon 200701, South Korea. [Lee, D. S.] Kyungpook Natl Univ, Coll Nat Sci, Sch Life Sci & Biotechnol, Taegu 702701, South Korea. RP Chae, JI (reprint author), Korea Res Inst Biosci & Biotechnol, Ctr Regenerat Med, Taejon 305333, South Korea. EM lee1@knu.ac.kr FU Rural Development Administration [20070401034015, F104AD010004-06A0401-00410]; Kangwon National University, Republic of Korea FX This work was supported by a grant (Code no. 20070401034015) from the BioGreen 21 program and the KBRDG Initiative Research Program (F104AD010004-06A0401-00410), Rural Development Administration, and 2007 Research Grant from Kangwon National University, Republic of Korea. We also thank the supply of the rat from the Institute of Animal Resources, Kangwon National University, Republic of Korea. NR 19 TC 0 Z9 0 U1 1 U2 4 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 J9 MOL BIOL+ JI Mol. Biol. PD AUG PY 2008 VL 42 IS 4 BP 567 EP 571 DI 10.1134/S0026893308040122 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337AQ UT WOS:000258408300012 ER PT J AU Zvezdova, ES Grinenko, TS Pobezinskaya, EL Pobezinsky, LA Kazansky, DB AF Zvezdova, E. S. Grinenko, T. S. Pobezinskaya, E. L. Pobezinsky, L. A. Kazansky, D. B. TI Coreceptor function of CD4 in response to the MHC class I molecule SO MOLECULAR BIOLOGY LA English DT Article DE T cell; cloning; retrovirus; transduction; coreceptor; CD4; CD8; MHC; TCR ID T-CELLS; DIFFERENTIATION; ASSAY AB The specificity of the T-cell receptor (TCR) and its interaction with coreceptors play a crucial role in T-cell passing through developmental checkpoints and, eventually, determine the efficiency of adaptive immunity. The genes for the alpha and beta chains of TCR were cloned from T-cell hybridoma 1D1, which was obtained by fusion of BWZ.36CD8 alpha cells with CD8(+) memory cells specific for the H-2Kb MHC class I molecule. Retroviral transduction of the 1D1 TCR genes and the CD4 and CD8 coreceptor genes was used to obtain 4G4 thymoma variants that exposed the CD3/TCR complex together with CD4, CD8, or both of the coreceptors on their surface. Although the main function of CD4 is to stabilize the interaction of TCR with MHC class II molecules, CD4 was found to mediate the activation of transfected cells via TCR specific for the H-2K(b) MHC class I molecule. Moreover, CD4 proved to dominate over CD8, since the response of CD4(+)CD8(+) transfectants was suppressed by antibodies against CD4 and the A(b) MHC class II molecule but not to CD8. The response of CD4(+) transfectants was not due to a cross-reaction of 1D1 TCR with MHC class II molecules, because the transfectants did not respond to splenocytes of H-2(b) knockout mice, which were defective in the assembly of the MHC class I molecule/beta 2 microglobulin/peptide complex and did not expose the complex on cell surface. The domination was not due to sequestration of p56(lck) kinase, since CD4 devoid of the kinase-binding site was functional in 4G4 thymoma cells. The results were used to explain some features of intrathymic cell selection and assumed to provide an experimental basis for developing new methods of anticancer gene therapy. C1 [Zvezdova, E. S.; Kazansky, D. B.] Russian Acad Med Sci, Blokhin Canc Res Ctr, Moscow 115478, Russia. [Grinenko, T. S.] Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia. [Pobezinskaya, E. L.; Pobezinsky, L. A.] NCI, NIH, Bethesda, MD 20892 USA. RP Zvezdova, ES (reprint author), Russian Acad Med Sci, Blokhin Canc Res Ctr, Moscow 115478, Russia. EM kazansky@dataforce.net RI Zvezdova, Ekaterina/N-7860-2015; Grinenko, Tatyana/Q-7742-2016 FU Russian Foundation for Basic Research [05-04-497931a, 07-04-00567a]; ZAO Protek Introduction Center FX This work was supported by the Russian Foundation for Basic Research ( project nos. 05-04-497931a and 07-04-00567a) and a grant from ZAO Protek Introduction Center. NR 17 TC 3 Z9 3 U1 0 U2 3 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 J9 MOL BIOL+ JI Mol. Biol. PD AUG PY 2008 VL 42 IS 4 BP 588 EP 597 DI 10.1134/S0026893308040158 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337AQ UT WOS:000258408300015 ER PT J AU Yutin, N Makarova, KS Mekhedov, SL Wolf, YI Koonin, EV AF Yutin, Natalya Makarova, Kira S. Mekhedov, Sergey L. Wolf, Yuri I. Koonin, Eugene V. TI The deep archaeal roots of eukaryotes SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE archaea; eukaryotes; Euryarchaeota; Crenarchaeota; phylogenetic analysis ID LONG-BRANCH ATTRACTION; PROKARYOTIC EVOLUTION; COG DATABASE; GENOME TREES; ORIGIN; LIFE; NUCLEUS; SEQUENCES; PROTEOBACTERIA; MITOCHONDRIA AB The set of conserved eukaryotic protein-coding genes includes distinct subsets one of which appears to be most closely related to and, by inference, derived from archaea, whereas another one appears to be of bacterial, possibly, endosymbiotic origin. The "archaeal" genes of eukaryotes, primarily, encode components of information-processing systems, whereas the "bacterial" genes are predominantly operational. The precise nature of the archaeo-eukaryotic relationship remains uncertain, and it has been variously argued that eukaryotic informational genes evolved from the homologous genes of Euryarchaeota or Crenarchaeota (the major branches of extant archaea) or that the origin of eukaryotes lies outside the known diversity of archaea. We describe a comprehensive set of 355 eukaryotic genes of apparent archaeal origin identified through ortholog detection and phylogenetic analysis. Phylogenetic hypothesis testing using constrained trees, combined with a systematic search for shared derived characters in the form of homologous inserts in conserved proteins, indicate that, for the majority of these genes, the preferred tree topology is one with the eukaryotic branch placed outside the extant diversity of archaea although small subsets of genes show crenarchaeal and euryarchaeal affinities. Thus, the archaeal genes in eukaryotes appear to descend from a distinct, ancient, and otherwise uncharacterized archaeal lineage that acquired some euryarchaeal and crenarchaeal genes via early horizontal gene transfer. C1 [Yutin, Natalya; Makarova, Kira S.; Mekhedov, Sergey L.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Yutin, N (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 69 TC 89 Z9 90 U1 1 U2 16 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 AUG PY 2008 VL 25 IS 8 BP 1619 EP 1630 DI 10.1093/molbev/msn108 PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 328HO UT WOS:000257789200013 PM 18463089 ER PT J AU Ovcharenko, I AF Ovcharenko, Ivan TI Widespread ultraconservation divergence in primates SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE evolution; ultraconservation; gene regulation; comparative genomics ID CONSERVED NONCODING SEQUENCES; HUMAN GENOME; HOMINID GENOMES; ELEMENTS; REGIONS; NUCLEOTIDE; EVOLUTIONARY; SELECTION; ENHANCER; DATABASE AB The distribution and evolution of ultraconserved elements (UCEs, DNA stretches that are perfectly identical in primates and rodents) were examined in genomes of 3 primate species (human, chimpanzee, and rhesus macaque). It was found that the number of UCEs has decreased throughout primate evolution. At least 26% of ancestral UCEs have diverged in hominoids, whereas an additional 17% have accumulated one or more single nucleotide polymorphisms in the human genome. Sequence polymorphism analyses indicate that mutation fixation within an UCE can trigger a relaxation in the selective constraint on that element. Homogeneous mutation accumulations in UCEs served as a template by which purifying selection acted more effectively on protein-coding UCEs. Gene ontology annotation suggests that UCE sequence variation, primarily occurring in noncoding regions, might be linked to the reprogramming of the expression pattern of transcription factors and developmentally important genes. Many of these genes are expressed in the central nervous system. Finally, UCE sequence variability within human populations has been identified, including population-specific nonsynonymous changes in protein-coding regions. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Ovcharenko, I (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Natl Inst Hlth, Bethesda, MD 20894 USA. EM ovcharei@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 36 TC 10 Z9 11 U1 0 U2 4 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 AUG PY 2008 VL 25 IS 8 BP 1668 EP 1676 DI 10.1093/molbev/msn116 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 328HO UT WOS:000257789200018 PM 18492662 ER PT J AU Chaudhuri, P Colles, SM Bhat, M Van Wagoner, DR Birnbaumer, L Graham, LM AF Chaudhuri, Pinaki Colles, Scott M. Bhat, Manjunatha Van Wagoner, David R. Birnbaumer, Lutz Graham, Linda M. TI Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID RECEPTOR POTENTIAL CHANNELS; PROTEIN-COUPLED RECEPTOR; TRANSIENT RECEPTOR; TYROSINE PHOSPHORYLATION; TRPC6 CHANNEL; ACTIVATION; CALCIUM; LYSOPHOSPHATIDYLCHOLINE; INSERTION; MEMBRANE AB Canonical transient receptor potential (TRPC) channels are opened by classical signal transduction events initiated by receptor activation or depletion of intracellular calcium stores. Here, we report a novel mechanism for opening TRPC channels in which TRPC6 activation initiates a cascade resulting in TRPC5 translocation. When endothelial cells (ECs) are incubated in lysophosphatidylcholine (lysoPC), rapid translocation of TRPC6 initiates calcium influx that results in externalization of TRPC5. Activation of this TRPC6-5 cascade causes a prolonged increase in intracellular calcium concentration ([Ca2+](i)) that inhibits EC movement. When TRPC5 is down-regulated with siRNA, the lysoPC-induced rise in [Ca2+](i) is shortened and the inhibition of EC migration is lessened. When TRPC6 is down-regulated or EC from TRPC6(-/-)mice are studied, lysoPC has minimal effect on [Ca2+](i) and EC migration. In addition, TRPC5 is not externalized in response to lysoPC, supporting the dependence of TRPC5 translocation on the opening of TRPC6 channels. Activation of this novel TRPC channel cascade by lysoPC, resulting in the inhibition of EC migration, could adversely impact on EC healing in atherosclerotic arteries where lysoPC is abundant. C1 [Chaudhuri, Pinaki; Colles, Scott M.] Cleveland Clin, Dept Biomed Engn, Cleveland, OH 44195 USA. [Bhat, Manjunatha] Cleveland Clin, Ctr Anesthesiol Res, Cleveland, OH 44195 USA. [Van Wagoner, David R.] Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44195 USA. [Graham, Linda M.] Cleveland Clin, Dept Vasc Surg, Cleveland, OH 44195 USA. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Graham, LM (reprint author), Cleveland Clin, Dept Biomed Engn, Cleveland, OH 44195 USA. EM grahamL@ccf.org FU National Institutes of Health (NIH) [HL41178, HL64357]; National Heart, Lung, and Blood Institute; Intramural Research Program of the NIH FX The authors thank Laurie Castel for her invaluable assistance with the patch clamp studies. This work was supported in part by extramural grants HL41178 and HL64357 from the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (L.M.G.) and in part by the Intramural Research Program of the NIH (L.B.). NR 31 TC 45 Z9 49 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2008 VL 19 IS 8 BP 3203 EP 3211 DI 10.1091/mbc.E07-08-0765 PG 9 WC Cell Biology SC Cell Biology GA 347SD UT WOS:000259160400003 PM 18495872 ER PT J AU Johnson, TA Elbi, C Parekh, BS Hager, GL John, S AF Johnson, Thomas A. Elbi, Cem Parekh, Bhavin S. Hager, Gordon L. John, Sam TI Chromatin remodeling complexes interact dynamically with a glucocorticoid receptor-regulated promoter SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TUMOR VIRUS PROMOTER; LONG TERMINAL REPEAT; LIVING HUMAN-CELLS; NUCLEAR RECEPTORS; TRANSCRIPTION FACTORS; SWI/SNF COMPLEX; GENE-EXPRESSION; IN-VIVO; HISTONE MODIFICATIONS; RAPID EXCHANGE AB Brahma (BRM) and Brahma-related gene 1 (BRG1) are the ATP-dependent catalytic subunits of the SWI/SNF family of chromatin-remodeling complexes. These complexes are involved in essential processes such as cell cycle, growth, differentiation, and cancer. Using imaging approaches in a cell line that harbors tandem repeats of stably integrated copies of the steroid responsive MMTV-LTR (mouse mammary tumor virus-long terminal repeat), we show that BRG1 and BRM are recruited to the MMTV promoter in a hormone-dependent manner. The recruitment of BRG1 and BRM resulted in chromatin remodeling and decondensation of the MMTV repeat as demonstrated by an increase in the restriction enzyme accessibility and in the size of DNA fluorescence in situ hybridization (FISH) signals. This chromatin remodeling event was concomitant with an increased occupancy of RNA polymerase II and transcriptional activation at the MMTV promoter. The expression of ATPase-deficient forms of BRG1 (BRG1-K-R) or BRM (BRM-K-R) inhibited the remodeling of local and higher order MMTV chromatin structure and resulted in the attenuation of transcription. In vivo photo-bleaching experiments provided direct evidence that BRG1, BRG1-K-R, and BRM chromatin-remodeling complexes have distinct kinetic properties on the MMTV array, and they dynamically associate with and dissociate from MMTV chromatin in a manner dependent on hormone and a functional ATPase domain. Our data provide a kinetic and mechanistic basis for the BRG1 and BRM chromatin-remodeling complexes in regulating gene expression at a steroid hormone inducible promoter. C1 [Johnson, Thomas A.; Elbi, Cem; Hager, Gordon L.; John, Sam] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Parekh, Bhavin S.] Eli Lilly & Co, Indianapolis, IN 46221 USA. RP John, S (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM sam@mail.nih.gov FU National Institutes of Health; NCI; Center for Cancer Research FX We acknowledge Jim McNally for valuable discussions on FRAP. We thank Pamela Badger and Anindya Hendarwanto for technical assistance on FRAP analysis and tissue culture. We also thank Weidong Wang (NIA, Baltimore), Tony Imbalzano (U Mass, Worcester), and Kevin Gardner (NIH, NCI) for providing antibodies to BRG1, BRM, and pol II, respectively. We also thank Christian Muchardt (CARS, France) for providing us with BRM expression constructs. Imaging was carried out in the Fluorescence Imaging Facility, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute (NCI). This research was supported by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. NR 90 TC 57 Z9 57 U1 1 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2008 VL 19 IS 8 BP 3308 EP 3322 DI 10.1091/mbc.E08-02-0123 PG 15 WC Cell Biology SC Cell Biology GA 347SD UT WOS:000259160400014 PM 18508913 ER PT J AU Ashok, A Hegde, RS AF Ashok, Aarthi Hegde, Ramanujan S. TI Retrotranslocation of prion proteins from the endoplasmic reticulum by preventing GPI signal transamidation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHOR ATTACHMENT; QUALITY-CONTROL; TRANSGENIC MICE; WILD-TYPE; MAMMALIAN-CELLS; PRP GENE; COTRANSLATIONAL TRANSLOCATION; SUBCELLULAR TRAFFICKING; MEMBRANE-PROTEIN; SCRAPIE ISOFORM AB Neurodegeneration in diseases caused by altered metabolism of mammalian prion protein (PrP) can be averted by reducing PrP expression. To identify novel pathways for PrP down-regulation, we analyzed cells that had adapted to the negative selection pressure of stable overexpression of a disease-causing PrP mutant. A mutant cell line was isolated that selectively and quantitatively routes wild-type and various mutant PrPs for ER retrotranslocation and proteasomal degradation. Biochemical analyses of the mutant cells revealed that a defect in glycosylphosphatidylinositol (GPI) anchor synthesis leads to an unprocessed GPI-anchoring signal sequence that directs both ER retention and efficient retrotranslocation of PrP. An unprocessed GPI signal was sufficient to impart ER retention, but not retrotranslocation, to a heterologous protein, revealing an unexpected role for the mature domain in the metabolism of misprocessed GPI-anchored proteins. Our results provide new insights into the quality control pathways for unprocessed GPI-anchored proteins and identify transamidation of the GPI signal sequence as a step in PrP biosynthesis that is absolutely required for its surface expression. As each GPI signal sequence is unique, these results also identify signal recognition by the GPI- transamidase as a potential step for selective small molecule perturbation of PrP expression. C1 [Ashok, Aarthi; Hegde, Ramanujan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU National Institute of Child Health and Human Development at the National Institutes of Health FX We are grateful to N. Rane for generating and first noticing the behavior of A4 cells; to C. Wunder and A. Menon for advice on GPI and TLC analysis; J. Bonifacino (NIH, Bethesda, MD) and J. Lippincott-Schwartz (NIH) for reagents and useful discussions; G. Patterson for help with confocal microscopy; R. Schulein (FMP, Berlin, Germany) for constructs; M. Lehrman for advice on tunicamycin use; and our lab members for useful discussions. This work was supported by the intramural research program of the National Institute of Child Health and Human Development at the National Institutes of Health. NR 90 TC 27 Z9 27 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2008 VL 19 IS 8 BP 3463 EP 3476 DI 10.1091/mbc.E08-01-0087 PG 14 WC Cell Biology SC Cell Biology GA 347SD UT WOS:000259160400027 PM 18508914 ER PT J AU Liu, K Surendhran, K Nothwehr, SF Graham, TR AF Liu, Ke Surendhran, Kavitha Nothwehr, Steven F. Graham, Todd R. TI P4-ATPase requirement for AP-1/clathrin function in protein transport from the trans-Golgi network and early endosomes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID P-TYPE ATPASES; YEAST PLASMA-MEMBRANE; AMINOPHOSPHOLIPID TRANSLOCASE; SACCHAROMYCES-CEREVISIAE; PHOSPHOLIPID TRANSLOCATION; COATED VESICLES; IN-VIVO; CLATHRIN; COMPLEX; TRAFFICKING AB Drs2p is a resident type 4 P-type ATPase (P4-ATPase) and potential phospholipid translocase of the trans-Golgi network (TGN) where it has been implicated in clathrin function. However, precise protein transport pathways requiring Drs2p and how it contributes to clathrin-coated vesicle budding remain unclear. Here we show a functional codependence between Drs2p and the AP-1 clathrin adaptor in protein sorting at the TGN and early endosomes of Saccharomyces cerevisiae. Genetic criteria indicate that Drs2p and AP-1 operate in the same pathway and that AP-1 requires Drs2p for function. In addition, we show that loss of AP-1 markedly increases Drs2p trafficking to the plasma membrane, but does not perturb retrieval of Drs2p from the early endosome back to the TGN. Thus AP-1 is required at the TGN to sort Drs2p out of the exocytic pathway, presumably for delivery to the early endosome. Moreover, a conditional allele that inactivates Drs2p phospholipid translocase (flippase) activity disrupts its own transport in this AP-1 pathway. Drs2p physically interacts with AP-1; however, AP-1 and clathrin are both recruited normally to the TGN in drs2 Delta cells. These results imply that Drs2p acts independently of coat recruitment to facilitate AP-1/clathrin-coated vesicle budding from the TGN. C1 [Nothwehr, Steven F.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Liu, Ke; Surendhran, Kavitha; Graham, Todd R.] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. RP Graham, TR (reprint author), NIH, Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. EM tr.graham@vanderbilt.edu FU National Institutes of Health [GM62367] FX We thank Benjamin Glick (University of Chicago), Gregory Payne (University of California, Los Angeles), Susan Wente (Vanderbilt University), Scott Emr (Cornell University), Randy Schekman (University of California, Berkeley), and Hugh Pelham (Medical Research Council, Cambridge, United Kingdom) for providing plasmids, strains, and antibodies. We also thank Sophie Chen and J. Court Reese for assistance with plasmid and strain construction. This work was supported by Grant GM62367 from the National Institutes of Health to T. R. G. NR 50 TC 54 Z9 54 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2008 VL 19 IS 8 BP 3526 EP 3535 DI 10.1091/mbc.E08-01-0025 PG 10 WC Cell Biology SC Cell Biology GA 347SD UT WOS:000259160400032 PM 18508916 ER PT J AU Kitagaki, J Agama, KK Pommier, Y Yang, YL Weissman, AM AF Kitagaki, Jirouta Agama, Keli K. Pommier, Yves Yang, Yili Weissman, Allan M. TI Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2 SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID UBIQUITIN-PROTEIN LIGASE; DNA-DAMAGE; RING FINGER; IN-VIVO; EMBRYONIC LETHALITY; MDM2-DEFICIENT MICE; ANTICANCER AGENTS; CANCER-THERAPY; MDM2; DEGRADATION AB The tumor suppressor protein p53 is a potent inducer of apoptosis in transformed cells. Hdm2 is an ubiquitin ligase (E3) that acts as a major regulator of p53 by promoting its ubiquitylation and proteasomal degradation. For this reason, inhibiting the E3 activity of Hdm2 has been proposed as a therapeutic approach for cancers expressing wild-type p53. We previously identified a family of small molecules (HLI98s, 7-nitro-10-aryl-5-deazaflavins) that inhibit the E3 activity of Hdm2, increase cellular p53, and selectively kill transformed cells expressing wild-type p53. However, issues of both potency and solubility in aqueous solution limit the utility of the HL198s. Here, we report that a highly soluble derivative of the HL198s, which has a 5-dimethylaminopropylamino side chain but lacks the 10-aryl group (HLI373), has greater potency than the HL198s in stabilizing Hdm2 and p53, activating p53-dependent transcription, and inducing cell death. Furthermore, we show that HLI373 is effective in inducing apoptosis of several tumor cells lines that are sensitive to DNA-damaging agents. These results suggest that HLI373 could serve as a potential lead for developing cancer therapeutics based on inhibition of the ubiquitin ligase activity of Hdm2. C1 [Kitagaki, Jirouta; Yang, Yili; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Agama, Keli K.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Bldg 560,Room 22-103,1050 Boyles St, Frederick, MD 21702 USA. EM amw@nih.gov FU Intramural NIH HHS [Z01 BC010292-09] NR 50 TC 33 Z9 36 U1 0 U2 11 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 AUG PY 2008 VL 7 IS 8 BP 2445 EP 2454 DI 10.1158/1535-7163.MCT-08-0063 PG 10 WC Oncology SC Oncology GA 343NE UT WOS:000258860000020 PM 18723490 ER PT J AU Arnaoutova, I Cawley, NX Patel, N Kim, T Rathod, T Loh, YP AF Arnaoutova, Irina Cawley, Niamh X. Patel, Nimesh Kim, Taeyoon Rathod, Trushar Loh, Y. Peng TI Aquaporin 1 is important for maintaining secretory granule biogenesis in endocrine cells SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID WATER CHANNELS; PHYSIOLOGICAL IMPORTANCE; KNOCKOUT MICE; ION CHANNELS; PH; VESICLES; ATT-20; PC2; INVOLVEMENT; EXPRESSION AB Aquaporins (AQPs), a family of water channels expressed in epithelial cells, function to transport water in a bidirectional manner to facilitate transepithelial fluid absorption and secretion. Additionally, AQP1 and AQP5 are found in pancreatic zymogen granules and synaptic vesicles and are involved in vesicle swelling and exocytosis in exocrine cells and neurons. Here, we show AQP1 is in dense- core secretory granule (DCSG) membranes of endocrine tissue: pituitary and adrenal medulla. The need for AQP1 in endocrine cell function was examined by stable transfection of AQP1 antisense RNA into AtT20 cells, a pituitary cell line, to down- regulate AQP1 expression. These AQP1- deficient cells showed more than 60% depletion of DCSGs and significantly decreased DCSG protein levels, including proopiomelanocotin/pro-ATCH and prohormone convertase 1/3, but not non-DCSG proteins. Pulse-chase studies revealed that whereas DCSG protein synthesis was unaffected, approximately 50% of the newly synthesized proopiomelanocortin was degraded within 1 h. Low levels of ACTH were released upon stimulation, indicating that the small number of DCSGs that were made in the presence of the residual AQP1 were functionally competent for exocytosis. Analysis of anterior pituitaries from AQP1 knockout mice showed reduced prohormone convertase 1/3, carboxypeptidase E, and ACTH levels compared to wild- type mice demonstrating that our results observed in AtT20 cells can be extended to the animal model. Thus, AQP1 is important for maintaining DCSG biogenesis and normal levels of hormone secretion in pituitary endocrine cells. C1 [Arnaoutova, Irina; Cawley, Niamh X.; Patel, Nimesh; Kim, Taeyoon; Rathod, Trushar; Loh, Y. Peng] NICHHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), NICHHD, Cellular Neurobiol Sect, NIH, Bldg 49,Room 5A22,49 Convent Dr, Bethesda, MD 20892 USA. EM lohp@mail.noh.gov FU Intramural NIH HHS NR 38 TC 19 Z9 19 U1 1 U2 1 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 AUG PY 2008 VL 22 IS 8 BP 1924 EP 1934 DI 10.1210/me.2007-0434 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 330NE UT WOS:000257949300014 PM 18511498 ER PT J AU McVie-Wylie, AJ Lee, KL Qiu, H Jin, X Do, H Gotschall, R Thurberg, BL Rogers, C Raben, N O'Callaghan, M Canfield, W Andrews, L McPherson, JM Mattaliano, R AF McVie-Wylie, A. J. Lee, K. L. Qiu, H. Jin, X. Do, H. Gotschall, R. Thurberg, B. L. Rogers, C. Raben, N. O'Callaghan, M. Canfield, W. Andrews, L. McPherson, J. M. Mattaliano, Rj. TI Biochemical and pharmacological characterization of different recombinant acid alpha-glucosidase preparations evaluated for the treatment of Pompe disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE enzyme replacement therapy; Pompe disease; lysosomal storage disorder; recombinant proteins; glycoproteins; mannose-6-phosphate receptor; mannose receptor ID ENZYME REPLACEMENT THERAPY; INFANTILE; GLYCOGEN; MILK; MICE; PRECURSOR; RECEPTOR; OLIGOSACCHARIDES; GLYCOPROTEINS; DEFICIENCY AB Pompe disease results in the accumulation of lysosomal glycogen in multiple tissues due to a deficiency of acid alpha-glucosidase (GAA). Enzyme replacement therapy for Pompe disease was recently approved in Europe, the U.S., Canada, and Japan using a recombinant human GAA (Myozyme, alglucosidase alfa) produced in CHO cells (CHO-GAA). During the development of alglucosidase alfa, we examined the in vitro and in vivo properties of CHO cell-derived rhGAA, an rhGAA purified from the milk of transgenic rabbits, as well as an experimental version of rhGAA containing additional mannose-6-phosphate intended to facilitate muscle targeting. Biochemical analyses identified differences in rhGAA N-termini, glycosylation types and binding properties to several carbohydrate receptors. In a mouse model of Pompe disease, glycogen was more efficiently removed from the heart than from skeletal muscle for all enzymes, and overall, the CHO cell-derived rhGAA reduced glycogen to a greater extent than that observed with the other enzymes. The results of these preclinical studies, combined with biochemical characterization data for the three molecules described within, led to the selection of the CHO-GAA for clinical development and registration as the first approved therapy for Pompe disease. (C) 2008 Elsevier Inc. All rights reserved. C1 [McVie-Wylie, A. J.; Lee, K. L.; Qiu, H.; Jin, X.; Thurberg, B. L.; Rogers, C.; O'Callaghan, M.; Andrews, L.; McPherson, J. M.; Mattaliano, Rj.] Genzyme Corp, Biol Res & Dev, Framingham, MA 01701 USA. [Do, H.; Gotschall, R.; Canfield, W.] Genzyme Corp, Glycobiol Res Inst, Oklahoma City, OK 73104 USA. [Raben, N.] NIAMS, Arthritis & Rheumatism Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP McVie-Wylie, AJ (reprint author), Genzyme Corp, Biol Res & Dev, 1 Mt Rd, Framingham, MA 01701 USA. EM alison.mcviewylie@genzyme.com FU Intramural NIH HHS [Z01 AR041099-17] NR 35 TC 38 Z9 38 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2008 VL 94 IS 4 BP 448 EP 455 DI 10.1016/j.ymgme.2008.04.009 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 330IT UT WOS:000257935000011 PM 18538603 ER PT J AU Cmarik, JL AF Cmarik, Joan L. TI From Bioinformatics to Bioassays: Gleaning Insights into Protein Structure-Function from Disease-Associated nsSNPs SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID SINGLE-NUCLEOTIDE POLYMORPHISMS; CANCER SUSCEPTIBILITY; HUMAN GENOME; BRCA2; MUTATIONS; GENES; ELEMENTS; DATABASE; KINASES C1 NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Cmarik, JL (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21702 USA. FU Intramural NIH HHS NR 26 TC 1 Z9 1 U1 0 U2 0 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 AUG 1 PY 2008 VL 8 IS 4 BP 162 EP 164 DI 10.1124/mi.8.4.5 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 366IF UT WOS:000260473400003 PM 18829841 ER PT J AU Kawasaki, BT Hurt, EM Mistree, T Farrar, WL AF Kawasaki, Brian T. Hurt, Elaine M. Mistree, Tashan Farrar, William L. TI Targeting Cancer Stem Cells with Phytochemicals SO MOLECULAR INTERVENTIONS LA English DT Review ID ACUTE MYELOID-LEUKEMIA; MAMMARY STEM/PROGENITOR CELLS; PROSTATE-SPECIFIC ANTIGEN; GREEN TEA POLYPHENOLS; TRANS-RETINOIC ACID; PHASE-II TRIAL; MULTIDRUG-RESISTANCE; PANCREATIC-CANCER; SIGNALING PATHWAYS; SELF-RENEWAL AB Cancer, second only to heart disease, is the leading cause of death in the US. Although progress has been made in the early detection of cancer and in improvements of cancer therapies, the ability to provide long-term survival has been limited. Increasing evidence suggests that a minute, biologically unique population of cancer stem cells (SCs) exists in most neoplasms and may be responsible for tumor initiation, progression, metastasis, and relapse. Characterization of cancer SCs has led to the identification of key cellular activities that may make cancer SCs vulnerable to therapeutic interventions that target drug-effluxing capabilities, stem cell pathways, anti-apoptotic mechanisms, and induction of differentiation. Phytochemicals, compounds made from fruits, vegetables, and grains, possess anti-cancer properties and represent a promising therapeutic approach for the prevention and treatment of many cancers. This review summarizes the evidence for the cancer SC hypothesis and discusses the potential mechanisms by which phytochemicals might target cancer SCs. C1 [Kawasaki, Brian T.; Hurt, Elaine M.; Mistree, Tashan; Farrar, William L.] NCI, Cancer Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Kawasaki, BT (reprint author), NCI, Cancer Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Office of Dietary Supplements FX We would like to thank members of the Farrar laboratory for their helpful discussions and editing contributions, especially George Klarmann. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. In addition, this work was funded in part by the Office of Dietary Supplements, National Institutes of Health. The content of this paper does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 106 TC 64 Z9 66 U1 0 U2 4 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 AUG 1 PY 2008 VL 8 IS 4 BP 174 EP 184 DI 10.1124/mi.8.4.9 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 366IF UT WOS:000260473400005 PM 18829843 ER PT J AU Harinarayanan, R Murphy, H Cashel, M AF Harinarayanan, Rajendran Murphy, Helen Cashel, Michael TI Synthetic growth phenotypes of Escherichia coli lacking ppGpp and transketolase A (tktA) are due to ppGpp-mediated transcriptional regulation of tktB SO MOLECULAR MICROBIOLOGY LA English DT Article ID STRESS-RESPONSE; SIGMA(S)-DEPENDENT GENES; STRINGENT RESPONSE; STATIONARY-PHASE; DKSA; MUTANTS; SPOT; PROMOTERS; PROTEIN; (P)PPGPP AB Many physiological adjustments to nutrient changes involve ppGpp. Recent attempts to deduce ppGpp regulatory effects using proteomics or gene profiling can rigorously identify proteins or transcripts, but the functional significance is often unclear. Using a random screen for synthetic lethals we found a ppGpp-dependent functional pathway that operates through transketolase B (TktB), and which is 'buffered' in wildtype strain by the presence of an isozyme, transketolase A (TktA). Transketolase activity is required in cells to make erythrose-4-phosphate, a precursor of aromatic amino acids and vitamins. By studying tktB-dependent nutritional requirements as well as measuring activities using PtalA-tktB'-IacZ transcriptional reporter fusion, we show positive transcriptional regulation of the taIA-tktB operon by ppGpp. Our results show the existence of RpoS-dependent and RpoS-independent modes of positive regulation by ppGpp. Both routes of activation are magnified by elevating ppGpp levels with a spoT mutation (spoT-R39A) defective in hydrolase but not synthetase activity or with the stringent suppressor mutations rpoB-A532 Delta or rpoB-T563P in the absence of ppGpp. C1 [Harinarayanan, Rajendran; Murphy, Helen; Cashel, Michael] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Harinarayanan, R (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM harinarr@mail.nih.gov FU NICHD/NIH FX We would like to thank Manjula Reddy for discussions that inspired this study and for sharing plasmid pMA2 and Dick D'Ari making suggestions for the manuscript. This work is supported by the intramural research programme of NICHD/NIH. NR 46 TC 12 Z9 12 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2008 VL 69 IS 4 BP 882 EP 894 DI 10.1111/j.1365-2958.2008.06317.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 339RM UT WOS:000258595000009 PM 18532980 ER PT J AU Li, LH Chen, T Stanton, JD Sueyoshi, T Negishi, M Wang, HB AF Li, Linhao Chen, Tao Stanton, Joseph D. Sueyoshi, Tatsuya Negishi, Masahiko Wang, Hongbing TI The peripheral benzodiazepine receptor ligand 1-(2-chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide is a novel antagonist of human constitutive androstane receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID CYP2B6 GENE-EXPRESSION; PREGNANE-X-RECEPTOR; NUCLEAR RECEPTOR; ACTIVE/ANDROSTANE RECEPTOR; XENOBIOTIC INDUCTION; ENHANCER MODULE; AGONIST LIGAND; MOUSE-LIVER; CROSS-TALK; CAR AB As a promiscuous xenobiotic sensor, the constitutive androstane receptor (CAR; NR1I3) regulates the expression of multiple drug-metabolizing enzymes and transporters in liver. The constitutively activated nature of CAR in the cell-based transfection assays has hindered its use as a predictor of metabolism-based drug-drug interactions. Here, we have identified 1-(2-chlorophenylmethylpropyl)-3- isoquinoline-carboxamide (PK11195), a typical peripheral benzodiazepine receptor (PBR) ligand, as a selective and potent inhibitor of human (h) CAR. In cell-based transfection assays, PK11195 inhibited the constitutive activity of hCAR more than 80% at the concentration of 10 mu M, and the PK11195-inhibited activity was efficiently reactivated by the direct CAR activator, 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime, but not by the indirect hCAR activator, phenobarbital. Mammalian two-hybrid and GST pull-down assays showed that PK11195 repressed the interactions of hCAR with the coactivators steroid receptor coactivator-1 and glucocorticoid receptor-interacting protein 1 to inhibit hCAR activity. The inhibition by PK11195 specifically occurred to the hCAR: PK1195 strongly activated human pregnane X receptor (PXR), whereas it did not alter the activity of the mouse CAR and mouse PXR. In addition, PBR played no role in the PK11195 inhibition of hCAR because the inhibition fully occurred in the HeLa cells in which the PBR was knocked down by small interfering RNA. In the Car(-/-) mouse liver, PK11195 translocated enhanced yellow fluorescent protein-hCAR into the nucleus. These results are consistent with the conclusion that PK11195 is a novel hCAR-specific antagonist that represses the CAR-coactivator interactions to inhibit the receptor activity inside the nucleus. Thus, PK11195 can be used as a chemical tool for studying the molecular basis of CAR function. C1 [Li, Linhao; Chen, Tao; Stanton, Joseph D.; Wang, Hongbing] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Sueyoshi, Tatsuya; Negishi, Masahiko] Natl Inst Environm & Hlth Sci, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC USA. RP Wang, HB (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, 20 Penn St, Baltimore, MD 21201 USA. EM hwang@rx.umaryland.edu RI Li, Linhao/A-6348-2013; chen, Tao/I-4900-2013 FU Intramural NIH HHS [Z01 ES080040-22]; NIDDK NIH HHS [DK061652, R01 DK061652-06, R01 DK061652] NR 41 TC 60 Z9 63 U1 0 U2 4 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 AUG PY 2008 VL 74 IS 2 BP 443 EP 453 DI 10.1124/mol.108.046656 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 329GH UT WOS:000257854400016 PM 18492798 ER PT J AU Choi, K Mollapour, E Choi, JH Shears, SB AF Choi, Kuicheon Mollapour, Elahe Choi, Jae H. Shears, Stephen B. TI Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase SO MOLECULAR PHARMACOLOGY LA English DT Article ID INOSITOL PYROPHOSPHATES; HYPEROSMOTIC STRESS; DEATH; CELLS; PENTAKISPHOSPHATE; HEXAKISPHOSPHATE; PHOSPHORYLATION; POLYPHOSPHATES; DICTYOSTELIUM; PURIFICATION AB Cells aggressively defend adenosine nucleotide homeostasis; intracellular biosensors detect variations in energetic status and communicate with other cellular networks to initiate adaptive responses. Here, we demonstrate some new elements of this communication process, and we show that this networking is compromised by off-target, bioenergetic effects of some popular pharmacological tools. Treatment of cells with 5-aminoimidazole-4- carboxamide ribonucleoside (AICAR), so as to simulate elevated AMP levels, reduced the synthesis of bis-diphosphoinositol tetrakisphosphate ([PP](2)-InsP(4)), an intracellular signal that phosphorylates proteins in a kinase-independent reaction. This was a selective effect; levels of other inositol phosphates were unaffected by AICAR. By genetically manipulating cellular AMP-activated protein kinase activity, we showed that it did not mediate these effects of AICAR. Instead, we conclude that the simulation of deteriorating adenosine nucleotide balance itself inhibited [PP](2)-InsP(4) synthesis. This conclusion is consistent with our demonstrating that oligomycin elevated cellular [AMP] and selectively inhibited [PP](2)-InsP(4) synthesis without affecting other inositol phosphates. In addition, we report that the short-term increases in [PP](2)-InsP(4) levels normally seen during hyperosmotic stress were attenuated by 2-(2-chloro-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide (PD184352). The latter is typically considered an exquisitely specific mitogen-activated protein kinase kinase (MEK) inhibitor, but small interfering RNA against MEK or extracellular signal-regulated kinase revealed that this mitogen-activated protein kinase pathway was not involved. Instead, we demonstrate that [PP](2)-InsP(4) synthesis was inhibited by PD184352 through its nonspecific effects on cellular energy balance. Two other MEK inhibitors, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio) butadiene (U0126) and 2'-amino-3'-methoxyflavone (PD98059), had similar off-target effects. We conclude that the levels and hence the signaling strength of [PP](2)-InsP(4) is supervised by cellular adenosine nucleotide balance, signifying a new link between signaling and bioenergetic networks. C1 [Choi, Kuicheon; Mollapour, Elahe; Choi, Jae H.; Shears, Stephen B.] NIEHS, Inositide Signaling Grp, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signaling Grp, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov FU Intramural NIH HHS [Z01 ES080046-19] NR 37 TC 24 Z9 25 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 AUG PY 2008 VL 74 IS 2 BP 527 EP 536 DI 10.1124/mol.107.044628 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 329GH UT WOS:000257854400024 PM 18460607 ER PT J AU Slifstein, M Kolachana, B Simpson, EH Tabares, P Cheng, B Duvall, M Frankle, WG Weinberger, DR Laruelle, M Abi-Dargham, A AF Slifstein, M. Kolachana, B. Simpson, E. H. Tabares, P. Cheng, B. Duvall, M. Frankle, W. Gordon Weinberger, D. R. Laruelle, M. Abi-Dargham, A. TI COMT genotype predicts cortical-limbic D1 receptor availability measured with [C-11]NNC112 and PET SO MOLECULAR PSYCHIATRY LA English DT Article DE dopamine; D1 receptor; COMT; catechol-O-methyltransferase; PET; [C-11]NNC 112 ID RAT PREFRONTAL CORTEX; METHYLTRANSFERASE VAL(158)MET GENOTYPE; WORKING-MEMORY; DOPAMINE D-1; HUMAN BRAIN; FUNCTIONAL POLYMORPHISM; GENE POLYMORPHISM; CEREBRAL-CORTEX; MESSENGER-RNA; NO EVIDENCE AB A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D-1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D-1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [C-11] NNC112. We compared [C-11] NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [C-11]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [C-11] NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [C-11] NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia. C1 [Slifstein, M.; Tabares, P.; Duvall, M.; Frankle, W. Gordon; Abi-Dargham, A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Kolachana, B.; Weinberger, D. R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Simpson, E. H.] Columbia Univ, Coll Phys & Surg, Ctr Neurobiol & Behav, New York, NY 10032 USA. [Cheng, B.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA. [Laruelle, M.] Glaxo SmithKline, London, England. [Abi-Dargham, A.] Columbia Univ, Coll Phys & Surg, Dept Radiol, New York, NY 10032 USA. RP Slifstein, M (reprint author), Columbia Univ, Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr,Box No 31, New York, NY 10032 USA. EM mms218@columbia.edu OI Simpson, Eleanor/0000-0002-9092-2230; Frankle, William/0000-0003-0356-4197 NR 40 TC 105 Z9 105 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD AUG PY 2008 VL 13 IS 8 BP 821 EP 827 DI 10.1038/mp.2008.19 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 328DM UT WOS:000257777900006 PM 18317466 ER PT J AU Shaham, O Wei, R Wang, TJ Ricciardi, C Lewis, GD Vasan, RS Carr, SA Thadhani, R Gerszten, RE Mootha, VK AF Shaham, Oded Wei, Ru Wang, Thomas J. Ricciardi, Catherine Lewis, Gregory D. Vasan, Ramachandran S. Carr, Steven A. Thadhani, Ravi Gerszten, Robert E. Mootha, Vamsi K. TI Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE glucose homeostasis; insulin sensitivity; metabolic profiling ID BILE-ACIDS; LEUCINE TURNOVER; OBESITY; STARVATION; RESISTANCE; OXIDATION; SALVAGE; SERUM AB Glucose ingestion after an overnight fast triggers an insulin-dependent, homeostatic program that is altered in diabetes. The full spectrum of biochemical changes associated with this transition is currently unknown. We have developed a mass spectrometry-based strategy to simultaneously measure 191 metabolites following glucose ingestion. In two groups of healthy individuals (n = 22 and 25), 18 plasma metabolites changed reproducibly, including bile acids, urea cycle intermediates, and purine degradation products, none of which were previously linked to glucose homeostasis. The metabolite dynamics also revealed insulin's known actions along four key axes proteolysis, lipolysis, ketogenesis, and glycolysis-reflecting a switch from catabolism to anabolism. In pre-diabetics (n = 25), we observed a blunted response in all four axes that correlated with insulin resistance. Multivariate analysis revealed that declines in glycerol and leucine/isoleucine (markers of lipolysis and proteolysis, respectively) jointly provide the strongest predictor of insulin sensitivity. This observation indicates that some humans are selectively resistant to insulin's suppression of proteolysis, whereas others, to insulin's suppression of lipolysis. Our findings lay the groundwork for using metabolic profiling to define an individual's 'insulin response profile', which could have value in predicting diabetes, its complications, and in guiding therapy. C1 [Shaham, Oded; Wei, Ru; Lewis, Gregory D.; Carr, Steven A.; Gerszten, Robert E.; Mootha, Vamsi K.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Shaham, Oded] Harvard MIT Div Hlth Sci Technol, Cambridge, MA USA. [Shaham, Oded; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wang, Thomas J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Wang, Thomas J.; Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Wang, Thomas J.; Lewis, Gregory D.; Gerszten, Robert E.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Ricciardi, Catherine; Thadhani, Ravi] MIT, Gen Clin Res Ctr, Cambridge, MA 02139 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Cardiol & Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Dept Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 5-806, Boston, MA 02114 USA. EM vamsi@hms.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU Bioinformatics and Integrative Genomics from the National Human Genome Research Institute; National Institutes of Health (NIH) [R01-HL-086875, R01-HL083197]; Heart Failure Society of America and the Harvard/ MIT Clinical Investigator Training Program; NIH [U01HL083141, MO1-RR01066]; Donald W Reynolds Foundation; e Broad Institute Scientific Planning and Allocation of Resources Committee; Framingham Heart Study [N01-HC-25195] FX We thank Joseph Avruch, Ronald Kahn, Barbara Kahn, Sudha Biddinger, and Mark Herman for helpful comments on the paper; Toshimori Kitami for glucose uptake measurements; and Alice M McKenney for assistance in preparing figures. OS was supported by a training grant for Bioinformatics and Integrative Genomics from the National Human Genome Research Institute. TJW was supported by the National Institutes of Health (NIH) (R01-HL-086875 and R01-HL083197). GDL was supported by the Heart Failure Society of America and the Harvard/ MIT Clinical Investigator Training Program. REG was supported by the NIH (U01HL083141), the Donald W Reynolds Foundation, and Fondation Leducq. VKM was supported by a Burroughs Wellcome Career Award in the Biomedical Sciences and a Howard Hughes Medical Institute Early Career Physician Scientist Award. This study was supported by a generous grant from the Broad Institute Scientific Planning and Allocation of Resources Committee, a General Clinical Research Center grant awarded by the NIH to the Massachusetts Institute of Technology General Clinical Research Center (MO1-RR01066), and a NIH/ National Heart Lung and Blood Institute contract supporting the Framingham Heart Study (N01-HC-25195). NR 26 TC 184 Z9 188 U1 2 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD AUG PY 2008 VL 4 AR 214 DI 10.1038/msb.2008.50 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 344NS UT WOS:000258935100003 PM 18682704 ER PT J AU Dobrovoiskaia, MA Clogston, JD Neun, BW Hall, JB Patri, AK McNeil, SE AF Dobrovoiskaia, Marina A. Clogston, Jeffrey D. Neun, Barry W. Hall, Jennifer B. Patri, Anil K. McNeil, Scott E. TI Method for analysis of nanoparticle hemolytic properties in vitro SO NANO LETTERS LA English DT Article ID RED-BLOOD-CELLS; PEGYLATED LIPOSOMAL DOXORUBICIN; DELIVERY-SYSTEMS; CONTACT TIME; LYSIS; COMPATIBILITY; GEMCITABINE; COMBINATION; PROPOFOL; CANCER AB Hemolysis (destruction of red blood cells) in vivo can lead to anemia, jaundice, and other pathological conditions; therefore the hemolytic potential of all intravenously administered pharmaceuticals must be evaluated. Nanotechnology-derived devices and drug carriers are emerging as alternatives to conventional small-molecule drugs, and in vitro evaluation of their biocompatibility with blood components is a necessary part of early preclinical development. The small size and unique physicochemical properties of nanoparticles may cause their interactions with erythrocytes to differ from those observed for conventional pharmaceuticals and may also cause interference with standardized in vitro tests. Separating true hemolytic responses from the false-positive or false-negative results caused by particle interference is important for correct interpretation of these tests. Here we describe validation of an in vitro assay for the analysis of nanoparticle hemolytic properties and discuss observed nanointerferences with the assay. We propose alternative methods to avoid misleading results from nanoparticles and discuss the potential relevance of nanoparticle in vitro hemolytic properties to in vivo systems. C1 [Dobrovoiskaia, Marina A.; Clogston, Jeffrey D.; Neun, Barry W.; Hall, Jennifer B.; Patri, Anil K.; McNeil, Scott E.] NCI, SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA. RP Dobrovoiskaia, MA (reprint author), NCI, SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, 1050 Boyles St,Bldg 469, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We are grateful to Drs. Mansoor Amiji, Mark Kester, Eric Simanek and C60 Inc. for providing various nanoparticle formulations. NR 33 TC 184 Z9 188 U1 2 U2 40 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 J9 NANO LETT JI Nano Lett. PD AUG PY 2008 VL 8 IS 8 BP 2180 EP 2187 DI 10.1021/nl0805615 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 337MR UT WOS:000258440700012 PM 18605701 ER PT J AU Gibson, F Anderson, L Babnigg, G Baker, M Berth, M Binz, PA Borthwick, A Cash, P Day, BW Friedman, DB Garland, D Gutstein, HB Hoogland, C Jones, NA Khan, A Klose, J Lamond, AI Lemkin, PF Lilley, KS Minden, J Morris, NJ Paton, NW Pisano, MR Prime, JE Rabilloud, T Stead, DA Taylor, CF Voshol, H Wipat, A Jones, AR AF Gibson, Frank Anderson, Leigh Babnigg, Gyorgy Baker, Mark Berth, Matthias Binz, Pierre-Alain Borthwick, Andy Cash, Phil Day, Billy W. Friedman, David B. Garland, Donita Gutstein, Howard B. Hoogland, Christine Jones, Neil A. Khan, Alamgir Klose, Joachim Lamond, Angus I. Lemkin, Peter F. Lilley, Kathryn S. Minden, Jonathan Morris, Nicholas J. Paton, Norman W. Pisano, Michael R. Prime, John E. Rabilloud, Thierry Stead, David A. Taylor, Chris F. Voshol, Hans Wipat, Anil Jones, Andrew R. TI Guidelines for reporting the use of gel electrophoresis in proteomics SO NATURE BIOTECHNOLOGY LA English DT Letter C1 [Gibson, Frank; Morris, Nicholas J.] Univ Newcastle Upon Tyne, Inst Cell & Mol Biosci, Sch Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Anderson, Leigh] Plasma Proteome Inst, Washington, DC 20009 USA. [Babnigg, Gyorgy] Argonne Natl Lab, Argonne, IL 60439 USA. [Baker, Mark; Khan, Alamgir] Australian Proteome Anal Facil Ltd, Sydney, NSW 2109, Australia. [Baker, Mark; Khan, Alamgir] Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. [Berth, Matthias] Decodon GmbHW, D-17489 Greifswald, Germany. [Binz, Pierre-Alain; Hoogland, Christine] Swiss Inst Bioinformat, CH-1211 Geneva 4, Switzerland. [Binz, Pierre-Alain] GeneBio SA, CH-1206 Geneva, Switzerland. [Borthwick, Andy] Cuthbert House, Nonlinear Dynam, Newcastle Upon Tyne NE1 2ET, Tyne & Wear, England. [Cash, Phil] Univ Aberdeen, Dept Med Microbiol, Aberdeen AB25 2ZD, Scotland. [Day, Billy W.] Univ Pittsburgh, Proteom Core Lab, Dept Chem, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. [Friedman, David B.] Vanderbilt Univ, Mass Spectrometry Res Ctr, Proteom Lab, Nashville, TN 37232 USA. [Garland, Donita] NEI, NIH, Bethesda, MD 20892 USA. [Gutstein, Howard B.] Univ Texas MD Anderson Canc Ctr, Dept Anesthesiol, Houston, TX 77030 USA. [Gutstein, Howard B.] Univ Texas MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. [Jones, Neil A.] GlaxoSmithKline R&D, Genet Res, Genom & Proteom Sci, Dis & Biomarker Proteom, Stevenage SG1 2NY, Herts, England. [Klose, Joachim] Univ Med Berlin, Charite, Inst Human Genet, D-13353 Berlin, Germany. [Lamond, Angus I.] Univ Dundee, Wellcome Trust Bioctr MSI WTB Complex, Dundee DD1 5EH, Scotland. [Lemkin, Peter F.] NCI, Frederick, MD 21702 USA. [Lilley, Kathryn S.] Univ Cambridge, Dept Biochem, Cambridge Ctr Proteom, Cambridge CB2 1QR, England. [Minden, Jonathan] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Paton, Norman W.] Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. [Pisano, Michael R.] Proteom Res Serv Inc, Ann Arbor, MI 48108 USA. [Prime, John E.] KuDOS Pharmaceut, Cambridge CB4 0WG, England. [Rabilloud, Thierry] CEA, INSERM, DRDC, ICH,U548, F-38054 Grenoble, France. [Stead, David A.] Univ Aberdeen, Sch Med Sci, Aberdeen AB25 2ZD, Scotland. [Taylor, Chris F.] European Bioinformat Inst, EMBL Outstn, Cambridge, England. [Taylor, Chris F.] NERC, Environm Bioinformat Ctr, Oxford OX1 3SR, England. [Voshol, Hans] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Wipat, Anil] Univ Newcastle Upon Tyne, Sch Comp Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Jones, Andrew R.] Univ Liverpool, Fac Vet Sci, Dept Preclin Vet Sci, Liverpool L69 7ZJ, Merseyside, England. RP Gibson, F (reprint author), Univ Newcastle Upon Tyne, Inst Cell & Mol Biosci, Sch Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. EM frank.gibson@ncl.ac.uk OI Hoogland, Christine/0000-0002-7341-1551; Morris, Nicholas/0000-0002-8389-7508; Lamond, Angus/0000-0001-6204-6045; Jones, Andrew/0000-0001-6118-9327; Taylor, Christopher/0000-0002-9666-798X; Binz, Pierre-Alain/0000-0002-0045-7698; Gibson, Frank/0000-0003-3382-1748; Baker, Mark/0000-0001-5858-4035; Paton, Norman/0000-0003-2008-6617 FU Biotechnology and Biological Sciences Research Council [BB/C511613/1]; Wellcome Trust [073980] NR 2 TC 39 Z9 40 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2008 VL 26 IS 8 BP 863 EP 864 DI 10.1038/nbt0808-863 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 335WX UT WOS:000258325500014 PM 18688234 ER PT J AU Taylor, CF Field, D Sansone, SA Aerts, J Apweiler, R Ashburner, M Ball, CA Binz, PA Bogue, M Booth, T Brazma, A Brinkman, RR Clark, AM Deutsch, EW Fiehn, O Fostel, J Ghazal, P Gibson, F Gray, T Grimes, G Hancock, JM Hardy, NW Hermjakob, H Julian, RK Kane, M Kettner, C Kinsinger, C Kolker, E Kuiper, M Le Novere, N Leebens-Mack, J Lewis, SE Lord, P Mallon, AM Marthandan, N Masuya, H McNally, R Mehrle, A Morrison, N Orchard, S Quackenbush, J Reecy, JM Robertson, DG Rocca-Serra, P Rodriguez, H Rosenfelder, H Santoyo-Lopez, J Scheuermann, RH Schober, D Smith, B Snape, J Stoeckert, CJ Tipton, K Sterk, P Untergasser, A Vandesompele, J Wiemann, S AF Taylor, Chris F. Field, Dawn Sansone, Susanna-Assunta Aerts, Jan Apweiler, Rolf Ashburner, Michael Ball, Catherine A. Binz, Pierre-Alain Bogue, Molly Booth, Tim Brazma, Alvis Brinkman, Ryan R. Clark, Adam Michael Deutsch, Eric W. Fiehn, Oliver Fostel, Jennifer Ghazal, Peter Gibson, Frank Gray, Tanya Grimes, Graeme Hancock, John M. Hardy, Nigel W. Hermjakob, Henning Julian, Randall K., Jr. Kane, Matthew Kettner, Carsten Kinsinger, Christopher Kolker, Eugene Kuiper, Martin Le Novere, Nicolas Leebens-Mack, Jim Lewis, Suzanna E. Lord, Phillip Mallon, Ann-Marie Marthandan, Nishanth Masuya, Hiroshi McNally, Ruth Mehrle, Alexander Morrison, Norman Orchard, Sandra Quackenbush, John Reecy, James M. Robertson, Donald G. Rocca-Serra, Philippe Rodriguez, Henry Rosenfelder, Heiko Santoyo-Lopez, Javier Scheuermann, Richard H. Schober, Daniel Smith, Barry Snape, Jason Stoeckert, Christian J., Jr. Tipton, Keith Sterk, Peter Untergasser, Andreas Vandesompele, Jo Wiemann, Stefan TI Promoting coherent minimum reporting guidelines for biological and biomedical investigations: the MIBBI project SO NATURE BIOTECHNOLOGY LA English DT Article ID SCIENTIFIC JOURNALS; MICROARRAY DATA; STANDARDS; INFORMATION; SPECIFICATION; ANNOTATION C1 [Taylor, Chris F.; Sansone, Susanna-Assunta; Apweiler, Rolf; Brazma, Alvis; Hermjakob, Henning; Le Novere, Nicolas; Orchard, Sandra; Rocca-Serra, Philippe; Schober, Daniel; Sterk, Peter] European Bioinformat Inst, Hinxton CB10 1SD, Cambs, England. [Taylor, Chris F.; Field, Dawn; Sansone, Susanna-Assunta; Booth, Tim; Gray, Tanya; Morrison, Norman] NERC, Environm Bioinformat Ctr, Oxford OX1 3SR, England. [Field, Dawn; Gray, Tanya] Oxford Ctr Ecol & Hydrol, Mol Evolut & Bioinformat Grp, Oxford OX1 3SR, England. [Aerts, Jan] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. [Ashburner, Michael] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Ball, Catherine A.] Stanford Univ, Dept Biochem, Stanford Microarray Database, Stanford, CA 94305 USA. [Binz, Pierre-Alain] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Binz, Pierre-Alain] Geneva Bioinformat GeneBio SA, CH-1206 Geneva, Switzerland. [Bogue, Molly] Jackson Lab, Jax Mouse Phenome Project, Bar Harbor, ME 04609 USA. [Brinkman, Ryan R.] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. [Clark, Adam Michael] Lance Armstrong Fdn, Austin, TX 78716 USA. [Deutsch, Eric W.] Inst Syst Biol, Seattle, WA 98103 USA. [Fiehn, Oliver] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Fostel, Jennifer] NIEHS, Res Triangle Pk, NC 27709 USA. [Fostel, Jennifer] Lockheed Martin Informat Technol, Res Triangle Pk, NC 27709 USA. [Ghazal, Peter; Grimes, Graeme; Santoyo-Lopez, Javier] Univ Edinburgh, Sch Med, Div Pathway Med, Edinburgh EH16 4SB, Midlothian, Scotland. [Gibson, Frank; Lord, Phillip] Newcastle Univ, Sch Comp Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Hancock, John M.; Mallon, Ann-Marie] MRC, Bioinformat Grp, Mammalian Genet Unit, Harwell OX11 0RD, Oxon, England. [Hardy, Nigel W.] Aberystwyth Univ, Dept Comp Sci, Aberystwyth SY23 3DB, Dyfed, Wales. [Julian, Randall K., Jr.] Indigo BioSyst Inc, Carmel, IN 46032 USA. [Kane, Matthew] Natl Sci Fdn, Div Mol & Cellular Biosci, Arlington, VA 22230 USA. [Kettner, Carsten] Beilstein Inst Forderung Chem Wissensch, D-60487 Frankfurt, Germany. [Kinsinger, Christopher; Rodriguez, Henry] NCI, Off Technol & Ind Relat, Off Director, Bethesda, MD 20892 USA. [Kolker, Eugene] Seattle Childrens Hosp Res Inst, Seattle, WA 98101 USA. [Kolker, Eugene] Seattle Childrens Hosp & Reg Med Ctr, Seattle, WA 98105 USA. [Kuiper, Martin] Univ Ghent VIB, Dept Plant Syst Biol, B-9052 Ghent, Belgium. [Kuiper, Martin] Univ Ghent, B-9052 Ghent, Belgium. [Kuiper, Martin] Norwegian Univ Sci & Technol, Dept Biol, N-7491 Trondheim, Norway. [Leebens-Mack, Jim] Univ Georgia, Dept Plant Biol, Athens, GA 30602 USA. [Lewis, Suzanna E.] Univ Calif Berkeley, Dept Mol & Cellular Biol, Berkeley, CA 94729 USA. [Marthandan, Nishanth; Scheuermann, Richard H.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Masuya, Hiroshi] RIKEN, Genom Sci Ctr, Tsukuba, Ibaraki 3050074, Japan. [McNally, Ruth] Univ Lancaster, Inst Adv Studies, ESRC CESAGen, Lancaster LA1 4YD, England. [Mehrle, Alexander; Rosenfelder, Heiko; Wiemann, Stefan] German Canc Res Ctr, Div Mol Genome Anal, D-69120 Heidelberg, Germany. [Morrison, Norman] Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. [Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Dana Farber Canc Inst,Dept Canc Biol, Boston, MA 02115 USA. [Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat,Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Reecy, James M.] Iowa State Univ, Dept Anim Sci, Ctr Integrated Anim Genom, Ames, IA 50011 USA. [Robertson, Donald G.] Bristol Myers Squibb Co, Princeton, NJ 08543 USA. [Smith, Barry] SUNY Buffalo, Dept Philosophy, Buffalo, NY 14260 USA. [Smith, Barry] SUNY Buffalo, Ctr Excellence Bioinformat & Life Sci, Buffalo, NY 14260 USA. [Snape, Jason] AstraZeneca UK Ltd, Brixham TQ5 8BA, Devon, England. [Stoeckert, Christian J., Jr.] Ctr Bioinformat, Dept Genet, Philadelphia, PA 19104 USA. [Tipton, Keith] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. [Untergasser, Andreas] Wageningen Univ, Dept Plant Sci, Mol Biol Lab, Wageningen, Netherlands. [Vandesompele, Jo] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. RP Taylor, CF (reprint author), European Bioinformat Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambs, England. EM chris.taylor@ebi.ac.uk; dfield@ceh.ac.uk; sansone@ebi.ac.uk RI Aerts, Jan/C-4374-2008; Field, Dawn/C-1653-2010; Booth, Tim/C-6751-2011; Hancock, John/A-2442-2009; Le Novere, Nicolas/F-9973-2010; Vandesompele, Jo/G-3086-2010; Kolker, Eugene/C-6711-2008; Santoyo-Lopez, Javier/C-9714-2012; Wiemann, Stefan/E-4424-2013; Brinkman, Ryan/B-1108-2008; Masuya, Hiroshi/A-6442-2016; Smith, Barry/A-9525-2011 OI Hermjakob, Henning/0000-0001-8479-0262; Kettner, Carsten/0000-0002-8697-6842; Scheuermann, Richard/0000-0003-1355-892X; Kuiper, Martin/0000-0002-1171-9876; Vandesompele, Jo/0000-0001-6274-0184; Brazma, Alvis/0000-0001-5988-7409; Sterk, Peter/0000-0003-1668-7778; Sansone, Susanna-Assunta/0000-0001-5306-5690; Taylor, Christopher/0000-0002-9666-798X; Binz, Pierre-Alain/0000-0002-0045-7698; Lewis, Suzanna/0000-0002-8343-612X; Gibson, Frank/0000-0003-3382-1748; Orchard, Sandra/0000-0002-8878-3972; Gray, Tanya/0000-0003-1561-7364; Apweiler, Rolf/0000-0001-7078-200X; Hancock, John/0000-0003-2991-2217; Le Novere, Nicolas/0000-0002-6309-7327; Santoyo-Lopez, Javier/0000-0003-1988-5059; Wiemann, Stefan/0000-0003-4683-3174; Brinkman, Ryan/0000-0002-9765-2990; Masuya, Hiroshi/0000-0002-3392-466X; Smith, Barry/0000-0003-1384-116X FU Biotechnology and Biological Sciences Research Council [E025080/1, BB/E025080/1, BB/E006248/1]; Medical Research Council [MC_U142684171]; NHGRI NIH HHS [U54 HG004028]; NIBIB NIH HHS [EB005034-01, R01 EB005034, R01 EB005034-04] NR 21 TC 251 Z9 254 U1 4 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2008 VL 26 IS 8 BP 889 EP 896 DI 10.1038/nbt.1411 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 335WX UT WOS:000258325500022 PM 18688244 ER PT J AU Wang, JH Lozier, J Johnson, G Kirshner, S Verthelyi, D Pariser, A Shores, E Rosenberg, A AF Wang, Jinhai Lozier, Jay Johnson, Gibbes Kirshner, Susan Verthelyi, Daniela Pariser, Anne Shores, Elizabeth Rosenberg, Amy TI Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment SO NATURE BIOTECHNOLOGY LA English DT Article ID ACID ALPHA-GLUCOSIDASE; T-CELL TOLERANCE; FACTOR-VIII INHIBITORS; LONG-TERM ACCEPTANCE; HUMAN GROWTH-HORMONE; SEVERE HEMOPHILIA-A; DISEASE TYPE-II; REPLACEMENT THERAPY; IMMUNE TOLERANCE; FABRY-DISEASE AB Lysosomal storage diseases are characterized by deficiencies in lysosomal enzymes, allowing accumulation of target substrate in cells and eventually causing cell death. Enzyme replacement therapy is the principal treatment for most of these diseases. However, these therapies are often complicated by immune responses to the enzymes, blocking efficacy and causing severe adverse outcomes by neutralizing product activity. It is thus crucial to understand the relationships between genetic mutations, endogenous residual enzyme proteins (cross-reactive immunologic material), development of neutralizing antibodies and their impact on clinical outcomes of lysosomal storage diseases. For patients in whom neutralizing antibodies may cause severe adverse clinical outcomes, it is paramount to develop tolerance inducing protocols to preclude, where predictable, or treat such life-threatening responses. C1 [Wang, Jinhai; Johnson, Gibbes; Kirshner, Susan; Verthelyi, Daniela; Shores, Elizabeth; Rosenberg, Amy] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Proteins, Off Biotechnol Prod, Bethesda, MD 20892 USA. [Lozier, Jay] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Pariser, Anne] US FDA, Ctr Drug Evaluat & Res, Div Gastroenterol Prod, Off New Drugs, Silver Spring, MD 20993 USA. RP Rosenberg, A (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Therapeut Proteins, Off Biotechnol Prod, NIH Bldg 29B,8800 Rockville Pike, Bethesda, MD 20892 USA. EM amy.rosenberg@fda.hhs.gov FU Intramural NIH HHS [Z01 SC003811-33] NR 88 TC 81 Z9 81 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2008 VL 26 IS 8 BP 901 EP 908 DI 10.1038/nbt.1484 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 335WX UT WOS:000258325500024 PM 18688246 ER PT J AU Gavard, J Gutkind, JS AF Gavard, Julie Gutkind, J. Silvio TI VE-cadherin and claudin-5: it takes two to tango SO NATURE CELL BIOLOGY LA English DT Editorial Material ID BETA-CATENIN; JUNCTIONS; ADHESION; MICE; PERMEABILITY; DEFICIENCY; BLOCKADE; FOXO C1 [Gavard, Julie] Univ Paris 05, CNRS, UMR8104, INSERM,Inst Cochin, F-75014 Paris, France. [Gutkind, J. Silvio] NIH, Oral & Pharyngeal Canc Branch, Natl Inst Dent, Bethesda, MD 20892 USA. [Gutkind, J. Silvio] NIH, Craniofacial Branch, Bethesda, MD 20892 USA. RP Gavard, J (reprint author), Univ Paris 05, CNRS, UMR8104, INSERM,Inst Cochin, 22 Rue Mechain, F-75014 Paris, France. EM julie.gavard@inserm.fr; gutkind@dir.nidcr.nih.gov RI Gutkind, J. Silvio/A-1053-2009; Gavard, Julie/I-5487-2012 OI Gavard, Julie/0000-0002-7985-9007 NR 16 TC 36 Z9 37 U1 1 U2 11 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 AUG PY 2008 VL 10 IS 8 BP 883 EP 885 DI 10.1038/ncb0808-883 PG 4 WC Cell Biology SC Cell Biology GA 333IV UT WOS:000258147100004 PM 18670447 ER PT J AU Lee, HS Nishanian, TG Mood, K Bong, YS Daar, IO AF Lee, Hyun-Shik Nishanian, Tagvor G. Mood, Kathleen Bong, Yong-Sik Daar, Ira O. TI EphrinB1 controls cell-cell junctions through the Par polarity complex SO NATURE CELL BIOLOGY LA English DT Article ID COLORECTAL-CANCER PROGRESSION; RECEPTOR TYROSINE KINASE; EPH RECEPTOR; EPITHELIAL TIGHT; XENOPUS EMBRYOS; PROTEIN PAR6; EYE FIELD; REVERSE; ADHESION; PHOSPHORYLATION AB A body of evidence is emerging that shows a requirement for ephrin ligands in the proper migration of cells, and the formation of cell and tissue boundaries. These processes are dependent on the cell-cell adhesion system, which plays a crucial role in normal morphogenetic processes during development, as well as in invasion and metastasis(1-9). Although ephrinB ligands are bi-directional signalling molecules, the precise mechanism by which ephrinB1 signals through its intracellular domain to regulate cell-cell adhesion in epithelial cells remains unclear. Here, we present evidence that ephrinB1 associates with the Par polarity complex protein Par-6 (a scaffold protein required for establishing tight junctions) and can compete with the small GTPase Cdc42 for association with Par-6. This competition causes inactivation of the Par complex, resulting in the loss of tight junctions. Moreover, the interaction between ephrinB1 and Par-6 is disrupted by tyrosine phosphorylation of the intracellular domain of ephrinB1. Thus, we have identified a mechanism by which ephrinB1 signalling regulates cell-cell junctions in epithelial cells, and this may influence how we devise therapeutic interventions regarding these molecules in metastatic disease. C1 [Lee, Hyun-Shik; Nishanian, Tagvor G.; Mood, Kathleen; Bong, Yong-Sik; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Daar, IO (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM daar@ncifcrf.gov RI Lee, Hyun-Shik/G-3555-2011; OI Daar, Ira/0000-0003-2657-526X FU Intramural NIH HHS [Z01 BC010006-12, Z99 CA999999] NR 35 TC 50 Z9 50 U1 0 U2 1 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 AUG PY 2008 VL 10 IS 8 BP 979 EP 986 DI 10.1038/ncb1758 PG 8 WC Cell Biology SC Cell Biology GA 333IV UT WOS:000258147100016 PM 18604196 ER PT J AU Duyn, J Koretsky, AP AF Duyn, Jeff Koretsky, Alan P. TI Magnetic resonance imaging of neural circuits SO NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE LA English DT Article DE cerebral architecture; circuit function; cortical anatomy; functional MRI; neuronal tract tracing ID MANGANESE-ENHANCED MRI; IRON-OXIDE NANOPARTICLES; HIGH-RESOLUTION MRI; SPINAL-CORD-INJURY; IN-VIVO DETECTION; HUMAN BRAIN; ALZHEIMERS-DISEASE; MULTIPLE-SCLEROSIS; FUNCTIONAL CONNECTIVITY; CLINICAL-APPLICATIONS AB A major goal of modern MRI research is to be able to image neural circuits in the central nervous system. Critical to this mission is the ability to describe a number of important parameters associated with neural circuits. These parameters include neural architecture, functional activation of neural circuits, anatomical and functional connectivity of neural circuits, and factors that might alter neural circuits, such as trafficking of immune cells and brain precursor cells in the brain. Remarkably, a variety of work in human and animal brains has demonstrated that all these features of neural circuits can be visualized with MRI. In this Article we provide a brief summary of the new directions in neural imaging research, which should prove useful in future analyses of normal and pathological human brains and in studies of animal models of neurological and psychiatric disorders. At present, few MRI data characterizing the neural circuits in the heart are available, but in this Article we discuss the applicable present developments and the prospects for the future. C1 [Duyn, Jeff; Koretsky, Alan P.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Duyn, J (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov RI Duyn, Jozef/F-2483-2010; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08] NR 71 TC 5 Z9 5 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1743-4297 J9 NAT CLIN PRACT CARD JI Nat. Clin. Pract. Cardiovasc. Med. PD AUG PY 2008 VL 5 SU 2 BP S71 EP S78 DI 10.1038/ncpcardio1248 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 329LB UT WOS:000257868000011 PM 18641610 ER PT J AU Rider, LG Leschek, EW AF Rider, Lisa G. Leschek, Ellen W. TI Does early growth hormone therapy prevent glucocorticoid-associated growth retardation in children with JIA? SO NATURE CLINICAL PRACTICE RHEUMATOLOGY LA English DT Editorial Material DE bone; glucocorticoid; growth hormone; growth retardation; juvenile idiopathic arthritis ID JUVENILE IDIOPATHIC ARTHRITIS C1 [Rider, Lisa G.] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, NIH, Bethesda, MD 20892 USA. [Leschek, Ellen W.] NIDDK, Type Diabet TrialNet Program 1, NIH, Bethesda, MD USA. RP Rider, LG (reprint author), Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, NIH, CRC 4-2352,MSC 1301,10 Ctr Dr, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458 FU Intramural NIH HHS NR 6 TC 0 Z9 0 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 AUG PY 2008 VL 4 IS 8 BP 394 EP 395 DI 10.1038/ncprheum0845 PG 2 WC Rheumatology; Social Issues SC Rheumatology; Social Issues GA 331VE UT WOS:000258039900003 PM 18607398 ER PT J AU McBride, CM Alford, SH Reid, RJ Larson, EB Baxevanis, AD Brody, LC AF McBride, Colleen M. Alford, Sharon Hensley Reid, Robert J. Larson, Eric B. Baxevanis, Andreas D. Brody, Lawrence C. TI Putting science over supposition in the arena of personalized genomics SO NATURE GENETICS LA English DT Editorial Material ID HEALTH BEHAVIOR-CHANGE; MEDICINE; DISEASES AB We explore the process of going from genome discovery to evaluation of medical impact and discuss emerging challenges faced by the scientific community. the need to confront these challenges is heightened in a climate where unregulated genetic tests are being marketed directly to the general public(1,2). Specifically, we characterize the delicate balance involved in deciding when genomic discoveries such as gene-disease associations are 'ready' to be evaluated as potential tools to improve health. We recommend that a considerable research commitment be made now in order to successfully bridge the rapidly widening gap between gene-disease association research and the critical (but slower and more involved) investigations into public health and clinical utility. Lastly, we describe a large, ongoing, early-phase research project, the multiplex Initiative, which is examining issues related to the utility of genetic susceptibility testing for common health conditions. C1 [McBride, Colleen M.] Natl Genome Res Inst, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Alford, Sharon Hensley] Henry Ford Hosp, Detroit, MI 48202 USA. [Reid, Robert J.; Larson, Eric B.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. [Baxevanis, Andreas D.; Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP McBride, CM (reprint author), Natl Genome Res Inst, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. EM cmcbride@mail.nih.gov; lbrody@helix.nih.gov FU Intramural NIH HHS [Z01 HG200344-01] NR 18 TC 63 Z9 63 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2008 VL 40 IS 8 BP 939 EP 942 DI 10.1038/ng0808-939 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 331QF UT WOS:000258026900006 PM 18665132 ER PT J AU Bryceson, YT Ljunggren, HG AF Bryceson, Yenan T. Ljunggren, Hans-Gustaf TI Arrestin NK cell cytotoxicity SO NATURE IMMUNOLOGY LA English DT Editorial Material ID TYROSINE-PHOSPHATASE SHP-1; INHIBITORY RECEPTORS AB A key regulator of the balance of signals that activate effector mechanisms versus those that restrain them, beta-arrestin 2 mediates the inhibition of natural killer cell cytotoxicity. C1 [Bryceson, Yenan T.; Ljunggren, Hans-Gustaf] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Ctr Infect Med, S-14186 Stockholm, Sweden. [Bryceson, Yenan T.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bryceson, YT (reprint author), Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Ctr Infect Med, S-14186 Stockholm, Sweden. EM yenan.bryceson@gmail.com; hans-gustaf.ljunggren@ki.se OI Bryceson, Yenan/0000-0002-7783-9934 NR 11 TC 2 Z9 2 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2008 VL 9 IS 8 BP 835 EP 836 DI 10.1038/ni0808-835 PG 2 WC Immunology SC Immunology GA 328EN UT WOS:000257780700005 PM 18645590 ER PT J AU Draper, SJ Moore, AC Goodman, AL Long, CA Holder, AA Gilbert, SC Hill, F Hill, AVS AF Draper, Simon J. Moore, Anne C. Goodman, Anna L. Long, Carole A. Holder, Anthony A. Gilbert, Sarah C. Hill, Fergal Hill, Adrian V. S. TI Effective induction of high-titer antibodies by viral vector vaccines SO NATURE MEDICINE LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; C4B-BINDING PROTEIN; MALARIA VACCINE; PROTECTION; IMMUNITY; ANTIGEN; MICE; IMMUNOGENICITY; IMMUNIZATION; FRAGMENT AB Protein-in-adjuvant vaccines have shown limited success against difficult diseases such as blood-stage malaria. Here we show that a recombinant adenovirus-poxvirus prime-boost immunization regime (known to induce strong T cell immunogenicity) can also induce very strong antigen-specific antibody responses, and we identify a simple complement-based adjuvant to further enhance immunogenicity. Antibodies induced against a blood-stage malaria antigen by this viral vector platform are highly effective against Plasmodium yoelii parasites in mice and against Plasmodium falciparum in vitro. C1 [Draper, Simon J.; Moore, Anne C.; Goodman, Anna L.; Gilbert, Sarah C.; Hill, Adrian V. S.] Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, US NIH, Rockville, MD 20852 USA. [Holder, Anthony A.] Natl Inst Med Res, Div Parasitol, London NW7 1AA, England. [Hill, Fergal] Imaxio, F-69007 Lyon, France. RP Draper, SJ (reprint author), Univ Oxford, Jenner Inst, Old Rd Campus Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England. EM simon.draper@ndm.ox.ac.uk RI HILL, Adrian/C-1306-2008; Draper, Simon/F-1758-2011; Holder, Anthony/A-7554-2013; OI Draper, Simon/0000-0002-9415-1357; Holder, Anthony/0000-0002-8490-6058; Gilbert, Sarah/0000-0002-6823-9750; Moore , Anne/0000-0003-3656-4230 FU Intramural NIH HHS [Z01 AI001020-02, Z01 AI001020-01]; Medical Research Council [, G0600424, G0700735, MC_U117532067]; Wellcome Trust NR 16 TC 88 Z9 90 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2008 VL 14 IS 8 BP 819 EP 821 DI 10.1038/nm.1850 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 334QY UT WOS:000258237500027 PM 18660818 ER PT J AU Shedden, K Taylor, JMG Enkemann, SA Tsao, MS Yeatman, TJ Gerald, WL Eschrich, S Jurisica, I Giordano, TJ Misek, DE Chang, AC Zhu, CQ Strumpf, D Hanash, S Shepherd, FA Ding, K Seymour, L Naoki, K Pennell, N Weir, B Verhaak, R Ladd-Acosta, C Golub, T Gruidl, M Sharma, A Szoke, J Zakowski, M Rusch, V Kris, M Viale, A Motoi, N Travis, W Conley, B Seshan, VE Meyerson, M Kuick, R Dobbin, KK Lively, T Jacobson, JW Beer, DG AF Shedden, Kerby Taylor, Jeremy M. G. Enkemann, Steven A. Tsao, Ming-Sound Yeatman, Timothy J. Gerald, William L. Eschrich, Steven Jurisica, Igor Giordano, Thomas J. Misek, David E. Chang, Andrew C. Zhu, Chang Qi Strumpf, Daniel Hanash, Samir Shepherd, Frances A. Ding, Keyue Seymour, Lesley Naoki, Katsuhiko Pennell, Nathan Weir, Barbara Verhaak, Roel Ladd-Acosta, Christine Golub, Todd Gruidl, Michael Sharma, Anupama Szoke, Janos Zakowski, Maureen Rusch, Valerie Kris, Mark Viale, Agnes Motoi, Noriko Travis, William Conley, Barbara Seshan, Venkatraman E. Meyerson, Matthew Kuick, Rork Dobbin, Kevin K. Lively, Tracy Jacobson, James W. Beer, David G. CA Director's Challenge Consortium Mo TI Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study SO NATURE MEDICINE LA English DT Article ID CANCER AB Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas. C1 [Lively, Tracy; Jacobson, James W.] NCI, Cancer Diag Program, Rockville, MD 20852 USA. [Shedden, Kerby] Univ Michigan, S Univ 1085, Dept Stat, Ann Arbor, MI 48109 USA. [Shedden, Kerby; Taylor, Jeremy M. G.; Misek, David E.; Chang, Andrew C.; Hanash, Samir; Kuick, Rork; Beer, David G.] Univ Michigan, Ctr Canc, Ann Arbor, MI 48109 USA. [Taylor, Jeremy M. G.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Enkemann, Steven A.; Yeatman, Timothy J.; Gruidl, Michael; Sharma, Anupama] Univ S Florida, Dept Surg, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Tsao, Ming-Sound; Jurisica, Igor; Zhu, Chang Qi; Strumpf, Daniel; Shepherd, Frances A.] Ontario Canc Inst, Univ Hlth Network, Toronto, ON M5G 2M9, Canada. [Tsao, Ming-Sound; Jurisica, Igor; Zhu, Chang Qi; Strumpf, Daniel; Shepherd, Frances A.] Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. [Gerald, William L.; Szoke, Janos; Zakowski, Maureen; Rusch, Valerie; Kris, Mark; Viale, Agnes; Motoi, Noriko; Travis, William] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Giordano, Thomas J.] Univ Michigan, Dept Pathol, Univ Hosp 2G3320054, Ann Arbor, MI 48109 USA. [Misek, David E.; Chang, Andrew C.; Beer, David G.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Ding, Keyue; Seymour, Lesley] Queens Univ, Kingston, ON K7L 3N6, Canada. [Ding, Keyue; Seymour, Lesley] Inst Canc Res, Canada Clin Trials Grp, Kingston, ON K7L 3N6, Canada. [Naoki, Katsuhiko; Pennell, Nathan; Weir, Barbara; Verhaak, Roel; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Dept Med Oncol, Boston, MA 02115 USA. [Ladd-Acosta, Christine; Golub, Todd; Meyerson, Matthew] 7 Cambridge Ctr, Broad Inst, Cambridge, MA 02142 USA. [Conley, Barbara] Michigan State Univ, Dept Med, Clin Ctr B414, E Lansing, MI 48824 USA. [Seshan, Venkatraman E.] Columbia Univ, New York, NY 10032 USA. [Dobbin, Kevin K.] Natl Canc Inst, Biometr Res Branch, Rockville, MD 20852 USA. RP Jacobson, JW (reprint author), NCI, Cancer Diag Program, EPN 6035A,6130 Execut Blvd, Rockville, MD 20852 USA. EM jacobsonj@ctep.nci.nih.gov; dgbeer@umich.edu RI Meyerson, Matthew/E-7123-2012; Eschrich, Steven/K-6848-2013; Motoi, Noriko/A-9718-2009; OI Motoi, Noriko/0000-0001-7098-3311; Kris, Mark/0000-0002-7317-5341; Chang, Andrew/0000-0001-9506-0425; Giordano, Thomas/0000-0003-0641-8873 NR 18 TC 498 Z9 505 U1 3 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2008 VL 14 IS 8 BP 822 EP 827 DI 10.1038/nm.1790 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 334QY UT WOS:000258237500028 ER PT J AU Kuznetsov, SG Liu, PT Sharan, SK AF Kuznetsov, Sergey G. Liu, Pentao Sharan, Shyam K. TI Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2 SO NATURE MEDICINE LA English DT Article ID UNKNOWN CLINICAL-SIGNIFICANCE; SEQUENCE VARIANTS; HOMOLOGOUS RECOMBINATION; CANCER-RISK; CROSS-LINKS; MICE; HYPERSENSITIVITY; RADIATION; REPAIR; CHROMOSOME AB Individuals with mutations in breast cancer susceptibility genes BRCA1 and BRCA2 have up to an 80% risk of developing breast cancer by the age of 70. Sequencing-based genetic tests are now available to identify mutation carriers in an effort to reduce mortality through prevention and early diagnosis. However, lack of a suitable functional assay hinders the risk assessment of more than 1,900 BRCA1 and BRCA2 variants in the Breast Cancer Information Core database that do not clearly disrupt the gene product. We have established a simple, versatile and reliable assay to test for the functional significance of mutations in BRCA2 using mouse embryonic stem cells (ES cells) and bacterial artificial chromosomes and have used it to classify 17 sequence variants. The assay is based on the ability of human BRCA2 to complement the loss of endogenous Brca2 in mouse ES cells. This technique may also serve as a paradigm for functional analysis of mutations found in other genes linked to human diseases. C1 [Kuznetsov, Sergey G.; Liu, Pentao; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, 1050 Boyles St, Frederick, MD 21702 USA. EM sharans@mail.nih.gov OI Kuznetsov, Sergey/0000-0002-5662-9700 FU Intramural NIH HHS [Z01 BC010387-08] NR 29 TC 45 Z9 47 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2008 VL 14 IS 8 BP 875 EP 881 DI 10.1038/nm.1719 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 334QY UT WOS:000258237500036 PM 18607349 ER PT J AU Conklin, BR Hsiao, EC Claeysen, S Dumuis, A Srinivasan, S Forsayeth, JR Guettier, JM Chang, WC Pei, Y McCarthy, KD Nissenson, RA Wess, J Bockaert, J Roth, BL AF Conklin, Bruce R. Hsiao, Edward C. Claeysen, Sylvie Dumuis, Aline Srinivasan, Supriya Forsayeth, John R. Guettier, Jean-Marc Chang, W. C. Pei, Ying McCarthy, Ken D. Nissenson, Robert A. Wess, Juergen Bockaert, Joeal Roth, Bryan L. TI Engineering GPCR signaling pathways with RASSLs SO NATURE METHODS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; DESIGNED G(I)-COUPLED RECEPTOR; SYNTHETIC LIGANDS RASSL; CONDITIONAL EXPRESSION; CONSTITUTIVE ACTIVITY; ACTIVATION; MICE; DISRUPTION; DISEASE; MODEL AB We are creating families of designer G protein coupled receptors (GPCRs) to allow for precise spatiotemporal control of GPCR signaling in vivo. These engineered GPCRs, called receptors activated solely by synthetic ligands (RASSLs), are unresponsive to endogenous ligands but can be activated by nanomolar concentrations of pharmacologically inert, drug-like small molecules. Currently, RASSLs exist for the three major GPCR signaling pathways (G(s), G(i) and G(q)). We review these advances here to facilitate the use of these powerful and diverse tools. C1 Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94122 USA. Univ Calif San Francisco, Dept Cellular, San Francisco, CA 94122 USA. Univ Calif San Francisco, Dept Mol Pharmacol, San Francisco, CA 94122 USA. Univ Calif San Francisco, Vet Affairs Med Ctr, Endocrine Res Unit, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94121 USA. CNRS, UMR 5203, Inst Genom Fonctionnelle, F-34094 Montpellier, France. Inst Natl Sante & Rech Med, U661, F-34094 Montpellier, France. Univ Montpellier, F-34094 Montpellier, France. Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94103 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Grad Program Pharmaceut Sci & Pharmacogenom, San Francisco, CA 94143 USA. Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Conklin, BR (reprint author), Gladstone Inst Cardiovasc Dis, 1650 Owens St, San Francisco, CA 94158 USA. EM bconklin@gladstone.ucsf.edu RI Roth, Bryan/F-3928-2010; Claeysen, Sylvie/C-8599-2014 OI Claeysen, Sylvie/0000-0002-0576-5518 FU NCRR NIH HHS [C06 RR018928]; NHLBI NIH HHS [HL60664-07, R01 HL060664, R01 HL060664-08, R01 HL060664-09, R01 HL060664-10, R01 HL060664-11]; NIDDK NIH HHS [R01 DK072071, DK072071, R01 DK035323, R56 DK072071]; NIMH NIH HHS [R01 MH061887, U19 MH082441, U19 MH082441-020001, U19MH82441] NR 37 TC 120 Z9 120 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD AUG PY 2008 VL 5 IS 8 BP 673 EP 678 DI 10.1038/nmeth.1232 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 332IT UT WOS:000258077400009 PM 18668035 ER PT J AU Carriba, P Navarro, G Ciruela, F Ferre, S Casado, V Agnati, L Cortes, A Mallol, J Fuxe, K Canela, EI Lluis, C Franco, R AF Carriba, Paulina Navarro, Gemma Ciruela, Francisco Ferre, Sergi Casado, Vicent Agnati, Luigi Cortes, Antoni Mallol, Josefa Fuxe, Kjell Canela, Enric I. Lluis, Carmen Franco, Rafael TI Detection of heteromerization of more than two proteins by sequential BRET-FRET SO NATURE METHODS LA English DT Article ID RESONANCE ENERGY-TRANSFER; COUPLED RECEPTORS; LIVING CELLS; ADENOSINE A(2A); CANNABINOID CB1; KINASE CASCADES; G-ALPHA; DIMERIZATION; ACTIVATION; GAMMA AB Identification of higher-order oligomers in the plasma membrane is essential to decode the properties of molecular networks controlling intercellular communication. We combined bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) in a technique called sequential BRET-FRET (SRET) that permits identification of heteromers formed by three different proteins. In SRET, the oxidation of a Renilla luciferase (Rluc) substrate by an Rluc fusion protein triggers acceptor excitation of a second fusion protein by BRET and subsequent FRET to a third fusion protein. We describe two variations of SRET that use different Rluc substrates with appropriately paired acceptor fluorescent proteins. Using SRET, we identified complexes of cannabinoid CB(1), dopamine D(2) and adenosine A(2A) receptors in living cells. SRET is an invaluable technique to identify heteromeric complexes of more than two neurotransmitter receptors, which will allow us to better understand how signals are integrated at the molecular level. C1 Ctr Appl Med Res, Pamplona 31008, Spain. Univ Barcelona, Dept Biochem & Mol Biol, Fac Biol, E-08028 Barcelona, Spain. Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Univ Modena, Dept Biochem Sci, I-41100 Modena, Italy. Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. Univ Barcelona, Ctr Invest Biomed Red Sobre Enfermedades Neurodeg, Inst Invest Biomed August Pi & Sunyer, E-08028 Barcelona, Spain. RP Franco, R (reprint author), Ctr Appl Med Res, Neurociencias Avda Pio XII 55, Pamplona 31008, Spain. EM rfranco@unav.es RI Canela, Enric I./M-8726-2013; Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; OI Canela, Enric I./0000-0003-4992-7440; Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919; Fuxe, Kjell/0000-0001-8491-4288; Casado, Vicent/0000-0002-1764-3825 FU Intramural NIH HHS NR 30 TC 171 Z9 175 U1 4 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD AUG PY 2008 VL 5 IS 8 BP 727 EP 733 DI 10.1038/nmeth.1229 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 332IT UT WOS:000258077400017 PM 18587404 ER PT J AU Baker, CI AF Baker, Chris I. TI Face to face with cortex SO NATURE NEUROSCIENCE LA English DT Editorial Material ID CORTICAL NETWORK; TEMPORAL CORTEX; MACAQUE; PATCHES; NEURONS; LOBE; MAPS; FMRI AB Two new studies in Science and Nature Neuroscience combine functional magnetic resonance imaging and electrical microstimulation to reveal face-selective temporal and frontal areas and their connectivity. C1 US Natl Inst Mental Hlth, Lab Brain & Cognit, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Baker, CI (reprint author), US Natl Inst Mental Hlth, Lab Brain & Cognit, US Natl Inst Hlth, 10 Ctr Dr,Bldg 10,Room 3N228, Bethesda, MD 20892 USA. EM bakerchris@mail.nih.gov OI Baker, Chris/0000-0001-6861-8964 NR 15 TC 1 Z9 1 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2008 VL 11 IS 8 BP 862 EP 864 DI 10.1038/nn0808-862 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 330UU UT WOS:000257969100005 PM 18660838 ER PT J AU Li, MF Chang, TH Silberberg, SD Swartz, KJ AF Li, Mufeng Chang, Tsg-Hui Silberberg, Shai D. Swartz, Kenton J. TI Gating the pore of P2X receptor channels SO NATURE NEUROSCIENCE LA English DT Article ID NUCLEOTIDE-GATED CHANNELS; TRANSMEMBRANE DOMAIN; POTASSIUM CHANNELS; STRUCTURAL MOTIF; CELL-SURFACE; ION CHANNELS; K+ CHANNEL; RESIDUES; REARRANGEMENTS; SELECTIVITY AB Three families of ligand-activated ion channels mediate synaptic communication between excitable cells in mammals. For pentameric channels related to nicotinic acetylcholine receptors and tetrameric channels such as glutamate receptors, the pore-forming and gate regions have been studied extensively. In contrast, little is known about the structure of trimeric P2X receptor channels, a family of channels that are activated by ATP and are important in neuronal signaling, pain transmission and inflammation. To identify the pore-forming and gate regions in P2X receptor channels, we introduced cysteine residues throughout the two transmembrane (TM) segments and studied their accessibility to thiol-reactive compounds and ions. Our results show that TM2 lines the central ion-conduction pore, TM1 is positioned peripheral to TM2 and the flow of ions is minimized in the closed state by a gate formed by the external region of TM2. C1 [Li, Mufeng; Chang, Tsg-Hui; Silberberg, Shai D.; Swartz, Kenton J.] US Natl Inst Neurol Disorders & Stroke, Mol Phys & Biophys Sect, Porter Neurosci Res Ctr, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Silberberg, SD (reprint author), US Natl Inst Neurol Disorders & Stroke, Mol Phys & Biophys Sect, Porter Neurosci Res Ctr, US Natl Inst Hlth, 35 Convent Dr,MSC 3701, Bethesda, MD 20892 USA. EM silberbs@ninds.nih.gov; swartzk@ninds.nih.gov RI Li, Mufeng/A-7859-2010 FU Intramural NIH HHS [ZIA NS003018-03] NR 36 TC 67 Z9 70 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2008 VL 11 IS 8 BP 883 EP 887 DI 10.1038/nn.2151 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 330UU UT WOS:000257969100012 PM 18587390 ER PT J AU Lundberg, JO Weitzberg, E Gladwin, MT AF Lundberg, Jon O. Weitzberg, Eddie Gladwin, Mark T. TI Downsides to the nitrate-nitrite-nitric oxide pathway in physiology and therapeutics? Reply from Lundberg, Weitzberg and Gladwin SO NATURE REVIEWS DRUG DISCOVERY LA English DT Letter ID VASODILATION; REDUCTION; HUMANS C1 [Lundberg, Jon O.; Weitzberg, Eddie] Karolinska Inst, Dept Physiol & Pharmacol, Sect Anesthesiol & Intens Care, SE-17177 Stockholm, Sweden. [Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Gladwin, Mark T.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Lundberg, JO (reprint author), Karolinska Inst, Dept Physiol & Pharmacol, Sect Anesthesiol & Intens Care, SE-17177 Stockholm, Sweden. EM jon.lundberg@ki.se; eddie.weitzberg@ki.se; mgladwin@mail.nih.gov NR 15 TC 0 Z9 0 U1 3 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD AUG PY 2008 VL 7 IS 8 DI 10.1038/nrd2466-c2 PG 1 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 332QQ UT WOS:000258098600018 ER PT J AU Mindell, JA AF Mindell, Joseph A. TI The chloride channel's appendix SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID CLC PROTEINS; PERMEATION; ANION AB All CLC proteins transport Cl(-) across membranes. However, the family includes both Cl(-) channels and Cl(-)/H(+) antiporters, proteins once thought to operate by dramatically different mechanisms. An apparent evolutionary relic, a proton-transport apparatus in a CLC channel, reveals deep intertwinings between channel and transporter mechanisms. C1 NINDS, Membrane Transport Biophys Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mindell, JA (reprint author), NINDS, Membrane Transport Biophys Unit, Porter Neurosci Res Ctr, NIH, 35 Convent Dr,Bldg 35,MSC 3701, Bethesda, MD 20892 USA. EM mindellj@ninds.nih.gov OI Mindell, Joseph/0000-0002-6952-8247 NR 17 TC 5 Z9 5 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2008 VL 15 IS 8 BP 781 EP 783 DI 10.1038/nsmb0808-781 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 333ZC UT WOS:000258191100006 PM 18679432 ER PT J AU Zhou, Z Feng, HQ Hansen, DF Kato, H Luk, E Freedberg, DI Kay, LE Wu, C Bai, YW AF Zhou, Zheng Feng, Hanqiao Hansen, D. Flemming Kato, Hidenori Luk, Ed Freedberg, Daron I. Kay, Lewis E. Wu, Carl Bai, Yawen TI NMR structure of chaperone Chz1 complexed with histones H2A.Z-H2B SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID NUCLEOSOME CORE PARTICLE; CRYSTAL-STRUCTURE; EXCHANGE; H2AZ AB The NMR structure of budding yeast chaperone Chz1 complexed with histones H2A.Z-H2B has been determined. Chz1 forms a long irregular chain capped by two short alpha-helices, and uses both positively and negatively charged residues to stabilize the histone dimer. A molecular model that docks Chz1 onto the nucleosome has implications for its potential functions. C1 [Zhou, Zheng; Feng, Hanqiao; Kato, Hidenori; Luk, Ed; Wu, Carl; Bai, Yawen] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hansen, D. Flemming; Kay, Lewis E.] Univ Toronto, Dept Med Genet Biochem & Chem, Toronto, ON M5S 1A8, Canada. [Freedberg, Daron I.] US FDA, NMR Spect Lab Bacterial Polysaccharides, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov OI Luk, Ed/0000-0002-6619-2258 FU Intramural NIH HHS [Z01 BC010808-01] NR 10 TC 54 Z9 55 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2008 VL 15 IS 8 BP 868 EP 869 DI 10.1038/nsmb.1465 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 333ZC UT WOS:000258191100023 PM 18641662 ER PT J AU Hollander, MC Balogh, AR Liwanag, J Han, W Linnoila, I Anver, MR Dennis, P AF Hollander, M. Christine Balogh, Andria R. Liwanag, Jaminelli Han, Wei Linnoila, Ilona Anver, Miriam R. Dennis, Phillip TI Strain-specific spontaneous and NNK-mediated tumorigenesis in Pten +/- mice SO NEOPLASIA LA English DT Article ID CELL LUNG-CANCER; K-RAS PROTOONCOGENE; TUMORS; MOUSE; ACTIVATION; SUSCEPTIBILITY; EXPRESSION; PATHWAY; CARCINOGENESIS; NITROSAMINES AB Pten is a negative regulator of the Akt pathway, and its inactivation is believed to be an etiological factor in many tumor types. Pten +/- mice are susceptible to a variety of spontaneous tumor types, depending on strain background. Pten +/- mice, in lung tumor-sensitive and -resistant background strains, were treated with a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether allelic Pten deletion can cooperate with NNK in carcinogenesis in lung or other tissues. In lung tumor-resistant C57BL/6 Pten +/- or +/+ mice, NNK treatment did not lead to any lung tumors and did not increase the incidence or severity of tumors previously reported for this strain. In contrast, in a lung tumor-susceptible pseudo -A/J strain, there was a dose-dependent increase in lung tumor size in Pten +/- compared with +/+ mice, although there was no increase in multiplicity. No other tumor types were observed in pseudo -A/J Pten +/- mice regardless of NNK treatment. Lung tumors from these Pten +/- mice had K-ras mutations, retained Pten expression and had similar Akt pathway activation as lung tumors from +/+ mice. Therefore, deletion of a single copy of Pten does not substantially add to the lung tumor phenotype conferred by mutation of K-ras by NNK, and there is likely no selective advantage for loss of the second Pten allele in lung tumor initiation. C1 [Dennis, Phillip] NCI, Med Oncol Branch, NIH, Bethesda, MD 20889 USA. RP Dennis, P (reprint author), NCI, Med Oncol Branch, NIH, 8901 Wisconsin Ave,Bldg 8,Rm 5101, Bethesda, MD 20889 USA. EM dennisp@mail.nih.gov NR 28 TC 12 Z9 13 U1 0 U2 0 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD AUG PY 2008 VL 10 IS 8 BP 866 EP 872 DI 10.1593/neo.08406 PG 7 WC Oncology SC Oncology GA 336YA UT WOS:000258401500012 PM 18683321 ER PT J AU Isenberg, JS Hyodo, F Ridnour, LA Shannon, CS Wink, DA Krishna, MC Roberts, DD AF Isenberg, Jeff S. Hyodo, Fuminori Ridnour, Lisa A. Shannon, Caitlin S. Wink, David A. Krishna, Murali C. Roberts, David D. TI Thrombospondin 1 and vasoactive agents indirectly alter tumor blood flow SO NEOPLASIA LA English DT Article ID NITRIC-OXIDE SYNTHASE; VASCULAR-PERMEABILITY; LIVER METASTASES; CELL-LINES; EXPERIMENTAL-MODEL; ISCHEMIC TISSUE; BREAST-CANCER; ANGIOGENESIS; EXPRESSION; PROGRESSION AB Nitric oxide ( NO) plays important physiological roles in the vasculature to regulate angiogenesis, blood flow, and hemostasis. In solid tumors, NO is generally acknowledged to mediate angiogenic responses to several growth factors. This contrasts with conflicting evidence that NO can acutely increase tumor perfusion through local vasodilation or diminish perfusion by preferential relaxation of peripheral vascular beds outside the tumor. Because thrombospondin 1 (TSP1) is an important physiological antagonist of NO in vascular cells, we examined whether, in addition to inhibiting tumor angiogenesis, TSP1 can acutely regulate tumor blood flow. We assessed this activity of TSP1 in the context of perfusion responses to NO as a vasodilator and epinephrine as a vasoconstrictor. Nitric oxide treatment of wild type and TSP1 null mice decreased perfusion of a syngeneic melanoma, whereas epinephrine transiently increased tumor perfusion. Acute vasoactive responses were also independent of the level of tumor-expressed TSP1 in a melanoma xenograft, but recovery of basal perfusion was modulated by TSP1 expression. In contrast, overexpression of truncated TSP1 lacking part of its CD47 binding domain lacked this modulating activity. These data indicate that TSP1 primarily regulates long-term vascular responses in tumors, in part, because the tumor vasculature has a limited capacity to acutely respond to vasoactive agents. C1 [Roberts, David D.] NIH, Bethesda, MD 20892 USA. 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; OI Roberts, David/0000-0002-2481-2981; `, Caitlin/0000-0002-1680-421X FU Intramural NIH HHS NR 63 TC 22 Z9 22 U1 0 U2 2 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD AUG PY 2008 VL 10 IS 8 BP 886 EP U94 DI 10.1593/neo.08264 PG 12 WC Oncology SC Oncology GA 336YA UT WOS:000258401500014 PM 18670646 ER PT J AU Lonn, S Rothman, N Shapiro, WR Fine, HA Selker, RG Black, PM Loeffler, JS Hutchinson, AA Inskip, PD AF Lonn, Stefan Rothman, Nathaniel Shapiro, William R. Fine, Howard A. Selker, Robert G. Black, Peter M. Loeffler, Jay S. Hutchinson, Amy A. Inskip, Peter D. TI Genetic variation in insulin-like growth factors and brain tumor risk SO NEURO-ONCOLOGY LA English DT Article DE central nervous system; glioma; insulin-like growth factor; meningioma; single nucleotide polymorphism ID FACTOR-I RECEPTOR; HARDY-WEINBERG EQUILIBRIUM; PROSTATE-CANCER RISK; BINDING PROTEIN-3; TUMORIGENESIS; POLYMORPHISMS; ASSOCIATIONS; ETIOLOGY; ADULTS; IGF1 AB Many studies support a role for insulin-like growth factors (IGFs) in the regulation of tumor cell biology. We hypothesized that single-nucleotide polymorphisms (SNPs) in IGF genes are risk factors for glioma and meningioma. To test the hypothesis, we examined associations of brain tumor risk with nine variants in five IGF genes in a hospital-based case-control study. The study was conducted at hospitals in Boston, Phoenix, and Pittsburgh between 1994 and 1998. Eligible cases were individuals (18 years or older) newly diagnosed with glioma or meningioma. Controls were selected among patients who were admitted to the same hospitals for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race, and distance from residence. The present analysis was restricted to non-Hispanic whites. DNA was extracted from blood samples collected from 354 glioma cases, 133 meningioma cases, and 495 control individuals. We evaluated nine SNPs in five IGF genes (IGF1, IGF1R, IGF2, IGF2R, and IGFBP3). The majority of the analyzed IGF SNPs did not display statistically significant associations with glioma or meningioma. For glioma, one IGF1R SNP (rs2272037) indicated a possible association. No indications of asso-ciation were seen for glioblastoma, but for low-grade gliomas, the odds ratio under a dominant model was 0.56 (95% confidence interval [CI], 0.35-0.90) for IGF1 rs6220, 2.98 (95% CI, 1.65-5.38) for IGF1R rs2272037, and 1.60 (95% CI, 0.90-2.83) for IGF1R rs2016347. Overall, our results do not provide strong evidence of associations of brain tumor risk with IGF polymorphic variants but identify several associations for glioma that warrant further examination in other, larger studies. C1 [Lonn, Stefan; Rothman, Nathaniel; Inskip, Peter D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fine, Howard A.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Shapiro, William R.] St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ USA. [Selker, Robert G.] Western Penn Hosp, Pittsburgh, PA 15224 USA. [Black, Peter M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Loeffler, Jay S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Hutchinson, Amy A.] NCI, Div Canc Epidemiol & Genet, Core Genotyping Facil, Adv Technol Ctr,SAIC Frederick Inc, Frederick, MD 21701 USA. RP Lonn, S (reprint author), NCI, Div Canc Epidemiol & Genet, Room 7053,6120 Execut Blvd, Bethesda, MD 20892 USA. EM Stefan.Lonn@ki.se FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. government. NR 20 TC 17 Z9 17 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2008 VL 10 IS 4 BP 553 EP 559 DI 10.1215/15228517-2008-026 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 340XS UT WOS:000258678900004 PM 18562769 ER PT J AU Mautner, VF Asuagbor, FA Dombi, E Funsterer, C Kluwe, L Wenzel, R Widemann, BC Friedman, JM AF Mautner, Victor-F. Asuagbor, Florence A. Dombi, Eva Fuensterer, Carsten Kluwe, Lan Wenzel, Ralf Widemann, Brigitte C. Friedman, Jan M. TI Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1 SO NEURO-ONCOLOGY LA English DT Article DE malignant peripheral nerve sheath tumor; MRI; neurofibromas; neurofibromatosis 1 ID NERVE SHEATH TUMORS; NF1 GENE; EMISSION-TOMOGRAPHY; TYPE-1; MPNST; PET; MALIGNANCY; MANAGEMENT; MORTALITY; FREQUENCY AB People with neurofibromatosis 1 (NF1) have multiple benign neurofibromas and a 10% lifetime risk of developing malignant peripheral nerve sheath tumors (MPNSTs). Most MPNSTs develop from benign plexiform neurofibromas, so the burden of benign tumors may be a risk factor for developing MPNST. We studied 13 NF1 patients with MPNSTs and 26 age-and sex-matched controls (NF1 patients who did not have MPNSTs) with detailed clinical examinations and whole-body MRI to characterize their body burden of internal benign neurofibromas. Internal plexiform neurofibromas were identified in 22 (56%) of the 39 NF1 patients studied. All six of the NF1 patients with MPNSTs under 30 years of age had neurofibromas visualized on whole-body MRI, compared to only 3 of 11 matched NF1 controls under age 30 (p < 0.05). Both the median number of plexiform neurofibromas (p < 0.05) and the median neurofibroma volume (p < 0.01) on whole- body MRI were significantly greater among MPNST patients younger than 30 years of age than among controls. No significant differences in whole- body MRI findings were observed between NF1 patients with MPNSTs and controls who were 30 years of age or older. Whole-body MRI of NF1 patients allows assessment of the burden of internal neurofibromas, most of which are not apparent on physical examination. Whole-body imaging of young NF1 patients may allow those at highest risk for developing MPNST to be identified early in life. Close surveillance of these high-risk patients may permit earlier diagnosis and more effective treatment of MPNSTs that develop. C1 [Mautner, Victor-F.; Asuagbor, Florence A.] Univ Hosp Eppendorf, Dept Maxillofacial Surg, Hamburg, Germany. [Kluwe, Lan] Univ Hosp Eppendorf, Lab Tumor Biol & Dev Disorders, Hamburg, Germany. [Asuagbor, Florence A.; Fuensterer, Carsten; Wenzel, Ralf] MRI Inst, Hamburg Othmarschen, Germany. [Dombi, Eva; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Friedman, Jan M.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. RP Friedman, JM (reprint author), Womens & Childrens Hosp, Med Genet Res Unit, Box 153,4500 Oak St, Vancouver, BC V6H 3N1, Canada. EM frid@interchange.ubc.ca NR 44 TC 53 Z9 53 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2008 VL 10 IS 4 BP 593 EP 598 DI 10.1215/15228517-2008-011 PG 6 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 340XS UT WOS:000258678900009 PM 18559970 ER PT J AU Chang, SM Lamborn, KR Kuhn, JG Yung, WKA Gilbert, MR Wen, PY Fine, HA Mehta, MP DeAngelis, LM Lieberman, FS Cloughesy, TF Robins, HI Abrey, LE Prados, MD AF Chang, Susan M. Lamborn, Kathleen R. Kuhn, John G. Yung, W. K. Alfred Gilbert, Mark R. Wen, Patrick Y. Fine, Howard A. Mehta, Minesh P. DeAngelis, Lisa M. Lieberman, Frank S. Cloughesy, Timothy F. Robins, H. Ian Abrey, Lauren E. Prados, Michael D. CA N Amer Brain Tumor Consortium TI Neurooncology clinical trial design for targeted therapies: Lessons learned from the North American Brain Tumor Consortium SO NEURO-ONCOLOGY LA English DT Review DE brain tumor; clinical trials; North American Brain Tumor Consortium; targeted therapies ID RECURRENT MALIGNANT GLIOMA; PHASE-II TRIAL; GROWTH-FACTOR RECEPTOR; GLIOBLASTOMA-MULTIFORME; DRUG DEVELOPMENT; ANTIEPILEPTIC DRUGS; ANTICANCER THERAPY; IRINOTECAN CPT-11; TASK-FORCE; CANCER AB The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study. C1 [Chang, Susan M.; Lamborn, Kathleen R.; Prados, Michael D.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Kuhn, John G.] Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. [Yung, W. K. Alfred; Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fine, Howard A.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Mehta, Minesh P.; Robins, H. Ian] Univ Wisconsin Hosp, Madison, WI USA. [DeAngelis, Lisa M.; Abrey, Lauren E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lieberman, Frank S.] Univ Pittsburgh, Med Ctr Canc Pavil, Div Neurooncol, Pittsburgh, PA USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, David Geffen Sch Med, Neurooncol Program, Los Angeles, CA 90095 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. RP Chang, SM (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 400 Parnassus Ave,A-808, San Francisco, CA 94143 USA. EM changs@neurosurg.ucsf.edu RI Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; mehta, minesh/0000-0002-4812-5713 FU NCATS NIH HHS [UL1 TR000005]; NCI NIH HHS [CA 105663-03, CA 16672, CA 62399, CA 62405, CA 62407-13, CA 62412, CA 62421, CA 62422, CA 62426, U01 CA062399]; NCRR NIH HHS [1U11RR025011, M01-RR00056, M01-RR00079, M01-RR0865] NR 45 TC 20 Z9 20 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2008 VL 10 IS 4 BP 631 EP 642 DI 10.1215/15228517-2008-021 PG 12 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 340XS UT WOS:000258678900014 PM 18559968 ER PT J AU van Dyck, CH Avery, RA MacAvoy, MG Marek, KL Quinlan, DM Baldwin, RM Seibyl, JP Innis, RB Arnsten, AFT AF van Dyck, Christopher H. Avery, Robert A. MacAvoy, Martha G. Marek, Kenneth L. Quinlan, Donald M. Baldwin, Ronald M. Seibyl, John P. Innis, Robert B. Arnsten, Amy F. T. TI Striatal dopamine transporters correlate with simple reaction time in elderly subjects SO NEUROBIOLOGY OF AGING LA English DT Article DE aging; simple reaction time; finger tapping; dopamine transporter; dopamine; [I-123]beta-CIT; SPECT ID POSITRON EMISSION TOMOGRAPHY; HEALTHY-HUMAN SUBJECTS; AGE-DEPENDENT DECLINE; HUMAN-BRAIN; PARKINSONS-DISEASE; UPTAKE SITES; MOVEMENT INITIATION; RECEPTORS; BINDING; SPECT AB The decline in motor performance that accompanies advanced age has unclear neurobiological substrates but may relate, in part, to degeneration of the nigrostriatal dopamine system. This research tested the hypothesis that striatal dopamine transporter (DAT) availability in healthy elderly individuals was related to measures of motor performance. Thirty-six healthy volunteers (18 male, 18 female) who ranged in age from 68 to 88 (75.4 +/- 4.9 years) received a neuropsychological evaluation that included two primary motor measures (tested with dominant hand): (1) simple reaction time (SRT); and (2) finger tapping (FT). Subjects underwent SPECT scanning with [I-123]2 beta-carbomethoxy-3 beta(4-iodophenyl)tropane ([I-123]beta-CIT) for measurement of striatal DAT availability. A ratio of specific to nondisplaceable brain uptake (i.e., V3 '' = [striatal - occipital]/occipital), a measure proportional to the binding potential (B-max/K-D), was derived. SRT was significantly correlated with striatal DAT availability with or without controlling for the contribution of age. However, contrary to hypothesis, FT was not correlated with striatal DAT availability. Comparison measures, including episodic memory and general intelligence, were also unrelated to striatal DAT availability. These results demonstrate that a loss of nigrostriatal dopaminergic function likely contributes to slowing of reaction speed with advancing age. (c) 2007 Elsevier Inc. All rights reserved. C1 [van Dyck, Christopher H.] Yale Univ, Sch Med, Alzheimers Dis Res Unit, Dept Psychiat, New Haven, CT 06510 USA. [van Dyck, Christopher H.; Arnsten, Amy F. T.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA. [Marek, Kenneth L.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Seibyl, John P.] Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Innis, Robert B.] NIMH, IRP, Natl Inst Hlth, Bethesda, MD 20892 USA. RP van Dyck, CH (reprint author), Yale Univ, Sch Med, Alzheimers Dis Res Unit, Dept Psychiat, 1 Church St,Suite 600, New Haven, CT 06510 USA. EM christopher.vandyck@yale.edu OI Avery, Robert/0000-0003-1453-7282 FU Intramural NIH HHS; NIMH NIH HHS [R01 MH058620, R43-MH48243, R01 MH058620-02, R01 MH058620-01A2, MH58620] NR 53 TC 11 Z9 11 U1 1 U2 2 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 AUG PY 2008 VL 29 IS 8 BP 1237 EP 1246 DI 10.1016/j.neurobiolaging.2007.02.012 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 321KF UT WOS:000257302900014 PM 17363113 ER PT J AU Stephan, KE Riera, JJ Deco, G Horwitz, B AF Stephan, Klaas Enno Riera, Jorge J. Deco, Gustavo Horwitz, Barry TI The Brain Connectivity Workshops: Moving the frontiers of computational systems neuroscience SO NEUROIMAGE LA English DT Editorial Material DE neural systems analysis; effective connectivity; nonlinear dynamics; fMRI; EEG; MEG; DCM; model comparison; resting state; microcircuits ID PRIMATE CEREBRAL-CORTEX; CENTRAL-NERVOUS-SYSTEM; DYNAMIC CAUSAL-MODELS; NEURAL MASS MODEL; FUNCTIONAL CONNECTIVITY; NEURONAL DYNAMICS; STOCHASTIC RESONANCE; EVOKED-RESPONSES; WORKING-MEMORY; LOW-FREQUENCY AB Understanding the link between neurobiology and cognition requires that neuroscience moves beyond mere structure-function correlations. An explicit systems perspective is needed in which putative mechanisms of how brain function is constrained by brain structure are mathematically formalized and made accessible for experimental investigation. Such a systems approach critically rests on a better understanding of brain connectivity, in its various forms. Since 2002, frontier topics of connectivity and neural system analysis have been discussed in a multidisciplinary annual meeting, the Brain Connectivity Workshop (BCW), bringing together experimentalists and theorists from various fields. This article summarizes some of the main discussions at the two most recent workshops, 2006 at Sendai, Japan, and 2007 at Barcelona, Spain: (i) investigation of cortical micro- and macrocircuits, (ii) models of neural dynamics at multiple scales, (iii) analysis of "resting state" networks, and (iv) linking anatomical to functional connectivity. Finally, we outline some central challenges and research trajectories in computational systems neuroscience for the next years. (C) 2008 Elsevier Inc. All rights reserved. C1 [Stephan, Klaas Enno] UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Stephan, Klaas Enno] Univ Zurich, BWL, Ctr Study Social & Neural Syst, Inst Empir Res Econ, CH-8006 Zurich, Switzerland. [Riera, Jorge J.] Tohoku Univ, IDAC, Sendai, Miyagi 980, Japan. [Deco, Gustavo] Univ Pompeu Fabra, ICREA, Dept Technol, Barcelona, Spain. [Horwitz, Barry] NIDCD, Brain Imaging & Modeling Sect, NIH, Bethesda, MD USA. RP Stephan, KE (reprint author), UCL, Wellcome Trust Ctr Neuroimaging, 12 Queen Sq, London WC1N 3BG, England. EM k.stephan@fil.ion.ucl.ac.uk RI Bonatti, Luca /E-9048-2011; Brain and Cognition, Center/H-5448-2011; Deco, Gustavo/A-6341-2008; OI Deco, Gustavo/0000-0002-8995-7583; Stephan, Klaas Enno/0000-0002-8594-9092 FU Intramural NIH HHS [NIH0010163596, Z01 DC000057-08]; Wellcome Trust [056750] NR 101 TC 30 Z9 30 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2008 VL 42 IS 1 BP 1 EP 9 DI 10.1016/j.neuroimage.2008.04.167 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 332TC UT WOS:000258105000001 PM 18511300 ER PT J AU Sanchez-Pernaute, R Wang, JQ Kuruppu, D Cao, L Tueckmantel, W Kozikowski, A Isacson, O Brownell, AL AF Sanchez-Pernaute, R. Wang, J. -Q. Kuruppu, D. Cao, L. Tueckmantel, W. Kozikowski, A. Isacson, O. Brownell, A. -L. TI Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates SO NEUROIMAGE LA English DT Article ID DOPA-INDUCED DYSKINESIA; RAT MODEL; DISEASE; ANTAGONISM; MODULATION; BLOCKADE; LOOP AB The interplay between dopamine and glutamate in the basal ganglia regulates critical aspects of motor learning and behavior. Metabotropic glutamate receptors (mGluR) are increasingly regarded as key modulators of neuroadaptation in these circuits, in normal and disease conditions. Using PET, we demonstrate a significant upregulation of mGluR type 5 in the striatum of MPTP-lesioned, parkinsonian primates' providing the basis for therapeutic exploration of mGluR5 antagonists in Parkinson disease. (C) 2008 Elsevier Inc. All rights reserved. C1 [Wang, J. -Q.; Kuruppu, D.; Cao, L.; Brownell, A. -L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sanchez-Pernaute, R.; Isacson, O.; Brownell, A. -L.] Harvard Univ, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02178 USA. [Sanchez-Pernaute, R.; Isacson, O.] McLean Hosp, Neuroregenerat Labs, Belmont, MA 02178 USA. [Tueckmantel, W.; Kozikowski, A.] Acenta Discovery Inc, Tucson, AZ USA. RP Brownell, AL (reprint author), Massachusetts Gen Hosp, Bartlett Hall 504R, Boston, MA 02114 USA. EM abrownell@partners.org RI Cao, Lei/B-3254-2012 OI Cao, Lei/0000-0003-4018-9496 FU NIBIB NIH HHS [1R01 EB001850, R01 EB001850, R01 EB001850-04, R01 EB012864]; NIMH NIH HHS [R01 MH091684]; NINDS NIH HHS [1P50 NS39793, P50 NS039793, P50 NS039793-059001, P50 NS039793-08] NR 20 TC 26 Z9 26 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2008 VL 42 IS 1 BP 248 EP 251 DI 10.1016/j.neuroimage.2008.04.170 PG 4 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 332TC UT WOS:000258105000024 PM 18501638 ER PT J AU Lowell, SY Poletto, CJ Knorr-Chung, BR Reynolds, RC Simonyan, K Ludlow, CL AF Lowell, Soren Y. Poletto, Christopher J. Knorr-Chung, Bethany R. Reynolds, Richard C. Simonyan, Kristina Ludlow, Christy L. TI Sensory stimulation activates both motor and sensory components of the swallowing system SO NEUROIMAGE LA English DT Article ID CEREBRAL CORTICAL REPRESENTATION; PRIMARY SOMATOSENSORY CORTEX; HUMAN PARIETAL OPERCULUM; IMAGINED HAND MOVEMENTS; INTERINDIVIDUAL VARIABILITY; THERMAL APPLICATION; AREAS 3A; FMRI; BRAIN; HUMANS AB Volitional swallowing in humans involves the coordination of both brainstem and cerebral swallowing control regions. Peripheral sensory inputs are necessary for safe and efficient swallowing, and their importance to the patterned components of swallowing has been demonstrated. However, the role of sensory inputs to the cerebral system during volitional swallowing is less clear. We used four conditions applied during functional magnetic resonance imaging to differentiate between sensory, motor planning, and motor execution components for cerebral control of swallowing. Oral air pulse stimulation was used to examine the effect of sensory input, covert swallowing was used to engage motor planning for swallowing, and overt swallowing was used to activate the volitional swallowing system. Breath-holding was also included to determine whether its effects could account for the activation seen during overt swallowing. Oral air pulse stimulation, covert swallowing and overt swallowing all produced activation in the primary motor cortex, cingulate cortex, putamen and insula. Additional regions of the swallowing cerebral system that were activated by the oral air pulse stimulation condition included the primary and secondary somatosensory cortex and thalamus. Although air pulse stimulation was on the right side only, bilateral cerebral activation occurred. On the other hand, covert swallowing minimally activated sensory regions, but did activate the supplementary motor area and other motor regions. Breath-holding did not account for the activation during overt swallowing. The effectiveness of oral-sensory stimulation for engaging both sensory and motor components of the cerebral swallowing system demonstrates the importance of sensory input in cerebral swallowing control. C1 [Lowell, Soren Y.; Poletto, Christopher J.; Knorr-Chung, Bethany R.; Simonyan, Kristina; Ludlow, Christy L.] NINDS, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. [Reynolds, Richard C.] NIMH, NIH, Bethesda, MD 20892 USA. RP Ludlow, CL (reprint author), 10 Ctr Dr,MSC 1416, Bethesda, MD 20892 USA. EM ludlowc@ninds.nih.gov OI Simonyan, Kristina/0000-0001-7444-0437; Ludlow, Christy/0000-0002-2015-6171 FU Intramural NIH HHS [Z01 NS002980-09, Z99 NS999999] NR 60 TC 53 Z9 56 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 AUG 1 PY 2008 VL 42 IS 1 BP 285 EP 295 DI 10.1016/j.neuroimage.2008.04.234 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 332TC UT WOS:000258105000028 PM 18515150 ER PT J AU Oh, U Jacobson, S AF Oh, Unsong Jacobson, Steven TI Treatment of HTLV-I-associated myelopathy/tropical spastic paraparesis: Toward rational targeted therapy SO NEUROLOGIC CLINICS LA English DT Article ID VIRUS TYPE-I; T-CELL LEUKEMIA; CENTRAL-NERVOUS-SYSTEM; TYPE-1 PROVIRAL LOAD; SPINAL-CORD LESIONS; NEUROLOGIC DISEASE; PERIPHERAL-BLOOD; INTERFERON-ALPHA; HAM/TSP PATIENTS; HTLV-1-ASSOCIATED MYELOPATHY AB The treatment of HAM/TSP is a challenge. No agent has shown to significantly modify the long-term disability associated with HAM/TSP. Advances in our understanding of the pathogenesis of HAM/TSP have led to the identification of several biomarkers and therapeutic targets. Clinical trials in HAM/TSP continue to be opportunities for further qualification and refinement of biomarkers and therapeutic targets. The validation of HAM/TSP relevant biomarkers and the identification of new targets remain key challenges in the development of effective targeted therapy in HAM/TSP. C1 [Oh, Unsong; Jacobson, Steven] NINDS, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Neuroimmunol Branch, Viral Immunol Sect, 10 Ctr Dr,Bldg 10 Rm 5C103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002817-18, Z01 NS003040-01] NR 95 TC 26 Z9 26 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 0733-8619 J9 NEUROL CLIN JI Neurol. Clin. PD AUG PY 2008 VL 26 IS 3 BP 781 EP + DI 10.1016/j.ncl.2008.03.008 PG 19 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 344EX UT WOS:000258910500010 PM 18657726 ER PT J AU Gehlert, DR Cippitelli, A Thorsell, A Le, AD Hipskind, PA Hamdouchi, C Lu, J Hembre, EJ Cramer, J Song, M McKinzie, D Morin, M Ciccocioppo, R Heilig, M AF Gehlert, D. R. Cippitelli, A. Thorsell, A. Le, A. D. Hipskind, P. A. Hamdouchi, C. Lu, J. Hembre, E. J. Cramer, J. Song, M. McKinzie, D. Morin, M. Ciccocioppo, R. Heilig, M. TI MTIP: a novel brain penetrant, orally available corticotropin-releasing hormone receptor 1 (CRH-R1) antagonist for treatment of alcoholism SO NEUROPEPTIDES LA English DT Meeting Abstract CT Conference on Neuropeptide - Functions, Dysfunctions and Therapeutic Options CY APR 19-21, 2007 CL Santorini, GREECE SP Tachykinins 2007 Grp, European Neuropeptide Club 2007, US Summer Neuropeptide Conf C1 [Gehlert, D. R.; Hipskind, P. A.; Hamdouchi, C.; Lu, J.; Hembre, E. J.; Cramer, J.; Song, M.; McKinzie, D.; Morin, M.] Eli Lilly & Co, Lilly Res Lab, Discovery Res, Indianapolis, IN 46285 USA. [Cippitelli, A.; Thorsell, A.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Cippitelli, A.; Ciccocioppo, R.] Univ Camerino, Dept Expt Med & Publ Hlth, I-62032 Camerino, Italy. [Le, A. D.] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada. NR 0 TC 0 Z9 0 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 AUG PY 2008 VL 42 IS 4 BP 484 EP 484 PG 1 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 352BM UT WOS:000259470200069 ER PT J AU Ferrada, C Ferre, S Casado, V Cortes, A Justinova, Z Barnes, C Canela, EI Goldberg, SR Leurs, R Lluis, C Franco, R AF Ferrada, Carla Ferre, Sergi Casado, Vicent Cortes, Antonio Justinova, Zuzana Barnes, Chanel Canela, Enric I. Goldberg, Steven R. Leurs, Rob Lluis, Carme Franco, Rafael TI Interactions between histamine H-3 and dopamine D-2 receptors and the implications for striatal function SO NEUROPHARMACOLOGY LA English DT Article DE histamine H-3 receptor; dopamine D-2 receptor; receptor heteromer; striatum ID TERM RESERPINIZED MICE; RAT-BRAIN; ADENOSINE RECEPTORS; NERVOUS-SYSTEM; CELL-MEMBRANE; RELEASE; D-1; ACTIVATION; MODULATION; INHIBITION AB The striatum contains a high density of histamine H-3 receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H-3 and dopamine D-1 receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H-3 and dopamine D-2 receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H-3 and D-1 and also between H-3 and dopamine D-2 receptors. The selective H-3 receptor agonist imetit inhibited, while the H-3 receptor antagonist thioperamide potentiated locomotor activation induced by either the D-1 receptor agonist SKF 38393 or the D-2 receptor agonist quinpirole. High scores of locomotor activity were obtained with H-3 receptor blockade plus D-1 and D-2 receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H-3-D-2 receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H-3 receptors with several H-3 receptor agonists significantly decreased the affinity of D-2 receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H-3 (but not H-4) receptors were found to form heteromers with D-2 receptors. This study demonstrates an important role of postsynaptic H-3 receptors in the modulation of dopaminergic transmission by means of a negative modulation of D-2 receptor function. Published by Elsevier Ltd. C1 [Ferre, Sergi; Justinova, Zuzana; Barnes, Chanel; Goldberg, Steven R.] Natl Inst Drug Abuse, Intramural Res Program, Natl Inst Hlth, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Ferrada, Carla; Casado, Vicent; Cortes, Antonio; Canela, Enric I.; Lluis, Carme; Franco, Rafael] Univ Barcelona, Inst Invest Biomed August Pi Sunyer, CIBERNED, E-08028 Barcelona, Spain. [Ferrada, Carla; Casado, Vicent; Cortes, Antonio; Canela, Enric I.; Lluis, Carme; Franco, Rafael] Univ Barcelona, Dept Biochem & Mol Biol, Fac Biol, E-08028 Barcelona, Spain. [Leurs, Rob] VU Drug Discovery Ctr, Div Med Chem, Leiden, Netherlands. [Leurs, Rob] Vrije Univ Amsterdam, Amsterdam Ctr Drug Res, Fac Sci, Amsterdam, Netherlands. RP Ferre, S (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Natl Inst Hlth, Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011; Canela, Enric I./M-8726-2013; Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; OI Justinova, Zuzana/0000-0001-5793-7484; Canela, Enric I./0000-0003-4992-7440; Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Casado, Vicent/0000-0002-1764-3825 FU Ministerio de Ciencia y Tecnologia [SAF2006-05481]; Fundacio La Marato TV3 [060110]; National Institutes of Health, National Institute on Drug Abuse, Department of Health and Human Services FX This research was supported in part by grants from "Ministerio de Ciencia y Tecnologia" (SAF2006-05481), "Fundacio La Marato TV3" (grant 060110) and by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse, Department of Health and Human Services. NR 43 TC 80 Z9 82 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD AUG PY 2008 VL 55 IS 2 BP 190 EP 197 DI 10.1016/j.neuropharm.2008.05.008 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 337MN UT WOS:000258440300008 PM 18547596 ER PT J AU Brady, LS Giffin, RB Woodcock, J Cassell, GH Holmes, EW AF Brady, Linda S. Giffin, Robert B. Woodcock, Janet Cassell, Gail H. Holmes, Edward W. TI Grand challenges for psychiatric drug discovery: A perspective SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material C1 [Brady, Linda S.] NIMH, Div Neurosci & Basic Behav Sci, Natl Inst Hlth, Bethesda, MD 20892 USA. [Giffin, Robert B.] Natl Acad Sci, Inst Med, Washington, DC 20418 USA. [Woodcock, Janet] US FDA, Rockville, MD 20857 USA. [Cassell, Gail H.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Holmes, Edward W.] Univ Calif, Star Biomed Res Council, La Jolla, CA USA. RP Brady, LS (reprint author), NIMH, Div Neurosci & Basic Behav Sci, Natl Inst Hlth, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 MH999999] NR 3 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 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2008 VL 33 IS 9 BP 2047 EP 2047 DI 10.1038/npp.2008.54 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 325XN UT WOS:000257622200001 PM 18626470 ER PT J AU Conn, PJ Roth, BL AF Conn, P. Jeffrey Roth, Bryan L. TI Opportunities and challenges of psychiatric drug discovery: Roles for scientists in academic, industry, and government settings SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE schizophrenia; depression; anxiety disorders; drug discovery; drug development; psychiatric disorders ID METABOTROPIC GLUTAMATE RECEPTORS; POSITIVE ALLOSTERIC MODULATOR; ATYPICAL ANTIPSYCHOTIC-DRUGS; DESIGNED MULTIPLE LIGANDS; N-DESMETHYLCLOZAPINE; BIPOLAR DISORDER; MUSCARINIC RECEPTORS; MOLECULAR-STRUCTURE; DEPRESSED-PATIENTS; 5-HT2B RECEPTORS AB Despite significant progress in understanding the biological systems and mechanisms involved in CNS disorders, use of this knowledge to realize practical gains in psychiatric care has been slow. To gain further insight into the reasons for failure and success in CNS drug discovery, preclinical predictors of success and failure for CNS drug discovery were evaluated for drugs developed for schizophrenia, depression, and anxiety. Specifically, we examined the success rate for drugs that had entered at least the later stages of preclinical research. Almost 500 compounds (140 antipsychotic; 211 antidepressant; 143 anxiolytic) were classified based on their molecular target(s) and evaluated based on preclinical validation, whether preclinical studies predicted clinical efficacy, and whether the compound displayed greater efficacy than 'onventional treatment' Results varied with indication but suggest that preclinical models have modest to good ability to predict overall clinical efficacy and adverse effect liability but are less able to predict efficacy greater than conventional treatment. In order to fully realize the potential therapeutic impact of recent basic science discoveries, it will be critical to increase attention on rigorous target validation at each step of the drug discovery process and focus efforts on developing new tools and clinical models that can be used for proof-of-concept studies in early clinical development. Also, increased attention should be focused on the development of early predictors of adverse effects of candidate compounds. C1 [Conn, P. Jeffrey] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. RP Conn, PJ (reprint author), Vanderbilt Univ, Med Ctr, Dept Pharmacol, Vanderbilt Program Drug Discovery, 23rd Ave,S & Pierce 417D PRB, Nashville, TN 37232 USA. EM jeff.conn@vanderbilt.edu RI Roth, Bryan/F-3928-2010; Conn, Peter/D-7848-2012 FU NIMH NIH HHS [R01 MH061887, U19 MH082441] NR 87 TC 42 Z9 42 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2008 VL 33 IS 9 BP 2048 EP 2060 DI 10.1038/sj.npp.1301638 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 325XN UT WOS:000257622200002 PM 18216778 ER PT J AU Mathew, SJ Manji, HK Charney, DS AF Mathew, Sanjay J. Manji, Husseini K. Charney, Dennis S. TI Novel drugs and therapeutic targets for severe mood disorders SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE therapeutics; monoamine; glutamate; ketamine; mood stabilizer; mood disorders ID GLYCOGEN-SYNTHASE KINASE-3; MAJOR DEPRESSIVE DISORDER; CELLULAR PLASTICITY CASCADES; CORTICOTROPIN-RELEASING FACTOR; POSITRON-EMISSION-TOMOGRAPHY; OPEN-LABEL TRIAL; EMERGING EXPERIMENTAL THERAPEUTICS; MAGNETIC-RESONANCE-SPECTROSCOPY; SEROTONIN TRANSPORTER BINDING; GENERALIZED ANXIETY DISORDER AB Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D- aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists ( targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties. C1 [Mathew, Sanjay J.; Charney, Dennis S.] Mt Sinai Sch Med, Dept Psychiat, Mood & Anxiety Disorders Program, New York, NY 10029 USA. [Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Mathew, SJ (reprint author), Mt Sinai Sch Med, Dept Psychiat, Mood & Anxiety Disorders Program, 1 Gustave L Levy Pl,Box 1217, New York, NY 10029 USA. EM sanjay.mathew@mssm.edu RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X FU NIMH NIH HHS [K23MH0 69656, U19-MH-069056] NR 133 TC 118 Z9 124 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2008 VL 33 IS 9 BP 2080 EP 2092 DI 10.1038/sj.npp.1301652 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 325XN UT WOS:000257622200004 PM 18172433 ER PT J AU Tsujimoto, S AF Tsujimoto, Satoshi TI The prefrontal cortex: Functional neural development during early childhood SO NEUROSCIENTIST LA English DT Review DE children; cognitive development; working memory; fMRI; NIRS ID NEAR-INFRARED SPECTROSCOPY; VISUOSPATIAL WORKING-MEMORY; AGE-RELATED-CHANGES; LATENT VARIABLE ANALYSIS; HUMAN CEREBRAL-CORTEX; COGNITIVE-DEVELOPMENT; OPTICAL TOPOGRAPHY; BRAIN-DEVELOPMENT; GENERAL INTELLIGENCE; RESPONSE-INHIBITION AB The prefrontal cortex plays an essential role in various cognitive functions, such as planning and reasoning, yet little is known about how such neural mechanisms develop during childhood, particularly in young children. To better understand this issue, the present article reviews the literature on the development of the prefrontal cortex during early childhood, focusing mainly on the changes in structural architecture, neural activity, and cognitive abilities. Neuroanatomically, the prefrontal cortex undergoes considerable maturation during childhood, including a reduction of synaptic and neuronal density, a growth of dendrites, and an increase in white matter volume, thereby forming distributed neural networks appropriate for complex cognitive processing. Concurrently, behavioral performance of various cognitive tasks improves with age, and intercorrelations among performance on each task become weak through development. Furthermore, the correlation between subcategories of intelligence test decreases as general intellectual efficiency increases. In addition, recent neuroimaging findings suggest that the prefrontal cortex is already functional in 4-year-olds and becomes organized into focal, fine-tuned systems through later development. The literature reviewed suggests that fractionation of the functional neural systems plays a key role in the development of prefrontal cortex and such fractionating process has already commenced in preschool children. C1 [Tsujimoto, Satoshi] Hokkaido Univ, Grad Sch Med, Lab Cognit Neurobiol, Sapporo, Hokkaido, Japan. RP Tsujimoto, S (reprint author), NIMH, Lab Syst Neurosci, Bldg 49,Room B1EE17,49 Convent Dr,MSC 4401, Bethesda, MD 20892 USA. EM tsujimotos@mail.nih.gov RI Tsujimoto, Satoshi/B-8223-2011 NR 134 TC 80 Z9 82 U1 10 U2 39 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD AUG PY 2008 VL 14 IS 4 BP 345 EP 358 DI 10.1177/1073858408316002 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 332SZ UT WOS:000258104700012 PM 18467667 ER PT J AU Ilias, I Pacak, K AF Ilias, Ioannis Pacak, Karel TI A clinical overview of pheochromocytomas/paragangliomas and carcinoid tumors SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE pheochromocytomas; paragangliomas; radionuclide imaging; carcinoid tumors ID POSITRON-EMISSION-TOMOGRAPHY; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; NEUROENDOCRINE TUMORS; MALIGNANT PHEOCHROMOCYTOMA; BIOCHEMICAL-DIAGNOSIS; OCTREOTIDE SCINTIGRAPHY; PLASMA METANEPHRINES; I-131 METAIODOBENZYLGUANIDINE; I-123 METAIODOBENZYLGUANIDINE; METASTATIC PHEOCHROMOCYTOMA AB Pheochromocytomas/paragangliomas are rare tumors; most are sporadic. Biochemical proof of disease is better with measurement of plasma metanephrines and less cumbersome than determinations in urine; its implementation is expanding. Anatomical imaging with computed tomography or magnetic resonance imaging should be followed by functional (nuclear medicine) imaging: chromaffin tumor-specific specific methods are preferred. Treatment is surgical; for nonoperable disease other options are available. overall 5-year survival is 50%. Carcinoid tumors derive From serotonin-producing enterochromaffin cells in the fore-, mid- or hindgut. Biochemical screening (and follow-up) is done with measurements of 5-hydroxyindoloacetic acid ill Urine. For most carcinoids, functional imaging is better than other modalities in localizing primary tumors. Surgery is the treatment of choice; nonresectable tumors are treated with somatostatin analogs or chemotherapy. Overall 5-year survival for patients with carcinoids is 67%. Published by Elsevier Inc. C1 [Pacak, Karel] NICHHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. [Ilias, Ioannis] E Venizelou Hosp, Dept Endocrinol, GR-11521 Athens, Greece. RP Pacak, K (reprint author), NICHHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. EM iiliasmd@yahoo.com; karel@mail.nih.gov FU Intramural NIH HHS [Z01 HD008735-07] NR 92 TC 22 Z9 26 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD AUG PY 2008 VL 35 SU 1 BP S27 EP S34 DI 10.1016/j.nucmedbio.2008.04.007 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 342JX UT WOS:000258781500005 PM 18707631 ER PT J AU Cho, Y Song, SH Lee, JJ Choi, N Kim, CG Dean, A Kim, A AF Cho, Youngran Song, Sang-Hyun Lee, Jong Joo Choi, Narae Kim, Chul Geun Dean, Ann Kim, AeRi TI The role of transcriptional activator GATA-1 at human beta-globin HS2 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LOCUS-CONTROL REGION; CHROMATIN DOMAIN ACTIVATION; HYPERSENSITIVE SITE 2; RNA-POLYMERASE-II; ERYTHROID-DIFFERENTIATION; HISTONE METHYLATION; GENE-EXPRESSION; CELL-LINE; NF-E2; ACETYLATION AB GATA-1 is an erythroid activator that binds beta-globin gene promoters and DNase I hypersensitive sites (HSs) of the beta-globin locus control region (LCR). We investigated the direct role of GATA-1 interaction at the LCR HS2 enhancer by mutating its binding sites within minichromosomes in erythroid cells. Loss of GATA-1 in HS2 did not compromise interaction of NF-E2, a second activator that binds to HS2, nor was DNase I hypersensitivity at HS2 or the promoter of a linked epsilon-globin gene altered. Reduction of NF-E2 using RNAi confirmed the overall importance of this activator in establishing LCR HSs. However, recruitment of the histone acetyltransferase CBP and RNA pol II to HS2 was diminished by GATA-1 loss. Transcription of epsilon-globin was severely compromised with loss of RNA pol II from the transcription start site and reduction of H3 acetylation and H3K4 di- and tri-methylation in coding sequences. In contrast, widespread detection of H3K4 mono-methylation was unaffected by loss of GATA-1 in HS2. These results support the idea that GATA-1 interaction in HS2 has a prominent and direct role in co-activator and pol II recruitment conferring active histone tail modifications and transcription activation to a target gene but that it does not, by itself, play a major role in establishing DNase I hypersensitivity. C1 [Cho, Youngran; Choi, Narae; Kim, AeRi] Pusan Natl Univ, Dept Mol Biol, Coll Nat Sci, Pusan 609735, South Korea. [Song, Sang-Hyun; Dean, Ann] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Lee, Jong Joo; Kim, Chul Geun] Hanyang Univ, Dept Life Sci, Coll Nat Sci, Seoul 133791, South Korea. RP Kim, A (reprint author), Pusan Natl Univ, Dept Mol Biol, Coll Nat Sci, Pusan 609735, South Korea. EM kimaeri@pusan.ac.kr FU Intramural NIH HHS NR 36 TC 19 Z9 20 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 AUG PY 2008 VL 36 IS 14 BP 4521 EP 4528 DI 10.1093/nar/gkn368 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 335YG UT WOS:000258330900009 PM 18586828 ER PT J AU Davis, CD Ross, SA AF Davis, Cindy D. Ross, Sharon A. TI Evidence for dietary regulation of microRNA expression in cancer cells SO NUTRITION REVIEWS LA English DT Review DE cancer; curcumin; folate; microRNA; retinoic acid ID ACUTE PROMYELOCYTIC LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR-SUPPRESSOR NETWORK; GENE-EXPRESSION; DOWN-REGULATION; REPRESSION; APOPTOSIS; ROLES; SELECTION; PROFILES AB MicroRNAs (miRNAs) are an abundant class of short noncoding RNAs that are widely expressed in mammalian cells and are important in post-translational gene regulation, including regulation of cell proliferation, apoptosis, and differentiation processes. miRNAs are involved in cancer initiation and progression and their expression patterns serve as phenotypic signatures of different cancers. Recent evidence suggests that dietary components as diverse as folate, retinoids, and curcumin exert cancer-protective effects through modulation of miRNA expression. miRNAs may be useful as biomarkers of cancer prevention or nutritional status, as well as serve as potential molecular targets that are influenced by dietary interventions. (C) 2008 International Life Sciences Institute. C1 [Davis, Cindy D.; Ross, Sharon A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, 6130 Execut Blvd,Suite 3159, Bethesda, MD 20892 USA. EM davisci@mail.nih.gov NR 37 TC 56 Z9 57 U1 1 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD AUG PY 2008 VL 66 IS 8 BP 477 EP 482 DI 10.1111/j.1753-4887.2008.00080.x PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 332JF UT WOS:000258078600007 PM 18667010 ER PT J AU Lee, MP Dunn, BK AF Lee, Maxwell P. Dunn, Barbara K. TI Influence of genetic inheritance on global epigenetic states and cancer risk prediction with DNA methylation signature: challenges in technology and data analysis SO NUTRITION REVIEWS LA English DT Article; Proceedings Paper CT Symposium on Diet, Epigenetic Events, and Cancer Prevention CY SEP 26-27, 2007 CL Natl Inst Hlth, Bethesda, MD HO Natl Inst Hlth C1 [Lee, Maxwell P.] NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Dunn, Barbara K.] NCI, Basic Prevent Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Lee, MP (reprint author), NCI, Lab Populat Genet, Ctr Canc Res, Bldg 41,Room D702,41 Lib Dr, Bethesda, MD 20892 USA. EM leemax@mail.nih.gov FU Intramural NIH HHS NR 1 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD AUG PY 2008 VL 66 IS 8 SU 1 BP S69 EP S72 DI 10.1111/j.1753-4887.2008.00072.x PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 332QW UT WOS:000258099200019 PM 18673495 ER PT J AU Pogribny, IP Tryndyak, VP Ross, SA Beland, FA AF Pogribny, Igor P. Tryndyak, Volodymyr P. Ross, Sharon A. Beland, Frederick A. TI Differential expression of microRNAs during hepatocarcinogenesis induced by methyl deficiency in rats SO NUTRITION REVIEWS LA English DT Article; Proceedings Paper CT Symposium on Diet, Epigenetic Events, and Cancer Prevention CY SEP 26-27, 2007 CL Natl Inst Hlth, Bethesda, MD HO Natl Inst Hlth ID HEPATOCELLULAR-CARCINOMA; CANCER; CELLS; CARCINOGENESIS; APOPTOSIS; PATHWAY; E2F3 C1 [Pogribny, Igor P.; Tryndyak, Volodymyr P.; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Ross, Sharon A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 12 TC 9 Z9 10 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD AUG PY 2008 VL 66 IS 8 SU 1 BP S33 EP S35 DI 10.1111/j.1753-4887.2008.00064.x PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 332QW UT WOS:000258099200010 PM 18673486 ER PT J AU Ross, SA Dwyer, J Umar, A Kagan, J Verma, M Van Bemmel, DM Dunn, BK AF Ross, Sharon A. Dwyer, Johanna Umar, Asad Kagan, Jacob Verma, Mukesh Van Bemmel, Dana M. Dunn, Barbara K. TI Introduction: diet, epigenetic events and cancer prevention SO NUTRITION REVIEWS LA English DT Editorial Material C1 [Ross, Sharon A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Dwyer, Johanna] Off Director, Off Dietary Supplements, NIH, Bethesda, MD USA. [Dwyer, Johanna] Tufts Univ, Jean Mayer Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Umar, Asad] NCI, Gastrointestinal & Other Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Kagan, Jacob] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Verma, Mukesh] NCI, Host Susceptibil Factors Branch, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20892 USA. [Dunn, Barbara K.] NCI, Basic Prevent Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Ross, SA (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, US Dept HHS,NIH, 6130 Execut Blvd,EPN 3157,MSC 7328, Bethesda, MD 20892 USA. EM rosssha@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU Intramural NIH HHS [Z99 CA999999] NR 4 TC 20 Z9 21 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD AUG PY 2008 VL 66 IS 8 SU 1 BP S1 EP S6 DI 10.1111/j.1753-4887.2008.00055.x PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 332QW UT WOS:000258099200001 PM 18673478 ER PT J AU Shukitt-Hale, B Lau, FC Carey, AN Galli, RL Spangler, EL Ingram, DK Joseph, JA AF Shukitt-Hale, Barbara Lau, Francis C. Carey, Amanda N. Galli, Rachel L. Spangler, Edward L. Ingram, Donald K. Joseph, James A. TI Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus SO NUTRITIONAL NEUROSCIENCE LA English DT Article DE Morris water maze; memory; inflammation; aging; oxidative stress; antioxidants; anti-inflammatories; dietary supplementation; blueberries; piroxicam; OX-6; cytokines; flavonoids ID GROWTH-FACTOR-I; NEURONAL SIGNAL-TRANSDUCTION; WATER-MAZE; AGED RATS; ARACHIDONIC-ACID; DIETARY SUPPLEMENTATION; BEHAVIORAL DEFICITS; ANTIINFLAMMATORY PROPERTIES; ALZHEIMER-DISEASE; OXIDATIVE STRESS AB Cognitive impairment in age-related neurodegenerative diseases such as Alzheimer's disease may be partly due to long-term exposure and increased susceptibility to inflammatory insults. In the current study, we investigated whether polyphenols in blueberries can reduce the deleterious effects of inflammation induced by central administration of kainic acid by altering the expression of genes associated with inflammation. To this end, 4-month-old male Fischer-344 (F344) rats were fed a control, 0.015% piroxicam (an NSAID) or 2% blueberry diet for 8 weeks before either Ringer's buffer or kainic acid was bilaterally micro-infused into the hippocampus. Two weeks later, following behavioral evaluation, the rats were killed and total RNA from the hippocampus was extracted and used in real-time quantitative RT-PCR (qRT-PCR) to analyze the expression of inflammation-related genes. Kainic acid had deleterious effects on cognitive behavior as kainic acid-injected rats on the control diet exhibited increased latencies to find a hidden platform in the Morris water maze compared to Ringer's buffer-injected rats and utilized non-spatial strategies during probe trials. The blueberry diet, and to a lesser degree the piroxicam diet, was able to improve cognitive performance. Immunohistochemical analyses of OX-6 expression revealed that kainic acid produced an inflammatory response by increasing the OX-6 positive areas in the hippocampus of kainic acid-injected rats. Kainic acid up-regulated the expression of the inflammatory cytokines IL-1 beta and TNF-alpha, the neurotrophic factor IGF-1, and the transcription factor NF-kappa B. Blueberry and piroxicam supplementations were found to attenuate the kainic acid-induced increase in the expression of IL-1 beta, TNF-alpha, and NF-kappa 1B, while only blueberry was able to augment the increased IGF-1 expression. These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions, perhaps via alteration of gene expression. C1 [Shukitt-Hale, Barbara; Lau, Francis C.; Carey, Amanda N.; Joseph, James A.] Tufts Univ, USDA, HNRCA, ARS, Boston, MA 02111 USA. [Galli, Rachel L.] Simmons Coll, Dept Psychol, Boston, MA 02115 USA. [Spangler, Edward L.; Ingram, Donald K.] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Shukitt-Hale, B (reprint author), Tufts Univ, USDA, HNRCA, ARS, 711 Washington St, Boston, MA 02111 USA. EM barbara.shukitthale@ars.usda.gov FU USDA; Alzheimer's Association FX This research was supported, in part, by the USDA and the Alzheimer's Association. The authors would like to thank Laura Simon and Donna Bielinski for assisting with data collection. NR 80 TC 59 Z9 63 U1 6 U2 12 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1028-415X J9 NUTR NEUROSCI JI Nutr. Neurosci. PD AUG PY 2008 VL 11 IS 4 BP 172 EP 182 DI 10.1179/147683008X301487 PG 11 WC Neurosciences; Nutrition & Dietetics SC Neurosciences & Neurology; Nutrition & Dietetics GA 470LB UT WOS:000267975100005 PM 18681986 ER PT J AU Ding, JZ Kritchevsky, SB Harris, TB Burke, GL Detrano, RC Szklo, M Carr, JJ AF Ding, Jingzhong Kritchevsky, Stephen B. Harris, Tamara B. Burke, Gregory L. Detrano, Robert C. Szklo, Moyses Carr, J. Jeffrey CA Multi Ethnic Study Atherosclerosis TI The association of pericardial fat with calcified coronary plaque SO OBESITY LA English DT Article ID PERIVASCULAR ADIPOSE-TISSUE; HEART-DISEASE; CARDIOVASCULAR-DISEASE; COMPUTED-TOMOGRAPHY; ARTERY-DISEASE; ATHEROSCLEROSIS MESA; RISK-FACTOR; OBESITY; INFLAMMATION; MECHANISMS AB Background: Pericardial fat has a higher secretion of inflammatory cytokines than subcutaneous fat. Cytokines released from pericardial fat around coronary arteries may act locally on the adjacent cells. Objective: We examined the relationship between pericardial fat and calcified coronary plaque. Methods and Procedures: Participants in the community-based Multi-Ethnic Study of Atherosclerosis (MESA) underwent a computed tomography (CT) scan for the assessment of calcified coronary plaque in 2000/2002. We measured the volume of pericardial fat using these scans in 159 whites and blacks without symptomatic coronary heart disease from Forsyth County, NC, aged 55-74 years. Results: Calcified coronary plaque was observed in 91 participants (57%). After adjusting for height, a 1 s.d. increment in pericardial fat was associated with an increased odds of calcified coronary plaque (odds ratio (95% confidence interval): 1.92 (1.27, 2.90)). With further adjustment of other cardiovascular factors, pericardial fat was still significantly associated with calcified coronary plaque. This relationship did not differ by gender and ethnicity. On the other hand, BMI and height-adjusted waist circumference were not associated with calcified coronary plaque. Discussion: Pericardial fat is independently associated with calcified coronary plaque. C1 [Ding, Jingzhong; Kritchevsky, Stephen B.] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Burke, Gregory L.] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Detrano, Robert C.] Los Angeles Biomed Res Inst, Div Cardiol, Torrance, CA USA. [Szklo, Moyses] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Carr, J. Jeffrey] Wake Forest Univ, Sch Med, Dept Radiol, Winston Salem, NC 27109 USA. RP Ding, JZ (reprint author), Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. EM jding@wfubmc.edu RI Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Kritchevsky, Stephen/0000-0003-3336-6781 FU NHLBI NIH HHS [N01 HC 95160, N01 HC 95159, N01 HC 95161, N01 HC 95162, N01 HC 95163, N01 HC 95164, N01 HC 95165, N01 HC 95169, N01HC95159, N01HC95165, N01HC95169, R01 HL 085323, R01 HL085323]; NIA NIH HHS [P30 AG 21332, P30 AG021332] NR 34 TC 88 Z9 89 U1 0 U2 3 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 AUG PY 2008 VL 16 IS 8 BP 1914 EP 1919 DI 10.1038/oby.2008.278 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 335OM UT WOS:000258299900029 PM 18535554 ER PT J AU Rothney, MP Schaefer, EV Neumann, MM Choi, L Chen, KY AF Rothney, Megan P. Schaefer, Emily V. Neumann, Megan M. Choi, Leena Chen, Kong Y. TI Validity of physical activity intensity predictions by ActiGraph, Actical, and RT3 accelerometers SO OBESITY LA English DT Article ID ENERGY-EXPENDITURE; TRIAXIAL ACCELEROMETER; ACTIVITY MONITORS; CALIBRATION; OUTPUT AB Objective: Accelerometers are promising tools for characterizing physical activity (PA) patterns in free-living persons. To date, validation of energy expenditure (EE) predictions from accelerometers has been restricted to short laboratory or simulated free-living protocols. This study seeks to determine the capabilities of eight previously published regression equations for three commercially available accelerometers to predict summary measures of daily EE. Methods and Procedures: Study participants were outfitted with ActiGraph, Actical, and RT3 accelerometers, while measurements were simultaneously made during overnight stays in a room calorimeter, which provided minute-by-minute EE measurements, in a diverse subject population (n = 85). Regression equations for each device were used to predict the minute-by-minute metabolic equivalents (METs) along with the daily PA level (PAL). Results: Two RT3 regressions and one ActiGraph regression were not significantly different from calorimeter measured PAL. When data from the entire visit were divided into four intensity categories-sedentary, light, moderate, and vigorous-significant (P < 0.001) over- and underpredictions were detected in numerous regression equations and intensity categories. Discussion: Most EE prediction equations showed differences of < 2% in the moderate and vigorous intensity categories. These differences, though small in magnitude, may limit the ability of these regressions to accurately characterize whether specific PA goals have been met in the field setting. New regression equations should be developed if more accurate prediction of the daily PAL or higher precision in determining the time spent in specific PA intensity categories is desired. C1 [Rothney, Megan P.; Schaefer, Emily V.] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA. [Neumann, Megan M.] Vanderbilt Univ, Med Ctr, Div Gastroenterol, Dept Med, Nashville, TN 37235 USA. [Choi, Leena] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN 37235 USA. [Chen, Kong Y.] NIDDK, NIH, Clin Endocrinol Branch, Bethesda, MD USA. RP Rothney, MP (reprint author), Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA. EM rothneym@niddk.nih.gov OI Chen, Kong/0000-0002-0306-1904 FU Intramural NIH HHS [Z99 DK999999]; NCRR NIH HHS [M01 RR000095, RR 00095]; NHLBI NIH HHS [HL 082988, R01 HL082988]; NIDDK NIH HHS [DK 02973, K25 DK002973, R01 DK069465]; PHS HHS [DL 069465] NR 25 TC 70 Z9 71 U1 0 U2 11 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 AUG PY 2008 VL 16 IS 8 BP 1946 EP 1952 DI 10.1038/oby.2008.279 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 335OM UT WOS:000258299900034 PM 18535553 ER PT J AU Norian, JM Stratton, P AF Norian, John M. Stratton, Pamela TI Labial fusion - A rare complication of chronic graft- versus-host disease SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID BONE-MARROW; TRANSPLANTATION AB BACKGROUND: Hematopoetic stem cell transplantation may be complicated by genital graft-versus-host (GVH) disease and may uncommonly result in labial fusion. CASE: A 22-year-old woman with a history of Ewing's sarcoma and acute myelogenous leukemia received chemotherapy and total-body irradiation followed by a matched, unrelated donor hematopoetic stem cell transplantation. After transplantation, she developed chronic GVH disease involving the skin, eyes, mouth, and joints. Concomitant vulvar pruritus was presumed to be a fungal infection but, in fact, was genital GVH disease manifesting as labial fusion. Topical estrogen, topical steroids, and surgical division of the labia were successful. CONCLUSION: Genital GVH disease should be considered in women with genital tract complaints after hematopoetic stem cell transplantation. Labial fusion secondary to chronic GVH disease may be treated successfully with surgery and medical therapy. C1 [Stratton, Pamela] NICHD, NIH, Reprod Biol & Med Branch, CRC, Bethesda, MD 20892 USA. RP Stratton, P (reprint author), NICHD, NIH, Reprod Biol & Med Branch, CRC, Bldg 10,1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM ps79c@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 8 TC 9 Z9 10 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 AUG PY 2008 VL 112 IS 2 BP 437 EP 439 DI 10.1097/01.AOG.0000299876.18200.8d PN 2 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 334QV UT WOS:000258237200009 PM 18669755 ER PT J AU Yauger, BJ Gorden, P Park, J Cochran, E Stratton, P AF Yauger, Belinda J. Gorden, Phillip Park, Jean Cochran, Elaine Stratton, Pamela TI Effect of depot medroxyprogesterone acetate on glucose tolerance in generalized lipodystrophy SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID INSULIN AB BACKGROUND: Lipodystrophy is a rare condition causing severe insulin resistance and frank diabetes. Depot medroxyprogesterone acetate (DMPA), a commonly used contraceptive, may worsen glucose tolerance in diabetics and those with lipodystrophy. CASE: A young woman with generalized lipodystrophy, who previously required greater than 1,000 units of insulin daily, had a normal hemoglobin A1c on leptin and metformin only. After an injection of DMPA, she developed severe hyperglycemia. Her levels returned to near normal only with extremely high doses of insulin (up to 1,700 units/d) and increased doses of leptin and metformin. CONCLUSION: Progestin-only contraceptives may detrimentally affect glucose tolerance, particularly in patients with lipodystrophy, a cause of severe insulin resistance and leptin deficiency. One DMPA injection appeared to profoundly alter glucose metabolism in this patient with frank diabetes resulting from lipodystrophy. The effect of progestin-only contraceptives on glucose tolerance should be monitored closely in any diabetic patient. C1 [Yauger, Belinda J.] NICHD, RBMB, NIH, CRC, Bethesda, MD 20892 USA. NIH, Walter Reed Army Med Ctr, Natl Naval Med Ctr, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Div Reprod Endocrinol & Infertil, Washington, DC 20307 USA. NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD USA. RP Yauger, BJ (reprint author), NICHD, RBMB, NIH, CRC, 10 Ctr Dr,Bldg 10,1-3140, Bethesda, MD 20892 USA. EM yaugerbe@mail.nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 8 TC 3 Z9 3 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 AUG PY 2008 VL 112 IS 2 BP 445 EP 447 DI 10.1097/AOG.0b013e3181662d17 PN 2 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 334QV UT WOS:000258237200012 PM 18669758 ER PT J AU Serra, C Kogevinas, M Silverman, DT Turuguet, D Tardon, A Garcia-Closas, R Carrato, A Castano-Vinyals, G Fernandez, F Stewart, P Benavides, FG Gonzalez, S Serra, A Rothman, N Malats, N Dosemeci, M AF Serra, C. Kogevinas, M. Silverman, D. T. Turuguet, D. Tardon, A. Garcia-Closas, R. Carrato, A. Castano-Vinyals, G. Fernandez, F. Stewart, P. Benavides, F. G. Gonzalez, S. Serra, A. Rothman, N. Malats, N. Dosemeci, M. TI Work in the textile industry in Spain and bladder cancer SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID OCCUPATIONAL EXPOSURES; URINARY-BLADDER; RISK; MONTREAL; SMOKING; CANADA; MEN AB Background/objective: Textile manufacturing is a complex industry that has frequently been associated with bladder cancer. However, results have not been consistent. This study investigated the risk of bladder cancer in Spanish textile workers. Methods: We analysed data from a multicentre hospital-based case-control study carried out in Spain (1998-2001) including 1219 cases of bladder cancer and 1271 controls. Of those, 126 cases and 122 controls reported a history of employment in the textile industry. Lifetime occupational history was obtained using a computer-assisted personal interview. Occupations, locations and materials used in the textile industry were assessed using a detailed questionnaire and expert assessment. Results: Overall, no increased risk of bladder cancer was found for textile workers, including duration of employment analysis. Increased risks were observed for weavers (OR = 1.82, 95% CI 0.95 to 3.47), for workers in winding/warping/sizing (OR 4.11, 95% CI 1.58 to 10.71) and for those exposed to synthetic materials (OR 1.89, 95% CI 1.00 to 3.56). Working for more than 10 years appeared to be associated with an increased risk for weavers (OR 2.27, 95% CI 0.97 to 5.34), for those who had ever worked in winding/warping/sizing (OR 11.03, 95% CI 1.37, 88.89), for workers in the weaving room ( OR 2.94, 95% CI 1.24 to 7.01) and for those exposed to synthetic (OR 2.62, 95% CI 1.14 to 6.01) or cotton (OR 2.00, 95% CI 1.04 to 3.87) materials. Statistically significant higher risks were also found for specific combinations of occupations or locations with exposure to synthetics and cotton. Conclusions: There was no overall increased risk for textile workers, but increased risks were found for specific groups of workers. Our findings indicate that observed risks in previous studies may be better evaluated by analysis of materials used or section worked within the industry and occupation. C1 [Serra, C.; Benavides, F. G.] Univ Pompeu Fabra, Unit Occupat Hlth Res, Dept Expt & Hlth Sci, Barcelona 08003, Spain. [Serra, C.] Corporacio Parc Tauli, Sabadell, Spain. [Kogevinas, M.; Castano-Vinyals, G.; Fernandez, F.; Malats, N.] CREAL, Municipal Inst Med Res, Barcelona, Spain. [Kogevinas, M.] Univ Crete, Sch Med, Dept Social Med, Iraklion, Greece. [Silverman, D. T.; Stewart, P.; Rothman, N.; Dosemeci, M.] Natl Canc Inst, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD USA. [Tardon, A.; Gonzalez, S.] Univ Oviedo, Oviedo, Spain. [Garcia-Closas, R.] Hosp Univ Canarias, San Cristobal la Laguna, Spain. [Carrato, A.] Hosp Gen Elche, Elche, Spain. [Castano-Vinyals, G.] CIBER Salud Publ & Epidemiol, Barcelona, Spain. RP Serra, C (reprint author), Univ Pompeu Fabra, Unit Occupat Hlth Res, Dept Expt & Hlth Sci, PRBB Bldg,1st Floor Room 171-01,C Dr Aiguader 88, Barcelona 08003, Spain. EM serra@upf.edu RI Benavides, Fernando/A-5137-2008; Serra, C/E-6879-2014; Kogevinas, Manolis/C-3918-2017; OI Benavides, Fernando/0000-0003-0747-2660; Serra, C/0000-0001-8337-8356; Castano-Vinyals, Gemma/0000-0003-4468-1816; Malats, Nuria/0000-0003-2538-3784 FU Intramural NIH HHS NR 41 TC 9 Z9 9 U1 3 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 2008 VL 65 IS 8 BP 552 EP 559 DI 10.1136/oem.2007.035667 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 329QQ UT WOS:000257885200007 PM 18045847 ER PT J AU Jain, L Figg, WD AF Jain, Lokesh Figg, William D. TI Polypharmacy in view of advances in cancer treatment SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID BREAST-CANCER; THERAPY; SIGNATURES C1 [Figg, William D.] NCI, Pharmacol Sect, Clin Pharmacol Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 11 TC 0 Z9 0 U1 0 U2 1 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2008 VL 22 IS 9 BP 1055 EP + PG 3 WC Oncology SC Oncology GA 342WX UT WOS:000258815400011 ER PT J AU Hodge, JW Guha, C Neefjes, J Gulley, JL AF Hodge, James W. Guha, Chandan Neefjes, Jacques Gulley, James L. TI Synergizing radiation therapy and immunotherapy for curing incurable cancers - Opportunities and challenges SO ONCOLOGY-NEW YORK LA English DT Article ID DENDRITIC CELL MATURATION; HEAT-SHOCK PROTEINS; CD8(+) T-CELLS; TUMOR-CELLS; PROSTATE-CANCER; IMMUNE-RESPONSES; RADIOTHERAPY; IRRADIATION; DEATH; CALRETICULIN AB The combination of radiation therapy and immunotherapy holds particular promise as a strategy for cancer therapeutics. Evidence suggests that immunotherapy is most beneficial alone when employed early in the disease process or in combination with standard therapies (eg, radiation) later in the disease process. Indeed, radiation may act synergistically with immunotherapy to enhance immune responses, inhibit immunosuppression, and/or alter the phenotype of tumor cells, thus rendering them more susceptible to immune-mediated killing. As monotherapies, both immunotherapy and radiation may be insufficient to eliminate tumor masses. However, following immunization with a cancer vaccine, the destruction of even a small percentage of tumor cells by radiation could result in crosspriming and presentation of tumor antigens to the immune system, thereby potentiating antitumor responses. Learning how to exploit radiation-induced changes to tumor-cell antigens, and how to induce effective immune responses to these cumulatively immunogenic stimuli, is an exciting frontier in cancer therapy research. This review examines mechanisms by which many forms of radiation therapy can induce or augment antitumor immune responses as well as preclinical systems demonstrating that immunotherapy can be effectively combined with radiation therapy. Finally, we review current clinical trials where standard-of-care radiation therapy is being combined with immunotherapy. C1 [Hodge, James W.; Gulley, James L.] NCI, Recombinant Vaccine Grp, Lab Tumor Immunol & Biol, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Guha, Chandan] Albert Einstein Coll Med, Dept Radiat Oncol, Bronx, NY 10467 USA. [Neefjes, Jacques] Netherlands Canc Inst, Tumor Biol Div, Amsterdam, Netherlands. RP Hodge, JW (reprint author), NCI, Recombinant Vaccine Grp, Lab Tumor Immunol & Biol, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [ZIA BC010945-02] NR 40 TC 40 Z9 40 U1 1 U2 7 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2008 VL 22 IS 9 BP 1064 EP 1070 PG 7 WC Oncology SC Oncology GA 342WX UT WOS:000258815400012 PM 18777956 ER PT J AU Meyerle, CB Dahr, SS Wetjen, NM Jirawuthiworavong, GV Butman, JA Lonser, RR Oldfield, E Rodriguez-Coleman, H Wong, WT Chew, EY AF Meyerle, Catherine B. Dahr, Sam S. Wetjen, Nicholas M. Jirawuthiworavong, Guy V. Butman, John A. Lonser, Russell R. Oldfield, Edward Rodriguez-Coleman, Hanna Wong, Wai T. Chew, Emily Y. TI Clinical course of retrobulbar hemangioblastomas in von Hippel-Lindau disease SO OPHTHALMOLOGY LA English DT Article ID OPTIC-NERVE HEMANGIOBLASTOMA AB Objective: To report clinical findings of rare retrobulbar optic nerve hemangioblastomas associated with von Hippel-Lindau disease (VHL). Design: Retrospective observational case series. Participants: Nine patients with VHL. Methods: The clinical course and magnetic resonance imaging findings of patients with VHL and hemangioblastomas affecting the anterior visual pathway from the intraorbital optic nerve to the optic chiasm are reviewed. Main Outcome Measure: Clinical course of retrobulbar optic nerve hemangioblastomas. Results: The mean age of VHL diagnosis was 24 14 years, and mean follow-up was 5 4 years. All had other CNS lesions and retinal hemangioblastomas. Approximately 50% (5/9) had a previous enucleation or had visual acuity loss (4/9), some due to other VHL ocular complications. Four patients underwent surgical resection of an intracranial hemangioblastoma. Growth patterns and pathology are similar to those of other hemangioblastomas in the CNS. Conclusions: Although these lesions are rare, patients with VHL who present with signs of optic neuropathy should be evaluated for anterior visual pathway hemangioblastomas impinging on the optic nerve from the orbit to the chiasm. On neuroimaging, the hemangioblastomas may demonstrate chiasmal or optic tract edema, associated cysts, and T-2 flow voids. Lesions may remain radiologically and clinically stable, evolve radiographically with no visual or neurological progression, or progress clinically and radiographically. Patients at risk for visual loss should be considered for surgical resection. Close coordination among neuroradiology, neurosurgery, and ophthalmology patient care teams is advised for optimal management of these patients. C1 [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Wetjen, Nicholas M.; Butman, John A.] Diagnost Radiol Magnuson Clin Ctr, Bethesda, MD USA. [Lonser, Russell R.; Oldfield, Edward] NINCDS, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 3-2531, Bethesda, MD 20892 USA. EM echew@nei.nih.gov RI Butman, John/A-2694-2008; Wong, Wai/B-6118-2017; OI Wong, Wai/0000-0003-0681-4016; Butman, John/0000-0002-1547-9195 FU Intramural NIH HHS [Z99 EY999999, ZIE EY000487-01] NR 19 TC 5 Z9 5 U1 0 U2 1 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 AUG PY 2008 VL 115 IS 8 BP 1382 EP 1389 DI 10.1016/j.ophtha.2008.01.027 PG 8 WC Ophthalmology SC Ophthalmology GA 334QW UT WOS:000258237300020 PM 18395800 ER PT J AU Harrison, WW Begley, CG Liu, HX Chen, MH Garcia, M Smith, JA AF Harrison, Wendy W. Begley, Carolyn G. Liu, Haixia Chen, Minhua Garcia, Michelle Smith, Janine A. TI Menisci and fullness of the blink in dry eye SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE tear film; dry eye; incomplete blink; tear meniscus height; tear breakup ID HUMAN TEAR FILM; LIPID LAYER; REPEATABILITY; SENSITIVITY; STABILITY; PATTERNS; CORNEAL; BREAKUP; HEIGHT AB Purpose. This study was to investigate the role of the upper meniscus in tear film formation and blinking. Methods. One microliter of 2% fluorescein was instilled under the upper lid of 15 dry eye (DE) and 15 control subjects. Subjects were instructed to blink partially and hold the eye open as long as possible, and analysis of tear breakup dynamics was used to quantify the area of breakup. This procedure was repeated following a full blink. Meniscus height was measured from digital videos. Results. Both menisci were significantly decreased in DE compared with controls (p < 0.02, t test). Tear breakup dynamics analysis showed that significantly greater areas of breakup occurred with full compared with incomplete blinks in DE (p < 0.003 Mann Whitney U test), but not in controls. Conclusions. A stable tear film can be deposited by the upper meniscus alone following a partial blink, without contribution from the lower meniscus. The increased tear stability of partial blinks in DE may be due to less stretching of the already fragile tear film compared with a full blink, which covers more surface area. C1 [Harrison, Wendy W.; Begley, Carolyn G.; Liu, Haixia; Chen, Minhua; Garcia, Michelle] Indiana Univ, Sch Optometry, Bloomington, IN USA. [Smith, Janine A.] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Harrison, WW (reprint author), Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. EM wwh@berkeley.edu RI Liu, Haixia/B-2631-2010; Liu, Haixia/E-1435-2011 NR 34 TC 28 Z9 29 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD AUG PY 2008 VL 85 IS 8 BP 706 EP 714 DI 10.1097/OPX.0b013e318181ae02 PG 9 WC Ophthalmology SC Ophthalmology GA 337WZ UT WOS:000258467500013 PM 18677235 ER PT J AU Hillel, AT Kapoor, A Simaan, N Taylor, RH Flint, P AF Hillel, Alexander T. Kapoor, Ankur Simaan, Nabil Taylor, Russell H. Flint, Paul TI Applications of robotics for laryngeal surgery SO OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID LASER SURGERY; CANINE MODEL; CHILDREN; SAFETY; AIRWAY; TORS AB The authors present the clinical application of robotics to laryngeal surgery in terms of enhancement of surgical precision and performance of other minimally invasive procedures not feasible with current instrumentation. Presented in this article are comparisons of human arm with robotic arm in terms of degrees of freedom and discussion of surgeries and outcomes with use of the robotic arm. Robotic equipment for laryngeal surgery has the potential to overcome many of the limitations of endolaryngeal procedures by improving optics, increasing instrument degrees of freedom, and modulating tremor. Outside of laryngology, a multiarmed robotic system would have utility in microvascular surgery, procedures at the base of the skull, sinus surgery, and single-port gastrointestinal and thoracic access surgery. C1 [Hillel, Alexander T.; Flint, Paul] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Kapoor, Ankur] NIH, Bethesda Clin Ctr, Bethesda, MD 20892 USA. [Simaan, Nabil] Columbia Univ, Dept Mech Engn, New York, NY 10027 USA. [Taylor, Russell H.] Johns Hopkins Univ, Dept Comp Sci, Whiting Sch Engn, Baltimore, MD 21218 USA. RP Flint, P (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 601 N Caroline St,6th Floor,JHOC 6163, Baltimore, MD 21287 USA. EM pflint@jhmi.edu FU NIBIB NIH HHS [R21 EB004457] NR 27 TC 34 Z9 35 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0030-6665 J9 OTOLARYNG CLIN N AM JI Otolaryngol. Clin. N. Am. PD AUG PY 2008 VL 41 IS 4 BP 781 EP + DI 10.1016/j.otc.2008.01.021 PG 12 WC Otorhinolaryngology SC Otorhinolaryngology GA 328IS UT WOS:000257792700010 PM 18570959 ER PT J AU Igarashi, H Ito, T Kuwano-Kojima, M Takayanagi, R Coy, DH Jensen, RT AF Igarashi, Hisato Ito, Tetsuhide Kuwano-Kojima, Mizuho Takayanagi, Ryoichi Coy, David H. Jensen, Robert T. TI Involvement of VPAC1 and VPAC2 receptors in increasing local pancreatic blood flow in anesthetized rats SO PANCREAS LA English DT Letter ID SECRETION C1 [Igarashi, Hisato; Ito, Tetsuhide; Kuwano-Kojima, Mizuho; Takayanagi, Ryoichi] Kyushu Univ, Dept Med & Bioregulatory Sci, Grad Sch Med Sci, Fukuoka 812, Japan. [Coy, David H.] Tulane Univ, Hlth Sci Ctr, Peptide Res Labs, Dept Med, New Orleans, LA 70118 USA. [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Igarashi, H (reprint author), Kyushu Univ, Dept Med & Bioregulatory Sci, Grad Sch Med Sci, Fukuoka 812, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp FU Intramural NIH HHS NR 10 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD AUG PY 2008 VL 37 IS 2 BP 236 EP 238 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 331LB UT WOS:000258012600027 PM 18665096 ER PT J AU Orlov, N Shamir, L Macura, T Johnston, J Eckley, DM Goldberg, IG AF Orlov, Nikita Shamir, Lior Macura, Tomasz Johnston, Josiah Eckley, D. Mark Goldberg, Ilya G. TI WND-CHARM: Multi-purpose image classification using compound image transforms SO PATTERN RECOGNITION LETTERS LA English DT Article DE image classification; biological imaging; image features; high dimensional classification ID FACE RECOGNITION; SUBCELLULAR STRUCTURES; MICROSCOPIC IMAGES; ROTATION-INVARIANT; FEATURE-EXTRACTION; GABOR FEATURES; RETRIEVAL; TEXTURE; PATTERNS; SCALE AB We describe a multi-purpose image classifier that can be applied to a wide variety of image classification tasks without modifications or fine-tuning, and yet provide classification accuracy comparable to state-of-the-art task-specific image classifiers. The proposed image classifier first extracts a large set of 1025 image features including polynomial decompositions, high contrast features, pixel statistics, and textures. These features are computed on the raw image, transforms of the image, and transforms of transforms of the image. The feature values are then used to classify test images into a set of pre-defined image classes. This classifier was tested on several different problems including biological image classification and face recognition. Although we cannot make a claim of universality, our experimental results show that this classifier performs as well or better than classifiers developed specifically for these image classification tasks. Our classifier's high performance on a variety of classification problems is attributed to (i) a large set of features extracted from images; and (ii) an effective feature selection and weighting algorithm sensitive to specific image classification problems. The algorithms are available for free download from http://www.openmicroscopy.org. Published by Elsevier B.V. C1 [Orlov, Nikita; Shamir, Lior; Macura, Tomasz; Johnston, Josiah; Eckley, D. Mark; Goldberg, Ilya G.] NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Macura, Tomasz] Univ Cambridge, Comp Lab, Cambridge CB2 3QG, England. RP Shamir, L (reprint author), NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, 333 Cassell Dr,Suite 3000, Baltimore, MD 21224 USA. EM shamirl@mail.nih.gov RI Goldberg, Ilya/H-5307-2011; Eckley, Mark/M-3526-2014 OI Goldberg, Ilya/0000-0001-8514-6110; Eckley, Mark/0000-0003-2296-5164 FU Intramural NIH HHS [Z01 AG000671-06, NIH0012688432]; NIAMS NIH HHS [R01 AR052615, R01 AR052615-03] NR 66 TC 84 Z9 86 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8655 EI 1872-7344 J9 PATTERN RECOGN LETT JI Pattern Recognit. Lett. PD AUG 1 PY 2008 VL 29 IS 11 BP 1684 EP 1693 DI 10.1016/j.patrec.2008.04.013 PG 10 WC Computer Science, Artificial Intelligence SC Computer Science GA 333UC UT WOS:000258177000010 PM 18958301 ER PT J AU Pahwa, S Read, JS Yin, W Matthews, Y Shearer, W Diaz, C Rich, K Mendez, H Thompson, B AF Pahwa, Savita Read, Jennifer S. Yin, Wanrong Matthews, Yvonne Shearer, William Diaz, Clemente Rich, Kenneth Mendez, Hermann Thompson, Bruce CA Women Infants Transmission Study TI CD4(+)/CD8(+) T cell ratio for diagnosis of HIV-1 infection in infants: Women and Infants Transmission Study SO PEDIATRICS LA English DT Article DE HIV diagnosis; perinatal HIV transmission; HIV-exposed infants; CD4(+)/CD8(+) T cell ratio ID IMMUNODEFICIENCY-VIRUS-INFECTION; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; LYMPHOCYTE SUBSETS; PREDICT MORTALITY; TYPE-1 INFECTION; CHILDREN; SETTINGS; BLOOD; DYSFUNCTION AB OBJECTIVE. In this study, we tested the hypothesis that the CD4(+)/CD8(+) T cell ratio could predict HIV infection status in HIV-exposed infants. METHODS. CD4(+)/CD8(+) T cell ratios were determined from data for live-born singleton infants who had been prospectively enrolled in the Women and Infants Transmission Study. Data for 2208 infants with known HIV infection status (179 HIV-infected and 2029 uninfected infants) were analyzed. RESULTS. Receiver operating characteristic curves indicated that the CD4(+)/CD8(+) T cell ratio performed better than the proportion of CD4(+) T cells for diagnosis of HIV infection as early as 2 months of age, and this relationship was unaffected by adjustment for maternal race/ethnicity, infant birth weight, gestational age, and gender. At 4 months of age, 90% specificity for HIV diagnosis was associated with 60% sensitivity. For ease of use, graphical estimates based on cubic splines for the time-dependent parameters in a Box-Cox transformation (L), the median (M), and the coefficient of variation (S) were used to create LMS centile curves to show the sensitivity and specificity of CD4(+)/CD8(+) T cell ratios in HIV-infected and uninfected infants until 12 months of age. At 6 months of age, a simplified equation that incorporated sequential CD4(+)/CD8(+) T cell ratios and hematocrit values resulted in improved receiver operating characteristic curves, with 94% positive predictive value and 98% negative predictive value. The positive and negative predictive values remained above 90% in simulated infant populations over a wide range of HIV infection prevalence values. CONCLUSIONS. In the absence of virological diagnosis, a presumptive diagnosis of HIV infection status can be made on the basis of CD4(+)/CD8(+) T cell ratios in HIV-1-exposed infants after 2 months of age; sensitivity and specificity can be improved at 6 months by using a discriminant analysis equation. C1 [Pahwa, Savita] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. [Pahwa, Savita] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Yin, Wanrong; Matthews, Yvonne; Thompson, Bruce] Clin Trials & Surveys Corp, Baltimore, MD USA. [Shearer, William] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Diaz, Clemente] Univ Puerto Rico, Dept Pediat, San Juan, PR 00936 USA. [Rich, Kenneth] Univ Illinois, Dept Pediat, Chicago, IL USA. [Mendez, Hermann] SUNY, Dept Pediat, Brooklyn, NY USA. RP Pahwa, S (reprint author), Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, 1580 NW 10th Ave,BCRI 712, Miami, FL 33136 USA. EM spahwa@med.miami.edu FU NCRR NIH HHS [GCRC RR000188, GCRC RR000645, M01 RR000188, K01 RR000188, M01 RR000645]; NIAID NIH HHS [U01 AI 034841, U01 AI 034858, U01 AI034858, U01 AI 050274-01, U01 AI050274, N01 AI085339, U01 AI034841]; NICHD NIH HHS [U01 HD 041983, U01 HD 036117, U01 HD041983, U01 HD036117]; NIDA NIH HHS [U01 DA015054, U01 DA015053, U01 DA 015053, U01 DA 015054] NR 35 TC 14 Z9 16 U1 0 U2 6 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 AUG PY 2008 VL 122 IS 2 BP 331 EP 339 DI 10.1542/peds.2007-2308 PG 9 WC Pediatrics SC Pediatrics GA 333HB UT WOS:000258142500015 PM 18676551 ER PT J AU Rothman, EF Edwards, EM Heeren, T Hingson, RW AF Rothman, Emily F. Edwards, Erika M. Heeren, Timothy Hingson, Ralph W. TI Adverse childhood experiences predict earlier age of drinking onset: Results from a representative US sample of current or former drinkers SO PEDIATRICS LA English DT Article DE age of drinking onset; drinking initiation; adverse childhood experiences ID ALCOHOL-USE; UNINTENTIONAL INJURY; COLLEGE-STUDENTS; 1ST DRINK; HIGH-RISK; INVOLVEMENT; ADOLESCENTS; MOTIVES; HEALTH; INITIATION AB OBJECTIVE. Our goal was to determine whether adverse childhood experiences predicted the age at which drinking was initiated and drinking motives in a representative sample of current or former drinkers in the United States. METHODS. In 2006, a probability sample of 3592 US current or former drinkers aged 18 to 39 were surveyed. Multinomial logistic regression examined whether each of 10 adverse childhood experiences was associated with earlier ages of drinking onset, controlling for demographics, parental alcohol use, parental attitudes toward drinking, and peers' drinking in adolescence. We also examined whether there was a graded relationship between the number of adverse childhood experiences and age of drinking onset and whether adverse childhood experiences were related to selfreported motives for drinking during the first year that respondents drank. RESULTS. Sixty-six percent of respondents reported >= 1 adverse childhood experiences, and 19% reported experiencing >= 4. The most commonly reported adverse childhood experiences were parental separation/ divorce (41.3%), living with a household member who was a problem drinker (28.7%), mental illness of a household member (24.8%), and sexual abuse (19.1%). Of the 10 specific adverse childhood experiences assessed, 5 were significantly associated with initiating drinking at <= 14 years of age (compared with at >= 21 years of age) after adjustment for confounders, including physical abuse, sexual abuse, having a mentally ill household member, substance abuse in the home, and parental discord or divorce. Compared with those without adverse childhood experiences, respondents with adverse childhood experiences were substantially more likely to report that they drank to cope during the first year that they used alcohol. CONCLUSIONS. Results suggest that children with particular adverse childhood experiences may initiate drinking earlier than their peers and that they may be more likely to drink to cope with problems (rather than for pleasure or to be social). C1 [Rothman, Emily F.] Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Crosstown Ctr, Boston, MA 02118 USA. [Edwards, Erika M.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Heeren, Timothy] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Hingson, Ralph W.] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. RP Rothman, EF (reprint author), Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Crosstown Ctr, 715 Albany St,Floor 3, Boston, MA 02118 USA. EM erothman@bu.edu OI Rothman, Emily/0000-0003-0113-2577; Heeren, Timothy/0000-0001-5643-3559 FU NIAAA NIH HHS [P60AA013759] NR 38 TC 59 Z9 63 U1 1 U2 14 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 AUG PY 2008 VL 122 IS 2 BP E298 EP E304 DI 10.1542/peds.2007-3412 PG 7 WC Pediatrics SC Pediatrics GA 333HB UT WOS:000258142500046 PM 18676515 ER PT J AU Rutherford, JM Wang, JB Xu, H Dersch, CM Partilla, JS Rice, KC Rothman, RB AF Rutherford, John M. Wang, Jiabei Xu, Heng Dersch, Christina M. Partilla, John S. Rice, Kenner C. Rothman, Richard B. TI Evidence for a mu-delta opioid receptor complex in CHO cells co-expressing mu and delta opioid peptide receptors SO PEPTIDES LA English DT Article DE opioid receptor; dimerization; GPCR; morphine; ligand binding ID I-125 BETA-ENDORPHIN; OPIATE RECEPTOR; CROSS-LINKING; HIGH-AFFINITY; BINDING-SITE; AGONISTS; ANTAGONISTS; MODULATION; LIGANDS; BRAIN AB Based on non-competitive binding interactions we suggested that mu and delta receptors associate as a mu/delta receptor complex in rat brain. We hypothesized that the same non-competitive binding interactions observed in rat brain will be seen in CHO cells that co-express mu and delta receptors, but not in cells that express just mu or delta receptors. We used CHO cells expressing the cloned human mu receptor, cloned human delta receptor, or cloned mouse delta/human mu ("dimer cell"). Cell membranes were prepared from intact cells pretreated with 100 nM SUPERFIT. [(3)H][D-Ala(2), D-Leu(5)]enkephalin binding assays followed published procedures. SUPERFIT, a delta-selective irreversible ligand, decreased [(3)H][D-Ala(2), D-Leu(5)]enkephalin binding to delta receptors by similar to 75% and to mu receptors by similar to 50% in dimer cells. SUPERFIT treatment did not decrease [(3)H][D-Ala(2), D-Leu(5)]enkephalin binding to mu cells. The IC(50) values observed in SUPERFIT-treated dimer cells were: [D-Pen(2) D-Pen(5)]enkephalin (1820 nM) and morphine (171 nM). Saturation binding experiments with SUPERFIT-treated dimer cells showed that [D-Pen(2), D-Pen(5)]enkephalin (5000 nM) was a competitive inhibitor. In contrast, morphine (1000 nM) lowered the B(max) from 1944 fmol/mg to 1276 fmol/mg protein (35% decrease). Both [D-Pen(2) D-Pen(5)]enkephalin and morphine competitively inhibited [(3)H][D-Ala(2), D-Leu(5)]enkephalin binding to SUPERFIT-treated mu cells. The results indicate that the mu-delta opioid receptor complex defined on the basis of non-competitive binding interactions in rat brain over 20 years ago likely occurs as a consequence of the formation of mu-delta heterodimers. SUPERFIT-treated dimer cells may provide a useful model to study the properties of mu-delta heterodimers. Published by Elsevier Inc. C1 [Rutherford, John M.; Xu, Heng; Dersch, Christina M.; Partilla, John S.; Rice, Kenner C.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, Intramural Res Program, Natl Inst Hlth,DHHS, Baltimore, MD 21224 USA. [Wang, Jiabei] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, Natl Inst Hlth,DHHS, Suite 4500,Triad Bldg,333 Cassell Dr, Baltimore, MD 21224 USA. EM rrothman@mail.nih.gov FU National Institute on Drug Abuse (JBW) [DA11925]; NIH; National Institute on Drug Abuse FX This research was supported in part by USPHS grant DA1192S from the National Institute on Drug Abuse (JBW) and the Intramural Research Program of the NIH, National Institute on Drug Abuse. NR 21 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD AUG PY 2008 VL 29 IS 8 BP 1424 EP 1431 DI 10.1016/j.peptides.2008.03.019 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 341XG UT WOS:000258748300020 PM 18472184 ER PT J AU Jelinkova, I Vavra, V Jindrichova, M Obsil, T Zemkova, HW Zemkova, H Stojilkovic, SS AF Jelinkova, Irena Vavra, Vojtech Jindrichova, Marie Obsil, Tomas Zemkova, Hana W. Zemkova, Hana Stojilkovic, Stanko S. TI Identification of P2X(4) receptor transmembrane residues contributing to channel gating and interaction with ivermectin SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE purinergic signaling; ATP-gated receptor-channels; transmembrane domains; deactivation; helical wheel projection ID CHLORIDE CHANNEL; CAENORHABDITIS-ELEGANS; CATION PERMEABILITY; ATP; DOMAIN; AVERMECTIN-B1A; REARRANGEMENTS; DEACTIVATION; SEGMENTS; TRIMERS AB Ivermectin (IVM), a large macrocyclic lactone, specifically enhances P2X4 receptor-channel function by interacting with residues of transmembrane (TM) helices in the open conformation state. In this paper, we used cysteine-scanning mutagenesis of rat P2X4-TMs to identify and map residues of potential importance for channel gating and interaction with IVM. The receptor function was unchanged by mutations in 29 different residues, and among them, the IVM effects were altered in Gln(36), Leu(40), Val(43), Val(47), Trp(50), Asn(338), Gly(342), Leu(346), Ala(349), and Ile(356) mutants. The substitution-sensitive Arg(33) and Cys(353) mutants could also be considered as IVM-sensitive hits. The pattern of these 12 residues was consistent with helical topology of both TMs, with every third or fourth amino acid affected by substitution. These predominantly hydrophobic-nonpolar residues are also present in the IVM-sensitive Schistosoma mansoni P2X subunit. They lie on the same side of their helices and could face lipids in the open conformation state and provide the binding pocket for IVM. In contrast, the IVM-independent hits Met(31), Tyr(42), Gly(45), Val(49), Gly(340), Leu(343), Ala(344), Gly(347), Thr(350), Asp(354), and Val(357) map on the opposite side of their helices, probably facing the pore of receptor or protein and playing important roles in gating. C1 [Jelinkova, Irena; Vavra, Vojtech; Jindrichova, Marie; Obsil, Tomas; Zemkova, Hana] Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, CR-14220 Prague 4, Czech Republic. [Obsil, Tomas] Charles Univ Prague, Dept Phys & Macromol Chem, Fac Sci, Prague, Czech Republic. [Zemkova, Hana W.; Stojilkovic, Stanko S.] NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD USA. RP Zemkova, H (reprint author), Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, Videnska 1083, CR-14220 Prague 4, Czech Republic. EM zemkova@biomed.cas.cz RI Vavra, Vojtech/C-1857-2012; Zemkova, Hana/C-1844-2012; Jindrichova, Marie/C-3401-2012; Obsil, Tomas/B-7142-2012; Jindrichova, Marie/H-4320-2014 OI Obsil, Tomas/0000-0003-4602-1272; FU Intramural NIH HHS NR 38 TC 40 Z9 42 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD AUG PY 2008 VL 456 IS 5 BP 939 EP 950 DI 10.1007/s00424-008-0450-4 PG 12 WC Physiology SC Physiology GA 314QX UT WOS:000256825000014 PM 18427835 ER PT J AU Covington, D Tilson, H Watts, H Beckerman, K Zhang, S Lehman, H AF Covington, Deborah Tilson, Hugh Watts, Heather Beckerman, Karen Zhang, Sherry Lehman, Heidi TI Value of recruiting "100% Reporters" in a pregnancy registry: The antiretroviral pregnancy registry experience SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Covington, Deborah] Kendle, Registries & Epidemiol, Wilmington, NC USA. [Tilson, Hugh] Univ N Carolina, Chapel Hill, NC USA. [Watts, Heather] NICHHD, Maternal AIDS Branch, Rockville, MD USA. [Beckerman, Karen] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Zhang, Sherry] Gilead Sci Inc, Drug Safety, Foster City, CA 94404 USA. [Lehman, Heidi] Merck & Co Inc, Merck Res Labs, N Wales, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 520 BP S228 EP S228 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100520 ER PT J AU Freedman, AN Sansbury, LB Liu, G AF Freedman, Andrew N. Sansbury, Leah B. Liu, Geoffrey TI Linking pharmacoepidemiology with pharmacogenomics: Opportunities to incorporate genomics into pharmacoepidemiology studies SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Freedman, Andrew N.; Sansbury, Leah B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Liu, Geoffrey] Univ Toronto, Ontario Canc Inst, Princess Margaret Hosp, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 300 BP S132 EP S132 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100301 ER PT J AU Gagne, JJ Wang, PS Schneeweiss, S AF Gagne, Joshua J. Wang, Philip S. Schneeweiss, Sebastian TI Patterns of patient monitoring after initiation of antidepressant medications SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Gagne, Joshua J.; Schneeweiss, Sebastian] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wang, Philip S.] NIMH, Bethesda, MD 20892 USA. RI Schneeweiss, Sebastian/C-2125-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 045 BP S20 EP S20 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100046 ER PT J AU Halldorsdottir, V Almarsdottir, AB Gudmundsson, A Nikulasdottir, H Harris, TB Launer, L Eiriksdottir, G Gudnason, V AF Halldorsdottir, Vilborg Almarsdottir, Anna Birna Gudmundsson, Adalsteinn Nikulasdottir, Hjalmfridur Harris, Tamara B. Launer, Lenore Eiriksdottir, Gudny Gudnason, Vilmundur TI Pattern and prevalence of herbal and dietary supplements in an elderly cohort: AGES-Reykjavik study SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Halldorsdottir, Vilborg; Almarsdottir, Anna Birna] Univ Iceland, Fac Pharm, Reykjavik, Iceland. [Gudmundsson, Adalsteinn] Landspitali Univ Hosp, Reykjavik, Iceland. [Gudmundsson, Adalsteinn; Nikulasdottir, Hjalmfridur; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heat Assoc, Kopavogur, Iceland. [Harris, Tamara B.; Launer, Lenore] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Gudmundsson, Adalsteinn; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 277 BP S122 EP S122 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100278 ER PT J AU Huang, B Grant, BF Dawson, DA Chou, SP Stinson, FF Pickering, RP AF Huang, Boji Grant, Bridget F. Dawson, Deborah A. Chou, S. Patricia Stinson, Frederick F. Pickering, Roger P. TI The prospective association of insomnia with non-medical sedative use disorder SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Huang, Boji; Grant, Bridget F.; Dawson, Deborah A.; Chou, S. Patricia; Stinson, Frederick F.; Pickering, Roger P.] NIAAA, LEB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 221 BP S97 EP S97 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100222 ER PT J AU M'ikanatha, NM Sandt, CH Localio, R Tewari, D Russo, A Altekruse, SF Tait, J Hydock, M Reynolds, S Chiller, TM Rankin, S Lautenbach, E McDermott, P AF M'ikanatha, Nkuchia M. Sandt, Carol H. Localio, Russell Tewari, Deepanker Russo, Anthony Altekruse, Sean F. Tait, James Hydock, Michael Reynolds, Stanley Chiller, Tom M. Rankin, Shelley Lautenbach, Ebbing McDermott, Patrick CA PA Antimicrobial Resistance TI Prevalence of drug-resistant Salmonella from retail chicken and comparison with human clinical isolates SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [M'ikanatha, Nkuchia M.] Penn Dept Hlth, Harrisburg, PA 17108 USA. [M'ikanatha, Nkuchia M.; Localio, Russell; Rankin, Shelley; Lautenbach, Ebbing] Univ Penn, Philadelphia, PA 19104 USA. [Tewari, Deepanker; Hydock, Michael] Penn Dept Agr, Harrisburg, PA USA. [Altekruse, Sean F.] NIH, Bethesda, MD 20892 USA. [Chiller, Tom M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [McDermott, Patrick] US FDA, Ctr Vet Med, Laurel, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 512 BP S224 EP S225 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100512 ER PT J AU Sansbury, LB Potosky, AL Weiss-Smith, SR Freedman, AN AF Sansbury, Leah B. Potosky, Arnie L. Weiss-Smith, Sheila R. Freedman, Andrew N. TI Review: The use of common pharmaceuticals and nutraceuticals and the prevention of cancer SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sansbury, Leah B.; Potosky, Arnie L.; Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Weiss-Smith, Sheila R.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 093 BP S41 EP S41 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100094 ER PT J AU Schneeweiss, S Patrick, AR Dormuth, CR Maclure, M Canning, CF Wang, PS AF Schneeweiss, Sebastian Patrick, Amanda R. Dormuth, Colin R. Maclure, Malcolm Canning, Claire F. Wang, Philip S. TI The effect of prescription drug policy changes on mental health service use in British Columbia SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Schneeweiss, Sebastian; Patrick, Amanda R.; 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, Victoria, BC, Canada. [Wang, Philip S.] NIMH, Bethesda, MD 20892 USA. RI Schneeweiss, Sebastian/C-2125-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 472 BP S207 EP S208 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100472 ER PT J AU Stolk, P Souverein, PC Wilting, I Leufkens, HGM Klein, DF Rapoport, SI Heerdink, ER AF Stolk, Pieter Souverein, Patrick C. Wilting, Ingeborg Leufkens, Hubert G. M. Klein, Donald F. Rapoport, Stanley I. Heerdink, Eibert R. TI Taking low dose aspirin is associated with more stable drug treatment for lithium users SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Stolk, Pieter; Souverein, Patrick C.; Wilting, Ingeborg; Leufkens, Hubert G. M.; Heerdink, Eibert R.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Fac Sci, Div Pharmacoepidemiol & Pharmacotherapy, Utrecht, Netherlands. [Wilting, Ingeborg] Univ Med Ctr Utrecht, Dept Clin Pharm, Utrecht, Netherlands. [Klein, Donald F.] Columbia Univ, Dept Psychiat, New York, NY USA. [Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RI Heerdink, Eibert/H-6007-2014 OI Heerdink, Eibert/0000-0002-5946-7209 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 049 BP S22 EP S22 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100050 ER PT J AU Tsai, HT Wilson, W Dunleavy, K Landgren, O AF Tsai, Huei-Ting Wilson, Wyndham Dunleavy, Kieron Landgren, Ola TI Risk of acute myocardial infarction after CHOP-like chemotherapy +/- rituximab among older pts with diffuse large B-cell lymphoma: A Population-based study in the US SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Tsai, Huei-Ting; Wilson, Wyndham; Dunleavy, Kieron; Landgren, Ola] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 626 BP S274 EP S274 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100626 ER PT J AU Zito, JM Valluri, S Hundley, SD Safer, DJ Gardner, JF Maneval, M Korelitz, JJ McNally, DL Taylor-Zapata, P Mattison, DR AF Zito, Julie M. Valluri, Satish Hundley, Sarah D. Safer, Daniel J. Gardner, James F. Maneval, Mark Korelitz, James J. McNally, Diane L. Taylor-Zapata, Perdita Mattison, Donald R. TI Impact of comorbid disruptive disorders on pharmacotherapy for attention-deficit/hyperactivity disorder in publicly-insured US youth SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zito, Julie M.; Valluri, Satish; Hundley, Sarah D.; Gardner, James F.; Maneval, Mark; McNally, Diane L.] Univ Maryland, PHSR, Baltimore, MD 21201 USA. [Zito, Julie M.] UMB Sch Med, Baltimore, MD USA. [Safer, Daniel J.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Gardner, James F.] WESTAT Corp, Rockville, MD 20850 USA. [Taylor-Zapata, Perdita] NICHHD, Rockville, MD USA. [Mattison, Donald R.] NIH, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 452 BP S198 EP S199 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100452 ER PT J AU Hindorff, LA Lemaitre, RN Smith, NL Bis, JC Marciante, KD Rice, KM Lumley, T Enquobahrie, DA Li, G Heckbert, SR Psaty, BM AF Hindorff, Lucia A. Lemaitre, Rozenn N. Smith, Nicholas L. Bis, Joshua C. Marciante, Kristin D. Rice, Kenneth M. Lumley, Thomas Enquobahrie, Daniel A. Li, Guo Heckbert, Susan R. Psaty, Bruce M. TI Common genetic variation in six lipid-related and statin-related genes, statin use and risk of incident nonfatal myocardial infarction and stroke SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE epidemiology; 3-hydroxy-3-methylglutaryl-coenzyme A; myocardial infarction; pharmacogenetics; statins; stroke ID DENSITY-LIPOPROTEIN CHOLESTEROL; ESTER TRANSFER PROTEIN; HEPATIC LIPASE; CARDIOVASCULAR-DISEASE; THERAPY; POLYMORPHISMS; PHARMACOGENOMICS; ASSOCIATION; VARIANT AB Objective Genetic polymorphisms are associated with lipid-lowering response to statins, but generalizeability to disease endpoints is unclear. The association between 82 common single nucleotide polymorphisms (SNPs) in six lipid-related or statin-related genes (ABCB1, CETP, HMGCR, LDLR, LIPC, NOS3) and incident nonfatal myocardial infarction (MI) and ischemic stroke was analyzed according to current statin use and overall in a population-based case-control study (856 MI, 368 stroke, 2686 controls). Methods Common SNPs were chosen from resequencing data using pairwise linkage disequilibrium. Gene-level analyses (testing global association within a gene) and SNP-level analyses (comparing the number of observed vs. expected associations across all genes) were performed using logistic regression, setting nominal statistical significance at P value of less than 0.05. Results No gene-level interactions with statin use on MI or stroke were identified. Across all genes, two SNP-statin interactions on MI were observed (one ABCB1, one LIPC) and five interactions on stroke (one CETP, four LIPC). The strongest SNP-statin interaction was for synonymous CETP SNP rs5883 on stroke (P=0.008). Gene-level associations were present for LIPC and M I (P=0.026), but not other genes or outcomes. SNP-level associations included three SNPs with MI (one LDLR, two LIPC) and two SNPs with stroke (one CETR one LDLR). The number of observed SNP associations was no greater than expected by chance. Conclusion Several potential novel associations or interactions of SNPs in ABCB1, CETR LDLR, and LIPC with MI and stroke were identified; however, our results should be regarded as hypothesis generating until corroborated by other studies. C1 [Hindorff, Lucia A.; Lemaitre, Rozenn N.; Smith, Nicholas L.; Bis, Joshua C.; Marciante, Kristin D.; Rice, Kenneth M.; Lumley, Thomas; Enquobahrie, Daniel A.; Li, Guo; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Hindorff, Lucia A.; Smith, Nicholas L.; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rice, Kenneth M.; Lumley, Thomas; Li, Guo] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Smith, Nicholas L.] Off Res & Dev, Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. RP Hindorff, LA (reprint author), NHGRI, NIH, 5635 Fishers Lane,Suite 4076, Bethesda, MD 20892 USA. EM hindorffl@mail.nih.gov RI Li, Guo/E-5613-2012; Rice, Kenneth/A-4150-2013 OI Rice, Kenneth/0000-0001-5779-4495 FU NHLBI NIH HHS [R01 HL 68986, R01 HL 43201, R01 HL 60739, R01 HL 68639, R01 HL 73410, R01 HL 74745, R01 HL043201, R01 HL043201-13, R01 HL060739, R01 HL060739-04, R01 HL068639, R01 HL068639-04, R01 HL068986, R01 HL068986-04, R01 HL073410, R01 HL073410-04, R01 HL074745, R01 HL074745-04, R01 HL091244, T32 HL 07902, T32 HL007902, T32 HL007902-11]; NIA NIH HHS [R01 AG 09556, R01 AG009556, R01 AG009556-09] NR 17 TC 19 Z9 20 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1744-6872 EI 1744-6880 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD AUG PY 2008 VL 18 IS 8 BP 677 EP 682 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 330SI UT WOS:000257962700004 PM 18622260 ER PT J AU Fostel, J Wu, AHB Munafo, MR AF Fostel, Jennifer Wu, Alin H. B. Munafo, Marcus R. TI Consortia-driven advances in biomarker discovery SO PHARMACOGENOMICS LA English DT Article C1 [Fostel, Jennifer] NIEHS, Global Hlth Sector, SRA Int Inc, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Wu, Alin H. B.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94110 USA. [Munafo, Marcus R.] Univ Bristol, Dept Expt Psychol, Bristol BS8 1TU, Avon, England. RP Fostel, J (reprint author), NIEHS, Global Hlth Sector, SRA Int Inc, Lab Resp Biol, MD F1-05-111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM fostel@niebs.nih.gov; wualan@labmed2.ucsf.edu; marcus.munafo@bristol.ac.uk NR 2 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD AUG PY 2008 VL 9 IS 8 BP 1001 EP 1002 DI 10.2217/14622416.9.8.1001 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 339FI UT WOS:000258563100009 ER PT J AU Baumann, MH Clark, RD Rothman, RB AF Baumann, Michael H. Clark, Robert D. Rothman, Richard B. TI Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine (MDMA) is correlated with dialysate levels of serotonin and dopamine in rat brain SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE ambulation; dopamine; MDMA; microdialysis; serotonin; stereotypy ID FREELY-MOVING RATS; MEDIAL PREFRONTAL CORTEX; SINGLE-UNIT ACTIVITY; NUCLEUS-ACCUMBENS; 5-HT RECEPTORS; D-AMPHETAMINE; DIFFERENTIAL INVOLVEMENT; STEREOTYPED BEHAVIOR; RELEASE; ECSTASY AB (+/-)-3,4-Methylenedioxymethamphetmine (MDMA, or Ecstasy) is an illicit drug that evokes transporter-mediated release of monoamines, including serotonin (5-HT) and dopamine (DA). Here we monitored the effects of MDMA on neurochemistry and motor activity in rats, as a means to evaluate relationships between 5-HT, DA, and behavior. Male rats undergoing in vivo microdialysis were housed in chambers equipped with photobeams for measurement of ambulation (i.e., forward locomotion) and stereotypy (i.e., head weaving and forepaw treading). Microdialysis probes were placed into the n. accumbens, striatum or prefrontal cortex in separate groups of rats. Dialysate samples were assayed for 5-HT and DA by microbore HPLC-ECD. Rats received two i.v. injections of MDMA, 1 mg/kg followed by 3 mg/kg 60 min later; neurochemical and locomotor parameters were measured concurrently. MDMA produced dose-related elevations in extracellular 5-HT and DA in all regions, with the magnitude of 5-HT release always exceeding that of DA release. MDMA-induced ambulation was positively correlated with dialysate DA levels in all regions (P < 0.05-0.0001) and with dialysate 5-HT in striatum and cortex (P < 0.001-0.0001). Stereotypy was strongly correlated with dialysate 5-HT in all areas (P < 0.001-0.0001) and with dialysate DA in accumbens and striatum (P < 0.001-0.0001). These data support previous work and suggest the complex spectrum of behaviors produced by MDMA involves 5-HT and DA in a region- and modality-specific manner. Published by Elsevier Inc. C1 [Baumann, Michael H.; Clark, Robert D.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Baumann, MH (reprint author), NIDA, Clin Psychopharmacol Sect, IRP, NIH,DHHS, 333 Cassell Dr,Suite 4500, Baltimore, MD 21224 USA. EM mbaumann@mail.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 100 TC 59 Z9 59 U1 0 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 AUG PY 2008 VL 90 IS 2 BP 208 EP 217 DI 10.1016/j.pbb.2008.02.018 PG 10 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 323ZW UT WOS:000257488300010 PM 18403002 ER PT J AU Ravits, J Traynor, BJ AF Ravits, John Traynor, Bryan J. TI Current and Future Directions in Genomics of Amyotrophic Lateral Sclerosis SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article ID LASER CAPTURE MICRODISSECTION; SPINAL MOTOR-NEURONS; MOUSE MODEL; DIFFERENTIAL EXPRESSION; MICROARRAY TECHNOLOGY; WIDE ASSOCIATION; GENE-EXPRESSION; MESSENGER-RNA; DNA MICROARRAYS; ALS AB New knowledge of the structure and function of the human genome and novel genomic technologies are being applied to the study of sporadic amyotrophic lateral sclerosis (ALS). These studies can examine tens to hundreds of thousands of items at once, and depend on sophisticated computer processing. Current studies are focused on genetic susceptibility and gene expression and future studies will likely focus on structural variation, gene regulation and non-protein coding regions. The hope is that they will lead to deeper understanding of molecular aspects of the disease and to rational therapeutic targets. C1 [Ravits, John] Benaroya Res Inst Virginia Mason, Seattle, WA 98101 USA. [Ravits, John] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Ravits, John] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA. [Traynor, Bryan J.] NINDS, NIH, Neurogenet Branch, Bethesda, MD 20892 USA. RP Ravits, J (reprint author), Benaroya Res Inst Virginia Mason, 1201 9th Ave, Seattle, WA 98101 USA. EM jravits@benaroyaresearch.org RI Traynor, Bryan/G-5690-2010 FU National Institute of Health [R21 NS051738OIAI]; Department of Defense; Moyer Foundation; Juniper Foundation; Benaroya Foundation FX Dr. Ravits' work was supported by the National Institute of Health (R21 NS051738OIAI), Department of Defense (USAMRMC Proposal #06054001), the Moyer Foundation, the Juniper Foundation, the Benaroya Foundation, and private philanthropists. NR 78 TC 3 Z9 3 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 1047-9651 J9 PHYS MED REHABIL CLI JI Phys. Med. Rehabil. Clin. N. Am. PD AUG PY 2008 VL 19 IS 3 BP 461 EP + DI 10.1016/j.pmr.2008.04.001 PG 18 WC Rehabilitation SC Rehabilitation GA 437ND UT WOS:000265493300006 PM 18625410 ER PT J AU Le Pape, E Wakamatsu, K Ito, S Wolber, R Hearing, VJ AF Le Pape, Elodie Wakamatsu, Kazumasa Ito, Shosuke Wolber, Rainer Hearing, Vincent J. TI Regulation of eumelanin/pheomelanin synthesis and visible pigmentation in melanocytes by ligands of the melanocortin 1 receptor SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE eumelanin; pheomelanin; MC1R; ASP; alpha MSH; PTU; tyrosinase ID AGOUTI-SIGNALING-PROTEIN; CULTURED HUMAN MELANOCYTES; HUMAN-MELANOMA CELLS; STIMULATING HORMONE; SKIN COLOR; ALPHA-MELANOTROPIN; IN-VITRO; EUMELANIN; GENE; MELANOGENESIS AB The production of melanin in the hair and skin is tightly regulated by the melanocortin 1 receptor (MC1R) whose activation is controlled by two secreted ligands, alpha-melanocyte stimulating hormone (alpha MSH) and agouti signal protein (ASP). As melanin is extremely stable, lasting years in biological tissues, the mechanism underlying the relatively rapid decrease in visible pigmentation elicited by ASP is of obvious interest. In this study, the effects of ASP and alpha MSH on the regulation of melanin synthesis and on visible pigmentation were assessed in normal murine melanocytes and were compared with the quick depigmenting effect of the tyrosinase inhibitor, phenylthiourea (PTU). alpha MSH increased pheomelanin levels prior to increasing eumelanin content over 4 days of treatment. Conversely, ASP switched off the pigment synthesis pathway, reducing eu- and pheo-melanin synthesis within 1 day of treatment that was proportional to the decrease in tyrosinase protein level and activity. These results demonstrate that the visible depigmentation of melanocytes induced by ASP does not require the degradation of existing melanin but rather is due to the dilution of existing melanin by melanocyte turnover, which emphasizes the importance of pigment distribution to visible color. C1 [Le Pape, Elodie; Hearing, Vincent J.] NCI, Pigment Cell Biol Sect, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wakamatsu, Kazumasa; Ito, Shosuke] Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Aichi, Japan. [Wolber, Rainer] Beiersdorf AG, R&D, Skin Res Ctr, Hamburg, Germany. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM hearingv@nih.gov OI Ito, Shosuke/0000-0001-9182-5144; Wakamatsu, Kazumasa/0000-0003-1748-9001 FU Intramural NIH HHS [Z01 BC010784-01] NR 45 TC 37 Z9 37 U1 1 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD AUG PY 2008 VL 21 IS 4 BP 477 EP 486 DI 10.1111/j.1755-148X.2008.00479.x PG 10 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 325EM UT WOS:000257571300011 PM 18627531 ER PT J AU Wolber, R Schlenz, K Wakamatsu, K Smuda, C Nakanishi, Y Hearing, VJ Ito, S AF Wolber, Rainer Schlenz, Kathrin Wakamatsu, Kazumasa Smuda, Christoph Nakanishi, Yukiko Hearing, Vincent J. Ito, Shosuke TI Pigmentation effects of solar-simulated radiation as compared with UVA and UVB radiation SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE ultraviolet; solar radiation; melanin; eumelanin; pheomelanin; 5-S-cysteinyldopa; 5(6)-hydroxy-6(5)-methoxyindole-2-carboxylic acid ID HUMAN SKIN; ULTRAVIOLET-RADIATION; HUMAN EPIDERMIS; MELANIN CONTENT; OXIDATION; 3,4-DIHYDROXYPHENYLALANINE; EUMELANIN; SERUM; HEMODIALYSIS; PHEOMELANIN AB Different wavelengths of ultraviolet (UV) radiation elicit different responses in the skin. UVA induces immediate tanning and persistent pigment darkening through oxidation of pre-existing melanin or melanogenic precursors, while UVB induces delayed tanning which takes several days or longer to develop and requires activation of melanocytes. We compared the effects of a 2-week repetitive exposure of human skin to solar-simulated radiation (SSR), UVA or UVB at doses eliciting comparable levels of visible tanning and measured levels of melanins and melanin-related metabolites. Levels of eumelanin and pheomelanin were significantly higher in the order of SSR, UVB, UVA or unexposed control skin. Levels of free 5-S-cysteinyldopa (5SCD) were elevated about 4-fold in SSR- or UVB-exposed skin compared with UVA-exposed or control skin. Levels of protein-bound form of 5SCD tended to be higher in SSR- or UVB-exposed skin than in UVA-exposed or control skin. Total levels of 5-hydroxy-6-methoxyindole-2-carboxylic acid (5H6MI2C) and 6H5MI2C were higher in SSR- than in UVB-exposed or control skin. These results show that SSR is more effective in promoting delayed tanning than UVB radiation alone, suggesting a synergistic effect of UVA radiation. Furthermore, free 5SCD may serve as a good marker of the effect of SSR and UVB. C1 [Wakamatsu, Kazumasa; Nakanishi, Yukiko; Ito, Shosuke] Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Aichi, Japan. [Wolber, Rainer; Schlenz, Kathrin; Smuda, Christoph] Beiersdorf AG, R& D, Skin Res Ctr, Hamburg, Germany. [Hearing, Vincent J.] NCI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Ito, S (reprint author), Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Aichi, Japan. EM sito@fujita-hu.ac.jp OI Ito, Shosuke/0000-0001-9182-5144; Wakamatsu, Kazumasa/0000-0003-1748-9001 FU Intramural NIH HHS [Z01 BC009100-21] NR 29 TC 35 Z9 39 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD AUG PY 2008 VL 21 IS 4 BP 487 EP 491 DI 10.1111/j.1755-148X.2008.00470.x PG 5 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 325EM UT WOS:000257571300012 PM 18627527 ER PT J AU King, CL May, K Grube, M Malhotra, I Long, C Mandaliya, K Fusch, C Schneider, H AF King, Christopher L. May, Karen Grube, Marcus Malhotra, Indu Long, Carole Mandaliya, Kishor Fusch, Christoph Schneider, Henning TI Placental malaria and antibody-dependent transplacental transfer of malaria antigens SO PLACENTA LA English DT Meeting Abstract CT 14th Meeting of the International-Federation-of-Placental-Associations/12th Meeting of the European-Placenta-Group (IFPA/EPG) CY SEP 10-13, 2008 CL Seggau Castle, AUSTRIA SP Int Federat Placenta Assoc, European Placenta Grp C1 [King, Christopher L.; Malhotra, Indu] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [King, Christopher L.; Malhotra, Indu] Vet Affairs Med Ctr, Cleveland, OH USA. [May, Karen; Grube, Marcus; Fusch, Christoph] Ernst Moritz Arndt Univ Greifswald, Dept Pharmacol, D-17487 Greifswald, Germany. [May, Karen; Grube, Marcus; Fusch, Christoph] Ernst Moritz Arndt Univ Greifswald, Dept Pediat, D-17487 Greifswald, Germany. [Long, Carole] NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Mandaliya, Kishor] Mombasa Gen Hosp, Pathol Serv Kenyan Minist Hlth, Mombasa, Kenya. [Schneider, Henning] Univ Bern, Dept Obstet & Gynecol, CH-3012 Bern, Switzerland. NR 0 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD AUG PY 2008 VL 29 IS 8 BP A4 EP A4 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 345XM UT WOS:000259031100025 ER PT J AU Ahn, S Lee, G Yang, SJ Lee, D Lee, S Shin, HS Kim, MC Lee, KN Palmer, DC Theoret, MR Jenkinson, EJ Anderson, G Restifo, NP Kim, MG AF Ahn, Sejin Lee, Gwanghee Yang, Soo Jung Lee, Deokjae Lee, Seunghyuk Shin, Hyo Sun Kim, Min Cheol Lee, Kee Nyung Palmer, Douglas C. Theoret, Marc R. Jenkinson, Eric J. Anderson, Graham Restifo, Nicholas P. Kim, Moon Gyo TI TSCOT(+) thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation SO PLOS BIOLOGY LA English DT Article ID PROMISCUOUS GENE-EXPRESSION; SELF-ANTIGEN POOLS; NEGATIVE SELECTION; T-CELLS; STROMAL CELLS; AUTOIMMUNE REGULATOR; POSITIVE SELECTION; CLONAL DELETION; DENDRITIC CELLS; MULTIPLE LEVELS AB Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT)-expressing thymic stromal cells (TDLacZ). The thymus of this mouse contains approximately 4,300 TSCOT(+) cells, each expressing several thousand molecules of the LacZ antigen. TSCOT(+) cells express the cortical marker CDR1, CD40, CD80, CD54, and major histocompatibility complex class II (MHCII). When examining endogenous responses directed against LacZ, we observed significant tolerance. This was evidenced in a diverse T cell repertoire as measured by both a CD4 T cell proliferation assay and an antigen-specific antibody isotype analysis. This tolerance process was at least partially independent of Autoimmune Regulatory Element gene expression. When TDLacZ mice were crossed to a novel CD4 T cell receptor (TCR) transgenic reactive against LacZ (BgII), there was a complete deletion of double-positive thymocytes. Fetal thymic reaggregate culture of CD45-and UEA-depleted thymic stromal cells from TDLacZ and sorted TCR-bearing thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells for the deletion. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT(+) cells. C1 [Lee, Deokjae; Kim, Moon Gyo] Inha Univ, Res Ctr Mol & Cellular Biol, Inchon, South Korea. [Ahn, Sejin; Lee, Gwanghee; Yang, Soo Jung; Lee, Kee Nyung] NIAID, Lab Cellular & Mol Immunol, Bethesda, MD 20892 USA. [Lee, Seunghyuk; Shin, Hyo Sun; Kim, Min Cheol; Kim, Moon Gyo] Inha Univ, Dept Biol Sci, Inchon, South Korea. [Palmer, Douglas C.; Theoret, Marc R.; Restifo, Nicholas P.] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. [Palmer, Douglas C.; Theoret, Marc R.; Restifo, Nicholas P.] Univ Birmingham, Inst Biomed Res, MRC, Ctr Immune Regulat, Birmingham B15 2TT, W Midlands, England. RP Kim, MG (reprint author), Inha Univ, Res Ctr Mol & Cellular Biol, Inchon, South Korea. EM mgkim@inha.ac.kr RI Palmer, Douglas/B-9454-2008; Restifo, Nicholas/A-5713-2008; OI Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU Ministry of Science and Technology [34689-1]; Korean Government [2006-34673-1] FX This work was supported by the Molecular and Cellular BioDiscovery Research Program 34689-1 grant from the Ministry of Science and Technology and by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2006-34673-1). NR 71 TC 9 Z9 9 U1 0 U2 0 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 AUG PY 2008 VL 6 IS 8 BP 1746 EP 1757 AR e191 DI 10.1371/journal.pbio.0060191 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 341UA UT WOS:000258739400017 PM 18684012 ER PT J AU La Camera, G Richmond, BJ AF La Camera, Giancarlo Richmond, Barry J. TI Modeling the Violation of Reward Maximization and Invariance in Reinforcement Schedules SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID MONKEY ORBITOFRONTAL CORTEX; NEURONAL SIGNALS; VENTRAL STRIATUM; MATCHING BEHAVIOR; DECISION-MAKING; DORSAL STRIATUM; RHINAL CORTEX; SUNK COST; CHOICE; PSYCHOLOGY AB It is often assumed that animals and people adjust their behavior to maximize reward acquisition. In visually cued reinforcement schedules, monkeys make errors in trials that are not immediately rewarded, despite having to repeat error trials. Here we show that error rates are typically smaller in trials equally distant from reward but belonging to longer schedules (referred to as "schedule length effect''). This violates the principles of reward maximization and invariance and cannot be predicted by the standard methods of Reinforcement Learning, such as the method of temporal differences. We develop a heuristic model that accounts for all of the properties of the behavior in the reinforcement schedule task but whose predictions are not different from those of the standard temporal difference model in choice tasks. In the modification of temporal difference learning introduced here, the effect of schedule length emerges spontaneously from the sensitivity to the immediately preceding trial. We also introduce a policy for general Markov Decision Processes, where the decision made at each node is conditioned on the motivation to perform an instrumental action, and show that the application of our model to the reinforcement schedule task and the choice task are special cases of this general theoretical framework. Within this framework, Reinforcement Learning can approach contextual learning with the mixture of empirical findings and principled assumptions that seem to coexist in the best descriptions of animal behavior. As examples, we discuss two phenomena observed in humans that often derive from the violation of the principle of invariance: "framing,'' wherein equivalent options are treated differently depending on the context in which they are presented, and the "sunk cost'' effect, the greater tendency to continue an endeavor once an investment in money, effort, or time has been made. The schedule length effect might be a manifestation of these phenomena in monkeys. C1 [La Camera, Giancarlo; Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP La Camera, G (reprint author), NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bldg 9, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov FU Intramural Research Program, NIMH; NIMH, NIH; United States Government FX Work supported by the Intramural Research Program, NIMH. The views expressed in this article do not necessarily represent the views of the NIMH, NIH, or the United States Government. NR 62 TC 14 Z9 14 U1 1 U2 4 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 AUG PY 2008 VL 4 IS 8 AR e1000131 DI 10.1371/journal.pcbi.1000131 PG 17 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 360EX UT WOS:000260041300028 PM 18688266 ER PT J AU McQueen, PG McKenzie, FE AF McQueen, Philip G. McKenzie, F. Ellis TI Host Control of Malaria Infections: Constraints on Immune and Erythropoeitic Response Kinetics SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PLASMODIUM-VIVAX MALARIA; TUMOR-NECROSIS-FACTOR; RED-BLOOD-CELLS; RETROSPECTIVE EXAMINATION; FEBRILE TEMPERATURES; CEREBRAL MALARIA; BONE-MARROW; IN-VITRO; FALCIPARUM; DYNAMICS AB The two main agents of human malaria, Plasmodium vivax and Plasmodium falciparum, can induce severe anemia and provoke strong, complex immune reactions. Which dynamical behaviors of host immune and erythropoietic responses would foster control of infection, and which would lead to runaway parasitemia and/or severe anemia? To answer these questions, we developed differential equation models of interacting parasite and red blood cell (RBC) populations modulated by host immune and erythropoietic responses. The model immune responses incorporate both a rapidly responding innate component and a slower-responding, long-term antibody component, with several parasite developmental stages considered as targets for each type of immune response. We found that simulated infections with the highest parasitemia tended to be those with ineffective innate immunity even if antibodies were present. We also compared infections with dyserythropoiesis (reduced RBC production during infection) to those with compensatory erythropoiesis (boosted RBC production) or a fixed basal RBC production rate. Dyserythropoiesis tended to reduce parasitemia slightly but at a cost to the host of aggravating anemia. On the other hand, compensatory erythropoiesis tended to reduce the severity of anemia but with enhanced parasitemia if the innate response was ineffective. For both parasite species, sharp transitions between the schizont and the merozoite stages of development (i.e., with standard deviation in intra-RBC development time <= 2.4 h) were associated with lower parasitemia and less severe anemia. Thus tight synchronization in asexual parasite development might help control parasitemia. Finally, our simulations suggest that P. vivax can induce severe anemia as readily as P. falciparum for the same type of immune response, though P. vivax attacks a much smaller subset of RBCs. Since most P. vivax infections are nonlethal (if debilitating) clinically, this suggests that P. falciparum adaptations for countering or evading immune responses are more effective than those of P. vivax. C1 [McQueen, Philip G.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [McKenzie, F. Ellis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP McQueen, PG (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM mcqueenp@mail.nih.gov FU National Institutes of Health; US Department of Health and Human Services, Bethesda, Maryland FX This research was supported by the Intramural Research Program of the National Institutes of Health through the Center for Information Technology and the John E. Fogarty International Center, US Department of Health and Human Services, Bethesda, Maryland. NR 66 TC 15 Z9 15 U1 2 U2 3 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 AUG PY 2008 VL 4 IS 8 AR e1000149 DI 10.1371/journal.pcbi.1000149 PG 15 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 360EX UT WOS:000260041300016 PM 18725923 ER PT J AU Zotenko, E Mestre, J O'Leary, DP Przytycka, TM AF Zotenko, Elena Mestre, Julian O'Leary, Dianne P. Przytycka, Teresa M. TI Why Do Hubs in the Yeast Protein Interaction Network Tend To Be Essential: Reexamining the Connection between the Network Topology and Essentiality SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; GENE ESSENTIALITY; COMPLEX NETWORKS; GENOMIC DATA; CENTRALITY; IDENTIFICATION; EVOLUTIONARY; BETWEENNESS; MAP AB The centrality-lethality rule, which notes that high-degree nodes in a protein interaction network tend to correspond to proteins that are essential, suggests that the topological prominence of a protein in a protein interaction network may be a good predictor of its biological importance. Even though the correlation between degree and essentiality was confirmed by many independent studies, the reason for this correlation remains illusive. Several hypotheses about putative connections between essentiality of hubs and the topology of protein-protein interaction networks have been proposed, but as we demonstrate, these explanations are not supported by the properties of protein interaction networks. To identify the main topological determinant of essentiality and to provide a biological explanation for the connection between the network topology and essentiality, we performed a rigorous analysis of six variants of the genomewide protein interaction network for Saccharomyces cerevisiae obtained using different techniques. We demonstrated that the majority of hubs are essential due to their involvement in Essential Complex Biological Modules, a group of densely connected proteins with shared biological function that are enriched in essential proteins. Moreover, we rejected two previously proposed explanations for the centrality-lethality rule, one relating the essentiality of hubs to their role in the overall network connectivity and another relying on the recently published essential protein interactions model. C1 [Zotenko, Elena; Mestre, Julian] Max Planck Inst Informat, Saarbrucken, Germany. [O'Leary, Dianne P.] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. [O'Leary, Dianne P.] Univ Maryland, Inst Adv Comp Studies, College Pk, MD 20742 USA. [Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Zotenko, E (reprint author), Max Planck Inst Informat, Saarbrucken, Germany. EM przytyck@ncbi.nlm.nih.gov OI Zotenko, Elena/0000-0002-0256-3195 FU Intramural Research Program of the NIH; National Library of Medicine; NSF [CCF-0514213] FX TMP and EZ were supported by the Intramural Research Program of the NIH and the National Library of Medicine. DPO was supported by NSF Grant CCF-0514213. NR 37 TC 172 Z9 176 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2008 VL 4 IS 8 AR e1000140 DI 10.1371/journal.pcbi.1000140 PG 16 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 360EX UT WOS:000260041300036 PM 18670624 ER PT J AU Irimia, M Roy, SW AF Irimia, Manuel Roy, Scott William TI Evolutionary Convergence on Highly-Conserved 3 ' Intron Structures in Intron-Poor Eukaryotes and Insights into the Ancestral Eukaryotic Genome SO PLOS GENETICS LA English DT Article ID SPLICEOSOMAL INTRONS; PLASMODIUM-REICHENOWI; TRICHOMONAS-VAGINALIS; GIARDIA-LAMBLIA; GENES; SEQUENCE; SITES; TRANSCRIPTS; FALCIPARUM; SELECTION AB The presence of spliceosomal introns in eukaryotes raises a range of questions about genomic evolution. Along with the fundamental mysteries of introns' initial proliferation and persistence, the evolutionary forces acting on intron sequences remain largely mysterious. Intron number varies across species from a few introns per genome to several introns per gene, and the elements of intron sequences directly implicated in splicing vary from degenerate to strict consensus motifs. We report a 50-species comparative genomic study of intron sequences across most eukaryotic groups. We find two broad and striking patterns. First, we find that some highly intron-poor lineages have undergone evolutionary convergence to strong 39 consensus intron structures. This finding holds for both branch point sequence and distance between the branch point and the 39 splice site. Interestingly, this difference appears to exist within the genomes of green alga of the genus Ostreococcus, which exhibit highly constrained intron sequences through most of the intron-poor genome, but not in one much more intron-dense genomic region. Second, we find evidence that ancestral genomes contained highly variable branch point sequences, similar to more complex modern intron-rich eukaryotic lineages. In addition, ancestral structures are likely to have included polyT tails similar to those in metazoans and plants, which we found in a variety of protist lineages. Intriguingly, intron structure evolution appears to be quite different across lineages experiencing different types of genome reduction: whereas lineages with very few introns tend towards highly regular intronic sequences, lineages with very short introns tend towards highly degenerate sequences. Together, these results attest to the complex nature of ancestral eukaryotic splicing, the qualitatively different evolutionary forces acting on intron structures across modern lineages, and the impressive evolutionary malleability of eukaryotic gene structures. C1 [Irimia, Manuel] Univ Barcelona, Fac Biol, Dept Genet, Barcelona, Spain. [Roy, Scott William] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Irimia, M (reprint author), Univ Barcelona, Fac Biol, Dept Genet, Barcelona, Spain. EM mirimia@gmail.com; scottwroy@gmail.com RI Irimia, Manuel/E-3040-2010; OI Irimia, Manuel/0000-0002-2179-2567 FU Spanish Ministerio of Educacion y Ciencia [BFU2005-00252]; Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS FX Manuel Irimia was funded by the Spanish Ministerio of Educacion y Ciencia, through the FPI grant (BFU2005-00252), and Scott William Roy by the Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. NR 48 TC 39 Z9 39 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2008 VL 4 IS 8 AR e1000148 DI 10.1371/journal.pgen.1000148 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 365MN UT WOS:000260410800026 PM 18688272 ER PT J AU Morgan, C Marthas, M Miller, C Duerr, A Cheng-Mayer, C Desrosiers, R Flores, J Haigwood, N Hu, SL Johnson, RP Lifson, J Montefiori, D Moore, J Robert-Guroff, M Robinson, H Self, S Corey, L AF Morgan, Cecilia Marthas, Marta Miller, Christopher Duerr, Ann Cheng-Mayer, Cecilia Desrosiers, Ronald Flores, Jorge Haigwood, Nancy Hu, Shiu-Lok Johnson, R. Paul Lifson, Jeffrey Montefiori, David Moore, John Robert-Guroff, Marjorie Robinson, Harriet Self, Steven Corey, Lawrence TI The use of nonhuman primate models in HIV vaccine development SO PLOS MEDICINE LA English DT Review ID SIMIAN IMMUNODEFICIENCY VIRUS; AIDS VACCINE; CHALLENGE; SIVMAC239; LIVE C1 [Morgan, Cecilia; Duerr, Ann; Corey, Lawrence] Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, Seattle, WA 98104 USA. [Marthas, Marta] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Miller, Christopher] Univ Calif Davis, Calif Natl Primate Res Ctr, Dept Pathol Microbiol & Immunol, Sch Vet Med, Davis, CA 95616 USA. [Cheng-Mayer, Cecilia] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Desrosiers, Ronald] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. [Flores, Jorge] NIAID, Div Aids, Bethesda, MD 20892 USA. [Haigwood, Nancy] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Hu, Shiu-Lok] Univ Washington, Washington Natl Primate Res Ctr, Dept Pharmaceut & Microbiol, Seattle, WA 98195 USA. [Lifson, Jeffrey] NCI, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD USA. [Montefiori, David] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Moore, John] Cornell Univ, Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. [Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Bethesda, MD 20892 USA. [Robinson, Harriet] Emory Vaccine Ctr, Atlanta, GA USA. [Self, Steven] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. RP Morgan, C (reprint author), Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, 1124 Columbia St, Seattle, WA 98104 USA. EM cmorgan@fhcrc.org RI Hu, Shiu-Lok/A-3196-2008 OI Hu, Shiu-Lok/0000-0003-4336-7964 NR 15 TC 68 Z9 68 U1 0 U2 7 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 AUG PY 2008 VL 5 IS 8 BP 1200 EP 1204 AR e173 DI 10.1371/journal.pmed.0050173 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 341TY UT WOS:000258739200009 PM 18700814 ER PT J AU Nelson, MI Edelman, L Spiro, DJ Boyne, AR Bera, J Halpin, R Ghedin, E Miller, MA Simonsen, L Viboud, C Holmes, EC AF Nelson, Martha I. Edelman, Laurel Spiro, David J. Boyne, Alex R. Bera, Jayati Halpin, Rebecca Ghedin, Elodie Miller, Mark A. Simonsen, Lone Viboud, Cecile Holmes, Edward C. TI Molecular epidemiology of A/H3N2 and A/H1N1 influenza virus during a single epidemic season in the United States SO PLOS PATHOGENS LA English DT Article ID A VIRUSES; ADAMANTANE RESISTANCE; HEMAGGLUTININ GENE; H3N2 VIRUSES; EVOLUTION; SPREAD; REASSORTMENT; MORTALITY; WORLDWIDE; SELECTION AB To determine the spatial and temporal dynamics of influenza A virus during a single epidemic, we examined whole-genome sequences of 284 A/H1N1 and 69 A/H3N2 viruses collected across the continental United States during the 2006-2007 influenza season, representing the largest study of its kind undertaken to date. A phylogenetic analysis revealed that multiple clades of both A/H1N1 and A/H3N2 entered and co-circulated in the United States during this season, even in localities that are distant from major metropolitan areas, and with no clear pattern of spatial spread. In addition, co-circulating clades of the same subtype exchanged genome segments through reassortment, producing both a minor clade of A/H3N2 viruses that appears to have re-acquired sensitivity to the adamantane class of antiviral drugs, as well as a likely antigenically distinct A/H1N1 clade that became globally dominant following this season. Overall, the co-circulation of multiple viral clades during the 2006-2007 epidemic season revealed patterns of spatial spread that are far more complex than observed previously, and suggests a major role for both migration and reassortment in shaping the epidemiological dynamics of human influenza A virus. C1 [Nelson, Martha I.; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Edelman, Laurel] Surveillance Data Inc, Plymouth Meeting, PA USA. [Spiro, David J.; Boyne, Alex R.; Bera, Jayati; Halpin, Rebecca] J Craig Venter Inst, Rockville, MD USA. [Ghedin, Elodie] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. [Miller, Mark A.; Viboud, Cecile; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Washington, DC USA. RP Nelson, MI (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Simonsen, Lone/0000-0003-1535-8526; Holmes, Edward/0000-0001-9596-3552 FU NIH [GM080533-01] FX This research was funded in part by NIH grant number GM080533-01 to ECH. NR 45 TC 56 Z9 59 U1 0 U2 4 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 AUG PY 2008 VL 4 IS 8 AR e1000133 DI 10.1371/journal.ppat.1000133 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 356MU UT WOS:000259783100021 PM 18725925 ER PT J AU Fulcutake, M Hishimoto, A Nishiguchi, N Nushida, H Ueno, Y Shirakawa, O Maeda, K AF Fulcutake, Masaaki Hishimoto, Akitoyo Nishiguchi, Naoki Nushida, Hideyuki Ueno, Yasuhiro Shirakawa, Osamu Maeda, Kiyoshi TI Association of alpha(2A)-adrenergic receptor gene polymorphism with susceptibility to suicide in Japanese females SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE alpha(2A)-adrenergic receptor; haplotype; Japanese; single nucleotide polymorphism; suicide ID ADRENERGIC-RECEPTOR GENE; AGONIST BINDING-SITES; FUNCTIONAL POLYMORPHISM; DEPRESSED SUICIDES; COMPLETED SUICIDE; PROMOTER REGION; MOOD DISORDERS; FRONTAL-CORTEX; VICTIMS; BRAIN AB Objectives: It has been suggested that noradrenergic system abnormalities are involved in suicide. Postmortem brain studies have shown that molecular and functional alterations in alpha(2A)-adrenergic receptor-induced signal transduction are associated with suicide and depression. Recently, a single nucleotide polymorphism (SNP) within a coding region of the alpha(2A)-adrenergic receptor gene (ADRA2A), which results in an Asn-to-Lys change at amino acid 251 (N251K), has been implicated in susceptibility to suicide in Caucasians. The aim of our study is to determine whether genetic variants of the ADRA2A gene are also associated with suicide in a Japanese population. Methods: Three SNPs, C-1291G, N251K and rs3750625C/A, and one insertion/deletion polymorphism in the ADRA2A gene were genotyped in 184 completed suicides and 221 control subjects with the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Results: Neither variation of the N251K SNP nor the insertion/deletion polymorphism was found in our Japanese samples. The C-1291G SNP in the promoter region was found to be significantly associated with Suicide in females (P=0.043 and 0.013 for genotypic and allelic comparisons, respectively). One of the common haplotypes, CC of C-1291G and rs3750625C/A, was also associated with suicide in females (P=0.015). These associations were also significant in the female violent suicide victims (P=0.009 and 0.009 for allelic and CC haplotypic comparisons, respectively). Although the significance was nominal, it was maintained even after correction for multiple comparisons. By contrast, neither of these two SNPs showed any association with violent and/or non-violent suicide in males. Conclusion: Our results raise the possibility that promoter genetic variation in the ADR42A gene is associated with either suicide or violent suicide in females. (C) 2008 Elsevier file. All rights reserved. C1 [Fulcutake, Masaaki; Hishimoto, Akitoyo; Nishiguchi, Naoki; Maeda, Kiyoshi] Kobe Univ, Grad Sch, Dept Psychiat, Chou Ku, Kobe, Hyogo 6500017, Japan. [Hishimoto, Akitoyo] NIDA, IRP, Mol Neurobiol Branch, Baltimore, MD USA. [Nushida, Hideyuki; Ueno, Yasuhiro] Kobe Univ, Grad Sch, Dept Legal Med, Kobe, Hyogo 6500017, Japan. [Shirakawa, Osamu] Kinki Univ, Sch Med, Dept Neuropsychiat, Osaka 589, Japan. RP Fulcutake, M (reprint author), Kobe Univ, Grad Sch, Dept Psychiat, Chou Ku, 7-5-1 Kusunoki Cho, Kobe, Hyogo 6500017, Japan. EM masaaaki@med.kobe-u.ac.jp FU Ministry of Health, Labor and Welfare, Japan; Ministry of Education, Science, Culture and Sports, Japan FX We thank Mrs. Y. Nagashima for her technical assistance. This research was supported by a Research Grant for Nervous and Mental Disorders and Health Sciences from the Ministry of Health, Labor and Welfare, Japan, and by grants from the Ministry of Education, Science, Culture and Sports, Japan. NR 45 TC 0 Z9 0 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD AUG 1 PY 2008 VL 32 IS 6 BP 1428 EP 1433 DI 10.1016/j.pnpbp.2008.02.003 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 342YJ UT WOS:000258819200008 ER PT J AU Rosa, AO Kaster, MP Binfare, RW Morales, S Martin-Aparicio, E Navarro-Rico, ML Martinez, A Medina, M Garcia, AG Lopez, MG Rodrigues, ALS AF Rosa, Angelo O. Kaster, Manuella P. Binfare, Ricardo W. Morales, Susana Martin-Aparicio, Ester Luisa Navarro-Rico, Maria Martinez, Ana Medina, Miguel Garcia, Antonio G. Lopez, Manuela G. Rodrigues, Ana Lucia S. TI Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE antidepressant; forced swimming test; glycogen synthase kinase-3 beta; peroxisome proliferator-activated receptor gamma; thiadiazolidinone ID GLYCOGEN-SYNTHASE KINASE-3-BETA; PROLIFERATOR-ACTIVATED RECEPTORS; MAJOR DEPRESSIVE DISORDER; FORCED SWIM TEST; INFLAMMATORY RESPONSE; BIPOLAR DISORDER; MOOD DISORDERS; MOUSE; NEURODEGENERATION; INHIBITION AB Glycogen synthase kinase-3 beta (GSK-3 beta) is an enzyme that phosphorylates glycogen synthase, thereby inhibiting glycogen synthesis. Besides this role, it is now believed that this enzyme plays an important role in the pathophysiology of many brain diseases including depression. Some inhibitors of this enzyme have shown antidepressant effects in animal models. This study investigated the effects of a novel thiadiazolidinone NP031115, a putative GSK-3 beta inhibitor, and the well-established GSK-3 beta inhibitor AR-A014418 in the mouse forced swimming test (FST), a model widely used to evaluate antidepressant activity. We found that NP031115 had an IC(50) of 1.23 and 6.5 mu M for GSK-3 beta and GSK-3 alpha, respectively. NP031115 (0.5 and 5 mg/kg, i.p.), in a way similar to imipramine (15 mg/kg, i.p), fluoxetine (32 mg/kg, i.p), AR-A014418 (9 mg/kg, i.p.), and rosiglitazone (5 mu g/site, i.c.v.). significantly reduced immobility time in the FST. NP031115 at the higher dose and AR-A014418 (9 mg/kg, i.p.) reduced locomotion in the open-field test. Rosiglitazone (30 mu M), AR-A014418 (1 mu M), PG(J2). (10 mu M), and NP031115 (1, 10 and 25 mu M) activate PPAR gamma in CHO transfected cells. GW-9662 (10 mu g/site, i.c.v, a PPAR gamma antagonist) administered 15 min before NP03115 (5 mg/kg, i.p.) or co-administered with rosiglitazone (5 mu g/site, i.c.v.) prevented the antidepressant-like effect of these drugs in the FST. The results of this study show that NP031115 can exhibit an antidepressant effect, likely by inhibiting GSK-3 beta and enhancing PPAR gamma activity. (C) 2008 Elsevier Inc. All rights reserved. C1 [Rosa, Angelo O.; Garcia, Antonio G.; Lopez, Manuela G.] Univ Autonoma Madrid, Sch Med, Dept Pharmacol, Madrid 28029, Spain. [Kaster, Manuella P.; Binfare, Ricardo W.; Rodrigues, Ana Lucia S.] Univ Fed Santa Catarina, Ctr Biol Sci, Dept Biochem, BR-88040900 Florianopolis, SC, Brazil. [Morales, Susana; Martin-Aparicio, Ester; Luisa Navarro-Rico, Maria; Martinez, Ana; Medina, Miguel] Neuropharma, Madrid 28760, Spain. RP Rosa, AO (reprint author), NIA, NIH, BPMS, Bethesda, MD 20892 USA. EM angelo_oscar@hotmail.com RI Kaster, Manuella /D-5028-2013; Martinez, Ana/L-6414-2014; Rodrigues, Ana Lucia/P-6869-2015; Lopez, Manuela/D-2164-2015; OI Kaster, Manuella /0000-0003-0258-6204; Martinez, Ana/0000-0002-2707-8110; Rodrigues, Ana Lucia/0000-0001-6285-8780; Lopez, Manuela/0000-0003-4461-8788; Garcia Garcia, Antonio/0000-0002-6517-3565; Medina, Miguel/0000-0002-7016-5340; da Rosa, Angelo/0000-0003-3715-4751 FU Neuropharma (Madrid, Spain),; Fundacion Medica Mutua Madrilena (Spain); Spanish Ministry of Education and Science [PHB2007-0004-PC]; CNPq/Brazil; Fundacion Teofilo Hernando FX This study was supported by Neuropharma (Madrid, Spain), Fundacion Medica Mutua Madrilena (Spain) to AGG, and the Spanish Ministry of Education and Science (Programa Hispano-Brasileno de Cooperacion Interuniversitaria) Ref. PHB2007-0004-PC to MGL. ALSR is a receipt of a research fellowship from CNPq/Brazil. We also thank the Fundacion Teofilo Hernando for continued support. NR 48 TC 77 Z9 81 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD AUG 1 PY 2008 VL 32 IS 6 BP 1549 EP 1556 DI 10.1016/j.pnpbp.2008.05.020 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 342YJ UT WOS:000258819200029 PM 18579278 ER PT J AU Prueitt, RL Yi, M Hudson, RS Wallace, TA Howe, TM Yfantis, HG Lee, DH Stephens, RM Liu, CG Calin, GA Croce, CM Ambs, S AF Prueitt, Robyn L. Yi, Ming Hudson, Robert S. Wallace, Tiffany A. Howe, Tiffany M. Yfantis, Harris G. Lee, Dong. H. Stephens, Robert M. Liu, Chang-Gong Calin, George A. Croce, Carlo M. Ambs, Stefan TI Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer SO PROSTATE LA English DT Article DE invasion; prostate tumor; gene expression profile; microRNA ID PROGNOSTIC-SIGNIFICANCE; RADICAL PROSTATECTOMY; FREE SURVIVAL; CARCINOMA; CELLS; BIOPSIES; TISSUES; GENOME; GROWTH; MICROARRAYS AB BACKGROUND. Perineural invasion (PNI) is the dominant pathway for local invasion in prostate cancer. To date, only few studies have investigated the molecular differences between prostate tumors with PNI and those without it. METHODS. To evaluate the involvement of both microRNAs and protein-coding genes in PNI, we determined their genome-wide expression with a custom microRNA microarray and Affymetrix GeneChips in 50 prostate adenocarcinomas with PNI and 7 without it. In situ hybridization (ISH) and immunohistochemistry was used to validate candidate genes. RESULTS. Unsupervised classification of the 57 adenocarcinomas revealed two clusters of tumors with distinct global microRNA expression. One cluster contained all non-PNI tumors and a subgroup of PNI tumors. Significance analysis of microarray data yielded a list of microRNAs associated with PNI. At a false discovery rate (FDR) <10%, 19 microRNAs were higher expressed in PNI tumors than in non-PNI tumors. The most differently expressed microRNA was miR-224. ISH showed that this microRNA is expressed by perineural cancer cells. The analysis of protein-coding genes identified 34 transcripts that were differently expressed by PNI status (FDR < 10%). These transcripts were down-regulated in PNI tumors. Many of those encoded metallothioneins and proteins with mitochondrial localization and involvement in cell metabolism. Consistent with the microarray data, perineural cancer cells tended to have lower metallothionein expression by immunohistochemistry than nonperineural cancer cells. CONCLUSIONS. Although preliminary, our findings suggest that alterations in microRNA expression, mitochondrial function, and cell metabolism occur at the transition from a noninvasive prostate tumor to a tumor with PNI. C1 [Prueitt, Robyn L.; Hudson, Robert S.; Wallace, Tiffany A.; Howe, Tiffany M.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Yi, Ming; Stephens, Robert M.] NCI Frederick SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD USA. [Yfantis, Harris G.; Lee, Dong. H.] Baltimore Vet Affairs Med Ctr, Pathol & Lab Med, Baltimore, MD USA. [Liu, Chang-Gong; Croce, Carlo M.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Liu, Chang-Gong; Croce, Carlo M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Calin, George A.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, Natl Inst Hlth, Bldg 37 Room 3050B, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov FU Intramural NIH HHS [Z01 BC010499-05]; NCI NIH HHS [CA081534, CA128609, P01 CA081534, R01 CA128609] NR 51 TC 113 Z9 122 U1 2 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD AUG 1 PY 2008 VL 68 IS 11 BP 1152 EP 1164 DI 10.1002/pros.20786 PG 13 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 331OK UT WOS:000258021300002 PM 18459106 ER PT J AU Chandrasekaran, V Lee, CJ Duke, RE Perera, L Pedersen, LG AF Chandrasekaran, Vasu Lee, Chang Jun Duke, Robert E. Perera, Lalith Pedersen, Lee G. TI Computational study of the putative active form of protein Z (PZa): Sequence design and structural modeling SO PROTEIN SCIENCE LA English DT Article DE protein Z (PZ); sequence design; active form of protein Z (PZa); homology modeling; molecular dynamics simulation; molecular docking ID ALPHA-LYTIC PROTEASE; BLOOD-COAGULATION FACTOR; PARTICLE MESH EWALD; CRYSTAL-STRUCTURE; SUBSTRATE-SPECIFICITY; ENZYME SPECIFICITY; DYNAMIC CONTROL; FACTOR VIIA; PLASMA; INHIBITOR AB Although protein Z ( PZ) has a domain arrangement similar to the essential coagulation proteins FVII, FIX, FX, and protein C, its serine protease ( SP)- like domain is incomplete and does not exhibit proteolytic activity. We have generated a trial sequence of putative activated protein Z ( PZa) by identifying amino acid mutations in the SP- like domain that might reasonably resurrect the serine protease catalytic activity of PZ. The structure of the activated form was then modeled based on the proposed sequence using homology modeling and solvent- equilibrated molecular dynamics simulations. In silico docking of inhibitors of FVIIa and FXa to the putative active site of equilibrated PZa, along with structural comparison with its homologous proteins, suggest that the designed PZa can possibly act as a serine protease. C1 [Chandrasekaran, Vasu; Lee, Chang Jun; Duke, Robert E.; Pedersen, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Duke, Robert E.; Perera, Lalith; Pedersen, Lee G.] NIEHS, Struct Biol Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, Chem CB 3290, Chapel Hill, NC 27599 USA. EM lee_pedersen@unc.edu RI pedersen, lee/A-8567-2009; perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU NHLBI NIH HHS [HL-06350, P01 HL006350] NR 39 TC 3 Z9 3 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2008 VL 17 IS 8 BP 1354 EP 1361 DI 10.1110/ps.034801.108 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 332CA UT WOS:000258058200007 PM 18493021 ER PT J AU Kwon, D Vannucci, M Song, JJ Jeong, J Pfeiffer, RM AF Kwon, Deukwoo Vannucci, Marina Song, Joon Jin Jeong, Jaesik Pfeiffer, Ruth M. TI A novel wavelet-based thresholding method for the pre-processing of mass spectrometry data that accounts for heterogeneous noise SO PROTEOMICS LA English DT Article DE discrete wavelet transform; heteroscedastic errors; mass spectrometry; SELDI-TOF MS ID TIME-SERIES; SPECTRA; VARIANCE; QUANTIFICATION; TRANSFORM; SHRINKAGE; SERUM AB In recent years there has been an increased interest in using protein mass spectroscopy to discriminate diseased from healthy individuals with the aim of discovering molecular markers for disease. A crucial step before any statistical analysis is the pre-processing of the mass spectrometry data. Statistical results are typically strongly affected by the specific pre-processing techniques used. One important pre-processing step is the removal of chemical and instrumental noise from the mass spectra. Wavelet denoising techniques are a standard method for denoising. Existing techniques, however, do not accommodate errors that vary across the mass spectrum, but instead assume a homogeneous error structure. In this paper we propose a novel wavelet denoising approach that deals with heterogeneous errors by incorporating a variance change point detection method in the thresholding procedure. We study our method on real and simulated mass specrometry data and show that it improves on performances of peak detection methods. C1 [Kwon, Deukwoo; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Vannucci, Marina] Rice Univ, Dept Stat, Houston, TX 77251 USA. [Song, Joon Jin] Univ Arkansas, Dept Math Sci, Fayetteville, AR 72701 USA. [Jeong, Jaesik] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Kwon, D (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Rm 7045, Rockville, MD 20852 USA. EM kwonde@mail.nih.gov FU NHI/NHGRI [R01HG003319]; NSF [DMS-0605001]; Arkansas Biosciences Institute (ABI) FX We thank Eric Fung and Christine Yip from Vermillion for making the data available to us. The authors also thank the referees for useful comments. Vannucci is supported by NHI/NHGRI grant R01HG003319 and by NSF award DMS-0605001. Song is partially supported by Arkansas Biosciences Institute (ABI). NR 24 TC 22 Z9 22 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1615-9853 J9 PROTEOMICS JI Proteomics PD AUG PY 2008 VL 8 IS 15 BP 3019 EP 3029 DI 10.1002/pmic.200701010 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 338JG UT WOS:000258503400004 PM 18615428 ER PT J AU Ross, J Berrettini, W Coryell, W Gershon, ES Badner, JA Kelsoe, JR McInnis, MG McMahon, FJ Murphy, DL Nurnberger, JI Foroud, T Rice, JP Scheftner, WB Zandi, P Edenberg, H Byerley, W AF Ross, Jessica Berrettini, Wade Coryell, William Gershon, Elliot S. Badner, Judith A. Kelsoe, John R. McInnis, Melvin G. McMahon, Francis J. Murphy, Dennis L. Nurnberger, John I., Jr. Foroud, Tatiana Rice, John P. Scheftner, William B. Zandi, Peter Edenberg, Howard Byerley, William TI Genome-wide parametric linkage analyses of 644 bipolar pedigrees suggest susceptibility loci at chromosomes 16 and 20 SO PSYCHIATRIC GENETICS LA English DT Article DE bipolar disorder; chromosome 16; chromosome 20; complex disorder; genetics; gene mapping; linkage analysis; parametric analysis ID AFFECTIVE-DISORDER; NATIONAL-INSTITUTE; LOD SCORES; GENETICS; SCAN; GENES; MISSPECIFICATION; SCHIZOPHRENIA; METAANALYSIS; REPLICATION AB Objective Our aim is to map chromosomal regions that harbor loci that increase susceptibility to bipolar disorder. Methods We analyzed 644 bipolar families ascertained by the National Institute of Mental Health Human Genetics Initiative for bipolar disorder. The families have been genotyped with microsatellite loci spaced every approximately 10 cM or less across the genome. Earlier analyses of these pedigrees have been limited to nonparametric (model-free) methods and thus, information from unaffected subjects with genotypes was not considered. In this study, we used parametric analyses assuming dominant and recessive transmission and specifying a maximum penetrance of 70%, so that information from unaffecteds could be weighed in the linkage analyses. As in previous linkage analyses of these pedigrees, we analyzed three diagnostic categories: model 1 included only bipolar I and schizoaffective, bipolar cases (1565 patients of whom approximately 4% were schizoaffective, bipolar); model 2 included all individuals in model 1 plus bipolar II patients (1764 total individuals); and model 3 included all individuals in model 2 with the addition of patients with recurrent major depressive disorder (2046 total persons). Results Assuming dominant inheritance the highest genome-wide pair-wise logarithm of the odds (LOD) score was 3.2 with D16S749 using model 2 patients. Multipoint analyses of this region yielded a maximum LOD score of 4.91. Under recessive transmission a number of chromosome 20 markers were positive and multipoint analyses of the area gave a maximum LOD of 3.0 with model 2 cases. Conclusion The chromosome 16p and 20 regions have been implicated by some studies and the data reported herein provide additional suggestive evidence of bipolar susceptibility genes in these regions. C1 [Byerley, William] Univ Calif San Francisco, Langley Porter Psychiat Inst, Dept Psychiat, San Francisco, CA 94132 USA. [Berrettini, Wade] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Coryell, William] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Gershon, Elliot S.; Badner, Judith A.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Scheftner, William B.] Rush Univ, Dept Psychiat, Chicago, IL 60612 USA. [Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [McMahon, Francis J.] Indiana Univ, Mood & Anxiety Program, Natl Inst Mental Hlth Intramural Res Program, US Dept Hlth & Human Serv,Sch Med, Bloomington, IN 47405 USA. [Murphy, Dennis L.] Indiana Univ, Clin Sci Lab, Natl Inst Mental Hlth Intramural Res Program, Dept Hlth & Human Serv,Sch Med, Bloomington, IN 47405 USA. [Nurnberger, John I., Jr.] Indiana Univ, Sch Med, Dept Psychiat, Bloomington, IN 47405 USA. [Foroud, Tatiana; Edenberg, Howard] Indiana Univ, Sch Med, Dept Med & Mol Genet, Bloomington, IN 47405 USA. [Edenberg, Howard] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Bloomington, IN 47405 USA. [Rice, John P.] Washington Univ, Dept Psychiat, Washington, DC USA. [Zandi, Peter] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21218 USA. RP Byerley, W (reprint author), Univ Calif San Francisco, Langley Porter Psychiat Inst, Dept Psychiat, 401 Parnassus, San Francisco, CA 94132 USA. EM william.byerley@ucsf.edu RI McInnis, Melvin/F-6963-2012; OI McInnis, Melvin/0000-0002-0375-6247; Nurnberger, John/0000-0002-7674-1767; McMahon, Francis/0000-0002-9469-305X; Edenberg, Howard/0000-0003-0344-9690 FU NIMH NIH HHS [R25 MH060482, MH 060482] NR 47 TC 11 Z9 11 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD AUG PY 2008 VL 18 IS 4 BP 191 EP 198 PG 8 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 331OF UT WOS:000258020800007 PM 18628681 ER PT J AU Keyes, KM Hatzenbuehler, ML Alberti, P Narrow, WE Grant, BF Hasin, DS AF Keyes, Katherine M. Hatzenbuehler, Mark L. Alberti, Philip Narrow, William E. Grant, Bridget F. Hasin, Deborah S. TI Service utilization differences for axis I psychiatric and substance use disorders between white and black adults SO PSYCHIATRIC SERVICES LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; MENTAL-HEALTH-SERVICES; ALCOHOL-USE DISORDER; DSM-III-R; INTERVIEW SCHEDULE AUDADIS; COMORBIDITY SURVEY REPLICATION; GENERAL-POPULATION SAMPLE; UNITED-STATES; ETHNIC-DIFFERENCES; DRUG MODULES AB Objective: Although studies have shown disparities between black and white populations in service utilization for mental disorders, little information exists on whether such disparities apply equally across disorders. The objective of this study was to examine racial differences in lifetime prevalence of service utilization for mood and anxiety disorders and for alcohol and drug use disorders, with controls for predisposing, enabling, and need-for-service variables unequally distributed between racial-ethnic groups. Methods: Data were from a face-to-face epidemiologic survey of 32,752 non-Hispanic white or black adults ages 18 and older residing in households and group quarters in the United States. Main outcome measures were treatment for mood, anxiety, and alcohol and drug use disorders. Results: White adults were consistently more likely than black adults to have had treatment for mood disorders (odds ratio [OR]=2.16, 95% confidence interval [CI]=1.80-2.59) and anxiety disorders (OR=1.77, 95% CI=1.43-2.19) after adjustment for predisposing and enabling factors and need for service (severity of disorder). In contrast no evidence of lower service utilization for treatment of alcohol use disorders emerged among black respondents (OR=.87, 95% CI=.69-1.10). Moreover, white respondents with drug use disorders were significantly less likely than black respondents to receive treatment for a drug problem (OR=.64, 95% CI=.47-.88). Conclusions: Differences in treatment between black and white adults depended on the specific disorder and type of treatment considered. Prevention and intervention strategies should address disorder-specific disparities in services received. C1 [Keyes, Katherine M.; Alberti, Philip] Columbia Univ, Dept Epidemiol, New York, NY 10032 USA. [Hatzenbuehler, Mark L.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Narrow, William E.] Amer Psychiat Inst Res & Educ, Arlington, VA USA. [Grant, Bridget F.] NIAAA, Div Intramural Clin & Biol Res, Bethesda, MD 20892 USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD 20892 USA. RP Hasin, DS (reprint author), Columbia Univ, Dept Psychiat, 1051 Riverside Dr,Box 123, New York, NY 10032 USA. EM hasind@nypdrat.cpmc.columbia.edu FU Intramural NIH HHS [Z01 AA000449-04]; NIAAA NIH HHS [K05 AA014223, K05-AA-014223] NR 78 TC 49 Z9 49 U1 2 U2 8 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 AUG PY 2008 VL 59 IS 8 BP 893 EP 901 DI 10.1176/appi.ps.59.8.893 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 333YZ UT WOS:000258190800012 PM 18678687 ER PT J AU Shiloh, S Koehly, L Jenkins, J Martin, J Hadley, D AF Shiloh, S. Koehly, L. Jenkins, J. Martin, J. Hadley, D. TI Monitoring coping style moderates emotional reactions to genetic testing for hereditary nonpolyposis colorectal cancer: a longitudinal study SO PSYCHO-ONCOLOGY LA English DT Article DE HNPCC; genetic testing; monitoring coping style; cancer; oncology ID FAMILY SYSTEM CHARACTERISTICS; BREAST SELF-EXAMINATION; PSYCHOLOGICAL IMPACT; OVARIAN-CANCER; CARDIAC-CATHETERIZATION; INFORMATION-SEEKING; SCREENING PRACTICES; MUTATION CARRIERS; FOLLOW-UP; DISTRESS AB Objectives: The emotional effects of genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) provided within a counseling program were assessed among 253 individuals. Methods: Assessments were scheduled at baseline before testing, and again after 6 and 12 months post-test. Negative emotional reactions were evaluated using the Revised Impact of Event Scale and the Center for Epidemiological Studies-Depression Scale. Monitoring coping style was assessed at baseline using the Miller Behavioral Style Scale. Results: Mean reductions were indicated in distress and depression levels within the first 6 months after counseling and testing. High monitors were generally more distressed than low monitors, specifically if they had indeterminate or positive results. Conclusions: Genetic counseling and testing for HNPCC do not result in long-term distress for most people. Of the variables investigated, only time and coping style have main effects on emotional reactions, and the impacts of mutation status are moderated by coping style. Psychological interventions, aimed to alleviate adverse emotional effects, were suggested for certain participants, i.e. recipients of positive or indeterminate results who are high monitors. Published in 2008 by John Wiley & Sons, Ltd. C1 [Shiloh, S.] Tel Aviv Univ, Dept Psychol, IL-69978 Tel Aviv, Israel. [Koehly, L.; Jenkins, J.; Hadley, D.] NHGRI, Social Networks Methods Sect, Social & Behav Res Branch, Bethesda, MD USA. [Martin, J.] Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. RP Shiloh, S (reprint author), Tel Aviv Univ, Dept Psychol, IL-69978 Tel Aviv, Israel. EM shoshi@freud.tau.ac.il FU NHGRI NIH HHS [#95-HG-0165] NR 78 TC 33 Z9 35 U1 0 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD AUG PY 2008 VL 17 IS 8 BP 746 EP 755 DI 10.1002/pon.1338 PG 10 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 346GF UT WOS:000259056100003 PM 18615871 ER PT J AU Mellon, S Gold, R Janisse, J Cichon, M Tainsky, MA Simon, MS Korczak, J AF Mellon, Suzanne Gold, Robin Janisse, James Cichon, Michelle Tainsky, Michael A. Simon, Michael S. Korczak, Jeannette TI Risk perception and cancer worries in families at increased risk of familial breast/ovarian cancer SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; oncology; risk perception; cancer worries; family ID BREAST-OVARIAN CANCER; QUALITY-OF-LIFE; PSYCHOLOGICAL DISTRESS; HEREDITARY BREAST; COUPLES ADJUSTMENT; RANDOMIZED TRIAL; DECISION-MAKING; COPING STYLE; COLON-CANCER; WOMEN AB While families at increased risk for familial breast/ovarian cancer continue to overestimate their cancer risk with increased cancer worries about the future, few studies have examined factors that affect inherited cancer risk perception and cancer worries in both survivors and unaffected female relatives. The purpose of this study was to examine variables that may affect cancer worries and risk perceptions from a family-based perspective in a racially diverse, community-based, random sample of 146 dyads consisting of adult female breast and/or ovarian cancer survivors and their unaffected female relatives (N = 292). Results indicated that coping style, self-efficacy, partner's income, family role relationship, and cancer risk perception were significant contributors to the survivors' and their unaffected relatives' cancer worries. Significant variables for perception of cancer risk for both survivors and relatives included income, race, family history of cancer, and cancer worries. Relatives had a higher perception of cancer risk, whereas survivors had more cancer worries. Additionally, the level of cancer worries reported by one member of the dyad was related to the amount of worries reported by the other. The results from this study underscore the importance of clinicians addressing concerns of both affected and unaffected members of families at increased risk of cancer to assist them in managing cancer worries and having realistic risk appraisals to make informed decisions about their own and their family's health surveillance options. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Mellon, Suzanne] Univ Detroit Mercy, Coll Hlth Profess, Detroit, MI 48221 USA. [Mellon, Suzanne; Tainsky, Michael A.; Simon, Michael S.; Korczak, Jeannette] Karmanos Canc Inst, Detroit, MI USA. [Gold, Robin] Oakwood Hlth Syst, Dearborn, MI USA. [Janisse, James; Cichon, Michelle; Tainsky, Michael A.; Simon, Michael S.] Wayne State Univ, Detroit, MI USA. [Korczak, Jeannette] NCI, Div Extramural Activ, Bethesda, MD 20892 USA. RP Mellon, S (reprint author), Univ Detroit Mercy, Coll Hlth Profess, 4001 W McNichols, Detroit, MI 48221 USA. EM mellonsk@udmercy.edu FU NIH; NINR [R21 NR008584-01] FX This study was supported by a grant from NIH, NINR R21 NR008584-01 NR 60 TC 21 Z9 21 U1 4 U2 9 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD AUG PY 2008 VL 17 IS 8 BP 756 EP 766 DI 10.1002/pon.1370 PG 11 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 346GF UT WOS:000259056100004 PM 18613300 ER PT J AU Smith, AW Dougall, AL Posluszny, DM Somers, TJ Rubinstein, WS Baum, A AF Smith, Ashley Wilder Dougall, Angela Liegey Posluszny, Donna M. Somers, Tamara J. Rubinstein, Wendy S. Baum, Andrew TI Psychological distress and quality of life associated with genetic testing for breast cancer risk SO PSYCHO-ONCOLOGY LA English DT Article DE genetic testing; cancer; psychological outcomes; BRCA1 and BRCA2; stress ID OVARIAN-CANCER; COLORECTAL-CANCER; FAMILY-HISTORY; WOMEN; BRCA1; IMPACT; MUTATION; SAMPLE; SUSCEPTIBILITY; MORBIDITY AB This study investigated short- and long-term psychological outcomes associated with BRCA1/2 genetic testing in women with a personal or family history of breast cancer. Participants included 126 women considering genetic testing. Questionnaires were administered prior to testing, one week, three and six months after result disclosure. Results indicated no systematic effects of testing based on personal cancer history. Mutation carriers and women who elected not to be tested reported greater perceived risk and intrusive and avoidant thoughts at follow-up time points than did women who received negative (uninformative) or variant results. Mutation carriers reported more distress at the three-month follow-up but by six months the effects of test result oil distress dissipated and groups were comparable. Cluster analyses identified two groups of individuals based on distress at baseline; these groups were used to predict psychological outcomes after testing. Distress remained constant in both groups: those who were high at baseline remained high and those who were low remained low. Test results did not moderate this effect. Results suggest that genetic testing for BRCA1/2 does not increase distress or have deleterious effects on quality of life over the long term. However, sub-groups of women may report more distress over time. These data indicate the need for more targeted counseling to individuals who report high levels of distress when considering genetic testing. Copyright (C) 2007 John Wiley & Sons, Ltd. C1 [Smith, Ashley Wilder] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Smith, Ashley Wilder] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dougall, Angela Liegey; Somers, Tamara J.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Posluszny, Donna M.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA. [Rubinstein, Wendy S.] Evanston NW Healthcare Ctr Med Genet, Evanston, IL USA. [Rubinstein, Wendy S.] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Baum, Andrew] Univ Pittsburgh, Sch Med, Dept Psychiat & Psychol, Pittsburgh, PA USA. RP Smith, AW (reprint author), 6130 Execut Blvd,MSC 7344,Execut Plaza N,Room 409, Bethesda, MD 20892 USA. EM smithas@mail.nih.gov FU National Institute of Mental Health [MH54837] FX This research was supported by a grant from the National Institute of Mental Health (MH54837). NR 44 TC 35 Z9 36 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD AUG PY 2008 VL 17 IS 8 BP 767 EP 773 DI 10.1002/pon.1291 PG 7 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 346GF UT WOS:000259056100005 PM 17992698 ER PT J AU Koehly, LM Peters, JA Kuhn, N Hoskins, L Letocha, A Kenen, R Loud, J Greene, MH AF Koehly, Laura M. Peters, June A. Kuhn, Natalia Hoskins, Lindsey Letocha, Anne Kenen, Regina Loud, Jennifer Greene, Mark H. TI Sisters in hereditary breast and ovarian cancer families: communal coping, social integration, and psychological well-being SO PSYCHO-ONCOLOGY LA English DT Article DE social support; communal coping; hereditary breast and ovarian cancer; sisters; psychological distress ID RISK PERCEPTIONS; SUPPORT; BRCA1; SUSCEPTIBILITY; NETWORKS; WOMEN; TIES; DISTRESS; EMOTIONS; PATTERNS AB Objective: We investigated the association between psychological distress and indices of social integration and communal coping among sisters from hereditary breast and ovarian cancer (HBOC) families. Sample and methods: Sixty-five sisters from 31 HBOC families completed the Brief Symptom Inventory-18 and the Colored Eco-Genetic Relationship Map, which identified members of participants' social support networks. Hierarchical linear models were used for all analyses to account for the clustering of sisters within families. Results: Intra-family correlation coefficients suggested that sisters shared perceptions of breast cancer risk and worry, but not ovarian cancer risk and worry. Further, sisters demonstrated shared levels of anxiety and somatization, but not depressive symptoms. Communal coping indices quantifying shared support resources were negatively related to anxiety and somatization. The number of persons with whom cancer risk information was shared exhibited a positive trend with somatization. Social integration, as measured by the size of participants' emotional support network, was negatively associated with anxiety. Lower depression scores were observed among participants with more persons playing multiple support roles and fewer persons providing tangible assistance. Conclusion: Understanding how support relationships impact well-being among persons adjusting to HBOC risk, and the particular role of family in that process, will facilitate developing appropriate management approaches to help cancer-prone families adjust to their cancer risk. Published in 2008 by John Wiley & Sons Ltd. C1 [Koehly, Laura M.; Kuhn, Natalia; Letocha, Anne] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Peters, June A.; Hoskins, Lindsey; Loud, Jennifer; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Kenen, Regina] Coll New Jersey, Ewing, NJ USA. RP Koehly, LM (reprint author), 31 Ctr Dr,31-B-B37D, Bethesda, MD USA. EM koehlyl@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute; Intramural Research Program of the National Cancer Institute to NCIs Clinical Genetics Branch [NO2-CP-11019, NO2-CP-65504] FX We are very grateful to the families, and the sisters in particular, who participated in NCI protocol 01-C-0009: Breast Imaging Screening Studies in Women at High Genetic Risk of Breast Cancer Annual Follow-up Study and NCI protocol 78-C-0039: Clinical, Laboratory. and Epidemiologic Characterization of Individuals and Families at High Risk of Cancer. We would like to thank Sato Ashida, Andy Baxevanis, Alan Guttmacher Kim Kaphingst, Aunchalee Loscalzo, Colleen McBride, Suzanne O'Neill, and Bruce Simons-Morton for their comments on an earlier draft of the article; and Ron Kase, Ann Carr, Kathy Nichols, Nicole Dupre, and Usha Singh of Westat for their help with data management. This research was supported, in part, by funding from the Intramural Research Program of the National Human Genome Research Institute, by funding from the Intramural Research Program of the National Cancer Institute to NCIs Clinical Genetics Branch, and by Support services contracts NO2-CP-11019 and NO2-CP-65504 with Westat. NR 53 TC 39 Z9 39 U1 0 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD AUG PY 2008 VL 17 IS 8 BP 812 EP 821 DI 10.1002/pon.1373 PG 10 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 346GF UT WOS:000259056100011 PM 18688790 ER PT J AU Mueller, SC Temple, V Oh, E VanRyzin, C Williams, A Cornwell, B Grillon, C Pine, DS Ernst, M Merke, DP AF Mueller, S. C. Temple, V. Oh, E. VanRyzin, C. Williams, A. Cornwell, B. Grillon, C. Pine, D. S. Ernst, M. Merke, D. P. TI Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH) SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE spatial navigation; hormones; sex differences; steroids; brain development; adolescents ID SEX-DIFFERENCES; 21-HYDROXYLASE DEFICIENCY; WATER-MAZE; MEADOW VOLES; PERFORMANCE; NAVIGATION; CHILDREN; AGE; ADOLESCENTS; RELIABILITY AB Major questions remain about the exact role of hormones in cognition. Furthermore, the extent to which early perturbation in steroid function affects human brain development continues to be a wide open area of research. Congenital adrenal hyperplasia (CAH), a genetic disorder of steroid dysfunction characterized in part by in utero over-production of testosterone, was used as a natural model for addressing this question. Here, CAH (n = 54, mean age 17.53, 31 female) patients were compared to healthy age- and sex-matched individuals (n 55, mean age = 19.02, 22 female) on a virtual equivalent of the Morris Water Maze task [Morris, R., 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47-60], an established measure of sex differences in spatial cognition in rodents. Findings revealed that females with CAH with the most severe form of the disease and expected highest level of in utero exposure to androgens were found to perform similarly to both healthy mates and CAH mates, whereas strong sex differences were apparent in milder forms of the disorder and in controls. Moreover, advanced bone age, an indicator of tong-term childhood exposure to testosterone was correlated with improved performance. The results indicate that individuals exposed to both excess androgens prenatally and prolonged exposure during childhood may manifest tong-lasting changes in cognitive function. Such finding suggests a pivotal role of hormonal function on brain development in humans, mirroring results from the animal literature. Published by Elsevier Ltd. C1 [Mueller, S. C.; Temple, V.; Williams, A.; Cornwell, B.; Grillon, C.; Pine, D. S.; Ernst, M.] NIMH, MAP, NIH, Bethesda, MD 20892 USA. [Oh, E.; VanRyzin, C.; Merke, D. P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Mueller, SC (reprint author), NIMH, MAP, NIH, 15K North Dr, Bethesda, MD 20892 USA. EM msven@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health and (in part) by the Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation. NR 33 TC 39 Z9 40 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD AUG PY 2008 VL 33 IS 7 BP 973 EP 980 DI 10.1016/j.psyneuen.2008.04.005 PG 8 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 344FG UT WOS:000258911600008 PM 18675711 ER PT J AU Grillon, C AF Grillon, Christian TI Models and mechanisms of anxiety: evidence from startle studies SO PSYCHOPHARMACOLOGY LA English DT Review DE startle; fear-potentiated startle; fear; anxiety; experimental models; anxiety disorders ID FEAR-POTENTIATED STARTLE; CORTICOTROPIN-RELEASING-FACTOR; POSTTRAUMATIC-STRESS-DISORDER; LIGHT-ENHANCED STARTLE; ACOUSTIC STARTLE; STRIA TERMINALIS; BED NUCLEUS; PANIC DISORDER; PARAVENTRICULAR NUCLEUS; CONDITIONED FEAR AB Rationale Preclinical data indicates that threat stimuli elicit two classes of defensive behaviors, those that are associated with imminent danger and are characterized by flight or fight (fear), and those that are associated with temporally uncertain danger and are characterized by sustained apprehension and hypervigilance (anxiety). Objective The objectives of the study are to (1) review evidence for a distinction between fear and anxiety in animal and human experimental models using the startle reflex as an operational measure of aversive states, (2) describe experimental models of anxiety, as opposed to fear, in humans, (3) examine the relevance of these models to clinical anxiety. Results The distinction between phasic fear to imminent threat and sustained anxiety to temporally uncertain danger is suggested by psychopharmacological and behavioral evidence from ethological studies and can be traced back to distinct neuroanatomical systems, the amygdala and the bed nucleus of the stria terminalis. Experimental models of anxiety, not fear, are relevant to non-phobic anxiety disorders. Conclusions Progress in our understanding of normal and abnormal anxiety is critically dependent on our ability to model sustained aversive states to temporally uncertain threat. C1 [Grillon, Christian] NIMH, MAP, Bethesda, MD 20892 USA. [Grillon, Christian] NIMH, Unit Affect Psychophysiol, Mood & Anxiety Disorder Program, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, MAP, 15K N Dr,Bldg 15K,Room 113,MSC 2670, Bethesda, MD 20892 USA. EM Christian.grillon@nih.gov FU Intramural NIH HHS [Z01 MH002798-06] NR 154 TC 158 Z9 161 U1 14 U2 46 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2008 VL 199 IS 3 BP 421 EP 437 DI 10.1007/s00213-007-1019-1 PG 17 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 322NS UT WOS:000257383200007 PM 18058089 ER PT J AU Miller, G Melo, D Martz, H Bertelli, L AF Miller, G. Melo, D. Martz, H. Bertelli, L. TI AN EMPIRICAL MULTIVARIATE LOG-NORMAL DISTRIBUTION REPRESENTING UNCERTAINTY OF BIOKINETIC PARAMETERS FOR Cs-137 SO RADIATION PROTECTION DOSIMETRY LA English DT Article AB A simplified biokinetic model for Cs-137 has six parameters representing transfer of material to and from various compartments. Using a Bayesian analysis, the joint probability distribution of these six parameters is determined empirically for two cases with quite a lot of bioassay data. The distribution is found to be a multivariate log-normal. Correlations between different parameters are obtained. The method utilises a fairly large number of pre-determined forward biokinetic calculations, whose results are stored in interpolation tables. Four different methods to sample the multidimensional parameter space with a limited number of samples are investigated: random, stratified, Latin Hypercube sampling with a uniform distribution of parameters and importance sampling using a lognormal distribution that approximates the posterior distribution. The importance sampling method gives much smaller sampling uncertainty. No sampling method-dependent differences are perceptible for the uniform distribution methods. C1 [Miller, G.; Martz, H.; Bertelli, L.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA. [Melo, D.] NCI, Bethesda, MD 20892 USA. RP Miller, G (reprint author), Los Alamos Natl Lab, Los Alamos, NM 87545 USA. EM guthriemiller@gmail.com FU Los Alamos National Laboratory/US Department of Energy FX This work was funded in part by Los Alamos National Laboratory/US Department of Energy. NR 12 TC 4 Z9 4 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD AUG PY 2008 VL 131 IS 2 BP 198 EP 211 DI 10.1093/rpd/ncn131 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 373PL UT WOS:000260984100006 PM 18420573 ER PT J AU Bhatti, P Doody, MM Preston, DL Kampa, D Ron, E Weinstock, RW Simon, S Edwards, AA Sigurdson, AJ AF Bhatti, Parveen Doody, Michele M. Preston, Dale L. Kampa, Diane Ron, Elaine Weinstock, Robert W. Simon, Steven Edwards, Alan A. Sigurdson, Alice J. TI Increased frequency of chromosome translocations associated with diagnostic X-ray examinations SO RADIATION RESEARCH LA English DT Article ID SELLAFIELD NUCLEAR FACILITY; US RADIOLOGIC TECHNOLOGISTS; BREAST-CANCER MORTALITY; ATOMIC-BOMB SURVIVORS; BIOLOGICAL DOSIMETRY; RADIATION-EXPOSURE; COMPUTED-TOMOGRAPHY; IONIZING-RADIATION; MEDICAL RADIATION; CLEANUP WORKERS AB Informative studies of cancer risks associated with medical radiation are difficult to conduct owing to low radiation doses, poor recall of diagnostic X rays, and long intervals before cancers occur. Chromosome aberrations have been associated with increased cancer risk and translocations are a known radiation biomarker. Seventy-nine U.S. radiologic technologists were selected for blood collection, and translocations were enumerated by whole chromosome painting. We developed a dose score to the red bone marrow for medical radiation exposure from X-ray examinations reported by the technologists that they received as patients. Using Poisson regression, we analyzed translocations in relation to the dose scores. Each dose score unit approximated 1 mGy. The estimated mean cumulative red bone marrow radiation dose score was 42 (range 1-265). After adjustment for age, occupational radiation, and radiotherapy for benign conditions, translocation frequencies significantly increased with increasing red bone marrow dose score with an estimate of 0.007 translocations per 100 CEs per score unit (95% CI, 0.002 to 0.013; P = 0.01). Chromosome damage has been linked with elevated cancer risk, and we found that cumulative radiation exposure from medical X-ray examinations was associated with increased numbers of chromosome translocations. (C) 2008 by Radiation Research society. C1 [Bhatti, Parveen; Doody, Michele M.; Ron, Elaine; Simon, Steven; Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Kampa, Diane] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN USA. [Preston, Dale L.] HiroSoft Int Corp, Seattle, WA USA. [Weinstock, Robert W.] Res Triangle Inst, Bethesda, MD USA. [Edwards, Alan A.] Hlth Protect Agcy, Radiat Protect Div, Didcot, Oxon, England. RP Bhatti, P (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 7049,MSC 7238, Bethesda, MD 20892 USA. EM bhattip@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 34 TC 13 Z9 14 U1 0 U2 3 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 AUG PY 2008 VL 170 IS 2 BP 149 EP 155 DI 10.1667/RR1422.1 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 331IY UT WOS:000258007100002 PM 18666821 ER PT J AU Hendee, WR Cleary, K Ehman, RL Fullerton, GD Grundfest, WS Haller, J Kelley, CA Meyer, AE Murphy, RF Phillips, W Torchilin, VP AF Hendee, William R. Cleary, Kevin Ehman, Richard L. Fullerton, Gary D. Grundfest, Warren S. Haller, John Kelley, Christine A. Meyer, Anne E. Murphy, Robert F. Phillips, William Torchilin, Vladimir P. TI Bioengineering and Imaging Research Opportunities Workshop V: Summary of findings on imaging and characterizing structure and function in native and engineered tissues SO RADIOLOGY LA English DT Editorial Material ID MAGNETIC-RESONANCE ELASTOGRAPHY; WHITE PAPER; MICROSCOPY; RECOMMENDATIONS; VISUALIZATION; SYSTEMS; CANCER C1 [Hendee, William R.] Med Coll Wisconsin, Dept Radiat Oncol, Milwaukee, WI 53226 USA. [Cleary, Kevin] Georgetown Univ, Washington, DC USA. [Ehman, Richard L.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Fullerton, Gary D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Grundfest, Warren S.] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA. [Haller, John] NIBIB, NIH, Bethesda, MD USA. [Kelley, Christine A.] NIBIB, Div Discovery Sci & Technol, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Meyer, Anne E.] SUNY Coll Buffalo, Biomat Grad Program, Buffalo, NY 14222 USA. [Murphy, Robert F.] Carnegie Mellon Univ, Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA. [Phillips, William] Univ Texas San Antonio, Med Ctr, Dept Radiol, San Antonio, TX USA. [Torchilin, Vladimir P.] Northeastern Univ, Ctr Pharmaceut Biotechnol & Nanomed, Boston, MA 02115 USA. RP Hendee, WR (reprint author), Med Coll Wisconsin, Dept Radiat Oncol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM whendee@mcw.edu NR 26 TC 1 Z9 1 U1 0 U2 0 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 AUG PY 2008 VL 248 IS 2 BP 342 EP 347 DI 10.1148/radiol.2482080456 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329KL UT WOS:000257866400006 PM 18641242 ER PT J AU Poff, JA Allen, CT Traughber, B Colunga, A Xie, JW Chen, Z Wood, BJ Van Waes, C Li, KCP Frenkel, V AF Poff, Jason A. Allen, Clint T. Traughber, Bryan Colunga, Aric Xie, Jianwu Chen, Zhong Wood, Bradford J. Van Waes, Carter Li, King C. P. Frenkel, Victor TI Pulsed high-intensity focused ultrasound enhances apoptosis and growth inhibition of squamous cell carcinoma xenografts with proteasome inhibitor bortezomib SO RADIOLOGY LA English DT Article ID FACTOR-KAPPA-B; MULTIPLE-MYELOMA; TUMOR-MODEL; CANCER; ANGIOGENESIS; ACTIVATION; THERAPY; PATHWAY; THROMBOLYSIS; DELIVERY AB Purpose: To investigate whether combining pulsed high-intensity focused ultrasound (HIFU) with the chemotherapeutic drug bortezomib could improve antitumor activity against murine squamous cell carcinoma (SCC) tumors. Materials and Methods: All experiments were conducted with animal care and use committee approval. Murine SCC cells were implanted subcutaneously in C3H mice. When tumors reached 100 mm(3), mice were randomized to one of three groups for twice weekly intraperitoneal injections of 1.5 mg of bortezomib per kilogram of body weight, a proteasome inhibitor (n = 10); 1.0 mg/kg bortezomib (n = 11); or a control vehicle (n = 12). Within each group, half of the mice received pulsed HIFU exposure to their tumors immediately prior to each injection. The time for tumors to reach 650 mm3 was compared among groups. Additional tumors were stained with terminal deoxynucledotidyl transferase-mediated dUTP nick end labeling and CD31 to assess apoptotic index and blood vessel density, respectively. Results: Tumors in the control group, pulsed HIFU and control group, and 1.0 mg/kg of bortezomib alone group reached the size end point in 5.2 days +/- 0.8 (standard deviation), 5.3 days +/- 0.8, and 5.6 days +/- 1.1, respectively. However, pulsed HIFU and 1.0 mg/kg bortezomib increased the time to end point to 9.8 days +/- 2.9 (P < .02), not significantly different from the 8.8 days +/- 2.1 in tumors treated with 1.5 mg/kg bortezomib alone (P > .05). Combination therapy was also associated with a significantly higher apoptotic index (P < .05). Conclusion: Treatment of tumors with pulsed HIFU lowered the threshold level for efficacy of bortezomib, resulting in significant tumor cytotoxicity and growth inhibition at lower dose levels. (C) RSNA, 2008. C1 [Poff, Jason A.; Traughber, Bryan; Colunga, Aric; Xie, Jianwu; Wood, Bradford J.; Li, King C. P.; Frenkel, Victor] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Allen, Clint T.; Chen, Zhong; Van Waes, Carter] NIDCD, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Frenkel, V (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM vfrenkel@cc.nih.gov OI Colunga, Aric/0000-0003-2801-7149 FU Howard Hughes Medical Institute; Intramural NIH HHS [Z99 CL999999]; NIDCD NIH HHS [Z01 DC000016] NR 33 TC 35 Z9 37 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2008 VL 248 IS 2 BP 485 EP 491 DI 10.1148/radiol.2482071674 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329KL UT WOS:000257866400021 PM 18574138 ER PT J AU Subramaniam, RP Chen, C Crump, KS DeVoney, D Fox, JF Portier, CJ Schlosser, PM Thompson, CM White, P AF Subramaniam, Ravi P. Chen, Chao Crump, Kenny S. DeVoney, Danielle Fox, John F. Portier, Christopher J. Schlosser, Paul M. Thompson, Chad M. White, Paul TI Uncertainties in biologically-based modeling of formaldehyde-induced respiratory cancer risk: Identification of key issues SO RISK ANALYSIS LA English DT Article DE biologically-based dose response; formaldehyde; two-stage cancer model ID PROTEIN CROSS-LINKS; EPITHELIAL-CELL PROLIFERATION; DOSE-RESPONSE RELATIONSHIPS; INHALED FORMALDEHYDE; QUANTITATIVE-ANALYSIS; FLUX PREDICTIONS; RAT-LIVER; ORAL KERATINOCYTES; DEATH APOPTOSIS; HUMAN NOSE AB In a series of articles and a health-risk assessment report, scientists at the CIIT Hamner Institutes developed a model (CIIT model) for estimating respiratory cancer risk due to inhaled formaldehyde within a conceptual framework incorporating extensive mechanistic information and advanced computational methods at the toxicokinetic and toxicodynamic levels. Several regulatory bodies have utilized predictions from this model; on the other hand, upon detailed evaluation the California EPA has decided against doing so. In this article, we study the CIIT model to identify key biological and statistical uncertainties that need careful evaluation if such two-stage clonal expansion models are to be used for extrapolation of cancer risk from animal bioassays to human exposure. Broadly, these issues pertain to the use and interpretation of experimental labeling index and tumor data, the evaluation and biological interpretation of estimated parameters, and uncertainties in model specification, in particular that of initiated cells. We also identify key uncertainties in the scale-up of the CIIT model to humans, focusing on assumptions underlying model parameters for cell replication rates and formaldehyde-induced mutation. We discuss uncertainties in identifying parameter values in the model used to estimate and extrapolate DNA protein cross-link levels. The authors of the CIIT modeling endeavor characterized their human risk estimates as "conservative in the face of modeling uncertainties." The uncertainties discussed in this article indicate that such a claim is premature. C1 [Subramaniam, Ravi P.; Chen, Chao; DeVoney, Danielle; Fox, John F.; Schlosser, Paul M.; Thompson, Chad M.; White, Paul] US EPA, NCEA, ORD, Washington, DC 20460 USA. [Crump, Kenny S.] Louisiana Tech Univ, Ruston, LA 71270 USA. [Portier, Christopher J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Subramaniam, RP (reprint author), US EPA, NCEA, ORD, Mailcode 8623-P,1200 Penn Ave, Washington, DC 20460 USA. EM Subramaniam.Ravi@epa.gov RI Portier, Christopher/A-3160-2010; OI Portier, Christopher/0000-0002-0954-0279; Schlosser, Paul/0000-0002-9699-9108 FU Intramural NIH HHS [Z01 ES048002-20] NR 70 TC 12 Z9 12 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0272-4332 J9 RISK ANAL JI Risk Anal. PD AUG PY 2008 VL 28 IS 4 BP 907 EP 923 DI 10.1111/j.1539-6924.2008.01083.x PG 17 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA 332JB UT WOS:000258078200009 PM 18564991 ER PT J AU Berezhkovskii, AM Dagdug, L Zitserman, VY Makhnovskii, YA AF Berezhkovskii, A. M. Dagdug, L. Zitserman, V. Yu. Makhnovskii, Yu. A. TI Retardation of diffusion in porous media with stagnation zones SO RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TRANSPORT; KINETICS; CHANNEL; BRAIN AB The problem of diffusion in a porous medium with stagnation zones, which reduce the rate of transport of particles, is considered. A method based on the concept of entropy barriers associated with the small size of inlets into the stagnation zone is used to solve the diffusion problem. This method made it possible to reduce the diffusion problem in 3D structures to a set of one-dimensional equations that can be solved analytically. The calculations yielded an exact value of the effective diffusion coefficient, which is reduced due to random delays in the stagnation zones, and the transition time required to attain this reduction. C1 [Berezhkovskii, A. M.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dagdug, L.] Univ Mexico City, Dept Phys, Mexico City, DF, Mexico. [Zitserman, V. Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. [Makhnovskii, Yu. A.] Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 117912, Russia. RP Berezhkovskii, AM (reprint author), NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X FU Russian Foundation for Basic Research [06-03-32373] FX Two of the authors (V. Yu. Z. and Yu. A. M.) acknowledge the support of the Russian Foundation for Basic Research, project no. 06-03-32373. NR 12 TC 0 Z9 0 U1 0 U2 3 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 1990-7931 J9 RUSS J PHYS CHEM B+ JI Russ. J. Phys. Chem. B PD AUG PY 2008 VL 2 IS 4 BP 650 EP 656 DI 10.1134/S1990793108040246 PG 7 WC Physics, Atomic, Molecular & Chemical SC Physics GA 349DE UT WOS:000259258200024 ER PT J AU Bond, E Adams, WC Perbeck, L Seder, RA Andersson, J Lore, K AF Bond, Emily Adams, William C. Perbeck, Leif Seder, Robert A. Andersson, Jan Lore, Karin TI Targeting of vaccine components to human dendritic cells in the skin SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Scandinavian-Society-for-Immunology CY AUG 12-15, 2008 CL Stockholm, SWEDEN SP Scandinavian Soc Immunol C1 [Bond, Emily; Adams, William C.; Andersson, Jan; Lore, Karin] Karolinska Inst, Ctr Infect Med, Dept Med, Stockholm, Sweden. [Perbeck, Leif] Karolinska Univ Hosp Solna, Dept Surg, Stockholm, Sweden. [Seder, Robert A.] NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM emily.bond@ki.se; william.adams@ki.se; leif.perbeck@karolinska.se; rseder@mail.nih.gov; jan.andersson@ki.se; karin.lore@ki.se NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD AUG PY 2008 VL 68 IS 2 MA 69 BP 221 EP 222 PG 2 WC Immunology SC Immunology GA 324JU UT WOS:000257515700080 ER PT J AU Khosro, M Magnus, B Monica, H Jacob, M Ahlborg, N AF Khosro, Masjedi Magnus, Bruze Monica, Hindsen Jacob, Minang Ahlborg, Niklas TI Is the variability of nickel patch test reactivity over time associated with fluctuations in the systemic T-cell reactivity to nickel? SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Scandinavian-Society-for-Immunology CY AUG 12-15, 2008 CL Stockholm, SWEDEN SP Scandinavian Soc Immunol C1 [Khosro, Masjedi] Stockholm Univ, Dept Immunol, S-10691 Stockholm, Sweden. [Magnus, Bruze; Monica, Hindsen] Univ Lund Hosp, Malmo, Sweden. [Jacob, Minang] AIDS Vaccine Program, NCI Frederick, SAIC Frederick Inc, Frederick, MD USA. [Ahlborg, Niklas] Mabtech Res & Dev, Stockholm, Sweden. EM khosro@mabtech.com; Mag-nus.Bruze@med.lu.se; Monica.Hind-sen@med.lu.se; jtminang@yahoo.com; niklas@mabtech.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD AUG PY 2008 VL 68 IS 2 MA 92 BP 233 EP 233 PG 1 WC Immunology SC Immunology GA 324JU UT WOS:000257515700102 ER PT J AU Douagi, I Gujer, C Sundling, C Adams, WC Smed-Sorensen, A Seder, RA Karlsson-Hedestam, G Lore, K AF Douagi, Iyadh Gujer, Cornelia Sundling, Christopher Adams, William C. Smed-Soerensen, Anna Seder, Robert A. Karlsson-Hedestam, Gunilla Lore, Karin TI Human B cell responses to toll-like receptor ligands are differentially modulated by myloid and plasmacytoid dendritic cells SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Scandinavian-Society-for-Immunology CY AUG 12-15, 2008 CL Stockholm, SWEDEN SP Scandinavian Soc Immunol C1 [Douagi, Iyadh; Sundling, Christopher] Swedish Inst Infect Dis Control, Stockholm, Sweden. [Gujer, Cornelia; Adams, William C.; Lore, Karin] Ctr Infect Med, Karolinska Inst, Dept Med, Stockholm, Sweden. [Smed-Soerensen, Anna] Genentech Inc, San Francisco, CA 94080 USA. [Seder, Robert A.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Karlsson-Hedestam, Gunilla] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. EM iyadh.douagi@smi.ki.se; cornelia.gujer@smi.ki.se; Christopher.sun-dling@smi.ki.se; wil-liam.adams@ki.se; anna.smed.sorensen@medhs.ki.se; rsed-er@mail.nih.gov; gunilla.Karlsson.Hede-stam@ki.se; karin.lore@ki.se NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD AUG PY 2008 VL 68 IS 2 MA 100 BP 238 EP 238 PG 1 WC Immunology SC Immunology GA 324JU UT WOS:000257515700110 ER PT J AU Adams, W Bond, E Havenga, M Holterman, L Goudsmit, J Hedestam, GK Koup, R Lore, K AF Adams, William Bond, Emily Havenga, Menzo Holterman, Lennart Goudsmit, Jaap Hedestam, Gunilla Karlsson Koup, Richard Lore, Karin TI Adenovirus serotype 5 infects human dendritic cells via a CAR-independent receptor pathway mediated by lactoferrin and C-type lectin receptors SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Scandinavian-Society-for-Immunology CY AUG 12-15, 2008 CL Stockholm, SWEDEN SP Scandinavian Soc Immunol C1 [Adams, William] Karolinska Inst, Ctr Infect Med, Stockholm, Sweden. [Bond, Emily] Karolinska Inst, Dept Med, Solna, Sweden. [Havenga, Menzo; Holterman, Lennart; Goudsmit, Jaap] Crucell Holland BV, Leiden, Netherlands. [Hedestam, Gunilla Karlsson] Karolinska Inst, MTC, Solna, Sweden. [Koup, Richard] NIAID VRC, NIH, Bethesda, MD USA. [Lore, Karin] Karolinska Inst, Ctr Infect Med, Solna, Sweden. EM William.adams@ki.se; emily.bond@ki.se; Menzo.Havenga@crucell.com; Lennart.Holterman@crucell.com; Jaap.Goudsmit@crucell.com; Gunilla.Karlsson.Hedestam@ki.se; rkoup@mail.nih.gov; karin.lore@ki.se NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD AUG PY 2008 VL 68 IS 2 MA 108 BP 242 EP 242 PG 1 WC Immunology SC Immunology GA 324JU UT WOS:000257515700118 ER PT J AU Meyer, JM Davis, VG McEvoy, JP Goff, DC Nasrallah, HA Davis, SM Daumit, GL Hsiao, J Swartz, MS Stroup, TS Lieberman, JA AF Meyer, Jonathan M. Davis, Vicki G. McEvoy, Joseph P. Goff, Donald C. Nasrallah, Henry A. Davis, Sonia M. Daumit, Gail L. Hsiao, John Swartz, Marvin S. Stroup, T. Scott Lieberman, Jeffrey A. TI Impact of antipsychotic treatment on nonfasting triglycerides in the CATIE Schizophrenia Trial phase 1 SO SCHIZOPHRENIA RESEARCH LA English DT Article DE antipsychotic; schizophrenia; cardiovascular risk; lipids; triglycerides; nonfasting ID ISCHEMIC-HEART-DISEASE; METABOLIC SYNDROME; RISK; EFFICACY; WOMEN AB Background: Recent literature documents a stronger association between nonfasting triglycerides (TG) and cardiovascular risk compared to fasting TG. Given concerns over antipsychotic effects on serum TG, this analysis explored changes in nonfasting TG in phase I of the CATIE Schizophrenia Trial. Methods: Change in nonfasting TG, adjusted for baseline value, was compared between antipsychotic treatment groups using subjects with nonfasting laboratory assessments at baseline and 3 months. Results: Among the 246 subjects there were significant treatment differences in 3-month change from baseline (p = 0.009). The greatest increases in Median and adjusted Mean nonfasting TG levels were seen among those randomized to quetiapine (Mean+54.7 Mg/dl, median+26 mg/dl) and olarizapine (mean+23.4 mg/dl, median+26.5 mg/dl), while ziprasidone was neutral (mean+0.0 mg/dl, median+8mg/dl), and decreases were seen with risperidone(mean-18.4 mg/dl, median-6.5 mg/dl) and prephenazine (mean-1.3 mg/dl, median-22 mg/dl). Pairwise comparisons indicated a significant between-group difference for perphenazine vs. olanzapine (p=0.002) and a trend for perplienazine vs. quetiapine (p=0.006). Conclusions: This analysis provides further evidence for differential antipsychotic metabolic liabilities, and confirms signals for the effects of olanzapine and quetiapine on serum TG seen in earlier CATIE analyses. Future consensus recommendations will clarify the role of nonfasting TG monitoring in routine clinical practice. (C) 2008 Elsevier B.V. All rights reserved. C1 [Meyer, Jonathan M.] VA San Diego Healthcare Syst, San Diego, CA 92161 USA. [Meyer, Jonathan M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Davis, Vicki G.] Univ N Carolina, Collaborat Studies Coordinating Ctr, Bank Amer Ctr, Dept Biostat, Chapel Hill, NC 27514 USA. [McEvoy, Joseph P.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [McEvoy, Joseph P.] John Umstead Hosp, Butner, NC 27509 USA. [Goff, Donald C.] Harvard Univ, Dept Psychiat, Cambridge, MA 02138 USA. [Goff, Donald C.] Massachusetts Gen Hosp, Lindemann Mental Hlth Ctr, Freedom Trail Clin, Schizophrenia Program, Boston, MA 02114 USA. [Nasrallah, Henry A.] Univ Cincinnati, Cincinnati, OH 45267 USA. [Davis, Sonia M.] Quintiles Inc, Biostatistics, Morrisville, NC 27560 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, New York, NY 10032 USA. RP Meyer, JM (reprint author), VA San Diego Healthcare Syst, 3350 La Jolla Village Dr,116A, San Diego, CA 92161 USA. EM jmmeyer@ucsd.edu; Vicki.Davis@mail.cscc.unc.edu; jpmcevoy@duke.edu; goff@psych.mgh.harvard.edu; NASRALHA@ucmail.uc.edu; sonia.davis@quintiles.com; 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 National Institute of Mental health (NIMH) [N01MH90001] FX The CATIE Trials were supported by National Institute of Mental health (NIMH) grant #N01MH90001. We wish to acknowledge the contributions of all investigators, study personnel and subjects from all of the CATIE Schizophrenia Trial sites. NR 15 TC 47 Z9 49 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2008 VL 103 IS 1-3 BP 104 EP 109 DI 10.1016/j.schres.2008.04.023 PG 6 WC Psychiatry SC Psychiatry GA 338CC UT WOS:000258481500011 PM 18534821 ER PT J AU Wei, L Laurence, A O'Shea, JJ AF Wei, Lai Laurence, Arian O'Shea, John J. TI New insights into the roles of Stat5a/b and Stat3 in T cell development and differentiation SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Stat5a/b; Stat3; Cytokines; Immunoregulation; T cell development and differentiation; Th17; Treg ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; COLONY-STIMULATING FACTOR; MICE LACKING EXPRESSION; EPIDERMAL-GROWTH-FACTOR; RECEPTOR-GAMMA CHAIN; HYPER-IGE SYNDROME; LYMPHOID DEVELOPMENT; MAMMARY-GLAND; CUTTING EDGE; HELPER-CELL AB T cell development and differentiation is carefully orchestrated by a series of cytokines. The importance of STAT family proteins in mediating signals by these cytokines is well-known, but new information on the role of STATs in novel aspects of T cell function and T cell subsets continues to accumulate. Recent studies have placed Stat5a/b and Stat3 center stage in T cell development and differentiation. Stat5a/b are indispensable in T regulatory (Treg) cell development and maintenance, and negatively regulate T helper 17 (Th17) cell differentiation. Conversely, Stat3 is essential for Th17 differentiation and inhibits Treg cells. The balance of Treg and Th17 cells is thought to be critical in maintaining immune tolerance, while preserving effective host defense. Therefore, Stat5a/b and Stat3 are emerging to be key players in T cell differentiation and homeostasis. Published by Elsevier Ltd. C1 [Wei, Lai; Laurence, Arian; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), 10 Ctr Dr,MSC 1616,10-6N204, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009; Wei, Lai/D-1088-2014 OI Laurence, Arian/0000-0003-0942-8292; FU Intramural Research Programs of NIAMS FX This work was supported by the Intramural Research Programs of NIAMS. NR 148 TC 54 Z9 56 U1 0 U2 7 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 AUG PY 2008 VL 19 IS 4 BP 394 EP 400 DI 10.1016/j.semcdb.2008.07.011 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 397NW UT WOS:000262670400011 PM 18708155 ER PT J AU Safaeian, M Kiddugavu, M Gravitt, PE Gange, SJ Ssekasanvu, J Murokora, D Sklar, M Serwadda, D Wawer, MJ Shah, KV Gray, R AF Safaeian, M. Kiddugavu, M. Gravitt, P. E. Gange, S. J. Ssekasanvu, J. Murokora, D. Sklar, M. Serwadda, D. Wawer, M. J. Shah, K. V. Gray, R. TI Prevalence and risk factors for carcinogenic human papillomavirus infections in rural Rakai, Uganda SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article; Proceedings Paper CT 23rd International Papillomavirus Conference and Clinical Workshop CY SEP 01-07, 2006 CL Prague, CZECH REPUBLIC ID HUMAN-IMMUNODEFICIENCY-VIRUS; CERVICAL-CANCER; WOMEN; WORLDWIDE; PCR AB Objective: To investigate self-administered vaginal swabs for assessing prevalence and correlates of carcinogenic human papillomavirus (HPV) infection in rural Rakai, Uganda. Methods: 1003 sexually experienced women enrolled in a community cohort provided self- administered vaginal swabs collected at annual, home- based surveys. Carcinogenic HPV prevalence, adjusted odds ratios (AOR), 95% confidence intervals (CI) and associated risk factors were determined. Results: Carcinogenic HPV prevalence was 19.2%: 46.6% among HIV positive and 14.8% among HIV negative women (p < 0.001). Type-specific prevalence ranged from 2.0% (HPV 16 and 52) to 0.2% (HPV 31). Age- specific HPV prevalence decreased significantly (p < 0.001) among HIV negative women; however, the decrease among HIV positive women was not as pronounced (p= 0.1). Factors independently associated with carcinogenic HPV infection were HIV (AOR 4.82, CI 3.10 to 7.53), age (AOR 4.97, 95% CI 2.19 to 11.26 for 15 - 19 year olds compared to 40+ years), more than two sex partners in the past year (AOR 2.21, CI 1.10 to 4.43) and self- reported herpes zoster, candidiasis or tuberculosis (AOR 4.52, CI 1.01 to 20.31). Married women were less likely to have prevalent carcinogenic HPV (AOR 0.46, CI 0.30 to 0.70). Conclusions: HPV prevalence and correlates measured using self- administered vaginal swabs were similar to studies that use cervical samples. Thus, self- collection can be used as a substitute for cervical specimens and provide an important tool for research in populations unwilling to undergo pelvic exam. C1 [Safaeian, M.; Gravitt, P. E.; Gange, S. J.] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Kiddugavu, M.; Ssekasanvu, J.; Murokora, D.; Serwadda, D.] Uganda Virus Res Inst, Entebbe, Uganda. [Kiddugavu, M.; Ssekasanvu, J.; Murokora, D.; Serwadda, D.] Rakai Hlth Sci Program, Entebbe, Uganda. [Sklar, M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Serwadda, D.] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. [Wawer, M. J.; Gray, R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Shah, K. V.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 6120 Execut Blvd,Suite 550, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov OI Gange, Stephen/0000-0001-7842-512X FU FIC NIH HHS [5D43TW00010]; NIAID NIH HHS [T32AI50056]; NICHD NIH HHS [5P30HD06826]; PHS HHS [R01 A134265, R01 A134826] NR 24 TC 15 Z9 15 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD AUG 1 PY 2008 VL 84 IS 4 BP 306 EP 311 DI 10.1136/sti.2007.027318 PG 6 WC Infectious Diseases SC Infectious Diseases GA 329AR UT WOS:000257839800016 PM 18385223 ER PT J AU Morin, A Doyon, J Dostie, V Baralkat, M Tahar, AH Korman, M Benali, H Karni, A Ungerleider, LG Carrier, J AF Morin, Amelie Doyon, Julien Dostie, Valerie Baralkat, Marc Tahar, Abdallah Hadj Korman, Maria Benali, Habib Karni, Avi Ungerleider, Leslie G. Carrier, Julie TI Motor sequence learning increases sleep spindles and fast frequencies in post-training sleep SO SLEEP LA English DT Article DE motor sequence learning; memory consolidation; sleep; sleep spindles; spectral analysis; memory ID DEPENDENT CHANGES; REM-SLEEP; MEMORY-SYSTEMS; STAGE-2 SLEEP; OSCILLATIONS; PLASTICITY; REPRESENTATION; PERFORMANCE; ACTIVATION; COMPLEXITY AB Study Objectives: To investigate polysomnographic (PSG) sleep and NREM sleep characteristics, including sleep spindles and spectral activity involved in offline consolidation of a motor sequence learning task. Design: Counterbalanced within-subject design Setting: Three weekly visits to the sleep laboratory. Participants: Fourteen healthy participants aged between 20 and 30 years (8 women). Interventions: Motor sequence learning (MSL) task or motor control (CTRL) task before sleep. Measurements and Results: Subjects were trained on either the MSL or CTRL task in the evening and retested 12 hours later the following morning on the same task after a night of PSG sleep recording. Total number and duration of sleep spindles and spectral power between 0.5 and 24 Hz were quantified during NREM sleep. After performing the MSL task, subjects exhibited a large increase in number and duration of sleep spindles compared to after the CTRL task. Higher sigma (sigma; 13 Hz) and beta (beta; 18-20 Hz) spectral power during the post-training night's sleep were also observed after the MSL task. Conclusions: These results provide evidence that sleep spindles are involved in the offline consolidation of a new sequence of finger movements known to be sleep dependent. Moreover, they expand on prior findings by showing that changes in NREM sleep following motor learning are specific to consolidation (and learning), and not to nonspecific motor activity. Finally, these data demonstrate, for the first time, higher fast rhythms (beta frequencies) during sleep after motor learning. C1 [Morin, Amelie; Dostie, Valerie; Carrier, Julie] Hop Sacre Coeur, Ctr Etud Sommeil & Rythmes Biol, Lab Chronobiol, Montreal, PQ H4J 1C5, Canada. [Morin, Amelie; Doyon, Julien; Dostie, Valerie; Baralkat, Marc; Tahar, Abdallah Hadj; Benali, Habib; Carrier, Julie] Inst Univ Geriatrie Montreal, Funct Neuroimaging Unit, Montreal, PQ, Canada. [Morin, Amelie; Doyon, Julien; Dostie, Valerie; Baralkat, Marc; Tahar, Abdallah Hadj; Carrier, Julie] Univ Montreal, Dept Psychol, Ctr Rech Neuropsychol & Cognit, Montreal, PQ H3C 3J7, Canada. [Benali, Habib] Univ Paris 06, CHU Pitie Salpetriere, Inst Natl Sante & Rech Med, UMR 678, Paris, France. [Korman, Maria; Karni, Avi] Univ Haifa, Brain Behav Ctr, Lab Funct Brain Imaging & Learning Res, Har Hakarmel, Israel. [Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Carrier, J (reprint author), Hop Sacre Coeur, Ctr Etud Sommeil & Rythmes Biol, Lab Chronobiol, 5400 Gouin Blvd W, Montreal, PQ H4J 1C5, Canada. EM julie.carrier.1@umontreal.ca OI Korman, Maria/0000-0003-1895-0189 NR 40 TC 87 Z9 91 U1 2 U2 6 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD AUG 1 PY 2008 VL 31 IS 8 BP 1149 EP 1156 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 332VK UT WOS:000258111000012 PM 18714787 ER PT J AU Senay, I AF Senay, Ibrahim TI Spatial proximity to category boundaries enhances stereotype-based judgments SO SOCIAL COGNITION LA English DT Article ID PERCEPTUAL DISCRIMINATION; SOCIAL CATEGORIZATIONS; PERSON MEMORY; ACCENTUATION; MEMBERS; PREJUDICE; SALIENCE; GENDER; FIT; SEX AB Past studies showed that stereotype-based differences between two social groups are accentuated when observers form their impressions about one group in the presence of the other. Here it was shown that inter-category differences are further accentuated as a function of contrasting group members' proximity to each other while social judgments are made. When pictures of two males and two females were presented in the order of female-female-male-male, a male and a female were judged to be more different from each other on gender-stereotypical, but not on gender-neutral characteristics, if their pictures were at (i.e., the two middle positions), as opposed to farther away from, the category boundary. The results show the moderating role of proximity to spatial boundaries during a social judgment in the accentuation of stereotypical differences between members from different social groups. C1 NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Senay, I (reprint author), NHGRI, Social & Behav Res Branch, NIH, Bldg 31,Rm B1B54g,31 Ctr Dr, MSC-2073, Bethesda, MD 20892 USA. EM senayi@mail.nih.gov NR 28 TC 0 Z9 0 U1 0 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0278-016X J9 SOC COGNITION JI Soc. Cogn. PD AUG PY 2008 VL 26 IS 4 BP 438 EP 446 DI 10.1521/soco.2008.26.4.438 PG 9 WC Psychology, Social SC Psychology GA 337IY UT WOS:000258431000004 ER PT J AU Tuckson, RV Willard, HF AF Tuckson, Reed V. Willard, Huntington F. TI A letter response to Chaufan's "How much can a large population study on genes, environments, their interactions and common diseases contribute to the health of the American people?" (65 : 8,2007,1730-1741) SO SOCIAL SCIENCE & MEDICINE LA English DT Letter C1 [Tuckson, Reed V.] SACGHS Task Force Large Populat Studies, Natl Inst Hlth, Off Biotechnol Activ, Bethesda, MD 20892 USA. RP Tuckson, RV (reprint author), SACGHS Task Force Large Populat Studies, Natl Inst Hlth, Off Biotechnol Activ, 6705 Rockledge Dr,Suite 750, Bethesda, MD 20892 USA. EM segery@od.nih.gov NR 3 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 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD AUG PY 2008 VL 67 IS 4 BP 673 EP 674 DI 10.1016/j.socscimed.2008.04.011 PG 2 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 346HY UT WOS:000259060600020 PM 18534733 ER PT J AU Debrey, SM Yu, H Lynch, JK Lovblad, KO Wright, VL Janket, SJD Baird, AE AF Debrey, Sarah M. Yu, Hua Lynch, John K. Loevblad, Karl-Olof Wright, Violet L. Janket, Sok-Ja D. Baird, Alison E. TI Diagnostic accuracy of magnetic resonance angiography for internal carotid artery disease - A systematic review and meta-analysis SO STROKE LA English DT Review DE carotid arteries; carotid artery stenosis; magnetic resonance angiography; angiography; contrast-enhanced magnetic resonance angiography ID DIGITAL-SUBTRACTION-ANGIOGRAPHY; ENHANCED MR-ANGIOGRAPHY; X-RAY ANGIOGRAPHY; SPIRAL CT ANGIOGRAPHY; OF-THE-LITERATURE; CONVENTIONAL ANGIOGRAPHY; DUPLEX ULTRASONOGRAPHY; SUPRAAORTIC ARTERIES; INTEROBSERVER VARIABILITY; CATHETER ANGIOGRAPHY AB Background and Purpose - Accurate diagnosis of the degree of internal carotid artery (ICA) stenosis is needed for decisions regarding optimal stroke prevention. Noninvasive magnetic resonance angiography (MRA) is being proposed and used as a replacement for the gold standard, intra-arterial angiography. Our purpose was to perform a systematic review and diagnostic meta-analysis to determine the sensitivity and specificity of time-of-flight (TOF) MRA and contrast-enhanced (CE) MRA for the detection of (1) high-grade (>= 70% to 99%) ICA stenoses; ( 2) ICA occlusions; ( 3) moderately severe (50% to 69%) ICA stenoses; and ( 4) compare the overall accuracy of the 2 MRA techniques. Methods - The medical literature on MRA and the diagnosis of ICA steno-occlusive disease was reviewed through the PubMed, EMBASE, and SCOPUS databases. All publication years were included through to November 2006. Studies were eligible for inclusion if they compared the accuracy of TOF or CE MRA for the detection of ICA disease against intra-arterial angiography and reported sufficient data. Results - The overall sensitivity of TOF MRA for the detection of >= 70% to 99% ICA stenoses was 91.2% (95% CI: 88.9% to 93.1%) with a specificity of 88.3% (86.7% to 89.7%), whereas the sensitivity of CE MRA was 94.6% (92.4% to 96.4%) with a specificity of 91.9% (90.3% to 93.4%). For the detection of ICA occlusions, the sensitivity of TOF MRA was 94.5% ( 91.2% to 96.8%) and the specificity was 99.3% (98.9% to 99.6%), whereas the sensitivity and specificity values for CE MRA were 99.4% (96.8% to 100%) and 99.6% (99.2% to 99.9%), respectively. For moderately severe ( 0% to 69%) stenoses, TOF MRA had a sensitivity of only 37.9% (29.3% to 47.1%) and a specificity of 92.1% (89.6% to 94.1%); for CE MRA, the pooled sensitivity value was somewhat better at 65.9% (57.0% to 74.0%), whereas the specificity was 93.5% (91.3% to 95.3%). Conclusions - TOF MRA and CE MRA showed high accuracy for the detection of high- grade ICA stenoses and occlusions with CE MRA having the edge over TOF MRA, but had only poor (TOF MRA) to fair (CE MRA) sensitivity for the detection of moderately severe stenoses. C1 [Debrey, Sarah M.; Yu, Hua; Lynch, John K.; Wright, Violet L.; Baird, Alison E.] NINDS, NIH, Stroke Neurosci Unit, Bethesda, MD 20892 USA. Boston Univ, Sch Dent Med, Boston, MA 02215 USA. HUG Hop Cantonal, Geneva, Switzerland. RP Baird, AE (reprint author), Suny Downstate Med Ctr, Div Cerebrovasc Dis & Stroke, 450 Clarkson Ave,Box 1213, Brooklyn, NY 11203 USA. EM alison.baird@downstate.edu OI Janket, Sok-Ja/0000-0003-0078-3992; lovblad, karl-olof/0000-0003-2768-9779 FU Intramural NIH HHS NR 78 TC 63 Z9 69 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2008 VL 39 IS 8 BP 2237 EP 2248 DI 10.1161/STROKEAHA.107.509877 PG 12 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 331DR UT WOS:000257993400009 PM 18556586 ER PT J AU Calzone, KA Soballe, PW AF Calzone, Kathleen A. Soballe, Peter W. TI Genetic testing for cancer susceptibility SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; FAMILIAL BREAST-CANCER; LYNCH-SYNDROME; CARRIER PROBABILITIES; COMPUTER-PROGRAM; OVARIAN-CANCER; BRCA1; HISTORY; MUTATION; RISK AB Genetic testing for mutations in genes associated with an inherited predisposition to cancer is rapidly Moving Outside specialty genetic services and into mainstream health care. Surgeons, as front-line providers of cancer care, are uniquely positioned to identify those who may benefit from genetic testing and institute changes to their health care management based on those results. This article provides an overview of the critical elements of the process of genetic testing for cancer susceptibility. C1 [Calzone, Kathleen A.] NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20889 USA. [Soballe, Peter W.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. RP Calzone, KA (reprint author), NCI, NIH, Ctr Canc Res, Genet Branch, 8901 Wisconsin Ave,Bldg 8 RM 5101, Bethesda, MD 20889 USA. EM calzonek@mail.nih.gov NR 58 TC 4 Z9 4 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 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2008 VL 88 IS 4 BP 705 EP + DI 10.1016/j.suc.2008.05.003 PG 18 WC Surgery SC Surgery GA 346SI UT WOS:000259089100004 PM 18672137 ER PT J AU Jatoi, I Anderson, WF AF Jatoi, Ismail Anderson, William F. TI Management of women who have a genetic predisposition for breast cancer SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article ID BRCA2 MUTATION CARRIERS; BILATERAL PROPHYLACTIC MASTECTOMY; SURGICAL ADJUVANT BREAST; OF-CLINICAL-ONCOLOGY; BOWEL PROJECT P-1; OVARIAN-CANCER; SUSCEPTIBILITY GENE; SCREENING MAMMOGRAPHY; PREVENTION TRIAL; RISK-ASSESSMENT AB The management of women who have a genetic predisposition for breast cancer requires careful planning. Women who have BRCA 1 and BRCA 2 mutations are at increased risk for breast cancer and for other cancers as well, particularly ovarian cancer. Screening, prophlyactic surgery, and chemoprevention are commonly utilized strategies in the management of these patients, and women may choose more than one of these strategies. No randomized prospective trials have assessed the impact of these strategies specifically in mutaiton carriers. All patients should be informed that screening, prophylactic surgery, and chemoprevention have the potential for harm as well as benefit. C1 [Jatoi, Ismail] Uniformed Serv Univ Hlth Sci, Natl Naval Med Ctr, Breast Care Ctr, Bethesda, MD 20889 USA. [Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Jatoi, I (reprint author), Uniformed Serv Univ Hlth Sci, Natl Naval Med Ctr, Breast Care Ctr, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM ismail.jatoi@us.army.mil FU Intramural NIH HHS NR 72 TC 12 Z9 12 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 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2008 VL 88 IS 4 BP 845 EP + DI 10.1016/j.suc.2008.04.007 PG 19 WC Surgery SC Surgery GA 346SI UT WOS:000259089100010 PM 18672143 ER PT J AU Vinod, KY Yalamanchili, R Thanos, PK Vadasz, C Cooper, TB Volkow, ND Hungund, BL AF Vinod, K. Yaragudri Yalamanchili, Ratnakumar Thanos, Panayotis K. Vadasz, Csaba Cooper, Thomas B. Volkow, Nora D. Hungund, Basalingappa L. TI Genetic and pharmacological manipulations of the CB(1) receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice SO SYNAPSE LA English DT Article DE alcohol; striatum; CB(1) receptor; G-protein; endocannabinoid; anandamide ID ACID AMIDE HYDROLASE; NUCLEUS-ACCUMBENS; KNOCKOUT MICE; ALCOHOL DEPENDENCE; DOPAMINE RELEASE; ANTAGONIST SR141716A; DBA/2 MICE; SP RATS; BRAIN; WITHDRAWAL AB Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB, receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (136) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB, receptor significantly reduced the ethanol preference. Although the stimulation of the CB(1) receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in 136 than in D2 mice. The antagonism of CB(1) receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in 136 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB(1) -/- mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB(1) receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB(1) receptor-stimulated G-protein activation in the striatum of 136 compared to D2 mice. Innate differences in the CB(1) receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB(1) receptor may have therapeutic potential in the treatment of ethanol dependence. C1 [Vinod, K. Yaragudri; Yalamanchili, Ratnakumar; Cooper, Thomas B.; Hungund, Basalingappa L.] Nathan S Kline Inst Psychiat Res, Div Analyt Psychopharmacol, Orangeburg, NY 10962 USA. [Vinod, K. Yaragudri; Cooper, Thomas B.; Hungund, Basalingappa L.] New York State Psychiat Inst & Hosp, Div Analyt Psychopharmacol, New York, NY 10032 USA. [Vinod, K. Yaragudri] NYU, Sch Med, Dept Child & Adolescent Psychiat, New York, NY USA. [Thanos, Panayotis K.] Brookhaven Natl Lab, Dept Med, Behav Pharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. [Vadasz, Csaba] Nathan S Kline Inst Psychiat Res, Lab Neurobehav Genet, Orangeburg, NY 10962 USA. [Vadasz, Csaba; Cooper, Thomas B.] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Cooper, Thomas B.; Hungund, Basalingappa L.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA. RP Hungund, BL (reprint author), Nathan S Kline Inst Psychiat Res, Div Analyt Psychopharmacol, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA. EM hungund@nki.rfmh.org FU Intramural NIH HHS [Z01 AA000551-04]; NIAAA NIH HHS [AA13003, N01AA22008, R01 AA013003] NR 51 TC 35 Z9 35 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-4476 J9 SYNAPSE JI Synapse PD AUG PY 2008 VL 62 IS 8 BP 574 EP 581 DI 10.1002/syn.20533 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 323VT UT WOS:000257477200003 PM 18509854 ER PT J AU Liu, F Thomas, J Burke, TR AF Liu, Fa Thomas, Joshua Burke, Terrence R., Jr. TI Synthesis of a homologous series of side-chain-extended orthogonally protected aminooxy-containing amino acids SO SYNTHESIS-STUTTGART LA English DT Article DE oxime; peptidomimetic; aldehydes; combinatorial chemistry ID EXPEDITED LIBRARY SYNTHESIS; RING-CLOSING METATHESIS; CHEMOSELECTIVE LIGATION; PEPTIDE-SYNTHESIS; SURROGATES AB Practical methodology is reported for the synthesis of a homologous series of side-chain-extended amino acids containing aminooxy functionality bearing orthogonal protection suitable for Fmoc peptide synthesis. These reagents may be useful for the preparation of libraries containing fragments joined by peptide linkers. C1 [Liu, Fa; Thomas, Joshua; Burke, Terrence R., Jr.] NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. RP Liu, F (reprint author), NCI, Med Chem Lab, CCR, NIH, Bldg 376,1050 Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov FU NIH FX This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick. NR 20 TC 9 Z9 9 U1 0 U2 6 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD AUG PY 2008 IS 15 BP 2432 EP 2438 DI 10.1055/s-2008-1078600 PG 7 WC Chemistry, Organic SC Chemistry GA 336OO UT WOS:000258374700020 PM 19122755 ER PT J AU Hillyer, CD Blumberg, N Glynn, SA Ness, PM AF Hillyer, Christopher D. Blumberg, Neil Glynn, Simone A. Ness, Paul M. CA NHLBI Working Grp Transfusion Reci TI Transfusion recipient epidemiology and outcomes research: possibilities for the future SO TRANSFUSION LA English DT Editorial Material ID POLYMERASE-CHAIN-REACTION; INTENSIVE-CARE UNIT; SICKLE-CELL-DISEASE; PLATELET TRANSFUSIONS; BLOOD-TRANSFUSION; CARDIAC-SURGERY; CRITICALLY-ILL; MORTALITY; COAGULOPATHY; ASSOCIATION AB The National Heart, Lung, and Blood Institute (NHLBI) supports major research programs related to the field of transfusion medicine, which encompass blood banking, the practice of transfusion medicine itself, and cellular therapies. Specific programmatic elements have included 1) the Transfusion Medicine/Hemostasis Clinical Trials Network (TMH CTN) charged with conducting clinical trials in transfusion medicine and hemostasis; 2) the Retrovirus Epidemiology Donor Study-II (REDS-II), which includes domestic and international efforts dedicated to blood donor safety and blood availability issues; 3) the Specialized Centers of Clinically Oriented Research (SCCOR) in Transfusion Biology and Medicine that include two major projects, the Biologic and Immunologic Aspects of Transfusion Medicine Program and the Transfusion and Lung Injury Program, and 4) the Transfusion Therapy Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS), a Phase III clinical trial that has as its major goal to determine whether a more aggressive transfusion strategy in surgery patients with cardiovascular disease (or risk factors) is associated with improved functional recovery and decreased risk of adverse postoperative outcomes. Notably, none of these programs supports epidemiologic and clinical outcomes research focused on transfusion recipients. Thus, on October 31, 2007, a Working Group on Transfusion Recipient Epidemiology and Outcomes Research was convened by the NHLBI. This group was asked to discuss the current status of the field, identify critical research needs, and make recommendations to the NHLBI program staff. C1 Emory Univ Hosp, Blood Bank, Atlanta, GA 30322 USA. Univ Rochester, Blood Bank, Rochester, NY USA. NHLBI, DBDR, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Blood Bank, Bethesda, MD USA. RP Hillyer, CD (reprint author), D655 EUH Blood Bank, Atlanta, GA 30322 USA. EM chillye@emory.edu NR 53 TC 24 Z9 25 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2008 VL 48 IS 8 BP 1530 EP 1537 DI 10.1111/j.1537-2995.2008.01807.x PG 8 WC Hematology SC Hematology GA 332IX UT WOS:000258077800001 PM 18564389 ER PT J AU Glynn, SA AF Glynn, Simone A. TI Blood supply safety: an NHLBI perspective SO TRANSFUSION LA English DT Editorial Material ID TRANSMITTED VIRAL-INFECTIONS; DONORS; RISK; SURVEILLANCE; VIRUS; NETHERLANDS; STRATEGY; HCV C1 NHLBI, DBDR, Bethesda, MD 20892 USA. RP Glynn, SA (reprint author), NHLBI, DBDR, Bldg 10, Bethesda, MD 20892 USA. EM glynnsa@nhlbi.nih.gov NR 20 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2008 VL 48 IS 8 BP 1541 EP 1544 PG 4 WC Hematology SC Hematology GA 332IX UT WOS:000258077800003 PM 18713102 ER PT J AU Wang, JK Sheldon, SL Klein, HG Leitman, SF Stroncek, DF AF Wang, Jeanne K. Sheldon, Sherry L. Klein, Harvey G. Leitman, Susan F. Stroncek, David F. TI Sporadic leukoreduction filter failure during red blood cell component preparation: beware of rapid filtration SO TRANSFUSION LA English DT Letter ID REDUCTION; PLATELETS C1 [Wang, Jeanne K.; Sheldon, Sherry L.; Klein, Harvey G.; Leitman, Susan F.; Stroncek, David F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Wang, JK (reprint author), NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM wangjean@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2008 VL 48 IS 8 BP 1766 EP 1767 PG 2 WC Hematology SC Hematology GA 332IX UT WOS:000258077800033 PM 18713104 ER PT J AU Irimia, M Rukov, JL Penny, D Vinther, J Garcia-Fernandez, J Roy, SW AF Irimia, Manuel Rukov, Jakob Lewin Penny, David Vinther, Jeppe Garcia-Fernandez, Jordi Roy, Scott William TI Origin of introns by "intronization' of exonic sequences SO TRENDS IN GENETICS LA English DT Article ID GENES; GAIN; CONSERVATION; GENOMES; CAENORHABDITIS; EVOLUTION; PATTERNS; NUMBER; MOUSE AB The mechanisms of spliceosomal intron creation have proved elusive. Here we describe a new mechanism: the recruitment of internal exonic sequences ('intronization') in Caenorhabditis species. The numbers of intronization events and introns gained by other mechanisms are similar, suggesting that intronization significantly contributes to recent intron creation in nematodes. Intronization is more common than the reverse process, loss of splicing of retained introns. Finally, these findings link alternative splicing with modern intron creation. C1 [Roy, Scott William] Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Irimia, Manuel; Garcia-Fernandez, Jordi] Univ Barcelona, Fac Biol, Dept Genet, E-08028 Barcelona, Spain. [Rukov, Jakob Lewin; Vinther, Jeppe] Univ Copenhagen, Dept Biol, Mol Evolut Grp, DK-2200 Copenhagen, Denmark. [Penny, David] Massey Univ, Allan Wilson Ctr Mol Evolut & Ecol, Palmerston North, New Zealand. RP Roy, SW (reprint author), Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. EM royscott@ncbi.nlm.nih.gov RI Irimia, Manuel/E-3040-2010; Vinther, Jeppe/A-8172-2012; Garcia-Fernandez, Jordi/B-3839-2013; OI Vinther, Jeppe/0000-0002-3847-3853; Garcia-Fernandez, Jordi/0000-0001-5677-5970; Irimia, Manuel/0000-0002-2179-2567 FU Intramural NIH HHS NR 30 TC 49 Z9 49 U1 1 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD AUG PY 2008 VL 24 IS 8 BP 378 EP 381 DI 10.1016/j.tig.2008.05.007 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 336JD UT WOS:000258359200003 PM 18597887 ER PT J AU Rouault, TA Tong, WH AF Rouault, Tracey A. Tong, Wing Hang TI Iron-sulfur cluster biogenesis and human disease SO TRENDS IN GENETICS LA English DT Review ID CYTOSOLIC FE/S PROTEINS; FRIEDREICHS-ATAXIA; SCAFFOLD PROTEIN; SACCHAROMYCES-CEREVISIAE; REGULATORY PROTEINS; YEAST FRATAXIN; MONOTHIOL GLUTAREDOXINS; SUCCINATE-DEHYDROGENASE; MICROCYTIC ANEMIA; OXIDATIVE STRESS AB Iron-sulfur (Fe-S) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Human Fe-S cluster assembly proteins are frequently encoded by single genes, and inherited defects in some of these genes cause disease. Recently, the spectrum of diseases attributable to abnormal Fe-S cluster biogenesis has extended beyond Friedreich ataxia to include a sideroblastic anemia with deficiency of glutaredoxin 5 and a myopathy associated with a deficiency of a Fe-S cluster assembly scaffold protein, ISCU. Mutations within other mammalian Fe-S cluster assembly genes could be causative for human diseases that manifest distinctive combinations of tissue-specific impairments. Thus, defects in the iron-sulfur cluster biogenesis pathway could underlie many human diseases. C1 [Rouault, Tracey A.; Tong, Wing Hang] NICHHD, NIH, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, NIH, Program Mol Med, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov; wing@box-w.nih.gov FU Intramural NIH HHS [Z01 HD008814-01] NR 81 TC 206 Z9 209 U1 2 U2 19 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD AUG PY 2008 VL 24 IS 8 BP 398 EP 407 DI 10.1016/j.tig.2008.05.008 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 336JD UT WOS:000258359200006 PM 18606475 ER PT J AU Gao, HM Hong, JS AF Gao, Hui-Ming Hong, Jau-Shyong TI Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression SO TRENDS IN IMMUNOLOGY LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; PROTECTS DOPAMINERGIC-NEURONS; LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; PRIMARY MIDBRAIN CULTURES; MICROGLIAL NADPH OXIDASE; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; SUBSTANTIA-NIGRA; NEUROTROPHIC FACTOR; MOUSE MODEL AB Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases. C1 [Gao, Hui-Ming; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Pharmacol Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Neuropharmacol Sect, Pharmacol Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. EM Gao2@niehs.nih.gov RI gao, huiming/C-8454-2012 FU National Institute of Health, National Institute of Environmental Health Sciences FX The authors thank R. Smeyne, J. McGinty, H. Chen and J. Zhang for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Health, National Institute of Environmental Health Sciences. NR 89 TC 258 Z9 274 U1 2 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2008 VL 29 IS 8 BP 357 EP 365 DI 10.1016/j.it.2008.05.002 PG 9 WC Immunology SC Immunology GA 338BV UT WOS:000258480800003 PM 18599350 ER PT J AU Diep, BA Otto, M AF Diep, Binh An Otto, Michael TI The role of virulence determinants in community-associated MRSA pathogenesis SO TRENDS IN MICROBIOLOGY LA English DT Review ID RESISTANT STAPHYLOCOCCUS-AUREUS; PANTON-VALENTINE LEUKOCIDIN; SOFT-TISSUE INFECTIONS; CATABOLIC MOBILE ELEMENT; CASSETTE CHROMOSOME MEC; METHICILLIN-RESISTANT; ALPHA-TOXIN; NECROTIZING PNEUMONIA; WESTERN-AUSTRALIA; SKIN INFECTIONS AB The recent emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) marked a quantum change in the biology and epidemiology of a major human pathogen. Various virulence determinants unique to CA-MRSA have been uncovered recently, which shed light on how these strains spread easily and sustainably among humans and frequently cause severe disease. The role of the Panton Valentine leukocidin (PVL) in CA-MRSA pathogenesis is a matter of much debate. Although epidemiological data have indicated a role for PVL in the CA-MRSA disease process, recent data from relevant animal models indicate that PVL does not impact virulence of prevalent CA-MRSA strains. Identifying specialized pathogenic traits of CA-MRSA remains a challenge that will yield new diagnostic tools and therapeutic targets for drug and vaccine development. Here, we discuss the roles of PVL, the arginine catabolic mobile element and phenol-soluble modulins in the pathogenesis of prevalent CA-MRSA strains. C1 [Otto, Michael] NIAID, NIH, Hamilton, MT 59840 USA. [Diep, Binh An] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94110 USA. RP Otto, M (reprint author), NIAID, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural NIH HHS [Z99 AI999999, ZIA AI000904-08] NR 69 TC 171 Z9 178 U1 1 U2 20 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD AUG PY 2008 VL 16 IS 8 BP 361 EP 369 DI 10.1016/j.tim.2008.05.002 PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 342XM UT WOS:000258816900002 PM 18585915 ER PT J AU Espeland, MA Regensteiner, JG Jaramillo, SA Gregg, E Knowler, WC Wagenknecht, LE Bahnson, J Haffner, S Hill, J Hiatt, WR AF Espeland, Mark A. Regensteiner, Judith G. Jaramillo, Sarah A. Gregg, Edward Knowler, William C. Wagenknecht, Lynne E. Bahnson, Judy Haffner, Steven Hill, James Hiatt, William R. CA Look AHEAD Study Grp TI Measurement characteristics of the ankle-brachial index: results from the Action for Health in Diabetes study SO VASCULAR MEDICINE LA English DT Article DE diagnostic error; peripheral arterial disease; sensitivity and specificity ID PERIPHERAL ARTERIAL-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTORS AB Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle-brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2-3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30-40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk. C1 [Espeland, Mark A.] Wake Forest Univ, Dept Biostat Sci, Sch Med, Winston Salem, NC 27157 USA. [Regensteiner, Judith G.; Hill, James; Hiatt, William R.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Gregg, Edward] Ctr Dis Control & Prevent, Atlanta, GA USA. [Knowler, William C.] NIDDK, Diabetes Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Haffner, Steven] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Hiatt, William R.] Colorado Prevent Ctr, Denver, CO USA. RP Espeland, MA (reprint author), Wake Forest Univ, Dept Biostat Sci, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mespelan@wfubmc.edu OI Kriska, Andrea/0000-0002-3522-0869; Kahn, Steven/0000-0001-7307-9002; Redmon, J. Bruce/0000-0002-1883-9467 FU Department of Health and Human Services; National Institutes of Health [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; Centers for Disease Control and Prevention; The Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01-RR-02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center [M01-RR-01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01-RR-00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR00211-40]; University of Pittsburgh General Clinical Research Center [M01RR000056 44]; NIH [DK 046204]; University of Washington / Veterans Affairs Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs FX This study is supported by the Department of Health and Human Services through the following cooperative agreements from the National Institutes of Health: DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992. The following federal agencies have contributed support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; and the Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01-RR-02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center (M01-RR-01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01-RR-00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR00211-40); the University of Pittsburgh General Clinical Research Center (M01RR000056 44) and NIH grant (DK 046204); and the University of Washington / Veterans Affairs Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs. The following organizations have committed to make major contributions to Look AHEAD: Federal Express; Health Management Resources; Johnson & Johnson, LifeScan Inc.; Optifast-Novartis Nutrition; Roche Pharmaceuticals; Ross Product Division of Abbott Laboratories; and Slim-Fast Foods Company. NR 16 TC 8 Z9 8 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD AUG PY 2008 VL 13 IS 3 BP 225 EP 233 DI 10.1177/1358863X08091338 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 346PS UT WOS:000259081900003 PM 18687759 ER PT J AU Lund, JR Paoloni, M Kurzman, I Padilla, M Argyle, DJ AF Lund, J. R. Paoloni, M. Kurzman, I. Padilla, M. Argyle, D. J. TI Inhibition of canine telomerase in vitro and in vivo using RNAi: Further development of a natural canine model for telomerase-based cancer therapies SO VETERINARY JOURNAL LA English DT Article DE canine; telomerase; RNA interference; haemangiosarcoma ID CELLS; EXPRESSION; GROWTH; DELIVERY AB Despite advances in cancer therapy, cancer related morbidity and mortality among humans and companion animals remains high, and there is a clear need to develop novel targeted therapies. Expression of the enzyme telomerase has emerged as a central unifying mechanism underlying the immortal phenotype of canine cancer cells and has thus become a candidate for targeted molecular therapies. In this study, the value of telomerase inhibition to target telomerase expressing cancer cells was explored using the novel mechanism of RNA interference (RNAi). Using a Lentiviral expression construct, targeting the RNA component of canine telomerase was effective at inhibiting telomerase in vitro and tumour growth in vivo, but possible resistance mechanisms are highlighted. As canine telomerase biology is more closely related to human telomerase biology than the murine system, it is proposed that this study highlights the value of natural canine models to study anti-telomerase therapies for human patients. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Lund, J. R.; Paoloni, M.; Kurzman, I.; Padilla, M.] Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. [Argyle, D. J.] Univ Edinburgh, Royal Dick Sch Vet Studies, Hosp Small Anim, Easter Bush Vet Ctr, Roslin EH25 9RG, Midlothian, England. RP Argyle, DJ (reprint author), NCI, Comparat Oncol Program, Ctr Canc Res, NIH, Room 2144, Bethesda, MD 20892 USA. EM david.argyle@ed.ac.uk NR 22 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1090-0233 J9 VET J JI Vet. J. PD AUG PY 2008 VL 177 IS 2 BP 192 EP 197 DI 10.1016/j.tvjl.2007.09.015 PG 6 WC Veterinary Sciences SC Veterinary Sciences GA 323PA UT WOS:000257457600008 PM 17981480 ER PT J AU Yang, LJ Sanchez, A Ward, JM Murphy, BR Collins, PL Bukreyev, A AF Yang, Lijuan Sanchez, Anthony Ward, Jerrold M. Murphy, Brian R. Collins, Peter L. Bukreyev, Alexander TI A paramyxovirus-vectored intranasal vaccine against Ebola virus is immunogenic in vector-immune animals SO VIROLOGY LA English DT Article DE Ebola; virus; vaccine; immunogenicity; respiratory; immunization; antibody ID PROTECTS NONHUMAN-PRIMATES; RHESUS-MONKEYS; HEMAGGLUTININ-NEURAMINIDASE; MONOCLONAL-ANTIBODIES; FUSION GLYCOPROTEINS; ANTI-AD5 IMMUNITY; REPLICATION; ADENOVIRUS; INFECTION; TYPE-3 AB Ebola virus (EBOV) causes outbreaks of a highly lethal hemorrhagic fever in humans. The virus can be transmitted by direct contact as well as by aerosol and is considered a potential bioweapon. Because direct immunization of the respiratory tract should be particularly effective against infection of mucosal surfaces, we previously developed an intranasal vaccine based on replication-competent human parainfluenza virus type 3 (HPIV3) expressing EBOV glycoprotein GP (HPIV3/EboGP) and showed that it is immunogenic and protective against a high dose parenteral EBOV challenge. However, because the adult human population has considerable immunity to HPIV3, which is a common human pathogen, replication and immunogenicity of the vaccine in this population might be greatly restricted. Indeed, in the present study, replication of the vaccine in the respiratory tract of HPIV3-immune guinea pigs was found to be restricted to undetectable levels. This restriction appeared to be based on both neutralizing antibodies and cellular or other components of the immunity to HPIV3. Surprisingly, even though replication of HPIV3/EboGP was highly restricted in HPIV3-immune animals, it induced a high level of EBOV-specific antibodies that nearly equaled that obtained in HPIV3-naive animals. We also show that the previously demonstrated presence of functional GP in the vector particle was not associated with increased replication in the respiratory tract nor with spread beyond the respiratory tract of HPIV3-naive guinea pigs, indicating that expression and functional incorporation of the attachment/penetration glycoprotein of this systemic virus did not mediate a change in tissue tropism. Published by Elsevier Inc. C1 [Yang, Lijuan; Murphy, Brian R.; Collins, Peter L.; Bukreyev, Alexander] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Sanchez, Anthony] Ctr Dis Control & Prevent, Special Pathogens Branch, Div Viral & Rickettsial Dis, Atlanta, GA 30333 USA. [Ward, Jerrold M.] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6505,50 S Dr,MSC 8007, Bethesda, MD 20892 USA. EM ab176v@nih.gov FU Intramural NIH HHS [Z99 AI999999, Z01 AI000938-04] NR 42 TC 20 Z9 24 U1 1 U2 6 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 AUG 1 PY 2008 VL 377 IS 2 BP 255 EP 264 DI 10.1016/j.virol.2008.04.029 PG 10 WC Virology SC Virology GA 320HE UT WOS:000257223500005 PM 18570964 ER PT J AU Vasilakis, N Fokam, EB Hanson, CT Weinberg, E Sall, AA Whitehead, SS Hanley, KA Weaver, SC AF Vasilakis, Nikos Fokam, Eric B. Hanson, Christopher T. Weinberg, Ethan Sall, Amadou A. Whitehead, Stephen S. Hanley, Kathryn A. Weaver, Scott C. TI Genetic and phenotypic characterization of sylvatic dengue virus type 2 strains SO VIROLOGY LA English DT Review DE dengue virus (DENV); sylvatic DENV; endemic DENV; phylogenetic and phenotypic analysis ID WEST-NILE-VIRUS; YELLOW-FEVER VIRUS; CLINICAL LABORATORY RESPONSES; JAPANESE ENCEPHALITIS-VIRUS; RNA SECONDARY STRUCTURE; 3' UNTRANSLATED REGION; STEM-LOOP STRUCTURE; ENVELOPE PROTEIN; FLAVIVIRUS RNA; 3'-NONCODING REGION AB The four serotypes of endemic dengue viruses (DENV) circulate between humans and peridomestic Aedes mosquitoes. At present endemic DENV infect 100 million people per year, and a third of the global population is at risk. In contrast, sylvatic DENV strains are maintained in a transmission cycle between nonhuman primates and sylvatic Aedes species, and are evolutionarily and ecologically distinct from endemic DENV strains. Phylogenetic analyses place sylvatic strains basal to each of the endemic serotypes, supporting the hypothesis that each of the endemic DENV sercitypes emerged independently from sylvatic ancestors. We utilized complete genome analyses of both sylvatic and endemic DENV serotype 2 (DENV-2) to expand our understanding of their genetic relationships. A high degree of conservation was observed in both the 5'- and 3'-untranslated genome regions, whereas considerable differences at the nucleotide and amino acid levels were observed within the open reading frame. Additionally, replication of the two genotypes was compared in cultured cells, where endemic DENV strains produced a significantly higher output of progeny in human liver cells, but not in monkey kidney or mosquito cells. Understanding the genetic relationships and phenotypic differences between endemic and sylvatic DENV genotypes may provide valuable insight into DENV emergence and guide monitoring of future outbreaks. (C) 2008 Elsevier Inc. All rights reserved. C1 [Vasilakis, Nikos; Weaver, Scott C.] Univ Texas Galveston, Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [Vasilakis, Nikos; Weaver, Scott C.] Univ Texas Galveston, Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Fokam, Eric B.] Univ Buea, Dept Bot & Zool, Buea, Cameroon. [Hanson, Christopher T.; Weinberg, Ethan; Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Sall, Amadou A.] Inst Pasteur, Dakar, Senegal. [Hanley, Kathryn A.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. RP Weaver, SC (reprint author), Univ Texas Galveston, Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. EM vasilan@pitt.edu; sweaver@utmb.edu RI Weaver, Scott/D-6490-2011; OI Weinberg, Ethan/0000-0002-5605-8995 FU Intramural NIH HHS; NCRR NIH HHS [P20 RR016480, P20 RR016480-05, P20 RR016480-055560]; PHS HHS [T01/CCT622892] NR 108 TC 35 Z9 36 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 AUG 1 PY 2008 VL 377 IS 2 BP 296 EP 307 DI 10.1016/j.virol.2008.04.044 PG 12 WC Virology SC Virology GA 320HE UT WOS:000257223500010 PM 18570968 ER PT J AU Berkower, I Patel, C Ni, YS Virnik, K Xiang, ZX Spadaccini, A AF Berkower, Ira Patel, Chiraag Ni, Yisheng Virnik, Konstantin Xiang, Zhexin Spadaccini, Angelo TI Targeted deletion in the beta 20-beta 21 loop of HIV envelope glycoprotein gp120 exposes the CD4 binding site for antibody binding SO VIROLOGY LA English DT Article DE HIV; envelope glycoprotein gp120; neutralizing antibodies; CD4 binding site; targeted deletion ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; RECEPTOR-BINDING; NEUTRALIZING ANTIBODIES; CD4-BOUND STATE; EPITOPE; IMMUNOGENICITY; RECOGNIZES; REGIONS; VACCINE AB Different isolates of HIV-1 are known to vary in antibody binding and sensitivity to neutralization. In response to selective pressure, the virus may conceal important neutralizing determinants, such as the CD4 binding site on gp120, through steric hindrance or conformational masking. The 3D structure of gp120 shows five loop structures that surround the CD4 binding site (CD4BS) and may restrict antibody access to the site. We have generated gp120 mutants lacking each of these loops and characterized them with a panel of monoclonal antibodies, including b12 and F105. A targeted deletion in the beta 20-beta 21 loop resulted in gp120 with enhanced binding of both monoclonals. Enhancement of b12 binding suggests reduced steric hindrance, since the antibody is relatively insensitive to conformation. Enhanced binding of F105, which depends strongly on the protein conformation, suggests that the mutation may allow gp120 to move more freely into the liganded form. The same viral strategies that limit antibody binding may also inhibit antibody induction. Modified forms of gp120, in which the CD4 binding site is more exposed and accessible to antibodies, could provide novel immunogens for eliciting antibodies to this broadly shared neutralizing determinant. Published by Elsevier Inc. C1 [Berkower, Ira; Patel, Chiraag; Ni, Yisheng; Virnik, Konstantin; Spadaccini, Angelo] US FDA, Immunoregulat Lab, DVP, Off Vaccine Res & Review,Ctr Biol, Bethesda, MD 20892 USA. [Xiang, Zhexin] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol,DHHS, Bethesda, MD 20892 USA. RP Berkower, I (reprint author), US FDA, Immunoregulat Lab, DVP, Off Vaccine Res & Review,Ctr Biol, Bldg 29,Room 523,NIH Campus, Bethesda, MD 20892 USA. EM ira.berkower@fda.hhs.gov FU Intramural NIH HHS NR 52 TC 12 Z9 13 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 AUG 1 PY 2008 VL 377 IS 2 BP 330 EP 338 DI 10.1016/j.virol.2008.0:3.040 PG 9 WC Virology SC Virology GA 320HE UT WOS:000257223500013 PM 18519142 ER PT J AU Sheliga, BM FitzGibbon, EJ Miles, FA AF Sheliga, B. M. FitzGibbon, E. J. Miles, F. A. TI Spatial summation properties of the human ocular following response (OFR): Evidence for nonlinearities due to local and global inhibitory interactions SO VISION RESEARCH LA English DT Article DE visual motion; winner-take-all; normalization ID VERGENCE EYE-MOVEMENTS; CORTICAL AREA MST; TRANSPARENT MOTION PERCEPTION; TEMPORAL VISUAL AREA; TAKE-ALL MECHANISM; SHORT-LATENCY; RECEPTIVE-FIELDS; BINOCULAR DISPARITY; NEURONAL-ACTIVITY; MACAQUE MONKEY AB Ocular following responses (OFRs) are the initial tracking eye movements that can be elicited at ultra-short latency by sudden motion of a textured pattern. A recent study used motion stimuli consisting of two large coextensive sine-wave gratings with the same orientation but different spatial frequency and moving in 1/4-wavelength steps in the same or opposite directions: when the two gratings differed in contrast by more than about an octave then the one with the higher contrast completely dominated the OFR and the one with lower contrast lost its influence as though suppressed [Sheliga, B. M., Kodaka, Y., FitzGibbon, E. J., & Miles, F. A. (2006). Human ocular following initiated by competing image motions: Evidence for a winner-take-all mechanism. Vision Research, 46, 2041-2060]. This winner-take-all (WTA) outcome was attributed to nonlinear interactions in the form of mutual inhibition between the mechanisms sensing the competing motions. In the present study, we recorded the initial horizontal OFRs to the horizontal motion of two vertical sine-wave gratings that differed in spatial frequency and were each confined to horizontal strips that extended the full width of our display (45 degrees) but were only 1-2 degrees high. The two gratings could be coextensive or separated by a vertical gap of up to 8 degrees, and each underwent motion consisting of successive 1/4-wavelength steps. Initial OFRs showed strong dependence on the relative contrasts of the competing gratings and when these were coextensive this dependence was always highly nonlinear (WTA), regardless of whether the two gratings moved in the same or opposite direction. When the two gratings moved in opposite directions the nonlinear interactions were purely local: with a vertical gap of 1 degrees or more between the gratings OFRs approximated the linear sum of the responses to each grating alone. On the other hand, when the two gratings moved in the same direction the nonlinear interactions were more global: even with a gap of 8 degrees-the largest separation tried-OFRs were still substantially less than predicted by the linear sum. When the motions were in the same direction, we postulate two nonlinear interactions: local mutual inhibition (resulting in WTA) and global divisive inhibition (resulting in normalization). Motion stimuli whose responses were totally suppressed by coextensive opponent motion of higher contrast were rendered invisible to normalization, suggesting that the local interactions responsible for the WTA behavior here occur at an earlier stage of neural processing than the global interactions responsible for normalization. Published by Elsevier Ltd. C1 [Sheliga, B. M.; FitzGibbon, E. J.; Miles, F. A.] NEI, Sensorimotor Res Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Sheliga, BM (reprint author), NEI, Sensorimotor Res Lab, Natl Inst Hlth, Bldg 49 Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM bms@lsr.nei.nih.gov FU Intramural NIH HHS [Z01 EY000153-24] NR 68 TC 14 Z9 14 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD AUG PY 2008 VL 48 IS 17 BP 1758 EP 1776 DI 10.1016/j.visres.2008.05.017 PG 19 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 334SB UT WOS:000258240400002 PM 18603279 ER PT J AU Baker, CI Dilks, DD Peli, E Kanwisher, N AF Baker, Chris I. Dilks, Daniel D. Peli, Eli Kanwisher, Nancy TI Reorganization of visual processing in macular degeneration: Replication and clues about the role of foveal loss SO VISION RESEARCH LA English DT Article DE V1; cortical reorganization; fMRI; cortical plasticity; deprivation ID SCANNING LASER OPHTHALMOSCOPE; SURFACE-BASED ANALYSIS; CORTICAL REORGANIZATION; RESTRICTED DEAFFERENTATION; MAP REORGANIZATION; RETINAL LOCATION; DIGIT AMPUTATION; STRIATE CORTEX; ADULT MONKEYS; LESIONS AB We previously reported large-scale reorganization of visual processing (i.e., activation of "foveal" cortex by peripheral stimuli) in two individuals with loss of foveal input from macular degeneration [Baker, C.I., Peli, E., Knouf, N., & Kanwisher, N. G. (2005). Reorganization of visual processing in macular degeneration. Journal of Neuroscience, 25(3), 614-618]. Here, we replicate this result in three new individuals. Further, we test the hypothesis that this reorganization is dependent on complete loss of foveal input. In two other individuals with extensive retinal lesions but some foveal sparing we found no evidence for reorganization. We conclude that large-scale reorganization of visual processing in MD occurs only in the complete absence of functional foveal vision. Published by Elsevier Ltd. C1 [Baker, Chris I.] NIMH, NIH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Dilks, Daniel D.; Kanwisher, Nancy] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Dilks, Daniel D.; Kanwisher, Nancy] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Peli, Eli] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Kanwisher, Nancy] MGH, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02129 USA. RP Baker, CI (reprint author), NIMH, NIH, Lab Brain & Cognit, 10 Ctr Dr,Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM bakerchris@mail.nih.gov; dilks@mit.edu OI Baker, Chris/0000-0001-6861-8964 FU NIH [EY016559, EY005957]; Kirschstein-NRSA [EY017507] FX We express our sincere thanks to the participants with macular degeneration. We also thank the Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, MIT, Cambridge, MA, and the Martinos Center for Biomedical Imaging, Charlestown, MA. This work was supported by NIH grants EY016559 (N.K.), EY005957 (E.P.), a Kirschstein-NRSA EY017507 (D.D.D.), and by Dr. and Mrs. Joseph Byrne. NR 33 TC 68 Z9 70 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD AUG PY 2008 VL 48 IS 18 BP 1910 EP 1919 DI 10.1016/j.visres.2008.05.020 PG 10 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 339EE UT WOS:000258560100007 PM 18620725 ER PT J AU Huter, EN Stummvoll, GH Shevach, EM AF Huter, E. N. Stummvoll, G. H. Shevach, E. M. TI Antigen-specific TGF beta-induced Treg suppress Th17-mediated autoimmune disease SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Huter, E. N.; Shevach, E. M.] NIAID, Bethesda, MD 20892 USA. [Stummvoll, G. H.] Med Univ Vienna, Dept Rheumatol, Vienna, Austria. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD AUG PY 2008 VL 120 SU 1 BP 6 EP 6 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 350QB UT WOS:000259367100013 ER PT J AU Flatz, L Hegazy, AN Verschoor, A Bergthaler, A Lohning, M Pinschewer, DD AF Flatz, L. Hegazy, A. N. Verschoor, A. Bergthaler, A. Loehning, M. Pinschewer, D. D. TI Propagation-deficient LCMV-derived vaccine vector efficiently targets dendritic cells to induce potent T and B cell responses against immunogens of choice SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Flatz, L.; Bergthaler, A.; Pinschewer, D. D.] Dept Pathol & Immunol, Geneva, Switzerland. [Flatz, L.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Hegazy, A. N.; Verschoor, A.; Bergthaler, A.; Loehning, M.; Pinschewer, D. D.] Univ Zurich, Inst Expt Immunol, CH-8091 Zurich, Switzerland. [Hegazy, A. N.; Loehning, M.] Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD AUG PY 2008 VL 120 SU 1 BP 19 EP 19 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 350QB UT WOS:000259367100055 ER PT J AU Wiege, K Ali, SR Konrad, S Piekorz, R Gohla, A Nurnberg, B Birnbaumer, L Schmidt, RE Gessner, JE AF Wiege, K. Ali, S. R. Konrad, S. Piekorz, R. Gohla, A. Nuernberg, B. Birnbaumer, L. Schmidt, R. E. Gessner, J. E. TI A specific role for Ga(i2) in innate immune cell migration during homeostasis and inflammation SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Wiege, K.; Konrad, S.; Schmidt, R. E.; Gessner, J. E.] Clin Immunol & Rheumatol, Hannover, Germany. [Ali, S. R.] Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92103 USA. [Gohla, A.; Nuernberg, B.] Uni Kliniken Dusseldorf, Inst Biochem & Mol Biol 2, Dusseldorf, Germany. [Birnbaumer, L.] Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC USA. RI ali, syed/J-6124-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD AUG PY 2008 VL 120 SU 1 BP 100 EP 100 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 350QB UT WOS:000259367100323 ER PT J AU Prots, I Skapenko, A Lipsky, PE Schulze-Koops, H AF Prots, I. Skapenko, A. Lipsky, P. E. Schulze-Koops, H. TI The neuropeptide npT1 is specifically expressed in human CD25+ regulatory T cells SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Prots, I.; Skapenko, A.; Schulze-Koops, H.] Univ Munich, Med Poliklin, Div Rheumatol, D-8000 Munich, Germany. [Lipsky, P. E.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD AUG PY 2008 VL 120 SU 1 BP 174 EP 174 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 350QB UT WOS:000259367100569 ER PT J AU Suzman, DL McLaughlin, M Hu, ZH Kleiner, DE Wood, B Lempicki, RA Mican, JM Suffredini, A Masur, H Polis, MA Kottilil, S AF Suzman, Daniel L. McLaughlin, Mary Hu, Zonghui Kleiner, David E. Wood, Brad Lempicki, Richard A. Mican, JoAnn M. Suffredini, Anthony Masur, Henry Polis, Michael A. Kottilil, Shyam TI Identification of novel markers for liver fibrosis in HIV/hepatitis C virus coinfected individuals using genomics-based approach SO AIDS LA English DT Article; Proceedings Paper CT 14th Conference on Retroviruses and Opportunistic Infections CY FEB 25-28, 2007 CL Los Angeles, CA DE biopsy; genomics; hepatitis C virus; HIV; liver fibrosis ID CHRONIC HEPATITIS-C; AMINOPEPTIDASE-N; HIV COINFECTION; INFECTED PATIENTS; EXPRESSION; PROGRESSION; PREDICTION; CIRRHOSIS; THERAPY; IMPACT AB Objective: The degree of liver fibrosis is a determinant for initiation of therapy for hepatitis C virus. Liver biopsy is invasive, risky and costly, but is required to assess fibrosis. This study intended to identify novel noninvasive markers to accurately assess fibrosis in HIV/hepatitis C virus coinfection. Methods: Using 100 biopsies from 68 HIV/hepatitis C virus coinfected patients, we developed a predictive model consisting of six serum markers along with age and antiretroviral therapy experience. DNA microarray analysis of peripheral blood mononuclear cells associated with a subset of 51 biopsies obtained from 28 patients was performed and incorporated into a second model. Results: The eight-marker model yielded an area under the receiver operating characteristic curve of 0.904. Combined analysis of clinical and DNA microarray data in the 51-biopsy subset identified two genes (alanine amino peptidase-N and mitogen-activated protein kinase kinase-3) that predicted fibrosis with high significance. The four-marker model that included the two genes and two serum markers had an area under the receiver operating characteristic curve of 0.852, which did not differ significantly from the eight-marker model on this subset (area under the receiver operating characteristic curve = 0.856, P = 0.96). Conclusion: Both models accurately predicted fibrosis with an accuracy of 87.9%, thereby sparing 83% of patients from obtaining a biopsy. DNA microarray analysis can be invaluable in identifying novel biomarkers of liver fibrosis. (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Suzman, Daniel L.; McLaughlin, Mary; Lempicki, Richard A.; Mican, JoAnn M.; Polis, Michael A.; Kottilil, Shyam] NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. [Hu, Zonghui] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, NIH, Bethesda, MD 20892 USA. [Wood, Brad] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Suffredini, Anthony; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), Bldg 10 Magnuson CC,11N204 10 Ctr Dr, Bethesda, MD USA. EM skottilil@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268; Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS [Z01 AI000390-24] NR 27 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2008 VL 22 IS 12 BP 1433 EP 1439 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 331YI UT WOS:000258048100006 PM 18614866 ER PT J AU Dror, O Schneidman-Duhovny, D Shulman-Peleg, A Nussinov, R Wolfson, HJ Sharan, R AF Dror, Oranit Schneidman-Duhovny, Dina Shulman-Peleg, Alexandra Nussinov, Ruth Wolfson, Haim J. Sharan, Roded TI Structural similarity of genetically interacting proteins SO BMC SYSTEMS BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; YEAST; NETWORKS; EVOLUTIONARY; SEQUENCES; ALIGNMENT; DATABASE; GENOME AB Background: The study of gene mutants and their interactions is fundamental to understanding gene function and backup mechanisms within the cell. The recent availability of large scale genetic interaction networks in yeast and worm allows the investigation of the biological mechanisms underlying these interactions at a global scale. To date, less than 2% of the known genetic interactions in yeast or worm can be accounted for by sequence similarity. Results: Here, we perform a genome-scale structural comparison among protein pairs in the two species. We show that significant fractions of genetic interactions involve structurally similar proteins, spanning 7-10% and 14% of all known interactions in yeast and worm, respectively. We identify several structural features that are predictive of genetic interactions and show their superiority over sequence-based features. Conclusion: Structural similarity is an important property that can explain and predict genetic interactions. According to the available data, the most abundant mechanism for genetic interactions among structurally similar proteins is a common interacting partner shared by two genetically interacting proteins. C1 [Dror, Oranit; Schneidman-Duhovny, Dina; Shulman-Peleg, Alexandra; Wolfson, Haim J.; Sharan, Roded] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM oranit@tau.ac.il; duhovka@tau.ac.il; shulmana@tau.ac.il; ruthn@ncifcrf.gov; wolfson@tau.ac.il; roded@tau.ac.il RI Wolfson, Haim/A-1837-2011 FU Alon Fellowship; Israeli Ministry of Science Eshkol Fellowship; Clore PhD Fellowship; Israel Science Foundation [281/05]; NIAID; NIH [1UC1AI067231]; Binational US-Israel Science Foundation (BSF); Hermann Minkowski-Minerva Center for Geometry at TAU; National Cancer Institute; National Institutes of Health [NO1-CO-12400]; Center for Cancer Research FX We thank Maxim Shatsky, Nir Yosef and Tomer Shlomi for their help with various stages of the analysis. RS was supported by an Alon Fellowship. The research of OD was supported by the Israeli Ministry of Science Eshkol Fellowship. The research of AS-P was supported by the Clore PhD Fellowship. The research of HJW has been supported in part by the Israel Science Foundation (grant no. 281/05), by the NIAID, NIH (grant No. 1UC1AI067231), by the Binational US-Israel Science Foundation (BSF) and by the Hermann Minkowski-Minerva Center for Geometry at TAU. This publication has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract NO1-CO-12400. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 26 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD JUL 31 PY 2008 VL 2 AR 69 DI 10.1186/1752-0509-2-69 PG 7 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 343RD UT WOS:000258870600001 PM 18671848 ER PT J AU Lee, KY Myung, KJ AF Lee, Kyoo-Young Myung, Kyungjae TI PCNA modifications for regulation of post-replication repair pathways SO MOLECULES AND CELLS LA English DT Review DE damage bypass; PCNA ubiquitination; post-replication repair; RAD6/RAD18 complex; template switching; translesion synthesis; UBC13/MMS2/RAD5 complex ID CELL NUCLEAR ANTIGEN; DNA-POLYMERASE-ETA; STALLED REPLICATION FORKS; THYMINE DIMER BYPASS; SACCHAROMYCES-CEREVISIAE; TRANSLESION SYNTHESIS; UBIQUITIN-BINDING; REV1 PROTEIN; DAMAGED DNA; XERODERMA-PIGMENTOSUM AB Stalled DNA replication forks activate specific DNA repair mechanism called post-replication repair (PRR) pathways that simply bypass DNA damage. The bypassing of DNA damage by PRR prevents prolonged stalling of DNA replication that could result in double strand breaks (DSBs). Proliferating cell nuclear antigen (PCNA) functions to initiate and choose different bypassing pathways of PRR. In yeast, DNA replication forks stalled by DNA damage induces monoubiquitination of PCNA at K164, which is catalyzed by Rad6/Rad18 complex. PCNA monoubiquitination triggers the replacement of replicative polymerase with special translesion synthesis (TLS) polymerases that are able to replicate past DNA lesions. The PCNA interaction motif and/or the ubiquitin binding motif in most TILS polymerases seem to be important for the regulation of TLS. The TLS pathway is usually error-prone because TILS polymerases; have low fidelity and no proofreading activity. PCNA can also be further polyubiquitinated by Ubc13/ Mms2/Rad5 complex, which adds an ubiquitin chain onto monoubiquitinated K164 of PCNA. PCNA polyubiquitination directs a different PRR pathway known as error-free damage avoidance, which uses the newly synthesized sister chromatid as a template to bypass DNA damage presumably through template switching mechanism. Mammalian homologues of all of the yeast PRR proteins have been identified, thus PRR is well conserved throughout evolution. Mutations of some PRR genes are associated with a higher risk for cancers in mice and human patients, strongly supporting the importance of PRR as a tumor suppressor pathway. C1 [Lee, Kyoo-Young; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, KJ (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM kmyung@nhgri.nih.gov FU Intramural NIH HHS [ZIA HG012003-08] NR 83 TC 75 Z9 76 U1 2 U2 4 PU KOREAN SOC MOLECULAR & CELLULAR BIOLOGY PI SEOUL PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD JUL 31 PY 2008 VL 26 IS 1 BP 5 EP 11 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 335YT UT WOS:000258332200002 PM 18525240 ER PT J AU Root, CM Masuyama, K Green, DS Enell, LE Nassel, DR Lee, CH Wang, JW AF Root, Cory M. Masuyama, Kaoru Green, David S. Enell, Lina E. Nassel, Dick R. Lee, Chi-Hon Wang, Jing W. TI A presynaptic gain control mechanism fine-tunes olfactory behavior SO NEURON LA English DT Article ID DROSOPHILA ANTENNAL LOBE; GABA(B) RECEPTORS; FLY BRAIN; SENSORY NEURONS; INFORMATION; INHIBITION; CALCIUM; MAP; REPRESENTATIONS; INTERNEURONS AB Early sensory processing can play a critical role in sensing environmental cues. We have investigated the physiological and behavioral function of gain control at-the first synapse of olfactory processing in Drosophila. Olfactory receptor neurons (ORNs) express the GABA(B) receptor (GABA(B)R), and its expression expands the dynamic range of ORN synaptic transmission that is preserved in projection neuron responses. Strikingly, each ORN channel has a unique baseline level of GABA(B)R expression. ORNs that sense the aversive odorant CO(2) do not express GABA(B)Rs and do not have significant pre-synaptic inhibition. In contrast, pheromone-sensing ORNs express a high level of GABA(B)Rs and exhibit strong presynaptic inhibition. Furthermore, pheromone-dependent mate localization is impaired in flies that lack GABA(B)Rs in specific ORNs. These findings indicate that different olfactory receptor channels employ heterogeneous presynaptic gain control as a mechanism to allow an animal's innate behavioral responses to match its ecological needs. C1 [Root, Cory M.; Masuyama, Kaoru; Green, David S.; Wang, Jing W.] Univ Calif San Diego, Neurobiol Sect, Div Biol Sci, La Jolla, CA 92093 USA. [Enell, Lina E.; Nassel, Dick R.] Stockholm Univ, Dept Zool, S-10691 Stockholm, Sweden. [Lee, Chi-Hon] NICHHD, NIH, Bethesda, MD 20892 USA. RP Wang, JW (reprint author), Univ Calif San Diego, Neurobiol Sect, Div Biol Sci, La Jolla, CA 92093 USA. EM jw800@ucsd.edu RI Wang, Jing/C-3885-2008; Lee, Chi-Hon/G-9190-2012; Marion-Poll, Frederic/D-8882-2011 OI Wang, Jing/0000-0001-6291-5802; Marion-Poll, Frederic/0000-0001-6824-0180 FU NIDCD NIH HHS [R01 DC009597, R01 DC009597-01, R01DC009597] NR 47 TC 156 Z9 157 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 31 PY 2008 VL 59 IS 2 BP 311 EP 321 DI 10.1016/j.neuron.2008.07.003 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 334WR UT WOS:000258252700015 PM 18667158 ER PT J AU Miki, T Zwingman, TA Wakamori, M Lutz, CM Cook, SA Hosford, DA Herrup, K Fletcher, CF Mori, Y Frankel, WN Letts, VA AF Miki, T. Zwingman, T. A. Wakamori, M. Lutz, C. M. Cook, S. A. Hosford, D. A. Herrup, K. Fletcher, C. F. Mori, Y. Frankel, W. N. Letts, V. A. TI Two novel alleles of tottering with distinct Ca(v)2.1 calcium channel neuropathologies SO NEUROSCIENCE LA English DT Article DE tottering alleles; Ca(v)2.1 calcium channels; semi-dominant mutation ID FAMILIAL HEMIPLEGIC MIGRAINE; EPISODIC ATAXIA TYPE-2; CORTICAL SPREADING DEPRESSION; CEREBELLAR PURKINJE-CELLS; CA2+ CHANNELS; TRANSMITTER RELEASE; MISSENSE MUTATION; MUTANT MOUSE; SYNAPTIC-TRANSMISSION; PROGRESSIVE ATAXIA AB The calcium channel CACNA1A gene encodes the pore-forming, voltage-sensitive subunit of the voltage-dependent calcium Ca(v)2.1 type channel. Mutations in this gene have been linked to several human disorders, including familial hemiplegic migraine, episodic ataxia 2 and spinocerebellar ataxia type 6. The mouse homologue, Cacna1a, is associated with the tottering, Cacna1a(tg), mutant series. Here we describe two new missense mutant alleles, Cacna1a(tg-4J) and Cacna1a(Tg-5J). The Cacna1a(tg-4J) mutation is a valine to alanine mutation at amino acid 581, in segment S5 of domain II. The recessive Cacna1a(tg-4J) mutant exhibited the ataxia, paroxysmal dyskinesia and absence seizures reminiscent of the original tottering mouse. The Cacna1a(tg-4J) mutant also showed altered activation and inactivation kinetics of the Ca(v)2.1 channel, not previously reported for other tottering alleles. The semi-dominant Cacna1a(tg-5J) mutation changed a conserved arginine residue to glutamine at amino acid 1252 within segment S4 of domain III. The heterozygous mouse was ataxic and homozygotes rarely survived. The Cacna1a(Tg-5J) mutation caused a shift in both voltage activation and inactivation to lower voltages, showing that this arginine residue is critical for sensing Ca(v)2.1 voltage changes. These two tottering mouse models illustrate how novel allelic variants can contribute to functional studies of the Ca(v)2.1 calcium channel. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Lutz, C. M.; Cook, S. A.; Frankel, W. N.; Letts, V. A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Miki, T.; Wakamori, M.; Mori, Y.] Kyoto Univ, Mol Biol Lab, Dept Synthet Chem & Biol Chem, Grad Sch Engn, Kyoto 6158510, Japan. [Zwingman, T. A.] Allen Inst Brain Sci, Seattle, WA 98103 USA. [Hosford, D. A.] Targacept Inc, Winston Salem, NC 27101 USA. [Herrup, K.] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA. [Fletcher, C. F.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Letts, VA (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM verity.letts@jax.org FU NCI NIH HHS [P30 CA034196, CA 34196]; NCRR NIH HHS [P40 RR001183, P40 RR 01183]; NINDS NIH HHS [R01 NS032801, NS 32801, R01 NS020591-25, R01 NS032801-13, R01 NS020591] NR 51 TC 26 Z9 26 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 JUL 31 PY 2008 VL 155 IS 1 BP 31 EP 44 DI 10.1016/j.neuroscience.2008.05.028 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 334WW UT WOS:000258253300005 PM 18597946 ER PT J AU Lisco, A Vanpouille, C AF Lisco, Andrea Vanpouille, Christophe TI HSV-2 suppression and the incidence of HIV SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Lisco, Andrea; Vanpouille, Christophe] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Lisco, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM liscoa@mail.nih.gov NR 2 TC 6 Z9 6 U1 0 U2 1 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 JUL 31 PY 2008 VL 359 IS 5 BP 535 EP 535 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 331VC UT WOS:000258039700027 PM 18669436 ER PT J AU Zhu, HH Yang, YR Zhang, H Han, Y Li, YF Zhang, Y Yin, DM He, QH Zhao, ZQ Blumberg, PM Han, JS Wang, Y AF Zhu, Haihao Yang, Yanrui Zhang, Hua Han, Yan Li, Yafang Zhang, Ying Yin, Dongmin He, Qihua Zhao, Zhiqi Blumberg, Peter M. Han, Jisheng Wang, Yun TI Interaction between protein kinase D1 and transient receptor potential V1 in primary sensory neurons is involved in heat hypersensitivity SO PAIN LA English DT Article DE protein kinase D1 (PKD1); transient receptor potential V1 (TRPV1); inflammatory heat hypersensitivity; gene delivery; intrathecal injection ID DORSAL-ROOT GANGLIA; RAT SPINAL-CORD; NF-KAPPA-B; PERIPHERAL INFLAMMATION; PAIN HYPERSENSITIVITY; VANILLOID RECEPTOR-1; CAPSAICIN RECEPTOR; NEUROPATHIC PAIN; IN-VIVO; C-MU AB In previous studies we demonstrated that protein kinase D1 (PKD1/PKC mu) Could directly phosphorylate the transient receptor potential V1 (TRPV1) at its N-terminal region and enhance the function of TRPV1 in CHO cells stably transfected with TRPV1. In the Current study we assessed the involvement of PKD1 in pain modulation and explored the possible interaction between PKD1 and TRPV1 in rat inflammatory heat hypersensitivity. PKD1 was translocated to cytoplasmic membrane fraction and was trans-phosphorylated only in membrane fraction but not in cytoplasmic fraction of dorsal root ganglia (DRG) at 2 and 6 h after Complete Freund's Adjuvant (CFA) treatment. Pre i.t. injection of PKD1 antisense for 4 d or post-i.t. injection for 4 d both alleviated CFA-induced thermal hypersensitivity. Likewise. overexpression of PKD1 in DRG significantly enhanced. while dominant negative PKD1 (DN-PKD1) partly attenuated. heat hypersensitivity. Both PKD1 and TRPV1 were translocated to the cytoplasmic membrane in DRG 6 h after CFA treatment and. at that time. PKID1 interacted with TRPV1 by co-immunoprecipitation in DRG. Electrophysiological measurements indicated that DRG with overexpression of PKID1 were more sensitive to low dose capsaicin than those expressing DN-PKD1. The average magnitude of the peak inward current evoked by capsaicin was greater in the DRG over-expressing PKD1 than in those expressing DN-PKD1. Furthermore. overexpressed PKD1 could up regulate. whereas PKD1 antisense could knock down TRPV1 content in DRG through posttranscriptional regulation manner. We concluded that PKD1 in DRG, through interaction with TRPV1. is involved in developing and maintaining inflammatory heat hypersensitivity. (C) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Zhu, Haihao; Yang, Yanrui; Han, Yan; Li, Yafang; Zhang, Ying; Yin, Dongmin; Han, Jisheng; Wang, Yun] Peking Univ, Neurosci Res Inst, Beijing 100083, Peoples R China. [Zhu, Haihao; Yang, Yanrui; Han, Yan; Li, Yafang; Zhang, Ying; Yin, Dongmin; Han, Jisheng; Wang, Yun] Peking Univ, Dept Neurobiol, Key Lab Neurosci, Beijing 100083, Peoples R China. [Zhang, Hua; Zhao, Zhiqi] Fudan Univ, Inst Neurobiol, Shanghai 200433, Peoples R China. [He, Qihua] Peking Univ, Healthy Analyt Ctr, Beijing 100871, Peoples R China. [Blumberg, Peter M.] NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. RP Wang, Y (reprint author), Peking Univ, Neurosci Res Inst, 38 Xueyuan Rd, Beijing 100083, Peoples R China. EM wangy66@bjmu.edu.cn RI Han, Yan/G-6027-2014 FU Intramural NIH HHS NR 39 TC 7 Z9 10 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL 31 PY 2008 VL 137 IS 3 BP 574 EP 588 DI 10.1016/j.pain.2007.10.025 PG 15 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 336JG UT WOS:000258359500016 PM 18063480 ER PT J AU Thiriet, N Amar, L Toussay, X Lardeux, V Ladenheim, B Becker, KG Cadet, JL Solinas, M Jaber, M AF Thiriet, Nathalie Amar, Lahouari Toussay, Xavier Lardeux, Viryinie Ladenheim, Bruce Becker, Kevin G. Cadet, Jean Lud Solinas, Marcello Jaber, Mohamed TI Environmental enrichment during adolescence regulates gene expression in the striatum of mice SO BRAIN RESEARCH LA English DT Article DE cDNA array; real time-PCR; western blot; PKC; epigenetic; dopamine; environmental enrichment ID PROTEIN-KINASE-C; STRUCTURAL-CHANGES; NUCLEUS-ACCUMBENS; CEREBRAL-CORTEX; BRAIN; MOUSE; PLASTICITY; RATS; NEURONS; COCAINE AB We have previously shown that environmental enrichment decreases the activating and rewarding effects of the psychostimulant cocaine and increases resistance to the neurotoxic effect of the Parkinson-inducing drug MPTP. These effects were accompanied by an increase in the striatal expression of the neurotrophin BDNF, an increase in the striatal levels of delta-Fos B and by a decrease in striatal levels of the dopamine transporter, the main molecular target for cocaine and MPTP. Here, we used cDNA arrays to investigate the effects of rearing mice in enriched environments from weaning to adulthood on the profile of expression of genes in the striatum focusing on genes involved in intracellular signalling and functioning. We found that mice reared in an enriched environment show several alterations in the levels of mRNA coding for proteins involved in cell proliferation, cell differentiation, signal transduction, transcription and translation, cell structure and metabolism. Several of these findings were further confirmed by real-time quantitative PCR and, in the case of protein kinase C lambda, also by western blot. These findings are the first description of alterations in striatal gene expression by an enriched environment. The striatal gene expression regulation by environment that we report here may play a role in the resistance to the effects of drugs of abuse and dopaminergic neurotoxins previously reported. (C) 2008 Elsevier B.V. All rights reserved. C1 [Thiriet, Nathalie; Amar, Lahouari; Toussay, Xavier; Lardeux, Viryinie; Solinas, Marcello; Jaber, Mohamed] Univ Poitiers, Inst Biol & Physiol Cellulaires, CNRS, UMR 6187, F-86022 Poitiers, France. [Becker, Kevin G.] NIA, Res Resources Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Ladenheim, Bruce; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Jaber, M (reprint author), Univ Poitiers, Inst Biol & Physiol Cellulaires, CNRS, UMR 6187, 40 Ave Recteur Pineau, F-86022 Poitiers, France. EM mohamed.jaber@univ-poitiers.fr RI Solinas, Marcello/M-3500-2016; OI Solinas, Marcello/0000-0002-0664-5964; Becker, Kevin/0000-0002-6794-6656 FU CNRS; Poitiers University; Fondation pour la Recherche Medicale; MILDT-INSERM; Region Poitou Charentes; DHHS/NIH NIA; NIDA FX This work was supported by the CNRS, Poitiers University, Fondation pour la Recherche Medicale (2003), MILDT-INSERM (2006-2007), Region Poitou Charentes (2006), and the Intramural Research programs of the DHHS/NIH NIA and NIDA. NR 58 TC 28 Z9 28 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 30 PY 2008 VL 1222 BP 31 EP 41 DI 10.1016/j.brainres.2008.05.030 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 338XB UT WOS:000258541600003 PM 18585688 ER PT J AU Nakaya, N Lee, HS Takada, Y Tzchori, I Tomarev, SI AF Nakaya, Naoki Lee, Hee-Sheung Takada, Yuichiro Tzchori, Itai Tomarev, Stanislav I. TI Zebrafish olfactomedin 1 regulates retinal axon elongation In vivo and is a modulator of Wnt signaling pathway SO JOURNAL OF NEUROSCIENCE LA English DT Article DE eye development; axonal extension; neuronal differentiation; Wnt signaling; WIF-1; morpholino oligonucleotides ID CENTRAL-NERVOUS-SYSTEM; OPEN-ANGLE GLAUCOMA; EMBRYONIC EXPRESSION; GENE-EXPRESSION; NEURAL-TUBE; GLYCOPROTEIN; PROTEIN; FIELD; INTERACTS; MYOCILIN AB Olfactomedin 1 (Olfm1) is a secreted glycoprotein belonging to a family of olfactomedin domain-containing proteins. It is involved in the regulation of neural crest production in chicken and promotes neuronal differentiation in Xenopus. Here, we investigate the functions of Olfm1 in zebrafish eye development. Overexpression of full-length Olfm1, and especially its BMY form lacking the olfactomedin domain, increased the thickness of the optic nerve and produced a more extended projection field in the optic tectum compared with control embryos. In contrast, injection of olfm1-morpholino oligonucleotide (Olfm1-MO) reduced the eye size, inhibited optic nerve extension, and increased the number of apoptotic cells in the retinal ganglion cell and inner nuclear layers. Overexpression of full-length Olfm1 increased the lateral separation of the expression domains of eye-field markers, rx3 and six3. The Olfm1-MO had the opposite effect. These data suggest that zebrafish Olfm1 may play roles in the early eye determination, differentiation, optic nerve extension, and branching of the retinal ganglion cell axon terminals, with the N-terminal region of Olfm1 being critical for these effects. Injection of RNA encoding WIF-1, a secreted inhibitor of Wnt signaling, caused changes in the expression pattern of rx3 similar to those observed after Olfm1-MO injection. Simultaneous overexpression of WIF-1 and Olfm1 abolished the WIF-1 effect. Physical interaction of WIF-1 and Olfm1 was demonstrated by coimmunoprecipitation experiments. We concluded that Olfm1 serves as a modulator of Wnt signaling. C1 [Tomarev, Stanislav I.] NEI, NIH, Sect Mol Mech Glaucoma, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. [Takada, Yuichiro] Natl Inst Deafness & Other Commun Disorders, Sect Translat Res Retinal & Macular Degenerat, NIH, Bethesda, MD 20892 USA. [Tzchori, Itai] Natl Inst Child Hlth & Dev, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, NIH, Sect Mol Mech Glaucoma, Mol & Dev Biol Lab, Bldg 7,Room 103,7 Mem Dr,MSC 0704, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov FU Intramural NIH HHS [Z01 EY000311-12, Z01 EY000318-10, Z99 EY999999] NR 44 TC 25 Z9 26 U1 1 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 JUL 30 PY 2008 VL 28 IS 31 BP 7900 EP 7910 DI 10.1523/JNEUROSCI.0617-08.2008 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 332DG UT WOS:000258061600019 PM 18667622 ER PT J AU Chavez, AE Diamond, JS AF Chavez, Andres E. Diamond, Jeffrey S. TI Diverse mechanisms underlie glycinergic feedback transmission onto rod biopolar cells in rat retina SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amacrine; AMPA receptor; Ca2+-induced Ca2+ release; calcium channels; feedback; gap junction; glutamate receptor; glycine; interneuron; retina; retinal bipolar cell ID AMACRINE CELLS; BIPOLAR CELLS; CAT RETINA; GANGLION-CELLS; RABBIT RETINA; NMDA RECEPTORS; ACTION-POTENTIALS; MAMMALIAN RETINA; RIBBON SYNAPSE; OLFACTORY-BULB AB Synaptic inhibition shapes visual signaling in the inner retina, but the physiology of most amacrine cells, the interneurons that mediate this inhibition, is poorly understood. Discerning the function of most individual amacrine cell types is a daunting task, because few molecular or morphological markers specifically distinguish between approximately two dozen different amacrine cell types. Here, we examine a functional subset of amacrine cells by pharmacologically isolating glycinergic inhibition and evoking feedback IPSCs in a single cell type, the rod bipolar cell (RBC), with brief glutamate applications in the inner plexiform layer. We find that glycinergic amacrine cells innervating RBCs receive excitatory inputs from ON and OFF bipolar cells primarily via NMDA receptors (NMDARs) and Ca2+- impermeable AMPA-type glutamate receptors. Glycine release from amacrine cells is triggered by Ca2+ influx through both voltage-gated Ca2+ (Ca-v) channels and NMDARs. These intracellular Ca2+ signals are amplified by Ca2+-induced Ca2+ release via both ryanodine and IP3 receptors, which are activated independently by Ca2+ influx through Cav channels and NMDARs, respectively. Glycinergic feedback signaling depends strongly, although not completely, on voltage-gated Na+ channels, and the spatial extent of feedback inhibition is expanded by gap junction connections between glycinergic amacrine cells. These results indicate that a diversity of mechanisms underlie glycinergic feedback inhibition onto RBCs, yet they highlight several physiological themes that appear to distinguish amacrine cell function. C1 [Chavez, Andres E.; Diamond, Jeffrey S.] Natl Inst Neurol Disorders & Stroke, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Diamond, JS (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Physiol Sect, NIH, 35 Convent Dr,Bldg 35,Room 3C 1000, Bethesda, MD 20892 USA. EM diamondj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU Intramural NIH HHS [Z01 NS003039-01] NR 69 TC 21 Z9 21 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 30 PY 2008 VL 28 IS 31 BP 7919 EP 7928 DI 10.1523/JNEUROSCI.0784-08.2008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 332DG UT WOS:000258061600021 PM 18667624 ER PT J AU Johnston, J Iser, WB Chow, DK Goldberg, IG Wolkow, CA AF Johnston, Josiah Iser, Wendy B. Chow, David K. Goldberg, Ilya G. Wolkow, Catherine A. TI Quantitative Image Analysis Reveals Distinct Structural Transitions during Aging in Caenorhabditis elegans Tissues SO PLOS ONE LA English DT Article ID GENE-EXPRESSION PROFILE; TRANSCRIPTIONAL PROFILE; DROSOPHILA-MELANOGASTER; SELECTIVE ATTENTION; CALORIC RESTRICTION; MUSCLE STRENGTH; HEALTHY-MEN; C-ELEGANS; LIFE-SPAN; MORTALITY AB Aging is associated with functional and structural declines in many body systems, even in the absence of underlying disease. In particular, skeletal muscles experience severe declines during aging, a phenomenon termed sarcopenia. Despite the high incidence and severity of sarcopenia, little is known about contributing factors and development. Many studies focus on functional aspects of aging-related tissue decline, while structural details remain understudied. Traditional approaches for quantifying structural changes have assessed individual markers at discrete intervals. Such approaches are inadequate for the complex changes associated with aging. An alternative is to consider changes in overall morphology rather than in specific markers. We have used this approach to quantitatively track tissue architecture during adulthood and aging in the C. elegans pharynx, the neuromuscular feeding organ. Using pattern recognition to analyze aged-grouped pharynx images, we identified discrete step-wise transitions between distinct morphologies. The morphology state transitions were maintained in mutants with pharynx neurotransmission defects, although the pace of the transitions was altered. Longitudinal measurements of pharynx function identified a predictive relationship between mid-life pharynx morphology and function at later ages. These studies demonstrate for the first time that adult tissues undergo distinct structural transitions reflecting postdevelopmental events. The processes that underlie these architectural changes may contribute to increased disease risk during aging, and may be targets for factors that alter the aging rate. This work further demonstrates that pattern analysis of an image series offers a novel and generally accessible approach for quantifying morphological changes and identifying structural biomarkers. C1 [Johnston, Josiah; Goldberg, Ilya G.] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Iser, Wendy B.; Chow, David K.; Wolkow, Catherine A.] NIA, Lab Neurosci, Intramural Res Program, NIH, Baltimore, MD USA. RP Johnston, J (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM igg@nih.gov; wolkowca@grc.nia.nih.gov RI Goldberg, Ilya/H-5307-2011 OI Goldberg, Ilya/0000-0001-8514-6110 FU National Institute on Aging, National Institutes of Health; Ellison Medical Foundation [New Scholar in Aging Award] FX The Wolkow and Goldberg labs are funded by the National Institute on Aging as part of the National Institutes of Health Intramural Research Program. This work was also supported by a New Scholar in Aging Award from the Ellison Medical Foundation (C.A.W.). NR 35 TC 31 Z9 37 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 JUL 30 PY 2008 VL 3 IS 7 AR e2821 DI 10.1371/journal.pone.0002821 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420QM UT WOS:000264304300040 PM 18665238 ER PT J AU Lyon, JA Angov, E Fay, MP Sullivan, JS Girourd, AS Robinson, SJ Bergmann-Leitner, ES Duncan, EH Darko, CA Collins, WE Long, CA Barnwell, JW AF Lyon, Jeffrey A. Angov, Evelina Fay, Michael P. Sullivan, Joann S. Girourd, Autumn S. Robinson, Sally J. Bergmann-Leitner, Elke S. Duncan, Elizabeth H. Darko, Christian A. Collins, William E. Long, Carole A. Barnwell, John W. TI Protection Induced by Plasmodium falciparum MSP1(42) Is Strain-Specific, Antigen and Adjuvant Dependent, and Correlates with Antibody Responses SO PLOS ONE LA English DT Article AB Vaccination with Plasmodium falciparum MSP1(42)/complete Freund's adjuvant (FA) followed by MSP1(42)/incomplete FA is the only known regimen that protects Aotus nancymaae monkeys against infection by erythrocytic stage malaria parasites. The role of adjuvant is not defined; however complete FA cannot be used in humans. In rodent models, immunity is strain-specific. We vaccinated Aotus monkeys with the FVO or 3D7 alleles of MSP1(42) expressed in Escherichia coli or with the FVO allele expressed in baculovirus (bv) combined with complete and incomplete FA, Montanide ISA-720 (ISA-720) or AS02A. Challenge with FVO strain P. falciparum showed that suppression of cumulative day 11 parasitemia was strain-specific and could be induced by E. coli expressed MSP1(42) in combination with FA or ISA-720 but not with AS02A. The coli42-FVO antigen induced a stronger protective effect than the bv42-FVO antigen, and FA induced a stronger protective effect than ISA-720. ELISA antibody (Ab) responses at day of challenge (DOC) were strain-specific and correlated inversely with c-day 11 parasitemia (r = -0.843). ELISA Ab levels at DOC meeting a titer of at least 115,000 ELISA Ab units identified the vaccinees not requiring treatment (noTx) with a true positive rate of 83.3% and false positive rate of 14.3%. Correlation between functional growth inhibitory Ab levels (GIA) and cumulative day 11 parasitemia was weaker (r = -0.511), and was not as predictive for a response of noTx. The lowest false positive rate for GIA was 30% when requiring a true positive rate of 83.3%. These inhibition results along with those showing that antigen/FA combinations induced a stronger protective immunity than antigen/ISA-720 or antigen/AS02 combinations are consistent with protection as ascribed to MSP1-specific cytophilic antibodies. Development of an effective MSP1(42) vaccine against erythrocytic stage P. falciparum infection will depend not only on antigen quality, but also upon the selection of an optimal adjuvant component. C1 [Lyon, Jeffrey A.; Angov, Evelina; Girourd, Autumn S.; Robinson, Sally J.; Bergmann-Leitner, Elke S.; Duncan, Elizabeth H.; Darko, Christian A.] Walter Reed Army Inst Res, Div Malaria Vaccine Dev, Silver Spring, MD 20910 USA. [Fay, Michael P.] NIAID, NIH, Biostat Res Branch, Bethesda, MD USA. [Sullivan, Joann S.; Collins, William E.; Barnwell, John W.] CDC, Natl Ctr Zoonot, Vector Borne & Enter Dis, Div Parasit Dis, Malaria Branch, Atlanta, GA USA. [Long, Carole A.] NIAID, NIH, Dept Malaria & Vector Res, Bethesda, MD USA. RP Lyon, JA (reprint author), Walter Reed Army Inst Res, Div Malaria Vaccine Dev, Silver Spring, MD 20910 USA. EM evelina.angov@us.army.mil RI Bergmann-Leitner, Elke/B-3548-2011; OI Bergmann-Leitner, Elke/0000-0002-8571-8956; Fay, Michael P./0000-0002-8643-9625 FU U.S. Agency for International Development [936?6001, AAG-P- 00-98-00006, AAG-P-00-98-00005]; National Institutes of Health and Centers for Disease Control and Prevention [NIAID YIAI-0438-03/ CDC C100-042]; United States Army Medical Research and Materiel Command FX This work was supported by the U.S. Agency for International Development under project number 936?6001, award number AAG-P- 00-98-00006, and award number AAG-P-00-98-00005, by the National Institutes of Health and Centers for Disease Control and Prevention Interagency Agreement under grant number NIAID YIAI-0438-03/ CDC C100-042, and by the United States Army Medical Research and Materiel Command. NR 52 TC 54 Z9 55 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 30 PY 2008 VL 3 IS 7 AR e2830 DI 10.1371/journal.pone.0002830 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420QM UT WOS:000264304300049 PM 18665258 ER PT J AU Sen, J Jacobs, A Caffrey, M AF Sen, Jayita Jacobs, Amy Caffrey, Michael TI Role of the HIV gp120 conserved domain 5 in processing and viral entry SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; 44 KDA ECTODOMAIN; ENVELOPE GLYCOPROTEIN; SIV GP41; MUTATIONAL ANALYSIS; CRYSTAL-STRUCTURE; DISULFIDE BOND; TYPE-1 ENV; CORE; CLEAVAGE AB The importance of the HIV gp120 conserved domain 5 (gp120-C5) to envelope function has been examined by alanine scanning mutagenesis and subsequent characterization of the mutagenic effects on viral entry and envelope expression, processing, and incorporation, as well as gp120 association with gp41. With respect to the wild-type gp120, mutational effects on viral entry fall into three classes: (1) functional (V489A, E492A, P493A, T499A, K500A, K502A, R503A, R504A, V505A, and V506A; (2) nonfunctional (I491A, L494A, V496A, and P498A); (3) enhanced (K490A, G495A, and Q507A). The nonfunctionality of the mutants is attributed to a combination of deleterious effects on processing, gp120-gp41 association, and membrane fusion. In the case of the nonfunctional mutant P498A, the introduction of the SOS mutation (A501C/T601C) results in substantially increased envelope processing and a gain of function. The effects of the mutants are interpreted with respect to the structures of gp41 and gp120. The extent of sensitivity of gp120-C5 to alanine substitutions underscores the importance of this domain to envelope function and suggests that gp120-C5 is an attractive and novel target for future drug discovery efforts. C1 [Sen, Jayita; Caffrey, Michael] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Jacobs, Amy] NCI Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. RP Caffrey, M (reprint author), Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. EM caffrey@uic.edu FU NIAID NIH HHS [R01 AI47674] NR 31 TC 22 Z9 23 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 29 PY 2008 VL 47 IS 30 BP 7788 EP 7795 DI 10.1021/bi800227z PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 329IA UT WOS:000257860100004 PM 18597484 ER PT J AU Johnson, KJ Alexander, BH Doody, MM Sigurdson, AJ Linet, MS Spector, LG Hoffbeck, RW Simon, SL Weinstock, RM Ross, JA AF Johnson, K. J. Alexander, B. H. Doody, M. M. Sigurdson, A. J. Linet, M. S. Spector, L. G. Hoffbeck, R. W. Simon, S. L. Weinstock, R. M. Ross, J. A. TI Childhood cancer in the offspring born in 1921-1984 to US radiologic technologists SO BRITISH JOURNAL OF CANCER LA English DT Article DE radiation; in utero; preconception; malignancy; aetiology; risk factors ID ATOMIC-BOMB SURVIVORS; NON-HODGKINS-LYMPHOMA; UNITED-STATES; YOUNG-PEOPLE; IONIZING-RADIATION; PARENTAL EXPOSURE; LEUKEMIA; MORTALITY; HEALTH; CHILDREN AB We examined the risk of childhood cancer (< 20 years) among 105 950 offspring born in 1921-1984 to US radiologic technologist (USRT) cohort members. Parental occupational in utero and preconception ionising radiation (IR) testis or ovary doses were estimated from work history data, badge dose data, and literature doses ( the latter doses before 1960). Female and male RTs reported a total of III and 34 haematopoietic malignancies and 115 and 34 solid tumours, respectively, in their offspring. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression. Leukaemia (n = 63) and solid tumours (n= 115) in offspring were not associated with maternal in utero or preconception radiation exposure. Risks for lymphoma (n= 44) in those with estimated doses of < 0.2, 0.2-1.0, and > 1.0 mGy vs no exposure were non-significantly elevated with HRs of 2.3, 1.8, and 2.7. Paternal preconception exposure to estimated cumulative doses above the 95th percentile ( >= 82 mGy, n = 6 cases) was associated with a non-significant risk of childhood cancer of 1.8 ( 95% CI 0.7-4.6). In conclusion, we found no convincing evidence of an increased risk of childhood cancer in the offspring of RTs in association with parental occupational radiation exposure. C1 [Johnson, K. J.; Spector, L. G.; Ross, J. A.] Univ Minnesota, Dept Pediat, Div Epidemiol Clin Res, Minneapolis, MN 55455 USA. [Alexander, B. H.; Hoffbeck, R. W.] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN 55455 USA. [Doody, M. M.; Sigurdson, A. J.; Linet, M. S.; Simon, S. L.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Spector, L. G.; Ross, J. A.] Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. [Weinstock, R. M.] RTI, Rockville, MD 20852 USA. RP Ross, JA (reprint author), Univ Minnesota, Dept Pediat, Div Epidemiol Clin Res, 420 Delaware St SE,MMC 422, Minneapolis, MN 55455 USA. EM rossx014@umn.edu OI Spector, Logan/0000-0003-2516-0222 FU NCI NIH HHS [N01CP31018, T32 CA099936, N01-CP-51016] NR 37 TC 16 Z9 16 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 29 PY 2008 VL 99 IS 3 BP 545 EP 550 DI 10.1038/sj.bjc.6604516 PG 6 WC Oncology SC Oncology GA 332IR UT WOS:000258077200027 PM 18665174 ER PT J AU Xie, JP Wu, EQ Zheng, ZJ Sullivan, PW Zhan, L Labarthe, DR AF Xie, Jipan Wu, Eric Q. Zheng, Zhi-Jie Sullivan, Patrick W. Zhan, Lin Labarthe, Darwin R. TI Patient-reported health status in coronary heart disease in the United States - Age, sex, racial, and ethnic differences SO CIRCULATION LA English DT Article DE coronary disease; health status; disparities; quality of life ID QUALITY-OF-LIFE; CHD MORTALITY; US VALUATION; TRENDS; WOMEN; EQ-5D; DISPARITIES; MEN; RESPONSIVENESS; PREVENTION AB Background - Coronary heart disease ( CHD) affects 15.8 million Americans. However, data on the national impact of CHD on health-related quality of life, particularly among people of different age, sex, racial, and ethnic groups, are limited. Methods and Results - Using data from the 2000 and 2002 Medical Expenditure Panel Survey, we examined various measures of patient-reported health status, including health-related quality of life, in the CHD and non-CHD populations and differences in the measures among demographic subgroups. These measures included short-form generic measures ( Short Form 12; Mental Component Summary-12 and Physical Component Summary-12) and EuroQol Group measures (EQ-5D index and EQ visual analog scale). Ordinary least- squares regressions were used to adjust for sociodemographic characteristics, risk factors, comorbidities, and proxy report. The adjusted difference between the CHD and non-CHD populations was - 1.2 for Mental Component Summary- 12 ( 2.4% of the score in the non-CHD population), - 4.6 for Physical Component Summary-12 (9.2%), -0.04 for EQ-5D (4.6%), and - 7.3 for EQ visual analog scale ( 9.0%) ( all P < 0.05). Differences among demographic subgroups were observed. Particularly, compared with whites, the differences between CHD and non- CHD in blacks were bigger in all measures except Physical Component Summary- 12. A significantly bigger difference in Mental Component Summary- 12 also was observed among Hispanics compared with non- Hispanics. Conclusions - CHD is associated with significant impairment of health- related quality of life and other patient- reported health status in the US adult population. Differences in the impairment associated with CHD exist across different age, racial, and ethnic groups. In addition to preventing CHD, effective public health interventions should be aimed at improving health- related quality of life and perceived health status in the CHD population, especially the most vulnerable groups. C1 [Xie, Jipan; Labarthe, Darwin R.] Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Xie, Jipan] Northrop Grumman, Atlanta, GA USA. [Wu, Eric Q.] Anal Grp Inc, Boston, MA USA. [Zheng, Zhi-Jie] NHLBI, Div Applicat Res Discoveries, Bethesda, MD 20892 USA. [Sullivan, Patrick W.] Univ Colorado, Denver, CO 80202 USA. [Zhan, Lin] Univ Toledo, Toledo, OH 43606 USA. RP Xie, JP (reprint author), Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Mailstop K-47,4770 Buford Hwy NE, Atlanta, GA 30341 USA. EM jipan.xie@gmail.com NR 33 TC 70 Z9 74 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 29 PY 2008 VL 118 IS 5 BP 491 EP 497 DI 10.1161/CIRCULATIONAHA.107.752006 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 331EC UT WOS:000257994500006 PM 18625894 ER PT J AU Santra, S Korber, BT Muldoon, M Barouch, DH Nabel, GJ Gao, F Hahn, BH Haynes, BF Letvin, NL AF Santra, Sampa Korber, Bette T. Muldoon, Mark Barouch, Dan H. Nabel, Gary J. Gao, Feng Hahn, Beatrice H. Haynes, Barton F. Letvin, Norman L. TI A centralized gene-based HIV-1 vaccine elicits broad cross-clade cellular immune responses in rhesus monkeys SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE consensus gene; cytotoxic T lymphocyte ID CONSENSUS ENVELOPE GLYCOPROTEIN; SUBTYPE-B ENVELOPE; NEUTRALIZING ANTIBODIES; IMMUNOGENICITY; ANTIGENICITY; SELECTION; PROTEIN; GP120; AIDS AB one of the major challenges that must be met in developing an HIV-1 vaccine is devising a strategy to generate cellular immunity with sufficient breadth to deal with the extraordinary genetic diversity of the virus. Amino acids in the envelopes of viruses from the same clade can differ by >15%, and those from different clades can differ by >30%. It has been proposed that creating immunogens using centralized HIV-1 gene sequences might provide a practical solution to this problem. Such centralized genes can be generated by employing a number of different strategies: consensus, ancestral, or center of tree sequences. These computer-generated sequences are a shorter genetic distance from any two contemporary virus sequences than those contemporary sequences are from each other. The present study was initiated to evaluate the breadth of cellular immunity generated through immunization of rhesus monkeys with vaccine constructs expressing either an HIV-1 global consensus envelope sequence (CON-S) or a single patient isolate clade B envelope sequence (clade B). We show that vaccine immunogens expressing the single centralized gene COWS generated cellular immune responses with significantly increased breadth compared with immunogens expressing a wild-type virus gene. In fact, COWS immunogens elicited cellular immune responses to 3- to 4-fold more discrete epitopes of the envelope proteins from clades A, C, and G than did clade B immunogens. These findings suggest that immunization with centralized genes is a promising vaccine strategy for developing a global vaccine for HIV-1 as well as vaccines for other genetically diverse viruses. C1 [Letvin, Norman L.] Harvard Univ, Sch Med, Div Viral Pathogenesis, Beth Israel Deaconess Med Ctr,Dept Med, Boston, MA 02215 USA. [Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA. [Korber, Bette T.] Santa Fe Inst, Santa Fe, NM 87501 USA. [Muldoon, Mark] Univ Manchester, Sch Math, Manchester M60 1QD, Lancs, England. [Nabel, Gary J.] NIAID, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Hahn, Beatrice H.] Univ Alabama, Birmingham, AL 35294 USA. [Gao, Feng; Haynes, Barton F.] Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Div Viral Pathogenesis, Beth Israel Deaconess Med Ctr,Dept Med, RE113,POB 15732, Boston, MA 02215 USA. EM nietvin@bidmc.harvard.edu RI Muldoon, Mark/C-7505-2009; OI Muldoon, Mark/0000-0002-5004-7195; Korber, Bette/0000-0002-2026-5757 FU NIAID NIH HHS [N01AI30034, N01-AI30033, N01AI30033, N01-AI30034, P01 AI061734, N01AI60005, P01-AI61734] NR 24 TC 51 Z9 52 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 JUL 29 PY 2008 VL 105 IS 30 BP 10489 EP 10494 DI 10.1073/pnas.0803352105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 334GZ UT WOS:000258211600040 PM 18650391 ER PT J AU Girard, MP Bansal, GR Pedroza-Martins, L Dodet, B Mehra, V Schito, M Mathieson, B Delfraissy, JF Bradac, J AF Girard, Marc P. Bansal, Geetha R. Pedroza-Martins, Livia Dodet, Betty Mehra, Vijay Schito, Marco Mathieson, Bonnie Delfraissy, Jean-Francois Bradac, James TI Mucosal immunity and HIV/AIDS vaccines - Report of an International Workshop, 28-30 October 2007 SO VACCINE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTE; BLOOD MONONUCLEAR-CELLS; GASTROINTESTINAL-TRACT; ANTIBODY-RESPONSES; RHESUS MACAQUES; HIV-INFECTION; TRANSEPITHELIAL TRANSPORT; MALE CIRCUMCISION; TYPE-1 INFECTION AB In October 2007, a joint ANRS-NIH workshop was held on "Mucosal immunity and HIV/AIDS vaccines" in Veyrier-du-Lac, France. Goal of the meeting was to discuss recent developments in the understanding of viral entry and dissemination at mucosal surfaces, rationale for designing vaccines to elicit mucosal immune responses by various routes of immunization, and the types of immune responses elicited. Lessons were drawn from existing vaccines against viral mucosal infections, from the recent failure of the Merck Ad5/HIV vaccine and from attempts at mucosal immunization against SIV. This report Summarizes the main concepts and conclusions that came out of the meeting. C1 [Bansal, Geetha R.; Mehra, Vijay; Bradac, James] NIAID, DAIDS, NIH, Bethesda, MD 20892 USA. [Pedroza-Martins, Livia; Delfraissy, Jean-Francois] French Natl Agcy Res AIDS & Viral Hepatitis, ANRS, Paris, France. [Mathieson, Bonnie] NIH, Off AIDS Res, OAR, Bethesda, MD 20892 USA. [Schito, Marco] NIAID, Henry Jackson Fdn, DAIDS, NIH, Bethesda, MD 20892 USA. [Girard, Marc P.] Univ Paris 07, Paris, France. [Dodet, Betty] Dodetbiosci, Lyon, France. RP Girard, MP (reprint author), 39 Rue Seignemartin, F-69008 Lyon, France. EM marc.girard36@wanadoo.fr RI Pedroza-Martins, Livia/C-4258-2008 NR 67 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 29 PY 2008 VL 26 IS 32 BP 3969 EP 3977 DI 10.1016/j.vaccine.2008.04.051 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 339XP UT WOS:000258610900003 PM 18513838 ER PT J AU Hoshino, Y Pesnicak, L Dowdell, KC Lacayo, J Dudek, T Knipe, DM Straus, SE Cohen, JI AF Hoshino, Yo Pesnicak, Lesley Dowdell, Kennichi C. Lacayo, Juan Dudek, Timothy Knipe, David M. Straus, Stephen E. Cohen, Jeffrey I. TI Comparison of immunogenicity and protective efficacy of genital herpes vaccine candidates herpes simplex virus 2 dl5-29 and dl5-29-41L in mice and guinea pigs SO VACCINE LA English DT Article DE genital herpes; vaccine; HSV-2; dl5-29; vhs; dl5-29-41L; guinea pig; mouse; CD8(+) T cell; neutralizing antibody; SCID mouse; intracranial infection ID SIMPLEX-VIRUS TYPE-2; RECOMBINANT GLYCOPROTEIN; INFECTION; IMMUNIZATION; REACTIVATION; PROTEIN; MUTANT; TRIAL; ACQUISITION; LATENCY AB A replication-defective herpes simplex virus (HSV)-2 vaccine, dl5-29, which is deleted for two essential early genes, UL5 and UL29, is highly immunogenic and protective in mice and guinea pigs. In a prior study, a derivative of HSV-2 dl5-29 termed dl5-29-41L, which has an additional deletion in UL41 (that encodes the virion-host shut-off protein), was more immunogenic and protective against challenge with wild-type HSV-2 in mice when compared with dl5-29. To determine if deletion of UL41 improves the efficacy of dl5-29 in protecting guinea pigs from HSV-2, animals were immunized with dl5-29, dl5-29-41L, or PBS. The geometric mean neutralizing antibody titers from the dl5-29 and dl5-29-41L recipients were comparable (10(1.97) and 10(2.19), respectively, in = 0.15). After intravaginal challenge with wild-type HSV-2, the dl5-29-41L and dl5-29 recipients shed similar titers of HSV-2 from the vagina. Mean acute disease severity scores, numbers of recurrences during 3 months after infection, and latent viral loads in sacral ganglia were similar for dl5-29 and dl5-29-41L (all p values >0.05). dl5-29 and dl5-29-41L completely protected mice from lethal challenge with HSV-2 and induced virus-specific CD8(+) T cells in the spleens of the animals. Thus, dl5-29 was as immunogenic and protective as dl5-29-41L under these conditions. dl5-29 was at least 250,000-fold less virulent than parental virus by intracranial inoculation in healthy mice, and caused no disease in SCID mice. Both dl5-29-41L and dl5-29 are equally effective and immunogenic in guinea pigs, and dl5-29 is very safe in immunocompromised animals. Published by Elsevier Ltd. C1 [Hoshino, Yo; Pesnicak, Lesley; Dowdell, Kennichi C.; Lacayo, Juan; Straus, Stephen E.; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dudek, Timothy; Knipe, David M.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bldg 10,Room 11N234,10 Ctr Dr,MSC 1888, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; NIH [AI057552] FX We thank Gowtham Mahalingam for helping to evaluate guinea pigs and Kening Wang for helpful suggestions.; Funding: This study was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases and NIH grant AI057552 to D.M.K. NR 25 TC 26 Z9 28 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 JUL 29 PY 2008 VL 26 IS 32 BP 4034 EP 4040 DI 10.1016/j.vaccine.2008.05.022 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 339XP UT WOS:000258610900011 PM 18565628 ER PT J AU Krause, J Unger, T Nocon, A Malaspinas, AS Kolokotronis, SO Stiller, M Soibelzon, L Spriggs, H Dear, PH Briggs, AW Bray, SCE O'Brien, SJ Rabeder, G Matheus, P Cooper, A Slatkin, M Paabo, S Hofreiter, M AF Krause, Johannes Unger, Tina Nocon, Aline Malaspinas, Anna-Sapfo Kolokotronis, Sergios-Orestis Stiller, Mathias Soibelzon, Leopoldo Spriggs, Helen Dear, Paul H. Briggs, Adrian W. Bray, Sarah C. E. O'Brien, Stephen J. Rabeder, Gernot Matheus, Paul Cooper, Alan Slatkin, Montgomery Paeaebo, Svante Hofreiter, Michael TI Mitochondrial genomes reveal an explosive radiation of extinct and extant bears near the Miocene-Pliocene boundary SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID PHYLOGENETIC TREE SELECTION; DNA-SEQUENCES; MAXIMUM-LIKELIHOOD; ANCIENT DNA; URSUS-ARCTOS; MULTIPLEX AMPLIFICATION; SUBSTITUTION RATES; MOLECULAR CLOCK; MIXED MODELS; BROWN BEARS AB Background: Despite being one of the most studied families within the Carnivora, the phylogenetic relationships among the members of the bear family (Ursidae) have long remained unclear. Widely divergent topologies have been suggested based on various data sets and methods. Results: We present a fully resolved phylogeny for ursids based on ten complete mitochondrial genome sequences from all eight living and two recently extinct bear species, the European cave bear (Ursus spelaeus) and the American giant short-faced bear (Arctodus simus). The mitogenomic data yield a well-resolved topology for ursids, with the sloth bear at the basal position within the genus Ursus. The sun bear is the sister taxon to both the American and Asian black bears, and this clade is the sister clade of cave bear, brown bear and polar bear confirming a recent study on bear mitochondrial genomes. Conclusion: Sequences from extinct bears represent the third and fourth Pleistocene species for which complete mitochondrial genomes have been sequenced. Moreover, the cave bear specimen demonstrates that mitogenomic studies can be applied to Pleistocene fossils that have not been preserved in permafrost, and therefore have a broad application within ancient DNA research. Molecular dating of the mtDNA divergence times suggests a rapid radiation of bears in both the Old and New Worlds around 5 million years ago, at the Miocene-Pliocene boundary. This coincides with major global changes, such as the Messinian crisis and the first opening of the Bering Strait, and suggests a global influence of such events on species radiations. C1 [Krause, Johannes; Unger, Tina; Nocon, Aline; Stiller, Mathias; Hofreiter, Michael] Max Planck Inst Evolutionary Anthropol, D-04103 Leipzig, Germany. [Malaspinas, Anna-Sapfo; Slatkin, Montgomery] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Kolokotronis, Sergios-Orestis] Columbia Univ, Dept Ecol Evolut & Environm Biol, New York, NY 10027 USA. [Kolokotronis, Sergios-Orestis] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA. [Soibelzon, Leopoldo] Museo La Plata, Dept Cient Paleontol Vertebrado, RA-1900 Buenos Aires, DF, Argentina. [Spriggs, Helen; Dear, Paul H.] MRC Lab Mol Biol, Cambridge CB2 2QH, England. [Bray, Sarah C. E.; Cooper, Alan] Univ Adelaide, Sch Earth & Environm Sci, Australian Ctr Ancient DNA, Adelaide, SA 5005, Australia. [O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Rabeder, Gernot] Univ Vienna, Dept Paleontol, A-1090 Vienna, Austria. [Matheus, Paul] Univ Alaska Fairbanks, Alaska Quaternary Ctr, Fairbanks, AK 99775 USA. RP Hofreiter, M (reprint author), Max Planck Inst Evolutionary Anthropol, Deutsch Pl 6, D-04103 Leipzig, Germany. EM krause@eva.mpg.de; tina.unger@medizin.uni-leipzig.de; nocon@eva.mpg.de; sapfo@berkeley.edu; koloko@amnh.org; stiller@eva.mpg.de; lsoibelzon@fcnym.unlp.edu.ar; hs397@cam.ac.uk; phd@mrc-lmb.cam.ac.uk; briggs@eva.mpg.de; sarah.bray@adelaide.edu.au; obrien@ncifcrf.gov; gernot.rabeder@univie.ac.at; matheus@northwestel.net; alan.cooper@adelaide.edu.au; slatkin@socrates.berkeley.edu; paabo@eva.mpg.de; hofreite@eva.mpg.de RI Dear, Paul/A-1162-2012; Cooper, Alan/E-8171-2012; Krause, Johannes/E-6640-2015; Kolokotronis, Sergios-Orestis/A-1910-2009; Hofreiter, Michael/A-3996-2017; OI Cooper, Alan/0000-0002-7738-7851; Krause, Johannes/0000-0001-5475-4690; Kolokotronis, Sergios-Orestis/0000-0003-3309-8465; Hofreiter, Michael/0000-0003-0441-4705; Bray, Sarah/0000-0001-7067-4551; Malaspinas, Anna-Sapfo/0000-0003-1001-7511 FU Max Planck Society; AMNH Conservation Genetics Research Fellowship; NIH [R01-GM40282] FX SB and AC were supported by the ARC, and gratefully acknowledge the assistance of the Canadian Museum of Nature, and D. Harington for the sample of the Arctodus specimen. We thank S. Giesser for help with the species distribution map design. JK, TU, AN, MS, AWB, SP and MH thank the Max Planck Society for financial support. SOK was supported by an AMNH Conservation Genetics Research Fellowship. ASM and MSlatkin were supported by NIH grant R01-GM40282. NR 78 TC 107 Z9 115 U1 13 U2 86 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 JUL 28 PY 2008 VL 8 AR 220 DI 10.1186/1471-2148-8-220 PG 12 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 346VA UT WOS:000259096500001 PM 18662376 ER PT J AU Atianjoh, FE Ladenheim, B Krasnova, IN Cadet, JL AF Atianjoh, Fidelis E. Ladenheim, Bruce Krasnova, Irina N. Cadet, Jean Lud TI Amphetamine causes dopamine depletion and cell death in the mouse olfactory bulb SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE neurotoxicity; striatum; TUNEL staining; DNA fragmentation ID D-METHAMPHETAMINE; RAT-BRAIN; NEURONS; DEPRESSION; NEUROTOXICITY; MECHANISMS; CIRCUITS; STUDENTS; ABUSERS; CORTEX AB Amphetamine is a neurotoxic psychostimulant that causes dopamine depletion and neuronal death in the rodent striaturn. In the present study, we sought to determine if toxic doses of the drug can also induce pathological changes in the mouse olfactory bulb. We found that injections of amphetamine (10 mg/kgx4, given 2 h apart) caused significant decreases in dopamine levels in that structure. This dose of the drug also induced substantial increases in the number of terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate (dNTP) nick end labeling (TUNEL)-positive cells in the olfactory bulb indicative of elevated DNA fragmentation. These results show that the toxic effects of amphetamine involve the olfactory bulb in addition to the striaturn. These observations need to be taken into consideration when discussing the clinical course of amphetamine addiction. Published by Elsevier B.V. C1 [Atianjoh, Fidelis E.; Ladenheim, Bruce; Krasnova, Irina N.; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Branch, Intramural Res Program, NIH DHHS, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Branch, Intramural Res Program, NIH DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM JCADET@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 33 TC 7 Z9 7 U1 1 U2 4 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 JUL 28 PY 2008 VL 589 IS 1-3 BP 94 EP 97 DI 10.1016/j.ejphar.2008.05.001 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 340EH UT WOS:000258628400016 PM 18544452 ER PT J AU Ni, W Zhou, HW Diaz, J Murphy, DL Haywood, JR Watts, SW AF Ni, Wei Zhou, Huawei Diaz, Jessica Murphy, Dennis L. Haywood, Joseph R. Watts, Stephanie W. TI Lack of the serotonin transporter does not prevent mineralocorticoid hypertension in rat and mouse SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE 5-HT; serotonin transporter; systemic hypertension ID 5-HYDROXYTRYPTAMINE TRANSPORTER; BLOOD-PRESSURE; KNOCKOUT RAT; PLATELET; PLASMA; SYSTEM; 5-HT; MICE AB We hypothesized that lack of a functional serotonin transporter (SERT) would increase basal blood pressure and enhance the development of deoxycorticosterone acetate (DOCA)-salt hypertension compared to wild type (WT) controls. Mean arterial blood pressure was measured in WT and SERT knockout (KO) mice and rat models through radiotelemetry. Basal blood pressures were not different between respective WT and KO. Moreover, blood pressure elevated similarly (similar to 50 mm Hg) in all strains given DOCA and salt. Thus, the lack of functional SERT did not prevent development of DOCA-salt induced hypertension or modify basal blood pressure significantly. (c) 2008 Elsevier B.V. All rights reserved. C1 [Ni, Wei; Zhou, Huawei; Diaz, Jessica; Haywood, Joseph R.; Watts, Stephanie W.] Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Watts, SW (reprint author), Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA. EM wattss@msu.edu OI Diaz, Jessica/0000-0001-8584-6766 FU NIH [HL81115] FX Supported by NIH HL81115. NR 21 TC 5 Z9 5 U1 0 U2 1 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 JUL 28 PY 2008 VL 589 IS 1-3 BP 225 EP 227 DI 10.1016/j.ejphar.2008.06.012 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 340EH UT WOS:000258628400039 PM 18573249 ER PT J AU Hegde, RS Kang, SW AF Hegde, Ramanujan S. Kang, Sang-Wook TI The concept of translocational regulation SO JOURNAL OF CELL BIOLOGY LA English DT Review ID SIGNAL RECOGNITION PARTICLE; MAMMALIAN ENDOPLASMIC-RETICULUM; PROTEIN TRANSLOCATION; PRION PROTEIN; COTRANSLATIONAL TRANSLOCATION; ER MEMBRANE; SEQUENCE RECEPTOR; TRANSPORT; DISEASE; COMPLEX AB Biological processes are regulated to provide cells with exquisite adaptability to changing environmental conditions and cellular demands. The mechanisms regulating secretory and membrane protein translocation into the endoplasmic reticulum (ER) are unknown. A conceptual framework for translocational regulation is proposed based on our current mechanistic understanding of ER protein translocation and general principles of regulatory control. C1 [Hegde, Ramanujan S.; Kang, Sang-Wook] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU Intramural NIH HHS NR 73 TC 63 Z9 64 U1 1 U2 4 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 JUL 28 PY 2008 VL 182 IS 2 BP 225 EP 232 DI 10.1083/jcb.200804157 PG 8 WC Cell Biology SC Cell Biology GA 335EZ UT WOS:000258274900003 PM 18644895 ER PT J AU Lombardi, M Castoria, G Migliaccio, A Barone, MV Di Stasio, R Ciociola, A Bottero, D Yamaguchi, H Appella, E Auricchio, F AF Lombardi, Maria Castoria, Gabriella Migliaccio, Antimo Barone, Maria Vittoria Di Stasio, Rosina Ciociola, Alessandra Bottero, Daniela Yamaguchi, Hiroshi Appella, Ettore Auricchio, Ferdinando TI Hormone-dependent nuclear export of estradiol receptor and DNA synthesis in breast cancer cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID FORKHEAD TRANSCRIPTION FACTORS; ESTROGEN-RECEPTOR; ANDROGEN RECEPTOR; SUBCELLULAR-LOCALIZATION; GLUCOCORTICOID-RECEPTOR; PROGESTERONE-RECEPTOR; PHOSPHORYLATION; SIGNAL; SRC; TRANSPORT AB In breast cancer cells, cytoplasmic localization of the estradiol receptor alpha (ER alpha) regulates estradiol-dependent S phase entry. We identified a nuclear export sequence (NES) in ER alpha and show that its export is dependent on both estradiol-mediated phosphatidylinositol-3-kinase (PI3K)/AKT activation and chromosome region maintenance 1 (CRM1). A Tat peptide containing the ER alpha NES disrupts ER alpha-CRM1 interaction and prevents nuclear export of ER alpha- and estradiol-induced DNA synthesis. NES-ER alpha mutants do not exit the nucleus and inhibit estradiol-induced S phase entry; ER alpha-dependent transcription is normal. ER alpha is associated with Forkhead proteins in the nucleus, and estradiol stimulates nuclear exit of both proteins. ER alpha knockdown or ER alpha NES mutations prevent ER alpha and Forkhead nuclear export. A mutant of forkhead in rhabdomyosarcoma (FKHR), which cannot be phosphorylated by estradiol-activated AKT, does not associate with ER alpha and is trapped in the nucleus, blocking S phase entry. In conclusion, estradiol-induced AKT-dependent phosphorylation of FKHR drives its association with ER alpha, thereby triggering complex export from the nucleus necessary for initiation of DNA synthesis and S phase entry. C1 [Lombardi, Maria; Castoria, Gabriella; Migliaccio, Antimo; Di Stasio, Rosina; Ciociola, Alessandra; Bottero, Daniela; Auricchio, Ferdinando] Univ Naples 2, Dipartimento Patol Gen, I-80138 Naples, Italy. [Barone, Maria Vittoria] Univ Naples Federico 2, Dipartimento Pediat, European Lab Food Induced Dis, I-80131 Naples, Italy. [Yamaguchi, Hiroshi; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Migliaccio, A (reprint author), Univ Naples 2, Dipartimento Patol Gen, I-80138 Naples, Italy. EM antimo.migliaccio@unina2.it OI BARONE, Maria Vittoria/0000-0001-6190-4917; Migliaccio, Antimo/0000-0002-4197-2055 FU Associazione Italiana per la Ricerca sul Cancro NR 57 TC 42 Z9 43 U1 0 U2 1 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 JUL 28 PY 2008 VL 182 IS 2 BP 327 EP 340 DI 10.1083/jcb.200712125 PG 14 WC Cell Biology SC Cell Biology GA 335EZ UT WOS:000258274900012 PM 18644889 ER PT J AU Sohn, HW Tolar, P Pierce, SK AF Sohn, Hae Won Tolar, Pavel Pierce, Susan K. TI Membrane heterogeneities in the formation of B cell receptor-Lyn kinase microclusters and the immune synapse SO JOURNAL OF CELL BIOLOGY LA English DT Article ID RESONANCE ENERGY-TRANSFER; ANTIGEN RECEPTOR; LIPID RAFTS; LIVING CELLS; GERMINAL-CENTERS; IGE RECEPTORS; T-CELLS; ACTIVATION; FLUORESCENCE; INITIATION AB Antigen binding to the B cell receptors (BCRs) induces BCR clustering, phosphorylation of BCRs by the Src family kinase Lyn, initiation of signaling, and formation of an immune synapse. We investigated B cells as they first encountered antigen on a membrane using live cell high resolution total internal reflection fluorescence microscopy in conjunction with fluorescence resonance energy transfer. Newly formed BCR microclusters perturb the local membrane microenvironment, leading to association with a lipid raft probe. This early event is BCR intrinsic and independent of BCR signaling. Association of BCR microclusters with membrane-tethered Lyn depends on Lyn activity and persists as microclusters accumulate and form an immune synapse. Membrane perturbation and BCR-Lyn association correlate both temporally and spatially with the transition of microclustered BCRs from a "closed" to an "open" active signaling conformation. Visualization and analysis of the earliest events in BCR signaling highlight the importance of the membrane microenvironment for formation of BCR Lyn complexes and the B cell immune synapse. C1 [Sohn, Hae Won; Tolar, Pavel; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov FU Intramural NIH HHS NR 35 TC 79 Z9 83 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 JUL 28 PY 2008 VL 182 IS 2 BP 367 EP 379 DI 10.1083/jcb.200802007 PG 13 WC Cell Biology SC Cell Biology GA 335EZ UT WOS:000258274900015 PM 18644892 ER PT J AU Vazquez, MV Berezhkovskii, AM Dagdug, L AF Vazquez, Marco-Vinicio Berezhkovskii, Alexander M. Dagdug, Leonardo TI Diffusion in linear porous media with periodic entropy barriers: A tube formed by contacting spheres SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article C1 [Vazquez, Marco-Vinicio; Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Berezhkovskii, Alexander M.] NIH, Ctr Informat Technol, Div Computat Biosci, Math & Stat Comp Lab, Bethesda, MD 20892 USA. RP Vazquez, MV (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Apartado Postal 55-534, Mexico City 09340, DF, Mexico. FU Intramural NIH HHS NR 10 TC 32 Z9 32 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUL 28 PY 2008 VL 129 IS 4 AR 046101 DI 10.1063/1.2955447 PG 2 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 333SB UT WOS:000258171500060 PM 18681682 ER PT J AU Wang, W Fang, HQ Groom, L Cheng, AW Zhang, WR Liu, J Wang, XH Li, KT Han, PD Zheng, M Yin, JH Wang, WD Mattson, MP Kao, JPY Lakatta, EG Sheu, SS Ouyang, KF Chen, J Dirksen, RT Cheng, HP AF Wang, Wang Fang, Huaqiang Groom, Linda Cheng, Aiwu Zhang, Wanrui Liu, Jie Wang, Xianhua Li, Kaitao Han, Peidong Zheng, Ming Yin, Jinhu Wang, Weidong Mattson, Mark P. Kao, Joseph P. Y. Lakatta, Edward G. Sheu, Shey-Shing Ouyang, Kunfu Chen, Ju Dirksen, Robert T. Cheng, Heping TI Superoxide flashes in single mitochondria SO CELL LA English DT Article ID PERMEABILITY TRANSITION PORE; CELL-DEATH; CYCLOPHILIN-D; CARDIAC MYOCYTES; OXIDATIVE STRESS; CYCLOSPORINE-A; CA2+ SPARKS; COMPLEX-III; RELEASE; OSCILLATIONS AB In quiescent cells, mitochondria are the primary source of reactive oxygen species (ROS), which are generated by leakiness of the electron transport chain (ETC). High levels of ROS can trigger cell death, whereas lower levels drive diverse and important cellular functions. We show here by employing a newly developed mitochondrial matrix-targeted superoxide indicator, that individual mitochondria undergo spontaneous bursts of superoxide generation, termed "superoxide flashes.'' Superoxide flashes occur randomly in space and time, exhibit all-or-none properties, and provide a vital source of superoxide production across many different cell types. Individual flashes are triggered by transient openings of the mitochondrial permeability transition pore stimulating superoxide production by the ETC. Furthermore, we observe a flurry of superoxide flash activity during reoxygenation of cardiomyocytes after hypoxia, which is inhibited by the cardioprotective compound adenosine. We propose that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases. C1 [Wang, Wang; Lakatta, Edward G.] NIA, NIH, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Cheng, Aiwu; Mattson, Mark P.] NIA, NIH, Neurosci Lab, Baltimore, MD 21224 USA. [Yin, Jinhu; Wang, Weidong] NIA, NIH, Genet Lab, Baltimore, MD 21224 USA. [Fang, Huaqiang; Zhang, Wanrui; Liu, Jie; Wang, Xianhua; Li, Kaitao; Han, Peidong; Zheng, Ming; Cheng, Heping] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Fang, Huaqiang; Zhang, Wanrui; Liu, Jie; Wang, Xianhua; Li, Kaitao; Han, Peidong; Zheng, Ming; Cheng, Heping] Peking Univ, Natl Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. [Groom, Linda; Sheu, Shey-Shing; Dirksen, Robert T.] Univ Rochester, Sch Med & Dent, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. [Kao, Joseph P. Y.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Ouyang, Kunfu; Chen, Ju] Univ Calif San Diego, Dept Med, San Diego, CA 92093 USA. RP Wang, W (reprint author), NIA, NIH, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. EM wangwang@umich.edu; chengp@pku.edu.cn RI Mattson, Mark/F-6038-2012; ouyang, kunfu/B-3073-2011; Chen, Ju/E-5579-2011; OI ouyang, kunfu/0000-0003-0292-375X; Wang, Wang/0000-0001-9093-412X FU Intramural NIH HHS; NHLBI NIH HHS [HL-33333, R01 HL033333, R01 HL033333-12, R01 HL093671]; NIAMS NIH HHS [AR44657, R01 AR044657, R01 AR044657-11, R29 AR044657]; NIGMS NIH HHS [R01 GM056481-02, R01 GM056481] NR 57 TC 359 Z9 367 U1 5 U2 61 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 25 PY 2008 VL 134 IS 2 BP 279 EP 290 DI 10.1016/j.cell.2008.06.017 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 329SU UT WOS:000257891700017 PM 18662543 ER PT J AU Neptune, ER Podowski, M Calvi, C Cho, JH Garcia, JGN Tuder, R Linnoila, RI Tsai, MJ Dietz, HC AF Neptune, Enid R. Podowski, Megan Calvi, Carla Cho, Jang-Hyeon Garcia, Joe G. N. Tuder, Rubin Linnoila, R. Ilona Tsai, Ming-Jer Dietz, Harry C. TI Targeted disruption of NeuroD, a proneural basic helix-loop-helix factor, impairs distal lung formation and neuroendocrine morphology in the neonatal lung SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENE-RELATED PEPTIDE; MARFAN-SYNDROME; NEUROEPITHELIAL BODIES; AIRWAY EPITHELIUM; ENDOCRINE-CELLS; HAMSTER LUNG; MOUSE MODEL; NULL MICE; DIFFERENTIATION; PROLIFERATION AB Despite the importance of airspace integrity in vertebrate gas exchange, the molecular pathways that instruct distal lung formation are poorly understood. Recently, we found that fibrillin-1 deficiency in mice impairs alveolar formation and recapitulates the pulmonary features of human Marfan syndrome. To further elucidate effectors involved in distal lung formation, we performed expression profiling analysis comparing the fibrillin1-deficient and wild-type developing lung. NeuroD, a basic helix-loop-helix transcription factor, fulfilled the expression criteria for a candidate mediator of distal lung development. We investigated its role in murine lung development using genetically targeted NeuroD-deficient mice. We found that NeuroD deficiency results in both impaired alveolar septation and altered morphology of the pulmonary neuroendocrine cells. NeuroD-deficient mice had enlarged alveoli associated with reduced epithelial proliferation in the airway and airspace compartments during development. Additionally, the neuroendocrine compartment in these mice manifested an increased number of neuroepithelial bodies but a reduced number of solitary pulmonary neuroendocrine cells in the neonatal lung. Overexpression of NeuroD in a murine lung epithelial cell line conferred a neuroendocrine phenotype characterized by the induction of neuroendocrine markers as well as increased proliferation. These results support an unanticipated role for NeuroD in the regulation of pulmonary neuroendocrine and alveolar morphogenesis and suggest an intimate connection between the neuroendocrine compartment and distal lung development. C1 [Neptune, Enid R.; Podowski, Megan; Calvi, Carla; Garcia, Joe G. N.] Johns Hopkins Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21205 USA. [Neptune, Enid R.; Dietz, Harry C.] Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. [Dietz, Harry C.] Johns Hopkins Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Tuder, Rubin] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Linnoila, R. Ilona] NCI, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Cho, Jang-Hyeon; Tsai, Ming-Jer] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Neptune, ER (reprint author), Johns Hopkins Univ, Sch Med, 1830 E Monument St,Rm 547, Baltimore, MD 21205 USA. EM eneptune@jhmi.edu; hdietz@jhmi.edu RI Garcia, Joe/E-8862-2010 FU Howard Hughes Medical Institute; Intramural NIH HHS; NHLBI NIH HHS [R01 HL 66554, HL 69340, K08 HL 067980, U01 HL 66583]; NIAMS NIH HHS [AR 41135]; NICHD NIH HHS [HD 17379]; NIDDK NIH HHS [DK 45641] NR 45 TC 15 Z9 18 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 JUL 25 PY 2008 VL 283 IS 30 BP 21160 EP 21169 DI 10.1074/jbc.M708692200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327RL UT WOS:000257746100058 PM 18339630 ER PT J AU Sweeney, SM Orgel, JP Fertala, A McAuliffe, JD Turner, KR Di Lullo, GA Chen, S Antipova, O Perumal, S Ala-Kokko, L Forlino, A Cabral, WA Barnes, AM Marini, JC Antonio, JDS AF Sweeney, Shawn M. Orgel, Joseph P. Fertala, Andrzej McAuliffe, Jon D. Turner, Kevin R. Di Lullo, Gloria A. Chen, Steven Antipova, Olga Perumal, Shiamalee Ala-Kokko, Leena Forlino, Antonella Cabral, Wayne A. Barnes, Aileen M. Marini, Joan C. Antonio, James D. San TI Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMPERFECTA/EHLERS-DANLOS-SYNDROME; AMINO-ACID-SEQUENCE; I COLLAGEN; OSTEOGENESIS-IMPERFECTA; BINDING-SITES; TRIPLE-HELIX; INTEGRINS ALPHA(1)BETA(1); DENTIN PHOSPHOPHORYN; COL1A1 MUTATION; GER SEQUENCE AB Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The "cell interaction domain" is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The "matrix interaction domain" may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging. C1 [Turner, Kevin R.; Di Lullo, Gloria A.; Antonio, James D. San] Thomas Jefferson Univ, Cardeza Fdn Hematol Res, Philadelphia, PA 19107 USA. [Turner, Kevin R.; Di Lullo, Gloria A.; Antonio, James D. San] Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA. [Sweeney, Shawn M.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Orgel, Joseph P.; Antipova, Olga; Perumal, Shiamalee] IIT, Dept Biol Chem & Phys Sci, Ctr Synchrotron Radiat Res & Instrumentat, Chicago, IL 60616 USA. [Fertala, Andrzej] Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. [McAuliffe, Jon D.] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. [Chen, Steven] Finch Univ Hlth Sci Chicago Med Sch, N Chicago, IL 60064 USA. [Ala-Kokko, Leena] Univ Oulu, Bioctr, Collagen Res Unit, Oulu, Finland. [Ala-Kokko, Leena] Univ Oulu, Dept Med Biochem & Mol Biol, Oulu, Finland. [Ala-Kokko, Leena] Connect Tissue Gene Tests, Allentown, PA 18103 USA. [Forlino, Antonella] Univ Pavia, Dept Biochem A Castellani, I-27100 Pavia, Italy. [Forlino, Antonella; Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bone & Extracellular Matrix Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Antonio, JDS (reprint author), Thomas Jefferson Univ, Cardeza Fdn Hematol Res, Rm 809 Curtis,1015 Walnut St, Philadelphia, PA 19107 USA. EM james.sanantonio@jefferson.edu RI ID, BioCAT/D-2459-2012; Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 FU NCRR NIH HHS [RR 08630, P41 RR008630, P41 RR008630-08, P41 RR008630-127842]; NHLBI NIH HHS [HL 053590, R01 HL053590-08]; NIAMS NIH HHS [AR 048544, AR 049604, R01 AR048544, R01 AR048544-04, R21 AR049604-03] NR 68 TC 125 Z9 128 U1 1 U2 21 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 JUL 25 PY 2008 VL 283 IS 30 BP 21187 EP 21197 DI 10.1074/jbc.M709319200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327RL UT WOS:000257746100061 PM 18487200 ER PT J AU Fauci, AS Johnston, MI Dieffenbach, CW Burton, DR Hammer, SM Hoxie, JA Martin, M Overbaugh, J Watkins, DI Mahmoud, A Greene, WC AF Fauci, Anthony S. Johnston, Margaret I. Dieffenbach, Carl W. Burton, Dennis R. Hammer, Scott M. Hoxie, James A. Martin, Malcolm Overbaugh, Julie Watkins, David I. Mahmoud, Adel Greene, Warner C. TI Perspective - HIV vaccine research: The way forward SO SCIENCE LA English DT Editorial Material ID IMMUNODEFICIENCY VIRUS SIVMAC239; MEMORY T-CELLS; AIDS VACCINE; CHALLENGE; INFECTION; PREVENTION; IMMUNITY; FAILURE; MONKEYS; TRIAL C1 [Fauci, Anthony S.; Johnston, Margaret I.; Dieffenbach, Carl W.; Martin, Malcolm; Mahmoud, Adel] NIAID, NIH, Bethesda, MD 20892 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Hammer, Scott M.] Columbia Univ, Med Ctr, Div Infect Dis, New York, NY 10032 USA. [Hoxie, James A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Overbaugh, Julie] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Watkins, David I.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53711 USA. [Mahmoud, Adel] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Greene, Warner C.] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. RP Fauci, AS (reprint author), NIAID, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov RI Mahmoud, Azza/S-1502-2016 FU Intramural NIH HHS NR 19 TC 175 Z9 182 U1 3 U2 19 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 25 PY 2008 VL 321 IS 5888 BP 530 EP 532 DI 10.1126/science.1161000 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329RS UT WOS:000257888900037 PM 18653883 ER PT J AU Grant, RM Hamer, D Hope, T Johnston, R Lange, J Lederman, MM Lieberman, J Miller, CJ Moore, JP Mosier, DE Richman, DD Schooley, RT Springer, MS Veazey, RS Wainberg, MA AF Grant, Robert M. Hamer, Dean Hope, Thomas Johnston, Rowena Lange, Joep Lederman, Michael M. Lieberman, Judy Miller, Christopher J. Moore, John P. Mosier, Donald E. Richman, Douglas D. Schooley, Robert T. Springer, Marty S. Veazey, Ronald S. Wainberg, Mark A. TI Perspective - Whither or wither microbicides? SO SCIENCE LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS TYPE-1; VAGINAL MICROBICIDE; DRUG-RESISTANCE; NONOXYNOL-9; HIV; STRATEGIES C1 [Grant, Robert M.] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94518 USA. [Grant, Robert M.] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94518 USA. [Hamer, Dean] NCI, NIH, Bethesda, MD 20817 USA. [Hope, Thomas] Northwestern Univ, Chicago, IL 60611 USA. [Johnston, Rowena] Fdn AIDS Res amfAR, New York, NY 10005 USA. [Lange, Joep] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Lederman, Michael M.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Lieberman, Judy] Harvard Univ, Sch Med, Div Aids, Boston, MA 02115 USA. [Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Moore, John P.] Cornell Univ, Weill Med Coll, New York, NY 10065 USA. [Mosier, Donald E.] Scripps Res Inst, La Jolla, CA 92037 USA. [Richman, Douglas D.] San Diego Healthcare Syst, La Jolla, CA 92093 USA. [Richman, Douglas D.; Schooley, Robert T.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Springer, Marty S.] Merck & Co Inc, Rahway, NJ 07090 USA. [Veazey, Ronald S.] Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. [Wainberg, Mark A.] McGill Univ, Jewish Gen Hosp, AIDS Ctr, Montreal, PQ H3T 1E2, Canada. RP Grant, RM (reprint author), Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94518 USA. RI Lieberman, Judy/A-2717-2015 FU NIAID NIH HHS [U19 AI076981, U19 AI076981-01] NR 19 TC 97 Z9 102 U1 0 U2 5 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 JUL 25 PY 2008 VL 321 IS 5888 BP 532 EP 534 DI 10.1126/science.1160355 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329RS UT WOS:000257888900038 PM 18653884 ER PT J AU Yin, XB Xia, LJ Sun, LG Luo, HH Wang, YH AF Yin, Xuebin Xia, Lijun Sun, Liguang Luo, Honghao Wang, Yuhong TI Animal excrement: A potential biomonitor of heavy metal contamination in the marine environment SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE animal excrement; heavy metal; bio-monitoring; Artic; Antarctica, Xisha Archipelago; marine environment ID KING-GEORGE-ISLAND; DICHLORO-DIPHENYL-TRICHLOROETHANES; SOUTH SHETLAND ISLANDS; ANTARCTIC SEAL HAIRS; TRACE-METALS; PENGUIN DROPPINGS; MERCURY CONCENTRATIONS; MYTILUS-EDULIS; DIET; SEDIMENTS AB To assess the feasibility of using animal excrement to biomonitor the extent of heavy metal contamination in the marine environment, concentrations of mercury (Hg), lead (Pb), copper (Cu) and zinc (Zn) in the fresh excrement of seabirds and marine mammals, along with other biomaterials, from the Arctic, Antarctica (West and East), and Xisha Archipelago of the South China Sea were determined. Results show that the excrement of marine animals at higher trophic levels generally contained high levels of Hg, demonstrating the biomagnification of Hg through food chains in different remote regions. Significant variations in metal accumulation in the excrements were observed among the distinctive geographical areas, with the highest Hg concentration in Xisha Archipelago and the highest Pb concentration in the Arctic, which reflects different levels of air metal pollution at various sampling locations. Concentrations of Cu in the excrements primarily correlate to the geochemical background levels in the regions. High Cu concentrations were found near the Great Wall Station in West Antarctica where a copper mineralized belt exists. No clear spatial variation pattern was found for Zn accumulation in the excrement. This study shows that animal excrement can be used as bioindicators for the level of metal contamination in the marine environment, with the advantages of easy sampling, accurate detection (i.e., with high levels of metal accumulation), and reconstructing historical metal contamination trends by long-term monitoring of sedimentary excrements. (C) 2008 Elsevier B.V. All rights reserved. C1 [Yin, Xuebin; Xia, Lijun; Sun, Liguang; Luo, Honghao] Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Anhui, Peoples R China. [Yin, Xuebin] USTC City U, Joint Adv Res Ctr, ALERT, Jiangsu 215123, Peoples R China. [Wang, Yuhong] Natl Inst Hlth, Bethesda, MD 20892 USA. RP Sun, LG (reprint author), Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Anhui, Peoples R China. EM slg@ustc.edu.cn NR 40 TC 31 Z9 33 U1 8 U2 60 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD JUL 25 PY 2008 VL 399 IS 1-3 BP 179 EP 185 DI 10.1016/j.scitotenv.2008.03.005 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA 325DQ UT WOS:000257569000019 PM 18466955 ER PT J AU Zanuy, D Flores-Ortega, A Casanovas, J Curco, D Nussinov, R Aleman, C AF Zanuy, David Flores-Ortega, Alejandra Casanovas, Jordi Curco, David Nussinov, Ruth Aleman, Carlos TI The energy landscape of a selective tumor-homing pentapeptide SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PROTEIN BUILDING-BLOCKS; AMINO ACID RESIDUES; MOLECULAR-DYNAMICS; NANOSTRUCTURE DESIGN; IN-VIVO; PEPTIDE; INHIBITORS; RESISTANT; BACKBONE; MODEL AB Recently, a potentially powerful strategy based on phage-display libraries has been presented to target tumors via homing peptides attached to nanoparticles. The Cys-Arg-Glu-Lys-Ala (CREKA) peptide sequence has been identified as a tumor-homing peptide that binds to clotted plasmas proteins present in tumor vessels and interstitium. The aim of this work consists of mapping the conformational profile of CREKA to identify the bioactive conformation. For this purpose, a conformational search procedure based on modified simulated annealing combined with molecular dynamics was applied to three systems that mimic the experimentally used conditions: (i) the free peptide; (ii) the peptide attached to a nanoparticle; and (iii) the peptide inserted in a phage display protein. In addition, the free peptide was simulated in an ionized aqueous solution environment, which mimics the ionic strength of the physiological medium. Accessible minima of all simulated systems reveal a multiple interaction pattern involving the ionized side chains of Arg, Glu, and Lys, which induces a P-turn motif in the backbone observed in all simulated CREKA systems. C1 [Zanuy, David; Flores-Ortega, Alejandra; Aleman, Carlos] Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, E-08028 Barcelona, Spain. [Casanovas, Jordi] Univ Lleida, Dept Quim, Escola Politecn Super, E-25001 Lleida, Spain. [Curco, David] Univ Barcelona, Dept Engn Quim, Fac Quim, E-08028 Barcelona, Spain. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res ,Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Dept Human Genet, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Zanuy, D (reprint author), Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, Diagonal 647, E-08028 Barcelona, Spain. EM david.zanuy@upc.edu; carlos.aleman@upc.edu RI Casanovas, Jordi/B-5435-2013; Zanuy, David/G-3930-2014 OI Casanovas, Jordi/0000-0002-4914-9194; Zanuy, David/0000-0001-7704-2178 FU Intramural NIH HHS [Z01 BC010440-06]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 29 TC 20 Z9 23 U1 1 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUL 24 PY 2008 VL 112 IS 29 BP 8692 EP 8700 DI 10.1021/jp711477k PG 9 WC Chemistry, Physical SC Chemistry GA 327IY UT WOS:000257724000039 PM 18588341 ER PT J AU Lichten, M AF Lichten, Michael TI Genomics - Thoroughly modern meiosis SO NATURE LA English DT Editorial Material C1 [Lichten, Michael] NCI, Biochem & Mol Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Lichten, M (reprint author), NCI, Biochem & Mol Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. EM lichten@helix.nih.gov RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 8 TC 1 Z9 1 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 24 PY 2008 VL 454 IS 7203 BP 421 EP 422 DI 10.1038/454421a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329IC UT WOS:000257860300033 PM 18650909 ER PT J AU Lee, TH Emanuel, EJ AF Lee, Thomas H. Emanuel, Ezekiel J. TI Tier 4 drugs and the fraying of the social compact SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID BREAST-CANCER; COSTS C1 [Lee, Thomas H.] Partners Healthcare Syst, Boston, MA 02199 USA. [Emanuel, Ezekiel J.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Lee, TH (reprint author), Partners Healthcare Syst, Boston, MA 02199 USA. NR 5 TC 42 Z9 42 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 24 PY 2008 VL 359 IS 4 BP 333 EP 335 DI 10.1056/NEJMp0804261 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 329FK UT WOS:000257852100001 PM 18650510 ER PT J AU Baek, N Woo, JM Han, C Choi, E Park, I Kim, DH Eddy, EM Cho, C AF Baek, Namhoe Woo, Jong-Min Han, Cecil Choi, Eunyoung Park, Inju Kim, Do Han Eddy, Edward M. Cho, Chunghee TI Characterization of eight novel proteins with male germ cell-specific expression in mouse SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article ID GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE-S; FIBROUS SHEATH; SPERM TAIL; BINDING-PROTEIN; SPERMATOZOA; TESTIS; SPERMATOGENESIS; IDENTIFICATION; FLAGELLUM; RHOPHILIN AB Background: Spermatogenesis and fertilization are highly unique processes. Discovery and characterization of germ cell-specific genes are important for the understanding of these reproductive processes. We investigated eight proteins encoded by novel spermatogenic cell-specific genes previously identified from the mouse round spermatid UniGene library. Methods: Polyclonal antibodies were generated against the novel proteins and western blot analysis was performed with various protein samples. Germ cell specificity was investigated using testes from germ cell-less mutant mice. Developmental expression pattern was examined in testicular germ cells, testicular sperm and mature sperm. Subcellular localization was assessed by cell surface biotin labeling and trypsinization. Protein localization and properties in sperm were investigated by separation of head and tail fractions, and extractabilities by a non-ionic detergent and urea. Results: The authenticity of the eight novel proteins and their specificity to spermatogenic cells were confirmed. In examining the developmental expression patterns, we found the presence of four proteins only in testicular germ cells, a single protein in testicular germ cells and testicular sperm, and three proteins in the testicular stages and mature sperm from the epididymis. Further analysis of the three proteins present in sperm disclosed that one is located at the surface of the acrosomal region and the other two are associated with cytoskeletal structures in the sperm flagellum. We name the genes for these sperm proteins Shsp1 (Sperm head surface protein 1), Sfap1 (Sperm flagellum associated protein 1) and Sfap2 (Sperm flagellum associated protein 2). Conclusion: We analyzed eight novel germ cell-specific proteins, providing new and inclusive information about their developmental and cellular characteristics. Our findings will facilitate future investigation into the biological roles of these novel proteins in spermatogenesis and sperm functions. C1 [Baek, Namhoe; Woo, Jong-Min; Han, Cecil; Choi, Eunyoung; Park, Inju; Kim, Do Han; Cho, Chunghee] Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. [Baek, Namhoe; Woo, Jong-Min; Han, Cecil; Choi, Eunyoung; Park, Inju; Kim, Do Han; Cho, Chunghee] Gwangju Inst Sci & Technol, Res Ctr Biomol Nanotechnol, Kwangju 500712, South Korea. [Eddy, Edward M.] NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cho, C (reprint author), Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. EM NamHo.Baek@celltrion.com; plot11@hanmail.net; yakcecil@hanmail.net; ibbnida@hotmail.com; seafood0980@hanmail.net; dhkim@gist.ac.kr; eddy@niehs.nih.gov; choch@gist.ac.kr FU Intramural NIH HHS NR 26 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD JUL 24 PY 2008 VL 6 AR 32 DI 10.1186/1477-7827-6-32 PG 12 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA 337XD UT WOS:000258467900001 PM 18652659 ER PT J AU Hall, PE Lathia, JD Caldwell, MA ffrench-Constant, C AF Hall, Peter E. Lathia, Justin D. Caldwell, Maeve A. ffrench-Constant, Charles TI Laminin enhances the growth of human neural stem cells in defined culture media SO BMC NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TRANSIT-AMPLIFYING CELLS; PRECURSOR CELLS; CYTOSKELETAL ORGANIZATION; TERMINAL DIFFERENTIATION; LIGAND INTERACTIONS; NEUROTROPHIC THEORY; INTEGRIN FUNCTION; SURFACE-MARKERS; HUMAN-PLACENTA AB Background: Human neural stem cells ( hNSC) have the potential to provide novel cell-based therapies for neurodegenerative conditions such as multiple sclerosis and Parkinson's disease. In order to realise this goal, protocols need to be developed that allow for large quantities of hNSC to be cultured efficiently. As such, it is important to identify factors which enhance the growth of hNSC. In vivo, stem cells reside in distinct microenvironments or niches that are responsible for the maintenance of stem cell populations. A common feature of niches is the presence of the extracellular matrix molecule, laminin. Therefore, this study investigated the effect of exogenous laminin on hNSC growth. Results: To measure hNSC growth, we established culture conditions using B27-supplemented medium that enable neurospheres to grow from human neural cells plated at clonal densities. Limiting dilution assays confirmed that neurospheres were derived from single cells at these densities. Laminin was found to increase hNSC numbers as measured by this neurosphere formation. The effect of laminin was to augment the proliferation/survival of the hNSC, rather than promoting the undifferentiated state. In agreement, apoptosis was reduced in dissociated neurospheres by laminin in an integrin beta 1-dependent manner. Conclusion: The addition of laminin to the culture medium enhances the growth of hNSC, and may therefore aid their large-scale production. C1 [Hall, Peter E.; Lathia, Justin D.; ffrench-Constant, Charles] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Hall, Peter E.; Lathia, Justin D.; Caldwell, Maeve A.; ffrench-Constant, Charles] Univ Cambridge, Cambridge Ctr Brain Repair, Cambridge CB2 1QP, England. [Lathia, Justin D.] NIH, Neurosci Lab, Baltimore, MD USA. [Caldwell, Maeve A.] Univ Bristol, Lab Integrat Neurosci & Endocrinol, Bristol, Avon, England. [ffrench-Constant, Charles] Queens Med Res Inst, MRC, Ctr Regenerat Med, Edinburgh, Midlothian, Scotland. RP ffrench-Constant, C (reprint author), Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP, England. EM peter.hall@keble.ox.ac.uk; justindlathia@gmail.com; Maeve.Caldwell@bristol.ac.uk; cffc@ed.ac.uk RI Messier, Claude/A-2322-2008 OI Messier, Claude/0000-0002-4791-1763 FU Wellcome Trust NR 79 TC 39 Z9 39 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD JUL 23 PY 2008 VL 9 AR 71 DI 10.1186/1471-2202-9-71 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 336GK UT WOS:000258352100002 PM 18651950 ER PT J AU Hammond, RS Lin, L Sidorov, MS Wikenheiser, AM Hoffman, DA AF Hammond, Rebecca S. Lin, Lin Sidorov, Michael S. Wikenheiser, Andrew M. Hoffman, Dax A. TI Protein kinase A mediates activity-dependent Kv4.2 channel trafficking SO JOURNAL OF NEUROSCIENCE LA English DT Article DE potassium channel; I-A; Kv4.2; trafficking; hippocampus; excitability; PKA ID LONG-TERM POTENTIATION; CA1 PYRAMIDAL NEURONS; DENDRITIC K+ CHANNELS; SYNAPTIC PLASTICITY; POTASSIUM CHANNELS; HIPPOCAMPAL; PHOSPHORYLATION; PATHWAY; PKA; MODULATION AB The A-type potassium channel subunit Kv4.2 influences hippocampal function through regulation of dendritic excitability, and changes in Kv4.2 surface expression alter synaptic plasticity. Recent data from our laboratory demonstrate that EGFP(enhanced green fluorescent protein)-tagged Kv4.2 channels located in dendritic spines are internalized in an activity-dependent manner after synaptic stimulation and during chemically induced long-term potentiation. However, the molecular trigger for Kv4.2 internalization remains unknown. Here we examined the role of protein kinase A (PKA) in Kv4.2 activity-dependent trafficking. In hippocampal neurons, PKA activation with forskolin or 8-Br-cAMP induced Kv4.2 internalization from dendritic spines, whereas PKA inhibition with H89 prevented AMPA-induced internalization. Furthermore, introduction of a point mutation at the C-terminal PKA phosphorylation site of Kv4.2 (S552A) prevented the AMPA-induced internalization of Kv4.2. Together, these data demonstrate that Kv4.2 activity-dependent internalization requires PKA phosphorylation of Kv4.2 at serine 522. C1 [Hammond, Rebecca S.; Lin, Lin; Sidorov, Michael S.; Wikenheiser, Andrew M.; Hoffman, Dax A.] NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Hoffman, DA (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, 35 Lincoln Dr,MSC 3715,Bldg 35,Room 3C 905, Bethesda, MD 20892 USA. EM hoffmand@mail.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU Intramural NIH HHS [Z01 HD008755-05, Z99 HD999999] NR 26 TC 45 Z9 45 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 23 PY 2008 VL 28 IS 30 BP 7513 EP 7519 DI 10.1523/JNEUROSCI.1951-08.2008 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 329OL UT WOS:000257877200007 PM 18650329 ER PT J AU Simmons, JM Saad, ZS Lizak, MJ Ortiz, M Koretsky, AP Richmond, BJ AF Simmons, Janine M. Saad, Ziad S. Lizak, Martin J. Ortiz, Michael Koretsky, Alan P. Richmond, Barry J. TI Mapping prefrontal circuits in vivo with manganese-enhanced magnetic resonance imaging in monkeys SO JOURNAL OF NEUROSCIENCE LA English DT Article DE orbitofrontal cortex; anterior cingulate cortex; striatum; neuroanatomy; tract tracing; nonhuman primate ID ORBITOFRONTAL CORTEX; BASAL GANGLIA; NEURONAL-ACTIVITY; CORTICAL INPUTS; MACAQUE MONKEY; RHESUS-MONKEY; CONNECTIONS; MRI; PROJECTIONS; STRIATUM AB Manganese-enhanced magnetic resonance imaging (MEMRI) provides a powerful tool to study multisynaptic circuits in vivo and thereby to link information about neural structure and function within individual subjects. Making the best use of MEMRI in monkeys requires minimizing manganese-associated neurotoxicity, maintaining sensitivity to manganese-dependent signal changes and mapping transport throughout the brain without a priori anatomical hypotheses. Here, we performed intracortical injections of isotonic MnCl2, comparisons of preinjection and postinjection scans, and voxelwise statistical mapping. Isotonic MnCl2 did not cause cell death at the injection site, damage to downstream targets of manganese transport, behavioral deficits, or changes in neuronal responsiveness. We detected and mapped manganese transport throughout cortical-subcortical circuits by using voxelwise statistical comparisons of at least 10 preinjection and two postinjection scans. We were able to differentiate between focal and diffuse projection fields and to distinguish between the topography of striatal projections from orbitofrontal and anterior cingulate cortex in a single animal. This MEMRI approach provides a basis for combining circuit-based anatomical analyses with simultaneous single-unit recordings and/or functional magnetic resonance imaging in individual monkeys. Such studies will enhance our interpretations of functional data and our understanding of how neuronal activity is transformed as it propagates through a circuit. C1 [Simmons, Janine M.; Ortiz, Michael; Richmond, Barry J.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Lizak, Martin J.; Koretsky, Alan P.] Natl Inst Neurol Disorders & Stroke, NMR Imaging Res Facil, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08, Z99 MH999999] NR 40 TC 17 Z9 17 U1 0 U2 6 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 JUL 23 PY 2008 VL 28 IS 30 BP 7637 EP 7647 DI 10.1523/JNEUROSCI.1488-08.2008 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 329OL UT WOS:000257877200018 PM 18650340 ER PT J AU Lipton, AS Heck, RW Primak, S McNeill, DR Wilson, DM Ellis, PD AF Lipton, A. S. Heck, R. W. Primak, S. McNeill, D. R. Wilson, D. M., III Ellis, P. D. TI Characterization of Mg2+ binding to the DNA repair protein apurinic/apyrimidic endonuclease 1 via solid-state Mg-25 NMR spectroscopy SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HUMAN ABASIC ENDONUCLEASE; MAJOR HUMAN; CRYSTAL-STRUCTURE; EXONUCLEASE-III; APE1; SITE; SENSITIVITY; RESOLUTION; RELAXATION; SPECIFICITY AB Apurinic/apyrimidinic endonuclease 1 (APE1), a member of the divalent cation-dependent phosphoesterase superfamily of proteins that retain the conserved four-layered alpha/beta-sandwich structural core, is an essential protein that functions as part of base excision repair to remove mutagenic and cytotoxic abasic sites from DNA. Using low-temperature solid-state Mg-25 NMR spectroscopy and various mutants of APE1, we demonstrate that Mg2+ binds to APE1 and a functional APE1-substrate DNA complex with an overall stoichiometry of one Mg2+ per mole of APE1 as predicted by the X-ray work of Tainer and co-workers (Mol, C. D.; Kuo, C. F.; Thayer, M. M.; Cunningham, R. P.; Tainer, J. A. Nature 1995, 374, 381-386). However, the NMR spectra show that the single Mg2+ site is disordered. We discuss the probable reasons for the disorder at the Mg2+ binding site. The most likely source of this disorder is arrangement of the protein-ligands about the Mg2+ (cis and trans isomers). The existence of these isomers reinforces the notion of the plasticity of the metal binding site within APE1. C1 [Lipton, A. S.; Heck, R. W.; Primak, S.; Ellis, P. D.] Pacific NW Natl Lab, Biol Sci Directorate, Richland, WA 99352 USA. [McNeill, D. R.; Wilson, D. M., III] NIA, Lab Mol Gerontol, GRC, IRP,NIH, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), Pacific NW Natl Lab, Biol Sci Directorate, K8-98,902 Battelle Blvd, Richland, WA 99352 USA. EM paul.ellis@pnl.gov FU Intramural NIH HHS [Z01 AG000743-06]; NIBIB NIH HHS [R01 EB002050, R01 EB003893, EB 003893, EB002050] NR 49 TC 37 Z9 38 U1 0 U2 9 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 JUL 23 PY 2008 VL 130 IS 29 BP 9332 EP 9341 DI 10.1021/ja0776881 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 328KE UT WOS:000257796500045 PM 18576638 ER PT J AU Hong, S Optican, LM AF Hong, Simon Optican, Lance M. TI Interaction between Purkinje Cells and Inhibitory Interneurons May Create Adjustable Output Waveforms to Generate Timed Cerebellar Output SO PLOS ONE LA English DT Article ID LONG-TERM DEPRESSION; METABOTROPIC GLUTAMATE-RECEPTOR; NICTITATING-MEMBRANE RESPONSES; CONDITIONED EYELID RESPONSE; INFERIOR OLIVE; REVERSIBLE INACTIVATIONS; INTERPOSITUS NUCLEUS; DECEREBRATE FERRET; NEURONAL-ACTIVITY; CLIMBING FIBERS AB We develop a new model that explains how the cerebellum may generate the timing in classical delay eyeblink conditioning. Recent studies show that both Purkinje cells (PCs) and inhibitory interneurons (INs) have parallel signal processing streams with two time scales: an AMPA receptor-mediated fast process and a metabotropic glutamate receptor (mGluR)-mediated slow process. Moreover, one consistent finding is an increased excitability of PC dendrites (in Larsell's lobule HVI) in animals when they acquire the classical delay eyeblink conditioning naturally, in contrast to in vitro studies, where learning involves long-term depression (LTD). Our model proposes that the delayed response comes from the slow dynamics of mGluR-mediated IP3 activation, and the ensuing calcium concentration change, and not from LTP/LTD. The conditioned stimulus (tone), arriving on the parallel fibers, triggers this slow activation in INs and PC spines. These excitatory (from PC spines) and inhibitory (from INs) signals then interact at the PC dendrites to generate variable waveforms of PC activation. When the unconditioned stimulus (puff), arriving on the climbing fibers, is coupled frequently with this slow activation the waveform is amplified (due to an increased excitability) and leads to a timed pause in the PC population. The disinhibition of deep cerebellar nuclei by this timed pause causes the delayed conditioned response. This suggested PC-IN interaction emphasizes a richer role of the INs in learning and also conforms to the recent evidence that mGluR in the cerebellar cortex may participate in slow motor execution. We show that the suggested mechanism can endow the cerebellar cortex with the versatility to learn almost any temporal pattern, in addition to those that arise in classical conditioning. C1 [Hong, Simon; Optican, Lance M.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Hong, S (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM LanceOptican@nih.gov FU Intramural Research Program of the National Eye Institute, NIH, DHHS FX This work was supported by the Intramural Research Program of the National Eye Institute, NIH, DHHS. No role of sponsor in any aspect of this work. NR 105 TC 11 Z9 11 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 JUL 23 PY 2008 VL 3 IS 7 AR e2770 DI 10.1371/journal.pone.0002770 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420PY UT WOS:000264302900040 PM 18648667 ER PT J AU Martin, B Brenneman, R Becker, KG Gucek, M Cole, RN Maudsley, S AF Martin, Bronwen Brenneman, Randall Becker, Kevin G. Gucek, Marjan Cole, Robert N. Maudsley, Stuart TI iTRAQ Analysis of Complex Proteome Alterations in 3xTgAD Alzheimer's Mice: Understanding the Interface between Physiology and Disease SO PLOS ONE LA English DT Article AB Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with accumulation of amyloid beta-peptide, synaptic degeneration and the death of neurons in the hippocampus, and temporal, parietal and frontal lobes of the cerebral cortex. Analysis of postmortem brain tissue from AD patients can provide information on molecular alterations present at the end of the disease process, but cannot discriminate between changes that are specifically involved in AD versus those that are simply a consequence of neuronal degeneration. Animal models of AD provide the opportunity to elucidate the molecular changes that occur in brain cells as the disease process is initiated and progresses. To this end, we used the 3xTgAD mouse model of AD to gain insight into the complex alterations in proteins that occur in the hippocampus and cortex in AD. The 3xTgAD mice express mutant presenilin-1, amyloid precursor protein and tau, and exhibit AD-like amyloid and tau pathology in the hippocampus and cortex, and associated cognitive impairment. Using the iTRAQ stable-isotope-based quantitative proteomic technique, we performed an in-depth proteomic analysis of hippocampal and cortical tissue from 16 month old 3xTgAD and non-transgenic control mice. We found that the most important groups of significantly altered proteins included those involved in synaptic plasticity, neurite outgrowth and microtubule dynamics. Our findings have elucidated some of the complex proteome changes that occur in a mouse model of AD, which could potentially illuminate novel therapeutic avenues for the treatment of AD and other neurodegenerative disorders. C1 [Martin, Bronwen; Brenneman, Randall; Maudsley, Stuart] NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Becker, Kevin G.] NIA, Biomed Res Ctr, Intramural Res Program, Res Resources Branch, Baltimore, MD USA. [Gucek, Marjan; Cole, Robert N.] Johns Hopkins Sch Med, Proteom Facil, Baltimore, MD USA. RP Martin, B (reprint author), NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. EM maudsleyst@grc.nia.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU Intramural Research Program of the National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. NR 55 TC 49 Z9 50 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 23 PY 2008 VL 3 IS 7 AR e2750 DI 10.1371/journal.pone.0002750 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420PY UT WOS:000264302900021 PM 18648646 ER PT J AU West, NP Wozniak, TM Valenzuela, J Feng, CG Sher, A Ribeiro, JMC Britton, WJ AF West, Nicholas P. Wozniak, Teresa M. Valenzuela, Jesus Feng, Carl G. Sher, Alan Ribeiro, Jose M. C. Britton, Warwick J. TI Immunological diversity within a family of cutinase-like proteins of Mycobacterium tuberculosis SO VACCINE LA English DT Article DE tuberculosis; cuntinase; vaccine; immunology ID CULTURE FILTRATE PROTEINS; DNA VACCINES; PROTECTIVE EFFICACY; SECRETED PROTEINS; BOVIS BCG; IDENTIFICATION; PURIFICATION; ANTIGENS; ELECTROPHORESIS; VIRULENCE AB Secreted proteins of Mycobacterium tuberculosis play key roles in the assembly of the mycobacterial cell wall, with many being major targets of the host immune response. To date, meaningful characterization of a significant proportion of this important group of proteins is lacking. Among the group of putatively secreted proteins of M. tuberculosis are 7 cutinase-like proteins (CLP), not previously characterized in terms of their immunogenicity or vaccine protective efficacy. Although the CLP vary in the degree of homology with one another, they all share a similar active catalytic triad, closely homologous to that of the cutinase of Fusarium solani. By construction of DNA vaccines of all 7 CLP, and expression and purification of soluble, recombinant CLP, this study addresses the immunological responses to these proteins. Clp1, 2, 3 and 6 were found to elicit significant IFN-gamma secretion in DNA immunized mice, with the antigens also demonstrating specificity in terms of CLP-generated T cell IFN-gamma release, with minimal cross reactivity of humoral responses. Finally, following delivery of DNA vaccines, Clp1, 2 and 6, conferred a moderate yet reproducible and significant level of protection in a murine aerosol model of M. tuberculosis infection. (C) 2008 Elsevier Ltd. All rights reserved. C1 [West, Nicholas P.; Wozniak, Teresa M.; Britton, Warwick J.] Centenary Inst Canc Med & Cell Biol, Mycobacteriol Res Program, Newtown, NSW 2042, Australia. [Valenzuela, Jesus; Ribeiro, Jose M. C.] NIAID, NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Feng, Carl G.; Sher, Alan] NIAID, NIH, Parasitol Lab, Bethesda, MD 20892 USA. [Britton, Warwick J.] Univ Sydney, Dept Med, Sydney, NSW 2006, Australia. RP West, NP (reprint author), Centenary Inst Canc Med & Cell Biol, Mycobacteriol Res Program, Locked Bag 6, Newtown, NSW 2042, Australia. EM n.west@centenary.org.au RI West, Nicholas/C-3119-2008; OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z99 AI999999, Z01 AI000932-05] NR 39 TC 23 Z9 23 U1 0 U2 0 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 JUL 23 PY 2008 VL 26 IS 31 BP 3853 EP 3859 DI 10.1016/j.vaccine.2008.05.007 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 331JR UT WOS:000258009000010 PM 18565629 ER PT J AU Cong, H Gu, QM Yin, HE Wang, JW Zhao, QL Zhou, HY Li, Y Zhang, JQ AF Cong, Hua Gu, Qin Min Yin, Hong En Wang, Jing Wen Zhao, Qun Li Zhou, Huai Yu Li, Ying Zhang, Jia Qin TI Multi-epitope DNA vaccine linked to the A(2)/B subunit of cholera toxin protect mice against Toxoplasma gondii SO VACCINE LA English DT Article DE multi-epitope; Toxoplasma gondii; DNA vaccine; cholera toxin ID EXCRETED-SECRETED ANTIGENS; CONGENITAL TOXOPLASMOSIS; MUCOSAL IMMUNIZATION; PARASITE CYSTS; ORAL INFECTION; ROP2 PROTEIN; CPG DNA; IMMUNITY; IMMUNOGENICITY; PLASMID AB The search for an effective vaccine against toxoplasmosis remains a challenging and elusive goal. Combination of epitopes from different stages of Toxoplasma gondii life cycle is an optimal strategy to overcome the antigen complexity of the parasite. Based on published epitope derived from several promising candidate vaccine antigens, we construct a DNA vaccine encoding multi-epitope of T gondii and CpG motif, with or without the A(2)/B subunit of cholera toxin as a genetic adjuvant. The immunity induced by this vaccine in BALB/c mice and the protection afforded against challenge with the highly virulent RH strain of T gondii is assessed. This vaccine was able to elicit a significant humoral and cellular immune response in vaccinated mice. Furthermore, CTXA(2)/B as a genetic adjuvant could enhance the magnitude of immune responses as well as increased survival rate in mice infected with the lethal RH tachyzoites. This study is the first report of a multi-epitope DNA construct strategy as a potential DNA vaccine against toxoplasmosis. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Cong, Hua; Gu, Qin Min; Zhao, Qun Li; Zhou, Huai Yu; Li, Ying; Zhang, Jia Qin] Shandong Univ, Dept Parasitol, Sch Med, Jinan 250012, Shandong, Peoples R China. [Yin, Hong En] NIH NIDCR, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. [Wang, Jing Wen] Affiliated Hosp, Shandong Med Inst, Jinan 250062, Shandong, Peoples R China. RP Gu, QM (reprint author), Shandong Univ, Dept Parasitol, Sch Med, 44 Wenhuaxi Rd, Jinan 250012, Shandong, Peoples R China. EM gqm1943@yahoo.com.cn NR 50 TC 33 Z9 39 U1 0 U2 5 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 JUL 23 PY 2008 VL 26 IS 31 BP 3913 EP 3921 DI 10.1016/j.vaccine.2008.04.046 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 331JR UT WOS:000258009000019 PM 18555564 ER PT J AU Tao, YG Xu, Y Xu, HE Simons, SS AF Tao, Yong-guang Xu, Yong Xu, H. Eric Simons, S. Stoney, Jr. TI Mutations of glucocorticoid receptor differentially affect AF2 domain activity in a steroid-selective manner to alter the potency and efficacy of gene induction and repression SO BIOCHEMISTRY LA English DT Article ID LIGAND-BINDING DOMAIN; TRANSCRIPTIONAL REGULATORY SURFACES; PARTIAL AGONIST ACTIVITY; DOSE-RESPONSE CURVE; NF-KAPPA-B; DNA-BINDING; ANTAGONIST COMPLEXES; ESTROGEN-RECEPTOR; PROGESTERONE-RECEPTORS; COREPRESSOR BINDING AB The transcriptional activity of steroid hormones is intimately associated with their structure. Deacylcortivazol (DAC) contains several features that were predicted to make it an inactive glucocorticoid. Nevertheless, gene induction and repression by complexes of glucocorticoid receptor (GR) with DAC occur with potency (lower EC50) greater than and efficacy (maximal activity, or A(max)) equal to those of the very active and smaller synthetic glucocorticoid dexamethasone (Dex). Guided by a recent X-ray structure of DAC bound to the GR ligand binding domain (LBD), we now report that several point mutants in the LBD have little effect on the binding of either agonist steroid. However, these same mutations dramatically alter the A(max) and/or EC50 of exogenous and endogenous genes in a manner that depends on steroid structure. In some cases, Dex is no longer a full agonist. These properties appear to result from a preferential inactivation of the AF2 activation domain in the GR LBD of Dex-bound, but not DAC-bound, receptors. The Dex-bound receptors display normal binding to, but a greatly reduced response to, the coactivator TIF2, thus indicating a defect in the transmission efficiency of GR-steroid complex information to the coactivator TIF2. In addition, all GR mutants that are active in gene induction with either Dex or DAC have greatly reduced activity in gene repression. This contrasts with the reports of GR mutations preferentially suppressing GR-mediated induction. The properties of these GR mutants in gene induction support the hypothesis that the A(max) and EC50 of GR-controlled gene expression can be independently modified, indicate that the receptor can be modified to favor activity with a specific agonist steroid, and suggest that new ligands with suitable substituents may be able to affect the same LBD conformational changes and thereby broaden the therapeutic applications of glucocorticoid steroids. C1 [Tao, Yong-guang; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, CEB, NIH, Bethesda, MD 20892 USA. [Xu, Yong; Xu, H. Eric] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, CEB, NIH, Bldg 10,Room 8N-307B, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov FU Intramural NIH HHS [Z01 DK057800-16, Z01 DK047040-01] NR 63 TC 19 Z9 20 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 JUL 22 PY 2008 VL 47 IS 29 BP 7648 EP 7662 DI 10.1021/bi800472w PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 326NB UT WOS:000257665100007 PM 18578507 ER PT J AU Jin, P Wang, E Ren, JQ Childs, R Shin, JW Khuu, H Marincola, FM Stroncek, DF AF Jin, Ping Wang, Ena Ren, Jiaqiang Childs, Richard Shin, Jeong Won Khuu, Hanh Marincola, Francesco M. Stroncek, David F. TI Differentiation of two types of mobilized peripheral blood stem cells by microRNA and cDNA expression analysis SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; CHRONIC LYMPHOCYTIC-LEUKEMIA; COLONY-STIMULATING FACTOR; CXCR4 ANTAGONIST AMD3100; G-CSF; RAPID MOBILIZATION; GENE-EXPRESSION; DOWN-REGULATION; CORD BLOOD; FACTOR-I AB Background: Mobilized-peripheral blood hematopoietic stem cells (HSCs) have been used for transplantation, immunotherapy, and cardiovascular regenerative medicine. Agents used for HSC mobilization include G-CSF and the CXCR4 inhibitor AMD3100 (plerixafor). The HSCs cells mobilized by each agent may contain different subtypes and have different functions. To characterize mobilized HSCs used for clinical applications, microRNA (miRNA) profiling and gene expression profiling were used to compare AMD3100-mobilized CD133+ cells from 4 subjects, AMD3100 plus G-CSF-mobilized CD133+ cells from 4 subjects and G-CSF-mobilized CD34+ cells from 5 subjects. The HSCs were compared to peripheral blood leukocytes (PBLs) from 7 subjects. Results: Hierarchical clustering of miRNAs separated HSCs from PBLs. miRNAs up-regulated in all HSCs included hematopoiesis-associated miRNA; miR-126, miR-10a, miR-221 and miR-17-92 cluster. miRNAs up-regulated in PBLs included miR-142-3p, -218, -21, and -379. Hierarchical clustering analysis of miRNA expression separated the AMD3100-mobilized CD133+ cells from G-CSF-mobilized CD34+ cells. Gene expression analysis of the HSCs naturally segregated samples according to mobilization and isolation protocol and cell differentiation status. Conclusion: HSCs and PBLs have unique miRNA and gene expression profiles. miRNA and gene expression microarrays maybe useful for assessing differences in HSCs. C1 [Jin, Ping; Wang, Ena; Ren, Jiaqiang; Shin, Jeong Won; Khuu, Hanh; Marincola, Francesco M.; Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Childs, Richard] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Shin, Jeong Won] Soonchunhyang Univ Hosp, Dept Lab Med, Seoul, South Korea. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM pjin@cc.nih.gov; EWang@cc.nih.gov; renj@cc.nih.gov; childsr@nhlbi.nih.gov; jwshin@hosp.sch.ac.kr; hkhuu@cc.nih.gov; Fmarincola@cc.nih.gov; Dstroncek@cc.nih.gov FU NIH, Bethesda, Maryland, USA FX We thank the Staff of the Dowling Clinic, DTM, CC, NIH for collecting the cells and the staff of the Cell Processing Laboratory, DTM, CC, NIH for isolating the CD34+ and CD133+ cells. The study was funded by the NIH, Bethesda, Maryland, USA. NR 58 TC 50 Z9 53 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 22 PY 2008 VL 6 AR 39 DI 10.1186/1479-5876-6-39 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 337JZ UT WOS:000258433700003 PM 18647411 ER PT J AU Mathews, DJH Sugarman, J Bok, H Blass, DM Coyle, JT Duggan, P Finkel, J Greely, HT Hillis, A Hoke, A Johnson, R Johnston, M Kahn, J Kerr, D Kurtzberg, J Liao, SM McDonald, JW McKhann, G Nelson, KB Rao, M Regenberg, A Siegel, AW Smith, K Solter, D Song, H Vescovi, A Young, W Gearhart, JD Faden, R AF Mathews, D. J. H. Sugarman, J. Bok, H. Blass, D. M. Coyle, J. T. Duggan, P. Finkel, J. Greely, H. T. Hillis, A. Hoke, A. Johnson, R. Johnston, M. Kahn, J. Kerr, D. Kurtzberg, J. Liao, S. M. McDonald, J. W. McKhann, G. Nelson, K. B. Rao, M. Regenberg, A. Siegel, A. W. Smith, K. Solter, D. Song, H. Vescovi, A. Young, W. Gearhart, J. D. Faden, R. TI Cell-based interventions for neurologic conditions - Ethical challenges for early human trials SO NEUROLOGY LA English DT Review ID EMBRYONIC STEM-CELLS; DEEP-BRAIN-STIMULATION; PARKINSONS-DISEASE; MULTIPLE-SCLEROSIS; TRANSPLANTATION; FUTILITY; SAFETY; ISSUES AB Background: Attempts to translate basic stem cell research into treatments for neurologic diseases and injury are well under way. With a clinical trial for one such treatment approved and in progress in the United States, and additional proposals under review, we must begin to address the ethical issues raised by such early forays into human clinical trials for cell-based interventions for neurologic conditions. Methods: An interdisciplinary working group composed of experts in neuroscience, cell biology, bioethics, law, and transplantation, along with leading disease researchers, was convened twice over 2 years to identify and deliberate on the scientific and ethical issues raised by the transition from preclinical to clinical research of cell-based interventions for neurologic conditions. Results: While the relevant ethical issues are in many respects standard challenges of human subjects research, they are heightened in complexity by the novelty of the science, the focus on the CNS, and the political climate in which the science is proceeding. Conclusions: Distinctive challenges confronting US scientists, administrators, institutional review boards, stem cell research oversight committees, and others who will need to make decisions about work involving stem cells and their derivatives and evaluate the ethics of early human trials include evaluating the risks, safety, and benefits of these trials, determining and evaluating cell line provenance, and determining inclusion criteria, informed consent, and the ethics of conducting early human trials in the public spotlight. Further study and deliberation by stakeholders is required to move toward professional and institutional policies and practices governing this research. C1 [Mathews, D. J. H.; Sugarman, J.; Bok, H.; Blass, D. M.; Duggan, P.; Finkel, J.; Hillis, A.; Hoke, A.; Johnson, R.; Kerr, D.; Liao, S. M.; McKhann, G.; Regenberg, A.; Siegel, A. W.; Smith, K.; Song, H.; Gearhart, J. D.; Faden, R.] Johns Hopkins Univ, Baltimore, MD USA. [Coyle, J. T.] Harvard Univ, Sch Med, Boston, MA USA. [Greely, H. T.] Stanford Univ, Stanford, CA 94305 USA. [Johnston, M.; McDonald, J. W.] Kennedy Krieger Inst, Baltimore, MD USA. [Kurtzberg, J.] Univ Minnesota, Minneapolis, MN USA. [Kurtzberg, J.] Duke Univ, Med Ctr, Durham, NC USA. [Nelson, K. B.] NIH, Bethesda, MD 20892 USA. [Rao, M.] Invitrogen Corp, Carlsbad, CA USA. [Solter, D.] Max Planck Inst Immunobiol, D-7800 Freiburg, Germany. [Vescovi, A.] Univ Milano Bicocca, Milan, Italy. [Young, W.] Rutgers State Univ, Piscataway, NJ USA. RP Mathews, DJH (reprint author), 100 N Charles St,Suite 740, Baltimore, MD 21201 USA. EM dmathews@jhmi.edu OI Hoke, Ahmet/0000-0003-1215-3373 NR 42 TC 39 Z9 41 U1 0 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 22 PY 2008 VL 71 IS 4 BP 288 EP 293 DI 10.1212/01.wnl.0000316436.13659.80 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 328LC UT WOS:000257798900013 PM 18463365 ER PT J AU Kimblin, N Peters, N Debrabant, A Secundino, N Egen, J Lawyer, P Fay, MP Kamhawi, S Sacks, D AF Kimblin, Nicola Peters, Nathan Debrabant, Alain Secundino, Nagila Egen, Jackson Lawyer, Phillip Fay, Michael P. Kamhawi, Shaden Sacks, David TI Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE leishmaniasis; vectors; bites; parasites ID LUTZOMYIA-LONGIPALPIS; PARASITE TRANSMISSION; PHLEBOTOMUS-PAPATASI; VECTOR; BITE; PROMASTIGOTES; MECHANISM; MEXICANA; MODELS; MICE AB Leishmaniasis is transmitted between mammalian hosts by the bites of bloodsucking vector sand flies. The dose of parasites transmitted to the mammalian host has never been directly determined. We developed a real-time PCR-based method to determine the number of Leishmania major parasites inoculated into the ears of living mice during feeding by individual infected flies (Phlebotomus duboscqi). The number of parasites transmitted varied over a wide range in the 58 ears in which Leishmania were detected and demonstrated a clear bimodal distribution. Most of the infected mice were inoculated with a low dose of <600 parasites. One in four received a higher dose of >1,000 and up to 100,000 cells. High-dose transmission was associated with a heavy midgut infection of >30,000 parasites, incomplete blood feeding, and transmission of a high percentage of the parasite load in the fly. To test the impact of inoculum size on infection outcome, we compared representative high- (5,000) and low- (100) dose intradermal needle infections in the ears of C57BL/6 mice. To mimic natural transmission, we used sand fly-derived metacyclic forms of L. major and preexposed the injection site to the bites of uninfected flies. Large lesions developed rapidly in the ears of mice receiving the high-dose inoculum. The low dose resulted in only minor pathology but a higher parasite titer in the chronic phase, and it established the host as an efficient long-term reservoir of infection back to vector sand flies. C1 [Kimblin, Nicola; Peters, Nathan; Secundino, Nagila; Lawyer, Phillip; Kamhawi, Shaden; Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Egen, Jackson] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Debrabant, Alain] US FDA, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM dsacks@nih.gov OI Egen, Jackson/0000-0003-2053-0837; Fay, Michael P./0000-0002-8643-9625 FU Intramural NIH HHS NR 27 TC 78 Z9 80 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2008 VL 105 IS 29 BP 10125 EP 10130 DI 10.1073/pnas.0802331105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 330BB UT WOS:000257913200051 PM 18626016 ER PT J AU van der Brug, MP Blackinton, J Chandran, J Hao, LY Lal, A Mazan-Mamczarz, K Martindale, J Xie, CS Ahmad, R Thomas, KJ Beilina, A Gibbs, JR Ding, JH Myers, AJ Zhan, M Cai, HB Bonini, NM Gorospe, M Cookson, MR AF van der Brug, Marcel P. Blackinton, Jeff Chandran, Jayanth Hao, Ling-Yang Lal, Ashish Mazan-Mamczarz, Krystyna Martindale, Jennifer Xie, Chengsong Ahmad, Rili Thomas, Kelly J. Beilina, Alexandra Gibbs, J. Raphael Ding, Jinhui Myers, Amanda J. Zhan, Ming Cai, Huaibin Bonini, Nancy M. Gorospe, Myriam Cookson, Mark R. TI RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene expression; oxidative stress; Parkinson's disease; translation ID UBIQUITIN-PROTEASOME SYSTEM; OXIDATIVE STRESS; ALPHA-SYNUCLEIN; DROSOPHILA DJ-1; MITOCHONDRIAL LOCALIZATION; DJ-1-DEFICIENT MICE; MESSENGER-RNA; DISEASE; APOPTOSIS; CELLS AB Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that DJ-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that DJ-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner. C1 [van der Brug, Marcel P.; Blackinton, Jeff; Ahmad, Rili; Thomas, Kelly J.; Beilina, Alexandra; Ding, Jinhui; Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Bethesda, MD 20892 USA. [Chandran, Jayanth; Xie, Chengsong; Cai, Huaibin] NIA, Transgen Unit, Bethesda, MD 20892 USA. [Gibbs, J. Raphael; Ding, Jinhui] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Lal, Ashish; Mazan-Mamczarz, Krystyna; Martindale, Jennifer; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. [Cookson, Mark R.] NIA, Res Resources Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Hao, Ling-Yang; Bonini, Nancy M.] Univ Penn, Howard Hughes Med Inst, Dept Biol, Philadelphia, PA 19104 USA. [Blackinton, Jeff] Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Unit, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov RI Myers, Amanda/B-1796-2010; Gibbs, J. Raphael/A-3984-2010; Cai, Huaibin/H-3359-2013 OI Myers, Amanda/0000-0002-3100-9396; Cai, Huaibin/0000-0002-8596-6108 FU Howard Hughes Medical Institute; Intramural NIH HHS; NIA NIH HHS [P01 AG009215, P01-AG09215] NR 35 TC 116 Z9 117 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 JUL 22 PY 2008 VL 105 IS 29 BP 10244 EP 10249 DI 10.1073/pnas.0708518105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 330BB UT WOS:000257913200071 PM 18626009 ER PT J AU Hendgen-Cotta, UB Merx, MW Shiva, S Schmitz, J Becher, S Klare, JP Steinhoff, HJ Goedecke, A Schrader, J Gladwin, MT Kelm, M Rassaf, T AF Hendgen-Cotta, Ulrike B. Merx, Marc W. Shiva, Sruti Schmitz, Joel Becher, Stefanie Klare, Johann P. Steinhoff, Heinz-Juergen Goedecke, Axel Schrader, Jueren Gladwin, Mark T. Kelm, Malte Rassaf, Tienush TI Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTOCHROME-C-OXIDASE; RED-BLOOD-CELLS; MITOCHONDRIAL RESPIRATION; SIGNALING MOLECULE; HYPOXIC CONDITIONS; NITROGEN MONOXIDE; FERRYL MYOGLOBIN; COMPLEX-I; NO; TISSUES AB The nitrite anion is reduced to nitric oxide (NO(center dot)) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO(center dot) signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ((+/+)) and knockout ((-/-)) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO(center dot) generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO(center dot) generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO(center dot) by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin(+/+) but not in myoglobin(-/-) hearts, nitrite treatment resulted in an improved recovery of post-ischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin(+/+) mice, whereas in myoglobin(-/-) mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation. myoglobin knockout mice. C1 [Hendgen-Cotta, Ulrike B.; Merx, Marc W.; Schmitz, Joel; Becher, Stefanie; Kelm, Malte; Rassaf, Tienush] Univ Hosp Aachen, Dept Med, Div Cardiol Pulmonol & Vasc Med, D-52074 Aachen, Germany. [Shiva, Sruti; Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Shiva, Sruti; Gladwin, Mark T.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Klare, Johann P.; Steinhoff, Heinz-Juergen] Univ Osnabruck, Dept Phys, D-46096 Osnabruck, Germany. [Goedecke, Axel; Schrader, Jueren] Univ Dusseldorf, Dept Cardiovasc Phys, D-40225 Dusseldorf, Germany. RP Rassaf, T (reprint author), Univ Hosp Aachen, Dept Med, Div Cardiol Pulmonol & Vasc Med, Pauwelsstr 30, D-52074 Aachen, Germany. EM trassaf@ukaachen.de RI Klare, Johann/C-1428-2009; Steinhoff, Heinz-Juergen/H-3791-2014 OI Klare, Johann/0000-0002-5761-5968; Steinhoff, Heinz-Juergen/0000-0002-5888-0157 NR 41 TC 219 Z9 221 U1 3 U2 30 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 JUL 22 PY 2008 VL 105 IS 29 BP 10256 EP 10261 DI 10.1073/pnas.0801336105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 330BB UT WOS:000257913200073 PM 18632562 ER PT J AU Sundgren, A Barchi, JJ AF Sundgren, Andreas Barchi, Joseph J., Jr. TI Varied presentation of the Thomsen-Friedenreich disaccharide tumor-associated carbohydrate antigen on gold nanoparticles SO CARBOHYDRATE RESEARCH LA English DT Article DE Thomsen-Friedenreich antigen; gold nanoparticles; glycopeptides; immunogen ID HUMAN PANCREATIC ADENOCARCINOMA; MEDIATED SELF-RECOGNITION; MARINE SPONGE CELLS; QUANTUM DOTS; HUMAN BREAST; GLYCONANOPARTICLES; CANCER; CARCINOMA; ADHESION; MUCIN AB Three-dimensional self-assembled monolayers of gold coated with the Thomsen-Friedenreich antigen (TF(ag)) disaccharide (beta-Galp-(1 -> 3)-GalpNAc) in a variety of presentations have been prepared and characterized. Anomalies in the size distribution of our originally synthesized TF(ag)-bearing nanoparticles as shown in dynamic light scattering experiments prompted us to explore the effect of antigen density on the uniformity of the particles. Gold nanoparticles containing a range of densities 'diluted' with copies of the PEG-thiol spacer unit showed that lower antigen density affords more uniform particles. We also wanted to study the constitution of the actual antigen by synthesizing nanoparticles not only with the linker-extended disaccharide, but also within the context of the surrounding peptide sequence where it may be presented in vivo. The synthesis of TF(ag)-containing glycopeptide thiols based on a mucin peptide repeating unit were prepared, assembled into gold nanoparticles and their physical properties evaluated. These novel multivalent tools should prove extremely useful in exploring the binding properties and immune response to this important carbohydrate antigen. Published by Elsevier Ltd. C1 [Barchi, Joseph J., Jr.] NCI, Med Chem Lab, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Frederick, MD 21702 USA. RP Barchi, JJ (reprint author), NCI, Med Chem Lab, 376 Boyles St,POB B,Bldg 376,Room 209, Frederick, MD 21702 USA. EM barchi@helix.nih.gov RI Barchi Jr., Joseph/N-3784-2014 FU Intramural NIH HHS [Z01 BC010451-06] NR 43 TC 28 Z9 28 U1 3 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD JUL 21 PY 2008 VL 343 IS 10-11 BP 1594 EP 1604 DI 10.1016/j.carres.2008.05.003 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 326KM UT WOS:000257657500008 PM 18502409 ER PT J AU Saksena, R Chernyak, A Kovac, P AF Saksena, Rina Chernyak, Anatoli Kovac, Pavol TI Synthesis of spacer-equipped di-, tri-, and the tetrasaccharide fragments of the deacetylated O-PS1 of Citrobacter gillenii O9a,9b, and a related pentasaccharide SO CARBOHYDRATE RESEARCH LA English DT Article DE Citrobacter gillenii; oligosaccbaride synthesis; D-4-NAc-rhamnooligosaccharides ID VIBRIO-CHOLERAE O-1; METHYL ALPHA-GLYCOSIDES; SEROTYPE INABA; O-POLYSACCHARIDE; D-MANNOSE; ANTIGEN; TERMINUS; OGAWA; PROTEINS; VIBRIO-CHOLERAE-O-1 AB The title rhamnooligosaccharides [alpha-D-Rhap4NAc-(1 -> 3)-O(-D-Rhap4NAc-1-O-(CH(2))(5)COOMe, alpha-D-Rhap4NAc-(1 -> 3)-alpha-D-Rhap4NAc-(1 3)-alpha-D-Rhap4NAc-1-O-(CH(2))(5)COOMe, alpha-D-Rhap4NAc-(1 -> 2)-alpha-D-Rhap4NAc-(1 -> 3)-alpha-D-Rhap4NAc-(1 -> 3)-alpha-D-Rhap4NAc-1-O-(CH(2))(5)COOMe, and alpha-D-Rhap4NAc-(1 -> 3)-alpha-D-Rhap4NAc-(1-2)-(alpha-D-Rhap4NAc-(1 -> 3)-alpha-D-Rhap4NAc(1 -> 3)-alpha-D-Rhap4NAc-1-O-(CH(2))(5)COOMe] were synthesized in a stepwise fashion from 5-methoxycarbonylpentyl 4-azido-4, 6-dideoxy-2-O-benzyl-alpha-D-mannopyranoside and orthogonally protected 1-thioglycoside glycosyl donors. The amorphous, final products were fully characterized as corresponding per-O-acetyl derivatives. Published by Elsevier Ltd. C1 [Saksena, Rina; Chernyak, Anatoli; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@belix.nih.gov FU Intramural NIH HHS [Z01 DK059701-34] NR 28 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD JUL 21 PY 2008 VL 343 IS 10-11 BP 1693 EP 1706 DI 10.1016/j.carres.2008.03.037 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 326KM UT WOS:000257657500017 PM 18436197 ER PT J AU Fiorillo, JA AF Fiorillo, Joseph Anthony TI Merkel cell carcinoma metastatic to the heart SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CARDIAC-TAMPONADE; CHEMOTHERAPY C1 NCI, Bethesda, MD 20892 USA. RP Fiorillo, JA (reprint author), NCI, Bethesda, MD 20892 USA. NR 15 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2008 VL 26 IS 21 BP 3643 EP 3644 DI 10.1200/JCO.2008.16.7866 PG 2 WC Oncology SC Oncology GA 331ZF UT WOS:000258050500029 PM 18640944 ER PT J AU Scher, HI Halabi, S Tannock, IF Morris, M Sternberg, CN Carducci, MA Eisenberger, MA Higano, C Bubley, GJ Dreicer, R Petrylak, DP Kantoff, P Basch, E Kelly, WK Figg, WD Small, EJ Beer, TM Wilding, G Martin, A Hussain, M AF Scher, Howard I. Halabi, Susan Tannock, Ian F. Morris, Michael Sternberg, Cora N. Carducci, Michael A. Eisenberger, Mario A. Higano, Celestia Bubley, Glenn J. Dreicer, Robert Petrylak, Daniel P. Kantoff, Philip Basch, Ethan Kelly, Wm Kevin Figg, William D. Small, Eric J. Beer, Tomasz M. Wilding, George Martin, Alison Hussain, Maha TI Trial design for metastatic castration-resistant prostate cancer - Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ANTIGEN; SURROGACY; IMPACT; MEN C1 [Scher, Howard I.; Morris, Michael; Basch, Ethan] Mem Sloan Kettering Canc Ctr, Sidney Kimmel Ctr Prostate & Urol Cancers, New York, NY 10021 USA. [Carducci, Michael A.; Eisenberger, Mario A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Halabi, Susan] Duke Univ, Med Ctr, Durham, NC USA. [Tannock, Ian F.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Sternberg, Cora N.] Sam Camillo Forlanini Hosp, Rome, Italy. [Higano, Celestia] Univ Washington, Seattle, WA 98195 USA. [Bubley, Glenn J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Dreicer, Robert] Cleveland Clin, Cleveland, OH 44106 USA. [Petrylak, Daniel P.] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Kantoff, Philip] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kelly, Wm Kevin] Yale Univ, Ctr Canc, New Haven, CT USA. [Figg, William D.; Martin, Alison] NCI, Bethesda, MD 20892 USA. [Small, Eric J.] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Beer, Tomasz M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Wilding, George] Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. [Hussain, Maha] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Scher, HI (reprint author), Mem Sloan Kettering Canc Ctr, Sidney Kimmel Ctr Prostate & Urol Cancers, 1275 York Ave, New York, NY 10021 USA. RI Figg Sr, William/M-2411-2016 NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2008 VL 26 IS 21 BP 3648 EP 3649 DI 10.1200/JCO.2008.17.2494 PG 3 WC Oncology SC Oncology GA 331ZF UT WOS:000258050500032 ER PT J AU Wang, HL Morales, M AF Wang, Hui-Ling Morales, Marisela TI Corticotropin-releasing factor binding protein within the ventral tegmental area is expressed in a subset of dopaminergic neurons SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE GABA; substantia nigra; dopamine; reward and stress ID STRESS-INDUCED RELAPSE; SUBSTANTIA-NIGRA; FACTOR CRF; FACTOR-RECEPTOR; RAT-BRAIN; TYROSINE-HYDROXYLASE; BEHAVIORAL-RESPONSES; PREFRONTAL CORTEX; HIGH-AFFINITY; HUMAN-PLASMA AB Corticotropin-releasing factor (CRF) and related peptides play a role in mediating neuronal effects of stress. These peptides mediate stress responses by their interactions with the CRF receptors and the CRF-binding protein (CRF-BP). Because the CRF-BP is implicated in neurotransmission within the ventral tegmental area (VTA), we investigated whether the CRF-BP is expressed in VTA neurons. By in situ hybridization, we detected cellular expression of CRF-BP mRNA in the VTA; no such expression was seen in neighboring substantia nigra pars compacta (SNC) or substantia nigra pars reticulata. By double in situ hybridization, we determined that VTA neurons with CRF-BP mRNA coexpressed transcripts encoding either tyrosine hydroxylase [TH; a marker for dopamine (DA) neurons] or glutamic acid decarboxylase [GAD; synthesizing enzyme of gamma-aminobutyric acid (GABA)]. Neurons with CRF-BP mRNA represented 25% of the total population of TH-expressing neurons and 28% of the total population of GAD-expressing neurons, indicating that discrete subpopulations of dopaminergic and GABAergic neurons are present in the VTA. Within the total population of neurons containing CRF-BP mRNA, 70% coexpressed TH mRNA and only 27% coexpressed GAD mRNA. As far as we are aware, we provide the first anatomical evidence that a molecule, CRF-BP, is encoded by DAergic neurons of the VTA but not by those of the SNC. We propose, based on the observation that the majority of VTA neurons expressing CRF-BP mRNA are DAergic, that in the VTA interactions of CRF-BP with CRF, or with CRF-related peptides, are likely to be mediated predominantly by DAergic neurons. C1 [Wang, Hui-Ling; Morales, Marisela] Natl Inst Drug Abuse, BRC, Intramural Res Program, Baltimore, MD 21224 USA. RP Morales, M (reprint author), Natl Inst Drug Abuse, BRC, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000508-01, Z99 DA999999] NR 71 TC 39 Z9 39 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 20 PY 2008 VL 509 IS 3 BP 302 EP 318 DI 10.1002/cne.21751 PG 17 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 312DB UT WOS:000256648200005 PM 18478589 ER PT J AU Wu, CO Tian, X Bang, HJ AF Wu, Colin O. Tian, Xin Bang, Heejung TI A varying-coefficient model for the evaluation of time-varying concomitant intervention effects in longitudinal studies SO STATISTICS IN MEDICINE LA English DT Article DE change-point models; concomitant intervention; longitudinal study; polynomial splines; shared-parameter model; varying-coefficient model ID ADDITIVE MIXED MODELS; MYOCARDIAL-INFARCTION; ENHANCING RECOVERY; SPLINE ESTIMATION; CLUSTERED DATA; MISSING DATA; INFERENCE; REGRESSION; BIOSTATISTICS; TUTORIAL AB Concomitant interventions are often introduced during a longitudinal clinical trial to patients who respond undesirably to the pre-specified treatments. In addition to the main objective of evaluating the pre-specified treatment effects, an important secondary objective in such a trial is to evaluate whether a concomitant intervention could change a patient's response over time. Because the initiation of a concomitant intervention may depend on the patient's general trend of pre-intervention outcomes, regression approaches that treat the presence of the intervention as a time-dependent covariate may lead to biased estimates for the intervention effects. Borrowing the techniques of Follmann and Wu (Biometrics 1995; 51:151-168) for modeling informative missing data, we propose a varying-coefficient mixed-effects model to evaluate the patient's longitudinal outcome trends before and after the patient's starting time of the intervention. By allowing the random coefficients to be correlated with the patient's starting time of the intervention, our model leads to less biased estimates of the intervention effects. Nonparametric estimation and inferences of the coefficient curves and intervention effects are developed using B-splines. Our methods are demonstrated through a longitudinal clinical trial in depression and heart disease and a simulation study. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Wu, Colin O.; Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Bang, Heejung] Cornell Univ, Weill Med Coll, Dept Publ Hlth, Div Biostat & Epidemiol, New York, NY 10021 USA. RP Wu, CO (reprint author), NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. EM wuc@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 28 TC 2 Z9 2 U1 2 U2 5 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 JUL 20 PY 2008 VL 27 IS 16 BP 3042 EP 3056 DI 10.1002/sim.3262 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 325DG UT WOS:000257567900004 PM 18351714 ER PT J AU Zolotukhin, AS Schneider, R Uranishi, H Bear, J Tretyakova, I Michalowski, D Smulevitch, S O'Keeffe, S Pavlakis, GN Felber, BK AF Zolotukhin, Andrei S. Schneider, Ralf Uranishi, Hiroaki Bear, Jenifer Tretyakova, Irina Michalowski, Daniel Smulevitch, Sergey O'Keeffe, Sean Pavlakis, George N. Felber, Barbara K. TI The RNA transport element RTE is essential for IAP LTR-retrotransposon mobility SO VIROLOGY LA English DT Article DE retrotransposition; retroelement; mRNA transport; nuclear export; CTE; retrovirus; HIV; SRV; NXF1; RBM15 ID HUMAN-IMMUNODEFICIENCY-VIRUS; SIMIAN RETROVIRUS TYPE-1; REV-RESPONSE ELEMENT; VIRAL MESSENGER-RNA; ENDOGENOUS RETROVIRUS; NUCLEAR-EXPORT; HTDV/HERV-K; GENE-EXPRESSION; GAG EXPRESSION; MOUSE GENOME AB We previously identified an RNA transport element (RTE) present at a high copy number in the mouse genome. Here, we show that a related element, RTE-D, is part of a mobile LTR-retrotransposon, which belongs to a family of intracisternal A-particle related elements (IAP). We demonstrate that RTE-D is essential for the mobility of the retrotransposon and it can be substituted by other known RNA export signals. RTE-deficient IAP transcripts are retained in the nucleus, while the RTE-containing transcripts accumulate in the cytoplasm allowing Gag protein expression. RTE-D acts as a posttranscriptional control element in a heterologous reporter mRNA and is activated by the cellular RNA binding protein 15 (RBM15), as reported for the previously described RTE. We identified a complex family of RTE-containing IAPs in mouse and mapped the active RTE-D-containing IAPs to the Mmr10 group of LTR-retrotransposons. These data reveal that, despite a complex evolutionary history, retroelements and retroviruses share the dependency on posttranscriptional regulation. Published by Elsevier Inc. C1 [Zolotukhin, Andrei S.; Bear, Jenifer; Tretyakova, Irina; Michalowski, Daniel; Smulevitch, Sergey; Felber, Barbara K.] NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. [Schneider, Ralf; O'Keeffe, Sean] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, Neuherberg, Germany. [Uranishi, Hiroaki; Pavlakis, George N.] NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Sect, Frederick, MD 21702 USA. RP Felber, BK (reprint author), NCI, Ctr Canc Res, Vaccine Branch, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. EM felber@ncifcrf.gov NR 58 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 JUL 20 PY 2008 VL 377 IS 1 BP 88 EP 99 DI 10.1016/j.virol.2008.04.002 PG 12 WC Virology SC Virology GA 317SR UT WOS:000257040700011 PM 18485438 ER PT J AU Nelson, JD Kinkead, H Brunel, FM Leaman, D Jensen, R Louis, JM Maruyama, T Bewley, CA Bowdish, K Clore, GM Dawson, PE Frederickson, S Mage, RG Richman, DD Burton, DR Zwick, MB AF Nelson, Josh D. Kinkead, Heather Brunel, Florence M. Leaman, Dan Jensen, Richard Louis, John M. Maruyama, Toshiaki Bewley, Carole A. Bowdish, Katherine Clore, G. Marius Dawson, Philip E. Frederickson, Shana Mage, Rose G. Richman, Douglas D. Burton, Dennis R. Zwick, Michael B. TI Antibody elicited against the gp41 N-heptad repeat (NHR) coiled-coil can neutralize HIV-1 with modest potency but non-neutralizing antibodies also bind to NHR mimetics SO VIROLOGY LA English DT Review DE antibody neutralization; HIV-1 gp41; phage display; fusion intermediate; six-helix bundle; vaccine design; epitope exposure; virus capture ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROXIMAL EXTERNAL REGION; HUMAN MONOCLONAL-ANTIBODY; GLYCOPROTEIN-MEDIATED FUSION; D-PEPTIDE INHIBITORS; ENVELOPE GLYCOPROTEIN; PHAGE LIBRARY; COMPARATIVE IMMUNOGENICITY; CONFORMATIONAL-CHANGES; GP120 GLYCOPROTEIN AB Following CD4 receptor binding to the HIV-1 envelope spike (Env), the conserved N-heptad repeat (NHR) region of gp41 forms a coiled-coil that is a precursor to the fusion reaction. Although it has been a target of drug and vaccine design, there are few monoclonal antibody (mAb) tools with which to probe the antigenicity and immunogenicity specifically of the NHR coiled-coil. Here, we have rescued HIV-1-neutralizing anti-NHR mAbs from immune phage display libraries that were prepared (i) from b9 rabbits immunized with a previously described mimetic of the NHR coiled-coil, N35(CCG)-N13, and (ii) from an HIV-1 infected individual. We describe a rabbit single-chain Fv fragment (scFv), 8K8, and a human Fab, DN9, which specifically recognize NHR coiled-coils that are unoccupied by peptide corresponding to the C-heptad repeat or CHR region of gp41 (e.g. C34). The epitopes of 8K8 and DN9 were found to partially overlap with that of a previously described anti-NHR mAb, IgG D5; however, SK8 and DN9 were much more specific than D5 for unoccupied NHR trimers. The mAbs, including a whole IgG SK8 molecule, neutralized primary HIV-1 of clades B and C in a pseudotyped virus assay with comparable, albeit relatively modest potency. Finally, a human Fab T3 and a rabbit serum (both non-neutralizing) were able to block binding of D5 and 8K8 to a gp41 NHR mimetic, respectively, but not the neutralizing activity of these mAbs. We conclude from these results that NHR coiled-coil analogs of HIV-1 gp41 elicit many Abs during natural infection and through immunization, but that due to limited accessibility to the corresponding region on fusogenic gp41 few can neutralize. Caution is therefore required in targeting the NHR for vaccine design. Nevertheless, the mAb panel may be useful as tools for elucidating access restrictions to the NHR of gp41 and in designing potential improvements to mimetics of receptor-activated Env. (c) 2008 Elsevier Inc. All rights reserved. C1 [Nelson, Josh D.; Kinkead, Heather; Leaman, Dan; Jensen, Richard; Burton, Dennis R.; Zwick, Michael B.] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. [Brunel, Florence M.; Dawson, Philip E.] Scripps Res Inst, Dept Chem & Cell Biol, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Biol Mol, La Jolla, CA 92037 USA. [Dawson, Philip E.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Louis, John M.; Clore, G. Marius] NIH, Chem Phys Lab, Bethesda, MD 20892 USA. [Bewley, Carole A.] NIDDK, NIH, Bethesda, MD 20892 USA. [Mage, Rose G.] NIAID, NIH, Immunol Lab, Bethesda, MD 20892 USA. [Maruyama, Toshiaki; Bowdish, Katherine; Frederickson, Shana] Alex Antibody Technol Inc, San Diego, CA 92121 USA. [Richman, Douglas D.] Univ Calif San Diego, Ctr AIDS Res, La Jolla, CA 92093 USA. [Richman, Douglas D.] VA San Diego Healthcare Syst, La Jolla, CA 92161 USA. RP Zwick, MB (reprint author), Scripps Res Inst, Dept Immunol, 10550 N Torrey Pines Rd IMM-2, La Jolla, CA 92037 USA. EM zwick@scripps.edu RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS; NIAID NIH HHS [R37 AI033292, AI 058763, AI 33292, R01 AI033292, R01 AI058763, R01 AI069993, R01 AI069993-01A2, R01 AI58763, R21 AI058725, R21 AI058725-01]; NIGMS NIH HHS [GM-46192, P01 GM048870, R01 GM046192] NR 104 TC 20 Z9 24 U1 2 U2 10 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 JUL 20 PY 2008 VL 377 IS 1 BP 170 EP 183 DI 10.1016/j.virol.2008.04.005 PG 14 WC Virology SC Virology GA 317SR UT WOS:000257040700020 PM 18499210 ER PT J AU Balaban, R AF Balaban, Robert TI The systems biology of the mammalian mitochondria SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetic Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Balaban, Robert] NHLBI, Bethesda, MD 20892 USA. EM balabanr@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S8 EP S8 DI 10.1016/j.bbabio.2008.05.038 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700028 ER PT J AU Cleland, MM Suen, DF Norris, KL Ryu, SW Youle, RJ AF Cleland, Megan M. Suen, Der-Fen Norris, Kristi L. Ryu, Seung-Wook Youle, Richard J. TI Mitofusin foci: Endogenous localization and apoptotic behavior SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetic Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Cleland, Megan M.; Suen, Der-Fen; Norris, Kristi L.; Ryu, Seung-Wook; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Cleland, Megan M.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. EM clelandme@ninds.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S56 EP S57 DI 10.1016/j.bbabio.2008.05.223 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700213 ER PT J AU Galperin, MY Koonin, EV Makarova, KS Mulkidjanian, AY AF Galperin, Michael Y. Koonin, Eugene V. Makarova, Kira S. Mulkidjanian, Armen Y. TI Energetics of the first bacteria as inferred from genome analysis SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetic Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Galperin, Michael Y.; Koonin, Eugene V.; Makarova, Kira S.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, Osnabruck, Germany. EM galperin@ncbi.nlm.nih.gov RI Mulkidjanian, Armen/J-8086-2013 OI Mulkidjanian, Armen/0000-0001-5844-3064 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S108 EP S108 DI 10.1016/j.bbabio.2008.05.424 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700414 ER PT J AU Kaila, VRI Hummer, G Wikstrom, M AF Kaila, Ville R. I. Hummer, Gerhard Wikstrom, Marten TI Fidelity of water-gated mechanism in cytochrome c oxidase SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetics Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Kaila, Ville R. I.; Wikstrom, Marten] Univ Helsinki, Inst Biotechnol, Programme Struct Biol & Biophys, Helsinki Bioenerget Grp, FI-00014 Helsinki, Finland. [Hummer, Gerhard] NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. EM ville.kaila@helsinki.fi RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S95 EP S95 DI 10.1016/j.bbabio.2008.05.371 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700361 ER PT J AU Rasola, A Chiara, F Castellaro, D Marin, O Petronilli, V Brusilow, WS Juhaszova, M Sollott, SJ Forte, M Bernardi, P AF Rasola, Andrea Chiara, Federica Castellaro, Diego Marin, Oriano Petronilli, Valeria Brusilow, William S. Juhaszova, Magdalena Sollott, Steven J. Forte, Michael Bernardi, Paolo TI Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetics Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Rasola, Andrea; Chiara, Federica; Castellaro, Diego; Petronilli, Valeria; Bernardi, Paolo] Univ Padua, CNR, Inst Neurosci, Padua, Italy. [Rasola, Andrea; Chiara, Federica; Castellaro, Diego; Petronilli, Valeria; Bernardi, Paolo] Univ Padua, Dept Biomed Sci, Padua, Italy. [Marin, Oriano] Univ Padua, Dept Biol Chem, Padua, Italy. [Marin, Oriano] Univ Padua, Venetian Inst Mol Med, Padua, Italy. [Brusilow, William S.] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI USA. [Juhaszova, Magdalena; Sollott, Steven J.] NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Forte, Michael] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97201 USA. EM 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 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S83 EP S83 DI 10.1016/j.bbabio.2008.05.325 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700315 ER PT J AU Thomas, KJ Sandebring, A Beilina, A van der Brug, M Cleland, MM Zambrano, I Miller, DW Unger, C Cowburn, R Youle, R Behbahani, H Cedazo-Minguez, A Cookson, MR AF Thomas, Kelly Jean Sandebring, Anna Beilina, Alexandra van der Brug, Marcel Cleland, Megan M. Zambrano, Ibardo Miller, David W. Unger, Christian Cowburn, Richard Youle, Richard Behbahani, Homira Cedazo-Minguez, Angel Cookson, Mark R. TI Altered mitochondrial dynamics caused by loss of PTEN-induced kinase 1 function, associated with recessive parkinsonism, are reversed by downregulation of Dynamin-related protein 1 SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetics Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Thomas, Kelly Jean; Sandebring, Anna; Beilina, Alexandra; van der Brug, Marcel; Zambrano, Ibardo; Miller, David W.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Sandebring, Anna; Cowburn, Richard; Behbahani, Homira; Cedazo-Minguez, Angel] Karolinska Inst, Alzheimer Res Ctr, Stockholm, Sweden. [Unger, Christian] Karolinska Inst, Dept Lab Med, Stockholm, Sweden. [Cleland, Megan M.; Youle, Richard] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM thomaskel@mail.nih.gov RI Cedazo-Minguez, Angel/C-6707-2012 OI Cedazo-Minguez, Angel/0000-0003-4626-4864 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S55 EP S55 DI 10.1016/j.bbabio.2008.05.219 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700209 ER PT J AU Youle, RJ AF Youle, R. J. TI The Bcl-2 family and mitochondria: In sickness and in health SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetic Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Youle, R. J.] Natl Inst Neurol Disorders & Stroke, NIH, Surg Neurol Branch, Biochem Sect, Bethesda, MD USA. EM youler@ninds.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S5 EP S5 DI 10.1016/j.bbabio.2008.05.026 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700016 ER PT J AU Yua, CA Cen, XW Ma, HW Yin, Y Yua, LD Esser, L Xia, D AF Yua, Chang-An Cen, Xiaowei Ma, He-Wen Yin, Ying Yua, Linda Esser, Lothar Xia, Di TI Domain conformational switch of the iron sulfur protein in cytochrome bc(1) complex is induced by the electron transfer from cytochrome b(L) to b(H) SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Meeting Abstract CT 15th European Bioenergetic Conference CY JUL 19-24, 2008 CL Trinity Coll, Dublin, IRELAND HO Trinity Coll C1 [Yua, Chang-An; Cen, Xiaowei; Ma, He-Wen; Yin, Ying; Yua, Linda] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. [Esser, Lothar; Xia, Di] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM changan.yu@okstate.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL 19 PY 2008 VL 1777 SU S BP S102 EP S102 DI 10.1016/j.bbabio.2008.05.400 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 331UI UT WOS:000258037700390 ER PT J AU Ryan, MC Zeeberg, BR Caplen, NJ Cleland, JA Kahn, AB Liu, H Weinstein, JN AF Ryan, Michael C. Zeeberg, Barry R. Caplen, Natasha J. Cleland, James A. Kahn, Ari B. Liu, Hongfang Weinstein, John N. TI SpliceCenter: A suite of web-based bioinformatic applications for evaluating the impact of alternative splicing on RT-PCR, RNAi, microarray, and peptide-based studies SO BMC BIOINFORMATICS LA English DT Article ID EXPRESSION; DATABASE; GENOME; ISOFORMS; RESOURCE; VARIANT; SIRNAS; P53 AB Background: Over 60% of protein-coding genes in vertebrates express mRNAs that undergo alternative splicing. The resulting collection of transcript isoforms poses significant challenges for contemporary biological assays. For example, RT-PCR validation of gene expression microarray results may be unsuccessful if the two technologies target different splice variants. Effective use of sequence-based technologies requires knowledge of the specific splice variant(s) that are targeted. In addition, the critical roles of alternative splice forms in biological function and in disease suggest that assay results may be more informative if analyzed in the context of the targeted splice variant. Results: A number of contemporary technologies are used for analyzing transcripts or proteins. To enable investigation of the impact of splice variation on the interpretation of data derived from those technologies, we have developed SpliceCenter. SpliceCenter is a suite of user-friendly, web-based applications that includes programs for analysis of RT-PCR primer/probe sets, effectors of RNAi, microarrays, and protein-targeting technologies. Both interactive and high-throughput implementations of the tools are provided. The interactive versions of SpliceCenter tools provide visualizations of a gene's alternative transcripts and probe target positions, enabling the user to identify which splice variants are or are not targeted. The high-throughput batch versions accept user query files and provide results in tabular form. When, for example, we used SpliceCenter's batch siRNA-Check to process the Cancer Genome Anatomy Project's large-scale shRNA library, we found that only 59% of the 50,766 shRNAs in the library target all known splice variants of the target gene, 32% target some but not all, and 9% do not target any currently annotated transcript. Conclusion: SpliceCenter http://discover.nci.nih.gov/splicecenter provides unique, user-friendly applications for assessing the impact of transcript variation on the design and interpretation of RTPCR, RNAi, gene expression microarrays, antibody-based detection, and mass spectrometry proteomics. The tools are intended for use by bench biologists as well as bioinformaticists. C1 [Ryan, Michael C.; Zeeberg, Barry R.; Kahn, Ari B.; Liu, Hongfang; Weinstein, John N.] Natl Canc Inst, Natl Inst Hlth, Genom Bioinformat Grp, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Ryan, Michael C.; Cleland, James A.] Tiger Team Consulting, Fairfax, VA USA. [Caplen, Natasha J.] Natl Canc Inst, Natl Inst Hlth, Gene Silencing Sect, Genet Branch, Bethesda, MD USA. [Liu, Hongfang] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. [Weinstein, John N.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. RP Weinstein, JN (reprint author), Natl Canc Inst, Natl Inst Hlth, Genom Bioinformat Grp, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM mryan@tigerteamconsulting.com; zeebergb@mail.nih.gov; ncaplen@mail.nih.gov; jcleland@tigerteamconsulting.com; Ari_Kahn@sra.com; hl224@georgetown.edu; jweinste@mdanderson.org RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU Intramural NIH HHS; NLM NIH HHS [R01 LM009959] NR 20 TC 20 Z9 20 U1 0 U2 5 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 JUL 18 PY 2008 VL 9 AR 313 DI 10.1186/1471-2105-9-313 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 333YL UT WOS:000258189400001 PM 18638396 ER PT J AU Franco, R Schoneveld, O Georgakilas, AG Panayiotidis, MI AF Franco, Rodrigo Schoneveld, Onard Georgakilas, Alexandros G. Panayiotidis, Mihalis I. TI Oxidative stress, DNA methylation and carcinogenesis SO CANCER LETTERS LA English DT Review DE oxidative stress; free radicals; reactive oxygen species; oxidative DNA damage; DNA methylation; epigenetics; gene expression; cancer ID HEPATOCELLULAR-CARCINOMA; CANCER DEVELOPMENT; TUMOR-GROWTH; GSTP1 GENE; CELLS; DAMAGE; HYPERMETHYLATION; PROGRESSION; EXPRESSION; APOPTOSIS AB Transformation of a normal cell to a malignant one requires phenotypic changes often associated with each of the initiation, promotion and progression phases of the carcinogenic process. Genes in each of these phases acquire alterations in their transcriptional activity that are associated either with hypermethylation-induced transcriptional repression (in the case of tumor suppressor genes) or hypomethylation-induced activation (in the case of oncogenes). Growing evidence supports a role of ROS-induced generation of oxidative stress in these epigenetic processes and as such we can hypothesize of potential mode(s) of action by which oxidative stress modulates epigenetic regulation of gene expression. This is of outmost importance given that various components of the epigenetic pathway and primarily aberrant DNA methylation patterns are used as potential biomarkers for cancer diagnosis and prognosis. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Panayiotidis, Mihalis I.] Univ Nevada, Sch Publ Hlth, Reno, NV 89557 USA. [Franco, Rodrigo; Schoneveld, Onard] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Georgakilas, Alexandros G.] E Carolina Univ, Dept Biol, Thomas Harriot Coll Arts & Sci, Greenville, NC 27858 USA. RP Panayiotidis, MI (reprint author), Univ Nevada, Sch Publ Hlth, MS-274, Reno, NV 89557 USA. EM mpanagiotidis@unr.edu RI Franco, Rodrigo/D-9470-2013; OI Franco, Rodrigo/0000-0003-3241-8615; Panagiotidis, Mihalis/0000-0002-1130-5972 FU Intramural NIH HHS NR 55 TC 268 Z9 276 U1 5 U2 36 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUL 18 PY 2008 VL 266 IS 1 SI SI BP 6 EP 11 DI 10.1016/j.canlet.2008.02.026 PG 6 WC Oncology SC Oncology GA 317VN UT WOS:000257048500003 PM 18372104 ER PT J AU Wang, E Marincola, FM AF Wang, Ena Marincola, Francesco M. TI Bottom up: A modular view of immunology SO IMMUNITY LA English DT Editorial Material ID RELEVANCE; CANCER C1 [Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM fmarincola@mail.cc.nih.gov FU Intramural NIH HHS [ZIA CL002118-04] NR 9 TC 24 Z9 24 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 18 PY 2008 VL 29 IS 1 BP 9 EP 11 DI 10.1016/j.immuni.2008.07.002 PG 3 WC Immunology SC Immunology GA 329YB UT WOS:000257905400005 PM 18631452 ER PT J AU Yang, XO Nurieva, R Martinez, GJ Kang, HS Chung, Y Pappu, BP Shah, B Chang, SH Schluns, KS Watowich, SS Feng, XH Jetten, AM Dong, C AF Yang, Xuexian O. Nurieva, Roza Martinez, Gustavo J. Kang, Hong Soon Chung, Yeonseok Pappu, Bhanu P. Shah, Bhavin Chang, Seon Hee Schluns, Kimberly S. Watowich, Stephanie S. Feng, Xin-Hua Jetten, Anton M. Dong, Chen TI Molecular antagonism and plasticity of regulatory and inflammatory T cell programs SO IMMUNITY LA English DT Article ID RECEPTOR ROR-GAMMA; TGF-BETA; GENERATION; FOXP3; DIFFERENTIATION; RESPONSES; T(H)17; SELF AB Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors ROR gamma t and ROR alpha. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation whereas STAT3, ROR gamma, and ROR alpha were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs. C1 [Yang, Xuexian O.; Nurieva, Roza; Martinez, Gustavo J.; Chung, Yeonseok; Pappu, Bhanu P.; Shah, Bhavin; Chang, Seon Hee; Schluns, Kimberly S.; Watowich, Stephanie S.; Dong, Chen] Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Kang, Hong Soon; Jetten, Anton M.] NIEHS, Cell Biol Sect, LRB, NIH, Res Triangle Pk, NC 27709 USA. [Feng, Xin-Hua] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Feng, Xin-Hua] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Dong, C (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. EM rnurieva@mdanderson.org; cdong@mdanderson.org RI dong, chen /B-3181-2009; OI dong, chen /0000-0002-0084-9130; Jetten, Anton/0000-0003-0954-4445; Chung, Yeonseok/0000-0001-5780-4841; Watowich, Stephanie/0000-0003-1969-659X FU Intramural NIH HHS [Z01 ES101586-05]; NCI NIH HHS [CA108454, R01 CA108454]; NIAID NIH HHS [R01 AI050746, R01 AI050746-01]; NIAMS NIH HHS [AR050772, R01 AR050772] NR 28 TC 613 Z9 638 U1 3 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 18 PY 2008 VL 29 IS 1 BP 44 EP 56 DI 10.1016/j.immuni.2008.05.007 PG 13 WC Immunology SC Immunology GA 329YB UT WOS:000257905400009 PM 18585065 ER PT J AU Meylan, F Davidson, TS Kahle, E Kinder, M Acharya, K Jankovic, D Bundoc, V Hodges, M Shevach, EM Keane-Myers, A Wang, ECY Siegel, RM AF Meylan, Francoise Davidson, Todd S. Kahle, Erin Kinder, Michelle Acharya, Krishika Jankovic, Dragana Bundoc, Virgilio Hodges, Marcus Shevach, Ethan M. Keane-Myers, Andrea Wang, Eddie C. Y. Siegel, Richard M. TI The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases SO IMMUNITY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ALLERGIC INFLAMMATION; TOXOPLASMA-GONDII; RHEUMATOID-ARTHRITIS; LUNG INFLAMMATION; DENDRITIC CELLS; TL1A; LIGAND; CYTOKINE; PROTEIN AB DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases. C1 [Meylan, Francoise; Kahle, Erin; Kinder, Michelle; Acharya, Krishika; Siegel, Richard M.] NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Jankovic, Dragana] NIAID, Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Bundoc, Virgilio; Hodges, Marcus; Keane-Myers, Andrea] NIAID, Allerg Inflammat Sect, Lab Allerg Dis, Bethesda, MD 20892 USA. [Davidson, Todd S.; Shevach, Ethan M.] NIAID, Cellular Immunol Sect, Immunol Lab, Bethesda, MD 20892 USA. [Wang, Eddie C. Y.] Cardiff Univ, Sch Med, Cardiff CF14 4XN, Wales. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 FU Intramural NIH HHS [Z01 AR041174-01]; Medical Research Council [G0300180, G0300180(65735), G0500617, G0500617(74644)] NR 32 TC 112 Z9 120 U1 3 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 18 PY 2008 VL 29 IS 1 BP 79 EP 89 DI 10.1016/j.immuni.2008.04.021 PG 11 WC Immunology SC Immunology GA 329YB UT WOS:000257905400012 PM 18571443 ER PT J AU Nurieva, RI Chung, Y Hwang, D Yang, XO Kang, HS Ma, L Wang, YH Watowich, SS Jetten, AM Tian, Q Dong, C AF Nurieva, Roza I. Chung, Yeonseok Hwang, Daehee Yang, Xuexian O. Kang, Hong Soon Ma, Li Wang, Yi-Hong Watowich, Stephanie S. Jetten, Anton M. Tian, Qiang Dong, Chen TI Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages SO IMMUNITY LA English DT Article ID CXC CHEMOKINE RECEPTOR-5; B-CELLS; GENE-EXPRESSION; ROR-GAMMA; DIFFERENTIATION; RESPONSES; AUTOIMMUNITY; IL-21; BETA; T(H)17 AB After activation, CD4(+) helper T (Th) cells differentiate into distinct effector subsets. Although chemokine (C-X-C motif]I receptor 5-expressing T follicular helper (Tfh) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that Tfh cells had a distinct gene expression profile and developed in vivo independently of the Th1 or Th2 cell lineages. Tfh cell generation was regulated by ICOS ligand (ICOSL) expressed on B cells and was dependent on interleukin-21 (IL-21), IL-6, and signal transducer and activator of transcription 3 (STAT3). However, unlike Th17 cells, differentiation of Tfh cells did not require transforming growth factor 0 (TGF-beta) or Th17-specific orphan nuclear receptors ROR alpha and ROR gamma in vivo. Finally, naive T cells activated in vitro in the presence of IL-21 but not TGF-beta signaling preferentially acquired Tfh gene expression and promoted germinal-center reactions in vivo. This study thus demonstrates that Tfh is a distinct Th cell lineage. C1 [Nurieva, Roza I.; Chung, Yeonseok; Yang, Xuexian O.; Wang, Yi-Hong; Watowich, Stephanie S.; Dong, Chen] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Nurieva, Roza I.; Chung, Yeonseok; Yang, Xuexian O.; Wang, Yi-Hong; Watowich, Stephanie S.; Dong, Chen] Univ Texas MD Anderson Canc Ctr, Grad Sch Biomed Sci, Houston, TX 77030 USA. [Hwang, Daehee] Pohang Univ Sci & Technol, Dept Chem Engn, Kyungbuk 790784, South Korea. [Hwang, Daehee] Pohang Univ Sci & Technol, Sch Interdisciplinary Biosci & Bioengn, Kyungbuk 790784, South Korea. [Kang, Hong Soon; Jetten, Anton M.] NIEHS, Cell Biol Sect, LRB, NIH, Res Triangle Pk, NC 27709 USA. [Tian, Qiang] Inst Syst Biol, Seattle, WA 98103 USA. RP Nurieva, RI (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. EM rnurieva@mdanderson.org; cdong@mdanderson.org RI dong, chen /B-3181-2009; OI dong, chen /0000-0002-0084-9130; Jetten, Anton/0000-0003-0954-4445; Chung, Yeonseok/0000-0001-5780-4841; Watowich, Stephanie/0000-0003-1969-659X FU Intramural NIH HHS [Z01 ES101586-05]; NIAID NIH HHS [R01 AI050746-05, R01 AI050746, R01 AI050746-01, R01 AI050761, R01 AI050761-05, R01 AI050761-06, R01 AI050761-07A1, R01 AI054912, R01 AI054912-01A3, R56 AI050761, R56 AI050761-07A2]; NIAMS NIH HHS [R01 AR050772, R01 AR050772-05, R01 AR050772-06, R01 AR050772-07, R01 AR050772-08] NR 43 TC 580 Z9 618 U1 2 U2 41 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 18 PY 2008 VL 29 IS 1 BP 138 EP 149 DI 10.1016/j.immuni.2008.05.009 PG 12 WC Immunology SC Immunology GA 329YB UT WOS:000257905400017 PM 18599325 ER PT J AU Chaussabel, D Quinn, C Shen, J Patel, P Glaser, C Baldwin, N Stichweh, D Blankenship, D Li, L Munagala, I Bennett, L Allantaz, F Mejias, A Ardura, M Kaizer, E Monnet, L Allman, W Randall, H Johnson, D Lanier, A Punaro, M Wittkowski, KM White, P Fay, J Klintmalm, G Ramilo, O Palucka, AK Banchereau, J Pascual, V AF Chaussabel, Damien Quinn, Charles Shen, Jing Patel, Pinakeen Glaser, Casey Baldwin, Nicole Stichweh, Dorothee Blankenship, Derek Li, Lei Munagala, Indira Bennett, Lynda Allantaz, Florence Mejias, Asuncion Ardura, Monica Kaizer, Ellen Monnet, Laurence Allman, Windy Randall, Henry Johnson, Diane Lanier, Aimee Punaro, Marilynn Wittkowski, Knut M. White, Perrin Fay, Joseph Klintmalm, Goran Ramilo, Octavio Palucka, A. Karolina Banchereau, Jacques Pascual, Virginia TI A modular analysis framework for blood genomics studies: Application to systemic lupus erythematosus SO IMMUNITY LA English DT Article ID CLINICAL-DISEASE ACTIVITY; GENE-EXPRESSION; MICROARRAY PLATFORMS; MONONUCLEAR-CELLS; MOLECULAR CLASSIFICATION; TRANSCRIPTIONAL PROFILES; CANCER; INTERFERON; SIGNATURES; REPRODUCIBILITY AB The analysis of patient blood transcriptional profiles offers a means to investigate the immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease data sets. Mapping changes in gene expression at the module level generated disease-specific transcriptional fingerprints that provide a stable framework for the visualization and functional interpretation of microarray data. These transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Thus, this work describes the implementation and application of a methodology designed to support systems-scale analysis of the human immune system in translational research settings. C1 [Chaussabel, Damien; Quinn, Charles; Shen, Jing; Patel, Pinakeen; Glaser, Casey; Baldwin, Nicole; Stichweh, Dorothee; Li, Lei; Munagala, Indira; Bennett, Lynda; Allantaz, Florence; Monnet, Laurence; Allman, Windy; Fay, Joseph; Palucka, A. Karolina; Banchereau, Jacques; Pascual, Virginia] Baylor Inst Immunol Res, Baylor NIAID Cooperat Ctr Translat Res Human Immu, Dallas, TX 75204 USA. [Chaussabel, Damien; Quinn, Charles; Shen, Jing; Patel, Pinakeen; Glaser, Casey; Baldwin, Nicole; Stichweh, Dorothee; Li, Lei; Munagala, Indira; Bennett, Lynda; Allantaz, Florence; Monnet, Laurence; Allman, Windy; Fay, Joseph; Palucka, A. Karolina; Banchereau, Jacques; Pascual, Virginia] Baylor Res Inst, Dallas, TX 75204 USA. [Patel, Pinakeen] Baylor Univ, Inst Biomed Studies, Waco, TX 75798 USA. [Blankenship, Derek] Baylor Hlth Care System, Inst Hlth Care Res & Improvement, Dallas, TX 75204 USA. [Mejias, Asuncion; Ardura, Monica; Kaizer, Ellen; Punaro, Marilynn; White, Perrin; Ramilo, Octavio] UT SW Med Ctr, Dallas, TX 75235 USA. [Mejias, Asuncion; Ardura, Monica; Kaizer, Ellen; Punaro, Marilynn; White, Perrin; Ramilo, Octavio] Childrens Med Ctr, Dallas, TX 75235 USA. [Randall, Henry; Johnson, Diane; Lanier, Aimee; Klintmalm, Goran] Baylor Reg Transplant Inst, Dallas, TX 75219 USA. [Punaro, Marilynn; Pascual, Virginia] Texas Scottish Rite Hosp Children, Dallas, TX 75219 USA. [Wittkowski, Knut M.] Rockefeller Univ, New York, NY 10021 USA. [Fay, Joseph] Charles A Sammons Canc Ctr, Dallas, TX 75204 USA. RP Chaussabel, D (reprint author), Baylor Inst Immunol Res, Baylor NIAID Cooperat Ctr Translat Res Human Immu, Dallas, TX 75204 USA. EM damienc@baylorhealth.edu; jacquesb@baylorhealth.edu RI Mejias, Maria Asuncion/E-3659-2011; Ardura, Monica/I-6295-2015; OI Ardura, Monica/0000-0002-2853-2581; Chaussabel, Damien/0000-0002-6131-7242 FU NCI NIH HHS [P01 CA084512, P01 CA084512-01A10003, P01 CA084512-020003, P01 CA084512-030003, P01 CA084512-040003, P01 CA084512-05A2, P01 CA084512-05A20005, P01 CA084512-05A29002, P01 CA084512-05A29004, P01 CA084512-06, P01 CA084512-060005, P01 CA084512-069002, P01 CA084512-069004, P01 CA084512-07, P01 CA084512-070005, P01 CA084512-079002, P01 CA084512-079004, R01 CA078846, R01 CA078846-01A1, R01 CA078846-02, R01 CA078846-03, R01 CA078846-04, R01 CA078846-05, R01 CA078846-06, R01 CA078846-07, R01 CA078846-08, R01 CA078846-09, R01 CA078846-10]; NIAID NIH HHS [R01 AI068842, R01 AI068842-01, R01 AI068842-02, R01 AI068842-03, R01 AI068842-04, U19 AI057234, U19 AI057234-01, U19 AI057234-010004, U19 AI057234-010005, U19 AI057234-010006, U19 AI057234-02, U19 AI057234-03, U19 AI057234-04, U19 AI057234-05, U19 AI057234-05S1, U19 AI057234-05S10012, U19 AI057234-05S10013, U19 AI057234-05S19003, U19 AI057234-06]; NIAMS NIH HHS [R01 AR050770, P50 AR054083, P50 AR054083-01, P50 AR054083-010001, P50 AR054083-019001, P50 AR054083-02, P50 AR054083-020001, P50 AR054083-029001, P50 AR054083-03, P50 AR054083-030001, P50 AR055503, P50 AR055503-010004, P50 AR055503-020004, R01 AR050770-01, R01 AR050770-02, R01 AR050770-03, R01 AR050770-04, R01 AR050770-05A1, R01 AR050770-06]; PHS HHS [R01 I068842, U19 AIO57234-02] NR 42 TC 287 Z9 289 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 18 PY 2008 VL 29 IS 1 BP 150 EP 164 DI 10.1016/j.immuni.2008.05.012 PG 15 WC Immunology SC Immunology GA 329YB UT WOS:000257905400018 PM 18631455 ER PT J AU Moulton, VR Kyttaris, VC Juang, YT Chowdhury, B Tsokos, GC AF Moulton, Vaishali R. Kyttaris, Vasileios C. Juang, Yuang-Taung Chowdhury, Bhabadeb Tsokos, George C. TI The RNA-stabilizing protein HuR regulates the expression of zeta chain of the human T cell receptor-associated CD3 complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; INCREASED CYCLOOXYGENASE-2 EXPRESSION; SPLICED 3'-UNTRANSLATED REGION; AU-RICH ELEMENTS; MESSENGER-RNA; TCR-ZETA; DECREASED EXPRESSION; BINDING-PROTEINS; TCR/CD3 COMPLEX AB T cell dysfunction is crucial to the pathogenesis of systemic lupus erythematosus (SLE); however, the molecular mechanisms involved in the deficient expression of the T cell receptor-associated CD3 zeta chain in SLE are not clear. SLE T cells express abnormally increased levels of an alternatively spliced isoform of CD3 zeta that lacks a 562-bp region in its 3'-untranslated region (UTR). We showed previously that two adenosine/uridine-rich elements (ARE) in this splice-deleted region of CD3 zeta transcript are critical for the mRNA stability and protein expression of CD3 zeta. In this study we show for the first time that the mRNA-stabilizing protein HuR binds to these two ARE bearing regions of CD3 zeta 3'-UTR. Knockdown of HuR resulted in decreased expression of the CD3 zeta chain, whereas overexpression led to the increase of CD3 zeta chain levels. Additionally, overexpression of HuR in human T cells resulted in increased mRNA stability of CD3 zeta. Our results identify the 3'-UTR of CD3 zeta as a novel target for the mRNA-stabilizing protein HuR. Thus, the absence of two critical AREs in the alternatively spliced CD3 zeta 3'-UTR found in SLE T cells may result in decreased HuR binding, representing a possible molecular mechanism contributing to the reduced stability and expression of CD3 zeta zeta in SLE. C1 [Moulton, Vaishali R.; Kyttaris, Vasileios C.; Juang, Yuang-Taung; Tsokos, George C.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Rheumatol,Dept Med, Boston, MA 02115 USA. [Chowdhury, Bhabadeb] NIAID, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Tsokos, GC (reprint author), 3330 Brookline Ave,E-CLS 937, Boston, MA 02115 USA. EM gtsokos@bidmc.harvard.edu FU NIAID NIH HHS [R01 AI042269, R01 AI 42269]; NIAMS NIH HHS [K23 AR055672-01A1, K23 AR055672] NR 44 TC 19 Z9 19 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 JUL 18 PY 2008 VL 283 IS 29 BP 20037 EP 20044 DI 10.1074/jbc.M710434200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CH UT WOS:000257565300019 PM 18505733 ER PT J AU Shrimali, RK Irons, RD Carlson, BA Sano, Y Gladyshev, VN Park, JM Hatfield, DL AF Shrimali, Rajeev K. Irons, Robert D. Carlson, Bradley A. Sano, Yasuyo Gladyshev, Vadim N. Park, Jin Mo Hatfield, Dolph L. TI Selenoproteins mediate T cell immunity through an antioxidant mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR STIMULATION; HYDROGEN-PEROXIDE; SELENIUM; MICE; ACTIVATION; GENERATION; RESPONSES; HEALTH AB Selenium is an essential dietary element with antioxidant roles in immune regulation, but there is little understanding of how this element acts at the molecular level in host defense and inflammatory disease. Selenium is incorporated into the amino acid selenocysteine (Sec), which in turn is inserted into selenoproteins in a manner dependent on Sec tRNA([Ser]Sec). To investigate the molecular mechanism that links selenium to T cell immunity, we generated mice with selenoprotein-less T cells by cell type-specific ablation of the Sec tRNA([Ser]Sec) gene (trsp). Herein, we show that these mutant mice exhibit decreased pools of mature T cells and a defect in T cell- dependent antibody responses. We also demonstrate that selenoprotein deficiency leads to oxidant hyperproduction in T cells and thereby suppresses T cell proliferation in response to T cell receptor stimulation. These findings offer novel insights into immune function of selenium and physiological antioxidants. C1 [Sano, Yasuyo; Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. [Shrimali, Rajeev K.; Irons, Robert D.; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Park, JM (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. EM jmpark@cbrc2.mgh.harvard.edu; hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU Intramural NIH HHS [Z01 BC005317-24]; NCI NIH HHS [CA 080946]; NIGMS NIH HHS [GM 065204] NR 23 TC 66 Z9 70 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 18 PY 2008 VL 283 IS 29 BP 20181 EP 20185 DI 10.1074/jbc.M802559200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CH UT WOS:000257565300034 PM 18487203 ER PT J AU Duverger, O Lee, D Hassan, MQ Chen, SX Jaisser, F Lian, JB Morasso, MI AF Duverger, Olivier Lee, Delia Hassan, Mohammad Q. Chen, Susie X. Jaisser, Frederic Lian, Jane B. Morasso, Maria I. TI Molecular consequences of a frameshifted DLX3 mutant leading to Tricho-Dento-Osseous syndrome SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DISTAL-LESS GENE; HOMEODOMAIN PROTEINS; MUTATIONS; DIFFERENTIATION; TRANSCRIPTION; ACTIVATION; SEQUENCE; RECRUITMENT; PATTERN; BINDING AB The homeodomain protein Distal-less-3 (Dlx3) plays a crucial role during embryonic development. This transcription factor is known to be essential for placental formation and to be involved in skin and skeletal organogenesis. In humans, a frameshift mutation in the coding sequence of the DLX3 gene results in an ectodermal dysplasia called Tricho-Dento-Osseous syndrome (TDO). The main features of this autosomal dominant disorder are defects in hair, teeth, and bone. To investigate the functional alterations caused by the mutated DLX3(TDO) isoform ex vivo, we used tetracycline-inducible osteoblastic and keratinocyte cell lines and calvarial derived osteoblasts in which the expression of DLX3(WT) and/ or DLX3(TDO) could be regulated and monitored. Immunocytochemical analysis revealed that both DLX3(WT) and DLX3(TDO) recombinant proteins are targeted to the nucleus. However, as demonstrated by electrophoresis mobility shift assay, DLX3(TDO) is not able to bind to the canonical Dlx3 binding site. Furthermore, we demonstrate that the frameshifted C-terminal domain in DLX3(TDO) is accountable for the loss of DNA binding activity because the C-terminal domain in DLX3(WT) is not required for DNA binding activity. Although DLX3(TDO) alone cannot bind to a Dlx3 responsive element, when DLX3(WT) and DLX3(TDO) are co-expressed they form a complex that can bind DNA. Concomitant with the inability to bind DNA, DLX3(TDO) has a defective transcriptional activity. Moreover, the transcriptional activity of DLX3(WT) is significantly reduced in the presence of the mutated isoform, indicating that DLX3(TDO) has a dominant negative effect on DLX3(WT) transcriptional activity. C1 [Duverger, Olivier; Lee, Delia; Chen, Susie X.; Morasso, Maria I.] NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. [Hassan, Mohammad Q.; Lian, Jane B.] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Jaisser, Frederic] Univ Paris 05, Coll France, INSERM, U772, F-75005 Paris, France. RP Morasso, MI (reprint author), NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. EM morassom@mail.nih.gov FU Intramural NIH HHS; NIDCR NIH HHS [R37 DE 012528, R37 DE012528] NR 33 TC 24 Z9 25 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 JUL 18 PY 2008 VL 283 IS 29 BP 20198 EP 20208 DI 10.1074/jbc.M709562200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CH UT WOS:000257565300036 PM 18492670 ER PT J AU Bugreev, DV Brosh, RM Mazin, AV AF Bugreev, Dmitry V. Brosh, Robert M., Jr. Mazin, Alexander V. TI RECQ1 possesses DNA branch migration activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRAND BREAK REPAIR; ROTHMUND-THOMSON-SYNDROME; BLOOMS-SYNDROME HELICASE; REPLICATION PROTEIN-A; SYNDROME GENE-PRODUCT; HUMAN RAD54 PROTEIN; HOMOLOGOUS RECOMBINATION; BIOCHEMICAL-CHARACTERIZATION; HOLLIDAY JUNCTIONS; WERNERS-SYNDROME AB RecQ helicases are essential for the maintenance of genome stability. Five members of the RecQ family have been found in humans, including RECQ1, RECQ5, BLM, WRN, and RECQ4; the last three are associated with human diseases. At this time, only BLM and WRN helicases have been extensively characterized, and the information on the other RecQ helicases has only started to emerge. Our current paper is focused on the biochemical properties of human RECQ1 helicase. Recent cellular studies have shown that RECQ1 may participate in DNA repair and homologous recombination, but the exact mechanisms of how RECQ1 performs its cellular functions remain largely unknown. Whereas RECQ1 possesses poor helicase activity, we found here that the enzyme efficiently promotes DNA branch migration. Further analysis revealed that RECQ1 catalyzes unidirectional three- stranded branch migration with a 3'-> 5' polarity. We show that this RECQ1 activity is instrumental in specific disruption of joint molecules (D- loops) formed by a 5' single- stranded DNA invading strand, which may represent dead end intermediates of homologous recombination in vivo. The newly found enzymatic properties of the RECQ1 helicase may have important implications for the function of RECQ1 in maintenance of genomic stability. C1 [Bugreev, Dmitry V.; Mazin, Alexander V.] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19102 USA. [Bugreev, Dmitry V.] Russian Acad Sci, Siberian Branch, Inst Chem Biol & Fundamental Med, Novosibirsk 630090, Russia. [Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Mazin, AV (reprint author), Drexel Univ, Coll Med, Dept Biochem & Mol Biol, 245 N 15th St,NCB Rm 10103, Philadelphia, PA 19102 USA. EM amazin@drexelmed.edu FU Intramural NIH HHS; NCI NIH HHS [CA 100839] NR 68 TC 41 Z9 41 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 JUL 18 PY 2008 VL 283 IS 29 BP 20231 EP 20242 DI 10.1074/jbc.M801582200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CH UT WOS:000257565300039 PM 18495662 ER PT J AU Beloglazova, N Brown, G Zimmerman, MD Proudfoot, M Makarova, KS Kudritska, M Kochinyan, S Wang, S Chruszcz, M Minor, W Koonin, EV Edwards, AM Savchenko, A Yakunin, AF AF Beloglazova, Natalia Brown, Greg Zimmerman, Matthew D. Proudfoot, Michael Makarova, Kira S. Kudritska, Marina Kochinyan, Samvel Wang, Shuren Chruszcz, Maksymilian Minor, Wladek Koonin, Eugene V. Edwards, Aled M. Savchenko, Alexei Yakunin, Alexander F. TI A novel family of sequence-specific endoribonucleases associated with the clustered regularly interspaced short palindromic repeats SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROVIDES ACQUIRED-RESISTANCE; MESSENGER-RNA INTERFERASES; ELECTRON-DENSITY MAPS; ESCHERICHIA-COLI; STREPTOCOCCUS-THERMOPHILUS; MYCOBACTERIUM-TUBERCULOSIS; DEFENSE-MECHANISM; CELL-DEATH; IDENTIFICATION; CRISPR AB Clustered regularly interspaced short palindromic repeats (CRISPRs) together with the associated CAS proteins protect microbial cells from invasion by foreign genetic elements using presently unknown molecular mechanisms. All CRISPR systems contain proteins of the CAS2 family, suggesting that these uncharacterized proteins play a central role in this process. Here we show that the CAS2 proteins represent a novel family of endoribonucleases. Six purified CAS2 proteins from diverse organisms cleaved single-stranded RNAs preferentially within U-rich regions. A representative CAS2 enzyme, SSO1404 from Sulfolobus solfataricus, cleaved the phosphodiester linkage on the 3'-side and generated 5'-phosphate- and 3'-hydroxyl-terminated oligonucleotides. The crystal structure of SSO1404 was solved at 1.6 angstrom resolution revealing the first ribonuclease with a ferredoxin-like fold. Mutagenesis of SSO1404 identified six residues (Tyr-9, Asp-10, Arg-17, Arg-19, Arg-31, and Phe-37) that are important for enzymatic activity and suggested that Asp-10 might be the principal catalytic residue. Thus, CAS2 proteins are sequence-specific endoribonucleases, and we propose that their role in the CRISPR-mediated anti-phage defense might involve degradation of phage or cellular mRNAs. C1 [Beloglazova, Natalia; Brown, Greg; Proudfoot, Michael; Kudritska, Marina; Kochinyan, Samvel; Edwards, Aled M.; Savchenko, Alexei; Yakunin, Alexander F.] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada. [Beloglazova, Natalia; Brown, Greg; Proudfoot, Michael; Kudritska, Marina; Kochinyan, Samvel; Edwards, Aled M.; Savchenko, Alexei; Yakunin, Alexander F.] Max Bell Res Ctr 5R407, Ontario Canc Inst, Toronto, ON M5G 2C4, Canada. [Zimmerman, Matthew D.; Wang, Shuren; Chruszcz, Maksymilian; Minor, Wladek] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. [Zimmerman, Matthew D.; Kudritska, Marina; Wang, Shuren; Chruszcz, Maksymilian; Minor, Wladek; Edwards, Aled M.; Savchenko, Alexei] Argonne Natl Lab, Midwest Ctr Struct Gen, Biosci Div, Argonne, IL 60439 USA. [Makarova, Kira S.; Koonin, Eugene V.] Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Yakunin, AF (reprint author), Univ Toronto, Banting & Best Dept Med Res, 112 Coll St, Toronto, ON M5G 1L6, Canada. EM a.iakounine@utoronto.ca RI Chruszcz, Maksymilian/E-6407-2011; Minor, Wladek/F-3096-2014; Yakunin, Alexander/J-1519-2014; Zimmerman, Matthew/N-9489-2013; OI Zimmerman, Matthew/0000-0002-6274-9493; Chruszcz, Maksymilian/0000-0001-7521-5485; Yakunin, Alexander/0000-0003-0813-6490; Minor, Wladek/0000-0001-7075-7090 FU Intramural NIH HHS; NIGMS NIH HHS [GM 074942, GM 62414] NR 64 TC 107 Z9 120 U1 2 U2 26 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 JUL 18 PY 2008 VL 283 IS 29 BP 20361 EP 20371 DI 10.1074/jbc.M803225200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CH UT WOS:000257565300052 PM 18482976 ER PT J AU Wistow, G Peterson, K Gao, J Buchoff, P Jaworski, C Bowes-Rickman, C Ebright, JN Hauser, MA Hoover, D AF Wistow, Graeme Peterson, Katherine Gao, James Buchoff, Patee Jaworski, Cynthia Bowes-Rickman, Catherine Ebright, Jessica N. Hauser, Michael A. Hoover, David TI NEIBank: Genomics and bioinformatics resources for vision research SO MOLECULAR VISION LA English DT Article ID SEQUENCE TAG ANALYSIS; GENE-EXPRESSION PROFILE; 6000 NONREDUNDANT TRANSCRIPTS; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; SPLICE VARIANTS; EYE TISSUES; PROJECT; DATABASE; TOOL AB NEIBank is an integrated resource for genomics and bioinformatics in vision research. It includes expressed sequence tag (EST) data and sequence-verified cDNA clones for multiple eye tissues of several species, web-based access to human eye-specific SAGE data through EyeSAGE, and comprehensive, annotated databases of known human eye disease genes and candidate disease gene loci. All expression- and disease-related data are integrated in EyeBrowse, an eye-centric genome browser. NEIBank provides a comprehensive overview of current knowledge of the transcriptional repertoires of eye tissues and their relation to pathology. C1 [Wistow, Graeme; Peterson, Katherine; Gao, James; Buchoff, Patee; Jaworski, Cynthia] NEI, Sect Mol Struct & Funct Gen, Natl Inst Hlth, Bethesda, MD 20892 USA. [Bowes-Rickman, Catherine; Ebright, Jessica N.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Hoover, David] Natl Inst Hlth, Helix Grp, Ctr Informat Technol, Bethesda, MD USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct Gen, Natl Inst Hlth, Bldg 7,Room 201, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov FU NEI NIH HHS [R01 EY11286, P30 EY005722, P30 EY005722-22, P30EY0054722, R01 EY011286, R01 EY013315, R01 EY13315] NR 37 TC 21 Z9 21 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 JUL 18 PY 2008 VL 14 IS 160 BP 1327 EP 1337 PG 11 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 336DS UT WOS:000258345100001 PM 18648525 ER PT J AU Przytycka, TM Jothi, R Aravind, L Lipman, DJ AF Przytycka, Teresa M. Jothi, Raja Aravind, L. Lipman, David J. TI Differences in evolutionary pressure acting within highly conserved ortholog groups SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID HORIZONTAL GENE-TRANSFER; MULTIPLE SEQUENCE ALIGNMENT; PHYLOGENY; RATIO AB Background: In highly conserved widely distributed ortholog groups, the main evolutionary force is assumed to be purifying selection that enforces sequence conservation, with most divergence occurring by accumulation of neutral substitutions. Using a set of ortholog groups from prokaryotes, with a single representative in each studied organism, we asked the question if this evolutionary pressure is acting similarly on different subgroups of orthologs defined as major lineages (e. g. Proteobacteria or Firmicutes). Results: Using correlations in entropy measures as a proxy for evolutionary pressure, we observed two distinct behaviors within our ortholog collection. The first subset of ortholog groups, called here informational, consisted mostly of proteins associated with information processing (i.e. translation, transcription, DNA replication) and the second, the non-informational ortholog groups, mostly comprised of proteins involved in metabolic pathways. The evolutionary pressure acting on non-informational proteins is more uniform relative to their informational counterparts. The non-informational proteins show higher level of correlation between entropy profiles and more uniformity across subgroups. Conclusion: The low correlation of entropy profiles in the informational ortholog groups suggest that the evolutionary pressure acting on the informational ortholog groups is not uniform across different clades considered this study. This might suggest "fine-tuning" of informational proteins in each lineage leading to lineage-specific differences in selection. This, in turn, could make these proteins less exchangeable between lineages. In contrast, the uniformity of the selective pressure acting on the non-informational groups might allow the exchange of the genetic material via lateral gene transfer. C1 [Przytycka, Teresa M.; Jothi, Raja; Aravind, L.; Lipman, David J.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Jothi, Raja] NHLBI, NIH, Bethesda, MD 20894 USA. RP Przytycka, TM (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov; jothi@mail.nih.gov; aravind@ncbi.nlm.nih.gov; lipman@ncbi.nlm.nih.gov RI Jothi, Raja/G-3780-2015 FU Intramural NIH HHS NR 24 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD JUL 17 PY 2008 VL 8 AR 208 DI 10.1186/1471-2148-8-208 PG 12 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 332SL UT WOS:000258103300001 PM 18637201 ER PT J AU Belew, AT Hepler, NL Jacobs, JL Dinman, JD AF Belew, Ashton T. Hepler, Nicholas L. Jacobs, Jonathan L. Dinman, Jonathan D. TI PRFdb: A database of computationally predicted eukaryotic programmed-1 ribosomal frameshift signals SO BMC GENOMICS LA English DT Article ID RNA SECONDARY STRUCTURE; INCLUDING PSEUDOKNOTS; ALGORITHM; EXPRESSION; RECODE; GENE AB Background: The Programmed Ribosomal Frameshift Database (PRFdb) provides an interface to help researchers identify potential programmed -1 ribosomal frameshift (-1 PRF) signals in eukaryotic genes or sequences of interest. Results: To identify putative -1 PRF signals, sequences are first imported from whole genomes or datasets, e. g. the yeast genome project and mammalian gene collection. They are then filtered through multiple algorithms to identify potential -1 PRF signals as defined by a heptameric slippery site followed by an mRNA pseudoknot. The significance of each candidate -1 PRF signal is evaluated by comparing the predicted thermodynamic stability (Delta G degrees) of the native mRNA sequence against a distribution of Delta G degrees values of a pool of randomized sequences derived from the original. The data have been compiled in a user-friendly, easily searchable relational database. Conclusion: The PRFdB enables members of the research community to determine whether genes that they are investigating contain potential - 1 PRF signals, and can be used as a metasource of information for cross referencing with other databases. It is available on the web at http://dinmanlab.umd.edu/prfdb. C1 [Belew, Ashton T.; Hepler, Nicholas L.; Jacobs, Jonathan L.; Dinman, Jonathan D.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20854 USA. [Jacobs, Jonathan L.] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Dinman, JD (reprint author), Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20854 USA. EM abelew@umd.edu; nlhepler@umd.edu; jacobsjon@mail.nih.gov; dinman@umd.edu OI Jacobs, Jonathan/0000-0001-5608-4256; Dinman, Jonathan/0000-0002-2402-9698 FU Howard Hughes Medical Institute; NIAID NIH HHS [T32 AI051967, T32 AI51967]; NIGMS NIH HHS [R01 GM058859, R21 GM068123]; NLM NIH HHS [F37 LM008333, F37 LM8333] NR 19 TC 23 Z9 23 U1 0 U2 7 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 JUL 17 PY 2008 VL 9 AR 339 DI 10.1186/1471-2164-9-339 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 333GA UT WOS:000258139800001 PM 18637175 ER PT J AU Hayton, K Gaur, D Liu, A Takahashi, J Henschen, B Singh, S Lambert, L Furuya, T Bouttenot, R Doll, M Nawaz, F Mu, JB Jiang, LB Miller, LH Wellems, TE AF Hayton, Karen Gaur, Deepak Liu, Anna Takahashi, Jonathan Henschen, Bruce Singh, Subhash Lambert, Lynn Furuya, Tetsuya Bouttenot, Rachel Doll, Michelle Nawaz, Fatima Mu, Jianbing Jiang, Lubin Miller, Louis H. Wellems, Thomas E. TI Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion SO CELL HOST & MICROBE LA English DT Article ID RED-BLOOD-CELLS; MALARIA PARASITES; MEROZOITE PROTEINS; AOTUS MONKEYS; WORLD MONKEY; RECEPTOR; ADAPTATION; STRAIN; SUSCEPTIBILITY; TRANSFORMATION AB Some human malaria Plasmodium falciparum parasites, but not others, also cause disease in Aotus monkeys. To identify the basis for this variation, we crossed two clones that differ in Aotus nancymaae virulence and mapped inherited traits of infectivity to erythrocyte invasion by linkage analysis. A major pathway of invasion was linked to polymorphisms in a putative erythrocyte binding protein, PfRH5, found in the apical region of merozoites. Polymorphisms of PfRH5 from the A. nancymaae-virulent parent transformed the nonvirulent parent to a virulent parasite. Conversely, replacements that removed these polymorphisms from PfRH5 converted a virulent progeny clone to a nonvirulent parasite. Further, a proteolytic fragment of PfRH5 from the infective parasites bound to A. nancymaae erythrocytes. Our results also suggest that PfRH5 is a parasite ligand for human infection, and that amino acid substitutions can cause its binding domain to recognize different human erythrocyte surface receptors. C1 [Hayton, Karen; Gaur, Deepak; Liu, Anna; Takahashi, Jonathan; Henschen, Bruce; Singh, Subhash; Furuya, Tetsuya; Bouttenot, Rachel; Doll, Michelle; Nawaz, Fatima; Mu, Jianbing; Jiang, Lubin; Miller, Louis H.; Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Lambert, Lynn; Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Wellems, TE (reprint author), NIAID, Lab Malaria & Vector Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twellems@niaid.nih.gov RI Furuya, Tetsuya/J-5916-2013; Furuya, Tetsuya/H-2412-2013 OI Furuya, Tetsuya/0000-0003-3979-7072 FU Intramural NIH HHS [Z01 AI000483-22] NR 50 TC 126 Z9 127 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUL 17 PY 2008 VL 4 IS 1 BP 40 EP 51 DI 10.1016/j.chom.2008.06.001 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 329ZF UT WOS:000257908400007 PM 18621009 ER PT J AU Rehak, NN Cecco, SA Hortin, GL AF Rehak, Nadja N. Cecco, Stacey A. Hortin, Glen L. TI Photolysis of bilirubin in serum specimens exposed to room lighting SO CLINICA CHIMICA ACTA LA English DT Letter DE serum bilirubin stability; bilirubin photolysis; heme oxygenase C1 [Rehak, Nadja N.; Cecco, Stacey A.; Hortin, Glen L.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Rehak, NN (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10,Rm 2C-407,Ctr Dr,MSC1508, Bethesda, MD 20892 USA. EM nrehak@cc.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JUL 17 PY 2008 VL 393 IS 2 BP 131 EP 131 DI 10.1016/j.cca.2008.03.007 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326JN UT WOS:000257654900013 ER PT J AU Lu, Z Liu, M Stribinskis, V Klinge, CM Ramos, KS Colburn, NH Li, Y AF Lu, Z. Liu, M. Stribinskis, V. Klinge, C. M. Ramos, K. S. Colburn, N. H. Li, Y. TI MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene SO ONCOGENE LA English DT Article DE miR-21; PDCD4; cell transformation; microRNA; tumor suppressor ID TUMOR-SUPPRESSOR GENE; INITIATION-FACTOR 4A; BREAST-CANCER; MICRO-RNA; EXPRESSION; PDCD4; TRANSLATION; SIGNATURE; BINDING; PROGRESSION AB MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively control expression of target genes in animals and plants. The microRNA-21 gene (mir-21) has been identified as the only miRNA commonly over-expressed in solid tumors of the lung, breast, stomach, prostate, colon, brain, head and neck, esophagus and pancreas. We initiated a screen to identify miR-21 target genes using a reporter assay and identified a potential miR-21 target in the 30-UTR of the programmed cell death 4 (PDCD4) gene. We cloned the full-length 30-UTR of human PDCD4 downstream of a reporter and found that mir-21 downregulated, whereas a modified antisense RNA to miR-21 upregulated report er activity. Moreover, deletion of the putative miR-21-binding site (miRNA regulatory element, MRE) from the 30-UTR of PDCD4, or mutations in the MRE abolished the ability of miR-21 to inhibit reporter activity, indicating that this MRE is a critical regulatory region. Western blotting showed that Pdcd4 protein levels were reduced by miR-21 in human and mouse cells, whereas quantitative real-time PCR revealed little difference at the mRNA level, suggesting translational regulation. Finally, overexpression of mir-21 in MCF-7 human breast cancer cells and mouse epidermal JB6 cells promoted soft agar colony formation by downregulating Pdcd4 protein levels. The demonstration that miR-21 promotes cell transformation supports the concept that mir-21 functions as an oncogene by a mechanism that involves translational repression of the tumor suppressor Pdcd4. C1 [Lu, Z.; Stribinskis, V.; Klinge, C. M.; Li, Y.] Univ Louisville, Sch Med, Ctr Genet & Mol Med, Louisville, KY 40292 USA. [Liu, M.] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai, Peoples R China. [Colburn, N. H.] NCI, Gene Regulat Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. RP Li, Y (reprint author), Univ Louisville, Dept Biochem & Mol Biol, 319 Abraham Flexner Way,Rm 513-A Building, Louisville, KY 40202 USA. EM yong.li@louisville.edu OI Klinge, Carolyn/0000-0002-3358-4378 FU NCI NIH HHS [R21-CA124811]; NIEHS NIH HHS [P30ES014443] NR 39 TC 422 Z9 458 U1 3 U2 49 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUL 17 PY 2008 VL 27 IS 31 BP 4373 EP 4379 DI 10.1038/onc.2008.72 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 326WY UT WOS:000257691100012 PM 18372920 ER PT J AU Driver, EC Pryor, SP Hill, P Turner, J Ruther, U Biesecker, LG Griffith, AJ Kelley, MW AF Driver, Elizabeth Carroll Pryor, Shannon P. Hill, Patrick Turner, Joyce Ruether, Ulrich Biesecker, Leslie G. Griffith, Andrew J. Kelley, Matthew W. TI Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cochlea; hair cell; development; Pallister-Hall syndrome; hedgehog; cell fate ID MAMMALIAN INNER-EAR; PALLISTER-HALL SYNDROME; HAIR-CELLS; SONIC HEDGEHOG; NOTCH LIGANDS; IN-VIVO; GLI3; COCHLEA; MATH1; MOUSE AB Auditory perception is mediated through a finite number of mechanosensory hair cells located in a specialized sensory epithelium within the inner ear. The formation of the appropriate number of hair cells and the location of those cells is crucial for normal auditory function. However, the factors that regulate the formation of this epithelium remain poorly understood. Truncating mutations in the transcription factor GLI3, a downstream effector of the Hedgehog (HH) pathway, lead to a partial loss of HH signaling and cause Pallister-Hall syndrome (PHS). Here, we report that cochleae from a mouse model of PHS(Gli3(Delta 699)), which produces only the truncated, repressor form of GLI3, have a variably penetrant phenotype that includes an increase in the size of the sensory epithelium and the development of large ectopic sensory patches in Kolliker's organ (KO). Consistent with the mouse model, some PHS individuals exhibit hearing loss across a broad range of frequencies. Moreover, inhibition of HH signaling in vitro results in an increase in the size of the prosensory domain, a precursor population that gives rise to the sensory epithelium, whereas treatment with Sonic hedgehog (SHH) inhibits prosensory formation. Finally, we demonstrate that HH signaling within the cochlea regulates expression of prosensory markers and that the effects of HH in KO are dependent on activation of Notch, an inducer of prosensory fate. These results suggest that HH signaling plays a key role in the specification, size, and location of the prosensory domain, and therefore of hair cells, within the cochlea. C1 [Driver, Elizabeth Carroll] Natl Inst Deafness & Other Commun Disorders, Natl Inst Hlth, Sect Dev Neurosci, Bethesda, MD 20892 USA. [Turner, Joyce; Biesecker, Leslie G.] NHGRI, Natl Inst Hlth, Human Dev Sect, Bethesda, MD 20892 USA. [Pryor, Shannon P.; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Natl Inst Hlth, Mol Biol & Genet Sect, Rockville, MD 20850 USA. [Hill, Patrick; Ruether, Ulrich] Univ Dusseldorf, Inst Anim Dev & Mol Biol, D-40225 Dusseldorf, Germany. RP Driver, EC (reprint author), Natl Inst Deafness & Other Commun Disorders, Natl Inst Hlth, Sect Dev Neurosci, Bldg 35,2A-205,35 Convent Dr,MSC3729, Bethesda, MD 20892 USA. EM drivere@nidcd.nih.gov FU Intramural NIH HHS [Z01 DC000059-08, Z01 HG200328-03, Z99 DC999999, Z01 DC000064-07] NR 48 TC 47 Z9 51 U1 0 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 16 PY 2008 VL 28 IS 29 BP 7350 EP 7358 DI 10.1523/JNEUROSCI.0312-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 326VT UT WOS:000257687900013 PM 18632939 ER PT J AU Barchi, JJ Karki, RG Nicklaus, MC Siddiqui, MA George, C Mikhailopulo, IA Marquez, VE AF Barchi, Joseph J., Jr. Karki, Rajeshri G. Nicklaus, Marc C. Siddiqui, Maqbool A. George, Clifford Mikhailopulo, Igor A. Marquez, Victor E. TI Comprehensive structural studies of 2',3"-difluorinated nucleosides: Comparison of theory, solution, and solid state SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUGAR RING CONFORMATION; COUPLING-CONSTANTS; FLUORINATED NUCLEOSIDES; X-RAY; NMR; GAUCHE; ADENOSINE; ANALOGS; DRUGS AB The conformations of three 2',3'-difluoro uridine nucleosides were studied by X-ray crystallography, NMR spectroscopy, and ab initio calculations in an attempt to define the roles that the two vicinal fluorine atoms play in the puckering preferences of the furanose ring. Two of the compounds examined contained fluorine atoms in either the arabino or xylo dispositions at C2' and C3' of a 2',3'-dideoxyuridine system. The third compound also incorporated fluorine atoms in the xylo configuration on the furanose ring but was substituted with a 6-azauracil base in place of uracil. A battery of NMR experiments in D2O solution was used to identify conformational preferences primarily from coupling constant and NOE data. Both H-1 and F-19 NMR data were used to ascertain the preferred sugar pucker of the furanose ring through the use of the program PSEUROT. Compound-dependent parameters used in the PSEUROT calculations were newly derived from complete sets of conformations calculated from high-level ab initio methods. The solution and theoretical data were compared to the conformations of each molecule in the solid state. It was shown that both gauche and antiperiplanar effects may be operative to maintain a pseudodiaxial arrangement of the C2' and C3' vicinal fluorine atoms. These data, along with previously reported data by us and others concerning monofluorinated nucleoside conformations, were used to propose a model of how fluorine influences different aspects of nucleoside conformations. C1 NCI, Med Chem Lab, Frederick, MD 21702 USA. Natl Inst Hlth, Frederick, MD 21702 USA. RP Barchi, JJ (reprint author), NCI, Med Chem Lab, 376 Boyles St,POB B, Frederick, MD 21702 USA. EM barchi@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; Barchi Jr., Joseph/N-3784-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS [Z01 BC010739-02] NR 44 TC 24 Z9 24 U1 1 U2 7 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 JUL 16 PY 2008 VL 130 IS 28 BP 9048 EP 9057 DI 10.1021/ja800964g PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 324GY UT WOS:000257507400036 PM 18558684 ER PT J AU Gail, MH AF Gail, Mitchell H. TI Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; PROSTATE-CANCER; SUSCEPTIBILITY; CHEMOPREVENTION; VALIDATION; TAMOXIFEN; VARIANTS; BRCA2; WOMEN; LOCI AB One purpose for seeking common alleles that are associated with disease is to use them to improve models for projecting individualized disease risk. Two genome-wide association studies and a study of candidate genes recently identified seven common single-nucleotide polymorphisms (SNPs) that were associated with breast cancer risk in independent samples. These seven SNPs were located in FGFR2, TNRC9 (now known as TOX3), MAP3K1, LSP1, CASP8, chromosomal region 8q, and chromosomal region 2q35. I used estimates of relative risks and allele frequencies from these studies to estimate how much these SNPs could improve discriminatory accuracy measured as the area under the receiver operating characteristic curve (AUC). A model with these seven SNPs (AUC = 0.574) and a hypothetical model with 14 such SNPs (AUC = 0.604) have less discriminatory accuracy than a model, the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT), that is based on ages at menarche and at first live birth, family history of breast cancer, and history of breast biopsy examinations (AUC = 0.607). Adding the seven SNPs to BCRAT improved discriminatory accuracy to an AUC of 0.632, which was, however, less than the improvement from adding mammographic density. Thus, these seven common alleles provide less discriminatory accuracy than BCRAT but have the potential to improve the discriminatory accuracy of BCRAT modestly. Experience to date and quantitative arguments indicate that a huge increase in the numbers of case patients with breast cancer and control subjects would be required in genome-wide association studies to find enough SNPs to achieve high discriminatory accuracy. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Executive Blvd,Rm 8032, Bethesda, MD 20892 USA. EM gailm@mail.nih.gov FU Intramural NIH HHS [Z01 CP010188-03] NR 20 TC 139 Z9 146 U1 0 U2 5 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 JUL 16 PY 2008 VL 100 IS 14 BP 1037 EP 1041 DI 10.1093/jnci/djn180 PG 5 WC Oncology SC Oncology GA 328HM UT WOS:000257789000012 PM 18612136 ER PT J AU Krueger, F Spampinato, MV Pardini, M Pajevic, S Wood, JN Weiss, GH Landgraf, S Grafman, J AF Krueger, Frank Spampinato, Maria Vittoria Pardini, Matteo Pajevic, Sinisa Wood, Jacqueline N. Weiss, George H. Landgraf, Steffen Grafman, Jordan TI Integral calculus problem solving: an fMRI investigation SO NEUROREPORT LA English DT Article DE arithmetic; dorsolateral prefrontal cortex; intraparietal sulcus; mathematics; superior parietal lobe ID MENTAL CALCULATION; MATHEMATICAL THINKING; PREFRONTAL CORTEX; PARIETAL CORTEX; ACTIVATION; BRAIN; DYSCALCULIA; AREAS; PET AB Only a subset of adults acquires specific advanced mathematical skills, such as integral calculus. The representation of more sophisticated mathematical concepts probably evolved from basic number systems; however its neuroanatomical basis is still unknown. Using fMRI, we investigated the neural basis of integral calculus while healthy participants were engaged in an integration verification task. Solving integrals activated a left-lateralized cortical network including the horizontal intraparietal sulcus, posterior superior parietal lobe, posterior cingulate gyrus, and dorsolateral prefrontal cortex. Our results indicate that solving of more abstract and sophisticated mathematical facts, such as calculus integrals, elicits a pattern of brain activation similar to the cortical network engaged in basic numeric comparison, quantity manipulation, and arithmetic problem solving. NeuroReport 19:1095-1099 (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Pajevic, Sinisa; Weiss, George H.] Ctr Informat Technol, Math & Stat Comp Lab, Div Computat Biosci, Bethesda, MD USA. [Spampinato, Maria Vittoria] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [Pardini, Matteo] Univ Genoa, Dept Neurosci Ophthalmol & Genet, Genoa, Italy. [Landgraf, Steffen] Univ Paris 06, Paris, France. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D43,MSC 1440, Bethesda, MD 20892 USA. EM Grafmanj@ninds.nih.gov RI Pardini, Matteo/F-8414-2010; OI Pardini, Matteo/0000-0002-4740-1982; Landgraf, Steffen/0000-0002-3423-8880; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS [Z01 NS002792-19] NR 25 TC 19 Z9 19 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 16 PY 2008 VL 19 IS 11 BP 1095 EP 1099 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 327KT UT WOS:000257728700003 PM 18596607 ER PT J AU Yuhki, N Mullikin, JC Beck, T Stephens, R O'Brien, SJ AF Yuhki, Naoya Mullikin, James C. Beck, Thomas Stephens, Robert O'Brien, Stephen J. TI Sequences, Annotation and Single Nucleotide Polymorphism of the Major Histocompatibility Complex in the Domestic Cat SO PLOS ONE LA English DT Article AB Two sequences of major histocompatibility complex (MHC) regions in the domestic cat, 2.976 and 0.362 Mbps, which were separated by an ancient chromosome break (55-80 MYA) and followed by a chromosomal inversion were annotated in detail. Gene annotation of this MHC was completed and identified 183 possible coding regions, 147 human homologues, possible functional genes and 36 pseudo/unidentified genes) by GENSCAN and BLASTN, BLASTP RepeatMasker programs. The first region spans 2.976 Mbp sequence, which encodes six classical class II antigens (three DRA and three DRB antigens) lacking the functional DP, DQ regions, nine antigen processing molecules (DOA/DOB, DMA/DMB, TAPASIN, and LMP2/LMP7, TAP1/TAP2), 52 class III genes, nineteen class I genes/gene fragments (FLAI-A to FLAI-S). Three class I genes (FLAI-H, I-K, I-E) may encode functional classical class I antigens based on deduced amino acid sequence and promoter structure. The second region spans 0.362 Mbp sequence encoding no class I genes and 18 cross-species conserved genes, excluding class I, II and their functionally related/ associated genes, namely framework genes, including three olfactory receptor genes. One previously identified feline endogenous retrovirus, a baboon retrovirus derived sequence (ECE1) and two new endogenous retrovirus sequences, similar to brown bat endogenous retrovirus (FERVmlu1, FERVmlu2) were found within a 140 Kbp interval in the middle of class I region. MHC SNPs were examined based on comparisons of this BAC sequence and MHC homozygous 1.9xWGS sequences and found that 11,654 SNPs in 2.84 Mbp (0.00411 SNP per bp), which is 2.4 times higher rate than average heterozygous region in the WGS (0.0017 SNP per bp genome), and slightly higher than the SNP rate observed in human MHC (0.00337 SNP per bp). C1 [Yuhki, Naoya; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Mullikin, James C.] NIH, Natl Human Genome Res Inst, Genome Technol Branch, Bethesda, MD USA. [Beck, Thomas] NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD USA. [Stephens, Robert] NCI, Advanced Biomed Comp Ctr, SAIC Frederick, Frederick, MD USA. RP Yuhki, N (reprint author), NCI, Lab Genom Divers, Frederick, MD 21701 USA. EM yuhki@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 46 TC 23 Z9 23 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 16 PY 2008 VL 3 IS 7 AR e2674 DI 10.1371/journal.pone.0002674 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417DX UT WOS:000264057200019 PM 18629345 ER PT J AU Coren, LV Shatzer, T Ott, DE AF Coren, Lori V. Shatzer, Teresa Ott, David E. TI CD45 immunoaffinity depletion of vesicles from Jurkat T cells demonstrates that exosomes contain CD45: no evidence for a distinct exosome/HIV-I budding pathway SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MULTIVESICULAR BODY; MEMBRANE-VESICLES; MICROVESICLES; PROTEINS; VIRIONS; MACROPHAGES; ACTIVATION; MOLECULES; COMPLEX AB The presence of relatively high levels of cellular protein contamination in density-purified virion preparations is a confounding factor in biochemical analyses of HIV and SIV produced from hematopoietic cells. A major source of this contamination is from vesicles, either microvesicles or exosomes, that have similar physical properties as virions. Thus, these particles can not be removed by size or density fractionation. Although virions and vesicles have similar cellular protein compositions, CD45 is excluded from HIV-I yet is present in vesicles produced from hematopoietic cells. By exploiting this finding, we have developed a CD45 immunoaffinity depletion procedure that removes vesicles from HIV-I preparations. While this approach has been successfully applied to virion preparations from several different cell types, some groups have concluded that "exosomes" from certain T cell lines, specifically Jurkat, do not contain CD45. If this interpretation is correct, then these vesicles could not be removed by CD45 immunoaffinity depletion. Here we show that dense vesicles produced by Jurkat and SupTI/CCR5 cells contain CD45 and are efficiently removed from preparations by CD45-immunoaffinity depletion. Also, contaminating cellular proteins were removed from virion preparations produced by these lines. Previously, the absence of CD45 from both "exosomes" and virions has been used to support the so called Trojan exosome hypothesis, namely that HIV-I is simply an exosome containing viral material. The presence of CD45 on vesicles, including exosomes, and its absence on virions argues against a specialized budding pathway that is shared by both exosomes and HIV-I. C1 [Coren, Lori V.; Shatzer, Teresa; Ott, David E.] Natl Canc Inst Frederick, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. RP Ott, DE (reprint author), Natl Canc Inst Frederick, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. EM coren@ncifcrf.gov; tshatzer@ncifcrf.gov; ott@ncifcrf.gov FU National Cancer Institute; National Institutes of Health [NOI-CO-12400] FX We thank James Hoxie, and Kendall Smith for the cell lines, and Claes Ohlen for helpful comments. The following reagent was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: Jurkat Clone E6-I from Dr. Arthur Weiss. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NOI-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U. S. Government. NR 24 TC 29 Z9 29 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUL 16 PY 2008 VL 5 AR 64 DI 10.1186/1742-4690-5-64 PG 5 WC Virology SC Virology GA 337XT UT WOS:000258469500001 PM 18631400 ER PT J AU Toyooka, N Zhou, DJ Nemoto, H Tezuka, Y Kadota, S Jones, TH Garraffo, HM Spande, TF Daly, JW AF Toyooka, Naoki Zhou, Dejun Nemoto, Hideo Tezuka, Yasuhiro Kadota, Shigetoshi Jones, Tappey H. Garraffo, H. Martin Spande, Thomas F. Daly, John W. TI First enantioselective synthesis of a hydroxyindolizidine alkaloid from the ant Myrmicaria melanogaster SO SYNLETT LA English DT Article DE hydroxyindolizidine; venoms of ant; Myrmicaria melanogaster; chelation control; new ant alkaloid ID NICOTINIC ACETYLCHOLINE-RECEPTORS; POISON-FROG ALKALOIDS; INDOLIZIDINE; METATHESIS AB The first enantioselective synthesis of the recently reported ant alkaloid I has been achieved starting from commercially available lactam 3 in seven steps and 25% overall yield. The proposed structure of the natural product was confirmed by comparison with synthetic 1 and its absolute configuration established as 3S,5R,8S,9S. C1 [Toyooka, Naoki; Zhou, Dejun; Nemoto, Hideo] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Toyama 9300194, Japan. [Tezuka, Yasuhiro; Kadota, Shigetoshi] Toyama Univ, Inst Nat Med, Toyama 9300194, Japan. [Jones, Tappey H.] Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. [Garraffo, H. Martin; Spande, Thomas F.; Daly, John W.] NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Toyooka, N (reprint author), Toyama Univ, Grad Sch Med & Pharmaceut Sci, Sugitani 2630, Toyama 9300194, Japan. EM toyooka@pha.u-toyama.ac.jp NR 19 TC 11 Z9 11 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0936-5214 EI 1437-2096 J9 SYNLETT JI Synlett PD JUL 16 PY 2008 IS 12 BP 1894 EP 1896 DI 10.1055/s-2008-1078502 PG 3 WC Chemistry, Organic SC Chemistry GA 331RN UT WOS:000258030400030 ER PT J AU Kontos, MC Jamal, SM Ornato, JP Tatum, JL Jesse, RL Anderson, FP AF Kontos, Michael C. Jamal, Sameer M. Ornato, Joseph P. Tatum, James L. Jesse, Robert L. Anderson, F. Philip TI Comparison of the Modification of Diet in Renal Disease and the Cockcroft-Gault equations for predicting mortality in patients admitted for exclusion of myocardial ischemia SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; ACUTE CORONARY SYNDROMES; SERUM CREATININE; INSUFFICIENCY; INFARCTION; FORMULAS; ADULTS AB Renal dysfunction is an important predictor of mortality in patients with acute coronary syndrome. Until recently, the Cockcroft-Gault (C-G) equation has been most commonly used to estimate renal function, although the Modification of Diet in Renal Disease (MDRD) equation is now recommended. Which equation better predicts mortality is unclear. Consecutive patients without ST elevation on the initial electrocardiogram admitted for exclusion of myocardial ischemia were included. Admission creatinine was used to estimate renal function, and 30-day and 1-year mortality were compared after classifying patients as having no (estimated glomerular filtration rate [eGFR] >= 60 ml/min/m(2)), moderate (eGFR 30 to 59 ml/min/m(2)), or severe (eGFR <30 ml/min/m(2)) renal dysfunction using the 2 equations. Of the 4,343 patients (49% women, 64% African-American) included, 16% had troponin I elevations consistent with myocardial infarction, and 1-year mortality was 10%. Agreement between the 2 equations was high (r = 0.87 p < 0.001, concordance 86%). Mortality was similar in the 2 renal function classifications, with no significant differences based on race or troponin I status at 30 days or 1 year. However, the area of the receiver operator characteristic curve was significantly larger for predicting I-year mortality with the C-G equation (0.75 [0.72 to 0.77] vs 0.71 [0.68 to 0.731; p < 0.01); both were superior to creatinine alone (0.68 [0.66 to 0.71]; p < 0.01 for both C-G and MDRD). Results for 30-day mortality were similar. In conclusion, the C-G equation appears to be superior to the MDRD equation for predicting short- and long-term mortality in patients admitted for exclusion of ischemia, although differences are minor. (C) 2008 Elsevier Inc. All rights reserved. C1 [Kontos, Michael C.; Jamal, Sameer M.; Ornato, Joseph P.; Jesse, Robert L.] NCI, Dept Internal Med, Div Cardiol, NIH, Bethesda, MD 20892 USA. [Kontos, Michael C.; Ornato, Joseph P.] Natl Canc Inst, Dept Emergency Med, NIH, Bethesda, MD USA. [Kontos, Michael C.] Natl Canc Inst, Dept Radiol, NIH, Bethesda, MD USA. [Anderson, F. Philip] Natl Canc Inst, Dept Pathol, Div Clin Chem, NIH, Bethesda, MD USA. [Tatum, James L.] Natl Canc Inst, Canc Imaging Program, Bethesda, MD USA. Virginia Commonwealth Univ, Richmond, VA USA. RP Kontos, MC (reprint author), NCI, Dept Internal Med, Div Cardiol, NIH, Bethesda, MD 20892 USA. EM mkontos@mcvh-vcu.edu NR 23 TC 13 Z9 13 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2008 VL 102 IS 2 BP 140 EP 145 DI 10.1016/j.amjcard.2008.03.023 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 327MZ UT WOS:000257734500006 PM 18602510 ER PT J AU Ahmed, B Merz, CNB Johnson, BD Bittner, V Berga, SL Braunstein, GD Hodgson, TK Smith, K Shaw, L Kelsey, SF Sopko, G AF Ahmed, Bina Merz, C. Noel Bairey Johnson, B. Delia Bittner, Vera Berga, Sarah L. Braunstein, Glenn D. Hodgson, T. Keta Smith, Karen Shaw, Leslee Kelsey, Sheryl F. Sopko, George CA WISE Study Grp TI Diabetes mellitus, hypothalamic hypoestrogenemia, and coronary artery disease in premenopausal women (from the National Heart, Lung, and Blood Institute sponsored WISE Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; RISK-FACTOR; INSULIN; ATHEROSCLEROSIS; RESPONSES; MEN AB Diabetes mellitus (DM) portends a higher risk of coronary heart disease mortality in women compared with men. This relationship appears to be independent of traditional cardiac risk factors; and the role of reproductive hormones has been postulated. We assessed the relationship between DM, hypothalamic hypoestrogenemia (HHE), angiographic coronary artery disease (CAD), and major adverse cardiovascular events (MACE) during a median of 5.9 years in premenopausal women enrolled in the WISE Study. We evaluated 95 premenopausal women from WISE who underwent coronary angiography for suspected ischemia and were not using exogenous reproductive hormones. Results showed no difference in age between women with (n = 30) and without (n = 65) DM (43 +/- 6 years). DM was associated with hypertension, HHE, angiographic CAD, and coronary artery severity score (all p < 0.05). Women with DM were twice as likely to have HHE (50% vs 26%; p = 0.02) compared with women without DM. The presence of both DM and HHE was associated with increased prevalence (40% vs 12% or 13%; p = 0.006) and severity of angiographic CAD (coronary artery severity score 19.9 +/- 19.2 vs 7.7 +/- 4.6 or 12.3 +/- 18.8; p = 0.008) compared with either HHE or DM alone, respectively. DM was moderately predictive of MACE. In conclusion, in premenopausal women undergoing coronary angiography for suspected myocardial ischemia, DM was associated with HHE. The presence of both DM and HHE predicted a greater burden of angiographic CAD. Prospective research is warranted to better understand causal relations between DM, endogenous hormones, and MACE in premenopausal women. (C) 2008 Elsevier Inc. All rights reserved. C1 [Ahmed, Bina; Merz, C. Noel Bairey; Braunstein, Glenn D.; Hodgson, T. Keta] Cedars Sinai Med Ctr, Cedars Sinai Res Inst, Div Cardiol, Dept Med, Los Angeles, CA 90048 USA. [Johnson, B. Delia; Kelsey, Sheryl F.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Bittner, Vera] Univ Alabama, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. [Berga, Sarah L.] Univ Pittsburgh, Div Reprod Endocrinol, Pittsburgh, PA USA. [Smith, Karen] Univ Florida, Dept Med, Div Cardiol, Gainesville, FL USA. [Shaw, Leslee] Atlanta Cardiovasc Res Inst, Atlanta, GA USA. [Sopko, George] NHLBI, NIH, Bethesda, MD 20892 USA. RP Ahmed, B (reprint author), Cedars Sinai Med Ctr, Cedars Sinai Res Inst, Div Cardiol, Dept Med, Los Angeles, CA 90048 USA. EM bina.ahmed@vtmednet.org OI Bittner, Vera/0000-0001-9456-850X FU NCRR NIH HHS [M01 RR000425, M01-RR00425]; NHLBI NIH HHS [N01HV68163, N01 HV068161, N01 HV068164, N01-HV-68163, N01HV68162, N01-HV-68162, N01 HV068163, N01 HV068162] NR 29 TC 10 Z9 11 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2008 VL 102 IS 2 BP 150 EP 154 DI 10.1016/j.amjcard.2008.03.029 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 327MZ UT WOS:000257734500008 PM 18602512 ER PT J AU Koshiol, J Lindsay, L Pimenta, JM Poole, C Jenkins, D Smith, JS AF Koshiol, Jill Lindsay, Lisa Pimenta, Jeanne M. Poole, Charles Jenkins, David Smith, Jennifer S. TI Persistent human papillomavirus infection and cervical neoplasia: A systematic review and meta-analysis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE human papillomavirus 16; human papillomavirus 18; longitudinal studies; papillomavirus infections; uterine cervical neoplasms ID SQUAMOUS INTRAEPITHELIAL LESIONS; RISK HUMAN-PAPILLOMAVIRUS; CARCINOMA IN-SITU; GENITAL HUMAN-PAPILLOMAVIRUS; RANDOMIZED CONTROLLED-TRIAL; CYTOLOGICALLY NORMAL WOMEN; 2001 CONSENSUS GUIDELINES; POSTMENOPAUSAL AGE WOMEN; HIV-SERONEGATIVE WOMEN; CAPTURE-II ASSAY AB Detection of persistent cervical carcinogenic human papillomavirus (HPV) DNA is used as a marker for cervical cancer risk in clinical trials. The authors performed a systematic review and meta-analysis of the association between persistent HPV DNA and high-grade cervical intraepithelial neoplasia (CIN2-3), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (together designated CIN2-3/HSIL+) to evaluate the robustness of HPV persistence for clinical use. MEDLINE and Current Contents were searched through January 30, 2006. Relative risks (RRs) were stratified by HPV comparison group. Of 2,035 abstracts, 41 studies were eligible for inclusion in the meta-analysis. Over 22,500 women were included in calculation of RRs for persistent HPV DNA detection and cervical neoplasia. RRs ranged from 1.3 (95% confidence interval: 1.1, 1.5) to 813.0 (95% confidence interval: 168.2, 3,229.2) for CIN2-3/HSIL+ versus < CIN2-3/HSIL+; 92% of RRs were above 3.0. Longer durations of infection (> 12 months), wider testing intervals, CIN2-3/HSIL+, and use of an HPV-negative reference group were consistently associated with higher RRs. Thus, HPV persistence was consistently and strongly associated with CIN2-3/HSIL+, despite wide variation in definitions and study methods. The magnitude of association varied by duration of persistence and testing interval. Precise definition and standardization of HPV testing, sampling procedure, and test interval are needed for reliable clinical testing. These findings validate HPV persistence as a clinical marker and endpoint. C1 [Koshiol, Jill] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Pimenta, Jeanne M.] GlaxoSmithKline Inc, Worldwide Epidemiol, Greenford, Middx, England. [Lindsay, Lisa; Jenkins, David] GlaxoSmithKline Biol, Rixensart, Belgium. [Poole, Charles; Smith, Jennifer S.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Koshiol, J (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, 6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.gov; jennifers@unc.edu NR 105 TC 181 Z9 197 U1 1 U2 16 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 JUL 15 PY 2008 VL 168 IS 2 BP 123 EP 137 DI 10.1093/aje/kwn036 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 322SE UT WOS:000257394800001 PM 18483125 ER PT J AU Castle, PE AF Castle, Philip E. TI Invited commentary: Is monitoring of human papillomavirus infection for viral persistence ready for use in cervical cancer screening? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE human papillomavirus 16; human papillomavirus 18; longitudinal studies; papillomavirus infections; uterine cervical neoplasms ID ATYPICAL SQUAMOUS-CELLS; 2006 CONSENSUS GUIDELINES; UNDETERMINED SIGNIFICANCE; INTRAEPITHELIAL NEOPLASIA; COSTA-RICA; MANAGEMENT STRATEGIES; QUALITY-CONTROL; FOLLOW-UP; WOMEN; DNA AB \Persistent cervical infections by approximately 15 carcinogenic genotypes of human papillomavirus (HPV) cause virtually all cases of cervical cancer and its immediate precancerous precursor, cervical intraepithelial neoplasia grade 3 or carcinoma in situ. As is shown in a meta-analysis by Koshiol et al. (Am J Epidemiol 2008;168:123-137), detection of carcinogenic HPV viral persistence could be used to identify women at the greatest risk of cervical precancer. Specifically, women who have carcinogenic HPV infection that persists for at least 1 year versus those whose infections clear are at significantly elevated risk of having or developing cervical precancer. However, before detection of HPV persistence can be used in cervical cancer screening, several considerations need to be addressed: 1) validation and Food and Drug Administration approval of a reliable HPV genotyping test, 2) rational clinical algorithms based on risk of precancer and cancer for the clinical management of HPV persistence, 3) clinician and patient acceptability of monitoring of HPV infections (including not responding excessively to the first positive HPV test and waiting 1-2 years for infections to either persist or resolve), and 4) patient compliance with recommended follow-up. Investigators will need to address these and other key issues in order to realize the potential utility of HPV viral monitoring for improving the accuracy of cervical cancer screening. C1 NCI, Div Canc Epiemiol & Genet, Bethesda, MD 20892 USA. RP Castle, PE (reprint author), NCI, Div Canc Epiemiol & Genet, 6120 Execut Blvd,EPS Room 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov NR 47 TC 22 Z9 23 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 JUL 15 PY 2008 VL 168 IS 2 BP 138 EP 144 DI 10.1093/aje/kwn037 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 322SE UT WOS:000257394800002 PM 18483124 ER PT J AU Koshiol, J Poole, C Chu, HT Pimenta, JM Lindsay, L Jenkins, D Smith, JS AF Koshiol, Jill Poole, Charles Chu, Haitao Pimenta, Jeanne M. Lindsay, Lisa Jenkins, David Smith, Jennifer S. TI The authors respond to "HPV Persistence and Cervical Cancer Screening" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID SQUAMOUS INTRAEPITHELIAL LESIONS; HUMAN-PAPILLOMAVIRUS DNA; CARCINOMA IN-SITU; HIGH-RISK HPV; INFECTION; NEOPLASIA; WOMEN; METAANALYSIS; ACCURACY; SMEARS C1 [Koshiol, Jill] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. RP Koshiol, J (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, 6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.gov; jennifers@unc.edu OI Chu, Haitao/0000-0003-0932-598X NR 25 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2008 VL 168 IS 2 BP 145 EP 148 DI 10.1093/aje/kwn129 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 322SE UT WOS:000257394800003 ER PT J AU Moore, SC Chow, WH Schatzkin, A Adams, KF Park, Y Ballard-Barbash, R Hollenbeck, A Leitzmann, MF AF Moore, Steven C. Chow, Wong-Ho Schatzkin, Arthur Adams, Kenneth F. Park, Yikyung Ballard-Barbash, Rachel Hollenbeck, Albert Leitzmann, Michael F. TI Physical activity during adulthood and adolescence in relation to renal cell cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adolescent; exercise; kidney; kidney neoplasms; motor activity; neoplasms ID KIDNEY CANCER; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; BLOOD-PRESSURE; ENERGY-INTAKE; RISK-FACTORS; INSULIN-LIKE; WEIGHT-LOSS; LIFE-STYLE; BODY-MASS AB Evidence for a relation between physical activity and renal cell cancer has been inconsistent. The authors examined physical activity in relation to renal cell cancer in a large, prospective US cohort study of 482,386 participants (289,503 men and 192,883 women) aged 50-71 years at baseline (1995-1996). At baseline, participants reported their frequency of exercise of at least 20 minutes' duration, intensity of daily routine activity, and frequency of physical activity during adolescence. During 8.2 years of follow-up (through December 2003), 1,238 cases of renal cell cancer were ascertained. In multivariate Cox regression models adjusted for renal cell cancer risk factors, the authors observed that current exercise, routine physical activity, and activity during adolescence were associated with a reduced risk of renal cell cancer. The multivariate relative risks for the highest activity level as compared with the lowest were 0.77 (95% confidence interval (CI): 0.64, 0.92; p(trend) = 0.10) for current exercise, 0.84 (95% CI: 0.57, 1.22; p(trend) = 0.03) for routine physical activity, and 0.82 (95% CI: 0.68, 1.00; p(trend) = 0.05) for activity during adolescence. The authors conclude that increased physical activity, including activity during adolescence, is associated with reduced risk of renal cell cancer. C1 [Moore, Steven C.; Chow, Wong-Ho; Schatzkin, Arthur; Adams, Kenneth F.; Park, Yikyung; Leitzmann, Michael F.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ballard-Barbash, Rachel] NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Moore, SC (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,MSC 7232, Bethesda, MD 20892 USA. EM moorest@mail.nih.gov RI Moore, Steven/D-8760-2016; OI Moore, Steven/0000-0002-8169-1661; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS; NCI NIH HHS [TU2 CA105666, TU2CA105666] NR 32 TC 25 Z9 25 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 JUL 15 PY 2008 VL 168 IS 2 BP 149 EP 157 DI 10.1093/aje/kwn102 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 322SE UT WOS:000257394800004 PM 18468990 ER PT J AU Brotman, RM Klebanoff, MA Nansel, TR Andrews, WW Schwebke, JR Zhang, J Yu, KF Zenilman, JM Scharfstein, DO AF Brotman, Rebecca M. Klebanoff, Mark A. Nansel, Tonja R. Andrews, William W. Schwebke, Jane R. Zhang, Jun Yu, Kai F. Zenilman, Jonathan M. Scharfstein, Daniel O. TI A longitudinal study of vaginal douching and bacterial vaginosis - A marginal structural modeling analysis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE confounding factors (epidemiology); epidemiologic methods; longitudinal studies; models; structural; vaginal douching; vaginosis; bacterial ID SEXUALLY-TRANSMITTED-DISEASES; IMMUNODEFICIENCY-VIRUS TYPE-1; MENSTRUAL-CYCLE; MICROBIAL-FLORA; WOMEN DOUCHE; MICROFLORA; LACTOBACILLI; ASSOCIATIONS; RISK; TRANSMISSION AB The etiology of bacterial vaginosis is unknown, and there are no long-term therapies for preventing this frequently recurring condition. Vaginal douching has been reported to be associated with bacterial vaginosis in observational studies. However, this association may be due to confounding by indication-that is, confounding by women douching in response to vaginal symptoms associated with bacterial vaginosis. The authors used marginal structural modeling to estimate the causal effect of douching on bacterial vaginosis risk while controlling for this confounding effect. In 1999-2002, nonpregnant women (n = 3,620) were recruited into a prospective study when they visited one of 12 public health clinics in Birmingham, Alabama, for routine care. Participants were assessed quarterly for 1 year. Bacterial vaginosis was based on a Nugent's Gram stain score of 7 or higher. Thirty-two percent of participants douched in every study interval, and 43.0% never douched. Of the 12,349 study visits, 40.2% were classified as involving bacterial vaginosis. The relative risk for regular douching as compared with no douching was 1.21 (95% confidence interval: 1.08, 1.38). These findings indicate that douching confers increased risk of disruption of vaginal flora. In the absence of a large randomized trial, these findings provide the best evidence to date for a risk of bacterial vaginosis associated with douching. C1 [Brotman, Rebecca M.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Brotman, Rebecca M.; Klebanoff, Mark A.; Nansel, Tonja R.; Zhang, Jun; Yu, Kai F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Andrews, William W.] Univ Alabama Birmingham, Sch Med, Dept Obstet & Gynecol, Birmingham, AL USA. [Schwebke, Jane R.] Univ Alabama Birmingham, Sch Med, Div Infect Dis, Birmingham, AL USA. [Zenilman, Jonathan M.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Scharfstein, Daniel O.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. RP Brotman, RM (reprint author), Johns Hopkins Bayview Med Ctr, Div Infect Dis, 4940 Eastern Ave,B-3 North, Baltimore, MD 21224 USA. EM rbrotman@jhsph.edu RI Brotman, Rebecca/H-5442-2011; OI Brotman, Rebecca/0000-0001-8762-6214; Nansel, Tonja/0000-0002-8298-7595 FU Intramural NIH HHS [Z01 HD002535-09]; NICHD NIH HHS [N01 HD083293] NR 68 TC 47 Z9 50 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2008 VL 168 IS 2 BP 188 EP 196 DI 10.1093/aje/kwn103 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 322SE UT WOS:000257394800008 PM 18503038 ER PT J AU Pletcher, MJ Bibbins-Domingo, K Lewis, CE Wei, GS Sidney, S Carr, JJ Vittinghoff, E McCulloch, CE Hulley, SB AF Pletcher, Mark J. Bibbins-Domingo, Kirsten Lewis, Cora E. Wei, Gina S. Sidney, Steve Carr, J. Jeffrey Vittinghoff, Eric McCulloch, Charles E. Hulley, Stephen B. TI Prehypertension during young adulthood and coronary calcium later in life SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; AMERICAN-HEART-ASSOCIATION; CHILDHOOD BLOOD-PRESSURE; JOINT NATIONAL COMMITTEE; INTIMA-MEDIA THICKNESS; ARTERY CALCIUM; COMPUTED-TOMOGRAPHY; ATHEROSCLEROTIC LESIONS; DISEASE RISK; US ADULTS AB Background: High blood pressure in middle age is a well-established risk factor for cardiovascular disease, but the consequences of low-level elevations during young adulthood are unknown. Objective: To measure the association between prehypertension exposure before age 35 years and coronary calcium later in life. Design: Prospective cohort study. Setting: Four communities in the United States. Participants: Black and white men and women age 18 to 30 years recruited for the CARDIA (Coronary Artery Risk Development in Young Adults) Study in 1985 through 1986 who were without hypertension before age 35 years. Measurements: Blood pressure trajectories for each participant were estimated by using measurements from 7 examinations over the course of 20 years. Cumulative exposure to blood pressure in the prehypertension range (systolic blood pressure of 120 to 139 mm Hg, or diastolic blood pressure of 80 to 89 mm Hg) from age 20 to 35 years was calculated in units of mm Hg-years (similar to pack-years of tobacco exposure) and related to the presence of coronary calcium measured at each participant's last examination (mean age, 44 years [SD, 4]). Results: Among 3560 participants, the 635 (18%) who developed prehypertension before age 35 years were more often black, male, overweight, and of lower socioeconomic status. Exposure to prehypertension before age 35 years, especially systolic prehypertension, showed a graded association with coronary calcium later in life (coronary calcium prevalence of 15%, 24%, and 38% for 0, 1 to 30, and > 30 mm Hg-years of exposure, respectively; P < 0.001). This association remained strong after adjustment for blood pressure elevation after age 35 years and other coronary risk factors and participant characteristics. Limitation: Coronary calcium, although a strong predictor of future coronary heart disease, is not a clinical outcome. Conclusion: Prehypertension during young adulthood is common and is associated with coronary atherosclerosis 20 years later. Keeping systolic pressure below 120 mrn Hg before age 35 years may provide important health benefits later in life. C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. Univ Alabama, Birmingham, AL USA. NHLBI, NIH, Bethesda, MD 20892 USA. Kaiser Permanente, Oakland, CA USA. Wake Forest Univ, Winston Salem, NC 27109 USA. RP Pletcher, MJ (reprint author), 185 Berry St,Suite 5700, San Francisco, CA 94107 USA. EM mpletcher@epi.ucsf.du RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 FU Intramural NIH HHS [Z99 HL999999]; NCI NIH HHS [R01 CA094107, R43 CA094612, R44 CA094612]; NHLBI NIH HHS [N01HC48047, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095, N01HC48048, N01HC48049, N01HC48050, N01HC95095] NR 51 TC 69 Z9 76 U1 0 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 15 PY 2008 VL 149 IS 2 BP 91 EP 99 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 329GA UT WOS:000257853700003 PM 18626048 ER PT J AU Godiksen, S Selzer-Plon, J Pedersen, EDK Abell, K Rasmussen, HB Szabo, R Bugge, TH Vogel, LK AF Godiksen, Sine Selzer-Plon, Joanna Pedersen, Esben D. K. Abell, Kathrine Rasmussen, Hanne B. Szabo, Roman Bugge, Thomas H. Vogel, Lotte K. TI Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary SO BIOCHEMICAL JOURNAL LA English DT Article DE endocytosis; hepatocyte growth factor activator inhibitor-1 (HAI-1); lysosomal degradation; proteolytic release.; transcytosis ID SERINE-PROTEASE MATRIPTASE; IN-VITRO; PROTEOLYTIC CLEAVAGE; EPITHELIAL-CELLS; BARRIER FUNCTION; O-GLYCOSYLATION; HUMAN TISSUES; TYPE-1 HAI-1; EXPRESSION; SECRETION AB HAI-1 [HGF (hepatocyte growth factor) activator inhibitor-1] is a Kunitz-type transmembrane serine protease inhibitor that forms inhibitor complexes with the trypsin-like serine protease, matriptase. HAI-1 is essential for mouse placental development and embryo survival and together with matriptase it is a key regulator of carcinogenesis. HAM is expressed in polarized epithelial cells, which have the plasma membrane divided by tight junctions into an apical and a basolateral domain. In the present study we show that HAI-1 at steady-state is mainly located on the basolateral membrane of both Madin-Darby canine kidney cells and mammary gland epithelial cells. After biosynthesis, HAI-1 is exocytosed mainly to the basolateral plasma membrane from where 15% of the HAI-1 molecules are proteolytically cleaved and released into the basolateral medium. The remaining membrane-associated HAI-1 is endocytosed and then recycles between the basolateral plasma membrane and endosomes for hours until it is transcytosed to the apical plasma membrane. Minor amounts of HAI-1 present at the apical plasma membrane are proteolytically cleaved and released into the apical medium. Full-length membrane-bound HAI-1 has a half-life of 1.5 h and is eventually degraded in the lysosomes, whereas proteolytically released HAI-1 is more stable. HAM is co-localized with its cognate protease, matriptase, at the basolateral plasma membrane. We suggest that HAI-1, in addition to its protease inhibitory function, plays a role in transporting matriptase as a matriptase-HAI-1 complex from the basolateral plama membrane to the apical plasma membrane, as matriptase is known to interact with prostasin, located at the apical plasma membrane. C1 [Godiksen, Sine; Selzer-Plon, Joanna; Pedersen, Esben D. K.; Abell, Kathrine; Vogel, Lotte K.] Univ Copenhagen, Panum Inst, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. [Rasmussen, Hanne B.] Univ Copenhagen, Panum Inst, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark. [Szabo, Roman; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, NIH, Proteases & Tissue Remodeling Unit, Bethesda, MD 20892 USA. RP Vogel, LK (reprint author), Univ Copenhagen, Panum Inst, Dept Cellular & Mol Med, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. EM vogel@imbg.ku.dk RI Rasmussen, Hanne /N-9652-2016 OI Rasmussen, Hanne /0000-0002-2218-5646 FU Intramural NIH HHS [Z99 DE999999] NR 39 TC 20 Z9 20 U1 1 U2 3 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JUL 15 PY 2008 VL 413 BP 251 EP 259 DI 10.1042/BJ20071496 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 328DL UT WOS:000257777800005 PM 18402552 ER PT J AU Banerjee, R Pennington, MW Garza, A Owens, IS AF Banerjee, Rajat Pennington, Matthew W. Garza, Amanda Owens, Ida S. TI Mapping the UDP-glucuronic acid binding site in UDP-glucuronosyltransferase-1A10 by homology-based modeling: Confirmation with biochemical evidence SO BIOCHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; GALACTOSE 4-EPIMERASE; SUBSTRATE-BINDING; CRYSTAL-STRUCTURE; LIVER-MICROSOMES; GLUCURONOSYLTRANSFERASE; PURIFICATION; BILIRUBIN; GLUCURONYLTRANSFERASE; IDENTIFICATION AB The UDP-glucuronosyltransferase (UGT) isozyme system is critical for protecting the body against endogenous and exogenous chemicals by linking glucuronic acid donated by UDP-glucuronic acid to a lipophilic acceptor substrate. UGTs convert metabolites, dietary constituents, and environmental toxicants to highly excretable glucuronides. Because of difficulties associated with purifying endoplasmic reticulum-bound UGTs for structural studies, we carried out homology-based computer modeling to aid analysis. The search found structural homology in Escherichia coli UDP-galactose 4-epimerase. Consistent with predicted similarities involving the common UDP moiety in substrate/inhibitor, UDP-glucose and UDP-hexanol amine caused competitive inhibition by Lineweaver-Burk plots. Among predicted binding sites N292, K314, K315, and K404 in UGT1A10, two informative sets of mutants K314R/Q/A/E/G and K404R/E had null activities or 2.7-fold higher/50% less activity, respectively. Scatchard analysis of binding data of the affinity ligand, 5-azidouridine-[beta-P-32]diphosphoglueuronic acid, to purified UGT1A10-His or UGT1A7-His revealed high- and low-affinity binding sites. 2-Nitro-5-thiocyanobenzoic acid-digested UGT1A10-His bound with the radiolabeled affinity ligand revealed an 11.3 and 14.3 kDa peptide associated with K314 and K404, respectively, in a discontinuous SDS-PAGE system. Similar treatment of 1A10HisK-314A bound with the ligand lacked both peptides; 1A10-HisK404R- and 1A10-HisK404E showed 1.3-fold greater and 50% less label in the 14.3 kDa peptide, respectively, compared to 1A10-His without affecting the 11.3 kDa peptide. Scatchard analysis of binding data of the affinity ligand to 1A10His-K404R and -K404E showed a 6-fold reduction and a large increase in K-d, respectively. Our results indicate that K314 and K404 are required UDP-glcA binding sites in 1A10, that K404 controls activity and high-affinity sites, and that K314 and K404 are strictly conserved in 70 aligned UGTs, except for S321, equivalent to K314, in UGT2B15 and 2B17 and I321 in the inactive UGT8, which suggests UGT2B15 and 2B17 contain suboptimal activity. Hence our data strongly support `UDP-glcA binding to K314 and K404 in UGT1A10. C1 [Banerjee, Rajat; Pennington, Matthew W.; Garza, Amanda; Owens, Ida S.] NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Owens, IS (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. EM owensi@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999, Z01 HD008751-06] NR 25 TC 9 Z9 9 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 15 PY 2008 VL 47 IS 28 BP 7385 EP 7392 DI 10.1021/bi8006127 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 324FX UT WOS:000257504200008 PM 18570380 ER PT J AU Kusumoto, R Dawut, L Marchetti, C Lee, JW Vindigni, A Ramsden, D Bohr, VA AF Kusumoto, Rika Dawut, Lala Marchetti, Caterina Lee, Jae Wan Vindigni, Alessandro Ramsden, Dale Bohr, Vilhelm A. TI Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing SO BIOCHEMISTRY LA English DT Article ID STRAND BREAK REPAIR; V(D)J RECOMBINATION; DNA ENDS; HELICASE ACTIVITY; SYNDROME GENE; HUMAN-CELLS; IN-VIVO; REPLICATION; INTERACTS; WRN AB Werner syndrome is a rare human disease characterized by the premature onset of aging-associated pathologies, cancer predisposition, and genomic instability. The Werner protein (WRN), which is defective in Werner syndrome (WS) patients, belongs to the RecQ family helicases and interacts with several DNA metabolic proteins, including DNA repair factors and telomere associated proteins. Nonhomologous end-joining (NHEJ) is an important pathway in the repair of DNA double strand breaks (DSBs), and the DNA-PK complex, composed of the heterodimer Ku 70/86 and the DNA-PK catalytic subunit (DNA-PKcs), together with the XRCC4-DNA ligase IV complex (X4L4), are major factors. One of the most prominent protein interactions of WRN is with Ku 70/86, and it is possible that WRN is involved in NHEJ via its associations with Ku 70/86 and DNA-PKcs. This study demonstrates that WRN physically interacts with the major NHEJ factor, X4L4, which stimulates WRN exonuclease but not its helicase activity. The human RecQ helicase, BLM, which possesses only helicase activity, does not bind to X4L4, and its helicase activity is not affected by X4L4. In a DNA end-joining assay, we find that a substrate, which is processed by WRN, is ligated by X4L4, thus further supporting the significance of their functional interaction. C1 [Kusumoto, Rika; Dawut, Lala; Lee, Jae Wan; Bohr, Vilhelm A.] NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. [Marchetti, Caterina; Vindigni, Alessandro] Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy. [Ramsden, Dale] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Ramsden, Dale] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. [Ramsden, Dale] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bohrv@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000726-15]; NCI NIH HHS [CA84442, R01 CA084442, R01 CA084442-09] NR 46 TC 37 Z9 41 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 JUL 15 PY 2008 VL 47 IS 28 BP 7548 EP 7556 DI 10.1021/bi702325t PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 324FX UT WOS:000257504200023 PM 18558713 ER PT J AU Hyun, M Bohr, VA Ahn, BC AF Hyun, Moonjung Bohr, Vilhelm A. Ahn, Byungchan TI Biochemical characterization of the WRN-1 RecQ helicase of Caenorhabditis elegans SO BIOCHEMISTRY LA English DT Article ID REPLICATION PROTEIN-A; WERNER-SYNDROME PROTEIN; ROTHMUND-THOMSON-SYNDROME; SYNDROME GENE-PRODUCT; DNA HELICASE; BLOOM-SYNDROME; HOLLIDAY JUNCTIONS; SUBSTRATE-SPECIFICITY; IONIZING-RADIATION; UNWINDING ACTIVITY AB The highly conserved RecQ helicases are essential for the maintenance of genomic stability. Werner syndrome protein, WRN, is one of five human RecQ helicase homologues, and a deficiency of the protein causes a hereditary premature aging disorder that is characterized by genomic instability. A WRN orthologue, wrn-1 lacking the exonuclease domain, has been identified in the nematode Caenorhabditis, elegans. wrn-1(RNAi) in C elegans has a shortened life span, increased sensitivity to DNA damage, and accelerated aging phenotypes. However, little is known about its enzymatic activity. We purified the recombinant C elegans WRN-1 protein (CeWRN-1) and then investigated its substrate specificity in vitro to improve our understanding of its function in vivo. We found that CeWRN-1 is an ATP-dependent 3'-5'helicase capable of unwinding a variety of DNA structures such as forked duplexes, Holliday junctions, bubble substrates, D-loops, and flap duplexes, and Y-tailed duplex substrates. Distinctly, CeWRN-1 is able to unwind a long forked duplex compared to human WRN. Furthermore, CeWRN-1 helicase activity on a long DNA duplex is stimulated by C. elegans replication protein A (CeRPA) that is shown to interact with CeWRN-1 by a dot blot. The ability of CeWRN-1 to unwind these DNA structures may improve the access for DNA repair and replication proteins that are important for preventing the accumulation of abnormal structures, contributing to genomic stability. C1 [Hyun, Moonjung; Ahn, Byungchan] Univ Ulsan, Dept Life Sci, Ulsan 680749, South Korea. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Gerontol Res Ctr, Natl Inst Hlth, Baltimore, MD 21224 USA. RP Ahn, BC (reprint author), Univ Ulsan, Dept Life Sci, Ulsan 680749, South Korea. EM bbccahn@ulsan.ac.kr FU Intramural NIH HHS [Z01 AG000726-15] NR 35 TC 16 Z9 19 U1 3 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 15 PY 2008 VL 47 IS 28 BP 7583 EP 7593 DI 10.1021/bi800197m PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 324FX UT WOS:000257504200027 PM 18558712 ER PT J AU Fanous, AH Neale, MC Webb, BT Straub, RE O'Neill, FA Walsh, D Riley, BP Kendler, KS AF Fanous, Ayman H. Neale, Michael C. Webb, Bradley T. Straub, Richard E. O'Neill, Francis A. Walsh, Dermot Riley, Brien P. Kendler, Kenneth S. TI Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families SO BIOLOGICAL PSYCHIATRY LA English DT Article DE chromosome 20; genetic; linkage; schizophrenia; subtypes ID BIPOLAR-AFFECTIVE-DISORDER; DTNBP1 DYSBINDIN GENE; GENOME SCAN; SCHIZOPHRENIA FAMILIES; SUSCEPTIBILITY GENES; VULNERABILITY LOCUS; CLINICAL-FEATURES; RISK HAPLOTYPE; FOLLOW-UP; HETEROGENEITY AB Background: Several lines of evidence suggest that the clinical heterogeneity of schizophrenia is due to genetic heterogeneity. Genetic heterogeneity may decrease the signal-to-noise ratio in linkage and association studies. Therefore, linkage studies of clinically homogeneous classes of psychotic illness may result in greater power to detect at least some loci. Methods: Latent class analysis was used to divide psychotic subjects from 270 Irish high-density families (N = 755) into six classes based on the Operational Criteria Checklist for Psychotic Illness. We heuristically call them Bipolar, Schizoaffective, Mania, Schizomania, Deficit Syndrome, and Core Schizophrenia. The latter four had prevalences of greater than .08 and were individually tested for linkage in a 10-cM nonparametric autosomal genomewide scan. Empirical significance was determined using 200 simulated genome scans. Results: Seven regions achieved empirical criteria for suggestive significance for at least one latent class: 5q23.2-q35.3, 8q13.1-q23.1, 10q23.33-q26.3, 12q21.2-q24.32,19q13.32-q13.43, 20p13-q22.3, and 21q11.2-q22.3. Five of 200 simulated scans resulted in seven suggestively significant loci (experiment-wide p = .03). Furthermore, at 20p13-p12.2, the Mania and Schizomania classes individually achieved criteria, whereas Deficit Syndrome had a suggestive logarithm of the odds peak 28 cM centromeric to this locus. Conclusions: Using empirically derived, clinically homogeneous phenotypes, four chromosomal regions were suggestively linked but provided little evidence of linkage using traditional operationalized criteria. This approach was particularly fruitful on chromosome 20, which had previously yielded little evidence of linkage. Future studies of psychiatric illness may increase their ability to detect linkage or association by using clinically homogeneous phenotypes. C1 [Fanous, Ayman H.] Washington VA Med Ctr, Washington, DC USA. [Fanous, Ayman H.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Fanous, Ayman H.; Neale, Michael C.; Webb, Bradley T.; Riley, Brien P.; Kendler, Kenneth S.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Neale, Michael C.; Kendler, Kenneth S.] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. [Straub, Richard E.] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [O'Neill, Francis A.] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Walsh, Dermot] Hlth Res Board, Dublin, Ireland. RP Fanous, AH (reprint author), 50 Irving St NW, Washington, DC 20422 USA. EM ayman.fanous@med.va.gov RI Webb, Bradley/B-1459-2009; OI Webb, Bradley/0000-0002-0576-5366; O'Neill, Francis Anthony/0000-0002-7531-7657 FU NIMH NIH HHS [R01 MH041953, IT-32 MH-20030, MH-41953, MH-45390, MH-52537, MH-65322, R01 MH068881] NR 60 TC 41 Z9 41 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2008 VL 64 IS 2 BP 121 EP 127 DI 10.1016/j.biopsych.2007.11.023 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 319TT UT WOS:000257187700006 PM 18255048 ER PT J AU Zonios, DI Falloon, J Bennett, JE Shaw, PA Chaitt, D Baseler, MW Adelsberger, JW Metcalf, JA Polis, MA Kovacs, SJ Kovacs, JA Davey, RT Lane, HC Masur, H Sereti, I AF Zonios, Dimitrios I. Falloon, Judith Bennett, John E. Shaw, Pamela A. Chaitt, Doreen Baseler, Michael W. Adelsberger, Joseph W. Metcalf, Julia A. Polis, Michael A. Kovacs, Stephen J. Kovacs, Joseph A. Davey, Richard T. Lane, H. Clifford Masur, Henry Sereti, Irini TI Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors SO BLOOD LA English DT Article ID CD4(+) T-LYMPHOCYTOPENIA; UNEXPLAINED OPPORTUNISTIC INFECTIONS; ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTION; PNEUMOCYSTIS-CARINII; IL-2 THERAPY; CELLS; PATIENT; IMMUNODEFICIENCY; AUTOIMMUNITY AB Idiopathic CD4+ lymphocytopenia (ICL) is a rare non-HIV-related syndrome with unclear natural history and prognosis. This prospective natural history cohort study describes the clinical course, CD4 T lymphocyte kinetics, outcome, and prognostic factors of ICL. Thirty-nine patients (17 men, 22 women) 25 to 85 years old with ICL were evaluated between 1992 and 2006, and 36 were followed for a median of 49.5 months. Cryptococcal and nontuberculous mycobacterial infections were the major presenting opportunistic infections. Seven patients presented with no infection. In 32, CD4 T-cell counts remained less than 300/mm(3) throughout the study period and in 7 normalized after an average of 31 months. Overall, 15 (41.6%) developed an opportunistic infection in follow-up, 5 (13.8%) of which were "AIDS-defining clinical conditions," and 4 (11.1 %) developed autoimmune diseases. Seven patients died, 4 from ICL-related opportunistic infections, within 42 months after diagnosis. Immunologic analyses revealed increased activation and turnover in CD4 but not CD8 T lymphocytes. CD8 T lymphocytopenia (< 180/mm(3)) and the degree of CD4 T cell activation (measured by HLA-DR expression) at presentation were associated with adverse outcome (opportunistic infection-related death; P = .003 and .02, respectively). This trial is registered at http://clinicaltrials. gov as #NCT00001319. C1 [Zonios, Dimitrios I.; Bennett, John E.] NIAID, Natl Inst Hlth, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Falloon, Judith; Chaitt, Doreen; Metcalf, Julia A.; Polis, Michael A.; Kovacs, Stephen J.; Davey, Richard T.; Lane, H. Clifford; Sereti, Irini] NIAID, Natl Inst Hlth, Immunoregulat Lab, Bethesda, MD 20892 USA. [Shaw, Pamela A.] NIAID, Natl Inst Hlth, Biostat Res Branch, Bethesda, MD 20892 USA. [Baseler, Michael W.; Adelsberger, Joseph W.] Sci Applicat Int Corp, NCI, Appl & Dev Res Support Program, Frederick, MD USA. [Masur, Henry] Natl Inst Hlth, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD USA. RP Sereti, I (reprint author), 9000 Rockville Pike,Bldg 10,Room 11C103, Bethesda, MD 20892 USA. EM dzonios@yahoo.com; isereti@mail.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 33 TC 98 Z9 100 U1 0 U2 2 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 JUL 15 PY 2008 VL 112 IS 2 BP 287 EP 294 DI 10.1182/blood-2007-12-127878 PG 8 WC Hematology SC Hematology GA 326YT UT WOS:000257696300017 PM 18456875 ER PT J AU Muranski, P Boni, A Antony, PA Cassard, L Irvine, KR Kaiser, A Paulos, CM Palmer, DC Touloukian, CE Ptak, K Gattinoni, L Wrzesinski, C Hinrichs, CS Kerstann, KW Feigenbaum, L Chan, CC Restifo, NP AF Muranski, Pawel Boni, Andrea Antony, Paul A. Cassard, Lydie Irvine, Kari R. Kaiser, Andrew Paulos, Chrystal M. Palmer, Douglas C. Touloukian, Christopher E. Ptak, Krzysztof Gattinoni, Luca Wrzesinski, Claudia Hinrichs, Christian S. Kerstann, Keith W. Feigenbaum, Lionel Chan, Chi-Chao Restifo, Nicholas P. TI Tumor-specific Th17-polarized cells eradicate large established melanoma SO BLOOD LA English DT Article ID CD4(+) T-CELLS; ROR-GAMMA-T; POTENT ANTITUMOR IMMUNITY; GROWTH-FACTOR-BETA; HELPER-CELLS; IFN-GAMMA; IN-VIVO; T(H)17 CELLS; TH1 CELLS; TRANSCRIPTIONAL REGULATION AB CD4(+) T cells can differentiate into multiple effector subsets, but the potential roles of these subsets in anti-tumor immunity have not been fully explored. Seeking to study the impact of CD4+ T cell polarization on tumor rejection in a model mimicking human disease, we generated a new MHC class II-restricted, T-cell receptor (TCR) transgenic mouse model in which CD4(+) T cells recognize a novel epitope in tyrosinase-related protein 1 (TRP-1), an antigen expressed by normal melanocytes and B16 murine melanoma. Cells could be robustly polarized into Th0, Th1, and Th17 subtypes in vitro, as evidenced by cytokine, chemokine, and adhesion molecule profiles and by surface markers, suggesting the potential for differential effector function in vivo. Contrary to the current view that Th1 cells are most important in tumor rejection, we found that Th17-polarized cells better mediated destruction of advanced B16 melanoma. Their therapeutic effect was critically dependent on interferon-gamma (IFN-gamma) production, whereas depletion of interleukin (IL)-17A and IL-23 had little impact. Taken together, these data indicate that the appropriate in vitro polarization of effector CD4(+) T cells is decisive for successful tumor eradication. This principle should be considered in designing clinical trials involving adoptive transfer-based immunotherapy of human malignancies. C1 [Muranski, Pawel; Boni, Andrea; Antony, Paul A.; Cassard, Lydie; Irvine, Kari R.; Kaiser, Andrew; Paulos, Chrystal M.; Palmer, Douglas C.; Touloukian, Christopher E.; Gattinoni, Luca; Wrzesinski, Claudia; Hinrichs, Christian S.; Kerstann, Keith W.; Restifo, Nicholas P.] NCI, Ctr Canc Res, Natl Inst Hlth, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Ptak, Krzysztof] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Feigenbaum, Lionel] Sci Applicat Int Corp, NCI, Frederick, MD USA. [Chan, Chi-Chao] NEI, Immunol Lab, Bethesda, MD 20892 USA. RP Muranski, P (reprint author), NCI, Ctr Canc Res, Natl Inst Hlth, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. EM muranskp@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Palmer, Douglas/B-9454-2008; Restifo, Nicholas/A-5713-2008; Muranski, Pawel/E-5572-2010; Kaiser, Andrew/C-2617-2012; OI Gattinoni, Luca/0000-0003-2239-3282; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 NR 93 TC 414 Z9 440 U1 2 U2 18 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 JUL 15 PY 2008 VL 112 IS 2 BP 362 EP 373 DI 10.1182/blood-2007-11-120998 PG 12 WC Hematology SC Hematology GA 326YT UT WOS:000257696300024 PM 18354038 ER PT J AU Marks, DI Perez, WS He, W Zhang, MJ Bishop, MR Bolwell, BJ Bredeson, CN Copelan, EA Gale, RP Gupta, V Hale, GA Isola, LM Jakubowski, AA Keating, A Klumpp, TR Lazarus, HM Liesveld, JL Maziarz, RT McCarthy, PL Sabloff, M Schiller, G Sierra, J Tallman, MS Waller, EK Wiernik, PH Weisdorf, DJ AF Marks, David I. Perez, Waleska S. He, Wensheng Zhang, Mei-Jie Bishop, Michael R. Bolwell, Brian J. Bredeson, Christopher N. Copelan, Edward A. Gale, Robert Peter Gupta, Vikas Hale, Gregory A. Isola, Luis M. Jakubowski, Ann A. Keating, Armand Klumpp, Thomas R. Lazarus, Hillard M. Liesveld, Jane L. Maziarz, Richard T. McCarthy, Philip L. Sabloff, Mitchell Schiller, Gary Sierra, Jorge Tallman, Martin S. Waller, Edmund K. Wiernik, Peter H. Weisdorf, Daniel J. TI Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; 2ND COMPLETE REMISSION; ALLOGENEIC TRANSPLANTATION; SURVIVAL; THERAPY; TRIAL; IMPACT; CHILDREN; FAILURE AB We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CRII) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 x 10(9)/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graftversus-host disease were 50%, 25%, and 43%, respectively. Five-year treatmentrelated mortality (TRIM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLAmismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 x 10(9)/L. Factors associated with poorer survival included WBC more than 100 x 10(9)/L, more than 8 weeks to CRII, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CRII survive 5 years after LIRD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results. C1 Univ Minnesota, Hosp & Clin, Minneapolis, MN 55455 USA. United Bristol Healthcare Trust, Adult BMT Unit, Bristol, England. Med Coll Wisconsin, Ctr Int BMT Res, Milwaukee, WI 53226 USA. NCI, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Cleveland, OH USA. Ctr Adv Studies Leukemia, Los Angeles, CA USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. St Jude Childrens Hosp, Memphis, TN 38105 USA. Mt Sinai Hosp, New York, NY 10029 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Fox Chase Temple BMT Program, Philadelphia, PA USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Univ Rochester, Med Ctr, Rochester, NY 14627 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Ottawa Hosp, Ottawa, ON, Canada. Univ Calif Los Angeles, Los Angeles, CA USA. Hosp Santa Creu & Sant Pau, Barcelona, Spain. NW Mem Hosp, Chicago, IL 60611 USA. Emory Univ Hosp, Atlanta, GA 30322 USA. Our Lady Mercy Med Ctr, Bronx, NY USA. Univ Minnesota, Minneapolis, MN USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Hosp & Clin, Mayo Mail Code 480,420 Delaware St SE, Minneapolis, MN 55455 USA. EM weisd001@umn.edu RI Lopez, Dulce/A-7700-2013 FU NCI NIH HHS [U24 CA076518, U24-CA76518] NR 28 TC 51 Z9 53 U1 0 U2 3 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 JUL 15 PY 2008 VL 112 IS 2 BP 426 EP 434 DI 10.1182/blood-2007-12-128918 PG 9 WC Hematology SC Hematology GA 326YT UT WOS:000257696300031 PM 18398065 ER PT J AU Klapper, JA Downey, SG Smith, FO Yang, JC Hughes, MS Kammula, US Sherry, RM Royal, RE Steinberg, SM Rosenberg, S AF Klapper, Jacob A. Downey, Stephanie G. Smith, Franz O. Yang, James C. Hughes, Marybeth S. Kammula, Udai S. Sherry, Richard M. Royal, Richard E. Steinberg, Seth M. Rosenberg, Steven TI High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma - A retrospective analysis of response and survival in patients treated in the Surgery Branch at the National Cancer Institute between 1986 and 2006 SO CANCER LA English DT Article DE renal cell carcinoma; interieukin-2; immunotherapy; metastatic ID PROSPECTIVE RANDOMIZED TRIAL; CARBONIC-ANHYDRASE-IX; SUBCUTANEOUS INTERLEUKIN-2; RECOMBINANT INTERLEUKIN-2; INTERFERON-ALPHA; PHASE-II; THERAPY; COMBINATION AB BACKGROUND. The treatment of metastatic renal cell carcinoma (RCC) with high-dose interleukin-2 (HD IL-2) has resulted in durable tumor regression in a minority of patients. The current study presents the authors' 20-year experience administering this immunotherapeutic agent. METHODS. Patients with metastatic RCC (n = 259) were treated with HD IL-2 alone from January 13, 1986 through December 31, 2006 at the Surgery Branch of the National Cancer Institute. Potential predictive factors for response and survival, both pretreatment and treatment-related, were first subjected to univariate analysis and then to multivariate logistic regression or a Cox proportional hazards model. Finally, the authors investigated Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic factors for survival to assess their predictive value in the patient population in the current study. RESULTS. A total of 23 patients experienced a complete response and 30 patients achieved a partial response, for an overall objective response rate of 20%. All partial responders had developed disease recurrence at the time of last follow-up, but only 4 complete responders had experienced disease recurrence by that time. Despite toxicities, only 2 patients developed treatment-related mortalities over this same time period. A higher baseline weight (P = .05) and MSKCC prognostic factors (P = .02) were found to be the variables most associated with response. For survival >4 years and overall survival, several pretreatment and treatmentrelated factors maintained significance, but none more so than response (P < .0001). CONCLUSIONS. HD IL-2 can induce complete tumor regression in a small number of patients, and many patients have experienced extended disease-free intervals. Given its relative safety, HD IL-2 should still be considered a first-line therapy in patients with metastatic RCC who have an overall good performance status. C1 [Klapper, Jacob A.; Downey, Stephanie G.; Smith, Franz O.; Yang, James C.; Hughes, Marybeth S.; Kammula, Udai S.; Sherry, Richard M.; Royal, Richard E.; Rosenberg, Steven] NCI, Surg Branch, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, Ctr Canc Res, Natl Inst Hlth, Bldg 10-CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM jamesyang@mall.nih.gov FU Intramural NIH HHS [NIH0012219327, Z01 SC003811-33] NR 27 TC 129 Z9 132 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2008 VL 113 IS 2 BP 293 EP 301 DI 10.1002/cncr.23552 PG 9 WC Oncology SC Oncology GA 322WM UT WOS:000257406000008 PM 18457330 ER PT J AU Borthakur, G Alvarado, Y Ravandi-Kashani, F Cortes, J Estrov, Z Faderl, S Ivy, P Bueso-Ramos, C Bekele, BN Giles, F AF Borthakur, Gautam Alvarado, Yesid Ravandi-Kashani, Farhad Cortes, Jorge Estrov, Zeev Faderl, Stefan Ivy, Percy Bueso-Ramos, Carlos Bekele, B. Nebiyou Giles, Francis TI Phase 1 study of XL119, a rebeccamycin analog, in patients with refractory hematologic malignancies SO CANCER LA English DT Article DE XL119; rebeccamycin analog; leukemia; phase 1 ID ENDOTHELIAL GROWTH-FACTOR; ACUTE MYELOID-LEUKEMIA; MYELODYSPLASTIC SYNDROMES; ANTIMICROBIAL PROPERTIES; TOPOISOMERASE-I; INHIBITION; ANTITUMOR; NSC-655649 AB BACKGROUND. XL119 is a water-soluble derivative of rebeccamycin with dose-dependent myelosuppression as dose-limiting toxicity in phase I studies of solid tumors. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of XL119 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. METHODS. Thirty-one patients were treated at 7 dose levels ranging from 140 to 260 mg/m(2)/daily times 5 in a 21-day cycle. Consenting patients had correlative biologic parameters studied. RESULTS. Dose-limiting toxicity was grade 3/4 mucositis. The recommended phase 2 dose in hematologic malignancies is 240 mg/m(2)/daily times 5 in a 21-day cycle. Clinically significant reduction in bone marrow blasts were seen in 5 patients and additional patients had reductions in peripheral blood blasts. However, the responses were transient. Changes of plasma vascular endothelial growth factor levels from Day 1 to Day 7 correlated negatively with changes in peripheral blood blasts from Day 1 to Day 7. CONCLUSIONS. Further assessment of XL119 in combination with other agents in patients with acute leukemias and high-risk myelodysplastic syndrome is warranted. C1 [Borthakur, Gautam; Alvarado, Yesid; Ravandi-Kashani, Farhad; Cortes, Jorge; Estrov, Zeev; Faderl, Stefan] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Ivy, Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Ctr, Bethesda, MD 20892 USA. [Bueso-Ramos, Carlos] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Bekele, B. Nebiyou] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Giles, Francis] Univ Texas Hlth Sci Ctr San Antonio, Div Hematol & Med Oncol, San Antonio, TX 78229 USA. RP Borthakur, G (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Unit 428, Houston, TX 77030 USA. EM gborthak@mdanderson.org FU NCI NIH HHS [P30 CA016672] NR 20 TC 4 Z9 4 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2008 VL 113 IS 2 BP 360 EP 366 DI 10.1002/cncr23559 PG 7 WC Oncology SC Oncology GA 322WM UT WOS:000257406000015 PM 18473351 ER PT J AU Sheen, V Tucker, MA Abramson, DH Seddon, JM Kleinerman, RA AF Sheen, Victoria Tucker, Margaret A. Abramson, David H. Seddon, Johanna M. Kleinerman, Ruth A. TI Cancer screening practices of adult survivors of retinoblastoma at risk of second cancers SO CANCER LA English DT Article DE retinoblastoma; cancer survivor; cancer screening; retrospective cohort study; mammography; radiation ID LONG-TERM SURVIVORS; FOLLOW-UP; CHILDHOOD-CANCER; BREAST-CANCER; TUMORS; MAMMOGRAPHY; GENE; CARE; RADIOTHERAPY; GUIDELINES AB BACKGROUND. The aim of the current study was to investigate the pattern of cancer screening behavior in adult retinoblastoma survivors, who are at high risk of developing second cancers. METHODS. Self-reported cancer screening practices were investigated in a cohort of retinoblastoma survivors to evaluate whether they were receiving adequate screening for specific cancers and compare these rates with those of other adult survivors of childhood cancer and the general population. The prevalence of breast self-examination, clinical breast examination, mammography, Papanicolaou (Pap) test, testicular self-examination, and magnetic resonance imaging (MRI) or computed tomography (CT) scanning was determined from computer-aided telephone interviews with 836 retinoblastoma survivors aged >18 years. RESULTS, Among female survivors, 87% had a Pap test within the past 2 years, and 76% of females age >40 years reported having a mammogram within the past 2 years; 17.4% of male survivors had performed monthly testicular self-examinations. A significantly higher proportion of hereditary compared with non-hereditary survivors reported having undergone an MRI or CT scan in the past 5 years. Higher education, greater contact with the medical care system, and having a second cancer were found to be associated positively with most screening practices. Cancer screening practices reported by retinoblastoma survivors were similar to national screening rates for breast, cervical, and testicular cancer. CONCLUSIONS. To the authors' knowledge, the current study provides the first report of cancer screening practices of retinoblastoma survivors. Survivors of hereditary retinoblastoma should be encouraged to maintain, if not increase, their current screening practices to ensure early detection of second cancers in this high-risk population. C1 [Sheen, Victoria; Tucker, Margaret A.; Kleinerman, Ruth A.] NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Services, Rockville, MD 20852 USA. [Sheen, Victoria] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Abramson, David H.] Mem Sloan Kettering Canc Ctr, Ophthalm Oncol Serv, New York, NY 10021 USA. [Seddon, Johanna M.] Tufts Univ New England Med Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. RP Kleinerman, RA (reprint author), NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Services, EPS 7044,6120 Execut Blvd, Rockville, MD 20852 USA. EM kleinerr@mail.nih.gov RI Tucker, Margaret/B-4297-2015; OI Kleinerman, Ruth/0000-0001-7415-2478 FU Intramural NIH HHS [ZIA CP010131-18] NR 31 TC 12 Z9 13 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2008 VL 113 IS 2 BP 434 EP 441 DI 10.1002/cncr.23564 PG 8 WC Oncology SC Oncology GA 322WM UT WOS:000257406000025 PM 18473349 ER PT J AU Reilly, KM Rubin, JB Gilbertson, RJ Garbow, JR Roussel, MF Gutmann, DH AF Reilly, Karlyne M. Rubin, Joshua B. Gilbertson, Richard J. Garbow, Joel R. Roussel, Martine F. Gutmann, David H. TI Rethinking brain tumors: The fourth Mouse Models of Human Cancers Consortium nervous system tumors workshop SO CANCER RESEARCH LA English DT Article ID GLIOMA GROWTH; MICE; NF1 C1 [Reilly, Karlyne M.] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Rubin, Joshua B.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Garbow, Joel R.] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. [Gutmann, David H.] Washington Univ, Dept Neurol, St Louis, MO 63130 USA. [Gilbertson, Richard J.; Roussel, Martine F.] St Jude Childrens Res Hosp, Memphis, TN USA. RP Reilly, KM (reprint author), NCI, Mouse Canc Genet Program, W 7th St & Ft Detrick,POB B,Bldg 560,Room 31-20, Frederick, MD 21702 USA. EM kreilly@ncifcrf.gov; gutmannd@wustl.edu OI Roussel, Martine F./0000-0002-1740-8139 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010541-05, Z01 BC010540-05] NR 13 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5508 EP 5511 DI 10.1158/0008-5472.CAN-08-0703 PG 4 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300003 PM 18632599 ER PT J AU Nguyen, P Cui, HM Bisht, KS Sun, LC Patel, K Lee, RS Kugoh, H Oshimura, M Feinberg, AP Gius, D AF Nguyen, Phuongmai Cui, Hengmi Bisht, Kheem S. Sun, Lunching Patel, Krish Lee, Richard S. Kugoh, Hiroyuki Oshimura, Mitsuo Feinberg, Andrew P. Gius, David TI CTCFL/BORIS is a methylation-independent DNA-binding protein that preferentially binds to the paternal H19 differentially methylated region SO CANCER RESEARCH LA English DT Article ID CTCF-BINDING; H19/IGF2 LOCUS; CANCER-CELLS; GENE; EXPRESSION; INSULATOR; SITES; IGF2; HYPOMETHYLATION; DEREPRESSION AB The CTCF paralog BORIS (brother of the regulator of imprinted sites) is an insulator DNA-binding protein thought to play a role in chromatin organization and gene expression. Under normal physiologic conditions, BORIS is predominantly expressed during embryonic male germ cell development; however, it is also expressed in tumors and tumor cell lines and, as such, has been classified as a cancer-germline or cancer-testis gene. It has been suggested that BORIS may be a pro-proliferative factor, whereas CTCF favors antiproliferation. BORIS and CTCF share similar zinc finger DNA-binding domains and seem to bind to identical target sequences. Thus, one critical question is the mechanism governing the DNA-binding specificity of these two proteins when both are present in tumor cells. Chromatin immunoprecipitation (ChIP) in HCT116 cells and their hypermethylated variant showed that BORIS binds to methylated DNA sequences, whereas CTCF binds to unmethylated DNA. Electromobility shift assays, using both whole-cell extracts and in vitro translated CTCF and BORIS protein, and methylation-specific ChIP PCR showed that BORIS is a methylation-independent DNA-binding protein. Finally, experiments in murine hybrid cells containing either the maternal or paternal human chromosome 11 showed that BORIS preferentially binds to the methylated paternal H19 differentially methylated region, suggesting a mechanism in which the affinity of CTCF for the unmethylated maternal allele directs the DNA binding of BORIS toward the paternal allele. C1 [Nguyen, Phuongmai; Bisht, Kheem S.; Sun, Lunching; Patel, Krish; Gius, David] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cui, Hengmi; Lee, Richard S.; Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Cui, Hengmi; Lee, Richard S.; Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Cui, Hengmi; Lee, Richard S.; Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Mol Biol, Baltimore, MD 21205 USA. [Cui, Hengmi; Lee, Richard S.; Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Dept Genet, Baltimore, MD 21205 USA. [Kugoh, Hiroyuki] Tottori Univ, Dept Biomed Sci, Inst Regenerat Med, Grad Sch Med Sci, Tottori 680, Japan. RP Gius, D (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM giusd@mail.nih.gov OI Lee, Richard/0000-0002-3454-8774 FU Intramural NIH HHS [Z01 BC010544-04]; NCI NIH HHS [R37 CA054358-18, CA65145, R01 CA065145, R37 CA054358] NR 17 TC 29 Z9 29 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5546 EP 5551 DI 10.1158/0008-5472.CAN-08-1005 PG 6 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300010 PM 18632606 ER PT J AU Wang, Y Dean, JL Millar, EKA Tran, TH McNeil, CM Burd, CJ Henshall, SM Utama, FE Witkiewicz, A Rui, H Sutherland, RL Knudsen, KE Knudsen, ES AF Wang, Ying Dean, Jeffry L. Millar, Ewan K. A. Tran, Thai Hong McNeil, Catriona M. Burd, Craig J. Henshall, Susan M. Utama, Fransiscus E. Witkiewicz, Agnieszka Rui, Hallgeir Sutherland, Robert L. Knudsen, Karen E. Knudsen, Erik S. TI Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; DEPENDENT KINASE-ACTIVITY; RETINOBLASTOMA PROTEIN; ANDROGEN RECEPTOR; CELLULAR-TRANSFORMATION; GENE-EXPRESSION; NUCLEAR EXPORT; PROGRESSION; PHOSPHORYLATION; CDK4 AB Cyclin D1 is a key mediator of cell cycle progression that is aberrantly regulated in multiple cancers, especially in breast cancers. A number of studies have indicated that a polymorphism in a splice donor site in the cyclin D1 gene is associated with alternative splicing and the production of the alternative cyclin D1b transcript. Furthermore, this polymorphism is selectively associated with disease outcomes. However, relatively little is known regarding the protein product of the alternatively spliced message, cyclin D1b. Using antibodies specific for cyclin D1b, it was found that this protein is readily detectable in a number of cancer cell lines and primary breast cancers. Whereas cyclin Dlb interacts with cyclin-dependent kinase 4 (CDK4), it is relatively inefficient at mediating RB phosphorylation and cell cycle progression in model systems due to the lack of exon 5 of cyclin D1-encoded sequences. However, cyclin Dlb protein levels are not significantly attenuated by DNA damage or antiestrogen treatment, indicating that the protein may have significant effect on the response to such therapeutic modalities. Whereas enforced expression of cyclin D1b was not sufficient to abrogate DNA damage checkpoint responses, it did efficiently overcome cell cycle arrest mediated by antiestrogen therapeutics. This action of cyclin Dlb was not associated with effects on estrogen receptor activity, but was rather dependent on functional association with CDK4. Combined, these studies indicate that the cyclin Dlb protein is aberrantly regulated and could contribute to therapeutic failure in the context of ER-positive breast cancer. C1 [Dean, Jeffry L.; Tran, Thai Hong; Utama, Fransiscus E.; Witkiewicz, Agnieszka; Rui, Hallgeir; Knudsen, Karen E.; Knudsen, Erik S.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Dean, Jeffry L.; Tran, Thai Hong; Utama, Fransiscus E.; Rui, Hallgeir; Knudsen, Karen E.; Knudsen, Erik S.] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA. [Witkiewicz, Agnieszka] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA. [Millar, Ewan K. A.; McNeil, Catriona M.; Henshall, Susan M.; Sutherland, Robert L.] St Vincents Hosp, Canc Res Program, Garvan Inst Med Res, Sydney, NSW 2010, Australia. [Millar, Ewan K. A.] St George Hosp, S Eastern Area Lab Serv, Dept Anat Pathol, Sydney, NSW, Australia. [Burd, Craig J.] NIEHS, Res Triangle Pk, NC 27709 USA. [Wang, Ying; Dean, Jeffry L.; Knudsen, Karen E.; Knudsen, Erik S.] Univ Cincinnati, Dept Cell & Canc Biol, Cincinnati, OH USA. RP Knudsen, ES (reprint author), 233 S 10th St,BLSB Room 1002, Philadelphia, PA 19107 USA. EM eknudsen@kimmelcancercenter.org RI McNeil, Catriona/F-6817-2010; OI Burd, Craig/0000-0002-6899-6751; Millar, Ewan/0000-0002-9778-3253 FU NCI NIH HHS [CA099996, R01 CA099996, R01 CA101841, R01 CA104213, R01-CA101841, R01-CA104213] NR 61 TC 37 Z9 38 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5628 EP 5638 DI 10.1158/0008-5472.CAN-07-3170 PG 11 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300019 PM 18632615 ER PT J AU Choi, JH Park, JT Davidson, B Morin, PJ Shih, IM Wang, TL AF Choi, Jung-Hye Park, Joon T. Davidson, Ben Morin, Patrice J. Shih, Ie-Ming Wang, Tian-Li TI Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion SO CANCER RESEARCH LA English DT Article ID CANCER; LIGAND; GENE; AMPLIFICATION; EXPRESSION; DELTA AB Notch3 gene amplification and pathway activation have been reported in ovarian serous carcinoma. However, the primary Notch3 ligand that initiates signal transduction in ovarian cancer remains unclear. In this report, we identify Jagged-1 as the highest expressed Notch ligand in ovarian tumor cells as well as in peritoneal mesothelial cells that are in direct contact with disseminated ovarian cancer cells. Cell-cell adhesion and cellular proliferation were reduced in Notch3-expressing ovarian cancer cells that were cocultured with Jagged-1 knockdown mesothelial and tumor feeder cells. Interaction of Notch3-expressing ovarian cancer cells with Jagged-1-expressing feeder cells activated the promoter activity of candidate Notch3 target genes, and this activity was attenuated by Notch3 siRNA. Constitutive expression of the Notch3 intracellular domain significantly suppressed the Jagged-1 shRNA-mediated growth inhibitory effect. In Notch3-expressing ovarian cancer cells, Jagged-1-stimulating peptides enhanced cellular proliferation, which was suppressed by gamma-secretase inhibitor and Notch3 siRNA. Taken together, our results show that Jagged-1 is the primary Notch3 ligand in ovarian carcinoma and Jagged-1/Notch3 interaction constitutes a juxtacrine loop promoting proliferation and dissemination of ovarian cancer cells within the intraperitoneal cavity. C1 [Choi, Jung-Hye; Park, Joon T.; Shih, Ie-Ming; Wang, Tian-Li] Johns Hopkins Med Inst, Dept Gynecol & Obstet, Baltimore, MD 21231 USA. [Choi, Jung-Hye; Park, Joon T.; Shih, Ie-Ming; Wang, Tian-Li] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. [Choi, Jung-Hye; Park, Joon T.; Shih, Ie-Ming; Wang, Tian-Li] Johns Hopkins Med Inst, Dept Oncol, Baltimore, MD 21231 USA. [Morin, Patrice J.] NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. [Choi, Jung-Hye] Kyung Hee Univ, Dept Oriental Pharm, Seoul, South Korea. [Davidson, Ben] Univ Oslo, Rikshosp, Med Ctr, Radium Hosp,Dept Pathol, Oslo, Norway. RP Wang, TL (reprint author), Johns Hopkins Med Inst, Dept Gynecol & Obstet, CRB 2,Room 306,1550 Orleans St, Baltimore, MD 21231 USA. EM tlw@jhmi.edu FU NCI NIH HHS [R01 CA103937, R01 CA103937-05, R01 CA103937-04, R01 CA129080, R01 CA129080-01A1] NR 17 TC 57 Z9 62 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5716 EP 5723 DI 10.1158/0008-5472.CAN-08-0001 PG 8 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300028 PM 18632624 ER PT J AU Lacey, JV Mutter, GL Ronnett, BM Loffe, OB Duggan, MA Rush, BB Glass, AG Richesson, DA Chatterjee, N Langholz, B Sherman, ME AF Lacey, James V., Jr. Mutter, George L. Ronnett, Brigitte M. Loffe, Olga B. Duggan, Maire A. Rush, Brenda B. Glass, Andrew G. Richesson, Douglas A. Chatterjee, Nilanjan Langholz, Bryan Sherman, Mark E. TI PTEN expression in endometrial biopsies as a marker of progression to endometrial carcinoma SO CANCER RESEARCH LA English DT Article ID COWDEN-SYNDROME; HYPERPLASIA; NEOPLASIA; PATHWAY; CANCER; MICE; TUMORIGENESIS; PRECANCERS; DIAGNOSIS AB Inactivation of PTEN tumor suppressor gene is common in endometrial carcinoma and its precursor, atypical endometrial hyperplasia (Ell). We compared PTEN expression via inummohistochemistry in endometrial biopsies diagnosed as EH in 138 cases, who were diagnosed with EH and then endometrial carcinoma at least I year later (median, 6 years), and 241 individually matched controls, who were diagnosed with EH but did not progress to carcinoma during equivalent follow-up. We assessed PTEN status (normal versus null) in index biopsies containing EH to estimate the relative risk (RR) of developing endometrial carcinoma up to 25 years later. Analysis of 115 cases and 193 controls with satisfactory assays revealed PTEN-null glands in index biopsies of 44% of cases and 49% of controls [P = 0.85; RR, 1.51; 95% confidence interval (0), 0.73-3.13]. For predicting progression to carcinoma, PTEN-null status had low sensitivity (44%; 95% CI, 45-54%) and specificity (51%; 95% CI, 44-58%). Among 105 cases with PTEN results for both index biopsy and carcinoma, 16% had a PTEN-null index biopsy, 23% had PTEN-null carcinoma, and 26% had both a PTEN-null index biopsy and carcinoma. Loss of PTEN expression in endometrial biopsies was neither associated with nor a sensitive and specific marker of subsequent progression to endometrial carcinoma. C1 [Lacey, James V., Jr.; Duggan, Maire A.; Richesson, Douglas A.; Sherman, Mark E.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Mutter, George L.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. [Loffe, Olga B.] Univ Maryland, Med Ctr, Dept Pathol, Baltimore, MD 21201 USA. [Ronnett, Brigitte M.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Rush, Brenda B.; Glass, Andrew G.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Langholz, Bryan] Univ So Calif, Keck Sch Med, Dept Prevent Med, Div Biostat, Los Angeles, CA 90033 USA. RP Lacey, JV (reprint author), 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. EM jimlacey@nih.gov RI Mutter, George/C-5819-2009 FU Intramural NIH HHS [Z01 CP010126-12] NR 25 TC 37 Z9 41 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 6014 EP 6020 DI 10.1158/0008-5472.CAN-08-1154 PG 7 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300062 PM 18632658 ER PT J AU Freidlin, B Korn, EL Gray, R Martin, A AF Freidlin, Boris Korn, Edward L. Gray, Robert Martin, Alison TI Multi-arm clinical trials of new agents: Some design considerations SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-III; MULTIPLE COMPARISONS; LUNG-CANCER; THERAPY; CARCINOMA AB A major challenge in the development of anticancer therapies is the considerable time and resources needed for conducting randomized clinical trials (RCT). There is a need for more efficient RCT designs that accelerate development, minimize costs, and make trials more appealing to patients. We review the statistical and logistical characteristics of multi-arm designs that compare several experimental treatments to a common control arm. In particular, we present a rationale for not requiring multiplicity adjustment in multi-arm trials that are designed for logistical efficiency. Relative to conducting separate RCTs for each experimental agent, this multi-arm design is shown to require a lower total sample size than multiple two-arm trials. C1 [Freidlin, Boris; Korn, Edward L.; Martin, Alison] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Freidlin, Boris; Korn, Edward L.; Martin, Alison] NCI, Div Canc Treatment & Diagnosis, Clin Invest Branch, Bethesda, MD 20892 USA. [Gray, Robert] Harvard Univ, Sch Publ Hlth, Eastern Cooperat Oncol Grp, Boston, MA 02115 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, EPN 8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 25 TC 38 Z9 38 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2008 VL 14 IS 14 BP 4368 EP 4371 DI 10.1158/1078-0432.CCR-08-0325 PG 4 WC Oncology SC Oncology GA 328GD UT WOS:000257785500002 PM 18628449 ER PT J AU Madan, RA Gulley, JL Schlom, J Steinberg, SM Liewehr, DJ Dahut, WL Arlen, PM AF Madan, Ravi A. Gulley, James L. Schlom, Jeffrey Steinberg, Seth M. Liewehr, David J. Dahut, William L. Arlen, Philip M. TI Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-CELLS; RADIATION; CHEMOTHERAPY; IMMUNOTHERAPY; ANTIANDROGEN; IRRADIATION; WITHDRAWAL; PHENOTYPE; CARCINOMA AB Purpose: We reported previously the first randomized study of any kind in patients with nonmetastatic, castrate-resistant prostate cancer. The study employed vaccine, the hormone nilutamide, and the combined therapy (crossover for each arm) with an endpoint of time to progression. We now report survival analyses at 6.5 years from the initiation of therapy with a median potential follow-up of 4.4 years. Experimental Design: Forty-two patients were randomized to receive either a poxvirus-based prostate-specific antigen (PSA) vaccine or nilutamide. Patients in either arm who developed increasing PSA without radiographic evidence of metastasis could cross over to receive the combined therapies. Results: Median survival among all patients was 4.4 years from date of enrollment. Median survival exhibited a trend toward improvement for patients initially randomized to the vaccine arm (median, 5.1 versus 3.4 years; P = 0.13). Starting from the on-study date, the retrospectively determined subset of 12 patients who initially received vaccine and then later received nilutamide suggested improved survival compared with the 8 patients who began with nilutamide and subsequently were treated with vaccine (median, 6.2 versus 3.7 years; P = 0.045). A subgroup analysis of patients randomized to the vaccine arm versus the nilutamide arm showed substantial improvements in survival if at baseline patients had a Gleason score <7 (P = 0.033) and PSA <20 ng/dL (P = 0.013) or who had prior radiation therapy (P = 0.018). Conclusions: These data indicate that patients with nonmetastatic castration-resistant prostate cancer (D0.5) who receive vaccine before second-line hormone therapy may potentially result in improved survival compared with patients who received hormone therapy and then vaccine. These data also suggest that patients with more indolent disease may derive greater clinical benefit from vaccine alone or vaccine before second-line hormone therapy compared with hormone therapy alone or hormone therapy followed by vaccine. These findings have potential implications for both the design and endpoint analysis of larger vaccine combination therapy trials. C1 [Madan, Ravi A.; Gulley, James L.; Schlom, Jeffrey; Arlen, Philip M.] NCI, Canc Res Ctr, NIH, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Madan, Ravi A.; Gulley, James L.; Schlom, Jeffrey; Dahut, William L.; Arlen, Philip M.] NCI, Canc Res Ctr, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Steinberg, Seth M.; Liewehr, David J.] NCI, Canc Res Ctr, NIH, Off Clin Director,Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Canc Res Ctr, NIH, Lab Tumor Immunol & Biol, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010666-03] NR 25 TC 80 Z9 82 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2008 VL 14 IS 14 BP 4526 EP 4531 DI 10.1158/1078-0432.CCR-07-5048 PG 6 WC Oncology SC Oncology GA 328GD UT WOS:000257785500022 PM 18628467 ER PT J AU Sissung, TM Baum, CE Deeken, J Price, DK Aragon-Ching, J Steinberg, SM Dahut, W Sparreboom, A Figg, WD AF Sissung, Tristan M. Baum, Caitlin E. Deeken, John Price, Douglas K. Aragon-Ching, Jeanny Steinberg, Seth M. Dahut, William Sparreboom, Alex Figg, William D. TI ABCB1 genetic variation influences the toxicity and clinical outcome of patients with androgen-independent prostate cancer treated with docetaxel SO CLINICAL CANCER RESEARCH LA English DT Article ID MULTIDRUG-RESISTANCE GENE; P-GLYCOPROTEIN EXPRESSION; HEMATOPOIETIC STEM-CELLS; BLOOD-BRAIN-BARRIER; OVARIAN-CANCER; PACLITAXEL CHEMOTHERAPY; ENDOTHELIAL-CELLS; POLYMORPHISMS; MDR1; THALIDOMIDE AB Purpose: Polymorphisms that are associated with ABCB1 expression and function may be linked to treatment efficacy and the development of neutropenia and neurotoxicity in patients with androgen-independent prostate cancer receiving docetaxel. Experimental Design: Patients with androgen-independent prostate cancer treated with docetaxel alone (n = 23) or docetaxel and thalidomide (n = 50) were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm. The data were then compared with duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel. Results: For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C linked alleles had improved overall survival after treatment (P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival (P = 0.045). After adjusting for a particular set of polymorphisms and diplotype groupings, a hazard ratio of 10.87 was found for patients carrying the 2677GG genotype versus patients carrying other genotypes (P = 0.0048) in the docetaxel and thalidomide cohort. Among both treatment arms together, individuals carrying the 2677GG genotype also had a significantly longer time to neuropathy (P = 0.035). Finally, there was a strong trend toward patients carrying the 2677TT-3435TT diplotype having higher grades of neutropenia (P = 0.053). Conclusion: The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes. C1 [Sissung, Tristan M.; Sparreboom, Alex; Figg, William D.] NCI, Ctr Canc Res, NIH, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Baum, Caitlin E.; Price, Douglas K.; Figg, William D.] NCI, Ctr Canc Res, NIH, Mol Pharmacol Sect, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Ctr Canc Res, NIH, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Aragon-Ching, Jeanny; Dahut, William; Figg, William D.] NCI, Ctr Canc Res, NIH, Mol Oncol Branch, Bethesda, MD 20892 USA. [Deeken, John] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. RP Figg, WD (reprint author), NCI, Ctr Canc Res, NIH, Clin Pharmacol Program, Bldg 10 Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Aragon-Ching, Jeanny/0000-0002-6714-141X FU Intramural NIH HHS [Z01 BC010453-06] NR 39 TC 76 Z9 79 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2008 VL 14 IS 14 BP 4543 EP 4549 DI 10.1158/1078-0432.CCR-07-4230 PG 7 WC Oncology SC Oncology GA 328GD UT WOS:000257785500024 PM 18628469 ER PT J AU Neale, G Su, X Morton, CL Phelps, D Gorlick, R Lock, RB Reynolds, CP Maris, JM Friedman, HS Dome, J Khoury, J Triche, TJ Seeger, RC Gilbertson, R Khan, J Smith, MA Houghton, PJ AF Neale, Geoffrey Su, Xiaoping Morton, Christopher L. Phelps, Doris Gorlick, Richard Lock, Richard B. Reynolds, C. Patrick Maris, John M. Friedman, Henry S. Dome, Jeffrey Khoury, Joseph Triche, Timothy J. Seeger, Robert C. Gilbertson, Richard Khan, Javed Smith, Malcolm A. Houghton, Peter J. TI Molecular characterization of the pediatric preclinical testing panel SO CLINICAL CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; VIVO ANTITUMOR-ACTIVITY; BRAIN-TUMOR XENOGRAFTS; IN-SITU HYBRIDIZATION; GLIOBLASTOMA-MULTIFORME; HUMAN MEDULLOBLASTOMA; GENE AMPLIFICATION; EWING SARCOMA; MODELS AB Purpose: Identifying novel therapeutic agents for the treatment of childhood cancers requires preclinical models that recapitulate the molecular characteristics of their respective clinical histotypes. Experimental Design and Results: Here, we have applied Affymetrix HG-U133Plus2 profiling to an expanded panel of models in the Pediatric Preclinical Testing Program. Profiling led to exclusion of two tumor lines that were of mouse origin and five osteosarcoma lines that did not cluster with human or xenograft osteosarcoma samples. We compared expression profiles of the remaining 87 models with profiles from 112 clinical samples representing the same histologies and show that model tumors cluster with the appropriate clinical histotype, once "immunosurveillance" genes (contributed by infiltrating immune cells in clinical samples) are eliminated from the analysis. Analysis of copy number alterations using the Affymetrix 100K single nuclecitide polymorphism GeneChip showed that the models have similar copy number alterations to their clinical counterparts. Several consistent copy number changes not reported previously were found (e.g., gain at 22q11.21 that was observed in 5 of 7 glioblastoma samples, loss at 16q22.3 that was observed in 5 of 9 Ewing's sarcoma and 4 of 12 rhabdomyosarcoma models, and amplification of 21q22.3 that was observed in 5 of 7 osteosarcoma models). We then asked whether changes in copy number were reflected by coordinate changes in gene expression. We identified 493 copy number-altered genes that are nonrandom and appear to identify histotype-specific programs of genetic alterations. Conclusions: These data indicate that the preclinical models accurately recapitulate expression profiles and genetic alterations common to childhood cancer, supporting their value in drug development. C1 [Morton, Christopher L.; Phelps, Doris; Houghton, Peter J.] St Jude Childrens Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA. [Dome, Jeffrey] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [Khoury, Joseph] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Gilbertson, Richard] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Neale, Geoffrey; Su, Xiaoping] St Jude Childrens Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Albert Einstein Coll Med, Bronx, NY USA. [Triche, Timothy J.] Childrens Hosp, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA. [Seeger, Robert C.] Childrens Hosp, Div Hematol Oncol, Los Angeles, CA 90027 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. Abramson Family Canc Res Inst, Philadelphia, PA USA. [Friedman, Henry S.] Duke Univ, Med Ctr, Durham, NC USA. [Khan, Javed] Natl Canc Inst, Oncogen Sect, Pediat Oncol Branch, NIH, Bethesda, MD USA. [Smith, Malcolm A.] Natl Canc Inst, Canc Therapy Evaluat Program, NIH, Bethesda, MD USA. RP Houghton, PJ (reprint author), St Jude Childrens Hosp, Dept Mol Pharmacol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM peter.houghton@stjude.org RI Houghton, Peter/E-3265-2011; Khan, Javed/P-9157-2014; Lock, Richard/G-4253-2013; OI Khan, Javed/0000-0002-5858-0488; Reynolds, C. Patrick/0000-0002-2827-8536 FU NCI NIH HHS [N01-CM-37027-23, R01 CA082830] NR 49 TC 68 Z9 71 U1 0 U2 2 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 JUL 15 PY 2008 VL 14 IS 14 BP 4572 EP 4583 DI 10.1158/1078-0432.CCR-07-5090 PG 12 WC Oncology SC Oncology GA 328GD UT WOS:000257785500028 PM 18628472 ER PT J AU Dutta, S Dietrich, JE Westerfield, M Varga, ZM AF Dutta, Sunit Dietrich, Jens-Erik Westerfield, Monte Varga, Zoltan M. TI Notch signaling regulates endocrine cell specification in the zebrafish anterior pituitary SO DEVELOPMENTAL BIOLOGY LA English DT Article DE adenohypophysis; cell differentiation; cranial; DAPT; delta; hormone; notch; organogenesis; patterning; placode ID PRIMARY NEUROGENESIS; NEURAL PRIMORDIUM; GENE-EXPRESSION; IN-VIVO; HEDGEHOG; DELTA; HOMOLOG; BRAIN; DIFFERENTIATION; HYPOTHALAMUS AB The vertebrate pituitary gland is a key endocrine control organ that contains six distinct hormone secreting cell types. In this study, we analyzed the role of direct cell-to-cell Delta-Notch signaling in zebrafish anterior pituitary cell type specification. We demonstrate that initial formation of the anterior pituitary placode is independent of Notch signaling. Later however, loss of Notch signaling in mind bomb (mib) mutant embryos or by DAPT treatment leads to increased numbers of lactotropes and loss of corticotropes in the anterior pars distalis (APD), increased number of thyrotropes and loss of somatotrope cell types in the posterior pars distalis (PPD), and fewer melanotropes in the posterior region of the adenohypophysis, the pars intermedia (PI). Conversely, Notch gain of function leads to the opposite result, loss of lactotrope and thyrotrope cell specification, and an increased number of corticotropes, melanotropes, and gonadotropes in the pituitary. Our results suggest that Notch acts on placodal cells, presumably as a permissive signal, to regulate progenitor cell specification to hormone secreting cell types. We propose that Notch mediated lateral inhibition regulates the relative numbers of specified hormone cell types in the three pituitary subdomains. (c) 2008 Published by Elsevier Inc. C1 [Varga, Zoltan M.] Univ Oregon, Zebrafish Int Resource Ctr, Eugene, OR 97403 USA. [Dutta, Sunit] NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Dietrich, Jens-Erik] MPI Mol Biomed, Dept Cell & Dev Biol, D-48149 Munster, Germany. [Westerfield, Monte] Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA. RP Varga, ZM (reprint author), Univ Oregon, Zebrafish Int Resource Ctr, Eugene, OR 97403 USA. EM zoltan@zebrafish.org FU NCRR NIH HHS [RR12546, P40 RR012546]; NICHD NIH HHS [HD22486, P01 HD022486]; NIDCD NIH HHS [R01 DC004186, DC04186, R01 DC004186-06] NR 44 TC 14 Z9 14 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2008 VL 319 IS 2 BP 248 EP 257 DI 10.1016/j.ydbio.2008.04.019 PG 10 WC Developmental Biology SC Developmental Biology GA 327NA UT WOS:000257734600008 PM 18534570 ER PT J AU Kittappa, R Chang, WW Awatramani, RB Mckay, RD AF Kittappa, Raja Chang, Wendy W. Awatramani, Rajeshwar B. McKay, Ronald D. TI The floor plate gene, foxa2, is required for the generation and maintenance of midbrain dopamine neurons SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the Society-for-Developmental-Biology CY JUL 25-30, 2008 CL Univ Penn, Philadelphia, PA SP Soc Dev Biol HO Univ Penn C1 [Kittappa, Raja; Chang, Wendy W.; McKay, Ronald D.] NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Awatramani, Rajeshwar B.] Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2008 VL 319 IS 2 MA 16 BP 468 EP 468 DI 10.1016/j.ydbio.2008.05.021 PG 1 WC Developmental Biology SC Developmental Biology GA 327NA UT WOS:000257734600041 ER EF