FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Vijayasarathy, C Sui, RF Zeng, Y Yang, GX Xu, F Caruso, RC Lewis, RA Ziccardi, L Sieving, PA AF Vijayasarathy, Camasamudram Sui, Ruifang Zeng, Yong Yang, Guoxing Xu, Fei Caruso, Rafael C. Lewis, Richard A. Ziccardi, Lucia Sieving, Paul A. TI Molecular Mechanisms Leading to Null-Protein Product from Retinoschisin (RS1) Signal-Sequence Mutants in X-Linked Retinoschisis (XLRS) Disease SO HUMAN MUTATION LA English DT Article DE retinoschisin; X-linked retinoschisis; XLRS; signal sequence; discoidin; splicing ID OPTICAL COHERENCE TOMOGRAPHY; JUVENILE RETINOSCHISIS; TRANSLATION INITIATION; ENDOPLASMIC-RETICULUM; CLINICAL-FEATURES; MAMMALIAN-CELLS; NATURAL-HISTORY; GENE DELIVERY; SPLICE-SITE; MUTATIONS AB Retinoschisin (RS1) is a cell-surface adhesion molecule expressed by photoreceptor and bipolar cells of the retina. The 24-kDa protein encodes two conserved sequence motifs: the initial signal sequence targets the protein for secretion while the larger discoidin domain is implicated in cell adhesion. RS1 helps to maintain the structural organization of the retinal cell layers and promotes visual signal transduction. RS1 gene mutations cause X-linked retinoschisis disease (XLRS) in males, characterized by early-onset central vision loss. We analyzed the biochemical consequences of several RS1 signal-sequence mutants (c.1A>T, c.35T>A, c.38T>C, and c.52G>A) found in our subjects. Expression analysis in COS-7 cells demonstrates that these mutations affect RS1 biosynthesis and result in an RS1 null phenotype by several different mechanisms. By comparison, discoidin-domain mutations generally lead to nonfunctional conformational variants that remain trapped inside the cell. XLRS disease has a broad heterogeneity in general, but subjects with the RS1 null-protein signal-sequence mutations are on the more severe end of the clinical phenotype. Results from the signal-sequence mutants are discussed in the context of the discoidin-domain mutations, clinical phenotypes, genotype-phenotype correlations, and implications for RS1 gene replacement therapy. Hum Mutat 31: 1251-1260, 2010. Published 2010 Wiley-Liss, Inc. C1 [Caruso, Rafael C.; Sieving, Paul A.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Vijayasarathy, Camasamudram; Zeng, Yong; Sieving, Paul A.] Natl Inst Deafness & Other Commun Disorders, Sect Translat Res Retinal & Macular Degenerat, NIH, Bethesda, MD USA. [Sui, Ruifang; Yang, Guoxing; Xu, Fei] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Ophthalmol, Beijing 100037, Peoples R China. [Lewis, Richard A.] Baylor Coll Med, Cullen Eye Inst, Houston, TX 77030 USA. [Ziccardi, Lucia] GB Bietti Eye Fdn, IRCCS, Rome, Italy. RP Sieving, PA (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 31 Ctr Dr,Room 6A03, Bethesda, MD 20892 USA. EM paulsieving@nei.nih.gov FU NIH; Foundation Fighting Blindness (FFB) [CD-CL-0808-0470-PUMCH] FX We thank Drs. Brian Brooks and Michael Redmond of NEI/NIH for useful discussions; Sean Finnegan for editorial assistance with manuscript preparation, and Doug Kesselring for help with illustrations. The author C. V. thanks Yogesh Sharma, B. E., M. S., of Patni Computer Systems, Mumbai, India. This research was supported by the Intramural Research Programs of the NIH. Dr. Ruifang Sui was a recipient of the Foundation Fighting Blindness (FFB Grant No. CD-CL-0808-0470-PUMCH). Dr. Richard Lewis is a Senior Scientific Investigator for Research to Prevent Blindness, New York. We thank the individuals and families reported here for their generous and continuing commitment to these programs. NR 63 TC 15 Z9 15 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2010 VL 31 IS 11 BP 1251 EP 1260 DI 10.1002/humu.21350 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 674XG UT WOS:000283783600016 PM 20809529 ER PT J AU Ye, XB Skjaerven, R Basso, O Baird, DD Eggesbo, M Uicab, LAC Haug, K Longnecker, MP AF Ye, Xibiao Skjaerven, Rolv Basso, Olga Baird, Donna D. Eggesbo, Merete Uicab, Lea Aurora Cupul Haug, Kjell Longnecker, Matthew P. TI In utero exposure to tobacco smoke and subsequent reduced fertility in females SO HUMAN REPRODUCTION LA English DT Article DE tobacco smoking; in utero exposure; fertility ID CIGARETTE-SMOKE; NEONATAL EXPOSURE; PRENATAL EXPOSURE; PREGNANT-WOMEN; TIME; RELIABILITY; INFERTILITY; MOTHER; ADULT; FETAL AB Animal studies have shown that in utero exposure to chemicals in tobacco smoke reduces female fertility, but epidemiological findings have been inconsistent. We examined the association between in utero exposure to tobacco smoke and female fertility among women in the Norwegian Mother and Child Cohort Study, enrolled from 1999 to 2007. Around the 17th week of pregnancy, participants reported how long they took to conceive (time to pregnancy), and whether their mother smoked while pregnant with the participant. This analysis included 48 319 planned pregnancies among women aged 15-44 years. We estimated fecundability odds ratios (FORs) using a discrete-time survival analysis, adjusting for age, education and adult tobacco smoking. The adjusted FOR for in utero exposure to tobacco smoke among all subjects was 0.96 [95% confidence interval (CI): 0.93, 0.98], among subjects reporting no adult tobacco smoking or passive exposure it was 0.96 (95% CI: 0.93, 0.99) and among subjects reporting adult tobacco smoking or passive exposure it was 0.95 (95% CI: 0.91, 0.99). We performed a probabilistic sensitivity analysis to estimate the effect of exposure and outcome misclassification on the results, and, as expected, the association became more pronounced after taking misclassification into account. This large cohort study supports a small-to-modest association between in utero exposure to tobacco smoke and reduced fertility. C1 [Ye, Xibiao; Basso, Olga; Baird, Donna D.; Uicab, Lea Aurora Cupul; Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Dept Human & Hlth Serv, Res Triangle Pk, NC 27709 USA. [Skjaerven, Rolv; Eggesbo, Merete] Norwegian Inst Publ Hlth, Div Epidemiol, N-0473 Oslo, Norway. [Skjaerven, Rolv; Haug, Kjell] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, N-5021 Bergen, Norway. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Human & Hlth Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM longnecl@niehs.nih.gov RI Basso, Olga/E-5384-2010; Baird, Donna/D-5214-2017; CUPUL UICAB, LEA/C-8699-2014; OI Basso, Olga/0000-0001-9298-4921; Baird, Donna/0000-0002-5544-2653; CUPUL UICAB, LEA/0000-0001-6190-4474; Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU National Institutes of Health; National Institute of Environmental Health Sciences; Norwegian Ministry of Health; NIH/NIEHS [N01-ES-85433]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, NIH/NIEHS (grant no. N01-ES-85433), NIH/NINDS (grant no. 1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant no. 151918/S10). NR 39 TC 21 Z9 21 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD NOV PY 2010 VL 25 IS 11 BP 2901 EP 2906 DI 10.1093/humrep/deq235 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 666OE UT WOS:000283124000026 PM 20817739 ER PT J AU Wright, JT Agodoa, LY Appel, L Cushman, WC Taylor, AL Obegdegbe, GG Osei, K Reed, J AF Wright, Jackson T., Jr. Agodoa, Lawrence Y. Appel, Lawrence Cushman, William C. Taylor, Anne L. Obegdegbe, Gbenga G. Osei, Kwame Reed, James TI New Recommendations for Treating Hypertension in Black Patients Evidence and/or Consensus? SO HYPERTENSION LA English DT Editorial Material ID BLOOD-PRESSURE CONTROL; TYPE-2 DIABETES-MELLITUS; KIDNEY-DISEASE; AASK TRIAL; PROGRESSION C1 [Wright, Jackson T., Jr.] Case Western Reserve Univ, Dept Med,William T Dahms Clin Res Unit,, Clin & Translat Sci Collaborat,Clin Hypertens Pro, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. [Agodoa, Lawrence Y.] NIDDK, Bethesda, MD USA. [Appel, Lawrence] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Cushman, William C.] Vet Affairs Med Ctr, Med Serv, Prevent Med Sect, Memphis, TN USA. [Taylor, Anne L.] Columbia Univ, Dept Med, Div Cardiol, New York, NY USA. [Obegdegbe, Gbenga G.] NYU, Sch Med, Dept Med, Div Internal Med, New York, NY USA. [Osei, Kwame] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Reed, James] Morehouse Coll Med, Dept Med, Div Endocrinol, Atlanta, GA USA. RP Wright, JT (reprint author), Case Western Reserve Univ, Dept Med,William T Dahms Clin Res Unit,, Clin & Translat Sci Collaborat,Clin Hypertens Pro, Div Nephrol & Hypertens, Bolwell Suite 2200,11100 Euclid Ave, Cleveland, OH 44106 USA. EM Jackson.Wright@case.edu FU NCRR NIH HHS [M01 RR000080]; NIDDK NIH HHS [U01 DK045381]; NIMHD NIH HHS [P60 MD002265] NR 14 TC 8 Z9 8 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 NOV PY 2010 VL 56 IS 5 BP 801 EP 803 DI 10.1161/HYPERTENSIONAHA.110.159566 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400524 PM 20921426 ER PT J AU Tian, JA Haller, S Periyasamy, S Brewster, P Zhang, H Adlakha, S Fedorova, OV Xie, ZJ Bagrov, AY Shapiro, JI Cooper, CJ AF Tian, Jiang Haller, Steven Periyasamy, Sankaridrug Brewster, Pamela Zhang, Haifeng Adlakha, Satjit Fedorova, Olga V. Xie, Zi-jian Bagrov, Alexei Y. Shapiro, Joseph I. Cooper, Christopher J. TI Renal Ischemia Regulates Marinobufagenin Release in Humans SO HYPERTENSION LA English DT Article DE renal artery stenosis; hypertension; cardiotonic steroids; marinobufagenin; renal artery stenting ID ENDOGENOUS CARDIOTONIC STEROIDS; EXPERIMENTAL UREMIC CARDIOMYOPATHY; OUABAIN-LIKE IMMUNOREACTIVITY; BOVINE ADRENOCORTICAL-CELLS; CONGESTIVE-HEART-FAILURE; ARTERY STENOSIS; SODIUM-PUMP; RENOVASCULAR DISEASE; ESSENTIAL-HYPERTENSION; ATPASE INHIBITION AB Cardiotonic steroids, including marinobufagenin, are a group of new steroid hormones found in plasma and urine of patients with congestive heart failure, myocardial infarction, and chronic renal failure. In animal studies, partial nephrectomy induces marinobufagenin elevation, cardiac hypertrophy, and fibrosis. The objective of this study is to test the effect of renal ischemia on marinobufagenin levels in humans with renal artery stenosis (RAS). To test this, plasma marinobufagenin levels were measured in patients with RAS of the Prospective Randomized Study Comparing Renal Artery Stenting With or Without Distal Protection, non-RAS patient controls who were scheduled for coronary angiography, and normal healthy individuals. Marinobufagenin levels were significantly higher in patients with RAS compared with those of the other 2 groups. Multivariate analysis shows that occurrence of RAS is independently related to marinobufagenin levels. In addition, renal artery revascularization by stenting partially reversed marinobufagenin levels in the patients with RAS (0.77 +/- 0.06 nmol/L at baseline; 0.66 +/- 0.06 nmol/L at 24 hours; and 0.61 +/- 0.05 nmol/L at 1 month). In conclusion, we have found that marinobufagenin levels are increased in patients with RAS, whereas reversal of renal ischemia by stenting treatment reduces marinobufagenin levels. These results suggest that RAS-induced renal ischemia may be a major cause of marinobufagenin release. (Hypertension. 2010;56:914-919.) C1 [Tian, Jiang] Univ Toledo, Dept Med, Div Cardiovasc, Coll Med, Toledo, OH 43614 USA. [Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Tian, JA (reprint author), Univ Toledo, Dept Med, Div Cardiovasc, Coll Med, 3000 Arlington Ave,MS 1118, Toledo, OH 43614 USA. EM Jiang.tian@utoledo.edu FU American Heart Association [0980027N]; National Institute on Aging, National Institutes of Health; Centocor, Inc; Cordis Corp; University of Toledo, Health Sciences Campus, Toledo, Ohio; National Institutes of Health for the Cardiovascular Outcomes in Renal Atherosclerotic Lesions Study [5U01HL071556-06]; Cordis Corp for RESIST FX This work is supported by the American Heart Association (0980027N). The work of A.Y.B. and O.V.F. was supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health. The RAS patient samples were from the RESIST, sponsored by the University of Toledo, Health Sciences Campus, Toledo, Ohio, and funded by Centocor Inc and Cordis Corp, both Johnson & Johnson companies.; C.J.C. and P.B. have received research grants from the Centocor, Inc, and Cordis Corp for RESIST and from the National Institutes of Health for the Cardiovascular Outcomes in Renal Atherosclerotic Lesions Study, 5U01HL071556-06. NR 50 TC 15 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 NOV PY 2010 VL 56 IS 5 BP 914 EP 919 DI 10.1161/HYPERTENSIONAHA.110.155564 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400546 PM 20823380 ER PT J AU Fedorova, OV Shilova, V Bagrov, AY AF Fedorova, Olga V. Shilova, Victoria Bagrov, Alexei Y. TI Mammalian Bufadienolides Start from Bile Acids: Silencing of Cyp27a1 Gene Suppresses Synthesis of Marinobufagenin by Human Trophoblast Cells SO HYPERTENSION LA English DT Meeting Abstract CT Conference on High Blood Pressure Research CY OCT 13-16, 2010 CL Washington, DC C1 [Fedorova, Olga V.; Shilova, Victoria; Bagrov, Alexei Y.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2010 VL 56 IS 5 BP E125 EP E125 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400334 ER PT J AU Lee, CR Pretorius, M Schuck, RN Burch, LH Williams, SM Zeldin, DC Brown, NJ AF Lee, Craig R. Pretorius, Mias Schuck, Robert N. Burch, Lauranell H. Williams, Scott M. Zeldin, Darryl C. Brown, Nancy J. TI Genetic Variation in Soluble Epoxide Hydrolase is Associated with Vascular Responsiveness to Bradykinin in Humans SO HYPERTENSION LA English DT Meeting Abstract CT Conference on High Blood Pressure Research CY OCT 13-16, 2010 CL Washington, DC C1 [Lee, Craig R.; Schuck, Robert N.] Univ N Carolina, Chapel Hill, NC USA. [Pretorius, Mias; Williams, Scott M.; Brown, Nancy J.] Vanderbilt Univ, Nashville, TN USA. [Burch, Lauranell H.; Zeldin, Darryl C.] NIEHS, NIH, Rsch Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2010 VL 56 IS 5 BP E148 EP E148 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400436 ER PT J AU Nikitina, E Mikhailov, AV Nikandrova, ES Frolova, E Fadeev, A Shman, VV Shapiro, JI Fedorova, OV Bagrov, AY AF Nikitina, Elena Mikhailov, Anton V. Nikandrova, Ekaterina S. Frolova, Elena Fadeev, Artem Shman, Vera V. Shapiro, Joseph I. Fedorova, Olga V. Bagrov, Alexei Y. TI In Preeclampsia, Endogenous Cardiotonic Steroids Induce Vascular Fibrosis and Impairment of Vasorelaxation SO HYPERTENSION LA English DT Meeting Abstract CT Conference on High Blood Pressure Research CY OCT 13-16, 2010 CL Washington, DC C1 [Nikitina, Elena; Frolova, Elena; Fadeev, Artem] Sechenov Inst Evolutionary Physiol & Biochem, St Petersburg, Russia. [Mikhailov, Anton V.] St Petersburg State Univ, Coll Med, St Petersburg, Russia. [Mikhailov, Anton V.; Nikandrova, Ekaterina S.; Shman, Vera V.] 17 Maternal Hosp, St Petersburg, Russia. [Shapiro, Joseph I.] Univ Toledo, Toledo, OH 43606 USA. [Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2010 VL 56 IS 5 BP E92 EP E92 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400179 ER PT J AU Paredes, DA Webster, BR Jackson-Weaver, O Kanagy, NL AF Paredes, Daniel A. Webster, Bradley R. Jackson-Weaver, Olan Kanagy, Nancy L. TI Augmented Endothelin-1 Dependent Vasoconstriction of Mesenteric Arteries from Rats Exposed to Intermittent Hypoxia Requires Phosphoinositide Dependent Kinase-1 Activation of PKC Delta Independent from PI3K Activation SO HYPERTENSION LA English DT Meeting Abstract CT Conference on High Blood Pressure Research CY OCT 13-16, 2010 CL Washington, DC C1 [Paredes, Daniel A.; Jackson-Weaver, Olan; Kanagy, Nancy L.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Webster, Bradley R.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 NOV PY 2010 VL 56 IS 5 BP E144 EP E144 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400422 ER PT J AU Shibao, CA Buchowski, MS Chen, KY Yu, C Biaggioni, I AF Shibao, Cyndya A. Buchowski, Maciej S. Chen, Kong Y. Yu, Chang Biaggioni, Italo TI Effect of Chronic Sympathetic Attenuation on Energy Metabolism SO HYPERTENSION LA English DT Meeting Abstract CT Conference on High Blood Pressure Research CY OCT 13-16, 2010 CL Washington, DC C1 [Shibao, Cyndya A.; Buchowski, Maciej S.; Yu, Chang; Biaggioni, Italo] Vanderbilt Univ, Nashville, TN USA. [Chen, Kong Y.] NIDDK, NIH, Bethesda, MD USA. RI Buchowski, Maciej/A-2683-2008 OI Buchowski, Maciej/0000-0002-0566-1743 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2010 VL 56 IS 5 BP E96 EP E96 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400198 ER PT J AU Spallek, B Konkel, A Westphal, C Marko, L DeGraff, LM Schubert, C Bradbury, JA Dechend, R Luft, FC Regitz-Zagrosek, V Zeldin, DC Muller, DN Schunck, WH Fischer, R AF Spallek, Bastian Konkel, Anne Westphal, Christina Marko, Lajos DeGraff, Laura M. Schubert, Carola Bradbury, J. Alyce Dechend, Ralf Luft, Friedrich C. Regitz-Zagrosek, Vera Zeldin, Darryl C. Muller, Dominik N. Schunck, Wolf-Hagen Fischer, Robert TI CYP2J2 Overexpression Protects against Arrhythmias in Two Different Models of Cardiac Hypertrophy SO HYPERTENSION LA English DT Meeting Abstract CT Conference on High Blood Pressure Research CY OCT 13-16, 2010 CL Washington, DC C1 [Spallek, Bastian; Luft, Friedrich C.] Expt Clin Rsch Cntr, Berlin, Germany. [Konkel, Anne; Marko, Lajos; Dechend, Ralf; Muller, Dominik N.; Schunck, Wolf-Hagen] Max Delbruck Ctr Mol Med, Berlin, Germany. [Westphal, Christina; Schubert, Carola; Regitz-Zagrosek, Vera; Fischer, Robert] Charite, Inst Gender Med, Berlin, Germany. [DeGraff, Laura M.; Bradbury, J. Alyce; Zeldin, Darryl C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2010 VL 56 IS 5 BP E78 EP E78 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 668AI UT WOS:000283240400122 ER PT J AU Castro, MA Yao, JH Pang, YX Lee, C Baker, E Butman, J Evangelou, IE Thomasson, D AF Castro, Marcelo A. Yao, Jianhua Pang, Yuxi Lee, Christabel Baker, Eva Butman, John Evangelou, Iordanis E. Thomasson, David TI Template-Based B-1 Inhomogeneity Correction in 3T MRI Brain Studies SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE B-1 inhomogeneity; brain; image registration; magnetic resonance images (MRI); T-1 mapping ID INTENSITY NONUNIFORMITY; RETROSPECTIVE CORRECTION; TISSUE CLASSIFICATION; RADIOFREQUENCY FIELD; AUTOMATIC CORRECTION; STEADY-STATE; FLIP ANGLES; IMAGES; SEGMENTATION; ACCURATE AB Low noise, high resolution, fast and accurate T-1 maps from MRI images of the brain can be performed using a dual flip angle method. However, B-1 field inhomogeneity, which is particularly problematic at high field strengths ( e. g., 3T), limits the ability of the scanner to deliver the prescribed flip angle, introducing errors into the T-1 maps that limit the accuracy of quantitative analyses based on those maps. A dual repetition time method was used for acquiring a B-1 map to correct that inhomogeneity. Additional inaccuracies due to misregistration of the acquired T-1-weighted images were corrected by rigid registration, and the effects of misalignment on the T-1 maps were compared to those of B-1 inhomogeneity in 19 normal subjects. However, since B-1 map acquisition takes up precious scanning time and most retrospective studies do not have B-1 map, we designed a template-based correction strategy. B-1 maps from different subjects were aligned using a twelve-parameter affine registration. Recomputed T-1 maps showed an important improvement with respect to the noncorrected maps: histograms of all corrected maps exhibited two peaks corresponding to white and gray matter tissues, while unimodal histograms were observed in all uncorrected maps because of the inhomogeneity. A method to detect the best nonsubject-specific B-1 correction based on a set of features was designed. The optimum set of weighting factors for those features was computed. The best available B-1 correction was detected in almost all subjects while corrections comparable to the T-1 map corrected using the B-1 map from the same subject were detected in the others. C1 [Castro, Marcelo A.; Yao, Jianhua; Pang, Yuxi; Lee, Christabel; Baker, Eva; Butman, John; Evangelou, Iordanis E.; Thomasson, David] NIH, DR&IS, Bethesda, MD 20892 USA. [Castro, Marcelo A.] Univ Tecnol Nacl, CONICET, Grp Invest & Desarrollo Bioingn GIBIO, RA-1179 Buenos Aires, DF, Argentina. [Pang, Yuxi] Philips Healthcare, Cleveland, OH 44102 USA. RP Castro, MA (reprint author), NIH, DR&IS, Bldg 10, Bethesda, MD 20892 USA. EM castroma@cc.nih.gov; jyao@cc.nih.gov; pangyu@mail.nih.gov; leechrist@cc.nih.gov; bakere@cc.nih.gov; jbutmana@cc.nih.gov; evangelouI@ninds.nih.gov; dthomasson@cc.nih.gov RI Butman, John/A-2694-2008; Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU CONICET (Argentina) FX Manuscript received July 10, 2009; revised May 26, 2010; accepted June 07, 2010. Date of publication June 21, 2010; date of current version November 03, 2010. The work of M. A. Castro was supported in part by CONICET (Argentina). Asterisk indicates corresponding author. NR 38 TC 3 Z9 3 U1 0 U2 3 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 NOV PY 2010 VL 29 IS 11 BP 1927 EP 1941 DI 10.1109/TMI.2010.2053552 PG 15 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 676TP UT WOS:000283941800010 PM 20570765 ER PT J AU Zhang, JQ Zhou, XB Wang, HH Suffredini, A Zhang, L Huang, YF Wong, S AF Zhang, Jianqiu Zhou, Xiaobo Wang, Honghui Suffredini, Anthony Zhang, Lin Huang, Yufei Wong, Stephen TI Bayesian Peptide Peak Detection for High Resolution TOF Mass Spectrometry SO IEEE TRANSACTIONS ON SIGNAL PROCESSING LA English DT Article DE Bayesian methods; Markov chain Monte Carlo; mass spectrometry; peptide peak detection; time-of-flight ID WAVELET TRANSFORM; SPECTRA; QUANTIFICATION; MALDI; NOISE AB In this paper, we address the issue of peptide ion peak detection for high resolution time-of-flight (TOF) mass spectrometry (MS) data. A novel Bayesian peptide ion peak detection method is proposed for TOF data with resolution of 10 000-15 000 full width at half-maximum (FWHW). MS spectra exhibit distinct characteristics at this resolution, which are captured in a novel parametric model. Based on the proposed parametric model, a Bayesian peak detection algorithm based on Markov chain Monte Carlo (MCMC) sampling is developed. The proposed algorithm is tested on both simulated and real datasets. The results show a significant improvement in detection performance over a commonly employed method. The results also agree with expert's visual inspection. Moreover, better detection consistency is achieved across MS datasets from patients with identical pathological condition. C1 [Zhang, Jianqiu; Huang, Yufei] Univ Texas San Antonio, Dept Elect & Comp Engn, San Antonio, TX 78249 USA. [Zhou, Xiaobo; Wong, Stephen] Texas Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Wang, Honghui; Suffredini, Anthony] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Zhang, Lin] China Univ Min Technol, Sch Informat & Elect Engn, Xuzhou 221116, Peoples R China. [Huang, Yufei] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. RP Zhang, JQ (reprint author), Univ Texas San Antonio, Dept Elect & Comp Engn, San Antonio, TX 78249 USA. EM michelle.zhang@utsa.edu; xzhou@tmhs.org FU San Antonio Life Sciences Institute; National Center For Research Resources [G12RR013646]; Methodist Hospital Scholarship; NIH [R01LM08696, R01LM009161, R01AG028928]; NSF [CCF-0546345]; Chinese Scholarship Council FX The associate editor coordinating the review of this manuscript and approving it for publication was Dr. Z. Jane Wang. The work of J. Zhang is funded by a San Antonio Life Sciences Institute-Research Enhancement grant and supported by a SALSI research enhancement grant and an award G12RR013646 from the National Center For Research Resources. The work of X. Zhou is funded in part by The Methodist Hospital Scholarship Award. The work of X. Zhou and S. Wong are also funded in part by NIH Grants R01LM08696, R01LM009161, and R01AG028928. The work of Y. Huang is supported by NSF Grant CCF-0546345. The work of L. Zhang is supported by the Chinese Scholarship Council. NR 22 TC 2 Z9 2 U1 1 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1053-587X J9 IEEE T SIGNAL PROCES JI IEEE Trans. Signal Process. PD NOV PY 2010 VL 58 IS 11 BP 5883 EP 5894 DI 10.1109/TSP.2010.2065226 PG 12 WC Engineering, Electrical & Electronic SC Engineering GA 670RI UT WOS:000283444600032 PM 21544266 ER PT J AU Chai, LYA Netea, MG Sugui, J Vonk, AG van de Sande, WWJ Warris, A Kwon-Chung, KJ Kullberg, BJ AF Chai, Louis Y. A. Netea, Mihai G. Sugui, Janyce Vonk, Alieke G. van de Sande, Wendy W. J. Warris, Adilia Kwon-Chung, Kyung J. Kullberg, Bart Jan TI Aspergillus fumigatus Conidial Melanin Modulates Host Cytokine Response SO IMMUNOBIOLOGY LA English DT Article DE beta-glucan; Dectin-1; Mannose receptor; Mannan; Melanin; Modulation ID CANDIDA-ALBICANS; CRYPTOCOCCUS-NEOFORMANS; PIGMENT BIOSYNTHESIS; IMMUNE RECOGNITION; FUNGAL MELANINS; BETA-GLUCAN; VIRULENCE; DECTIN-1; GENE; RECEPTOR AB Melanin biopigments have been linked to fungal virulence. Aspergillus fumigatus conidia are melanised and are weakly immunogenic. We show that melanin pigments on the surface of resting Aspergillus fumigatus conidia may serve to mask pathogen-associated molecular patterns (PAMPs)-induced cytokine response. The albino conidia induced significantly more proinflammatory cytokines in human peripheral blood mononuclear cells (PBMC), as compared to melanised wild-type conidia. Blocking dectin-1 receptor, Toll-like receptor 4 or mannose receptor decreased cytokine production induced by the albino but not by the wild type conidia. Moreover, albino conidia stimulated less potently, cytokine production in PBMC isolated from an individual with defective dectin-1, compared to the stimulation of cells isolated from healthy donors. These results suggest that beta-glucans, but also other stimulatory PAMPs like mannan derivatives, are exposed on conidial surface in the absence of melanin. Melanin may play a modulatory role by impeding the capability of host immune cells to respond to specific ligands on A. fumigatus. (C) 2009 Elsevier GmbH. All rights reserved. C1 [Chai, Louis Y. A.; Netea, Mihai G.; Kullberg, Bart Jan] Radboud Univ Nijmegen Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. [Chai, Louis Y. A.; Netea, Mihai G.; Warris, Adilia; Kullberg, Bart Jan] Nijmegen Inst Infect Inflammat & Immun N4i, Nijmegen, Netherlands. [Chai, Louis Y. A.] Natl Univ Singapore Hosp, Dept Med, Singapore 119074, Singapore. [Sugui, Janyce; Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Vonk, Alieke G.; van de Sande, Wendy W. J.] Erasmus MC, Univ Med Ctr Rotterdam, Dept Med Microbiol & Infect Dis, NL-3015 CE Rotterdam, Netherlands. [Warris, Adilia] Radboud Univ Nijmegen Med Ctr, Dept Pediat, Nijmegen, Netherlands. RP Netea, MG (reprint author), Radboud Univ Nijmegen Med Ctr, Dept Med 463, POB 9101,Geert Grootpl 8, NL-6525 GA Nijmegen, Netherlands. EM M.Netea@aig.umcn.nl RI Warris, Adilia/F-4882-2010; Kullberg, Bart Jan/C-8520-2013; Netea, Mihai/N-5155-2014; Warris, A./L-4745-2015 FU Ministry of Health, Singapore; Agency for Science, Technology and Research (A*STAR)/National Medical Research Council (NMRC), Singapore; Netherlands Organization for Scientific Research; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX L. Chai was supported by the Health Manpower Development Plan (HMDP) Fellowship, Ministry of Health, Singapore and the International Fellowship, Agency for Science, Technology and Research (A*STAR)/National Medical Research Council (NMRC), Singapore.; M.G. Netea was supported by a Vidi grant of the Netherlands Organization for Scientific Research.; J.A. Sugui and K.J. Kwon-Chung were supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 33 TC 49 Z9 51 U1 0 U2 9 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD NOV PY 2010 VL 215 IS 11 BP 915 EP 920 DI 10.1016/j.imbio.2009.10.002 PG 6 WC Immunology SC Immunology GA 684AN UT WOS:000284519500008 PM 19939494 ER PT J AU Zhu, JF Paul, WE AF Zhu, Jinfang Paul, William E. TI Peripheral CD4+T-cell differentiation regulated by networks of cytokines and transcription factors SO IMMUNOLOGICAL REVIEWS LA English DT Review DE T-helper cells; cytokines; transcription factors; T-cell differentiation ID FOLLICULAR-HELPER-CELLS; GROWTH-FACTOR-BETA; CD4(+) T-CELLS; ROR-GAMMA-T; LOCUS-CONTROL REGION; HYPER-IGE SYNDROME; TGF-BETA; GENE-EXPRESSION; TH2 CELLS; IN-VIVO AB CD4+ T cells, also known as T-helper (Th) cells, play an important role in orchestrating adaptive immune responses to various infectious agents. They are also involved in the induction of autoimmune and allergic diseases. Upon T-cell receptor (TCR)-mediated cell activation, naive CD4+ T cells can differentiate into at least four major lineages, Th1, Th2, Th17, and iTreg cells, that participate in different types of immune responses. Networks of cytokines and transcription factors are critical for determining CD4+ T-cell fates and effector cytokine production. Here, we review collaboration and cross-regulation between various essential cytokines in the activation/induction of key transcription factors during the process of Th cell differentiation towards these distinct lineages. We also discuss the interactions of key transcription factors at both genetic and protein levels and the function of the resulting network(s) in regulating the expression of effector cytokines. C1 [Zhu, Jinfang; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11N311, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 192 TC 214 Z9 218 U1 4 U2 29 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD NOV PY 2010 VL 238 BP 247 EP 262 DI 10.1111/j.1600-065X.2010.00951.x PG 16 WC Immunology SC Immunology GA 671MB UT WOS:000283509100018 PM 20969597 ER PT J AU Mineo, TWP Oliveira, CJF Gutierrez, FRS Silva, JS AF Mineo, Tiago W. P. Oliveira, Carlo J. F. Gutierrez, Fredy R. S. Silva, Joao S. TI Recognition by toll-like receptor 2 induces antigen-presenting cell activation and Th1 programming during infection by Neospora caninum SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article DE dendritic cells; MyD88; neosporosis; T helper 1 immune response; TLR2 ID DENDRITIC CELLS; TOXOPLASMA-GONDII; DEFINITIVE HOSTS; IMMUNE-RESPONSE; PARASITE; MICE; GAMMA; IL-12; TOLL-LIKE-RECEPTOR-2; DIFFERENTIATION AB Neospora caninum is an apicomplexan parasite responsible for major economic losses due to abortions in cattle. Toll-like receptors (TLRs) sense specific microbial products and direct downstream signaling pathways in immune cells, linking innate, and adaptive immunity. Here, we analyze the role of TLR2 on innate and adaptive immune responses during N. caninum infection. Inflammatory peritoneal macrophages and bone marrow-derived dendritic cells exposed to N. caninum-soluble antigens presented an upregulated expression of TLR2. Increased receptor expression was correlated to TLR2/MyD88-dependent antigen-presenting cell maturation and pro-inflammatory cytokine production after stimulation by antigens. Impaired innate responses observed after infection of mice genetically deficient for TLR2((-/-)) was followed by downregulation of adaptive T helper 1 (Th1) immunity, represented by diminished parasite-specific CD4(+) and CD8(+) T-cell proliferation, IFN-gamma:interleukin (IL)-10 ratio, and IgG subclass synthesis. In parallel, TLR2(-/-) mice presented higher parasite burden than wild-type (WT) mice at acute and chronic stages of infection. These results show that initial recognition of N. caninum by TLR2 participates in the generation of effector immune responses against N. caninum and imply that the receptor may be a target for future prophylactic strategies against neosporosis. Immunology and Cell Biology (2010) 88, 825-833; doi:10.1038/icb.2010.52; published online 20 April 2010 C1 [Mineo, Tiago W. P.] Univ Sao Paulo, FMRP, Sch Med Ribeirao Preto, Dept Biochem & Immunol,Immunoparasitol Lab, BR-14049900 Ribeirao Preto, SP, Brazil. [Mineo, Tiago W. P.] Univ Fed Uberlandia, Inst Biomed Sci, BR-38400 Uberlandia, MG, Brazil. [Oliveira, Carlo J. F.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Mineo, TWP (reprint author), Univ Sao Paulo, FMRP, Sch Med Ribeirao Preto, Dept Biochem & Immunol,Immunoparasitol Lab, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. EM tiago.mineo@pq.cnpq.br; jsdsilva@fmrp.usp.br RI Mineo, Tiago/B-4153-2009; Silva, Joao/A-4484-2008; Gutierrez, Fredy RS/C-3911-2009 OI Mineo, Tiago/0000-0002-2339-2743; Gutierrez, Fredy RS/0000-0001-9873-8342 FU CNPq [473178/2007-9]; FAPESP [2006/06803-4] FX We thank Cristiane M Milanezi, Dr Deise AO Silva, and Walter M Turato for technical assistance and Dr Neide M Silva, Djalma S Lima Jr, and Luciana Benevides for helpful suggestions. We also thank NIAID intramural editor Brenda Rae Marshall for assistance. TLR2-/- and MyD88-/- mice were originally provided by Dr Shizuo Akira (Osaka University, Osaka, Japan). This work was supported by the Brazilian funding agencies CNPq (473178/2007-9) and FAPESP (2006/06803-4). NR 39 TC 15 Z9 15 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD NOV-DEC PY 2010 VL 88 IS 8 BP 825 EP 833 DI 10.1038/icb.2010.52 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 678UC UT WOS:000284105400009 PM 20404835 ER PT J AU Zumbrun, SD Hanson, L Sinclair, JF Freedy, J Melton-Celsa, AR Rodriguez-Canales, J Hanson, JC O'Brien, AD AF Zumbrun, Steven D. Hanson, Leanne Sinclair, James F. Freedy, James Melton-Celsa, Angela R. Rodriguez-Canales, Jaime Hanson, Jeffrey C. O'Brien, Alison D. TI Human Intestinal Tissue and Cultured Colonic Cells Contain Globotriaosylceramide Synthase mRNA and the Alternate Shiga Toxin Receptor Globotetraosylceramide SO INFECTION AND IMMUNITY LA English DT Article ID ENTEROHEMORRHAGIC ESCHERICHIA-COLI; MICROVASCULAR ENDOTHELIAL-CELLS; VEROTOXIN RECEPTORS; GLYCOLIPID BINDING; EPITHELIAL-CELLS; SHIGELLA TOXIN; MOUSE COLON; HELA-CELLS; GLYCOSPHINGOLIPIDS; PATHOGENESIS AB Escherichia coli O157:H7 and other Shiga toxin (Stx)-producing E. coli (STEC) bacteria are not enteroinvasive but can cause hemorrhagic colitis. In some STEC-infected individuals, a life-threatening sequela of infection called the hemolytic uremic syndrome may develop that can lead to kidney failure. This syndrome is linked to the production of Stx by the infecting organism. For Stx to reach the kidney, the toxin must first penetrate the colonic epithelial barrier. However, the Stx receptor, globotriaosylceramide (Gb3), has been thought to be absent from human intestinal epithelial cells. Thus, the mechanisms by which the toxin associates with and traverses through the intestine en route to the kidneys have been puzzling aspects of STEC pathogenesis. In this study, we initially determined that both types of Stx made by STEC, Stx1 and Stx2, do in fact bind to colonic epithelia in fresh tissue sections and to a colonic epithelial cell line (HCT-8). We also discovered that globotetraosylceramide (Gb4), a lower-affinity toxin receptor derived from Gb3, is readily detectable on the surfaces of human colonic tissue sections and HCT-8 cells. Furthermore, we found that Gb3 is present on a fraction of HCT-8 cells, where it presumably functions to bind and internalize Stx1 and Stx2. In addition, we established by quantitative real-time PCR (qRT-PCR) that both fresh colonic epithelial sections and HCT-8 cells express Gb3 synthase mRNA. Taken together, our data suggest that Gb3 may be present in small quantities in human colonic epithelia, where it may compete for Stx binding with the more abundantly expressed glycosphingolipid Gb4. C1 [Zumbrun, Steven D.; Hanson, Leanne; Sinclair, James F.; Freedy, James; Melton-Celsa, Angela R.; O'Brien, Alison D.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Rodriguez-Canales, Jaime; Hanson, Jeffrey C.] NCI, Laser Capture Microdissect Core Facil, Pathol Lab, NIH, Bethesda, MD 20814 USA. RP O'Brien, AD (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM aobrien@usuhs.mil OI Rodriguez-Canales, Jaime/0000-0002-0885-2377; O'Brien, Alison/0000-0002-1315-3204 FU National Institutes of Health [AI57168, AI20148] FX This work was supported by grants AI57168 and AI20148 from the National Institutes of Health. NR 61 TC 26 Z9 26 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2010 VL 78 IS 11 BP 4488 EP 4499 DI 10.1128/IAI.00620-10 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 665RB UT WOS:000283052100005 PM 20732996 ER PT J AU Goodman, AL Epp, C Moss, D Holder, AA Wilson, JM Gao, GP Long, CA Remarque, EJ Thomas, AW Ammendola, V Colloca, S Dicks, MDJ Biswas, S Seibel, D van Duivenvoorde, LM Gilbert, SC Hill, AVS Draper, SJ AF Goodman, Anna L. Epp, C. Moss, D. Holder, A. A. Wilson, J. M. Gao, G. P. Long, C. A. Remarque, E. J. Thomas, A. W. Ammendola, V. Colloca, S. Dicks, M. D. J. Biswas, S. Seibel, D. van Duivenvoorde, L. M. Gilbert, S. C. Hill, A. V. S. Draper, S. J. TI New Candidate Vaccines against Blood-Stage Plasmodium falciparum Malaria: Prime-Boost Immunization Regimens Incorporating Human and Simian Adenoviral Vectors and Poxviral Vectors Expressing an Optimized Antigen Based on Merozoite Surface Protein 1 SO INFECTION AND IMMUNITY LA English DT Article ID CARBOXYL-TERMINAL FRAGMENT; T-CELL EPITOPES; PROTECTIVE IMMUNITY; ANTIBODY-RESPONSES; PARASITE GROWTH; RHESUS-MONKEYS; CLINICAL-TRIAL; LIVER STAGE; IN-VITRO; YOELII AB Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in-adjuvant vaccines to induce strong cellular immunity. Here we report the design of novel vectored Plasmodium falciparum vaccines capable of overcoming such limitations. We optimized an antigenic insert comprising the four conserved blocks of MSP-1 fused to tandemly arranged sequences that represent both allelic forms of the dimorphic 42-kDa C-terminal region. Inserts were expressed by adenoviral and poxviral vectors and employed in heterologous prime-boost regimens. Simian adenoviral vectors were used in an effort to circumvent preexisting immunity to human adenoviruses. In preclinical studies these vaccines induced potent cellular immune responses and high-titer antibodies directed against MSP-1. The antibodies induced were found to have growth-inhibitory activity against dimorphic allelic families of P. falciparum. These vectored vaccines should allow assessment in humans of the safety and efficacy of inducing strong cellular as well as cross-strain humoral immunity to P. falciparum MSP-1. C1 [Goodman, Anna L.; Dicks, M. D. J.; Biswas, S.; Gilbert, S. C.; Hill, A. V. S.; Draper, S. J.] Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. [Epp, C.; Seibel, D.] Univ Klinikum Heidelberg, Inst Hyg, Abt Parasitol, D-69120 Heidelberg, Germany. [Moss, D.; Holder, A. A.] Natl Inst Med Res, Div Parasitol, MRC, London NW7 1AA, England. [Gao, G. P.] Univ Penn, Gene Therapy Program, Div Transfus Med, Dept Pathol & Lab Med,Translat Res Labs, Philadelphia, PA 19104 USA. [Long, C. A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Remarque, E. J.; Thomas, A. W.] Biomed Primate Res Ctr, NL-2288 GJ Rijswijk, Netherlands. [Ammendola, V.; Colloca, S.] Okairos AG, I-00040 Rome, Italy. RP Goodman, AL (reprint author), Univ Oxford, Jenner Inst, Old Rd,Campus Res Bldg, Oxford OX3 7DQ, England. EM anna.goodman@nhs.net RI Draper, Simon/F-1758-2011; Holder, Anthony/A-7554-2013; Wilson, James/F-9220-2011; OI Draper, Simon/0000-0002-9415-1357; Holder, Anthony/0000-0002-8490-6058; Wilson, James/0000-0002-9630-3131; Dicks, Matthew/0000-0003-1909-7095; Gilbert, Sarah/0000-0002-6823-9750 FU Medical Research Council [G0600424, U117532067]; Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health; PATH/Malaria Vaccine Initiative; European Commission through the European Malaria Vaccine Development Association [LSH-2005-037506]; NIDDK [P30 DK-47757]; ReGenX FX This work was supported primarily by grant G0600424 and in part by funding agreement U117532067 from the Medical Research Council. In addition, this work was supported in part by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, and also by the PATH/Malaria Vaccine Initiative for support of the GIA Reference Center and by the European Commission through the European Malaria Vaccine Development Association, contract LSH-2005-037506. This work was also funded by NIDDK grant P30 DK-47757 (J.M.W.). S.J.D. is a Junior Research Fellow of Merton College, Oxford. A. V. S. H. is a Wellcome Trust Principal Research Fellow. A. L. G. was an MRC clinical training fellow while undertaking this research.; A.L.G., S. C. G., A. V. S. H., and S.J.D. are named inventors on patent applications covering vectored malaria vaccines and immunization regimens. Authors from Okairos are employees of and/or shareholders in Okairos, which is developing vectored malaria vaccines. J.M.W. is a consultant to ReGenX Holdings and is a founder of, holds equity in, and receives a grant from affiliates of ReGenX Holdings; in addition, he is an inventor on patents licensed to various biopharmaceutical companies, including affiliates of ReGenX Holdings. NR 60 TC 38 Z9 38 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2010 VL 78 IS 11 BP 4601 EP 4612 DI 10.1128/IAI.00315-10 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 665RB UT WOS:000283052100017 PM 20713623 ER PT J AU Mahajan, B Berzofsky, JA Boykins, RA Majam, V Zheng, H Chattopadhyay, R de la Vega, P Moch, JK Haynes, JD Belyakov, IM Nakhasi, HL Kumar, S AF Mahajan, Babita Berzofsky, Jay A. Boykins, Robert A. Majam, Victoria Zheng, Hong Chattopadhyay, Rana de la Vega, Patricia Moch, J. Kathleen Haynes, J. David Belyakov, Igor M. Nakhasi, Hira L. Kumar, Sanjai TI Multiple Antigen Peptide Vaccines against Plasmodium falciparum Malaria SO INFECTION AND IMMUNITY LA English DT Article ID B-CELL EPITOPES; RED-BLOOD-CELLS; CIRCUMSPOROZOITE PROTEIN; T-CELL; SYNTHETIC PEPTIDES; SPOROZOITE VACCINE; IMMUNE-RESPONSE; SURFACE-ANTIGEN; ANTIBODIES; IMMUNOGENICITY AB The multiple antigen peptide (MAP) approach is an effective method to chemically synthesize and deliver multiple T-cell and B-cell epitopes as the constituents of a single immunogen. Here we report on the design, chemical synthesis, and immunogenicity of three Plasmodium falciparum MAP vaccines that incorporated antigenic epitopes from the sporozoite, liver, and blood stages of the life cycle. Antibody and cellular responses were determined in three inbred (C57BL/6, BALB/c, and A/J) strains, one congenic (HLA-A2 on the C57BL/6 background) strain, and one outbred strain (CD1) of mice. All three MAPs were immunogenic and induced both antibody and cellular responses, albeit in a somewhat genetically restricted manner. Antibodies against MAP-1, MAP-2, and MAP-3 had an antiparasite effect that was also dependent on the mouse major histocompatibility complex background. Anti-MAP-1 (CSP-based) antibodies blocked the invasion of HepG2 liver cells by P. falciparum sporozoites (highest, 95.16% in HLA-A2 C57BL/6; lowest, 11.21% in BALB/c). Furthermore, antibodies generated following immunizations with the MAP-2 (PfCSP, PfLSA-1, PfMSP-1(42), and PfMSP-3b) and MAP-3 (PfRAP-1, PfRAP-2, PfSERA, and PfMSP-1(42)) vaccines were able to reduce the growth of blood stage parasites in erythrocyte cultures to various degrees. Thus, MAP-based vaccines remain a viable option to induce effective antibody and cellular responses. These results warrant further development and preclinical and clinical testing of the next generation of candidate MAP vaccines that are based on the conserved protective epitopes from Plasmodium antigens that are widely recognized by populations of divergent HLA types from around the world. C1 [Kumar, Sanjai] US FDA, Malaria Res Program, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Berzofsky, Jay A.; Belyakov, Igor M.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [de la Vega, Patricia; Moch, J. Kathleen; Haynes, J. David] USN, Med Res Ctr, Silver Spring, MD USA. [de la Vega, Patricia; Moch, J. Kathleen; Haynes, J. David] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Kumar, S (reprint author), US FDA, Malaria Res Program, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. EM Sanjai.kumar@fda.hhs.gov NR 63 TC 24 Z9 29 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2010 VL 78 IS 11 BP 4613 EP 4624 DI 10.1128/IAI.00533-10 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 665RB UT WOS:000283052100018 PM 20823210 ER PT J AU Henderson, DK Palmore, TN AF Henderson, David K. Palmore, Tara N. TI Critical Gaps in Knowledge of the Epidemiology and Pathophysiology of Healthcare-Associated Infections SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT 5th Decennial International Conference on Healthcare Associated Infections CY MAR 18-22, 2010 CL Atlanta, GA SP Soc Healthcare Epidemiol Amer, Ctr Dis Control & Prevention, Assoc Professionals Infect Control, Infect Diseases Soc Amer AB The past decade has witnessed an intense interest in healthcare-associated infections as well as increases in legislation and reporting requirements aimed at decreasing the number of these costly infections. In the next decade, healthcare epidemiology must address major gaps in understanding of the epidemiology and pathogenesis of healthcare-associated infections and in knowledge of the efficacy of interventions for healthcare-associated infections and the efficacy in implementing such interventions. C1 [Henderson, David K.; Palmore, Tara N.] NIH, Off Director, Ctr Clin, Bethesda, MD 20892 USA. [Palmore, Tara N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Off Director, Ctr Clin, Bldg 10,Room 6-1480,10 Ctr Dr MSC 1504, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 8 TC 10 Z9 10 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD NOV PY 2010 VL 31 SU 1 BP S4 EP S6 DI 10.1086/655984 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 675PE UT WOS:000283841800002 PM 20929367 ER PT J AU Henderson, DK AF Henderson, David K. TI Opportunists and Opportunities: The 2010 SHEA Lecture SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT 5th Decennial International Conference on Healthcare Associated Infections CY MAR 18-22, 2010 CL Atlanta, GA SP Soc Healthcare Epidemiol Amer, Ctr Dis Control & Prevention, Assoc Professionals Infect Control, Infect Dis Soc Amer ID HUMAN-IMMUNODEFICIENCY-VIRUS; LYMPHADENOPATHY-ASSOCIATED VIRUS; HEALTH-CARE WORKERS; OCCUPATIONAL EXPOSURES; UNIVERSAL PRECAUTIONS; HIV; PROPHYLAXIS; BLOOD; RISK AB My experience as a hospital epidemiologist at the National Institutes of Health Clinical Center has underscored the importance of aggressively managing infection with opportunistic pathogens and of taking advantage of opportunities as they arise (most often as crises). I review selected aspects of my career and use these as examples of the opportunists and opportunities now facing healthcare epidemiology. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Ctr Clin, Bldg 10,Room 6-1480,10 Ctr Dr MSC 1504, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD NOV PY 2010 VL 31 SU 1 BP S66 EP S69 DI 10.1086/655983 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 675PE UT WOS:000283841800019 PM 20929375 ER PT J AU Morens, DM Taubenberger, JK AF Morens, David M. Taubenberger, Jeffery K. TI Historical thoughts on influenza viral ecosystems, or behold a pale horse, dead dogs, failing fowl, and sick swine SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article; Proceedings Paper CT International Symposium on Neglected Influenza Viruses CY FEB 03-05, 2010 CL Amelia Island, FL DE Equine; history; influenza ID AVIAN H5N1 INFLUENZA; A VIRUSES; EQUINE INFLUENZA; PANDEMIC INFLUENZA; CANINE INFLUENZA; RISK-ASSESSMENT; NORTH-AMERICA; WILD BIRDS; EPIDEMIOLOGY; TRANSMISSION AB Objectives To understand human influenza in a historical context of viral circulation in avian species, mammals, and in the environment. Design Historical review. Setting Global events in a variety of circumstances over more than 3,000 years time. Sample Comprehensive review of the historical literature including all major publications on pandemic and panzootic influenza. Main Outcome Measures Influenza pandemics, panzootics, major epidemics and epizootics, and instances of interspecies transmission of influenza A. Results Extensive documentation of human and animal influenza over many centuries suggests that influenza A viruses have adapted to a variety of species and environmental milieu and are capable of switching between many different hosts under widely varying circumstances. Conclusions The genetic elements of influenza A viruses circulate globally in an extensive ecosystem comprised of many avian and mammalian species and a spectrum of environments. Unstable gene constellations found in avian species become stable viruses only upon switching to secondary hosts, but may then adapt and circulate independently. It may be desirable to think of influenza A viruses as existing and evolving in a large ecosystem involving multiple hosts and environments. Implications for understanding human influenza are discusssed. C1 [Morens, David M.] NIAID, NIH, OD, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, OD, Bldg 31,Room 7A-03, Bethesda, MD 20892 USA. EM dm270q@nih.gov FU Management & Delivery Branch, Document Delivery Section, NIH Library; History of Medicine Division, National Library of Medicine FX We thank Betty Murgolo and the staff of the Collection, Management & Delivery Branch, Document Delivery Section, NIH Library, and the staff of the History of Medicine Division, National Library of Medicine, for research support; and John Weddle for assistance with image reproduction. NR 120 TC 36 Z9 36 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD NOV PY 2010 VL 4 IS 6 BP 327 EP 337 DI 10.1111/j.1750-2659.2010.00148.x PG 11 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 669WY UT WOS:000283382100002 PM 20958926 ER PT J AU Morens, DM Taubenberger, JK AF Morens, David M. Taubenberger, Jeffery K. TI An avian outbreak associated with panzootic equine influenza in 1872: an early example of highly pathogenic avian influenza? SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article; Proceedings Paper CT International Symposium on Neglected Influenza Viruses CY FEB 03-05, 2010 CL Amelia Island, FL DE Avian influenza; epizootic; equine influenza; highly pathogenic avian influenza; influenza poultry ID PANDEMIC INFLUENZA AB Background An explosive fatal epizootic in poultry, prairie chickens, turkeys, ducks and geese, occurred over much of the populated United States between 15 November and 15 December 1872. To our knowledge the scientific literature contains no mention of the nationwide 1872 poultry outbreak. Objective To understand avian influenza in a historical context. Results The epizootic progressed in temporal-geographic association with a well-reported panzootic of equine influenza that had begun in Canada during the last few days of September 1872. The 1872 avian epizootic was universally attributed at the time to equine influenza, a disease then of unknown etiology but widely believed to be caused by the same transmissible respiratory agent that caused human influenza. Conclusions Another microbial agent could have caused the avian outbreak; however, its strong temporal and geographic association with the equine panzootic, and its clinical and epidemiologic features, are most consistent with highly pathogenic avian influenza. The avian epizootic could thus have been an early instance of highly pathogenic avian influenza. C1 [Morens, David M.; Taubenberger, Jeffery K.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dm270q@nih.gov FU NIH; NIAID FX This work was supported by the Intramural Research Program of the NIH and the NIAID. NR 30 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD NOV PY 2010 VL 4 IS 6 BP 373 EP 377 DI 10.1111/j.1750-2659.2010.00181.x PG 5 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 669WY UT WOS:000283382100008 PM 20958931 ER PT J AU Ribeiro, JMC Mans, BJ Arca, B AF Ribeiro, Jose M. C. Mans, Ben J. Arca, Bruno TI An insight into the sialome of blood-feeding Nematocera SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Salivary glands; Hematophagy; Mosquitoes; Sand flies; Black flies; Biting midges; Feeding; Vector ID VECTOR ANOPHELES-GAMBIAE; FLY LUTZOMYIA-LONGIPALPIS; MOSQUITO AEDES-AEGYPTI; ADULT FEMALE MOSQUITO; YELLOW-FEVER MOSQUITO; SALIVARY ADENOSINE-DEAMINASE; AMERICAN VISCERAL LEISHMANIASIS; ABUNDANT SECRETED PROTEINS; PHLEBOTOMINE SAND FLIES; TICK IXODES-SCAPULARIS AB Within the Diptera and outside the suborder Brachycera, the blood-feeding habit occurred at least twice, producing the present day sand flies, and the Culicomorpha, including the mosquitoes (Culicidae), black flies (Simulidae), biting midges (Ceratopogonidae) and frog feeding flies (Corethrellidae). Alternatives to this scenario are also discussed. Successful blood-feeding requires adaptations to antagonize the vertebrate's mechanisms of blood clotting, platelet aggregation, vasoconstriction, pain and itching, which are triggered by tissue destruction and immune reactions to insect products. Saliva of these insects provides a complex pharmacological armamentarium to block these vertebrate reactions. With the advent of transcriptomics, the sialomes (from the Greek word sialo = saliva) of at least two species of each of these families have been studied (except for the frog feeders), allowing an insight into the diverse pathways leading to today's salivary composition within the Culicomorpha, having the sand flies as an outgroup. This review catalogs 1288 salivary proteins in 10 generic classes comprising over 150 different protein families, most of which we have no functional knowledge. These proteins and many sequence comparisons are displayed in a hyperlinked spreadsheet that hopefully will stimulate and facilitate the task of functional characterization of these proteins, and their possible use as novel pharmacological agents and epidemiological markers of insect vector exposure. Published by Elsevier Ltd. C1 [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Mans, Ben J.] Onderstepoort Vet Inst, Pretoria, South Africa. [Mans, Ben J.] Univ Pretoria, Dept Vet Trop Dis, ZA-0002 Pretoria, South Africa. [Arca, Bruno] Univ Federico II, Dept Struct & Funct Biol, Naples, Italy. RP Ribeiro, JMC (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy,Room 2E32D, Rockville, MD 20852 USA. EM Jribeiro@niaid.nih.gov OI Arca, Bruno/0000-0002-4029-0984; Mans, Ben/0000-0002-0177-0029; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. Because J.M.C.R. is a government employee and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license. NR 173 TC 80 Z9 81 U1 2 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD NOV PY 2010 VL 40 IS 11 BP 767 EP 784 DI 10.1016/j.ibmb.2010.08.002 PG 18 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 673EA UT WOS:000283640700001 PM 20728537 ER PT J AU Song, SM Kole, S Precht, P Pazin, MJ Bernier, M AF Song, Shaoming Kole, Sutapa Precht, Patricia Pazin, Michael J. Bernier, Michel TI Activation of heat shock factor 1 plays a role in pyrrolidine dithiocarbamate-mediated expression of the co-chaperone BAG3 SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Hsp90; Pyrrolidine dithiocarbamate; Transcriptional regulation; Protein thiols; Chromatin immunoprecipitation ID FACTOR-KAPPA-B; NITRIC-OXIDE SYNTHASE; CANCER-CELLS; TRANSCRIPTION FACTOR-1; REPERFUSION INJURY; GENE-EXPRESSION; PROTEIN; APOPTOSIS; INHIBITION; DIFFERENTIATION AB Adaptive responses to physical and inflammatory stressors are mediated by transcription factors and molecular chaperones. The transcription factor heat shock factor 1 (HSF1) has been implicated in extending lifespan in part by increasing expression of heat shock response genes. Pyrrolidine dithiocarbamate (PDTC) is a small thiol compound that exerts in vivo and in vitro anti-inflammatory properties through mechanisms that remain unclear. Here we report that PDTC induced the release of monomeric HSF1 from the molecular chaperone heat shock protein 90 (Hsp90), with concomitant increase in HSF1 trimer formation, translocation to the nucleus, and binding to promoter of target genes in human HepG2 cells. siRNA-mediated silencing of HSF1 blocked BAG3 gene expression by PDTC. The protein levels of the cochaperone BAG3 and its interaction partner Hsp72 were stimulated by PDTC in a dose-dependent fashion, peaking at 6 h. Inhibition of Hsp90 function by geldanamycin derivatives and novobiocin elicited a pattern of FISH activation and BAG3 expression that was similar to PDTC. Chromatin immunoprecipitation studies showed that PDTC and the inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhanced the binding of HSF1 to the promoter of several target genes, including BAG3, HSPA1A, HSPA1B, FKBP4, STIP1 and UBB. Cell treatment with PDTC increased significantly the level of Hsp90 alpha thiol oxidation, a posttranslational modification known to inhibit its chaperone function. These results unravel a previously unrecognized mechanism by which PDTC and related compounds could confer cellular protection against inflammation through HSF1-induced expression of heat shock response genes. Published by Elsevier Ltd. C1 [Song, Shaoming; Bernier, Michel] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Precht, Patricia; Pazin, Michael J.] NIA, Lab Cellular & Mol Biol, NIH, Baltimore, MD 21224 USA. [Kole, Sutapa] MedStar Res Inst, Hyattsville, MD 20783 USA. RP Bernier, M (reprint author), NIA, Clin Invest Lab, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM songs2@mail.nih.gov; KoleS@grc.nia.nih.gov; prechtp@mail.nih.gov; pazinm@mail.nih.gov; Bernierm@mail.nih.gov OI Bernier, Michel/0000-0002-5948-368X; Pazin, Michael/0000-0002-7561-3640 FU NIH, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 37 TC 13 Z9 13 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD NOV PY 2010 VL 42 IS 11 BP 1856 EP 1863 DI 10.1016/j.biocel.2010.07.021 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 673YA UT WOS:000283698900017 PM 20692357 ER PT J AU Khalili, S Liu, YN Sumita, Y Maria, OM Blank, D Key, S Mezey, E Tran, SD AF Khalili, Saeed Liu, Younan Sumita, Yoshinori Maria, Ola M. Blank, David Key, Sharon Mezey, Eva Tran, Simon D. TI Bone marrow cells are a source of undifferentiated cells to prevent Sjogren's syndrome and to preserve salivary glands function in the non-obese diabetic mice SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Sjogren's syndrome; Bone marrow cells; Cell therapy; Xerostomia; Salivary gland; Saliva ID COLONY-STIMULATING FACTOR; MESENCHYMAL STEM-CELLS; NOD MICE; AUTOIMMUNE EXOCRINOPATHY; EPITHELIAL-CELLS; TRANSPLANTATION; DISEASE; REVERSAL; THERAPY; PATHOGENESIS AB Non-obese diabetic (NOD) mice develop Sjogren's-like syndrome (Ss) and a gradual loss of saliva secretory function. Our previous study showed that injections of matched normal spleen cells with Complete Freund's Adjuvant (CFA) reversed salivary gland dysfunction in 14-week-old NOD mice, which had established Ss. The spleen and bone marrow are closely related organs, and both are among the first sites of hematopoiesis during gestation. Noticing a rapidly increasing number of clinical trials using bone marrow (BM) cells treatments for autoimmune diseases, we tested if BM cells can prevent Ss and restore salivary glands' function. We injected CFA and MHC class I-matched normal BM cells in 7-week-old NOD mice, which had not yet developed Ss. We found at week 52 post-treatment that all NOD mice receiving BM cells and CFA had a recovery of salivary flow and were protected from Ss and diabetes. BM cells-treated mice had their salivary function restored quantitatively and qualitatively. Saliva flow was higher (p < 0.05) in BM cells-transplanted mice when compared to control mice, which continued to deteriorate over time. Total proteins, epidermal growth factor, amylase, and electrolytes concentrations in saliva of BM cells-treated mice were not significantly changed at week 44 and 52 post-therapy when compared to pre-therapy (when the mice did not have Ss). Restoration of salivary flow could have resulted from a combination of rescue and paracrine effects from BM cells. This study suggests that a combined immuno- and cell-based therapy can permanently prevent Ss and restored salivary function in NOD mice. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Khalili, Saeed; Liu, Younan; Sumita, Yoshinori; Maria, Ola M.; Tran, Simon D.] McGill Univ, Fac Dent, Montreal, PQ H3A 2B2, Canada. [Sumita, Yoshinori] Nagasaki Univ, Dept Regenerat Oral Surg, Nagasaki 852, Japan. [Blank, David] McGill Univ, Fac Med, Montreal, PQ H3A 2B2, Canada. [Key, Sharon; Mezey, Eva] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. RP Tran, SD (reprint author), McGill Univ, Fac Dent, 3640 Univ St,Room M-43, Montreal, PQ H3A 2B2, Canada. EM saeed.khalili@mail.mcgill.ca; younan.liu@mcgill.ca; y-sumita@nagasaki-u.ac.jp; ola.maria@mail.mcgill.ca; david.blank@muhc.mcgill.ca; KeyS@nidcr.nih.gov; mezeye@mail.nih.gov; simon.tran@mcgill.ca FU Canadian Institutes of Health Research (CIHR); Canada Research Chair; National Institute of Dental and Craniofacial Research (NIDCR), NIH FX We wish to thank Drs. R James Turner (NIDCR/NIH, for donating the NaKCl-cotransporter antibody), Mari Kaartinen, Dieter Reinhardt, Noreen Jane Bider, Jose Correa, Yonit Rebibo, and Neena Hanif. We also wish to thank the staff at the McGill University animal facility and the Centre for Bone and Periodontal Research. This study was supported in part by research funding from the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and the Intramural Research Program of the National Institute of Dental and Craniofacial Research (NIDCR), NIH. NR 39 TC 9 Z9 12 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD NOV PY 2010 VL 42 IS 11 BP 1893 EP 1899 DI 10.1016/j.biocel.2010.08.008 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 673YA UT WOS:000283698900021 PM 20732442 ER PT J AU Micozzi, D Pucciarelli, S Carpi, FM Costanzi, S De Sanctis, G Polzonetti, V Natalini, P Santarelli, IF Vita, A Vincenzetti, S AF Micozzi, Daniela Pucciarelli, Stefania Carpi, Francesco M. Costanzi, Stefano De Sanctis, Giampiero Polzonetti, Valeria Natalini, Paolo Santarelli, Ivano F. Vita, Alberto Vincenzetti, Silvia TI Role of tyrosine 33 residue for the stabilization of the tetrameric structure of human cytidine deaminase SO INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES LA English DT Article DE Cytidine deaminase; Site-directed mutagenesis; Molecular modeling; Circular dichroism ID CRYSTAL-STRUCTURE; PHARMACOLOGICAL CHAPERONES; CIRCULAR-DICHROISM; GLYCEROL; PROTEIN; EXPRESSION; RESOLUTION; INHIBITOR; DISEASE; RESCUE AB In the present work the effect of a mutation on tyrosine 33 residue (Y33G) of human cytidine deaminase (CDA) was investigated with regard to protein solubility and specific activity. Osmolytes and CDA ligands were used to increase the yield and the specific activity of the protein. The mutant enzyme was purified and subjected to a kinetic characterization and to stability studies. These investigations reinforced the hypothesis that in human CDA the side chain of Y33 is involved in intersubunit interactions with four glutamate residues (E108) forming a double latch that connects each of the two pairs of monomers of the tetrameric CDA. (C) 2010 Elsevier B.V. All rights reserved. C1 [Vita, Alberto; Vincenzetti, Silvia] Univ Camerino, Sch Vet Med Sci, I-62032 Camerino, MC, Italy. [Micozzi, Daniela; Pucciarelli, Stefania; Carpi, Francesco M.; De Sanctis, Giampiero; Polzonetti, Valeria; Natalini, Paolo] Sch Biosci & Biotechnol, I-62032 Camerino, MC, Italy. [Costanzi, Stefano] NIDDKD, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. [Santarelli, Ivano F.] Univ Camerino, Sch Pharm, I-62032 Camerino, MC, Italy. RP Vincenzetti, S (reprint author), Univ Camerino, Sch Vet Med Sci, Via Gentile 3 Varano, I-62032 Camerino, MC, Italy. EM daniela.micozzi@unicam.it; stefania.pucciarelli@unicam.it; francesco.carpi@unicam.it; StefanoC@intra.niddk.nih.gov; giampiero.desanctis@unicam.it; valeria.polzonetti@unicam.it; paolo.natalini@unicam.it; ivanofranco.santarelli@unicam.it; alberto.vita@unicam.it; silvia.vincenzetti@unicam.it RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS NR 27 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0141-8130 EI 1879-0003 J9 INT J BIOL MACROMOL JI Int. J. Biol. Macromol. PD NOV 1 PY 2010 VL 47 IS 4 BP 471 EP 482 DI 10.1016/j.ijbiomac.2010.07.001 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Applied; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 665AT UT WOS:000283007000008 PM 20637228 ER PT J AU Mani, H Merino, MJ AF Mani, Haresh Merino, Maria J. TI Mesothelial Neoplasms Presenting as, and Mimicking, Ovarian Cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Ovary; Mesothelioma; Mural nodule; Mucinous tumor ID PERITONEAL INCLUSION CYSTS; MUCINOUS TUMORS; MURAL NODULES; CLINICOPATHOLOGICAL ANALYSIS; MULTICYSTIC MESOTHELIOMA; ANAPLASTIC CARCINOMA; TRACT; WOMEN AB Mesotheliomas of the abdominal cavity are rare tumors that primarily involve the peritoneum, mesentery, and omentum. The involvement of the viscera is usually secondary to bulky and extensive serosal disease. We describe 7 cases of mesothelioma in which the initial manifestation was that of an ovarian mass. All patients underwent surgery with a primary diagnosis of ovarian cancer. Clinical histories, gross features, and histology slides were reviewed. Immunostains were performed on all cases and electron microscopy was performed in 2 cases. The patients ranged in age from 22 to 52 years and the lesions ranged in size from 3.8 to 9 cm. Of the 7 cases, 4 were predominantly cystic and 3 were solid. Histologically, all cystic tumors were multicystic mesothelioma, whereas the 3 solid tumors were diffuse malignant mesotheliomas. One patient had a borderline mucinous tumor with the mesothelioma occurring as a mural nodule, an association not described earlier. The oldest patient in this series had a diffuse malignant mesothelioma of the peritoneum with predominant ovarian surface involvement. Mesothelial neoplasms can present as ovarian masses in young women. Awareness of this presentation is important to establish appropriate management. C1 [Mani, Haresh; Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mjmerino@mail.nih.gov FU National Cancer Institute, National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 31 TC 6 Z9 9 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD NOV PY 2010 VL 29 IS 6 BP 523 EP 528 DI 10.1097/PGP.0b013e3181e6a3ee PG 6 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 668JK UT WOS:000283264400003 PM 20881862 ER PT J AU Lu, C Chen, Z AF Lu, Chi Chen, Zhi TI MOS hydrogen sensor with very fast response based on ulitra-thin thermal SiO2 film SO INTERNATIONAL JOURNAL OF HYDROGEN ENERGY LA English DT Article DE MOS capacitor; H-2 Sensor; Ultra thin thermal SiO2 film; Response time; SiO2 bulk trap ID SILICON DIOXIDE; SENSING PROPERTIES; OXIDE; INTERFACE; PALLADIUM; DIELECTRICS; TRANSISTOR; DIODES; STATES; CELLS AB An MOS capacitor type hydrogen gas sensor was fabricated with the structure of Ni/SiO2/Si by using conventional silicon wafer technologies Grown by dry oxidation at 900 C the thickness of the SiO2 film was only 24 A At 150 degrees C comparing to another MOS capacitor with 148 A thick oxide and otherwise identical configurations this sensor showed much faster response speed (the time interval to reach half of the magnitude of the steady state signal or t(50%) was only 4 s in response to 1% H-2 without deduction of the delay from the gas delivery system) as well as enhanced signal magnitude (about two times of the former for 1% H-2) Based on the hydrogen binding to the traps in the bulk SiO2 a mechanism was proposed to explain the very short response time on the device with the ultra thin SiO2 The gate leakage in the device is also discussed The presented sensor demonstrates a promising step in designing low cost H-2 detectors with very fast responses (C) 2010 Professor T Nejat Veziroglu Published by Elsevier Ltd All rights reserved C1 [Lu, Chi] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Lu, Chi; Chen, Zhi] Univ Kentucky, Dept Elect & Comp Engn, Lexington, KY 40506 USA. [Lu, Chi; Chen, Zhi] Univ Kentucky, Ctr Nanoscale Sci & Engn, Lexington, KY 40506 USA. RP Lu, C (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. FU Department of Energy [DE FG26 04NT42171]; National Science Foundation [ECS 0609064] FX This research work was supported by the Department of Energy (DE FG26 04NT42171) and National Science Foundation (ECS 0609064) We thank Dr Shibin Li and Ms Jing Guo for technical assistance NR 31 TC 9 Z9 9 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0360-3199 J9 INT J HYDROGEN ENERG JI Int. J. Hydrog. Energy PD NOV PY 2010 VL 35 IS 22 SI SI BP 12561 EP 12567 DI 10.1016/j.ijhydene.2010.08.031 PG 7 WC Chemistry, Physical; Electrochemistry; Energy & Fuels SC Chemistry; Electrochemistry; Energy & Fuels GA 681GA UT WOS:000284298200046 ER PT J AU Xu, JJ Yan, X Gao, RT Mao, LS Cotrim, AP Zheng, CY Zhang, CM Baum, BJ Wang, SL AF Xu, Junji Yan, Xing Gao, Runtao Mao, Lisha Cotrim, Ana P. Zheng, Changyu Zhang, Chunmei Baum, Bruce J. Wang, Songlin TI EFFECT OF IRRADIATION ON MICROVASCULAR ENDOTHELIAL CELLS OF PAROTID GLANDS IN THE MINIATURE PIG SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Salivary glands; Radiotherapy; Microvessel density; Endothelial cells; Sphingomyelinase ID RADIATION-INDUCED APOPTOSIS; ANIMAL-MODEL; ORAL-CAVITY; CERAMIDE; SPHINGOMYELINASE; PREVENTION; PROTECTION; DAMAGE; MICE AB Purpose: To evaluate the effect of irradiation on microvascular endothelial cells in miniature pig parotid glands. Methods and Materials: A single 25-Gy dose of irradiation (IR) was delivered to parotid glands of 6 miniature pigs. Three other animals served as non-IR controls. Local blood flow rate in glands was measured pre- and post-IR with an ultrasonic Doppler analyzer. Samples of parotid gland tissue were taken at 4 h, 24 h, 1 week, and 2 weeks after IR for microvascular density (MVD) analysis and sphingomyelinase (SMase) assay. Histopathology and immunohistochemical staining (anti-CD31 and anti-AQP1) were used to assess morphological changes. MVD was determined by calculating the number of CD31- or AQP1-stained cells per field. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay was used to detect apoptotic cells. The activity of acid and neutral Mg2+-dependent SMase (ASMase and NSMase, respectively) was also assayed. Results: Local parotid gland blood flow rate decreased rapidly at 4 h post-IR and remained below control levels throughout the 14-day observation period. Parotid MVD also declined from 4 to 24 hours and remained below control levels thereafter. The activity levels of ASMase and NSMase in parotid glands increased rapidly from 4 to 24 h post-IR and then declined gradually. The frequency of detecting apoptotic nuclei in the glands followed similar kinetics. Conclusions: Single-dose IR led to a significant reduction of MVD and local blood flow rate, indicating marked damage to microvascular endothelial cells in miniature pig parotid glands. The significant and rapid increases of ASMase and NSMase activity levels may be important in this IR-induced damage. (C) 2010 Elsevier Inc. C1 [Xu, Junji; Yan, Xing; Gao, Runtao; Mao, Lisha; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. [Xu, Junji; Yan, Xing; Gao, Runtao; Mao, Lisha; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Mol Lab Gene Therapy, Beijing 100050, Peoples R China. [Wang, Songlin] Capital Med Univ, Dept Biochem & Mol Biol, Sch Basic Med Sci, Beijing 100050, Peoples R China. [Cotrim, Ana P.; Zheng, Changyu; Baum, Bruce J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, DHHS, Bethesda, MD USA. RP Wang, SL (reprint author), Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Tian Tan Xi Li 4, Beijing 100050, Peoples R China. EM bbaum@dir.nidcr.nih.gov; slwang@ccmu.edu.cn FU National Natural Science Foundation of China [30430690]; National Special Foundation for Excellent Ph.D. [200778]; Division of Intramural Research of the National Institute of Dental and Craniofacial Research FX This study was supported by the National Natural Science Foundation of China (Grant 30430690), the National Special Foundation for Excellent Ph.D. paper, no. 200778, and the Division of Intramural Research of the National Institute of Dental and Craniofacial Research. NR 25 TC 21 Z9 22 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2010 VL 78 IS 3 BP 897 EP 903 DI 10.1016/j.ijrobp.2010.05.048 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 661MB UT WOS:000282731300036 PM 20832188 ER PT J AU Edelhauser, HF Rowe-Rendleman, CL Robinson, MR Dawson, DG Chader, GJ Grossniklaus, HE Rittenhouse, KD Wilson, CG Weber, DA Kuppermann, BD Csaky, KG Olsen, TW Kompella, UB Holers, VM Hageman, GS Gilger, BC Campochiaro, PA Whitcup, SM Wong, WT AF Edelhauser, Henry F. Rowe-Rendleman, Cheryl L. Robinson, Michael R. Dawson, Daniel G. Chader, Gerald J. Grossniklaus, Hans E. Rittenhouse, Kay D. Wilson, Clive G. Weber, David A. Kuppermann, Baruch D. Csaky, Karl G. Olsen, Timothy W. Kompella, Uday B. Holers, V. Michael Hageman, Gregory S. Gilger, Brian C. Campochiaro, Peter A. Whitcup, Scott M. Wong, Wai T. TI Ophthalmic Drug Delivery Systems for the Treatment of Retinal Diseases: Basic Research to Clinical Applications SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID PHOSPHATE NANOCOMPOSITE PARTICLES; ALTERNATIVE COMPLEMENT PATHWAY; BLOOD-BRAIN-BARRIER; OPTIC-NERVE HEAD; POSTERIOR SEGMENT; CHOROIDAL NEOVASCULARIZATION; INTRAOCULAR IMPLANTS; PIGMENT-EPITHELIUM; OCULAR BARRIERS; BREAST-CANCER C1 [Edelhauser, Henry F.] Emory Univ, Ctr Eye, Dept Ophthalmol, Atlanta, GA 30322 USA. [Rowe-Rendleman, Cheryl L.] Omar Consulting Grp, Princeton Jct, NJ USA. [Robinson, Michael R.; Whitcup, Scott M.] Allergan Pharmaceut Inc, Irvine, CA 92715 USA. [Chader, Gerald J.] Univ So Calif, Keck Sch Med, Doheny Eye Inst, Los Angeles, CA 90033 USA. [Rittenhouse, Kay D.] Pfizer, La Jolla, CA USA. [Wilson, Clive G.] Univ Strathclyde, Dept Pharmaceut Sci, Glasgow, Lanark, Scotland. [Weber, David A.] Macu Sight, Union City, CA USA. [Kuppermann, Baruch D.] Univ Calif Irvine, Sch Med, Gavin Herbert Eye Inst, Irvine, CA 92717 USA. [Csaky, Karl G.] Duke Univ, Sch Med, Dept Ophthalmol, Durham, NC USA. [Kompella, Uday B.] Univ Colorado Denver, Dept Pharmaceut Sci, Aurora, CO USA. [Holers, V. Michael] Taligen Therapeut, Boston, MA USA. [Hageman, Gregory S.] Univ Iowa, Cell Biol & Funct Genom Lab, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. [Gilger, Brian C.] N Carolina State Univ, Coll Vet Med, Dept Clin Sci, Raleigh, NC USA. [Campochiaro, Peter A.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Wong, Wai T.] NEI, NIH, Bethesda, MD 20892 USA. RP Edelhauser, HF (reprint author), Emory Univ, Ctr Eye, Dept Ophthalmol, 1365B Clifton Rd, Atlanta, GA 30322 USA. EM ophthfe@emory.edu RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU NIH [5P30EY006360-23, SR24 EY017045, R24 EY017404]; Alcon Research Institute; Research to Prevent Blindness FX Supported by NIH Core Grant 5P30EY006360-23 (HFE, HEG, TWO), NIH Grant SR24 EY017045 (HFE, HEG, UBK), and NIH Grant R24 EY017404 (GSH); the Alcon Research Institute (GSH); and an unrestricted grant from Research to Prevent Blindness (TWO). NR 77 TC 77 Z9 80 U1 1 U2 13 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 NOV PY 2010 VL 51 IS 11 BP 5403 EP 5420 DI 10.1167/iovs.10-5392 PG 18 WC Ophthalmology SC Ophthalmology GA 672BQ UT WOS:000283558400002 PM 20980702 ER PT J AU Lederman, RJ Faranesh, AZ AF Lederman, Robert J. Faranesh, Anthony Z. TI Getting Closer for High-Resolution Vascular MRI SO JACC-CARDIOVASCULAR IMAGING LA English DT Editorial Material DE angiography; atherosclerosis; interventional MRI C1 [Lederman, Robert J.; Faranesh, Anthony Z.] NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC1538, Bethesda, MD 20892 USA. OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS NR 6 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 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD NOV PY 2010 VL 3 IS 11 BP 1166 EP 1167 DI 10.1016/j.jcmg.2010.09.007 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 683UL UT WOS:000284501900010 PM 21071005 ER PT J AU Shebl, FM Engels, EA Goedert, JJ Chaturvedi, AK AF Shebl, Fatma M. Engels, Eric A. Goedert, James J. Chaturvedi, Anil K. TI Pulmonary Infections and Risk of Lung Cancer Among Persons With AIDS SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV/AIDS; inflammation; lung cancer; pulmonary infections; recurrent pneumonia; pneumocystis jirovecii pneumonia; tuberculosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; EPIDEMIOLOGIC EVIDENCE; BACTERIAL PNEUMONIA; HIV-INFECTION; TUBERCULOSIS; SMOKING; DISEASE; WOMEN; PEOPLE AB Lung cancer risk is significantly increased among persons with AIDS (PWA), and increased smoking may not explain all of the elevated risk, suggesting a role for additional cofactors. We investigated whether AIDS-defining pulmonary infections (recurrent pneumonia, Pneumocystis jirovecii pneumonia, and pulmonary tuberculosis) affected the risk of subsequent lung cancer over 10 years after AIDS onset among 322,675 PWA, whose records were linked with cancer registries in 11 US regions. We assessed lung cancer hazard ratios (HRs) using Cox regression and indirectly adjusted HRs for confounding by smoking. Individuals with recurrent pneumonia (n = 5317) were at significantly higher lung cancer risk than those without [HR = 1.63, 95% confidence interval (CI) = 1.08 to 2.46, adjusted for age, race, sex, HIV acquisition mode, CD4 count, and AIDS diagnosis year]. This association was especially strong among young PWA (<50 years HR = 1.99 vs. >= 50 years HR = 1.10) and was significantly elevated during 5-10 years after recurrent pneumonia diagnosis (HR = 2.41; 95% CI = 1.07 to 5.47). Although attenuated, HRs for recurrent pneumonia remained nonsignificantly elevated after indirect adjustment for smoking. Lung cancer risk was unrelated to tuberculosis [(n = 13,878) HR = 1.12, 95% CI = 0.82 to 1.53] or Pneumocystis jirovecii pneumonia [(n = 69,771) HR = 0.97, 95% CI = 0.80 to 1.18]. The increased lung cancer risk associated with recurrent pneumonia supports the hypothesis that chronic pulmonary inflammation arising from infections contributes to lung carcinogenesis. C1 [Shebl, Fatma M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. RP Shebl, FM (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, 6120 Execut Blvd, Rockville, MD 20852 USA. FU National Cancer Institute FX Supported by the Intramural Research Program of the National Cancer Institute. NR 24 TC 36 Z9 37 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 NOV 1 PY 2010 VL 55 IS 3 BP 375 EP 379 DI 10.1097/QAI.0b013e3181eef4f7 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 675RE UT WOS:000283847400017 PM 20736841 ER PT J AU Allison, SM Koenig, LJ Marhefka, SL Carter, RJ Abrams, EJ Bulterys, M Tepper, V Palumbo, PE Bachanas, PJ Farley, JJ AF Allison, Susannah M. Koenig, Linda J. Marhefka, Stephanie L. Carter, Rosalind J. Abrams, Elaine J. Bulterys, Marc Tepper, Vicki Palumbo, Paul E. Bachanas, Pamela J. Farley, John J. TI Assessing Medication Adherence of Perinatally HIV-Infected Children Using Caregiver Interviews SO JANAC-JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE LA English DT Article DE adherence assessment; HIV disease; knowledge of prescribed dosing frequency; pediatrics ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS INFECTION; CLINICAL MANAGEMENT; REPORTED ADHERENCE; SELF-REPORT; ADOLESCENTS; PREDICTORS; RECOMMENDATIONS; TRANSMISSION; STRATEGIES AB Medication adherence is critical for children's HIV treatment success, but obtaining accurate assessments is challenging when complex measurement technologies are not feasible. Our goal was to evaluate a multidimensional adherence interview designed to improve on existing adherence measures. Data from caregivers (N = 126) of perinatally infected children were analyzed to determine the ability of the revised interview guide to detect potential treatment nonadherence. Questions related to viral load (VL) on a bivariate level included proportion of doses taken in the previous 3 days and 6 months, caregivers' knowledge of prescribed dosing frequencies, and caregivers' reports of problems associated with medication administration. VL was not associated with 3-day recall of missed doses. In multivariate analyses, only caregivers' knowledge of prescribed dosing frequencies was uniquely associated with VL. Our modified interview appears to successfully identify family struggles with adherence and to have the capacity to help clinicians address medication adherence challenges. (Journal of the Association of Nurses in AIDS Care, 21, 478-488) Copyright (C) 2010 Association of Nurses in AIDS Care C1 [Koenig, Linda J.; Bulterys, Marc] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, NCHHSTP, Atlanta, GA USA. [Abrams, Elaine J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Marhefka, Stephanie L.] New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. [Carter, Rosalind J.] Med & Hlth Res Assoc NYC Inc, New York, NY USA. [Palumbo, Paul E.] Dartmouth Hitchcock Med Ctr, Int Pediat HIV Program, Hanover, NH USA. [Bachanas, Pamela J.] Emory Univ, Sch Med, Atlanta, GA USA. [Tepper, Vicki] Univ Maryland, Sch Med, Pediat AIDS Care & Evaluat Clin, Baltimore, MD 21201 USA. RP Allison, SM (reprint author), NIMH, Atlanta, GA USA. OI Marhefka, Stephanie/0000-0001-7708-1521 FU U.S. Centers for Disease Control and Prevention through MHRA of New York City [U64/CCU207228]; U.S. Centers for Disease Control and Prevention through UMDNJ-New Jersey Medical School [U64/CCU202219]; U.S. Centers for Disease Control and Prevention through University of Maryland School of Medicine [U64/CCU306825]; U.S. Centers for Disease Control and Prevention through Emory University School of Medicine [U64/CCU404456] FX This study was funded as a part of PACTS and PACTS-HOPE, which were funded by the U.S. Centers for Disease Control and Prevention through cooperative agreements U64/CCU207228 (MHRA of New York City), U64/CCU202219 (UMDNJ-New Jersey Medical School), U64/CCU306825 (University of Maryland School of Medicine), and U64/CCU404456 (Emory University School of Medicine). NR 24 TC 6 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1055-3290 J9 J ASSOC NURSE AIDS C JI J. Assoc. Nurses Aids Care PD NOV-DEC PY 2010 VL 21 IS 6 BP 478 EP 488 DI 10.1016/j.jana.2010.02.006 PG 11 WC Nursing SC Nursing GA 684SX UT WOS:000284570700006 PM 20452242 ER PT J AU Vogel, C Chan, A Gril, B Kim, SB Kurebayashi, J Liu, L Lu, YS Moon, H AF Vogel, Charles Chan, Arlene Gril, Brunilde Kim, Sung-Bae Kurebayashi, Junichi Liu, Li Lu, Yen-Shen Moon, Hanlim TI Management of ErbB2-positive Breast Cancer: Insights from Preclinical and Clinical Studies with Lapatinib SO JAPANESE JOURNAL OF CLINICAL ONCOLOGY LA English DT Review DE breast cancer; ErbB1; ErbB2; lapatinib; tyrosine kinase inhibitor; review ID TYROSINE KINASE INHIBITOR; PHASE-II TRIAL; BRAIN METASTASES; TRASTUZUMAB RESISTANCE; PLUS CAPECITABINE; 1ST-LINE TREATMENT; CNS METASTASES; GROWTH; RECEPTOR; THERAPY AB The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer. C1 [Vogel, Charles] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr Deerfield Beach, Deerfield Beach, FL 33442 USA. [Chan, Arlene] Mt Hosp, Perth, WA, Australia. [Gril, Brunilde] NCI, Womens Canc Sect, Mol Pharmacol Lab, NIH, Rockville, MD USA. [Kim, Sung-Bae] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Kurebayashi, Junichi] Kawasaki Med Univ, Dept Breast & Thyroid Surg, Okayama, Japan. [Liu, Li] GlaxoSmithKline Oncol Res & Dev, Collegeville, PA USA. [Lu, Yen-Shen] Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan. [Lu, Yen-Shen] Natl Taiwan Univ, Coll Med, Dept Internal Med, Taipei, Taiwan. [Moon, Hanlim] GlaxoSmithKline Oncol Res & Dev, Asia Pacific, Seoul, South Korea. RP Vogel, C (reprint author), Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr Deerfield Beach, 1192 E Newport Ctr Dr, Deerfield Beach, FL 33442 USA. EM drcvogel@aol.com FU GlaxoSmithKline Asia Pacific; US Department of Defense; GlaxoSmithKline; Genentech FX To enhance reader access to this peer-reviewed article, the authors opted for an open access publication. The open access and color printing publication charges for this article were funded by GlaxoSmithKline Asia Pacific.; Arlene Chan has received payments as an advisory board member from Roche and for speaking from Roche and GlaxoSmithKline; Junichi Kurebayashi has received payments for speaking from GlaxoSmithKline; Brunilde Gril has received grant support from the US Department of Defense Breast Cancer Research Program; Li Liu is an employee of and has shares in GlaxoSmithKline; Yen-Shen Lu has received grant support and payments for speaking from GlaxoSmithKline; Hanlim Moon is an employee of and has shares in GlaxoSmithKline; Charles Vogel has received grant support and payments for consulting and speaking from Genentech and grant support and payments for consulting, speaking and participation as a clinical trial investigator and advisory board member from GlaxoSmithKline. NR 76 TC 8 Z9 8 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0368-2811 EI 1465-3621 J9 JPN J CLIN ONCOL JI Jpn. J. Clin. Oncol. PD NOV PY 2010 VL 40 IS 11 BP 999 EP 1013 DI 10.1093/jjco/hyq084 PG 15 WC Oncology SC Oncology GA 673VN UT WOS:000283692300001 PM 20542996 ER PT J AU Sanislow, CA Pine, DS Quinn, KJ Kozak, MJ Garvey, MA Heinssen, RK Wang, PSE Cuthbert, BN AF Sanislow, Charles A. Pine, Daniel S. Quinn, Kevin J. Kozak, Michael J. Garvey, Marjorie A. Heinssen, Robert K. Wang, Philip Sung-En Cuthbert, Bruce N. TI Developing Constructs for Psychopathology Research: Research Domain Criteria SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE RDoC; psychopathology research constructs; research diagnoses ID MEDIAL PREFRONTAL CORTEX; FEAR; COGNITION; OXYTOCIN; AUTISM; SCHIZOPHRENIA; VASOPRESSIN; MECHANISMS; EMOTION; EXPRESSION AB There exists a divide between findings from integrative neuroscience and clinical research focused on mechanisms of psychopathology. Specifically, a clear correspondence does not emerge between clusters of complex clinical symptoms and dysregulated neurobiological systems, with many apparent redundancies. For instance, many mental disorders involve multiple disruptions in putative mechanistic factors (e.g., excessive fear, deficient impulse control), and different disrupted mechanisms appear to play major roles in many disorders. The Research Domain Criteria (RDoC) framework is a heuristic to facilitate the incorporation of behavioral neuroscience in the study of psychopathology. Such integration might be achieved by shifting the central research focus of the field away from clinical description to more squarely examine aberrant mechanisms. RDoC first aims to identify reliable and valid psychological and biological mechanisms and their disruptions, with an eventual goal of understanding how anomalies in these mechanisms drive psychiatric symptoms. This approach will require new methods to ascertain samples, relying on hypothesized psychopathological mechanisms to define experimental groups instead of traditional diagnostic categories. RDoC, by design, uncouples research efforts from clinically familiar categories to focus directly on fundamental mechanisms of psychopathology. RDoC proposes a matrix of domains and levels of analyses and invites the field to test and refine the framework. If RDoC is successful, the domains will ultimately relate to familiar psychopathologies in ways that promote new knowledge regarding etiology and more efficient development of new preventive and treatment interventions. C1 [Sanislow, Charles A.] Wesleyan Univ, Dept Psychol, Middletown, CT 06459 USA. [Pine, Daniel S.] NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Quinn, Kevin J.] NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. [Kozak, Michael J.; Cuthbert, Bruce N.] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. [Garvey, Marjorie A.] NIMH, Div Dev Translat Res, Bethesda, MD 20892 USA. [Heinssen, Robert K.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Sanislow, CA (reprint author), Wesleyan Univ, Dept Psychol, Judd Hall,207 High St, Middletown, CT 06459 USA. EM csanislow@wesleyan.edu NR 71 TC 269 Z9 271 U1 6 U2 60 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD NOV PY 2010 VL 119 IS 4 BP 631 EP 639 DI 10.1037/a0020909 PG 9 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA 680PP UT WOS:000284247200001 PM 20939653 ER PT J AU Ulrich, CM Taylor, C Soeken, K O'Donnell, P Farrar, A Danis, M Grady, C AF Ulrich, Connie M. Taylor, Carol Soeken, Karen O'Donnell, Patricia Farrar, Adrienne Danis, Marion Grady, Christine TI Everyday ethics: ethical issues and stress in nursing practice SO JOURNAL OF ADVANCED NURSING LA English DT Article DE autonomy; ethical issues; informed consent; nursing practice; patient rights; stress; survey ID INTENSIVE-CARE-UNIT; SOCIAL-WORKERS; MORAL DISTRESS; MANAGED CARE; NURSES; LIFE; END; PRACTITIONERS; PHYSICIANS; CONFLICT AB Aim. This paper is a report of a study of the type, frequency, and level of stress of ethical issues encountered by nurses in their everyday practice. Background. Everyday ethical issues in nursing practice attract little attention but can create stress for nurses. Nurses often feel uncomfortable in addressing the ethical issues they encounter in patient care. Methods. A self-administered survey was sent in 2004 to 1000 nurses in four states in four different census regions of the United States of America. The adjusted response rate was 52%. Data were analysed using descriptive statistics, cross-tabulations and Pearson correlations. Results. A total of 422 questionnaires were used in the analysis. The five most frequently occurring and most stressful ethical and patient care issues were protecting patients' rights; autonomy and informed consent to treatment; staffing patterns; advanced care planning; and surrogate decision-making. Other common occurrences were unethical practices of healthcare professionals; breaches of patient confidentiality or right to privacy; and end-of-life decision-making. Younger nurses and those with fewer years of experience encountered ethical issues more frequently and reported higher levels of stress. Nurses from different regions also experienced specific types of ethical problems more commonly. Conclusion. Nurses face daily ethical challenges in the provision of quality care. To retain nurses, targeted ethics-related interventions that address caring for an increasingly complex patient population are needed. C1 [Ulrich, Connie M.] Univ Penn, Dept Med Eth, Nursing Ctr Bioeth, Philadelphia, PA 19104 USA. [Ulrich, Connie M.] Univ Penn, Sch Nursing, New Courtland Ctr Transit & Hlth, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Taylor, Carol] Georgetown Univ, Ctr Bioeth, Washington, DC USA. [Soeken, Karen] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. [O'Donnell, Patricia] Inova Hlth Syst, Ctr Eth, Fairfax, VA USA. [Danis, Marion] NIH, Dept Social Work, Ctr Clin, Sect Eth & Hlth Policy, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Sect Human Subjects Res & Acting Chief, Bethesda, MD 20892 USA. RP Ulrich, CM (reprint author), Univ Penn, Dept Med Eth, Nursing Ctr Bioeth, Philadelphia, PA 19104 USA. EM culrich@nursing.upenn.edu FU Department of Bioethics and Department of Social Work, National Institutes of Health FX This research was supported by the Department of Bioethics and Department of Social Work, National Institutes of Health. The opinions expressed in this manuscript are solely those of the authors. We would also like to acknowledge the comments of the anonymous reviewers who provided critical feedback on the manuscript. NR 34 TC 32 Z9 33 U1 5 U2 27 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0309-2402 J9 J ADV NURS JI J. Adv. Nurs. PD NOV PY 2010 VL 66 IS 11 BP 2510 EP 2519 DI 10.1111/j.1365-2648.2010.05425.x PG 10 WC Nursing SC Nursing GA 660ZU UT WOS:000282691600014 PM 20735502 ER PT J AU Bousquet, J Mantzouranis, E Cruz, AA Ait-Khaled, N Baena-Cagnani, CE Bleecker, ER Brightling, CE Burney, P Bush, A Busse, WW Casale, TB Chan-Yeung, M Chen, RC Chowdhury, B Chung, KF Dahl, R Drazen, JM Fabbri, LM Holgate, ST Kauffmann, F Haahtela, T Khaltaev, N Kiley, JP Masjedi, MR Mohammad, Y O'Byrne, P Partridge, MR Rabe, KF Togias, A van Weel, C Wenzel, S Zhong, NS Zuberbier, T AF Bousquet, Jean Mantzouranis, Eva Cruz, Alvaro A. Ait-Khaled, Nadia Baena-Cagnani, Carlos E. Bleecker, Eugene R. Brightling, Chris E. Burney, Peter Bush, Andrew Busse, William W. Casale, Thomas B. Chan-Yeung, Moira Chen, Rongchang Chowdhury, Badrul Chung, Kian Fan Dahl, Ronald Drazen, Jeffrey M. Fabbri, Leonardo M. Holgate, Stephen T. Kauffmann, Francine Haahtela, Tari Khaltaev, Nikolai Kiley, James P. Masjedi, Mohammad R. Mohammad, Yousser O'Byrne, Paul Partridge, Martyn R. Rabe, Klaus F. Togias, Alkis van Weel, Christiaan Wenzel, Sally Zhong, Nanshan Zuberbier, Torsten TI Uniform definition of asthma severity, control, and exacerbations: Document presented for the World Health Organization Consultation on Severe Asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; severity; control; risk; definition; GARD ID TO-TREAT ASTHMA; LUNG-FUNCTION; INHALED CORTICOSTEROIDS; PRESCHOOL-CHILDREN; CHILDHOOD ASTHMA; RESEARCH-PROGRAM; LOW-INCOME; FOLLOW-UP; DEVELOPING-COUNTRIES; CLUSTER-ANALYSIS AB Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)." Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment. (J Allergy Clin Immunol 2010; 126: 926-38.) C1 [Bousquet, Jean] Hop Arnaud Villeneuve, Serv Malad Resp, Univ Hosp, F-34295 Montpellier 5, France. [Bousquet, Jean; Kauffmann, Francine] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France. [Bousquet, Jean; Kauffmann, Francine] UMRS 1018, Villejuif, France. [Mantzouranis, Eva] WHO, Geneva, Switzerland. [Cruz, Alvaro A.] Univ Fed Bahia, ProAR FMB, Salvador, BA, Brazil. [Ait-Khaled, Nadia] Union, Paris, France. [Baena-Cagnani, Carlos E.] Catholic Univ, Fac Med, Cordoba, Argentina. [Baena-Cagnani, Carlos E.] Univ Genoa, Sch Specializat, I-16126 Genoa, Italy. [Bleecker, Eugene R.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Brightling, Chris E.] Inst Lung Hlth, Leicester, Leics, England. [Burney, Peter; Bush, Andrew; Chung, Kian Fan] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Bush, Andrew] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, London SW7 2AZ, England. [Chung, Kian Fan] Royal Brompton Hosp, Biomed Res Unit, London, England. [Partridge, Martyn R.] Univ London Imperial Coll Sci Technol & Med, Charing Cross Hosp, NHLI Div, London SW7 2AZ, England. [Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. [Casale, Thomas B.] Creighton Univ, Omaha, NE 68178 USA. [Chan-Yeung, Moira] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Chen, Rongchang; Zhong, Nanshan] Guangzhou Med Coll, Guangzhou Inst Resp Dis, Guangzhou, Guangdong, Peoples R China. [Chowdhury, Badrul] US FDA, Silver Spring, MD USA. [Dahl, Ronald] Aarhus Univ Hosp, Aarhus, Denmark. [Drazen, Jeffrey M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fabbri, Leonardo M.] Univ Modena & Reggio Emilia, Modena, Italy. [Holgate, Stephen T.] Southampton Gen Hosp, Southampton, Hants, England. [Haahtela, Tari] Helsinki Univ Hosp, Skin & Allergy Hosp, Helsinki, Finland. [Khaltaev, Nikolai] Global Alliance Chron Resp Dis, Geneva, Switzerland. [Kiley, James P.] NHLBI, NIH, DHHS, Bethesda, MD 20892 USA. [Togias, Alkis] NIAID, Bethesda, MD 20892 USA. [Masjedi, Mohammad R.] NRITLD, CRDRC, Tehran, Iran. [Mohammad, Yousser] Tishreen Univ, Sch Med, Latakia, Syria. [O'Byrne, Paul] McMaster Univ, Dept Med, Hamilton, ON L8S 4L8, Canada. [Rabe, Klaus F.] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [van Weel, Christiaan] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Wenzel, Sally] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Zuberbier, Torsten] Charite Univ Med Berlin, Dept Dermatol & Allergy, Allergy Ctr Charite, Berlin, Germany. RP Bousquet, J (reprint author), Hop Arnaud Villeneuve, Serv Malad Resp, Univ Hosp, 371 Ave Doyen Gaston Giraud, F-34295 Montpellier 5, France. EM jean.bousquet@inserm.fr RI Dahl, Ronahl/F-8170-2013; Casale, Thomas/K-4334-2013; van Weel, Chris/D-4375-2009; Fabbri, Leonardo/I-4055-2012; Cruz, Alvaro/I-1676-2012; OI Casale, Thomas/0000-0002-3149-7377; van Weel, Chris/0000-0003-3653-4701; Fabbri, Leonardo/0000-0001-8894-1689; Cruz, Alvaro/0000-0002-7403-3871; O'Byrne, Paul/0000-0003-0979-281X; Masjedi, Mohammadreza/0000-0003-4964-3851; Chung, Kian Fan/0000-0001-7101-1426 FU EU [FOOD-CT-2004-506378]; World Health Organization Collaborating Center on Asthma and Rhinitis, Montpellier; Chiesi; Mantecorp (Brazil); CNPq (Brazil); National Research Council; Brazilian Ministry of Health; FAPESB State of Brazil Agency for Research; Wellcome Trust (UK); Novartis; GlaxoSmithKline; NIH/NHLBI; MedImmune; AstraZeneca; Department of Health (UK); NIH-NIAID; NIH-NHLBI; Ception; MRC UK; Asthma UK; Wellcome Trust; Abbott; Boehringer Ingelheim; Merck Sharp Dohme,; Nycomed; Roche; Pfizer; Menarini; Schering-Plough; Merck Sharp Dohme; UCB; Italian Ministry of Health; Italian Ministry for University and Research; Merck; Wyeth; Schering; Alexion; Forest; AZ; BI; Pearl; MSD; AS; Dutch Asthma Foundation (NAF); Netherlands Medical Research Council (Zon/Mw); Aerovance; Amgen FX In collaboration with the Global Allergy and Asthma European Network (GA2LEN), supported by the Sixth EU Framework program for research (contract no. FOOD-CT-2004-506378) and the World Health Organization Collaborating Center on Asthma and Rhinitis, Montpellier.; Disclosure of potential conflict of interest: J. Bousquet has received honorarium for scientific and advisory boards, lectures, and press conferences from Stallergenes, Actelion, Almirall, AstraZeneca, Chiesi, Ask, Merck, MSD, Novartis, OM Pharma, Sanofi-Aventis, Schering-Plough, Teva, and Uriach. A. A. Cruz has given talks for Novartis and GlaxoSmithKline; has received research support from Chiesi, Mantecorp (Brazil), CNPq (Brazil), National Research Council, Brazilian Ministry of Health, FAPESB State of Brazil Agency for Research, Wellcome Trust (UK), Novartis, and GlaxoSmithKline; is a member of the Planning Group for the Global Alliance against Chronic Respiratory Diseases; and is a member of the Executive Committee for the Global Initiative for Asthma and Allergic Rhinitis and its Impact on Asthma. E. R. Bleecker is a consultant for Aerovance, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer and has received research support from the NIH/NHLBI. C. E. Brightling is a consultant for MedImmune, AstraZeneca, and Roche and has received research support from MedImmune, AstraZeneca, and GlaxoSmithKline. P. Burney has received research support from the Department of Health (UK). W. W. Busse is on the Advisory Board for Altair, Amgen, Centocor, GlaxoSmithKline, Merck, Pfizer, Wyeth, and Johnson & Johnson; is a consultant for AstraZeneca, Boehringer Ingelheim, Novartis, TEVA, and GlaxoSmithKline; is a speaker for Merck; and has received research support from NIH-NIAID, NIH-NHLBI, Novartis, AstraZeneca, GlaxoSmithKline, MedImmune, and Ception. T. B. Casale is executive vice president of the AAAAI and is on the board of directors for WAO. R. Chen is a consultant on asthma and COPD for AstraZeneca and GlaxoSmithKline and has served as an expert witness on the topic of management of asthma. K. F. Chung is a consultant for Gilead; is on the advisory board for Merck and GlaxoSmithKline; and has received research support from MRC UK, Asthma UK, and Wellcome Trust. R. Dahl is a speaker for MSD, AstraZeneca, ALK, and GlaxoSmithKline; is a speaker and is on the advisory board for TEVA, Boehringer Ingelheim, UCB, Airsonett, Novartis, and Pfizer; is chairman for the Danish Respiratory Society; and is president of Interasma. L. M. Fabbri is a consultant for Nycomed, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Sigma Tau, AstraZeneca, Merck Sharp & Dohme, Novartis, Roche, and Pfizer; has received paid lecture fees from Abbott, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Nycomed, Roche, and Pfizer; and has received research support from Nycomed, Abbott, AstraZeneca, Boehringer Ingelheim, Menarini, Novartis, Schering-Plough, Chiesi, GlaxoSmithKline, Merck Sharp & Dohme, UCB, Pfizer, the Italian Ministry of Health, and the Italian Ministry for University and Research. S. T. Holgate is a consultant for MSD, Novartis, Synergen, Altair, Amgen, and Almiral and owns shares in Synergen. T. Haahtela has received honoraria from Astellas, AstraZeneca, Leiras, MSD, and Orion Pharma. P. O'Byrne is on the advisory board and has received speakers' honoraria from AstraZeneca and GlaxoSmithKline; is on the advisory board for Topigen, Wyeth, and Schering; and has received research support from AstraZeneca, GlaxoSmithKline, Merck, Wyeth, Schering, and Alexion. K. F. Rabe has received remuneration from Nycomed, Forest, AZ, BI, Chiesi, Pearl, MSD, and GlaxoSmithKline and has received research support from Chiesi, AS, BI, and Novartis. C.; van Weel has received research support from Boehringer Ingelheim, GlaxoSmithline, Novartis, the Dutch Asthma Foundation (NAF), and the Netherlands Medical Research Council (Zon/Mw). S. Wenzel is a consultant for Altair, Merck, GlaxoSmithKline, Amgen, and Pearl Therapeutics; is on the scientific advisory board for Amira; and has received research support from MedImmune, GlaxoSmithKline, Aerovance, and Amgen. T. Zuberbier is a consultant for Schering-Plough, Novartis, Leti, Stallergenes, Bayer Schering, Ansell, Kryolan, UCB, MSD, DST, Sanofi-Aventis, and Procter & Gamble; is on the editorial board of the Journal of Allergy, the scientific advisory board of the German Society for Allergy and Clinical Immunology, and the Expert Commission "Novel Food" of the German Federal Ministry of Consumer Protection; is chairman of the European Academy of Allergology and Clinical Immunology, Dermatology Section; is head of the European Center for Allergy Research Foundation; is a committee member of the WHO Initiative Allergic Rhinitis and its Impact on Asthma; is a member of the World Allergy Organization Communications Council; and is secretary general of the Global Allergy and Asthma European Network. E. Mantzouranis, N. Ait-Khaled, C. E. Baena-Cagnani, A. Bush, M. Chan-Yeung, B. Chowdhury, J. M. Drazen, F. Kauffmann, N. Khaltaev, J. P. Kiley, M. R. Masjedi, Y. Mohammad, M. R. Partridge, A. Togias, and N. Zhong have declared that they have no conflict of interest. NR 112 TC 242 Z9 251 U1 3 U2 36 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 NOV PY 2010 VL 126 IS 5 BP 926 EP 938 DI 10.1016/j.jaci.2010.07.019 PG 13 WC Allergy; Immunology SC Allergy; Immunology GA 674HB UT WOS:000283727100005 PM 20926125 ER PT J AU de Falco, S Esposito, G Venuti, P Bornstein, MH AF de Falco, Simona Esposito, Gianluca Venuti, Paola Bornstein, Marc H. TI Mothers and Fathers at Play with their Children with Down Syndrome: Influence on Child Exploratory and Symbolic Activity SO JOURNAL OF APPLIED RESEARCH IN INTELLECTUAL DISABILITIES LA English DT Article DE Down Syndrome; father; intellectual disabilities; parent-child interaction; play ID YOUNG-CHILDREN; PRETEND PLAY; INVOLVEMENT; PATTERNS; LANGUAGE; PARENTS; STRESS; COMMUNICATION; DISABILITIES; PERCEPTIONS AB Background Through play children exercise their emerging mental abilities, and for their part, when in collaborative play, caregivers often adjust their behaviours to assist their children's progress. In this study, we focused on comparisons between play of Down Syndrome (DS) children with their two parents as well as on comparisons between the two parents' play behaviours. Method Altogether 40 parent-child dyads participated: 20 children with DS (M age = 36.14 months) with their mothers and separately with their fathers. We coded participants' play behaviours during child solitary and mother-child and father-child collaborative sessions. Results Although children increased exploratory play from solitary to collaborative sessions with both parents, symbolic play increased only during joint play with fathers. Fathers displayed less symbolic and more exploratory activity compared to mothers. Mothers and fathers alike were attuned to their children, although fathers showed a higher degree of attunement. Conclusions This study shows that maternal and paternal contributions to DS child play skills are positive but different. During collaborative play children received specific and nonoverlapping scaffolding from their two parents, and fathers' contributions were unique. C1 [de Falco, Simona; Esposito, Gianluca; Venuti, Paola] Univ Trent, Dept Cognit Sci & Educ, Trento, Italy. [Bornstein, Marc H.] NICHHD, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. RP de Falco, S (reprint author), Dept Cognit Sci & Educ, Via Matteo Del Ben 5, I-38068 Rovereto, TN, Italy. EM defalco@form.unitn.it RI Esposito, Gianluca/B-1374-2012 OI Esposito, Gianluca/0000-0002-9442-0254 FU Intramural NIH HHS [ZIA HD001119-25] NR 62 TC 5 Z9 5 U1 1 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1360-2322 J9 J APPL RES INTELLECT JI J. Appl. Res. Intellect. Disabil. PD NOV PY 2010 VL 23 IS 6 BP 597 EP 605 DI 10.1111/j.1468-3148.2010.00558.x PG 9 WC Psychology, Educational; Rehabilitation SC Psychology; Rehabilitation GA 666ZQ UT WOS:000283162400003 PM 23275758 ER PT J AU Mattison, DR AF Mattison, Donald R. TI Untitled SO JOURNAL OF ATTENTION DISORDERS LA English DT Letter C1 [Mattison, Donald R.] NICHD, NIH, Bethesda, MD 20892 USA. EM mattisod@mail.nih.gov RI Mattison, Donald/C-2015-2009; OI Mattison, Donald/0000-0001-5623-0874 NR 23 TC 0 Z9 0 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 J9 J ATTEN DISORD JI J. Atten. Disord. PD NOV PY 2010 VL 14 IS 3 BP 203 EP 204 PG 2 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA 671NK UT WOS:000283512600001 PM 20978275 ER PT J AU Miyagawa, F Gutermuth, J Zhang, H Katz, SI AF Miyagawa, Fumi Gutermuth, Jan Zhang, Hong Katz, Stephen I. TI The use of mouse models to better understand mechanisms of autoimmunity and tolerance SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Autoimmunity; CD8 T cells; GvHD; Immunological tolerance; Transgenic mouse model ID T-CELL TOLERANCE; MAJOR HISTOCOMPATIBILITY COMPLEX; PERIPHERALLY EXPRESSED ANTIGENS; SELF-ANTIGENS; TRANSGENIC MICE; IN-VIVO; CROSS-PRESENTATION; DENDRITIC CELLS; STEADY-STATE; EFFECTOR FUNCTION AB A major emphasis of our studies has been on developing a better understanding of how and why the skin serves as a target for immune reactions as well as how the skin evades becoming a target for destruction. For these studies we developed transgenic mice that express a membrane-tethered form of a model self antigen, chicken ovalbumin (mOVA), under the control of a keratin 14 (K14) promoter. K14-mOVA transgenic mice that express OVA mRNA and protein in the epithelia have been assessed for their immune responsiveness to OVA and are being used as targets for T cells obtained from OT-1 transgenic mice whose CD8+ T cells carry a V alpha 2/V beta 5-transgenic T cell receptor with specificity for the OVA(257-264)-peptides (OVAp) in association with class I MHC antigens. Some of the K14-mOVA transgenic mice develop a graft-versus-host-like disease (GvHD) when the OT-1 cells are injected while others appear to be tolerant to the OT-1 cells. We found that gamma c cytokines, especially IL-15, determine whether autoimmunity or tolerance ensues in K14-mOVA Tg mice. We also developed transgenic mice that express soluble OVA under the control of a K14 promoter (K14-sOVA) that die within 5-8 days after adoptive transfer of OT-1 cells and identified these mice as a model for more acute GvHD-like reactions. Spontaneous autoimmunity occurs when these K14-sOVA mice are crossed with the OT-I mice. In contrast, we found that preventive or therapeutic OVAp injections induced a dose-dependent increase in survival. In this review the characterization of 5 strains of K14-OVATg mice and underlying mechanisms involved in autoimmune reactions in these Tg mice are discussed. We also describe a strategy to break tolerance and describe how the autoimmunity can be obviated using OVAp. Finally, a historical overview of using transgenic mice to assess the mechanisms of tolerance is also provided. Published by Elsevier Ltd. C1 [Miyagawa, Fumi; Gutermuth, Jan; Zhang, Hong; Katz, Stephen I.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Katz, SI (reprint author), NCI, Dermatol Branch, NIH, Bldg 31,Rm4C32, Bethesda, MD 20892 USA. EM katzs@od.niams.nih.gov NR 60 TC 33 Z9 34 U1 2 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD NOV PY 2010 VL 35 IS 3 SI SI BP 192 EP 198 DI 10.1016/j.jaut.2010.06.007 PG 7 WC Immunology SC Immunology GA 676HV UT WOS:000283902500005 PM 20655706 ER PT J AU McCullen, CA Benhammou, JN Majdalani, N Gottesman, S AF McCullen, Colleen A. Benhammou, Jihane N. Majdalani, Nadim Gottesman, Susan TI Mechanism of Positive Regulation by DsrA and RprA Small Noncoding RNAs: Pairing Increases Translation and Protects rpoS mRNA from Degradation SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI HFQ; BACTERIAL SMALL RNA; STAPHYLOCOCCUS-AUREUS; ENDORIBONUCLEASE-III; SIGMA(S) SUBUNIT; ANTISENSE RNA; GROWTH-PHASE; EXPRESSION; POLYMERASE; STABILITY AB Small noncoding RNAs (sRNAs) regulate gene expression in Escherichia coli by base pairing with mRNAs and modulating translation and mRNA stability. The sRNAs DsrA and RprA stimulate the translation of the stress response transcription factor RpoS by base pairing with the 5' untranslated region of the rpoS mRNA. In the present study, we found that the rpoS mRNA was unstable in the absence of DsrA and RprA and that expression of these sRNAs increased both the accumulation and the half-life of the rpoS mRNA. Mutations in dsrA, rprA, or rpoS that disrupt the predicted pairing sequences and reduce translation of RpoS also destabilize the rpoS mRNA. We found that the rpoS mRNA accumulates in an RNase E mutant strain in the absence of sRNA expression and, therefore, is degraded by an RNase E-mediated mechanism. DsrA expression is required, however, for maximal translation even when rpoS mRNA is abundant. This suggests that DsrA protects rpoS mRNA from degradation by RNase E and that DsrA has a further activity in stimulating RpoS protein synthesis. rpoS mRNA is subject to degradation by an additional pathway, mediated by RNase III, which, in contrast to the RNase E-mediated pathway, occurs in the presence and absence of DsrA or RprA. rpoS mRNA and RpoS protein levels are increased in an RNase III mutant strain with or without the sRNAs, suggesting that the role of RNase III in this context is to reduce the translation of RpoS even when the sRNAs are acting to stimulate translation. C1 [Gottesman, Susan] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 5132, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; National Research Service (National Institutes of Health) [F32 GM075392] FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by a National Research Service Award to C. A. M. (award F32 GM075392, National Institutes of Health). NR 64 TC 55 Z9 57 U1 1 U2 11 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 NOV PY 2010 VL 192 IS 21 BP 5559 EP 5571 DI 10.1128/JB.00464-10 PG 13 WC Microbiology SC Microbiology GA 662LD UT WOS:000282807900001 PM 20802038 ER PT J AU James, TD Cashel, M Hinton, DM AF James, Tamara D. Cashel, Michael Hinton, Deborah M. TI A Mutation within the beta Subunit of Escherichia coli RNA Polymerase Impairs Transcription from Bacteriophage T4 Middle Promoters SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ACTIVATOR MOTA INTERACTS; SIGMA(70) SUBUNIT; ASIA PROTEIN; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; DNA-REPLICATION; FLAP DOMAIN; T4 ASIA; GENE AB During infection of Escherichia coli, bacteriophage T4 usurps the host transcriptional machinery, redirecting it to the expression of early, middle, and late phage genes. Middle genes, whose expression begins about 1 min postinfection, are transcribed both from the extension of early RNA into middle genes and by the activation of T4 middle promoters. Middle-promoter activation requires the T4 transcriptional activator MotA and coactivator AsiA, which are known to interact with sigma(70), the specificity subunit of RNA polymerase. T4 motA amber [motA(Am)] or asiA(Am) phage grows poorly in wild-type E. coli. However, previous work has found that T4 motA(Am) does not grow in the E. coli mutant strain TabG. We show here that the RNA polymerase in TabG contains two mutations within its beta-subunit gene: rpoB(E835K) and rpoB(G1249D). We find that the G1249D mutation is responsible for restricting the growth of either T4 motA(Am) or asiA(Am) and for impairing transcription from MotA/AsiA-activated middle promoters in vivo. With one exception, transcription from tested T4 early promoters is either unaffected or, in some cases, even increases, and there is no significant growth phenotype for the rpoB(E835K G1249D) strain in the absence of T4 infection. In reported structures of thermophilic RNA polymerase, the G1249 residue is located immediately adjacent to a hydrophobic pocket, called the switch 3 loop. This loop is thought to aid in the separation of the RNA from the DNA-RNA hybrid as RNA enters the RNA exit channel. Our results suggest that the presence of MotA and AsiA may impair the function of this loop or that this portion of the beta subunit may influence interactions among MotA, AsiA, and RNA polymerase. C1 [James, Tamara D.; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. [Cashel, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Microbial Regulat, NIH, Bethesda, MD 20892 USA. RP Hinton, DM (reprint author), NIDDK, Gene Express & Regulat Sect, Lab Mol & Cellular Biol, NIH, Bldg 8,Room 2A-13, Bethesda, MD 20892 USA. EM dhinton@helix.nih.gov FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases; NIH, Eunice Kennedy Schriver National Institute of Child Health and Human Development; Ford Foundation FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (T.D.J. and D. M. H.) and by the NIH, Eunice Kennedy Schriver National Institute of Child Health and Human Development (M. C.). T.D.J. was also supported by a Ford Foundation predoctoral fellowship. NR 57 TC 4 Z9 4 U1 0 U2 3 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 NOV PY 2010 VL 192 IS 21 BP 5580 EP 5587 DI 10.1128/JB.00338-10 PG 8 WC Microbiology SC Microbiology GA 662LD UT WOS:000282807900003 PM 20729353 ER PT J AU Gandjbakhche, A Tromberg, B Kainerstorfer, JM AF Gandjbakhche, Amir Tromberg, Bruce Kainerstorfer, Jana Maria TI Optical Diagnostic and Biophotonic Methods from Bench to Bedside SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Editorial Material C1 [Gandjbakhche, Amir; Kainerstorfer, Jana Maria] NIH, Bethesda, MD 20892 USA. [Tromberg, Bruce] Univ Calif Irvine, Irvine, CA USA. RP Gandjbakhche, A (reprint author), NIH, Bethesda, MD 20892 USA. FU NCRR NIH HHS [P41 RR001192-30, P41 RR001192-31, P41 RR001192, P41 RR001192-29] NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD NOV-DEC PY 2010 VL 15 IS 6 AR 061701 DI 10.1117/1.3528224 PG 1 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 719AI UT WOS:000287171100008 PM 21198149 ER PT J AU Medvedev, AV Kainerstorfer, JM Borisov, SV Gandjbakhche, AH VanMeter, J AF Medvedev, Andrei V. Kainerstorfer, Jana M. Borisov, Sergey V. Gandjbakhche, Amir H. VanMeter, John TI "Seeing" electroencephalogram through the skull: imaging prefrontal cortex with fast optical signal SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE near-infrared spectroscopy; fast optical signal; event-related signal; electroencephalogram; independent component anaysis; visual object detection ID NEAR-INFRARED SPECTROSCOPY; INDEPENDENT COMPONENT ANALYSIS; TOP-DOWN FACILITATION; HUMAN BRAIN; LIGHT-SCATTERING; OBJECT RECOGNITION; VISUAL-CORTEX; MOTOR CORTEX; HUMAN ADULT; STIMULATION AB Near-infrared spectroscopy is a novel imaging technique potentially sensitive to both brain hemodynamics (slow signal) and neuronal activity (fast optical signal, FOS). The big challenge of measuring FOS noninvasively lies in the presumably low signal-to-noise ratio. Thus, detectability of the FOS has been controversially discussed. We present reliable detection of FOS from 11 individuals concurrently with electroencephalogram (EEG) during a Go-NoGo task. Probes were placed bilaterally over prefrontal cortex. Independent component analysis (ICA) was used for artifact removal. Correlation coefficient in the best correlated FOS EEG ICA pairs was highly significant (p < 10(-8)), and event-related optical signal (EROS) was found in all subjects. Several EROS components were similar to the event-related potential (ERP) components. The most robust "optical N200" at t = 225 ms coincided with the N200 ERP; both signals showed significant difference between targets and nontargets, and their timing correlated with subject's reaction time. Correlation between FOS and EEG even in single trials provides further evidence that at least some FOS components "reflect" electrical brain processes directly. The data provide evidence for the early involvement of prefrontal cortex in rapid object recognition. EROS is highly localized and can provide cost-effective imaging tools for cortical mapping of cognitive processes. (C) 2010 Society of Photo-Optical Instrumentation Engineers, [DO: 10.1117/1.3505007] C1 [Medvedev, Andrei V.; Borisov, Sergey V.; VanMeter, John] GUMC, CFMI, Washington, DC 20057 USA. [Kainerstorfer, Jana M.] Univ Vienna, Dept Phys, Vienna, Austria. [Kainerstorfer, Jana M.; Gandjbakhche, Amir H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Analyt & Funct Biophoton, Program Pediat Imaging & Tissue Sci, Bethesda, MD 20892 USA. RP Medvedev, AV (reprint author), GUMC, CFMI, Preclin Sci Bldg,LM 14,3900 Reservoir Rd NW, Washington, DC 20057 USA. EM am236@georgetown.edu FU NIH [R01 EB006589]; DARPA [HB1582-05-C-0045]; Nancy Lurie Marks Family Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health FX This work was supported by the NIH (Grant No. R01 EB006589 to A.M.), DARPA (Grant No. HB1582-05-C-0045 to J.V.), and The Nancy Lurie Marks Family Foundation. The work was also partially funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health. NR 42 TC 13 Z9 13 U1 0 U2 8 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD NOV-DEC PY 2010 VL 15 IS 6 AR 061702 DI 10.1117/1.3505007 PG 12 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 719AI UT WOS:000287171100009 PM 21198150 ER PT J AU Baldwin, JT Mann, DL AF Baldwin, J. Timothy Mann, Douglas L. TI NHLBI's Program for VAD Therapy for Moderately Advanced Heart Failure: The REVIVE-IT Pilot Trial SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Mechanical circulatory; support destination therapy; functional impairment; quality of life ID VENTRICULAR ASSIST DEVICE AB Background Ventricular assist devices (VADs) are used to bridge heart failure patients to transplantation to allow their own hearts to recover or as permanent (destination) therapy To date the use of VADs has been limited to late-stage heart failure patients because of the associated device risks In 2008 a National Heart Lung and Blood Institute (NHLBI) working group met to evaluate the treatment of heart failure using VADs and to advise the institute on how therapy for heart failure may be best advanced by clinical trials involving the devices Methods and Results Recognizing the improvements in VAD technology and in patient care and selection over the past decade the working group recommended that a trial be performed to assess the use of chronic VAD therapy in patients who are less ill than those currently eligible for destination therapy The hypothesis proposed for the trial is that VAD therapy may improve both survival and quality of life in moderately advanced heart failure patients who are neither inotrope-dependent nor exercise-intolerant and have not yet developed serious consequences such as malnourishment end-organ damage and immobility Conclusion Based on the group's recommendations NHLBI issued an RFP in 2009 for the REVIVE-IT Pilot Trail, which will serve to test the hypothesis and inform the pivotal trial (J Cardiac Fail 2010 16 855-858) C1 [Baldwin, J. Timothy] NHLBI, Adv Technol & Surg Branch, Basic & Early Technol Res Program, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Mann, Douglas L.] Washington Univ, Sch Med, Div Cardiovasc, St Louis, MO 63110 USA. RP Baldwin, JT (reprint author), NHLBI, Adv Technol & Surg Branch, Basic & Early Technol Res Program, Div Cardiovasc Sci, 2 Rockledge Ctr,Room 8206,6701 Rockledge Dr, Bethesda, MD 20892 USA. OI Mann, Douglas /0000-0002-2516-0145 NR 5 TC 52 Z9 53 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 NOV PY 2010 VL 16 IS 11 BP 855 EP 858 DI 10.1016/j.cardfail.2010.06.0414 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 680PT UT WOS:000284247600001 PM 21055648 ER PT J AU Nguyen, TL Xu, XM Gussio, R Ghosh, AK Hamel, E AF Nguyen, Tam Luong Xu, Xiaoming Gussio, Rick Ghosh, Arun K. Hamel, Ernest TI The Assembly-Inducing Laulimalide/Peloruside A Binding Site on Tubulin: Molecular Modeling and Biochemical Studies with [H-3]Peloruside A SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID MICROTUBULE-STABILIZING AGENTS; BIOLOGICAL EVALUATION; TAXOID SITE; PELORUSIDE-A; BETA-TUBULIN; COMMON PHARMACOPHORE; PURIFIED TUBULIN; CELLS RESISTANT; PACLITAXEL; ANALOGS AB We used synthetic peloruside A for the commercial preparation of [H-3]peloruside A. The radiolabeled compound bound to preformed tubulin polymer in amounts stoichiometric with the polymer's tubulin content, with an apparent K-d value of 0.35 mu M. A less active peloruside A analogue, (11-R)-peloruside A and laulimalide acted as competitive inhibitors of the binding of the [H-3]peloruside A, with apparent K-i values of 9.3 and 0.25 mu M, respectively. Paclitaxel, epothilone B, and discodermolide had essentially no ability to inhibit [H-3]peloruside A binding, confirming that these compounds bind to a different site on tubulin polymer. We modeled both laulimalide and peloruside A into the binding site on beta-tubulin that was identified by Huzil et al. (J. Mol. Biol. 2008, 378, 1016-1030), but our model provides a more reasonable structural basis for the protein-ligand interaction. There is a more complete desolvation of the peloruside A ligand and a greater array of favorable hydrophobic and electrostatic interactions exhibited by peloruside A at its beta-tubulin binding site. In addition, the protein architecture in our peloruside A binding model was suitable for binding laulimalide. With the generation of both laulimalide and peloruside A binding models, it was possible to delineate the structural basis for the greater activity of laulimalide relative to peloruside A and to rationalize the known structure-activity relationship data for both compounds. C1 [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Nguyen, Tam Luong] NCI, Target Struct Based Drug Discovery Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. [Xu, Xiaoming; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Xu, Xiaoming; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Gussio, Rick] NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. EM hamele@mail.nih.gov OI zaraat, javad/0000-0001-5341-7481 FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; National Institutes of Health [GM53386]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded 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 Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. This work was also funded in part by the National Institutes of Health (A.K.G., GM53386). NR 42 TC 28 Z9 29 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD NOV PY 2010 VL 50 IS 11 BP 2019 EP 2028 DI 10.1021/ci1002894 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 681VU UT WOS:000284350300010 PM 21028850 ER PT J AU Ma, ZY Ma, Y Sun, XL Ye, YP Shen, BZ Chen, XY Ito, Y AF Ma, Zhiyong Ma, Ying Sun, Xilin Ye, Yunpeng Shen, Baozhong Chen, Xiaoyuan Ito, Yoichiro TI Purification of optical imaging ligand-Cybesin by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE High-speed counter current chromatography; Spiral tube assembly; Isolation and purification; Cybesin; Cypate Bombesin Peptide Analogue; Conjugate; Pancreas tumor ID TUMORS AB Fluorescent Cybesin (Cypate-Bombesin Peptide Analogue Conjugate) was synthesized from Indocyanine Green (ICG) and the bombesin receptor ligand as a contrast agent for detecting pancreas tumors However the LC-MS analysis indicated that the target compound was only a minor component in the reaction mixture Since preparative HPLC can hardly separate such a small amount of the target compound directly from the original crude reaction mixture without a considerable adsorptive loss onto the solid support high-speed counter-current chromatography (HSCCC) was used for purification since the method uses no solid support and promises high sample recovery A suitable two-phase solvent system composed of hexane/ethyl acetate/methanol/methyl t-butyl ether/acetonitnle/water) at a volume ratio of 1 1 1 4 4 7 was selected based on the partition coefficient of Cybesin (K approximate to 0 9) determined by LC-MS The separation was performed in two steps using the same solvent system with lower aqueous mobile phase From 400 mg of the crude reaction mixture the first separation yielded 7 7 mg of fractions containing the target compound at 12 8% purity and in the second run 1 mg of Cybesin was obtained at purity of 94 0% with a sample recovery rate of over 95% based on the LC-MS analysis Published by Elsevier B V C1 [Ma, Ying; Sun, Xilin; Ye, Yunpeng; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Ma, Zhiyong] Harbin Med Coll, Coll Pharm, Harbin 150081, Peoples R China. [Ma, Zhiyong; Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Sun, Xilin; Shen, Baozhong] Harbin Med Coll, Affiliated Hosp 4, Dept Med Imaging & Nucl Med, Harbin 150001, Peoples R China. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, 31 Ctr Dr 31-1C22, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA HL005107-02] NR 10 TC 1 Z9 1 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD NOV 1 PY 2010 VL 878 IS 29 BP 3039 EP 3043 DI 10.1016/j.jchromb.2010.09.007 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 679CP UT WOS:000284137300013 PM 20933483 ER PT J AU Vogelzangs, N Beekman, ATF Milaneschi, Y Bandinelli, S Ferrucci, L Penninx, BWJH AF Vogelzangs, Nicole Beekman, Aartjan T. F. Milaneschi, Yuri Bandinelli, Stefania Ferrucci, Luigi Penninx, Brenda W. J. H. TI Urinary Cortisol and Six-Year Risk of All-Cause and Cardiovascular Mortality SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PITUITARY-ADRENAL AXIS; METABOLIC SYNDROME; MYOCARDIAL-INFARCTION; ADIPOSE-TISSUE; BLOOD-PRESSURE; STRESS; DISEASE; CALCIFICATION; INFLAMMATION; DECLINE AB Context: The stress hormone cortisol has been linked with unfavorable cardiovascular risk factors, but longitudinal studies examining whether high levels of cortisol predict cardiovascular mortality are largely absent. Objective: The aim of this study was to examine whether urinary cortisol levels predict all-cause and cardiovascular mortality over 6 yr of follow-up in a general population of older persons. Design and Setting: Participants were part of the InCHIANTI study, a prospective cohort study in the older general population with 6 yr of follow-up. Participants: We studied 861 participants aged 65 yr and older. Main Outcome Measure: Twenty-four-hour urinary cortisol levels were assessed at baseline. In the following 6 yr, all-cause and cardiovascular mortality was ascertained from death certificates. Cardiovascular mortality included deaths due to ischemic heart disease and cerebrovascular disease. Results: During a mean follow-up of 5.7 (SD = 1.2) yr, 183 persons died, of whom 41 died from cardiovascular disease. After adjustment for sociodemographics, health indicators, and baseline cardiovascular disease, urinary cortisol did not increase the risk of noncardiovascular mortality, but it did increase cardiovascular mortality risk. Persons in the highest tertile of urinary cortisol had a five times increased risk of dying of cardiovascular disease (hazard ratio = 5.00; 95% confidence interval = 2.02-12.37). This effect was found to be consistent across persons with and without cardiovascular disease at baseline (p interaction = 0.78). Conclusions: High cortisol levels strongly predict cardiovascular death among persons both with and without preexisting cardiovascular disease. The specific link with cardiovascular mortality, and not other causes of mortality, suggests that high cortisol levels might be particularly damaging to the cardiovascular system. (J Clin Endocrinol Metab 95: 4959-4964, 2010) C1 [Vogelzangs, Nicole; Beekman, Aartjan T. F.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, NL-1081 HL Amsterdam, Netherlands. [Vogelzangs, Nicole; Beekman, Aartjan T. F.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 HL Amsterdam, Netherlands. [Milaneschi, Yuri; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21225 USA. [Milaneschi, Yuri] Tuscany Hlth Reg Agcy, I-50125 Florence, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil, I-50122 Florence, Italy. RP Vogelzangs, N (reprint author), AJ Ernststr 1187, NL-1081 HL Amsterdam, Netherlands. EM n.vogelzangs@vumc.nl FU Italian Ministry of Health [ICS 110.1/RS97.71]; U.S. National Institute on Aging [263 MD 916413, 263 MD 821336]; National Heart, Lung, and Blood Institute [1R01-HL972972]; Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging FX The InCHIANTI study was supported as a targeted project (Grant ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Grants 263 MD 916413 and 263 MD 821336). Data analyses were supported through Grant 1R01-HL972972 from the National Heart, Lung, and Blood Institute. Cortisol assays were supported by a professional services contract from the Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging. NR 36 TC 53 Z9 54 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2010 VL 95 IS 11 BP 4959 EP 4964 DI 10.1210/jc.2010-0192 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 675QB UT WOS:000283844400040 PM 20739384 ER PT J AU Esparza-Romero, J Valencia, ME Martinez, ME Ravussin, E Schulz, LO Bennett, PH AF Esparza-Romero, Julian Valencia, Mauro E. Martinez, Maria Elena Ravussin, Eric Schulz, Leslie O. Bennett, Peter H. TI Differences in Insulin Resistance in Mexican and U.S. Pima Indians with Normal Glucose Tolerance SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DIABETES-MELLITUS; PHYSICAL-ACTIVITY; ENZYMATIC DETERMINATION; PLASMA-GLUCOSE; PATHOGENESIS; CHOLESTEROL; POPULATIONS; DYSFUNCTION; OBESITY; RISK AB Context: Insulin resistance is a major risk factor for the development of type 2 diabetes in Pima Indians, a population with the highest prevalence of type 2 diabetes mellitus in the world. Their Mexican counterpart, living a traditional lifestyle in the mountains of Sonora, have at least 5 times less diabetes than the U. S. Pima Indians. Objective: We evaluated whether Mexican Pima Indians had lower insulin resistance than U. S. Pima Indians. Design and Patients: We compared fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR) in 194 Mexican Pima Indians (100 females, 94 males) and 449 U. S. Pima Indians (246 females, 203 males) with normal glucose tolerance from a cross-sectional study. Adjusted differences of log-transformed outcomes (fasting insulin and HOMA-IR) between groups were evaluated using multiple linear regression models and paired t test in a matched subset. Results: Unadjusted fasting insulin and HOMA-IR were much lower in the Mexican Pima Indians than in their U. S. counterparts. After adjusting by obesity, age, and sex, mean (95% confidence interval) for fasting insulin was 6.22 (5.34-7.24) vs. 13.56 mu U/ml (12.27-14.97) and for HOMA-IR 1.40 (1.20-1.64) vs. 3.07 (2.77-3.40), respectively, for Mexican Pima and U. S. Pima Indians. Results were confirmed in subset matched for age, sex, and body fat. Conclusion: Our results indicate that Mexican Pima Indians have lower insulin resistance in comparison with their genetically related U. S. counterparts, even after controlling for differences in obesity, age, and sex. This finding underscores the importance of lifestyle factors as protecting factors against insulin resistance in individuals with a high propensity to develop diabetes. (J Clin Endocrinol Metab 95: E358-E362, 2010) C1 [Esparza-Romero, Julian; Valencia, Mauro E.] AC, Ctr Invest Alimentac & Desarrollo, Hermosillo 83000, Sonora, Mexico. [Esparza-Romero, Julian; Martinez, Maria Elena] Univ Arizona, Div Epidemiol & Biostat, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ 85724 USA. [Martinez, Maria Elena] Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. [Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Schulz, Leslie O.] No Arizona Univ, Coll Hlth & Human Serv, Flagstaff, AZ 86011 USA. [Bennett, Peter H.] NIDDK, Phoenix Epidemiol & Clin Res Brach, NIH, Phoenix, AZ 85014 USA. RP Esparza-Romero, J (reprint author), Ctr Invest Alimentac & Desarrollo AC, Carretera la Victoria Km 0-6,Apartado Postal 1735, Hermosillo 83000, Sonora, Mexico. EM julian@ciad.mx NR 19 TC 13 Z9 13 U1 0 U2 4 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 NOV PY 2010 VL 95 IS 11 BP E358 EP E362 DI 10.1210/jc.2010-0297 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 675QB UT WOS:000283844400012 PM 20668044 ER PT J AU Schafer, AL Vittinghoff, E Lang, TF Sellmeyer, DE Harris, TB Kanaya, AM Strotmeyer, ES Cawthon, PM Cummings, SR Tylavsky, FA Scherzinger, AL Schwartz, AV AF Schafer, Anne L. Vittinghoff, Eric Lang, Thomas F. Sellmeyer, Deborah E. Harris, Tamara B. Kanaya, Alka M. Strotmeyer, Elsa S. Cawthon, Peggy M. Cummings, Steven R. Tylavsky, Frances A. Scherzinger, Ann L. Schwartz, Ann V. CA Hlth Aging Body Composition Hlth TI Fat Infiltration of Muscle, Diabetes, and Clinical Fracture Risk in Older Adults SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADIPOSE-TISSUE DISTRIBUTION; BODY-COMPOSITION; SKELETAL-MUSCLE; HIP FRACTURE; COMPUTED-TOMOGRAPHY; BLACK ADULTS; HEALTH; WOMEN; MEN; ATTENUATION AB Context: Older adults with type 2 diabetes are at higher risk for fracture compared with nondiabetic adults after adjustment for their higher bone mineral density. Infiltration of muscle by fat predicts increased risk of hip fracture. Objective: We investigated whether fat infiltration of muscle, which is greater in diabetic adults, is associated with all clinical fracture and whether it accounts for the increased fracture risk in those with diabetes. Design, Setting, and Participants: Data were analyzed from the Health, Aging, and Body Composition Study, a cohort of community-dwelling adults aged 70-79 yr. Glucose metabolism status and x-ray attenuation of thigh muscle were determined at baseline for 2762 participants. Main Outcome Measures: During a mean 8.2 +/- 2.3 yr follow-up, 331 participants reported at least one clinical fracture. Results: Fat infiltration of muscle was higher in those with diabetes or impaired glucose metabolism than in those with normal glucose metabolism (P < 0.001). Fat infiltration of muscle was independently associated with a 19% increased risk of incident clinical fracture (multivariate hazard ratio = 1.19; 95% confidence interval = 1.04-1.36); this association did not differ across glucose metabolism groups (P for interaction = 0.65). As previously reported, diabetes was associated with a greater fracture risk compared with normal glucose metabolism (hazard ratio = 1.42; 95% confidence interval = 1.07-1.89) after adjustment for bone mineral density, but further adjustment for fat infiltration of muscle did not attenuate this association. Conclusions: Fat infiltration of muscle predicts clinical fracture in older adults. Although fat infiltration of muscle is higher among those with diabetes, it does not account for their increased fracture risk. (J Clin Endocrinol Metab 95: E368-E372, 2010) C1 [Schafer, Anne L.; Kanaya, Alka M.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Vittinghoff, Eric; Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lang, Thomas F.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Sellmeyer, Deborah E.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Cawthon, Peggy M.; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Tylavsky, Frances A.] Univ Tennessee, Dept Prevent Med, Memphis, TN 38105 USA. [Scherzinger, Ann L.] Univ Colorado, Dept Radiol, Denver, CO 80045 USA. RP Schafer, AL (reprint author), 2200 Post St,Room C-409, San Francisco, CA 94115 USA. EM anne.schafer@ucsf.edu RI Lang, Thomas/B-2685-2012; Strotmeyer, Elsa/F-3015-2014; OI Lang, Thomas/0000-0002-3720-8038; Strotmeyer, Elsa/0000-0002-4093-6036 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institutes of Health National Institute on Aging; Merck FX This work was supported by the National Institute on Aging under contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging.; A.L.S., E.V., D.E.S., T.B.H., A.M.K., E.S.S., S.R.C., F.A.T., A.L.S., and A.V.S. have nothing to disclose. T.F.L. has received grant support from Merck. P.M.C. consults for Merck and Amgen. NR 20 TC 27 Z9 27 U1 2 U2 4 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 NOV PY 2010 VL 95 IS 11 BP E368 EP E372 DI 10.1210/jc.2010-0780 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 675QB UT WOS:000283844400014 PM 20668037 ER PT J AU Lie, HH Cella, D Gershon, R Shen, J Morales, LS Riley, W Hays, RD AF Lie, Honghu Cella, David Gershon, Richard Shen, Jie Morales, Leo S. Riley, William Hays, Ron D. TI Representativeness of the Patient-Reported Outcomes Measurement Information System Internet panel SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE PROMIS; Patient-reported outcomes; Resampling; Weighting; Raking; Equivalence testing ID WORLD-WIDE-WEB; DATA-COLLECTION; MAILED QUESTIONNAIRES; EQUIVALENCE; TESTS; DIFFERENCE; ONLINE; PROMIS; MODEL; EQ-5D AB Objectives: To evaluate the Patient-Reported Outcomes Measurement Information System (PROMIS), which collected data from an Internet polling panel, and to compare PROMIS with national norms. Study Design and Setting: We compared demographics and self-rated health of the PROMIS general Internet sample (N = 11,796) and one of its subsamples (n = 2,196) selected to approximate the joint distribution of demographics from the 2000 U.S. Census, with three national surveys and U.S. Census data. The comparisons were conducted using equivalence testing with weights created for PROMIS by raking. Results: The weighted PROMIS population and subsample had similar demographics compared with the 2000 U.S. Census, except that the subsample had a higher percentage of people with higher education than high school. Equivalence testing shows similarity between PROMIS general population and national norms with regard to body mass index, EQ-5D health index (EuroQol group defined descriptive system of health-related quality of life states consisting of five dimensions including mobility, self-care, usual activities, pain/discomfort, anxiety/depression), and self-rating of general health. Conclusion: Self-rated health of the PROMIS general population is similar to that of existing samples from the general U.S. population. The weighted PROMIS general population is more comparable to national norms than the unweighted population with regard to subject characteristics. The findings suggest that the representativeness of the Internet data is comparable to those from probability-based general population samples. (C) 2010 Elsevier Inc. All rights reserved. C1 [Lie, Honghu; Hays, Ron D.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, UCLA Dept Med, Los Angeles, CA 90095 USA. [Cella, David; Gershon, Richard] Northwestern Univ, Inst Healthcare Studies, Chicago, IL 60611 USA. [Shen, Jie] Univ Calif Los Angeles, UCLA Dept Stat, Los Angeles, CA 90095 USA. [Morales, Leo S.] Grp Hlth Res Inst, Seattle, WA USA. [Riley, William] NIMH, Div AIDS & Hlth Behav Res, Bethesda, MD 20892 USA. RP Lie, HH (reprint author), Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, UCLA Dept Med, 911 Broxton Plaza,Room 202, Los Angeles, CA 90095 USA. EM hhliu@ucla.edu RI Hays, Ronald/D-5629-2013 FU National Institutes of Health (NIH) through the NIH Roadmap for Medical Research [1U01-AR052177] FX This work was funded by the National Institutes of Health (NIH) through the NIH Roadmap for Medical Research Cooperative Agreement (1U01-AR052177). NR 43 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 EI 1878-5921 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD NOV PY 2010 VL 63 IS 11 BP 1169 EP 1178 DI 10.1016/j.jclinepi.2009.11.021 PG 10 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 663CW UT WOS:000282861600003 ER PT J AU Cella, D Riley, W Stone, A Rothrock, N Reeve, B Yount, S Amtmann, D Bode, R Buysse, D Choi, S Cook, K DeVellis, R DeWalt, D Fries, JF Gershon, R Hahn, EA Lai, JS Pilkonis, P Revicki, D Rose, M Weinfurt, K Hays, R AF Cella, David Riley, William Stone, Arthur Rothrock, Nan Reeve, Bryce Yount, Susan Amtmann, Dagmar Bode, Rita Buysse, Daniel Choi, Seung Cook, Karon DeVellis, Robert DeWalt, Darren Fries, James F. Gershon, Richard Hahn, Elizabeth A. Lai, Jin-Shei Pilkonis, Paul Revicki, Dennis Rose, Matthias Weinfurt, Kevin Hays, Ron CA PROMIS Cooperative Grp TI The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008 SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Outcome measures; Quality of life; Chronic disease; Item response theory; Patient-reported outcomes; PROMIS ID QUALITY-OF-LIFE; PHYSICAL FUNCTION; CLINICAL-TRIALS; SHORT-FORMS; PAIN; MODEL; SCHIZOPHRENIA; DISABILITY; SYMPTOMS; FATIGUE AB Objectives: Patient-reported outcomes (PROs) are essential when evaluating many new treatments in health care; yet, current measures have been limited by a lack of precision, standardization, and comparability of scores across studies and diseases. The Patient-Reported Outcomes Measurement Information System (PROMIS) provides item banks that offer the potential for efficient (minimizes item number without compromising reliability), flexible (enables optional use of interchangeable items), and precise (has minimal error in estimate) measurement of commonly studied PROs. We report results from the first large-scale testing of PROMIS items. Study Design and Setting: Fourteen item pools were tested in the U.S. general population and clinical groups using an online panel and clinic recruitment. A scale-setting subsample was created reflecting demographics proportional to the 2000 U.S. census. Results: Using item-response theory (graded response model), 11 item banks were calibrated on a sample of 21,133, measuring components of self-reported physical, mental, and social health, along with a 10-item Global Health Scale. Short forms from each bank were developed and compared with the overall bank and with other well-validated and widely accepted ("legacy") measures. All item banks demonstrated good reliability across most of the score distributions. Construct validity was supported by moderate to strong correlations with legacy measures. Conclusion: PROMIS item banks and their short forms provide evidence that they are reliable and precise measures of generic symptoms and functional reports comparable to legacy instruments. Further testing will continue to validate and test PROMIS items and banks in diverse clinical populations. (C) 2010 Elsevier Inc. All rights reserved. C1 [Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Riley, William] NHLBI, Bethesda, MD 20892 USA. [Stone, Arthur] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Reeve, Bryce] NCI, Bethesda, MD 20892 USA. [Amtmann, Dagmar; Cook, Karon] Univ Washington, Seattle, WA 98195 USA. [Buysse, Daniel; Pilkonis, Paul] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [DeVellis, Robert] Univ N Carolina, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC USA. [DeWalt, Darren] Univ N Carolina, Cecil G Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. [Fries, James F.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. [Revicki, Dennis] United BioSource Corp, Bethesda, MD USA. [Rose, Matthias] Univ Hamburg, Dept Med, Hamburg, Germany. [Weinfurt, Kevin] Duke Univ, Sch Med, Durham, NC USA. [Hays, Ron] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Cella, D (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, 710 N Lake Shore Dr, Chicago, IL 60611 USA. EM d-cella@northwestern.edu RI Hays, Ronald/D-5629-2013; Rose, Matthias/A-8920-2015; Fries, James/F-6271-2011; OI DeWalt, Darren/0000-0003-2270-751X FU Northwestern University, PI: David Cella, PhD [U02AR52177]; Duke University, PI: Kevin Weinfurt, PhD [U01AR52186]; University of North Carolina, PI: Darren DeWalt, MD, MPH [U01AR52181]; University of Pittsburgh, PI: Paul A. Pilkonis, PhD [U01AR52155]; Stanford University, PI: James Fries, MD [U01AR52158]; Stony Brook University, PI: Arthur Stone, PhD [U01AR52170]; University of Washington, PI: Dagmar Amtmann, PhD [U01AR52171] FX The Patient-Reported Outcomes Measurement Information System (PROMIS) is an NIH Roadmap initiative to develop a computerized system measuring PROs in respondents with a wide range of chronic diseases and demographic characteristics. This work was funded by cooperative agreements to a Statistical Coordinating Center (Northwestern University, PI: David Cella, PhD, U02AR52177) and six Primary Research Sites (Duke University, PI: Kevin Weinfurt, PhD, U01AR52186; University of North Carolina, PI: Darren DeWalt, MD, MPH, U01AR52181; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, U01AR52155; Stanford University, PI: James Fries, MD, U01AR52158; Stony Brook University, PI: Arthur Stone, PhD, U01AR52170; and University of Washington, PI: Dagmar Amtmann, PhD, U01AR52171). NIH Science Officers on this project have included Deborah Ader, PhD, Susan Czajkowski, PhD, Lawrence Fine, MD, DrPH, Louis Quatrano, PhD, Bryce Reeve, PhD, William Riley, PhD, Susana Serrate-Sztein, MD, and James Witter, MD, PhD. This manuscript was reviewed by the PROMIS Publications Subcommittee before external peer review. See the Web site at www.nihpromis. org for additional information on the PROM IS initiative. NR 44 TC 518 Z9 519 U1 2 U2 45 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD NOV PY 2010 VL 63 IS 11 BP 1179 EP 1194 DI 10.1016/j.jclinepi.2010.04.011 PG 16 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 663CW UT WOS:000282861600004 PM 20685078 ER PT J AU Rothrock, NE Hays, RD Spritzer, K Yount, SE Riley, W Cella, D AF Rothrock, Nan E. Hays, Ron D. Spritzer, Karen Yount, Susan E. Riley, William Cella, David TI Relative to the general US population, chronic diseases are associated with poorer health-related quality of life as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Chronic disease; Comorbidity; Quality of life; Outcome measures; Patient outcome assessment; Item response theory ID FUNCTIONAL ASSESSMENT; CANCER; THERAPY; COMORBIDITIES; ARTHRITIS; PROGRESS; FATIGUE; SCALE AB Objectives: The Patient-Reported Outcomes Measurement Information System (PROMIS) allows assessment of the impact of chronic conditions on health-related quality of life (HRQL) across diseases. We report on the HRQL impact of individual and comorbid conditions as well as conditions that are described as limiting activity. Study Design and Setting: Data were collected through online and clinic recruitment as part of the PROMIS item calibration sample (n = 21,133). Participants reported the presence or absence of 24 chronic health conditions and whether their activity was limited by each condition. Results: Across health status domains, the presence of a chronic condition was associated with poorer scores than those without a diagnosis, particularly for those individuals who reported that their condition was disabling. The magnitude of detriment in HRQL was more pronounced for individuals with two or more chronic conditions and could not be explained by sociodemographic factors. Patterns of HRQL deficits varied across disease and comorbidity status. Conclusion: The impact of chronic conditions, particularly when experienced with comorbid disease, is associated with detriments in HRQL. The negative impact on HRQL varies across symptoms and functional areas within a given condition. (C) 2010 Elsevier Inc. All rights reserved. C1 [Rothrock, Nan E.; Yount, Susan E.; Cella, David] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Hays, Ron D.; Spritzer, Karen] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Riley, William] NHLBI, Bethesda, MD 20892 USA. RP Rothrock, NE (reprint author), Northwestern Univ, Dept Med Social Sci, 625 N Michigan Ave,Suite 2700, Chicago, IL 60611 USA. EM n-rothrock@northwestern.edu RI Hays, Ronald/D-5629-2013 FU Northwestern University, PI: David Cella, PhD [U01AR52177]; Duke University, PI: Kevin Weinfurt, PhD [U01AR52186]; University of North Carolina, PI: Darren DeWalt, MD, MPH [U01AR52181]; University of Pittsburgh, PI: Paul A. Pilkonis, PhD [U01AR52155]; Stanford University, PI: James Fries, MD [U01AR52158]; Stony Brook University, PI: Arthur Stone, PhD [U01AR52170]; University of Washington, PI: Dagmar Amtmann, PhD [U01AR52171] FX The PROM IS is an NIH Roadmap initiative to develop a computerized system measuring PROs in respondents with a wide range of chronic diseases and demographic characteristics. PROMIS was funded by cooperative agreements to a Statistical Coordinating Center (Northwestern University, PI: David Cella, PhD, U01AR52177) and six Primary Research Sites (Duke University, PI: Kevin Weinfurt, PhD, U01AR52186; University of North Carolina, PI: Darren DeWalt, MD, MPH, U01AR52181; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, U01AR52155; Stanford University, PI: James Fries, MD, U01AR52158; Stony Brook University, PI: Arthur Stone, PhD, U01AR52170; and University of Washington, PI: Dagmar Amtmann, PhD, U01AR52171). NIH Science Officers on this project are Deborah Ader, PhD, Susan Czajkowski, PhD, Lawrence Fine, MD, DrPH, Louis Quatrano, PhD, Bryce Reeve, PhD, William Riley, PhD, and Susana Serrate-Sztein, PhD. This manuscript was reviewed by the PROMIS Publications Subcommittee before external peer review; see the Web site at www.nihpromis.org for additional information on the PROMIS cooperative group. NR 33 TC 81 Z9 82 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD NOV PY 2010 VL 63 IS 11 BP 1195 EP 1204 DI 10.1016/j.jclinepi.2010.04.012 PG 10 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 663CW UT WOS:000282861600005 PM 20688471 ER PT J AU Glynn, SA Boersma, BJ Dorsey, TH Yi, M Yfantis, HG Ridnour, LA Martin, DN Switzer, CH Hudson, RS Wink, DA Lee, DH Stephens, RM Ambs, S AF Glynn, Sharon A. Boersma, Brenda J. Dorsey, Tiffany H. Yi, Ming Yfantis, Harris G. Ridnour, Lisa A. Martin, Damali N. Switzer, Christopher H. Hudson, Robert S. Wink, David A. Lee, Dong H. Stephens, Robert M. Ambs, Stefan TI Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NITRIC-OXIDE SYNTHASE; ENDOTHELIAL GROWTH-FACTOR; SQUAMOUS-CELL CARCINOMA; BASAL-LIKE SUBTYPE; WILD-TYPE P53; GENE-EXPRESSION; TUMOR ANGIOGENESIS; P-CADHERIN; MACROPHAGE INFILTRATION; IL-8 EXPRESSION AB Inducible nitric oxide synthase (NOS2) is involved in wound healing, angiogenesis, and carcinogenesis. NOS2 upregulation and increased nitric oxide (NO) production affect the redox state of cells and can induce protein, lipid, and DNA modifications. To investigate whether NOS2 levels influence survival of breast cancer patients, we examined NOS2 expression and its association with tumor markers and survival in 248 breast tumors. In multivariable survival analysis, increased NOS2 predicted inferior survival in women with estrogen receptor alpha-negative (ER-negative) tumors. Microdissected tumor epithelium from ER-negative tumors with high NOS2 had increased IL-8 and a gene expression signature characteristic of basal-like breast cancer with poor prognosis. In cell culture, NO only induced selected signature genes in ER-negative breast cancer cells. ER transgene expression in ER-negative cells inhibited NO-induced upregulation of the stem cell marker CD44 and other proteins encoded by signature genes, but not of IL-8. Exposure to NO also enhanced cell motility and invasion of ER-negative cells. Last, pathway analysis linked the tumor NOS2 gene signature to c-Myc activation. Thus, NOS2 is associated with a basal-like transcription pattern and poor survival of ER-negative patients. C1 [Glynn, Sharon A.; Boersma, Brenda J.; Dorsey, Tiffany H.; Martin, Damali N.; Hudson, Robert S.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Glynn, Sharon A.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. [Yi, Ming; Stephens, Robert M.] NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21701 USA. [Yfantis, Harris G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Ridnour, Lisa A.; Switzer, Christopher H.; Wink, David A.] NCI, Tumor Biol Sect, Radiat Biol Branch, CCR, Bethesda, MD 20892 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, Room 3050B,37 Convent Dr MSC 4258, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Switzer, Christopher/D-9203-2013; Boersma, Brenda/A-9270-2009 OI Glynn, Sharon/0000-0003-1459-2580; Boersma, Brenda/0000-0002-8992-2735 FU NIH; National Cancer Institute; Center for Cancer Research; National Cancer Institute Cancer Prevention Fellowship; Health Research Board of Ireland FX This research was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and the Center for Cancer Research. We thank Raymond Jones, Audrey Salabes, Leoni Leondaridis, Glennwood Trivers, Elise Bowman, and personnel at the University of Maryland and the Baltimore Veterans Administration and the Surgery and Pathology Departments at the University of Maryland Medical Center, Baltimore Veterans Affairs Medical Center, Union Memorial Hospital, Mercy Medical Center, and Sinai Hospital for their contributions. Sharon A. Glynn is the recipient of an All-Ireland Cancer Consortium National Cancer Institute Cancer Prevention Fellowship, sponsored in part by the Health Research Board of Ireland. NR 79 TC 78 Z9 78 U1 0 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2010 VL 120 IS 11 BP 3843 EP 3854 DI 10.1172/JCI42059 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 672XU UT WOS:000283621800019 PM 20978357 ER PT J AU Chinnasamy, D Yu, ZY Theoret, MR Zhao, YB Shrimali, RK Morgan, RA Feldman, SA Restifo, NP Rosenberg, SA AF Chinnasamy, Dhanalakshmi Yu, Zhiya Theoret, Marc R. Zhao, Yangbing Shrimali, Rajeev K. Morgan, Richard A. Feldman, Steven A. Restifo, Nicholas P. Rosenberg, Steven A. TI Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CHIMERIC ANTIGEN RECEPTOR; CYTOTOXIC T-LYMPHOCYTES; CELL TRANSFER THERAPY; ADOPTIVE IMMUNOTHERAPY; ANTITUMOR-ACTIVITY; CANCER REGRESSION; IN-VIVO; ANTIANGIOGENIC THERAPY; ENDOTHELIAL GROWTH-FACTOR-RECEPTOR-2; METASTATIC MELANOMA AB Immunotherapies based on adoptive cell transfer are highly effective in the treatment of metastatic melanoma, but the use of this approach in other cancer histologies has been hampered by the identification of appropriate target molecules. Immunologic approaches targeting tumor vasculature provide a means for the therapy of multiple solid tumor types. We developed a method to target tumor vasculature, using genetically redirected syngeneic or autologous T cells. Mouse and human T cells were engineered to express a chimeric antigen receptor (CAR) targeted against VEGFR-2, which is overexpressed in tumor vasculature and is responsible for VEGF-mediated tumor progression and metastasis. Mouse and human T cells expressing the relevant VEGFR-2 CARs mediated specific immune responses against VEGFR-2 protein as well as VEGFR-2-expressing cells in vitro. A single dose of VEGFR-2 CAR-engineered mouse T cells plus exogenous IL-2 significantly inhibited the growth of 5 different types of established, vascularized syngeneic tumors in 2 different strains of mice and prolonged the survival of mice. T cells transduced. with VEGFR-2 CAR showed durable and increased tumor infiltration, correlating with their antitumor effect. This approach provides a potential method for the gene therapy of a variety of human cancers: C1 [Chinnasamy, Dhanalakshmi; Yu, Zhiya; Theoret, Marc R.; Zhao, Yangbing; Shrimali, Rajeev K.; Morgan, Richard A.; Feldman, Steven A.; Restifo, Nicholas P.; Rosenberg, Steven A.] NCI, Surg Branch, Clin Res Ctr, Bethesda, MD 20892 USA. [Zhao, Yangbing] Univ Penn, Dept Pathol & Lab Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Clin Res Ctr, Bldg 10 CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM SAR@mail.nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 NR 87 TC 70 Z9 74 U1 0 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2010 VL 120 IS 11 BP 3953 EP 3968 DI 10.1172/JCI43490 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 672XU UT WOS:000283621800029 PM 20978347 ER PT J AU Hiby, SE Apps, R Sharkey, AM Farrell, LE Gardner, L Mulder, A Claas, FH Walker, JJ Redman, CC Morgan, L Tower, C Regan, L Moore, GE Carrington, M Moffett, A AF Hiby, Susan E. Apps, Richard Sharkey, Andrew M. Farrell, Lydia E. Gardner, Lucy Mulder, Arend Claas, Frans H. Walker, James J. Redman, Christopher C. Morgan, Linda Tower, Clare Regan, Lesley Moore, Gudrun E. Carrington, Mary Moffett, Ashley TI Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2 SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NATURAL-KILLER-CELLS; IMMUNOGLOBULIN-LIKE RECEPTORS; CLASS-I MOLECULES; UTERINE NK CELLS; RECURRENT MISCARRIAGE; INHIBITORY RECEPTORS; SURFACE EXPRESSION; MONOCLONAL-ANTIBODIES; TROPHOBLAST CELLS; HUMAN-PREGNANCY AB Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells - specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells - influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2(+) trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success. C1 [Hiby, Susan E.; Apps, Richard; Sharkey, Andrew M.; Farrell, Lydia E.; Gardner, Lucy; Moffett, Ashley] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Hiby, Susan E.; Apps, Richard; Sharkey, Andrew M.; Farrell, Lydia E.; Gardner, Lucy; Moffett, Ashley] Ctr Trophoblast Res, Cambridge, England. [Apps, Richard; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21701 USA. [Apps, Richard; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Mulder, Arend; Claas, Frans H.] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands. [Walker, James J.] Univ Leeds, St James Univ Hosp, Leeds Inst Mol Med, Perinatal Res Grp, Leeds, W Yorkshire, England. [Walker, James J.; Redman, Christopher C.; Morgan, Linda] Univ Oxford, Genet Preeclampsia GOPEC Consortium, Oxford, England. [Redman, Christopher C.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford, England. [Morgan, Linda] Univ Nottingham, Dept Clin Chem, Inst Genet, Nottingham NG7 2RD, England. [Tower, Clare] St Marys Hosp, Maternal & Fetal Hlth Res Ctr, Manchester M13 0JH, Lancs, England. [Regan, Lesley] St Marys Hosp, Sch Med, Dept Obstet & Gynaecol, London W2 1PG, England. [Moore, Gudrun E.] UCL, Clin & Mol Genet Unit, Inst Child Hlth, London, England. RP Moffett, A (reprint author), Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP, England. EM am485@cam.ac.uk RI Sharkey, Andrew/H-7015-2013; Moffett, Ashley/J-9754-2013; Moore, Gudrun/A-2092-2009; OI Sharkey, Andrew/0000-0002-5072-7748; Walker, James/0000-0002-8922-083X; Farrell, Lydia/0000-0002-7643-6009 FU Wellcome Trust; British Heart Foundation; Wellbeing of Women; Centre for Trophoblast Research; King's College, University of Cambridge; National Cancer Institute, NIH [HHSN261200800001E]; Center for Cancer Research (National Cancer Institute, NIH FX These studies have been supported by the Wellcome Trust, the British Heart Foundation, Wellbeing of Women, Centre for Trophoblast Research, and King's College, University of Cambridge. We are grateful to Graham Burton and Charlie Loke for helpful discussions and Ying Qi for statistical advice. We would like to thank all the donors, the GOPEC Consortium, and research nurses for providing the samples, and the Anthony Nolan Trust for HLA-C typing and Luminex bead studies. This project was funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the Center for Cancer Research (National Cancer Institute, NIH). NR 63 TC 172 Z9 178 U1 4 U2 17 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2010 VL 120 IS 11 BP 4102 EP 4110 DI 10.1172/JCI43998 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 672XU UT WOS:000283621800041 PM 20972337 ER PT J AU Salit, RB Shea, YR Gea-Banacloche, J Fahle, GA Abu-Asab, M Sugui, JA Carpenter, AE Quezado, MM Bishop, MR Kwon-Chung, KJ AF Salit, R. B. Shea, Y. R. Gea-Banacloche, J. Fahle, G. A. Abu-Asab, M. Sugui, J. A. Carpenter, A. E. Quezado, M. M. Bishop, M. R. Kwon-Chung, K. J. TI Death by Edible Mushroom: First Report of Volvariella volvacea as an Etiologic Agent of Invasive Disease in a Patient following Double Umbilical Cord Blood Transplantation SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID BASIDIOMYCETOUS FUNGI; ADULT PATIENTS; IDENTIFICATION AB We describe a case of invasive fungal infection caused by Volvariella volvacea following double umbilical cord blood transplantation (UCBT). Although infections caused by several mushroom species have been documented, we believe this to be the first published report of invasive infection with Volvariella volvacea, an edible mushroom belonging to Agaricales. C1 [Salit, R. B.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20982 USA. [Shea, Y. R.; Fahle, G. A.] NCI, Dept Lab Med, NIH, Bethesda, MD 20982 USA. [Gea-Banacloche, J.; Carpenter, A. E.; Bishop, M. R.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20982 USA. [Abu-Asab, M.; Quezado, M. M.] NCI, Pathol Lab, NIH, Bethesda, MD 20982 USA. [Sugui, J. A.; Kwon-Chung, K. J.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20982 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov OI Abu-Asab, Mones/0000-0002-4047-1232 FU NIH, National Cancer Institute; National Institute of Allergy and Infectious Diseases; Department of Laboratory Medicine, Clinical Center, NIH FX This study was supported by funds from the Intramural Research Program of the NIH, National Cancer Institute and National Institute of Allergy and Infectious Diseases, and the Department of Laboratory Medicine, Clinical Center, NIH. NR 16 TC 4 Z9 4 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 NOV PY 2010 VL 48 IS 11 BP 4329 EP 4332 DI 10.1128/JCM.01222-10 PG 4 WC Microbiology SC Microbiology GA 672MK UT WOS:000283588500087 PM 20826647 ER PT J AU Smith, SM van Besien, K Karrison, T Dancey, J McLaughlin, P Younes, A Smith, S Stiff, P Lester, E Modi, S Doyle, LA Vokes, EE Pro, B AF Smith, Sonali M. van Besien, Koen Karrison, Theodore Dancey, Janet McLaughlin, Peter Younes, Anas Smith, Scott Stiff, Patrick Lester, Eric Modi, Sanjiv Doyle, L. Austin Vokes, Everett E. Pro, Barbara TI Temsirolimus Has Activity in Non-Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RAPAMYCIN INHIBITOR EVEROLIMUS; MAMMALIAN TARGET; FOLLICULAR LYMPHOMA; CYCLIN D1; C-MYC; MTOR; CANCER; TRIAL; ACTIVATION; EXPRESSION AB Purpose Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas. Patients and Methods We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas). Results Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. Conclusions Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases. J Clin Oncol 28: 4740-4746. (C) 2010 by American Society of Clinical Oncology C1 [Smith, Sonali M.] Univ Chicago, Chicago, IL 60637 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Oncol Care Associates, St Joseph, MI USA. Joliet Oncol Hematol Associates, Joliet, IL USA. NCI, Bethesda, MD 20892 USA. Loyola Univ, Med Ctr, Chicago, IL 60611 USA. RP Smith, SM (reprint author), Univ Chicago, 5841 S Maryland Ave MC2115, Chicago, IL 60637 USA. EM smsmith@medicine.bsd.uchicago.edu RI van Besien, Koen/G-4221-2012 OI van Besien, Koen/0000-0002-8164-6211 FU Wyeth; National Institutes of Health [N01-CM17102, NCT00290472] FX Research Funding: Sonali M. Smith, Wyeth; Supported by Grants No. N01-CM17102 and NCT00290472 from the National Institutes of Health. NR 31 TC 90 Z9 92 U1 1 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 NOV 1 PY 2010 VL 28 IS 31 BP 4740 EP 4746 DI 10.1200/JCO.2010.29.2813 PG 7 WC Oncology SC Oncology GA 672LQ UT WOS:000283585200027 PM 20837940 ER PT J AU Salvadore, G Quiroz, JA Machado-Vieira, R Henter, ID Manji, HK Zarate, CA AF Salvadore, Giacomo Quiroz, Jorge A. Machado-Vieira, Rodrigo Henter, Ioline D. Manji, Husseini K. Zarate, Carlos A., Jr. TI The Neurobiology of the Switch Process in Bipolar Disorder: A Review SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID ANTIDEPRESSANT-INDUCED MANIA; REM-SLEEP DEPRIVATION; CELLULAR PLASTICITY CASCADES; FAMILY-BASED ASSOCIATION; NEUROTROPHIC FACTOR GENE; LONG-TERM TREATMENT; DEPRESSED-PATIENTS; DOUBLE-BLIND; CYCLE ACCELERATION; I DISORDER AB Objective: The singular phenomenon of switching from depression to its opposite state of mania or hypomania, and vice versa, distinguishes bipolar disorder from all other psychiatric disorders. Despite the fact that it is a core aspect of the clinical presentation of bipolar disorder, the neurobiology of the switch process is still poorly understood. In this review, we summarize the clinical evidence regarding somatic interventions associated with switching, with a particular focus on the biologic underpinnings presumably involved in the switch process. Data Sources: Literature for this review was obtained through a search of the MEDLINE database (1966-2008) using the following keywords and phrases: switch, bipolar disorder, bipolar depression, antidepressant, SSRIs, tricyclic antidepressants, norepinephrine, serotonin, treatment emergent affective switch, mania, hypomania, HPA-axis, glucocorticoids, amphetamine, dopamine, and sleep deprivation. Study Selection: All English-language, peer-reviewed, published literature, including randomized controlled studies, naturalistic and open-label studies, and case reports, were eligible for inclusion. Data Synthesis: Converging evidence suggests that certain pharmacologic and nonpharmacologic interventions with very different mechanisms of action, such as sleep deprivation, exogenous corticosteroids, and dopaminergic agonists, can trigger mood episode switches in patients with bipolar disorder. The switch-inducing potential of antidepressants is unclear, although tricyclic antidepressants, which confer higher risk of switching than other classes of antidepressants, are a possible exception. Several neurobiological factors appear to be associated with both spontaneous and treatment-emergent mood episode switches; these include abnormalities in catecholamine levels, up-regulation of neurotrophic and neuroplastic factors, hypothalamic-pituitary-adrenal axis hyperactivity, and circadian rhythms. Conclusions: There is a clear need to improve our understanding of the neurobiology of the switch process; research in this field would benefit from the systematic and integrated assessment of variables associated with switching. J Clin Psychiatry 2010;71(11):1488-1501 (C) Copyright 2010 Physicians Postgraduate Press, Inc. C1 [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut Mood & Anxiety Disorders Program, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. [Quiroz, Jorge A.] Roche Pharmaceut, New York, NY USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut Mood & Anxiety Disorders Program, Mark O Hatfield Clin Res Ctr, 10 Ctr Dr,Unit 7SE,Rm 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU National Institute of Mental Health (Bethesda, Maryland); NARSAD FX This study was supported by the Intramural Research Program of the National Institute of Mental Health (Bethesda, Maryland) and a NARSAD Award (Dr Zarate). NR 158 TC 73 Z9 74 U1 3 U2 17 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD NOV PY 2010 VL 71 IS 11 BP 1488 EP 1501 DI 10.4088/JCP.09r05259gre PG 14 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 693MK UT WOS:000285228000011 PM 20492846 ER PT J AU Dolle, RE Le Bourdonnec, B Worm, K Morales, GA Thomas, CJ Zhang, W AF Dolle, Roland E. Le Bourdonnec, Bertrand Worm, Karin Morales, Guillermo A. Thomas, Craig J. Zhang, Wei TI Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009 SO JOURNAL OF COMBINATORIAL CHEMISTRY LA English DT Review ID SOLID-PHASE SYNTHESIS; MICROWAVE-ASSISTED SYNTHESIS; DIVERSITY-ORIENTED SYNTHESIS; 3-COMPONENT COUPLING REACTION; PYRROLE-IMIDAZOLE POLYAMIDES; FLUOROUS-MIXTURE SYNTHESIS; ONE-POT SYNTHESIS; PARALLEL SYNTHESIS; SMALL-MOLECULE; MULTICOMPONENT REACTIONS C1 [Dolle, Roland E.; Le Bourdonnec, Bertrand; Worm, Karin] Adolor Corp, Exton, PA 19341 USA. [Morales, Guillermo A.] Morales Consulting LLC, Carmel, IN 46032 USA. [Thomas, Craig J.] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Zhang, Wei] Univ Massachusetts, Dept Chem, Boston, MA 02125 USA. RP Dolle, RE (reprint author), Adolor Corp, 700 Penn Dr, Exton, PA 19341 USA. EM roland.e.dolle@gmail.com FU Intramural NIH HHS [ZIB TR000004-02] NR 382 TC 49 Z9 49 U1 1 U2 36 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-4766 J9 J COMB CHEM JI J. Comb. Chem. PD NOV-DEC PY 2010 VL 12 IS 6 BP 765 EP 806 DI 10.1021/cc100128w PG 42 WC Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary SC Chemistry; Pharmacology & Pharmacy GA 675FB UT WOS:000283810600001 PM 20923157 ER PT J AU Dimitrov, E Usdin, TB AF Dimitrov, Eugene Usdin, Ted Bjoern TI Tuberoinfundibular Peptide of 39 Residues Modulates the Mouse Hypothalamic-Pituitary-Adrenal Axis Via Paraventricular Glutamatergic Neurons SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE neuropeptide; presynaptic facilitation; stress; paraventricular nucleus; parathyroid hormone 2 receptor; neuroendocrine ID THYROTROPIN-RELEASING-HORMONE; VASOACTIVE-INTESTINAL-PEPTIDE; CENTRAL-NERVOUS-SYSTEM; PROLACTIN SECRETION; RAT-BRAIN; MESSENGER-RNA; NORADRENERGIC EXCITATION; MAGNOCELLULAR NEURONS; TYROSINE-HYDROXYLASE; MONOCLONAL-ANTIBODY AB Neurons in the subparafascicular area at the caudal border of the thalamus that contain the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) densely innervate several hypothalamic areas, including the paraventricular nucleus (PVN). These areas contain a matching distribution of TIP39's receptor, the parathyroid hormone receptor 2 (PTH2R). Frequent PTH2R coexpression with a vesicular glutamate transporter (VGlut2) suggests that TIP39 could presynaptically regulate glutamate release. By using immunohistochemistry we found CRH-ir neurons surrounded by PTH2R-ir fibers and TIP39-ir axonal projections in the PVN area of the mouse brain. Labeling hypothalamic neuroendocrine neurons by peripheral injection of fluorogold in PTH2-RlacZ knock-in mice showed that most PTH2Rs are on PVN and peri-PVN interneurons and not on neuroendocrine cells. Double fluorescent in situ hybridization revealed a high level of coexpression between PTH2R and VGlut2 mRNA by cells located in the PVN and nearby brain areas. Local TIP39 infusion (100 pmol) robustly increased pCREB-ir in the PVN and adjacent perinuclear zone. It also increased plasma corticosterone and decreased plasma prolactin. These effects of TIP39 on pCREB-ir, corticosterone, and prolactin were abolished by coinfusion of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonopentanoic acid (AP-5; 30 pmol each) and were absent in PTH2R knockout mice. Basal plasma corticosterone was slightly decreased in TIP39 knockout mice just before onset of their active phase. The present data indicate that the TIP39 ligand/PTH2 receptor system provides facilitatory regulation of the hypothalamic-pituitary-adrenal axis via hypothalamic glutamatergic neurons and that it may regulate other neuroendocrine systems by a similar mechanism. J. Comp. Neurol. 518: 4375-4394, 2010. Published 2010 Wiley-Liss, Inc.(dagger) C1 [Dimitrov, Eugene; Usdin, Ted Bjoern] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), Bldg 35,Room 1B-215,35 Convent Dr,MSC 3728, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov FU National Institute of Mental Health, NIH [ZIA MH002685-16] FX Grant sponsor: Intramural Program of the National Institute of Mental Health, NIH; Grant number: ZIA MH002685-16. NR 79 TC 11 Z9 11 U1 1 U2 5 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 NOV 1 PY 2010 VL 518 IS 21 BP 4375 EP 4394 DI 10.1002/cne.22462 PG 20 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 655MD UT WOS:000282253200008 PM 20853513 ER PT J AU Walker, MP DiAugustine, RP Zeringue, E Bunger, MK Schmitt, M Archer, TK Richards, RG AF Walker, Michael P. DiAugustine, Richard P. Zeringue, Ernest Bunger, Maureen K. Schmitt, Martina Archer, Trevor K. Richards, R. Gregg TI An IGF1/insulin receptor substrate-1 pathway stimulates a mitotic kinase (cdk1) in the uterine epithelium during the proliferative response to estradiol SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID CYCLIN-DEPENDENT KINASES; FACTOR-I RECEPTOR; CELL-CYCLE; GROWTH-FACTOR; HISTONE H1; M-PHASE; TARGETED DISRUPTION; SIGNAL-TRANSDUCTION; NULL MUTATION; RAT UTERUS AB Estrogens are potent mitogens for some target organs, such as the uterus, and cancers that develop in this organ might be linked to the proliferative action of these hormones. However, the mechanism by which estrogens influence the cell cycle machinery is not known. We found that a null mutation for the insulin receptor substrate (IRS)-1, a docking protein that is important for IGF1 signaling, compromised hormone-induced mitosis in the uterine epithelium; BrdU incorporation was not affected. This selective effect on mitosis was associated with a reduction in uterine cyclin B-associated kinase activity; cyclin A-associated kinase activity was not changed. The null mutation also reduced the extent of hormone-induced phosphorylation of endogenous uterine histone H1, as determined with phospho-specific antiserum. Uterine epithelial cyclin dependent kinase (cdk)1 was induced in response to hormone, but the level of the kinase protein, as determined by immunoblotting, was noticeably less in the irs1 null mutant than that in the wild-type (WT) mouse, especially around the time of peak mitosis (24 h). Since IRS-1 binds/activates phosphatidylinositol 3-kinase (PI3K), the absence of this docking protein could impair signaling of a known pathway downstream of AKT that stimulates translation of cell cycle components. Indeed, we found that phosphorylation of uterine AKT (Ser473) in irs1 null mutants was less than that in WTs following treatment. Based on earlier studies, it is also possible that an IGF1/IRS-1/PI3K/AKT pathway regulates posttranslational changes in cdk1. This model may provide insights as to how a growth factor pathway can mediate hormone action on cell proliferation. Journal of Endocrinology (2010) 207, 225-235 C1 [Walker, Michael P.; DiAugustine, Richard P.; Zeringue, Ernest; Bunger, Maureen K.; Schmitt, Martina; Archer, Trevor K.; Richards, R. Gregg] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Mail Drop D4-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH [Z01 ES071006-09] FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH; project number Z01 ES071006-09. NR 56 TC 8 Z9 8 U1 1 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD NOV PY 2010 VL 207 IS 2 BP 225 EP 235 DI 10.1677/JOE-10-0102 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 662RH UT WOS:000282828700011 PM 20798132 ER PT J AU Price, RA AF Price, Rebecca Anhang TI Association Between Physician Specialty and Uptake of New Medical Technologies: HPV Tests in Florida Medicaid SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE clinical guidelines; appropriate use; disparities; cancer screening; technology adoption ID CLINICAL-PRACTICE GUIDELINES; EARLY-DETECTION PROGRAM; UNITED-STATES; RACIAL DISPARITIES; CERVICAL CYTOLOGY; NATIONAL BREAST; CANCER; MANAGEMENT; ADOPTION; WOMEN AB BACKGROUND: It is well established that specialists often adopt new medical technologies earlier than generalists, and that racial and ethnic minority patients are less likely than White patients to receive many procedures and prescription drugs. However, little is known about the role that specialists or generalists may play in reducing racial and ethnic disparities in uptake of new medical technologies. Human papillomavirus (HPV) DNA tests, introduced as a cervical cancer screening tool in 2000, present a rich context for exploring patterns of use across patient and provider subgroups. OBJECTIVE: To identify patient characteristics and the provider specially associated with overall and appropriate use of HPV DNA tests over time, and to examine the associations between clinical guidelines and adoption of the test in an underserved population. DESIGN: Retrospective longitudinal study using Florida Medicaid administrative claims data. PARTICIPANTS: Cervical cancer screening test claims for 415,239 female beneficiaries ages 21 to 64 from July 2001 through June 2006. MAIN MEASURES: Overall and appropriate use of HPV DNA tests. KEY RESULTS: Although minority women were initially less likely than White women to receive HPV DNA tests, test use grew more rapidly among Black and Hispanic women compared to White women. Obstetricians/gynecologists were significantly more likely than primary care providers to administer HPV DNA tests. Release of the first set of clinical guidelines was associated with a large increase in the use of HPV DNA tests (adjusted odds ratio: 2.46, p<0.0001); subsequent guidelines were associated with more modest increases. CONCLUSIONS: Uptake of new cervical cancer screening protocols can occur quickly among traditionally underserved groups and may be aided by early adoption by specialists. C1 [Price, Rebecca Anhang] NCI, Clin Res Directorate, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Price, Rebecca Anhang] NCI, Appl Canc Screening Res Branch, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Price, RA (reprint author), NCI, Clin Res Directorate, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ranhang@post.harvard.edu FU Foundation for Informed Medical Decision Making; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The author gratefully acknowledges Paul Cleary, Richard Frank, and Sue Goldie for their thoughtful comments on earlier drafts of the manuscript, and Christina Fu for outstanding technical assistance. The author was supported, in part, by a George Bennett Fellowship from the Foundation for Informed Medical Decision Making.; This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health. under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 40 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2010 VL 25 IS 11 BP 1178 EP 1185 DI 10.1007/s11606-010-1415-9 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 672YN UT WOS:000283624000010 PM 20582485 ER PT J AU Caplan, LJ Ivins, B Poole, JH Vanderploeg, RD Jaffee, MS Schwab, K AF Caplan, Leslie J. Ivins, Brian Poole, John H. Vanderploeg, Rodney D. Jaffee, Michael S. Schwab, Karen TI The Structure of Postconcussive Symptoms in 3 US Military Samples SO JOURNAL OF HEAD TRAUMA REHABILITATION LA English DT Article DE concussion; neuropsychology; postconcussive symptoms; traumatic brain injury ID TRAUMATIC BRAIN-INJURY; HEAD-INJURY; COMPUTER; INTERVIEW; QUESTIONNAIRE; NUMBER; RISK AB Objective: To evaluate alternative models of symptom clusters for the 22-item Neurobehavioral Symptom Inventory. Participants: Three military samples, including 2 nonclinical samples (n = 2420, n = 4244) and 1 sample of individuals with recent head injury (n = 617). Methods: In the first sample, exploratory factor analysis of Neurobehavioral Symptom Inventory responses was performed with tests of significant factors and model fit. In the other 2 samples, confirmatory factor analysis evaluated the fit of 3 models: 2- and 3-factor models based on the initial exploratory factor analysis, and a 9-factor model based on prior research. Main Outcome Measures: The exploratory factor analysis used 2 tests for the number of factors: Parallel Analysis and Minimum Average Partial test. Confirmatory factor analysis models were evaluated using 2 measures of model fit, Root Mean Square Error of Approximation and Comparative Fit Index. Results: Postconcussive symptoms can be described accurately by the 9 factors. However, the model of 3 intercorrelated factors, reflecting cognitive, affective, and somatic/sensory symptoms, fits the data more parsimoniously with little loss in model fit. Conclusion: Although the 9-cluster result from prior research provides a valid description of the relations among items of the inventory, a 3-factor model, consisting of somatic/sensory, affective, and cognitive factors, provides nearly as good a fit to the data, with greater parsimony. We encourage clinicians and researchers to conceptualize the Neurobehavioral Symptom Inventory in terms of 3 coherent clusters of symptoms rather than as 22 individual items. C1 [Caplan, Leslie J.] NIMH, NIH, Bethesda, MD 20892 USA. [Ivins, Brian; Jaffee, Michael S.; Schwab, Karen] Def & Vet Brain Injury Ctr, Washington, DC USA. [Poole, John H.] Vet Affairs Hlth Care Syst, Palo Alto, CA USA. [Vanderploeg, Rodney D.] Def & Vet Brain Injury Ctr, James A Haley Vet Affairs Med Ctr, Palo Alto, CA USA. [Vanderploeg, Rodney D.] Univ S Florida, Dept Psychiat, Tampa, FL USA. [Vanderploeg, Rodney D.] Univ S Florida, Dept Behav Sci & Psychol, Tampa, FL USA. RP Caplan, LJ (reprint author), US Dept Educ, Natl Inst Disabil & Rehabil Res, 400 Maryland Ave SW, Washington, DC 20202 USA. EM Leslie.Caplan@ed.gov NR 29 TC 42 Z9 42 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-9701 J9 J HEAD TRAUMA REHAB JI J. Head Trauma Rehabil. PD NOV-DEC PY 2010 VL 25 IS 6 BP 447 EP 458 DI 10.1097/HTR.0b013e3181d5bdbd PG 12 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 679HA UT WOS:000284151300007 ER PT J AU Danis, M Kotwani, N Garrett, J Rivera, I Davies-Cole, J Carter-Nolan, P AF Danis, Marion Kotwani, Namrata Garrett, Joanne Rivera, Ivonne Davies-Cole, John Carter-Nolan, Pamela TI Priorities of Low-Income Urban Residents for Interventions to Address the Socio-Economic Determinants of Health SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Health status disparity; health promotion; poverty; resource allocation; public participation ID PARTNERSHIP; PATHWAYS; PROGRAM; ADULTS AB Objectives. To determine the priorities of low-income urban residents for interventions that address the socio-economic determinants of health. Methods. We selected and estimated the cost of 16 interventions related to education, housing, nutrition, employment, health care, healthy behavior, neighborhood improvement, and transportation. Low-income residents of Washington, D.C. (N=431) participated in decision exercises to prioritize these interventions. Results. Given a budget valued at approximately twice an estimated cost of medical and dental care ($885), the interventions ultimately prioritized by the greatest percentage of individuals were: health insurance (95%), housing vouchers (82%) dental care (82%), job training (72%), adult education (63%), counseling (68%), healthy behavior incentives (68%), and job placement (67%). The percentages of respondents who received support for housing, adult education, and job training and placement were far less than the percentage who prioritized these interventions. Conclusions. Poor and low-income residents' priorities may usefully inform allocation of social services that affect health. C1 [Danis, Marion] NIH, Sect Eth & Hlth Policy, Bioeth Consultat Serv, Dept Bioeth,Clin Ctr, Bethesda, MD 20892 USA. [Garrett, Joanne] Univ N Carolina, Chapel Hill, NC USA. [Carter-Nolan, Pamela] Howard Univ, Washington, DC USA. RP Danis, M (reprint author), NIH, Sect Eth & Hlth Policy, Bioeth Consultat Serv, Dept Bioeth,Clin Ctr, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM mdanis@nih.gov FU Intramural NIH HHS [ZIA CL010527-06] NR 51 TC 4 Z9 4 U1 1 U2 11 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 NOV PY 2010 VL 21 IS 4 BP 1318 EP 1339 PG 22 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 672YC UT WOS:000283622700021 PM 21099082 ER PT J AU Ji, JF Wang, XW AF Ji, Junfang Wang, Xin Wei TI A Yin-Yang balancing act of the lin28/let-7 link in tumorigenesis SO JOURNAL OF HEPATOLOGY LA English DT Article DE Lin28; Let-7; Human malignancy; Hepatocellular carcinoma ID HEPATOCELLULAR-CARCINOMA; CANCER; CELLS; IDENTIFICATION AB Multiple members of the let-7 family of miRNAs are often repressed in human cancers, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins lin28 and lin28B block let-7 precursors from being processed to mature miRNAs, suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that lin28 and lin28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency approximately 15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. lin28 and lin28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of lin28 and lin28B with poor clinical prognosis. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Ji, Junfang; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 NR 10 TC 18 Z9 21 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2010 VL 53 IS 5 BP 974 EP 975 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 673ZK UT WOS:000283702500027 PM 20739081 ER PT J AU Atha, DH Manne, U Grizzle, WE Wagner, PD Srivastava, S Reipa, V AF Atha, Donald H. Manne, Upender Grizzle, William E. Wagner, Paul D. Srivastava, Sudhir Reipa, Vytas TI Standards for Immunohistochemical Imaging: A Protein Reference Device for Biomarker Quantitation SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE p53; immunohistochemistry; standards; cancer biomarker quantitation; molecular imaging; protein immobilization; spectroscopy; microscopy ID STORED PARAFFIN SLIDES; STRAND CONFORMATION POLYMORPHISM; MARKER-IMMUNOSTAINING INTENSITY; P53 POINT MUTATIONS; CAPILLARY-ELECTROPHORESIS; NUCLEAR ACCUMULATION; COLORECTAL ADENOCARCINOMA; PROGNOSTIC-SIGNIFICANCE; SILICON NANOPARTICLES; TELOMERASE ACTIVITY AB We are developing a reference device to be used in the validation of immunohistochemical imaging of biomarkers by microscopy. The prototype device consists of p53 protein immobilized at various concentrations on a glass slide. The device is designed as a reference control to be used with assays that incorporate commercially available anti-p53 antibodies. p53 protein was characterized by mass spectrometry and covalently immobilized through amide linkage to the (3-aminopropyl)trietoxysilane-modified glass surface. This procedure is reproducible and provides a chemically stable product in high yield. The surface-bound protein was shown to be immunoreactive by its specific interaction with anti-p53 antibody (Ab) and detection by absorbance and fluorescence spectroscopy. Also, comparison was made with microscopic images of Ab-stained tissue samples, known to stain positive for p53. Further development will be required to establish accurate surface protein concentrations in the range required for specific clinical applications. (J Histochem Cytochem 58:1005-1014, 2010) C1 [Atha, Donald H.; Reipa, Vytas] Natl Inst Stand & Technol, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Manne, Upender; Grizzle, William E.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Wagner, Paul D.; Srivastava, Sudhir] NCI, Canc Prevent Div, Rockville, MD USA. RP Atha, DH (reprint author), Natl Inst Stand & Technol, Div Biochem Sci, Bldg 227,Room A243,Mail Stop 8311,100 Bur Dr, Gaithersburg, MD 20899 USA. EM donald.atha@nist.gov FU National Cancer Institute-Early Detection Research Network (EDRN); National Institute of Standards and Technology (NIST)-Biochemical Science Division [YI-CN5001]; EDRN Reference Laboratory at UAB [5U24CA086359-10] FX This work was funded in part by National Cancer Institute-Early Detection Research Network (EDRN) and National Institute of Standards and Technology (NIST)-Biochemical Science Division jointly under interagency agreement no. YI-CN5001 and by the EDRN Reference Laboratory at UAB (5U24CA086359-10). NR 46 TC 0 Z9 0 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD NOV PY 2010 VL 58 IS 11 BP 1005 EP 1014 DI 10.1369/jhc.2010.956342 PG 10 WC Cell Biology SC Cell Biology GA 666JV UT WOS:000283111900006 PM 20805583 ER PT J AU Xing, JJ Wu, FQ Wang, SA Krensky, AM Mody, CH Zheng, CF AF Xing, Junji Wu, Fuqing Wang, Shuai Krensky, Alan M. Mody, Christopher H. Zheng, Chunfu TI Granulysin Production and Anticryptococcal Activity Is Dependent upon a Far Upstream Enhancer That Binds STAT5 in Human Peripheral Blood CD4(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CRYPTOCOCCUS-NEOFORMANS; MYCOBACTERIUM-TUBERCULOSIS; REQUIRES GRANULYSIN; SIGNALING PATHWAYS; GENE-EXPRESSION; NATURAL-KILLER; DNA-BINDING; IFN-ALPHA; NK CELLS; ACTIVATION AB Previous studies have demonstrated that STAT5 is critical for expression of granulysin and antimicrobial activity. Because the signaling pathway and the resultant microbicidal activity are defective in HIV-infected patients, the mechanism by which STAT5 leads to granulysin expression is of great interest. In the current study, IL-2-stimulated CRL-2105 CD4(+) T cells expressed granulysin and killed Cryptococcus neoformans similar to primary CD4(+) T cells. The enhancer activity of the upstream element of the granulysin promoter was analyzed in primary CD4(+) T cells and CRL-2105 T cells with a luciferase reporter assay, and a STAT5 binding site, 18,302 to 18,177 bp upstream of the transcription start site, was identified as an enhancer. Additionally, the enhancer functioned in the context of heterologous SV40 promoter irrespective of its transcriptional orientation. Chromatin immunoprecipitation and EMSAs demonstrated that the enhancer element bound STAT5 both in vivo and in vitro, and mutation of the STAT5 binding site abrogated its enhancer activity. Furthermore, overexpression of a dominant negative STAT5a abolished the enhancer activity of the STAT5 binding site and abrogated the anticryptococcal activity of IL-2-stimulated primary CD4(+) T cells. Taken together, these data provide details about the complex regulation leading to granulysin expression and anticryptococcal activity in primary CD4(+) T cells. The Journal of Immunology, 2010, 185: 5074-5081. C1 [Xing, Junji; Wu, Fuqing; Wang, Shuai; Zheng, Chunfu] Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430071, Peoples R China. [Krensky, Alan M.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Mody, Christopher H.] Univ Calgary, Dept Internal Med, Calgary, AB T2N 4N1, Canada. [Mody, Christopher H.] Univ Calgary, Dept Microbiol & Infect Dis, Calgary, AB T2N 4N1, Canada. RP Zheng, CF (reprint author), Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, 44 Xiaohongshan, Wuhan 430071, Peoples R China. EM zheng.alan@hotmail.com OI Xing, Junji/0000-0002-3392-5427; Mody, Christopher H./0000-0001-7264-3679 FU National Natural Science Foundation of China [30972670]; Chinese Academy of Sciences [20071010-141]; Canadian Institutes for Health Research; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from the National Natural Science Foundation of China (30972670) and the Start-up Fund of the Hundred Talents Program of the Chinese Academy of Sciences (20071010-141) (to C.Z.), the Canadian Institutes for Health Research (to C. H. M.), and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to A.M.K.). NR 40 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2010 VL 185 IS 9 BP 5074 EP 5081 DI 10.4049/jimmunol.1001725 PG 8 WC Immunology SC Immunology GA 668DL UT WOS:000283248700020 PM 20889547 ER PT J AU Gordon, SN Cervasi, B Odorizzi, P Silverman, R Aberra, F Ginsberg, G Estes, JD Paiardini, M Frank, I Silvestri, G AF Gordon, Shari N. Cervasi, Barbara Odorizzi, Pamela Silverman, Randee Aberra, Faten Ginsberg, Gregory Estes, Jacob D. Paiardini, Mirko Frank, Ian Silvestri, Guido TI Disruption of Intestinal CD4(+) T Cell Homeostasis Is a Key Marker of Systemic CD4(+) T Cell Activation in HIV-Infected Individuals SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; LYMPHOID-TISSUE; GASTROINTESTINAL-TRACT; IMMUNE ACTIVATION; MICROBIAL TRANSLOCATION; AIDS PATHOGENESIS; TYPE-1 INFECTION; SIV INFECTION; SOOTY MANGABEYS AB HIV infection is associated with depletion of intestinal CD4(+) T cells, resulting in mucosal immune dysfunction, microbial translocation, chronic immune activation, and progressive immunodeficiency. In this study, we examined HIV-infected individuals with active virus replication (n = 15), treated with antiretroviral therapy (n = 13), and healthy controls (n = 11) and conducted a comparative analysis of T cells derived from blood and four gastrointestinal (GI) sites (terminal ileum, right colon, left colon, and sigmoid colon). As expected, we found that HIV infection is associated with depletion of total CD4(+) T cells as well as CD4(+) CCR5(+) T cells in all GI sites, with higher levels of these cells found in ART-treated individuals than in those with active virus replication. While the levels of both CD4(+) and CD8(+) T cell proliferation were higher in the blood of untreated HIV-infected individuals, only CD4(+) T cell proliferation was significantly increased in the gut of the same patients. We also noted that the levels of CD4(+) T cells and the percentages of CD4(+)Ki67(+) proliferating T cells are inversely correlated in both blood and intestinal tissues, thus suggesting that CD4(+) T cell homeostasis is similarly affected by HIV infection in these distinct anatomic compartments. Importantly, the level of intestinal CD4(+) T cells (both total and Th17 cells) was inversely correlated with the percentage of circulating CD4(+)Ki67(+) T cells. Collectively, these data confirm that the GI tract is a key player in the immunopathogenesis of HIV infection, and they reveal a strong association between the destruction of intestinal CD4(+) T cell homeostasis in the gut and the level of systemic CD4(+) T cell activation. The Journal of Immunology, 2010, 185: 5169-5179. C1 [Silvestri, Guido] Emory Univ, Div Microbiol & Immunol, Yerkes Natl Primate Res Ctr, Dept Pathol & Lab Med,Sch Med, Atlanta, GA 30329 USA. [Gordon, Shari N.; Cervasi, Barbara; Odorizzi, Pamela; Silverman, Randee; Aberra, Faten; Ginsberg, Gregory; Paiardini, Mirko; Frank, Ian; Silvestri, Guido] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Gordon, Shari N.; Cervasi, Barbara; Odorizzi, Pamela; Silverman, Randee; Aberra, Faten; Ginsberg, Gregory; Paiardini, Mirko; Frank, Ian; Silvestri, Guido] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Gordon, Shari N.] NCI, Anim Models & Vaccine Sect, NIH, Bethesda, MD 20892 USA. [Estes, Jacob D.] NCI, AIDS Vaccine Sect, SAIC Frederick, NIH, Bethesda, MD 20892 USA. RP Silvestri, G (reprint author), Emory Univ, Div Microbiol & Immunol, Yerkes Natl Primate Res Ctr, Dept Pathol & Lab Med,Sch Med, 929 Gatewood Rd, Atlanta, GA 30329 USA. EM gsilves@emory.edu FU University of Pennsylvania Center for AIDS Research; National Institutes of Health [R01 AI084836, P60DA005186]; W.W. Smith Foundation; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by the University of Pennsylvania Center for AIDS Research, by National Institutes of Health Grants R01 AI084836 (to M.P.) and P60DA005186 (to I.F.), and by the W.W. Smith Foundation (to G.S.). This work was funded in part with federal funds from National Cancer Institute, National Institutes of Health Contract No. HHSN261200800001E. NR 46 TC 60 Z9 60 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 NOV 1 PY 2010 VL 185 IS 9 BP 5169 EP 5179 DI 10.4049/jimmunol.1001801 PG 11 WC Immunology SC Immunology GA 668DL UT WOS:000283248700030 PM 20889546 ER PT J AU Park, KU Jin, P Sabatino, M Feng, J Civini, S Khuu, H Berg, M Childs, R Stroncek, D AF Park, Kyoung Un Jin, Ping Sabatino, Marianna Feng, Ji Civini, Sara Khuu, Hanh Berg, Maria Childs, Richard Stroncek, David TI Gene Expression Analysis of Ex Vivo Expanded and Freshly Isolated NK Cells From Cancer Patients SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE consistency; expansion; gene and microRNA; natural killer cells; potency ID NATURAL-KILLER-CELLS; TUMOR-NECROSIS-FACTOR; EMBRYONIC STEM-CELLS; IN-VIVO; T-CELL; IMMUNOTHERAPY; LYMPHOTOXIN; DIFFERENTIATION; GRANZYMES; PATTERNS AB The infusion of natural killer (NK) cells is a promising therapy for patients with advanced malignancies. Clinical expanded NK-cell products were compared with freshly isolated NK cells. Autologous peripheral blood mononuclear cells were collected by apheresis from 8 patients. NK cells were isolated by anti-CD3-negative selection followed by anti-CD56-positive selection. They were then expanded by co-culture with interleukin-2 and an irradiated Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line (EBV-TM-LCL) to produce 14 NK-cell products. Molecular changes in the 14 NK-cell products were characterized using gene and microRNA expression microarrays. EBV-TM-LCL feeder cells from 3 lots were also analyzed as they were expanded for over 90 days and each lot was used for multiple NK-cell expansions. The gene expression profiles among the 3 EBV-TM-LCL lots used showed no differences and were not affected by their time in culture. Freshly isolated and expanded NK cells had distinct gene and microRNA expression profiles. Compared with fresh NK cells, expanded NK cells overexpressed 1098 genes and 28 human microRNAs. Genes in the crosstalk between dendritic and NK cells and metabolic pathways were up-regulated in expanded NK cells, whereas genes in a number of immune function pathways were down-regulated. Among all the most up-regulated genes were the NK cell-activating receptor natural cytotoxicity triggering receptor 3, myxovirus restistance 1, lymphotoxin beta, and BCL2-associated X protein. Although some expanded NK-cell product variability was observed, perhaps related to patient factors, further studies on larger numbers of products will be needed to determine the impact of these differences on clinical outcomes. C1 [Park, Kyoung Un; Jin, Ping; Sabatino, Marianna; Feng, Ji; Civini, Sara; Khuu, Hanh; Stroncek, David] NHLBI, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Berg, Maria; Childs, Richard] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Park, Kyoung Un] Seoul Natl Univ Bundang Hosp, Dept Lab Med, Songnam, South Korea. RP Stroncek, D (reprint author), NHLBI, Dept Transfus Med, Ctr Clin, NIH, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov RI Park, Kyoung Un/J-5473-2012 FU Intramural NIH HHS [ZIA CL002119-03] NR 30 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2010 VL 33 IS 9 BP 945 EP 955 DI 10.1097/CJI.0b013e3181f71b81 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 671HS UT WOS:000283492300003 PM 20948442 ER PT J AU Inozume, T Hanada, KI Wang, QJ Ahmadzadeh, M Wunderlich, JR Rosenberg, SA Yang, JC AF Inozume, Takashi Hanada, Ken-ichi Wang, Qiong J. Ahmadzadeh, Mojgan Wunderlich, John R. Rosenberg, Steven A. Yang, James C. TI Selection of CD8(+)PD-1(+) Lymphocytes in Fresh Human Melanomas Enriches for Tumor-reactive T Cells SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE PD-1; PD-L1; TIL; tumor immunity; melanoma; tumor digest; tumor microenvironment ID INDUCED EXPRESSION; PD-1; CANCER; THERAPY; ANTIGEN; ACTIVATION; IMMUNOTHERAPY; CARCINOMA; RECEPTOR; MEMBER AB CD8(+) tumor-infiltrating lymphocytes (TILs) in human melanomas express high levels of PD-1 and are functionally impaired. However, adoptive cell therapy using in vitro-expanded TIL can be a highly effective therapy for patients with advanced melanoma. This discrepancy led us to further analyze the CD8(+)PD-1(+) TILs. We found that the percentage of PD-1-expressing CD8(+) T cells was higher in the tumor digests that generate tumor-reactive TILs after in vitro culture in interleukin-2 (P=0.0007). Also sorted and expanded CD8(+)PD-1(+) T cells in tumor digests showed much higher tumor-specific interferon-gamma production compared with CD8(+) PD-1(-) T cells. These results suggested that tumor-specific CD8(+) T cells in melanoma tumor digests are largely PD-1(+), and this population can recover function after culturing in interleukin-2. PD-1 has been reported as an inhibitory receptor on T cells. We found that the in vitro functional suppression of cultured-TILs from native levels of PD-L1 expression on melanomas was minimal, and moreover expression level of PD-1 on CD8(+) tumor-specific TILs decreased during the culture. As a consequence, the PD-1 receptor can be a useful biomarker for enriching tumor-specific T cells from fresh melanomas. C1 [Inozume, Takashi; Hanada, Ken-ichi; Wang, Qiong J.; Ahmadzadeh, Mojgan; Wunderlich, John R.; Rosenberg, Steven A.; Yang, James C.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, NIH, 9000 Rockville Pike,Bldg 10 CRC,Rm 3W-3840, Bethesda, MD 20892 USA. EM JamesYang@mail.nih.gov RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 NR 24 TC 31 Z9 30 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2010 VL 33 IS 9 BP 956 EP 964 DI 10.1097/CJI.0b013e3181fad2b0 PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 671HS UT WOS:000283492300004 PM 20948441 ER PT J AU Biryahwaho, B Dollard, SC Pfeiffer, RM Shebl, FM Munuo, S Amin, MM Hladik, W Parsons, R Mbulaiteye, SM AF Biryahwaho, Benon Dollard, Sheila C. Pfeiffer, Ruth M. Shebl, Fatma M. Munuo, Stella Amin, Minal M. Hladik, Wolfgang Parsons, Ruth Mbulaiteye, Sam M. TI Sex and Geographic Patterns of Human Herpesvirus 8 Infection in a Nationally Representative Population-Based Sample in Uganda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; SUB-SAHARAN AFRICA; KAPOSIS-SARCOMA; RISK-FACTORS; TRANSMISSION; SEROPREVALENCE; PREVALENCE; PARASITES; CANCER; ADULTS AB Background. Human herpesvirus 8 (HHV8), the infectious cause of Kaposi sarcoma, varies dramatically across Africa, suggesting that cofactors correlated with large-area geographic or environmental characteristics may influence risk of infection. Variation in HHV8 seropositivity across small-area regions within countries in Africa is unknown. We investigated this issue in Uganda, where Kaposi sarcoma distribution is uneven and well described. Methods. Archival samples from individuals aged 15-59 years randomly selected from a nationally representative 2004-2005 human immunodeficiency virus-AIDS serobehavioral survey were tested for HHV8 seropositivity with use of enzyme immunoassays based on synthetic peptides from the K8.1 and orf65 viral genes. Adjusted odds ratios and 95% confidence intervals (CIs) of association of HHV8 seropositivity with demographic risk factors were estimated. Results. Among 2681 individuals tested, HHV8 seropositivity was 55.4%. HHV8 seropositivity was lower in female than in male persons (adjusted odds ratio, 0.82 [95% CI, 0.69-0.97]) and increased 2.2% (95% CI, 1.0%-3.6%) in female persons and 1.2% (95% CI, 1.0%-2.3%) in male persons per year of age. HHV8 seropositivity was inversely associated with education (P = .01, for trend) and was elevated in the West Nile region, compared with the Central region (adjusted odds ratio, 1.49 [95% CI, 1.02-2.18]) but not with other regions. Conclusions. Our findings suggest that HHV8 seropositivity in Uganda may be influenced by cofactors correlated with small-area geography, age, sex, and education. C1 [Biryahwaho, Benon] Uganda Virus Res Inst, Entebbe, Uganda. [Hladik, Wolfgang] Ctr Dis Control & Prevent, Entebbe, Uganda. [Dollard, Sheila C.; Amin, Minal M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Pfeiffer, Ruth M.; Shebl, Fatma M.; Mbulaiteye, Sam M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Munuo, Stella; Parsons, Ruth] Informat Management Serv Inc, Rockville, MD USA. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Execut Plaza S,Rm 7080,MSC 7248, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services [HHSN2612009004060P, N02-CP-31003]; NCI; Centers for Disease Control and Prevention [IAA Y1CP903801] FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services (contract HHSN2612009004060P and Support Services contract N02-CP-31003); Inter-Agency Agreement between NCI and the Centers for Disease Control and Prevention (IAA Y1CP903801). NR 35 TC 13 Z9 13 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2010 VL 202 IS 9 BP 1347 EP 1353 DI 10.1086/656525 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 656VB UT WOS:000282367900008 PM 20863232 ER PT J AU Apetrei, C Gaufin, T Gautam, R Vinton, C Hirsch, V Lewis, M Brenchley, J Pandrea, I AF Apetrei, Cristian Gaufin, Thaidra Gautam, Rajeev Vinton, Carol Hirsch, Vanessa Lewis, Mark Brenchley, Jason Pandrea, Ivona TI Pattern of SIVagm Infection in Patas Monkeys Suggests that Host Adaptation to Simian Immunodeficiency Virus Infection May Result in Resistance to Infection and Virus Extinction SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT International Symposium on Natural Immunity to HIV CY NOV 15-17, 2009 CL Winnipeg, CANADA ID AFRICAN-GREEN MONKEYS; NONHUMAN PRIMATE HOSTS; CD4(+) T-CELLS; NATURAL HOSTS; WILD; TRANSMISSION; REPLICATION; PAUCITY; AIDS AB Patas monkeys were not reported to carry species-specific simian immunodeficiency virus (SIV), but cross-species transmission of SIVagm to patas monkeys occurred in the wild. We report that patas monkeys share immunophenotypic features with natural hosts of SIV; that is, low levels of CD4(+) T cells and low CCR5 expression on CD4(+) T cells. In 1 patas monkey with undetectable levels of CD4(+) T cells, experimental exposure to SIVagm did not result in infection. The other experimentally infected patas monkeys showed an infection pattern similar to SIV infection in natural hosts. Thus, down-regulation of CD4 and CCR5 expression on CD4(+) T cells may effectively control human immunodeficiency virus acquisition and result in SIV extinction. C1 [Apetrei, Cristian; Pandrea, Ivona] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA 15261 USA. [Apetrei, Cristian; Gaufin, Thaidra; Gautam, Rajeev] Tulane Natl Primate Res Ctr, Div Microbiol, Covington, LA USA. [Apetrei, Cristian; Gaufin, Thaidra; Gautam, Rajeev] Tulane Natl Primate Res Ctr, Div Comparat Pathol, Covington, LA USA. [Apetrei, Cristian] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. [Pandrea, Ivona] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA. [Vinton, Carol; Hirsch, Vanessa; Brenchley, Jason] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Lewis, Mark; Pandrea, Ivona] Bioqual, Rockville, MD USA. RP Apetrei, C (reprint author), Univ Pittsburgh, Ctr Vaccine Res, 9044 Biol Sci Tower 3,3501 5th Ave, Pittsburgh, PA 15261 USA. EM apetreic@pitt.edu FU National Institute of Allergy and Infectious Diseases and National Center for Research Resources, National Institutes of Health [R01 AI064066, R21 AI069935, R01 AI065325, R01 RR025781, RR-00168]; Bill and Melinda Gates Foundation; University of Manitoba FX National Institute of Allergy and Infectious Diseases and National Center for Research Resources, National Institutes of Health (grants R01 AI064066 and R21 AI069935, to I.P.; grant R01 AI065325, to C.A.; grant R01 RR025781, to C.A. and I.P.; and grant RR-00168, to the Tulane National Primate Research Center).; This article is part of a supplement entitled "Natural Immunity to HIV-1 Infection," sponsored by the Bill and Melinda Gates Foundation and the University of Manitoba. NR 16 TC 18 Z9 18 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2010 VL 202 SU 3 BP S371 EP S376 DI 10.1086/655970 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 656VK UT WOS:000282369000010 PM 20887227 ER PT J AU Lederman, MM Alter, G Daskalakis, DC Rodriguez, B Sieg, SF Hardy, G Cho, M Anthony, D Harding, C Weinberg, A Silverman, RH Douek, DC Margolis, L Goldstein, DB Carrington, M Goedert, JJ AF Lederman, Michael M. Alter, Galit Daskalakis, Demetre C. Rodriguez, Benigno Sieg, Scott F. Hardy, Gareth Cho, Michael Anthony, Donald Harding, Clifford Weinberg, Aaron Silverman, Robert H. Douek, Daniel C. Margolis, Leonid Goldstein, David B. Carrington, Mary Goedert, James J. TI Determinants of Protection among HIV-Exposed Seronegative Persons: An Overview SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT International Symposium on Natural Immunity to HIV CY NOV 15-17, 2009 CL Winnipeg, CANADA ID SIMIAN IMMUNODEFICIENCY VIRUS; KENYAN SEX WORKERS; DISEASE PROGRESSION; TYPE-1 INFECTION; T-CELLS; VAGINAL TRANSMISSION; GENETIC-VARIATION; BOOSTING REGIMEN; RESISTANCE; SUSCEPTIBILITY AB Both clinical experience and a growing medical literature indicate that some persons who have been exposed to human immunodeficiency virus (HIV) infection remain uninfected. Although in some instances this may represent good fortune, cohorts of uninfected persons have been reported who are considered at high risk for infection. In these cohorts a variety of characteristics have been proposed as mediating protection, but to date only the 32-base pair deletion in the chemokine (C-C motif) receptor 5 gene, which results in complete failure of cell surface expression of this coreceptor, has been associated with high-level protection from HIV infection. With this in mind, there are probably many other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. Because some of these factors are probably incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high-risk uninfected cohorts, who should undergo targeted studies of plausible mediators and broad screening for unexpected determinants of protection. C1 [Lederman, Michael M.; Rodriguez, Benigno; Sieg, Scott F.; Hardy, Gareth; Anthony, Donald; Harding, Clifford] Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Ctr AIDS Res, Cleveland, OH 44106 USA. [Weinberg, Aaron] Case Western Reserve Univ, Sch Dent, Cleveland, OH 44106 USA. [Silverman, Robert H.] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA. [Alter, Galit] Harvard Univ, Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02115 USA. [Daskalakis, Demetre C.] NYU, Sch Med, Div Infect Dis & Immunol, New York, NY USA. [Cho, Michael] Iowa State Univ, Coll Vet Med, Ames, IA USA. [Douek, Daniel C.] Natl Inst Allergy Immunol & Infect Dis, Human Immunol Sect, Vaccine Res Ctr, Bethesda, MD USA. [Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, NIH, Bethesda, MD 20892 USA. [Carrington, Mary] NCI, Expt Immunol Lab, SAIC Frederick, NIH, Frederick, MD 21701 USA. [Goldstein, David B.] Duke Univ, Inst Genome Sci & Policy, Ctr Human Genome Variat, Durham, NC USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, 2061 Cornell Rd, Cleveland, OH 44106 USA. EM MXL6@case.edu RI Rodriguez, Benigno/C-3365-2009 OI Rodriguez, Benigno/0000-0001-9736-7957 FU Center for AIDS Research at Case Western Reserve University, University Hospitals / Case Medical Center [AI -36219]; Bill and Melinda Gates Foundation; University of Manitoba FX Center for AIDS Research at Case Western Reserve University, University Hospitals / Case Medical Center (grant AI -36219).; This article is part of a supplement entitled "Natural Immunity to HIV-1 Infection," sponsored by the Bill and Melinda Gates Foundation and the University of Manitoba. NR 54 TC 29 Z9 30 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2010 VL 202 SU 3 BP S333 EP S338 DI 10.1086/655967 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 656VK UT WOS:000282369000003 PM 20887220 ER PT J AU Shearer, G Clerici, M AF Shearer, Gene Clerici, Mario TI Historical Perspective on HIV-Exposed Seronegative Individuals: Has Nature Done the Experiment for Us? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT International Symposium on Natural Immunity to HIV CY NOV 15-17, 2009 CL Winnipeg, CANADA ID T-LYMPHOCYTE RESPONSES; PERIPHERAL-BLOOD; DRUG-USERS; INFECTION; TYPE-1; TRANSMISSION; IMMUNITY; MUCOSAL; IMMUNOPATHOGENESIS; PROSTITUTES AB Multiple and frequent exposure to the human immunodeficiency virus (HIV) does not necessarily result in HIV infection. Approximately 15% of HIV exposed seronegative individuals repeatedly resist infection, a phenomenon that has been observed in all investigated HIV-exposed cohorts. This brief report provides a limited historic perspective of the discovery of these cohorts and outlines some of the immunologic and genetic parameters that are associated with resistance. We raise the possibility that assessing immunologic parameters of the phenomenon might provide insights that might be relevant for effective AIDS vaccine design. C1 [Clerici, Mario] Univ Milan, Cattedra Immunol, Sch Med, DISP LITA Vialba,Dept Biomed Sci & Technol, I-20157 Milan, Italy. [Shearer, Gene] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Clerici, Mario] IRECS, Don C Gnocchi Fdn, Milan, Italy. RP Clerici, M (reprint author), Univ Milan, Cattedra Immunol, Sch Med, DISP LITA Vialba,Dept Biomed Sci & Technol, Via GB Grassi 74, I-20157 Milan, Italy. EM mario.clerici@unimi.it OI Clerici, Mario/0000-0001-5920-6191 FU National Cancer Institute; Bill and Melinda Gates Foundation; University of Manitoba FX Intramural Research Program, National Cancer Institute.; This article is part of a supplement entitled "Natural Immunity to HIV-1 Infection," sponsored by the Bill and Melinda Gates Foundation and the University of Manitoba. NR 25 TC 14 Z9 14 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2010 VL 202 SU 3 BP S329 EP S332 DI 10.1086/655974 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 656VK UT WOS:000282369000002 PM 20887219 ER PT J AU Bagashev, A Fitzgerald, MC LaRosa, DF Rose, PP Cherry, S Johnson, AC Sullivan, KE AF Bagashev, Asen Fitzgerald, Michael C. LaRosa, David F. Rose, Patrick P. Cherry, Sara Johnson, Alfred C. Sullivan, Kathleen E. TI Leucine-Rich Repeat (in Flightless I) Interacting Protein-1 Regulates a Rapid Type I Interferon Response SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID INFLUENZA-A-VIRUS; RIG-I; NS1 PROTEIN; ANTIVIRAL RESPONSES; INNATE IMMUNITY; BETA-INTERFERON; RNA; INFECTION; CELLS; PATHWAY AB The cell autonomous response to viral infection is carefully regulated to induce type I interferons (IFNs), which in turn induce the establishment of an antiviral state. Leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) and LRRFIP2 are 2 related proteins that have been identified as interacting with MyD88 and Flightless I homolog, a leucine-rich repeat protein. LRRFIP2 positively regulates NFkB and macrophage cytokine production after lipopolysaccharide, but less is known about LRRFIP1. We hypothesized that LRRFIP1 could be more important in antiviral responses, as overexpression led to type I IFN production in a pilot study. The induction of type I IFNs occurred even in the absence of virus, but was enhanced by the presence of virus. Conversely, knockdown of LRRFIP1 compromised IFN expression. We found that LRRFIP1 was rapidly recruited to influenza-containing early endosomes in a p38-dependent fashion. This was specific for virus-containing endosomes as there was almost no colocalization of LRRFIP1 with early endosomes in the absence of virus. Further, LRRFIP1 was recruited to RNA-containing vesicles. Taken together, these data suggest that LRRFIP1 participates in cell responses to virus at early time points and is important for type I IFN induction. C1 [Bagashev, Asen; Fitzgerald, Michael C.; Sullivan, Kathleen E.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Allergy Immunol, Philadelphia, PA 19104 USA. [LaRosa, David F.] Univ Penn, Dept Med, Sch Med, Philadelphia, PA 19104 USA. [Rose, Patrick P.; Cherry, Sara] Univ Penn, Penn Genom Inst, Dept Microbiol, Philadelphia, PA 19104 USA. [Johnson, Alfred C.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sullivan, KE (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Allergy Immunol, Philadelphia, PA 19104 USA. EM sullivak@mail.med.upenn.edu RI Bagashev, Asen/D-2913-2011; OI Bagashev, Asen/0000-0001-9900-8106; Sullivan, Kathleen/0000-0003-4018-1646 FU NIH [RO1 RO1AI44127, NO1AI50024] FX The work reported in this article was supported by NIH RO1 RO1AI44127 and NO1AI50024. The authors would like to thank Bruce Beutler for the gift of the Unc-93B expression plasmid, and Michael Gale Jr. and Shizuo Akira for the RIG-I knockout and control MEFs. The authors also thank Phillip Johnson, Jeff Bergelson, and Joan Durbin for critical readings of the article. NR 37 TC 9 Z9 10 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD NOV PY 2010 VL 30 IS 11 BP 843 EP 852 DI 10.1089/jir.2010.0017 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 675UH UT WOS:000283862400007 PM 20586614 ER PT J AU Li, QL Sadowski, S Frank, M Chai, CL Varadi, A Ho, SY Lou, H Dean, M Thisse, C Thisse, B Uitto, J AF Li, Qiaoli Sadowski, Sara Frank, Michael Chai, Chunli Varadi, Andras Ho, Shiu-Ying Lou, Hong Dean, Michael Thisse, Christine Thisse, Bernard Uitto, Jouni TI The abcc6a Gene Expression Is Required for Normal Zebrafish Development SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PSEUDOXANTHOMA-ELASTICUM; MOLECULAR-GENETICS; PUTATIVE PATHOMECHANISMS; TOPOLOGY PREDICTION; CONNECTIVE TISSUES; DISEASE; TRANSPORTERS; PHENOTYPE; HETEROZYGOSITY; MINERALIZATION AB Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6 gene, which encodes a putative efflux transporter, ABCC6. The zebrafish (Danio rerio) has two ABCC6-related sequences. To study the function of abcc6 during zebrafish development, the mRNA expression levels were measured using RT-PCR and in situ hybridization. The abcc6a showed a relatively high level of expression at 5 days post-fertilization (d.p.f.) and the expression was specific to the Kupffer's vesicles. The abcc6b expression was evident at 6 hours post-fertilization (h.p.f.) and remained high up to 8 d.p.f., corresponding to embryonic kidney proximal tubules. Morpholinos were designed to both genes to prevent pre-mRNA splicing and block translation. Injection of the abcc6a morpholinos into 1-4 cell zebrafish embryos decreased gene expression by 54-81%, and induced a phenotype, pericardial edema and curled tail associated with death at around 8 d.p.f. Microinjecting zebrafish embryos with full-length mouse Abcc6 mRNA together with the morpholino completely rescued this phenotype. No phenotypic changes were observed when the abcc6b gene morpholino was injected into embryos with knockdown efficiency of 100%. These results suggest that abcc6a is an essential gene for normal zebrafish development and provide insight into the function of ABCC6, the gene mutated in PXE. C1 [Li, Qiaoli; Sadowski, Sara; Frank, Michael; Uitto, Jouni] Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. [Li, Qiaoli; Sadowski, Sara; Frank, Michael; Uitto, Jouni] Thomas Jefferson Univ, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA. [Chai, Chunli; Thisse, Christine; Thisse, Bernard] Univ Virginia, Sch Med, Dept Cell Biol, Charlottesville, VA 22908 USA. [Varadi, Andras] Hungarian Acad Sci, Inst Enzymol, Budapest, Hungary. [Ho, Shiu-Ying; Uitto, Jouni] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Lou, Hong] SAIC Frederick, Frederick, MD USA. [Dean, Michael] NCI FCRDC, Human Genet Sect, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Chai, Chunli] Southwest Univ, Coll Biotechnol, Chongqing 40076, Peoples R China. RP Uitto, J (reprint author), Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, 233 S,10th St,Suite 450 BLSB, Philadelphia, PA 19107 USA. EM Jouni.uitto@jefferson.edu RI Varadi, Andras/A-2055-2012; Dean, Michael/G-8172-2012; Li, Qiaoli/F-8383-2013 OI Dean, Michael/0000-0003-2234-0631; FU DHHS, NIH/NIAMS [R01 AR28450, R01 AR55225]; OTKA of Hungary [NI-68950]; University of Virginia FX We thank HsingYin Liu and Reid Oldenburg for technical assistance; Terry Hyslop and Jocelyn Andrel (Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University), and GianPaolo Guercio and Carol Kelly for help in the article preparation. These studies were supported by DHHS, NIH/NIAMS grants R01 AR28450 and R01 AR55225 (to JU), by OTKA NI-68950 of Hungary (to AV), and by the University of Virginia (to CT and BT). NR 30 TC 13 Z9 14 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2010 VL 130 IS 11 BP 2561 EP 2568 DI 10.1038/jid.2010.174 PG 8 WC Dermatology SC Dermatology GA 664MC UT WOS:000282963600008 PM 20596085 ER PT J AU Kronenberg, K Brosch, S Butsch, F Tada, Y Shibagaki, N Udey, MC von Stebut, E AF Kronenberg, Katharina Brosch, Sven Butsch, Florian Tada, Yayoi Shibagaki, Naotaka Udey, Mark C. von Stebut, Esther TI Vaccination with TAT-Antigen Fusion Protein Induces Protective, CD8(+) T Cell-Mediated Immunity Against Leishmania Major SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID FC-GAMMA RECEPTORS; DENDRITIC CELLS; CLASS-II; CPG OLIGODEOXYNUCLEOTIDES; INTRACELLULAR PATHOGEN; MURINE LEISHMANIASIS; PERSISTENT PARASITES; ANTITUMOR IMMUNITY; INTERFERON-GAMMA; EX-VIVO AB In murine leishmaniasis, healing is mediated by IFN-gamma-producing CD4(+) and CD8(+) T cells. Thus, an efficacious vaccine should induce Th1 and Tc1 cells. Dendritic cells (DCs) pulsed with exogenous proteins primarily induce strong CD4-dependent immunity; induction of CD8 responses has proven to be difficult. We evaluated the immunogenicity of fusion proteins comprising the protein transduction domain of HIV-1 TAT and the Leishmania antigen LACK (Leishmania homolog of receptors for activated C kinase), as TAT-fusion proteins facilitate major histocompatibility complex class I-dependent antigen presentation. In vitro, TAT-LACK-pulsed DCs induced stronger proliferation of Leishmania-specific CD8(+) T cells compared with DCs incubated with LACK alone. Vaccination with TAT-LACK-pulsed DCs or fusion proteins plus adjuvant in vivo significantly improved disease outcome in Leishmania major-infected mice and was superior to vaccination with DCs treated with LACK alone. Vaccination with DC+TAT-LACK resulted in stronger proliferation of CD8(+) T cells when compared with immunization with DC+LACK. Upon depletion of CD4(+) or CD8(+) T cells, TAT-LACK-mediated protection was lost. TAT-LACK-pulsed IL-12p40-deficient DCs did not promote protection in vivo. In summary, these data show that TAT-fusion proteins are superior in activating Leishmania-specific Tc1 cells when compared with antigen alone and suggest that IL-12-dependent preferential induction of antigen-specific CD8(+) cells promotes significant protection against this important human pathogen. C1 [Kronenberg, Katharina; Brosch, Sven; Butsch, Florian; von Stebut, Esther] Johannes Gutenberg Univ Mainz, Dept Dermatol, D-55131 Mainz, Germany. [Tada, Yayoi; Shibagaki, Naotaka; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP von Stebut, E (reprint author), Johannes Gutenberg Univ Mainz, Dept Dermatol, D-55131 Mainz, Germany. EM vonstebu@mail.uni-mainz.de FU World Health Organization (WHO); Deutsche Forschungsgemeinschaft [SFB 490, 548]; Johannes Gutenberg-University of Mainz; NIH, Center for Cancer Research, National Cancer Institute; Boehringer Ingelheim Fonds FX We thank Dr Steven Dowdy for supplying the TAT-HA protein-encoding plasmids and for helpful discussions, Dr David L Sacks for providing LACK plasmids, and Drs K Steinbrink and H Jonuleit for critically reading this paper. This work was supported in part by grants from the Special Programme for Research and Training in Tropical Diseases (TDR) of the World Health Organization (WHO) (to EvS/MCU), the Deutsche Forschungsgemeinschaft (SFB 490 and 548), the MAIFOR program of the Johannes Gutenberg-University of Mainz (to EvS), the Intramural Program of the NIH, Center for Cancer Research, National Cancer Institute (to MCU), and the Boehringer Ingelheim Fonds (Bifond Travel Grant; to KK). NR 46 TC 13 Z9 13 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2010 VL 130 IS 11 BP 2602 EP 2610 DI 10.1038/jid.2010.171 PG 9 WC Dermatology SC Dermatology GA 664MC UT WOS:000282963600013 PM 20574442 ER PT J AU Suzuki, R Liu, XB Olivera, A Aguiniga, L Yamashita, Y Blank, U Ambudkar, I Rivera, J AF Suzuki, Ryo Liu, Xibao Olivera, Ana Aguiniga, Lizath Yamashita, Yumi Blank, Ulrich Ambudkar, Indu Rivera, Juan TI Loss of TRPC1-mediated Ca2+ influx contributes to impaired degranulation in Fyn-deficient mouse bone marrow-derived mast cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE calcium; IgE; transient receptor potential cation channel 1 ID FC-EPSILON-RI; OPERATED CALCIUM-ENTRY; HIGH-AFFINITY RECEPTOR; TYROSINE PHOSPHORYLATION; IMMUNOGLOBULIN-E; IGE RECEPTOR; ACTIN MICROFILAMENTS; PLASMA-MEMBRANE; GENE-EXPRESSION; PORE SUBUNIT AB MC degranulation requires the influx of calcium from the extracellular environment. Orai1/STIM1 is essential to MC SOCE, as shown in rat peritoneal MCs, the rat MC lines (RBL-2H3), or in Orai1 null embryo liver-derived, cultured MCs. However, minimal information exists about the role of other calcium channels expressed on these cells. Here, we demonstrate that the nonselective TRPC1 participates in Fc epsilon RI-mediated calcium entry in mouse BMMCs. We found that Fyn null MCs, which have an impaired degranulation response, expressed reduced levels of TRPC1, had normal depletion of intracellular calcium stores but an impaired calcium influx, and failed to depolymerize cortical F-actin (a key step for granule-plasma membrane fusion). Partial RNAi silencing of TRPC1 expression in WT MCs (to the level of Fyn null MCs) mimicked the Fyn null defect in calcium influx, cortical F-actin depolymerization, and MC degranulation. Ectopic expression of Fyn or TRPC1 in Fyn null MCs restored calcium responses and cortical F-actin depolymerization and increased MC degranulation. Together with our findings that expression of Orai1 is not altered in Fyn null MCs, our findings suggest that TRPC1 participates in calcium influx and other key events required for MC degranulation. This demonstrates that in addition to a role described previously for Orai1 in promoting MC degranulation, nonselective cation channels participate in promoting the exocytotic response. J. Leukoc. Biol. 88: 863-875; 2010. C1 [Suzuki, Ryo; Olivera, Ana; Aguiniga, Lizath; Yamashita, Yumi; Rivera, Juan] NIAMSD, Mol Immunol Sect, Immunogenet Mol Lab, Bethesda, MD 20892 USA. [Liu, Xibao; Ambudkar, Indu] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Blank, Ulrich] INSERM, U699, Paris, France. [Blank, Ulrich] Univ Paris 07, Fac Med, Paris, France. RP Rivera, J (reprint author), NIAMS, NIH, Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov FU NIAMS; National Institute of Dental and Craniofacial Research, NIH; Office of Science and Technology, NIAMS FX This research was supported by the Intramural Research Programs of the NIAMS and the National Institute of Dental and Craniofacial Research, NIH. We are grateful for the support of the Flow Cytometry Section, the Laboratory Animal Care and Use Section, and the Light Imaging Section of the Office of Science and Technology, NIAMS. We thank Drs. Nevenka Medic, Dean D. Metcalfe, and Alasdair Gilfillan (NIAID, NIH) for personal communication. NR 71 TC 33 Z9 33 U1 1 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD NOV PY 2010 VL 88 IS 5 BP 863 EP 875 DI 10.1189/jlb.0510253 PG 13 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 692YG UT WOS:000285191200006 PM 20571036 ER PT J AU Basselin, M Rosa, AO Ramadan, E Cheon, Y Chang, L Chen, M Greenstein, D Wohltmann, M Turk, J Rapoport, SI AF Basselin, Mireille Rosa, Angelo O. Ramadan, Epolia Cheon, Yewon Chang, Lisa Chen, Mei Greenstein, Deanna Wohltmann, Mary Turk, John Rapoport, Stanley I. TI Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)beta (VIA)-deficient mice SO JOURNAL OF LIPID RESEARCH LA English DT Article DE Ca2+-independent phospholipase A(2); iPLA(2) knockout mouse; brain imaging; muscarinic receptor; arecoline ID INDEPENDENT PHOSPHOLIPASE A(2); MUSCARINIC ACETYLCHOLINE-RECEPTORS; ARACHIDONIC-ACID; FATTY-ACIDS; IN-VIVO; RAT HIPPOCAMPUS; DYSTONIA-PARKINSONISM; UNANESTHETIZED RATS; OXIDATIVE STRESS; EXPRESS GROUP AB Ca2+-independent phospholipase A(2)beta (iPLA(2)beta) selectively hydrolyzes docosahexaenoic acid (DHA, 22:6n-3) in vitro from phospholipid. Mutations in the PLA2G6 gene encoding this enzyme occur in patients with idiopathic neurodegeneration plus brain iron accumulation and dystoniaparkinsonism without iron accumulation, whereas mice lacking PLA2G6 show neurological dysfunction and neuropathology after 13 months. We hypothesized that brain DHA metabolism and signaling would be reduced in 4-month-old iPLA(2)beta-deficient mice without overt neuropathology. Saline or the cholinergic muscarinic M 1,3,5 receptor agonist arecoline (30 mg/kg) was administered to unanesthetized iPLA(2)beta(-/-), iPLA(2)beta(+/-), and iPLA(2)beta(+/+) mice, and [1-C-14]DHA was infused intravenously. DHA incorporation coefficients k* and rates J(in), representing DHA metabolism, were determined using quantitative autoradiography in 81 brain regions. iPLA(2)beta(-/-) or iPLA(2)beta(+/-) compared with iPLA(2)beta(+/+) mice showed widespread and significant baseline reductions in k* and J(in) for DHA. Arecoline increased both parameters in brain regions of iPLA(2)beta(+/+) mice but quantitatively less so in iPLA(2)beta(-/-) and iPLA(2)beta(+/-) mice. Consistent with iPLA(2)beta's reported ability to selectively hydrolyze DHA from phospholipid in vitro, iPLA(2)beta deficiency reduces brain DHA metabolism and signaling in vivo at baseline and following M 1,3,5 receptor activation. Positron emission tomography might be used to image disturbed brain DHA metabolism in patients with PLA2G6 mutations.-Basselin, M., A. O. Rosa, E. Ramadan, Y. Cheon, L. Chang, M. Chen, D. Greenstein, M. Wohltmann, J. Turk, and S. I. Rapoport. Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)beta (VIA)-deficient mice. J. Lipid Res. 51: 3166-3173. C1 [Basselin, Mireille; Rosa, Angelo O.; Ramadan, Epolia; Cheon, Yewon; Chang, Lisa; Chen, Mei; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. [Greenstein, Deanna] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Wohltmann, Mary; Turk, John] Washington Univ, Sch Med, Dept Med, Mass Spectrometry Facil, St Louis, MO 63110 USA. Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, St Louis, MO USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. EM sir@helix.nih.gov FU National Institute on Aging; National Institutes of Health; United States Public Health Service [R37-DK34388, P41-RR00954, P60-DK20579, P30-DK56341] FX This research was supported by the Intramural Research Program of the National Institute on Aging, the National Institutes of Health, and by United States Public Health Service Grants R37-DK34388, P41-RR00954, P60-DK20579, and P30-DK56341 to J.T. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or USPHS. NR 69 TC 23 Z9 24 U1 0 U2 3 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 NOV PY 2010 VL 51 IS 11 BP 3166 EP 3173 DI 10.1194/jlr.M008334 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 662LG UT WOS:000282808200009 PM 20686114 ER PT J AU Zhu, XW Owen, JS Wilson, MD Li, HT Griffiths, GL Thomas, MJ Hiltbold, EM Fessler, MB Parks, JS AF Zhu, Xuewei Owen, John S. Wilson, Martha D. Li, Haitao Griffiths, Gary L. Thomas, Michael J. Hiltbold, Elizabeth M. Fessler, Michael B. Parks, John S. TI Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol SO JOURNAL OF LIPID RESEARCH LA English DT Article DE free cholesterol; cytokines; immunology; lipid droplets; lymphocytes; retinoids ID INNATE IMMUNE RECOGNITION; CASSETTE TRANSPORTER A1; TANGIER-DISEASE; ABCA1-DEFICIENT MACROPHAGES; PLASMA-MEMBRANE; APOA-I; ATHEROSCLEROSIS; ACTIVATION; EXPRESSION; ACCUMULATION AB We previously showed that macrophages from macrophage-specifi c ATP-binding cassette transporter A1 (ABCA1) knockout (Abca1(-M/-M)) mice had an enhanced proinflammatory response to the Toll-like receptor (TLR) 4 agonist, lipopolysaccharide (LPS), compared with wild-type (WT) mice. In the present study, we demonstrate a direct association between free cholesterol (FC), lipid raft content, and hyper-responsiveness of macrophages to LPS in WT mice. Abca1(-M/-M) macrophages were also hyper-responsive to specific agonists to TLR2, TLR7, and TLR9, but not TLR3, compared with WT macrophages. We hypothesized that ABCA1 regulates macrophage responsiveness to TLR agonists by modulation of lipid raft cholesterol and TLR mobilization to lipid rafts. We demonstrated that Abca1(-M/-M) vs. WT macrophages contained 23% more FC in isolated lipid rafts. Further, mass spectrometric analysis suggested raft phospholipid composition was unchanged. Although cell surface expression of TLR4 was similar between Abca1(-M/-M) and WT macrophages, significantly more TLR4 was distributed in membrane lipid rafts in Abca1(-M/-M) macrophages. Abca1(-M/-M) macrophages also exhibited increased trafficking of the predominantly intracellular TLR9 into lipid rafts in response to TLR9-specifi c agonist (CpG). Collectively, our data suggest that macrophage ABCA1 dampens inflammation by reducing MyD88-dependent TLRs trafficking to lipid rafts by selective reduction of FC content in lipid rafts.-Zhu, X., J. S. Owen, M. D. Wilson, H. Li, G. L. Griffiths, M. J. Thomas, E. M. Hiltbold, M. B. Fessler, and J. S. Parks. Macrophage ABCA1 reduces MyD88-dependent Toll-like C1 [Zhu, Xuewei; Wilson, Martha D.; Parks, John S.] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol Lipid Sci, Winston Salem, NC 27106 USA. [Owen, John S.; Thomas, Michael J.; Parks, John S.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA. [Hiltbold, Elizabeth M.] Wake Forest Univ, Bowman Gray Sch Med, Dept Microbiol & Immunol, Winston Salem, NC 27103 USA. [Li, Haitao; Griffiths, Gary L.] NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. [Fessler, Michael B.] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. RP Parks, JS (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol Lipid Sci, 300 S Hawthorne Rd, Winston Salem, NC 27106 USA. EM jparks@wfubmc.edu FU National Institutes of Health [HL-49373, HL-094525, AT-27820]; American Heart Association [09POST2250225]; National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES102005]; National Institutes of Health Roadmap for Medical Research Initiative FX This work was supported by National Institutes of Health Grants HL-49373, HL-094525, and AT-27820 (J.S.P.), American Heart Association fellowship 09POST2250225 (X.Z.), and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences Z01 ES102005 (M.B.F.). The fPEG-cholesterol synthesis was supported by the National Institutes of Health Roadmap for Medical Research Initiative through its establishment of the Imaging Probe Development Center, administered by the National Heart, Lung, and Blood Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 46 TC 125 Z9 136 U1 1 U2 11 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 NOV PY 2010 VL 51 IS 11 BP 3196 EP 3206 DI 10.1194/jlr.M006486 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 662LG UT WOS:000282808200012 PM 20650929 ER PT J AU Madelin, G Lee, JS Inati, S Jerschow, A Regatte, RR AF Madelin, Guillaume Lee, Jae-Seung Inati, Souheil Jerschow, Alexej Regatte, Ravinder R. TI Sodium inversion recovery MRI of the knee joint in vivo at 7T SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Osteoarthritis; Cartilage; Sodium; Magnetic resonance imaging; Inversion recovery; Adiabatic inversion ID BOVINE ARTICULAR-CARTILAGE; FIXED CHARGE-DENSITY; MAGNETIC-RESONANCE; ADIABATIC PULSES; HUMAN BRAIN; NA-23 MRI; NMR AB The loss of proteoglycans (PG) in the articular cartilage is an early signature of osteoarthritis (OA). The ensuing changes in the fixed charge density in the cartilage can be directly linked to sodium concentration via charge balance. Sodium ions in the knee joint appear in two pools: in the synovial fluids or joint effusion where the ions are in free motion and bound within the cartilage tissue where the Na(+) ions have a restricted motion. The ions in these two compartments have therefore different T(1) and T(2) relaxation times. The purpose of this study is to demonstrate the feasibility of a fluid-suppressed 3D ultrashort TE radial sodium sequence by implementing an inversion recovery (IR) preparation of the magnetization at 7T. This method could allow a more accurate and more sensitive quantification of loss of PG in patients with OA. It is shown that adiabatic pulses offer significantly improved performance in terms of robustness to B(1) and B(0) inhomogeneities when compared to the hard pulse sequence. Power deposition considerations further pose a limit to the RF inversion power, and we demonstrate in simulations and experiments how a practical compromise can be struck between clean suppression of fluid signals and power deposition levels. Two IR sequences with different types of inversion pulses (a rectangular pulse and an adiabatic pulse) were tested on a liquid phantom, ex vivo on a human knee cadaver and then in vivo on five healthy volunteers, with a (Nyquist) resolution of similar to 3.6 mm and a signal-to-noise ratio of similar to 30 in cartilage without IR and similar to 20 with IR. Due to specific absorption rate limitations, the total acquisition time was similar to 17 min for the 3D radial sequence without inversion or with the rectangular IR, and 24:30 min for the adiabatic IR sequence. It is shown that the adiabatic IR sequence generates a more uniform fluid suppression over the whole sample than the rectangular IR sequence. (C) 2010 Elsevier Inc. All rights reserved. C1 [Madelin, Guillaume; Lee, Jae-Seung; Jerschow, Alexej] NYU, Dept Chem, New York, NY 10012 USA. [Madelin, Guillaume; Lee, Jae-Seung; Regatte, Ravinder R.] NYU, Med Ctr, Ctr Biomed Imaging, New York, NY 10012 USA. [Inati, Souheil] NIH, Bethesda, MD 20892 USA. RP Jerschow, A (reprint author), NYU, Dept Chem, 550 1St Ave, New York, NY 10012 USA. EM alexej.jerschow@nyu.edu; ravinder.regatte@nyumc.org RI Regatte, Ravinder/K-2364-2014; Lee, Jae-Seung/A-5669-2009; OI Regatte, Ravinder/0000-0002-4607-7682; Lee, Jae-Seung/0000-0002-8571-0663; Jerschow, Alexej/0000-0003-1521-9219; Inati, Souheil/0000-0001-5596-9554; Madelin, Guillaume/0000-0002-5556-5792 FU US NIH [1RO1AR053133, 1R01AR056260, 1R21AR055724] FX This work was supported by US NIH Grants 1RO1AR053133, 1R01AR056260 and 1R21AR055724. The authors would like to thank Graham Wiggins and Ryan Brown for repairing and optimizing the sodium knee coil prior to the in vivo experiments. NR 30 TC 39 Z9 39 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD NOV PY 2010 VL 207 IS 1 BP 42 EP 52 DI 10.1016/j.jmr.2010.08.003 PG 11 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 673AU UT WOS:000283631400006 PM 20813569 ER PT J AU McCoy, BN Raffel, SJ Lopez, JE Schwan, TG AF McCoy, Brandi N. Raffel, Sandra J. Lopez, Job E. Schwan, Tom G. TI Bloodmeal Size and Spirochete Acquisition of Ornithodoros hermsi (Acari: Argasidae) During Feeding SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Borrelia hermsii; relapsing fever; ticks; quantitative PCR ID SUBGENUS PERSICARGAS IXODOIDEA; RELAPSING FEVER; BORRELIA-BURGDORFERI; MAJOR SEROTYPES; MEAL WEIGHT; TICK; MOUBATA; GROWTH AB Ornithodoros hermsi Wheeler (Acari: Argasidae) is the vector of Borrelia hermsii, the primary cause of tick-borne relapsing fever in North America. This tick is one of the smallest Ornithodoros species involved with the biological transmission of spirochetes; yet, the amount of blood ingested while feeding is unknown. Therefore, we determined the amount of blood O. hermsi ingested during a bloodmeal to establish its potential for spirochete acquisition while feeding on an infected host. Ticks at different developmental stages were weighed before and after feeding and the volume of blood ingested was calculated. Females ingested the most blood, averaging approximate to 15 mu l per meal, but late-stage nymphs took in the most blood in proportion to unfed body weight. A cohort of nymphs was weighed three more times during the 48 h after feeding, which demonstrated that O. hermsi may have excreted coxal fluid ranging from 24 -36% of the bloodmeal weight. We also developed a quantitative polymerase chain reaction method to determine the number of spirochetes ingested and maintained within the ticks after feeding. The density of spirochetes in ticks having just engorged was slightly less than in the host's blood, hi the first 5 d after feeding, the number of spirochetes within the ticks declined from the number initially ingested but then remained constant through 15 d. These observations establish a basis for future studies to determine the minimum number of spirochetes required in the host's blood to allow O. hermsi to become persistently infected and transmit during subsequent bloodmeals. C1 [McCoy, Brandi N.; Raffel, Sandra J.; Lopez, Job E.; Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Schwan, TG (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM tschwan@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Paul Policastro for providing the RML colony ticks used in this study, Michael Fay for statistical help, and Philip Stewart and Joseph Hinnebusch for review of the manuscript. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 31 TC 11 Z9 11 U1 0 U2 5 PU ENTOMOLOGICAL SOC AMER PI LANHAM PA 10001 DEREKWOOD LANE, STE 100, LANHAM, MD 20706-4876 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD NOV PY 2010 VL 47 IS 6 BP 1164 EP 1172 DI 10.1603/ME10175 PG 9 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 684RR UT WOS:000284567500027 PM 21175068 ER PT J AU Sharma, A Rodrigues, J Kajla, MK Agrawal, N Adak, T Bhatnagar, RK AF Sharma, Anil Rodrigues, Janneth Kajla, Mayur K. Agrawal, Neema Adak, T. Bhatnagar, Raj K. TI Expression Profile of Prophenoloxidase-Encoding (acppo6) Gene of Plasmodium vivax-Refractory Strain of Anopheles culicifacies SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Anopheles culicifacies; prophenoloxidase; refractory; Plasmodium vinckei petteri ID MOSQUITO AEDES-AEGYPTI; BOMBYX-MORI; HEMOCYTES; MELANIZATION; PHENOLOXIDASE; INFECTIONS; GAMBIAE; PHAGOCYTOSIS; PURIFICATION; SILKWORM AB Anopheles culicifacies is the main vector for transmission of Plasmodium vicar malaria in the Indian subcontinent. A strain of Art. culicifacies isolated from its natural niche displayed complete refractoriness to P. vicar by melanotic encapsulation of ookinetes. Prophenoloxidases are key components of the phenoloxidase cascade that leads to recognition and melanization of invading organisms. We isolated and cloned prophenoloxidase-encoding acppo6 gene of An. culicifacies and analyzed its expression profile under various regimens of immune challenge. The aeppo6 was differentially expressed during various stages of larval development. The acppo6 transcription was also up-regulated in response to bacteria and Plasmodium vinckei petteri challenge. The transcript levels of the acppo6 gene were higher in naive adult refractory female mosquitoes as compared with female susceptible mosquitoes. Furthermore, the induction of acppo6 in the susceptible strain upon Plasmodium infection was negligible as compared with that of the refractory strain. The observation is suggestive of the role of acppo6 in effectuating a melanotic response in Plasmodium-incompetent naturally occurring refractory An. culicifacies strain. C1 [Sharma, Anil; Rodrigues, Janneth; Agrawal, Neema; Bhatnagar, Raj K.] Int Ctr Genet Engn & Biotechnol, Insect Resistance Grp, New Delhi 110067, India. [Sharma, Anil; Adak, T.] Natl Inst Malaria Res, Sector 8, New Delhi 110077, India. [Rodrigues, Janneth] NIH, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Kajla, Mayur K.] Univ Wisconsin, Dept Entomol, Madison, WI 53706 USA. RP Bhatnagar, RK (reprint author), Int Ctr Genet Engn & Biotechnol, Insect Resistance Grp, PO 10504,Aruna Asaf Ali Marg, New Delhi 110067, India. EM raj@icgeb.res.in RI Adak, Tridibes/C-2501-2011; khan, raja/B-5726-2012; Sharma, Anil/F-4248-2011; OI Sharma, Anil/0000-0003-2264-2007 FU Indian Council of Medical Research; University Grant Commission FX This work was supported by a project grant from the Indian Council of Medical Research. A.S. was supported by the Research Fellowship of University Grant Commission. NR 27 TC 1 Z9 1 U1 0 U2 1 PU ENTOMOLOGICAL SOC AMER PI LANHAM PA 10001 DEREKWOOD LANE, STE 100, LANHAM, MD 20706-4876 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD NOV PY 2010 VL 47 IS 6 BP 1220 EP 1226 DI 10.1603/ME10033 PG 7 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 684RR UT WOS:000284567500034 PM 21175075 ER PT J AU Killian, JK Walker, RL Suuriniemi, M Jones, L Scurci, S Singh, P Cornelison, R Harmon, S Boisvert, N Zhu, J Wang, YH Bilke, S Davis, S Giaccone, G Smith, WI Meltzer, PS AF Killian, J. Keith Walker, Robert L. Suuriniemi, Miia Jones, Laura Scurci, Stephanie Singh, Parvati Cornelison, Robert Harmon, Shannon Boisvert, Nichole Zhu, Jack Wang, Yonghong Bilke, Sven Davis, Sean Giaccone, Giuseppe Smith, William I., Jr. Meltzer, Paul S. TI Archival Fine-Needle Aspiration Cytopathology (FNAC) Samples Untapped Resource for Clinical Molecular Profiling SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID POLYMERASE-CHAIN-REACTION; FOLLICULAR LYMPHOMA; STAINS AB Microarray technologies provide high resolution maps of chromosome imbalances and epigenomic aberrations in the cancer cell genome Such assays are often sensitive to sample DNA integrity, voiding the utility of many archival pathology specimens and necessitating the special handling of prospective clinical specimens We have identified the remarkable preservation of higher molecular weight DNA m archival fine needle aspiration cytopathology specimens from patients greater than 10 years of age We further demonstrate the outstanding technical performance of 57 fine needle aspiration cytopathology samples for aberration detection on high resolution comparative genomic hybridization array, DNA methylation, and single nucleotide polymorphism genotyping platforms Forty four of 46 malignant aspirates in this study manifested unequivocal genomic aberrations Importantly, matched Papanicolaou and Diff Quik fine needle aspiration cytopathology samples showed critical differences in DNA preservation and DNA integrity Overall, this study identifies a largely untapped reserve of human pathology specimens for molecular profiling studies, with ramifications for the prospective collection of clinical biospecimens (J Mol Diagn 2010, 12, 739-745, DOI 10.2353/jmoldx.2010.090238) C1 [Killian, J. Keith; Walker, Robert L.; Suuriniemi, Miia; Jones, Laura; Scurci, Stephanie; Singh, Parvati; Cornelison, Robert; Harmon, Shannon; Boisvert, Nichole; Zhu, Jack; Wang, Yonghong; Bilke, Sven; Davis, Sean; Meltzer, Paul S.] NCI, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Giaccone, Giuseppe] NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Smith, William I., Jr.] Suburban Hosp, Dept Pathol, Bethesda, MD USA. RP Meltzer, PS (reprint author), 37 Convent Dr,BG 37,RM 6138,MSC 4265, Bethesda, MD 20892 USA. RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Davis, Sean/0000-0002-8991-6458 FU NIH National Cancer Institute Center for Cancer Research FX Supported in part by the Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research NR 12 TC 41 Z9 41 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2010 VL 12 IS 6 BP 739 EP 745 DI 10.2353/jmoldx.2010.090233 PG 7 WC Pathology SC Pathology GA 677FE UT WOS:000283973700002 PM 20959611 ER PT J AU Xi, L Pham, T Pham, T Giaccone, G Raffeld, M AF Xi, L. Pham, T. Pham, T. Giaccone, G. Raffeld, M. TI Implementation of Novel Pyrosequencing and Capillary Electrophoresis Assays to Screen for Common Mutations of EGFR in Non Small Cell Lung Cancer SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology CY NOV 18-20, 2010 CL San Jose, CA SP Assoc Mol Pathol C1 [Xi, L.; Pham, T.; Pham, T.; Giaccone, G.; Raffeld, M.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2010 VL 12 IS 6 BP 904 EP 905 PG 2 WC Pathology SC Pathology GA 677FE UT WOS:000283973700227 ER PT J AU Leary, TJO Fowler, CB Waybright, TJ Veenstra, TD Mason, JT AF Leary, T. J. O. Fowler, C. B. Waybright, T. J. Veenstra, T. D. Mason, J. T. TI High Pressure Assisted Extraction for the Improved Proteomic Analysis of Formalin Fixed Paraffin Embedded Tissue SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology CY NOV 18-20, 2010 CL San Jose, CA SP Assoc Mol Pathol C1 [Leary, T. J. O.] Vet Hlth Adm, Washington, DC USA. [Fowler, C. B.; Mason, J. T.] Armed Forces Inst Pathol, Rockville, MD USA. [Fowler, C. B.] Maryland VA Hlth Care Syst, Rockville, MD USA. [Waybright, T. J.; Veenstra, T. D.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2010 VL 12 IS 6 BP 914 EP 914 PG 1 WC Pathology SC Pathology GA 677FE UT WOS:000283973700269 ER PT J AU Eiden, L Ait-Ali, D Holighaus, Y Mustafa, T Stroth, N AF Eiden, Lee Ait-Ali, Djida Holighaus, Yvonne Mustafa, Tomris Stroth, Nikolas TI PACAP signaling to target genes through cyclic AMP and calcium during the stress response SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Meeting Abstract CT 9th International Symposium on VIP, PACAP and Related Peptides CY OCT 05-08, 2009 CL Kagoshima, JAPAN C1 [Eiden, Lee; Ait-Ali, Djida; Holighaus, Yvonne; Mustafa, Tomris; Stroth, Nikolas] NIMH, Mol Neurosci Sect, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD NOV PY 2010 VL 42 IS 3 SI SI BP 296 EP 297 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 666EL UT WOS:000283095400051 ER PT J AU Eiden, L Samal, B Braxton, R Akala, M Ait-Ali, D AF Eiden, Lee Samal, Babru Braxton, Richard Akala, Mariam Ait-Ali, Djida TI Signaling pathways involved in PACAP and cytokine interactions regulating adrenomedullary neuropeptide biosynthesis SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Meeting Abstract CT 9th International Symposium on VIP, PACAP and Related Peptides CY OCT 05-08, 2009 CL Kagoshima, JAPAN C1 [Eiden, Lee; Samal, Babru; Braxton, Richard; Akala, Mariam; Ait-Ali, Djida] NIMH, Mol Neurosci Sect, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD NOV PY 2010 VL 42 IS 3 SI SI BP 315 EP 315 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 666EL UT WOS:000283095400093 ER PT J AU Pan, L Kardono, LBS Riswan, S Chai, H de Blanco, EJC Pannell, CM Soejarto, DD McCloud, TG Newman, DJ Kinghorn, AD AF Pan, Li Kardono, Leonardus B. S. Riswan, Soedarsono Chai, Heebyung de Blanco, Esperanza J. Carcache Pannell, Caroline M. Soejarto, Djaja Doel McCloud, Thomas G. Newman, David J. Kinghorn, A. Douglas TI Isolation and Characterization of Minor Analogues of Silvestrol and Other Constituents from a Large-Scale Re-collection of Aglaia foveolata SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID (-)-SILVESTROL; DERIVATIVES; TRITERPENES; (-)-EPISILVESTROL; CONFORMATION; REVISION; CELLS AB Two new minor silvestrol analogues [2 '''-episilvestrol (1) and 2 ''',5 '''-diepisilvestrol (2)], together with a new 21-norbaccharane-type triterpene (3), two new 3,4-secodammarane triterpenes (4 and 5), and a new eudesmane sesquiterpene (6), as well as nine known compounds, were isolated from a large-scale re-collection of the CHCl(3)-soluble extract of the stem bark of Aglaia foveolata obtained in Kalimantan, Indonesia. The structures of the new compounds were established by interpretation of their spectroscopic data. All of the isolates were tested for cytotoxicity against HT-29 cells. The new silvestrol analogues, 1 and 2, were considerably less active as cytotoxic agents than silvestrol (7) and episilvestrol (5 '''-episilvestrol) (8) against this cell line, showing the importance of the configuration at C-2 ''' in mediating such activity within this compound class. Several of the compounds isolated were also evaluated in a NF-kappa B (p65) inhibition assay. C1 Ohio State Univ, Div Med Chem, Coll Pharm, Columbus, OH 43210 USA. [Kardono, Leonardus B. S.] Indonesian Inst Sci, Res Ctr Chem, Tangerang 15310, Indonesia. [Riswan, Soedarsono] Indonesian Inst Sci, Herbarium Bogoriense, Biol Res Ctr, Bogor 16122, Indonesia. [de Blanco, Esperanza J. Carcache] Ohio State Univ, Coll Pharm, Div Pharm Practice & Adm, Columbus, OH 43210 USA. [Pannell, Caroline M.] Univ Oxford, Dept Plant Sci, Oxford OX1 3RA, England. [Soejarto, Djaja Doel] Univ Illinois, Program Collaborat Res Pharmaceut Sci, Coll Pharm, Chicago, IL 60612 USA. [Soejarto, Djaja Doel] Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, Chicago, IL 60612 USA. [McCloud, Thomas G.] SAIC Frederick Inc, Frederick, MD 21702 USA. [Newman, David J.] NCI Frederick, Fairview Ctr, Frederick, MD 21702 USA. RP Kinghorn, AD (reprint author), Ohio State Univ, Div Med Chem & Pharmacognosy, Coll Pharm, Columbus, OH 43210 USA. EM kinghorn.4@osu.edu RI Pan, Li/G-4943-2011; OI zaraat, javad/0000-0001-5341-7481; Kinghorn, A. Douglas/0000-0002-6647-8707 FU NCI, NIH [U19 CA52956, P01 CA125066] FX This study was supported, in part, by grants U19 CA52956 and P01 CA 125066 (awarded to A.D.K.) from NCI, NIH. We are grateful to Dr. J. Orjala and Mr. M. Totura of the University of Illinois at Chicago for performing an initial large-scale extraction of the plant material. Mr. M. Harris, SAIC-Frederick, Inc., is acknowledged for assistance with plant fractionation studies. We thank Mr. J. Fowble, College of Pharmacy, The Ohio State University, and Dr. C.-H. Yuan, OSU Campus Chemical Instrument Center, for facilitating the acquisition of the 400 and 600 MHz NMR spectra. We acknowledge Dr. M. Apsega, Campus Chemical Instrument Center, The Ohio State University, for the mass spectrometric data. NR 24 TC 33 Z9 33 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD NOV PY 2010 VL 73 IS 11 BP 1873 EP 1878 DI 10.1021/np100503q PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 684OL UT WOS:000284559100022 PM 20939540 ER PT J AU Hirata, Y Shimokawa, N Oh-hashi, K Yu, ZX Kiuchi, K AF Hirata, Yoko Shimokawa, Norihiro Oh-hashi, Kentaro Yu, Zu-Xi Kiuchi, Kazutoshi TI Acidification of the Golgi apparatus is indispensable for maturation but not for cell surface delivery of Ret SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE bafilomycin A1; concanamycin A; EGFR; PC12 cells; Ret ID GROWTH-FACTOR RECEPTOR; PROTOONCOGENE PRODUCTS; LIGAND-BINDING; BREFELDIN-A; H+-ATPASE; GLYCOSYLATION; TRAFFICKING; INHIBITION; EXPRESSION; MUTATIONS AB P>We examined the effect of concanamycin A and bafilomycin A1, inhibitors of the vacuolar proton-ATPase, on maturation and expression of Ret, a tyrosine kinase receptor for glial cell line-derived neurotrophic factor. Ret appeared as 150- and 170-kDa bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels and both forms were sensitive to peptide-N-glycosidase F. Western and immunocytochemical analyses revealed that the 150-kDa immature form of Ret accumulated in the Golgi apparatus upon treatment with vacuolar proton-ATPase inhibitors, whereas, the 170-kDa mature form of Ret was dramatically decreased. The result suggests that glycosylation of Ret during the conversion from immature forms to mature forms is pH sensitive, and is likely initiated in the acidic trans-Golgi apparatus. In contrast, glycosylation of nascent receptors to become immature receptors appeared to be pH insensitive, and are likely to take place in the endoplasmic reticulum. The immature form of Ret was present in the plasma membrane when the cells were treated with the vacuolar proton-ATPase inhibitors. In conclusion, the acidification of the Golgi apparatus is crucial for maturation of Ret but not indispensable for trafficking of receptors to the membrane. C1 [Hirata, Yoko; Shimokawa, Norihiro; Oh-hashi, Kentaro; Kiuchi, Kazutoshi] Gifu Univ, Fac Engn, Dept Biomol Sci, Gifu 50111, Japan. [Yu, Zu-Xi] NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. [Hirata, Yoko; Kiuchi, Kazutoshi] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Gifu, Japan. RP Hirata, Y (reprint author), 1-1 Yanagido, Gifu 5011193, Japan. EM yokoh@gifu-u.ac.jp FU Japan Society for the Promotion of Science FX This work was supported in part by the Grants-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science. NR 30 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2010 VL 115 IS 3 BP 606 EP 613 DI 10.1111/j.1471-4159.2010.06966.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 664RE UT WOS:000282979400006 PM 20796177 ER PT J AU Connaughton, VP Nelson, R AF Connaughton, Victoria P. Nelson, Ralph TI Spectral Responses in Zebrafish Horizontal Cells Include a Tetraphasic Response and a Novel UV-Dominated Triphasic Response SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CYPRINID FISH RETINA; TURTLE RETINA; CARP RETINA; SENSITIVE CONES; GOLDFISH RETINA; COLOR OPPONENCY; OIL DROPLETS; WAVELENGTH DISCRIMINATION; ULTRAVIOLET SENSITIVITY; SYNAPTIC CONTACTS AB Connaughton VP, Nelson R. Spectral responses in zebrafish horizontal cells include a tetraphasic response and a novel UV-dominated triphasic response. J Neurophysiol 104: 2407-2422, 2010. First published July 7, 2010; doi:10.1152/jn.00644.2009. Zebrafish are tetra-chromats with red (R, 570 nm), green (G, 480 nm), blue (B, 415 nm), and UV (U, 362 nm) cones. Although neurons in other cyprinid retinas are rich in color processing neural circuitry, spectral responses of individual neurons in zebrafish retina, a genetic model for vertebrate color vision, are yet to be studied. Using dye-filled sharp microelectrodes, horizontal cell voltage responses to light stimuli of different wavelengths and irradiances were recorded in a superfused eyecup. Spectral properties were assessed both qualitatively and quantitatively. Six spectral classes of horizontal cell were distinguished. Two monophasic response types (L1 and L2) hyperpolarized at all wavelengths. L1 sensitivities peaked at 493 nm, near the G cone absorbance maximum. Modeled spectra suggest equally weighted inputs from both R and G cones and, in addition, a "hidden opponency" from blue cones. These were classified as R-/G-/(b+). L2 sensitivities were maximal at 563 nm near the R cone absorbance peak; modeled spectra were dominated by R cones, with lesser G cone contributions. B and UV cone signals were small or absent. These are R-/g-. Four chromatic (C-type) horizontal cells were either depolarized (+) or hyperpolarized (-) depending on stimulus wavelength. These types are biphasic (R+/G-/B-) with peak excitation at 467 nm, between G and B cone absorbance peaks, UV triphasic (r-/G+/U-) with peak excitation at 362 nm similar to UV cones, and blue triphasic (r-/G+/B-/u-) and blue tetraphasic (r-/G+/B-/u+), with peak excitation at 409 and 411 nm, respectively, similar to B cones. UV triphasic and blue tetraphasic horizontal cell spectral responses are unique and were not anticipated in previous models of distal color circuitry in cyprinids. C1 [Connaughton, Victoria P.] American Univ, Dept Biol, Washington, DC 20016 USA. [Nelson, Ralph] Natl Inst Neurol Disorders & Stroke, Neural Circuitry Unit, NIH, Rockville, MD USA. RP Connaughton, VP (reprint author), American Univ, Dept Biol, 4400 Massachusetts Ave, Washington, DC 20016 USA. EM vconn@american.edu FU National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 59 TC 17 Z9 17 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD NOV PY 2010 VL 104 IS 5 BP 2407 EP 2422 DI 10.1152/jn.00644.2009 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 695SD UT WOS:000285392000010 PM 20610786 ER PT J AU Molkov, YI Abdala, APL Bacak, BJ Smith, JC Paton, JFR Rybak, IA AF Molkov, Yaroslav I. Abdala, Ana P. L. Bacak, Bartholomew J. Smith, Jeffrey C. Paton, Julian F. R. Rybak, Ilya A. TI Late-Expiratory Activity: Emergence and Interactions With the Respiratory CPG SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID STEM-SPINAL-CORD; PRE-BOTZINGER COMPLEX; MAMMALIAN BRAIN-STEM; RHYTHM GENERATION; IN-VITRO; NEWBORN RAT; RETROTRAPEZOID NUCLEUS; PREBOTZINGER COMPLEX; PACEMAKER NEURONS; FUNCTIONAL ARCHITECTURE AB Molkov YI, Abdala APL, Bacak BJ, Smith JC, Paton JFR, Rybak IA. Late-expiratory activity: emergence and interactions with the respiratory CPG. J Neurophysiol 104: 2713-2729, 2010. First published September 8, 2010; doi:10.1152/jn.00334.2010. The respiratory rhythm and motor pattern are hypothesized to be generated by a brain stem respiratory network with a rhythmogenic core consisting of neural populations interacting within and between the pre-Botzinger (pre-BotC) and Botzinger (BotC) complexes and controlled by drives from other brain stem compartments. Our previous large-scale computational model reproduced the behavior of this network under many different conditions but did not consider neural oscillations that were proposed to emerge within the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) and drive preinspiratory (or late-expiratory, late-E) discharges in the abdominal motor output. Here we extend the analysis of our previously published data and consider new data on the generation of abdominal late-E activity as the basis for extending our computational model. The extended model incorporates an additional late-E population in RTN/pFRG, representing a source of late-E oscillatory activity. In the proposed model, under normal metabolic conditions, this RTN/pFRG oscillator is inhibited by BotC/pre-BotC circuits, and the late-E oscillations can be released by either hypercapnia-evoked activation of RTN/pFRG or by hypoxia-dependent suppression of RTN/pFRG inhibition by BotC/pre-BotC. The proposed interactions between BotC/pre-BotC and RTN/pFRG allow the model to reproduce several experimentally observed behaviors, including quantal acceleration of abdominal late-E oscillations with progressive hypercapnia and quantal slowing of phrenic activity with progressive suppression of pre-BotC excitability, as well as to predict a release of late-E oscillations by disinhibition of RTN/pFRG under normal conditions. The extended model proposes mechanistic explanations for the emergence of RTN/pFRG oscillations and their interaction with the brain stem respiratory network. C1 [Molkov, Yaroslav I.; Bacak, Bartholomew J.; Rybak, Ilya A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. [Abdala, Ana P. L.; Paton, Julian F. R.] Univ Bristol, Sch Med Sci, Bristol Heart Inst, Dept Physiol & Pharmacol, Bristol BS8 1TD, Avon, England. [Smith, Jeffrey C.] Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD USA. RP Rybak, IA (reprint author), Drexel Univ, Coll Med, Dept Neurobiol & Anat, 2900 Queen Ln, Philadelphia, PA 19129 USA. EM rybak@drexel.edu RI Abdala, Ana Paula/G-9104-2014; OI Abdala, Ana Paula/0000-0001-6051-2591; Paton, Julian/0000-0001-7410-2913 FU National Institute of Neurological Disorders and Stroke [R01 NS-057815]; NIH, NINS; Royal Society FX This study was supported by National Institute of Neurological Disorders and Stroke Grant R01 NS-057815 to I. A. Rybak and in part by the Intramural Research Program of the NIH, NINS funding to J. C. Smith. J.F.R. Paton is the recipient of a Royal Society Wolfson Research Merit Award. NR 73 TC 43 Z9 43 U1 0 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD NOV PY 2010 VL 104 IS 5 BP 2713 EP 2729 DI 10.1152/jn.00334.2010 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 695SD UT WOS:000285392000036 PM 20884764 ER PT J AU Kelly, TAN Katagiri, Y Vartanian, KB Kumar, P Chen, II Rosoff, WJ Urbach, JS Geller, HM AF Kelly, Terri-Ann N. Katagiri, Yasuhiro Vartanian, Keri B. Kumar, Pramukta Chen, Inn-Inn Rosoff, William J. Urbach, Jeffery S. Geller, Herbert M. TI Localized Alteration of Microtubule Polymerization in Response to Guidance Cues SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE axonal guidance; CSPG; EB3; particle tracking; PC12 cells; NGF ID CHONDROITIN SULFATE PROTEOGLYCANS; NERVE GROWTH-FACTOR; SPINAL-CORD-INJURY; NEURITE OUTGROWTH; AXONAL GROWTH; PHEOCHROMOCYTOMA CELLS; QUANTITATIVE-ANALYSIS; CONE GUIDANCE; NEURONS; RHO AB Inhibition of microtubule dynamic instability prevents growth cone turning in response to guidance cues, yet specific changes in microtubule polymerization as growth cones encounter boundaries have not been investigated. In this study, we examined the rate and direction of microtubule polymerization in response to soluble nerve growth factor (NGF) and immobilized chondroitin sulfate proteoglycans (CSPGs) by expressing enhanced GFP-EB3 in rat pheochromocytoma (PC12) cells. GFP-EB3 comets were monitored in live cells using time-lapse epifluorescent microscopy. With an automated tracking system, the rate of microtubule polymerization was calculated as the frame-to-frame displacement of EB3 comets. Our results demonstrate that the rate of microtubule polymerization is increased following NGF treatment, whereas contact with CSPGs decreases microtubule polymerization rates. This reduction in microtubule polymerization rates was specifically localized to neurites in direct contact with CSPGs and not at noncontacting neurites. Additionally, we found an increase in the percentage of microtubules polymerizing in the retrograde direction in neurites at CSPG boundaries, with a concomitant decrease in the rate of retrograde microtubule polymerization. These results implicate localized changes in microtubule dynamics as an important component of the growth cone response to guidance cues. (c) 2010 Wiley-Liss, Inc. C1 [Kelly, Terri-Ann N.; Katagiri, Yasuhiro; Vartanian, Keri B.; Chen, Inn-Inn; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Kelly, Terri-Ann N.; Kumar, Pramukta; Rosoff, William J.; Urbach, Jeffery S.] Georgetown Univ, Dept Phys, Washington, DC 20057 USA. RP Geller, HM (reprint author), NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM geller@helix.nih.gov OI Urbach, Jeffrey/0000-0002-1593-520X; Geller, Herbert/0000-0002-7048-6144 FU Intramural NIH HHS [ZIA HL006021-01] NR 51 TC 15 Z9 17 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD NOV 1 PY 2010 VL 88 IS 14 BP 3024 EP 3033 DI 10.1002/jnr.22478 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 662GK UT WOS:000282795200004 PM 20806407 ER PT J AU Chen, ZY Wang, L Asavaritkrai, P Noguchi, CT AF Chen, Zhi-Yong Wang, Li Asavaritkrai, Pundit Noguchi, Constance Tom TI Up-Regulation of Erythropoietin Receptor by Nitric Oxide Mediates Hypoxia Preconditioning SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE erythropoietin; nitric oxide; hypoxia; neuroprotection; receptor expression ID NF-KAPPA-B; RETINAL DEGENERATION; CEREBRAL-ISCHEMIA; TRANSGENIC MICE; ACUTE STROKE; IN-VITRO; EXPRESSION; BRAIN; PROTECTS; NEUROPROTECTION AB Erythropoietin (Epo), known to stimulate erythroid progenitor cell survival, proliferation, and differentiation, has been shown to be neuroprotective against brain ischemia in animal models. Both Epo and Epo receptor (EpoR) are expressed in the brain and are up-regulated by hypoxia. Brain Epo signaling can stimulate neural cell survival and prevent neuron apoptosis. Neurons from EpoR null mice exhibit marked increased sensitivity to hypoxia. In endothelial cells, Epo has been shown to stimulate nitric oxide (NO) production, particularly at low pO(2). We found here that the EpoR expression on neural cells and Epo's neuroprotective effect were regulated by NO. Hypoxia increased NO production as well as EpoR expression, and inhibition of NOS activity reduced the proportion of EpoR-expressing neurons induced at low pO(2). Conversely, addition of NO donor to cultures grown under normoxia induced EpoR. Similarly, NO donor increased EpoR promoter activity in a reporter gene assay, suggesting that NO regulates EpoR at the transcription level. Preincubation of neurons with NO results in induction of EpoR, which gives rise to protection against hypoxia even in the absence of exogenous Epo, although at high concentration NO is toxic. These data provide evidence of a role for NO in Epo activity in brain and suggest links between NO production, EpoR expression, and Epo signaling in neuroprotection. Published 2010 Wiley-Liss, Inc.(dagger) C1 [Chen, Zhi-Yong; Wang, Li; Asavaritkrai, Pundit; Noguchi, Constance Tom] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Noguchi, CT (reprint author), NIDDK, Mol Med Branch, NIH, Bldg 10,Room 9N319,10 Ctr Dr,MSC 1822, Bethesda, MD 20892 USA. EM cnoguchi@helix.nih.gov NR 40 TC 12 Z9 14 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD NOV 1 PY 2010 VL 88 IS 14 BP 3180 EP 3188 DI 10.1002/jnr.22473 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 662GK UT WOS:000282795200019 PM 20806411 ER PT J AU Niu, G Chen, XY AF Niu, Gang Chen, Xiaoyuan TI Apoptosis Imaging: Beyond Annexin V SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE apoptosis; molecular imaging; phosphatidylserine; caspases; optical imaging; PET AB Induction of apoptosis is the primary mechanism through which most chemotherapies cause tumor cell death. Early assessment of tumor response is required to manage patients in terms of quality of life versus intensive chemotherapy. Although imaging with radiolabeled annexin V has been intensively investigated, it is still not sufficiently mature for clinical application. This article will summarize various alternative imaging techniques for visualization of phosphatidylserine externalization, activity of caspases, and mitochondrial membrane potential. Such imaging studies will promote the identification of novel molecular targets and the development of highly specific apoptosis-detecting imaging probes with potential clinical applications. It is highly possible that quantitative imaging of apoptosis will greatly improve clinical decision making in apoptosis-related diseases. C1 [Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Niu, Gang] Ctr Clin, Imaging Sci Training Program, Bethesda, MD USA. RP Niu, G (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, 9 Mem Dr,9-1W111, Bethesda, MD 20892 USA. EM niug@mail.nih.gov; shawn.chen@nih.gov FU Radiology and Imaging Sciences Department of NIH Clinical Center; NIBIB, NIH FX This work is supported in part by an Imaging Sciences Training Fellowship jointly funded by the Radiology and Imaging Sciences Department of NIH Clinical Center and by the Intramural Research Program, NIBIB, NIH. We thank Dr. Henry S. Eden for proofreading the manuscript. NR 6 TC 60 Z9 67 U1 0 U2 13 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD NOV PY 2010 VL 51 IS 11 BP 1659 EP 1662 DI 10.2967/jnumed.110.078584 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 674RQ UT WOS:000283766000029 PM 20956479 ER PT J AU Jacobson, O Weiss, ID Kiesewetter, DO Farber, JM Chen, XY AF Jacobson, Orit Weiss, Ido D. Kiesewetter, Dale O. Farber, Joshua M. Chen, Xiaoyuan TI PET of Tumor CXCR4 Expression with 4-F-18-T140 SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE T140 peptide; CXCR4; PET; F-18-fluoride ID CHEMOKINE RECEPTOR CXCR4; CANCER METASTASIS; BREAST-CANCER; BONE-MARROW; ANTAGONISTS; MICROENVIRONMENT; CELLS; XENOGRAFTS; GROWTH; T140 AB Expression of the chemokine receptor CXCR4 by cancers has been shown to correlate with tumor aggressiveness and poor prognosis and may also contribute to metastatic seeding of organs that express its ligand SDF-1. However, fully optimized PET agents for determining CXCR4 expression by tumor cells in vivo are not yet available. This study aims to develop a stable, F-18-labeled peptide that enables in vivo quantification of CXCR4 in cancer. Methods: 4-F-benzoyl-TN14003 (4-F-T140), a short peptide antagonist of CXCR4 with 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl protecting groups on the E-amino groups of the lysine residues, was labeled with F-18-fluoride via N-succinimidyl-4-F-18-fluorobenzoate conjugation, followed by deprotection to give 4-F-18-T140 that was exclusively labeled on the alpha-amine at the N terminus. Cell binding, migration, biodistribution, and small-animal PET studies of 4-F-18-T140 were performed. Results: 4-F-T140 was radiolabeled by coupling with N-succinimidyl-4-F-18-fluorobenzoate, with an overall decay-corrected radiochemical yield of 15% +/- 5% calculated from the start of synthesis. The mean measured specific activity (+/- SD) was 7 +/- 2 GBq/mu mol (0.19 +/- 0.05 Ci/mu mol), and radiochemical purity was greater than 99%. 4-F-18-T140 was found to bind specifically to red blood cells in vitro and in vivo. The binding of 4-F-18-T140 to red blood cells was blocked with a small amount of cold 4-F-T140, which led to higher uptake of 4-F-18-T140 by Chinese hamster ovarian (CHO)-CXCR4 tumors. Biodistribution experiments at 3 h after injection with the addition of 10 mu g of cold 4-F-T140 showed a 3.03 +/- 0.31 percentage injected dose per gram uptake in CHO-CXCR4 tumors, with a tumor-to-blood ratio of 27.1 +/- 8.7 and a tumor-to-muscle ratio of 21.6 +/- 7.1. PET studies demonstrated clear visualization of CXCR4-transfected, but not CXCR4-negative, CHO tumors. Conclusion: 4-F-18-T140 can be used as a PET tracer to image tumor expression of CXCR4, with a high tumor-to-background ratio. The knowledge of whether tumors express or do not express CXCR4 might be beneficial in determining appropriate treatment and monitoring. C1 [Jacobson, Orit; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Weiss, Ido D.; Farber, Joshua M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed, NIH, Bldg 31,Room 1C22,31 Ctr Dr MSC 2281, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) FX We thank Dr. Amnon Peled from Hadassah-Hebrew University Medical Center, Jerusalem, Israel, for fruitful discussions. We also thank Dr. Henry S. Eden for proof-reading this manuscript. This research was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). NR 33 TC 44 Z9 45 U1 0 U2 18 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD NOV PY 2010 VL 51 IS 11 BP 1796 EP 1804 DI 10.2967/jnumed.110.079418 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 674RQ UT WOS:000283766000048 PM 20956475 ER PT J AU Kalisch, BJ Lee, H Rochman, M AF Kalisch, Beatrice J. Lee, Hyunhwa Rochman, Monica TI Nursing staff teamwork and job satisfaction SO JOURNAL OF NURSING MANAGEMENT LA English DT Article DE job satisfaction; nurse staffing; nursing assistant; nursing teamwork; registered nurse ID REGISTERED NURSES; WORK; CARE; PERCEPTIONS; ASSISTANTS; TURNOVER; SUPPORT; AGE; METAANALYSIS; ATTITUDES AB Aim The aim of the present study was to explore the influence of unit characteristics, staff characteristics and teamwork on job satisfaction with current position and occupation. Background Teamwork has been associated with a higher level of job satisfaction but few studies have focused on the acute care inpatient hospital nursing team. Methods This was a cross-sectional study with a sample of 3675 nursing staff from five hospitals and 80 patient care units. Participants completed the Nursing Teamwork Survey (NTS). Results Participants' levels of job satisfaction with current position and satisfaction with occupation were both higher when they rated their teamwork higher (P < 0.001) and perceived their staffing as adequate more often (P < 0.001). Type of unit influenced both satisfaction variables (P < 0.05). Additionally, education, gender and job title influenced satisfaction with occupation (P < 0.05) but not with current position. Conclusions Results of this present study demonstrate that within nursing teams on acute care patient units, a higher level of teamwork and perceptions of adequate staffing leads to greater job satisfaction with current position and occupation. Implications for Nursing Management Findings suggest that efforts to improve teamwork and ensure adequate staffing in acute care settings would have a major impact on staff satisfaction. C1 [Kalisch, Beatrice J.; Rochman, Monica] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Kalisch, Beatrice J.; Lee, Hyunhwa] NINR, NIH, Div Intramural Res, Bethesda, MD 20892 USA. RP Kalisch, BJ (reprint author), Univ Michigan, Sch Nursing, 400 N Ingalls St, Ann Arbor, MI 48109 USA. EM bkalisch@umich.edu FU Michigan Center for Health Intervention, University of Michigan School of Nursing; National Institutes of Health, National Institute of Nursing Research [P30 NR009000] FX This project was funded by The Michigan Center for Health Intervention, University of Michigan School of Nursing, National Institutes of Health, National Institute of Nursing Research (P30 NR009000). NR 53 TC 47 Z9 51 U1 7 U2 34 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0966-0429 J9 J NURS MANAGE JI J. Nurs. Manag. PD NOV PY 2010 VL 18 IS 8 SI SI BP 938 EP 947 DI 10.1111/j.1365-2834.2010.01153.x PG 10 WC Management; Nursing SC Business & Economics; Nursing GA 680ZB UT WOS:000284274900007 PM 21073567 ER PT J AU Yetley, EA Pfeiffer, CM Schleicher, RL Phinney, KW Lacher, DA Christakos, S Eckfeldt, JH Fleet, JC Howard, G Hoofnagle, AN Hui, SL Lensmeyer, GL Massaro, J Peacock, M Rosner, B Wiebe, D Bailey, RL Coates, PM Looker, AC Sempos, C Johnson, CL Picciano, MF AF Yetley, Elizabeth A. Pfeiffer, Christine M. Schleicher, Rosemary L. Phinney, Karen W. Lacher, David A. Christakos, Sylvia Eckfeldt, John H. Fleet, James C. Howard, George Hoofnagle, Andrew N. Hui, Siu L. Lensmeyer, Gary L. Massaro, Joseph Peacock, Munro Rosner, Bernard Wiebe, Donald Bailey, Regan L. Coates, Paul M. Looker, Anne C. Sempos, Christopher Johnson, Clifford L. Picciano, Mary Frances CA Vitamin D Roundtable NHANES TI NHANES Monitoring of Serum 25-Hydroxyvitamin D: A Roundtable Summary SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on NHANES Monitoring of Serum 25(OH)D - Assay Challenges and Options for Resolving Them CY JUL 27-28, 2009 CL Rockville, MD ID TANDEM MASS-SPECTROMETRY; CIRCULATING 25-HYDROXYVITAMIN-D; ASSAYS; ACCURACY; STANDARDIZATION; DISEASE; D-3 AB A roundtable to discuss monitoring of serum 25-hydroxyvitamin D [25(OH)D] in the NHANES was held in late July 2009. Topics included the following: 1) options for dealing with assay fluctuations in serum 25(OH)D in the NHANES conducted between 1988 and 2006; 2) approaches for transitioning between the RIA used in the NHANES between 1988 and 2006 to the liquid chromatography tandem MS (LC-MS/MS) measurement procedure to be used in NHANES 2007 and later; 31 approaches for integrating the recently available standard reference material for vitamin D in human serum (SAM 972) from the National Institute of Standards and Technology (NIST) into the NHANES; 41 questions regarding whether the C-3 epimer of 25-hydroxyvitamin D3 [3-epi-25(OH)D3] should be measured in NHANES 2007 and later; and 5) identification of research and educational needs. The roundtable experts agreed that the NHANES data needed to be adjusted to control for assay fluctuations and offered several options for addressing this issue. The experts suggested that the LC-MS/MS measurement procedure developed by NIST could serve as a higher order reference measurement procedure. They noted the need for a commutability study for the recently released NIST SRM 972 across a range of measurement procedures. They suggested that federal agencies and professional organizations work with manufacturers to improve the quality and comparability of measurement procedures across all laboratories. The experts noted the preliminary nature of the evidence of the 3-epi-25(OH)D3 but felt that it should be measured in 2007 NHANES and later. J. Nutr. 140: 2030S-2045S, 2010. C1 [Yetley, Elizabeth A.; Bailey, Regan L.; Coates, Paul M.; Sempos, Christopher; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Pfeiffer, Christine M.; Schleicher, Rosemary L.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Phinney, Karen W.] NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Lacher, David A.; Looker, Anne C.; Johnson, Clifford L.] Ctr Dis Control & Prevent, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Christakos, Sylvia] Univ Med & Dent New Jersey, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Fleet, James C.] Purdue Univ, Dept Foods & Nutr, W Lafayette, IN 47906 USA. [Howard, George] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. [Hoofnagle, Andrew N.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Hui, Siu L.; Peacock, Munro] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Lensmeyer, Gary L.] Univ Wisconsin Hosp & Clin, Clin Toxicol Lab, Madison, WI 53792 USA. [Massaro, Joseph] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Rosner, Bernard] Harvard Univ, Channing Lab, Harvard Med Sch, Boston, MA 02155 USA. [Wiebe, Donald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI 53792 USA. RP Yetley, EA (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM beth@yetley.com OI Fleet, James/0000-0002-0142-9517 FU NIDDK NIH HHS [R01 DK038961, R01 DK038961-22] NR 40 TC 62 Z9 64 U1 1 U2 6 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD NOV PY 2010 VL 140 IS 11 BP 2030S EP 2045S DI 10.3945/jn.110.121483 PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 671RD UT WOS:000283525700020 PM 20881084 ER PT J AU Koutros, S Alavanja, MCR Lubin, JH Sandler, DP Hoppin, JA Lynch, CF Knott, C Blair, A Freeman, LEB AF Koutros, Stella Alavanja, Michael C. R. Lubin, Jay H. Sandler, Dale P. Hoppin, Jane A. Lynch, Charles F. Knott, Charles Blair, Aaron Freeman, Laura E. Beane TI An Update of Cancer Incidence in the Agricultural Health Study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID FARMER PESTICIDE APPLICATORS; NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; PHYSICAL-ACTIVITY; OCCUPATIONAL-EXPOSURE; LUNG-CANCER; PROSTATE-CANCER; CUTANEOUS MELANOMA; MULTIPLE-MYELOMA; LIP CANCER AB Objective: Our objective is to reevaluate cancer incidence among Agricultural Health Study participants. Methods: Standardized incidence ratios (SIRs) and relative standardized ratios were calculated. Results: A significant excess of prostate cancer was seen for private and commercial applicators (SIR = 1.19, 95% CI 1.14, 1.25 and SIR = 1.28, 95% CI = 1.00, 1.61, respectively). Excesses were observed for lip cancer (SIR = 1.97, 95% CI = 1.02, 3.44) and multiple myeloma (SIR = 1.42, 95% CI = 1.00, 1.95) among private applicators from North Carolina and for marginal zone lymphoma among Iowa spouses (SIR = 2.34, 95% CI = 1.21, 4.09). Conclusions: Although lower rates of smoking and increased physical activity probably contribute to the lower overall cancer incidence, agricultural exposures including pesticides, viruses, bacteria, sunlight, and other chemicals may increase risks for specific cancer sites. C1 [Koutros, Stella] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Sandler, Dale P.; Hoppin, Jane A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Lynch, Charles F.] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Knott, Charles] Battelle Mem Inst, Durham, NC USA. RP Koutros, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8115,MSC 7240, Rockville, MD 20852 USA. EM koutross@mail.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics [Z01CP010119]; National Institute of Environmental Health Sciences [Z01ES049030] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01CP010119) and National Institute of Environmental Health Sciences (Z01ES049030). NR 71 TC 62 Z9 62 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD NOV PY 2010 VL 52 IS 11 BP 1098 EP 1105 DI 10.1097/JOM.0b013e3181f72b7c PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 678GD UT WOS:000284061200006 PM 21063187 ER PT J AU Wang, J Iannotti, RJ Luk, JW Nansel, TR AF Wang, Jing Iannotti, Ronald J. Luk, Jeremy W. Nansel, Tonja R. TI Co-occurrence of Victimization from Five Subtypes of Bullying: Physical, Verbal, Social Exclusion, Spreading Rumors, and Cyber SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE cyber victimization; latent class analysis; physical and psychological problems; victimization ID LATENT CLASS ANALYSIS; PEER VICTIMIZATION; INDIRECT AGGRESSION; SCHOOL; ADOLESCENTS; PREVALENCE; ASSOCIATION; INVOLVEMENT; ADJUSTMENT; CHILDREN AB Objective To examine co-occurrence of five subtypes of peer victimization. Methods Data were obtained from a national sample of 7,475 US adolescents in grades 6 through 10 in the 2005/2006 Health Behavior in School-Aged Children (HBSC) study. Latent class analyses (LCA) were conducted on victimization by physical, verbal, social exclusion, spreading rumors, and cyber bullying. Results Three latent classes were identified, including an all-types victims class (9.7% of males and 6.2% of females), a verbal/relational victims class (28.1% of males and 35.1% of females), and a nonvictim class (62.2% of males and 58.7% of females). Males were more likely to be all-type victims. There was a graded relationship between the three latent classes and level of depression, frequency of medically attended injuries, and medicine use, especially among females. Conclusions Increased co-occurrence of victimization types put adolescents at greater risks for poorer physical and psychological outcomes. C1 [Wang, Jing] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Bethesda, MD 20892 USA. [Luk, Jeremy W.] Univ Washington, Seattle, WA 98195 USA. RP Wang, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, 6100 Bldg Room,7B13 MSC 7510, Bethesda, MD 20892 USA. EM wangji2@mail.nih.gov RI castro, teresa/G-2533-2011; OI castro, teresa/0000-0002-7148-9443; Nansel, Tonja/0000-0002-8298-7595 FU Intramural NIH HHS [Z99 HD999999] NR 29 TC 74 Z9 78 U1 4 U2 28 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD NOV-DEC PY 2010 VL 35 IS 10 BP 1103 EP 1112 DI 10.1093/jpepsy/jsq048 PG 10 WC Psychology, Developmental SC Psychology GA 666MI UT WOS:000283119100005 PM 20488883 ER PT J AU Davis, AS Hintz, SR Van Meurs, KP Li, L Das, A Stoll, BJ Walsh, MC Pappas, A Bell, EF Laptook, AR Higgins, RD AF Davis, Alexis S. Hintz, Susan R. Van Meurs, Krisa P. Li, Lei Das, Abhik Stoll, Barbara J. Walsh, Michele C. Pappas, Athina Bell, Edward F. Laptook, Abbot R. Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Seizures in Extremely Low Birth Weight Infants Are Associated with Adverse Outcome SO JOURNAL OF PEDIATRICS LA English DT Article ID NEONATAL SEIZURES; ELECTROGRAPHIC SEIZURES; DEVELOPING BRAIN; PRETERM INFANTS; CEREBRAL-PALSY; UNITED-STATES; AGE; CHILDREN; RISK AB Objective To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants. Study design A total of 6499 ELBW infants (401-1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n = 414) and without (n = 6085) clinical seizures during the initial hospitalization. Using multivariate logistic regression modeling, we examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables. Results Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio, 3.15; 95% CI, 2.37-4.19). Conclusion ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors. (J Pediatr 2010; 157: 720-5). C1 [Davis, Alexis S.; Hintz, Susan R.; Van Meurs, Krisa P.] Stanford Univ, Div Neonatal Dev Med, Stanford, CA 94305 USA. [Li, Lei] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Walsh, Michele C.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Pappas, Athina] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Providence, RI 02912 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. RP Davis, AS (reprint author), Stanford Univ, Sch Med, Div Neonatol, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA. EM alexis.davis@stanford.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX Supported by the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) for the Neonatal Research Network's Generic Database Study and Follow-up Study. The authors declare no conflicts of interest. NR 34 TC 15 Z9 17 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD NOV PY 2010 VL 157 IS 5 BP 720 EP U47 DI 10.1016/j.jpeds.2010.04.065 PG 8 WC Pediatrics SC Pediatrics GA 665OS UT WOS:000283045900008 PM 20542294 ER PT J AU Mittal, P Romero, R Tarca, AL Gonzalez, J Draghici, S Xu, Y Dong, Z Nhan-Chang, CL Chaiworapongsa, T Lye, S Kusanovic, JP Lipovich, L Mazaki-Tovi, S Hassan, SS Mesiano, S Kim, CJ AF Mittal, Pooja Romero, Roberto Tarca, Adi L. Gonzalez, Juan Draghici, Sorin Xu, Yi Dong, Zhong Nhan-Chang, Chia-Ling Chaiworapongsa, Tinnakorn Lye, Stephen Kusanovic, Juan Pedro Lipovich, Leonard Mazaki-Tovi, Shali Hassan, Sonia S. Mesiano, Sam Kim, Chong Jai TI Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Aldehyde dehydrogenase (ALDH2); chemokine C-C motif ligand 2 (CCL2/MCP-1); chemokine C-X-C motif ligand 6 (CXCL6/GCP2); FK506 binding-protein 5 (FKBP5); heparin binding EGF-like growth factor (HBEGF); inflammasome; inflammation; interleukin (IL)-6,-8; leukocyte immunoglobulin-like receptor, subfamily A, member 5 (LIL-RA5/LIR9); microarray; nuclear factor of kappa light chain gene enhancer in B-cells inhibitor zeta (NFKBIZ); parturition; pregnancy; progesterone; prostaglandin-endoperoxide synthase-2 (PTGS2/COX2); suppressor of cytokine signaling 3 (SOCS3); systems biology ID HUMAN-FETAL MEMBRANES; SMOOTH-MUSCLE-CELLS; FACTOR-KAPPA-B; TUMOR-NECROSIS-FACTOR; FUNCTIONAL PROGESTERONE WITHDRAWAL; CORTICOTROPIN-RELEASING HORMONE; SPONTANEOUS PRETERM LABOR; INFLAMMATORY RESPONSE SYNDROME; AMNIOTIC-FLUID INTERLEUKIN-6; MESSENGER-RNA EXPRESSION AB Aims: To characterize the transcriptome of human myometrium during spontaneous labor at term. Methods: Myometrium was obtained from women with (n=19) and without labor (n=20). Illumina (R) HumanHT-12 microarrays were utilized. Moderated t-tests and false discovery rate adjustment of P-values were applied. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for a select set of differentially expressed genes in a separate set of samples. Enzyme-linked immunosorbent assay and Western blot were utilized to confirm differential protein production in a third sample set. Results: 1) Four hundred and seventy-one genes were differentially expressed; 2) gene ontology analysis indicated enrichment of 103 biological processes and 18 molecular functions including: a) inflammatory response; b) cytokine activity; and c) chemokine activity; 3) systems biology pathway analysis using signaling pathway impact analysis indicated six significant pathways: a) cytokine-cytokine receptor interaction; b) Jak-STAT signaling; and c) complement and coagulation cascades; d) NOD-like receptor signaling pathway; e) systemic lupus erythematosus; and f) chemokine signaling pathway; 4) qRT-PCR confirmed over-expression of prostaglandin-endoperoxide synthase-2, heparin binding epidermal growth factor (EGF)-like growth factor, chemokine C-C motif ligand 2 (CCL2/MCP1), leukocyte immunoglobulin-like receptor, subfamily A member 5, interleukin (IL)-8, IL-6, chemokine C-X-C motif ligand 6 (CXCL6/GCP2), nuclear factor of kappa light chain gene enhancer in B-cells inhibitor zeta, suppressor of cytokine signaling 3 (SOCS3) and decreased expression of FK506 binding-protein 5 and aldehyde dehydrogenase in labor; 5) IL-6, CXCL6, CCL2 and SOCS3 protein expression was significantly higher in the term labor group compared to the term not in labor group. Conclusions: Myometrium of women in spontaneous labor at term is characterized by a stereotypic gene expression pattern consistent with over-expression of the inflammatory response and leukocyte chemotaxis. Differential gene expression identified with microarray was confirmed with qRT-PCR using an independent set of samples. This study represents an unbiased description of the biological processes involved in spontaneous labor at term based on transcriptomics. C1 [Mittal, Pooja; Romero, Roberto; Tarca, Adi L.; Gonzalez, Juan; Draghici, Sorin; Xu, Yi; Dong, Zhong; Nhan-Chang, Chia-Ling; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Hassan, Sonia S.; Kim, Chong Jai] Wayne State Univ, Hutzel Womens Hosp, NICHD, Perinatol Res Branch,NIH,DHHS, Detroit, MI 48201 USA. [Mittal, Pooja; Romero, Roberto; Tarca, Adi L.; Gonzalez, Juan; Draghici, Sorin; Xu, Yi; Dong, Zhong; Nhan-Chang, Chia-Ling; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Chong Jai] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Mittal, Pooja; Romero, Roberto; Gonzalez, Juan; Nhan-Chang, Chia-Ling; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto; Tarca, Adi L.; Lipovich, Leonard] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Tarca, Adi L.; Draghici, Sorin] Wayne State Univ, Sch Med, Dept Comp Sci, Detroit, MI 48201 USA. [Lye, Stephen] Univ Toronto, Dept Obstet & Gynecol, Toronto, ON, Canada. [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Mesiano, Sam] Case Western Reserve Univ, Dept Reprod Biol, Cleveland, OH 44106 USA. [Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. RP Mittal, P (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD, Perinatol Res Branch,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM pmittal@med.wayne.edu; prbchiefstaff@med.wayne.edu RI Draghici, Sorin/B-3074-2013; Lye, Stephen/E-7269-2013 OI Draghici, Sorin/0000-0002-0786-8377; FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. We wish to thank Dr. Susan Land and Dan Lott at the Applied Genomics Technology Center of Wayne State University for performing the microarrays and to acknowledge the contributions of the nursing staff of the Perinatology Research Branch and Hutzel Women's Hospital. NR 343 TC 46 Z9 48 U1 3 U2 19 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD NOV PY 2010 VL 38 IS 6 BP 617 EP 643 DI 10.1515/JPM.2010.097 PG 27 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 678TB UT WOS:000284102500010 PM 20629487 ER PT J AU Forbes, CE Schmader, T AF Forbes, Chad E. Schmader, Toni TI Retraining Attitudes and Stereotypes to Affect Motivation and Cognitive Capacity Under Stereotype Threat SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article DE stereotype threat; attitudes; stereotypes; motivation; working memory ID WOMENS MATH PERFORMANCE; WORKING-MEMORY CAPACITY; ACHIEVEMENT-MOTIVATION; MERE EFFORT; IMPLICIT; ASSOCIATIONS; PERSPECTIVE; ACTIVATION; SETTINGS; BEHAVIOR AB In a series of experiments, a retraining paradigm was used to test the effects of attitudes and stereotypes on individuals' motivation and cognitive capacity in stereotype-threatening contexts. Women trained to have a more positive math attitude exhibited increased math motivation (Study 1). This effect was not observed for men but was magnified among women when negative stereotypes were either primed subtly (Study 2) or indirectly reinforced (Study 3). Although attitudes had no effect on working memory capacity, women retrained to associate their gender with being good at math exhibited increased working memory capacity (Studies 3 and 4), which in turn mediated increased math performance (Study 4) in a stereotype-threatening context. Results suggest that although positive attitudes can motivate stigmatized individuals to engage with threatening domains, stereotypes need to be retrained to give them the cognitive capacity critical for success. Implications for interventions to reduce stereotype threat are discussed. C1 [Forbes, Chad E.] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. [Schmader, Toni] Univ British Columbia, Dept Psychol, Vancouver, BC, Canada. RP Forbes, CE (reprint author), NIH, Dept Radiol & Imaging Sci, Bldg 10,Room 7D49,10 Ctr Dr, Bethesda, MD 20892 USA. EM forbesce@cc.nih.gov FU NIMH NIH HHS [R01 MH071749, 1R01MH071749] NR 60 TC 38 Z9 41 U1 2 U2 36 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 NOV PY 2010 VL 99 IS 5 BP 740 EP 754 DI 10.1037/a0020971 PG 15 WC Psychology, Social SC Psychology GA 679WO UT WOS:000284191700002 PM 20822288 ER PT J AU Chattopadhyay, M Velazquez, CA Pruski, A Nia, KV Abdellatif, KR Keefer, LK Kashfi, K AF Chattopadhyay, Mitali Velazquez, Carlos A. Pruski, April Nia, Kamran V. Abdellatif, Khaled R. Keefer, Larry K. Kashfi, Khosrow TI Comparison between 3-Nitrooxyphenyl acetylsalicylate (NO-ASA) and O-2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA) as Safe Anti-Inflammatory, Analgesic, Antipyretic, Antioxidant Prodrugs SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NITRIC-OXIDE RELEASE; GASTROINTESTINAL SAFETY; BIOLOGICAL EVALUATION; COLORECTAL-CANCER; ASPIRIN; NSAIDS; DRUGS; RISK; RAT; INFLAMMATION AB Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O-2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses. For antiulcerogenic study, 6 h after administration, the number and size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for prostaglandin E-2 (PGE(2)), superoxide dismutase (SOD), and malondialdehyde determination. For anti-inflammatory study, 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6 h. For antipyretic study, 1 h after dosing, fever was induced by intraperitoneal LPS, and body core temperatures measured for 5 h. For analgesic study, time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NO-ASA and NONO-ASA were equipotent as analgesic and anti-inflammatory agents but were better than aspirin. Despite a drastic reduction of PGE(2) in stomach tissue, both prodrugs were devoid of gastric side effects. Lipid peroxidation induced by aspirin was higher than that observed by prodrugs. SOD activity induced by both prodrugs was similar, but approximately 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and antipyretic assays in vivo, and it showed an equivalent safety profile in the stomach. These results underscore the use of N-diazeniumdiolate moieties in drug design. C1 [Chattopadhyay, Mitali; Pruski, April; Nia, Kamran V.; Kashfi, Khosrow] CUNY, Dept Physiol & Pharmacol, Sch Med, New York, NY 10031 USA. [Velazquez, Carlos A.; Abdellatif, Khaled R.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. [Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. RP Kashfi, K (reprint author), CUNY, Dept Physiol & Pharmacol, Sch Med, 138th St & Convent Ave, New York, NY 10031 USA. EM kashfi@med.cuny.edu RI Keefer, Larry/N-3247-2014; OI Keefer, Larry/0000-0001-7489-9555; Abdellatif, Khaled/0000-0002-5815-9677 FU National Institutes of Health National Cancer Institute, Division of Basic Sciences, Center for Cancer Research [ZIA-BC005673] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health National Cancer Institute, Division of Basic Sciences, Center for Cancer Research [Project ZIA-BC005673]. NR 39 TC 13 Z9 14 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD NOV PY 2010 VL 335 IS 2 BP 443 EP 450 DI 10.1124/jpet.110.171017 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 666TM UT WOS:000283143200020 PM 20679133 ER PT J AU Banks, ML Rice, KC Negus, SS AF Banks, Matthew L. Rice, Kenner C. Negus, S. Stevens TI Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID TAIL-WITHDRAWAL PROCEDURE; FORMALIN TEST; THERMAL HYPERALGESIA; PAIN MODULATION; SPINAL-CORD; MORPHINE; RATS; NOCICEPTION; ANALGESIA; PATHWAYS AB Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine < morphine < methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine > morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine. C1 [Banks, Matthew L.; Negus, S. Stevens] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Negus, SS (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 N 12th St,POB 980613, Richmond, VA 23298 USA. EM ssnegus@vcu.edu RI Banks, Matthew/K-4429-2014 OI Banks, Matthew/0000-0003-4949-5246 FU National Institutes of Health National Institute on Drug Abuse [R01-DA011460, T32-DA007027]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA011460, T32-DA007027]; the Intramural Research Programs of the National Institute on Drug Abuse; and the National Institute on Alcohol Abuse and Alcoholism. NR 40 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD NOV PY 2010 VL 335 IS 2 BP 497 EP 505 DI 10.1124/jpet.110.169276 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 666TM UT WOS:000283143200027 PM 20675432 ER PT J AU Spruijt-Metz, D Troiano, R Thornquist, M Sirard, J Redline, S Berrigan, D AF Spruijt-Metz, Donna Troiano, Richard Thornquist, Mark Sirard, John Redline, Susan Berrigan, David TI Objective and Subjective Measures of Physical Activity in Youth: Emerging Challenges for Analysis and Interpretation SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Meeting Abstract DE accelerometry; self-report; adolescents; sleep; measurement ID UNITED-STATES; EXERCISE; SLEEP C1 [Spruijt-Metz, Donna] Univ So Calif, Los Angeles, CA USA. [Troiano, Richard; Berrigan, David] NCI, NIH, Bethesda, MD 20892 USA. [Thornquist, Mark] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Sirard, John] Univ Minnesota, Minneapolis, MN USA. [Redline, Susan] Case Western Reserve Univ, Cleveland, OH 44106 USA. NR 5 TC 1 Z9 1 U1 0 U2 5 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD NOV PY 2010 VL 7 SU 3 BP S322 EP S324 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 679RR UT WOS:000284179000013 ER PT J AU Perez-Rodriguez, MM Weinstein, S New, AS Bevilacqua, L Yuan, QP Zhou, ZF Hodgkinson, C Goodman, M Koenigsberg, HW Goldman, D Siever, LJ AF Perez-Rodriguez, M. Mercedes Weinstein, Shauna New, Antonia S. Bevilacqua, Laura Yuan, Qiaoping Zhou, Zhifeng Hodgkinson, Colin Goodman, Marianne Koenigsberg, Harold W. Goldman, David Siever, Larry J. TI Tryptophan-hydroxylase 2 haplotype association with borderline personality disorder and aggression in a sample of patients with personality disorders and healthy controls SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Borderline personality disorder; TPH2; Suicidal behavior; Affective instability; Impulsive aggression ID CENTRAL SEROTONERGIC FUNCTION; ISOFORM TPH2 GENE; IMPULSIVE-AGGRESSION; PROLACTIN RESPONSE; D-FENFLURAMINE; CEREBROSPINAL-FLUID; VIOLENT OFFENDERS; MAJOR DEPRESSION; TRANSMISSION DISEQUILIBRIUM; POLYMORPHIC VARIANTS AB Background There is a decreased serotonergic function in impulsive aggression and borderline personality disorder (BPD) and genetic association studies suggest a role of serotonergic genes in impulsive aggression and BPD Only one study has analyzed the association between the tryptophan-hydroxylase 2 (TPH2) gene and BPD A TPH2 "risk" haplotype has been described that is associated with anxiety depression and suicidal behavior Methods We assessed the relationship between the previously identified risk" haplotype at the TPH2 locus and BPD diagnosis impulsive aggression affective lability and suicidal/parasuicidal behaviors in a well-characterized clinical sample of 103 healthy controls (HCs) and 251 patients with personality disorders (109 with BPD) A logistic regression including measures of depression affective lability and aggression scores in predicting risk" haplotype was conducted Results The prevalence of the "risk" haplotype was significantly higher in patients with BPD compared to HCs Those with the "risk" haplotype have higher aggression and affect lability scores and more suicidal/parasuicidal behaviors than those without it In the logistic regression model affect lability was the only significant predictor and it correctly classified 83 1% of the subjects as risk or non-risk haplotype carriers Conclusions We found an association between the previously described TPH2 risk haplotype and BPD diagnosis affective lability suicidal/parasuicidal behavior and aggression scores (C) 2010 Elsevier Ltd All rights reserved C1 [Perez-Rodriguez, M. Mercedes; Weinstein, Shauna; New, Antonia S.; Goodman, Marianne; Koenigsberg, Harold W.; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Weinstein, Shauna; New, Antonia S.; Goodman, Marianne; Koenigsberg, Harold W.; Siever, Larry J.] James J Peters Vet Affairs Med Ctr, Mental Hlth Patient Care Ctr, Bronx, NY 10468 USA. [Bevilacqua, Laura; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Siever, LJ (reprint author), James J Peters Vet Adm Med Ctr, 3rd Floor,Room 3B,20 130 W Kingsbridge Rd, Bronx, NY 10468 USA. RI Perez Rodriguez, Maria/B-9410-2013; Goldman, David/F-9772-2010 OI Perez Rodriguez, Maria/0000-0001-5137-1993; Goldman, David/0000-0002-1724-5405 FU National Institute of Mental Health [MH56140, MH63875]; Veterans Affairs [7609-028, 9001-03-0051]; Veterans Affairs VISN 3 Mental Illness Research Education & Clinical Center; National Center for Research Resources (NCRR) [MO1-RR-00071] FX This research was supported by Grants MH56140 & MH63875 from the National Institute of Mental Health to Larry J Siever by a Veterans Affairs Merit Review Grant (7609-028) to Larry J Siever and by the Veterans Affairs VISN 3 Mental Illness Research Education & Clinical Center; This publication was made possible by Grant Number MO1-RR-00071 from the National Center for Research Resources (NCRR) a component of the National Institutes of Health (NIH) Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH; This work was supported in part by a VA Merit award to Dr New (9001-03-0051) New (PI)- Intermediate Phenotypes for Borderline Personality Disorder and a VA Career Development Award to Dr Goodman NR 78 TC 30 Z9 34 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD NOV PY 2010 VL 44 IS 15 BP 1075 EP 1081 DI 10.1016/j.jpsychires.2010.03.014 PG 7 WC Psychiatry SC Psychiatry GA 684RJ UT WOS:000284566700013 PM 20451217 ER PT J AU Matabosch, X Ying, L Serra, M Wassif, CA Porter, FD Shackleton, C Watson, G AF Matabosch, Xavier Ying, Lee Serra, Montserrat Wassif, Christopher A. Porter, Forbes D. Shackleton, Cedric Watson, Gordon TI Increasing cholesterol synthesis in 7-dehydrosterol reductase (DHCR7) deficient mouse models through gene transfer SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Smith-Lemli-Opitz syndrome (SLOS); DHCR7; AAV; Gene therapy ID LEMLI-OPITZ-SYNDROME; RECOMBINANT ADENOASSOCIATED VIRUS; PRENATAL-DIAGNOSIS; SYNDROME SLOS; VII MICE; DIETARY-CHOLESTEROL; CARRIER FREQUENCY; MASS-SPECTROMETRY; LYSOSOMAL STORAGE; INBORN-ERRORS AB Smith-Lemli-Opitz syndrome (SLOS) is caused by deficiency in the terminal step of cholesterol biosynthesis: the conversion of 7-dehydrocholesterol (7DHC) to cholesterol (C), catalyzed by 7-dehydrocholesterol reductase (DHCR7). This disorder exhibits several phenotypic traits including dysmorphia and mental retardation with a broad range of severity. There are few proven treatment options. That most commonly used is a high cholesterol diet that seems to enhance the quality of life and improve behavioral characteristics of patients, although these positive effects are controversial. The goal of our study was to investigate the possibility of restoring DHCR7 activity by gene transfer. We constructed an adeno-associated virus (MV) vector containing the DHCR7 gene. After we infused this vector into affected mice, the introduced DHCR7 gene could be identified in liver, mRNA was expressed and a functional enzyme was produced. Evidence of functionality came from the ability to partially normalize the serum ratio of 7DHC/C in treated animals, apparently by increasing cholesterol production with concomitant decrease in 7DHC precursor. By 5 weeks after treatment the mean ratio (for 7 animals) had fallen to 0.05 while the ratio for untreated littermate controls had risen to 0.14. This provides proof of principle that gene transfer can ameliorate the genetic defect causing SLOS and provides a new experimental tool for studying the pathogenesis of this disease. If effective in humans, it might also offer a possible alternative to exogenous cholesterol therapy. However, it would not offer a complete cure for the disorder as many of the negative implications of defective synthesis are already established during prenatal development. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Matabosch, Xavier; Ying, Lee; Serra, Montserrat; Shackleton, Cedric; Watson, Gordon] Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA. [Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Shackleton, Cedric] Univ Birmingham, CEDAM, Inst Biomed Res, Birmingham B15 2TT, W Midlands, England. RP Watson, G (reprint author), Childrens Hosp, Oakland Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA. EM gwatson@chori.org OI Serra, Montserrat/0000-0002-5528-2418; Matabosch, Xavier/0000-0001-8442-7957; Wassif, Christopher/0000-0002-2524-1420 FU National Institutes of Health [R01HD053036]; Smith-Lemli-Opitz/RSH Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Generalitat de Catalunya [2007 BP-A 00101]; Howard Hughes Medical Institute's Undergraduate Biological Science Education Initiative FX We thank Kevin Hua for technical help and Dr. Berna Watson for statistical analysis. This work was supported by National Institutes of Health Grant R01HD053036 (CS) and a grant from the Smith-Lemli-Opitz/RSH Foundation (GW). This work was also supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Serra was awarded a Beatriu de Pinos postdoctoral fellowship from Generalitat de Catalunya (2007 BP-A 00101). Amb el suport del Comissionat per a Universitats i Recerca del Departament d'Innovacio, Universitats i Empresa de la Generalitat de Catalunya. Lee Ying was awarded a fellowship from Howard Hughes Medical Institute's Undergraduate Biological Science Education Initiative; Biology Fellows Program at University of California Berkeley. NR 41 TC 5 Z9 6 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD NOV PY 2010 VL 122 IS 5 BP 303 EP 309 DI 10.1016/j.jsbmb.2010.08.004 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 682ZU UT WOS:000284442300001 PM 20800683 ER PT J AU Dull, A Goncharova, E Hager, G McMahon, JB AF Dull, Angie Goncharova, Ekaterina Hager, Gordon McMahon, James B. TI Development of an image analysis screen for estrogen receptor alpha (ER alpha) ligands through measurement of nuclear translocation dynamics SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Estrogen receptor; High-content screening; Cell-based assay; Nuclear translocation; Cytotoxicity ID HEALTHY POSTMENOPAUSAL WOMEN; BREAST EPITHELIAL-CELLS; NONALCOHOLIC STEATOHEPATITIS; PLUS PROGESTIN; TAMOXIFEN; CANCER; TRIAL; CARCINOGENS; KIDNEY; LIVER AB We have developed a robust high-content assay to screen for novel estrogen receptor alpha (ER alpha) agonists and antagonists by quantitation of cytoplasmic to nuclear translocation of an estrogen receptor chimera in 384-well plates. The screen utilizes a green fluorescent protein tagged-glucocorticoid/estrogen receptor (GFP-GRER) chimera which consisted of the N-terminus of the glucocorticoid receptor fused to the human ER ligand binding domain. The GFP-GRER exhibited cytoplasmic localization in the absence of ER alpha ligands, and translocated to the nucleus in response to stimulation with ER alpha agonists or antagonists. The BD Pathway 435 imaging system was used for image acquisition, analysis of translocation dynamics, and cytotoxicity measurements. The assay was validated with known ER alpha agonists and antagonists, and the Library of Pharmacologically Active Compounds (LOPAC 1280). Additionally, screening of crude natural product extracts demonstrated the robustness of the assay, and the ability to quantitate the effects of toxicity on nuclear translocation dynamics. The GFP-GRER nuclear translocation assay was very robust, with z' values >0.7, CVs <5%, and has been validated with known ER ligands, and inclusion of cytotoxicity filters will facilitate screening of natural product extracts. This assay has been developed for future primary screening of synthetic, pure natural products, and natural product extracts libraries available at the National Cancer Institute at Frederick. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Dull, Angie] NCI, Mol Targets Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Goncharova, Ekaterina] NCI, Data Management Serv Inc, Frederick, MD 21702 USA. [Hager, Gordon] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, Frederick, MD 21702 USA. [McMahon, James B.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Dull, A (reprint author), NCI, Mol Targets Lab, SAIC Frederick Inc, Mailstop 538-01, Frederick, MD 21702 USA. EM dulla@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research 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 HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 21 TC 8 Z9 8 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD NOV PY 2010 VL 122 IS 5 BP 341 EP 351 DI 10.1016/j.jsbmb.2010.08.009 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 682ZU UT WOS:000284442300006 PM 20816963 ER PT J AU Vu, HN Miller, WJ O'Connor, SA He, M Schafer, PH Payvandi, F Muller, GW Stirling, DI Libutti, SK AF Vu, Huan N. Miller, Walter J. O'Connor, Sarah A. He, Mei Schafer, Peter H. Payvandi, Faribourz Muller, George W. Stirling, David I. Libutti, Steven K. TI CC-5079: A Small Molecule with MKP1, Antiangiogenic, and Antitumor Activity SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE angiogenesis; Selcids; small molecule inhibitor ID CELL-PROLIFERATION; AGENTS; ANGIOGENESIS; BEVACIZUMAB; INHIBITION; MECHANISM; TUBULIN; CANCER AB Introduction. CC-5079, a small molecule inhibitor of tubulin polymerization and phosphodiesterase-4 activity, was evaluated for antiangiogenic and antitumor activities. Materials and Methods. First, CC-5079 in vitro activity on human umbilical vein endothelial cells (HU-VECs), fibroblasts, and MC38 were evaluated by proliferation, migration, and invasion assays. Second, CC-5079 effect on microvessel formation was evaluated ex vivo by chick chorioallantoic membrane (CAM), rat aortic rings assays, and with directed in vivo angiogenesis assay (DIVAA). Third, CC-5079 antitumor effect was determined in treatment of C57BL/6 mice with MC38 tumors. Finally, CC-5079 modulation of MKP1 in HUVECs, human fibroblast, and MC38 were determined by RNA isolation for qRT-PCR. Results. At the 0.1 mu M concentration CC-5079 significantly inhibited HUVEC, fibroblast, and MC38 proliferation and migration (all P < 0.001). At the 0.1 mu M concentration, CC-5079 also inhibited HUVEC invasion (P < 0.05) but not fibroblast. In the CAM and rat aortic ring assays, CC-5079 at 0.1 mu M inhibited microvessel formation (P < 0.05). By DIVAA, CC-5079 at 1 mg/kg/d continuous delivered inhibited microvessel formation (P < 0.05). Intraperitoneal CC-5079 was well tolerated and inhibited the growth of subcutaneous MC38 at 100 mg/kg/d (P < 0.01). By qRT-PCR, CC-5079 stimulated MKP1 expression in HUVEC and fibroblast. Conclusion. CC-5079 demonstrated stimulation of MKP1 antiangiogenic, and antitumor properties. Published by Elsevier Inc. C1 [Vu, Huan N.; Miller, Walter J.; O'Connor, Sarah A.; He, Mei; Libutti, Steven K.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Schafer, Peter H.; Payvandi, Faribourz; Muller, George W.; Stirling, David I.] Celgene Corp, Summit, NJ USA. RP Vu, HN (reprint author), VCU Surg Oncol, W Hosp 7-406B,1200 E Broad St, Richmond, VA 23298 USA. EM HNVU@VCU.EDU FU Celgene Corporation; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Celgene Corporation and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and performed at the Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. NR 18 TC 5 Z9 5 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD NOV PY 2010 VL 164 IS 1 BP 116 EP 125 DI 10.1016/j.jss.2009.01.031 PG 10 WC Surgery SC Surgery GA 672XX UT WOS:000283622100021 PM 19726061 ER PT J AU Beachkofsky, TM Sapp, JC Biesecker, LG Darling, TN AF Beachkofsky, Thomas M. Sapp, Julie C. Biesecker, Leslie G. Darling, Thomas N. TI Progressive overgrowth of the cerebriform connective tissue nevus in patients with Proteus syndrome SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE cerebriform connective tissue nevus; overgrowth; progression; Proteus syndrome ID DIAGNOSTIC-CRITERIA; MANAGEMENT; SKIN AB Background: Proteus syndrome is a rare overgrowth disorder that almost always affects the skin. Objective: Our purpose was to evaluate progression of skin lesion:; in patients with Proteus syndrome. Methods: Skin findings were documented in 36 patients with Proteus syndrome. Progression of skin lesions in 16 of these patients was assessed by comparing photographs obtained on repeated visits for an average total duration of 53 months. Results: The skin lesion most characteristic of Proteus syndrome, the cerebriform connective tissue nevus, showed progression in 13 children but not in 3 adults. The cerebriform connective tissue nevus progressed by expansion into previously uninvolved skin, increased thickness, and development of new lesions. Lipomas increased in size, number, or both in 8 of 10 children with lipomas. In contrast, epidermal nevi and Vascular malformations generally did not spread or increase in number. Limitations: Only 3 adults with Proteus syndrome were evaluated longitudinally. Conclusion: The cerebriform connective tissue nevus in Proteus syndrome grows throughout childhood but tends to remain stable in adulthood. (J Am Acad Dermatol 2010;63:799-804.) C1 [Beachkofsky, Thomas M.; Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Sapp, Julie C.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Darling, TN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM tdarling@usuhs.mil OI Darling, Thomas/0000-0002-5161-1974 FU Sulzberger Laboratory for Dermatologic Research; National Institutes of Health, National Human Genome Research Institute FX Supported by Sulzberger Laboratory for Dermatologic Research, and the Intramural Research Program of the National Institutes of Health, National Human Genome Research Institute. NR 19 TC 11 Z9 12 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD NOV PY 2010 VL 63 IS 5 BP 799 EP 804 DI 10.1016/j.jaad.2009.12.012 PG 6 WC Dermatology SC Dermatology GA 675EP UT WOS:000283809300008 PM 20709429 ER PT J AU Hoggle, LB Yadrick, MM Ayres, EJ AF Hoggle, Lindsey Blevins Yadrick, Martin M. Ayres, Elaine J. TI A Decade of Work Coming Together: Nutrition Care, Electronic Health Records, and the HITECH Act SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Editorial Material C1 [Hoggle, Lindsey Blevins] Hlth Project Partners LLC, Gaithersburg, MD USA. [Yadrick, Martin M.] Computrition Inc, Nutr Informat, Los Angeles, CA USA. [Ayres, Elaine J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. RP Hoggle, LB (reprint author), Hlth Project Partners LLC, Gaithersburg, MD USA. NR 10 TC 6 Z9 6 U1 0 U2 3 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD NOV PY 2010 VL 110 IS 11 BP 1606 EP + DI 10.1016/j.jada.2010.09.019 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 675JF UT WOS:000283825700002 PM 21034868 ER PT J AU Xue, QL Beamer, BA Chaves, PHM Guralnik, JM Fried, LP AF Xue, Qian-Li Beamer, Brock A. Chaves, Paulo H. M. Guralnik, Jack M. Fried, Linda P. TI Heterogeneity in Rate of Decline in Grip, Hip, and Knee Strength and the Risk of All-Cause Mortality: The Women's Health and Aging Study II SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE handgrip strength; hip strength; knee strength; mortality; older women ID RANDOMIZED CONTROLLED-TRIAL; MUSCLE STRENGTH; OLDER WOMEN; HANDGRIP STRENGTH; SKELETAL-MUSCLE; PHYSICAL-ACTIVITY; MEN; ADULTS; MASS; PREDICTORS AB OBJECTIVES: To assess the relationship between rate of change in muscle strength and all-cause mortality. DESIGN: Prospective observational study of the causes and course of physical disability. SETTING: Twelve contiguous ZIP code areas in Baltimore, Maryland. PARTICIPANTS: Three hundred seven community-dwelling women aged 70 to 79 at study baseline. MEASUREMENTS: The outcome was all-cause mortality (1994-2009); predictors included up to seven repeated measurements of handgrip, knee extension, and hip flexion strength, with a median follow-up time of 10 years. Demographic factors, body mass index, smoking status, number of chronic diseases, depressive symptoms, physical activity, interleukin-6, and albumin were assessed at baseline and included as confounders. The associations between declining muscle strength and mortality were assessed using a joint longitudinal and survival model. RESULTS: Grip and hip strength declined an average of 1.10 and 1.31 kg/year between age 70 and 75 and 0.50 and 0.39 kg/year thereafter, respectively; knee strength declined at a constant rate of 0.57 kg/year. Faster rates of decline in grip and hip strength, but not knee strength, independently predicted mortality after accounting for baseline levels and potential confounders (hazard ratio (HR) = 51.33, 95% confidence interval (95%) CI = 1.06-1.67, HR = 1.14, 95% CI = 0.91-1.41, and 2.62, 95% CI = 1.43-4.78 for every 0.5 standard deviation increase in rate of decline in grip, knee, and hip strength, respectively). CONCLUSION: Monitoring the rate of decline in grip and hip flexion strength in addition to absolute levels may greatly improve the identification of women most at risk of dying. J Am Geriatr Soc 58:2076-2084, 2010. C1 [Xue, Qian-Li; Chaves, Paulo H. M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Xue, Qian-Li; Chaves, Paulo H. M.] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD USA. [Beamer, Brock A.] Univ Maryland, Sch Med, Div Gerontol, Baltimore, MD 21201 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Guralnik, Jack M.] NIA, NIH, Bethesda, MD 20892 USA. RP Xue, QL (reprint author), 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM qxue@jhsph.edu FU National Institute on Aging (NIA), National Institutes of Health (NIH) [P30-AG02133, R01-AG11703, R01-AG023701] FX This study was supported by the Johns Hopkins Older Americans Independence Center under Contracts P30-AG02133, R01-AG11703, and R01-AG023701 from the National Institute on Aging (NIA), National Institutes of Health (NIH). Dr. Guralnik was supported in part by the Intramural Research Program, NIA, NIH. NR 34 TC 31 Z9 32 U1 2 U2 11 PU WILEY-BLACKWELL PUBLISHING, INC 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 NOV PY 2010 VL 58 IS 11 BP 2076 EP 2084 DI 10.1111/j.1532-5415.2010.03154.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 676WT UT WOS:000283950100004 PM 21054287 ER PT J AU Alley, DE Koster, A Mackey, D Cawthon, P Ferrucci, L Simonsick, EM Yu, BB Hardy, S Goodpaster, B Sarkisian, C Houston, DK Kritchevsky, SB Cummings, S Lee, JS Tylavsky, FA Newman, A Harris, T AF Alley, Dawn E. Koster, Annemarie Mackey, Dawn Cawthon, Peggy Ferrucci, Luigi Simonsick, Eleanor M. Yu, Binbing Hardy, Susan Goodpaster, Bret Sarkisian, Catherine Houston, Denise K. Kritchevsky, Stephen B. Cummings, Steven Lee, Jung-Sun Tylavsky, Frances A. Newman, Anne Harris, Tamara CA Hlth Aging & Body Composition Stud TI Hospitalization and Change in Body Composition and Strength in a Population-Based Cohort of Older Persons SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE lean mass; weight loss; function; hospitalization; strength ID BED REST; WEIGHT CHANGE; MUSCLE MASS; ADULTS; FRAILTY; HEALTH; WOMEN; DISABILITY; MORTALITY; RECOVERY AB OBJECTIVES: To examine the association between hospitalization and annual changes in body composition and strength in older adults. DESIGN: Cohort study. SETTING: Clinic examinations in Pittsburgh, Pennsylvania, or Memphis, Tennessee. PARTICIPANTS: Well-functioning adults aged 70 to 79 who participated in the Health, Aging and Body Composition Study. MEASUREMENTS: Hospitalizations were reported at annual clinic visits and in semiannual phone interviews. In the event of death or reported hospitalization, hospitalizations were adjudicated according to medical record review. Dual X-ray absorptiometry (DXA) assessments of total, lean, and fat mass were conducted in six annual examinations, and measures of knee extensor strength were conducted in two annual examinations. RESULTS: DXA assessments followed 2,309 hospitalizations. In men and women, hospitalization in the previous year was associated with greater declines in total mass (- 0.76 and -0.81 kg, respectively), fat mass (-0.41 and -0.54 kg), and lean mass (-0.33 and -0.25 kg) (P < .001 for all) than in nonhospitalized participants, after adjustment for demographics and baseline values. Hospitalization was associated with strength declines in men (-4.02 Nm, P = .046) but not in women. Relationships were similar after adjusting for health behaviors and chronic conditions, although the association between hospitalization and strength was attenuated. Associations increased with number of days hospitalized; hospitalizations totaling 8 days or more in the previous year were associated with significantly greater loss of total, lean, and fat mass and loss of strength in both sexes than in nonhospitalized participants. CONCLUSION: Hospitalization is associated with significant changes in body composition and strength in older persons. These effects appear particularly important in persons hospitalized for 8 or more days per year. J Am Geriatr Soc 58:2085-2091, 2010. C1 [Alley, Dawn E.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Koster, Annemarie; Yu, Binbing; Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Mackey, Dawn; Cawthon, Peggy; Cummings, Steven] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Ferrucci, Luigi; Simonsick, Eleanor M.] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Hardy, Susan; Goodpaster, Bret; Newman, Anne] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Newman, Anne] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA USA. [Sarkisian, Catherine] Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. [Houston, Denise K.; Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Lee, Jung-Sun] Univ Georgia, Coll Publ Hlth, Athens, GA 30602 USA. [Tylavsky, Frances A.] Univ Tennessee, Dept Epidemiol, Memphis, TN USA. RP Alley, DE (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. EM dalley@epi.umaryland.edu RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institutes of Health, National Institute on Aging (NIA); Organized Research Center on Aging at the University of Maryland, Baltimore; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-2106] FX D. Houston received a speaker honorarium from Abbott Nutrition Health Institute. All other authors have no financial disclosure to report. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA) and by the Organized Research Center on Aging at the University of Maryland, Baltimore. The Health ABC Study is funded under NIA Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-2106. NR 25 TC 22 Z9 23 U1 4 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC 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 NOV PY 2010 VL 58 IS 11 BP 2085 EP 2091 DI 10.1111/j.1532-5415.2010.03144.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 676WT UT WOS:000283950100005 PM 21054288 ER PT J AU Young, Y Boyd, CM Guralnik, JM Fried, LP AF Young, Yuchi Boyd, Cynthia M. Guralnik, Jack M. Fried, Linda P. TI Does Self-Reported Function Correspond to Objective Measures of Functional Impairment? SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Aging; disability; impairments ID PHYSICAL PERFORMANCE; OLDER-ADULTS; PRECLINICAL DISABILITY; WOMENS HEALTH; MOBILITY DISABILITY; RISK; DEPENDENCE; VALIDITY; DECLINE; DISEASE AB Introduction: The relationship between self-reported function and objective measures of physiological function among disabled older women was analyzed to determine the validity of self-reported function, and to identify the hierarchy of self-reported task difficulty most associated with loss of independence as a basis to inform treatment progress goals. Methods: A randomly selected population of older women with moderate to high disability was selected from community-dwelling women 65 to 101 years old from the Women's Health and Aging Study I baseline evaluation (n = 987). Cross-sectional analyses evaluated the association of self-reported function with objective physiological impairment measures. Results: The results indicated that (1) disabled older women self-reported a broad range of physical function levels; (2) self-reported function correlated closely with objective measures of physiological impairments; (3) "preclinical disability," as measured by self-reported modification of task performance in the absence of perceived difficulty, has validity even in a disabled population, and identifies a group intermediate between those who are high functioning in a task and those with difficulty; and (4) there is an apparent gradation in physiological impairment measures with reported loss of functional independence. Conclusion: These findings suggest the validity of self-report functional disability measures and the potential to use these measures to identify already-disabled older adults at risk for further functional degradation and potential targets for intervention. (1 Am Med Dir Assoc 2010; 11: 645-653) C1 [Young, Yuchi] SUNY Albany, Sch Publ Hlth, Rensselaer, NY 12144 USA. [Fried, Linda P.] Columbia Univ, Joseph L Mailman Sch Publ Hlth, New York, NY USA. [Guralnik, Jack M.; Fried, Linda P.] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Boyd, Cynthia M.; Fried, Linda P.] Johns Hopkins Med Inst, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. [Guralnik, Jack M.] NIA, Bethesda, MD 20892 USA. RP Young, Y (reprint author), SUNY Albany, Sch Publ Hlth, 1 Univ Pl,Room 171, Rensselaer, NY 12144 USA. EM yyoung@albany.edu FU National Institutes of Health [R37-AG 19905, N01AG1-2112]; National Institute on Aging, National Institutes of Health FX This work was supported by National Institutes of Health grant R37-AG 19905 and contract N01AG1-2112. Supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 29 TC 14 Z9 14 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD NOV PY 2010 VL 11 IS 9 BP 645 EP 653 DI 10.1016/j.jamda.2009.12.084 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 681UA UT WOS:000284344100006 PM 21029999 ER PT J AU Fung, KW McDonald, C Srinivasan, S AF Fung, Kin Wah McDonald, Clement Srinivasan, Suresh TI The UMLS-CORE project: a study of the problem list terminologies used in large healthcare institutions SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID MEDICAL LANGUAGE SYSTEM; VOCABULARY; TOOL AB Objective To study existing problem list terminologies (PLTs), and to identify a subset of concepts based on standard terminologies that occur frequently in problem list data. Design Problem list terms and their usage frequencies were collected from large healthcare institutions. Measurement The pattern of usage of the terms was analyzed. The local terms were mapped to the Unified Medical Language System (UMLS). Based on the mapped UMLS concepts, the degree of overlap between the PLTs was analyzed. Results Six institutions submitted 76 237 terms and their usage frequencies in 14 million patients. The distribution of usage was highly skewed. On average, 21% of unique terms already covered 95% of usage. The most frequently used 14 395 terms, representing the union of terms that covered 95% of usage in each institution, were exhaustively mapped to the UMLS. 13 261 terms were successfully mapped to 6776 UMLS concepts. Less frequently used terms were generally less 'mappable' to the UMLS. The mean pairwise overlap of the PLTs was only 21% (median 19%). Concepts that were shared among institutions were used eight times more often than concepts unique to one institution. A SNOMED Problem List Subset of frequently used problem list concepts was identified. Conclusions Most of the frequently used problem list terms could be found in standard terminologies. The overlap between existing PLTs was low. The use of the SNOMED Problem List Subset will save developmental effort, reduce variability of PLTs, and enhance interoperability of problem list data. C1 [Fung, Kin Wah; McDonald, Clement; Srinivasan, Suresh] Natl Lib Med, Bethesda, MD 20894 USA. RP Fung, KW (reprint author), Natl Lib Med, Bldg 38A,Rm9S914,MSC-3826,8600 Rockville Pike, Bethesda, MD 20894 USA. EM kfung@mail.nih.gov FU National Institutes of Health; National Library of Medicine FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Library of Medicine. NR 22 TC 19 Z9 19 U1 0 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2010 VL 17 IS 6 BP 675 EP 680 DI 10.1136/jamia.2010.007047 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 676GV UT WOS:000283899900011 PM 20962130 ER PT J AU Johnson, SB Whitney, G McAuliffe, M Wang, HL McCreedy, E Rozenblit, L Evans, CC AF Johnson, Stephen B. Whitney, Glen McAuliffe, Matthew Wang, Hailong McCreedy, Evan Rozenblit, Leon Evans, Clark C. TI Using global unique identifiers to link autism collections SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID PERSONAL IDENTIFIERS AB Objective To propose a centralized method for generating global unique identifiers to link collections of research data and specimens. Design The work is a collaboration between the Simons Foundation Autism Research Initiative and the National Database for Autism Research. The system is implemented as a web service: an investigator inputs identifying information about a participant into a client application and sends encrypted information to a server application, which returns a generated global unique identifier. The authors evaluated the system using a volume test of one million simulated individuals and a field test on 2000 families (over 8000 individual participants) in an autism study. Measurements Inverse probability of hash codes; rate of false identity of two individuals; rate of false split of single individual; percentage of subjects for which identifying information could be collected; percentage of hash codes generated successfully. Results Large-volume simulation generated no false splits or false identity. Field testing in the Simons Foundation Autism Research Initiative Simplex Collection produced identifiers for 96% of children in the study and 77% of parents. On average, four out of five hash codes per subject were generated perfectly (only one perfect hash is required for subsequent matching). Discussion The system must achieve balance among the competing goals of distinguishing individuals, collecting accurate information for matching, and protecting confidentiality. Considerable effort is required to obtain approval from institutional review boards, obtain consent from participants, and to achieve compliance from sites during a multicenter study. Conclusion Generic unique identifiers have the potential to link collections of research data, augment the amount and types of data available for individuals, support detection of overlap between collections, and facilitate replication of research findings. C1 [Johnson, Stephen B.] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA. [Johnson, Stephen B.; Whitney, Glen] Simons Fdn, New York, NY USA. [McAuliffe, Matthew; Wang, Hailong; McCreedy, Evan] NIH, Bethesda, MD 20892 USA. [Rozenblit, Leon; Evans, Clark C.] Prometheus Res LLC, New Haven, CT USA. RP Johnson, SB (reprint author), Columbia Univ, Dept Biomed Informat, 622 W 168th St,VC 558, New York, NY 10032 USA. EM sbj2@columbia.edu OI Rozenblit, Leon/0000-0001-5243-6752 FU Simons Foundation Autism Research Initiative (SFARI); National Database for Autism Research (NDAR); National Institute of Mental Health; NIH FX This work was supported by the Simons Foundation Autism Research Initiative (SFARI) and the National Database for Autism Research (NDAR), National Institute of Mental Health. Other Funders: NIH; Simons Foundation Autism Research Initiative; National Database for Autism Research; National Institute of Mental Health. NR 17 TC 34 Z9 34 U1 1 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2010 VL 17 IS 6 BP 689 EP 695 DI 10.1136/jamia.2009.002063 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 676GV UT WOS:000283899900013 PM 20962132 ER PT J AU Pathak, J Peters, L Chute, CG Bodenreider, O AF Pathak, Jyotishman Peters, Lee Chute, Christopher G. Bodenreider, Olivier TI Comparing and evaluating terminology services application programming interfaces: RxNav, UMLSKS and LexBIG SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID MEDICAL LANGUAGE SYSTEM AB To facilitate the integration of terminologies into applications, various terminology services application programming interfaces (API) have been developed in the recent past. In this study, three publicly available terminology services API, RxNav, UMLSKS and LexBIG, are compared and functionally evaluated with respect to the retrieval of information from one biomedical terminology, RxNorm, to which all three services provide access. A list of queries is established covering a wide spectrum of terminology services functionalities such as finding RxNorm concepts by their name, or navigating different types of relationships. Test data were generated from the RxNorm dataset to evaluate the implementation of the functionalities in the three API. The results revealed issues with various aspects of the API implementation (eg, handling of obsolete terms by LexBIG) and documentation (eg, navigational paths used in RxNav) that were subsequently addressed by the development teams of the three API investigated. Knowledge about such discrepancies helps inform the choice of an API for a given use case. C1 [Pathak, Jyotishman; Chute, Christopher G.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Peters, Lee; Bodenreider, Olivier] US Natl Lib Med, Bethesda, MD USA. RP Pathak, J (reprint author), Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. EM pathak.jyotishman@mayo.edu RI lyp, maggie/G-1471-2011 FU NHGRI [U01HG04599]; NLM FX This research is supported in part by NHGRI grant U01HG04599 (eMERGE) and the Intramural Research Program at NLM. NR 11 TC 1 Z9 1 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2010 VL 17 IS 6 BP 714 EP 719 DI 10.1136/jamia.2009.001149 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 676GV UT WOS:000283899900017 PM 20962136 ER PT J AU Calcagno, AM Salcido, CD Gillet, JP Wu, CP Fostel, JM Mumau, MD Gottesman, MM Varticovski, L Ambudkar, SV AF Calcagno, Anna Maria Salcido, Crystal D. Gillet, Jean-Pierre Wu, Chung-Pu Fostel, Jennifer M. Mumau, Melanie D. Gottesman, Michael M. Varticovski, Lyuba Ambudkar, Suresh V. TI Prolonged Drug Selection of Breast Cancer Cells and Enrichment of Cancer Stem Cell Characteristics SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; ALDEHYDE DEHYDROGENASE-ACTIVITY; MULTIDRUG-RESISTANCE; CARCINOMA-CELLS; P-GLYCOPROTEIN; GLUCOSYLCERAMIDE SYNTHASE; LUNG-CANCER; NUDE-MICE; IN-VITRO; EXPRESSION AB Background Cancer stem cells are presumed to have virtually unlimited proliferative and self-renewal abilities and to be highly resistant to chemotherapy, a feature that is associated with overexpression of ATP-binding cassette transporters. We investigated whether prolonged continuous selection of cells for drug resistance enriches cultures for cancer stem-like cells. Methods Cancer stem cells were defined as CD44+/CD24- cells that could self-renew (ie, generate cells with the tumorigenic CD44+/CCD24- phenotype), differentiate, invade, and form tumors in vivo. We used doxorubicin-selected MCF-7/ADR cells, weakly tumorigenic parental MCF-7 cells, and MCF-7/MDR, an MCF-7 subline with forced expression of ABCB1 protein. Cells were examined for cell surface markers and side-population fractions by microarray and flow cytometry, with in vitro invasion assays, and for ability to form mammospheres. Xenograft tumors were generated in mice to examine tumorigenicity (n = 52). The mRNA expression of multidrug resistance genes was examined in putative cancer stem cells and pathway analysis of statistically significantly differentially expressed genes was performed. All statistical tests were two-sided. Results Pathway analysis showed that MCF-7/ADR cells express mRNAs from ABCB1 and other genes also found in breast cancer stem cells (eg, CD44, TGFB1, and SNAI1). MCF-7/ADR cells were highly invasive, formed mammospheres, and were tumorigenic in mice. In contrast to parental MCF-7 cells, more than 30% of MCF-7/ADR cells had a CD44+/CCD24- phenotype, could self-renew, and differentiate (ie, produce CD44+/CCD24- and CD44+/CD24+ cells) and overexpressed various multidrug resistance-linked genes (including ABCB1, CCNE1, and MMP9). MCF-7/ADR cells were statistically significantly more invasive in Matrigel than parental MCF-7 cells (MCF-7 cells = 0.82 cell per field and MCF-7/ADR = 7.51 cells per field, difference = 6.69 cells per field, 95% confidence interval = 4.82 to 8.55 cells per field, P < .001). No enrichment in the CD44+/CCD24- or CD133+ population was detected in MCF-7/MDR. Conclusion The cell population with cancer stem cell characteristics increased after prolonged continuous selection for doxorubicin resistance. C1 [Calcagno, Anna Maria; Gillet, Jean-Pierre; Wu, Chung-Pu; Gottesman, Michael M.; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Salcido, Crystal D.; Mumau, Melanie D.; Varticovski, Lyuba] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fostel, Jennifer M.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2120, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI gillet, jean-pierre/A-3714-2012; Calcagno, Anna Maria/A-5617-2012; OI Calcagno, Anna Maria/0000-0002-0804-2753 FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; NIGMS; NIH; National Institutes of Environmental Health Sciences [HHSN273200700046U] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. A. M. C. was supported by the NIGMS Pharmacology Research Associate (PRAT) Program. J.F. was supported by the Intramural Research Program of the NIH and National Institutes of Environmental Health Sciences, contract HHSN273200700046U. NR 71 TC 112 Z9 122 U1 6 U2 20 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 NOV PY 2010 VL 102 IS 21 BP 1637 EP 1652 DI 10.1093/jnci/djq361 PG 16 WC Oncology SC Oncology GA 676PA UT WOS:000283923300009 PM 20935265 ER PT J AU Safaeian, M Porras, C Schiffman, M Rodriguez, AC Wacholder, S Gonzalez, P Quint, W van Doorn, LJ Sherman, ME Xhenseval, V Herrero, R Hildesheim, A AF Safaeian, Mahboobeh Porras, Carolina Schiffman, Mark Rodriguez, Ana Cecilia Wacholder, Sholom Gonzalez, Paula Quint, Wim van Doorn, Leen-Jan Sherman, Mark E. Xhenseval, Valerie Herrero, Rolando Hildesheim, Allan CA Costa Rican Vaccine Trial Grp TI Epidemiological Study of Anti-HPV16/18 Seropositivity and Subsequent Risk of HPV16 and -18 Infections SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; RANDOMIZED CONTROLLED-TRIAL; VIRUS-LIKE PARTICLES; AGED 16-26 YEARS; COSTA-RICA; QUADRIVALENT VACCINE; ANTIBODY-RESPONSE; CERVICAL-CANCER; BROAD-SPECTRUM; DOUBLE-BLIND AB Background Infection with human papillomavirus (HPV) 16 or HPV18 elicits an antibody response, but whether the elicited antibodies protect women against subsequent infection by a homologous HPV type compared with seronegative women is unknown. Methods Study participants were women aged 18-25 years at enrollment in the control group of the ongoing National Cancer Institute-sponsored, community-based, randomized HPV16/18 Costa Rica Vaccine Trial. At enrollment, 2813 participants were negative for cervical HPV16 DNA and 2950 for HPV18 DNA. Women were interviewed regarding sociodemographic data and medical and health history. Medical and pelvic examinations were conducted for all consenting sexually experienced women. Serum samples taken at enrollment were tested for total HPV16/18 antibodies with a polyclonal enzyme-linked immunosorbent assay, and cervical specimens were tested for type-specific HPV DNA over 4 years of follow-up. Using Poisson regression, we compared rate ratios of newly detected cervical HPV16 or HPV18 infection among homologous HPV-seropositive and HPV-seronegative women, adjusting for age, education, marital status, lifetime number of sexual partners, and smoking. Results There were 231 newly detected HPV16 infections during 5886 person-years among HPV16-seronegative women compared with 12 newly detected HPV16 infections during 581 person-years among HPV16-seropositive women with the highest HPV16 sero-levels. There were 136 newly detected HPV18 infections during 6352 person-years among HPV18-seronegative women compared with six new infections detected during 675 person-years among HPV18 seropositives with the highest sero-levels. After controlling for risk factors associated with newly detected HPV infection, having high HPV16 antibody titer at enrollment was associated with a reduced risk of subsequent HPV16 infection (women in the highest tertile of HPV16 antibody titers, adjusted rate ratio = 0.50, 95% confidence interval = 0.26 to 0.86 vs HPV16-seronegative women). Similarly, having high HPV18 antibody titer at enrollment was associated with a reduced risk of subsequent HPV18 infection (women in the highest tertile of HPV18 antibody titers, adjusted rate ratio = 0.36, 95% confidence interval = 0.14 to 0.76 vs HPV18-seronegative women). Conclusion In this study population, having high antibody levels against HPV16 and HPV18 following natural infection was associated with reduced risk of subsequent HPV16 and HPV18 infections. C1 [Safaeian, Mahboobeh] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, Rockville, MD 20852 USA. [Porras, Carolina; Rodriguez, Ana Cecilia; Gonzalez, Paula; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Quint, Wim; van Doorn, Leen-Jan] DDL Diagnost Lab, Voorburg, Netherlands. [Xhenseval, Valerie] GlaxoSmithKline Biol, Rixensart, Belgium. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, 6120 Execut Blvd,Ste 550, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU National Cancer Institute, National Institutes of Health; National Institutes of Health Office of Research on Women's Health FX Intramural Research Program of the National Cancer Institute, National Institutes of Health. National Institutes of Health Office of Research on Women's Health. NR 26 TC 91 Z9 92 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD NOV PY 2010 VL 102 IS 21 BP 1653 EP 1662 DI 10.1093/jnci/djq384 PG 10 WC Oncology SC Oncology GA 676PA UT WOS:000283923300010 PM 20944077 ER PT J AU Subramanian, J Simon, R AF Subramanian, Jyothi Simon, Richard TI Re: Gene Expression-Based Prognostic Signatures in Lung Cancer: Ready for Clinical Use? Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Subramanian, Jyothi; Simon, Richard] NCI, Biometr Res Branch, Dept Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, Dept Canc Treatment & Diag, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov NR 3 TC 1 Z9 1 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD NOV PY 2010 VL 102 IS 21 BP 1678 EP 1679 DI 10.1093/jnci/djq386 PG 2 WC Oncology SC Oncology GA 676PA UT WOS:000283923300015 ER PT J AU Gierach, GL Brinton, LA Sherman, ME AF Gierach, Gretchen L. Brinton, Louise A. Sherman, Mark E. TI Lobular Involution, Mammographic Density, and Breast Cancer Risk: Visualizing the Future? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID TISSUE COMPOSITION; ASSOCIATION; WOMEN; AGE C1 [Gierach, Gretchen L.; Brinton, Louise A.; Sherman, Mark E.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Gierach, GL (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Ste 550,Rm 5016,MSC 7234, Rockville, MD 20852 USA. EM gierachg@mail.nih.gov RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016 OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522 FU Intramural NIH HHS NR 19 TC 1 Z9 2 U1 0 U2 1 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 NOV PY 2010 VL 102 IS 22 BP 1685 EP U18 DI 10.1093/jnci/djq433 PG 3 WC Oncology SC Oncology GA 682VW UT WOS:000284432100002 PM 21037117 ER PT J AU Freedman, AN Sansbury, LB Figg, WD Potosky, AL Smith, SRW Khoury, MJ Nelson, SA Weinshilboum, RM Ratain, MJ McLeod, HL Epstein, RS Ginsburg, GS Schilsky, RL Liu, G Flockhart, DA Ulrich, CM Davis, RL Lesko, LJ Zineh, I Randhawa, G Ambrosone, CB Relling, MV Rothman, N Xie, H Spitz, MR Ballard-Barbash, R Doroshow, JH Minasian, LM AF Freedman, Andrew N. Sansbury, Leah B. Figg, William D. Potosky, Arnold L. Smith, Sheila R. Weiss Khoury, Muin J. Nelson, Stefanie A. Weinshilboum, Richard M. Ratain, Mark J. McLeod, Howard L. Epstein, Robert S. Ginsburg, Geoffrey S. Schilsky, Richard L. Liu, Geoffrey Flockhart, David A. Ulrich, Cornelia M. Davis, Robert L. Lesko, Lawrence J. Zineh, Issam Randhawa, Gurvaneet Ambrosone, Christine B. Relling, Mary V. Rothman, Nat Xie, Heng Spitz, Margaret R. Ballard-Barbash, Rachel Doroshow, James H. Minasian, Lori M. TI Cancer Pharmacogenomics and Pharmacoepidemiology: Setting a Research Agenda to Accelerate Translation SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID RECEIVING ADJUVANT TAMOXIFEN; BREAST-CANCER; COLORECTAL-CANCER; LUNG-CANCER; THERAPY; CYP2D6; SURVIVAL; CYP2D6-ASTERISK-10; ASSOCIATION; MUTATIONS AB Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice. C1 [Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rothman, Nat] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Minasian, Lori M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Potosky, Arnold L.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Hlth Serv Res, Washington, DC USA. [Smith, Sheila R. Weiss] Univ Maryland, Sch Pharm, Ctr Drug Safety, Baltimore, MD 21201 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Weinshilboum, Richard M.] Mayo Clin, Coll Med, Div Clin Pharmacol, Rochester, MN USA. [Ratain, Mark J.] Univ Chicago, Med Ctr, Canc Res Ctr, Chicago, IL 60637 USA. [McLeod, Howard L.] Univ N Carolina, UNC Inst Pharmacogenom & Individualized Therapy, Chapel Hill, NC USA. [Epstein, Robert S.] Medco Hlth Solut Inc, Franklin Lakes, NJ USA. [Ginsburg, Geoffrey S.] Duke Univ, Duke Inst Genome Sci & Policy, Ctr Genom Med, Durham, NC USA. [Schilsky, Richard L.] Univ Chicago, Med Ctr, Hematol Oncol Sect, Chicago, IL 60637 USA. [Liu, Geoffrey] Univ Toronto, Ontario Canc Inst, Princess Margaret Hosp, Toronto, ON, Canada. [Flockhart, David A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Ulrich, Cornelia M.] German Canc Res Ctr, Div Prevent Oncol, D-6900 Heidelberg, Germany. [Ulrich, Cornelia M.] Natl Ctr Tumor Dis, Heidelberg, Germany. [Ulrich, Cornelia M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Davis, Robert L.] Kaiser Permanente, Ctr Hlth Res, Atlanta, GA USA. [Lesko, Lawrence J.; Zineh, Issam] US FDA, Off Clin Pharmacol & Biopharmaceut, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Randhawa, Gurvaneet] Agcy Healthcare Res & Qual, Ctr Outcomes & Evidence, Rockville, MD USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Relling, Mary V.] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Xie, Heng] NIH, Natl Ctr Res Resources, Div Clin Res Resources, Bethesda, MD 20892 USA. [Spitz, Margaret R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Freedman, AN (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd,Rm 5128, Bethesda, MD 20892 USA. EM andrew_freedman@nih.gov RI Figg Sr, William/M-2411-2016 FU NCI NIH HHS [R01 CA132780] NR 22 TC 26 Z9 26 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD NOV PY 2010 VL 102 IS 22 BP 1698 EP 1705 DI 10.1093/jnci/djq390 PG 8 WC Oncology SC Oncology GA 682VW UT WOS:000284432100008 PM 20944079 ER PT J AU Annunziata, CM Birrer, MJ AF Annunziata, Christina M. Birrer, Michael J. TI Re: CD157 in Ovarian Carcinoma: How Does It Help Us? Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Birrer, Michael J.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Annunziata, Christina M.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Birrer, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM mbirrer@partners.org RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 3 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 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD NOV PY 2010 VL 102 IS 22 BP 1741 EP U79 DI 10.1093/jnci/djq395 PG 2 WC Oncology SC Oncology GA 682VW UT WOS:000284432100013 ER PT J AU Ballas, SK Bauserman, RL McCarthy, WF Waclawiw, MA AF Ballas, Samir K. Bauserman, Robert L. McCarthy, William F. Waclawiw, Myron A. CA Investigators Multictr Study TI The Impact of Hydroxyurea on Career and Employment of Patients With Sickle Cell Anemia SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE sickle cell anemia; hydroxyurea ID RANDOMIZED CONTROLLED-TRIAL; DISEASE; QUALITY; LIFE; PAIN; HEMOGLOBIN; GABAPENTIN; NEUROPATHY AB The purpose of this study was to determine the association between hydroxyurea treatment and changes in employment status if any among patients with sickle cell anemia enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) To that end we compared the employment status among treatment responders treatment nonresponders and placebo groups of patients enrolled in MSH during the clinical trial and follow up periods Treatment with hydroxyurea did not significantly (p > 05) affect employment status but there was a trend for more consistent employment in the hydroxyurea group Given the fact that patients enrolled in MSH had moderate to severe disease with irreversible complications such as avascular necrosis it would be attractive to hypothesize that future treatment of young patients with hydroxyurea could prevent or mitigate the incidence of complications of sickle cell anemia and hence improve the employment status of treated patients C1 [Ballas, Samir K.] Thomas Jefferson Univ, Dept Med, Cardeza Fdn, Philadelphia, PA 19107 USA. [Bauserman, Robert L.; McCarthy, William F.] Maryland Med Res Inst, Baltimore, MD USA. [Bauserman, Robert L.] NHLBI, Bethesda, MD 20892 USA. RP Ballas, SK (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Cardeza Fdn Hematol Res, Sickle Cell Ctr, 1015 Walnut St, Philadelphia, PA 19107 USA. FU National Heart Lung and Blood Institute [NO1 HB 67129, UO1 HL45696] FX This study was funded by National Heart Lung and Blood Institute contracts NO1 HB 67129 and UO1 HL45696 NR 27 TC 9 Z9 9 U1 0 U2 1 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 NOV PY 2010 VL 102 IS 11 BP 993 EP 999 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 689HC UT WOS:000284917700003 PM 21141286 ER PT J AU Kemp, CD Kitano, M Kerkar, S Ripley, RT Marquardt, JU Schrump, DS Avital, I AF Kemp, Clinton D. Kitano, Mio Kerkar, Sid Ripley, R. Taylor Marquardt, Jens U. Schrump, David S. Avital, Itzhak TI Pulmonary Resection for Metastatic Gastric Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Gastric; Cancer; Lung; Pulmonary; Metastasectomy ID LONG-TERM SURVIVAL; PHASE-II TRIAL; COLORECTAL-CARCINOMA; SURGICAL RESECTION; METASTASECTOMY; ADENOCARCINOMA; OXALIPLATIN; GASTRECTOMY; RECURRENCE; SURGERY AB Introduction: Sixteen percent of patients with gastric cancer will develop pulmonary metastases. Standard of care for these patients is systemic chemotherapy with a median survival of 6 months and a 5-year survival of only 2%. Our aim was to critically evaluate the published data on pulmonary resection for metastatic gastric cancer (MGC) and to analyze the potential rationale for surgical management to determine which patients may benefit from this approach. Methods: The Pubmed and SCOPUS databases were queried for all studies reporting on pulmonary resections for MGC. All available clinicopathologic data were analyzed. Results: Twenty-one studies from 1975 to 2008 reported 48 pulmonary resections in 43 patients including five repeat resections and four extrapulmonary metastasectomies. Eighty-two percent (34/43) of patients had solitary lesions with a median size of 24 mm (4-90 mm). Median time from gastrectomy to pulmonary resection was 35 months (0-120 months). At a median follow-up of 23 months, 15 of 43 (35%) patients were alive without disease, and two patients died without disease. Median survival was 29 months (3-84 months) after pulmonary metastasectomy and 65 months (5-180 months) after gastrectomy. Fifty-six percent (24/43) of patients had another recurrence at a median of 12 months (range: 6-48 months) after resection including 30% (13/43) of patients with pulmonary recurrences. Overall 5-year survival was 33%. Conclusions: Pulmonary metastasectomy for MGC can potentially result in long-term survival in a highly selected group of patients and should be considered for those who present with small, isolated lesions after a prolonged disease-free interval. C1 [Kemp, Clinton D.; Kitano, Mio; Kerkar, Sid; Ripley, R. Taylor; Schrump, David S.; Avital, Itzhak] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Marquardt, Jens U.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Avital, I (reprint author), NCI, Surg Branch, NIH, Bldg 10 Hatfield CRC,Room 4-3961,10 Ctr Dr, Bethesda, MD 20892 USA. EM avitali@mail.nih.gov NR 40 TC 15 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2010 VL 5 IS 11 BP 1796 EP 1805 DI 10.1097/JTO.0b013e3181ed3514 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 671HG UT WOS:000283491100014 PM 20881648 ER PT J AU Espinoza, J Lee, W Comstock, C Romero, R Yeo, L Rizzo, G Paladini, D Vinals, F Achiron, R Gindes, L Abuhamad, A Sinkovskaya, E Russell, E Yagel, S AF Espinoza, Jimmy Lee, Wesley Comstock, Christine Romero, Roberto Yeo, Lami Rizzo, Giuseppe Paladini, Dario Vinals, Fernando Achiron, Reuven Gindes, Liat Abuhamad, Alfred Sinkovskaya, Elena Russell, Evie Yagel, Simcha TI Collaborative Study on 4-Dimensional Echocardiography for the Diagnosis of Fetal Heart Defects The COFEHD Study SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE congenital heart defects; fetal echocardiography; 4-dimensional ultrasonography; prenatal diagnosis ID SPATIOTEMPORAL IMAGE CORRELATION; COLOR DOPPLER ULTRASOUND; VENTRICULAR SEPTAL-DEFECT; PRENATAL-DIAGNOSIS; 3-DIMENSIONAL ECHOCARDIOGRAPHY; CONOTRUNCAL ANOMALIES; PULMONARY-ARTERIES; INVERSION MODE; 3D SONOGRAPHY; INTERNET LINK AB Objective. Congenital anomalies are the leading cause of infant mortality in the United States, and congenital heart defects (CHDs) are the most common type of birth defects. Recently, 4-dimensional ultrasonography (4DUS) with spatiotemporal image correlation (STIC) has been introduced for fetal echocardiography. Accumulating evidence indicates that 4DUS with STIC may facilitate the examination of the fetal heart. Our objectives were to determine the accuracy of 4DUS for the diagnosis of CHDs and the agreement among centers. Methods. This study included 7 centers with expertise in 4D fetal echocardiography. Fetuses with and without confirmed heart defects were scanned between 18 and 26 weeks, and their volume data sets were uploaded onto a centralized file transfer protocol server. Intercenter agreement was determined using a kappa statistic for multiple raters. Results. Ninety volume data sets were randomly selected for blinded analysis. Overall, the median (range) sensitivity, specificity, positive and negative predictive values, and false-positive and -negative rates for the identification of fetuses with CHDs were 93% (77%-100%), 96% (84%-100%), 96% (83%-100%), 93% (79%-100%), 4.8% (2.7%-25%), and 6.8% (5%-22%), respectively. The most frequent CHDs were conotruncal anomalies (36%). There was excellent intercenter agreement (kappa = 0.97). Conclusions. (1) Four-dimensional volume data sets can be remotely acquired and accurately interpreted by different centers. (2) Among centers with technical expertise, 4DUS is an accurate and reliable method for fetal echocardiography. C1 [Espinoza, Jimmy; Lee, Wesley; Comstock, Christine; Russell, Evie] William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48073 USA. [Romero, Roberto; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, Roberto; Yeo, Lami] Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI USA. [Rizzo, Giuseppe] Univ Roma Tor Vergata, Dept Obstet & Gynecol, Rome, Italy. [Paladini, Dario] Univ Naples Federico 2, Dept Obstet & Gynecol, Naples, Italy. [Vinals, Fernando] Ctr AGB Ultrasonog, Clin Sanat Aleman, Concepcion, Chile. [Achiron, Reuven; Gindes, Liat] Chaim Sheba Med Ctr, Dept Obstet & Gynecol, IL-52621 Tel Hashomer, Israel. [Abuhamad, Alfred; Sinkovskaya, Elena] Eastern Virginia Med Sch, Dept Obstet & Gynecol, Norfolk, VA 23501 USA. [Yagel, Simcha] Hebrew Univ Jerusalem, Dept Obstet & Gynecol, Hadassah Med Ctr, Jerusalem, Israel. RP Espinoza, J (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3501 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM jimmy.espinoza@beaumont.edu RI Paladini, Dario/E-1784-2013; OI RIZZO, Giuseppe/0000-0002-5525-4353 NR 84 TC 26 Z9 28 U1 0 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD NOV PY 2010 VL 29 IS 11 BP 1573 EP 1580 PG 8 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 685ZP UT WOS:000284666900006 PM 20966468 ER PT J AU Benhammou, JN Boris, RS Pacak, K Pinto, PA Linehan, WM Bratslavsky, G AF Benhammou, Jihane N. Boris, Ronald S. Pacak, Karel Pinto, Peter A. Linehan, W. Marston Bratslavsky, Gennady TI Functional and Oncologic Outcomes of Partial Adrenalectomy for Pheochromocytoma in Patients With von Hippel-Lindau Syndrome After at Least 5 Years of Followup SO JOURNAL OF UROLOGY LA English DT Article DE pheochromocytoma; von Hippel-Lindau disease; adrenalectomy; neoplastic syndromes, hereditary ID LAPAROSCOPIC PARTIAL ADRENALECTOMY; SPARING-SURGERY; HEREDITARY PHEOCHROMOCYTOMA; PARTIAL NEPHRECTOMY; NATURAL-HISTORY; DISEASE; EXPERIENCE; PARAGANGLIOMAS; SCINTIGRAPHY; FEASIBILITY AB Purpose: Although the safety and feasibility of partial adrenalectomy in patients with von Hippel-Lindau syndrome have been established, long-term outcomes have not been examined. In this study we evaluate the recurrence and functional outcomes in a von Hippel-Lindau syndrome cohort treated for pheochromocytoma with partial adrenalectomy with a followup of at least 5 years. Materials and Methods: We reviewed the records of patients with von Hippel-Lindau syndrome treated with partial adrenalectomy for pheochromocytoma at the National Cancer Institute. Demographic, germline mutation status, surgical indication, oncologic and functional outcome data were collected. Local recurrence was defined as radiographic evidence of recurrent tumor on the ipsilateral side of partial adrenalectomy. Patients were considered steroid dependent if they required steroids at most recent followup. Results: A total of 36 partial adrenalectomies for pheochromocytoma were performed in 26 patients with von Hippel-Lindau syndrome between September 1995 and December 2003. Of these cases 23 were performed open and 13 were performed laparoscopically. Prior surgical history was obtained for all patients. At a median followup of 9.25 years (range 5 to 46) metastatic pheochromocytoma had not developed in any patients. In 3 patients (11%) there were 5 local recurrences treated with surgical extirpation or active surveillance. All recurrences were asymptomatic and detected by radiographic imaging on followup. In addition, 3 of 26 patients (11%) subsequently required partial adrenalectomy for pheochromocytoma on the contralateral adrenal gland. In the entire cohort only 3 patients became steroid dependent (11%). Conclusions: Outcomes of partial adrenalectomy in patients with von Hippel-Lindau syndrome with pheochromocytoma are encouraging at long-term followup and should be recommended as a primary surgical approach whenever possible. Adrenal sparing surgery can obviate the need for steroid replacement in the majority of patients. Local recurrence rates appear to be infrequent and can be managed successfully with subsequent observation or intervention. C1 [Benhammou, Jihane N.; Boris, Ronald S.; Pacak, Karel; Pinto, Peter A.; Linehan, W. Marston; Bratslavsky, Gennady] NCI, Urol Oncol Branch, Ctr Canc Res, NIH,Dept Hlth Human Serv, Bethesda, MD 20892 USA. RP Bratslavsky, G (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH,Dept Hlth Human Serv, Bldg 10 Room 1-5940, Bethesda, MD 20892 USA. EM bratslag@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 18 Z9 19 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 NOV PY 2010 VL 184 IS 5 BP 1855 EP 1859 DI 10.1016/j.juro.2010.06.102 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 660XG UT WOS:000282679200009 PM 20846682 ER PT J AU Pinto, PA AF Pinto, Peter A. TI Laparoscopic Partial Adrenalectomy SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 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 NOV PY 2010 VL 184 IS 5 BP 1860 EP 1860 DI 10.1016/j.juro.2010.08.051 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 660XG UT WOS:000282679200010 PM 20880555 ER PT J AU Venkatesan, AM Kundu, S Sacks, D Wallace, MJ Wojak, JC Rose, SC Clark, TWI d'Othee, BJ Itkin, M Jones, RS Miller, DL Owens, CA Rajan, DK Stokes, LS Swan, TL Towbin, RB Cardella, JF AF Venkatesan, Aradhana M. Kundu, Sanjoy Sacks, David Wallace, Michael J. Wojak, Joan C. Rose, Steven C. Clark, Timothy W. I. d'Othee, B. Janne Itkin, Maxim Jones, Robert S. Miller, Donald L. Owens, Charles A. Rajan, Dheeraj K. Stokes, LeAnn S. Swan, Timothy L. Towbin, Richard B. Cardella, John F. TI Practice Guideline for Adult Antibiotic Prophylaxis during Vascular and Interventional Radiology Procedures SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Editorial Material ID UTERINE ARTERY EMBOLIZATION; INTRAHEPATIC PORTOSYSTEMIC SHUNTS; PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; RESISTANT STAPHYLOCOCCUS-AUREUS; QUALITY IMPROVEMENT GUIDELINES; CLINICAL-PRACTICE GUIDELINES; AMERICAN-HEART-ASSOCIATION; SURGICAL-WOUND-INFECTION; BLOOD-STREAM INFECTIONS; LIVER-ABSCESS FORMATION C1 [Venkatesan, Aradhana M.] NIH, Ctr Intervent Oncol Ridiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Miller, Donald L.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. [Miller, Donald L.] Natl Naval Med Ctr, Dept Radiol, Bethesda, MD USA. [d'Othee, B. Janne] Univ Maryland, Med Ctr, Dept Radiol, Div Intervent Radiol, Baltimore, MD 21201 USA. [Kundu, Sanjoy] Scarborough Gen Hosp, Dept Med Imaging, Scarborough, ON, Canada. [Rajan, Dheeraj K.] Univ Toronto, Univ Hlth Network, Div Vasc & Intervent Radiol, Dept Med Imaging, Toronto, ON, Canada. [Sacks, David] Reading Hosp Med Ctr, Dept Intervent Radiol, W Reading, England. [Jones, Robert S.] Reading Hosp Med Ctr, Infect Dis Sect, W Reading, England. [Itkin, Maxim] Univ Penn, Med Ctr, Dept Radiol, Div Intervent Radiol, Philadelphia, PA 19104 USA. [Cardella, John F.] Geisinger Hlth Syst, Dept Radiol, Danville, PA USA. [Wallace, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Intervent Radiol, Houston, TX 77030 USA. [Wojak, Joan C.] Our Lady Lourdes Med Ctr, Dept Radiol, Lafayette, LA USA. [Rose, Steven C.] Univ Calif San Diego, Med Ctr, Dept Radiol, San Diego, CA 92103 USA. [Clark, Timothy W. I.] NYU, Sch Med, NYU Med Ctr, Dept Intervent Radiol, New York, NY USA. [Owens, Charles A.] Univ Illinois, Med Ctr, Dept Radiol, Chicago, IL USA. [Owens, Charles A.] Univ Illinois, Dept Surg, Med Ctr, Chicago, IL 60680 USA. [Stokes, LeAnn S.] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA. [Swan, Timothy L.] Marshfield Clin Fdn Med Res & Educ, Dept Radiol, Marshfield, WI USA. [Towbin, Richard B.] Phoenix Childrens Hosp, Dept Radiol, Phoenix, AZ USA. RP Venkatesan, AM (reprint author), Care of Katsarelis D, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. RI Janne d'Othee, Bertrand/E-8467-2010 NR 125 TC 68 Z9 77 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD NOV PY 2010 VL 21 IS 11 BP 1611 EP 1630 DI 10.1016/j.jvir.2010.07.018 PG 20 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 680OL UT WOS:000284244200001 PM 21029949 ER PT J AU Miyagi, E Brown, CR Opi, S Khan, M Goila-Gaur, R Kao, S Walker, RC Hirsch, V Strebel, K AF Miyagi, Eri Brown, Charles R. Opi, Sandrine Khan, Mohammad Goila-Gaur, Ritu Kao, Sandra Walker, Robert C., Jr. Hirsch, Vanessa Strebel, Klaus TI Stably Expressed APOBEC3F Has Negligible Antiviral Activity SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; REVERSE TRANSCRIPTION; VIRAL-RNA; ANTIRETROVIRAL FACTOR; CYTIDINE DEAMINATION; HIV-1 REPLICATION; A MUTATIONS; VIF PROTEIN; DNA AB APOBEC3F (A3F) is a member of the family of cytidine deaminases that is often coexpressed with APOBEC3G (A3G) in cells susceptible to HIV infection. A3F has been shown to have strong antiviral activity in transient-expression studies, and together with A3G, it is considered the most potent cytidine deaminase targeting HIV. Previous analyses suggested that the antiviral properties of A3F can be dissociated from its catalytic deaminase activity. We were able to confirm the deaminase-independent antiviral activity of exogenously expressed A3F; however, we also noted that exogenous expression was associated with very high A3F mRNA and protein levels. In analogy to our previous study of A3G, we produced stable HeLa cell lines constitutively expressing wild-type or deaminase-defective A3F at levels that were more in line with the levels of endogenous A3F in H9 cells. A3F expressed in stable HeLa cells was packaged into Vif-deficient viral particles with an efficiency similar to that of A3G and was properly targeted to the viral nucleoprotein complex. Surprisingly, however, neither wild-type nor deaminase-defective A3F inhibited HIV-1 infectivity. These results imply that the antiviral activity of endogenous A3F is negligible compared to that of A3G. C1 [Strebel, Klaus] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bldg 4,Room 310,4 Ctr Dr MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU NIH; NIH, NIAID FX Antibodies to Vif (MAb 319) and A3F were obtained from Michael Malim through the NIH AIDS Research and Reference Reagent Program. The vector for expression of A3F was obtained from Matija Peterlin and Yong-Hui Zheng through the NIH AIDS Research and Reference Reagent Program. This work was supported in part by a grant from the NIH Intramural AIDS Targeted Antiviral Program to K. S. and by the Intramural Research Program of the NIH, NIAID. NR 57 TC 32 Z9 32 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 NOV PY 2010 VL 84 IS 21 BP 11067 EP 11075 DI 10.1128/JVI.01249-10 PG 9 WC Virology SC Virology GA 660LE UT WOS:000282643400013 PM 20702622 ER PT J AU Du, M Butchi, NB Woods, T Morgan, TW Peterson, KE AF Du, Min Butchi, Niranjan B. Woods, Tyson Morgan, Timothy W. Peterson, Karin E. TI Neuropeptide Y Has a Protective Role during Murine Retrovirus-Induced Neurological Disease SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; VIRUS-INFECTION; BRAIN DISEASE; IMMUNE-SYSTEM; RECEPTORS; MICE; PROTEIN; NEUROPATHOGENESIS; SEIZURES; CONTRIBUTE AB Viral infections in the central nervous system (CNS) can lead to neurological disease either directly by infection of neurons or indirectly through activation of glial cells and production of neurotoxic molecules. Understanding the effects of virus-mediated insults on neuronal responses and neurotrophic support is important in elucidating the underlying mechanisms of viral diseases of the CNS. In the current study, we examined the expression of neurotrophin-and neurotransmitter-related genes during infection of mice with neurovirulent polytropic retrovirus. In this model, virus-induced neuropathogenesis is indirect, as the virus predominantly infects macrophages and microglia and does not productively infect neurons or astrocytes. Virus infection is associated with glial cell activation and the production of proinflammatory cytokines in the CNS. In the current study, we identified increased expression of neuropeptide Y (NPY), a pleiotropic growth factor which can regulate both immune cells and neuronal cells, as a correlate with neurovirulent virus infection. Increased levels of Npy mRNA were consistently associated with neurological disease in multiple strains of mice and were induced only by neurovirulent, not avirulent, virus infection. NPY protein expression was primarily detected in neurons near areas of virus-infected cells. Interestingly, mice deficient in NPY developed neurological disease at a faster rate than wild-type mice, indicating a protective role for NPY. Analysis of NPY-deficient mice indicated that NPY may have multiple mechanisms by which it influences virus-induced neurological disease, including regulating the entry of virus-infected cells into the CNS. C1 [Du, Min; Butchi, Niranjan B.; Woods, Tyson; Peterson, Karin E.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Morgan, Timothy W.] Louisiana State Univ, Dept Pathobiol Sci, Sch Vet Med, Baton Rouge, LA 70803 USA. RP Peterson, KE (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM petersonka@niaid.nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 FU NIH; National Center for Research Resources [IP20RR020159] FX This work was supported in part by the Intramural Research Program of the NIH and in part by National Center for Research Resources grant IP20RR020159. NR 38 TC 16 Z9 16 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 NOV PY 2010 VL 84 IS 21 BP 11076 EP 11088 DI 10.1128/JVI.01022-10 PG 13 WC Virology SC Virology GA 660LE UT WOS:000282643400014 PM 20702619 ER PT J AU Yu, C Boon, D McDonald, SL Myers, TG Tomioka, K Nguyen, H Engle, RE Govindarajan, S Emerson, SU Purcell, RH AF Yu, Claro Boon, Denali McDonald, Shannon L. Myers, Timothy G. Tomioka, Keiko Nguyen, Hanh Engle, Ronald E. Govindarajan, Sugantha Emerson, Suzanne U. Purcell, Robert H. TI Pathogenesis of Hepatitis E Virus and Hepatitis C Virus in Chimpanzees: Similarities and Differences SO JOURNAL OF VIROLOGY LA English DT Article ID GENE-EXPRESSION; NUCLEOTIDE-SEQUENCE; IMMUNE-RESPONSES; INFECTION; PROTEIN; RNA; IDENTIFICATION; CELLS; LIVER; HISTOLOGY AB The chimpanzee is the only animal model for investigating the pathogenesis of viral hepatitis types A through E in humans. Studies of the host response, including microarray analyses, have relied on the close relationship between these two primate species: chimpanzee samples are commonly tested with human-based reagents. In this study, the host responses to two dissimilar viruses, hepatitis E virus (HEV) and hepatitis C virus (HCV), were compared in multiple experimentally infected chimpanzees. Affymetrix U133 + 2.0 human microarray chips were used to assess the entire transcriptome in serial liver biopsies obtained over the course of the infections. Respecting the limitations of microarray probes designed for human target transcripts to effectively assay chimpanzee transcripts, we conducted probe-level analysis of the microarray data in conjunction with a custom mapping of the probe sequences to the most recent human and chimpanzee genome sequences. Time points for statistical comparison were chosen based on independently measured viremia levels. Regardless of the viral infection, the alignment of differentially expressed genes to the human genome sequence resulted in a larger number of genes being identified when compared with alignment to the chimpanzee genome sequence. This probably reflects the lesser refinement of gene annotation for chimpanzees. In general, the two viruses demonstrated very distinct temporal changes in host response genes, although both RNA viruses induced genes that were involved in many of the same biological systems, including interferon-induced genes. The host response to HCV infection was more robust in the magnitude and number of differentially expressed genes compared to HEV infection. C1 [Yu, Claro; Boon, Denali; McDonald, Shannon L.; Tomioka, Keiko; Nguyen, Hanh; Engle, Ronald E.; Emerson, Suzanne U.; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Myers, Timothy G.] NIAID, Res & Technol Branch, NIH, Bethesda, MD 20892 USA. [Govindarajan, Sugantha] Rancho Los Amigos Med Ctr, Dept Pathol, Downey, CA 90241 USA. RP Purcell, RH (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr,Bldg 50,Rm 6523, Bethesda, MD 20892 USA. EM rpurcell@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases; Laboratory of Immunopathogenesis and Bioinformatics at SAIC-Frederick, Inc. FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.; We thank Stacy Ricklefs and Karin Bok for providing guidance on developing the qRT-PCR procedure. We are grateful to Jun Yang, Brandie Fullmer, Marjorie Bosche, and Wuxing Yuan, the Laboratory of Immunopathogenesis and Bioinformatics at SAIC-Frederick, Inc., for their support and for performing the chip hybridization; and Kathleen Meyer for assisting with the GEO submission. Lastly, we thank Marisa St. Claire, Max Shapiro, and Charlene Shaver for the care and handling of the chimpanzees in this study. NR 48 TC 32 Z9 32 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2010 VL 84 IS 21 BP 11264 EP 11278 DI 10.1128/JVI.01205-10 PG 15 WC Virology SC Virology GA 660LE UT WOS:000282643400032 PM 20739520 ER PT J AU Kim, S Kim, N Presson, AP An, DS Mao, SH Bonifacino, AC Donahue, RE Chow, SA Chen, ISY AF Kim, Sanggu Kim, Namshin Presson, Angela P. An, Dong Sung Mao, Si Hua Bonifacino, Aylin C. Donahue, Robert E. Chow, Samson A. Chen, Irvin S. Y. TI High-Throughput, Sensitive Quantification of Repopulating Hematopoietic Stem Cell Clones SO JOURNAL OF VIROLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; GENE-THERAPY; VECTOR INTEGRATION; RETROVIRAL VECTORS; LENTIVIRAL VECTOR; CD34(+) CELLS; SCID-X1; EXPRESSION; PROLIFERATION AB Retroviral vector-mediated gene therapy has been successfully used to correct genetic diseases. However, a number of studies have shown a subsequent risk of cancer development or aberrant clonal growths due to vector insertion near or within proto-oncogenes. Recent advances in the sequencing technology enable high-throughput clonality analysis via vector integration site (VIS) sequencing, which is particularly useful for studying complex polyclonal hematopoietic progenitor/stem cell (HPSC) repopulation. However, clonal repopulation analysis using the current methods is typically semiquantitative. Here, we present a novel system and standards for accurate clonality analysis using 454 pyrosequencing. We developed a bidirectional VIS PCR method to improve VIS detection by concurrently analyzing both the 5' and the 3' vector-host junctions and optimized the conditions for the quantitative VIS sequencing. The assay was validated by quantifying the relative frequencies of hundreds of repopulating HPSC clones in a nonhuman primate. The reliability and sensitivity of the assay were assessed using clone-specific real-time PCR. The majority of tested clones showed a strong correlation between the two methods. This assay permits high-throughput and sensitive assessment of clonal populations and hence will be useful for a broad range of gene therapy, stem cell, and cancer research applications. C1 [Chen, Irvin S. Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Chow, Samson A.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Presson, Angela P.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. [Mao, Si Hua; Chen, Irvin S. Y.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Presson, Angela P.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90095 USA. [Kim, Sanggu; Presson, Angela P.; An, Dong Sung; Mao, Si Hua; Chow, Samson A.; Chen, Irvin S. Y.] Univ Calif Los Angeles, UCLA AIDS Inst, Los Angeles, CA 90095 USA. [An, Dong Sung] Univ Calif Los Angeles, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Kim, Namshin] Korea Res Inst Biosci & Biotechnol, Taejon 305806, South Korea. [Bonifacino, Aylin C.; Donahue, Robert E.] NHLBI, Hematol Branch, NIH, Rockville, MD 20850 USA. RP Chen, ISY (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, 615 Charles E Young Dr S,BSRB 173, Los Angeles, CA 90095 USA. EM syuchen@mednet.ucla.edu FU NIH [AI055281-06A2, CA68859]; California Institute of Regenerative Medicine [RS1-00172-01]; UCLA AIDS Institute/Center for AIDS Research [AI28697]; National Heart, Lung, and Blood Institute, NIH FX This study was partly funded by the NIH (AI055281-06A2 and CA68859), the California Institute of Regenerative Medicine (RS1-00172-01), and the UCLA AIDS Institute/Center for AIDS Research (AI28697) and was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH. NR 36 TC 8 Z9 8 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 NOV PY 2010 VL 84 IS 22 BP 11771 EP 11780 DI 10.1128/JVI.01355-10 PG 10 WC Virology SC Virology GA 670KM UT WOS:000283420500016 PM 20844053 ER PT J AU Levine, JR Prescott, J Brown, KS Best, SM Ebihara, H Feldmann, H AF Levine, Jessica R. Prescott, Joseph Brown, Kyle S. Best, Sonja M. Ebihara, Hideki Feldmann, Heinz TI Antagonism of Type I Interferon Responses by New World Hantaviruses SO JOURNAL OF VIROLOGY LA English DT Article ID SIN-NOMBRE HANTAVIRUS; INNATE IMMUNE-RESPONSES; TO-PERSON TRANSMISSION; HEPATITIS-C VIRUS; INFLUENZA-A VIRUS; RIG-I; NUCLEOCAPSID PROTEIN; PULMONARY SYNDROME; NS1 PROTEIN; ANDES VIRUS AB Evasion of interferon (IFN)-mediated antiviral signaling is a common defense strategy for pathogenic RNA viruses. To date, research on IFN antagonism by hantaviruses is limited and has focused on only a subset of the numerous recognized hantavirus species. The host IFN response has two phases, an initiation phase, resulting in the induction of alpha/beta IFN (IFN-alpha/beta), and an amplification phase, whereby IFN-alpha/beta signals through the Jak/STAT pathway, resulting in the establishment of the cellular antiviral state. We examined interactions between these critical host responses and the New World hantaviruses. We observed delayed cellular responses in both Andes virus (ANDV)- and Sin Nombre virus (SNV)-infected A549 and Huh7-TLR3 cells. We found that IFN-beta induction is inhibited by coexpression of ANDV nucleocapsid protein (NP) and glycoprotein precursor (GPC) and is robustly inhibited by SNV GPC alone. Downstream amplification by Jak/STAT signaling is also inhibited by SNV GPC and by either NP or GPC of ANDV. Therefore, ANDV- and SNV-encoded proteins have the potential for inhibiting both IFN-beta induction and signaling, with SNV exhibiting the more potent antagonism ability. Herein we identify ANDV NP, a previously unrecognized inhibitor of Jak/STAT signaling, and show that IFN antagonism by ANDV relies on expression of both the glycoproteins and NP, whereas the glycoproteins appear to be sufficient for antagonism by SNV. These data suggest that IFN antagonism strategies by hantaviruses are quite variable, even between species with similar disease phenotypes, and may help to better elucidate species-specific pathogenesis. C1 [Ebihara, Hideki] NIAID, Rocky Mt Labs, Virol Lab, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Levine, Jessica R.] Univ Calif Davis, Sch Vet Med, Davis, CA 95616 USA. [Levine, Jessica R.; Brown, Kyle S.; Ebihara, Hideki; Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB R3E 3R2, Canada. [Brown, Kyle S.; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J9, Canada. RP Ebihara, H (reprint author), NIAID, Rocky Mt Labs, Virol Lab, Div Intramural Res,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM ebiharah@niaid.nih.gov; feldmannh@niaid.nih.gov OI Spengler, Jessica R./0000-0002-5383-0513 FU Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health; Public Health Agency of Canada; University of California, Davis, School of Veterinary Medicine FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, and the Public Health Agency of Canada. J.L. was supported by funding from the Veterinary Scientist Training Program and the Students Training in Advanced Research programs of the University of California, Davis, School of Veterinary Medicine. NR 63 TC 24 Z9 24 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 NOV PY 2010 VL 84 IS 22 BP 11790 EP 11801 DI 10.1128/JVI.00916-10 PG 12 WC Virology SC Virology GA 670KM UT WOS:000283420500018 PM 20844031 ER PT J AU Chutinimitkul, S Herfst, S Steel, J Lowen, AC Ye, JQ van Riel, D Schrauwen, EJA Bestebroer, TM Koel, B Burke, DF Sutherland-Cash, KH Whittleston, CS Russell, CA Wales, DJ Smith, DJ Jonges, M Meijer, A Koopmans, M Rimmelzwaan, GF Kuiken, T Osterhaus, ADME Garcia-Sastre, A Perez, DR Fouchier, RAM AF Chutinimitkul, Salin Herfst, Sander Steel, John Lowen, Anice C. Ye, Jianqiang van Riel, Debby Schrauwen, Eefje J. A. Bestebroer, Theo M. Koel, Bjorn Burke, David F. Sutherland-Cash, Kyle H. Whittleston, Chris S. Russell, Colin A. Wales, David J. Smith, Derek J. Jonges, Marcel Meijer, Adam Koopmans, Marion Rimmelzwaan, Guus F. Kuiken, Thijs Osterhaus, Albert D. M. E. Garcia-Sastre, Adolfo Perez, Daniel R. Fouchier, Ron A. M. TI Virulence-Associated Substitution D222G in the Hemagglutinin of 2009 Pandemic Influenza A(H1N1) Virus Affects Receptor Binding SO JOURNAL OF VIROLOGY LA English DT Article ID SINGLE AMINO-ACID; LOWER RESPIRATORY-TRACT; A H1N1 VIRUS; MOLECULAR-BASIS; SEVERE DISEASE; H5N1 VIRUSES; HUMAN AIRWAY; HONG-KONG; HUMANS; TRANSMISSION AB The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities. D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated. pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs. The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands. Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex alpha 2,3- and alpha 2,6-linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of alpha 2,6 binding. Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans. C1 [Chutinimitkul, Salin; Herfst, Sander; van Riel, Debby; Schrauwen, Eefje J. A.; Bestebroer, Theo M.; Koel, Bjorn; Smith, Derek J.; Rimmelzwaan, Guus F.; Kuiken, Thijs; Osterhaus, Albert D. M. E.; Fouchier, Ron A. M.] Erasmus MC, Natl Influenza Ctr, Rotterdam, Netherlands. [Chutinimitkul, Salin; Herfst, Sander; van Riel, Debby; Schrauwen, Eefje J. A.; Bestebroer, Theo M.; Koel, Bjorn; Smith, Derek J.; Rimmelzwaan, Guus F.; Kuiken, Thijs; Osterhaus, Albert D. M. E.; Fouchier, Ron A. M.] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Steel, John; Lowen, Anice C.; Garcia-Sastre, Adolfo] Mt Sinai Sch Med, Dept Microbiol, New York, NY USA. [Ye, Jianqiang; Perez, Daniel R.] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Burke, David F.; Russell, Colin A.; Smith, Derek J.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Sutherland-Cash, Kyle H.; Whittleston, Chris S.; Wales, David J.] Univ Cambridge, Univ Chem Labs, Cambridge CB2 1EW, England. [Jonges, Marcel; Meijer, Adam; Koopmans, Marion] Natl Inst Publ Hlth & Environm, Lab Infect Dis & Screening, NL-3720 BA Bilthoven, Netherlands. [Garcia-Sastre, Adolfo] Mt Sinai Sch Med, Div Infect Dis, Dept Med, New York, NY USA. [Osterhaus, Albert D. M. E.] Mt Sinai Sch Med, Global Hlth & Emerging Pathogens Inst, New York, NY USA. [Russell, Colin A.; Smith, Derek J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Fouchier, RAM (reprint author), Erasmus MC, Dept Virol, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM r.fouchier@erasmusmc.nl RI burke, david/C-2091-2013; Wei, Jianjian/F-7788-2011; Fouchier, Ron/A-1911-2014; OI Wei, Jianjian/0000-0001-8859-8462; Fouchier, Ron/0000-0001-8095-2869; burke, david/0000-0001-8830-3951; Osterhaus, Albert/0000-0002-6074-1172; Garcia-Sastre, Adolfo/0000-0002-6551-1827; Russell, Colin/0000-0002-2113-162X; Perez, Daniel/0000-0002-6569-5689 FU NIAID-NIH [HHSN266200700010C]; European Union [223498]; NIH [DP1-OD000490-01]; HFSP; EPSRC FX This study was financed through NIAID-NIH contract HHSN266200700010C and by the European Union FP7 European Management Platform for Emerging and Re-emerging Infectious Disease Entities (EMPERIE) project (223498). D.J.S. and D. F. B. were supported by NIH Director's Pioneer Award DP1-OD000490-01. C. A. R. thanks the HFSP for support, and C. S. W. and D.J.W. thank the EPSRC for support. NR 56 TC 110 Z9 115 U1 3 U2 18 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2010 VL 84 IS 22 BP 11802 EP 11813 DI 10.1128/JVI.01136-10 PG 12 WC Virology SC Virology GA 670KM UT WOS:000283420500019 PM 20844044 ER PT J AU Horton, DL McElhinney, LM Marston, DA Wood, JLN Russell, CA Lewis, N Kuzmin, IV Fouchier, RAM Osterhaus, ADME Fooks, AR Smith, DJ AF Horton, D. L. McElhinney, L. M. Marston, D. A. Wood, J. L. N. Russell, C. A. Lewis, N. Kuzmin, I. V. Fouchier, R. A. M. Osterhaus, A. D. M. E. Fooks, A. R. Smith, D. J. TI Quantifying Antigenic Relationships among the Lyssaviruses SO JOURNAL OF VIROLOGY LA English DT Article ID RABIES VIRUS GLYCOPROTEIN; LAGOS-BAT-VIRUS; A H3N2 VIRUSES; DUVENHAGE VIRUS; PHYLOGENETIC-RELATIONSHIPS; GENETIC EVOLUTION; CROSS-PROTECTION; INFLUENZA; DYNAMICS; VACCINES AB All lyssaviruses cause fatal encephalitis in mammals. There is sufficient antigenic variation within the genus to cause variable vaccine efficacy, but this variation is difficult to characterize quantitatively: sequence analysis cannot yet provide detailed antigenic information, and antigenic neutralization data have been refractory to high-resolution robust interpretation. Here, we address these issues by using state-of-the-art antigenic analyses to generate a high-resolution antigenic map of a global panel of 25 lyssaviruses. We compared the calculated antigenic distances with viral glycoprotein ectodomain sequence data. Although 67% of antigenic variation was predictable from the glycoprotein amino acid sequence, there are in some cases substantial differences between genetic and antigenic distances, thus highlighting the risk of inferring antigenic relationships solely from sequence data at this time. These differences included epidemiologically important antigenic differences between vaccine strains and wild-type rabies viruses. Further, we quantitatively assessed the antigenic relationships measured by using rabbit, mouse, and human sera, validating the use of nonhuman experimental animals as a model for determining antigenic variation in humans. The use of passive immune globulin is a crucial component of rabies postexposure prophylaxis, and here we also show that it is possible to predict the reactivity of immune globulin against divergent lyssaviruses. C1 [Horton, D. L.; McElhinney, L. M.; Marston, D. A.; Fooks, A. R.] Vet Labs Agcy Weybridge, Addlestone KT15 3NB, Surrey, England. [Horton, D. L.; Wood, J. L. N.; Lewis, N.] Cambridge Infect Dis Consortium, Dept Vet Med, Cambridge CB2 1DQ, England. [Horton, D. L.; Russell, C. A.; Lewis, N.; Smith, D. J.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Kuzmin, I. V.] Ctr Dis Control & Prevent, Div Viral & Rickettsial Dis, Atlanta, GA 30333 USA. [Fouchier, R. A. M.; Osterhaus, A. D. M. E.; Smith, D. J.] Erasmus MC, Dept Virol, NL-3015 GE Rotterdam, Netherlands. [Russell, C. A.; Smith, D. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [McElhinney, L. M.; Fooks, A. R.] Univ Liverpool, Natl Ctr Zoonosis Res, Neston CH64 7TE, England. RP Horton, DL (reprint author), Vet Labs Agcy Weybridge, Addlestone KT15 3NB, Surrey, England. EM d.horton@vla.defra.gsi.gov.uk RI McElhinney, Lorraine/C-7997-2011; Marston, Denise/D-7993-2011; Horton, Daniel/D-9909-2011; Wood, James/A-1626-2008; APHA, Staff publications/E-6082-2010; Fooks, Anthony/F-5418-2010; Fouchier, Ron/A-1911-2014; OI McElhinney, Lorraine/0000-0002-6022-348X; Marston, Denise/0000-0001-9215-088X; Horton, Daniel/0000-0002-9126-2756; Wood, James/0000-0002-0258-3188; Fouchier, Ron/0000-0001-8095-2869; Russell, Colin/0000-0002-2113-162X FU Cambridge Infectious Diseases Consortium; DEFRA Veterinary Training and Research Initiative; DEFRA [SEO420, SEO423, SEO424]; NIH part of the NIH road map for medical research [DP1-OD000490-01, 223498]; European Union; Human Frontier Science Program [P0050/2008]; Alborada Trust; Science and Technology Directorate, Department of Homeland Security; Royal Society, London; Clare College, Cambridge FX D. L. H., J.L.N.W., and N.L. were supported by the Cambridge Infectious Diseases Consortium, a DEFRA Veterinary Training and Research Initiative. D. A. M., L. M. M., and A. R. F. were supported by DEFRA grants SEO420, SEO423, and SEO424. D.J.S. and C. A. R. were supported by an NIH Director's Pioneer Award, part of the NIH road map for medical research, through grant DP1-OD000490-01; 223498 EMPERIE, an FP7 grant from the European Union; and program grant P0050/2008 from the Human Frontier Science Program. J.L.N.W. was also supported by the Alborada Trust and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security. C. A. R. was also supported by a University Research Fellowship from the Royal Society, London, and a research fellowship from Clare College, Cambridge. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 32 Z9 33 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 NOV PY 2010 VL 84 IS 22 BP 11841 EP 11848 DI 10.1128/JVI.01153-10 PG 8 WC Virology SC Virology GA 670KM UT WOS:000283420500023 PM 20826698 ER PT J AU Min, JY Vogel, L Matsuoka, Y Lu, B Swayne, D Jin, H Kemble, G Subbarao, K AF Min, Ji-Young Vogel, Leatrice Matsuoka, Yumiko Lu, Bin Swayne, David Jin, Hong Kemble, George Subbarao, Kanta TI A Live Attenuated H7N7 Candidate Vaccine Virus Induces Neutralizing Antibody That Confers Protection from Challenge in Mice, Ferrets, and Monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID INFLUENZA-A VIRUS; AVIAN-INFLUENZA; PANDEMIC INFLUENZA; HEALTHY-ADULTS; TEMPERATURE SENSITIVITY; COMMERCIAL POULTRY; BRITISH-COLUMBIA; HEMAGGLUTININ; PATHOGENICITY; GENERATION AB A live attenuated H7N7 candidate vaccine virus was generated by reverse genetics using the modified hemagglutinin (HA) and neuraminidase (NA) genes of highly pathogenic (HP) A/Netherlands/219/03 (NL/03) (H7N7) wild-type (wt) virus and the six internal protein genes of the cold-adapted (ca) A/Ann Arbor/6/60 ca (AA ca) (H2N2) virus. The reassortant H7N7 NL/03 ca vaccine virus was temperature sensitive and attenuated in mice, ferrets, and African green monkeys (AGMs). Intranasal (i.n.) administration of a single dose of the H7N7 NL/03 ca vaccine virus fully protected mice from lethal challenge with homologous and heterologous H7 viruses from Eurasian and North American lineages. Two doses of the H7N7 NL/03 ca vaccine induced neutralizing antibodies in serum and provided complete protection from pulmonary replication of homologous and heterologous wild-type H7 challenge viruses in mice and ferrets. One dose of the H7N7 NL/03 ca vaccine elicited an antibody response in one of three AGMs that was completely protected from pulmonary replication of the homologous wild-type H7 challenge virus. The contribution of CD8(+) and/or CD4(+) T cells to the vaccine-induced protection of mice was evaluated by T-cell depletion; T lymphocytes were not essential for the vaccine-induced protection from lethal challenge with H7 wt viruses. Additionally, passively transferred neutralizing antibody induced by the H7N7 NL/03 ca virus protected mice from lethality following challenge with H7 wt viruses. The safety, immunogenicity, and efficacy of the H7N7 NL/03 ca vaccine virus in mice, ferrets, and AGMs support the evaluation of this vaccine virus in phase I clinical trials. C1 [Min, Ji-Young; Vogel, Leatrice; Matsuoka, Yumiko; Subbarao, Kanta] NIAID, LID, NIH, Bethesda, MD 20892 USA. [Lu, Bin; Jin, Hong; Kemble, George] Medimmune Inc, Mountain View, CA 94043 USA. [Swayne, David] ARS, SE Poultry Res Lab, USDA, Athens, GA 30605 USA. RP Subbarao, K (reprint author), NIAID, LID, NIH, 33 North Dr,MSC 3203,Room 3E13C1, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU NIAID, NIH FX This research was performed as part of a Cooperative Research and Development Agreement (CRADA) between the Laboratory of Infectious Diseases, NIAID, and MedImmune and was supported in part by the Intramural Research Program of the NIAID, NIH. NR 42 TC 34 Z9 35 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 NOV PY 2010 VL 84 IS 22 BP 11950 EP 11960 DI 10.1128/JVI.01305-10 PG 11 WC Virology SC Virology GA 670KM UT WOS:000283420500034 PM 20810733 ER PT J AU Koh, Y Amano, M Towata, T Danish, M Leshchenko-Yashchuk, S Das, D Nakayama, M Tojo, Y Ghosh, AK Mitsuya, H AF Koh, Yasuhiro Amano, Masayuki Towata, Tomomi Danish, Matthew Leshchenko-Yashchuk, Sofiya Das, Debananda Nakayama, Maki Tojo, Yasushi Ghosh, Arun K. Mitsuya, Hiroaki TI In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors SO JOURNAL OF VIROLOGY LA English DT Article ID POTENT ACTIVITY; GAG PROTEIN; RECOMBINATION; PI; MUTATIONS; SUBSTITUTIONS; PREVALENCE; EMERGENCE; TMC114; LIGAND AB We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1(MIX)) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1MIX became highly resistant to DRV, with a 50% effective concentration (EC50) similar to 333-fold greater than that against HIV-1(NL4-3). HIV-1(MIX) at passage 51 (HIV-1(MIXP51)) replicated well in the presence of 5 mu M DRV and contained 14 mutations. HIV-1(MIXP51) was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1(MIXP51) had a resemblance with HIV-1(C) of the HIV-1(MIX) population, and selection using HIV-1(C) was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1(CP51), likely contributed to conferring a replication advantage on HIV-1(MIXP51) by reducing intravirion cyclophilin A content. HIV-1(MIXP51) apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1(MIX) through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1(MIXP51) should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents. C1 [Koh, Yasuhiro; Amano, Masayuki; Towata, Tomomi; Danish, Matthew; Nakayama, Maki; Tojo, Yasushi; Mitsuya, Hiroaki] Kumamoto Univ, Dept Infect Dis, Grad Sch Med & Pharmaceut Sci, Kumamoto 8608556, Japan. [Koh, Yasuhiro; Amano, Masayuki; Towata, Tomomi; Danish, Matthew; Nakayama, Maki; Tojo, Yasushi; Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol, Grad Sch Med & Pharmaceut Sci, Kumamoto 8608556, Japan. [Leshchenko-Yashchuk, Sofiya; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Leshchenko-Yashchuk, Sofiya; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Das, Debananda; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Dept Infect Dis, Sch Med, 1-1-1 Honjo, Kumamoto 8608556, Japan. EM hmitsuya@helix.nih.gov RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health [GM 53386]; Japan Society for the Promotion of Science (JSPS-RFTF) [97L00705]; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Labor and Welfare of Japan FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (D.D. and H.M.), a grant from the National Institutes of Health (GM 53386, to A.K.G.), a grant from a Research for the Future Program of Japan Society for the Promotion of Science (JSPS-RFTF 97L00705, to H.M.), a Grant-in-Aid for Scientific Research (Priority Areas, to H.M.) from the Ministry of Education, Culture, Sports, Science, and Technology (Monbu-Kagakusho) of Japan (H.M.), and a Grant for Promotion of AIDS Research from the Ministry of Health, Labor and Welfare (Kosei-Rodosho) of Japan (to H.M.). NR 26 TC 31 Z9 31 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2010 VL 84 IS 22 BP 11961 EP 11969 DI 10.1128/JVI.00967-10 PG 9 WC Virology SC Virology GA 670KM UT WOS:000283420500035 PM 20810732 ER PT J AU Yan, YH Liu, QP Wollenberg, K Martin, C Buckler-White, A Kozak, CA AF Yan, Yuhe Liu, Qingping Wollenberg, Kurt Martin, Carrie Buckler-White, Alicia Kozak, Christine A. TI Evolution of Functional and Sequence Variants of the Mammalian XPR1 Receptor for Mouse Xenotropic Gammaretroviruses and the Human-Derived Retrovirus XMRV SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA VIRUSES; CELL-SURFACE RECEPTOR; CHRONIC-FATIGUE-SYNDROME; MUS-MUSCULUS-MOLOSSINUS; HOST-RANGE; INFECTIOUS RETROVIRUS; MAXIMUM-LIKELIHOOD; GENUS MUS; WILD MICE; C VIRUSES AB Genetic conflicts between retroviruses and their receptors result in the evolution of novel host entry restrictions and novel virus envelopes, and such variants can influence trans-species transmission. We screened rodents and other mammals for sequence variation in the Xpr1 receptor for the mouse xenotropic or polytropic mouse leukemia viruses (X-MLVs or P-MLVs, respectively) of the gammaretrovirus family and for susceptibility to mouse-derived X/P-MLVs and to XMRV (xenotropic murine leukemia virus-related virus), an X-MLV-like virus isolated from humans with prostate cancer and chronic fatigue syndrome. We identified multiple distinct susceptibility phenotypes; these include the four known Xpr1 variants in Mus and a novel fifth Xpr1 gene found in Mus molossinus and Mus musculus. We describe the geographic and species distribution of the Mus Xpr1 variants but failed to find the X-MLV-restrictive laboratory mouse allele in any wild mouse. We used mutagenesis and phylogenetic analysis to evaluate the functional contributions made by constrained, variable, and deleted residues. Rodent Xpr1 is under positive selection, indicating a history of host-pathogen conflicts; several codons under selection have known roles in virus entry. All non-Mus mammals are susceptible to mouse X-MLVs, but some restrict other members of the X/P-MLV family, and the resistance of hamster and gerbil cells to XMRV indicates that XMRV has unique receptor requirements. We show that the hypervariable fourth extracellular XPR1 loop (ECL4) contains three evolutionarily constrained residues that do not contribute to receptor function, we identify two novel residues important for virus entry (I579 and T583), and we describe a unique pattern of ECL4 variation in the three virus-restrictive Xpr1 variants found in MLV-infected house mice; these mice carry different deletions in ECL4, suggesting either that these sites or loop size affects receptor function. C1 [Yan, Yuhe; Liu, Qingping; Martin, Carrie; Buckler-White, Alicia; Kozak, Christine A.] NIAID, NIH, LMM, Bethesda, MD 20892 USA. [Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, NIH, LMM, Bldg 4,Room 329,4 Ctr Dr MSC 0460, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov OI Blanchard, Carrie/0000-0002-1236-4245 FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 54 TC 24 Z9 24 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2010 VL 84 IS 22 BP 11970 EP 11980 DI 10.1128/JVI.01549-10 PG 11 WC Virology SC Virology GA 670KM UT WOS:000283420500036 PM 20844050 ER PT J AU Murray, SM Down, CM Boulware, DR Stauffer, WM Cavert, WP Schacker, TW Brenchley, JM Douek, DC AF Murray, Shannon M. Down, Carrie M. Boulware, David R. Stauffer, William M. Cavert, Winston P. Schacker, Timothy W. Brenchley, Jason M. Douek, Daniel C. TI Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV Infection SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL-ACTIVATION; LYMPHOCYTE-ACTIVATION; HYDROXYCHLOROQUINE; CD4(+); CD38; ZIDOVUDINE AB Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38(+) HLA-DR(+) CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals. C1 [Murray, Shannon M.; Down, Carrie M.; Brenchley, Jason M.; Douek, Daniel C.] NIAID, Human Immunol Sect, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Boulware, David R.; Stauffer, William M.; Cavert, Winston P.; Schacker, Timothy W.] Univ Minnesota, Dept Med, Div Infect Dis & Int Med, Minneapolis, MN 55455 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, NIH, Vaccine Res Ctr, 40 Convent Dr,Room 4500, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov RI Boulware, David/B-5516-2011; Boulware, David/I-4533-2013; OI Boulware, David/0000-0002-4715-0060 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [5U01-AI1027661-19]; Minnesota Medical Foundation; International Center for Antiviral Research and Epidemiology FX This work was supported in part by the Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (5U01-AI1027661-19); the Minnesota Medical Foundation; and the International Center for Antiviral Research and Epidemiology (I CARE). NR 22 TC 70 Z9 71 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2010 VL 84 IS 22 BP 12082 EP 12086 DI 10.1128/JVI.01466-10 PG 5 WC Virology SC Virology GA 670KM UT WOS:000283420500048 PM 20844049 ER PT J AU Muniyappa, R Veldhuis, JD Harman, SM Sorkin, JD Blackman, MR AF Muniyappa, Ranganath Veldhuis, Johannes D. Harman, S. Mitchell Sorkin, John D. Blackman, Marc R. TI Effects of Testosterone Administration on Nocturnal Cortisol Secretion in Healthy Older Men SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Testosterone; Cortisol ID PITUITARY-ADRENAL AXIS; RANDOMIZED CONTROLLED-TRIAL; SEX-DIFFERENCES; GROWTH-HORMONE; DEHYDROEPIANDROSTERONE SECRETION; PSYCHOSOCIAL STRESS; PLASMA-CORTISOL; STEROID-HORMONE; AGED WOMEN; GENDER AB In animal studies, testosterone decreases, whereas estrogen increases, cortisol production. In one clinical study, short-term testosterone replacement attenuated corticotrophin-releasing hormone-stimulated cortisol secretion during leuprolide-induced hypogonadism in young men. The effects of longer term testosterone treatment on spontaneous cortisol secretion in younger or older men are unknown. In a randomized, double-masked placebo-controlled study, we assessed the effects of testosterone supplementation (100 mg intramuscular every 2 week) for 26 weeks on nocturnal cortisol secretory dynamics in healthy older men. Testosterone administration increased early morning serum concentrations of free testosterone by 34%, decreased sex hormone-binding globulin by 20%, and did not alter early morning concentrations of cortisol-binding globulin or cortisol compared with placebo treatment. Testosterone did not significantly alter nocturnal mean and integrated cortisol concentrations, cortisol burst frequency, mass/burst, basal secretion, pulsatile cortisol production rate, pattern regularity, or approximate entropy. We conclude that low-dose testosterone supplementation for 26 weeks does not affect spontaneous nocturnal cortisol secretion in healthy older men. C1 [Muniyappa, Ranganath] Natl Ctr Complementary & Alternat Med, Diabet Unit, Clin Invest Lab, Natl Inst Hlth, Bethesda, MD USA. [Veldhuis, Johannes D.] Mayo Clin, Clin Translat Res Ctr, Mayo Sch Grad Med Educ, Endocrine Res Unit, Rochester, MN USA. [Harman, S. Mitchell; Blackman, Marc R.] NIA, Endocrinol Sect, Clin Invest Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. [Harman, S. Mitchell] Kronos Longev Res Inst, Phoenix, AZ USA. [Sorkin, John D.] NIA, Metab Sect, Clin Invest Lab, Natl Inst Hlth, Baltimore, MD USA. [Sorkin, John D.; Blackman, Marc R.] Baltimore Vet Affairs Med Ctr Geriatr Res Educ &, Dept Vet Affairs, Baltimore, MD USA. [Sorkin, John D.] Univ Maryland, Sch Med, Claude D Pepper Older Amer Independence Ctr, Baltimore, MD 21201 USA. [Blackman, Marc R.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Blackman, Marc R.] Vet Affairs Med Ctr, Res Serv, Washington, DC 20422 USA. RP Blackman, MR (reprint author), Washington DC VA Med Ctr, Res Serv 151, 50 Irving St, Washington, DC 20422 USA. EM marc.blackman@va.gov FU National Center for Complementary and Alternative Medicine, Bethesda, Maryland; National Institute on Aging, Baltimore, Maryland; National Institutes of Health [RO-1 AG11005, DK073148]; National Center for Research Resources, National Institutes of Health, Bethesda, Maryland [MO-1-RR-02719]; Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatrics Research, Education and Clinical Center; Claude D. Pepper Older Americans Independence Center at the University of Maryland [P60-AG-12583]; Research Service, Veterans Affairs Medical Center, Washington DC FX Intramural Research Programs of the National Center for Complementary and Alternative Medicine to R. M., Bethesda, Maryland and the National Institute on Aging, Baltimore, Maryland; National Institutes of Health Research Grants RO-1 AG11005 to M. R. B. and DK073148 to J.D.V.; General Clinical Research Center Grant MO-1-RR-02719 to M. R. B. from the National Center for Research Resources, National Institutes of Health, Bethesda, Maryland; Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatrics Research, Education and Clinical Center; Claude D. Pepper Older Americans Independence Center Grant P60-AG-12583 to J.D.S. at the University of Maryland; and the Research Service, Veterans Affairs Medical Center, Washington DC to M.R.B. NR 49 TC 4 Z9 4 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD NOV PY 2010 VL 65 IS 11 BP 1185 EP 1192 DI 10.1093/gerona/glq128 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 666PW UT WOS:000283129300005 PM 20675620 ER PT J AU Cannon, CZ Kissling, GE Hoenerhoff, MJ King-Herbert, AP Blankenship-Paris, T AF Cannon, Coralie Zegre Kissling, Grace E. Hoenerhoff, Mark J. King-Herbert, Angela P. Blankenship-Paris, Terry TI Evaluation of dosages and routes of administration of tramadol analgesia in rats using hot-plate and tail-flick tests SO LAB ANIMAL LA English DT Article ID TRANS-O-DEMETHYLTRAMADOL; ACTIVE METABOLITE; IN-VITRO; PAIN; MODEL; EFFICACY; BUPRENORPHINE; MORPHINE; MOUSE; PHARMACOKINETICS AB Tramadol is an opioid-Like analgesic with relatively mild side effects. Because it is inexpensive and is not classified as a controlled substance by the US federal government, the authors wanted to evaluate its applicability as a practical and effective analgesic in male Sprague Dawley rats. They measured the efficacy of four dosages (4, 12.5, 25 or 50 mg tramadol per kg body weight) and three routes of administration (per os (p.o.) in a flavored gelatin cube, subcutaneous (s.c.) or intraperitoneal (i.p.)) using the hot-plate test and the tail-flick test, which were carried out 1 week apart. Rats that were dosed p.o. were given flavored gelatin cubes without tramadol on the 2 d before testing to help them become acclimated to the gelatin, in an effort to increase the likelihood that they would consume the gelatin on the testing day. Results from the hot-plate and tail-flick tests for rats that were given tramadol p.o. were similar before and after administration, regardless of tramadol dosage, suggesting that this route of administration was not effective. The s.c. route of administration was effective at dosages of 25 mg and 50 mg tramadol per kg body weight, although these dosages also resulted in sedation and skin lesions. The i.p. route of administration was also effective at dosages of 12.5 mg, 25 mg and 50 mg tramadol per kg body weight, though sedation was observed at dosages of 25 mg and 50 mg per kg body weight. Intraperitoneal administration of 12.5 mg tramadol per kg body weight had no notable side effects, and the authors plan to further study this dosage and route of administration in a rodent surgical model of pain. C1 [Cannon, Coralie Zegre; Hoenerhoff, Mark J.; King-Herbert, Angela P.] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC USA. [Kissling, Grace E.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. [Blankenship-Paris, Terry] Natl Inst Environm Hlth Sci, Comparat Med Branch, Res Triangle Pk, NC USA. RP Cannon, CZ (reprint author), Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC USA. EM cannonc@niehs.nih.gov FU National Institutes of Health; National Institute of Environmental Health Sciences FX We thank Danielle Waxer, Page Myers, James Clark, Sandy Hackney, Jenetta Jackson and Keisha Chavis for their assistance and support of the research and care of the animals. We thank Dr. Larry Wright for assistance in literature evaluation. We thank Dr. Sheryl Moy, Dr. Greg Travlos and Dr. Gregory Cannon for their extensive reviews of the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 47 TC 13 Z9 13 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD NOV PY 2010 VL 39 IS 11 BP 342 EP 351 PG 12 WC Veterinary Sciences SC Veterinary Sciences GA 674RR UT WOS:000283766100011 PM 20962760 ER PT J AU Morisot, S Wayne, AS Bohana-Kashtan, O Kaplan, IM Gocke, CD Hildreth, R Stetler-Stevenson, M Walker, RL Davis, S Meltzer, PS Wheelan, SJ Brown, P Jones, RJ Shultz, LD Civin, CI AF Morisot, S. Wayne, A. S. Bohana-Kashtan, O. Kaplan, I. M. Gocke, C. D. Hildreth, R. Stetler-Stevenson, M. Walker, R. L. Davis, S. Meltzer, P. S. Wheelan, S. J. Brown, P. Jones, R. J. Shultz, L. D. Civin, C. I. TI High frequencies of leukemia stem cells in poor-outcome childhood precursor-B acute lymphoblastic leukemias SO LEUKEMIA LA English DT Article DE childhood acute lymphoblastic leukemia; leukemia stem cells; xenograft ID ACUTE MYELOID-LEUKEMIA; PRIMITIVE HEMATOPOIETIC-CELL; TUMOR-GROWTH NEED; NOD-SCID MICE; INITIATING CELLS; NOD/SCID MICE; BONE-MARROW; CANCER; ENGRAFTMENT; MOUSE AB In order to develop a xenograft model to determine the efficacy of new therapies against primary human precursor-B acute lymphoblastic leukemia (ALL) stem cells (LSCs), we used the highly immunodeficient non-obese diabetic (NOD). Cg-Prkdc(scid) IL2rg(tmlWjl)/SzJ (NOD-severe combined immune deficient (scid) IL2rg(-/-)) mouse strain. Intravenous transplantation of 2 of 2 ALL cell lines and 9 of 14 primary ALL cases generated leukemia-like proliferations in recipient mice by 1-7 months after transplant. Leukemias were retransplantable, and the immunophenotypes, gene rearrangements and expression profiles were identical or similar to those of the original primary samples. NOD-scid mice transplanted with the same primary samples developed similar leukemias with only a slightly longer latency than did NOD-scid-IL2Rg(-/-) mice. In this highly sensitive NOD-scid-IL2Rg(-/-) -based assay, 1-100 unsorted primary human ALL cells from five of five tested patients, four of whom eventually experienced leukemia relapse, generated leukemias in recipient mice. This very high frequency of LSCs suggests that a hierarchical LSC model is not valuable for poor-outcome ALL. Leukemia (2010) 24, 1859-1866; doi:10.1038/leu.2010.184; published online 26 August 2010 C1 [Morisot, S.; Bohana-Kashtan, O.; Kaplan, I. M.; Hildreth, R.; Civin, C. I.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Morisot, S.; Bohana-Kashtan, O.; Kaplan, I. M.; Hildreth, R.; Civin, C. I.] Univ Maryland, Sch Med, Ctr Stem Cell Biol & Regenerat Med, Baltimore, MD 21201 USA. [Wayne, A. S.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Gocke, C. D.] Johns Hopkins Med Inst, Dept Pathol, Mol Diagnost Lab, Baltimore, MD 21205 USA. [Gocke, C. D.] Johns Hopkins Med Inst, Dept Oncol, Mol Diagnost Lab, Baltimore, MD 21205 USA. [Stetler-Stevenson, M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Walker, R. L.; Davis, S.; Meltzer, P. S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wheelan, S. J.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Div Biostat & Bioinformat, Baltimore, MD USA. [Brown, P.] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Jones, R. J.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, Baltimore, MD USA. [Shultz, L. D.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Civin, CI (reprint author), Univ Maryland, Sch Med, Dept Pediat, BRB 14-023,655 W Baltimore St, Baltimore, MD 21201 USA. EM CCivin@som.umaryland.edu OI Davis, Sean/0000-0002-8991-6458 FU Leukemia & Lymphoma Society [6082-08]; National Foundation for Cancer Research, National Institutes of Health [P01CA070970]; CIC [CA34196]; NIH; National Cancer Institute and Center for Cancer Research FX This research was supported in part by grants from the Leukemia & Lymphoma Society (Translational Grant 6082-08), National Foundation for Cancer Research, National Institutes of Health (P01CA070970) to CIC and CA34196 to the Jackson Lab. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute and Center for Cancer Research. NR 57 TC 27 Z9 27 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD NOV PY 2010 VL 24 IS 11 BP 1859 EP 1866 DI 10.1038/leu.2010.184 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 678EV UT WOS:000284057400005 PM 20739953 ER PT J AU Mailankody, S Mena, E Yuan, CM Balakumaran, A Kuehl, WM Landgren, O AF Mailankody, Sham Mena, Esther Yuan, Constance M. Balakumaran, Arun Kuehl, W. Michael Landgren, Ola TI Molecular and biologic markers of progression in monoclonal gammopathy of undetermined significance to multiple myeloma SO LEUKEMIA & LYMPHOMA LA English DT Review DE Myeloma; MGUS; smoldering myeloma; prognosis; molecular imaging; molecular profiling ID GENE-EXPRESSION PROFILES; INDEPENDENT RISK-FACTOR; PLASMA-CELL DYSCRASIAS; LIGHT-CHAIN RATIO; CHROMOSOMAL-ABNORMALITIES; SIGNIFICANCE MGUS; LEUKEMIA GENOME; RAS MUTATIONS; UNITED-STATES; LONG-TERM AB Multiple myeloma (MM) is a malignant plasma cell dyscrasia localized in the bone marrow. Recent studies have shown that MM is preceded in virtually all cases by a premalignant state called monoclonal gammopathy of undetermined significance (MGUS). This review focuses on non-IgM MGUS and its progression to MM. Although certain clinical markers of MGUS progression have been identified, it currently is not possible to accurately determine individual risk of progression. This review focuses on the various biologic and molecular markers that could be used to determine the risk of MM progression. A better understanding of the pathogenesis will allow us to define the biological high-risk precursor disease and, ultimately, to develop early intervention strategies designed to delay and prevent full-blown MM.= 3 MET.min(-1) for >= 10 min (moderate-to vigorous-intensity PA (MVPA)) and >= 6 MET.min(-1) for >= 10 min (vigorous-intensity PA (VPA)). Self-reported PA was also assessed with a questionnaire. Accelerometry and self-reported PA data were compared across categories of BMI, sex, race, age, fitness, diabetes medication usage, and history of cardiovascular disease. Results: Self-reported PA was lower at higher levels of BMI, was higher in males, was lowest for African-American/black, and was positively associated with fitness. Multivariate analyses for accelerometer-measured MVPA and VPA showed that more PA bouts per day, minutes per bout, METs per minute, and MET-minutes were associated with higher fitness. For MVPA, bouts per day were higher in men, and METs per minute were higher in women. For VPA, bouts per day was positively associated with increasing age and differed by race/ethnicity. METs per minute were significantly lower at higher levels of BMI and in women. Diabetes medication usage and history of cardiovascular disease were not associated with patterns of PA examined. Conclusions: Results provide information on factors that contribute to PA patterns in adults with T2DM when PA is assessed using both objective and subjective measures. These data may inform interventions to improve PA in adults with T2DM. C1 [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Phys Act & Weight Management Res Ctr, Pittsburgh, PA 15260 USA. [Gregg, Edward] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Knowler, William] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Kelley, David E.] Merck & Co Inc, Rahway, NJ 07065 USA. [Lang, Wei; Walkup, Michael P.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Miller, Gary D.; Rejeski, W. Jack; Ribisl, Paul] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [Pi-Sunyer, F. Xavier] St Lukes Roosevelt Hosp, Dept Med, New York, NY USA. [Regensteiner, Judith G.] Univ Colorado Denver, Sch Med, Aurora, CO USA. RP Jakicic, JM (reprint author), Univ Pittsburgh, Dept Hlth & Phys Act, Phys Act & Weight Management Res Ctr, 140 Trees Hall, Pittsburgh, PA 15260 USA. EM jjakicic@pitt.edu FU NCATS NIH HHS [UL1 TR000005]; NCRR NIH HHS [M01 RR001346, M01 RR000051, M01 RR000056, M01 RR001066, M01 RR002719]; NHLBI NIH HHS [R01 HL070257, R01 HL070257-01A1]; NIDDK NIH HHS [P30 DK017047, P30 DK046204, P30 DK048520, U01 DK056990, U01 DK056992, U01 DK057002, U01 DK057008, U01 DK057078, U01 DK057131, U01 DK057135, U01 DK057136, U01 DK057149, U01 DK057151, U01 DK057154, U01 DK057171, U01 DK057177, U01 DK057178, U01 DK057182, U01 DK057219] NR 21 TC 28 Z9 29 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD NOV PY 2010 VL 42 IS 11 BP 1995 EP 2005 DI 10.1249/MSS.0b013e3181e054f0 PG 11 WC Sport Sciences SC Sport Sciences GA 667XZ UT WOS:000283231900004 PM 20386337 ER PT J AU Tom, SE Kuh, D Guralnik, JM Mishra, GD AF Tom, Sarah E. Kuh, Diana Guralnik, Jack M. Mishra, Gita D. TI Self-reported sleep difficulty during the menopausal transition: results from a prospective cohort study SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Menopause; Hysterectomy; Sleep; Longitudinal; Menopausal symptoms ID WOMENS HEALTH; NATURAL MENOPAUSE; MULTIETHNIC COMMUNITY; RISK-FACTOR; SYMPTOMS; MIDLIFE; DISTURBANCE; QUALITY; AGE; HYSTERECTOMY AB Objective: The aim of this study was to examine the relationship between menopausal transition status and self-reported sleep difficulty. Methods: With the use of data on women participating in the Medical Research Council National Survey of Health and Development who have been followed up from birth in March 1946 (n = 962), relationships between menopausal transition status and self-reported sleep difficulty were assessed annually in women between ages 48 and 54 years. Results: Menopausal transition status was related to severe self-reported sleep difficulty. The odds of reporting severe self-reported sleep difficulty were increased approximately by 2- to 3.5-fold (95% CI ranges from 1.08-3.27 to 1.99-6.04) for women in most menopausal transition statuses compared with women who remained premenopausal. After adjustment for current psychological, vasomotor, and somatic symptoms and waking frequently at night to use the toilet, only women who had a hysterectomy remained at an increased risk for moderate sleep difficulty. Conclusions: The modest relationship between menopausal transition status and moderate sleep difficulty may be related to greater variation in individual definitions of moderate difficulty. Attention to the level of sleep difficulty in this group of women will assist in the decision to address current health symptoms versus sleep itself. Women without prior health problems may experience severe self-reported sleeping difficulty during the menopausal transition and require tailored care from health professionals. C1 [Tom, Sarah E.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Kuh, Diana; Mishra, Gita D.] Royal Free & Univ Coll Med Sch, MRC, Unit Lifelong Hlth & Ageing, London WC1E 6BT, England. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Tom, SE (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM tom.s@ghc.org RI Mishra, Gita/F-8052-2011 OI Mishra, Gita/0000-0001-9610-5904 FU National Institute on Aging, National Institutes of Health; Medical Research Council, United Kingdom FX This study was supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health and the Medical Research Council, United Kingdom. NR 35 TC 23 Z9 23 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD NOV-DEC PY 2010 VL 17 IS 6 BP 1128 EP 1135 DI 10.1097/gme.0b013e3181dd55b0 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 677LK UT WOS:000283993700010 PM 20551846 ER PT J AU Allison, MA Manson, JE Aragaki, A Langer, RD Rossouw, J Curb, D Martin, LW Phillips, L Stefanick, ML Cochrane, BB Sarto, G Barnhart, J O'Sullivan, MJ Johnson, KC Gass, M Trevisan, M Woods, NF AF Allison, Matthew A. Manson, JoAnn E. Aragaki, Aaron Langer, Robert D. Rossouw, Jacques Curb, David Martin, Lisa W. Phillips, Lawrence Stefanick, Marcia L. Cochrane, Barbara B. Sarto, Gloria Barnhart, Janice O'Sullivan, Mary Jo Johnson, Karen C. Gass, Margery Trevisan, Maurizio Woods, Nancy F. TI Vasomotor symptoms and coronary artery calcium in postmenopausal women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Calcium; Coronary; Vasomotor symptoms; Women; Menopause; Atherosclerosis ID RANDOMIZED CONTROLLED-TRIAL; AMERICAN-HEART-ASSOCIATION; BONE-MINERAL DENSITY; VASCULAR CALCIFICATION; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS MESA; COMPUTED-TOMOGRAPHY; RANCHO BERNARDO; HORMONE-THERAPY; RISK-FACTORS AB Objective: We assessed whether vasomotor symptoms (VMS) are associated with coronary artery calcium (CAC) and how hormone therapy (HT) may influence this association. Methods: Participants were a subset of women aged 50 to 59 years with a history of hysterectomy who were enrolled in the Women's Health Initiative (WHI) estrogen-alone clinical trial and underwent a CT scan of the chest at the end of the trial to determine CAC. Participants provided information about VMS (hot flashes and/or night sweats), as well as HT use, on self-administered questionnaires at trial baseline. Results: The sample consisted of 918 women with a mean (SD) age of 55.1 (2.8) years at WHI randomization and 64.8 (2.9) years at CAC ascertainment. The prevalence of a CAC score higher than 0 was 46%, whereas the prevalence of a CAC score of 10 or higher and higher than 100 was 39% and 19%, respectively. At randomization, 77% reported a history of any VMS at any time before or at enrollment in the WHI, whereas 20% reported any VMS present only at enrollment. Compared with those without a history of any VMS and after adjustment for potential confounders, a history of any VMS at any time up to and including WHI enrollment was associated with significantly reduced odds for CAC higher than 0 (odds ratio, 0.66; 95% CI, 0.45-0.98). Moreover, as duration of HT increased, the inverse association between any VMS and CAC moved toward the null. Conclusions: A history of any VMS was significantly associated with reduced odds for CAC independent of traditional cardiovascular disease risk factors and other relevant covariates. This association seems to be influenced by duration of HT. C1 [Allison, Matthew A.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Aragaki, Aaron] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Langer, Robert D.] Jackson Hole Ctr Prevent Med, Jackson, WY USA. [Rossouw, Jacques] NHLBI, NIH, Bethesda, MD 20892 USA. [Curb, David] Univ Hawaii, Honolulu, HI 96822 USA. [Martin, Lisa W.] George Washington Univ, Washington, DC USA. [Phillips, Lawrence] Emory Univ, Atlanta, GA 30322 USA. [Stefanick, Marcia L.] Stanford Univ, Stanford, CA 94305 USA. [Cochrane, Barbara B.; Woods, Nancy F.] Univ Washington, Seattle, WA 98195 USA. [Sarto, Gloria] Univ Wisconsin, Madison, WI USA. [Barnhart, Janice] Albert Einstein Univ, Bronx, NY USA. [O'Sullivan, Mary Jo] Univ Miami, Miami, FL USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Gass, Margery] Univ Cincinnati, Cincinnati, OH USA. [Trevisan, Maurizio] Hlth Sci Syst Nevada Syst Higher Educ, Las Vegas, NV USA. RP Allison, MA (reprint author), 9500 Gilman Dr,Mailcode 0965, La Jolla, CA 92093 USA. EM mallison@ucsd.edu OI Martin, Lisa Warsinger/0000-0003-4352-0914; Allison, Matthew/0000-0003-0777-8272 FU National Institutes of Health; American Heart Association; National Heart, Lung, and Blood Institute; US Department of Health and Human Services FX Support for this research was provided by contracts with the National Institutes of Health and a grant from the American Heart Association. The National Heart, Lung, and Blood Institute and =US Department of Health and Human Services funds the Women's Health Initiative (WHI) program and provided support for the WHI Coronary Artery Calcium Study ancillary study. Wyeth provided study pills (active and placebo) for the WHI Conjugated Equine Estrogens trial but had no other role in the study. This work was also supported in part by a grant from the American Heart Association (M.A. Allison). The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NR 44 TC 21 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD NOV-DEC PY 2010 VL 17 IS 6 BP 1136 EP 1145 DI 10.1097/gme.0b013e3181e664dc PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 677LK UT WOS:000283993700011 PM 20651617 ER PT J AU Wickerham, DL AF Wickerham, D. L. TI Counseling Women On Ways To Prevent Breast Cancer SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 21st Annual Meeting of the North-American-Menopause-Society CY OCT 06-09, 2010 CL Chicago, IL SP N Amer Menopause Soc C1 [Wickerham, D. L.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD NOV-DEC PY 2010 VL 17 IS 6 BP 1211 EP 1211 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 677LK UT WOS:000283993700031 ER PT J AU Nelson, LM AF Nelson, Lawrence M. TI Primary Ovarian Insufficiency is Not an Early Menopause SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 21st Annual Meeting of the North-American-Menopause-Society CY OCT 06-09, 2010 CL Chicago, IL SP N Amer Menopause Soc C1 [Nelson, Lawrence M.] NICHD, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD NOV-DEC PY 2010 VL 17 IS 6 BP 1212 EP 1213 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 677LK UT WOS:000283993700040 ER PT J AU Huang, B Troese, MJ Howe, D Ye, SJ Sims, JT Heinzen, RA Borjesson, DL Carlyon, JA AF Huang, Bernice Troese, Matthew J. Howe, Dale Ye, Shaojing Sims, Jonathan T. Heinzen, Robert A. Borjesson, Dori L. Carlyon, Jason A. TI Anaplasma phagocytophilum APH_0032 is expressed late during infection and localizes to the pathogen-occupied vacuolar membrane SO MICROBIAL PATHOGENESIS LA English DT Article DE Pathogenesis; Anaplasma; Ehrlichia; Pathogen-occupied vacuole; Intravacuolar pathogen ID IV SECRETION SYSTEM; MAJOR SURFACE PROTEIN-2; EHRLICHIA-CHAFFEENSIS; INCLUSION MEMBRANE; TANDEM REPEATS; EVASION MECHANISMS; MESSENGER-RNA; NADPH OXIDASE; CELLS; GENE AB Anaplasma phagocytophilum infects neutrophils and myeloid, endothelial, and tick cell lines to reside within a host cell-derived vacuole that is indispensible for its survival. Here, we identify APH_0032 as an Anaplasma-derived protein that associates with the A. phagocytophilum-occupied vacuolar membrane (AVM). APH_0032 is a 66.1 kDa acidic protein that electrophoretically migrates with an apparent molecular weight of 130 kDa. It contains a predicted transmembrane domain and tandemly arranged direct repeats that comprise 46% of the protein. APH_0032 is undetectable on Anaplasma organisms bound to the surfaces of HL-60 cells, but is detected on the AVM and surfaces of intravacuolar bacteria beginning 24 h post-infection. APH_0032 localizes to the AVM in HL-60, THP-1, HMEC-1, and ISE6 cells. APH_0032, along with APH_1387, which encodes a confirmed AVM protein, is transcribed during A. phagocytophilum infection of tick salivary glands and murine neutrophils. APH_0032 localizes to the AVM in neutrophils recovered from infected mice. The Legionella pneumophila Dot/IcM type IV secretion system (T4SS) can heterologously secrete a CyaA-tagged version of the A. phagocytophilum VirB/D T4SS effector, AnkA, but fails to secrete CyaA-tagged APH_0032 or APH_1387. These data confirm APH_0032 as an Anaplasma-derived AVM protein and hint that neither it nor APH_1387 are T4SS effectors. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Huang, Bernice; Troese, Matthew J.; Carlyon, Jason A.] Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Howe, Dale; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Ye, Shaojing; Sims, Jonathan T.] Univ Kentucky, Coll Med, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40504 USA. [Borjesson, Dori L.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. RP Carlyon, JA (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, Mol Med Res Bldg,1220 E Broad St,Room 4052,POB 98, Richmond, VA 23298 USA. EM jacarlyon@vcu.edu FU NIH-NINDS Center [5P30NS047463]; NIH [DK065039, AI072683]; National Research Fund for Tick-Borne Diseases FX We acknowledge Curtis Nelson for openly discussing his unpublished observations; Erol Fikrig for providing HGA patient antisera and seronegative sera; J. Stephen Dumler for providing mAb 20B4; Sukanya Narasimhan for providing RNA isolated from uninfected and A. phagocytophilum-infected tick salivary glands; Ulrike Munderloh for providing A. phagocytophilum-infected ISE6 cells; Howard Shuman for providing L pneumophila JR32 and LELA3118 strains; Jere W. McBride and Richard T. Marconi for helpful discussions; and Naomi Walker, Dexter Reneer, and Aaron Wolen for technical assistance. The Virginia Commonwealth University Department of Neurobiology & Anatomy Microscopy Facility is supported, in part, by funding from NIH-NINDS Center core grant 5P30NS047463.; Supported by NIH grants DK065039 and AI072683 and funding from the National Research Fund for Tick-Borne Diseases. NR 57 TC 27 Z9 28 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD NOV PY 2010 VL 49 IS 5 BP 273 EP 284 DI 10.1016/j.micpath.2010.06.009 PG 12 WC Immunology; Microbiology SC Immunology; Microbiology GA 641KL UT WOS:000281124100008 PM 20600793 ER PT J AU Zou, TT Rao, JN Liu, L Xiao, L Yu, TX Jiang, P Gorospe, M Wang, JY AF Zou, Tongtong Rao, Jaladanki N. Liu, Lan Xiao, Lan Yu, Ting-Xi Jiang, Ping Gorospe, Myriam Wang, Jian-Ying TI Polyamines Regulate the Stability of JunD mRNA by Modulating the Competitive Binding of Its 3 ' Untranslated Region to HuR and AUF1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; REPRESSES CDK4 TRANSCRIPTION; PROXIMAL PROMOTER REGION; C-MYC EXPRESSION; PROTEIN HUR; OXIDATIVE STRESS; GENE-EXPRESSION; MUCOSAL GROWTH; DEPLETION; P53 AB Polyamines critically regulate all mammalian cell growth and proliferation by mechanisms such as the repression of growth-inhibitory proteins, including JunD. Decreasing the levels of cellular polyamines stabilizes JunD mRNA without affecting its transcription, but the exact mechanism whereby polyamines regulate JunD mRNA degradation has not been elucidated. RNA-binding proteins HuR and AUF1 associate with labile mRNAs bearing AU-rich elements located in the 3' untranslated regions (3'-UTRs) and modulate their stability. Here, we show that JunD mRNA is a target of HuR and AUF1 and that polyamines modulate JunD mRNA degradation by altering the competitive binding of HuR and AUF1 to the JunD 3'-UTR. The depletion of cellular polyamines enhanced HuR binding to JunD mRNA and decreased the levels of JunD transcript associated with AUF1, thus stabilizing JunD mRNA. The silencing of HuR increased AUF1 binding to the JunD mRNA, decreased the abundance of HuR-JunD mRNA complexes, rendered the JunD mRNA unstable, and prevented increases in JunD mRNA and protein in polyamine-deficient cells. Conversely, increasing the cellular polyamines repressed JunD mRNA interaction with HuR and enhanced its association with AUF1, resulting in an inhibition of JunD expression. These results indicate that polyamines modulate the stability of JunD mRNA in intestinal epithelial cells through HuR and AUF1 and provide new insight into the molecular functions of cellular polyamines. C1 [Zou, Tongtong; Rao, Jaladanki N.; Liu, Lan; Xiao, Lan; Yu, Ting-Xi; Jiang, Ping; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Zou, Tongtong; Rao, Jaladanki N.; Liu, Lan; Xiao, Lan; Yu, Ting-Xi; Jiang, Ping; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Zou, Tongtong; Rao, Jaladanki N.; Liu, Lan; Yu, Ting-Xi; Jiang, Ping; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, IRP, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Baltimore Vet Affairs Med Ctr 112, 10 N Greene St, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU Department of Veterans Affairs; NIH [DK-57819, DK-61972, DK-68491]; NIA-IRP, NIH FX This work was supported by a merit review grant (to J.-Y.W.) from the Department of Veterans Affairs and by NIH grants DK-57819, DK-61972, and DK-68491 (to J.-Y.W.). J.-Y.W. is a Research Career Scientist, Medical Research Service, U.S. Department of Veterans Affairs. M. G. is supported by the NIA-IRP, NIH. NR 64 TC 36 Z9 37 U1 0 U2 2 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 NOV PY 2010 VL 30 IS 21 BP 5021 EP 5032 DI 10.1128/MCB.00807-10 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 661SO UT WOS:000282748600004 PM 20805360 ER PT J AU Suzuki, Y Holmes, JB Cerritelli, SM Sakhuja, K Minczuk, M Holt, IJ Crouch, RJ AF Suzuki, Yutaka Holmes, J. Bradley Cerritelli, Susana M. Sakhuja, Kiran Minczuk, Michal Holt, Ian J. Crouch, Robert J. TI An Upstream Open Reading Frame and the Context of the Two AUG Codons Affect the Abundance of Mitochondrial and Nuclear RNase H1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article AB RNase H1 in mammalian cells is present in nuclei and mitochondria. Its absence in mitochondria results in embryonic lethality due to the failure to amplify mitochondrial DNA (mtDNA). Dual localization to mitochondria and nuclei results from differential translation initiation at two in-frame AUGs (M1 and M27) of a single mRNA. Here we show that expression levels of the two isoforms depend on the efficiency of translation initiation at each AUG codon and on the presence of a short upstream open reading frame (uORF) resulting in the mitochondrial isoform being about 10% as abundant as the nuclear form. Translation initiation at the M1 AUG is restricted by the uORF, while expression of the nuclear isoform requires reinitiation of ribosomes at the M27 AUG after termination of uORF translation or new initiation by ribosomes skipping the uORF and the M1 AUG. Such translational organization of RNase H1 allows tight control of expression of RNase H1 in mitochondria, where its excess or absence can lead to cell death, without affecting the expression of the nuclear RNase H1. C1 [Suzuki, Yutaka; Holmes, J. Bradley; Cerritelli, Susana M.; Sakhuja, Kiran; Crouch, Robert J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Holmes, J. Bradley; Minczuk, Michal; Holt, Ian J.] MRC, Mitochondrial Biol Unit, Cambridge CB2 0XY, England. RP Crouch, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, 6 Ctr Dr,MSC2790, Bethesda, MD 20892 USA. EM robert_crouch@nih.gov OI Suzuki, Yutaka/0000-0001-7504-9464 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; U.K. Medical Research Council FX This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. Yutaka Suzuki was a Japan Society for the Promotion of Science Research Fellow in Biomedical and Behavioral Research at the National Institutes of Health. J. Bradley Holmes is a National Institutes of Health-Cambridge University Biomedical Research Scholar. Michal Minczuk and Ian Holt are supported by the U.K. Medical Research Council. NR 37 TC 28 Z9 28 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2010 VL 30 IS 21 BP 5123 EP 5134 DI 10.1128/MCB.00619-10 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 661SO UT WOS:000282748600012 PM 20823270 ER PT J AU Dev, K Qiu, HF Dong, JS Zhang, F Barthlme, D Hinnebusch, AG AF Dev, Kamal Qiu, Hongfang Dong, Jinsheng Zhang, Fan Barthlme, Dominik Hinnebusch, Alan G. TI The beta/Gcd7 Subunit of Eukaryotic Translation Initiation Factor 2B (eIF2B), a Guanine Nucleotide Exchange Factor, Is Crucial for Binding eIF2 In Vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article AB Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor (GEF) for eukaryotic translation initiation factor 2, which stimulates formation of the eIF2-GTP-Met-tRNA(i)(Met) ternary complex (TC) in a manner inhibited by phosphorylated eIF2 [eIF2(alpha P)]. While eIF2B contains five subunits, the epsilon/Gcd6 subunit is sufficient for GEF activity in vitro. The delta/Gcd2 and beta/Gcd7 subunits function with alpha/Gcn3 in the eIF2B regulatory subcomplex that mediates tight, inhibitory binding of eIF2(alpha P)-GDP, but the essential functions of delta/Gcd2 and beta/Gcd7 are not well understood. We show that the depletion of wild-type beta/Gcd7, three lethal beta/Gcd7 amino acid substitutions, and a synthetically lethal combination of substitutions in beta/Gcd7 and eIF2 alpha all impair eIF2 binding to eIF2B without reducing epsilon/Gcd6 abundance in the native eIF2B-eIF2 holo-complex. Additionally, beta/Gcd7 mutations that impair eIF2B function display extensive allele-specific interactions with mutations in the S1 domain of eIF2 alpha (harboring the phosphorylation site), which binds to eIF2B directly. Consistent with this, beta/Gcd7 can overcome the toxicity of eIF2(alpha P) and rescue native eIF2B function when overexpressed with delta/Gcd2 or gamma/Gcd1. In aggregate, these findings provide compelling evidence that beta/Gcd7 is crucial for binding of substrate by eIF2B in vivo, beyond its dispensable regulatory role in the inhibition of eIF2B by eIF (alpha P). C1 [Dev, Kamal; Qiu, Hongfang; Dong, Jinsheng; Zhang, Fan; Barthlme, Dominik; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NIH, Bldg 6,Room 230, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI Barthelme, Dominik/E-8452-2010; university, shoolini/K-9336-2015 FU NIH FX This work was supported in part by the Intramural Research Program of the NIH. NR 50 TC 12 Z9 12 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 NOV PY 2010 VL 30 IS 21 BP 5218 EP 5233 DI 10.1128/MCB.00265-10 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 661SO UT WOS:000282748600020 PM 20805354 ER PT J AU Duffy, SP Shing, J Saraon, P Berger, LC Eiden, MV Wilde, A Tailor, CS AF Duffy, Simon P. Shing, Jennifer Saraon, Punit Berger, Lloyd C. Eiden, Maribeth V. Wilde, Andrew Tailor, Chetankumar S. TI The Fowler Syndrome-Associated Protein FLVCR2 Is an Importer of Heme SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FELINE-LEUKEMIA-VIRUS; DIAMOND-BLACKFAN ANEMIA; AMINO-ACID TRANSPORTER; HYDRANENCEPHALIC-HYDROCEPHALIC SYNDROME; CELL-SURFACE RECEPTORS; MEGALOBLASTIC-ANEMIA; PROLIFERATIVE VASCULOPATHY; THIAMINE TRANSPORTER; IRON HOMEOSTASIS; SUBGROUP C AB Mutations in FLVCR2, a cell surface protein related by homology and membrane topology to the heme exporter/retroviral receptor FLVCR1, have recently been associated with Fowler syndrome, a vascular disorder of the brain. We previously identified FLVCR2 to function as a receptor for FY981 feline leukemia virus (FeLV). However, the cellular function of FLVCR2 remains unresolved. Here, we report the cellular function of FLVCR2 as an importer of heme, based on the following observations. First, FLVCR2 binds to hemin-conjugated agarose, and binding is competed by free hemin. Second, mammalian cells and Xenopus laevis oocytes expressing FLVCR2 display enhanced heme uptake. Third, heme import is reduced after the expression of FLVCR2-specific small interfering RNA (siRNA) or after the binding of the FY981 FeLV envelope protein to the FLVCR2 receptor. Finally, cells overexpressing FLVCR2 are more sensitive to heme toxicity, a finding most likely attributable to enhanced heme uptake. Tissue expression analysis indicates that FLVCR2 is expressed in a broad range of human tissues, including liver, placenta, brain, and kidney. The identification of a cellular function for FLVCR2 will have important implications in elucidating the pathogenic mechanisms of Fowler syndrome and of phenotypically associated disorders. C1 [Duffy, Simon P.; Shing, Jennifer; Saraon, Punit; Tailor, Chetankumar S.] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada. [Duffy, Simon P.; Berger, Lloyd C.; Wilde, Andrew; Tailor, Chetankumar S.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Eiden, Maribeth V.] NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Tailor, CS (reprint author), Hosp Sick Children, Cell Biol Program, Room 7129,Elm Wing,555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM chetankumar.tailor@sickkids.ca OI Duffy, Simon/0000-0002-1301-6031 FU Canadian Institutes of Health Research [MOP-79541]; Sickkids Foundation [XG07-028R]; Hospital for Sick Children FX This work was supported by Canadian Institutes of Health Research grant MOP-79541, by Sickkids Foundation grant XG07-028R, and by a Restracomp award to S.P.D. provided by the Hospital for Sick Children. NR 49 TC 28 Z9 30 U1 0 U2 2 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 NOV PY 2010 VL 30 IS 22 BP 5318 EP 5324 DI 10.1128/MCB.00690-10 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 673JX UT WOS:000283656700006 PM 20823265 ER PT J AU Swanwick, CC Shapiro, ME Vicini, S Wenthold, RJ AF Swanwick, Catherine Croft Shapiro, Marietta E. Vicini, Stefano Wenthold, Robert J. TI Flotillin-1 mediates neurite branching induced by synaptic adhesion-like molecule 4 in hippocampal neurons SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE Rat; Lipid rafts; Dendritic arborization; Development; Adhesion molecules ID LIPID-RAFT PROTEINS; EXOCYST COMPLEX; MEMBRANE MICRODOMAINS; RHO-GTPASES; REGGIE/FLOTILLIN PROTEINS; SIGNAL-TRANSDUCTION; FILOPODIA FORMATION; AXON REGENERATION; NMDA-RECEPTORS; PDZ PROTEINS AB Proper development of neurons in the hippocampus is essential for learning and memory. Our laboratory previously discovered a family of synaptic adhesion-like molecules (SALMs) which induce neurite outgrowth in this brain region (Wang et al., 2006). Here we establish flotillin-1 (flot-1) as a molecular mediator of neurite branching for SALM4. Knockdown of flot-1 alone in cultured hippocampal neurons using siRNA from 3-7 days in vitro (DIV) impaired neurite branching, whereas overexpression of flot-1 during the same time period increased the number of processes and branching. We show that induction of neurite outgrowth by flot-1 depends on amino acids 134-151 as well as lipid raft microdomains, SoHo proteins to regulate the actin cytoskeleton, and the exocyst complex to deliver new membrane proteins to growing neurites. When each of SALMs 1-5 was overexpressed, siRNA knockdown of flot-1 prevented neurite branching by SALM4. Overall, our data reveal a flot-1 signaling pathway for hippocampal neurite branching that is regulated by SALM4. (C) 2010 Published by Elsevier Inc. C1 [Swanwick, Catherine Croft; Shapiro, Marietta E.; Wenthold, Robert J.] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Vicini, Stefano] Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA. RP Swanwick, CC (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bldg 50,Room 4146,50 South Dr, Bethesda, MD 20892 USA. EM swanwickc@mail.nih.gov FU National Institute of General Medical Sciences FX We thank Ya-Xian Wang for culturing the hippocampal neurons. We are also grateful to Alan Saltiel, Benjamin Nichols, Pietro DeCamilli, Dorit Ron, and Eunjoon Kim for cDNA constructs and to Shu-Chan Hsu for antibodies and cDNA constructs. In addition, we thank members of the Wenthold Lab for providing comments and suggestions on this manuscript. This study was funded by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders and a Pharmacology Research Associate (PRAT) Fellowship from the National Institute of General Medical Sciences. NR 68 TC 10 Z9 12 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD NOV PY 2010 VL 45 IS 3 BP 213 EP 225 DI 10.1016/j.mcn.2010.06.012 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 654YP UT WOS:000282207500002 PM 20600927 ER PT J AU Fukuda, Y Berry, TL Nelson, M Hunter, CL Fukuhara, K Imai, H Ito, S Granholm-Bentley, AC Kaplan, AP Mutoh, T AF Fukuda, Yu Berry, Thomas L. Nelson, Matthew Hunter, Christopher L. Fukuhara, Koki Imai, Hideki Ito, Shinji Granholm-Bentley, Ann-Charlotte Kaplan, Allen P. Mutoh, Tatsuro TI Stimulated neuronal expression of brain-derived neurotrophic factor by Neurotropin SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE Neurotropin; Brain-derived neurotrophic factor; CREB pathway; TrkB; Ts65Dn mice; Down's syndrome; Radial-arm maze ID NERVE GROWTH-FACTOR; ADULT HIPPOCAMPAL NEUROGENESIS; AMYLOID PRECURSOR PROTEIN; SPINAL DORSAL-HORN; GENE-EXPRESSION; MOUSE MODEL; WORKING-MEMORY; DOWNS-SYNDROME; CNS DISORDERS; CHRONIC PAIN AB Expression of brain-derived neurotrophic factor (BDNF) was stimulated in human neuroblastoma SH-SY5Y cells by a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin (R)), an analgesic widely used in Japan for treatment of disorders associated with chronic pain, with the optimal dosage at 10 mNU/mL This stimulation was accompanied by activations of p42/44 MAP kinase, CREB and c-Fos expression. Inhibitors of MAP kinases or PI 3-kinase prevented the stimulatory action of Neurotropin, indicating that neuronal TrkB/CREB pathway mediates the action. Repetitive oral administration of Neurotropin (200 NU/kg/day, 3 months) prevented the age-dependent decline in hippocampal BDNF expression in Ts65Dn mice, a model of Down's syndrome. This effect was associated with the improvement of spatial cognition of the mice. These results open an intriguing new strategy in which Neurotropin may prove beneficial treatment for neurodegenerative disorders. (C) 2010 Elsevier Inc. All rights reserved. C1 [Fukuda, Yu; Ito, Shinji; Mutoh, Tatsuro] Fajita Hlth Univ, Sch Med, Dept Neurol, Toyoake, Aichi 4701192, Japan. [Fukuda, Yu; Berry, Thomas L.; Fukuhara, Koki; Kaplan, Allen P.] Med Univ S Carolina, Konishi MUSC Inst Inflammat Res, Charleston, SC 29425 USA. [Fukuda, Yu; Berry, Thomas L.; Fukuhara, Koki; Kaplan, Allen P.] Med Univ S Carolina, Dept Med, Div Pulm & Crit Care Med Allergy & Clin Immunol, Charleston, SC 29425 USA. [Nelson, Matthew; Hunter, Christopher L.; Granholm-Bentley, Ann-Charlotte] Med Univ S Carolina, Dept Neurosci, Ctr Aging, Charleston, SC 29425 USA. [Fukuhara, Koki] NINR, NIH, Bethesda, MD 20892 USA. [Fukuda, Yu; Fukuhara, Koki; Imai, Hideki] Nippon Zoki Pharmaceut Co Ltd, Chuo Ku, Osaka 5410046, Japan. RP Mutoh, T (reprint author), Fajita Hlth Univ, Sch Med, Dept Neurol, Kutsukake Cho, Toyoake, Aichi 4701192, Japan. EM tmutoh@fujita-hu.ac.jp NR 59 TC 15 Z9 18 U1 2 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD NOV PY 2010 VL 45 IS 3 BP 226 EP 233 DI 10.1016/j.mcn.2010.06.013 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 654YP UT WOS:000282207500003 PM 20600926 ER PT J AU Cooper, O Hargus, G Deleidi, M Blak, A Osborn, T Marlow, E Lee, K Levy, A Perez-Torres, E Yow, A Isacson, O AF Cooper, Oliver Hargus, Gunnar Deleidi, Michela Blak, Alexandra Osborn, Teresia Marlow, Elizabeth Lee, Kristen Levy, Adam Perez-Torres, Eduardo Yow, Alyssa Isacson, Ole TI Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE FOXA2; HNF3b; A9; A10; Splice variant; Induced; Pluripotent; Stem; Embryonic; Neural ID EMBRYONIC STEM-CELLS; SONIC HEDGEHOG; FLOOR PLATE; GENE-EXPRESSION; SUBSTANTIA-NIGRA; SPINAL-CORD; RAT MODEL; IN-VITRO; IDENTITY; INDUCTION AB The cardinal motor symptoms of Parkinson's disease (PD) are caused by the vulnerability to dysfunction and degeneration of ventral midbrain (VM) dopaminergic (DA) neurons. A major limitation for experimental studies of current ES/iPS cell differentiation protocols is the lack of VM DA neurons with a stable phenotype as defined by an expression marker code of FOXA2/TH/beta-tubulin. Here we demonstrate a combination of three modifications that were required to produce VM DA neurons. Firstly, early and specific exposure to 10(-8) M (low dose) retinoic acid improved the regional identity of neural progenitor cells derived from human ES cells, PD or healthy subject-specific iPS cells. Secondly, a high activity form of human sonic hedgehog established a sizeable FOXA2(+) neural progenitor cell population in vitro. Thirdly, early exposure to FGF8a, rather than Fgf8b, and WNT1 was required for robust differentiation of the FOXA2(+) floor plate-like human neural progenitor cells into FOXA2(+) DA neurons. FOXA2(+) DA neurons were also generated when this protocol was adapted to feeder-free conditions. In summary, this new human ES and iPS cell differentiation protocol using FGF8a, WNT1, low dose retinoic acid and a high activity form of SHH can generate human VM DA neurons that are required for relevant new bioassays, drug discovery and cell based therapies for PD. (C) 2010 Elsevier Inc. All rights reserved. C1 [Cooper, Oliver] Harvard Univ, Sch Med, NINDS Udall Parkinsons Dis Res Ctr Excellence, McLean Hosp,Neuroregenerat Labs,Ctr Neuroregenera, Belmont, MA 02478 USA. RP Cooper, O (reprint author), Harvard Univ, Sch Med, NINDS Udall Parkinsons Dis Res Ctr Excellence, McLean Hosp,Neuroregenerat Labs,Ctr Neuroregenera, MRC 103,115 Mill St, Belmont, MA 02478 USA. EM ocooper@mclean.harvard.edu OI Cooper, Oliver/0000-0001-6567-7491 FU Udall Parkinson's Disease Center of Excellence [P50 NS39793]; Michael Stern Foundation [WX81XWH-05-1-0555]; Orchard Foundation; Consolidated Anti-Aging Foundation; Harold and Ronna Cooper Family; Deutsche Forschungsgemeinschaft [HA5589/1-1]; Harvard Medical School/National Institute on Aging [5T32AG00222-17] FX During the review of this paper, another paper providing mechanistic data for human FOXA2 expressing neural precursor cell differentiation from ES cells was published (Fasano et al., 2010). Our study was supported by the Udall Parkinson's Disease Center of Excellence Grant P50 NS39793, Michael Stern Foundation (WX81XWH-05-1-0555), Orchard Foundation, the Consolidated Anti-Aging Foundation and the Harold and Ronna Cooper Family. G.H. received a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (HA5589/1-1). T.O. received a Molecular Biology of Neurodegeneration postdoctoral fellowship from Harvard Medical School/National Institute on Aging (5T32AG00222-17). NR 56 TC 92 Z9 95 U1 6 U2 37 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD NOV PY 2010 VL 45 IS 3 BP 258 EP 266 DI 10.1016/j.mcn.2010.06.017 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 654YP UT WOS:000282207500006 PM 20603216 ER PT J AU Wei, XM Prickett, TD Viloria, CG Molinolo, A Lin, JC Cardenas-Navia, I Cruz, P Rosenberg, SA Davies, MA Gershenwald, JE Lopez-Otin, C Samuels, Y AF Wei, Xiaomu Prickett, Todd D. Viloria, Cristina G. Molinolo, Alfredo Lin, Jimmy C. Cardenas-Navia, Isabel Cruz, Pedro Rosenberg, Steven A. Davies, Michael A. Gershenwald, Jeffrey E. Lopez-Otin, Carlos Samuels, Yardena CA NISC Comparative Sequencing Progra TI Mutational and Functional Analysis Reveals ADAMTS18 Metalloproteinase as a Novel Driver in Melanoma SO MOLECULAR CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR; PROTEOLYTIC ACTIVITIES; COLORECTAL CANCERS; EMERGING ROLES; HUMAN BREAST; IDENTIFICATION; MULTIPLE; MATRIX; INACTIVATION; METASTASIS AB The disintegrin-metalloproteinases with thrombospondin domains (ADAMTS) genes have been suggested to function as tumor suppressors as several have been found to be epigenetically silenced in various cancers. We performed a mutational analysis of the ADAMTS gene family in human melanoma and identified a large fraction of melanomas to harbor somatic mutations. To evaluate the functional consequences of the most commonly mutated gene, ADAMTS18, six of its mutations were biologically examined. ADAMTS18 mutations had little effect on melanoma cell growth under standard conditions, but reduced cell dependence on growth factors. ADAMTS18 mutations also reduced adhesion to laminin and increased migration in vitro and metastasis in vivo. Melanoma cells expressing mutant ADAMTS18 had reduced cell migration after short hairpin RNA-mediated knockdown of ADAMTS18, suggesting that ADAMTS18 mutations promote growth, migration, and metastasis in melanoma. Mol Cancer Res; 8(11); 1513-25. (C) 2010 AACR. C1 [Wei, Xiaomu; Prickett, Todd D.; Cardenas-Navia, Isabel; Cruz, Pedro; Samuels, Yardena; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Molinolo, Alfredo] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. [Viloria, Cristina G.; Lopez-Otin, Carlos] Univ Oviedo, Dept Bioquim & Biol Mol, Inst Univ Oncol, Oviedo, Spain. [Lin, Jimmy C.] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD USA. [Lin, Jimmy C.] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. RP Samuels, Y (reprint author), NHGRI, NIH Intramural Sequencing Ctr, NIH, Room 5140,Bldg 50,50 South Dr,MSC 8000, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov RI Lopez-Otin, Carlos/C-6657-2013 OI Lopez-Otin, Carlos/0000-0001-6964-1904 FU National Human Genome Research Institute, NIH; Ministerio de Ciencia e Innovacion-Spain; Fundacion "M. Botin"; European Union; University of Texas; M.D. Anderson Cancer Center; Melanoma Informatics, Tissue Resource, and Pathology Core [P50 CA93459] FX National Human Genome Research Institute, NIH (Y. Samuels); Ministerio de Ciencia e Innovacion-Spain, Fundacion "M. Botin", European Union (FP7 Micro-EnviMet; C. Lopez-Otin); and in part by the University of Texas M.D. Anderson Cancer Center Melanoma Specialized Programs of Research Excellence and the Melanoma Informatics, Tissue Resource, and Pathology Core (grant P50 CA93459). NR 47 TC 21 Z9 23 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD NOV PY 2010 VL 8 IS 11 BP 1513 EP 1525 DI 10.1158/1541-7786.MCR-10-0262 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 684TF UT WOS:000284571500007 PM 21047771 ER PT J AU Wang, YA James, M Wen, WD Lu, Y Szabo, E Lubet, RA You, M AF Wang, Yian James, Michael Wen, Weidong Lu, Yan Szabo, Eva Lubet, Ronald A. You, Ming TI Chemopreventive Effects of Pioglitazone on Chemically Induced Lung Carcinogenesis in Mice SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; SQUAMOUS-CELL CARCINOMA; PPAR-GAMMA; A/J MICE; COLON CARCINOGENESIS; TRANSGENIC MICE; BREAST-CANCER; CHINESE HERBS; MOUSE MODELS; P53 AB Pioglitazone [(RS)-5-(4-[2-(5-ethylpyridin-2-yl) ethoxy] benzyl) thiazolidine-2,4-dione] is a ligand of nuclear receptor peroxisome proliferator-activated receptor. that is approved for the treatment of type II diabetes mellitus. Activation of peroxisome proliferator-activated receptor. has been associated with anticancer activities in a variety of cancer cell lines through inhibition of proliferation and promotion of apoptosis. We examined the effect of pioglitazone on lung cancer development in carcinogen-induced lung adenocarcinoma and squamous cell carcinoma (SCC). When pioglitazone was administered beginning 8 weeks after the first carcinogen treatment when microscopic adenomas already existed, pioglitazone significantly inhibited tumor load (sum of tumor volume per lung in average) by 64% (P < 0.05) in p53(wt/wt) mice and 50% (P < 0.05) in p53(wt/Ala135Val) mice in the lung adenocarcinoma model. Delayed administration of pioglitazone caused a limited (35%, P < 0.05) decrease in lung SCC. Induction of apoptosis occurred in both model systems. These data show that pioglitazone significantly inhibited progression of both adenocarcinoma and SCC in the two mouse model systems. Mol Cancer Ther; 9(11); 3074-82. (C) 2010 AACR. C1 [Wang, Yian; James, Michael; Wen, Weidong; Lu, Yan; You, Ming] Washington Univ, Dept Surg, Sch Med, St Louis, MO 63110 USA. [Szabo, Eva; Lubet, Ronald A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Wang, Yian; James, Michael; Wen, Weidong; Lu, Yan; You, Ming] Washington Univ, Alvin J Siteman Canc Ctr, Sch Med, St Louis, MO 63110 USA. RP Wang, YA (reprint author), Washington Univ, Dept Surg, Sch Med, Campus Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. EM wangyi@wustl.edu NR 46 TC 25 Z9 26 U1 1 U2 2 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 NOV PY 2010 VL 9 IS 11 BP 3074 EP 3082 DI 10.1158/1535-7163.MCT-10-0510 PG 9 WC Oncology SC Oncology GA 677ND UT WOS:000283998200022 PM 21045137 ER PT J AU Poltoratsky, V Heacock, M Kissling, GE Prasad, R Wilson, SH AF Poltoratsky, Vladimir Heacock, Michelle Kissling, Grace E. Prasad, Rajendra Wilson, Samuel H. TI Mutagenesis dependent upon the combination of activation-induced deaminase expression and a double-strand break SO MOLECULAR IMMUNOLOGY LA English DT Article DE Activation induced deaminase; AID; Base excision repair; Somatic hypermutation; Double strand breaks; Mutagenesis ID INDUCED CYTIDINE DEAMINASE; CLASS SWITCH RECOMBINATION; BASE EXCISION-REPAIR; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; ANTIBODY REPERTOIRE; DNA DEAMINATION; URACIL EXCISION AB We explored DNA metabolic events potentially relevant to somatic hypermutation (SHM) of immunoglobulin genes using a yeast model system Double-strand break (DSB) formation has been discussed as a possible component of the SHM process during immunoglobulin gene maturation Yet possible mechanisms linking DSB formation with mutagenesis have not been well understood In the present study a linkage between mutagenesis in a reporter gene and a double-strand break at a distal site was examined as a function of activation-induced deaminase (AID) expression Induction of the DSB was found to be associated with mutagenesis in a genomic marker gene located 7 kb upstream of the break site mutagenesis was strongest with the combination of AID expression and DSB induction The mutation spectrum of this DSB and AID-mediated mutagenesis was characteristic of replicative bypass of uracil in one strand and was dependent on expression of DNA polymerase delta (Pol delta) These results in a yeast model system illustrate that the combination of DSB induction and AID expression could be associated with mutagenesis observed in SHM Implications of these findings for SHM of immunoglobulin genes in human B cells are discussed Published by Elsevier Ltd C1 [Poltoratsky, Vladimir; Heacock, Michelle; Prasad, Rajendra; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233,MD F1 12, Res Triangle Pk, NC 27709 USA. FU NIH National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159] FX We thank Michael Resnick and Dmitry Gordenin for useful comments on the manuscript and Bonnie Mesmer for editorial assistance This research was supported by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences (Z01-ES050158 & Z01-ES050159) NR 54 TC 5 Z9 6 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD NOV-DEC PY 2010 VL 48 IS 1-3 BP 164 EP 170 DI 10.1016/j.molimm.2010.08.013 PG 7 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 701GI UT WOS:000285806000018 PM 20828826 ER PT J AU Uhl, GR Drgon, T Johnson, C Ramoni, MF Behm, FM Rose, JE AF Uhl, George R. Drgon, Tomas Johnson, Catherine Ramoni, Marco F. Behm, Frederique M. Rose, Jed E. TI Genome-Wide Association for Smoking Cessation Success in a Trial of Precessation Nicotine Replacement SO MOLECULAR MEDICINE LA English DT Article ID SAMPLE-SIZE CALCULATIONS; MOLECULAR-GENETICS; LUNG-CANCER; DEPENDENCE; BEHAVIOR; GENES; METAANALYSIS; ADDICTION; DISEASE; POWER AB Abilities to successfully quit smoking display substantial evidence for heritability in classic and molecular genetic studies. Genome-wide association (GWA) studies have demonstrated single-nucleotide polymorphisms (SNPs) and haplotypes that distinguish successful quitters from individuals who were unable to quit smoking in clinical trial participants and in community samples. Many of the subjects in these clinical trial samples were aided by nicotine replacement therapy (NRI). We now report novel GWA results from participants in a clinical trial that sought dose/response relationships for "precessation" NRT. In this trial, 369 European-American smokers were randomized to 21 or 42 mg NRT, initiated 2 wks before target quit dates. Ten-week continuous smoking abstinence was assessed on the basis of self-reports and carbon monoxide levels. SNP genotyping used Affymetrix 6.0 arrays. GWA results for smoking cessation success provided no P value that reached "genome-wide" significance. Compared with chance, these results do identify (a) more clustering of nominally positive results within small genomic regions, (b) more overlap between these genomic regions and those identified in six prior successful smoking cessation GWA studies and (c) sets of genes that fall into gene ontology categories that appear to be biologically relevant. The 1,000 SNPs with the strongest associations form a plausible Bayesian network; no such network is formed by randomly selected sets of SNPs. The data provide independent support, based on individual genotyping, for many loci previously nominated on the basis of data from genotyping in pooled DNA samples. These results provide further support for the idea that aid for smoking cessation may be personalized on the basis of genetic predictors of outcome. (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org C1 [Uhl, George R.; Drgon, Tomas; Johnson, Catherine] NIDA, Mol Neurobiol Branch, Natl Inst Hlth Intramural Res Program, NIH IRP, Baltimore, MD USA. [Ramoni, Marco F.] Harvard Massachusetts Inst Technol MIT, Childrens Hosp Informat Program, Div Hlth Sci & Technol, Boston, MA USA. [Behm, Frederique M.; Rose, Jed E.] Duke Univ, Dept Psychiat, Durham, NC 27706 USA. [Behm, Frederique M.; Rose, Jed E.] Duke Univ, Ctr Nicotine & Smoking Cessat Res, Durham, NC 27706 USA. RP Uhl, GR (reprint author), Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov; rose0003@mc.duke.edu FU National Institutes of Health (NIH), National Institute on Drug Abuse, Department of Health and Human Services; Philip Morris USA (Richmond, VA, USA) FX This study was supported by the National Institutes of Health (NIH)-Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services (GRU); a grant to Duke University (JE Rose, principal investigator) from Philip Morris USA (Richmond, VA, USA). The funders had no role in the planning or execution of the study, data analysis or publication of results. We are grateful for help from Joseph E. Herskovic, PhD, Eric C. Westman, MD, Qing-Rong Liu, PhD, and Donna Walther, MS. The underlying clinical trial was registered with clinicaltrials. gov (ID# NCT00734617). This study used BioBase (http: / /biobase-international. corn), installed on the Helix System at the Center for Information Technology (CIT), National Institutes of Health, Bethesda, Maryland (http:/ /helix.nih.gov). NR 31 TC 30 Z9 31 U1 1 U2 7 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD NOV-DEC PY 2010 VL 16 IS 11-12 BP 513 EP 526 DI 10.2119/molmed.2010.00052 PG 14 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 679TL UT WOS:000284183600008 PM 20811658 ER PT J AU Sharifi, N Qi, J Bane, S Sharma, S Li, R Robey, R Figg, WD Farrar, WL Kingston, DGI AF Sharifi, Nima Qi, Jun Bane, Susan Sharma, Shubhada Li, Rui Robey, Robert Figg, William D. Farrar, William L. Kingston, David G. I. TI Survivin Is Not Induced by Novel Taxanes SO MOLECULAR PHARMACEUTICS LA English DT Article DE Taxanes; chemotherapy; survivin; paclitaxel; prostate cancer; breast cancer; lung cancer ID BREAST-CANCER CELLS; PROSTATE-CANCER; LUNG-CANCER; CHEMOTHERAPY; EXPRESSION; MITOXANTRONE; PREDNISONE; PACLITAXEL; DOCETAXEL; APOPTOSIS AB Taxanes are a critical component of chemotherapy for breast, prostate, lung and other cancers. Initial or acquired tumor resistance to taxanes is therefore one of the most important issues in oncology. Survivin is a prosurvival gene whose expression is a poor prognostic feature. Survivin is induced acutely upon exposure to taxanes and coordinates resistance to taxane-mediated cell death, although the exact mechanism of taxane-mediated survivin induction is not clear. Here, we describe the synthesis of a series of novel taxanes, with modifications on the 7- or 10-position of the taxane backbone, as well as the side chain. We found that the novel taxanes with modifications at the 10-position have robust tubulin binding and tubulin polymerization activity. Gene expression profiling and quantitative PCR of cells treated with the 10-position conjugates reveals that the effect of treatment with a subset of these novel taxanes lacks a gene expression signature, including survivin induction, which is characteristically induced with paclitaxel treatment. Furthermore, we show that this gene expression signature is not due to differences in G2/M arrest. Cell sensitivity studies suggest that the inability to induce survivin is associated with increased drug cytotoxicity and apoptosis. This work suggests that taxanes that effectively bind tubulin need not invariably induce survivin as a mechanism of drug resistance. C1 [Sharifi, Nima; Li, Rui] Univ Texas SW Med Ctr Dallas, Div Hematol Oncol, Dallas, TX 75390 USA. [Qi, Jun; Kingston, David G. I.] Virginia Polytech Inst & State Univ, Dept Chem, Blacksburg, VA 24061 USA. [Bane, Susan; Sharma, Shubhada] SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. [Robey, Robert; Figg, William D.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Farrar, William L.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. RP Sharifi, N (reprint author), Univ Texas SW Med Ctr Dallas, Div Hematol & Oncol, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM nima.sharifi@utsouthwestern.edu RI Bane, Susan/C-1414-2013; Figg Sr, William/M-2411-2016; OI Bane, Susan/0000-0002-4270-6314; Kingston, David/0000-0001-8944-246X FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; U.S. Army Medical Research and Materiel Command [PC050292]; Howard Hughes Medical Institute; Prostate Cancer Foundation FX This publication was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-CO-12400, with funds from Grant No. PC050292 from the U.S. Army Medical Research and Materiel Command, a Howard Hughes Medical Institute Physician-Scientist Early Career Award, and with a Prostate Cancer Foundation Young Investigator Award. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 23 TC 4 Z9 4 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV-DEC PY 2010 VL 7 IS 6 BP 2216 EP 2223 DI 10.1021/mp100211k PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 688QG UT WOS:000284865900032 PM 20863081 ER PT J AU Arcos-Burgos, M Jain, M Acosta, MT Shively, S Stanescu, H Wallis, D Domene, S Velez, JI Karkera, JD Balog, J Berg, K Kleta, R Gahl, WA Roessler, E Long, R Lie, J Pineda, D Londono, AC Palacio, JD Arbelaez, A Lopera, F Elia, J Hakonarson, H Johansson, S Knappskog, PM Haavik, J Ribases, M Cormand, B Bayes, M Casas, M Ramos-Quiroga, JA Hervas, A Maher, BS Faraone, SV Seitz, C Freitag, CM Palmason, H Meyer, J Romanos, M Walitza, S Hemminger, U Warnke, A Romanos, J Renner, T Jacob, C Lesch, KP Swanson, J Vortmeyer, A Bailey-Wilson, JE Castellanos, FX Muenke, M AF Arcos-Burgos, M. Jain, M. Acosta, M. T. Shively, S. Stanescu, H. Wallis, D. Domene, S. Velez, J. I. Karkera, J. D. Balog, J. Berg, K. Kleta, R. Gahl, W. A. Roessler, E. Long, R. Lie, J. Pineda, D. Londono, A. C. Palacio, J. D. Arbelaez, A. Lopera, F. Elia, J. Hakonarson, H. Johansson, S. Knappskog, P. M. Haavik, J. Ribases, M. Cormand, B. Bayes, M. Casas, M. Ramos-Quiroga, J. A. Hervas, A. Maher, B. S. Faraone, S. V. Seitz, C. Freitag, C. M. Palmason, H. Meyer, J. Romanos, M. Walitza, S. Hemminger, U. Warnke, A. Romanos, J. Renner, T. Jacob, C. Lesch, K-P Swanson, J. Vortmeyer, A. Bailey-Wilson, J. E. Castellanos, F. X. Muenke, M. TI A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication SO MOLECULAR PSYCHIATRY LA English DT Article DE ADHD; complex trait; gene; LPHN3; genetics; latrophilin ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; GENOME-WIDE ASSOCIATION; H-1-MAGNETIC RESONANCE SPECTROSCOPY; ALPHA-LATROTOXIN RECEPTOR; LINKAGE DISEQUILIBRIUM; FOLLOW-UP; CHILDREN; RISK; POLYMORPHISM AB Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD. Molecular Psychiatry (2010) 15, 1053-1066; doi:10.1038/mp.2010.6; published online 16 February 2010 C1 [Arcos-Burgos, M.; Jain, M.; Acosta, M. T.; Shively, S.; Stanescu, H.; Wallis, D.; Domene, S.; Velez, J. I.; Karkera, J. D.; Balog, J.; Berg, K.; Kleta, R.; Gahl, W. A.; Roessler, E.; Long, R.; Bailey-Wilson, J. E.; Muenke, M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Shively, S.; Lie, J.; Vortmeyer, A.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Pineda, D.; Londono, A. C.; Palacio, J. D.; Arbelaez, A.; Lopera, F.] Univ Antioquia, Neurosci Grp, Medellin, Colombia. [Elia, J.; Hakonarson, H.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Johansson, S.; Knappskog, P. M.; Haavik, J.] Univ Bergen, Dept Biomed, Sect Biochem & Mol Biol, Bergen, Norway. [Ribases, M.; Casas, M.; Ramos-Quiroga, J. A.] Hosp Univ Vall dHebron, Dept Psychiat, Barcelona, Catalonia, Spain. [Cormand, B.] Univ Barcelona, Fac Biol, Dept Genet, CIBER ER,IBUB, Barcelona, Catalonia, Spain. [Bayes, M.] Ctr Nacl Genotipado CeGen, Genes & Dis Program, CRG, CIBER ESP, Barcelona, Catalonia, Spain. [Casas, M.; Ramos-Quiroga, J. A.] Univ Autonoma Barcelona, Dept Psychiat & Legal Med, Catalonia, Spain. [Hervas, A.] Hosp Mutua de Terrassa, Child & Adolescent Mental Hlth Unit, Barcelona, Catalonia, Spain. [Maher, B. S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Maher, B. S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Human Genet, Richmond, VA USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Seitz, C.; Freitag, C. M.] Saarland Univ Hosp, Dept Child & Adolescent Psychiat, Homburg, Saar, Germany. [Palmason, H.; Meyer, J.] Univ Trier, Grad Sch Psychobiol, Div Neurobehav Genet, Trier, Germany. [Romanos, M.; Walitza, S.; Hemminger, U.; Warnke, A.; Renner, T.; Lesch, K-P] Univ Wurzburg, Dept Child & Adolescent Psychiat & Psychotherapy, Wurzburg, Germany. [Romanos, J.; Renner, T.; Jacob, C.; Lesch, K-P] Univ Wurzburg, Dept Psychiat & Psychotherapy, Wurzburg, Germany. [Renner, T.; Lesch, K-P] Univ Wurzburg, Dept Mol & Psychobiol, Wurzburg, Germany. [Swanson, J.] Univ Calif Irvine, UCI Child Dev Ctr, Irvine, CA USA. [Castellanos, F. X.] NYU, Ctr Child Study, New York, NY USA. RP Muenke, M (reprint author), NHGRI, NIH, 35 Convent Dr,Bldg 35,Room 1B203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov RI Renner, Tobias/I-2120-2013; Maher, Brion/F-9185-2010; Johansson, Stefan/C-4394-2011; Cormand, Bru/H-5338-2015; Lesch, Klaus-Peter/J-4906-2013; Romanos, Marcel/D-7695-2017; OI Haavik, Jan/0000-0001-7865-2808; Ramos-Quiroga, Josep Antoni/0000-0003-1622-0350; Ribases, Marta/0000-0003-1039-1116; Castellanos, Francisco/0000-0001-9192-9437; Faraone, Stephen/0000-0002-9217-3982; Johansson, Stefan/0000-0002-2298-7008; Cormand, Bru/0000-0001-5318-4382; Lesch, Klaus-Peter/0000-0001-8348-153X; Bailey-Wilson, Joan/0000-0002-9153-2920; Walitza, Susanne/0000-0002-8161-8683 FU Division of Intramural Research, NHGRI, NIH; COLCIENCIAS [1115-04-12010, 11150418083]; Deutsche Forschungsgemeinschaft [KFO 125/1-1, SFB 581]; 'Ministerio de Sanidad y Politica Social', Spain; Instituto de Salud Carlos III-FIS [PI041267, PI042010, PI040524, PI080519]; Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR [2009GR971] FX We are grateful to the families who participated in this research. This research was supported by the Division of Intramural Research, NHGRI, NIH and in part by COLCIENCIAS, Grants 1115-04-12010, 11150418083, and by the Deutsche Forschungsgemeinschaft (KFO 125/1-1, SFB 581). This study used the high-performance computational capabilities of the SGI Origin 2000 system at the Center for Information Technology, National Institutes of Health, Bethesda, MD and the services of the NHGRI Genomics Core under the supervision of Marypat S Jones and Chandra Settara. Darryl Leja provided graphical assistance to the figures. N Steigerwald provided technical assistance in the DNA German sample processing. Mahim Jain, Sharon B Shively and Sabina Domene are doctoral students in the NIH Graduate Partnerships Program, at Oxford University, George Washington University and the University of Buenos Aires, respectively. Some of this work is to be presented to the above programs in partial fulfillment of the requirements for the PhD degree. Authors from Spain are grateful to Anna Bielsa, Xavier Gastaminza, Rosa Bosch, Monica Fernandez Anguiano and Silvia Rodriguez-Ben for their participation in the clinical assessment and to Cristina Sanchez-Mora for laboratory assistance. MR is a recipient of a Miguel de Servet contract from the 'Ministerio de Sanidad y Politica Social', Spain. Financial support was received from 'Instituto de Salud Carlos III-FIS' (PI041267, PI042010, PI040524, PI080519) and 'Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR' (2009GR971). SNP genotyping of the Spanish samples was performed at the Barcelona node of the 'Centro Nacional de Genotipado' (CEGEN; www.cegen.org). NR 59 TC 96 Z9 98 U1 8 U2 14 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 NOV PY 2010 VL 15 IS 11 BP 1053 EP 1066 DI 10.1038/mp.2010.6 PG 14 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 669LP UT WOS:000283352400002 PM 20157310 ER PT J AU Nierenberg, AA Akiskal, HS Angst, J Hirschfeld, RM Merikangas, KR Petukhova, M Kessler, RC AF Nierenberg, A. A. Akiskal, H. S. Angst, J. Hirschfeld, R. M. Merikangas, K. R. Petukhova, M. Kessler, R. C. TI Bipolar disorder with frequent mood episodes in the national comorbidity survey replication (NCS-R) SO MOLECULAR PSYCHIATRY LA English DT Article DE bipolar disorder; rapid-cycling bipolar disorder; mania; hypomania; national comorbidity survey replication (NCS-R); comorbidity; treatment ID TREATMENT ENHANCEMENT PROGRAM; WORLD-HEALTH-ORGANIZATION; WEEKLY SYMPTOMATIC STATUS; DSM-IV; NATURAL-HISTORY; RATING-SCALE; VALIDITY; VERSION; PREVALENCE; DISABILITY AB Virtually nothing is known about the epidemiology of rapid cycling bipolar disorder (BPD) in community samples. Nationally representative data are reported here for the prevalence and correlates of a surrogate measure of DSM-IV rapid cycling BPD from the National Comorbidity survey Replication (NCS-R), a national survey of the US household population. DSM-IV disorders were assessed in the NCS-R with the WHO Composite International Diagnostic Interview (CIDI). Although the CIDI did not assess rapid cycling, it did assess the broader category of 12-month BPD with frequent mood episodes (FMEs), having at least four episodes of mania/hypomania or major depression in the 12 months before interview. Roughly one-third of NCS-R respondents with lifetime DSM-IV BPD and half with 12-month BPD met criteria for FME. FME was associated with younger age-of-onset (of BP-I, but not BP-II) and higher annual persistence (73% of the years since first onset of illness with an episode) than non-FME BPD. No substantial associations of FME vs non-FME BPD were found with socio-demographics, childhood risk factors (parental mental disorders, other childhood adversities) or comorbid DSM-IV disorders. However, FME manic episodes had greater clinical severity than non-FME episodes (assessed with a fully structured version of the Young Mania Rating Scale) and FME hypomanic episodes had greater role impairment than non-FME episodes (assessed with the Sheehan Disability Scales). Whether these indicators of severity merely reflect attenuated effects of rapid cycling or independent effects of sub-threshold rapid cycling warrants further study given the high proportion of lifetime cases who met criteria for FME. Molecular Psychiatry (2010) 15, 1075-1087; doi:10.1038/mp.2009.61; published online 30 June 2009 C1 [Petukhova, M.; Kessler, R. C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Nierenberg, A. A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Akiskal, H. S.] Univ Calif San Diego, Int Mood Ctr, San Diego, CA 92103 USA. [Akiskal, H. S.] VA Psychiat Serv, San Diego, CA USA. [Angst, J.] Univ Zurich, Hosp Psychiat, Zurich, Switzerland. [Hirschfeld, R. M.] Univ Texas Med Branch, Dept Psychiat & Behav Sci, Galveston, TX USA. [Merikangas, K. R.] NIMH, Intramural Res Program, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu FU National Institute of Mental Health (NIMH) [U01-MH60220]; National Institute of Drug Abuse, the Substance Abuse and Mental Health Services Administration; Robert Wood Johnson Foundation [044780]; John W Alden Trust; John D and Catherine T MacArthur Foundation; Pfizer Foundation; US Public Health Service [R13 MH066849, R01 MH069864, R01 DA016558]; Eli Lilly and Company; Glaxo-SmithKline; Ortho-McNeil Pharmaceutical, Inc; Pan American Health Organization FX The National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse, the Substance Abuse and Mental Health Services Administration, the Robert Wood Johnson Foundation (Grant #044780) and the John W Alden Trust. Additional support for preparation of this paper was provided by Ortho-McNeil Janssen Scientific Affairs, LLC. Collaborating NCS-R investigators include Ronald C Kessler (Principal Investigator, Harvard Medical School), Kathleen Merikangas (Co-Principal Investigator, NIMH), James Anthony (Michigan State University), William Eaton (The Johns Hopkins University), Meyer Glantz (NIDA), Doreen Koretz (Harvard University), Jane McLeod (Indiana University), Mark Olfson (Columbia University College of Physicians and Surgeons), Harold Pincus (University of Pittsburgh), Greg Simon (Group Health Cooperative), T Bedirhan Ustun (World Health Organization), Michael Von Korff (Group Health Cooperative), Philip Wang (Harvard Medical School), Kenneth Wells (UCLA), Elaine Wethington (Cornell University) and Hans-Ulrich Wittchen (Max Planck Institute of Psychiatry). The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies or US Government. A complete list of NCS publications and the full text of all NCS-R instruments can be found at http://www.hcp.med.harvard.edu/ncs. Send correspondence to NCS@hcp.med.harvard.edu. The NCS-R is carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centers for assistance with instrumentation, fieldwork and consultation on data analysis. These activities were supported by the John D and Catherine T MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13 MH066849, R01 MH069864, and R01 DA016558), Eli Lilly and Company, Glaxo-SmithKline, Ortho-McNeil Pharmaceutical, Inc. and the Pan American Health Organization. A complete list of WMH publications and instruments can be found at (http://www.hcp.med.harvard.edu/wmhcidi). The views expressed in this article do not necessarily represent the view of the NIMH, NIH or HHS of the US Government. NR 41 TC 12 Z9 12 U1 2 U2 5 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 NOV PY 2010 VL 15 IS 11 BP 1075 EP 1087 DI 10.1038/mp.2009.61 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 669LP UT WOS:000283352400004 PM 19564874 ER PT J AU Sul, J Fine, HA AF Sul, Joohee Fine, Howard A. TI Malignant Gliomas: New Translational Therapies SO MOUNT SINAI JOURNAL OF MEDICINE LA English DT Article DE angiogenesis; epigenencs; glioblastoma; glioma stem cells; immunotherapy; malignant glioma; molecular profiles; signal transduction pathways; translational research; tyrosine kinase inhibitors ID PHASE-II TRIAL; HUMAN-BRAIN-TUMORS; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY; RECURRENT GLIOBLASTOMA-MULTIFORME; NEWLY-DIAGNOSED GLIOBLASTOMA; GROWTH-FACTOR-BETA; CANCER STEM-CELL; CD8(+) T-CELLS; DENDRITIC CELLS; IN-VIVO AB Malignant gliomas ale the most common primary brain tumors in adults and carry a dismal piognosis Despite aggressive therapy with maximal safe surgical resection, radiation and chemotherapy, these tumors invariably are refractory to or become resistant to treatment and recur Gliomas are highly infiltrative cancers and display remarkable genetic heterogeneity making them challenging to treat Recent progress has been made in understanding the molecular and genetic composition of these tumors and from this, promising new targets for therapy have emerged In particular, anti-angiogenesis therapies have led to modest success in disease control In addition, the growing body of research in cancer immunology as well as cancer stem cells has made inroads in our understanding of tumorgenesis Translational research has been particularly crucial to the development of these therapies as much preclinical and clinical work is needed to develop the rationale for treatments, to develop biomarkers of drug activity and to elucidate mechanisms of resistance This brief overview will discuss some of the pivotal advances made in the pursuit of improved outcomes and survival for patients with this devastating disease Mt Sinai J Med 77 655-666, 2010 (C) 2010 Mount Sinai School of Medicine C1 [Sul, Joohee; Fine, Howard A.] NINDS, Neurooncol Branch, NCI, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NINDS, Neurooncol Branch, NCI, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 95 TC 12 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0027-2507 EI 1931-7581 J9 MT SINAI J MED JI Mt. Sinai J. Med. PD NOV-DEC PY 2010 VL 77 IS 6 BP 655 EP 666 DI 10.1002/msj.20223 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 691KY UT WOS:000285079900008 PM 21105127 ER PT J AU Dai, H Navath, RS Balakrishnan, B Guru, BR Mishra, MK Romero, R Kannan, RM Kannan, S AF Dai, Hui Navath, Raghavendra S. Balakrishnan, Bindu Guru, Bharath Raja Mishra, Manoj K. Romero, Roberto Kannan, Rangaramanujam M. Kannan, Sujatha TI Intrinsic targeting of inflammatory cells in the brain by polyamidoamine dendrimers upon subarachnoid administration SO NANOMEDICINE LA English DT Article DE cerebral palsy; microglia-targeted drug delivery to the brain neuroinflammation; PAMAM dendrimers ID CENTRAL-NERVOUS-SYSTEM; MICROGLIAL CELLS; RAT-BRAIN; IN-VIVO; SCAVENGER RECEPTOR; DELIVERY; BIODISTRIBUTION; NANOPARTICLES; AGENTS; PHARMACOKINETICS AB Aim: Understanding the interactions between nanomaterials and disease processes is crucial for designing effective therapeutic approaches. This article explores the unusual neuroinflammation targeting of dendrimers (with no targeting ligands) in the brain, with significant consequences for nanoscale materials in medicine. Method: The in vivo biodistribution of fluorescent-labeled neutral generation-4-polyamidoamine dendrimers (similar to 4 nm) in a rabbit model of cerebral palsy was explored following subarachnoid administration. Results: These dendrimers, with no targeting ligands, were localizing in activated microglia and astrocytes (cells responsible for neuroinflammation), even in regions far moved from the site of injection, in newborn rabbits with maternal inflammation-induced cerebral palsy. Conclusion: This intrinsic ability of dendrimers to localize inactivated microglia and astrocytes can enable targeted delivery of therapeutics in disorders such as cerebral palsy, Alzheimer's and multiple sclerosis. C1 [Dai, Hui; Navath, Raghavendra S.; Guru, Bharath Raja; Romero, Roberto; Kannan, Rangaramanujam M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinotol Res Branch, NIH, Detroit, MI 48201 USA. [Dai, Hui; Navath, Raghavendra S.; Guru, Bharath Raja; Romero, Roberto; Kannan, Rangaramanujam M.] NICHD, NIH, DHHS, Detroit, MI 48201 USA. [Dai, Hui; Balakrishnan, Bindu; Kannan, Sujatha] Wayne State Univ, Childrens Hosp Michigan, Dept Pediat Crit Care Med, Detroit, MI 48201 USA. [Navath, Raghavendra S.; Mishra, Manoj K.; Kannan, Rangaramanujam M.] Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. RP Kannan, RM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinotol Res Branch, NIH, Detroit, MI 48201 USA. EM rkannan.wsu@gmail.com RI Guru, Bharath/G-8822-2015; Guru, Bharath/P-6333-2015 OI Guru, Bharath/0000-0003-2542-7740; Guru, Bharath/0000-0001-6735-2180 FU NICHD; NIH; Perinatology Research Branch, Eunice Kennedy Shriver NICHD; DHHS; Ralph C Wilson Medical Research Foundation; [IK08HD050652] FX This work is funded in part by IK08HD050652, NICHD, NIH and the Perinatology Research Branch, Eunice Kennedy Shriver NICHD, NIH, DHHS, and the Ralph C Wilson Medical Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 46 TC 42 Z9 42 U1 1 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD NOV PY 2010 VL 5 IS 9 BP 1317 EP 1329 DI 10.2217/NNM.10.89 PG 13 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 705KR UT WOS:000286127800007 PM 21128716 ER PT J AU Oberdoerffer, P AF Oberdoerffer, Philipp TI An age of fewer histones SO NATURE CELL BIOLOGY LA English DT Editorial Material ID GENE-EXPRESSION; LIFE-SPAN; HUMAN-CELLS; ACETYLATION; SENESCENCE; TELOMERES C1 NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Oberdoerffer, P (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. EM oberdoerfferp@mail.nih.gov NR 16 TC 4 Z9 4 U1 0 U2 4 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 NOV PY 2010 VL 12 IS 11 BP 1029 EP 1031 DI 10.1038/ncb1110-1029 PG 3 WC Cell Biology SC Cell Biology GA 674CO UT WOS:000283711500004 PM 21045802 ER PT J AU Hummer, G AF Hummer, Gerhard TI MOLECULAR BINDING Under water's influence SO NATURE CHEMISTRY LA English DT News Item ID LIGAND-BINDING; CAVITY; SITE C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS [ZIA DK029036-04] NR 9 TC 62 Z9 62 U1 3 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1755-4330 J9 NAT CHEM JI Nat. Chem. PD NOV PY 2010 VL 2 IS 11 BP 906 EP 907 DI 10.1038/nchem.885 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 669MG UT WOS:000283354300003 PM 20966940 ER PT J AU Ryazanova, LV Rondon, LJ Zierler, S Hu, ZX Galli, J Yamaguchi, TP Mazur, A Fleig, A Ryazanov, AG AF Ryazanova, Lillia V. Rondon, Lusliany J. Zierler, Susanna Hu, Zhixian Galli, Joanna Yamaguchi, Terry P. Mazur, Andrzej Fleig, Andrea Ryazanov, Alexey G. TI TRPM7 is essential for Mg2+ homeostasis in mammals SO NATURE COMMUNICATIONS LA English DT Article ID SECONDARY HYPOCALCEMIA; ION-CHANNEL; PROTEIN-KINASES; ALPHA-KINASES; MAGNESIUM; HYPOMAGNESEMIA; MUTATION; DOMAIN; CELL; CURRENTS AB Mg2+ is the second-most abundant cation in animal cells and is an essential cofactor in numerous enzymatic reactions. The molecular mechanisms controlling Mg2+ balance in the organism are not well understood. In this study, we report identification of TRPM7, a bifunctional protein containing a protein kinase fused to an ion channel, as a key regulator of whole body Mg2+ homeostasis in mammals. We generated TRPM7-deficient mice with the deletion of the kinase domain. Homozygous TRPM7(Delta kinase) mice demonstrated early embryonic lethality, whereas heterozygous mice were viable, but developed signs of hypomagnesaemia and revealed a defect in intestinal Mg2+ absorption. Cells derived from heterozygous TRPM7(Delta kinase) mice demonstrated reduced TRPM7 currents that had increased sensitivity to the inhibition by Mg2+. Embryonic stem cells lacking TRPM7 kinase domain displayed a proliferation arrest phenotype that can be rescued by Mg2+ supplementation. Our results demonstrate that TRPM7 is essential for the control of cellular and whole body Mg2+ homeostasis. C1 [Ryazanova, Lillia V.; Hu, Zhixian; Ryazanov, Alexey G.] Univ Med & Dent New Jersey, Dept Pharmacol, RW Johnson Med Sch, Piscataway, NJ 08854 USA. [Rondon, Lusliany J.; Galli, Joanna; Mazur, Andrzej] Univ Auvergne, UNH, INRA, UMR 1019,CRNH Auvergne, F-63000 Clermont Ferrand, France. [Rondon, Lusliany J.; Galli, Joanna; Mazur, Andrzej] Univ Auvergne, Clermont Univ, Unite Nutr Humaine, F-63000 Clermont Ferrand, France. [Zierler, Susanna; Fleig, Andrea] Univ Hawaii, Queens Ctr Biomed Res, Lab Cell & Mol Signaling, Queens Ctr Biomed Res, Honolulu, HI 96813 USA. [Zierler, Susanna; Fleig, Andrea] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96813 USA. [Galli, Joanna] Wroclaw Univ Environm & Life Sci, Fac Vet Med, PL-50375 Wroclaw, Poland. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH Frederick, Frederick, MD 21702 USA. RP Ryazanov, AG (reprint author), Univ Med & Dent New Jersey, Dept Pharmacol, RW Johnson Med Sch, 675 Hoes Lane, Piscataway, NJ 08854 USA. EM ryazanag@umdnj.edu RI Zierler, Susanna/E-2070-2012 OI Zierler, Susanna/0000-0002-4684-0385 FU NIH [P01GM078195]; Austrian Science Fund (F.W.F.) [J2784] FX We thank Stephanie Johne, Dominique Bayle, Jean-Claude Tressol, Catherine Besson and Severine Thien for technical support. We are grateful to Reinhold Penner for stimulating discussions, Maxim Dorovkov and Inna Nikonorova for their help and advice, and to Jonathan Eggenschwiler for critical reading of the manuscript. This study was supported by NIH Grant P01GM078195 (A. G. R., A. F.) and Austrian Science Fund (F.W.F.) Grant J2784 (S.Z.). NR 30 TC 99 Z9 102 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV PY 2010 VL 1 AR 109 DI 10.1038/ncomms1108 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 732YE UT WOS:000288224800007 PM 21045827 ER PT J AU Peterson, J Campbell, J AF Peterson, Jane Campbell, Joseph TI Marker papers and data citation SO NATURE GENETICS LA English DT Letter C1 [Peterson, Jane; Campbell, Joseph] NHGRI, NIH, Bethesda, MD 20892 USA. RP Peterson, J (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 1 U2 18 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 NOV PY 2010 VL 42 IS 11 BP 919 EP 919 DI 10.1038/ng1110-919 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 671VW UT WOS:000283540500003 PM 20980982 ER PT J AU Speliotes, EK Willer, CJ Berndt, SI Monda, KL Thorleifsson, G Jackson, AU Allen, HL Lindgren, CM Luan, J Magi, R Randall, JC Vedantam, S Winkler, TW Qi, L Workalemahu, T Heid, IM Steinthorsdottir, V Stringham, HM Weedon, MN Wheeler, E Wood, AR Ferreira, T Weyant, RJ Segre, AV Estrada, K Liang, LM Nemesh, J Park, JH Gustafsson, S Kilpelanen, TO Yang, JA Bouatia-Naji, N Esko, T Feitosa, MF Kutalik, Z Mangino, M Raychaudhuri, S Scherag, A Smith, AV Welch, R Zhao, JH Aben, KK Absher, DM Amin, N Dixon, AL Fisher, E Glazer, NL Goddard, ME Heard-Costa, NL Hoesel, V Hottenga, JJ Johansson, A Johnson, T Ketkar, S Lamina, C Li, SX Moffatt, MF Myers, RH Narisu, N Perry, JRB Peters, MJ Preuss, M Ripatti, S Rivadeneira, F Sandholt, C Scott, LJ Timpson, NJ Tyrer, JP van Wingerden, S Watanabe, RM White, CC Wiklund, F Barlassina, C Chasman, DI Cooper, MN Jansson, JO Lawrence, RW Pellikka, N Prokopenko, I Shi, JX Thiering, E Alavere, H Alibrandi, MTS Almgren, P Arnold, AM Aspelund, T Atwood, LD Balkau, B Balmforth, AJ Bennett, AJ Ben-Shlomo, Y Bergman, RN Bergmann, S Biebermann, H Blakemore, AIF Boes, T Bonnycastle, LL Bornstein, SR Brown, MJ Buchanan, TA Busonero, F Campbell, H Cappuccio, FP Cavalcanti-Proenca, C Chen, YDI Chen, CM Chines, PS Clarke, R Coin, L Connell, J Day, INM den Heijer, M Duan, JB Ebrahim, S Elliott, P Elosua, R Eiriksdottir, G Erdos, MR Eriksson, JG Facheris, MF Felix, SB Fischer-Posovszky, P Folsom, AR Friedrich, N Freimer, NB Fu, M Gaget, S Gejman, PV Geus, EJC Gieger, C Gjesing, AP Goel, A Goyette, P Grallert, H Grassler, J Greenawalt, DM Groves, CJ Gudnason, V Guiducci, C Hartikainen, AL Hassanali, N Hall, AS Havulinna, AS Hayward, C Heath, AC Hengstenberg, C Hicks, AA Hinney, A Hofman, A Homuth, G Hui, J Igl, W Iribarren, C Isomaa, B Jacobs, KB Jarick, I Jewell, E John, U Jorgensen, T Jousilahti, P Jula, A Kaakinen, M Kajantie, E Kaplan, LM Kathiresan, S Kettunen, J Kinnunen, L Knowles, JW Kolcic, I Konig, IR Koskinen, S Kovacs, P Kuusisto, J Kraft, P Kvaloy, K Laitinen, J Lantieri, O Lanzani, C Launer, LJ Lecoeur, C Lehtimaki, T Lettre, G Liu, JJ Lokki, ML Lorentzon, M Luben, RN Ludwig, B Manunta, P Marek, D Marre, M Martin, NG McArdle, WL McCarthy, A McKnight, B Meitinger, T Melander, O Meyre, D Midthjell, K Montgomery, GW Morken, MA Morris, AP Mulic, R Ngwa, JS Nelis, M Neville, MJ Nyholt, DR O'Donnell, CJ O'Rahilly, S Ong, KK Oostra, B Pare, G Parker, AN Perola, M Pichler, I Pietilainen, KH Platou, CGP Polasek, O Pouta, A Rafelt, S Raitakari, O Rayner, NW Ridderstrale, M Rief, W Ruokonen, A Robertson, NR Rzehak, P Salomaa, V Sanders, AR Sandhu, MS Sanna, S Saramies, J Savolainen, MJ Scherag, S Schipf, S Schreiber, S Schunkert, H Silander, K Sinisalo, J Siscovick, DS Smit, JH Soranzo, N Sovio, U Stephens, J Surakka, I Swift, AJ Tammesoo, ML Tardif, JC Teder-Laving, M Teslovich, TM Thompson, JR Thomson, B Tonjes, A Tuomi, T van Meurs, JBJ van Ommen, GJ Vatin, V Viikari, J Visvikis-Siest, S Vitart, V Vogel, CIG Voight, BF Waite, LL Wallaschofski, H Walters, GB Widen, E Wiegand, S Wild, SH Willemsen, G Witte, DR Witteman, JC Xu, JF Zhang, QY Zgaga, L Ziegler, A Zitting, P Beilby, JP Farooqi, IS Hebebrand, J Huikuri, HV James, AL Kahonen, M Levinson, DF Macciardi, F Nieminen, MS Ohlsson, C Palmer, LJ Ridker, PM Stumvoll, M Beckmann, JS Boeing, H Boerwinkle, E Boomsma, DI Caulfield, MJ Chanock, SJ Collins, FS Cupples, LA Smith, GD Erdmann, J Froguel, P Gronberg, H Gyllensten, U Hall, P Hansen, T Harris, TB Hattersley, AT Hayes, RB Heinrich, J Hu, FB Hveem, K Illig, T Jarvelin, MR Kaprio, J Karpe, F Khaw, KT Kiemeney, LA Krude, H Laakso, M Lawlor, DA Metspalu, A Munroe, PB Ouwehand, WH Pedersen, O Penninx, BW Peters, A Pramstaller, PP Quertermous, T Reinehr, T Rissanen, A Rudan, I Samani, NJ Schwarz, PEH Shuldiner, AR Spector, TD Tuomilehto, J Uda, M Uitterlinden, A Valle, TT Wabitsch, M Waeber, G Wareham, NJ Watkins, H Wilson, JF Wright, AF Zillikens, MC Chatterjee, N McCarroll, SA Purcell, S Schadt, EE Visscher, PM Assimes, TL Borecki, IB Deloukas, P Fox, CS Groop, LC Haritunians, T Hunter, DJ Kaplan, RC Mohlke, KL O'Connell, JR Peltonen, L Schlessinger, D Strachan, DP van Duijn, CM Wichmann, HE Frayling, TM Thorsteinsdottir, U Abecasis, GR Barroso, I Boehnke, M Stefansson, K North, KE McCarthy, MI Hirschhorn, JN Ingelsson, E Loos, RJF AF Speliotes, Elizabeth K. Willer, Cristen J. Berndt, Sonja I. Monda, Keri L. Thorleifsson, Gudmar Jackson, Anne U. Allen, Hana Lango Lindgren, Cecilia M. Luan, Jian'an Maegi, Reedik Randall, Joshua C. Vedantam, Sailaja Winkler, Thomas W. Qi, Lu Workalemahu, Tsegaselassie Heid, Iris M. Steinthorsdottir, Valgerdur Stringham, Heather M. Weedon, Michael N. Wheeler, Eleanor Wood, Andrew R. Ferreira, Teresa Weyant, Robert J. Segre, Ayellet V. Estrada, Karol Liang, Liming Nemesh, James Park, Ju-Hyun Gustafsson, Stefan Kilpelaenen, Tuomas O. Yang, Jian Bouatia-Naji, Nabila Esko, Tonu Feitosa, Mary F. Kutalik, Zoltan Mangino, Massimo Raychaudhuri, Soumya Scherag, Andre Smith, Albert Vernon Welch, Ryan Zhao, Jing Hua Aben, Katja K. Absher, Devin M. Amin, Najaf Dixon, Anna L. Fisher, Eva Glazer, Nicole L. Goddard, Michael E. Heard-Costa, Nancy L. Hoesel, Volker Hottenga, Jouke-Jan Johansson, Asa Johnson, Toby Ketkar, Shamika Lamina, Claudia Li, Shengxu Moffatt, Miriam F. Myers, Richard H. Narisu, Narisu Perry, John R. B. Peters, Marjolein J. Preuss, Michael Ripatti, Samuli Rivadeneira, Fernando Sandholt, Camilla Scott, Laura J. Timpson, Nicholas J. Tyrer, Jonathan P. van Wingerden, Sophie Watanabe, Richard M. White, Charles C. Wiklund, Fredrik Barlassina, Christina Chasman, Daniel I. Cooper, Matthew N. Jansson, John-Olov Lawrence, Robert W. Pellikka, Niina Prokopenko, Inga Shi, Jianxin Thiering, Elisabeth Alavere, Helene Alibrandi, Maria T. S. Almgren, Peter Arnold, Alice M. Aspelund, Thor Atwood, Larry D. Balkau, Beverley Balmforth, Anthony J. Bennett, Amanda J. Ben-Shlomo, Yoav Bergman, Richard N. Bergmann, Sven Biebermann, Heike Blakemore, Alexandra I. F. Boes, Tanja Bonnycastle, Lori L. Bornstein, Stefan R. Brown, Morris J. Buchanan, Thomas A. Busonero, Fabio Campbell, Harry Cappuccio, Francesco P. Cavalcanti-Proenca, Christine Chen, Yii-Der Ida Chen, Chih-Mei Chines, Peter S. Clarke, Robert Coin, Lachlan Connell, John Day, Ian N. M. den Heijer, Martin Duan, Jubao Ebrahim, Shah Elliott, Paul Elosua, Roberto Eiriksdottir, Gudny Erdos, Michael R. Eriksson, Johan G. Facheris, Maurizio F. Felix, Stephan B. Fischer-Posovszky, Pamela Folsom, Aaron R. Friedrich, Nele Freimer, Nelson B. Fu, Mao Gaget, Stefan Gejman, Pablo V. Geus, Eco J. C. Gieger, Christian Gjesing, Anette P. Goel, Anuj Goyette, Philippe Grallert, Harald Graessler, Juergen Greenawalt, Danielle M. Groves, Christopher J. Gudnason, Vilmundur Guiducci, Candace Hartikainen, Anna-Liisa Hassanali, Neelam Hall, Alistair S. Havulinna, Aki S. Hayward, Caroline Heath, Andrew C. Hengstenberg, Christian Hicks, Andrew A. Hinney, Anke Hofman, Albert Homuth, Georg Hui, Jennie Igl, Wilmar Iribarren, Carlos Isomaa, Bo Jacobs, Kevin B. Jarick, Ivonne Jewell, Elizabeth John, Ulrich Jorgensen, Torben Jousilahti, Pekka Jula, Antti Kaakinen, Marika Kajantie, Eero Kaplan, Lee M. Kathiresan, Sekar Kettunen, Johannes Kinnunen, Leena Knowles, Joshua W. Kolcic, Ivana Koenig, Inke R. Koskinen, Seppo Kovacs, Peter Kuusisto, Johanna Kraft, Peter Kvaloy, Kirsti Laitinen, Jaana Lantieri, Olivier Lanzani, Chiara Launer, Lenore J. Lecoeur, Cecile Lehtimaeki, Terho Lettre, Guillaume Liu, Jianjun Lokki, Marja-Liisa Lorentzon, Mattias Luben, Robert N. Ludwig, Barbara Manunta, Paolo Marek, Diana Marre, Michel Martin, Nicholas G. McArdle, Wendy L. McCarthy, Anne McKnight, Barbara Meitinger, Thomas Melander, Olle Meyre, David Midthjell, Kristian Montgomery, Grant W. Morken, Mario A. Morris, Andrew P. Mulic, Rosanda Ngwa, Julius S. Nelis, Mari Neville, Matt J. Nyholt, Dale R. O'Donnell, Christopher J. O'Rahilly, Stephen Ong, Ken K. Oostra, Ben Pare, Guillaume Parker, Alex N. Perola, Markus Pichler, Irene Pietilaeinen, Kirsi H. Platou, Carl G. P. Polasek, Ozren Pouta, Anneli Rafelt, Suzanne Raitakari, Olli Rayner, Nigel W. Ridderstrale, Martin Rief, Winfried Ruokonen, Aimo Robertson, Neil R. Rzehak, Peter Salomaa, Veikko Sanders, Alan R. Sandhu, Manjinder S. Sanna, Serena Saramies, Jouko Savolainen, Markku J. Scherag, Susann Schipf, Sabine Schreiber, Stefan Schunkert, Heribert Silander, Kaisa Sinisalo, Juha Siscovick, David S. Smit, Jan H. Soranzo, Nicole Sovio, Ulla Stephens, Jonathan Surakka, Ida Swift, Amy J. Tammesoo, Mari-Liis Tardif, Jean-Claude Teder-Laving, Maris Teslovich, Tanya M. Thompson, John R. Thomson, Brian Toenjes, Anke Tuomi, Tiinamaija van Meurs, Joyce B. J. van Ommen, Gert-Jan Vatin, Vincent Viikari, Jorma Visvikis-Siest, Sophie Vitart, Veronique Vogel, Carla I. G. Voight, Benjamin F. Waite, Lindsay L. Wallaschofski, Henri Walters, G. Bragi Widen, Elisabeth Wiegand, Susanna Wild, Sarah H. Willemsen, Gonneke Witte, Daniel R. Witteman, Jacqueline C. Xu, Jianfeng Zhang, Qunyuan Zgaga, Lina Ziegler, Andreas Zitting, Paavo Beilby, John P. Farooqi, I. Sadaf Hebebrand, Johannes Huikuri, Heikki V. James, Alan L. Kaehoenen, Mika Levinson, Douglas F. Macciardi, Fabio Nieminen, Markku S. Ohlsson, Claes Palmer, Lyle J. Ridker, Paul M. Stumvoll, Michael Beckmann, Jacques S. Boeing, Heiner Boerwinkle, Eric Boomsma, Dorret I. Caulfield, Mark J. Chanock, Stephen J. Collins, Francis S. Cupples, L. Adrienne Smith, George Davey Erdmann, Jeanette Froguel, Philippe Greonberg, Henrik Gyllensten, Ulf Hall, Per Hansen, Torben Harris, Tamara B. Hattersley, Andrew T. Hayes, Richard B. Heinrich, Joachim Hu, Frank B. Hveem, Kristian Illig, Thomas Jarvelin, Marjo-Riitta Kaprio, Jaakko Karpe, Fredrik Khaw, Kay-Tee Kiemeney, Lambertus A. Krude, Heiko Laakso, Markku Lawlor, Debbie A. Metspalu, Andres Munroe, Patricia B. Ouwehand, Willem H. Pedersen, Oluf Penninx, Brenda W. Peters, Annette Pramstaller, Peter P. Quertermous, Thomas Reinehr, Thomas Rissanen, Aila Rudan, Igor Samani, Nilesh J. Schwarz, Peter E. H. Shuldiner, Alan R. Spector, Timothy D. Tuomilehto, Jaakko Uda, Manuela Uitterlinden, Andre Valle, Timo T. Wabitsch, Martin Waeber, Gerard Wareham, Nicholas J. Watkins, Hugh Wilson, James F. Wright, Alan F. Zillikens, M. Carola Chatterjee, Nilanjan McCarroll, Steven A. Purcell, Shaun Schadt, Eric E. Visscher, Peter M. Assimes, Themistocles L. Borecki, Ingrid B. Deloukas, Panos Fox, Caroline S. Groop, Leif C. Haritunians, Talin Hunter, David J. Kaplan, Robert C. Mohlke, Karen L. O'Connell, Jeffrey R. Peltonen, Leena Schlessinger, David Strachan, David P. van Duijn, Cornelia M. Wichmann, H-Erich Frayling, Timothy M. Thorsteinsdottir, Unnur Abecasis, Goncalo R. Barroso, Ines Boehnke, Michael Stefansson, Kari North, Kari E. McCarthy, Mark I. Hirschhorn, Joel N. Ingelsson, Erik Loos, Ruth J. F. CA MAGIC TI Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GASTRIC-INHIBITORY POLYPEPTIDE; MELANOCORTIN-4 RECEPTOR GENE; GLUCOSE-HOMEOSTASIS; COMMON VARIANTS; ADULT OBESITY; EARLY-ONSET; FTO GENE; FAT MASS; RISK AB Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. C1 [Brown, Morris J.] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge, England. [Speliotes, Elizabeth K.; Vedantam, Sailaja; Guiducci, Candace; Thomson, Brian; Hirschhorn, Joel N.] Broad Inst, Metab Initiat & Program Med & Populat Genet, Cambridge, MA USA. [Speliotes, Elizabeth K.; Kaplan, Lee M.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Willer, Cristen J.; Jackson, Anne U.; Stringham, Heather M.; Weyant, Robert J.; Welch, Ryan; Scott, Laura J.; Jewell, Elizabeth; Teslovich, Tanya M.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. 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[Lindgren, Cecilia M.; Prokopenko, Inga; Bennett, Amanda J.; Groves, Christopher J.; Hassanali, Neelam; Neville, Matt J.; Rayner, Nigel W.; Robertson, Neil R.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Luan, Jian'an; Kilpelaenen, Tuomas O.; Zhao, Jing Hua; Ong, Ken K.; Sandhu, Manjinder S.; Wareham, Nicholas J.; Loos, Ruth J. F.] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Vedantam, Sailaja; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Vedantam, Sailaja; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Vedantam, Sailaja; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Winkler, Thomas W.; Heid, Iris M.] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Qi, Lu; Workalemahu, Tsegaselassie; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. 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[Nemesh, James; Raychaudhuri, Soumya; Kathiresan, Sekar] MIT, Cambridge, MA 02139 USA. [Segre, Ayellet V.; Voight, Benjamin F.; McCarroll, Steven A.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Estrada, Karol; Amin, Najaf; Rivadeneira, Fernando; van Wingerden, Sophie; Hofman, Albert; van Meurs, Joyce B. J.; Witteman, Jacqueline C.; Uitterlinden, Andre; van Duijn, Cornelia M.] Erasmus Med Ctr MC, Dept Epidemiol, Rotterdam, Netherlands. [Estrada, Karol; Peters, Marjolein J.; Rivadeneira, Fernando; van Meurs, Joyce B. J.; Uitterlinden, Andre; Zillikens, M. Carola] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Estrada, Karol; Peters, Marjolein J.; Rivadeneira, Fernando; Hofman, Albert; van Meurs, Joyce B. J.; Witteman, Jacqueline C.; Uitterlinden, Andre; Zillikens, M. Carola; van Duijn, Cornelia M.] Netherlands Consortium Healthy Aging NCHA, Netherlands Genom Initiat NGI Sponsored, Rotterdam, Netherlands. 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[Goddard, Michael E.] Univ Melbourne, Parkville, Vic 3052, Australia. [Goddard, Michael E.] Dept Primary Ind, Melbourne, Australia. [Heard-Costa, Nancy L.; Atwood, Larry D.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Hoesel, Volker] Tech Univ Munich, Chair Biomath, D-8046 Garching, Germany. [Hottenga, Jouke-Jan; Geus, Eco J. C.; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ VU Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Johansson, Asa; Igl, Wilmar; Gyllensten, Ulf] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, Uppsala, Sweden. [Johansson, Asa] Norwegian Univ Sci & Technol NTNU, Fac Med, Dept Canc Res & Mol Med, Trondheim, Norway. [Johnson, Toby] Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Johnson, Toby; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Genome Ctr, London, England. [Johnson, Toby; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Lamina, Claudia] Innsbruck Med Univ3, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria. [Moffatt, Miriam F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Narisu, Narisu; Bonnycastle, Lori L.; Chines, Peter S.; Erdos, Michael R.; Morken, Mario A.; Swift, Amy J.; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Preuss, Michael; Koenig, Inke R.; Ziegler, Andreas] Univ Klinikum Schleswig Holstein, Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Ripatti, Samuli; Pellikka, Niina; Kettunen, Johannes; Perola, Markus; Silander, Kaisa; Surakka, Ida; Widen, Elisabeth; Kaprio, Jaakko; Peltonen, Leena] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Ripatti, Samuli; Pellikka, Niina; Kettunen, Johannes; Perola, Markus; Silander, Kaisa; Surakka, Ida; Peltonen, Leena] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Unit Publ Hlth Genom, Helsinki, Finland. [Sandholt, Camilla; Gjesing, Anette P.; Hansen, Torben; Pedersen, Oluf] Hagedorn Res Inst, Gentofte, Denmark. [Timpson, Nicholas J.; Day, Ian N. M.; Smith, George Davey; Lawlor, Debbie A.] MRC Ctr Causal Anal Translat Epidemiol, Dept Social Med, Bristol, Avon, England. [Tyrer, Jonathan P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Watanabe, Richard M.; Bergman, Richard N.; Buchanan, Thomas A.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [White, Charles C.; Ngwa, Julius S.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Barlassina, Christina; Macciardi, Fabio] Univ Milan, Dept Med Surg & Dent, Milan, Italy. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Cooper, Matthew N.; Lawrence, Robert W.; Hui, Jennie; Palmer, Lyle J.] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Crawley, WA, Australia. [Jansson, John-Olov] Univ Gothenburg, Dept Physiol, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden. [Alibrandi, Maria T. S.; Lanzani, Chiara; Manunta, Paolo] Univ Vita Salute San Raffaele, Div Nephrol & Dialysis, Milan, Italy. [Almgren, Peter; Groop, Leif C.] Lund Univ, Dept Clin Sci, Ctr Diabet, Malmo, Sweden. [Arnold, Alice M.; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Arnold, Alice M.] Collaborat Hlth Studies Coordinating Ctr, Seattle, WA USA. [Balkau, Beverley] Ctr Res Epidemiol & Publ Hlth, INSERM, Ctr Rech Epidimiol & Sante Populat CESP, U1018, Villejuif, France. [Balkau, Beverley] Univ Paris 11, UMRS 1018, Villejuif, France. [Balmforth, Anthony J.; Hall, Alistair S.] Univ Leeds, LIGHT, MCRC, Leeds, W Yorkshire, England. [Ben-Shlomo, Yoav] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Biebermann, Heike; Wiegand, Susanna; Krude, Heiko] Charite, Inst Expt Paediat Endocrinol, D-13353 Berlin, Germany. [Blakemore, Alexandra I. F.; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Bornstein, Stefan R.; Ludwig, Barbara] Univ Dresden, Dept Med 3, Dresden, Germany. [Buchanan, Thomas A.] Univ So Calif, Keck Sch Med, Div Endocrinol, Los Angeles, CA 90033 USA. [Busonero, Fabio; Sanna, Serena; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Campbell, Harry; Wild, Sarah H.; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Cappuccio, Francesco P.] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Chen, Yii-Der Ida; Haritunians, Talin] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Clarke, Robert] Radcliffe Infirm, Clin Trial Serv Unit, Oxford OX2 6HE, England. [Coin, Lachlan; Elliott, Paul; Sovio, Ulla; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Fac Med, Dept Epidemiol & Biostat, London, England. [Connell, John] Univ Dundee, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland. [den Heijer, Martin; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6525 ED Nijmegen, Netherlands. [den Heijer, Martin] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. [Duan, Jubao; Gejman, Pablo V.; Sanders, Alan R.] Northshore Univ Healthsyst, Evanston, IL USA. [Ebrahim, Shah] London Sch Hyg & Trop Med, London WC1, England. [Ebrahim, Shah] S Asia Network Chron Dis, New Delhi, India. [Elliott, Paul] Ctr Environm & Hlth, MRC Hlth Protect Agcy HPA, London, England. [Elosua, Roberto] Ctr Invest Biomed Red CIBER Epidemiol & Salud Pub, Barcelona, Spain. [Elosua, Roberto] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Isomaa, Bo; Tuomi, Tiinamaija] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Facheris, Maurizio F.; Hicks, Andrew A.; Pichler, Irene; Pramstaller, Peter P.] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy. [Facheris, Maurizio F.; Hicks, Andrew A.; Pichler, Irene; Pramstaller, Peter P.] Univ Lubeck, Lubeck, Germany. [Facheris, Maurizio F.; Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Felix, Stephan B.] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, Greifswald, Germany. [Fischer-Posovszky, Pamela; Wabitsch, Martin] Dept Pediat & Adolescent Med, Pediat Endocrinol Diabet & Obes Unit, Ulm, Germany. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Friedrich, Nele; Schipf, Sabine; Wallaschofski, Henri] Ernst Moritz Arndt Univ Greifswald, Inst Klin Chem & Lab Med, Greifswald, Germany. [Freimer, Nelson B.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. [Fu, Mao; Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Goel, Anuj; Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Goyette, Philippe; Lettre, Guillaume; Tardif, Jean-Claude] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Graessler, Juergen] Univ Dresden, Dept Med 3, Dresden, Germany. [Greenawalt, Danielle M.] Merck & Co Inc, Merck Res Labs, Boston, MA USA. [Hartikainen, Anna-Liisa; Pouta, Anneli] Univ Oulu, Dept Clin Sci Obstet & Gynecol, Oulu, Finland. [Havulinna, Aki S.; Jousilahti, Pekka; Koskinen, Seppo; Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland. [Hayward, Caroline; Vitart, Veronique; Wright, Alan F.] Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Heath, Andrew C.] Washington Univ, Sch Med, Dept Psychiat & Midwest Alcoholism Res Ctr, St Louis, MO USA. [Hengstenberg, Christian] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Hengstenberg, Christian] Univ Regensburg, Med Ctr, Regensburg, Germany. [Hinney, Anke; Scherag, Susann; Vogel, Carla I. G.; Hebebrand, Johannes] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, Essen, Germany. [Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Hui, Jennie; Beilby, John P.; Stumvoll, Michael] PathWest Lab Western Australia, Dept Mol Genet, QEII Med Ctr, Nedlands, WA, Australia. [Hui, Jennie; Beilby, John P.; James, Alan L.; Palmer, Lyle J.] Sir Charles Gairdner Hosp, Busselton Populat Med Res Fdn Inc, Nedlands, WA 6009, Australia. [Iribarren, Carlos] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Iribarren, Carlos] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari, Finland. [Jacobs, Kevin B.] NCI, SAIC Frederick Inc, Core Genotyping Facil, Frederick, MD 21701 USA. [Jarick, Ivonne] Univ Marburg, Inst Med Biometry & Epidemiol, Marburg, Germany. [John, Ulrich] Ernst Moritz Arndt Univ Greifswald, Inst Epidemiol & Sozialmed, Greifswald, Germany. [Jorgensen, Torben] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Jula, Antti] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Populat Studies Unit, Turku, Finland. [Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Kajantie, Eero] Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, Helsinki, Finland. [Kajantie, Eero] Univ Helsinki, Hosp Dist Helsinki & Uusimaa HUS, Helsinki, Finland. [Kaplan, Lee M.] Massachusetts Gen Hosp, Massachusetts Gen Hosp MGH Weight Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Boston Univ, Framingham, MA USA. [Kathiresan, Sekar; O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kinnunen, Leena; Tuomilehto, Jaakko; Valle, Timo T.] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Knowles, Joshua W.; Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Kolcic, Ivana; Polasek, Ozren; Zgaga, Lina] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41000, Croatia. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Kvaloy, Kirsti; Midthjell, Kristian; Platou, Carl G. P.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway. [Laitinen, Jaana] Finnish Inst Occupat Hlth, Oulu, Finland. [Lantieri, Olivier] Inst Interreg Sante IRSA, La Riche, France. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol, NIH, Bethesda, MD 20892 USA. [Lehtimaeki, Terho] Univ Tampere, Dept Clin Chem, FIN-33101 Tampere, Finland. [Lehtimaeki, Terho] Tampere Univ Hosp, Tampere, Finland. [Lettre, Guillaume; Tardif, Jean-Claude] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Liu, Jianjun] Genome Inst Singapore, Singapore, Singapore. [Lokki, Marja-Liisa] Univ Helsinki, Transplantat Lab, Haartman Inst, Helsinki, Finland. [Lorentzon, Mattias; Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, Gothenburg, Sweden. [Luben, Robert N.; Sandhu, Manjinder S.; Khaw, Kay-Tee] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Marre, Michel] Bichat Claude Bernard Univ Hosp, AP HP, Dept Endocrinol Diabetol & Nutr, Paris, France. [Marre, Michel] Univ Nancy 1, Cardiovasc Genet Res Unit, Nancy, France. [Martin, Nicholas G.] Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4006, Australia. [McArdle, Wendy L.] Univ Bristol, Dept Social Med, Avon Longitudinal Study Parents & Children ALSPAC, Bristol, Avon, England. [McCarthy, Anne] Bord Taighde Slainte, Res Board, Div Hlth, Dublin, Ireland. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Meitinger, Thomas] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Human Genet, Neuherberg, Germany. [Melander, Olle; Ridderstrale, Martin] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Montgomery, Grant W.] Queensland Inst Med Res, Mol Epidemiol Lab, Brisbane, Qld 4006, Australia. [Mulic, Rosanda; Rudan, Igor] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia. [Nyholt, Dale R.] Queensland Inst Med Res, Neurogenet Lab, Brisbane, Qld 4006, Australia. [O'Donnell, Christopher J.] NHLBI, NIH, Framingham, MA USA. [O'Rahilly, Stephen; Farooqi, I. Sadaf] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England. [Oostra, Ben] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Pare, Guillaume] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Parker, Alex N.] Amgen Inc, Cambridge, MA USA. [Pietilaeinen, Kirsi H.; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Pietilaeinen, Kirsi H.; Rissanen, Aila] Univ Helsinki, Cent Hosp, Dept Psychiat, Obes Res Unit, Helsinki, Finland. [Platou, Carl G. P.] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Med, Levanger, Norway. [Polasek, Ozren] Gen Info Ltd, Zagreb, Croatia. [Pouta, Anneli; Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Oulu, Finland. [Rafelt, Suzanne; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol, FIN-20520 Turku, Finland. [Rief, Winfried] Univ Marburg, Marburg, Germany. [Ruokonen, Aimo] Univ Oulu, Dept Clin Sci & Clin Chem, Oulu, Finland. [Rzehak, Peter; Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Saramies, Jouko] S Karelia Cent Hosp, Lappeenranta, Finland. [Savolainen, Markku J.] Univ Oulu, Dept Clin Sci & Internal Med, Oulu, Finland. [Schipf, Sabine] Inst Community Med, Greifswald, Germany. [Schreiber, Stefan] Univ Kiel, Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, Kiel, Germany. [Schreiber, Stefan] Univ Kiel, Dept Internal Med 1, Kiel, Germany. [Schunkert, Heribert; Erdmann, Jeanette] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Sinisalo, Juha; Nieminen, Markku S.] Univ Helsinki, Cent Hosp, Cardiovasc Lab, Div Cardiol, Helsinki, Finland. [Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA USA. [Smit, Jan H.; Penninx, Brenda W.] Vrije Univ Amsterdam Med Ctr, Inst Extramuraal Geneeskundig Onderzoek EMGO Inst, Dept Psychiat, Amsterdam, Netherlands. [Stephens, Jonathan; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Stephens, Jonathan; Ouwehand, Willem H.] Natl Hlth Serv NHS Blood & Transplant, Cambridge Ctr, Cambridge, England. [Thompson, John R.; Samani, Nilesh J.] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc, Leicester, Leics, England. [Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, Leipzig, Germany. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Toenjes, Anke] Univ Leipzig, Coordinat Ctr Clin Trials, Leipzig, Germany. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Res Program Mol Med, Helsinki, Finland. [van Ommen, Gert-Jan] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [van Ommen, Gert-Jan] Leiden Univ, Med Ctr, Ctr Med Syst Biol, Leiden, Netherlands. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Viikari, Jorma] Turku Univ Hosp, FIN-20520 Turku, Finland. [Visvikis-Siest, Sophie] INSERM, Cardiovasc Genet team, CIC 9501, Nancy, France. [Witte, Daniel R.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Xu, Jianfeng] Wake Forest Univ, Ctr Human Genom, Winston Salem, NC 27109 USA. [Zitting, Paavo] Lapland Cent Hosp, Dept Physiatr, Rovaniemi, Finland. [Beilby, John P.] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia. [Huikuri, Heikki V.] Univ Oulu, Dept Internal Med, SF-90220 Oulu, Finland. [James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Kaehoenen, Mika] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kaehoenen, Mika] Tampere Univ Hosp, Tampere, Finland. 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[Pedersen, Oluf] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark. [Pedersen, Oluf] Univ Copenhagen, Inst Biomed Sci, Copenhagen, Denmark. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Reinehr, Thomas] Univ Witten Herdecke, Vest Hosp Children & Adolescents, Inst Paediat Nutr Med, Datteln, Germany. [Schwarz, Peter E. H.] Univ Dresden, Dept Med 3, Dresden, Germany. [Tuomilehto, Jaakko] Baltimore Vet Adm, Geriatr Res & Educ Clin Ctr, Med Ctr, Baltimore, MD USA. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Shuldiner, Alan R.; Waeber, Gerard] Univ Hosp, CHUV, Dept Internal Med, Lausanne, Switzerland. [Purcell, Shaun; Peltonen, Leena] MIT, Cambridge, MA 02139 USA. [Purcell, Shaun; Peltonen, Leena] Broad Inst Harvard, Cambridge, MA 02139 USA. [Purcell, Shaun] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Schadt, Eric E.] Pacific Biosci, Menlo Pk, CA USA. [Schadt, Eric E.] Sage Bionetworks, Seattle, WA USA. [Borecki, Ingrid B.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Peltonen, Leena] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Strachan, David P.] Univ London, Div Community Hlth Sci, London, England. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Barroso, Ines] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England. [North, Kari E.] Univ N Carolina, Sch Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Brown, MJ (reprint author), Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge, England. EM boehnke@umich.edu; kstefans@decode.is; kari_north@unc.edu; mark.mccarthy@drl.ox.ac.uk; joelh@broadinstitute.org; erik.ingelsson@ki.se; ruth.loos@mrc-epid.cam.ac.uk RI kinnunen, leena/B-7059-2012; Li, Shengxu/D-8915-2012; Spector, Tim/F-6533-2012; Ridderstrale, Martin/F-7678-2012; Kilpelainen, Tuomas/F-8569-2012; Lango Allen, Hana/G-9026-2012; Rudan, Igor/I-1467-2012; Johansson, Asa/G-5270-2011; Deloukas, Panos/B-2922-2013; Thiering, Elisabeth/B-3342-2013; Grallert, Harald/B-3424-2013; Nyholt, Dale/C-8384-2013; Colaus, PsyColaus/K-6607-2013; Lamina, Claudia/F-7608-2010; Kaplan, Robert/A-2526-2011; Hinney, Anke/D-6953-2011; Meyre, David/D-7315-2011; Beckmann, Jacques S /A-9772-2008; Peters, Annette/A-6117-2011; Abecasis, Goncalo/B-7840-2010; Polasek, Ozren/B-6002-2011; Schreiber, Stefan/B-6748-2008; Voight, Benjamin/F-1775-2011; Aspelund, Thor/F-4826-2011; Segre, Ayellet/E-9800-2010; Aspelund, Thor/C-5983-2008; Kiemeney, Lambertus/D-3357-2009; Visvikis-Siest, Sophie/H-2324-2014; Pramstaller, Peter/C-2357-2008; Cooper, Matthew/J-4420-2014; Palmer, Lyle/K-3196-2014; Witte, Daniel/C-1722-2008; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Ziegler, Andreas/G-4246-2012; Macciardi, Fabio/N-3768-2014; Aben, Katja/G-9686-2016; Yang, Jian/A-5852-2010; Smith, Albert/K-5150-2015; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; BOUATIA-NAJI, NABILA/D-5863-2013; Coin, Lachlan/A-9001-2014; Schwarz, Peter/B-5127-2013; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Davey Smith, George/A-7407-2013; Mulic, Rosanda/D-6914-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; OI kinnunen, leena/0000-0001-8739-4812; Lango Allen, Hana/0000-0002-7803-8688; Rudan, Igor/0000-0001-6993-6884; Johansson, Asa/0000-0002-2915-4498; Deloukas, Panos/0000-0001-9251-070X; Hinney, Anke/0000-0001-5659-0706; Beckmann, Jacques S /0000-0002-9741-1900; Polasek, Ozren/0000-0002-5765-1862; Schreiber, Stefan/0000-0003-2254-7771; Aspelund, Thor/0000-0002-7998-5433; Kiemeney, Lambertus/0000-0002-2368-1326; Visvikis-Siest, Sophie/0000-0001-8104-8425; Cooper, Matthew/0000-0003-1139-3682; Palmer, Lyle/0000-0002-1628-3055; Witte, Daniel/0000-0002-0769-2922; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Ziegler, Andreas/0000-0002-8386-5397; Macciardi, Fabio/0000-0003-0537-4266; Aben, Katja/0000-0002-0214-2147; Yang, Jian/0000-0003-2001-2474; Smith, Albert/0000-0003-1942-5845; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Coin, Lachlan/0000-0002-4300-455X; Schwarz, Peter/0000-0001-6317-7880; Davey Smith, George/0000-0002-1407-8314; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Thiering, Elisabeth/0000-0002-5429-9584; Soranzo, Nicole/0000-0003-1095-3852; Peters, Marjolein/0000-0003-3167-9063; Bouatia-Naji, Nabila/0000-0001-5424-2134; Willer, Cristen/0000-0001-5645-4966; Kaakinen, Marika/0000-0002-9228-0462; Pichler, Irene/0000-0001-8251-0757; Heard-Costa, Nancy/0000-0001-9730-0306; Goddard, Michael/0000-0001-9917-7946; Magi, Reedik/0000-0002-2964-6011; Marre, Michel/0000-0002-3071-1837; sanna, serena/0000-0002-3768-1749; Monsalve, Beatriz Elena/0000-0002-5994-866X; Johnson, Toby/0000-0002-5998-3270; Cappuccio, Francesco Paolo/0000-0002-7842-5493; Myers, Richard/0000-0002-8365-2674; Cupples, L. Adrienne/0000-0003-0273-7965; Brown, Matthew A/0000-0003-0538-8211; Abecasis, Goncalo/0000-0003-1509-1825; Esko, Tonu/0000-0003-1982-6569; Manunta, Paolo/0000-0003-3976-9696; Zgaga, Lina/0000-0003-4089-9703; Luben, Robert/0000-0002-5088-6343; Gieger, Christian/0000-0001-6986-9554; Scherag, Andre/0000-0002-9406-4704; Hayes, Richard/0000-0002-0918-661X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Tuomi, Tiinamaija/0000-0002-8306-6202; John, Ulrich/0000-0003-0587-5298; Karpe, Fredrik/0000-0002-2751-1770; Jorgensen, Torben/0000-0001-9453-2830; Watkins, Hugh/0000-0002-5287-9016; Perola, Markus/0000-0003-4842-1667; Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Ouwehand, Willem/0000-0002-7744-1790; Kaprio, Jaakko/0000-0002-3716-2455; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Bergmann, Sven/0000-0002-6785-9034; Sinisalo, Juha/0000-0002-0169-5137; de Geus, Eco/0000-0001-6022-2666; Martin, Nicholas/0000-0003-4069-8020; Farooqi, Sadaf/0000-0001-7609-3504 FU Academy of Finland [10404, 77299, 104781, 114382, 117797, 120315]; ADA; Amgen; Agency for Science, Technology and Research of Singapore (AstarSTAR); ALF/LUA; Althingi (the Icelandic Parliament); AstraZeneca; Augustinus Foundation; Australian National Health and Medical Research Council [241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672]; Australian Research Council (ARC) [DP0770096]; Becket Foundation; Biocenter (Finland); Biomedicum Helsinki Foundation; Boston Obesity Nutrition Research Center; British Diabetes Association [1192]; British Heart Foundation [97020, PG/02/128]; Busselton Population Medical Research Foundation; Cambridge Institute for Medical Research; Cambridge National Institute of Health Research (NIHR) Comprehensive Biomedical Research Centre; CamStrad (UK); Cancer Research UK; Centre for Medical Systems Biology (The Netherlands); Centre for Neurogenomics and Cognitive Research (The Netherlands); Chief Scientist Office of the Scottish Government; Contrat Plan Etat Region (France); Danish Centre for Health Technology Assessment; Danish Diabetes Association; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; Deutsche Forschungsgemeinschaft (DFG) [HE 1446/4-1]; Department of Health (UK); Diabetes UK; Diabetes and Inflammation Laboratory; Donald W. Reynolds Foundation; Dresden University of Technology; Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission [QLG1-CT-2000-01643, QLG2-CT-2002-01254, LSHC-CT-2005, LSHG-CT-2006-018947, LSHG-CT-2004-518153, LSH-2006-037593, LSHM-CT-2007-037273, HEALTH- F2-2008-ENGAGE, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, 205419, 212111, 245536, SOC 9520140805F02, WLRT-2001-01254]; Federal Ministry of Education and Research (Germany) [01AK803, 01EA9401, 01GI0823, 01GI0826, 01GP0209, 01GP0259, 01GS0820, 01GS0823, 01GS0824, 01GS0825, 01GS0830, 01GS0831, 01IG07015, 01KU0903, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Federal State of Mecklenburg-West Pomerania; European Social Fund; Eve Appeal; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Foundation for Pediatric Research, Finnish Medical Society; Finska Lakaresallskapet, Paivikki and Sakari Sohlberg Foundation, Folkhalsan Research Foundation; Fond Europeen pour le Developpement Regional (France); Fondation LeDucq (Paris, France); Foundation for Life and Health in Finland; Foundation for Strategic Research (Sweden); Genetic Association Information Network; German Research Council [KFO-152]; German National Genome Research Net 'NGFNplus' [FKZ 01GS0823]; German Research Center for Environmental Health; Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Goteborg Medical Society; Great Wine Estates Auctions; Gyllenberg Foundation; Health Care Centers in Vasa, Narpes and Korsholm; Healthway, Western Australia; Helmholtz Center Munich; Helsinki University Central Hospital, Hjartavernd (the Icelandic Heart Association); INSERM (France); Ib Henriksen Foundation; Interdisziplinares Zentrum fur Klinische Forschung (IZKF) [B27]; Jalmari and Rauha Ahokas Foundation; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International (JDRF); Karolinska Institute; Knut and Alice Wallenberg Foundation; Leenaards Foundation; Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LUCAMP); Lundberg Foundation; Marie Curie Intra-European Fellowship; Medical Research Council (UK) [G0000649, G0000934, G9521010D, G0500539, G0600331, G0601261]; Ministry of Cultural Affairs and Social Ministry of the Federal State of Mecklenburg-West Pomerania; Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Ministry of Internal Affairs and Health (Denmark); Ministry of Science, Education and Sport of the Republic of Croatia [216-1080315-0302]; Ministry of Science, Research and the Arts Baden-Wurttemberg; Montreal Heart Institute Foundation; Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Narpes Health Care Foundation; National Cancer Institute; National Health and Medical Research Council of Australia; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute for Health Research Oxford Biomedical Research Centre FX Funding was provided by Academy of Finland (10404, 77299, 104781, 114382, 117797, 120315, 121584, 124243, 126775, 126925, 127437, 129255, 129269, 129306, 129494, 129680, 130326, 209072, 210595, 213225, 213506 and 216374); ADA Mentor-Based Postdoctoral Fellowship; Amgen; Agency for Science, Technology and Research of Singapore (A*STAR); ALF/LUA research grant in Gothenburg; Althingi (the Icelandic Parliament); AstraZeneca; Augustinus Foundation; Australian National Health and Medical Research Council (241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485 and 613672); Australian Research Council (ARC grant DP0770096); Becket Foundation; Biocenter (Finland); Biomedicum Helsinki Foundation; Boston Obesity Nutrition Research Center; British Diabetes Association (1192); British Heart Foundation (97020; PG/02/128); Busselton Population Medical Research Foundation; Cambridge Institute for Medical Research; Cambridge National Institute of Health Research (NIHR) Comprehensive Biomedical Research Centre; CamStrad (UK); Cancer Research UK; Centre for Medical Systems Biology (The Netherlands); Centre for Neurogenomics and Cognitive Research (The Netherlands); Chief Scientist Office of the Scottish Government; Contrat Plan Etat Rrgion (France); Danish Centre for Health Technology Assessment; Danish Diabetes Association; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; Deutsche Forschungsgemeinschaft (DFG; HE 1446/4-1); Department of Health (UK); Diabetes UK; Diabetes and Inflammation Laboratory; Donald W.; Reynolds Foundation; Dresden University of Technology Funding Grant; Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission (DG XII; QLG1-CT-2000-01643, QLG2-CT-2002-01254, LSHC-CT-2005, LSHG-CT-2006-018947, LSHG-CT-2004-518153, LSH-2006-037593, LSHM-CT-2007-037273, HEALTH-F2-2008ENGAGE, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, FP7/2007-2013, 205419, 212111, 245536, SOC 95201408 05F02 and WLRT-2001-01254); Federal Ministry of Education and Research (Germany) (01AK803, 01EA9401, 01GI0823, 01GI0826, 01GP0209, 01GP0259, 01GS0820, 01GS0823, 01GS0824, 01GS0825, 01GS0830, 01GS0831, 01IG07015, 01KU0903, 01ZZ9603, 01ZZ0103, 01ZZ0403 and 03ZIK012); Federal State of Mecklenburg-West Pomerania; European Social Fund; Eve Appeal; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Foundation for Pediatric Research, Finnish Medical Society; Finska Lakaresallskapet, Paivikki and Sakari Sohlberg Foundation, Folkhalsan Research Foundation; Fond Europeen pour le Developpement Regional (France); Fondation LeDucq (Paris, France); Foundation for Life and Health in Finland; Foundation for Strategic Research (Sweden); Genetic Association Information Network; German Research Council (KFO-152); German National Genome Research Net 'NGFNplus' (FKZ 01GS0823); German Research Center for Environmental Health; Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Goteborg Medical Society; Great Wine Estates Auctions; Gyllenberg Foundation; Health Care Centers in Vasa, Narpes and Korsholm; Healthway, Western Australia; Helmholtz Center Munich; Helsinki University Central Hospital, Hjartavernd (the Icelandic Heart Association); INSERM (France); Ib Henriksen Foundation; Interdisziplinares Zentrum fur Klinische Forschung (IZKF) (B27); Jalmari and Rauha Ahokas Foundation; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International (JDRF); Karolinska Institute; Knut and Alice Wallenberg Foundation; Leenards Foundation; Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LUCAMP); Lundberg Foundation; Marie Curie Intra-European Fellowship; Medical Research Council (UK) (G0000649, G0000934, G9521010D, G0500539, G0600331 and G0601261, PrevMetSyn); Ministry of Cultural Affairs and Social Ministry of the Federal State of Mecklenburg-West Pomerania; Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Ministry of Internal Affairs and Health (Denmark); Ministry of Science, Education and Sport of the Republic of Croatia (216-1080315-0302); Ministry of Science, Research and the Arts Baden-Wurttemberg; Montreal Heart Institute Foundation; Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Narpes Health Care Foundation; National Cancer Institute; National Health and Medical Research Council of Australia; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute for Health Research Oxford Biomedical Research Centre; National Institute for Health Research comprehensive Biomedical Research Centre; US National Institutes of Health (263-MA-410953, AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, CA047988, CA65725, CA87969, CA49449, CA67262, CA50385, DA12854, DK58845, DK46200, DK062370, DK063491, DK072193, HG002651, HL084729, HHSN268200625226C, HL71981, K23-DK080145, K99-HL094535, M01-RR00425, MH084698, N01-AG12100, NO1-AG12109, N01-H; 15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55015, N01-HC55016, N01-HC55018, N01-HC55019, N01-HC55020, N01-N01HC-55021, N01-HC55022, N01-HC55222, N01-HC75150, N01-HC85079, N01-HC85080, N01-HG-65403, N01-HC85081, N01-HC85082, N01-HC85083, N01-HC85084, N01-HC85085, N01-HC85086, N02-HL64278, P30-DK072488, R01-AG031890, R01-DK073490, R01-DK075787, R01DK068336, R01DK075681, R01-HL59367, R01-HL086694, R01-HL087641, R01-HL087647, R01-HL087652, R01-HL087676, R01-HL087679, R01-HL087700, R01-HL088119, R01-MH59160, R01-MH59565, R01-MH59566, R01-MH59571, R01-MH59586, R01-MH59587, R01-MH59588, R01-MH60870, R01-MH60879, R01-MH61675, R01-MH63706, R01-MH67257, R01-MH79469, R01-MH79470, R01-MH81800, RL1-MH083268, UO1-CA098233, U01-DK062418, U01-GM074518, U01-HG004402, U01-HG004399, U01-HL72515, U01-HL080295, U01-HL084756, U54-RR020278, T32-HG00040, UL1-RR025005 and Z01-HG000024); National Alliance for Research on Schizophrenia and Depression (NARSAD); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (NWO) (904-61-090, 904-61-193, 480-04-004, 400-05-717, SPI 56-464-1419, 175.010.2005.011 and 911-03-012); Nord-Trondelag County Council; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Norwegian Institute of Public Health; Ollqvist Foundation; Oxford NIHR Biomedical Research Centre; Organization for the Health Research and Development (10-000-1002); Paavo Nurmi Foundation; Paul Michael Donovan Charitable Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Pew Scholar for the Biomedical Sciences; Public Health and Risk Assessment, Health and Consumer Protection (2004310); Research Foundation of Copenhagen County; Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Robert Dawson Evans Endowment; Royal Society (UK); Royal Swedish Academy of Science; Sahlgrenska Center for Cardiovascular and Metabolic Research (CMR, no. A305: 188); Siemens Healthcare, Erlangen, Germany; Sigrid Juselius Foundation; Signe and Ane Gyllenberg Foundation; Science Funding programme (UK); Social Insurance Institution of Finland; Sderberg's Foundation; South Tyrol Ministry of Health; South Tyrolean Sparkasse Foundation; State of Bavaria; Stockholm County Council (560183); Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Medical Research Council (8691, K2007-66X-20270-01-3, K2010-54X-09894-19-3, K2010-54X-09894-19-3 and 2006-3832); Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation (33CSCO-122661, 310000-112552 and 3100AO-116323/1); Torsten and Ragnar Soderberg's Foundation; Universite Henri Poincare-Nancy 1, Region Lorraine, Communaute Urbaine du Grand Nancy; University Hospital Medical funds to Tampere; University Hospital Oulu, Finland; University of Oulu, Finland (75617); Vastra Gotaland Foundation; Walter E. Nichols, M. D., and Eleanor Nichols endowments; Wellcome Trust (068545, 072960, 075491, 076113, 077016, 079557, 079895, 081682, 083270, 085301 and 086596); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource; and Yrjo Jahnsson Foundation. NR 54 TC 1268 Z9 1297 U1 33 U2 278 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 NOV PY 2010 VL 42 IS 11 BP 937 EP U53 DI 10.1038/ng.686 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 671VW UT WOS:000283540500010 PM 20935630 ER PT J AU Heid, IM Jackson, AU Randall, JC Winkler, TW Qi, L Steinthorsdottir, V Thorleifsson, G Zillikens, MC Speliotes, EK Magi, R Workalemahu, T White, CC Bouatia-Naji, N Harris, TB Berndt, SI Ingelsson, E Willer, CJ Weedon, MN Luan, JA Vedantam, S Esko, T Kilpelainen, TO Kutalik, Z Li, SX Monda, KL Dixon, AL Holmes, CC Kaplan, LM Liang, LM Min, JL Moffatt, MF Molony, C Nicholson, G Schadt, EE Zondervan, KT Feitosa, MF Ferreira, T Allen, HL Weyant, RJ Wheeler, E Wood, AR Estrada, K Goddard, ME Lettre, G Mangino, M Nyholt, DR Purcell, S Smith, AV Visscher, PM Yang, JA McCarroll, SA Nemesh, J Voight, BF Absher, D Amin, N Aspelund, T Coin, L Glazer, NL Hayward, C Heard-Costa, NL Hottenga, JJ Johansson, A Johnson, T Kaakinen, M Kapur, K Ketkar, S Knowles, JW Kraft, P Kraja, AT Lamina, C Leitzmann, MF McKnight, B Morris, AP Ong, KK Perry, JRB Peters, MJ Polasek, O Prokopenko, I Rayner, NW Ripatti, S Rivadeneira, F Robertson, NR Sanna, S Sovio, U Surakka, I Teumer, A van Wingerden, S Vitart, V Zhao, JH Cavalcanti-Proenca, C Chines, PS Fisher, E Kulzer, JR Lecoeur, C Narisu, N Sandholt, C Scott, LJ Silander, K Stark, K Tammesoo, ML Teslovich, TM Timpson, NJ Watanabe, RM Welch, R Chasman, DI Cooper, MN Jansson, JO Kettunen, J Lawrence, RW Pellikka, N Perola, M Vandenput, L Alavere, H Almgren, P Atwood, LD Bennett, AJ Biffar, R Bonnycastle, LL Bornstein, SR Buchanan, TA Campbell, H Day, INM Dei, M Dorr, M Elliott, P Erdos, MR Eriksson, JG Freimer, NB Fu, M Gaget, S Geus, EJC Gjesing, AP Grallert, H Grassler, J Groves, CJ Guiducci, C Hartikainen, AL Hassanali, N Havulinna, AS Herzig, KH Hicks, AA Hui, JN Igl, W Jousilahti, P Jula, A Kajantie, E Kinnunen, L Kolcic, I Koskinen, S Kovacs, P Kroemer, HK Krzelj, V Kuusisto, J Kvaloy, K Laitinen, J Lantieri, O Lathrop, GM Lokki, ML Luben, RN Ludwig, B McArdle, WL McCarthy, A Morken, MA Nelis, M Neville, MJ Pare, G Parker, AN Peden, JF Pichler, I Pietilainen, KH Platou, CGP Pouta, A Ridderstrale, M Samani, NJ Saramies, J Sinisalo, J Smit, JH Strawbridge, RJ Stringham, HM Swift, AJ Teder-Laving, M Thomson, B Usala, G van Meurs, JBJ van Ommen, GJ Vatin, V Volpato, CB Wallaschofski, H Walters, GB Widen, E Wild, SH Willemsen, G Witte, DR Zgaga, L Zitting, P Beilby, JP James, AL Kahonen, M Lehtimaki, T Nieminen, MS Ohlsson, C Palmer, LJ Raitakari, O Ridker, PM Stumvoll, M Tonjes, A Viikari, J Balkau, B Ben-Shlomo, Y Bergman, RN Boeing, H Smith, GD Ebrahim, S Froguel, P Hansen, T Hengstenberg, C Hveem, K Isomaa, B Jorgensen, T Karpe, F Khaw, KT Laakso, M Lawlor, DA Marre, M Meitinger, T Metspalu, A Midthjell, K Pedersen, O Salomaa, V Schwarz, PEH Tuomi, T Tuomilehto, J Valle, TT Wareham, NJ Arnold, AM Beckmann, JS Bergmann, S Boerwinkle, E Boomsma, DI Caulfield, MJ Collins, FS Eiriksdottir, G Gudnason, V Gyllensten, U Hamsten, A Hattersley, AT Hofman, A Hu, FB Illig, T Iribarren, C Jarvelin, MR Kao, WHL Kaprio, J Launer, LJ Munroe, PB Oostra, B Penninx, BW Pramstaller, PP Psaty, BM Quertermous, T Rissanen, A Rudan, I Shuldiner, AR Soranzo, N Spector, TD Syvanen, AC Uda, M Uitterlinden, A Volzke, H Vollenweider, P Wilson, JF Witteman, JC Wright, AF Abecasis, GR Boehnke, M Borecki, IB Deloukas, P Frayling, TM Groop, LC Haritunians, T Hunter, DJ Kaplan, RC North, KE O'Connell, JR Peltonen, L Schlessinger, D Strachan, DP Hirschhorn, JN Assimes, TL Wichmann, HE Thorsteinsdottir, U van Duijn, CM Stefansson, K Cupples, LA Loos, RJF Barroso, I McCarthy, MI Fox, CS Mohlke, KL Lindgren, CM AF Heid, Iris M. Jackson, Anne U. Randall, Joshua C. Winkler, Thomas W. Qi, Lu Steinthorsdottir, Valgerdur Thorleifsson, Gudmar Zillikens, M. Carola Speliotes, Elizabeth K. Maegi, Reedik Workalemahu, Tsegaselassie White, Charles C. Bouatia-Naji, Nabila Harris, Tamara B. Berndt, Sonja I. Ingelsson, Erik Willer, Cristen J. Weedon, Michael N. Luan, Jianan Vedantam, Sailaja Esko, Tonu Kilpelaeinen, Tuomas O. Kutalik, Zoltan Li, Shengxu Monda, Keri L. Dixon, Anna L. Holmes, Christopher C. Kaplan, Lee M. Liang, Liming Min, Josine L. Moffatt, Miriam F. Molony, Cliona Nicholson, George Schadt, Eric E. Zondervan, Krina T. Feitosa, Mary F. Ferreira, Teresa Allen, Hana Lango Weyant, Robert J. Wheeler, Eleanor Wood, Andrew R. Estrada, Karol Goddard, Michael E. Lettre, Guillaume Mangino, Massimo Nyholt, Dale R. Purcell, Shaun Smith, Albert Vernon Visscher, Peter M. Yang, Jian McCarroll, Steven A. Nemesh, James Voight, Benjamin F. Absher, Devin Amin, Najaf Aspelund, Thor Coin, Lachlan Glazer, Nicole L. Hayward, Caroline Heard-Costa, Nancy L. Hottenga, Jouke-Jan Johansson, Asa Johnson, Toby Kaakinen, Marika Kapur, Karen Ketkar, Shamika Knowles, Joshua W. Kraft, Peter Kraja, Aldi T. Lamina, Claudia Leitzmann, Michael F. McKnight, Barbara Morris, Andrew P. Ong, Ken K. Perry, John R. B. Peters, Marjolein J. Polasek, Ozren Prokopenko, Inga Rayner, Nigel W. Ripatti, Samuli Rivadeneira, Fernando Robertson, Neil R. Sanna, Serena Sovio, Ulla Surakka, Ida Teumer, Alexander van Wingerden, Sophie Vitart, Veronique Zhao, Jing Hua Cavalcanti-Proenca, Christine Chines, Peter S. Fisher, Eva Kulzer, Jennifer R. Lecoeur, Cecile Narisu, Narisu Sandholt, Camilla Scott, Laura J. Silander, Kaisa Stark, Klaus Tammesoo, Mari-Liis Teslovich, Tanya M. Timpson, Nicholas John Watanabe, Richard M. Welch, Ryan Chasman, Daniel I. Cooper, Matthew N. Jansson, John-Olov Kettunen, Johannes Lawrence, Robert W. Pellikka, Niina Perola, Markus Vandenput, Liesbeth Alavere, Helene Almgren, Peter Atwood, Larry D. Bennett, Amanda J. Biffar, Reiner Bonnycastle, Lori L. Bornstein, Stefan R. Buchanan, Thomas A. Campbell, Harry Day, Ian N. M. Dei, Mariano Doerr, Marcus Elliott, Paul Erdos, Michael R. Eriksson, Johan G. Freimer, Nelson B. Fu, Mao Gaget, Stefan Geus, Eco J. C. Gjesing, Anette P. Grallert, Harald Graessler, Juergen Groves, Christopher J. Guiducci, Candace Hartikainen, Anna-Liisa Hassanali, Neelam Havulinna, Aki S. Herzig, Karl-Heinz Hicks, Andrew A. Hui, Jennie Igl, Wilmar Jousilahti, Pekka Jula, Antti Kajantie, Eero Kinnunen, Leena Kolcic, Ivana Koskinen, Seppo Kovacs, Peter Kroemer, Heyo K. Krzelj, Vjekoslav Kuusisto, Johanna Kvaloy, Kirsti Laitinen, Jaana Lantieri, Olivier Lathrop, G. Mark Lokki, Marja-Liisa Luben, Robert N. Ludwig, Barbara McArdle, Wendy L. McCarthy, Anne Morken, Mario A. Nelis, Mari Neville, Matt J. Pare, Guillaume Parker, Alex N. Peden, John F. Pichler, Irene Pietilainen, Kirsi H. Platou, Carl G. P. Pouta, Anneli Ridderstrale, Martin Samani, Nilesh J. Saramies, Jouko Sinisalo, Juha Smit, Jan H. Strawbridge, Rona J. Stringham, Heather M. Swift, Amy J. Teder-Laving, Maris Thomson, Brian Usala, Gianluca van Meurs, Joyce B. J. van Ommen, Gert-Jan Vatin, Vincent Volpato, Claudia B. Wallaschofski, Henri Walters, G. Bragi Widen, Elisabeth Wild, Sarah H. Willemsen, Gonneke Witte, Daniel R. Zgaga, Lina Zitting, Paavo Beilby, John P. James, Alan L. Kahonen, Mika Lehtimaki, Terho Nieminen, Markku S. Ohlsson, Claes Palmer, Lyle J. Raitakari, Olli Ridker, Paul M. Stumvoll, Michael Toenjes, Anke Viikari, Jorma Balkau, Beverley Ben-Shlomo, Yoav Bergman, Richard N. Boeing, Heiner Smith, George Davey Ebrahim, Shah Froguel, Philippe Hansen, Torben Hengstenberg, Christian Hveem, Kristian Isomaa, Bo Jorgensen, Torben Karpe, Fredrik Khaw, Kay-Tee Laakso, Markku Lawlor, Debbie A. Marre, Michel Meitinger, Thomas Metspalu, Andres Midthjell, Kristian Pedersen, Oluf Salomaa, Veikko Schwarz, Peter E. H. Tuomi, Tiinamaija Tuomilehto, Jaakko Valle, Timo T. Wareham, Nicholas J. Arnold, Alice M. Beckmann, Jacques S. Bergmann, Sven Boerwinkle, Eric Boomsma, Dorret I. Caulfield, Mark J. Collins, Francis S. Eiriksdottir, Gudny Gudnason, Vilmundur Gyllensten, Ulf Hamsten, Anders Hattersley, Andrew T. Hofman, Albert Hu, Frank B. Illig, Thomas Iribarren, Carlos Jarvelin, Marjo-Riitta Kao, W. H. Linda Kaprio, Jaakko Launer, Lenore J. Munroe, Patricia B. Oostra, Ben Penninx, Brenda W. Pramstaller, Peter P. Psaty, Bruce M. Quertermous, Thomas Rissanen, Aila Rudan, Igor Shuldiner, Alan R. Soranzo, Nicole Spector, Timothy D. Syvanen, Ann-Christine Uda, Manuela Uitterlinden, Andre Voelzke, Henry Vollenweider, Peter Wilson, James F. Witteman, Jacqueline C. Wright, Alan F. Abecasis, Goncalo R. Boehnke, Michael Borecki, Ingrid B. Deloukas, Panos Frayling, Timothy M. Groop, Leif C. Haritunians, Talin Hunter, David J. Kaplan, Robert C. North, Kari E. O'Connell, Jeffrey R. Peltonen, Leena Schlessinger, David Strachan, David P. Hirschhorn, Joel N. Assimes, Themistocles L. Wichmann, H-Erich Thorsteinsdottir, Unnur van Duijn, Cornelia M. Stefansson, Kari Cupples, L. Adrienne Loos, Ruth J. F. Barroso, Ines McCarthy, Mark I. Fox, Caroline S. Mohlke, Karen L. Lindgren, Cecilia M. CA MAGIC TI Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; BODY-FAT; METABOLIC RISK; ABDOMINAL ADIPOSITY; GLUCOSE-HOMEOSTASIS; SUSCEPTIBILITY LOCI; INSULIN-RESISTANCE; COMMON VARIANTS; OBESITY AB Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 x 10(-9) to P = 1.8 x 10(-40)) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 x 10(-3) to P = 1.2 x 10(-13)). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. 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[Sandholt, Camilla; Gjesing, Anette P.; Hansen, Torben; Pedersen, Oluf] Hagedorn Res Inst, Gentofte, Denmark. [Stark, Klaus] Univ Regensburg, Med Ctr, Clin & Policlin Internal Med 2, Regensburg, Germany. [Timpson, Nicholas John; Day, Ian N. M.; Smith, George Davey; Lawlor, Debbie A.] MRC Ctr Causal Anal Translat Epidemiol, Dept Social Med, Bristol, Avon, England. [Watanabe, Richard M.; Buchanan, Thomas A.; Bergman, Richard N.] Univ So Calif, Keck Sch Med, Dept Phys & Biophys, Los Angeles, CA 90033 USA. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Cooper, Matthew N.; Lawrence, Robert W.; Hui, Jennie; Palmer, Lyle J.] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Crawley, WA, Australia. [Jansson, John-Olov] Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Sahlgrenska Acad, Gothenburg, Sweden. [Vandenput, Liesbeth; Ohlsson, Claes] Univ Gothenburg, Inst Med, Dept Internal Med, Sahlgrenska Acad, Gothenburg, Sweden. [Almgren, Peter; Groop, Leif C.] Lund Univ, Ctr Diabet, Dept Clin Sci, Malmo, Sweden. [Biffar, Reiner] Zentrum Zahn Mund & Kieferheilkunde, Greifswald, Germany. [Bornstein, Stefan R.; Graessler, Juergen; Ludwig, Barbara] Univ Dresden, Dept Med 3, Dresden, Germany. [Buchanan, Thomas A.] Univ So Calif, Keck Sch Med, Div Endocrinol, Los Angeles, CA 90033 USA. [Campbell, Harry; Wild, Sarah H.; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Doerr, Marcus] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, Greifswald, Germany. [Elliott, Paul] Ctr Environm & Hlth, MRC Hlth Protect Agcy HPA, London, England. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.; Kajantie, Eero; Peltonen, Leena] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.; Isomaa, Bo; Tuomi, Tiinamaija] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Freimer, Nelson B.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. [Fu, Mao; Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Hartikainen, Anna-Liisa; Pouta, Anneli] Univ Oulu, Dept Clin Sci Obstet & Gynecol, Oulu, Finland. [Havulinna, Aki S.; Jousilahti, Pekka; Koskinen, Seppo; Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland. [Herzig, Karl-Heinz] Univ Oulu, Dept Physiol, Inst Biomed, Oulu, Finland. [Herzig, Karl-Heinz] Kuopio Univ Hosp, Dept Psychiat, SF-70210 Kuopio, Finland. [Hicks, Andrew A.; Pichler, Irene; Volpato, Claudia B.; Pramstaller, Peter P.] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy. [Hui, Jennie; Beilby, John P.] QEII Med Ctr, Dept Mol Genet, PathW Lab Western Australia, Nedlands, WA, Australia. [Hicks, Andrew A.; Pichler, Irene; Volpato, Claudia B.; Pramstaller, Peter P.] Univ Lubeck, Affiliated Inst, Lubeck, Germany. [Hui, Jennie; Beilby, John P.; James, Alan L.; Palmer, Lyle J.] Sir Charles Gairdner Hosp, Busselton Populat Med Res Fdn Inc, Nedlands, WA, Australia. [Jula, Antti] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Populat Studies Unit, Turku, Finland. [Kajantie, Eero] Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, Helsinki, Finland. [Kinnunen, Leena; Tuomilehto, Jaakko; Valle, Timo T.] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. [Kroemer, Heyo K.] Ernst Moritz Arndt Univ Greifswald, Inst Pharmakol, Greifswald, Germany. [Krzelj, Vjekoslav; Rudan, Igor] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kvaloy, Kirsti; Platou, Carl G. P.; Hveem, Kristian; Midthjell, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway. [Laitinen, Jaana] Finnish Inst Occupat Hlth, Oulu, Finland. [Lantieri, Olivier] Inst Interreg Sante IRSA, La Riche, France. [Lathrop, G. Mark] Ctr Natl Genotypage, Paris, France. [Lokki, Marja-Liisa] Univ Helsinki, Haartman Inst, Transplantat Lab, Helsinki, Finland. [Luben, Robert N.; Khaw, Kay-Tee] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [McArdle, Wendy L.] Univ Bristol, Dept Social Med, Avon Longitudinal Study Parents & Children ALSPAC, Bristol, Avon, England. [McCarthy, Anne] Res Board, Div Hlth, Dublin, Ireland. [Pare, Guillaume] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Parker, Alex N.] Amgen Inc, Cambridge, MA USA. [Peden, John F.] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Pietilainen, Kirsi H.; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Finnish Twin Cohort Study, Helsinki, Finland. [Pietilainen, Kirsi H.; Rissanen, Aila] Univ Helsinki, Cent Hosp, Dept Psychiat, Obes Res Unit, Helsinki, Finland. [Platou, Carl G. P.] Levanger Hosp, Nord Trondelag Hlth Trust, Dept Med, Levanger, Norway. [Ridderstrale, Martin] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Biomed Res Unit Cardiovasc Dis, Leicester Natl Inst Hlth Res NIHR, Leicester, Leics, England. [Saramies, Jouko] S Karelia Cent Hosp, Lappeenranta, Finland. [Sinisalo, Juha; Nieminen, Markku S.] Univ Helsinki, Cent Hosp, Cardiovasc Lab, Div Cardiol, Helsinki, Finland. [Smit, Jan H.; Penninx, Brenda W.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Inst Extramuraal Geneeskundig Onderzoek EMGO Inst, Amsterdam, Netherlands. [Strawbridge, Rona J.; Hamsten, Anders] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Atherosclerosis Res Unit, Stockholm, Sweden. [van Ommen, Gert-Jan] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [van Ommen, Gert-Jan] Leiden Univ, Med Ctr, Ctr Med Syst Biol, Leiden, Netherlands. [Wallaschofski, Henri] Ernst Moritz Arndt Univ Greifswald, Inst Klin Chem & Lab Med, Greifswald, Germany. [Witte, Daniel R.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Zitting, Paavo] Lapland Cent Hosp, Dept Physiatr, Rovaniemi, Finland. [Beilby, John P.] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia. [James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kahonen, Mika; Lehtimaki, Terho] Tampere Univ Hosp, Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, FIN-33101 Tampere, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol, FIN-20520 Turku, Finland. [Stumvoll, Michael; Toenjes, Anke] Univ Leipzig, Dept Med, Leipzig, Germany. [Stumvoll, Michael] Univ Leipzig, Leipziger Interdisziplinarer Forschungskomplex Mo, Leipzig, Germany. [Toenjes, Anke] Univ Leipzig, Coordinat Ctr Clin Trials, Leipzig, Germany. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Balkau, Beverley] INSERM Ctr Rech Epidemiol & Sante Populat CESP, F-01018 Villejuif, France. [Balkau, Beverley] Univ Paris Sud 11, Unit Mixte Rech Sante UMRS 1018, Villejuif, France. [Ben-Shlomo, Yoav] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Ebrahim, Shah] London Sch Hyg & Trop Med, London WC1, England. [Ebrahim, Shah] S Asia Network Chron Dis, New Delhi, India. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Hansen, Torben] Univ So Denmark, Fac Hlth Sci, Odense, Denmark. [Hengstenberg, Christian] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Hengstenberg, Christian] Univ Regensburg, Med Ctr, Innere Med 2, Regensburg, Germany. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari, Finland. [Jorgensen, Torben] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Karpe, Fredrik; McCarthy, Mark I.] Churchill Hosp, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LJ, England. [Marre, Michel] Bichat Claude Bernard Univ Hosp, AP HP, Dept Endocrinol Diabetol & Nutr, Paris, France. [Marre, Michel] Univ Henri Poincar Nancy 1, Cardiovasc Genet Res Unit, Nancy, France. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Pedersen, Oluf] Univ Copenhagen, Inst Biomed Sci, Copenhagen, Denmark. [Pedersen, Oluf] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark. [Schwarz, Peter E. H.] Univ Dresden, Dept Med Prevent & Care Diabet 3, Dresden, Germany. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Res Program Mol Med, Helsinki, Finland. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Arnold, Alice M.] Collaborat Hlth Studies Coordinating Ctr, Seattle, WA USA. [Beckmann, Jacques S.] Univ Lausanne Hosp, CHUV, Serv Med Genet, Lausanne, Switzerland. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Iribarren, Carlos] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Iribarren, Carlos] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol & Med, Baltimore, MD USA. [Kaprio, Jaakko] Natl Inst Hlth & Welf, Dept Mental Hlth, Helsinki, Finland. [Kaprio, Jaakko] Unit Child & Adolescent Mental Hlth, Substance Abuse Serv, Helsinki, Finland. [Oostra, Ben] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Shuldiner, Alan R.] Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Voelzke, Henry] Inst Community Med, Greifswald, Germany. [Vollenweider, Peter] Univ Lausanne Hosp, CHUV, Dept Internal Med, Lausanne, Switzerland. [Borecki, Ingrid B.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Haritunians, Talin] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [North, Kari E.] Univ N Carolina, Sch Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Peltonen, Leena] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Strachan, David P.] Univ London, Div Community Hlth Sci, London, England. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Barroso, Ines] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge, England. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA USA. RP Lindgren, CM (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM iris.heid@klinik.uni-regensburg.de; mark.mccarthy@drl.ox.ac.uk; foxca@nhlbi.nih.gov; mohlke@med.unc.edu; celi@well.ox.ac.uk RI Schwarz, Peter/B-5127-2013; Davey Smith, George/A-7407-2013; Krzelj, Vjekoslav/D-6491-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Witte, Daniel/C-1722-2008; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Yang, Jian/A-5852-2010; Smith, Albert/K-5150-2015; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; BOUATIA-NAJI, NABILA/D-5863-2013; Coin, Lachlan/A-9001-2014; Lango Allen, Hana/G-9026-2012; Lamina, Claudia/F-7608-2010; Rudan, Igor/I-1467-2012; Deloukas, Panos/B-2922-2013; Grallert, Harald/B-3424-2013; Nyholt, Dale/C-8384-2013; Colaus, PsyColaus/K-6607-2013; Zondervan, Krina/M-1143-2013; Pramstaller, Peter/C-2357-2008; Cooper, Matthew/J-4420-2014; Strawbridge, Rona/H-5422-2012; Johansson, Asa/G-5270-2011; Palmer, Lyle/K-3196-2014; Polasek, Ozren/B-6002-2011; Beckmann, Jacques S /A-9772-2008; Voight, Benjamin/F-1775-2011; Aspelund, Thor/F-4826-2011; Stark, Klaus/D-3813-2009; Aspelund, Thor/C-5983-2008; kinnunen, leena/B-7059-2012; Li, Shengxu/D-8915-2012; Spector, Tim/F-6533-2012; Ridderstrale, Martin/F-7678-2012; Kilpelainen, Tuomas/F-8569-2012; Kaplan, Robert/A-2526-2011; Abecasis, Goncalo/B-7840-2010; OI Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Tuomi, Tiinamaija/0000-0002-8306-6202; Vandenput, Liesbeth/0000-0002-1712-6131; Karpe, Fredrik/0000-0002-2751-1770; Jorgensen, Torben/0000-0001-9453-2830; Visscher, Peter/0000-0002-2143-8760; Abecasis, Goncalo/0000-0003-1509-1825; Esko, Tonu/0000-0003-1982-6569; Peters, Marjolein/0000-0003-3167-9063; Luben, Robert/0000-0002-5088-6343; Kaakinen, Marika/0000-0002-9228-0462; Pichler, Irene/0000-0001-8251-0757; Heard-Costa, Nancy/0000-0001-9730-0306; Goddard, Michael/0000-0001-9917-7946; Magi, Reedik/0000-0002-2964-6011; Marre, Michel/0000-0002-3071-1837; sanna, serena/0000-0002-3768-1749; Johnson, Toby/0000-0002-5998-3270; Cupples, L. Adrienne/0000-0003-0273-7965; Schwarz, Peter/0000-0001-6317-7880; Davey Smith, George/0000-0002-1407-8314; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Soranzo, Nicole/0000-0003-1095-3852; Zgaga, Lina/0000-0003-4089-9703; Bouatia-Naji, Nabila/0000-0001-5424-2134; Willer, Cristen/0000-0001-5645-4966; Witte, Daniel/0000-0002-0769-2922; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Yang, Jian/0000-0003-2001-2474; Smith, Albert/0000-0003-1942-5845; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Coin, Lachlan/0000-0002-4300-455X; Lango Allen, Hana/0000-0002-7803-8688; Rudan, Igor/0000-0001-6993-6884; Deloukas, Panos/0000-0001-9251-070X; Zondervan, Krina/0000-0002-0275-9905; Cooper, Matthew/0000-0003-1139-3682; Strawbridge, Rona/0000-0001-8506-3585; Johansson, Asa/0000-0002-2915-4498; Palmer, Lyle/0000-0002-1628-3055; Polasek, Ozren/0000-0002-5765-1862; Beckmann, Jacques S /0000-0002-9741-1900; Stark, Klaus/0000-0002-7832-1942; Aspelund, Thor/0000-0002-7998-5433; kinnunen, leena/0000-0001-8739-4812; Eriksson, Johan/0000-0002-2516-2060; Kaprio, Jaakko/0000-0002-3716-2455; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Bergmann, Sven/0000-0002-6785-9034; Sinisalo, Juha/0000-0002-0169-5137; de Geus, Eco/0000-0001-6022-2666 FU Academy of Finland [104781, 120315, 129269, 117797, 121584, 126925, 129418, 129568, 77299, 124243, 129680, 129494, 10404, 213506, 114382, 126775, 127437, 129255, 129306, 130326, 209072, 210595, 213225, 216374]; ADA [N02-HL-6-4278]; ALF/LUA Gothenburg; Althingi (the Icelandic Parliament); Amgen; Augustinus Foundation; Becket Foundation; Biocentrum Helsinki; Biomedicum Helsinki Foundation; Boston Obesity Nutrition Research Center [DK46200]; British Diabetes Association [1192]; British Diabetic Association Research; British Heart Foundation [97020, PG/02/128]; Busselton Population Medical Research Foundation; Cambridge NIHR Comprehensive Biomedical Research Centre; CamStrad; Chief Scientist Office of the Scottish Government; Contrat Plan Etat Region de France; Danish Centre for Health Technology Assessment; Danish Diabetes Association; Danish Ministry of Internal Affairs and Health; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; DIAB Core (German Network of Diabetes); Diabetes UK; Donald W. Reynolds Foundation; Dresden University of Technology; Med Drive; EMGO+ institute; Emil and Vera Cornell Foundation; Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Estonian Government [SF0180142s08]; European Commission [2004310, 212111, 205419, 245536, DG XII, HEALTH-F4-2007-201413, FP7/2007-2013, QLG1-CT-2000-01643, QLG2-CT-2002-01254, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHG-CT-2004-512066, LSHM-CT-2007-037273, EU/WLRT-2001-01254, LSHG-CT-2004-518153, SOC 95201408 05F02]; Federal Ministry of Education and Research, Germany [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 01 EA 9401]; Federal State of Mecklenburg-West Pomerania; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Pediatric Research; Finnish Foundation of Cardiovascular Research; Finnish Medical Society; Finska Lakaresallskapet; Finnish Ministry of Education; Folkhalsan Research Foundation; Fond Europeen pour le Developpement Regional; Fondation LeDucq; Foundation for Life and Health in Finland; GEN-AU 'GOLD' from Austria; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]; German National Genome Research Net NGFN2 and NGFNplus [01GS0823, FKZ 01GS0823]; German Research Council [KFO-152]; GlaxoSmithKline; Goteborg Medical Society; Gyllenberg Foundation; Health Care Center in Vasa; Healthway, Western Australia; Helmholtz Center Munich; Helsinki University Central Hospital; Hjartavernd (the Icelandic Heart Association); Ib Henriksen Foundation; IZKF [B27]; Jalmari and Rauha Ahokas Foundation; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International (JDRF); Karolinska Institute and the Stockholm County Council [560183]; Knut and Alice Wallenberg Foundation; Lundbeck Foundation Centre of Applied Medical Genomics; Knut Krohn, Microarray Core Facility of the Interdisciplinary Centre for Clinical Research (IZKF), University of Leipzig, Germany; MC Health; Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania, Germany; South Tyrol Ministry of Health; Ministry of Science, Education and Sport of the Republic of Croatia [216-1080315-0302]; Medical Research Council UK [G0000649, G0601261, G9521010D, G0000934, G0500539, G0600331]; Montreal Heart Institute Foundation; MRC Centre for Obesity-Related Metabolic Disease; Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Narpes Health Care Foundation; National Health and Medical Research Council of Australia and the Great Wine Estates Auctions; Netherlands Centre for Medical Systems Biology [SPI 56-464-1419]; Netherlands Ministry for Health; Welfare and Sports; Netherlands Ministry of Education, Culture and Science; Netherlands Genomics Initiative; Netherlands Consortium [050-060-810]; Netherlands Organisation of Scientific Research Netherlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Investments [175.010.2005.011, 911-03-012, 904-61-090, 904-61-193, 480-04-004, 400-05-717]; National Institute on Aging; US National Institutes of Health [CA047988, CA65725, CA87969, CA49449, CA67262, CA50385, DK075787, DK062370, DK58845, DK072193, K23-DK080145, K99HL094535, N01-HC85079, N01-HC85086, N01-HG-65403, N01-AG-12100, N01-HC-25195, N01-HC35129, N01-HC15103, N01-HC55222, N01-HC75150, N01-HC45133, N01-HC55015, N01-HC55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-AG-1-2109, HL71981, HG005581, HG002651, HL084729, HL043851, HHSN268200625226C, MH084698, P30-DK072488, R01 HL087652, R01-HL087641, R01-HL59367, R01-HL086694, R01-HL087647, R01-HL087679, R01-HL087700, R01-AG031890, R01-HL088119, R01-DK068336, R01-DK075681, R01-DK-073490, R01-DK075787, R01-MH63706, U01-HL72515, U01-GM074518, U01-HL084756, U01-HG004399, UO1-CA098233, UL1-RR025005, U01-HG004402, U01-DK062418, U01 HL080295, T32-HG00040, 263-MA-410953, 1RL1-MH083268-01, 1Z01-HG000024]; National Institute for Health Research (NIHR); Neuroscience Campus Amsterdam; Novo Nordisk Foundation; Novo Nordisk Inc.; Ollqvist Foundation; Paavo Nurmi Foundation; Paivikki and Sakari Sohlberg Foundation; Pew Scholarship for the Biomedical Sciences; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly [014-93-015]; Sahlgrenska Center for Cardiovascular and Metabolic Research (CMR) [A305:188]; Siemens Healthcare, Erlangen, Germany; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; Social Ministry of the Federal State of Mecklenburg-West Pomerania, Germany; South Tyrolean Sparkasse Foundation; State of Bavaria, Germany; Support for Science Funding programme; Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research (SSF); Swedish Medical Research Council [8691, K2007-66X-20270-01-3, K2010-54X-09894-19-3]; Swedish Society of Medicine; Swiss National Science Foundation [33CSCO-122661]; Royal Society; Royal Swedish Academy of Science; Torsten and Ragnar Soderberg's Foundation; Turku University Hospitals; UK Department of Health Policy Research Programme; University and Research of the Autonomous Province of Bolzano; University Hospital Medical; University Hospital Oulu, Biocenter, University of Oulu, Finland [75617]; Vastra Gotaland Foundation; Wellcome Trust [077016/Z/05/Z, 068545/Z/02, 072960, 076113, 083270, 085301, 079557, 081682, 075491, 076113/B/04/Z, 091746/Z/10/Z, 079895, WT086596/Z/08/Z]; Western Australian Genetic Epidemiology Resource; Western Australian DNA Bank (both National Health and Medical Research Council of Australia Enabling Facilities); Yrjo Jahnsson Foundation; AstraZeneca AB; Lundberg Foundation; Swedish Heart-Lung Foundation; Research Foundation of Copenhagen County; Health care center in Nerpes; Health care center in Korsholm FX Funding for this study was provided by the Academy of Finland (grants 104781, 120315, 129269, 117797, 121584, 126925, 129418, 129568, 77299, 124243, 213506, 129680, 129494, 10404, 213506, 129680, 114382, 126775, 127437, 129255, 129306, 130326, 209072, 210595, 213225 and 216374); an ADA Mentor-Based Postdoctoral Fellowship grant; Affymetrix, Inc., for genotyping services (N02-HL-6-4278); ALF/LUA Gothenburg; Althingi (the Icelandic Parliament); Amgen; AstraZeneca AB; Augustinus Foundation; Becket Foundation; Biocentrum Helsinki; Biomedicum Helsinki Foundation; Boston Obesity Nutrition Research Center (DK46200); British Diabetes Association (1192); British Diabetic Association Research; British Heart Foundation (97020, PG/02/128); Busselton Population Medical Research Foundation; Cambridge NIHR Comprehensive Biomedical Research Centre; CamStrad; Chief Scientist Office of the Scottish Government; Contrat Plan Etat Region de France; Danish Centre for Health Technology Assessment; Danish Diabetes Association; Danish Ministry of Internal Affairs and Health; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; DIAB Core (German Network of Diabetes); Diabetes UK; Donald W.; Reynolds Foundation; Dresden University of Technology Funding Grant, Med Drive; EMGO+ institute; Emil and Vera Cornell Foundation; Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Estonian Government SF0180142s08; European Commission (2004310, 212111, 205419, 245536, DG XII, HEALTH-F4-2007-201413, FP7/2007-2013, QLG1-CT-2000-01643, QLG2-CT-2002-01254, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHG-CT-2004-512066, LSHM-CT-2007-037273, EU/WLRT-2001-01254, LSHG-CT-2004-518153, SOC 95201408 05F02, Marie Curie Intra-European Fellowship); Federal Ministry of Education and Research, Germany (01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 01 EA 9401); Federal State of Mecklenburg-West Pomerania; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Pediatric Research; Finnish Foundation of Cardiovascular Research; Finnish Medical Society; Finska Lakaresallskapet; Finnish Ministry of Education; Folkhalsan Research Foundation; Fond Europeen pour le Developpement Regional; Fondation LeDucq; Foundation for Life and Health in Finland; GEN-AU 'GOLD' from Austria; German Bundesministerium fuer Forschung und Technology (# 01 AK 803 A-H, # 01 IG 07015 G); German National Genome Research Net NGFN2 and NGFNplus (01GS0823, FKZ 01GS0823); German Research Council (KFO-152); GlaxoSmithKline; Goteborg Medical Society; Gyllenberg Foundation; Health Care Centers in Vasa, Narpes and Korsholm; Healthway, Western Australia; Helmholtz Center Munich; Helsinki University Central Hospital; Hjartavernd ( the Icelandic Heart Association); Ib Henriksen Foundation; IZKF (B27); Jalmari and Rauha Ahokas Foundation; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International (JDRF); Karolinska Institute and the Stockholm County Council (560183); Knut and Alice Wallenberg Foundation; Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care; Knut Krohn, Microarray Core Facility of the Interdisciplinary Centre for Clinical Research (IZKF), University of Leipzig, Germany; Lundberg Foundation; MC Health; Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania, Germany; South Tyrol Ministry of Health; Ministry of Science, Education and Sport of the Republic of Croatia (216-1080315-0302); Medical Research Council UK (G0000649, G0601261, 9521010D, G0000934, G0500539, G0600331, PrevMetSyn); Montreal Heart Institute Foundation; MRC Centre for Obesity-Related Metabolic Disease; Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Narpes Health Care Foundation; National Health and Medical Research Council of Australia and the Great Wine Estates Auctions; Netherlands Centre for Medical Systems Biology (SPI 56-464-1419); Netherlands Ministry for Health, Welfare and Sports; Netherlands Ministry of Education, Culture and Science; Netherlands Genomics Initiative; Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation of Scientific Research Netherlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Investments (175.010.2005.; 011, 911-03-012, 904-61-090, 904-61-193, 480-04-004, 400-05-717); National Institute on Aging Intramural Research Program; US National Institutes of Health (CA047988, CA65725, CA87969, CA49449, CA67262, CA50385, DK075787, DK062370, DK58845, DK072193, K23-DK080145, K99HL094535, N01-HC85079 through N01-HC85086, N01-HG-65403, N01-AG-12100, N01-HC-25195, N01-HC35129, N01-HC15103, N01-HC55222, N01-HC75150, N01-HC45133, N01-HC55015, N01-HC55016, N01-HC-55018, N01-HC-5019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-AG-1-2109, HL71981, HG005581, HG002651, HL084729, HL043851, HHSN268200625226C, K23-DK080145, MH084698, P30-DK072488, R01-DK075787, R01 HL087652, R01-HL087641, R01-HL59367, R01-HL086694, R01-HL087647, R01-HL087679, R01-HL087700, R01-AG031890, R01-HL088119, R01-DK068336, R01-DK075681, R01-DK-073490, R01-DK075787, R01-MH63706, U01-HL72515, U01-GM074518, U01-HL084756, U01-HG004399, UO1-CA098233, UL1-RR025005, UL1-RR025005, U01-HG004402, U01-DK062418, U01 HL080295, T32-HG00040, 263-MA-410953, 1RL1-MH083268-01, intramural project 1Z01-HG000024); National Institute for Health Research (NIHR); Neuroscience Campus Amsterdam; Novo Nordisk Foundation; Novo Nordisk Inc., Research Foundation of Copenhagen County; Ollqvist Foundation; Paavo Nurmi Foundation; Paivikki and Sakari Sohlberg Foundation; Pew Scholarship for the Biomedical Sciences; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly (014-93-015, RIDE, RIDE2); Sahlgrenska Center for Cardiovascular and Metabolic Research (CMR, A305:188); Siemens Healthcare, Erlangen, Germany; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; Social Ministry of the Federal State of Mecklenburg-West Pomerania, Germany; South Tyrolean Sparkasse Foundation; State of Bavaria, Germany; Support for Science Funding programme; Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research (SSF); Swedish Heart-Lung Foundation; Swedish Medical Research Council (8691, K2007-66X-20270-01-3, K2010-54X-09894-19-3); Swedish Society of Medicine; Swiss National Science Foundation (33CSCO-122661); the Royal Society; the Royal Swedish Academy of Science; Torsten and Ragnar Soderberg's Foundation; Turku University Hospitals; UK Department of Health Policy Research Programme; University and Research of the Autonomous Province of Bolzano; University Hospital Medical funds to Tampere; University Hospital Oulu, Biocenter, University of Oulu, Finland (75617); Vastra Gotaland Foundation; Wellcome Trust (077016/Z/05/Z, 068545/Z/02, 072960, 076113, 083270, 085301, 079557, 081682, 075491, 076113/B/04/Z, 091746/Z/10/Z, 079895, WT086596/Z/08/Z, WT Research Career Development Fellowship; WT Career Development Award); Western Australian Genetic Epidemiology Resource and the Western Australian DNA Bank (both National Health and Medical Research Council of Australia Enabling Facilities); Yrjo Jahnsson Foundation. NR 61 TC 408 Z9 419 U1 9 U2 79 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 NOV PY 2010 VL 42 IS 11 BP 949 EP U160 DI 10.1038/ng.685 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 671VW UT WOS:000283540500011 PM 20935629 ER PT J AU Rothman, N Garcia-Closas, M Chatterjee, N Malats, N Wu, XF Figueroa, JD Real, FX Van den Berg, D Matullo, G Baris, D Thun, M Kiemeney, LA Vineis, P De Vivo, I Albanes, D Purdue, MP Rafnar, T Hildebrandt, MAT Kiltie, AE Cussenot, O Golka, K Kumar, R Taylor, JA Mayordomo, JI Jacobs, KB Kogevinas, M Hutchinson, A Wang, ZW Fu, YP Prokunina-Olsson, L Burdett, L Yeager, M Wheeler, W Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Johnson, A Schwenn, M Karagas, MR Schned, A Andriole, G Grubb, R Black, A Jacobs, EJ Diver, WR Gapstur, SM Weinstein, SJ Virtamo, J Cortessis, VK Gago-Dominguez, M Pike, MC Stern, MC Yuan, JM Hunter, DJ McGrath, M Dinney, CP Czerniak, B Chen, M Yang, HS Vermeulen, SH Aben, KK Witjes, JA Makkinje, RR Sulem, P Besenbacher, S Stefansson, K Riboli, E Brennan, P Panico, S Navarro, C Allen, NE Bueno-De-Mesquita, HB Trichopoulos, D Caporaso, N Landi, MT Canzian, F Ljungberg, B Tjonneland, A Clavel-Chapelon, F Bishop, DT Teo, MTW Knowles, MA Guarrera, S Polidoro, S Ricceri, F Sacerdote, C Allione, A Cancel-Tassin, G Selinski, S Hengstler, JG Dietrich, H Fletcher, T Rudnai, P Gurzau, E Koppova, K Bolick, SCE Godfrey, A Xu, ZL Sanz-Velez, JI Garcia-Prats, MD Sanchez, M Valdivia, G Porru, S Benhamou, S Hoover, RN Fraumeni, JF Silverman, DT Chanock, SJ AF Rothman, Nathaniel Garcia-Closas, Montserrat Chatterjee, Nilanjan Malats, Nuria Wu, Xifeng Figueroa, Jonine D. Real, Francisco X. Van den Berg, David Matullo, Giuseppe Baris, Dalsu Thun, Michael Kiemeney, Lambertus A. Vineis, Paolo De Vivo, Immaculata Albanes, Demetrius Purdue, Mark P. Rafnar, Thorunn Hildebrandt, Michelle A. T. Kiltie, Anne E. Cussenot, Olivier Golka, Klaus Kumar, Rajiv Taylor, Jack A. Mayordomo, Jose I. Jacobs, Kevin B. Kogevinas, Manolis Hutchinson, Amy Wang, Zhaoming Fu, Yi-Ping Prokunina-Olsson, Ludmila Burdett, Laurie Yeager, Meredith Wheeler, William Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Johnson, Alison Schwenn, Molly Karagas, Margaret R. Schned, Alan Andriole, Gerald, Jr. Grubb, Robert, III Black, Amanda Jacobs, Eric J. Diver, W. Ryan Gapstur, Susan M. Weinstein, Stephanie J. Virtamo, Jarmo Cortessis, Victoria K. Gago-Dominguez, Manuela Pike, Malcolm C. Stern, Mariana C. Yuan, Jian-Min Hunter, David J. McGrath, Monica Dinney, Colin P. Czerniak, Bogdan Chen, Meng Yang, Hushan Vermeulen, Sita H. Aben, Katja K. Witjes, J. Alfred Makkinje, Remco R. Sulem, Patrick Besenbacher, Soren Stefansson, Kari Riboli, Elio Brennan, Paul Panico, Salvatore Navarro, Carmen Allen, Naomi E. Bueno-de-Mesquita, H. Bas Trichopoulos, Dimitrios Caporaso, Neil Landi, Maria Teresa Canzian, Federico Ljungberg, Borje Tjonneland, Anne Clavel-Chapelon, Francoise Bishop, David T. Teo, Mark T. W. Knowles, Margaret A. Guarrera, Simonetta Polidoro, Silvia Ricceri, Fulvio Sacerdote, Carlotta Allione, Alessandra Cancel-Tassin, Geraldine Selinski, Silvia Hengstler, Jan G. Dietrich, Holger Fletcher, Tony Rudnai, Peter Gurzau, Eugen Koppova, Kvetoslava Bolick, Sophia C. E. Godfrey, Ashley Xu, Zongli Sanz-Velez, Jose I. Garcia-Prats, Maria D. Sanchez, Manuel Valdivia, Gabriel Porru, Stefano Benhamou, Simone Hoover, Robert N. Fraumeni, Joseph F., Jr. Silverman, Debra T. Chanock, Stephen J. TI A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci SO NATURE GENETICS LA English DT Article ID CONFERS SUSCEPTIBILITY; UDP-GLUCURONOSYLTRANSFERASES; RECOMBINATION HOTSPOTS; TELOMERASE MUTATIONS; PULMONARY-FIBROSIS; SEQUENCE VARIANT; COMMON VARIANTS; CHROMOSOME 8Q24; DOWN-REGULATION; CELL-CARCINOMA AB We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 x 10(-12)) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 x 10(-11)) on 19q12 maps to CCNE1 and rs11892031 (P = 1 x 10(-7)) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 x 10(-11)) and a tag SNP for NAT2 acetylation status (P = 4 x 10(-11)), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis. C1 [Rothman, Nathaniel; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Figueroa, Jonine D.; Baris, Dalsu; Albanes, Demetrius; Purdue, Mark P.; Fu, Yi-Ping; Prokunina-Olsson, Ludmila; Black, Amanda; Weinstein, Stephanie J.; Caporaso, Neil; Landi, Maria Teresa; Hoover, Robert N.; Fraumeni, Joseph F., Jr.; Silverman, Debra T.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Malats, Nuria; Real, Francisco X.] Spanish Natl Canc Res Ctr, Madrid, Spain. [Wu, Xifeng; Hildebrandt, Michelle A. T.; Chen, Meng; Yang, Hushan] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Van den Berg, David; Cortessis, Victoria K.; Gago-Dominguez, Manuela; Pike, Malcolm C.; Stern, Mariana C.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Matullo, Giuseppe] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Matullo, Giuseppe; Vineis, Paolo; Guarrera, Simonetta; Polidoro, Silvia; Ricceri, Fulvio; Sacerdote, Carlotta; Allione, Alessandra] Human Genet Fdn HuGeF, Turin, Italy. [Thun, Michael; Jacobs, Eric J.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kiemeney, Lambertus A.; Vermeulen, Sita H.; Aben, Katja K.] Radboud Univ Nijmegen Med Ctr, Dept Epidemiol Biostat & Hlth Technol Assessment, Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Comprehens Canc Ctr E, Nijmegen, Netherlands. [Kiemeney, Lambertus A.; Witjes, J. Alfred] Radboud Univ Nijmegen Med Ctr, Dept Urol, Nijmegen, Netherlands. [Vineis, Paolo; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, London, England. [De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Rafnar, Thorunn; Sulem, Patrick; Besenbacher, Soren; Stefansson, Kari] DeCODE Genet, Reykjavik, Iceland. [Kiltie, Anne E.] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford, England. [Cussenot, Olivier] Tenon Hosp, AP HP, Dept Urol, Paris, France. [Cussenot, Olivier; Cancel-Tassin, Geraldine] Ctr Rech Pathol Prostat, Paris, France. [Golka, Klaus; Selinski, Silvia; Hengstler, Jan G.] Leibniz Res Ctr Working Environm & Human Factor, Dortmund, Germany. [Kumar, Rajiv] German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany. [Taylor, Jack A.; Bolick, Sophia C. E.; Godfrey, Ashley; Xu, Zongli] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Mayordomo, Jose I.; Sanchez, Manuel; Valdivia, Gabriel] Univ Zaragoza, Zaragoza, Spain. [Jacobs, Kevin B.; Hutchinson, Amy; Wang, Zhaoming; Burdett, Laurie; Yeager, Meredith] SAIC Frederick Inc, Natl Canc Inst Frederick, Core Genotype Facil, Frederick, MD USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis] Municipal Inst Med Res, Barcelona, Spain. [Kogevinas, Manolis; Tardon, Adonina; Navarro, Carmen] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Tardon, Adonina] Univ Oviedo, Inst Univ Oncol, Oviedo, Spain. [Carrato, Alfredo] Ramon & Cajal Univ Hosp, Madrid, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Lloreta, Josep] Univ Pompeu Fabra, Hosp Mar Inst Municipal Invest Med IMIM, Barcelona, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Karagas, Margaret R.; Schned, Alan] Dartmouth Med Sch, Hanover, NH USA. [Andriole, Gerald, Jr.; Grubb, Robert, III] Washington Univ, Sch Med, Dept Urol, St Louis, MO USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki, Finland. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Yuan, Jian-Min] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Hunter, David J.; McGrath, Monica] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Dinney, Colin P.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Czerniak, Bogdan] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Vermeulen, Sita H.; Makkinje, Remco R.] Radboud Univ Nijmegen Med Ctr, Dept Human Genet, Nijmegen, Netherlands. [Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Panico, Salvatore] Univ Naples Federico 2, Dept Clin & Expt Med, Naples, Italy. [Navarro, Carmen] Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Ljungberg, Borje] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Tjonneland, Anne] Inst Canc Epidemiol, Danish Canc Soc, Copenhagen, Denmark. [Clavel-Chapelon, Francoise] Paris S Univ, Inst Gustave Roussy, Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Bishop, David T.; Teo, Mark T. W.; Knowles, Margaret A.] Univ Leeds, St Jamess Univ Hosp, Leeds Inst Mol Med, Leeds, W Yorkshire, England. [Sacerdote, Carlotta] Univ Turin, Canc Epidemiol Unit, Turin, Italy. [Dietrich, Holger] Paul Gerhardt Fdn, Dept Urol, Wittenberg, Germany. [Fletcher, Tony] Inst Hyg & Trop Med, London, England. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Gurzau, Eugen] Univ Babes Bolyai, Ctr Environm Hlth, R-3400 Cluj Napoca, Romania. [Koppova, Kvetoslava] State Hlth Inst, Banska Bystrica, Slovakia. [Sanz-Velez, Jose I.; Garcia-Prats, Maria D.] San Jorge Univ Hosp, Huesca, Spain. [Porru, Stefano] Univ Brescia, Sect Occupat Med & Ind Hyg, Dept Expt & Appl Med, Brescia, Italy. [Benhamou, Simone] CEPH, Fdn Jean Dausset, U946, INSERM, Paris, France. [Benhamou, Simone] Inst Gustave Roussy, UMR8200, CNRS, Villejuif, France. RP Garcia-Closas, M (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM montse.garciaclosas@icr.ac.uk RI Purdue, Mark/C-9228-2016; Vermeulen, H.H.M./L-4716-2015; Aben, Katja/G-9686-2016; Benhamou, Simone/K-6554-2015; Matullo, Giuseppe/K-6383-2016; Panico, Salvatore/K-6506-2016; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; Albanes, Demetrius/B-9749-2015; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Makkinje, Remco/Q-2406-2015; Mayordomo, Jose/K-3453-2013; Hengstler, Jan/O-1415-2013; Witjes, Fred/N-9665-2013; Kiemeney, Lambertus/D-3357-2009; Serra, C/E-6879-2014; Clavel-Chapelon, Francoise/G-6733-2014; Lloreta, J/I-2112-2014 OI MATULLO, Giuseppe/0000-0003-0674-7757; Yuan, Jian-Min/0000-0002-4620-3108; Sacerdote, Carlotta/0000-0002-8008-5096; xu, zongli/0000-0002-9034-8902; Bishop, Tim/0000-0002-8752-8785; taylor, jack/0000-0001-5303-6398; Besenbacher, Soren/0000-0003-1455-1738; Cancel-Tassin, Geraldine/0000-0002-9583-6382; Purdue, Mark/0000-0003-1177-3108; Aben, Katja/0000-0002-0214-2147; Panico, Salvatore/0000-0002-5498-8312; Kumar, Rajiv/0000-0002-6093-0395; Kiltie, Anne/0000-0001-7208-2912; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Real, Francisco X/0000-0001-9501-498X; Allione, Alessandra/0000-0001-9599-309X; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Kiemeney, Lambertus/0000-0002-2368-1326; Serra, C/0000-0001-8337-8356; Lloreta, J/0000-0003-1644-9470 FU National Cancer Institute, US National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with federal funds from the National Cancer Institute, US National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 52 TC 214 Z9 221 U1 1 U2 43 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 NOV PY 2010 VL 42 IS 11 BP 978 EP U98 DI 10.1038/ng.687 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 671VW UT WOS:000283540500015 PM 20972438 ER PT J AU Dinarello, C Arend, W Sims, J Smith, D Blumberg, H O'Neill, L Goldbach-Mansky, R Pizarro, T Hoffman, H Bufler, P Nold, M Ghezzi, P Mantovani, A Garlanda, C Boraschi, D Rubartelli, A Netea, M van der Meer, J Joosten, L Mandrup-Poulsen, T Donath, M Lewis, E Pfeilschifter, J Martin, M Kracht, M Muehl, H Novick, D Lukic, M Conti, B Solinger, A Peyman, K van de Veerdonk, F Gabel, C AF Dinarello, Charles Arend, William Sims, John Smith, Dirk Blumberg, Hal O'Neill, Luke Goldbach-Mansky, Raphaela Pizarro, Theresa Hoffman, H. Bufler, Philip Nold, Marcel Ghezzi, Pietro Mantovani, Alberto Garlanda, Cecilia Boraschi, Diana Rubartelli, Anna Netea, Mihai van der Meer, Jos Joosten, Leo Mandrup-Poulsen, Tom Donath, Marc Lewis, Eli Pfeilschifter, Josef Martin, Michael Kracht, Michael Muehl, H. Novick, Daniela Lukic, Miodrag Conti, Bruno Solinger, Alan Peyman, Kelk van de Veerdonk, Frank Gabel, Chiristopher TI IL-1 family nomenclature SO NATURE IMMUNOLOGY LA English DT Letter ID NF-KAPPA-B; INTERLEUKIN-1 FAMILY; MEMBERS; IDENTIFICATION C1 [Dinarello, Charles] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Arend, William] Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO USA. [Blumberg, Hal] Novo Nordisk Inflammat Res Ctr, Dept Cellular Immunol, Seattle, WA USA. [O'Neill, Luke] Trinity Coll Dublin, Dept Biochem, Dublin, Ireland. [Goldbach-Mansky, Raphaela] Natl Inst Hlth, Natl Inst Arthrit, Translat Autoinflammatory Dis Sect, Bethesda, MD USA. [Pizarro, Theresa] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Hoffman, H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Bufler, Philip] Univ Munich, Dept Pediat, Munich, Germany. [Nold, Marcel] Monash Univ, Monash Inst Med Res, Melbourne, Australia. [Ghezzi, Pietro] Brighton & Sussex Med Sch, Div Clin & Lab Investigat, Falmer, England. [Mantovani, Alberto; Garlanda, Cecilia] Ist Clin Humanitas, Dept Inflammat, Milan, Italy. [Boraschi, Diana] Inst Biomed Technol, Immunol Unit, Natl Res Council, Pisa, Italy. [Rubartelli, Anna] Natl Inst Canc Res, Genoa, Italy. [Netea, Mihai; van der Meer, Jos] Radboud Univ Nijmegen Med Ctr, Dept Med, Nijmegen, Netherlands. [Joosten, Leo] Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, NL-6525 ED Nijmegen, Netherlands. [Mandrup-Poulsen, Tom] Steno Diabet Ctr, Copenhagen, Denmark. [Donath, Marc] Univ Basel Hosp, Dept Diabet Endocrinol & Metab, CH-4031 Basel, Switzerland. [Lewis, Eli] Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. [Pfeilschifter, Josef] Goethe Univ Frankfurt, Frankfurt, Germany. [Martin, Michael] Justus Liebig Univ, Dept Biol & Chem, Giessen, Germany. [Kracht, Michael] Justus Liebig Univ, Rudolf Buchheim Inst Pharmacol, Giessen, Germany. [Muehl, H.] Univ Hosp Goethe Univ Frankfurt, Pharmazentrum Frankfurt, Frankfurt, Germany. [Novick, Daniela] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Lukic, Miodrag] United Arab Emirates Univ, Dept Microbiol & Immunol, Al Ain, U Arab Emirates. [Conti, Bruno] Scripps Res Inst, Dept Mol & Integrat Neurosci, La Jolla, CA 92037 USA. [Solinger, Alan] XOMA, Berkeley, CA USA. [Peyman, Kelk] Umea Univ, Umea, Sweden. [van de Veerdonk, Frank] Radboud Univ Nijmegen Med Ctr, Nijmegen, Netherlands. RP Dinarello, C (reprint author), Univ Colorado Denver, Dept Med, Aurora, CO USA. RI LEWIS, ELI/F-1552-2012; van de Veerdonk, Frank/C-7256-2008; Netea, Mihai/N-5155-2014; van der Meer, Jos/C-8521-2013; Garlanda, Cecilia/K-4601-2016; OI van de Veerdonk, Frank/0000-0002-1121-4894; van der Meer, Jos/0000-0001-5120-3690; Garlanda, Cecilia/0000-0002-1510-7703; Kelk, Peyman/0000-0003-1594-1738; Mantovani, Alberto/0000-0001-5578-236X; Nold, Marcel/0000-0001-9682-4618; Ghezzi, Pietro/0000-0003-0911-8358 FU Intramural NIH HHS [ZIA AR041138-11] NR 16 TC 105 Z9 119 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2010 VL 11 IS 11 BP 973 EP 973 DI 10.1038/ni1110-973 PG 1 WC Immunology SC Immunology GA 666PI UT WOS:000283127800002 PM 20959797 ER PT J AU Maecker, HT McCoy, JP AF Maecker, Holden T. McCoy, J. Philip, Jr. CA FOCIS Human Immunophenotyping Cons TI A model for harmonizing flow cytometry in clinical trials SO NATURE IMMUNOLOGY LA English DT Article ID FICOLL-HYPAQUE SEPARATION; BLOOD MONONUCLEAR-CELLS; WHOLE-BLOOD; T-CELLS; LYSIS TECHNIQUE; NORMAL ADULTS; ASSAYS; CRYOPRESERVATION; ANTICOAGULANT; INFORMATION C1 [Maecker, Holden T.] Stanford Univ, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [McCoy, J. Philip, Jr.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Maecker, HT (reprint author), Stanford Univ, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. EM maecker@stanford.edu OI Denny, Thomas/0000-0002-7364-8276 FU Intramural NIH HHS [ZIC HL005905-02, Z99 HL999999, ZIC HL005905-03, ZIC HL005905-04] NR 26 TC 55 Z9 57 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2010 VL 11 IS 11 BP 975 EP 978 DI 10.1038/ni1110-975 PG 4 WC Immunology SC Immunology GA 666PI UT WOS:000283127800003 PM 20959798 ER PT J AU Unterholzner, L Keating, SE Baran, M Horan, KA Jensen, SB Sharma, S Sirois, CM Jin, TC Latz, E Xiao, TS Fitzgerald, KA Paludan, SR Bowie, AG AF Unterholzner, Leonie Keating, Sinead E. Baran, Marcin Horan, Kristy A. Jensen, Soren B. Sharma, Shruti Sirois, Cherilyn M. Jin, Tengchuan Latz, Eicke Xiao, T. Sam Fitzgerald, Katherine A. Paludan, Soren R. Bowie, Andrew G. TI IFI16 is an innate immune sensor for intracellular DNA SO NATURE IMMUNOLOGY LA English DT Article ID CYTOSOLIC DNA; CYTOPLASMIC DNA; I INTERFERONS; IFN-BETA; RECOGNITION; PROTEIN; ACTIVATION; RNA; INFLAMMASOME; INDUCTION AB The detection of intracellular microbial DNA is critical to appropriate innate immune responses; however, knowledge of how such DNA is sensed is limited. Here we identify IFI16, a PYHIN protein, as an intracellular DNA sensor that mediates the induction of interferon-beta (IFN-beta). IFI16 directly associated with IFN-beta-inducing viral DNA motifs. STING, a critical mediator of IFN-beta responses to DNA, was recruited to IFI16 after DNA stimulation. Lowering the expression of IFI16 or its mouse ortholog p204 by RNA-mediated interference inhibited gene induction and activation of the transcription factors IRF3 and NF-kappa B induced by DNA and herpes simplex virus type 1 (HSV-1). IFI16 (p204) is the first PYHIN protein to our knowledge shown to be involved in IFN-beta induction. Thus, the PYHIN proteins IFI16 and AIM2 form a new family of innate DNA sensors we call 'AIM2-like receptors' (ALRs). C1 [Unterholzner, Leonie; Keating, Sinead E.; Baran, Marcin; Bowie, Andrew G.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland. [Horan, Kristy A.; Jensen, Soren B.; Paludan, Soren R.] Aarhus Univ, Dept Med Microbiol & Immunol, Aarhus, Denmark. [Jensen, Soren B.; Sharma, Shruti; Sirois, Cherilyn M.; Latz, Eicke; Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA USA. [Jin, Tengchuan; Xiao, T. Sam] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Latz, Eicke] Univ Bonn, Inst Clin Chem & Pharmacol, D-5300 Bonn, Germany. RP Bowie, AG (reprint author), Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland. EM agbowie@tcd.ie RI Xiao, Tsan/I-7616-2013; Xiao, Tsan/A-8590-2010; Jin, Tengchuan/B-5883-2014; Latz, Eicke/H-3951-2014; OI Xiao, Tsan/0000-0001-9688-475X; Sirois, Cherilyn M./0000-0002-5472-4288; Unterholzner, Leonie/0000-0001-9824-692X; Jin, Tengchuan/0000-0002-1395-188X; Latz, Eicke/0000-0003-1488-5666; Bowie, Andrew/0000-0001-5316-4373 FU Science Foundation Ireland [07/IN1/B934]; Irish Health Research Board; Danish Medical Research Council [09-072636]; Lundbeck Foundation [R17-A1528, R34-A3855]; US National Institutes of Health [AI083713, AI067497]; Faculty of Health Sciences, Aarhus FX We thank C. Liu (New York University) for antibody to p204; S. Akira (Osaka University) for Myd88-/-, Ticam1-/- and Zbp1-/- mice; T. Taniguchi (University of Tokyo) for Irf3-/- mice; M. Kelliher (University of Massachusetts Medical School) for Tnfrsf1a-/- mice; T. Mak (University of Toronto) for Tbk1-/- Tnfrsf1a-/- mice; G. Barber (University of Miami) for Tmem173-/- femurs; D. Golenbock (University of Massachusetts Medical School) for immortalized BMDMs lacking MyD88 or TRIF; I. Julkunen (National Public Health Institute, Finland) for Sendai virus; and S. Corr (Trinity College Dublin) for Listeria monocytogenes DNA. Supported by Science Foundation Ireland (07/IN1/B934 to L.U., S.E.K., M.B. and A.G.B.), the Irish Health Research Board (S.E.K. and A.G.B.), the Danish Medical Research Council (09-072636 to S.R.P.), the Lundbeck Foundation (R17-A1528 to S.R.P. and R34-A3855 to K.A.H.), the US National Institutes of Health (AI083713 and AI067497 to K.A.F.; Division of Intramural Research, National Institute of Allergy and Infectious Diseases to T.S.X.) and the Faculty of Health Sciences, Aarhus (S.B.J.). NR 42 TC 571 Z9 599 U1 9 U2 71 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2010 VL 11 IS 11 BP 997 EP U42 DI 10.1038/ni.1932 PG 9 WC Immunology SC Immunology GA 666PI UT WOS:000283127800009 PM 20890285 ER PT J AU Strober, W AF Strober, Warren TI Gut microbes: friends or fiends? SO NATURE MEDICINE LA English DT Editorial Material ID INFLAMMATORY BOWEL DISEASES; IMMUNE-SYSTEM; T-CELLS; MICROFLORA C1 US Natl Inst Allergy & Infect Dis, Mucosal Immun Sect, Host Def Lab, Bethesda, MD USA. RP Strober, W (reprint author), US Natl Inst Allergy & Infect Dis, Mucosal Immun Sect, Host Def Lab, Bethesda, MD USA. EM wstrober@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000354-25] NR 14 TC 11 Z9 12 U1 1 U2 5 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 NOV PY 2010 VL 16 IS 11 BP 1195 EP 1197 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 675TV UT WOS:000283860100023 PM 21052070 ER PT J AU De Keersmaecker, K Real, PJ Della Gatta, G Palomero, T Sulis, ML Tosello, V Van Vlierberghe, P Barnes, K Castillo, M Sole, X Hadler, M Lenz, J Aplan, PD Kelliher, M Kee, BL Pandolfi, PP Kappes, D Gounari, F Petrie, H Van der Meulen, J Speleman, F Paietta, E Racevskis, J Wiernik, PH Rowe, JM Soulier, J Avran, D Cave, H Dastugue, N Raimondi, S Meijerink, JPP Cordon-Cardo, C Califano, A Ferrando, AA AF De Keersmaecker, Kim Real, Pedro J. Della Gatta, Giusy Palomero, Teresa Luisa Sulis, Maria Tosello, Valeria Van Vlierberghe, Pieter Barnes, Kelly Castillo, Mireia Sole, Xavier Hadler, Michael Lenz, Jack Aplan, Peter D. Kelliher, Michelle Kee, Barbara L. Pandolfi, Pier Paolo Kappes, Dietmar Gounari, Fotini Petrie, Howard Van der Meulen, Joni Speleman, Frank Paietta, Elisabeth Racevskis, Janis Wiernik, Peter H. Rowe, Jacob M. Soulier, Jean Avran, David Cave, Helene Dastugue, Nicole Raimondi, Susana Meijerink, Jules P. P. Cordon-Cardo, Carlos Califano, Andrea Ferrando, Adolfo A. TI The TLX1 oncogene drives aneuploidy in T cell transformation SO NATURE MEDICINE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION; TRANSGENIC MICE; MUTATIONS; HOX11; SURVIVAL; BCL11B; NOTCH1; LYMPHOMAGENESIS; LYMPHOCYTES AB The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer. C1 [De Keersmaecker, Kim; Real, Pedro J.; Della Gatta, Giusy; Palomero, Teresa; Luisa Sulis, Maria; Tosello, Valeria; Van Vlierberghe, Pieter; Barnes, Kelly; Hadler, Michael; Califano, Andrea; Ferrando, Adolfo A.] Columbia Univ, Inst Canc Genet, New York, NY 10027 USA. [De Keersmaecker, Kim] VIB, Dept Mol & Dev Genet, Louvain, Belgium. [De Keersmaecker, Kim] Katholieke Univ Leuven, Ctr Human Genet, Louvain, Belgium. [Palomero, Teresa; Castillo, Mireia; Cordon-Cardo, Carlos; Ferrando, Adolfo A.] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA. [Luisa Sulis, Maria; Ferrando, Adolfo A.] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA. [Sole, Xavier] Inst Invest Biomed Bellvitge, Biomarkers & Susceptibil Unit, Catalan Inst Oncol, Barcelona, Spain. [Sole, Xavier] IDIBELL, Biomed Res Ctr Network Epidemiol & Publ Hlth, Catalan Inst Oncol, Barcelona, Spain. [Lenz, Jack] Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10467 USA. [Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kelliher, Michelle] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA USA. [Kee, Barbara L.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Dept Med, Beth Israel Deaconess Canc Ctr, Boston, MA USA. [Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Canc Ctr, Boston, MA 02115 USA. [Kappes, Dietmar] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Gounari, Fotini] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Petrie, Howard] Scripps Res Inst, Dept Canc Biol, Jupiter, FL USA. [Van der Meulen, Joni; Speleman, Frank] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Paietta, Elisabeth; Racevskis, Janis; Wiernik, Peter H.] Montefiore Med Ctr, North Div, New York, NY USA. [Paietta, Elisabeth; Racevskis, Janis; Wiernik, Peter H.] New York Med Coll, New York, NY USA. [Rowe, Jacob M.] Technion Israel Inst Technol, Haifa, Israel. [Soulier, Jean; Avran, David] Hop St Louis, AP HP, Hematol Lab, Paris, France. [Soulier, Jean; Avran, David] Hop St Louis, INSERM, U944, Paris, France. [Soulier, Jean; Avran, David] Univ Paris 07, Hop St Louis, Inst Univ Hematol, Paris, France. [Cave, Helene] Univ Paris 07, Hop Robert Debre, AP HP, Dept Genet, Paris, France. [Dastugue, Nicole] Hop Purpan, Hematol Lab, Toulouse, France. [Raimondi, Susana] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Meijerink, Jules P. P.] Sophia Childrens Univ Hosp, Erasmus MC, Dept Pediat Oncology Hematol, Rotterdam, Netherlands. [Califano, Andrea] Columbia Univ, Joint Ctr Syst Biol, New York, NY USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. RP Ferrando, AA (reprint author), Columbia Univ, Inst Canc Genet, New York, NY 10027 USA. EM af2196@columbia.edu RI Califano, Andrea/F-7239-2012; Van Vlierberghe, Pieter/G-8894-2013; Castillo-Martin, Mireia/H-6152-2013; Real, Pedro/K-2994-2014; Aplan, Peter/K-9064-2016; Ferrando, Adolfo /Q-7026-2016; Meijerink, Jules/D-4393-2017; OI De Keersmaecker, Kim/0000-0002-7420-9531; Van Vlierberghe, Pieter/0000-0001-9063-7205; Real, Pedro/0000-0001-7968-5353; Meijerink, Jules/0000-0002-6860-798X; Sole, Xavier/0000-0002-2197-3325; Tosello, Valeria/0000-0001-9560-340X FU New York Community Trust; US National Institutes of Health [R01CA120196, R01CA129382, CA21765, U24 CA114737]; Eastern Cooperative Oncology Group tumor bank; European Organization for Research and Treatment of Cancer Children Leukemia Group; Leukemia & Lymphoma Society Scholar Award; US National Institutes of Health; Fonds voor Wetenschappelijk Onderzoek-Vlaanderen; Belgian American Educational Foundation; France National Cancer Institute FX This work was supported by a Blood Disease Research Project research grant from The New York Community Trust (A.A.F.); the US National Institutes of Health (grants R01CA120196 and R01CA129382 to A.A.F.; CA21765 to S.R. and U24 CA114737 to E.P.), the Spanish Ministry of Science and Innovation (fellowship EX-2006-0739 to P.J.R.), a Canceropole Ile-de-France Research research grant (J.S.), the Eastern Cooperative Oncology Group tumor bank and the European Organization for Research and Treatment of Cancer Children Leukemia Group, the Leukemia & Lymphoma Society Scholar Award (A.A.F.) and the Intramural Program of the US National Institutes of Health (P.D.A.). K.D.K. is a postdoctoral researcher funded by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen and a recipient of a Belgian American Educational Foundation fellowship. D.A. is recipient of a predoctoral fellowship from the France National Cancer Institute. We are also grateful to T. Ludwig for helpful discussions, to J.C. Zuniga-Pflucker (University of Toronto) for the OP9-DL1 cells, to F. Gounari (University of Chicago) for the pUC1017 vector and S. Cory (Walter and Eliza Hall Institute of Medical Research) and H.G. Wendel (Memorial Sloan Kettering Cancer Center) for the Vav-Bcl2 mouse line. NR 35 TC 63 Z9 64 U1 0 U2 5 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 NOV PY 2010 VL 16 IS 11 BP 1321 EP U65 DI 10.1038/nm.2246 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 675TV UT WOS:000283860100045 PM 20972433 ER PT J AU Kummar, S Chen, HX Wright, J Holbeck, S Millin, MD Tomaszewski, J Zweibel, J Collins, J Doroshow, JH AF Kummar, Shivanni Chen, Helen X. Wright, John Holbeck, Susan Millin, Myrtle Davis Tomaszewski, Joseph Zweibel, James Collins, Jerry Doroshow, James H. TI Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID RENAL-CELL CARCINOMA; METASTATIC COLORECTAL-CANCER; PHASE-II TRIAL; SYNTHETIC LETHAL SCREEN; ADP-RIBOSE POLYMERASE; EARLY CLINICAL-TRIALS; BREAST-CANCER; LUNG-CANCER; KINASE INHIBITOR; DRUG-DEVELOPMENT AB The rapid development of new therapeutic agents that target specific molecular pathways involved in tumour cell proliferation provides an unprecedented opportunity to achieve a much higher degree of biochemical specificity than previously possible with traditional chemotherapeutic anticancer agents. However, the lack of specificity of these established chemotherapeutic drugs allowed a relatively straightforward approach to their use in combination therapies. Developing a paradigm for combining new, molecularly targeted agents, on the other hand, is substantially more complex. The abundance of molecular data makes it possible, at least in theory, to predict how such agents might interact across crucial growth control networks. Initial strategies to examine molecularly targeted agent combinations have produced a small number of successes in the clinic. However, for most of these combination strategies, both in preclinical models and in patients, it is not clear whether the agents being combined actually hit their targets to induce growth inhibition. Here, we consider the initial approach of the US National Cancer Institute (NCI) to the evaluation of combinations of molecularly targeted anticancer agents in patients and provide a description of several new approaches that the NCI has initiated to improve the effectiveness of combination-targeted therapy for cancer. C1 [Kummar, Shivanni; Doroshow, James H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Helen X.; Wright, John; Holbeck, Susan; Millin, Myrtle Davis; Tomaszewski, Joseph; Zweibel, James; Collins, Jerry; Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX The authors wish to express their appreciation to the members of the National Cancer Institute's Cancer Therapy Evaluation Program who have overseen the clinical trials described in this paper and the members of the National Cancer Institute's Developmental Therapeutics Program who have had an essential role in coordinating the initiatives outlined in the paper. This work was supported by federal funds from the National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or the policies of the US Department of Health and Human Services nor does the mention of trade names, commercial products or organizations imply endorsement by the US government. NR 90 TC 91 Z9 94 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD NOV PY 2010 VL 9 IS 11 BP 843 EP 856 DI 10.1038/nrd3216 PG 14 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 673II UT WOS:000283652500023 PM 21031001 ER PT J AU Pierce, SK Liu, WL AF Pierce, Susan K. Liu, Wanli TI The tipping points in the initiation of B cell signalling: how small changes make big differences SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID RESONANCE ENERGY-TRANSFER; RECEPTOR TYROSINE KINASES; SINGLE-MOLECULE TRACKING; BASOPHIL LEUKEMIA-CELLS; RESPONSES IN-VIVO; ANTIGEN RECEPTOR; PLASMA-MEMBRANE; SYNAPSE FORMATION; LIPID RAFTS; LYMPH-NODE AB B cells are selected by the binding of antigen to clonally distributed B cell receptors (BCRs), triggering signalling cascades that result in B cell activation. With the recent application of high-resolution live-cell imaging, we are gaining an understanding of the events that initiate BCR signalling within seconds of its engagement with antigen. These observations are providing a molecular explanation for fundamental aspects of B cell responses, including antigen affinity discrimination and the value of class switching, as well as insights into the underlying causes of B cell tumorigenesis. Advances in our understanding of the earliest molecular events that follow antigen binding to the BCR may provide a general framework for the initiation of signalling in the adaptive immune system. C1 [Pierce, Susan K.; Liu, Wanli] NIAID, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, NIH, Rockville, MD 20852 USA. EM spierce@niaid.nih.gov RI liu, wanli/H-5690-2011 OI liu, wanli/0000-0003-2624-6802 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank J. Brzostowski for expert comments on live-cell imaging techniques. This work has been supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 83 TC 75 Z9 76 U1 2 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD NOV PY 2010 VL 10 IS 11 BP 767 EP 777 DI 10.1038/nri2853 PG 11 WC Immunology SC Immunology GA 670NM UT WOS:000283431100013 PM 20935671 ER PT J AU Bluestone, JA Auchincloss, H Nepom, GT Rotrosen, D Clair, EWS Turka, LA AF Bluestone, Jeffrey A. Auchincloss, Hugh Nepom, Gerald T. Rotrosen, Daniel Clair, E. William St. Turka, Laurence A. TI TIMELINE The Immune Tolerance Network at 10 years: tolerance research at the bedside SO NATURE REVIEWS IMMUNOLOGY LA English DT Article ID FACILITATED ALLERGEN BINDING; RENAL-TRANSPLANT TOLERANCE; REGULATORY T-CELLS; IN-VIVO; MARROW-TRANSPLANTATION; MULTIPLE-SCLEROSIS; RUSH IMMUNOTHERAPY; ACUTE REJECTION; COMBINED KIDNEY; CO-STIMULATION AB Immune tolerance-inducing therapies reprogramme immune cells to eliminate pathogenic immune responses while preserving protective immunity. The Immune Tolerance Network (ITN), sponsored by the US National Institutes of Health, was established in 1999 to evaluate new tolerance-inducing therapies and carry out mechanistic studies using a unique interactive approach in partnership with industry, academia and foundations. Ten years later, the ITN has carried out approximately 36 clinical trials and tolerance studies examining innovative tolerogenic approaches in the settings of allergy, autoimmune diseases and organ transplantation. ITN investigators have published more than 80 original research papers based on this work. This Timeline article summarizes the progress and challenges of clinical research in the ITN. C1 [Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Auchincloss, Hugh; Rotrosen, Daniel] NIAID, Bethesda, MD 20817 USA. [Nepom, Gerald T.] Benaroya Res Inst, Seattle, WA 98101 USA. [Clair, E. William St.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Turka, Laurence A.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Transplant Inst, Boston, MA 02115 USA. RP Bluestone, JA (reprint author), Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. EM jeff.bluestone@ucsf.edu FU NIAID; JDRF; FAI; NIDDK FX We thank the many people inside the ITN, NIAID and Rho, as well as the immunology community at large, for the hard work, support and creative ideas that have helped the ITN to flourish. Special thanks to the ITN funders - NIAID, JDRF, FAI and NIDDK - and to all the companies who have worked with the ITN and its clinical investigators. NR 45 TC 31 Z9 34 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD NOV PY 2010 VL 10 IS 11 BP 797 EP 803 DI 10.1038/nri2869 PG 7 WC Immunology SC Immunology GA 670NM UT WOS:000283431100016 PM 20972473 ER PT J AU Pepin, KM Lass, S Pulliam, JRC Read, AF Lloyd-Smith, JO AF Pepin, Kim M. Lass, Sandra Pulliam, Juliet R. C. Read, Andrew F. Lloyd-Smith, James O. TI Identifying genetic markers of adaptation for surveillance of viral host jumps SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID INFLUENZA-A VIRUS; RESPIRATORY-SYNDROME-CORONAVIRUS; EMERGING INFECTIOUS-DISEASES; VESICULAR STOMATITIS-VIRUS; EQUINE ENCEPHALITIS-VIRUS; EXPERIMENTAL EVOLUTION; WITHIN-HOST; IN-VIVO; MOLECULAR EPIDEMIOLOGY; ENVELOPE GLYCOPROTEIN AB Adaptation is often thought to affect the likelihood that a virus will be able to successfully emerge in a new host species. If so, surveillance for genetic markers of adaptation could help to predict the risk of disease emergence. However, adaptation is difficult to distinguish conclusively from the other processes that generate genetic change. In this Review we survey the research on the host jumps of influenza A, severe acute respiratory syndrome-coronavirus, canine parvovirus and Venezuelan equine encephalitis virus to illustrate the insights that can arise from combining genetic surveillance with microbiological experimentation in the context of epidemiological data. We argue that using a multidisciplinary approach for surveillance will provide a better understanding of when adaptations are required for host jumps and thus when predictive genetic markers may be present. C1 [Pepin, Kim M.] Penn State Univ, Dept Phys, University Pk, PA 16802 USA. [Pulliam, Juliet R. C.; Read, Andrew F.; Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pulliam, Juliet R. C.; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolut Biol, Los Angeles, CA 90095 USA. [Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16827 USA. [Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, Dept Entomol, University Pk, PA 16827 USA. RP Pepin, KM (reprint author), Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA. EM kmp29@psu.edu RI Pulliam, Juliet/A-6516-2008; Lloyd-Smith, James/K-4080-2012 OI Pulliam, Juliet/0000-0003-3314-8223; Lloyd-Smith, James/0000-0001-7941-502X FU Research and Policy for Infectious Diseases Dynamics (RAPIDD) of the Science and Technology Directorate; Department of Homeland Security and Fogarty International Center; National Institutes of Health; National Science Foundation [0742373, DEB-0520468, EF-0928690]; De Logi Chair in Biological Sciences FX This work was supported by the Research and Policy for Infectious Diseases Dynamics (RAPIDD) programme of the Science and Technology Directorate, the Department of Homeland Security and Fogarty International Center and the National Institutes of Health. K. M. P. was also supported by National Science Foundation grant 0742373; S. L. was supported by National Science Foundation grant DEB-0520468 to P. Hudson; J.L.-S. was supported by National Science Foundation grant EF-0928690 and the De Logi Chair in Biological Sciences. NR 117 TC 55 Z9 55 U1 3 U2 39 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD NOV PY 2010 VL 8 IS 11 BP 802 EP 813 DI 10.1038/nrmicro2440 PG 12 WC Microbiology SC Microbiology GA 665RY UT WOS:000283054400017 PM 20938453 ER PT J AU Wang, LW Yang, JK Kabaleeswaran, V Rice, AJ Cruz, AC Park, AY Yin, QA Damko, E Jang, SB Raunser, S Robinson, CV Siegel, RM Walz, T Wu, H AF Wang, Liwei Yang, Jin Kuk Kabaleeswaran, Venkataraman Rice, Amanda J. Cruz, Anthony C. Park, Ah Young Yin, Qian Damko, Ermelinda Jang, Se Bok Raunser, Stefan Robinson, Carol V. Siegel, Richard M. Walz, Thomas Wu, Hao TI The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; MACROMOLECULAR ASSEMBLIES; SIGNALING COMPLEX; CRYSTAL-STRUCTURE; APOPTOSIS; RECEPTOR; PROTEIN; SUPERFAMILY; INHIBITION; MECHANISM AB The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program. Mutations in Fas that disrupt the DISC cause autoimmune lymphoproliferative syndrome (ALPS). Here we show that the Fas-FADD death domain (DD) complex forms an asymmetric oligomeric structure composed of 5-7 Fas DD and 5 FADD DD, whose interfaces harbor ALPS-associated mutations. Structure-based mutations disrupt the Fas-FADD interaction in vitro and in living cells; the severity of a mutation correlates with the number of occurrences of a particular interaction in the structure. The highly oligomeric structure explains the requirement for hexameric or membrane-bound FasL in Fas signaling. It also predicts strong dominant negative effects from Fas mutations, which are confirmed by signaling assays. The structure optimally positions the FADD death effector domain (DED) to interact with the caspase-8 DED for caspase recruitment and higher-order aggregation. C1 [Wang, Liwei; Yang, Jin Kuk; Kabaleeswaran, Venkataraman; Yin, Qian; Damko, Ermelinda; Jang, Se Bok; Wu, Hao] Weill Cornell Med Coll, Dept Biochem, New York, NY USA. [Yang, Jin Kuk] Soongsil Univ, Dept Chem, Seoul, South Korea. [Rice, Amanda J.; Raunser, Stefan; Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Cruz, Anthony C.; Siegel, Richard M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Park, Ah Young; Robinson, Carol V.] Univ Oxford, Dept Chem, Oxford, England. [Jang, Se Bok] Pusan Natl Univ, Dept Mol Biol, Pusan, South Korea. [Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Wu, H (reprint author), Weill Cornell Med Coll, Dept Biochem, New York, NY USA. EM haowu@med.cornell.edu OI Siegel, Richard/0000-0001-5953-9893; Raunser, Stefan/0000-0001-9373-3016 FU US National Institutes of Health [R01-AI50872]; Korea Science and Engineering Foundation (KOSEF); Long-term Overseas Dispatch Program for Pusan National University's Tenure-track Faculty; Biotechnology and Biological Sciences Research Council; Royal Society; Walters-Kundert Trust; National Center for Research Resources at the US National Institutes of Health [RR-15301] FX We thank Y.C. Park for earlier work on this project and K. Rajashankar, I. Kourinov and N. Sukumar for help with data collection. This work was supported by US National Institutes of Health grant R01-AI50872 (H.W.), the Post-doctoral Fellowship Program of Korea Science and Engineering Foundation (KOSEF) (J.K.Y.), the 2008 Long-term Overseas Dispatch Program for Pusan National University's Tenure-track Faculty (S.B.J.), the Biotechnology and Biological Sciences Research Council (A.Y.P.), the Royal Society (C.V.R.) and the Walters-Kundert Trust (C.V.R.). Diffraction data collection was conducted at the Northeastern Collaborative Access Team beam lines of the Advanced Photon Source at Argonne National Laboratory, supported by award RR-15301 from the National Center for Research Resources at the US National Institutes of Health. S.R. was a fellow of the German Academy of Sciences Leopoldina (BMBF-LPD 9901/8-163). T.W. is an investigator of the Howard Hughes Medical Institute. NR 43 TC 122 Z9 130 U1 3 U2 19 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 NOV PY 2010 VL 17 IS 11 BP 1324 EP U176 DI 10.1038/nsmb.1920 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 674TQ UT WOS:000283773200009 PM 20935634 ER PT J AU Klover, PJ Muller, WJ Robinson, GW Pfeiffer, RM Yamaji, D Hennighausen, L AF Klover, Peter J. Muller, William J. Robinson, Gertraud W. Pfeiffer, Ruth M. Yamaji, Daisuke Hennighausen, Lothar TI Loss of STAT1 from Mouse Mammary Epithelium Results in an Increased Neu-Induced Tumor Burden SO NEOPLASIA LA English DT Article ID BREAST-CANCER; TARGETED DISRUPTION; I INTERFERON; IFN-ALPHA; IMMUNITY; GENE; RADIATION; MELANOMA; INNATE; MODELS AB Type I and type II classes of interferons (IFNs) signal through the JAK/STAT1 pathway and are known to be important in adaptive and innate immune responses and in protection against tumors. Although STAT1 is widely considered a tumor suppressor, it remains unclear, however, if this function occurs in tumor cells ( cell autonomous) or if STAT1 acts primarily through immune cells. Here, the question of whether STAT1 has a cell autonomous role in mammary tumor formation was addressed in a mouse model of ERBB2/neu-induced breast cancer in the absence and presence of STAT1. For this purpose, mice that carry floxed Stat1 alleles, which permit cell-specific removal of STAT1, were generated. To induce tumors only in mammary cells lacking STAT1, Stat1 floxed mice were crossed with transgenic mice that express cre recombinase and the neu oncogene under the mouse mammary tumor virus LTR (Stat1fl/fl NIC). Stat1 was effectively deleted in mammary epithelium of virgin Stat1fl/fl NIC females. Time-to-tumor onset was significantly shorter in Stat1fl/fl NIC females than in WT NIC ( Wilcoxon rank sum test, P = .02). The median time-to-tumor onset in the Stat1fl/fl NIC mice was 49.4 weeks, whereas it was 62.4 weeks in the WT NIC mice. These results suggest that STAT1 in mammary epithelial cells may play a role in suppressing tumorigenesis. The Stat1 floxed allele described in this study is also a unique resource to determine the cellular targets of IFNs and STAT1 action, which should aid our understanding and appreciation of these pathways. C1 [Klover, Peter J.; Robinson, Gertraud W.; Yamaji, Daisuke; Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Muller, William J.] McGill Univ, Ctr Hlth, Dept Med, Montreal, PQ, Canada. [Muller, William J.] McGill Univ, Ctr Hlth, Dept Biochem, Montreal, PQ, Canada. [Pfeiffer, Ruth M.] NCI, Biostat Branch, NIH, Rockville, MD USA. RP Klover, PJ (reprint author), 8 Ctr Dr,Bldg 8,Room 107, Bethesda, MD 20817 USA. EM peter_klover@yahoo.com RI Pfeiffer, Ruth /F-4748-2011; Robinson, Gertraud/I-2136-2012 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute FX This work was supported by the National Institutes of Health intramural research programs of National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute. NR 20 TC 42 Z9 44 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 NOV PY 2010 VL 12 IS 11 BP 899 EP 905 DI 10.1593/neo.10716 PG 7 WC Oncology SC Oncology GA 693FB UT WOS:000285208900005 PM 21076615 ER PT J AU Moustakas, A Iwamoto, FM Kreisl, TN Sul, J Kim, L Butman, J Albert, P Fine, HA AF Moustakas, Argirios Iwamoto, Fabio M. Kreisl, Teri N. Sul, Joohee Kim, Lyndon Butman, John Albert, Paul Fine, Howard A. TI PHASE II TRIAL OF ENZASTAURIN (ENZ) WITH BEVACIZUMAB (BV) IN ADULTS WITH RECURRENT GLIOBLASTOMA (GEM) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT Advances in Inflammatory Bowel Diseases Crohns and Colitis Foundations National Clinical and Research Conference CY DEC 09-12, 2010 CL Hollywood, FL C1 [Moustakas, Argirios; Iwamoto, Fabio M.; Kreisl, Teri N.; Sul, Joohee; Butman, John; Albert, Paul; Fine, Howard A.] NCI, NIH, Bethesda, MD 20892 USA. [Kim, Lyndon] UMass, Amherst, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 NOV PY 2010 VL 12 SU 4 BP 37 EP 37 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 691LX UT WOS:000285082400160 ER PT J AU Inskip, PD Hoover, RN Devesa, SS AF Inskip, Peter D. Hoover, Robert N. Devesa, Susan S. TI Brain cancer incidence trends in relation to cellular telephone use in the United States SO NEURO-ONCOLOGY LA English DT Article DE brain cancer; cellular telephones; epidemiology; SEER ID CENTRAL-NERVOUS-SYSTEM; MOBILE PHONES; TUMOR-INCIDENCE; TIME TRENDS; 1900 MHZ; RATES; RISK AB The use of cellular telephone has grown explosively during the past two decades, and there are now more than 279 million wireless subscribers in the United States. If cellular phone use causes brain cancer, as some suggest, the potential public health implications could be considerable. One might expect the effects of such a prevalent exposure to be reflected in general population incidence rates, unless the induction period is very long or confined to very long-term users. To address this issue, we examined temporal trends in brain cancer incidence rates in the United States, using data collected by the Surveillance, Epidemiology, and End Results (SEER) Program. Log-linear models were used to estimate the annual percent change in rates among whites. With the exception of the 20-29-year age group, the trends for 1992-2006 were downward or flat. Among those aged 20-29 years, there was a statistically significant increasing trend between 1992 and 2006 among females but not among males. The recent trend in 20-29-year-old women was driven by a rising incidence of frontal lobe cancers. No increases were apparent for temporal or parietal lobe cancers, or cancers of the cerebellum, which involve the parts of the brain that would be more highly exposed to radiofrequency radiation from cellular phones. Frontal lobe cancer rates also rose among 20-29-year-old males, but the increase began earlier than among females and before cell phone use was highly prevalent. Overall, these incidence data do not provide support to the view that cellular phone use causes brain cancer. C1 [Inskip, Peter D.; Hoover, Robert N.; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Inskip, PD (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 7052, Bethesda, MD 20892 USA. FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This research was supported by intramural funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 20 TC 43 Z9 45 U1 8 U2 55 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 NOV PY 2010 VL 12 IS 11 BP 1147 EP 1151 DI 10.1093/neuonc/noq077 PG 5 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 673EU UT WOS:000283642700007 PM 20639214 ER PT J AU Stranahan, AM Lee, K Becker, KG Zhang, YQ Maudsley, S Martin, B Cutler, RG Mattson, MP AF Stranahan, Alexis M. Lee, Kim Becker, Kevin G. Zhang, Yonqing Maudsley, Stuart Martin, Bronwen Cutler, Roy G. Mattson, Mark P. TI Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice SO NEUROBIOLOGY OF AGING LA English DT Article DE Wheel running; Hippocampus; Aging; Cognition; Gene expression ID LONG-TERM POTENTIATION; RAT HIPPOCAMPUS; ENVIRONMENTAL ENRICHMENT; SYNAPTIC PLASTICITY; NERVOUS-SYSTEM; NEUROGENESIS; EXERCISE; BRAIN; PATHWAYS; PROTEIN AB Physical activity preserves cognition in the aging brain, but the mechanisms remain obscure. In order to identify candidate genes and pathways responsible for the preservation of cognitive function by exercise, we trained mice that had been exposed to lifelong running or sedentary lifestyle for 16 months in the hippocampus-dependent water maze. After water maze training, we analyzed the expression of 24,000 genes in the hippocampus using Illumina bead microarray. Runners show greater activation of genes associated with synaptic plasticity and mitochondrial function, and also exhibit significant downregulation of genes associated with oxidative stress and lipid metabolism. Running also modified the effects of learning on the expression of genes involved in cell excitability, energy metabolism, and insulin, MAP kinase and Wnt signaling. These results suggest that the enhancement of cognitive function by lifelong exercise is associated with an altered transcriptional profile following learning. Published by Elsevier Inc. C1 [Stranahan, Alexis M.; Lee, Kim; Martin, Bronwen; Cutler, Roy G.; Mattson, Mark P.] NIA, Cellular & Mol Neurosci Sect, Neurosci Lab, Biomed Res Ctr, Baltimore, MD 21224 USA. [Becker, Kevin G.; Zhang, Yonqing] NIA, Gene Express & Genom Unit, Res Resources Branch, Biomed Res Ctr, Baltimore, MD 21224 USA. [Maudsley, Stuart] NIA, Receptor Pharmacol Sect, Neurosci Lab, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Cellular & Mol Neurosci Sect, Neurosci Lab, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM astrana1@jhu.edu; mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; OI Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. We would like to thank Xiangru Xu for valuable discussions. The authors have no actual or potential conflicts of interest. NR 31 TC 60 Z9 61 U1 2 U2 7 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 NOV PY 2010 VL 31 IS 11 BP 1937 EP 1949 DI 10.1016/j.neurobiolaging.2008.10.016 PG 13 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 663SC UT WOS:000282907800011 PM 19070401 ER PT J AU Cippitelli, A Zook, M Bell, L Damadzic, R Eskay, RL Schwandt, M Heilig, M AF Cippitelli, Andrea Zook, Michelle Bell, Lauren Damadzic, Ruslan Eskay, Robert L. Schwandt, Melanie Heilig, Markus TI Reversibility of object recognition but not spatial memory impairment following binge-like alcohol exposure in rats SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE Memory; Learning; Recognition; Hippocampus; Entorhinal ID BRAIN-DAMAGE; ETHANOL-CONSUMPTION; NONSPATIAL CHANGES; ENTORHINAL CORTEX; ADULT RATS; RETROHIPPOCAMPAL LESIONS; NEURONAL DEGENERATION; COGNITIVE DEFICITS; PREFRONTAL CORTEX; HIPPOCAMPUS AB Excessive alcohol use leads to neurodegeneration in several brain structures including the hippocampal dentate gyrus and the entorhinal cortex Cognitive deficits that result are among the most insidious and debilitating consequences of alcoholism The object exploration task (OET) provides a sensitive measurement of spatial memory impairment Induced by hippocampal and cortical damage In this study we examine whether the observed neurotoxicity produced by a 4-day binge ethanol treatment results in long-term memory impairment by observing the time course of reactions to spatial change (object configuration) and non-spatial change (object recognition) Wistar rats were assessed for their abilities to detect spatial configuration in the OFT at 1 week and 10 weeks following the ethanol treatment in which ethanol groups received 9-15 g/kg/day and achieved blood alcohol levels over 300 mg/dl At 1 week results indicated that the binge alcohol treatment produced impairment in both spatial memory and non-spatial object recognition performance Unlike the controls ethanol treated rats did not increase the duration or number of contacts with the displaced object in the spatial memory task nor did they increase the duration of contacts with the novel object in the object recognition task After 10 weeks spatial memory remained impaired in the ethanol treated rats but object recognition ability was recovered Our data suggest that episodes of binge like alcohol exposure result in long-term and possibly permanent impairments in memory for the configuration of objects during exploration whereas the ability to detect non-spatial changes is only temporarily affected Published by Elsevier Inc C1 [Cippitelli, Andrea; Zook, Michelle; Bell, Lauren; Damadzic, Ruslan; Eskay, Robert L.; Schwandt, Melanie; Heilig, Markus] NIAAA, LCTS, NIH, Bethesda, MD 20892 USA. RP Cippitelli, A (reprint author), NIAAA, LCTS, NIH, 10 Ctr Dr 1-5330, Bethesda, MD 20892 USA. RI Schwandt, Melanie/L-9866-2016; OI Heilig, Markus/0000-0003-2706-2482 NR 50 TC 17 Z9 17 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD NOV PY 2010 VL 94 IS 4 BP 538 EP 546 DI 10.1016/j.nlm.2010.09.006 PG 9 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 681GF UT WOS:000284298700012 PM 20849966 ER PT J AU Gu, H Salmeron, BJ Ross, TJ Geng, XJ Zhan, W Stein, EA Yang, YH AF Gu, Hong Salmeron, Betty Jo Ross, Thomas J. Geng, Xiujuan Zhan, Wang Stein, Elliot A. Yang, Yihong TI Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity SO NEUROIMAGE LA English DT Article ID DRUG-ADDICTION; CINGULATE CORTEX; MOTOR CORTEX; NEURAL BASIS; HUMAN BRAIN; ABUSERS; NETWORKS; REWARD; MRI; THALAMUS AB Preclinical models have consistently demonstrated the importance of the mesocorticolimbic (MCL) brain reward system in drug dependence, with critical molecular and cellular neuroadaptations identified within these structures following chronic cocaine administration Cocaine dependent individuals manifest alterations in reward functioning that may relate to changes induced by cocaine or to pre-existing differences related to vulnerability to addiction. The circuit level manifestations of these drug-induced plastic changes and predispositions to drug dependence are poorly understood in preclinical models and virtually unknown in human drug dependence Using whole-brain resting-state fMRI connectivity analysis with 'seed voxels' placed within individual nodes of the MCL system, we report network-specific functional connectivity strength decreases in cocaine users within distinct circuits of the system, including between ventral tegmental area (VIA) and a region encompassing thalamus/lentiform nucleus/nucleus accumbens, between amygdala and medial prefrontal cortex (mPFC). and between hippocampus and dorsal mPFC Further, regression analysis on regions showing significant functional connectivity decrease in chronic cocaine users revealed that the circuit strength between VTA and thalamus/lentiform nucleus/nucleus accumbens was negatively correlated with years of cocaine use This is the first evidence of circuit-related changes in human cocaine dependence and is consistent with the range of cognitive and behavioral disruptions seen in cocaine dependence. As potential circuit level biomarkers of cocaine dependence, these circuit alterations may be usefully applied in treatment development and monitoring treatment outcome Published by Elsevier Inc C1 [Gu, Hong; Salmeron, Betty Jo; Ross, Thomas J.; Geng, Xiujuan; Zhan, Wang; Stein, Elliot A.; Yang, Yihong] Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Yang, YH (reprint author), Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200,Room 07A709, Baltimore, MD 21224 USA. RI Ross, Thomas/B-7469-2008; Geng, Xiujuan/I-3852-2012; Salmeron, Betty Jo/M-1793-2016 OI Ross, Thomas/0000-0002-7745-3572; Salmeron, Betty Jo/0000-0003-1699-9333 FU National Institute on Drug Abuse FX Supported by the Intramural Research Program of the National Institute on Drug Abuse NR 68 TC 120 Z9 125 U1 1 U2 30 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 NOV 1 PY 2010 VL 53 IS 2 BP 593 EP 601 DI 10.1016/j.neuroimage.2010.06.066 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 648JB UT WOS:000281688000023 PM 20603217 ER PT J AU Waltz, JA Schweitzer, JB Ross, TJ Kurup, PK Salmeron, BJ Rose, EJ Gold, JM Stein, EA AF Waltz, James A. Schweitzer, Julie B. Ross, Thomas J. Kurup, Pradeep K. Salmeron, Betty J. Rose, Emma J. Gold, James M. Stein, Elliot A. TI Abnormal Responses to Monetary Outcomes in Cortex, but not in the Basal Ganglia, in Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE schizophrenia; dopamine; reinforcement; basal ganglia; ventromedial prefrontal cortex ID STRIATAL REWARD PREDICTION; EVENT-RELATED FMRI; DECISION-MAKING; NEGATIVE SYMPTOMS; NEURAL RESPONSE; FRONTAL-CORTEX; RATING-SCALE; DYSFUNCTION; DISSOCIATION; ACTIVATION AB Psychosis has been associated with aberrant brain activity concurrent with both the anticipation and integration of monetary outcomes. The extent to which abnormal reward-related neural signals can be observed in chronic, medicated patients with schizophrenia (SZ), however, is not clear. In an fMRI study involving 17 chronic outpatients with SZ and 17 matched controls, we used a monetary incentive delay (MID) task, in which different-colored shapes predicted gains, losses, or neutral outcomes. Subjects needed to respond to a target within a time window in order to receive the indicated gain or avoid the indicated loss. Group differences in blood-oxygen-level-dependent responses to cues and outcomes were assessed through voxel-wise whole-brain analyses and regions-of-interest analyses in the neostriatum and prefrontal cortex (PFC). Significant group by outcome valence interactions were observed in the medial and lateral PFC, lateral temporal cortex, and amygdalae, such that controls, but not patients, showed greater activation for gains, relative to losses. In the striatum, neural activity was modulated by outcome magnitude in both groups. Additionally, we found that ratings of negative symptoms in patients correlated with sensitivity to obtained losses in medial PFC, obtained gains in lateral PFC, and anticipated gains in left ventral striatum. Sensitivity to obtained gains in lateral PFC also correlated with positive symptom scores in patients. Our findings of systematic relationships between clinical symptoms and neural responses to stimuli associated with rewards and punishments offer promise that reward-related neural responses may provide sensitive probes of the effectiveness of treatments for negative symptoms. Neuropsychopharmacology (2010) 35, 2427-2439; doi: 10.1038/npp.2010.126; published online 18 August 2010 C1 [Waltz, James A.; Gold, James M.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21228 USA. [Schweitzer, Julie B.] Univ Calif Davis, Sch Med, Dept Psychiat, Sacramento, CA 95817 USA. [Ross, Thomas J.; Kurup, Pradeep K.; Salmeron, Betty J.; Rose, Emma J.; Stein, Elliot A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. RP Waltz, JA (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, POB 21247, Baltimore, MD 21228 USA. EM jwaltz@mprc.umaryland.edu RI Ross, Thomas/B-7469-2008; Rose, Emma/A-9960-2010; Salmeron, Betty Jo/M-1793-2016 OI Ross, Thomas/0000-0002-7745-3572; Rose, Emma/0000-0001-5365-4794; Salmeron, Betty Jo/0000-0003-1699-9333 FU National Institutes of Mental Health [1 K12 RR023250-01, P30 MH068580-01, 1 R24 MH72647-01A1]; National Institute on Drug Abuse FX This research was made possible by Grant Nos. 1 K12 RR023250-01, P30 MH068580-01, and 1 R24 MH72647-01A1 from the National Institutes of Mental Health and the Intramural Research Program of the National Institute on Drug Abuse. Sharon August and Kimberly Warren assisted with screening and neuropsychological assessments. These data were presented, in part, at the 38th annual meeting of the Society for Neuroscience, in Washington, DC.; James M Gold receives royalty payments from sales of the BACS (Brief Assessment of Cognition in Schizophrenia) battery (Keefe et al, 2004). He has had consulting relationships with Merck Pharmaceuticals, AstraZeneca Pharmaceuticals, Solvay Pharmaceuticals, and GlaxoSmithKline. None of these relationships represent a conflict of interest, regarding this work. All other authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NR 61 TC 62 Z9 63 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2010 VL 35 IS 12 BP 2427 EP 2439 DI 10.1038/npp.2010.126 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 664LA UT WOS:000282960200012 PM 20720534 ER PT J AU Furey, ML Khanna, A Hoffman, EM Drevets, WC AF Furey, Maura L. Khanna, Ashish Hoffman, Elana M. Drevets, Wayne C. TI Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE depression; gender; antidepressant; antimuscarinic; anticholinergic ID LOW-DOSE PHYSOSTIGMINE; REM INDUCTION TEST; GENDER-DIFFERENCES; AFFECTIVE-DISORDERS; MAJOR DEPRESSIVES; RECEPTOR-BINDING; SEX-DIFFERENCES; RATING-SCALE; CHRM2 GENE; ACETYLCHOLINE AB Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4 mu g/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group x block interaction (F = 21.0, p<0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F = 8.4, p = 0.006). The treatment group x block interaction was also significant in males (F = 3.8, p = 0.043) and females (F = 35.6, p<0.001) separately. A block x gender interaction (F = 7.4, p = 0.009) indicated that the response magnitude was larger in women. The treatment x block interaction was significant for the HAM-A across gender (F = 12.0, p<0.001), and was significant for females (F = 24.9, p<0.001) but not for males (F = 1.3, p = 0.30). When comparing the baseline block to study end, the block x gender interaction (F = 12.6, p = 0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men. Neuropsychopharmacology (2010) 35, 2479-2488; doi: 10.1038/npp.2010.131; published online 25 August 2010 C1 [Furey, Maura L.; Hoffman, Elana M.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Khanna, Ashish] American Univ, Caribbean Sch Med, Coral Gables, FL USA. [Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. RP Furey, ML (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, 15K N Dr,Bldg 15K,Room 115B, Bethesda, MD 20892 USA. EM mfurey@mail.nih.gov RI Furey, Maura/H-5273-2013 FU NIH; NIMH-DIRP FX We thank Mark Opal and Summer Peck for technical support, Michele Drevets and Joan Williams for patient recruitment and evaluation, David Luckenbaugh for statistical advice, and Paul Carlson, Alan Mallinger, Andy Speer, Carlos Zarate, Meena Vythilingam, and the 5SW Day Hospital nursing staff for medical support. This research was supported by the NIH NIMH-DIRP. NR 55 TC 44 Z9 47 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2010 VL 35 IS 12 BP 2479 EP 2488 DI 10.1038/npp.2010.131 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 664LA UT WOS:000282960200016 PM 20736989 ER PT J AU Ikemoto, S AF Ikemoto, Satoshi TI Brain reward circuitry beyond the mesolimbic dopamine system: A neurobiological theory SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Motivation; Affective arousal; Conditioned place preference; Module; Median and dorsal raphe nuclei; GABA; Glutamate; Seeking; Depression; Mania; Addiction ID VENTRAL TEGMENTAL AREA; MEDIAN RAPHE NUCLEUS; INTRACRANIAL SELF-STIMULATION; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; HIPPOCAMPAL THETA-RHYTHM; PHA-L ANALYSIS; CONDITIONED PLACE PREFERENCE; LATERAL HYPOTHALAMIC AREA; FOS-LIKE IMMUNOREACTIVITY; WHEAT-GERM-AGGLUTININ AB Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward. To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area. Published by Elsevier Ltd. C1 NIDA, Behav Neurosci Res Branch, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Res Branch, NIH, US Dept HHS, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM Satoshi.Ikemoto@nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU National Institute on Drug Abuse FX The present work was supported by the Intramural Research Program of the National Institute on Drug Abuse. I would like to thank Dr. Emily Wentzell for editorial assistance and my group's members - Fiori Vollrath-Smith, Sierra Webb, Drs. Tom Jhou and Mingliang Tang - for comments on an earlier version of the manuscript. Tom also helped me on the RMTg section. NR 278 TC 135 Z9 143 U1 5 U2 57 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD NOV PY 2010 VL 35 IS 2 SI SI BP 129 EP 150 DI 10.1016/j.neubiorev.2010.02.001 PG 22 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 681UG UT WOS:000284344900002 PM 20149820 ER PT J AU Ghitza, UE Zhai, HF Wu, P Airavaara, M Shaham, Y Lu, L AF Ghitza, Udi E. Zhai, Haifeng Wu, Ping Airavaara, Mikko Shaham, Yavin Lu, Lin TI Role of BDNF and GDNF in drug reward and relapse: A review SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Addiction; Alcohol; Cocaine; Craving; Drug self-administration; Extinction; Heroin; Incubation; Mesocorticolimbic dopamine system; Neuroadaptations; Relapse; Reinstatement ID MESOLIMBIC DOPAMINE SYSTEM; VENTRAL TEGMENTAL AREA; CONDITIONED-PLACE PREFERENCE; CORTICOTROPIN-RELEASING-FACTOR; COCAINE-SEEKING BEHAVIOR; NEUROTROPHIC FACTOR EXPRESSION; PRIMING-INDUCED REINSTATEMENT; LONG-LASTING POTENTIATION; STRESS-INDUCED RELAPSE; NECROSIS-FACTOR-ALPHA AB Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors that are critical for the growth, survival, and differentiation of developing neurons. These neurotrophic factors also play important roles in the survival and function of adult neurons, learning and memory, and synaptic plasticity. Since the mid-1990s, investigators have studied the role of BDNF and GDNF in the behavioral effects of abused drugs and in the neuroadaptations induced by repeated exposure to drugs in the mesocorticolimbic dopamine system. Here, we review rodent studies on the role of BDNF and GDNF in drug reward, as assessed in the drug self-administration and the conditioned place preference procedures, and in drug relapse, as assessed in extinction and reinstatement procedures. Our main conclusion is that whether BDNF or GDNF would facilitate or inhibit drug-taking behaviors depends on the drug type, the brain site, the addiction phase (initiation, maintenance, or abstinence/relapse), and the time interval between site-specific BDNF or GDNF injections and the reward- and relapse-related behavioral assessments. Published by Elsevier Ltd. C1 [Airavaara, Mikko; Shaham, Yavin] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Zhai, Haifeng; Wu, Ping; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100871, Peoples R China. [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. RP Shaham, Y (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD USA. EM yshaham@intra.nida.nih.gov; linlu@bjmu.edu.cn RI shaham, yavin/G-1306-2014; OI Airavaara, Mikko/0000-0002-2026-1609 FU National Basic Research Program of China [2009CB522004]; Natural Science Foundation of China [30725016]; NIDA, NIH FX This work was supported by the National Basic Research Program of China (2009CB522004) and the Natural Science Foundation of China (No: 30725016) and the Intramural Program of NIDA, NIH. NR 177 TC 85 Z9 90 U1 1 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD NOV PY 2010 VL 35 IS 2 SI SI BP 157 EP 171 DI 10.1016/j.neubiorev.2009.11.009 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 681UG UT WOS:000284344900004 PM 19914287 ER PT J AU Heilig, M Thorsell, A Sommer, WH Hansson, AC Ramchandani, VA George, DT Hommer, D Barr, CS AF Heilig, Markus Thorsell, Annika Sommer, Wolfgang H. Hansson, Anita C. Ramchandani, Vijay A. George, David T. Hommer, Daniel Barr, Christina S. TI Translating the neuroscience of alcoholism into clinical treatments: From blocking the buzz to curing the blues SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Alcoholism; Reward; Opioids; Pharmacogenetics; Stress; Anxiety; Amygdala; Corticotropin-releasing hormone; Substance P; Neurokinin ID CORTICOTROPIN-RELEASING-FACTOR; OPIOID RECEPTOR GENE; ANXIETY-LIKE BEHAVIOR; SINGLE-NUCLEOTIDE POLYMORPHISM; INTERMITTENT ETHANOL EXPOSURE; WITHDRAWAL-INDUCED ANXIETY; SUBSTANCE-P RECEPTORS; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; DEPENDENT RATS AB Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential. Published by Elsevier Ltd. C1 [Heilig, Markus; Thorsell, Annika; Sommer, Wolfgang H.; Hansson, Anita C.; Ramchandani, Vijay A.; George, David T.; Hommer, Daniel; Barr, Christina S.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Sommer, Wolfgang H.; Hansson, Anita C.] Cent Inst Mental Hlth, Dept Psychopharmacol, D-6800 Mannheim, Germany. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,10-1E-5334, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482; Sommer, Wolfgang/0000-0002-5903-6521; Thorsell, Annika/0000-0003-3535-3845 FU NIAAA FX The research from the NIAAA Laboratory of Clinical and Translational Studies reviewed here is supported by intramural NIAAA funding. NR 143 TC 61 Z9 62 U1 3 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD NOV PY 2010 VL 35 IS 2 SI SI BP 334 EP 344 DI 10.1016/j.neubiorev.2009.11.018 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 681UG UT WOS:000284344900015 PM 19941895 ER PT J AU Church, MW Wapner, RJ Mele, LM Johnson, F Dudley, DJ Spong, CY Peaceman, AM Moawad, AH O'Sullivan, MJ Miodovnik, M AF Church, Michael W. Wapner, Ronald J. Mele, Lisa M. Johnson, Francee Dudley, Donald J. Spong, Catherine Y. Peaceman, Alan M. Moawad, Atef H. O'Sullivan, Mary J. Miodovnik, Menachem CA Eunice Kennedy Shriver Natl Inst C TI Repeated courses of antenatal corticosteroids: Are there effects on the infant's auditory brainstem responses? SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Antenatal corticosteroid (AC); Auditory brainstem response (ABR); Betamethasone; Brain development; Hearing; Premature birth ID PRENATAL GLUCOCORTICOIDS; MATERNAL INJECTIONS; PREMATURE-INFANTS; PRETERM DELIVERY; HEARING-LOSS; OUTCOMES; GROWTH; SHEEP; MATURATION; SINGLE AB Our objective was to assess the effects of repeated antenatal corticosteroid treatments on the neonatal auditory brainstem response (ABR), a sensitive measure of neonatal brain maturity and auditory function. To achieve this, we performed and blindly evaluated neonatal ABRs on a subset of infants delivering within a multicenter randomized placebo-controlled clinical trial comparing single versus repeated courses of antenatal corticosteroid treatments for women at 23-31 weeks gestation who remained at increased risk for preterm birth. The women were randomly assigned to either the single or the repeated antenatal corticosteroid treatment group. Women in the repeated antenatal corticosteroid group received weekly antenatal corticosteroid treatments until 34 weeks gestation or until they reached a study-determined limited number of courses, whereas women in the single antenatal corticosteroid group received an initial course of corticosteroid followed by weekly placebo injections. We performed ABR testing on their infants prior to discharge. The latencies of waves I, III and V and the peak-to-trough amplitudes of waves I and V were compared between those in the single (n = 27) and repeated antenatal corticosteroid treatment (n = 24) groups. The majority of repeated antenatal corticosteroid infants (20 of 24) were exposed to >= 4 antenatal corticosteroid treatments. Even though gestational age was similar between our subset of single and repeated antenatal corticosteroid treatment groups, infant birth weight and length and head circumference were significantly smaller in the repeated antenatal corticosteroid group (p<0.05). Despite these differences in birth sizes, there were no significant group differences in the ABR wave latencies or amplitudes. We concluded that our repeated antenatal corticosteroid treatments, in comparison to a single treatment, did not significantly benefit or harm the neonatal ABR despite significant effects on birth size. (C) 2010 Elsevier Inc. All rights reserved. C1 [Church, Michael W.] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. [Wapner, Ronald J.] Drexel Univ, Coll Med, Philadelphia, PA 19103 USA. [Mele, Lisa M.] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. [Johnson, Francee] Ohio State Univ, Columbus, OH 43210 USA. [Dudley, Donald J.] Univ Utah, Salt Lake City, UT 84132 USA. [Spong, Catherine Y.] NICHHD, Bethesda, MD 20892 USA. [Peaceman, Alan M.] Northwestern Univ, Chicago, IL 60611 USA. [Moawad, Atef H.] Univ Chicago, Chicago, IL 60637 USA. [O'Sullivan, Mary J.] Univ Miami, Miami, FL 33136 USA. [Miodovnik, Menachem] Univ Cincinnati, Cincinnati, OH 45267 USA. RP Church, MW (reprint author), CS Mott Ctr Human Growth & Dev, 275 E Hancock, Detroit, MI 48201 USA. EM mchurch@med.wayne.edu OI Peaceman, Alan/0000-0002-4515-4850; Berghella, Vincenzo/0000-0003-2854-0239 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD27917, HD27905, HD27861, HD27915, HD34122, HD34208, HD34136, HD40512, HD36801] FX This study was funded by grants HD27917, HD27905, HD27861, HD27915, HD34122, HD34208, HD34136, HD40512, and HD36801 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. There were no conflicts of interest to report. Other participating members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network are as follows:; Drexel University; M. DiVito, A. Sciscione, V. Berghella, P. Trauffer, M. Pollock, M. Talucci, M. Goodman; Wayne State University; Y. Sorokin, M. Dombrowski, G. Norman, A. Millinder, C. Sudz, D. Driscoll; George Washington University, Biostatistics Center; E. Thom, F. Galbis-Reig, A. Das, L. Leuchtenburg, D. Johnson; Ohio State University; J. Iams, M. Landon, S. Meadows, P. Shubert; University of Utah; M. Varner, K. Anderson, A. Guzman, A. Crowley, M. Fuller, S. Bohning NR 41 TC 7 Z9 8 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD NOV-DEC PY 2010 VL 32 IS 6 BP 605 EP 610 DI 10.1016/j.ntt.2010.05.006 PG 6 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 692BY UT WOS:000285127700004 PM 20553856 ER PT J AU Kubben, N Voncken, JW Misteli, T AF Kubben, Nard Voncken, Jan Willem Misteli, Tom TI Mapping of protein- and chromatin-interactions at the nuclear lamina SO NUCLEUS-AUSTIN LA English DT Review DE laminopathies; lamin A; protein interactions; chromatin interactions; mass spectrometry; oneSTrEP; immunoprecipitation; affinity purification; chromatin immunoprecipitation; DamID AB The nuclear envelope and the lamina define the nuclear periphery and are implicated in many nuclear processes including chromatin organization, transcription and DNA replication. Mutations in lamin A proteins, major components of the lamina, interfere with these functions and cause a set of phenotypically diverse diseases referred to as laminopathies. The phenotypic diversity of laminopathies is thought to be the result of alterations in specific protein-and chromatin interactions due to lamin A mutations. Systematic identification of lamin A-protein and -chromatin interactions will be critical to uncover the molecular etiology of laminopathies. Here we summarize and critically discuss recent technology to analyze lamina-protein and-chromatin interactions. C1 [Kubben, Nard] Maastricht Univ, Med Ctr, Ctr Heart Failure Res, Maastricht, Netherlands. [Kubben, Nard; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Voncken, Jan Willem] Maastricht Univ, Med Ctr, Dept Mol Genet, Maastricht, Netherlands. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM Mistelit@mail.nih.gov FU Intramural NIH HHS [ZIA BC010309-11] NR 78 TC 14 Z9 14 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD NOV-DEC PY 2010 VL 1 IS 6 BP 460 EP 471 DI 10.4161/nucl.1.6.13513 PG 12 WC Cell Biology SC Cell Biology GA V28GG UT WOS:000208668700002 PM 21327087 ER PT J AU Rafikova, ER Melikov, K Chernomordik, LV AF Rafikova, Elvira R. Melikov, Kamran Chernomordik, Leonid V. TI Cytosol-dependent membrane fusion in ER, nuclear envelope and nuclear pore assembly Biological implications SO NUCLEUS-AUSTIN LA English DT Article DE nuclear envelope; endoplasmic reticulum; nuclear pore complex; membrane fusion; Xenopus egg extract; liposome AB Endoplasmic reticulum and nuclear envelope rearrangements after mitosis are often studied in the reconstitution system based on Xenopus egg extract. In our recent work we partially replaced the membrane vesicles in the reconstitution mix with protein-free liposomes to explore the relative contributions of cytosolic and transmembrane proteins. Here we discuss our finding that cytosolic proteins mediate fusion between membranes lacking functional transmembrane proteins and the role of membrane fusion in endoplasmic reticulum and nuclear envelope reorganization. Cytosol-dependent liposome fusion has allowed us to restore, without adding transmembrane nucleoporins, functionality of nuclear pores, their spatial distribution and chromatin decondensation in nuclei formed at insufficient amounts of membrane material and characterized by only partial decondensation of chromatin and lack of nuclear transport. Both the mechanisms and the biological implications of the discovered coupling between spatial distribution of nuclear pores, chromatin decondensation and nuclear transport are discussed. C1 [Rafikova, Elvira R.] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Melikov, Kamran; Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. RP Chernomordik, LV (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. EM chernoml@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We thank Sergei Pourmal for critical reading of the manuscript. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (L.V.C.). NR 41 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD NOV-DEC PY 2010 VL 1 IS 6 BP 487 EP 491 DI 10.4161/nucl.1.6.13514 PG 5 WC Cell Biology SC Cell Biology GA V28GG UT WOS:000208668700006 PM 21327091 ER PT J AU Kubben, N Voncken, JW Demmers, J Calis, C van Almen, G Pinto, Y Misteli, T AF Kubben, Nard Voncken, Jan Willem Demmers, Jeroen Calis, Chantal van Almen, Geert Pinto, Yigal Misteli, Tom TI Identification of differential protein interactors of lamin A and progerin SO NUCLEUS-AUSTIN LA English DT Article DE laminopathies; lamin A; progerin; Hutchinson-Gilford progeria syndrome; protein interactions; mass spectrometry; oneSTrEP pull-down AB The nuclear lamina is an interconnected meshwork of intermediate filament proteins underlying the nuclear envelope. The lamina is an important regulator of nuclear structural integrity as well as nuclear processes, including transcription, DNA replication and chromatin remodeling. The major components of the lamina are A-and B-type lamins. Mutations in lamins impair lamina functions and cause a set of highly tissue-specific diseases collectively referred to as laminopathies. The phenotypic diversity amongst laminopathies is hypothesized to be caused by mutations affecting specific protein interactions, possibly in a tissue-specific manner. Current technologies to identify interaction partners of lamin A and its mutants are hampered by the insoluble nature of lamina components. To overcome the limitations of current technologies, we developed and applied a novel, unbiased approach to identify lamin A-interacting proteins. This approach involves expression of the high-affinity OneSTrEP-tag, precipitation of lamin-protein complexes after reversible protein cross-linking and subsequent protein identification by mass spectrometry. We used this approach to identify in mouse embryonic fibroblasts and cardiac myocyte NklTAg cell lines proteins that interact with lamin A and its mutant isoform progerin, which causes the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS). We identified a total of 313 lamina-interacting proteins, including several novel lamin A interactors, and we characterize a set of 35 proteins which preferentially interact with lamin A or progerin. C1 [Kubben, Nard; van Almen, Geert] Maastricht Univ, Cardiovasc Res Inst Maastricht, Ctr Heart Failure Res, Maastricht, Netherlands. [Voncken, Jan Willem] Maastricht Univ, Dept Mol Genet, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands. [Calis, Chantal] Maastricht Univ, Dept Clin Genet, Maastricht, Netherlands. [Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Demmers, Jeroen] Erasmus MC, Prote Ctr, Rotterdam, Netherlands. [Pinto, Yigal] Med Ctr, Heart Failure Res Ctr, Amsterdam, Netherlands. RP Pinto, Y (reprint author), Med Ctr, Heart Failure Res Ctr, Amsterdam, Netherlands. EM Mistelit@mail.nih.gov OI Demmers, Jeroen/0000-0002-8757-9611 FU National Institutes of Health (NIH), NCI, Center for Cancer Research; Dutch Heart Foundation; ZonMW; EU-KP7 FX We thank Gunter Blobel, Brian Burke, Thomas Schwartz, Larry Gerace and Peter Lloyd Jones for kindly sharing expression plasmids. Thijs Konsten is thanked for his help in optimization of the OST pull-down assay. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research, grants from the Dutch Heart Foundation, ZonMW and the EU-KP7 grant 'Inheritance'. NR 72 TC 33 Z9 34 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD NOV-DEC PY 2010 VL 1 IS 6 BP 513 EP 525 DI 10.4161/nucl.1.6.13512 PG 13 WC Cell Biology SC Cell Biology GA V28GG UT WOS:000208668700010 PM 21327095 ER PT J AU Gardner, D AF Gardner, Deborah TI For Health Care Reform to Survive We Must Stick to the Facts SO NURSING ECONOMICS LA English DT Editorial Material C1 NIH, Off Org Dev, Ctr Clin, Bethesda, MD 20892 USA. RP Gardner, D (reprint author), NIH, Off Org Dev, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD NOV-DEC PY 2010 VL 28 IS 6 BP 401 EP + PG 3 WC Nursing SC Nursing GA 704HH UT WOS:000286041200006 PM 21291061 ER PT J AU Mitchell, SA Fisher, CA Hastings, CE Silverman, LB Wallen, GR AF Mitchell, Sandra A. Fisher, Cheryl A. Hastings, Clare E. Silverman, Leanne B. Wallen, Gwenyth R. TI A thematic analysis of theoretical models for translational science in nursing: Mapping the field SO NURSING OUTLOOK LA English DT Article ID FOCUSED KNOWLEDGE TRANSLATION; CLINICAL-RESEARCH ENTERPRISE; RESEARCH INITIATIVE QUERI; HEALTH-CARE-SYSTEMS; TOBACCO-DEPENDENCE; SMOKING-CESSATION; PUBLIC-HEALTH; CANCER CONTROL; IMPLEMENTATION FIDELITY; DISSEMINATION RESEARCH AB The quantity and diversity of conceptual models in translational science may complicate rather than advance the use of theory. This paper offers a comparative thematic analysis of the models available to inform knowledge development, transfer, and utilization. Literature searches identified 47 models for knowledge translation. Four thematic areas emerged: (1) evidence-based practice and knowledge transformation processes, (2) strategic change to promote adoption of new knowledge, (3) knowledge exchange and synthesis for application and inquiry, and (4) designing and interpreting dissemination research. This analysis distinguishes the contributions made by leaders and researchers at each phase in the process of discovery, development, and service delivery. It also informs the selection of models to guide activities in knowledge translation. A flexible theoretical stance is essential to simultaneously develop new knowledge and accelerate the translation of that knowledge into practice behaviors and programs of care that support optimal patient outcomes. C1 [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, Appl Res Program, Bethesda, MD 20892 USA. [Mitchell, Sandra A.; Fisher, Cheryl A.; Hastings, Clare E.; Silverman, Leanne B.; Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Mitchell, SA (reprint author), NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, Appl Res Program, 6130 Execut Blvd,MSC 7344,EPN4020, Bethesda, MD 20892 USA. EM mitchlis@mail.nih.gov RI lyp, maggie/G-1471-2011 FU National Institutes of Health, Clinical Center, Nursing Research and Translational Science, Nursing and Patient Care Services FX We gratefully acknowledge Josanne Revoir, RN, MS, National Institutes of Health Clinical Center for her assistance with development of figures. This work was supported by the National Institutes of Health, Clinical Center, Nursing Research and Translational Science, Nursing and Patient Care Services. NR 164 TC 27 Z9 28 U1 7 U2 42 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD NOV-DEC PY 2010 VL 58 IS 6 SI SI BP 287 EP 300 DI 10.1016/j.outlook.2010.07.001 PG 14 WC Nursing SC Nursing GA 686XW UT WOS:000284734100004 PM 21074646 ER PT J AU Bradley, DP Johnson, LA Zhang, ZM Subar, AF Troiano, RP Schatzkin, A Schoeller, DA AF Bradley, David P. Johnson, Lindsey A. Zhang, Zhumin Subar, Amy F. Troiano, Richard P. Schatzkin, Arthur Schoeller, Dale A. TI Effect of smoking status on total energy expenditure SO NUTRITION & METABOLISM LA English DT Article ID DOUBLY LABELED WATER; CIGARETTE-SMOKING; WEIGHT-GAIN; BODY-WEIGHT; PHYSICAL-ACTIVITY; DIETARY-INTAKE; CALORIC-INTAKE; METABOLIC-RATE; UNITED-STATES; SOCIAL-CLASS AB Individuals who smoke generally have a lower body mass index (BMI) than nonsmokers. The relative roles of energy expenditure and energy intake in maintaining the lower BMI, however, remain controversial. We tested the hypothesis that current smokers have higher total energy expenditure than never smokers in 308 adults aged 40-69 years old of which 47 were current smokers. Energy expenditure was measured by doubly labeled water during a two week period in which the subjects lived at home and performed their normal activities. Smoking status was determined by questionnaire. There were no significant differences in mean BMI (mean +/- SD) between smokers and never smokers for either males (27.8+5.1 kg/m(2) vs. 27.5+4.0 kg/m(2)) or females (26.5+5.3 kg/m(2) vs. 28.1+6.6 kg/m(2)), although the difference in females was of similar magnitude to previous reports. Similarly, total energy expenditure of male smokers (3069+764 kcal/d) was not significantly different from that of never smokers (2854+468 kcal/d), and that of female smokers (2266+387 kcal/d) was not different from that of never smokers (2330+415 kcal/d). These findings did not change after adjustment for age, fat-free mass and self-reported physical activity. Using doubly labeled water, we found no evidence of increased energy expenditure among smokers, however, it should be noted that BMI differences in this cohort also did not differ by smoking status. C1 [Johnson, Lindsey A.; Zhang, Zhumin; Schoeller, Dale A.] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. [Bradley, David P.] Univ Wisconsin, Dept Endocrinol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Johnson, Lindsey A.] Univ Wisconsin, Catering & Conf Serv, Madison, WI 53706 USA. [Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Subar, Amy F.; Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Schoeller, DA (reprint author), Univ Wisconsin, Dept Nutr Sci, 1415 Linden Dr, Madison, WI 53706 USA. EM dschoell@nutrisci.wisc.edu OI Troiano, Richard/0000-0002-6807-989X NR 43 TC 6 Z9 6 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD NOV 1 PY 2010 VL 7 AR 81 DI 10.1186/1743-7075-7-81 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 683MQ UT WOS:000284480300001 PM 21040542 ER PT J AU Preis, SR Massaro, JM Robins, SJ Hoffmann, U Vasan, RS Irlbeck, T Meigs, JB Sutherland, P D'Agostino, RB O'Donnell, CJ Fox, CS AF Preis, Sarah R. Massaro, Joseph M. Robins, Sander J. Hoffmann, Udo Vasan, Ramachandran S. Irlbeck, Thomas Meigs, James B. Sutherland, Patrice D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. Fox, Caroline S. TI Abdominal Subcutaneous and Visceral Adipose Tissue and Insulin Resistance in the Framingham Heart Study SO OBESITY LA English DT Article ID FATTY-ACID-METABOLISM; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; MUSCLE COMPOSITION; MEASUREMENT SITE; RISK-FACTORS; OBESE MEN; SENSITIVITY; GLUCOSE AB Insulin resistance is associated with central obesity and an increased risk of cardiovascular disease. Our objective is to examine the association between abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) and insulin resistance, to determine which fat depot is a stronger correlate of insulin resistance, and to assess whether there was an interaction between SAT, VAT, and age, sex, or BMI. Participants without diabetes from the Framingham Heart Study (FHS), who underwent multidetector computed tomography to assess SAT and VAT (n = 3,093; 48% women; mean age 50.4 years; mean BMI 27.6 kg/m(2)), were evaluated. Insulin resistance was measured using the homeostasis model and defined as HOMA(IR) >= 75th percentile. Logistic regression models, adjusted for age, sex, smoking, alcohol, menopausal status, and hormone replacement therapy use, were used to assess the association between fat measures and insulin resistance. The odds ratio (OR) for insulin resistance per standard deviation increase in SAT was 2.5 (95% confidence interval (CI): 2.2-2.7; P < 0.0001), whereas the OR for insulin resistance per standard deviation increase in VAT was 3.5 (95% CI: 3.1-3.9; P < 0.0001). Overall, VAT was a stronger correlate of insulin resistance than SAT (P < 0.0001 for SAT vs. VAT comparison). After adjustment for BMI, the OR of insulin resistance for VAT was 2.2 (95% CI: 1.9-2.5; P < 0.0001). We observed an interaction between VAT and BMI for insulin (P interaction = 0.0004), proinsulin (P interaction = 0.003), and HOMA(IR) (P interaction = 0.003), where VAT had a stronger association in obese individuals. In conclusion, SAT and VAT are both correlates of insulin resistance; however, VAT is a stronger correlate of insulin resistance than SAT. C1 [Preis, Sarah R.; Robins, Sander J.; Vasan, Ramachandran S.; Sutherland, Patrice; D'Agostino, Ralph B., Sr.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Preis, Sarah R.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Robins, Sander J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Robins, Sander J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Irlbeck, Thomas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program, Boston, MA USA. [Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol & Metab, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Preis, Sarah/0000-0002-9360-4166; Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; NIDDK [K24 DK080140]; GlaxoSmithKline; Sanofi-Aventis; [R01DK080739] FX This study was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195). R. S. V. was supported in part by R01DK080739. J.B.M. is supported by NIDDK K24 DK080140.; J.B.M. currently has research grants from GlaxoSmithKline and Sanofi-Aventis, and has consulting agreements with Eli Lilly, Interleukin Genetics, Kalypsys, and Outcomes Science. The other authors declared no conflict of interest. NR 32 TC 116 Z9 123 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD NOV PY 2010 VL 18 IS 11 BP 2191 EP 2198 DI 10.1038/oby.2010.59 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 671GE UT WOS:000283487700022 PM 20339361 ER PT J AU Laughon, SK Reddy, UM Sun, LP Zhang, J AF Laughon, S. Katherine Reddy, Uma M. Sun, Liping Zhang, Jun TI Precursors for Late Preterm Birth in Singleton Gestations SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID NEAR-TERM INFANTS; UNITED-STATES; PREECLAMPSIA; HYPERTENSION; MORTALITY; OUTCOMES AB OBJECTIVE: To characterize precursors for late preterm birth in singletons and incidences of neonatal morbidities and perinatal mortality by gestational age and precursor. METHODS: Using retrospective observational data, we compared 15,136 gestations born late preterm with 170,593 deliveries between 37 0/7 and 41 6/7 weeks. We defined the following categories of precursors for late preterm delivery: "spontaneous labor," "premature rupture of the membranes (preterm PROM)," "indicated" delivery, and "unknown." Incidences of neonatal morbidities were calculated according to category of precursor stratified by gestational age at delivery. Neonatal morbidities and mortality associated with potentially avoidable deliveries (eg, "soft" precursors or elective) were compared between late preterm births and neonates born at 37-40 weeks. RESULTS: Late preterm birth comprised 7.8% of all births and 65.7% of preterm births. Percentages of precursors were 29.8% spontaneous labor, 32.3% preterm PROM, 31.8% "indicated" (obstetric, maternal, or fetal condition), and 6.1% unknown. Different precursors for delivery were associated with varying incidences of neonatal morbidity. One in 15 neonates delivered late preterm for "soft" or elective precursors, and neonatal morbidity and mortality were increased compared with delivery at or after 37 weeks for these same indications. CONCLUSION: A significant number of late preterm births were potentially avoidable. Elective deliveries should be postponed until 39 weeks of gestation. (Obstet Gynecol 2010;116:1047-55) C1 [Laughon, S. Katherine; Reddy, Uma M.; Sun, Liping; Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Laughon, SK (reprint author), NICHD, Epidemiol Branch, NIH, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM laughonsk@mail.nih.gov OI Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX The data included in this article were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract No. HHSN267200603425C. NR 16 TC 37 Z9 42 U1 0 U2 1 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 NOV PY 2010 VL 116 IS 5 BP 1047 EP 1055 DI 10.1097/AOG.0b013e3181f73f97 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 669EK UT WOS:000283329000008 PM 20966688 ER PT J AU Reddy, UM Laughon, SK Sun, LP Troendle, J Willinger, M Zhang, J AF Reddy, Uma M. Laughon, S. Katherine Sun, Liping Troendle, James Willinger, Marian Zhang, Jun TI Prepregnancy Risk Factors for Antepartum Stillbirth in the United States SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MATERNAL AGE; UNEXPLAINED STILLBIRTH; FETAL-DEATH; PREGNANCY; DELIVERY; SMOKING; COHORT; WOMEN AB OBJECTIVE: To identify possible prepregnancy risk factors for antepartum stillbirth and to determine whether these factors identify women at higher risk for term stillbirth. METHODS: This retrospective cohort study of prepregnancy risk factors compared 712 singleton antepartum stillbirths with 174,097 singleton live births at or after 23 weeks of gestation. The risk of term antepartum stillbirth then was assessed in a subset of 155,629 singleton pregnancies. RESULTS: In adjusted multivariable analyses, African-American race, Hispanic ethnicity, maternal age 35 years or older, nulliparity, prepregnancy body mass index (BMI) 30 or higher, preexisting diabetes, chronic hypertension, smoking, and alcohol use were independently associated with stillbirth. Prior cesarean delivery and history of preterm birth were associated with increased stillbirth risk in multiparous women. The risk of a term stillbirth for women who were white, 25-29 years old, normal weight, multiparous, no chronic hypertension, and no preexisting diabetes was 0.8 per 1,000. Term stillbirth risk increased with the following conditions: preexisting diabetes (3.1 per 1,000), chronic hypertension (1.7 per 1,000), African-American race (1.8 per 1,000), maternal age 35 years or older (1.3 per 1,000), BMI 30 or higher (1 per 1,000), and nulliparity (0.9 per 1,000). CONCLUSION: There are multiple independent risk factors for antepartum stillbirth. However, the value of individual risk factors of race, parity, advanced maternal age (35-39 years old), and BMI to predict term stillbirth is poor. Our results do not support routine antenatal surveillance for any of these risk factors when present in isolation. (Obstet Gynecol 2010;116:1119-26) C1 [Reddy, Uma M.; Laughon, S. Katherine; Sun, Liping; Troendle, James; Willinger, Marian; Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Reddy, UM (reprint author), 6100 Execut Blvd,Room 4B03F, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov OI Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX The data included in this article were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract No. HHSN267200603425C. NR 19 TC 46 Z9 49 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD NOV PY 2010 VL 116 IS 5 BP 1119 EP 1126 DI 10.1097/AOG.0b013e3181f903f8 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 669EK UT WOS:000283329000017 PM 20966697 ER PT J AU Signore, C AF Signore, Caroline TI No Time for Complacency: Labor Inductions, Cesarean Deliveries, and the Definition of "Term" Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 NICHHD, Bethesda, MD 20892 USA. RP Signore, C (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD NOV PY 2010 VL 116 IS 5 BP 1219 EP 1219 DI 10.1097/AOG.0b013e3181f7399d PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 669EK UT WOS:000283329000034 ER PT J AU Schiffman, M Wentzensen, N AF Schiffman, Mark Wentzensen, Nicolas TI From Human Papillomavirus to Cervical Cancer Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Schiffman, Mark; Wentzensen, Nicolas] NCI, Rockville, MD USA. RP Schiffman, M (reprint author), NCI, Rockville, MD USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD NOV PY 2010 VL 116 IS 5 BP 1221 EP 1222 DI 10.1097/AOG.0b013e3181fa7d13 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 669EK UT WOS:000283329000039 ER PT J AU Peplonska, B Stewart, P Szeszenia-Dabrowska, N Lissowska, J Brinton, LA Gromiec, JP Brzeznicki, S Yang, XHR Sherman, M Garcia-Closas, M Blair, A AF Peplonska, Beata Stewart, Patricia Szeszenia-Dabrowska, Neonila Lissowska, Jolanta Brinton, Louise A. Gromiec, Jan Piotr Brzeznicki, Slawomir Yang, Xiaohong R. Sherman, Mark Garcia-Closas, Montserrat Blair, Aaron TI Occupational exposure to organic solvents and breast cancer in women SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID ESTROGEN-RECEPTOR; RISK-FACTORS; POPULATION; MORTALITY; CHEMICALS; TISSUE; HYPOTHESIS; SHANGHAI; WORKERS; CYP2E1 AB Background Although studies in rodents suggest possible associations between exposure to organic solvents and breast cancer, the evidence in humans is limited. Methods We evaluated job histories of 2383 incident breast cancer cases diagnosed during 2000-2003, and 2502 controls who participated in a large population-based case-control study in Poland. Industrial hygienists reviewed occupational histories and developed exposure metrics for total organic solvents and benzene. Unconditional logistic regression analyses estimated ORs and 95% CIs as the measure of association with breast cancer, controlling for breast cancer risk factors. Stratified analyses examined the potential modification by known breast cancer risk factors. Associations were also evaluated by oestrogen and progesterone receptor status and by other clinical characteristics of the tumours using polytomous regression analyses. Results Women who ever worked at jobs with organic solvents exposure had a small, non-significant increase in breast cancer risk (OR=1.16; 95% CI 0.99 to 1.4). A significant association was present for oestrogen receptor- and progesterone receptor-negative tumours (OR 1.40; 95% CI 1.1 to 1.8), but there was no association with tumours with both positive receptors (OR 0.97; 95% CI 0.8 to 1.2 (p heterogeneity: 0.008)). We did not observe trends with increasing level of exposure. Known breast cancer risk factors did not modify the association between organic solvents and breast cancer risk. No association with breast cancer was found for benzene exposure (OR 1.00; 95% CI 0.8 to 1.3). Conclusion Our study provides weak evidence for a possible association between occupational exposure to organic solvents as a class and breast cancer risk. The association might be limited to hormone receptor-negative tumours. C1 [Peplonska, Beata; Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Dept Environm Epidemiol, PL-91348 Lodz, Poland. [Stewart, Patricia; Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Div Canc Epidemiol & Prevent, Warsaw, Poland. [Brinton, Louise A.; Yang, Xiaohong R.; Sherman, Mark; Garcia-Closas, Montserrat] NCI, Hormonal & Reprod Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Gromiec, Jan Piotr; Brzeznicki, Slawomir] Nofer Inst Occupat Med, Dept Chem Hazards, PL-91348 Lodz, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. RP Peplonska, B (reprint author), Nofer Inst Occupat Med, Dept Environm Epidemiol, Teresy 8 St, PL-91348 Lodz, Poland. EM beatap@imp.lodz.pl RI Brinton, Louise/G-7486-2015; BRZEZNICKI, SLAWOMIR/G-4762-2010; Szeszenia-Dabrowska, Neonila/F-7190-2010; Peplonska, Beata/F-6004-2010; Garcia-Closas, Montserrat /F-3871-2015 OI Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799; Garcia-Closas, Montserrat /0000-0003-1033-2650 FU National Cancer Institute, National Institutes of Health [NCI N01-CP-91013] FX The study was supported by Intramural Funds of the National Cancer Institute, National Institutes of Health (contract number: NCI N01-CP-91013). NR 36 TC 8 Z9 8 U1 2 U2 8 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 NOV PY 2010 VL 67 IS 11 BP 722 EP 729 DI 10.1136/oem.2009.046557 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 667EM UT WOS:000283175500002 PM 19819862 ER PT J AU Ehsanian, R Brown, M Lu, H Yang, XP Pattatheyil, A Yan, B Duggal, P Chuang, R Doondeea, J Feller, S Sudol, M Chen, Z Van Waes, C AF Ehsanian, R. Brown, M. Lu, H. Yang, X. P. Pattatheyil, A. Yan, B. Duggal, P. Chuang, R. Doondeea, J. Feller, S. Sudol, M. Chen, Z. Van Waes, C. TI YAP dysregulation by phosphorylation or Delta Np63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets SO ONCOGENE LA English DT Article DE YAP; p53; Delta Np63; p73; apoptosis; cancer ID SQUAMOUS-CELL CARCINOMA; YES-ASSOCIATED PROTEIN; NF-KAPPA-B; GROWTH-FACTOR-RECEPTOR; TUMOR-SUPPRESSOR; WW DOMAIN; PROANGIOGENIC CYTOKINES; HIPPO PATHWAY; DNA-DAMAGE; ACTIVATION AB Overexpression of the Yes-associated protein (YAP), and TP53 family members Delta Np63 and p73, have been independently detected in subsets of head and neck squamous cell carcinomas (HNSCCs). YAP may serve as a nuclear cofactor with Delta Np63 and p73, but the functional role of YAP and their potential relationship in HNSCCs are unknown. In this study, we show that in a subset of HNSCC lines and tumors, YAP expression is increased but localized in the cytoplasm in association with increased AKT and YAP phosphorylation, and with decreased expression of Delta Np63 and p73. In another subset, YAP expression is decreased but detectable in the nucleus in association with lower AKT and YAP phosphorylation, and with increased Delta Np63 and p73 expression. Inhibiting AKT decreased serine-127 phosphorylation and enhanced nuclear translocation of YAP. Delta Np63 bound to the YAP promoter and suppressed its expression. Transfection of a YAP-serine-127-alanine phosphoacceptor-site mutant or Delta Np63 knockdown significantly increased nuclear YAP and cell death. Conversely, YAP knockdown enhanced cell proliferation, survival, migration and cisplatin chemoresistance. Thus, YAP function as a tumor suppressor may alternatively be dysregulated by AKT phosphorylation at serine-127 and cytoplasmic sequestration, or by transcriptional repression by Delta Np63, in different subsets of HNSCC. AKT and/or Delta Np63 are potential targets for enhancing YAP-mediated apoptosis and chemosensitivity in HNSCCs. Oncogene (2010) 29, 6160-6171; doi:10.1038/onc.2010.339; published online 23 August 2010 C1 [Ehsanian, R.; Brown, M.; Lu, H.; Yang, X. P.; Pattatheyil, A.; Yan, B.; Duggal, P.; Chuang, R.; Chen, Z.; Van Waes, C.] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Ehsanian, R.] Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD 20817 USA. [Ehsanian, R.] NIH Oxford Univ Stanford Univ, Sch Med, Grad Partnership Program, NIH, Bethesda, MD USA. [Brown, M.] NIH, NIH Pfizer Clin Res Training Program, Bethesda, MD USA. [Doondeea, J.; Feller, S.] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [Sudol, M.] Weis Ctr Res, Geisinger Clin, Lab Signal Transduct & Prote Profiling, Danville, PA 17822 USA. [Sudol, M.] Mt Sinai Sch Med, Dept Med, New York, NY USA. RP Van Waes, C (reprint author), NIDCD, Head & Neck Surg Branch, NIH, 10-5D55,MSC 1419, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU NIDCD [Z1ADC-000073, Z1ADC-000074]; Head and Neck Cancer Charity; Pennsylvania Department of Health FX We thank Drs Tsutomu Oka, Maie St John and Ms Cindy Clark for their critical review; Ning Yeh, Dr Liesl Nottingham, Dr Jay Friedman, Dr Yansong Bian and Jonah Cohen for technical assistance; and Dr Paul Albert for assistance with statistical analysis. This study was supported by the NIDCD Intramural project Z1ADC-000073, Z1ADC-000074, Head and Neck Cancer Charity Grant and the Breast Cancer Coalition Grant from the Pennsylvania Department of Health. NR 52 TC 30 Z9 33 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD NOV PY 2010 VL 29 IS 46 BP 6160 EP 6171 DI 10.1038/onc.2010.339 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 681XD UT WOS:000284356500008 PM 20729916 ER PT J AU Chew, EY Kim, J Sperduto, RD Datiles, MB Coleman, HR Thompson, DJS Milton, RC Clayton, JA Hubbard, LD Danis, RP Ferris, FL AF Chew, Emily Y. Kim, Jonghyeon Sperduto, Robert D. Datiles, Manuel B., III Coleman, Hanna R. Thompson, Darby J. S. Milton, Roy C. Clayton, Janine A. Hubbard, Larry D. Danis, Ronald P. Ferris, Frederick L., III TI Evaluation of the Age-Related Eye Disease Study Clinical Lens Grading System AREDS Report No. 31 SO OPHTHALMOLOGY LA English DT Article ID OPACITIES CLASSIFICATION-SYSTEM; II LOCS-II; WEIGHTED KAPPA; AGREEMENT; RELIABILITY; COEFFICIENT AB Purpose: To examine the grading (interrater) reliability of the Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System (ARLNS). Design: Evaluation of diagnostic test or technology. Participants: One hundred fifty volunteers (284 eyes). Methods: Participants with lens opacities of varying severity were independently graded at the slit lamp for cataract severity by 2 examiners (retinal or anterior segment specialists) using the ARLNS, which employs 3 standard photographs of increasing severity for classifying each of the 3 major types of opacity. Lens photographs were taken and graded at a reading center using the more detailed AREDS System for Classifying Cataracts from photographs. Main Outcome Measures: The Pearson correlation, weighted-kappa, and limits-of-agreement statistics were used to assess the interrater agreement of the gradings. Results: Examinations were performed on 284 lenses (150 participants). Tests of interrater reliability between pairs of clinicians showed substantial agreement between clinicians for cortical and posterior subcapsular opacities and moderate agreement for nuclear opacities. A similar pattern and strength of agreement was present when comparing scores of retinal versus anterior segment specialists. Interrater agreement between clinical and reading center gradings was not as great as inter-clinician agreement. Conclusions: Interrater agreements were in the moderate to substantial range for the clinical assessment of lens opacities. Inherent differences in cataract classification systems that rely on slit lamp vs photographic assessments of lens opacities may explain some of the disagreement noted between slit lamp and photographic gradings. Given the interrater reliability statistics for clinicians and the simplicity of the grading procedure, ARLNS is presented for use in studies requiring a simple, inexpensive method for detecting the presence and severity of the major types of lens opacities. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2010; 117: 2112-2119 (C) 2010 by the American Academy of Ophthalmology. C1 [Chew, Emily Y.] EMMES Corp, AREDS Coordinating Ctr, Rockville, MD 20850 USA. [Chew, Emily Y.; Datiles, Manuel B., III; Coleman, Hanna R.; Clayton, Janine A.; Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Hubbard, Larry D.; Danis, Ronald P.] Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI 53706 USA. RP Chew, EY (reprint author), EMMES Corp, AREDS Coordinating Ctr, 401 N Washington St, Rockville, MD 20850 USA. EM aredspub@emmes.com OI Datiles, Manuel III B./0000-0003-4660-1664 FU National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland FX Supported by contracts from the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. NR 18 TC 16 Z9 16 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 NOV PY 2010 VL 117 IS 11 BP 2112 EP U299 DI 10.1016/j.ophtha.2010.02.033 PG 11 WC Ophthalmology SC Ophthalmology GA 668JI UT WOS:000283264200012 PM 20561686 ER PT J AU Zhao, JL Ellwein, LB Cui, H Ge, JA Guan, HJ Lv, JH Ma, XZ Yin, JL Yin, ZQ Yuan, YS Liu, H AF Zhao, Jialiang Ellwein, Leon B. Cui, Hao Ge, Jian Guan, Huaijin Lv, Jianhua Ma, Xianzhi Yin, Jinglin Yin, Zheng Qin Yuan, Yuansheng Liu, Hu TI Prevalence and Outcomes of Cataract Surgery in Rural China The China Nine-Province Survey SO OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; VISUAL-ACUITY; EYE SURVEY; SHUNYI COUNTY; DOUMEN COUNTY; OLDER ADULTS; BLINDNESS; POPULATION; DISTRICT; VISION AB Purpose: To investigate the prevalence and visual acuity (VA) outcomes of cataract surgery in rural populations throughout China. Design: Population-based, cross-sectional study. Participants: Forty-five thousand seven hundred forty-seven adults 50 years of age and older. Methods: Geographically defined cluster sampling was used in randomly selecting a cross-section of residents from a representative rural county within each of 9 provinces in mainland China. Participants underwent VA measurements, refraction, and a slit-lamp examination at local examination sites; those with previous cataract surgery were queried as to the year and type of surgical facility. Surgical procedure and evidence of surgery complications were noted during the examination. The principal cause of visual impairment was identified for eyes with VA of 20/40 or worse. Main Outcome Measures: Cataract surgery procedure, presenting and best-corrected distance VA, and causes of visual impairment. Results: Of 50 395 enumerated eligible persons, 45 747 (90.8%) were examined and tested for VA. The overall prevalence of cataract surgery was 2.09%. Surgical coverage among those with VA worse than 20/200 in both eyes because of cataract was 35.7%. Unoperated cataract was associated with older age, female gender, lack of education, and geographic area (province). Among the 1174 cataract-operated eyes, 31.1% had presenting VA of 20/32 or better, 15.4% had presenting VA of 20/40 to 20/63, 30.0% had presenting VA worse than 20/63 to 20/200, and 23.5% had presenting VA worse than 20/200. With best correction, the percentages were 57.6%, 6.2%, 18.5%, and 17.7%, respectively. Posterior capsule opacification, refractive error, and retinal disorders were the main causes in cataract-operated eyes with VA worse than 20/63. Conclusions: Two thirds of those with bilateral visual impairment or blindness because of cataract remain in need of sight-restoring surgery. Posterior capsule opacification and refractive error, both readily amenable to treatment, were common in cataract-operated eyes. Sustained government efforts to provide access to affordable modern cataract surgery with a greater emphasis on postoperative follow-up and the quality of VA outcomes are needed. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2010; 117: 2120-2128 (C) 2010 by the American Academy of Ophthalmology. C1 [Zhao, Jialiang; Liu, Hu] Beijing Union Med Coll Hosp, Dept Ophthalmol, Beijing 100730, Peoples R China. [Zhao, Jialiang; Liu, Hu] Chinese Acad Med Sci, Beijing 100037, Peoples R China. [Ellwein, Leon B.] NEI, NIH, Bethesda, MD 20892 USA. [Cui, Hao] Harbin Med Coll, Affiliated Hosp 1, Dept Ophthalmol, Harbin, Peoples R China. [Ge, Jian] Sun Yat Sen Univ, Zhongshan Eye Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Guan, Huaijin] Nantong Univ, Affiliated Hosp, Dept Ophthalmol, Nantong, Peoples R China. [Lv, Jianhua] Xingtai Eye Hosp, Xingtai, Hebei, Peoples R China. [Ma, Xianzhi] Peoples Hosp Xinjiang, Dept Ophthalmol, Urumqi, Peoples R China. [Yin, Jinglin] Peoples Hosp Jiangxi, Dept Ophthalmol, Nanchang, Peoples R China. [Yin, Zheng Qin] Third Mil Med Univ, Southwest Hosp, Dept Ophthalmol, Chongqing, Peoples R China. [Yuan, Yuansheng] Yunnan Med Coll, Attached Hosp 1, Dept Ophthalmol, Kunming, Peoples R China. RP Zhao, JL (reprint author), Beijing Union Med Coll Hosp, Dept Ophthalmol, 1 Shuai Fu Yuan, Beijing 100730, Peoples R China. EM zhaojialiang@medmail.com.cn FU Chinese Ministry of Health, Beijing, China; World Health Organization, Geneva, Switzerland (under National Institutes of Health [Bethesda, Maryland] [N01-EY-2103]; Lions Clubs International Foundation, Oak Brook, Illinois, USA FX Supported by the Chinese Ministry of Health, Beijing, China; the World Health Organization, Geneva, Switzerland (under National Institutes of Health [Bethesda, Maryland] contract no.: N01-EY-2103); and the Lions Clubs International Foundation, Oak Brook, Illinois, USA. The World Health Organization participated in the design of the study. NR 16 TC 35 Z9 44 U1 2 U2 8 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 NOV PY 2010 VL 117 IS 11 BP 2120 EP 2128 DI 10.1016/j.ophtha.2010.03.005 PG 9 WC Ophthalmology SC Ophthalmology GA 668JI UT WOS:000283264200013 PM 20663565 ER PT J AU Jakubovics, NS Kolenbrander, PE AF Jakubovics, N. S. Kolenbrander, P. E. TI The road to ruin: the formation of disease-associated oral biofilms SO ORAL DISEASES LA English DT Review DE antigen I; II protein; autoinducer-2; biofilm matrix; coaggregation; dental plaque; oral streptococcus ID ANTIGEN-I/II FAMILY; AGGREGATIBACTER ACTINOBACILLUS ACTINOMYCETEMCOMITANS; DENTAL PLAQUE BACTERIA; STREPTOCOCCUS-MUTANS; PORPHYROMONAS-GINGIVALIS; FUSOBACTERIUM-NUCLEATUM; ACTINOMYCES-NAESLUNDII; GENE-EXPRESSION; CELL-SURFACE; VEILLONELLA-ATYPICA AB The colonization of oral surfaces by micro-organisms occurs in a characteristic sequence of stages, each of which is potentially amenable to external intervention. The process begins with the adhesion of bacteria to host receptors on epithelial cells or in the salivary pellicle covering tooth surfaces. Interbacterial cell-cell binding interactions facilitate the attachment of new species and increase the diversity of the adherent microbial population. Microbial growth in oral biofilms is influenced by the exchange of chemical signals, metabolites and toxic products between neighbouring cells. Bacterial cells on tooth surfaces (dental plaque) produce extracellular polymers such as complex carbohydrates and nucleic acids. These large molecules form a protective matrix that contributes to the development of dental caries and, possibly, to periodontitis. The identification of key microbial factors underlying each step in the formation of oral biofilms will provide new opportunities for preventative or therapeutic measures aimed at controlling oral infectious diseases. C1 [Jakubovics, N. S.] Newcastle Univ, Sch Dent Sci, Newcastle Upon Tyne NE2 4BW, Tyne & Wear, England. [Kolenbrander, P. E.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Jakubovics, NS (reprint author), Newcastle Univ, Sch Dent Sci, Newcastle Upon Tyne NE2 4BW, Tyne & Wear, England. EM nick.jakubovics@ncl.ac.uk OI Jakubovics, Nicholas/0000-0001-6667-0515 NR 80 TC 59 Z9 60 U1 3 U2 37 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD NOV PY 2010 VL 16 IS 8 BP 729 EP 739 DI 10.1111/j.1601-0825.2010.01701.x PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 666EE UT WOS:000283094500003 PM 20646235 ER PT J AU Vardanyan, M Melemedjian, OK Price, TJ Ossipov, MH Lai, J Roberts, E Boos, TL Deschamps, JR Jacobson, AE Rice, KC Porreca, F AF Vardanyan, Marina Melemedjian, Ohannes K. Price, Theodore J. Ossipov, Michael H. Lai, Josephine Roberts, Ed Boos, Terrence L. Deschamps, Jeffrey R. Jacobson, Arthur E. Rice, Kenner C. Porreca, Frank TI Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist SO PAIN LA English DT Article DE Pancreatitis; Pain; Mechanisms; Interleukin-6 ID PERIPHERAL-NERVE INJURY; RHEUMATOID-ARTHRITIS; CAPSAICIN RECEPTOR; NEUROPATHIC PAIN; DOUBLE-BLIND; CHAN SU; IL-6; RATS; NEURONS; CANCER AB Pancreatic pain resulting from chronic inflammation of the pancreas is often intractable and clinically difficult to manage with available analgesics reflecting the need for more effective therapies. The mechanisms underlying pancreatitis pain are not well understood. Here, the possibility that interleukin-6 (IL-6) may promote pancreatitis pain was investigated with TB-2-081 (3-O-formyl-20R,21-epoxyresibufogenin, EBRF), a small molecule IL-6 receptor antagonist that was semi-synthetically derived from natural sources. The potential activity and mechanism of TB-2-081 were investigated following the induction of persistent pancreatitis using dibutyltin dichloride (DBTC) in rats. TB-2-081 displaces the binding of IL-6 to the human recombinant soluble IL-6 receptor with apparent high affinity and inhibits IL-6 mediated cell growth. Systemic or oral, but not intrathecal, administration of TB-2-081 reversed DBTC-induced abdominal hypersensitivity in a dose-and time-dependent manner. IL-6 levels were significantly up-regulated in the dorsal root ganglia (DRG) of rats with pancreatitis on day 6 after DBTC injection. IL-6-enhanced capsaicin-evoked release of calcitonin gene-related peptide from cultured DRG neurons was blocked by TB-2-081. Our data demonstrate that TB-2-081 acts as a systemically available and orally active small molecule IL-6 receptor antagonist. TB-2-081 effectively reduces pancreatitis-induced pain through peripheral mechanisms that are likely due to (a) increased expression of IL-6 in the DRG and (b) IL-6-mediated sensitization of nociceptive neurons. The activity of TB-2-081 implicates an important role for IL-6 in sustaining pancreatitis pain. Strategies targeting IL-6 actions through small molecule antagonists may offer novel approaches to improve the therapy of chronic pancreatitis and other chronic pain states. (C) 2010 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Vardanyan, Marina; Melemedjian, Ohannes K.; Price, Theodore J.; Ossipov, Michael H.; Lai, Josephine; Porreca, Frank] Univ Arizona, Dept Pharmacol, Coll Med, Tucson, AZ 85724 USA. [Roberts, Ed] Scripps Res Inst, La Jolla, CA 92037 USA. [Boos, Terrence L.; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, Drug Design & Synth Sect, Chem Biol Res Branch, NIDA,NIH, Bethesda, MD 20892 USA. [Deschamps, Jeffrey R.] USN, Struct Matter Lab, Res Lab, Washington, DC 20375 USA. RP Porreca, F (reprint author), Univ Arizona, Dept Pharmacol, Coll Med, Tucson, AZ 85724 USA. EM frankp@email.arizona.edu RI Price, Theodore/A-5094-2010; OI Deschamps, Jeffrey/0000-0001-5845-0010; Price, Theodore/0000-0002-6971-6221 FU National Institute on Drug Abuse (NIDA) [Y1-DA6002]; National Institute on Alcohol Abuse and Alcoholism; NIH [NS065926, DA023513] FX The research of the Drug Design and Synthesis Section, CBRB, NIDA & NIAAA, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism. We thank NIDA for support of the X-ray crystallographic studies (NIDA Contract Y1-DA6002). This work was also funded by NIH Grants NS065926 and DA023513. NR 44 TC 20 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD NOV PY 2010 VL 151 IS 2 BP 257 EP 265 DI 10.1016/j.pain.2010.05.022 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 662QJ UT WOS:000282826100009 PM 20599324 ER PT J AU Colloca, L Petrovic, P Wager, TD Ingvar, M Benedetti, F AF Colloca, Luana Petrovic, Predrag Wager, Tor D. Ingvar, Martin Benedetti, Fabrizio TI How the number of learning trials affects placebo and nocebo responses SO PAIN LA English DT Article DE Expectations; Conditioning; Pain; Somatosensorial perception; Placebo; Nocebo ID ANALGESIA; EXPECTANCY; ANTICIPATION; EXPECTATIONS; PERSONALITY; EXPERIENCE; NETWORK; HUMANS; PAIN; SKIN AB Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 [Colloca, Luana] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Colloca, Luana] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Colloca, Luana; Benedetti, Fabrizio] Univ Turin, Dept Neurosci, Sch Med, Turin, Italy. [Colloca, Luana; Benedetti, Fabrizio] Natl Inst Neurosci, Turin, Italy. [Petrovic, Predrag; Ingvar, Martin] Karolinska Inst, MR Res Ctr, Stockholm, Sweden. [Petrovic, Predrag; Ingvar, Martin] Karolinska Inst, Osher Ctr, Dept Clin Neurosci, Stockholm, Sweden. [Wager, Tor D.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. RP Colloca, L (reprint author), NIH, Ctr Clin, Dept Bioeth, Bldg 10-1C118, Bethesda, MD 20892 USA. EM luana.colloca@unito.it OI Colloca, Luana/0000-0002-6503-4709; Ingvar, Martin/0000-0002-9041-5714 FU International Association for Study of Pain (IASP); Regione Piemonte; Istituto San Paolo di Torino; Volkswagen Foundation FX This research was supported by grants from the International Association for Study of Pain (IASP) Collaborative Research Grant, from the Regione Piemonte, from the Istituto San Paolo di Torino, and from the Volkswagen Foundation. NR 49 TC 77 Z9 79 U1 2 U2 39 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD NOV PY 2010 VL 151 IS 2 BP 430 EP 439 DI 10.1016/j.pain.2010.08.007 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 662QJ UT WOS:000282826100027 PM 20817355 ER PT J AU Goldberg, ME Schwartzman, RJ Torjman, MC Wainer, IW AF Goldberg, Michael E. Schwartzman, Robert J. Torjman, Marc C. Wainer, Irving W. TI Ketamine Infusion Successful in Some Patients SO PAIN PHYSICIAN LA English DT Letter ID REGIONAL PAIN SYNDROME C1 [Goldberg, Michael E.; Torjman, Marc C.] UMDNJ, Cooper Univ Hosp, Dept Anesthesiol, Newark, NJ USA. [Schwartzman, Robert J.] Drexel Univ, Coll Med, Dept Neurol, Philadelphia, PA 19104 USA. [Wainer, Irving W.] NIA, Clin Invest Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Goldberg, ME (reprint author), UMDNJ, Cooper Univ Hosp, Dept Anesthesiol, Newark, NJ USA. EM goldberg-Mike@cooperhealth.edu NR 7 TC 2 Z9 2 U1 0 U2 3 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD NOV-DEC PY 2010 VL 13 IS 6 BP E371 EP E372 PG 2 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 857KV UT WOS:000297718300004 PM 21102974 ER PT J AU Phipps, S Buckholt, K Fernandez, I Wiener, L Noll, R AF Phipps, Sean Buckholt, Kelli Fernandez, Ialy Wiener, Lori Noll, Robert TI PEDIATRIC ONCOLOGISTS' PRACTICES OF PRESCRIBING SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI'S) FOR CHILDREN AND ADOLESCENTS WITH CANCER: A MULTI-SITE STU SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Phipps, Sean; Buckholt, Kelli] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Fernandez, Ialy; Noll, Robert] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Wiener, Lori] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2010 VL 55 IS 5 BP 817 EP 818 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 663SN UT WOS:000282910200147 ER PT J AU Kovar, H Mestdagh, P Kauer, M Ban, J Bilke, S Schwentner, R Speleman, F Meltzer, P Vandesompele, J AF Kovar, Heinrich Mestdagh, Pieter Kauer, Max Ban, Jozef Bilke, Sven Schwentner, Raphaela Speleman, Frank Meltzer, Paul Vandesompele, Jo TI AN INTEGRATED GENOMICS APPROACH UNRAVELS A ROLE FOR MICRO-RNAS IN EWS-FLI1 DRIVEN EWINGS SARCOMA PATHOGENESIS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Kovar, Heinrich; Kauer, Max; Ban, Jozef; Schwentner, Raphaela] St Anna Childrens Hosp, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Mestdagh, Pieter; Speleman, Frank; Vandesompele, Jo] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Bilke, Sven; Meltzer, Paul] NCI, NIH, Genet Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2010 VL 55 IS 5 BP 875 EP 875 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 663SN UT WOS:000282910200349 ER PT J AU Horowitz, L Ballard, E Teach, SJ Bosk, A Rosenstein, DL Joshi, P Dalton, ME Pao, M AF Horowitz, Lisa Ballard, Elizabeth Teach, Stephen J. Bosk, Abigail Rosenstein, Donald L. Joshi, Paramjit Dalton, Marc E. Pao, Maryland TI Feasibility of Screening Patients With Nonpsychiatric Complaints for Suicide Risk in a Pediatric Emergency Department A Good Time to Talk? SO PEDIATRIC EMERGENCY CARE LA English DT Article DE suicide; screening; nonpsychiatric patients; feasibility ID PUBLIC-HEALTH; MENTAL-HEALTH; UNITED-STATES; CLINICAL-TRIAL; PRIMARY-CARE; BEHAVIOR; YOUTH; IMPLEMENTATION; ADOLESCENTS; CHILDHOOD AB Objective: Screening children for suicide risk when they present to the emergency department (ED) with nonpsychiatric complaints could lead to better identification and treatment of high-risk youth. Before suicide screening protocols can be implemented for nonpsychiatric patients in pediatric EDs, it is essential to determine whether such efforts are feasible. Methods: As part of an instrument validation study, ED patients (10-21 years old) with both psychiatric and nonpsychiatric presenting complaints were recruited to take part in suicide screening. Clinically significant suicidal thoughts, as measured by the Suicidal Ideation Questionnaire, and suicidal behaviors were assessed, as well as patient opinions about suicide screening. Recruitment rates for the study as well as impact on length of stay were assessed. Results: Of the 266 patients and parents approached for the study, 159 (60%) agreed to participate. For patients entering the ED for nonpsychiatric reasons (n = 106), 5.7% (n = 6) reported previous suicidal behavior, and 5.7% (n = 6) reported clinically significant suicidal ideation. There were no significant differences for mean length of stay in the ED for nonpsychiatric patients with positive triggers and those who screened negative (means, 382 [SD, 198] and 393 [SD, 166] minutes, respectively; P = 0.80). Ninety-six percent of participants agreed that suicide screening should occur in the ED. Conclusions: Suicide screening of nonpsychiatric patients in the ED is feasible in terms of acceptability to parents, prevalence of suicidal thoughts and behaviors, practicality to ED flow, and patient opinion. Future endeavors should address brief screening tools validated on nonpsychiatric populations. C1 [Horowitz, Lisa; Ballard, Elizabeth; Bosk, Abigail; Pao, Maryland] NIMH, NIH, Bethesda, MD 20892 USA. [Ballard, Elizabeth] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Div Emergency Med, Washington, DC 20010 USA. [Rosenstein, Donald L.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Joshi, Paramjit] Childrens Natl Med Ctr, Dept Psychiat, Washington, DC 20010 USA. [Dalton, Marc E.] Psychiat Inst Washington DC, Court Urgent Care Clin, Washington, DC USA. RP Horowitz, L (reprint author), NIMH, NIH, 10 CRC,Room 6-5362,10 Ctr Dr, Bethesda, MD 20892 USA. EM horowitzl@mail.nih.gov FU National Institutes of Health; National Institute of Mental Health FX The research for this article was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Mental Health. NR 39 TC 20 Z9 20 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-5161 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD NOV PY 2010 VL 26 IS 11 BP 787 EP 792 DI 10.1097/PEC.0b013e3181fa8568 PG 6 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA 675NW UT WOS:000283838400001 PM 20944511 ER PT J AU Perez, MA Gordon, A Sanchez, F Narvaez, F Gutierrez, G Ortega, O Nunez, A Harris, E Balmaseda, A AF Angeles Perez, Maria Gordon, Aubree Sanchez, Felix Narvaez, Federico Gutierrez, Gamaliel Ortega, Oscar Nunez, Andrea Harris, Eva Balmaseda, Angel TI SEVERE COINFECTIONS OF DENGUE AND PANDEMIC INFLUENZA A H1N1 VIRUSES SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE dengue; influenza; coinfection; Nicaragua; children ID RISK-FACTORS; CHILDREN; ASTHMA; BURDEN AB Here we report on 4 hospitalized patients with dengue-influenza virus coinfections. All patients were RT-PCR positive for dengue virus and pandemic influenza A H1N1. Clinical findings at presentation ranged from influenza-like illness to severe dengue. Clinical progression of the infections varied, but all developed dengue symptoms and had interstitial infiltrates. Three cases required intensive care management and 1 case was fatal. C1 [Harris, Eva] Univ Calif Berkeley, Sch Publ Hlth, Div Infect Dis & Vaccinol, Berkeley, CA 94720 USA. [Angeles Perez, Maria; Sanchez, Felix; Narvaez, Federico] Minist Salud, Hosp Infantil Manuel de Jesus Rivera, Managua, Nicaragua. [Gordon, Aubree] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Narvaez, Federico; Gutierrez, Gamaliel; Ortega, Oscar] Sustainable Sci Inst, Managua, Nicaragua. [Nunez, Andrea; Balmaseda, Angel] Minist Salud, Dept Virol, Ctr Nacl Diagnost & Referencia, Managua, Nicaragua. RP Harris, E (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Infect Dis & Vaccinol, 1 Barker Hall, Berkeley, CA 94720 USA. EM eharris@berkeley.edu OI Gordon, Aubree/0000-0002-9352-7877 FU Pediatric Dengue Vaccine Initiative [VE-1]; NIH [AI65359]; Fogarty International Center FX Supported by the Pediatric Dengue Vaccine Initiative grant VE-1 (to E.H.), NIH grant AI65359 (to E.H.), and the Fogarty International Center. NR 10 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD NOV PY 2010 VL 29 IS 11 BP 1052 EP 1055 DI 10.1097/INF.0b013e3181e6c69b PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 671HT UT WOS:000283492400018 PM 20811315 ER PT J AU Boyd, H Feenstra, B Geller, F Feingold, E Ryckman, K Shaffer, J Laurie, C Zhang, Q Doheny, K Pugh, E Manolio, T Marazita, M Melbye, M Murray, J AF Boyd, H. Feenstra, B. Geller, F. Feingold, E. Ryckman, K. Shaffer, J. Laurie, C. Zhang, Q. Doheny, K. Pugh, E. Manolio, T. Marazita, M. Melbye, M. Murray, J. CA GENEVA Consortium TI A GENOME-WIDE ASSOCIATION STUDY OF SPONTANEOUS PRETERM DELIVERY SO PEDIATRIC RESEARCH LA English DT Meeting Abstract C1 [Boyd, H.; Feenstra, B.; Geller, F.; Melbye, M.] Statens Serum Inst, DK-2300 Copenhagen, Denmark. [Feingold, E.; Shaffer, J.; Marazita, M.] Univ Pittsburgh, Pittsburgh, PA USA. [Ryckman, K.; Murray, J.] Univ Iowa, Iowa City, IA USA. [Laurie, C.; Zhang, Q.] Univ Washington, Seattle, WA 98195 USA. [Doheny, K.; Pugh, E.] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. [Manolio, T.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD NOV PY 2010 VL 68 SU 1 MA 292 BP 150 EP 150 PG 1 WC Pediatrics SC Pediatrics GA V25LO UT WOS:000208479700293 ER PT J AU Delaney-Black, V Chiodo, LM Hannigan, JH Greenwald, MK Janisse, J Patterson, G Huestis, MA Ager, J Sokol, RJ AF Delaney-Black, Virginia Chiodo, Lisa M. Hannigan, John H. Greenwald, Mark K. Janisse, James Patterson, Grace Huestis, Marilyn A. Ager, Joel Sokol, Robert J. TI Just Say "I Don't": Lack of Concordance Between Teen Report and Biological Measures of Drug Use SO PEDIATRICS LA English DT Article DE cocaine; opiates; teen; drug use ID HAIR ANALYSIS; SELF-REPORT; COCAINE USE; HOUSEHOLD SURVEY; SUBSTANCE-ABUSE; CANNABIS USE; VALIDITY; URINE; TESTS; EXPOSURE AB BACKGROUND: Prevalence estimates of illicit drug use by teens are typically generated from confidential or anonymous self-report. While data comparing teen self-report with biological measures are limited, adult studies identify varying degrees of under-reporting. METHODS: Hair analyses for cocaine, opiates and marijuana were compared to confidential teen self-and parent-reported teen drug use in a longitudinal cohort of >400 high-risk urban teens and parents. RESULTS: Both teens and parents substantially underreported recent teen cocaine and opiate use. However, compared with parents, teens were more likely to deny biomarker-verified cocaine use. Teen specimens (hair) were 52 times more likely to identify cocaine use compared with self-report. Parent hair analyses for cocaine and opiate use were 6.5 times and 5.5 times, respectively, more likely to indicate drug use than were parental self-report. The lack of concordance between self-report and bioassay occurred despite participant's knowledge that a "certificate of confidentiality" protected both teen and adult participants, and that the biological specimens would be tested for drugs. CONCLUSIONS: These findings confirm prior reports of adult under-reporting of their own drug use while extending our understanding of teen's self-admitted drug use. The lack of concordance between teen self-or parent-reported teen drug use and biomarkers confirm our concerns that both teen-and parent-reported teen drug use is limited, at least for youth in high-risk urban settings. Methods of ascertainment other than self-or parent-report must be considered when health care providers, researchers and public health agencies attempt to estimate teen drug-use prevalence. Pediatrics 2010;126:887-893 C1 [Delaney-Black, Virginia; Patterson, Grace] Wayne State Univ, Carmen & Ann Adams Dept Pediat, Detroit, MI USA. [Hannigan, John H.; Sokol, Robert J.] Wayne State Univ, Coll Nursing, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Hannigan, John H.] Wayne State Univ, Dept Psychol, Detroit, MI 48202 USA. [Greenwald, Mark K.] Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI USA. [Janisse, James; Ager, Joel] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Hannigan, John H.] Wayne State Univ, Merrill Palmer Skillman Inst, Detroit, MI USA. [Hannigan, John H.; Sokol, Robert J.] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Detroit, MI USA. [Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. RP Delaney-Black, V (reprint author), Childrens Hosp Michigan, Carmen & Ann Adams Dept Pediat, 3901 Beaubien St, Detroit, MI 48201 USA. EM vdelaney@med.wayne.edu RI Chiodo, Lisa/G-1427-2015 OI Chiodo, Lisa/0000-0001-7052-3569 FU National Institutes of Health (NIH); National Institute of Drug Abuse [R01-DA08524, R01-DA016373] FX Funded by the National Institutes of Health (NIH).; This work was supported by National Institute of Drug Abuse grants R01-DA08524 and R01-DA016373. NR 44 TC 36 Z9 36 U1 1 U2 7 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 NOV PY 2010 VL 126 IS 5 BP 887 EP 893 DI 10.1542/peds.2009-3059 PG 7 WC Pediatrics SC Pediatrics GA 673GY UT WOS:000283648700046 PM 20974792 ER PT J AU Avila, EM Uzel, G Hsu, A Milner, JD Turner, ML Pittaluga, S Freeman, AF Holland, SM AF Avila, Elizabeth Mannino Uzel, Gulbu Hsu, Amy Milner, Joshua D. Turner, Maria L. Pittaluga, Stefania Freeman, Alexandra F. Holland, Steven M. TI Highly Variable Clinical Phenotypes of Hypomorphic RAG1 Mutations SO PEDIATRICS LA English DT Article DE severe combined immunodeficiency; SCID; granuloma; Mycobacterium avium complex; MAC; Omenn syndrome ID SEVERE COMBINED IMMUNODEFICIENCY; OMENN-SYNDROME; DEFECTS; AUTOIMMUNITY; CELLS; IMMUNITY; DISEASES; GAMMA AB Hypomorphic mutations that lead to "leaky" severe combined immunodeficiency presentation with partial protein function are increasingly being identified. Mutations in recombination-activating genes (RAGs) 1 and 2 cause immunodeficiency and dysregulation ranging from severe combined immunodeficiency to Omenn syndrome to more mild immunodeficiencies. We report here the cases of 3 patients with hypomorphic RAG1 mutations with distinct presentations. One patient had granulomatous skin disease and disseminated nontuberculous mycobacteria; the second patient presented with predominantly autoimmune manifestations; and the third patient presented with relatively late onset of infections and had isolated T-cell lymphopenia. These disparate and atypical presentations of hypomorphic RAG1 mutations highlight the role of RAG1 in immune function and autoimmunity and expand the disease spectrum linked to these genes. Pediatrics 2010; 126: e1248-e1252 C1 [Avila, Elizabeth Mannino; Uzel, Gulbu; Hsu, Amy; Freeman, Alexandra F.; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Avila, Elizabeth Mannino] Duke Univ, Sch Med, Durham, NC USA. [Avila, Elizabeth Mannino] NIAID, NIH, Pfizer Clin Res Training Program, Bethesda, MD 20892 USA. [Milner, Joshua D.; Turner, Maria L.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Milner, Joshua D.; Turner, Maria L.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bldg 10,Room 11N234,9000 Rockville Pike, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov FU National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health (NIH); Pfizer Inc FX Funded by the National Institutes of Health (NIH).; This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health (NIH). For Dr Avila, this research was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for the National Institutes of Health from Pfizer Inc). NR 17 TC 27 Z9 29 U1 0 U2 1 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 NOV PY 2010 VL 126 IS 5 BP E1248 EP E1252 DI 10.1542/peds.2009-3171 PG 5 WC Pediatrics SC Pediatrics GA 673GY UT WOS:000283648700029 PM 20956421 ER PT J AU Carlo, WA Goudar, SS Jehan, I Chomba, E Tshefu, A Garces, A Parida, S Althabe, F McClure, EM Derman, RJ Goldenberg, RL Bose, C Hambidge, M Panigrahi, P Buekens, P Chakraborty, H Hartwell, TD Moore, J Wright, LL AF Carlo, Waldemar A. Goudar, Shivaprasad S. Jehan, Imtiaz Chomba, Elwyn Tshefu, Antoinette Garces, Ana Parida, Sailajanandan Althabe, Fernando McClure, Elizabeth M. Derman, Richard J. Goldenberg, Robert L. Bose, Carl Hambidge, Michael Panigrahi, Pinaki Buekens, Pierre Chakraborty, Hrishikesh Hartwell, Tyler D. Moore, Janet Wright, Linda L. CA First Breath Study Grp TI High Mortality Rates for Very Low Birth Weight Infants in Developing Countries Despite Training SO PEDIATRICS LA English DT Article DE neonatal mortality; perinatal mortality; stillbirth; developing countries; health care systems; very low birth weight; prematurity ID PERINATAL-MORTALITY; NEONATAL DEATHS; CARE; IMPACT; INTERVENTIONS; STILLBIRTHS; HEALTH AB OBJECTIVE: The goal was to determine the effect of training in newborn care and resuscitation on 7-day (early) neonatal mortality rates for very low birth weight (VLBW) infants. The study was designed to test the hypothesis that these training programs would reduce neonatal mortality rates for VLBW infants. METHODS: Local instructors trained birth attendants from 96 rural communities in 6 developing countries in protocol and data collection, the World Health Organization Essential Newborn Care (ENC) course, and a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP), by using a train-the-trainer model. To test the impact of ENC training, data on infants of 500 to 1499 g were collected by using a before/after, active baseline, controlled study design. A cluster-randomized, controlled trial design was used to test the impact of the NRP. RESULTS: A total of 1096 VLBW (500-1499 g) infants were enrolled, and 98.5% of live-born infants were monitored to 7 days. All-cause, 7-day neonatal mortality, stillbirth, and perinatal mortality rates were not affected by ENC or NRP training. CONCLUSIONS: Neither ENC nor NRP training of birth attendants decreased 7-day neonatal, stillbirth, or perinatal mortality rates for VLBW infants born at home or at first-level facilities. Encouragement of delivery in a facility where a higher level of care is available may be preferable when delivery of a VLBW infant is expected. Pediatrics 2010;126:e1072-e1080 C1 [Carlo, Waldemar A.] Univ Alabama Birmingham, Sch Med, Dept Pediat, Div Neonatol, Birmingham, AL 35249 USA. [Carlo, Waldemar A.; Chomba, Elwyn] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Goudar, Shivaprasad S.] Jawaharlal Nehru Med Coll, Dept Pediat, Belgaum, India. [Jehan, Imtiaz] Aga Khan Univ, Sch Med, Dept Pediat, Karachi, Pakistan. [Chomba, Elwyn] Univ Teaching Hosp, Dept Pediat & Child Hlth, Lusaka, Zambia. [Tshefu, Antoinette] Kinshasa Sch Publ Hlth, Dept Publ Hlth, Kinshasa, Zaire. [Garces, Ana] San Carlos Univ, Sch Med, Dept Pediat, Guatemala City, Guatemala. [Parida, Sailajanandan] Sriramchandra Bhanja Med Coll, Dept Pediat, Cuttack, Orissa, India. [Althabe, Fernando; Hartwell, Tyler D.; Moore, Janet] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [McClure, Elizabeth M.; Chakraborty, Hrishikesh] RTI Int, Dept Stat & Epidemiol, Durham, NC USA. [Derman, Richard J.] Univ Missouri, Sch Med, Dept Pediat, Kansas City, MO 64108 USA. [Goldenberg, Robert L.] Drexel Univ, Dept Pediat, Coll Med, Philadelphia, PA 19104 USA. [Bose, Carl] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC USA. [Hambidge, Michael] Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA. [Panigrahi, Pinaki] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Buekens, Pierre] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Res Mothers & Children, Bethesda, MD USA. RP Carlo, WA (reprint author), Univ Alabama Birmingham, Sch Med, Dept Pediat, Div Neonatol, 176F Suite 9380,619 S 19th St, Birmingham, AL 35249 USA. EM wcarlo@peds.uab.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research [U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD040636, U01 HD040574]; Bill and Melinda Gates Foundation; National Institutes of Health (NIH) FX This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research (grants U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD040636, and U01 HD040574) and the Bill and Melinda Gates Foundation. Eunice Kennedy Shriver National Institute of Child Health and Human Development staff members participated in the study design, study conduct, data interpretation, and manuscript editing. Neither funding agency limited the ability to complete the research as planned. The authors had full control of the primary data.; Funded by the National Institutes of Health (NIH). NR 28 TC 18 Z9 19 U1 0 U2 2 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 NOV PY 2010 VL 126 IS 5 BP E1072 EP E1080 DI 10.1542/peds.2010-1183 PG 9 WC Pediatrics SC Pediatrics GA 673GY UT WOS:000283648700010 PM 20937655 ER PT J AU Carlo, WA McClure, EM Chomba, E Chakraborty, H Hartwell, T Harris, H Lincetto, O Wright, LL AF Carlo, Waldemar A. McClure, Elizabeth M. Chomba, Elwyn Chakraborty, Hrishikesh Hartwell, Tyler Harris, Hillary Lincetto, Ornella Wright, Linda L. TI Newborn Care Training of Midwives and Neonatal and Perinatal Mortality Rates in a Developing Country SO PEDIATRICS LA English DT Article DE neonatal mortality; perinatal mortality; developing countries; health systems; effectiveness ID CHILD SURVIVAL; SRI-LANKA; INTERVENTIONS; STRATEGIES; IMPACT; HOSPITALS; PAKISTAN; HEALTH AB OBJECTIVE: This study was designed to test the hypothesis that 2 training programs would reduce incrementally 7-day neonatal mortality rates for low-risk institutional deliveries. METHODS: Using a train-the-trainer model, certified research midwives sequentially trained the midwives who performed deliveries in low-risk, first-level, urban, community health clinics in 2 cities in Zambia in the protocol and data collection, in the World Health Organization Essential Newborn Care (ENC) course (universal precautions and cleanliness, routine neonatal care, resuscitation, thermoregulation, breastfeeding, kangaroo care, care of small infants, and common illnesses), and in the American Academy of Pediatrics Neonatal Resuscitation Program (in-depth basic resuscitation). Data were collected during 3 periods, after implementation of each training course. RESULTS: A total of 71 689 neonates were enrolled in the 3 study periods. All-cause, 7-day neonatal mortality rates decreased from 11.5 deaths per 1000 live births to 6.8 deaths per 1000 live births after ENC training (relative risk: 0.59 [95% confidence interval: 0.48-0.77]; P < .001), because of decreases in rates of deaths attributable to birth asphyxia and infection. Perinatal mortality rates but not stillbirth rates decreased. The 7-day neonatal mortality rate was decreased further after Neonatal Resuscitation Program training, after correction for loss to follow-up monitoring. CONCLUSIONS: ENC training for midwives reduced 7-day neonatal mortality rates in low-risk clinics. Additional in-depth basic training in neonatal resuscitation may reduce mortality rates further. Pediatrics 2010;126:e1064-e1071 C1 [Carlo, Waldemar A.] Univ Alabama, Women & Infants Ctr 9380, Div Neonatol, Dept Pediat,Sch Med, Birmingham, AL 35233 USA. [Carlo, Waldemar A.; Chomba, Elwyn] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [McClure, Elizabeth M.; Chakraborty, Hrishikesh; Hartwell, Tyler; Harris, Hillary] RTI Int, Dept Stat & Epidemiol, Durham, NC USA. [Chomba, Elwyn] Univ Zambia, Univ Teaching Hosp, Dept Paediat & Child Hlth, Lusaka, Zambia. [Lincetto, Ornella] World Hlth Org Country Off Hanoi, Dept Child & Adolescent Hlth, Hanoi, Vietnam. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. RP Carlo, WA (reprint author), Univ Alabama, Women & Infants Ctr 9380, Div Neonatol, Dept Pediat,Sch Med, 1700 6th Ave S, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu FU National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research [HD43475, HD404636]; Bill and Melinda Gates Foundation FX Funded by the National Institutes of Health (NIH).; This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research (grants HD43475 and HD404636) and the Bill and Melinda Gates Foundation. NR 28 TC 25 Z9 26 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD NOV PY 2010 VL 126 IS 5 BP E1064 EP E1071 DI 10.1542/peds.2009-3464 PG 8 WC Pediatrics SC Pediatrics GA 673GY UT WOS:000283648700009 PM 20937659 ER PT J AU Chiu, CT Chuang, DM AF Chiu, Chi-Tso Chuang, De-Maw TI Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Apoptosis; Brain-derived neurotrophic factor (BDNF); Glycogen synthase kinase 3 (GSK-3); Lithium; Neurodegenerative diseases; Neuroprotection ID GLYCOGEN-SYNTHASE KINASE-3; AMYOTROPHIC-LATERAL-SCLEROSIS; FRAGILE-X-SYNDROME; ENDOTHELIAL GROWTH-FACTOR; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TISSUE-PLASMINOGEN ACTIVATOR; CEREBELLAR GRANULE NEURONS; CYCLIN-DEPENDENT KINASE-5; GLOBAL CEREBRAL-ISCHEMIA; AGGREGATE-PRONE PROTEINS AB Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases. Published by Elsevier Inc. C1 [Chiu, Chi-Tso; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bldg 10,Room 3D38,10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU NIMH, NIH FX This work was supported by the Intramural Research Program of the NIMH, NIH. The authors thank Dr. Joshua Hunsberger, Peter Leeds, and Ioline Henter of the Mood and Anxiety Disorder Program, NIMH, NIH, for critical review and editorial assistance of this manuscript. NR 474 TC 103 Z9 109 U1 5 U2 33 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD NOV PY 2010 VL 128 IS 2 BP 281 EP 304 DI 10.1016/j.pharmthera.2010.07.006 PG 24 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 670FP UT WOS:000283406900003 PM 20705090 ER PT J AU Friedly, J Standaert, C Chan, L AF Friedly, Janna Standaert, Christopher Chan, Leighton TI Epidemiology of Spine Care: The Back Pain Dilemma SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article DE Low back pain; Epidemiology; Low back pain treatments; Low back pain outcomes; Spine interventions ID EPIDURAL STEROID INJECTIONS; LUMBAR RADICULAR PAIN; INTRADISCAL ELECTROTHERMAL THERAPY; EVIDENCE-INFORMED MANAGEMENT; AMBULATORY SURGERY CENTERS; UNITED-STATES; DOUBLE-BLIND; CONTROLLED-TRIAL; OLDER-ADULTS; DEGENERATIVE SPONDYLOLISTHESIS AB In this article the epidemiology of back pain and the use of a variety of treatments for back pain in the United States are reviewed The dilemma faced by medical providers caring for patients with low back pain is examined in the context of epidemiologic data Back pain is becoming increasingly common and a growing number of treatment options are being used with increasing frequency in clinical practice However, limited evidence exists to demonstrate the effectiveness of these treatments In addition, health-related quality of life for persons with back pain is not improving despite the availability and use of an expanding array of treatments This dilemma poses a difficult challenge for medical providers treating individual patients who suffer from back pain C1 [Friedly, Janna] Univ Washington, Dept Rehabil Med, Seattle, WA 98104 USA. [Standaert, Christopher] Univ Washington Sports & Spine Phys, Harborview Med Ctr, Seattle, WA 98104 USA. [Chan, Leighton] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Friedly, J (reprint author), Univ Washington, Dept Rehabil Med, 325 9th Ave, Seattle, WA 98104 USA. FU Intramural NIH HHS [ZIA CL060073-03] NR 106 TC 29 Z9 32 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 1047-9651 J9 PHYS MED REH CLIN N JI Phys. Med. Rehabil. Clin. N. Am. PD NOV PY 2010 VL 21 IS 4 BP 659 EP + DI 10.1016/j.pmr.2010.08.002 PG 20 WC Rehabilitation SC Rehabilitation GA 687PJ UT WOS:000284790100003 PM 20977955 ER PT J AU Moreau, NG Simpson, KN Teefey, SA Damiano, DL AF Moreau, Noelle G. Simpson, Kit N. Teefey, Sharlene A. Damiano, Diane L. TI Muscle Architecture Predicts Maximum Strength and Is Related to Activity Levels in Cerebral Palsy SO PHYSICAL THERAPY LA English DT Article ID CROSS-SECTIONAL AREA; MOTOR FUNCTION; LOWER-LIMB; CHILDREN; ADOLESCENTS; THICKNESS; GASTROCNEMIUS; RELIABILITY; VALIDITY; MEN AB Background. Muscle architecture is known to be predictive of muscle function. However, it is unknown whether this relationship is similar in children and adolescents with and without cerebral palsy (CP). Objective. The objective of this study was to determine whether the architecture of the rectus femoris (RF) and vastus lateralis (VL) muscles was predictive of maximum voluntary knee extensor torque in children and adolescents with and without CP and whether these measures were related to activity and participation levels. Design. A case-control design was used. Methods. Eighteen participants with CP (mean age=12.0 years, SD=3.2) at Gross Motor Function Classification System (GMFCS) levels I through IV and 12 age-matched peers with typical development (mean age=12.3 years, SD=3.9) were evaluated. Muscle thickness, fascicle length, and fascicle angle of the RF and VL muscles were measured with 2-dimensional, B-mode ultrasound imaging. The activity and participation measures used for participants with CP were the Pediatric Outcomes Data Collection Instrument (PODCI) and the Activities Scale for Kids, Performance Version (ASKp). Results. When age and GMFCS level were controlled for, VL muscle thickness was the best predictor of knee extensor isometric torque in the group with CP (R(2)=.85). This prediction was similar to the prediction from VL muscle thickness and age in participants with typical development (R(2)=.91). Rectus femoris muscle fascicle length was significantly correlated with the Sports and Physical Functioning Scale of the PODCI (rho=.49), and VL muscle fascicle angle was correlated with the Transfers and Basic Mobility Scale of the PODCI (r=.47) and with ASKp Locomotion subdomain (r=.50). Limitations. A limitation of this study was the small sample size. Conclusions. Ultrasound measures of VL muscle thickness, adjusted for age and GMFCS level, were highly predictive of maximum torque and have the potential to serve as surrogate measures of voluntary strength (force-generating capacity) in children and adolescents with and without CP. C1 [Moreau, Noelle G.] Med Univ S Carolina, Dept Hlth Profess, Charleston, SC 29425 USA. [Simpson, Kit N.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Teefey, Sharlene A.] Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Moreau, NG (reprint author), Med Univ S Carolina, Dept Hlth Profess, 77 President St,MSC 700, Charleston, SC 29425 USA. EM moreau@musc.edu RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU PT, MPT; GE Healthcare; National Center for Medical Rehabilitation Research/National Institutes of Health [T32HD007434-16]; Section on Pediatrics of the American Physical Therapy Association; NIH Clinical Center FX The authors thank Chris Stanley for assistance with data collection and processing and Dr Janice Brunstrom-Hernandez and Jennifer Miros, PT, MPT, for their support and assistance with recruitment. They thank GE Healthcare and Tania Gordley, Applications Specialist for GE Healthcare Ultrasound, for their support and technical assistance with this project.; Dr Moreau was a postdoctoral fellow in the Movement Science Program at Washington University, St Louis, Missouri, when this study was conducted and was supported by a National Center for Medical Rehabilitation Research/National Institutes of Health grant (T32HD007434-16). This project also was supported by a clinical research grant from the Section on Pediatrics of the American Physical Therapy Association. This research was supported, in part, by the Intramural Research Program of the NIH Clinical Center. NR 41 TC 32 Z9 34 U1 1 U2 6 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD NOV PY 2010 VL 90 IS 11 BP 1619 EP 1630 DI 10.2522/ptj.20090377 PG 12 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 673MC UT WOS:000283666200007 PM 20847035 ER PT J AU Li, RHH Churchill, GA AF Li, Renhua H. Churchill, Gary A. TI Epistasis contributes to the genetic buffering of plasma HDL cholesterol in mice SO PHYSIOLOGICAL GENOMICS LA English DT Article DE structural equation model ID INBRED MOUSE STRAINS; ARTERY-DISEASE; ATHEROSCLEROSIS; LOCI; EXPRESSION; CROSSES; LESIONS; DIET; ARCHITECTURE; METABOLISM AB Li RH, Churchill GA. Epistasis contributes to the genetic buffering of plasma HDL cholesterol in mice. Physiol Genomics 42A: 228-234, 2010. First published September 21, 2010; doi: 10.1152/physiolgenomics.00044.2010.-Stressful environmental factors, such as a high-fat diet, can induce responses in the expression of genes that act to maintain physiological homeostasis. We observed variation in plasma concentrations of high-density lipoprotein (HDL) cholesterol across inbred mouse strains in response to high dietary fat intake. Several strains, including C57BL/6J, have stable levels of plasma HDL independent of diet, whereas other strains, including DBA2/J, show marked changes in plasma HDL. To explore this phenomenon further, we used publicly available data from a C57BL/6J x DBA/2J intercross to identify genetic factors that associate with HDL under high-fat diet conditions. Our analysis identified an epistatic interaction that plays a role in the buffering of HDL levels in C57BL/6J mice, and we have identified Arl4d as a candidate gene that mediates this effect. Structural modeling further elucidates the interaction of genetic factors that contribute to the robustness of HDL in response to high-fat diet in the C57BL/6J strain. C1 [Li, Renhua H.] Natl Inst Digest Dis Diabet & Kidney Dis, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Li, Renhua H.; Churchill, Gary A.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Li, RHH (reprint author), Natl Inst Digest Dis Diabet & Kidney Dis, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM lir3@niddk.nih.gov FU National Institute of General Medical Sciences [GM-070683, GM-076468] FX This study was supported by National Institute of General Medical Sciences Grants GM-070683 and GM-076468. NR 42 TC 2 Z9 2 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD NOV PY 2010 VL 42A IS 4 BP 228 EP 234 DI 10.1152/physiolgenomics.00044.2010 PG 7 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 686GP UT WOS:000284685100002 PM 20858711 ER PT J AU Alvarenga, PH Francischetti, IMB Calvo, E Sa-Nunes, A Ribeiro, JMC Andersen, JF AF Alvarenga, Patricia H. Francischetti, Ivo M. B. Calvo, Eric Sa-Nunes, Anderson Ribeiro, Jose M. C. Andersen, John F. TI The Function and Three-Dimensional Structure of a Thromboxane A(2)/Cysteinyl Leukotriene-Binding Protein from the Saliva of a Mosquito Vector of the Malaria Parasite SO PLOS BIOLOGY LA English DT Article ID PLATELET COLLAGEN RECEPTORS; BLOOD-FEEDING ARTHROPODS; RHODNIUS-PROLIXUS; HIGH-AFFINITY; HUMAN-SKIN; EICOSANOID MEDIATORS; ANOPHELES-GAMBIAE; SMOOTH-MUSCLE; SHAPE CHANGE; SOFT TICKS AB The highly expressed D7 protein family of mosquito saliva has previously been shown to act as an anti-inflammatory mediator by binding host biogenic amines and cysteinyl leukotrienes (CysLTs). In this study we demonstrate that AnSt-D7L1, a two-domain member of this group from Anopheles stephensi, retains the CysLT binding function seen in the homolog AeD7 from Aedes aegypti but has lost the ability to bind biogenic amines. Unlike any previously characterized members of the D7 family, AnSt-D7L1 has acquired the important function of binding thromboxane A(2) (TXA(2)) and its analogs with high affinity. When administered to tissue preparations, AnSt-D7L1 abrogated Leukotriene C-4 (LTC4)-induced contraction of guinea pig ileum and contraction of rat aorta by the TXA(2) analog U46619. The protein also inhibited platelet aggregation induced by both collagen and U46619 when administered to stirred platelets. The crystal structure of AnSt-D7L1 contains two OBP-like domains and has a structure similar to AeD(7). In AnSt-D7L1, the binding pocket of the C-terminal domain has been rearranged relative to AeD7, making the protein unable to bind biogenic amines. Structures of the ligand complexes show that CysLTs and TXA(2) analogs both bind in the same hydrophobic pocket of the N-terminal domain. The TXA(2) analog U46619 is stabilized by hydrogen bonding interactions of the omega-5 hydroxyl group with the phenolic hydroxyl group of Tyr 52. LTC4 and occupies a very similar position to LTE4 in the previously determined structure of its complex with AeD7. As yet, it is not known what, if any, new function has been acquired by the rearranged C-terminal domain. This article presents, to our knowledge, the first structural characterization of a protein from mosquito saliva that inhibits collagen mediated platelet activation. C1 [Alvarenga, Patricia H.; Francischetti, Ivo M. B.; Calvo, Eric; Sa-Nunes, Anderson; Ribeiro, Jose M. C.; Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Alvarenga, Patricia H.] Univ Fed Rural Rio de Janeiro, Lab Bioquim & Fisiol Artropodes, Dept Quim, Seropedica, Brazil. [Sa-Nunes, Anderson] Univ Sao Paulo, Inst Ciencias Biomed, Lab Imunol Expt, Dept Imunol, BR-05508 Sao Paulo, Brazil. RP Alvarenga, PH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM jandersen@niaid.nih.gov RI Sa-Nunes, Anderson/D-8667-2012; OI Sa-Nunes, Anderson/0000-0002-1859-4973; Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU NIAID FX This work was funded by the intramural research program of the NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 24 Z9 24 U1 1 U2 6 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 NOV PY 2010 VL 8 IS 11 AR e1000547 DI 10.1371/journal.pbio.1000547 PG 15 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 687ES UT WOS:000284762300019 PM 21152418 ER PT J AU Colina, C Palavicini, JP Srikumar, D Holmgren, M Rosenthal, JJC AF Colina, Claudia Palavicini, Juan Pablo Srikumar, Deepa Holmgren, Miguel Rosenthal, Joshua J. C. TI Regulation of Na+/K+ ATPase Transport Velocity by RNA Editing SO PLOS BIOLOGY LA English DT Article ID NA/K PUMP CURRENT; VOLTAGE-DEPENDENCE; NERVOUS-SYSTEM; SODIUM-PUMP; POTASSIUM CHANNELS; NA,K PUMP; DROSOPHILA; SUBUNIT; GIANT; NA+,K+-ATPASE AB Because firing properties and metabolic rates vary widely, neurons require different transport rates from their Na+/K+ pumps in order to maintain ion homeostasis. In this study we show that Na+/K+ pump activity is tightly regulated by a novel process, RNA editing. Three codons within the squid Na+/K+ ATPase gene can be recoded at the RNA level, and the efficiency of conversion for each varies dramatically, and independently, between tissues. At one site, a highly conserved isoleucine in the seventh transmembrane span can be converted to a valine, a change that shifts the pump's intrinsic voltage dependence. Mechanistically, the removal of a single methyl group specifically targets the process of Na+ release to the extracellular solution, causing a higher turnover rate at the resting membrane potential. C1 [Colina, Claudia; Palavicini, Juan Pablo; Rosenthal, Joshua J. C.] Univ Puerto Rico, Inst Neurobiol, San Juan, PR 00901 USA. [Srikumar, Deepa; Holmgren, Miguel] Natl Inst Neurol Disorders & Stroke, Mol Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD USA. [Rosenthal, Joshua J. C.] Univ Puerto Rico, Dept Biochem, San Juan, PR 00936 USA. RP Colina, C (reprint author), Univ Puerto Rico, Inst Neurobiol, Med Sci Campus, San Juan, PR 00901 USA. EM holmgren@ninds.nih.gov; joshua.rosenthal@upr.edu FU NSF [IBN-0344070, NIH 2 U54 NS039405-06, NIH 1 R01 NS064259]; National Institutes of Health, National Institute of Neurological Disorders and Stroke; RCMI [G12 RR 03051]; NCRR-AABRE [P20 RR16470]; NIH-SCORE [S06GM08102]; University of Puerto Rico Biology Department; NSF-CREST [0206200] FX This work was directly supported by NSF IBN-0344070, NIH 2 U54 NS039405-06, NIH 1 R01 NS064259, and the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. Part of the work was conducted in the Molecular Biology Core Facility at the Institute of Neurobiology that is supported by RCMI grant #G12 RR 03051. DNA sequencing at the Sequencing and Genotyping facility, University of Puerto Rico-Rio Piedras is supported in part by NCRR-AABRE Grant #P20 RR16470, NIH-SCORE grant #S06GM08102, University of Puerto Rico Biology Department, and NSF-CREST grant #0206200. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 14 Z9 14 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2010 VL 8 IS 11 AR e1000540 DI 10.1371/journal.pbio.1000540 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 687ES UT WOS:000284762300012 PM 21124885 ER PT J AU Shamir, L Delaney, JD Orlov, N Eckley, DM Goldberg, IG AF Shamir, Lior Delaney, John D. Orlov, Nikita Eckley, D. Mark Goldberg, Ilya G. TI Pattern Recognition Software and Techniques for Biological Image Analysis SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID FLUORESCENCE-MICROSCOPE IMAGES; NONLINEAR DIMENSIONALITY REDUCTION; GENE-EXPRESSION PATTERNS; QUANTITATIVE-ANALYSIS; BIOIMAGE INFORMATICS; SUBCELLULAR STRUCTURES; FLY EMBRYOS; CELLS; SEGMENTATION; ENVIRONMENT AB The increasing prevalence of automated image acquisition systems is enabling new types of microscopy experiments that generate large image datasets. However, there is a perceived lack of robust image analysis systems required to process these diverse datasets. Most automated image analysis systems are tailored for specific types of microscopy, contrast methods, probes, and even cell types. This imposes significant constraints on experimental design, limiting their application to the narrow set of imaging methods for which they were designed. One of the approaches to address these limitations is pattern recognition, which was originally developed for remote sensing, and is increasingly being applied to the biology domain. This approach relies on training a computer to recognize patterns in images rather than developing algorithms or tuning parameters for specific image processing tasks. The generality of this approach promises to enable data mining in extensive image repositories, and provide objective and quantitative imaging assays for routine use. Here, we provide a brief overview of the technologies behind pattern recognition and its use in computer vision for biological and biomedical imaging. We list available software tools that can be used by biologists and suggest practical experimental considerations to make the best use of pattern recognition techniques for imaging assays. C1 [Shamir, Lior; Delaney, John D.; Orlov, Nikita; Eckley, D. Mark; Goldberg, Ilya G.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Shamir, L (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM igg@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 NIH, National Institute on Aging [Z01:AG000685-02] FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging (Z01:AG000685-02). The funders had no role in the decision to publish or preparation of the manuscript. NR 64 TC 55 Z9 56 U1 0 U2 25 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD NOV PY 2010 VL 6 IS 11 AR e1000974 DI 10.1371/journal.pcbi.1000974 PG 10 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 684WH UT WOS:000284585400001 PM 21124870 ER PT J AU Aksenova, A Volkov, K Maceluch, J Pursell, ZF Rogozin, IB Kunkel, TA Pavlov, YI Johansson, E AF Aksenova, Anna Volkov, Kirill Maceluch, Jaroslaw Pursell, Zachary F. Rogozin, Igor B. Kunkel, Thomas A. Pavlov, Youri I. Johansson, Erik TI Mismatch Repair-Independent Increase in Spontaneous Mutagenesis in Yeast Lacking Non-Essential Subunits of DNA Polymerase epsilon SO PLOS GENETICS LA English DT Article ID EUKARYOTIC REPLICATION FORK; SACCHAROMYCES-CEREVISIAE; HOMONUCLEOTIDE RUNS; MUTATION AVOIDANCE; GENOMIC DELETIONS; LIGATABLE NICK; S PHASE; DELTA; FIDELITY; ZETA AB Yeast DNA polymerase epsilon (Pol epsilon) is a highly accurate and processive enzyme that participates in nuclear DNA replication of the leading strand template. In addition to a large subunit (Pol2) harboring the polymerase and proofreading exonuclease active sites, Pol epsilon also has one essential subunit (Dpb2) and two smaller, non-essential subunits (Dpb3 and Dpb4) whose functions are not fully understood. To probe the functions of Dpb3 and Dpb4, here we investigate the consequences of their absence on the biochemical properties of Pol epsilon in vitro and on genome stability in vivo. The fidelity of DNA synthesis in vitro by purified Pol2/Dpb2, i.e. lacking Dpb3 and Dpb4, is comparable to the four-subunit Pol e holoenzyme. Nonetheless, deletion of DPB3 and DPB4 elevates spontaneous frameshift and base substitution rates in vivo, to the same extent as the loss of Pol epsilon proofreading activity in a pol2-4 strain. In contrast to pol2-4, however, the dpb3 Delta dpb4 Delta does not lead to a synergistic increase of mutation rates with defects in DNA mismatch repair. The increased mutation rate in dpb3 Delta dpb4 Delta strains is partly dependent on REV3, as well as the proofreading capacity of Pol delta. Finally, biochemical studies demonstrate that the absence of Dpb3 and Dpb4 destabilizes the interaction between Pol epsilon and the template DNA during processive DNA synthesis and during processive 3' to 5'exonucleolytic degradation of DNA. Collectively, these data suggest a model wherein Dpb3 and Dpb4 do not directly influence replication fidelity per se, but rather contribute to normal replication fork progression. In their absence, a defective replisome may more frequently leave gaps on the leading strand that are eventually filled by Pol zeta or Pol delta, in a post-replication process that generates errors not corrected by the DNA mismatch repair system. C1 [Aksenova, Anna; Volkov, Kirill; Maceluch, Jaroslaw; Johansson, Erik] Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden. [Pursell, Zachary F.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Pursell, Zachary F.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Pavlov, Youri I.] Univ Nebraska Med Ctr, Eppley Inst Res Canc, Dept Biochem & Mol Biol, Omaha, NE USA. [Pavlov, Youri I.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. RP Aksenova, A (reprint author), Tufts Univ, Dept Biol, Medford, MA 02155 USA. EM erik.johansson@medchem.umu.se RI Aksenova, Anna/O-8309-2015 OI Aksenova, Anna/0000-0002-1601-1615 FU Swedish Research Council; Swedish Cancer Society; Smartafonden; Samfundet Wenner-Grenska stiftelsen; Kempestiftelserna; Swedish Royal Academy of Sciences; National Library of Medicine at National Institutes of Health/DHHS; Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065070]; UNMC Cancer Center [2008 LB506 NE DHHS]; NCI [1 R01 CA129925-01A1, 5R01CA129925-03] FX This work was in part supported by the Swedish Research Council (EJ), Swedish Cancer Society (EJ), Smartafonden (EJ), Samfundet Wenner-Grenska stiftelsen (EJ), Kempestiftelserna (EJ), The Swedish Royal Academy of Sciences (EJ), the Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS (IBR), Project Z01 ES065070 (TAK) from the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences, and the UNMC Cancer Center Pilot Grants 2008 LB506 NE DHHS grant, NCI grant 1 R01 CA129925-01A1, and NCI grant 5R01CA129925-03 (YIP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 24 Z9 25 U1 0 U2 7 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 NOV PY 2010 VL 6 IS 11 AR e1001209 DI 10.1371/journal.pgen.1001209 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 684WX UT WOS:000284587100023 PM 21124948 ER PT J AU Pomerantz, MM Shrestha, Y Flavin, RJ Regan, MM Penney, KL Mucci, LA Stampfer, MJ Hunter, DJ Chanock, SJ Schafer, EJ Chan, JA Tabernero, J Baselga, J Richardson, AL Loda, M Oh, WK Kantoff, PW Hahn, WC Freedman, ML AF Pomerantz, Mark M. Shrestha, Yashaswi Flavin, Richard J. Regan, Meredith M. Penney, Kathryn L. Mucci, Lorelei A. Stampfer, Meir J. Hunter, David J. Chanock, Stephen J. Schafer, Eric J. Chan, Jennifer A. Tabernero, Josep Baselga, Jose Richardson, Andrea L. Loda, Massimo Oh, William K. Kantoff, Philip W. Hahn, William C. Freedman, Matthew L. TI Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN GENE-EXPRESSION; FUNCTIONAL-ANALYSIS; COLORECTAL-CANCER; SECRETORY PROTEIN; EPITHELIAL-CELLS; FAMILY-HISTORY; NUDE MICE; MULTIPLE; SUSCEPTIBILITY AB Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states. C1 [Pomerantz, Mark M.; Shrestha, Yashaswi; Schafer, Eric J.; Loda, Massimo; Kantoff, Philip W.; Hahn, William C.; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Pomerantz, Mark M.; Regan, Meredith M.; Mucci, Lorelei A.; Stampfer, Meir J.; Hunter, David J.; Richardson, Andrea L.; Loda, Massimo; Kantoff, Philip W.; Hahn, William C.] Harvard Univ, Sch Med, Boston, MA USA. [Shrestha, Yashaswi; Schafer, Eric J.; Loda, Massimo; Hahn, William C.; Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Shrestha, Yashaswi; Schafer, Eric J.; Loda, Massimo; Hahn, William C.; Freedman, Matthew L.] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA USA. [Flavin, Richard J.; Loda, Massimo] Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Regan, Meredith M.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Penney, Kathryn L.; Mucci, Lorelei A.; Stampfer, Meir J.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mucci, Lorelei A.; Stampfer, Meir J.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Stampfer, Meir J.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chan, Jennifer A.] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada. [Tabernero, Josep; Baselga, Jose] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Barcelona, Spain. [Richardson, Andrea L.; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Oh, William K.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. RP Pomerantz, MM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM freedman@broadinstitute.org RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 FU Howard Hughes Medical Institute; Doris Duke Clinical Scientist Development Award; Claudia Adams Barr award; US National Institutes of Health [R01 CA129435]; Mayer Foundation; H.L. Snyder Medical Foundation; Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (National Cancer Institute) [5P50CA90381]; Emerald Foundation, Inc.; William L. Edwards-Prostate Cancer Foundation; Prostate Cancer Foundation; John Snyder Medical Foundation FX MLF is a Howard Hughes Medical Institute Physician-Scientist Early Career Awardee (www.hhmi.org), a recipient of a 2006 Doris Duke Clinical Scientist Development Award (www.ddcf.org), and a recipient of a 2009 Claudia Adams Barr award (www.dana-farber.org). This work was supported by grants from the US National Institutes of Health (R01 CA129435 to MLF), the Mayer Foundation (to MLF), the H.L. Snyder Medical Foundation (to MLF), the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (National Cancer Institute Grant No. 5P50CA90381), and the Emerald Foundation, Inc. (to MLF). MMP is supported by the William L. Edwards-Prostate Cancer Foundation Young Investigator Award (www.prostatecancerfoundation.org). WCH receives support from the Prostate Cancer Foundation and the John Snyder Medical Foundation (snydermf.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 39 Z9 40 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2010 VL 6 IS 11 AR e1001204 DI 10.1371/journal.pgen.1001204 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 684WX UT WOS:000284587100018 PM 21085629 ER PT J AU Adar, SD Klein, R Klein, BEK Szpiro, AA Cotch, MF Wong, TY O'Neill, MS Shrager, S Barr, RG Siscovick, DS Daviglus, ML Sampson, PD Kaufman, JD AF Adar, Sara D. Klein, Ronald Klein, Barbara E. K. Szpiro, Adam A. Cotch, Mary Frances Wong, Tien Y. O'Neill, Marie S. Shrager, Sandi Barr, R. Graham Siscovick, David S. Daviglus, Martha L. Sampson, Paul D. Kaufman, Joel D. TI Air Pollution and the Microvasculature: A Cross-Sectional Assessment of In Vivo Retinal Images in the Population-Based Multi-Ethnic Study of Atherosclerosis (MESA) SO PLOS MEDICINE LA English DT Article ID DIESEL-EXHAUST INHALATION; ACUTE ARTERIAL VASOCONSTRICTION; PARTICULATE MATTER EXPOSURE; CORONARY-HEART-DISEASE; LONG-TERM EXPOSURE; CARDIOVASCULAR-DISEASE; VESSEL DIAMETERS; VASCULAR CALIBER; MYOCARDIAL-INFARCTION; MACULAR DEGENERATION AB Background: Long-and short-term exposures to air pollution, especially fine particulate matter (PM(2.5)), have been linked to cardiovascular morbidity and mortality. One hypothesized mechanism for these associations involves microvascular effects. Retinal photography provides a novel, in vivo approach to examine the association of air pollution with changes in the human microvasculature. Methods and Findings: Chronic and acute associations between residential air pollution concentrations and retinal vessel diameters, expressed as central retinal arteriolar equivalents (CRAE) and central retinal venular equivalents (CRVE), were examined using digital retinal images taken in Multi-Ethnic Study of Atherosclerosis (MESA) participants between 2002 and 2003. Study participants (46 to 87 years of age) were without clinical cardiovascular disease at the baseline examination (2000-2002). Long-term outdoor concentrations of PM2.5 were estimated at each participant's home for the 2 years preceding the clinical exam using a spatio-temporal model. Short-term concentrations were assigned using outdoor measurements on the day preceding the clinical exam. Residential proximity to roadways was also used as an indicator of long-term traffic exposures. All associations were examined using linear regression models adjusted for subject-specific age, sex, race/ethnicity, education, income, smoking status, alcohol use, physical activity, body mass index, family history of cardiovascular disease, diabetes status, serum cholesterol, glucose, blood pressure, emphysema, C-reactive protein, medication use, and fellow vessel diameter. Short-term associations were further controlled for weather and seasonality. Among the 4,607 participants with complete data, CRAE were found to be narrower among persons residing in regions with increased long-and short-term levels of PM(2.5). These relationships were observed in a joint exposure model with -0.8 mm (95% confidence interval [CI]-1.1 to -0.5) and -0.4 mu m (95% CI -0.8 to 0.1) decreases in CRAE per interquartile increases in long-(3 mu g/m(3)) and short-term (9 mu g/m(3)) PM(2.5) levels, respectively. These reductions in CRAE are equivalent to 7-and 3-year increases in age in the same cohort. Similarly, living near a major road was also associated with a -0.7 mu m decrease (95% CI -1.4 to 0.1) in CRAE. Although the chronic association with CRAE was largely influenced by differences in exposure between cities, this relationship was generally robust to control for city-level covariates and no significant differences were observed between cities. Wider CRVE were associated with living in areas of higher PM(2.5) concentrations, but these findings were less robust and not supported by the presence of consistent acute associations with PM(2.5). Conclusions: Residing in regions with higher air pollution concentrations and experiencing daily increases in air pollution were each associated with narrower retinal arteriolar diameters in older individuals. These findings support the hypothesis that important vascular phenomena are associated with small increases in short-term or long-term air pollution exposures, even at current exposure levels, and further corroborate reported associations between air pollution and the development and exacerbation of clinical cardiovascular disease. C1 [Adar, Sara D.; Siscovick, David S.; Kaufman, Joel D.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Adar, Sara D.; Kaufman, Joel D.] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Adar, Sara D.; O'Neill, Marie S.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Szpiro, Adam A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Wong, Tien Y.] Univ Melbourne, Dept Ophthalmol, Melbourne, Vic, Australia. [Wong, Tien Y.; Shrager, Sandi] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [O'Neill, Marie S.] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Barr, R. Graham] Columbia Univ Med Ctr, Dept Med, New York, NY USA. [Barr, R. Graham] Columbia Univ Med Ctr, Dept Epidemiol, New York, NY USA. [Siscovick, David S.; Kaufman, Joel D.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Daviglus, Martha L.] Northwestern Univ, Dept Prevent Med & Med, Chicago, IL 60611 USA. [Sampson, Paul D.] Univ Washington, Dept Stat, Seattle, WA 98195 USA. RP Adar, SD (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. EM sadar@umich.edu RI Kaufman, Joel/B-5761-2008; Adar, Sara/L-2278-2016; OI Kaufman, Joel/0000-0003-4174-9037; Adar, Sara/0000-0001-8383-485X; Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU Environmental Protection Agency [RD831697]; National Eye Institute [EY000403]; National Heart, Lung, Blood Institute [HL69979, N01-HC- 95159, N01-HC-95165, N01-HC-95169]; National Institutes of Environmental Health Sciences [K24ES013195, P50ES015915, P30ES07033, R01ES016932] FX This work was supported by awards RD831697 from the Environmental Protection Agency; EY000403 from the National Eye Institute; HL69979, N01-HC- 95159 through N01-HC-95165, and N01-HC-95169 from the National Heart, Lung, Blood Institute; and K24ES013195, P50ES015915, P30ES07033 and R01ES016932 from the National Institutes of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 33 Z9 33 U1 3 U2 12 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 NOV PY 2010 VL 7 IS 11 AR e1000372 DI 10.1371/journal.pmed.1000372 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 688BE UT WOS:000284822600013 PM 21152417 ER PT J AU Baas, DC Despriet, DD Gorgels, TGMF Bergeron-Sawitzke, J Uitterlinden, AG Hofman, A van Duijn, CM Merriam, JE Smith, RT Barile, GR ten Brink, JB Vingerling, JR Klaver, CCW Allikmets, R Dean, M Bergen, AAB AF Baas, Dominique C. Despriet, Dominiek D. Gorgels, Theo G. M. F. Bergeron-Sawitzke, Julie Uitterlinden, Andre G. Hofman, Albert van Duijn, Cornelia M. Merriam, Joanna E. Smith, R. Theodore Barile, Gaetano R. ten Brink, Jacoline B. Vingerling, Johannes R. Klaver, Caroline C. W. Allikmets, Rando Dean, Michael Bergen, Arthur A. B. TI The ERCC6 Gene and Age-Related Macular Degeneration SO PLOS ONE LA English DT Article ID COMPLEMENT FACTOR-H; COCKAYNE-SYNDROME; OXIDATIVE STRESS; RISK; REPAIR; POLYMORPHISM; MACULOPATHY; ROTTERDAM; VARIANT; DAMAGE AB Background: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. Methodology/Principal Findings: Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P = 0.018). Conclusions/Significance: Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants. C1 [Baas, Dominique C.; Gorgels, Theo G. M. F.; ten Brink, Jacoline B.; Bergen, Arthur A. B.] Royal Netherlands Acad Arts & Sci KNAW, Dept Clin & Mol Ophthalmogenet, Netherlands Inst Neurosci NIN, Amsterdam, Netherlands. [Despriet, Dominiek D.; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Bergeron-Sawitzke, Julie] SAIC Frederick, Basic Sci Program, Human Genet Sect, Frederick, MD USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Merriam, Joanna E.; Smith, R. Theodore; Barile, Gaetano R.; Allikmets, Rando] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. [Merriam, Joanna E.; Smith, R. Theodore; Barile, Gaetano R.; Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10027 USA. [Dean, Michael] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA. [Bergen, Arthur A. B.] Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. [Bergen, Arthur A. B.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. RP Baas, DC (reprint author), Royal Netherlands Acad Arts & Sci KNAW, Dept Clin & Mol Ophthalmogenet, Netherlands Inst Neurosci NIN, Amsterdam, Netherlands. EM a.bergen@nin.knaw.nl RI Dean, Michael/G-8172-2012; Bergen, Arthur/J-3637-2013; OI Dean, Michael/0000-0003-2234-0631; smith, theodore/0000-0002-1693-943X FU Merck & Co, Inc., NJ, USA; Nederlandse Vereniging ter Voorkoming van Blindheid; Dutch Macula Foundation; LSBS; Oogfonds Nederland; de Rotterdamse Vereniging Blindenbelangen; Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE),; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam; National Eye Institute [EY13435, EY017404]; Macula Vision Research Foundation; Kaplen Foundation; Wigdeon Point Charitable Foundation; Research to Prevent Blindness, Inc.; Merck Co; Ministry of Education, Culture and Science FX This work was in part supported by an unrestricted research grant from Merck & Co, Inc., NJ, USA and the Nederlandse Vereniging ter Voorkoming van Blindheid, The Dutch Macula Foundation, the LSBS, the Oogfonds Nederland, de Rotterdamse Vereniging Blindenbelangen (to A. A. B.). The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project nr. 050-060-810, and funding from the Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Columbia University study population is supported in part by the grants from the National Eye Institute EY13435 and EY017404; the Macula Vision Research Foundation; Kaplen Foundation; Wigdeon Point Charitable Foundation and an unrestricted grant to the Department of Ophthalmology, Columbia University, from Research to Prevent Blindness, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The funding of Merck & Co was an unrestricted grant to A. A. B. and did not, in any way, interfere with the conception and/or design and/or outcome and/or publication of this study. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 50 TC 9 Z9 10 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 NOV 1 PY 2010 VL 5 IS 11 AR e13786 DI 10.1371/journal.pone.0013786 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 673FY UT WOS:000283645700009 PM 21072178 ER PT J AU Das, SR Puigbo, P Hensley, SE Hurt, DE Bennink, JR Yewdell, JW AF Das, Suman R. Puigbo, Pere Hensley, Scott E. Hurt, Darrell E. Bennink, Jack R. Yewdell, Jonathan W. TI Glycosylation Focuses Sequence Variation in the Influenza A Virus H1 Hemagglutinin Globular Domain SO PLOS PATHOGENS LA English DT Article ID N-LINKED GLYCOSYLATION; HYDROXY AMINO-ACID; INTRACELLULAR-TRANSPORT; RECEPTOR-BINDING; MEMBRANE GLYCOPROTEIN; MONOCLONAL-ANTIBODIES; ANTIGENIC STRUCTURE; SITES; GLYCANS; VIRULENCE AB Antigenic drift in the influenza A virus hemagglutinin (HA) is responsible for seasonal reformulation of influenza vaccines. Here, we address an important and largely overlooked issue in antigenic drift: how does the number and location of glycosylation sites affect HA evolution in man? We analyzed the glycosylation status of all full-length H1 subtype HA sequences available in the NCBI influenza database. We devised the "flow index'' (FI), a simple algorithm that calculates the tendency for viruses to gain or lose consensus glycosylation sites. The FI predicts the predominance of glycosylation states among existing strains. Our analyses show that while the number of glycosylation sites in the HA globular domain does not influence the overall magnitude of variation in defined antigenic regions, variation focuses on those regions unshielded by glycosylation. This supports the conclusion that glycosylation generally shields HA from antibody-mediated neutralization, and implies that fitness costs in accommodating oligosaccharides limit virus escape via HA hyperglycosylation. C1 [Das, Suman R.; Hensley, Scott E.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Puigbo, Pere] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Hurt, Darrell E.] NIAID, Computat Biol Bioinformat & Computat Biosci Branc, Bethesda, MD 20892 USA. RP Das, SR (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI Puigbo, Pere/A-2214-2008; yewdell, jyewdell@nih.gov/A-1702-2012; Das, Suman/C-8760-2009 FU Division of Intramural Research, National Institutes of Health FX This work was supported by the Division of Intramural Research, the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 59 Z9 60 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2010 VL 6 IS 11 AR e1001211 DI 10.1371/journal.ppat.1001211 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 684WP UT WOS:000284586300044 PM 21124818 ER PT J AU Dobson, DE Kamhawi, S Lawyer, P Turco, SJ Beverley, SM Sacks, DL AF Dobson, Deborah E. Kamhawi, Shaden Lawyer, Phillip Turco, Salvatore J. Beverley, Stephen M. Sacks, David L. TI Leishmania major Survival in Selective Phlebotomus papatasi Sand Fly Vector Requires a Specific SCG-Encoded Lipophosphoglycan Galactosylation Pattern SO PLOS PATHOGENS LA English DT Article ID PROTOZOAN PARASITE LEISHMANIA; SECRETED ACID-PHOSPHATASE; SURFACE LIPOPHOSPHOGLYCAN; RECOGNITION RECEPTORS; FLIES; DONOVANI; STAGE; PROMASTIGOTES; MIDGUT; POLYMORPHISMS AB Phlebotomine sand flies that transmit the protozoan parasite Leishmania differ greatly in their ability to support different parasite species or strains in the laboratory: while some show considerable selectivity, others are more permissive. In "selective'' sand flies, Leishmania binding and survival in the fly midgut typically depends upon the abundant promastigote surface adhesin lipophosphoglycan (LPG), which exhibits species-and strain-specific modifications of the dominant phosphoglycan (PG) repeat units. For the "selective'' fly Phlebotomus papatasi PpapJ, side chain galactosyl-modifications (scGal) of PG repeats play key roles in parasite binding. We probed the specificity and properties of this scGal-LPG PAMP (Pathogen Associated Molecular Pattern) through studies of natural isolates exhibiting a wide range of galactosylation patterns, and of a panel of isogenic L. major engineered to express similar scGal-LPG diversity by transfection of SCG-encoded beta 1,3-galactosyltransferases with different activities. Surprisingly, both 'poly-scGal' and 'null-scGal' lines survived poorly relative to PpapJ-sympatric L. major FV1 and other 'mono-scGal' lines. However, survival of all lines was equivalent in P. duboscql, which naturally transmit L. major strains bearing 'null-scGal'-LPG PAMPs. We then asked whether scGal-LPG-mediated interactions were sufficient for PpapJ midgut survival by engineering Leishmania donovani, which normally express unsubstituted LPG, to express a 'PpapJ-optimal' scGal-LPG PAMP. Unexpectedly, these "L. major FV1-cloaked'' L. donovani-SCG lines remained unable to survive within PpapJ flies. These studies establish that midgut survival of L. major in PpapJ flies is exquisitely sensitive to the scGal-LPG PAMP, requiring a specific 'mono-scGal' pattern. However, failure of 'mono-scGal' L. donovani-SCG lines to survive in selective PpapJ flies suggests a requirement for an additional, as yet unidentified L. major-specific parasite factor(s). The interplay of the LPG PAMP and additional factor(s) with sand fly midgut receptors may determine whether a given sand fly host is "selective'' or "permissive'', with important consequences to both disease transmission and the natural co-evolution of sand flies and Leishmania. C1 [Dobson, Deborah E.; Beverley, Stephen M.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Kamhawi, Shaden; Lawyer, Phillip; Sacks, David L.] NIH, Parasit Dis Lab, Intracellular Parasite Biol Sect, Bethesda, MD 20892 USA. [Turco, Salvatore J.] Univ Kentucky, Med Ctr, Dept Mol & Cellular Biochem, Lexington, KY USA. RP Dobson, DE (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. EM dedobson@borcim.wustl.edu OI Beverley, Stephen/0000-0001-5319-0811 FU US National Institutes of Health [AI31078, AI20941] FX This work was supported by US National Institutes of Health grants AI31078 (SMB, SJT) and AI20941 (DED, SMB, SJT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 20 Z9 20 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2010 VL 6 IS 11 AR e1001185 DI 10.1371/journal.ppat.1001185 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 684WP UT WOS:000284586300019 PM 21085609 ER PT J AU Gustchina, E Li, M Louis, JM Anderson, DE Lloyd, J Frisch, C Bewley, CA Gustchina, A Wlodawer, A Clore, GM AF Gustchina, Elena Li, Mi Louis, John M. Anderson, D. Eric Lloyd, John Frisch, Christian Bewley, Carole A. Gustchina, Alla Wlodawer, Alexander Clore, G. Marius TI Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41 SO PLOS PATHOGENS LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; TERMINAL HEPTAD REPEATS; MEDIATED CELL-FUSION; POTENT INHIBITORS; MEMBRANE-FUSION; PHAGE LIBRARY; ENVELOPE GLYCOPROTEIN; PEPTIDE INHIBITOR; MASS-SPECTROMETRY; ENTRY INHIBITION AB The conserved internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41 is transiently exposed during the fusion process by forming a pre-hairpin intermediate, thus representing an attractive target for the design of fusion inhibitors and neutralizing antibodies. In previous studies we reported a series of broadly neutralizing mini-antibodies derived from a synthetic naive human combinatorial antibody library by panning against a mimetic of the trimeric N-HR coiled coil, followed by affinity maturation using targeted diversification of the CDR-H2 loop. Here we report crystal structures of the N-HR mimetic 5-Helix with two Fabs that represent the extremes of this series: Fab 8066 is broadly neutralizing across a wide panel of B and C type HIV-1 viruses, whereas Fab 8062 is non-neutralizing. The crystal structures reveal important differences in the conformations of the CDR-H2 loops in the complexes that propagate into other regions of the antigen-antibody interface, and suggest that both neutralization properties and affinity for the target can be attributed, at least in part, to the differences in the interactions of the CDR-H2 loops with the antigen. Furthermore, modeling of the complex of an N-HR trimer with three Fabs suggests that the CDR-H2 loop may be involved in close intermolecular contacts between neighboring antibody molecules, and that such contacts may hinder the formation of complexes between the N-HR trimer and more than one antibody molecule depending on the conformation of the bound CDR-H2 loop which is defined by its interactions with antigen. Comparison with the crystal structure of the complex of 5-Helix with another neutralizing monoclonal antibody known as D5, derived using an entirely different antibody library and panning procedure, reveals remarkable convergence in the optimal sequence and conformation of the CDR-H2 loop. C1 [Gustchina, Elena; Louis, John M.; Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Anderson, D. Eric; Lloyd, John] NIDDKD, Prote & Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. [Frisch, Christian] MorphoSys AG, AbD Serotec, Martinsried, Germany. [Bewley, Carole A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gustchina, E (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM gustchia@mail.nih.gov; wlodawer@nih.gov; mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIDDK; National Cancer Institute, Center for Cancer Research at the NIH; National Cancer Institute, NIH [HHSN261200800001E]; Office of the Director of the NIH FX We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. This project was supported in part by the Intramural Research Programs of the NIDDK (to G. M. C. and C. A. B.) and National Cancer Institute, Center for Cancer Research (to A. W.) at the NIH, by the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G. M. C. and C. A. B.), and with Federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E (M. L.). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 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 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2010 VL 6 IS 11 AR e1001182 DI 10.1371/journal.ppat.1001182 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 684WP UT WOS:000284586300016 PM 21085615 ER PT J AU Wang, YE Park, A Lake, M Pentecost, M Torres, B Yun, TE Wolf, MC Holbrook, MR Freiberg, AN Lee, B AF Wang, Yao E. Park, Arnold Lake, Michael Pentecost, Mickey Torres, Betsabe Yun, Tatyana E. Wolf, Mike C. Holbrook, Michael R. Freiberg, Alexander N. Lee, Benhur TI Ubiquitin-Regulated Nuclear-Cytoplasmic Trafficking of the Nipah Virus Matrix Protein Is Important for Viral Budding SO PLOS PATHOGENS LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; PLASMA-MEMBRANE; TYPE-1 GAG; FUSION PROTEINS; EXPORT SIGNALS; INFECTED-CELLS; SENDAI-VIRUS; V-PROTEIN; IN-VIVO; PHASE-I AB Paramyxoviruses are known to replicate in the cytoplasm and bud from the plasma membrane. Matrix is the major structural protein in paramyxoviruses that mediates viral assembly and budding. Curiously, the matrix proteins of a few paramyxoviruses have been found in the nucleus, although the biological function associated with this nuclear localization remains obscure. We report here that the nuclear-cytoplasmic trafficking of the Nipah virus matrix (NiV-M) protein and associated post-translational modification play a critical role in matrix-mediated virus budding. Nipah virus (NiV) is a highly pathogenic emerging paramyxovirus that causes fatal encephalitis in humans, and is classified as a Biosafety Level 4 (BSL4) pathogen. During live NiV infection, NiV-M was first detected in the nucleus at early stages of infection before subsequent localization to the cytoplasm and the plasma membrane. Mutations in the putative bipartite nuclear localization signal (NLS) and the leucine-rich nuclear export signal (NES) found in NiV-M impaired its nuclear-cytoplasmic trafficking and also abolished NiV-M budding. A highly conserved lysine residue in the NLS served dual functions: its positive charge was important for mediating nuclear import, and it was also a potential site for monoubiquitination which regulates nuclear export of the protein. Concordantly, overexpression of ubiquitin enhanced NiV-M budding whereas depletion of free ubiquitin in the cell (via proteasome inhibitors) resulted in nuclear retention of NiV-M and blocked viral budding. Live Nipah virus budding was exquisitely sensitive to proteasome inhibitors: bortezomib, an FDA-approved proteasome inhibitor for treating multiple myeloma, reduced viral titers with an IC(50) of 2.7 nM, which is 100-fold less than the peak plasma concentration that can be achieved in humans. This opens up the possibility of using an "off-the-shelf'' therapeutic against acute NiV infection. C1 [Wang, Yao E.; Park, Arnold; Lake, Michael; Pentecost, Mickey; Torres, Betsabe; Wolf, Mike C.; Lee, Benhur] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. [Yun, Tatyana E.; Holbrook, Michael R.; Freiberg, Alexander N.] Univ Texas Med Branch, Dept Pathol, Galveston, TX USA. [Holbrook, Michael R.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. [Lee, Benhur] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA. [Lee, Benhur] Univ Calif Los Angeles, UCLA AIDS Inst, Los Angeles, CA USA. RP Wang, YE (reprint author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. EM bleebhl@ucla.edu RI Lee, Benhur/A-8554-2016; OI Lee, Benhur/0000-0003-0760-1709; Park, Arnold/0000-0001-8916-2230 FU Cellular and Molecular Biology Training grant [T32 GM007185]; UCLA [AI07323]; NIH [U01 AI082100, R01 AI069317, U01 AI070495, GM055052]; National Science Foundation [HRD-0603239]; Pacific Southwest Regional Center of Excellence for Biodefense & Emerging Infectious Diseases [U54 AI065359]; UCLA AIDS Institute; CFAR [P30 AI028697]; Burroughs Wellcome Fund; Rockefeller Brothers Fund FX This work was supported by the Cellular and Molecular Biology Training grant (T32 GM007185) to A. P., the Molecular Pathogenesis Training Grant and UCLA Warsaw Fellowship to M. C. W. (AI07323), and NIH grants to B. L. (U01 AI070495, U01 AI082100, R01 AI069317), M. R. H. (U01 AI070495, U01 AI082100) and A.N.F. (U01 AI070495, U01 AI082100). B. T. was supported by a National Science Foundation grant (HRD-0603239) and the Maximizing Student Diversity Program (NIH grant GM055052). We also acknowledge support from the Pacific Southwest Regional Center of Excellence for Biodefense & Emerging Infectious Diseases (U54 AI065359) and the UCLA AIDS Institute and CFAR (P30 AI028697). B. L. also thanks the Burroughs Wellcome Fund and the Rockefeller Brothers Fund for providing initial unrestricted funds to explore new fields. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 55 Z9 59 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2010 VL 6 IS 11 AR e1001186 DI 10.1371/journal.ppat.1001186 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 684WP UT WOS:000284586300020 PM 21085610 ER PT J AU Agalliu, I Leanza, SM Smith, L Trent, JM Carpten, JD Bailey-Wilson, JE Burk, RD AF Agalliu, Ilir Leanza, Suzanne M. Smith, Lorie Trent, Jeffrey M. Carpten, John D. Bailey-Wilson, Joan E. Burk, Robert D. TI Contribution of HPC1 (RNASEL) and HPCX Variants to Prostate Cancer in a Founder Population SO PROSTATE LA English DT Article DE prostate cancer; genetic susceptibility; RNASEL; founder population; HPCX ID SUSCEPTIBILITY LOCUS HPCX; 2-5A-DEPENDENT RNASE; LINKAGE ANALYSIS; GENE; FAMILIES; RISK; ASSOCIATION; HEREDITARY; MUTATION; METAANALYSIS AB BACKGROUND. Prostate cancer is a genetically complex disease with locus and disease heterogeneity. The RNASEL gene and HPCX locus have been implicated in hereditary prostate cancer; however, their contributions to sporadic forms of this malignancy remain uncertain. METHODS. Associations of prostate cancer with two variants in the RNASEL gene (a founder mutation, 471delAAAG, and a non-synonymous SNP, rs486907), and with five microsatellite markers in the HPCX locus, were examined in 979 cases and 1,251 controls of Ashkenazi Jewish descent. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models. RESULTS. There was an inverse association between RNASEL rs486907 and prostate cancer in younger men (<65 years) and those with a first-degree relative with prostate cancer; men with AA genotype had ORs of 0.64 and 0.47 (both P < 0.05), respectively, in comparison to men with GG genotype. Within the HPCX region, there were positive associations for allele 135 of bG82i1.1 marker (OR = 1.77, P = 0.01) and allele 188 of DXS1205 (OR = 1.65, P = 0.02). In addition, allele 248 of marker D33 was inversely associated (OR = 0.65, P = 0.05) with Gleason score >= 7 tumors. CONCLUSIONS. Results suggest that variants in RNASEL contribute to susceptibility to early onset and familial forms of prostate cancer, whereas HPCX variants are associated with prostate cancer risk and tumor aggressiveness. The observation that a mutation predicted to completely inactivate RNASEL protein was not associated with prostate cancer, but that a missense variant was associated, suggests that the effect is due to either partial inactivation of the protein, and/or acquisition of a new protein activity. Prostate 70: 1716-1727, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Leanza, Suzanne M.; Smith, Lorie; Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat Genet, Bronx, NY 10461 USA. [Agalliu, Ilir; Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Trent, Jeffrey M.] Translat Genom Res Inst TGen, Phoenix, AZ USA. [Carpten, John D.; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, Bethesda, MD 20892 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Bronx, NY 10467 USA. RP Burk, RD (reprint author), Albert Einstein Coll Med, Dept Pediat Genet, 1300 Morris Pk Ave,Ullmann Bldg,Room 515, Bronx, NY 10461 USA. EM robert.burk@einstein.yu.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU US Army, Department of Defense [PC001076]; Albert Einstein College of Medicine; National Human Genome Research Institute, National Institutes of Health FX We thank Stacey Fishman, Gloria Ho, Nicolas Schlecht, Victor Kamensky, Mindy Ginsberg, Leonid Strizhevsky, Rochelle Demsky, Peggy Cottrel, Betsy Vibert, Kit Tam, and Lydia Chiu for their help with study design and data collection. We are grateful to all men who participated in this study for their time, effort and collaboration. This project was supported by the US Army, Department of Defense grant (PC001076), in part by a translational-medicine grant from the Albert Einstein College of Medicine and in part by the Intramural program of the National Human Genome Research Institute, National Institutes of Health. Ilir Agalliu was supported by university funds from the Albert Einstein College of Medicine. NR 51 TC 15 Z9 15 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD NOV 1 PY 2010 VL 70 IS 15 BP 1716 EP 1727 DI 10.1002/pros.21207 PG 12 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 672EO UT WOS:000283566000012 PM 20564318 ER PT J AU Chun, PW Lewis, MS AF Chun, Paul W. Lewis, Marc S. TI Planck-Benzinger Thermal Work Function: Thermodynamic Characterization of the Carboxy-Terminus of p53 Peptide Fragments SO PROTEIN JOURNAL LA English DT Article ID TUMOR-SUPPRESSOR P53; BIOLOGICAL-SYSTEMS; MOLECULAR SWITCH; CRYSTAL-STRUCTURE; OLIGOMERIZATION DOMAIN; TETRAMERIZATION DOMAIN; TRANSFORMING DOMAIN; RIBONUCLEASE-A; WATER-VAPOR; PROTEIN P53 AB The thermodynamic parameters for six p53 carboxy-terminus peptide fragments as determined by analytical ultracentrifugal analysis were compared over the experimental temperature range of 275-310 K to evaluate the Gibbs free energy change as a function of temperature, Delta G (o) (T), from 0 to 400 K using our general linear third-order fitting function, Delta G (o) (T) = alpha + beta T (2) + gamma T (3). Data obtained at the typical experimental temperature range are not sufficient to accurately describe the variations observed in the oligomerization of these p53 fragments. It is necessary to determine a number of thermodynamic parameters, all of which can be precisely assessed using this general third-order linear fitting function. These are the heat of reaction, innate temperature-invariant enthalpy, compensatory temperatures and the thermodynamic molecular switch occurring at the thermal set point. This methodology can be used to distinguish the characteristic structure and stability of p53 carboxy-terminal fragments or other p53 mutants. It should be used for the thermodynamic characterization of any interacting biological system. C1 [Chun, Paul W.] Univ Florida, Dept Biochem & Mol Biol, Coll Med, Gainesville, FL 32610 USA. [Lewis, Marc S.] NIH, Natl Ctr Res Resources, Biomed Engn & Instrumentat Program, Bethesda, MD 20892 USA. RP Chun, PW (reprint author), Univ Florida, Dept Biochem & Mol Biol, Coll Med, Gainesville, FL 32610 USA. EM pwchun@ufl.edu NR 73 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1572-3887 J9 PROTEIN J JI Protein J. PD NOV PY 2010 VL 29 IS 8 BP 617 EP 630 DI 10.1007/s10930-010-9286-9 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 685QY UT WOS:000284644400011 PM 21086029 ER PT J AU Sayer, JM Agniswamy, J Weber, IT Louis, JM AF Sayer, Jane M. Agniswamy, Johnson Weber, Irene T. Louis, John M. TI Autocatalytic maturation, physical/chemical properties, and crystal structure of Group N HIV-1 protease: Relevance to drug resistance SO PROTEIN SCIENCE LA English DT Article DE HIV/AIDS; retroviral protease; dimer dissociation; enzyme kinetics; calorimetry; crystal structure; polyprotein processing ID VIRUS TYPE-1 PROTEASE; ACTIVE-SITE; INHIBITOR; STABILITY; MONOMER; POTENT; IDENTIFICATION; MUTATIONS; SEQUENCE; CAMEROON AB The mature protease from Group N human immunodeficiency virus Type 1 (HIV-1) (PR1(N)) differs in 20 amino acids from the extensively studied Group M protease (PRIM) at positions corresponding to minor drug-resistance mutations (DRMs). The first crystal structure (1.09 angstrom resolution) of PR1(N) with the clinical inhibitor darunavir (DRV) reveals the same overall structure as PR1(M), but with a slightly larger inhibitor-binding cavity. Changes in the 10s loop and the flap hinge propagate to shift one flap away from the inhibitor, whereas L89F and substitutions in the 60s loop perturb inhibitor-binding residues 29-32. However, kinetic parameters of PR1(N) closely resemble those of PR1(M), and calorimetric results are consistent with similar binding affinities for DRV and two other clinical PIs, suggesting that minor DRMs coevolve to compensate for the detrimental effects of drug-specific major DRMs. A miniprecursor (TFR1-61-PR1(N)) comprising the transframe region (TFR) fused to the N-terminus of PR1(N) undergoes autocatalytic cleavage at the TFR/PR1(N) site concomitant with the appearance of catalytic activity characteristic of the dimeric, mature enzyme. This cleavage is inhibited at an equimolar ratio of precursor to DRV (similar to 6 mu M), which partially stabilizes the precursor dimer from a monomer. However, cleavage at L34/W35 within the TFR, which precedes the TFR1-61/PR1(N) cleavage at pH <= 5, is only partially inhibited. Favorable properties of PR1(N) relative to PR1(M) include its suitability for column fractionation by size under native conditions and >10-fold higher dimer dissociation constant (150 nM). Exploiting these properties may facilitate testing of potential dimerization inhibitors that perturb early precursor processing steps. C1 [Sayer, Jane M.; Louis, John M.] NIDDK, NIH, LCP, DHHS, Bethesda, MD 20892 USA. [Agniswamy, Johnson; Weber, Irene T.] Georgia State Univ, Dept Biol, Mol Basis Dis Program, Atlanta, GA 30303 USA. RP Louis, JM (reprint author), NIDDK, NIH, LCP, DHHS, Bldg 5,Room B2-29, Bethesda, MD 20892 USA. EM johnl@intra.niddk.nih.gov FU NIH [GM062920]; NIDDK; Office of the Director, NIH; U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX Grant sponsor: NIH; Grant number: GM062920; Grant sponsors: Intramural Research Program of the NIDDK, Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH.; This research was authored, in whole or in part, by National Institutes of Health staff. The authors thank Annie Aniana for technical assistance and the staff at the Southeast Regional-Collaborative Access Team (SER-CAT) at the Advanced Photon Source, Argonne National Laboratory, for assistance during X-ray data collection. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. DRV, ATV, and SQV were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH and DMP323 from DuPont Pharmaceuticals. NR 54 TC 14 Z9 14 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD NOV PY 2010 VL 19 IS 11 BP 2055 EP 2072 DI 10.1002/pro.486 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 674PG UT WOS:000283759000004 PM 20737578 ER PT J AU Sun, P Austin, BP Tozser, J Waugh, DS AF Sun, Ping Austin, Brian P. Toezser, Jozsef Waugh, David S. TI Structural determinants of tobacco vein mottling virus protease substrate specificity SO PROTEIN SCIENCE LA English DT Article DE tobacco vein mottling virus; tobacco etch virus; crystal structure; protease ID POLYPROTEIN CLEAVAGE SITE; ELECTRON-DENSITY MAPS; MACROMOLECULAR STRUCTURES; NUCLEAR INCLUSION; ACTIVE-SITE; IN-VIVO; PURIFICATION; EXPRESSION; NIA; PROTEINASES AB Tobacco vein mottling virus (TVMV) is a member of the Potyviridae, one of the largest families of plant viruses. The TVMV genome is translated into a single large polyprotein that is subsequently processed by three virally encoded proteases. Seven of the nine cleavage events are carried out by the NIa protease. Its homolog from the tobacco etch virus (TEV) is a widely used reagent for the removal of affinity tags from recombinant proteins. Although TVMV protease is a close relative of TEV protease, they exhibit distinct sequence specificities. We report here the crystal structure of a catalytically inactive mutant TVMV protease (K65A/K67A/C151A) in complex with a canonical peptide substrate (Ac-RETVRFQSD) at 1.7-angstrom resolution. As observed in several crystal structures of TEV protease, the C-terminus (similar to 20 residues) of TVMV protease is disordered. Unexpectedly, although deleting the disordered residues from TEV protease reduces its catalytic activity by -10-fold, an analogous truncation mutant of TVMV protease is significantly more active. Comparison of the structures of TEV and TVMV protease in complex with their respective canonical substrate peptides reveals that the S3 and S4 pockets are mainly responsible for the differing substrate specificities. The structure of TVMV protease suggests that it is less tolerant of variation at the P1' position than TEV protease. This conjecture was confirmed experimentally by determining kinetic parameters k(cat) and K(m) for a series of oligopeptide substrates. Also, as predicted by the cocrystal structure, we confirm that substitutions in the P6 position are more readily tolerated by TVMV than TEV protease. C1 [Sun, Ping; Austin, Brian P.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD USA. [Toezser, Jozsef] Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, Debrecen, Hungary. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD USA. EM waughd@mail.nih.gov RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 FU NIH, National Cancer Institute, Center for Cancer Research; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX Grant sponsor: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.; The authors thank Scott Cherry and Kerri Penrose for technical assistance. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 37 TC 10 Z9 11 U1 0 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD NOV PY 2010 VL 19 IS 11 BP 2240 EP 2251 DI 10.1002/pro.506 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 674PG UT WOS:000283759000020 PM 20862670 ER PT J AU Ruge, H Muller, SC Braver, TS AF Ruge, Hannes Mueller, Sven C. Braver, Todd S. TI Brief Reports: Anticipating the consequences of action: An fMRI study of intention-based task preparation SO PSYCHOPHYSIOLOGY LA English DT Article DE Action selection; Action effects; Attention; Cognitive control; Task switching ID MEDIAL FRONTAL-CORTEX; DORSOLATERAL PREFRONTAL CORTEX; COGNITIVE CONTROL; FUNCTIONAL MRI; WILLED ACTION; MECHANISMS; ATTENTION; SELECTION; AREAS; MAINTENANCE AB A key component of task preparation may be to anticipate the consequences of task-appropriate actions. This task switching study examined whether such type of "intentional" preparatory control relies on the presentation of explicit action effects. Preparatory BOLD activation in a condition with task-specific motion effect feedback was compared to identical task conditions with accuracy feedback only. Switch-related activation was found selectively in the effect feedback condition in the middle mid-frontal gyrus and in the anterior intraparietal sulcus. Consistent with research on attentional control, the posterior superior parietal lobule exhibited switch-related preparatory activation irrespective of feedback type. To conclude, preparatory control can occur via complementary attentional and intentional neural mechanisms depending on whether meaningful task-specific action effects lead to the formation of explicit effect representations. C1 [Ruge, Hannes] Tech Univ Dresden, Fak Math & Nat Wissensch, Fachrichtung Psychol, Neuroimaging Ctr, D-01062 Dresden, Germany. [Ruge, Hannes] Tech Univ Dresden, Dept Psychol, Inst Gen Psychol Biopsychol & Methods Psychol, D-01062 Dresden, Germany. [Mueller, Sven C.] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. [Braver, Todd S.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. RP Ruge, H (reprint author), Tech Univ Dresden, Fak Math & Nat Wissensch, Fachrichtung Psychol, Neuroimaging Ctr, D-01062 Dresden, Germany. EM ruge@psychologie.tu-dresden.de RI Ruge, Hannes/K-4634-2015 OI Ruge, Hannes/0000-0001-9793-3859 FU NIMH NIH HHS [R01 MH066078, R01 MH066078-08] NR 42 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD NOV PY 2010 VL 47 IS 6 BP 1019 EP 1027 DI 10.1111/j.1469-8986.2010.01027.x PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 663HU UT WOS:000282874800004 PM 20477978 ER PT J AU Beydoun, MA Shroff, MR Beydoun, HA Zonderman, AB AF Beydoun, May A. Shroff, Monal R. Beydoun, Hind A. Zonderman, Alan B. TI Serum Folate, Vitamin B-12, and Homocysteine and Their Association With Depressive Symptoms Among U.S. Adults SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depression; folate; vitamin B-12; homocysteine; adults ID HEALTHY ELDERLY INDIVIDUALS; LATE-LIFE DEPRESSION; FOLIC-ACID; PLASMA HOMOCYSTEINE; BRAIN ATROPHY; PSYCHIATRIC-DISORDERS; DIETARY-FOLATE; UNITED-STATES; CELL FOLATE; RISK-FACTOR AB To examine, in a nationally representative sample of U.S. adults, the associations of serum folate, vitamin B-12, and total homocysteine (tHcy) levels with depressive symptoms. Several nutritional and physiological factors have been linked to depression in adults, including low folate and vitamin B-12 and elevated tHcy levels. Methods: Data on U.S. adults (age, 20-85 years; n = 2524) from the National Health and Nutrition Examination Survey during the period 2005 to 2006 were used. Depressive symptoms were measured with the Patient Health Questionnaire (PHQ), and elevated symptoms were defined as a PHQ total score of Serum folate, vitamin B-12, and tHcy were mainly expressed as tertiles. Multiple ordinary least square (OLS), logistic, and zero-inflated Poisson regression models were conducted in the main analysis. Results: Overall, mean PHQ score was significantly higher among women compared with men. Elevated depressive symptoms (PHQ score of >= 10) were inversely associated with folate status, particularly among women (fully adjusted odds ratio [tertiles T(3), versus T(1)] = 0.37; 95% confidence interval, 0.17-0.86), but not significantly related to tHcy or vitamin B-12. No interaction was noted between the three exposures in affecting depressive symptoms. In older adults (50 years) and both sexes combined, tHcy was positively associated with elevated depressive symptoms (fully adjusted odds ratio [tertiles T(2) versus T,] = 3.01; 95% confidence interval, 1.01-9.03), although no significant dose-response relationship was found. Conclusions: Future interventions to improve mental health outcomes among U.S. adults should take into account dietary and other factors that would increase levels of serum folate. C1 [Beydoun, May A.] NIA, NIH, Biomed Res Ctr, IRP, Baltimore, MD 21224 USA. [Shroff, Monal R.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging/National Institutes of Health/Intramural Research Program FX This research was supported entirely by the National Institute on Aging, Intramural Research Program (National Institute on Aging/National Institutes of Health/Intramural Research Program). NR 72 TC 31 Z9 37 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD NOV-DEC PY 2010 VL 72 IS 9 BP 862 EP 873 DI 10.1097/PSY.0b013e3181f61863 PG 12 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 685ZA UT WOS:000284665400005 PM 20841559 ER PT J AU Connerney, I Sloan, RP Shapiro, PA Bagiella, E Seckman, C AF Connerney, Ingrid Sloan, Richard P. Shapiro, Peter A. Bagiella, Emilia Seckman, Charlotte TI Depression Is Associated With Increased Mortality 10 Years After Coronary Artery Bypass Surgery SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depression; coronary bypass; mortality; Diagnostic Interview Schedule; Beck Depression Inventory ID ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED-CONTROLLED-TRIAL; RISK-FACTOR; CARDIAC MORTALITY; HEART-DISEASE; GRAFT-SURGERY; SYMPTOMS; EVENTS; METAANALYSIS; SURVIVAL AB Objective: To determine if depression is independently associated with cardiac and all-cause mortality 10 years after coronary artery bypass graft (CABG) surgery. Although many studies have examined the relationship of depression and mortality in patients with myocardial infarction, there is less understanding of the relationship between depression and long-term mortality after CABG surgery. Methods: In a prospective study, we collected data on 309 patients hospitalized after CABG surgery. Before discharge, patients were assessed for depression using the Diagnostic Interview Schedule and the Beck Depression Inventory (BDI). Subsequently, mortality data were obtained from the National Center for Health Statistics and supplemented with phone interviews. Results: Sixty-three (20%) patients met modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder (MDD) and 87 (28%) had BDI scores of >= 10, indicating elevated depressive symptoms. Time-to-event or last follow-up phone contact ranged from 9 days to 11.5 years (median, 9.3 years). The overall mortality rate was 37.9% (117 of 309), with 20.1% (62 of 309) due to cardiac causes. Cox proportional hazard modeling showed that age (hazard ratio [HR], 1.04; p = .005), left ventricular ejection fraction (EF) (EF <0.35 [HR], 3.9;p < .001; EF, 0.35-0.49 [HR], 1.9; p = .03), and MDD (HR, 1.8; p = .04) were independent predictors of cardiac mortality. The BDI and the cognitive-affective symptoms subset of BDI symptoms were also predictors of cardiac mortality. Age, EF, and diabetes predicted all-cause mortality, but MDD did not. Conclusions: Depression, assessed both in structured interview and by BDI, was significantly associated with elevated cardiac mortality 10 years after CABG surgery. C1 [Connerney, Ingrid] Univ Maryland, Med Ctr, Div Qual & Safety, Baltimore, MD 21201 USA. [Sloan, Richard P.; Shapiro, Peter A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Bagiella, Emilia] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Seckman, Charlotte] NIH, Bethesda, MD 20892 USA. RP Connerney, I (reprint author), Univ Maryland, Med Ctr, Div Qual & Safety, 22 S Greene St,Box 316, Baltimore, MD 21201 USA. EM iconnerney@umm.edu FU University of Maryland Medical Center; Nathaniel Wharton Fund; National Heart Lung and Blood Institute [R01 HL072057] FX The work was supported, in part, by the University of Maryland Medical Center (I.C.) and the Nathaniel Wharton Fund (IC., P.A.S.), as well as Grant R01 HL072057 from the National Heart Lung and Blood Institute (R.P.S.). NR 39 TC 51 Z9 53 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD NOV-DEC PY 2010 VL 72 IS 9 BP 874 EP 881 DI 10.1097/PSY.0b013e3181f65fc1 PG 8 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 685ZA UT WOS:000284665400006 PM 20841558 ER PT J AU Riley, WT Rothrock, N Bruce, B Christodolou, C Cook, K Hahn, EA Cella, D AF Riley, William T. Rothrock, Nan Bruce, Bonnie Christodolou, Christopher Cook, Karon Hahn, Elizabeth A. Cella, David TI Patient-reported outcomes measurement information system (PROMIS) domain names and definitions revisions: further evaluation of content validity in IRT-derived item banks SO QUALITY OF LIFE RESEARCH LA English DT Article DE Content validity; Conceptual framework; Domain definition; Item response theory AB Content validity of patient-reported outcomes (PROs) is evaluated primarily during item development, but subsequent psychometric analyses, particularly for item response theory (IRT)-derived scales, often result in considerable item pruning and potential loss of content. After selecting items for the PROMIS banks based on psychometric and content considerations, we invited external content expert reviews of the degree to which the initial domain names and definitions represented the calibrated item bank content. A minimum of four content experts reviewed each item bank and recommended a domain name and definition based on item content. Domain names and definitions then were revealed to the experts who rated how well these names and definitions fit the bank content and provided recommendations for definition revisions. These reviews indicated that the PROMIS domain names and definitions remained generally representative of bank content following item pruning, but modifications to two domain names and minor to moderate revisions of all domain definitions were needed to optimize fit with the item bank content. This reevaluation of domain names and definitions following psychometric item pruning, although not previously documented in the literature, appears to be an important procedure for refining conceptual frameworks and further supporting content validity. C1 [Riley, William T.] NHLBI, Bethesda, MD 20892 USA. [Rothrock, Nan; Hahn, Elizabeth A.; Cella, David] Northwestern Univ, Chicago, IL 60611 USA. [Bruce, Bonnie] Stanford Univ, Stanford, CA 94305 USA. [Christodolou, Christopher] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Cook, Karon] Univ Washington, Seattle, WA 98195 USA. RP Riley, WT (reprint author), NHLBI, 6701 Rockledge Dr,MSC 7936, Bethesda, MD 20892 USA. EM wiriley@mail.nih.gov FU Northwestern University, PI [U01AR52177]; Duke University, PI [U01AR52186]; University of North Carolina, PI [U01AR52181]; University of Pittsburgh, PI [U01AR52155]; Stanford University, PI [U01AR52158]; Stony Brook University, PI [U01AR52170]; University of Washington, PI [U01AR52171]; NIH FX The patient-reported outcomes measurement information system (PROMIS) is a National Institutes of Health (NIH) Roadmap initiative to develop a computerized system measuring patient-reported outcomes in respondents with a wide range of chronic diseases and demographic characteristics. PROMIS was funded by cooperative agreements to a Statistical Coordinating Center (Northwestern University, PI: David Cella, PhD, U01AR52177) and six Primary Research Sites (Duke University, PI: Kevin Weinfurt, PhD, U01AR52186; University of North Carolina, PI: Darren DeWalt, MD, MPH, U01AR52181; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, U01AR52155; Stanford University, PI: James Fries, MD, U01AR52158; Stony Brook University, PI: Arthur Stone, PhD, U01AR52170; and University of Washington, PI: Dagmar Amtmann, PhD, U01AR52171). NIH Science Officers on this project have included Deborah Ader, PhD, Susan Czajkowski, PhD, Lawrence Fine, MD, DrPH, Laura Lee Johnson, PhD, Louis Quatrano, PhD, Bryce Reeve, PhD, William Riley, PhD, Susana Serrate-Sztein, MD, and James Witter, MD, PhD. This manuscript was reviewed by the PROMIS Publications Subcommittee prior to external peer review. See the Web site at www.nihpromis.org for additional information on the PROMIS cooperative group. NR 18 TC 43 Z9 43 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD NOV PY 2010 VL 19 IS 9 BP 1311 EP 1321 DI 10.1007/s11136-010-9694-5 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 671KZ UT WOS:000283506100008 PM 20593306 ER PT J AU Bhatti, P Yong, LC Doody, MM Preston, DL Kampa, DM Ramsey, MJ Ward, EM Edwards, AA Ron, E Tucker, JD Sigurdson, AJ AF Bhatti, Parveen Yong, Lee C. Doody, Michele M. Preston, Dale L. Kampa, Diane M. Ramsey, Marilyn J. Ward, Elizabeth M. Edwards, Alan A. Ron, Elaine Tucker, James D. Sigurdson, Alice J. TI Diagnostic X-ray examinations and increased chromosome translocations: evidence from three studies SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article ID RADIATION-INDUCED TRANSLOCATIONS; US RADIOLOGIC TECHNOLOGISTS; INCREASED FREQUENCY; IONIZING-RADIATION; MEDICAL RADIATION; COMPUTED-TOMOGRAPHY; CANCER-RISKS; EXPOSURE; CT; COHORT AB Controversy regarding potential health risks from increased use of medical diagnostic radiologic examinations has come to public attention. We evaluated whether chromosome damage, specifically translocations, which are a potentially intermediate biomarker for cancer risk, was increased after exposure to diagnostic X-rays, with particular interest in the ionizing radiation dose-response below the level of approximately 50 mGy. Chromosome translocation frequency data from three separately conducted occupational studies of ionizing radiation were pooled together. Studies 1 and 2 included 79 and 150 medical radiologic technologists, respectively, and study 3 included 83 airline pilots and 50 university faculty members (total = 155 women and 207 men; mean age = 62 years, range 34-90). Information on personal history of radiographic examinations was collected from a detailed questionnaire. We computed a cumulative red bone marrow (RBM) dose score based on the numbers and types of X-ray examinations reported with 1 unit approximating 1 mGy. Poisson regression analyses were adjusted for age and laboratory method. Mean RBM dose scores were 49, 42, and 11 for Studies 1-3, respectively (overall mean = 33.5, range 0-303). Translocation frequencies significantly increased with increasing dose score (P < 0.001). Restricting the analysis to the lowest dose scores of under 50 did not materially change these results. We conclude that chromosome damage is associated with low levels of radiation exposure from diagnostic X-ray examinations, including dose scores of approximately 50 and lower, suggesting the possibility of long-term adverse health effects. C1 [Bhatti, Parveen] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA USA. [Bhatti, Parveen; Doody, Michele M.; Ron, Elaine; Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Yong, Lee C.] NIOSH, Cincinnati, OH 45226 USA. [Preston, Dale L.] HiroSoft Int Corp, Seattle, WA USA. [Kampa, Diane M.] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN USA. [Ramsey, Marilyn J.] Lawrence Livermore Natl Lab, Livermore, CA USA. [Ward, Elizabeth M.] Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. [Edwards, Alan A.] Hlth Protect Agcy, Radiat Protect Div, Didcot, Oxon, England. [Tucker, James D.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. RP Bhatti, P (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, POB 19024,M4-B874, Seattle, WA USA. EM pbhatti@fhcrc.org FU Division of Cancer Epidemiology and Genetics, National Cancer Institute; National Institute for Occupational Safety and Health; National Cancer Institute [Y1CP802904]; US DOE by the Lawrence Livermore National Laboratory [W-7405-ENG-48] FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute and in part by an interagency agreement between the National Institute for Occupational Safety and Health and the National Cancer Institute (contract Y1CP802904). Work was performed in part under the auspices of the US DOE by the Lawrence Livermore National Laboratory under contract no. W-7405-ENG-48. We thank the two anonymous reviewers for their helpful comments on the manuscript. NR 31 TC 14 Z9 15 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD NOV PY 2010 VL 49 IS 4 BP 685 EP 692 DI 10.1007/s00411-010-0307-z PG 8 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 671KS UT WOS:000283504900015 PM 20602108 ER PT J AU Huff, J Chan, P Melnick, R AF Huff, James Chan, Po Melnick, Ronald TI Clarifying carcinogenicity of ethylbenzene SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Editorial Material DE Cancer bioassay; Carcinogenesis; Chemicals; Long-term study; Occupational cancer; Primary prevention ID INDUCED HEPATOCYTE PROLIFERATION; NATIONAL TOXICOLOGY PROGRAM; HUMAN CANCER HAZARDS; MAJOR RISK FACTOR; CELL-PROLIFERATION; CHEMICAL CARCINOGENESIS; LIVER CARCINOGENESIS; TUMOR-INDUCTION; TOXICITY; MECHANISMS AB Ethylbenzene has been evaluated for carcinogenic activity in Fischer rats and B6C3F1 mice exposed by inhalation (Chan et al., 1998; Chan, 1999) and in Sprague-Dawley rats after oral exposure (Maltoni et al., 1985,1997). Bioassay findings are summarized below to expand on those not stated clearly or completely in Saghir et al. (2010). Overall in these three studies animals exposed to ethylbenzene had increased tumors in rats for kidneys, testes, head (including rare neuroesthesioepitheliomas), and total malignant tumors, whilst in mice tumor incidences were increased in the lung and liver (Huff. 2002). Thus ethylbenzene was carcinogenic by two exposure routes to both sexes of two species of rodents, two strains of rats, and one strain of mice, causing collectively tumors in five different target organs and a composite of "total malignant" tumors. Published by Elsevier Inc. C1 [Huff, James; Chan, Po; Melnick, Ronald] NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 39 TC 2 Z9 2 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD NOV PY 2010 VL 58 IS 2 BP 167 EP 169 DI 10.1016/j.yrtph.2010.08.011 PG 3 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 667OW UT WOS:000283204400002 PM 20723573 ER PT J AU Dragomir, AD Schroeder, JC Connolly, A Kupper, LL Hill, MC Olshan, AF Baird, DD AF Dragomir, Anca D. Schroeder, Jane C. Connolly, AnnaMarie Kupper, Larry L. Hill, Michael C. Olshan, Andrew F. Baird, Donna D. TI Potential Risk Factors Associated With Subtypes of Uterine Leiomyomata SO REPRODUCTIVE SCIENCES LA English DT Article DE epidemiology; uterine leiomyomata subtypes; smoking; sonogram ID BODY-SIZE; FIBROIDS; MYOMAS; WOMEN; SMOKING; UTERUS; HEALTH AB Objective: To compare potential risk factors for uterine leiomyomata (UL) subtypes among premenopausal African American and Caucasian women. Methods: This cross-sectional study included 986 premenopausal women, aged 35 to 49 years old, from the National Institute of Environmental Health Sciences (NIEHS) Uterine Fibroid Study (UFS). Uterine leiomyomata were subtyped as submucosal, intramural/subserosal, and diffuse, based on ultrasound examinations. Results: For both ethnic groups, age, age at menarche, body mass index, and current physical activity had similar associations across the 3 UL subtypes. Inverse associations with pregnancies after age 24 appeared to be stronger for the submucosal subtype. Current smoking was associated only with diffuse UL (adjusted odds ratio [aOR] = 1.97, 95% CI: 1.11, 3.51 in African Americans, aOR = 3.00, 95% CI: 1.07, 8.38 in Caucasians). Conclusions: Although the 2 focal UL subtypes had similar risk factor profiles, the diffuse UL subtype appeared to have a distinctive risk profile with regard to current smoking. Further study of the diffuse heterogeneity seen with uterine ultrasound is needed. C1 [Dragomir, Anca D.; Schroeder, Jane C.; Olshan, Andrew F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Connolly, AnnaMarie] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Kupper, Larry L.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Hill, Michael C.] George Washington Univ, Med Ctr, Dept Radiol, Washington, DC 20037 USA. [Baird, Donna D.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Dragomir, AD (reprint author), POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM dragomir@email.unc.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU NIH, National Institute of Environmental Health Sciences FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 22 TC 17 Z9 18 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD NOV PY 2010 VL 17 IS 11 BP 1029 EP 1035 DI 10.1177/1933719110376979 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 662NV UT WOS:000282815100008 PM 20693498 ER PT J AU Cooney, MA Louis, GMB Hediger, ML Vexler, A Kostyniak, PJ AF Cooney, Maureen A. Louis, Germaine M. Buck Hediger, Mary L. Vexler, Albert Kostyniak, Paul J. TI Organochlorine pesticides and endometriosis SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Endometriosis; Environment; Fecundity; Organochlorines; Pesticides; Reproductive toxicant ID HIGH PLASMA-CONCENTRATIONS; POLYCHLORINATED-BIPHENYLS; ITALIAN WOMEN; SERUM-LEVELS; EXPOSURE; RISK AB Limited study of persistent organochlorine pesticides (OCPs) and endometriosis has been conducted. One hundred women aged 18-40 years who were undergoing laparoscopy provided 20 cm(3) of blood for toxicologic analysis and surgeons completed operative reports regarding the presence of endometriosis. Gas chromatography with electron capture was used to quantify (ng/g serum) six OCPs. Logistic regression was utilized to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (Cl) for individual pesticides and groups based on chemical structure adjusting for current cigarette smoking and lipids. The highest tertile of aromatic fungicide was associated with a fivefold risk of endometriosis (aOR = 5.3: 95% CI, 1.2-23.6) compared to the lowest tertile. Similar results were found for t-nonachlor and HCB. These are the first such findings in a laproscopic cohort that suggest an association between OCP exposure and endometriosis. More prospective studies are necessary to ensure temporal ordering and confirm these findings. Published by Elsevier Inc. C1 [Cooney, Maureen A.; Louis, Germaine M. Buck; Hediger, Mary L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Vexler, Albert] SUNY Buffalo, Dept Biostat, Buffalo, NY 14214 USA. [Kostyniak, Paul J.] SUNY Buffalo, Dept Pharmacol & Toxicol, Sch Med & Biomed Sci, Buffalo, NY 14214 USA. RP Cooney, MA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Rm 7805, Rockville, MD 20852 USA. EM cooneyma@mail.nih.gov; louisg@mail.nih.gov; hedigerm@mail.nih.gov; avexler@buffalo.edu; pjkost@buffalo.edu OI Buck Louis, Germaine/0000-0002-1774-4490 FU National Institute of Environmental Health Sciences [R01ES09044]; Eunice Kennedy Shriver National Institute of Child Health & Human Development FX This work was supported in part with grants from the National Institute of Environmental Health Sciences (R01ES09044) and intramural resources of the Eunice Kennedy Shriver National Institute of Child Health & Human Development. NR 32 TC 16 Z9 17 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD NOV PY 2010 VL 30 IS 3 BP 365 EP 369 DI 10.1016/j.reprotox.2010.05.011 PG 5 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 654JT UT WOS:000282165000003 PM 20580667 ER PT J AU Doerge, DR Twaddle, NC Churchwell, MI Newbold, RR Delclos, KB AF Doerge, Daniel R. Twaddle, Nathan C. Churchwell, Mona I. Newbold, Retha R. Delclos, K. Barry TI Lactational transfer of the soy isoflavone, genistein, in Sprague-Dawley rats consuming dietary genistein (vol 21, pg 307, 2006) SO REPRODUCTIVE TOXICOLOGY LA English DT Correction C1 [Doerge, Daniel R.; Twaddle, Nathan C.; Churchwell, Mona I.; Delclos, K. Barry] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Newbold, Retha R.] NIEHS, Dev Endocrinol & Endocrine Disrupter Sect, Mol Toxicol Lab, NIH DHHS, Res Triangle Pk, NC 27709 USA. RP Doerge, DR (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM daniel.doerge@fda.hhs.gov NR 1 TC 0 Z9 0 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD NOV PY 2010 VL 30 IS 3 BP 493 EP 493 DI 10.1016/j.reprotox.2010.06.005 PG 1 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 654JT UT WOS:000282165000022 ER PT J AU Nussenblatt, RB Byrnes, G Sen, HN Yeh, S Faia, L Meyerle, C Wroblewski, K Li, ZQ Liu, BY Chew, E Sherry, PR Friedman, P Gill, F Ferris, F AF Nussenblatt, Robert B. Byrnes, Gordon Sen, H. Nida Yeh, Steven Faia, Lisa Meyerle, Catherine Wroblewski, Keith Li, Zhuqing Liu, Baoying Chew, Emily Sherry, Patti R. Friedman, Penelope Gill, Fred Ferris, Frederick, III TI A RANDOMIZED PILOT STUDY OF SYSTEMIC IMMUNOSUPPRESSION IN THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION WITH CHOROIDAL NEOVASCULARIZATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE age-related macular degeneration; immunosuppression; T cell; choroidal neovascularization ID RAPAMYCIN; THERAPY; SUSCEPTIBILITY; INFLAMMATION; SIROLIMUS; UVEITIS; VARIANT; ALPHA; CELLS; HTRA1 AB Background: Age-related macular degeneration remains the leading cause of irreversible blindness in the United States and the developed world. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications have become standard of care for the treatment of the wet form of the disease. Recent reports have demonstrated an association with various immune factors. We aimed to investigate the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. Methods: This was a pilot, Phase I/II, prospective, randomized, unmasked, single-center trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 of 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti-VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. Results: The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. Conclusion: These preliminary data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated. RETINA 30:1579-1587, 2010 C1 [Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Byrnes, Gordon] Retina Grp Washington, Fairfax, VA USA. [Wroblewski, Keith] Walter Reed Army Med Ctr, Dept Ophthalmol, Washington, DC USA. [Gill, Fred] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU National Eye Institute, National Institutes of Health, Bethesda, Maryland FX Supported by intramural funds of the National Eye Institute, National Institutes of Health, Bethesda, Maryland. NR 29 TC 38 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD NOV-DEC PY 2010 VL 30 IS 10 BP 1579 EP 1587 DI 10.1097/IAE.0b013e3181e7978e PG 9 WC Ophthalmology SC Ophthalmology GA 678HL UT WOS:000284064600004 PM 20847709 ER PT J AU Geisbert, TW Bausch, DG Feldmann, H AF Geisbert, Thomas W. Bausch, Daniel G. Feldmann, Heinz TI Prospects for immunisation against Marburg and Ebola viruses SO REVIEWS IN MEDICAL VIROLOGY LA English DT Review ID ATTENUATED RECOMBINANT VACCINE; PROTECTS NONHUMAN-PRIMATES; VESICULAR-STOMATITIS; HEMORRHAGIC-FEVER; GUINEA-PIGS; MOUSE MODEL; NEUTRALIZING ANTIBODIES; POSTEXPOSURE PROTECTION; ADENOVIRUS VECTORS; ALPHAVIRUS VECTORS AB For more than 30 years the filoviruses, Marburg virus and Ebola virus, have been associated with periodic outbreaks of hemorrhagic fever that produce severe and often fatal disease. The filoviruses are endemic primarily in resource-poor regions in Central Africa and are also potential agents of bioterrorism. Although no vaccines or antiviral drugs for Marburg or Ebola are currently available, remarkable progress has been made over the last decade in developing candidate preventive vaccines against filoviruses in nonhuman primate models. Due to the generally remote locations of filovirus outbreaks, a single-injection vaccine is desirable. Among the prospective vaccines that have shown efficacy in nonhuman primate models of filoviral hemorrhagic fever, two candidates, one based on a replication-defective adenovirus serotype 5 and the other on a recombinant VSV (rVSV), were shown to provide complete protection to nonhuman primates when administered as a single injection. The rVSV-based vaccine has also shown utility when administered for postexposure prophylaxis against filovirus infections. A VSV-based Ebola vaccine was recently used to manage a potential laboratory exposure. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab1, Galveston, TX USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol2, Galveston, TX USA. [Geisbert, Thomas W.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Geisbert, Thomas W.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Bausch, Daniel G.] Tulane Sch Publ Hlth & Trop Med, Dept Trop Med, New Orleans, LA USA. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab1, 301 Univ Blvd, Galveston, TX USA. EM twgeisbe@utmb.edu FU Intramural NIH HHS [Z99 AI999999] NR 89 TC 50 Z9 52 U1 1 U2 36 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1052-9276 J9 REV MED VIROL JI Rev. Med. Virol. PD NOV PY 2010 VL 20 IS 6 BP 344 EP 357 DI 10.1002/rmv.661 PG 14 WC Virology SC Virology GA 677ZL UT WOS:000284036600002 PM 20658513 ER PT J AU Rein, A AF Rein, Alan TI Nucleic acid chaperone activity of retroviral Gag proteins SO RNA BIOLOGY LA English DT Article DE retroviruses; Gag protein; RNA chaperone; HIV-1; protein-nucleic acid interaction ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 NUCLEOCAPSID PROTEIN; MURINE LEUKEMIA-VIRUS; PRIMER-BINDING-SITE; ROUS-SARCOMA-VIRUS; ASSEMBLY IN-VITRO; REVERSE TRANSCRIPTION; TRANSFER-RNA; GENOMIC RNA; STRUCTURAL BASIS AB Retrovirus particles in which the Gag protein has not yet been cleaved by the viral protease are termed immature particles. The viral RNA within these particles shows clear evidence of the action of a nucleic acid chaperone (NAC): the genomic RNA is dimeric, and a cellular tRNA molecule is annealed, by its 3' 18 nucleotides, to a complementary stretch in the viral RNA, in preparation for priming reverse transcription in the next round of infection. It seems very likely that the NAC that has catalyzed dimerization and tRNA annealing is the NC domain of the Gag protein itself. However, neither the dimeric linkage nor the tRNA: viral RNA complex has the same structure as those in mature virus particles: thus the conformational effects of Gag within the particles are not equivalent to those of the free NC protein present in mature particles. It is not known whether these dissimilarities reflect intrinsic differences in the NAC activities of Gag and NC, or limitations on Gag imposed by the structure of the immature particle. Analysis of the interactions of recombinant Gag proteins with nucleic acids is complicated by the fact that they result in assembly of virus-like particles. Nevertheless, the available data indicates that the affinity of Gag for nucleic acids can be considerably higher than that of free NC. This enhanced affinity may be due to contributions of the matrix domain, a positively charged region at the N-terminus of Gag; interactions of neighboring Gag molecules with each other may also increase the affinity due to cooperativity of the binding. Recombinant HIV-1 Gag protein clearly exhibits NAC activity. In two well-studied experimental systems, Gag was more efficient than NC, as its NAC effects could be detected at a significantly lower molar ratio of protein to nucleotide than with NC. In one system, binding of nucleic acid by the matrix domain of Gag retarded the Gag-induced annealing of two RNAs; this effect could be ameliorated by the competitive binding of inositol hexakisphosphate to the matrix domain. C1 Natl Canc Inst Frederick, HIV Drug Resistance Program, Frederick, MD USA. RP Rein, A (reprint author), Natl Canc Inst Frederick, HIV Drug Resistance Program, Frederick, MD USA. EM reina@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX I am grateful to Ioulia Rouzina, Judith Levin, Christopher Jones and Karin Musier-Forsyth for many helpful discussions. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 51 TC 18 Z9 18 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 J9 RNA BIOL JI RNA Biol. PD NOV-DEC PY 2010 VL 7 IS 6 SI SI BP 700 EP 705 DI 10.4161/rna.7.6.13685 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 736JN UT WOS:000288490500008 PM 21045546 ER PT J AU Mirambeau, G Lyonnais, S Gorelick, RJ AF Mirambeau, Gilles Lyonnais, Sebastien Gorelick, Robert J. TI Features, processing states and heterologous protein interactions in the modulation of the retroviral nucleocapsid protein function SO RNA BIOLOGY LA English DT Article DE capsid; HIV-1; nucleic acid chaperone; nucleocapsid protein; protease; retrovirus; reverse transcription; zinc-finger ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACID-CHAPERONE ACTIVITY; MURINE LEUKEMIA-VIRUS; REVERSE TRANSCRIPTION COMPLEXES; TYPE-1 GAG POLYPROTEIN; ROUS-SARCOMA-VIRUS; HIV-1 GENOMIC RNA; ZINC-FINGER STRUCTURES; PRIMER BINDING-SITE; IN-VITRO AB Nucleocapsid (NC) is central to retroviral replication. Nucleic acid chaperoning is a key function for NC through the action of its conserved basic amino acids and zinc-finger structures. NC manipulates genomic RNA from its packaging in the producer cell to reverse transcription into the infected host cell. This chaperone function, in conjunction with NCs aggregating properties, is up-modulated by successive NC processing events, from the Gag precursor to the fully mature protein, resulting in the condensation of the nucleocapsid within the capsid shell. Reverse transcription also depends on NC processing, whereas this process provokes NC dissociation from double-stranded DNA, leading to a preintegration complex (PIC), competent for host chromosomal integration. In addition NC interacts with cellular proteins, some of which are involved in viral budding, and also with several viral proteins. All of these properties are reviewed here, focusing on HIV-1 as a paradigmatic reference and highlighting the plasticity of the nucleocapsid architecture. C1 [Gorelick, Robert J.] NCI Frederick, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD USA. [Mirambeau, Gilles; Lyonnais, Sebastien] Univ Barcelona, Hosp Clin IDIBAPS, Infectious Dis & AIDS Unit, Barcelona, Spain. [Mirambeau, Gilles] Sorbonne Univ, Univ Paris 06, Fac Biol, Paris, France. RP Gorelick, RJ (reprint author), NCI Frederick, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD USA. EM gorelicr@mail.nih.gov OI Lyonnais, Sebastien/0000-0002-3154-8568 FU Marie Curie Intra-European Fellowship [237738]; National Cancer Institute, National Institutes of Health [N01-CO-12400, HHSN261200800001E] FX G.M. and S.L. are greatly indebted to Jose Maria Gatell and Laura Zamora for their kind hosting and support at the Infectious Disease and AIDS Unit. We wish to thank Sophie Brouillet, Joel Pothier (ABI, UPMC, Paris) and Anne Voinet (MTI-Universite Paris Diderot, Paris) for the alignment of HIV-1 NC sequences. We also wish to thank James A. Thomas (NCI-Frederick) and Judith G. Levin (NICHD, NIH) for critical reading of this manuscript. S.L. is funded by a Marie Curie Intra-European Fellowship IEF No 237738. (R.J.G.) this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts N01-CO-12400 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 124 TC 35 Z9 35 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD NOV-DEC PY 2010 VL 7 IS 6 SI SI BP 724 EP 734 DI 10.4161/rna.7.6.13777 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 736JN UT WOS:000288490500011 PM 21045549 ER PT J AU Levin, JG Mitra, M Mascarenhas, A Musier-Forsyth, K AF Levin, Judith G. Mitra, Mithun Mascarenhas, Anjali Musier-Forsyth, Karin TI Role of HIV-1 nucleocapsid protein in HIV-1 reverse transcription SO RNA BIOLOGY LA English DT Article DE nucleocapsid protein; HIV-1; nucleic acid chaperone; reverse transcription; Gag; zinc fingers; tRNA(3)(Lys); APOBEC3G; retroviruses ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACID-CHAPERONE ACTIVITY; STRAND DNA-SYNTHESIS; TRANSFER-RNA SYNTHETASE; MURINE LEUKEMIA-VIRUS; PRIMER BINDING-SITE; STRONG-STOP DNA; CENTRAL POLYPURINE TRACT; ZINC-FINGER STRUCTURES; IN-VITRO SYNTHESIS AB The HIV-1 nucleocapsid protein (NC) is a nucleic acid chaperone, which remodels nucleic acid structures so that the most thermodynamically stable conformations are formed. This activity is essential for virus replication and has a critical role in mediating highly specific and efficient reverse transcription. NC's function in this process depends upon three properties: (1) ability to aggregate nucleic acids; (2) moderate duplex destabilization activity; and (3) rapid on-off binding kinetics. Here, we present a detailed molecular analysis of the individual events that occur during viral DNA synthesis and show how NC's properties are important for almost every step in the pathway. Finally, we also review biological aspects of reverse transcription during infection and the interplay between NC, reverse transcriptase and human APOBEC3G, an HIV-1 restriction factor that inhibits reverse transcription and virus replication in the absence of the HIV-1 Vif protein. C1 [Levin, Judith G.; Mitra, Mithun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, Program Genom Differentiat, NIH, Bethesda, MD USA. [Mascarenhas, Anjali; Musier-Forsyth, Karin] Ohio State Univ, Ctr Retrovirus Res, Dept Chem, Columbus, OH 43210 USA. [Mascarenhas, Anjali; Musier-Forsyth, Karin] Ohio State Univ, Ctr Retrovirus Res, Dept Biochem, Columbus, OH 43210 USA. [Mascarenhas, Anjali; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, Program Genom Differentiat, NIH, Bethesda, MD USA. EM levinju@mail.nih.gov RI Mitra, Mithun/A-2133-2015 FU NIH (Eunice Kennedy Shriver National Institute of Child Health and Human Development); NIH [GM065056] FX This work was supported by the Intramural Research Program of the NIH (Eunice Kennedy Shriver National Institute of Child Health and Human Development) [J.G.L.] and NIH grant GM065056 [K.M.F.]. NR 256 TC 64 Z9 64 U1 2 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD NOV-DEC PY 2010 VL 7 IS 6 SI SI BP 754 EP 774 DI 10.4161/rna.7.6.14115 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 736JN UT WOS:000288490500014 PM 21160280 ER PT J AU Cuthbert, BN Insel, TR AF Cuthbert, Bruce N. Insel, Thomas R. TI Toward New Approaches to Psychotic Disorders: The NIMH Research Domain Criteria Project SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material ID KRAEPELINIAN DICHOTOMY; SCHIZOPHRENIA C1 [Cuthbert, Bruce N.; Insel, Thomas R.] NIH, Bethesda, MD 20892 USA. RP Cuthbert, BN (reprint author), NIH, 6001 Execut Blvd,MSC 9625, Bethesda, MD 20892 USA. EM bcuthber@mail.nih.gov NR 10 TC 144 Z9 145 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD NOV PY 2010 VL 36 IS 6 BP 1061 EP 1062 DI 10.1093/schbul/sbq108 PG 2 WC Psychiatry SC Psychiatry GA 673SR UT WOS:000283683800001 PM 20929969 ER PT J AU Li, QZ Zheng, G Liu, AY Li, ZH Yu, K AF Li QiZhai Zheng Gang Liu AiYi Li ZhaoHai Yu Kai TI Approximating probabilities of correlated events SO SCIENCE CHINA-MATHEMATICS LA English DT Article DE case-control; group sequential test; genetic association studies; MAX; parallelogram ID GENOME-WIDE ASSOCIATION; CLINICAL-TRIALS; NUISANCE PARAMETER; GENETIC-LINKAGE; TREND TESTS; RISK; STATISTICS; MAXIMUM; DESIGNS; CANCER AB Efron (1997) considered several approximations of p-values for simultaneous hypothesis testing. An extension of his approaches is considered here to approximate various probabilities of correlated events. Compared with multiple-integrations, our proposed method, the parallelogram formulas, based on a one-dimensional integral, not only substantially reduces the computational complexity but also maintains good accuracy. Applications of the proposed method to genetic association studies and group sequential analysis are investigated in detail. Numerical results including real data analysis and simulation studies demonstrate that the proposed method performs well. C1 [Li QiZhai] Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. [Li QiZhai; Li ZhaoHai; Yu Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zheng Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Liu AiYi] NICHHD, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. [Li ZhaoHai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Li, QZ (reprint author), Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. EM liqz@amss.ac.cn; zhengg@mail.nih.gov; liua@mail.nih.gov; zli@gwu.edu; yuka@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU NIH [EY014478]; National Natural Science Foundation of China [10901155] FX We would like to thank the editor and the reviewer for the insightful comments. We thank Dr. Barry Graubard and Dr. B.J. Stone for their valuable help. This research utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health (NIH), Bethesda, Maryland, USA (http://biowulf.nih.gov). K Yu and A Liu are supported by the Intramural Program of NIH; Q Li is supported in part by National Natural Science Foundation of China (Grant No.10901155); Z Li is supported in part by NIH (Grant No. EY014478). NR 24 TC 1 Z9 1 U1 0 U2 0 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1674-7283 J9 SCI CHINA MATH JI Sci. China-Math. PD NOV PY 2010 VL 53 IS 11 BP 2937 EP 2948 DI 10.1007/s11425-010-4053-0 PG 12 WC Mathematics, Applied; Mathematics SC Mathematics GA 682EB UT WOS:000284382200012 ER PT J AU Seeff, LB Ghany, MG AF Seeff, Leonard B. Ghany, Marc G. TI Management of Untreated and Nonresponder Patients with Chronic Hepatitis C SO SEMINARS IN LIVER DISEASE LA English DT Review DE Chronic hepatitis C; peginterferon; ribavirin; sustained virologic response; nonresponder; retreatment ID SUSTAINED VIROLOGICAL RESPONSE; ALPHA-2B PLUS RIBAVIRIN; CHRONIC HCV INFECTION; COMBINATION THERAPY; INTERFERON-ALPHA; VIRUS-INFECTION; FOLLOW-UP; HEPATOCELLULAR-CARCINOMA; ALTERNATIVE MEDICINE; MAINTENANCE THERAPY AB Hepatitis C infection has evolved in the past quarter century from a newly recognized entity without a known pathogen (non-A, non-B hepatitis) to one of the world's most prevalent causes of liver disease, an important source for hepatocellular carcinoma, and the major indication for liver transplantation. It is caused by a virus with a complex replication cycle that occurs in multiple genotypes, of which the four most prevalent (1, 2, 3, and 4) exhibit differences in clinical behavior and responses to therapy. Chronic hepatitis C virus (HCV) in particular has evolved from a disease with no known treatment to one with several primary treatment options, none of which is uniformly effective, and a growing list of secondary treatment options for those who have failed to respond to, or relapsed after initial therapy. As treatment is often associated with significant side effects, it is now a disease that presents clinicians with multiple important decisions: whom to treat, when and with what to treat them initially, and how to manage patients who have failed during initial therapy to achieve a sustained virological response, the gold standard of effective therapy. This review examines each of these important decisions, presenting evidence to help guide clinicians in their choices. The decisions are addressed sequentially as they arise during the initial evaluation and subsequent treatment of a typical, newly recognized patient with chronic HCV, and the considerations facing the clinician when the patient has failed to achieve an SVR. C1 [Seeff, Leonard B.] Hill Grp, Bethesda, MD 20817 USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. RP Seeff, LB (reprint author), Hill Grp, 6903 Rockledge Dr,Suite 540, Bethesda, MD 20817 USA. EM Mahler68@hotmail.com NR 65 TC 4 Z9 6 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD NOV PY 2010 VL 30 IS 4 BP 348 EP 360 DI 10.1055/s-0030-1267536 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 667UG UT WOS:000283219900004 PM 20960375 ER PT J AU Coseo, S Porras, C Hildesheim, A Rodriguez, AC Schiffman, M Herrero, R Wacholder, S Gonzalez, P Wang, SS Sherman, ME Jimenez, S Solomon, D Bougelet, C van Doorn, LJ Quint, W Safaeian, M AF Coseo, Sarah Porras, Carolina Hildesheim, Allan Cecilia Rodriguez, Ana Schiffman, Mark Herrero, Rolando Wacholder, Sholom Gonzalez, Paula Wang, Sophia S. Sherman, Mark E. Jimenez, Silvia Solomon, Diane Bougelet, Catherine van Doorn, Leen-Jan Quint, Wim Safaeian, Mahboobeh CA Costa Rica HPV Vaccine Trial CVT TI Seroprevalence and Correlates of Human Papillomavirus 16/18 Seropositivity Among Young Women in Costa Rica SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID VIRUS-LIKE PARTICLES; CERVICAL-CANCER; UNITED-STATES; VACCINE; INFECTION; TYPE-16; HPV; PREVALENCE; POPULATION; TRIAL AB Background: Serological indicators of human papillomavirus (HPV) infection are being used to differentiate HPV-naive from previously infected women in vaccine and epidemiologic/clinical studies. We investigated HPV16 and 18 seroepidemiology among young, unvaccinated women aged between 18 and 25. Materials and Methods: We conducted a cross-sectional evaluation of the enrollment visit in the ongoing community-based HPV16/18 Costa Rica Vaccine Trial. Prevaccination serum immunoglobulin G (IgG) antibodies were measured against HPV16 and HPV18 by enzyme-linked immunosorbent assay; cervical samples were tested for HPV DNA using Hybrid Capture 2 and SPF(10)/LiPA(25). Seroprevalence and its correlates were evaluated using unconditional logistic regression. Results: Among 5871 nonvirginal women, HPV16 and 18 seroprevalences were 30.8% and 28.1%, HPV16 and HPV18 DNA prevalences were 8.3% and 3.2%, respectively. About 37% of HPV16 DNA-positives and 42% of HPV18 DNA-positives were seronegative. Seroprevalence increased with time since sexual debut, whereas DNA prevalence did not. The correlates of HPV16 and/or 18 seropositivity were related to sexual behaviors, particularly higher number of lifetime sexual partners. There was no evidence of assay cross-reactivity as HPV16 seroprevalence was similar (approximately 34%) among women singly infected with genetically and nongenetically related species (alpha 9 and non-alpha 9); likewise, seropositivity to HPV18 was similar (approximately 30%) among women singly infected with alpha 7 and non-alpha 7 species. Conclusions: The increasing seroprevalence observed with time since first sex suggests that HPV serology is a cumulative marker of HPV exposure. However, many DNA infected women were seronegative; thus, serology is an imperfect measure of past exposure to cervical HPV, at best. Additionally, we found no evidence of assay cross-reactivity. C1 [Coseo, Sarah; Porras, Carolina; Hildesheim, Allan; Schiffman, Mark; Wacholder, Sholom; Wang, Sophia S.; Sherman, Mark E.; Safaeian, Mahboobeh] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cecilia Rodriguez, Ana; Herrero, Rolando; Gonzalez, Paula; Jimenez, Silvia] Fundac INCIENSA, Proyecto Epidemiol Guanacaste, Liberia, Costa Rica. [Solomon, Diane] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Bougelet, Catherine] GlaxoSmithKline Biol, Rixensart, Belgium. [van Doorn, Leen-Jan; Quint, Wim] DDL Diagnost Lab, Voorburg, Netherlands. RP Coseo, S (reprint author), Natl Canc Inst, NIH DHHS, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, 6120 Executive Blvd,EPS,Room 7079, Rockville, MD 20852 USA. EM coseose@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI [N01-CP-11005]; GSK [FDA BB-IND 7920]; NIH Office of Research on Women's Health FX Supported by intramural NCI (N01-CP-11005) with support from the NIH Office of Research on Women's Health and is conducted in agreement with the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GSK Biologicals, under a clinical trials agreement with NCI. GSK also provided support for aspects of the trial associated with the regulatory submission needs of the company under FDA BB-IND 7920. NCI and Costa Rican investigators make final editorial decisions on this presentation and subsequent publications; GSK has the right to review/comment. NR 29 TC 14 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD NOV PY 2010 VL 37 IS 11 BP 706 EP 714 DI 10.1097/OLQ.0b013e3181e1a2c5 PG 9 WC Infectious Diseases SC Infectious Diseases GA 671FY UT WOS:000283487100008 PM 20661178 ER PT J AU Miller, FG Kallmes, DF AF Miller, Franklin G. Kallmes, David F. TI The Case of Vertebroplasty Trials Promoting a Culture of Evidence-Based Procedural Medicine SO SPINE LA English DT Article ID OSTEOPOROTIC VERTEBRAL FRACTURES; PERCUTANEOUS VERTEBROPLASTY; RANDOMIZED-TRIAL C1 [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Kallmes, David F.] Mayo Clin, Dept Radiol, Rochester, MN USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 14 TC 11 Z9 11 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD NOV 1 PY 2010 VL 35 IS 23 BP 2023 EP 2026 DI 10.1097/BRS.0b013e3181ecd393 PG 4 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 671GX UT WOS:000283490100018 PM 20938382 ER PT J AU Pistollato, F Rampazzo, E Persano, L Abbadi, S Frasson, C Denaro, L D'Avella, D Panchision, DM Della Puppa, A Scienza, R Basso, G AF Pistollato, Francesca Rampazzo, Elena Persano, Luca Abbadi, Sara Frasson, Chiara Denaro, Luca D'Avella, Domenico Panchision, David M. Della Puppa, Alessandro Scienza, Renato Basso, Giuseppe TI Interaction of Hypoxia-Inducible Factor-1 alpha and Notch Signaling Regulates Medulloblastoma Precursor Proliferation and Fate SO STEM CELLS LA English DT Article DE Medulloblastoma; Cancer stem cells; Hypoxia; Notch1; Hypoxia-inducible factor-1 alpha ID CANCER STEM-CELLS; TUMOR-INITIATING CELLS; PROGENITOR CELLS; NEURON PRECURSORS; VASCULAR NICHE; BRAIN-TUMORS; MOUSE MODEL; GROWTH; EXPRESSION; GLIOBLASTOMA AB Medulloblastoma (MDB) is the most common brain malignancy of childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. Although interaction between hypoxia-inducible factor-1 alpha (HIF-1 alpha) and Notch signaling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here, we investigate whether hypoxia, through HIF-1 alpha stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133(+) and nestin(+) precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with gamma-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion. STEM CELLS 2010;28:1918-1929 C1 [Pistollato, Francesca; Rampazzo, Elena; Persano, Luca; Abbadi, Sara; Frasson, Chiara; Basso, Giuseppe] Univ Padua, Dept Pediat, SSD Clin & Expt Hematol, I-35128 Padua, Italy. [Denaro, Luca; D'Avella, Domenico; Della Puppa, Alessandro; Scienza, Renato] Univ Padua, Dept Neurosurg, I-35128 Padua, Italy. [Panchision, David M.] NIMH, Div Neurosci & Basic Behav Sci, NIH, Bethesda, MD 20892 USA. RP Persano, L (reprint author), Univ Padua, Dept Pediat, SSD Clin & Expt Hematol, Via Giustiniani 3, I-35128 Padua, Italy. EM luca.persano@unipd.it RI Persano, Luca/H-6416-2016; OI Persano, Luca/0000-0002-0050-3666; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Italian Association for the Fight against Neuroblastoma; Italian Association AIRC FX We thank Dr. Pier Giorgio Modena, from CRO, Aviano, Italy, for providing MDB-derived cells and Prof. Felice Giangaspero, from University of "La Sapienza" Rome, for providing a quote of MDB histological samples. We are grateful to Dr. Stefano Indraccolo for lentiviral vectors production and thank Dr. Andrea Zangrando for his help with image management. This research was supported by funds from the Italian Association for the Fight against Neuroblastoma (Pensiero Project) and the Italian Association AIRC (Interregional pediatric project grant). NR 64 TC 54 Z9 58 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD NOV PY 2010 VL 28 IS 11 BP 1918 EP 1929 DI 10.1002/stem.518 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 682IW UT WOS:000284395900002 PM 20827750 ER PT J AU Matsuda, H Shi, YB AF Matsuda, Hiroki Shi, Yun-Bo TI An Essential and Evolutionarily Conserved Role of Protein Arginine Methyltransferase 1 for Adult Intestinal Stem Cells During Postembryonic Development SO STEM CELLS LA English DT Article DE Adult organ-specific stem cell; Histone arginine methyltransferase; Transcriptional coactivator; Thyroid hormone receptor; Dedifferentiation ID THYROID-HORMONE RECEPTOR; XENOPUS-LAEVIS; AMPHIBIAN METAMORPHOSIS; TRANSCRIPTIONAL REGULATION; MEDIATED TRANSCRIPTION; LIMB REGENERATION; GENE-EXPRESSION; EPITHELIUM; PROLIFERATION; RECRUITMENT AB Organ-specific adult stem cells are critical for the homeo-stasis of adult organs and organ repair and regeneration. Unfortunately, it has been difficult to investigate the origins of these stem cells and the mechanisms of their development, especially in mammals. Intestinal remodeling during frog metamorphosis offers a unique opportunity for such studies. During the transition from an herbivorous tadpole to a carnivorous frog, the intestine is completely remodeled as the larval epithelial cells undergo apoptotic degeneration and are replaced by adult epithelial cells developed de novo. The entire metamorphic process is under the control of thyroid hormone, making it possible to control the development of the adult intestinal stem cells. Here, we show that the thyroid hormone receptor-coactivator protein arginine methyltransferase 1 (PRMT1) is upregulated in a small number of larval epithelial cells and that these cells dedifferentiate to become the adult stem cells. More importantly, transgenic overexpression of PRMT1 leads to increased adult stem cells in the intestine, and conversely, knocking down the expression of endogenous PRMT1 reduces the adult stem cell population. In addition, PRMT1 expression pattern during zebrafish and mouse development suggests that PRMT1 may play an evolutionally conserved role in the development of adult intestinal stem cells throughout vertebrates. These findings are not only important for the understanding of organ-specific adult stem cell development but also have important implications in regenerative medicine of the digestive tract. STEM CELLS 2010;28:2073-2083 C1 [Matsuda, Hiroki; Shi, Yun-Bo] NICHD, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bldg 18 T,Rm 106, Bethesda, MD 20892 USA. EM shi@helix.nih.gov FU Intramural NIH HHS [Z01 HD008858-01, Z01 HD001901-13, ZIA HD008858-04] NR 67 TC 22 Z9 22 U1 0 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD NOV PY 2010 VL 28 IS 11 BP 2073 EP 2083 DI 10.1002/stem.529 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 682IW UT WOS:000284395900017 PM 20872846 ER PT J AU Brook, JS Marcus, SE Zhang, CS Stimmel, MA Balka, EB Brook, DW AF Brook, Judith S. Marcus, Stephen E. Zhang, Chenshu Stimmel, Matthew A. Balka, Elinor B. Brook, David W. TI Adolescent Attributes and Young Adult Smoking Cessation Behavior SO SUBSTANCE USE & MISUSE LA English DT Article DE adolescent personal attributes; parental smoking; smoking cessation ID CIGARETTE-SMOKING; NICOTINE DEPENDENCE; SOCIAL SUPPORT; DRUG-USE; TRAJECTORIES; PREDICTORS; DEPRESSION; CHILDREN; SMOKERS; STRESS AB This study collected data five times between 1983 and 2002 from 400 participants who originally came from upstate New York. These participants completed structured interviews as did their mothers three times. LISREL analysis generally supported the hypothesized model. The results indicated that having parents who smoked and having low educational aspirations and expectations were associated with being unconventional, which, in turn, was related to having low emotional control and reporting more internalizing behaviors. Internalizing behaviors were directly associated with a lower likelihood of smoking cessation, as was parental smoking. Research and clinical implications are discussed and the limitations noted. C1 [Brook, Judith S.; Zhang, Chenshu; Stimmel, Matthew A.; Balka, Elinor B.; Brook, David W.] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA. [Marcus, Stephen E.] Natl Canc Inst, Rockville, MD USA. RP Brook, JS (reprint author), NYU, Sch Med, Dept Psychiat, 215 Lexington Ave,15th Floor, New York, NY 10016 USA. EM judith.brook@nyumc.org OI Zhang, Chenshu/0000-0002-3233-3905 FU National Cancer Institute [CA094845]; National Institute on Drug Abuse [DA03188, K05 DA00244] FX The authors greatly appreciate Dr. Martin Whiteman's suggestions for improving this report. This research was supported by grant CA094845 from the National Cancer Institute, grant DA03188, and Research Scientist Award K05 DA00244, both from the National Institute on Drug Abuse. NR 37 TC 5 Z9 5 U1 1 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PD NOV PY 2010 VL 45 IS 13 BP 2172 EP 2184 DI 10.3109/10826084.2010.484473 PG 13 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 673UE UT WOS:000283688100006 PM 20482339 ER PT J AU Biegon, A Kim, SW Alexoff, DL Jayne, M Carter, P Hubbard, B King, P Logan, J Muench, L Pareto, D Schlyer, D Shea, C Telang, F Wang, GJ Xu, YW Fowler, JS AF Biegon, Anat Kim, Sung Won Alexoff, David L. Jayne, Millard Carter, Pauline Hubbard, Barbara King, Payton Logan, Jean Muench, Lisa Pareto, Deborah Schlyer, David Shea, Colleen Telang, Frank Wang, Gene-Jack Xu, Youwen Fowler, Joanna S. TI Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-C-11]Vorozole SO SYNAPSE LA English DT Article DE estrogen; testosterone; androgens; steroidogenesis; imaging ID MESSENGER-RIBONUCLEIC-ACID; CENTRAL-NERVOUS-SYSTEM; CYTOCHROME-P450 AROMATASE; POSTMENOPAUSAL WOMEN; ESTROGEN-RECEPTORS; HUMAN FOREBRAIN; EXPRESSION; INHIBITOR; CYP19; RAT AB Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-C-11]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V-T) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced V-T in all regions, though the size of the reduction was region-dependent, ranging from similar to 70% blocking in thalamus and preoptic area to similar to 10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain. Synapse 64:801-807, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Biegon, Anat; Alexoff, David L.; Jayne, Millard; Carter, Pauline; Hubbard, Barbara; King, Payton; Logan, Jean; Schlyer, David; Shea, Colleen; Telang, Frank; Wang, Gene-Jack; Xu, Youwen; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Kim, Sung Won; Muench, Lisa] Natl Inst Alcoholism & Alcohol Abuse, Bethesda, MD USA. [Pareto, Deborah] CIBER BBN, Inst Alta Tecnol, Barcelona, Spain. [Wang, Gene-Jack; Fowler, Joanna S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Fowler, Joanna S.] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. RP Biegon, A (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM biegon@bnl.gov OI Logan, Jean/0000-0002-6993-9994 FU US Department of Energy OBER [DE-AC02-98CH10886]; NIH [R01 NS050285, K05DA020001]; General Clinical Research Center of Stony Brook University (NIH) [MO1RR10710] FX Contract grant sponsor: US Department of Energy OBER; Contract grant number: DE-AC02-98CH10886; Contract grant sponsor: NIH; Contract grant numbers: R01 NS050285 (to AB), K05DA020001 (to JSF); Contract grant sponsor: General Clinical Research Center of Stony Brook University (NIH); Contract grant number: MO1RR10710. NR 42 TC 44 Z9 45 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD NOV PY 2010 VL 64 IS 11 BP 801 EP 807 DI 10.1002/syn.20791 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 659AI UT WOS:000282539000001 PM 20842717 ER PT J AU Rothman, RB Baumann, MH Blough, BE Jacobson, AE Rice, KC Partilla, JS AF Rothman, Richard B. Baumann, Michael H. Blough, Bruce E. Jacobson, Arthur E. Rice, Kenner C. Partilla, John S. TI Evidence for Noncompetitive Modulation of Substrate-Induced Serotonin Release SO SYNAPSE LA English DT Article DE serotonin; MDMA; mCPP; transporter; 5HT2b receptor ID BIOGENIC-AMINE TRANSPORTERS; HUMAN DOPAMINE TRANSPORTER; IN-VITRO; COCAINE ADDICTION; STIMULANT ABUSE; 5-HT RELEASE; INHIBITORS; NOREPINEPHRINE; BENZTROPINE; RECEPTORS AB Prior work indicated that serotonin transporter (SERT) inhibitors competitively inhibit substrate-induced [(3)H]5-HT release, producing rightward shifts in the substrate-dose response curve and increasing the EC(50) value without altering the E(max). We hypothesized that this finding would not generalize across a number of SERT inhibitors and substrates, and that the functional dissociation constant (Ke) of a given SERT inhibitor would not be the same for all tested substrates. To test this hypothesis, we utilized a well-characterized [3H]5-HT release assay that measures the ability of a SERT substrate to release preloaded [(3)H]5-HT from rat brain synaptosomes. Dose-response curves were generated for six substrates (PAL-287 [naphthylisopropylamine], (+)-fenfluramine, (+)-norfenfluramine, mCPP [meta-chlorophenylpiperazine], (+/-)-MDMA, 5-HT) in the absence and presence of a fixed concentration of three SERT inhibitors (indatraline, BW723C86, EG-1-149 [4-(2-(benzhydryloxy)ethyl)-1-(4-bromobenzyl)piperidine oxalate]). Consistent with simple competitive inhibition, all SERT inhibitors increased the EC(50) value of all substrates. However, in many cases a SERT inhibitor decreased the En, x value as well, indicating that in the presence of the SERT inhibitor the substrate became a partial releaser. Moreover, the Ke values of a given SERT inhibitor differed among the six SERT substrates, indicating that each inhibitor/substrate combination had a unique interaction with the transporter. Viewed collectively, these findings suggest that it may be possible to design SERT inhibitors that differentially regulate SERT function. Synapse 64:862-869, 2010. (C) 2010 Wiley-Liss, Inc C1 [Rothman, Richard B.; Baumann, Michael H.; Partilla, John S.] NIDA, IRP, NIH, DHHS, Baltimore, MD USA. [Blough, Bruce E.] Res Triangle Inst Int, Chem & Life Sci Grp, Res Triangle Pk, NC USA. [Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, IRP, NIH,DHHS, Baltimore, MD USA. RP Rothman, RB (reprint author), NIDA, IRP, NIH, DHHS, Baltimore, MD USA. EM RROTHMAN@intra.nida.nih.gov FU National Institute on Drug Abuse, NIH; DHHS; NIDA [DA12970] FX This work was supported by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, and NIDA grant number DA12970 to Dr. Blough. NR 29 TC 8 Z9 8 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD NOV PY 2010 VL 64 IS 11 BP 862 EP 869 DI 10.1002/syn.20804 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 659AI UT WOS:000282539000009 PM 20842720 ER PT J AU Divi, RL Einem, TL Fletcher, SLL Shockley, ME Kuo, MM St Claire, MC Cook, A Nagashima, K Harbaugh, SW Harbaugh, JW Poirier, MC AF Divi, Rao L. Einem, Tracey L. Fletcher, Sarah L. Leonard Shockley, Marie E. Kuo, Maryanne M. St Claire, Marisa C. Cook, Anthony Nagashima, Kunio Harbaugh, Steven W. Harbaugh, Jeffrey W. Poirier, Miriam C. TI Progressive Mitochondrial Compromise in Brains and Livers of Primates Exposed In Utero to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) SO TOXICOLOGICAL SCIENCES LA English DT Article DE Zidovudine; Lamivudine; Stavudine; Didanosine; electron microscopy; mitochondrial DNA quantity; oxidative phosphorylation ID HUMAN-IMMUNODEFICIENCY-VIRUS; ERYTHROCEBUS-PATAS MONKEYS; ZIDOVUDINE PLUS LAMIVUDINE; UNINFECTED CHILDREN BORN; HIV-INFECTED MOTHERS; TERM RHESUS MACAQUES; ANTIRETROVIRAL THERAPY; PERINATAL EXPOSURE; CORD BLOOD; INFANTS AB Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these human exposures, we examined mitochondrial integrity at birth and 1 year in brain cortex and liver from offspring of retroviral-free Erythrocebus patas dams-administered human-equivalent NRTI doses for the last half (10 weeks) of gestation. Additional infants, followed for 1 year, were given the same drugs as their mothers for the first 6 weeks of life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. In brain and liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, and IV) showed minimal differences between unexposed and NRTI-exposed offspring at both times. Brain and liver mitochondria from most NRTI-exposed patas, both at birth and 1 year of age, contained significant (p < 0.05) morphological damage observed by electron microscopy (EM), based on scoring of coded photomicrographs. Brain and liver mitochondrial DNA (mtDNA) levels in NRTI-exposed patas were depleted significantly in the 3TC and d4T/3TC groups at birth and were depleted significantly (p < 0.05) at 1 year in all NRTI-exposed groups. In 1-year-old infants exposed in utero to NRTIs, mtDNA depletion was 28.8-51.8% in brain and 37.4-56.5% in liver. These investigations suggest that some NRTI-exposed human infants may sustain similar mitochondrial compromise in brain and liver and should be followed long term for cognitive integrity and liver function. C1 [Divi, Rao L.; Einem, Tracey L.; Fletcher, Sarah L. Leonard; Shockley, Marie E.; Kuo, Maryanne M.; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [St Claire, Marisa C.] NIAID, Div Clin Res, NIH, Frederick, MD 21702 USA. [Cook, Anthony; Harbaugh, Steven W.; Harbaugh, Jeffrey W.] Bioqual Inc, Rockville, MD 20850 USA. [Nagashima, Kunio] Sci Applications Int Corp Frederick, Electron Microscope Lab, Natl Canc Inst Frederick, Adv Technol Program, Ft Detrick, MD 21702 USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bldg 37,Room 4032,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM divir@exchange.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN2612008001E] FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN2612008001E. NR 44 TC 23 Z9 23 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2010 VL 118 IS 1 BP 191 EP 201 DI 10.1093/toxsci/kfq235 PG 11 WC Toxicology SC Toxicology GA 666DN UT WOS:000283092200021 PM 20702595 ER PT J AU Johnson-Lyles, DN Peifley, K Lockett, S Neun, BW Hansen, M Clogston, J Stern, ST McNeil, SE AF Johnson-Lyles, Denise N. Peifley, Kimberly Lockett, Stephen Neun, Barry W. Hansen, Matthew Clogston, Jeffrey Stern, Stephan T. McNeil, Scott E. TI Fullerenol cytotoxicity in kidney cells is associated with cytoskeleton disruption, autophagic vacuole accumulation, and mitochondrial dysfunction SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Fullerenol; Autophagy; Mitochondrial dysfunction ID DOXORUBICIN-INDUCED CARDIOTOXICITY; IN-VITRO; ACTIN CYTOSKELETON; MALIGNANT NEOPLASM; ENDOTHELIAL-CELLS; CARBON NANOTUBES; OXIDATIVE STRESS; CONTRAST AGENT; DEFICIENT MICE; C-60(OH)(24) AB Water soluble fullerenes, such as the hydroxylated fullerene, fullerenol (C(60)OH(x)), are currently under development for diagnostic and therapeutic biomedical applications in the field of nanotechnology. These molecules have been shown to undergo urinary clearance, yet there is limited data available on their renal biocompatibility. Here we examine the biological responses of renal proximal tubule cells (LLC-PK1) exposed to fullerenol. Fullerenol was found to be cytotoxic in the millimolar range, with viability assessed by the sulforhodamine B and trypan blue assays. Fullerenol-induced cell death was associated with cytoskeleton disruption and autophagic vacuole accumulation. Interaction with the autophagy pathway was evaluated in vitro by Lysotracker Red dye uptake. LC3-II marker expression and TEM. Fullerenol treatment also resulted in coincident loss of cellular mitochondrial membrane potential and ATP depletion, as measured by the Mitotracker Red dye and the luciferin-luciferase assays, respectively. Fullerenol-induced ATP depletion and loss of mitochondrial potential were partially ameliorated by co-treatment with the autophagy inhibitor, 3-methyladenine. In vitro fullerenol treatment did not result in appreciable oxidative stress, as measured by lipid peroxide and glutathione content. Based on these data, it is hypothesized that cytoskeleton disruption may be an initiating event in fullerenol cytotoxicity, leading to subsequent autophagy dysfunction and loss of mitochondrial capacity. As nanoparticle-induced cytoskeleton disruption, autophagic vacuole accumulation and mitochondrial dysfunction are commonly reported in the literature, the proposed mechanism may be relevant for a variety of nanomaterials. (C) 2010 Elsevier Inc. All rights reserved. C1 [Johnson-Lyles, Denise N.; Neun, Barry W.; Hansen, Matthew; Clogston, Jeffrey; Stern, Stephan T.; McNeil, Scott E.] SAIC Frederick Inc, NCI, Adv Technol Program, Nanotechnol Characterizat Lab NCL, Frederick, MD 21702 USA. [Peifley, Kimberly; Lockett, Stephen] SAIC Frederick Inc, NCI, Adv Technol Program, Opt Microscopy Anal Lab OMAL, Frederick, MD 21702 USA. RP Stern, ST (reprint author), SAIC Frederick Inc, NCI, Adv Technol Program, Nanotechnol Characterizat Lab NCL, POB B, Frederick, MD 21702 USA. EM sternstephan@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors would like to thank Jamie Rodriguez for assistance with the LC3 immunoblot and Timothy Potter for assistance with cell culture. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. 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 58 TC 77 Z9 78 U1 5 U2 46 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD NOV 1 PY 2010 VL 248 IS 3 BP 249 EP 258 DI 10.1016/j.taap.2010.08.008 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 667OO UT WOS:000283203600011 PM 20713077 ER PT J AU Sharma, AK FitzGerald, D AF Sharma, Ashima K. FitzGerald, David TI Pseudomonas exotoxin kills Drosophila S2 cells via apoptosis SO TOXICON LA English DT Article DE Pseudomonas exotoxin A; Apoptosis; Diphthamide; RNAi; Drice ID ADP-RIBOSYLATING TOXINS; ELONGATION FACTOR-II; DIPHTHERIA-TOXIN; RECOMBINANT IMMUNOTOXIN; VIRULENCE FACTORS; AERUGINOSA; DIPHTHAMIDE; CASPASE; GENE; BIOSYNTHESIS AB Pseudomonas exotoxin A (PE) is cytotoxic for eukaryotic cells because it enters cells by receptor-mediated endocytosis, translocates to the cell cytosol and ADP-ribosylates elongation factor 2 (EF2). However, the interaction of this toxin with eukaryotic cells and the mechanism of PE-mediated cell death have not been extensively characterized. The feasibility of carrying out a genome-wide RNAi screen, makes Drosophila melanogaster S2 cells as a good model system to identify essential genes in PE-mediated cytotoxicity, provided a suitable multi-well assay is developed. Here, using the alamarBlue (R) viability assay, we show that Drosophila S2 cells are sensitive to PE at picomolar concentrations and that toxin treatments provoke an increase in caspase activity. This prompted us to use RNAi to characterize the mechanism of cell death. Results indicated that PE-mediated death of S2 cells was dependent on the presence of diphthamide, the post translational modification of EF2, and on the presence of Drice, the terminal caspase of insect cells. RNAi to drice or chemical inhibition of caspase action by z-VAD-fmk protected cells from PE-mediated death. Protection from death by RNAi or z-VAD-fmk did not interfere with toxin delivery to the cytosol leading to inhibition of protein synthesis. Using a convenient alamarBlue (R) assay, our data confirms the cytotoxicity of PE for S2 cells and establishes apoptosis as the mode of PE-mediated death. This confirms the suitability of Drosophila cells as a convenient and simple model to elucidate the role of specific genes and proteins required for PE action. Published by Elsevier Ltd. C1 [Sharma, Ashima K.; FitzGerald, David] NCI, Biotherapy Sect, Mol Biol Lab, Ctr Canc Res,NIH,HHS, Bethesda, MD 20892 USA. RP FitzGerald, D (reprint author), NCI, Biotherapy Sect, Mol Biol Lab, Ctr Canc Res,NIH,HHS, 37 Convent Dr,Room 5124, Bethesda, MD 20892 USA. EM djpf@helix.nih.gov FU Intramural NIH HHS [Z01 BC008757-20] NR 39 TC 4 Z9 4 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD NOV PY 2010 VL 56 IS 6 BP 1025 EP 1034 DI 10.1016/j.toxicon.2010.07.007 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 655MK UT WOS:000282253900019 PM 20659495 ER PT J AU Rajagopalan, S AF Rajagopalan, Sumati TI Endosomal Signaling and a Novel Pathway Defined by the Natural Killer Receptor KIR2DL4 (CD158d) SO TRAFFIC LA English DT Review DE Akt; DNA-PKcs; endosomes; HLA-G; KIR2DL4; natural killer cell; pregnancy; signaling ID HUMAN NK CELLS; IFN-GAMMA PRODUCTION; HLA-G MOLECULE; INHIBITORY RECEPTORS; CUTTING EDGE; PROTEIN; ENDOCYTOSIS; TRANSDUCTION; PREGNANCY; TRAFFICKING AB In addition to ligand-induced activation of receptors at the cell surface, certain internalized receptor-ligand complexes are activated in endosomes which are, now recognized as important intracellular platforms of signal transduction. The major receptor families that signal from endosomes and illustrate the diversity and complexity of endosomal signaling include receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs) and toll-like receptors (TLRs). Natural killer (NK) cells, an important component of the innate immune system, not only provide a rapid defense against foreign invaders, such as bacteria and viruses, but also positively shape local responses by cytokine and chemokine secretion. The NK cell receptor KIR2DL4 (CD158d) utilizes a new mode of endosomal signaling after binding its ligand, soluble HLA-G, in the extracellular milieu. Internalization of the receptor and its ligand into endosomes and initiation of signaling at this site result in a proinflammatory and proangiogenic response with important functions at sites of ligand expression, such as at the maternal-fetal interface during early pregnancy. After a brief overview of the modes of endosomal signaling and its value in generating distinct physiological responses, this review will highlight the mechanism and physiological significance of a novel intracellular signaling pathway used by the endosome-resident immune receptor KIR2DL4. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Rajagopalan, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM sumi@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health FX The review was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health. I thank Eric Long for support and useful comments on the manuscript. NR 64 TC 25 Z9 31 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 EI 1600-0854 J9 TRAFFIC JI Traffic PD NOV PY 2010 VL 11 IS 11 BP 1381 EP 1390 DI 10.1111/j.1600-0854.2010.01112.x PG 10 WC Cell Biology SC Cell Biology GA 659MV UT WOS:000282571500001 PM 20854369 ER PT J AU Cho, ME Duan, Z Chamberlain, CE Reynolds, JC Ring, MS Mannon, RB AF Cho, M. E. Duan, Z. Chamberlain, C. E. Reynolds, J. C. Ring, M. S. Mannon, R. B. TI Cinacalcet Improves Bone Density in Post-Kidney Transplant Hyperparathyroidism SO TRANSPLANTATION PROCEEDINGS LA English DT Article ID SECONDARY HYPERPARATHYROIDISM; PERSISTENT HYPERPARATHYROIDISM; MINERAL DENSITY; HYPERCALCEMIA AB The recent availability of cinacalcet has provided a possible alternative to parathyroidectomy in kidney transplant patients with persistent hyperparathyroidism, but its effect on bone mass density (BMD) is unknown. From our database containing 163 kidney transplants performed at our center from 1999 to 2007, we compared recipients who received cinacalcet for persistent hypercalcemia and hyperparathyroidism following renal transplantation (n = 8) with up to two other posttransplant patients matched for age, sex, race, and graft function (n = 15). The outcome of the study was BMD changes from baseline to 12, 24, and 36 months post renal transplantation. Repeated-measures mixed model was used to assess the difference of BMD change between two groups. Cinacalcet therapy was started at a median of 9 (range = 1 to 24) months posttransplant with a mean dose 56 +/- 29 mg/d (mean duration = 1.6; range = 1 to 2.1 years). Cinacalcet therapy was associated with significant reduction of serum calcium compared to control. Cinacalcet therapy was associated with greater BMD increase at the hip over the 36-month posttransplant period. Cinacalcet was well tolerated. Our results suggest that cinacalcet may have a small but favorable effect on bone density following kidney transplantation. C1 [Cho, M. E.] NIDDK, NIH, Kidney Dis Branch, Bethesda, MD 20892 USA. [Duan, Z.] NIDDK, Off Director, Bethesda, MD 20892 USA. [Chamberlain, C. E.] NIH, Clin Ctr Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Mannon, R. B.] Univ Alabama, Dept Med, Div Nephrol, Birmingham, AL 35294 USA. RP Cho, ME (reprint author), NIDDK, NIH, Kidney Dis Branch, 9000 Rockville Pike,10 CRC 5-5750, Bethesda, MD 20892 USA. EM moniquec@intra.niddk.nih.gov FU NIDDK, NIH FX This analysis was supported by the Intramural Research Program of the NIDDK, NIH. NR 9 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 0041-1345 J9 TRANSPL P JI Transplant. Proc. PD NOV PY 2010 VL 42 IS 9 BP 3554 EP 3558 DI 10.1016/j.transproceed.2010.06.027 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 689ZO UT WOS:000284969800037 PM 21094814 ER PT J AU Ranganathan, S Fischbeck, KH AF Ranganathan, Srikanth Fischbeck, Kenneth H. TI Therapeutic approaches to spinal and bulbar muscular atrophy SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID MOTOR-NEURON DEGENERATION; EXPANDED ANDROGEN RECEPTOR; MOLECULAR-TARGETED THERAPY; TRANSGENIC MOUSE MODEL; KENNEDY-DISEASE; NEURODEGENERATIVE DISORDERS; POLYGLUTAMINE DISEASE; AXONAL-TRANSPORT; PROTEIN; SYSTEM AB Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism probably involves a toxic gain of function in the mutant protein, because other mutations that cause a loss of androgen receptor function result in a different phenotype and the mutant protein is toxic in mouse models. In these models, the toxicity is ligand-dependent and is associated with protein aggregation, as well as altered transcriptional regulation, axonal transport and mitochondria! function. Various therapeutic approaches have shown efficacy in mouse models, including androgen reduction, heat shock protein 90 (HSP90) inhibition and insulin-like growth factor (IGF)-1 overexpression. Clinical trials of androgen-reducing agents have had mixed results, with indications of efficacy but no proof of clinically meaningful benefit to date. These clinical studies have established outcome measures for future trials of other agents that have been beneficial in animal studies. C1 [Fischbeck, Kenneth H.] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Ranganathan, Srikanth] Lund Univ, Wallenberg Neurosci Ctr, Neuronal Survival Unit, S-22184 Lund, Sweden. RP Fischbeck, KH (reprint author), Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM kf@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003038-03, ZIA NS003037-03] NR 41 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD NOV PY 2010 VL 31 IS 11 BP 523 EP 527 DI 10.1016/j.tips.2010.08.005 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 683UE UT WOS:000284499900004 PM 20863580 ER PT J AU Basch, E Reeve, B Cleeland, C Sloan, J Schrag, D Atkinson, TM Mendoza, T Hay, J Abernethy, A Minasian, L Kwitkowski, V Trentacosti, AM Burke, L Sit, L Bruner, D AF Basch, E. Reeve, B. Cleeland, C. Sloan, J. Schrag, D. Atkinson, T. M. Mendoza, T. Hay, J. Abernethy, A. Minasian, L. Kwitkowski, V Trentacosti, A. M. Burke, L. Sit, L. Bruner, D. TI DEVELOPMENT OF THE PATIENT-REPORTED VERSION OF THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (PRO-CTCAE) SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Basch, E.; Atkinson, T. M.; Hay, J.; Sit, L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Reeve, B.] NCI, Bethesda, MD 20892 USA. [Cleeland, C.; Mendoza, T.] UTMD Anderson Canc Ctr, Houston, TX USA. [Sloan, J.] Mayo Clin, Rochester, MN USA. [Schrag, D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Abernethy, A.] Duke Univ, Durham, NC USA. [Minasian, L.] NCI, Rockville, MD USA. [Burke, L.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Bruner, D.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD NOV PY 2010 VL 13 IS 7 BP A274 EP A275 PG 2 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 662ON UT WOS:000282818001176 ER PT J AU Maringwa, J Quinten, C King, M Ringash, J Osoba, D Coens, C Martinelli, F Cleeland, C Flechtner, H Gotay, C Greimel, E Taphoorn, M Reeve, B Schmucker-Von Koch, J Weis, J Van den Bent, MJ Stupp, R Bottomley, A AF Maringwa, J. Quinten, C. King, M. Ringash, J. Osoba, D. Coens, C. Martinelli, F. Cleeland, C. Flechtner, H. Gotay, C. Greimel, E. Taphoorn, M. Reeve, B. Schmucker-Von Koch, J. Weis, J. Van den Bent, M. J. Stupp, R. Bottomley, A. TI MINIMAL CLINICALLY MEANINGFUL DIFFERENCES FOR THE EORTC QLQ-C30 AND EORTC QLQ-BN20 SCALES IN BRAIN CANCER PATIENTS SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Maringwa, J.; Quinten, C.; Coens, C.; Martinelli, F.; Bottomley, A.] European Org Res Treatment Canc, Brussels, Belgium. [King, M.] Univ Sydney, Sydney, NSW 2006, Australia. [Ringash, J.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Osoba, D.] Qual Life Consulting, W Vancouver, BC, Canada. [Cleeland, C.] UTMD Anderson Canc Ctr, Houston, TX USA. [Flechtner, H.] Univ Magdeburg, D-39106 Magdeburg, Germany. [Gotay, C.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Greimel, E.] Med Univ Graz, Graz, Austria. [Taphoorn, M.] Med Ctr Haaglanden Westeinde, The Hague, Netherlands. [Reeve, B.] NCI, Bethesda, MD 20892 USA. [Schmucker-Von Koch, J.] Univ Regensburg, Regensburg, Germany. [Weis, J.] Univ Freiburg, Freiburg, Germany. [Van den Bent, M. J.] AZ Rotterdam Daniel Den Hoed Klin, Rotterdam, Netherlands. [Stupp, R.] Univ Hosp CHUV, Lausanne, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD NOV PY 2010 VL 13 IS 7 BP A275 EP A276 PG 2 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 662ON UT WOS:000282818001181 ER PT J AU Cooper, TK Zhong, Q Krawczyk, M Tae, HJ Muller, GA Schubert, R Myers, LA Dietz, HC Talan, MI Briest, W AF Cooper, T. K. Zhong, Q. Krawczyk, M. Tae, H-J. Mueller, G. A. Schubert, R. Myers, L. A. Dietz, H. C. Talan, M. I. Briest, W. TI The Haploinsufficient Col3a1 Mouse as a Model for Vascular Ehlers-Danlos Syndrome SO VETERINARY PATHOLOGY LA English DT Article DE Col3a1; mouse model; vascular Ehlers-Danlos; haploinsufficient ID SYNDROME TYPE-IV; AORTIC-ANEURYSM; GENETIC FEATURES; MARFAN-SYNDROME; III COLLAGEN; MICE; PATHOGENESIS; WALL; THROMBOSIS; MUTATIONS AB Vascular Ehlers-Danlos syndrome is a rare genetic disorder resulting from mutations in the alpha-1 chain of type III collagen (COL3A1) and manifesting as tissue fragility with spontaneous rupture of the bowel, gravid uterus, or large or medium arteries. The heterozygous Col3a1 knockout mouse was investigated as a model for this disease. The collagen content in the abdominal aorta of heterozygotes was reduced, and functional testing revealed diminishing wall strength of the aorta in these mice. Colons were grossly and histologically normal, but reduced strength and increased compliance of the wall were found in heterozygotes via pressure testing. Although mice demonstrated no life-threatening clinical signs or gross lesions of vascular subtype Ehlers-Danlos syndrome type IV, thorough histological examination of the aorta of heterozygous mice revealed the presence of a spectrum of lesions similar to those observed in human patients. Lesions increased in number and severity with age (0/5 [0%] in 2-month-old males vs 9/9 [100%] in 14-month-old males, P < .05) and were more common in male than female mice (23/26 [88.5%] vs 14/30 [46.7%] in 9- to 21-month-old animals, P < .05). Haploinsufficiency for Col3al in mice recapitulates features of vascular Ehlers-Danlos syndrome in humans and can be used as an experimental model. C1 [Cooper, T. K.; Zhong, Q.] Penn State Coll Med, Dept Comparat Med, Milton S Hershey Med Ctr, Hershey, PA USA. [Krawczyk, M.; Tae, H-J.; Mueller, G. A.; Talan, M. I.; Briest, W.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Schubert, R.] Univ Heidelberg, Med Fac Mannheim, D-6900 Heidelberg, Germany. [Myers, L. A.; Dietz, H. C.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. RP Cooper, TK (reprint author), Penn State Hershey Med Ctr, Dept Comparat Med, H054,500 Univ Dr, Hershey, PA 17033 USA. EM tcooper@hmc.psu.edu OI Muller, Gerd A./0000-0002-4967-2487; Briest, Wilfried/0000-0003-4556-4849 FU National Institutes of Health National Institute on Aging; Howard Hughes Medical Institute; William S. Smilow Center for Marfan Syndrome Research (JHU); National Institutes of Health [R01AR41135] FX Work was funded in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging, the Howard Hughes Medical Institute, the William S. Smilow Center for Marfan Syndrome Research (JHU), and the National Institutes of Health grant R01AR41135. NR 40 TC 15 Z9 15 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD NOV PY 2010 VL 47 IS 6 BP 1028 EP 1039 DI 10.1177/0300985810374842 PG 12 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 689WP UT WOS:000284961900004 PM 20587693 ER PT J AU Lionakis, MS Kontoyiannis, DP AF Lionakis, Michail S. Kontoyiannis, Dimitrios P. TI The growing promise of Toll-deficient Drosophila melanogaster as a model for studying Aspergillus pathogenesis and treatment SO VIRULENCE LA English DT Article DE Drosophila; Aspergillus; mini-host model; virulence; antifungal efficacy ID INVASIVE PULMONARY ASPERGILLOSIS; ANTIMICROBIAL PEPTIDE GENES; ANTIFUNGAL DRUG EFFICACY; INNATE IMMUNE-RESPONSE; CRYPTOCOCCUS-NEOFORMANS; AMPHOTERICIN-B; QUANTITATIVE PCR; FUMIGATUS BURDEN; MURINE MODEL; VIRULENCE AB Despite considerable progress over recent years, the prognosis of invasive aspergillosis (IA) remains unfavorable, reflecting an incomplete understanding of Aspergillus pathogenesis and suboptimal antifungal efficacy in vivo. Mammalian host systems including rodents and rabbits are important tools in elucidating antifungal drug activity and the immunopathogenesis of IA. Nonetheless, they are hampered by limitations that impose a "bottleneck" in mass screening of novel antifungal compounds and putative Aspergillus virulence factors including their cost, labor intensity and ethical constraints. Drosophila melanogaster is an invertebrate host with a long track record of genetic studies and a simple yet highly conserved innate immune system. Herein, we describe our experience using this fly model as a facile, non-laborious, inexpensive pathosystem for high-throughput screening of novel antifungal compounds and putative Aspergillus mutants, and studying antifungal innate immunity. We present three infection protocols (i.e., injection, rolling, ingestion) that introduce Aspergillus either directly into the hemolymph or at different epithelial surfaces of Toll-deficient Drosophila flies. As a proof of principle, we demonstrate attenuated virulence of known hypovirulent Aspergillus strains and protection of Aspergillus-infected flies given oral Aspergillus-active agents such as voriconazole. These protocols can be adapted for similar studies of other fungal pathogens. Crossing and generation of Toll-deficient Drosophila flies takes three weeks; Aspergillus conidial preparation takes three days; fly inoculation depending on the infection assay takes one to 6-8 hours; and assessment of fly survival, Aspergillus strain virulence, Drosophila innate host parameters and/or drug activity takes 4-8 days. C1 [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Houston, TX 77030 USA. [Lionakis, Michail S.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kontoyiannis, DP (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Houston, TX 77030 USA. EM dkontoyi@mdanderson.org FU National Institutes of Health through MD Anderson's Cancer Center [CA016672] FX We thank Dr. Tony Ip for providing us with the wild-type and Toll-deficient Drosophila melanogaster and Dr. Georg Halder for helping us introduce this model into the Kontoyiannis laboratory. We also thank Drs. Russell Lewis, Georgios Chamilos, Ronen Ben-Ami, Greg Lamaris and Nathaniel Albert for their outstanding contributions in establishing Drosophila models of infection by several fungal pathogens in addition to Aspergillus species and for substantially expanding the applicability of this fly model. This research is supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672. NR 45 TC 15 Z9 15 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2150-5594 EI 2150-5608 J9 VIRULENCE JI Virulence PD NOV-DEC PY 2010 VL 1 IS 6 BP 488 EP 499 DI 10.4161/viru.1.6.13311 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 789NI UT WOS:000292521800004 PM 21178494 ER PT J AU Oguariri, RM Adelsberger, JW Baseler, MW Imamichi, T AF Oguariri, Raphael M. Adelsberger, Joseph W. Baseler, Michael W. Imamichi, Tomozumi TI Evaluation of the effect of pyrimethamine, an anti-malarial drug, on HIV-1 replication SO VIRUS RESEARCH LA English DT Article DE Pyrimethamine; DHFR; Anti-malaria; S-phase; HIV-1 replication; Nucleoside analog ID HUMAN-IMMUNODEFICIENCY-VIRUS; ERYTHROCYTE-MEMBRANE PROTEIN-1; HIGH-LEVEL RESISTANCE; REVERSE-TRANSCRIPTASE; CONGENITAL TOXOPLASMOSIS; CEREBRAL TOXOPLASMOSIS; LEUKEMIA-CELLS; ALPHA-DOMAINS; MALARIA; INFECTION AB Co-infection of human immunodeficiency virus (HIV) with malaria is one of the pandemic problems in Africa and parts of Asia. Here we investigated the impact of pyrimethamine (PYR) and two other clinical anti-malarial drugs (chloroquine [CO] or artemisinin [ART]) on HIV-1 replication. Peripheral blood mononuclear cells (PBMCs) or MT-2 cells were infected with HIV(NL4.3) strain and treated with different concentrations of the anti-malarial drugs. HIV-1 replication was measured using p24 ELISA. We show that 10 mu M CQ and ART inhibited HIV-1 replication by 76% and 60% in PBMCs, respectively, but not in MT-2 cells. In contrast, 10 mu M PYR enhanced HIV-1 replication in MT-2 cells by >10-fold. A series of molecular mechanism studies revealed that PYR increased intracellular HIV gag proteins without affecting the promoter or the reverse transcriptase activity. The effect of PYR was independent of HTLV-1 produced by MT-2 cells. Of interest, PYR treatment led to S-phase accumulation and increased AZT and d4T antiviral activity by similar to 4-fold. Taken together, we show that PYR significantly enhances HIV-1 replication by affecting the cellular machinery. Our results could be relevant for the management of malaria and HIV particularly in regions where HIV-1 and malaria epidemics overlap. (C) 2010 Elsevier B.V. All rights reserved. C1 [Oguariri, Raphael M.; Imamichi, Tomozumi] NCI, Lab Human Retrovirol, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Adelsberger, Joseph W.; Baseler, Michael W.] NCI, AIDS Monitoring Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Oguariri, Raphael M.; Adelsberger, Joseph W.; Baseler, Michael W.; Imamichi, Tomozumi] NCI, Clin Serv Program, Appl & Dev Directorate, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Oguariri, RM (reprint author), NCI, Lab Human Retrovirol, Sci Applicat Int Corp Frederick Inc, Bldg 550,Room 204, Frederick, MD 21702 USA. EM oguaririr@mail.nih.gov FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the National Institute of Allergy and Infectious Diseases. NR 52 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD NOV PY 2010 VL 153 IS 2 BP 269 EP 276 DI 10.1016/j.virusres.2010.08.018 PG 8 WC Virology SC Virology GA 672RR UT WOS:000283605100012 PM 20800626 ER PT J AU Kim, PS Read, SW AF Kim, Peter S. Read, Sarah W. TI Nanotechnology and HIV: potential applications for treatment and prevention SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID VAGINAL SHIV TRANSMISSION; PLACEBO-CONTROLLED TRIAL; ANTIRETROVIRAL THERAPY; NASAL IMMUNIZATION; DRUG-DELIVERY; DOUBLE-BLIND; SPL7013 GEL; VIRAL LOAD; IN-VITRO; VACCINE AB HIV/AIDS is a global pandemic and is the leading infectious cause of death among adults. Although antiretroviral (ARV) therapy has dramatically improved the quality of life and increased the life expectancy of those infected with HIV, life-long suppressive treatment is required and a cure for HIV infection remains elusive; frequency of dosing and drug toxicity as well as the development of viral resistance pose additional limitations. Furthermore, preventative measures such as a vaccine or microbicide are urgently needed to curb the rate of new infections. The capabilities inherent to nanotechnology hold much potential for impact in the field of HIV treatment and prevention. This article reviews the potential for the multidisciplinary field of nanotechnology to advance the fields of HIV treatment and prevention. (C) 2010 John Wiley & Sons, Inc. WIREs Nanomed Nanobiotechnol 2010 2 693-702 C1 [Kim, Peter S.; Read, Sarah W.] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. RP Read, SW (reprint author), NIAID, Div AIDS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM readsa@niaid.nih.gov NR 72 TC 19 Z9 19 U1 1 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5116 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD NOV-DEC PY 2010 VL 2 IS 6 BP 693 EP 702 DI 10.1002/wnan.118 PG 10 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 669YU UT WOS:000283387000009 PM 20860050 ER PT J AU Larsen, M Yamada, KM Musselmann, K AF Larsen, Melinda Yamada, Kenneth M. Musselmann, Kurt TI Systems analysis of salivary gland development and disease SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Review ID MOUSE SUBMANDIBULAR-GLAND; REGULATES BRANCHING MORPHOGENESIS; PRIMARY SJOGRENS-SYNDROME; EPITHELIAL MORPHOGENESIS; SIGNALING PLAYS; GENE-EXPRESSION; CELL; EGF; MODEL; ECTODYSPLASIN AB Branching morphogenesis is a crucial developmental process in which vertebrate organs generate extensive epithelial surface area while retaining a compact size. In the vertebrate submandibular salivary gland, branching morphogenesis is crucial for the generation of the large surface area necessary to produce sufficient saliva. However, in many salivary gland diseases, saliva-producing acinar cells are destroyed, resulting in dry mouth and secondary health conditions. Systems-based approaches can provide insights into understanding salivary gland development, function, and disease. The traditional approach to understanding these processes is the identification of molecular signals using reductionist approaches; we review current progress with such methods in understanding salivary gland development. Taking a more global approach, multiple groups are currently profiling the transcriptome, the proteome, and other 'omes' in both developing mouse tissues and in human patient samples. Computational methods have been successful in deciphering large data sets, and mathematical models are starting to make predictions regarding the contribution of molecules to the physical processes of morphogenesis and cellular function. A challenge for the future will be to establish comprehensive, publicly accessible salivary gland databases spanning the full range of genes and proteins; plans are underway to provide these resources to researchers in centralized repositories. The greatest challenge for the future will be to develop realistic models that integrate multiple types of data to both describe and predict embryonic development and disease pathogenesis. (C) 2010 John Wiley & Sons, Inc. WIREs Syst Biol Med 2010 2 670-682 C1 [Larsen, Melinda] SUNY Albany, Albany, NY 12222 USA. [Yamada, Kenneth M.; Musselmann, Kurt] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Larsen, M (reprint author), SUNY Albany, Albany, NY 12222 USA. EM mlarsen@albany.edu; kyamada@mail.nih.gov; Musselmannk@mail.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805; Larsen, Melinda/0000-0002-5026-2012 FU NIH/NIDCR [DE019244401, DE019197, RC1DE020402]; NIDCR FX The authors thank Dr. Michael Gerdes for useful discussions and critical reading of the manuscript. This work was sponsored in part by the NIH/NIDCR by grants DE019244401, DE019197 and RC1DE020402 (to M.L.) and NIDCR Intramural support (to K.M.Y.). NR 74 TC 16 Z9 17 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5094 J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD NOV-DEC PY 2010 VL 2 IS 6 BP 670 EP 682 DI 10.1002/wsbm.94 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 674DI UT WOS:000283713500004 PM 20890964 ER PT J AU Moses, W Weng, JL Sansano, I Peng, MA Khanafshar, E Ljung, BM Duh, QY Clark, OH Kebebew, E AF Moses, Willieford Weng, Julie Sansano, Ileana Peng, Miao Khanafshar, Elham Ljung, Britt-Marie Duh, Quan-Yang Clark, Orlo H. Kebebew, Electron TI Molecular Testing for Somatic Mutations Improves the Accuracy of Thyroid Fine-needle Aspiration Biopsy SO WORLD JOURNAL OF SURGERY LA English DT Article ID BRAF MUTATION; CYTOLOGY; NODULES; CARCINOMA; DIAGNOSIS; RET/PTC AB Thyroid fine-needle aspiration (FNA) biopsy is indeterminate or suspicious in up to 30% of cases and these patients are commonly subjected to at least a diagnostic hemithyroidectomy. If malignant on histology, a completion thyroidectomy is usually performed, which may be associated with higher morbidity. To determine the clinical utility of genetic testing in thyroid FNA biopsy, we conducted a prospective clinical trial. Four hundred seventeen patients with 455 thyroid nodules were enrolled and had genetic testing for common somatic mutations (BRAF, NRAS, KRAS) and gene rearrangements (RET/PTC1, RET/PTC3, RAS, TRK1) by PCR and direct sequencing and by nested PCR, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of genetic testing in thyroid FNA biopsy were determined based on the histologic diagnosis. One hundred twenty-five of 455 thyroid nodule FNA biopsies were indeterminate or suspicious on cytologic examination. Overall, 50 mutations were identified (23 BRAF, 4 RET/PTC1, 2 RET/PTC3, 21 NRAS) in the thyroid FNA biopsies. There were significantly more mutations detected in malignant thyroid nodules than in benign (P = 0.0001). For thyroid FNA biopsies that were indeterminate or suspicious, genetic testing had a sensitivity of 12%, specificity of 98%, PPV of 38%, and NPV of 65%. Genetic testing for somatic mutations in thyroid FNA biopsy samples is feasible and identifies a subset of malignant thyroid neoplasms that are indeterminate or suspicious on FNA biopsy. Genetic testing for common somatic genetic alterations thus could allow for more definitive initial thyroidectomy in those with positive results. C1 [Kebebew, Electron] NCI, Surg Branch, Bethesda, MD 20892 USA. [Moses, Willieford; Weng, Julie; Sansano, Ileana; Peng, Miao; Duh, Quan-Yang; Clark, Orlo H.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Khanafshar, Elham; Ljung, Britt-Marie] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. RP Kebebew, E (reprint author), NCI, Surg Branch, CRC Room 4-5952,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov NR 17 TC 87 Z9 89 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD NOV PY 2010 VL 34 IS 11 BP 2589 EP 2594 DI 10.1007/s00268-010-0720-0 PG 6 WC Surgery SC Surgery GA 658RG UT WOS:000282506500014 PM 20703476 ER PT J AU Sato, T Yamamoto, M Shimosato, T Klinman, DM AF Sato, Takashi Yamamoto, Masaki Shimosato, Takeshi Klinman, Dennis M. TI Accelerated wound healing mediated by activation of Toll-like receptor 9 SO WOUND REPAIR AND REGENERATION LA English DT Article ID ADENOSINE A(2A) RECEPTORS; ENDOTHELIAL GROWTH-FACTOR; BACTERIAL-DNA; CPG MOTIFS; ANGIOGENESIS; CELLS; INFLAMMATION; OLIGODEOXYNUCLEOTIDES; MACROPHAGES; CANCER AB Wound healing is mediated through complex interactions between circulating immune cells and local epithelial and endothelial cells. Elements of the innate immune system are triggered when Toll-like receptors (TLR) are stimulated by their cognate ligands, and previous studies suggest that such interactions can accelerate wound healing. This work examines the effect of treating excisional skin biopsies with immunostimulatory CpG oligodeoxynucleotides (ODN) that trigger via TLR9. Results indicate that CpG (but not control) ODN accelerate wound closure and reduce the total wound area exposed over time by > 40% (p < 0.01). TLR9 knockout mice, a strain unresponsive to the immunomodulatory effects of CpG stimulation, are unresponsive to ODN treatment and exhibit a general delay in healing when compared with wild-type mice. CpG ODN administration promoted the influx of macrophages to the wound site and increased the production of vascular endothelial growth factor, expediting neovascularization of the wound bed (p < 0.01 for both parameters). Stimulation via TLR9 thus represents a novel strategy to accelerate wound healing. C1 [Sato, Takashi; Yamamoto, Masaki; Shimosato, Takeshi; Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, Bldg 567 Rm 205 NCI Frederick, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Ministry of Education, Culture, Sports, Science and Technology of Japan [21790778]; Kanagawa Nanbyo Foundation FX This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (21790778) and from the Kanagawa Nanbyo Foundation. NR 34 TC 29 Z9 30 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD NOV-DEC PY 2010 VL 18 IS 6 BP 586 EP 593 DI 10.1111/j.1524-475X.2010.00632.x PG 8 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 677KJ UT WOS:000283991000097 PM 20946144 ER PT J AU Chen, M Chang, JS Nason, M Rangel, D Gall, JG Graham, BS Ledgerwood, JE AF Chen, M. Chang, J. S. Nason, M. Rangel, D. Gall, J. G. Graham, B. S. Ledgerwood, J. E. TI A flow cytometry-based assay to assess RSV-specific neutralizing antibody is reproducible, efficient and accurate SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE RSV; Neutralizing antibody; Reporter virus ID RESPIRATORY SYNCYTIAL VIRUS; HEALTHY-ADULTS; CLINICAL-TRIAL; INFECTION; CELLS AB Respiratory syncytial virus (RSV) is an important cause of respiratory infection in people of all ages, and is the leading cause of hospitalization in infants. Although commercially available monoclonal antibody is available for passive prophylaxis of neonates at risk of severe disease, there is no available vaccine to prevent RSV. Measurement of neutralizing activity will be a key endpoint for vaccine evaluation. Assessment of neutralizing antibody against RSV has been limited to traditional plaque reduction, which is time-consuming and inherently operator dependent and highly variable. Here, we describe a flow cytometry-based RSV-specific neutralization assay which is more rapid than traditional methods, highly sensitive and highly reproducible. Published by Elsevier B.V. C1 [Chen, M.; Graham, B. S.; Ledgerwood, J. E.] NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chang, J. S.] Kaohsiung Med Univ, Dept Renal Care, Coll Med, Kaohsiung 807, Taiwan. [Nason, M.] NIAID, Biostat Res Branch, Div Clin Res, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rangel, D.; Gall, J. G.] GenVec Inc, Gaithersburg, MD 20878 USA. RP Ledgerwood, JE (reprint author), NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH,US Dept Hlth & Human Serv, 40 Convent Dr, Bethesda, MD 20892 USA. EM Ledgerwood@mail.nih.gov NR 13 TC 19 Z9 20 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD OCT 31 PY 2010 VL 362 IS 1-2 BP 180 EP 184 DI 10.1016/j.jim.2010.08.005 PG 5 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 687BP UT WOS:000284749100023 PM 20727896 ER PT J AU Germain, RN AF Germain, Ronald N. TI Vaccines and the Future of Human Immunology SO IMMUNITY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; SPECTROMETRY-BASED PROTEOMICS; CYTOPLASMIC FREE CALCIUM; YELLOW-FEVER VACCINE; MEMORY B-CELLS; T-CELLS; MASS-SPECTROMETRY; PRIMARY IMMUNODEFICIENCIES; INFECTIOUS-DISEASES; MOLECULAR-CLONING AB In this issue of Immunity, a collection of detailed reviews summarizes needs, opportunities, and roadblocks to the development of new vaccines, all in the context of our current knowledge and understanding of key aspects of immune function and microbial interactions with the host This Perspective is designed to provide a broad overview that discusses our present limitations in designing effective novel vaccines for diseases that do not typically induce robust resistance in infected individuals and how the addition of a systems-level, multiplexed approach to the analysis of the human immune system can complement traditional highly focused research efforts to accelerate our progress toward this goal and the improvement of human health C1 [Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. [Germain, Ronald N.] NIAID, Program Syst Immunol & Infect Dis Modeling, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Germain, Ronald N.] NIH, Trans NIH Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIAID NIH FX I would like to especially thank my colleagues in the CHI for their efforts to develop a new way to gain understanding of the human immune system in health and disease and for their comments on a draft article that was used in part to prepare this Perspective I also would like to thank A Hayday B Pulendran M Davis C Benoist J Banchereau D Chaussabel and others for discussions that have helped formulate the ideas expressed here about a new beginning in the systematic analysis of human immunity This work was supported by the Intramural Research Program of NIAID NIH NR 89 TC 42 Z9 44 U1 0 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 OCT 29 PY 2010 VL 33 IS 4 BP 441 EP 450 DI 10.1016/j.immuni.2010.09.014 PG 10 WC Immunology SC Immunology GA 681GU UT WOS:000284300200002 PM 21029956 ER PT J AU Coffman, RL Sher, A Seder, RA AF Coffman, Robert L. Sher, Alan Seder, Robert A. TI Vaccine Adjuvants: Putting Innate Immunity to Work SO IMMUNITY LA English DT Review ID TOLL-LIKE RECEPTORS; T-CELL RESPONSES; PATTERN-RECOGNITION RECEPTORS; MONOPHOSPHORYL-LIPID-A; HEPATITIS-B-VACCINE; DOUBLE-STRANDED-RNA; DENDRITIC CELLS; ADAPTIVE IMMUNITY; IMMUNOSTIMULATORY DNA; ISCOMATRIX ADJUVANT AB Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens C1 [Coffman, Robert L.] Dynavax Technol Corp, Berkeley, CA 94710 USA. [Sher, Alan] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Seder, Robert A.] NIAID, Cellular Immunol Sect, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Coffman, RL (reprint author), Dynavax Technol Corp, Berkeley, CA 94710 USA. FU Intramural NIH HHS [ZIA AI001044-04] NR 111 TC 477 Z9 489 U1 22 U2 147 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 29 PY 2010 VL 33 IS 4 BP 492 EP 503 DI 10.1016/j.immuni.2010.10.002 PG 12 WC Immunology SC Immunology GA 681GU UT WOS:000284300200006 PM 21029960 ER PT J AU Ponugoti, B Kim, DH Xiao, Z Smith, Z Miao, J Zang, MW Wu, SY Chiang, CM Veenstra, TD Kemper, JK AF Ponugoti, Bhaskar Kim, Dong-Hyun Xiao, Zhen Smith, Zachary Miao, Ji Zang, Mengwei Wu, Shwu-Yuan Chiang, Cheng-Ming Veenstra, Timothy D. Kemper, Jongsook Kim TI SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ELEMENT-BINDING PROTEIN-1C; GAMMA COACTIVATOR 1-ALPHA; TRANSCRIPTIONAL COACTIVATOR; INSULIN REGULATION; ACID-METABOLISM; GENE ACTIVATION; PGC-1-ALPHA; PHOSPHORYLATION; ACETYLATION; DEGRADATION AB The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased lipogenic gene expression. Tandem mass spectrometry and mutagenesis studies revealed that SREBP-1c is acetylated by p300 at Lys-289 and Lys-309. Mechanistic studies using acetylation-defective mutants showed that SIRT1 deacetylates and inhibits SREBP-1c transactivation by decreasing its stability and its occupancy at the lipogenic genes. Remarkably, SREBP-1c acetylation levels were elevated in diet-induced obese mice, and hepatic overexpression of SIRT1 or treatment with resveratrol, a SIRT1 activator, daily for 1 week decreased acetylated SREBP-1c levels with beneficial functional outcomes. These results demonstrate an intriguing connection between elevated SREBP-1c acetylation and increased lipogenic gene expression, suggesting that abnormally elevated SREBP-1c acetylation increases SREBP-1c lipogenic activity in obese mice. Reducing acetylation of SREBP-1c by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes. C1 [Ponugoti, Bhaskar; Kim, Dong-Hyun; Smith, Zachary; Miao, Ji; Kemper, Jongsook Kim] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Xiao, Zhen; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc,NIH, Frederick, MD 21702 USA. [Zang, Mengwei] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Wu, Shwu-Yuan; Chiang, Cheng-Ming] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Biochem, Dallas, TX 75390 USA. [Wu, Shwu-Yuan; Chiang, Cheng-Ming] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Pharmacol, Dallas, TX 75390 USA. RP Kemper, JK (reprint author), 407 S Goodwin Ave, Urbana, IL 61801 USA. EM jongsook@uiuc.edu RI Sanguansri, Luz/B-6630-2011; PONUGOTI, BHASKAR/H-2230-2011; Miao, Ji /F-9398-2015; OI Sanguansri, Luz/0000-0003-1908-7604; Miao, Ji /0000-0003-0869-4492; Zang, Mengwei/0000-0002-2502-2586 FU National Institutes of Health [CA103867, CA124760, DK062777, DK80032]; NCI [N01-CO-12400]; American Diabetes Association FX This work was supported, in whole or in part, by National Institutes of Health Grants CA103867 and CA124760 (to C.-M. C.), DK062777, and DK80032 (to J. K. K.) and National Institutes of Health, NCI, Contract N01-CO-12400 (to T. D. V.). This work was also supported by an American Diabetes Association basic research award (to J. K. K.). NR 45 TC 163 Z9 175 U1 2 U2 20 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 29 PY 2010 VL 285 IS 44 BP 33959 EP 33970 DI 10.1074/jbc.M110.122978 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 669MD UT WOS:000283354000043 PM 20817729 ER PT J AU Zheng, YL Amin, ND Hu, YF Rudrabhatla, P Shukla, V Kanungo, J Kesavapany, S Grant, P Albers, W Pant, HC AF Zheng, Ya-Li Amin, Niranjana D. Hu, Ya-Fang Rudrabhatla, Parvathi Shukla, Varsha Kanungo, Jyotshnabala Kesavapany, Sashi Grant, Philip Albers, Wayne Pant, Harish C. TI A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; CELL-CYCLE; IN-VIVO; NEURODEGENERATIVE DISEASES; TRANSGENIC MODEL; NERVOUS-SYSTEM; A-BETA; PROTEIN AB The activity of Cdk5-p35 is tightly regulated in the developing and mature nervous system. Stress-induced cleavage of the activator p35 to p25 and a p10 N-terminal domain induces deregulated Cdk5 hyperactivity and perikaryal aggregations of hyperphosphorylated Tau and neurofilaments, pathogenic hallmarks in neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, respectively. Previously, we identified a 125-residue truncated fragment of p35 called CIP that effectively and specifically inhibited Cdk5-p25 activity and Tau hyperphosphorylation induced by A beta peptides in vitro, in HEK293 cells, and in neuronal cells. Although these results offer a possible therapeutic approach to those neurodegenerative diseases assumed to derive from Cdk5-p25 hyperactivity and/or A beta induced pathology, CIP is too large for successful therapeutic regimens. To identify a smaller, more effective peptide, in this study we prepared a 24-residue peptide, p5, spanning CIP residues Lys(245)-Ala(277). p5 more effectively inhibited Cdk5-p25 activity than did CIP in vitro. In neuron cells, p5 inhibited deregulated Cdk5-p25 activity but had no effect on the activity of endogenous Cdk5-p35 or on any related endogenous cyclin-dependent kinases in HEK293 cells. Specificity of p5 inhibition in cortical neurons may depend on the p10 domain in p35, which is absent in p25. Furthermore, we have demonstrated that p5 reduced A beta(1-42)-induced Tau hyperphosphorylation and apoptosis in cortical neurons. These results suggest that p5 peptide may be a unique and useful candidate for therapeutic studies of certain neurodegenerative diseases. C1 [Zheng, Ya-Li; Amin, Niranjana D.; Rudrabhatla, Parvathi; Shukla, Varsha; Grant, Philip; Albers, Wayne; Pant, Harish C.] NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Zheng, Ya-Li] Ningxia Peoples Hosp, Dept Nephrol, Ningxia 750021, Peoples R China. [Hu, Ya-Fang] NIDCR, Lab Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Kanungo, Jyotshnabala] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kesavapany, Sashi] Natl Univ Singapore, Dept Biochem, Yong Loo Lin Sch Med, Singapore 117697, Singapore. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 49,Rm 2A28,9000 Rockville Pike, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov RI Shukla, Varsha/G-5136-2010 FU National Institutes of Health, NINDS FX This work was supported, in whole or in part, by National Institutes of Health, NINDS, intramural funds. NR 74 TC 36 Z9 39 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 29 PY 2010 VL 285 IS 44 BP 34202 EP 34212 DI 10.1074/jbc.M110.134643 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 669MD UT WOS:000283354000065 PM 20720012 ER PT J AU Xi, SC Yang, MC Tao, YG Xu, H Shan, JG Inchauste, S Zhang, M Mercedes, L Hong, JA Rao, M Schrump, DS AF Xi, Sichuan Yang, Maocheng Tao, Yongguang Xu, Hong Shan, Jigui Inchauste, Suzanne Zhang, Mary Mercedes, Leandro Hong, Julie A. Rao, Mahadev Schrump, David S. TI Cigarette Smoke Induces C/EBP-beta-Mediated Activation of miR-31 in Normal Human Respiratory Epithelia and Lung Cancer Cells SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; MICRORNA EXPRESSION; COLORECTAL-CANCER; NEVER-SMOKERS; STEM-CELLS; TRANSFORMATION; CONDENSATE; WNT; PROLIFERATION; METASTASIS AB Background: Limited information is available regarding mechanisms by which miRNAs contribute to pulmonary carcinogenesis. The present study was undertaken to examine expression and function of miRNAs induced by cigarette smoke condensate (CSC) in normal human respiratory epithelia and lung cancer cells. Methodology: Micro-array and quantitative RT-PCR (qRT-PCR) techniques were used to assess miRNA and host gene expression in cultured cells, and surgical specimens. Software-guided analysis, RNA cross-link immunoprecipitation (CLIP), 39 UTR luciferase reporter assays, qRT-PCR, focused super-arrays and western blot techniques were used to identify and confirm targets of miR-31. Chromatin immunoprecipitation (ChIP) techniques were used to evaluate histone marks and transcription factors within the LOC554202 promoter. Cell count and xenograft experiments were used to assess effects of miR-31 on proliferation and tumorigenicity of lung cancer cells. Results: CSC significantly increased miR-31 expression and activated LOC554202 in normal respiratory epithelia and lung cancer cells; miR-31 and LOC554202 expression persisted following discontinuation of CSC exposure. miR-31 and LOC554202 expression levels were significantly elevated in lung cancer specimens relative to adjacent normal lung tissues. CLIP and reporter assays demonstrated direct interaction of miR-31 with Dickkopf-1 (Dkk-1) and DACT-3. Over-expression of miR-31 markedly diminished Dkk-1 and DACT3 expression levels in normal respiratory epithelia and lung cancer cells. Knock-down of miR-31 increased Dkk-1 and DACT3 levels, and abrogated CSC-mediated decreases in Dkk-1 and DACT-3 expression. Furthermore, over-expression of miR-31 diminished SFRP1, SFRP4, and WIF-1, and increased Wnt-5a expression. CSC increased H3K4Me3, H3K9/14Ac and C/EBP-beta levels within the LOC554202 promoter. Knock-down of C/EBP-beta abrogated CSC-mediated activation of LOC554202. Over-expression of miR-31 significantly enhanced proliferation and tumorigenicity of lung cancer cells; knock-down of miR-31 inhibited growth of these cells. Conclusions: Cigarette smoke induces expression of miR-31 targeting several antagonists of cancer stem cell signaling in normal respiratory epithelia and lung cancer cells. miR-31 functions as an oncomir during human pulmonary carcinogenesis. C1 [Xi, Sichuan; Yang, Maocheng; Inchauste, Suzanne; Zhang, Mary; Mercedes, Leandro; Hong, Julie A.; Rao, Mahadev; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Tao, Yongguang; Xu, Hong] NCI, Lab Canc Prevent, Frederick, MD 21701 USA. [Shan, Jigui] NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD 21701 USA. RP Xi, SC (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov FU National Institutes of Health FX This work was supported by National Institutes of Health intramural funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 67 Z9 73 U1 0 U2 13 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 OCT 29 PY 2010 VL 5 IS 10 AR e13764 DI 10.1371/journal.pone.0013764 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 673FU UT WOS:000283645300042 PM 21048943 ER PT J AU Mindell, JA AF Mindell, Joseph A. TI The Tao of Chloride Transporter Structure SO SCIENCE LA English DT Editorial Material ID CYTOPLASMIC DOMAIN; CRYSTAL-STRUCTURE; CHANNEL; SELECTIVITY; ANTIPORTER C1 NINDS, Membrane Transport Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mindell, JA (reprint author), NINDS, Membrane Transport Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM mindellj@ninds.nih.gov OI Mindell, Joseph/0000-0002-6952-8247 NR 18 TC 2 Z9 3 U1 0 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 29 PY 2010 VL 330 IS 6004 BP 601 EP 602 DI 10.1126/science.1198306 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 672KB UT WOS:000283580600027 PM 21030639 ER PT J AU Lu, KT Schwartzberg, PL AF Lu, Kristina T. Schwartzberg, Pamela L. TI To B or not to B SO BLOOD LA English DT Editorial Material ID IMMUNE-RESPONSES; SAP; SLAM; DEFICIENCY; FAMILIES C1 [Lu, Kristina T.; Schwartzberg, Pamela L.] NHGRI, Bethesda, MD 20892 USA. RP Lu, KT (reprint author), NHGRI, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 28 PY 2010 VL 116 IS 17 BP 3128 EP 3121 DI 10.1182/blood-2010-08-299222 PG 4 WC Hematology SC Hematology GA 672LE UT WOS:000283583700002 PM 21030566 ER PT J AU Lugli, E Goldman, CK Perera, LP Smedley, J Pung, R Yovandich, JL Creekmore, SP Waldmann, TA Roederer, M AF Lugli, Enrico Goldman, Carolyn K. Perera, Liyanage P. Smedley, Jeremy Pung, Rhonda Yovandich, Jason L. Creekmore, Stephen P. Waldmann, Thomas A. Roederer, Mario TI Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates SO BLOOD LA English DT Article ID CD8(+) T-CELLS; NATURAL-KILLER-CELLS; RHESUS MACAQUES; MEMORY CD4; NK CELLS; PROLIFERATION; NAIVE; INTERLEUKIN-15; EXPANSION; CYTOKINES AB Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)- and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 mu g/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short-and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T-and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extra-lymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4(+) and CD8(+) T cells. (Blood. 2010; 116(17):3238-3248) C1 [Lugli, Enrico; Roederer, Mario] NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Goldman, Carolyn K.; Perera, Liyanage P.; Waldmann, Thomas A.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Smedley, Jeremy; Pung, Rhonda; Yovandich, Jason L.; Creekmore, Stephen P.] NCI, Biol Resources Branch, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM roederer@nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Institute of Allergy and Infectious Diseases; National Cancer Institute, NIH FX This research was supported by the Intramural Programs of the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIH. NR 38 TC 44 Z9 45 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 28 PY 2010 VL 116 IS 17 BP 3238 EP 3248 DI 10.1182/blood-2010-03-275438 PG 11 WC Hematology SC Hematology GA 672LE UT WOS:000283583700019 PM 20631381 ER PT J AU Rai, G Kenyon, V Jadhav, A Schultz, L Armstrong, M Jameson, JB Hoobler, E Leister, W Simeonov, A Holman, TR Maloney, DJ AF Rai, Ganesha Kenyon, Victor Jadhav, Ajit Schultz, Lena Armstrong, Michelle Jameson, J. Brian, II Hoobler, Eric Leister, William Simeonov, Anton Holman, Theodore R. Maloney, David J. TI Discovery of Potent and Selective Inhibitors of Human Reticulocyte 15-Lipoxygenase-1 SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN LIPOXYGENASE INHIBITORS; PLATELET-TYPE 12-LIPOXYGENASE; HIGH-THROUGHPUT; PROSTATE CARCINOMA; ARACHIDONIC-ACID; CANCER CELLS; MAMMALIAN 15-LIPOXYGENASE; 12-HUMAN LIPOXYGENASE; SUBSTRATE-SPECIFICITY; BIOLOGICAL-ACTIVITIES AB There are a variety of lipoxygenases in the human body (hLO), each having a distinct role in cellular biology. Human reticulocyte 15-lipoxygenase-1 (15-hLO-1), which catalyzes the dioxygenation of 1,4-cis,cis-pentadiene-containing polyunsaturated fatty acids, is implicated in a number of diseases including cancer, atherosclerosis, and neurodegenerative conditions. Despite the potential therapeutic relevance of this target, few inhibitors have been reported that are both potent and selective. To this end, we have employed a quantitative high-throughput (qHTS) screen against similar to 74000 small molecules in search of reticulocyte 15-hLO-1 selective inhibitors. This screen led to the discovery of a novel chemotype for 15-hLO-1 inhibition, which displays nM potency and is > 7500-fold selective against the related isozymes, 5-hLO, platelet 12-hLO, epithelial 15-hLO-2, ovine cyclooxygenase-1, and human cyclooxygenase-2. In addition, kinetic experiments were performed which indicate that this class of inhibitor is tight binding, reversible, and appears not to reduce the active-site ferric ion. C1 [Kenyon, Victor; Armstrong, Michelle; Jameson, J. Brian, II; Hoobler, Eric; Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Rai, Ganesha; Jadhav, Ajit; Schultz, Lena; Leister, William; Simeonov, Anton; Maloney, David J.] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Holman, TR (reprint author), Univ Calif Santa Cruz, Dept Chem & Biochem, 250 Phys Sci Bldg, Santa Cruz, CA 95064 USA. EM holman@ucsc.edu; maloneyd@mail.nih.gov FU National Institute of Health [R01 GM56062, S10-RR20939]; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [R03 MH081283]; California Institute for Quantitative Biosciences for the UCSC MS Facility FX We thank Paul Shinn, Danielle van Leer, and James Bougie for assistance with compound management and purification. We also thank Dr. Matthew Jacobson and Chakrapani Kalyanaraman for helpful discussions during the preparation of this manuscript. Financial support was from the National Institute of Health grants R01 GM56062 (T.R.H.) and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (R03 MH081283 (T.R.H.)). Additional financial support was from NIH (S10-RR20939 (T.R.H.)) and the California Institute for Quantitative Biosciences for the UCSC MS Facility (T.R.H.). NR 61 TC 39 Z9 40 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 28 PY 2010 VL 53 IS 20 BP 7392 EP 7404 DI 10.1021/jm1008852 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 666HV UT WOS:000283106300012 PM 20866075 ER PT J AU Altshuler, D Durbin, RM Abecasis, GR Bentley, DR Chakravarti, A Clark, AG Collins, FS De la Vega, FM Donnelly, P Egholm, M Flicek, P Gabriel, SB Gibbs, RA Knoppers, BM Lander, ES Lehrach, H Mardis, ER McVean, GA Nickerson, D Peltonen, L Schafer, AJ Sherry, ST Wang, J Wilson, RK Gibbs, RA Deiros, D Metzker, M Muzny, D Reid, J Wheeler, D Wang, J Li, JX Jian, M Li, G Li, RQ Liang, HQ Tian, G Wang, B Wang, J Wang, W Yang, HM Zhang, XQ Zheng, HS Lander, ES Altshuler, DL Ambrogio, L Bloom, T Cibulskis, K Fennell, TJ Gabriel, SB Jaffe, DB Shefler, E Sougnez, CL Bentley, DR Gormley, N Humphray, S Kingsbury, Z Koko-Gonzales, P Stone, J McKernan, KJ Costa, GL Ichikawa, JK Lee, CC Sudbrak, R Lehrach, H Borodina, TA Dahl, A Davydov, AN Marquardt, P Mertes, F Nietfeld, W Rosenstiel, P Schreiber, S Soldatov, AV Timmermann, B Tolzmann, M Egholm, M Affourtit, J Ashworth, D Attiya, S Bachorski, M Buglione, E Burke, A Caprio, A Celone, C Clark, S Conners, D Desany, B Gu, L Guccione, L Kao, K Kebbel, A Knowlton, J Labrecque, M McDade, L Mealmaker, C Minderman, M Nawrocki, A Niazi, F Pareja, K Ramenani, R Riches, D Song, W Turcotte, C Wang, S Mardis, ER Dooling, D Fulton, L Fulton, R Weinstock, G Durbin, RM Burton, J Carter, DM Churcher, C Coffey, A Cox, A Palotie, A Quail, M Skelly, T Stalker, J Swerdlow, HP Turner, D De Witte, A Giles, S Gibbs, RA Wheeler, D Bainbridge, M Challis, D Sabo, A Yu, F Yu, J Wang, J Fang, XD Guo, XS Li, RQ Li, YR Luo, RB Tai, S Wu, HL Zheng, HC Zheng, XL Zhou, Y Yang, HM Marth, GT Garrison, EP Huang, W Indap, A Kural, D Lee, WP Leong, WF Huang, WC Indap, A Kural, D Lee, WP Leong, WF Quinlan, AR Stewart, C Stromberg, MP Ward, AN Wu, JT Lee, C Mills, RE Shi, XH Daly, MJ DePristo, MA Altshuler, DL Ball, AD Banks, E Bloom, T Browning, BL Cibulskis, K Fennell, TJ Garimella, KV Grossman, SR Handsaker, RE Hanna, M Hartl, C Jaffe, DB Kernytsky, AM Korn, JM Li, H Maguire, JR McCarroll, SA McKenna, A Nemesh, JC Philippakis, AA Poplin, RE Price, A Rivas, MA Sabeti, PC Schaffner, SF Shefler, E Shlyakhter, IA Cooper, DN Ball, EV Mort, M Phillips, AD Stenson, PD Sebat, J Makarov, V Ye, K Yoon, SC Bustamante, CD Clark, AG Boyko, A Degenhardt, J Gravel, S Gutenkunst, RN Kaganovich, M Keinan, A Lacroute, P Ma, X Reynolds, A Clarke, L Flicek, P Cunningham, F Herrero, J Keenen, S Kulesha, E Leinonen, R McLaren, W Radhakrishnan, R Smith, RE Zalunin, V Zheng-Bradley, XQ Korbel, JO Stutz, AM Humphray, S Bauer, M Cheetham, RK Cox, T Eberle, M James, T Kahn, S Murray, L Ye, K De La Vega, FM Fu, YT Hyland, FCL Manning, JM McLaughlin, SF Peckham, HE Sakarya, O Sun, YA Tsung, EF Batzer, MA Konkel, MK Walker, JA Sudbrak, R Albrecht, MW Amstislavskiy, VS Herwig, R Parkhomchuk, DV Sherry, ST Agarwala, R Khouri, H Morgulis, AO Paschall, JE Phan, LD Rotmistrovsky, KE Sanders, RD Shumway, MF Xiao, CL McVean, GA Auton, A Iqbal, Z Lunter, G Marchini, JL Moutsianas, L Myers, S Tumian, A Desany, B Knight, J Winer, R Craig, DW Beckstrom-Sternberg, SM Christoforides, A Kurdoglu, AA Pearson, J Sinari, SA Tembe, WD Haussler, D Hinrichs, AS Katzman, SJ Kern, A Kuhn, RM Przeworski, M Hernandez, RD Howie, B Kelley, JL Melton, SC Abecasis, GR Li, Y Anderson, P Blackwell, T Chen, W Cookson, WO Ding, J Kang, HM Lathrop, M Liang, LM Moffatt, MF Scheet, P Sidore, C Snyder, M Zhan, XW Zollner, S Awadalla, P Casals, F Idaghdour, Y Keebler, J Stone, EA Zilversmit, M Jorde, L Xing, JC Eichler, EE Aksay, G Alkan, C Hajirasouliha, I Hormozdiari, F Kidd, JM Sahinalp, SC Sudmant, PH Mardis, ER Chen, K Chinwalla, A Ding, L Koboldt, DC McLellan, MD Dooling, D Weinstock, G Wallis, JW Wendl, MC Zhang, QY Durbin, RM Albers, CA Ayub, Q Balasubramaniam, S Barrett, JC Carter, DM Chen, YA Conrad, DF Danecek, P Dermitzakis, ET Hu, M Huang, N Hurles, ME Jin, HJ Jostins, L Keane, TM Keane, TM Le, SQ Lindsay, S Long, QA MacArthur, DG Montgomery, SB Parts, L Stalker, J Tyler-Smith, C Walter, K Zhang, YJ Gerstein, MB Snyder, M Abyzov, A Abyzov, A Balasubramanian, S Bjornson, R Du, JA Grubert, F Habegger, L Haraksingh, R Jee, J Khurana, E Lam, HYK Leng, J Mu, XJ Urban, AE Zhang, ZD Li, YR Luo, RB Marth, GT Garrison, EP Kural, D Quinlan, AR Stewart, C Stromberg, MP Ward, AN Wu, JT Lee, C Mills, RE Shi, XH McCarroll, SA Banks, E DePristo, MA Handsaker, RE Hartl, C Korn, JM Li, H Nemesh, JC Sebat, J Makarov, V Ye, K Yoon, SC Degenhardt, J Kaganovich, M Clarke, L Smith, RE Zheng-Bradley, XQ Korbel, JO Humphray, S Cheetham, RK Eberle, M Kahn, S Murray, L Ye, K De la Vega, FM Fu, YT Peckham, HE Sun, YA Batzer, MA Konkel, MK Xiao, CL Iqbal, Z Desany, B Blackwell, T Snyder, M Xing, JC Eichler, EE Aksay, G Alkan, C Hajirasouliha, I Hormozdiari, F Kidd, JM Chen, K Chinwalla, A Ding, L McLellan, MD Wallis, JW Hurles, ME Conrad, DF Walter, K Zhang, YJ Gerstein, MB Snyder, M Abyzov, A Du, JA Grubert, F Haraksingh, R Jee, J Khurana, E Lam, HYK Leng, J Mu, XJ Urban, AE Zhang, ZD Gibbs, RA Bainbridge, M Challis, D Coafra, C Dinh, H Kovar, C Lee, S Muzny, D Nazareth, L Reid, J Sabo, A Yu, FL Yu, J Marth, GT Garrison, EP Indap, A Leong, WF Quinlan, AR Stewart, C Ward, AN Wu, JT Cibulskis, K Fennell, TJ Gabriel, SB Garimella, KV Hartl, C Shefler, E Sougnez, CL Wilkinson, J Clark, AG Gravel, S Grubert, F Clarke, L Flicek, P Smith, RE Zheng-Bradley, XQ Sherry, ST Khouri, HM Paschall, JE Shumway, MF Xiao, CL McVean, GA Katzman, SJ Abecasis, GR Blackwell, T Mardis, ER Dooling, D Fulton, L Fulton, R Koboldt, DC Durbin, RM Balasubramaniam, S Coffey, A Keane, TM MacArthur, DG Palotie, A Scott, C Stalker, J Tyler-Smith, C Gerstein, MB Balasubramanian, S Chakravarti, A Knoppers, BM Peltonen, L Abecasis, GR Bustamante, CD Gharani, N Gibbs, RA Jorde, L Kaye, JS Kent, A Li, T McGuire, AL McVean, GA Ossorio, PN Rotimi, CN Su, YY Toji, LH Tyler-Smith, C Brooks, LD Felsenfeld, AL McEwen, JE Abdallah, A Christopher, R Clemm, NC Collins, FS Duncanson, A Green, ED Guyer, MS Peterson, JL Schafer, AJ Abecasis, GR Altshuler, DL Auton, A Brooks, LD Durbin, RM Gibbs, RA Hurles, ME McVean, GA AF Altshuler, David Durbin, Richard M. Abecasis, Goncalo R. Bentley, David R. Chakravarti, Aravinda Clark, Andrew G. Collins, Francis S. De la Vega, Francisco M. Donnelly, Peter Egholm, Michael Flicek, Paul Gabriel, Stacey B. Gibbs, Richard A. Knoppers, Bartha M. Lander, Eric S. Lehrach, Hans Mardis, Elaine R. McVean, Gil A. Nickerson, DebbieA. Peltonen, Leena Schafer, Alan J. Sherry, Stephen T. Wang, Jun Wilson, Richard K. Gibbs, Richard A. Deiros, David Metzker, Mike Muzny, Donna Reid, Jeff Wheeler, David Wang, Jun Li, Jingxiang Jian, Min Li, Guoqing Li, Ruiqiang Liang, Huiqing Tian, Geng Wang, Bo Wang, Jian Wang, Wei Yang, Huanming Zhang, Xiuqing Zheng, Huisong Lander, Eric S. Altshuler, David L. Ambrogio, Lauren Bloom, Toby Cibulskis, Kristian Fennell, Tim J. Gabriel, Stacey B. Jaffe, David B. Shefler, Erica Sougnez, Carrie L. Bentley, David R. Gormley, Niall Humphray, Sean Kingsbury, Zoya Koko-Gonzales, Paula Stone, Jennifer McKernan, Kevin J. Costa, Gina L. Ichikawa, Jeffry K. Lee, Clarence C. Sudbrak, Ralf Lehrach, Hans Borodina, Tatiana A. Dahl, Andreas Davydov, Alexey N. Marquardt, Peter Mertes, Florian Nietfeld, Wilfiried Rosenstiel, Philip Schreiber, Stefan Soldatov, Aleksey V. Timmermann, Bernd Tolzmann, Marius Egholm, Michael Affourtit, Jason Ashworth, Dana Attiya, Said Bachorski, Melissa Buglione, Eli Burke, Adam Caprio, Amanda Celone, Christopher Clark, Shauna Conners, David Desany, Brian Gu, Lisa Guccione, Lorri Kao, Kalvin Kebbel, Andrew Knowlton, Jennifer Labrecque, Matthew McDade, Louise Mealmaker, Craig Minderman, Melissa Nawrocki, Anne Niazi, Faheem Pareja, Kristen Ramenani, Ravi Riches, David Song, Wanmin Turcotte, Cynthia Wang, Shally Mardis, Elaine R. Dooling, David Fulton, Lucinda Fulton, Robert Weinstock, George Durbin, Richard M. Burton, John Carter, David M. Churcher, Carol Coffey, Alison Cox, Anthony Palotie, Aarno Quail, Michael Skelly, Tom Stalker, James Swerdlow, Harold P. Turner, Daniel De Witte, Anniek Giles, Shane Gibbs, Richard A. Wheeler, David Bainbridge, Matthew Challis, Danny Sabo, Aniko Yu, Fuli Yu, Jin Wang, Jun Fang, Xiaodong Guo, Xiaosen Li, Ruiqiang Li, Yingrui Luo, Ruibang Tai, Shuaishuai Wu, Honglong Zheng, Hancheng Zheng, Xiaole Zhou, Yan Yang, Huanming Marth, Gabor T. Garrison, Erik P. Huang, Weichun Indap, Amit Kural, Deniz Lee, Wan-Ping Leong, Wen Fung Huang, Weichun Indap, Amit Kural, Deniz Lee, Wan-Ping Leong, Wen Fung Quinlan, Aaron R. Stewart, Chip Stromberg, Michael P. Ward, Alistair N. Wu, Jiantao Lee, Charles Mills, Ryan E. Shi, Xinghua Daly, Mark J. DePristo, Mark A. Altshuler, David L. Ball, Aaron D. Banks, Eric Bloom, Toby Browning, Brian L. Cibulskis, Kristian Fennell, Tim J. Garimella, Kiran V. Grossman, Sharon R. Handsaker, Robert E. Hanna, Matt Hartl, Chris Jaffe, David B. Kernytsky, Andrew M. Korn, Joshua M. Li, Heng Maguire, Jared R. McCarroll, Steven A. McKenna, Aaron Nemesh, James C. Philippakis, Anthony A. Poplin, Ryan E. Price, Alkes Rivas, Manuel A. Sabeti, Pardis C. Schaffner, Stephen F. Shefler, Erica Shlyakhter, Ilya A. Cooper, David N. Ball, Edward V. Mort, Matthew Phillips, Andrew D. Stenson, Peter D. Sebat, Jonathan Makarov, Vladimir Ye, Kenny Yoon, Seungtai C. Bustamante, Carlos D. Clark, Andrew G. Boyko, Adam Degenhardt, Jeremiah Gravel, Simon Gutenkunst, Ryan N. Kaganovich, Mark Keinan, Alon Lacroute, Phil Ma, Xia Reynolds, Andy Clarke, Laura Flicek, Paul Cunningham, Fiona Herrero, Javier Keenen, Stephen Kulesha, Eugene Leinonen, Rasko McLaren, WilliamM. Radhakrishnan, Rajesh Smith, Richard E. Zalunin, Vadim Zheng-Bradley, Xiangqun Korbel, Jan O. Stuetz, Adrian M. Humphray, Sean Bauer, Markus Cheetham, R. Keira Cox, Tony Eberle, Michael James, Terena Kahn, Scott Murray, Lisa Ye, Kai De La Vega, Francisco M. Fu, Yutao Hyland, Fiona C. L. Manning, Jonathan M. McLaughlin, Stephen F. Peckham, Heather E. Sakarya, Onur Sun, Yongming A. Tsung, Eric F. Batzer, Mark A. Konkel, Miriam K. Walker, Jerilyn A. Sudbrak, Ralf Albrecht, Marcus W. Amstislavskiy, Vyacheslav S. Herwig, Ralf Parkhomchuk, Dimitri V. Sherry, Stephen T. Agarwala, Richa Khouri, Hodam. Morgulis, Aleksandr O. Paschall, Justin E. Phan, Lon D. Rotmistrovsky, Kirill E. Sanders, Robert D. Shumway, Martin F. Xiao, Chunlin McVean, Gil A. Auton, Adam Iqbal, Zamin Lunter, Gerton Marchini, Jonathan L. Moutsianas, Loukas Myers, Simon Tumian, Afidalina Desany, Brian Knight, James Winer, Roger Craig, David W. Beckstrom-Sternberg, Steve M. Christoforides, Alexis Kurdoglu, Ahmet A. Pearson, Johnv. Sinari, Shripad A. Tembe, Waibhav D. Haussler, David Hinrichs, Angie S. Katzman, Sol J. Kern, Andrew Kuhn, Robert M. Przeworski, Molly Hernandez, Ryan D. Howie, Bryan Kelley, Joanna L. Melton, S. Cord Abecasis, Goncalo R. Li, Yun Anderson, Paul Blackwell, Tom Chen, Wei Cookson, William O. Ding, Jun Kang, Hyun Min Lathrop, Mark Liang, Liming Moffatt, Miriam F. Scheet, Paul Sidore, Carlo Snyder, Matthew Zhan, Xiaowei Zoellner, Sebastian Awadalla, Philip Casals, Ferran Idaghdour, Youssef Keebler, John Stone, Eric A. Zilversmit, Martine Jorde, Lynn Xing, Jinchuan Eichler, Evan E. Aksay, Gozde Alkan, Can Hajirasouliha, Iman Hormozdiari, Fereydoun Kidd, Jeffrey M. Sahinalp, S. Cenk Sudmant, Peter H. Mardis, Elaine R. Chen, Ken Chinwalla, Asif Ding, Li Koboldt, Daniel C. McLellan, Mike D. Dooling, David Weinstock, George Wallis, John W. Wendl, Michael C. Zhang, Qunyuan Durbin, Richard M. Albers, Cornelis A. Ayub, Qasim Balasubramaniam, Senduran Barrett, Jeffrey C. Carter, David M. Chen, Yuan Conrad, Donald F. Danecek, Petr Dermitzakis, Emmanouil T. Hu, Min Huang, Ni Hurles, Matt E. Jin, Hanjun Jostins, Luke Keane, Thomas M. Keane, Thomas M. Le, Si Quang Lindsay, Sarah Long, Quan MacArthur, Daniel G. Montgomery, Stephen B. Parts, Leopold Stalker, James Tyler-Smith, Chris Walter, Klaudia Zhang, Yujun Gerstein, Mark B. Snyder, Michael Abyzov, Alexej Abyzov, Alexej Balasubramanian, Suganthi Bjornson, Robert Du, Jiang Grubert, Fabian Habegger, Lukas Haraksingh, Rajini Jee, Justin Khurana, Ekta Lam, Hugo Y. K. Leng, Jing Mu, Xinmeng Jasmine Urban, Alexander E. Zhang, Zhengdong Li, Yingrui Luo, Ruibang Marth, Gabor T. Garrison, Erik P. Kural, Deniz Quinlan, Aaron R. Stewart, Chip Stromberg, Michael P. Ward, Alistair N. Wu, Jiantao Lee, Charles Mills, Ryan E. Shi, Xinghua McCarroll, Steven A. Banks, Eric DePristo, Mark A. Handsaker, Robert E. Hartl, Chris Korn, Joshua M. Li, Heng Nemesh, James C. Sebat, Jonathan Makarov, Vladimir Ye, Kenny Yoon, Seungtai C. Degenhardt, Jeremiah Kaganovich, Mark Clarke, Laura Smith, Richard E. Zheng-Bradley, Xiangqun Korbel, Jan O. Humphray, Sean Cheetham, R. Keira Eberle, Michael Kahn, Scott Murray, Lisa Ye, Kai De la Vega, Francisco M. Fu, Yutao Peckham, Heather E. Sun, Yongming A. Batzer, Mark A. Konkel, Miriam K. Xiao, Chunlin Iqbal, Zamin Desany, Brian Blackwell, Tom Snyder, Matthew Xing, Jinchuan Eichler, Evan E. Aksay, Gozde Alkan, Can Hajirasouliha, Iman Hormozdiari, Fereydoun Kidd, Jeffrey M. Chen, Ken Chinwalla, Asif Ding, Li McLellan, Mike D. Wallis, John W. Hurles, Matt E. Conrad, Donald F. Walter, Klaudia Zhang, Yujun Gerstein, Mark B. Snyder, Michael Abyzov, Alexej Du, Jiang Grubert, Fabian Haraksingh, Rajini Jee, Justin Khurana, Ekta Lam, Hugo Y. K. Leng, Jing Mu, Xinmeng Jasmine Urban, Alexander E. Zhang, Zhengdong Gibbs, Richard A. Bainbridge, Matthew Challis, Danny Coafra, Cristian Dinh, Huyen Kovar, Christie Lee, Sandy Muzny, Donna Nazareth, Lynne Reid, Jeff Sabo, Aniko Yu, Fuli Yu, Jin Marth, Gabor T. Garrison, Erik P. Indap, Amit Leong, Wen Fung Quinlan, Aaron R. Stewart, Chip Ward, Alistair N. Wu, Jiantao Cibulskis, Kristian Fennell, Tim J. Gabriel, Stacey B. Garimella, Kiran V. Hartl, Chris Shefler, Erica Sougnez, Carrie L. Wilkinson, Jane Clark, Andrew G. Gravel, Simon Grubert, Fabian Clarke, Laura Flicek, Paul Smith, Richard E. Zheng-Bradley, Xiangqun Sherry, Stephen T. Khouri, Hoda M. Paschall, Justin E. Shumway, Martin F. Xiao, Chunlin McVean, Gil A. Katzman, Sol J. Abecasis, Goncalo R. Blackwell, Tom Mardis, Elaine R. Dooling, David Fulton, Lucinda Fulton, Robert Koboldt, Daniel C. Durbin, Richard M. Balasubramaniam, Senduran Coffey, Allison Keane, Thomas M. MacArthur, Daniel G. Palotie, Aarno Scott, Carol Stalker, James Tyler-Smith, Chris Gerstein, Mark B. Balasubramanian, Suganthi Chakravarti, Aravinda Knoppers, Bartha M. Peltonen, Leena Abecasis, Goncalo R. Bustamante, Carlos D. Gharani, Neda Gibbs, Richard A. Jorde, Lynn Kaye, Jane S. Kent, Alastair Li, Taosha McGuire, Amy L. McVean, Gil A. Ossorio, Pilar N. Rotimi, Charles N. Su, Yeyang Toji, Lorraine H. Tyler-Smith, Chris Brooks, Lisa D. Felsenfeld, Adam L. McEwen, Jean E. Abdallah, Assya Juenger, Christopher R. Clemm, Nicholas C. Collins, Francis S. Duncanson, Audrey Green, Eric D. Guyer, Mark S. Peterson, Jane L. Schafer, Alan J. Abecasis, Goncalo R. Altshuler, David L. Auton, Adam Brooks, Lisa D. Durbin, Richard M. Gibbs, Richard A. Hurles, Matt E. McVean, Gil A. CA 1000 Genomes Project Consortium TI A map of human genome variation from population-scale sequencing SO NATURE LA English DT Article ID WIDE ASSOCIATION; GENE-EXPRESSION; RECOMBINATION HOTSPOTS; MEIOTIC RECOMBINATION; GENOTYPE IMPUTATION; RARE VARIANTS; HAPLOTYPE MAP; NUCLEOTIDE; DISEASES; COMMON AB The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research. C1 [Gabriel, Stacey B.; Lander, Eric S.; Lander, Eric S.; Ambrogio, Lauren; Cibulskis, Kristian; Fennell, Tim J.; Jaffe, David B.; Shefler, Erica; Sougnez, Carrie L.; Daly, Mark J.; DePristo, Mark A.; Ball, Aaron D.; Banks, Eric; Bloom, Toby; Cibulskis, Kristian; Fennell, Tim J.; Garimella, Kiran V.; Handsaker, Robert E.; Hanna, Matt; Hartl, Chris; Jaffe, David B.; Kernytsky, Andrew M.; Korn, Joshua M.; Li, Heng; Maguire, Jared R.; McCarroll, Steven A.; McKenna, Aaron; Nemesh, James C.; Philippakis, Anthony A.; Poplin, Ryan E.; Rivas, Manuel A.; Sabeti, Pardis C.; Schaffner, Stephen F.; Fu, Yutao; Banks, Eric; DePristo, Mark A.; Hartl, Chris; Korn, Joshua M.; Nemesh, James C.; Garimella, Kiran V.; Sougnez, Carrie L.; Wilkinson, Jane; Altshuler, David L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. 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[Mardis, Elaine R.; Wilson, Richard K.; Dooling, David; Fulton, Lucinda; Fulton, Robert; Weinstock, George; McLellan, Mike D.; Weinstock, George; Wallis, John W.; Wendl, Michael C.; Zhang, Qunyuan; Chen, Ken; Chinwalla, Asif; Ding, Li; McLellan, Mike D.; Wallis, John W.; Koboldt, Daniel C.] Washington Univ, Sch Med, Genome Ctr, St Louis, MO 63108 USA. [Marchini, Jonathan L.; Moutsianas, Loukas; Myers, Simon; Tumian, Afidalina; McVean, Gil A.] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Nickerson, DebbieA.; Aksay, Gozde; Sudmant, Peter H.; Kidd, Jeffrey M.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Schafer, Alan J.; Duncanson, Audrey] Wellcome Trust Res Labs, London NW1 2BE, England. [Sherry, Stephen T.; Agarwala, Richa; Khouri, Hodam.; Morgulis, Aleksandr O.; Paschall, Justin E.; Phan, Lon D.; Rotmistrovsky, Kirill E.; Sanders, Robert D.; Shumway, Martin F.; Xiao, Chunlin; Khouri, Hoda M.] US Natl Inst Hlth, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Wang, Jun; Li, Jingxiang; Jian, Min; Li, Guoqing; Li, Ruiqiang; Liang, Huiqing; Tian, Geng; Wang, Bo; Wang, Jian; Wang, Wei; Yang, Huanming; Zhang, Xiuqing; Zheng, Huisong; Fang, Xiaodong; Guo, Xiaosen; Li, Yingrui; Luo, Ruibang; Tai, Shuaishuai; Wu, Honglong; Zheng, Hancheng; Zheng, Xiaole; Zhou, Yan; Luo, Ruibang; Li, Taosha; Su, Yeyang] BGI Shenzhen, Shenzhen 518083, Peoples R China. Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark. [McKernan, Kevin J.; Costa, Gina L.; Ichikawa, Jeffry K.; Lee, Clarence C.; Fu, Yutao; Manning, Jonathan M.; McLaughlin, Stephen F.; Peckham, Heather E.; Tsung, Eric F.] Life Technol, Beverly, MA 01915 USA. [Dahl, Andreas] Biotechnol Ctr TU Dresden, Deep Sequencing Grp, D-01307 Dresden, Germany. [Rosenstiel, Philip; Schreiber, Stefan] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Affourtit, Jason; Ashworth, Dana; Attiya, Said; Bachorski, Melissa; Buglione, Eli; Burke, Adam; Caprio, Amanda; Celone, Christopher; Clark, Shauna; Conners, David; Desany, Brian; Gu, Lisa; Guccione, Lorri; Kao, Kalvin; Kebbel, Andrew; Knowlton, Jennifer; Labrecque, Matthew; McDade, Louise; Mealmaker, Craig; Minderman, Melissa; Nawrocki, Anne; Niazi, Faheem; Pareja, Kristen; Ramenani, Ravi; Riches, David; Song, Wanmin; Turcotte, Cynthia; Wang, Shally; Knight, James; Winer, Roger] Roche Appl Sci, Branford, CT 06405 USA. [Palotie, Aarno; Palotie, Aarno] Univ Helsinki, Dept Med Genet, Inst Mol Med FIMM, FIN-00290 Helsinki, Finland. [Palotie, Aarno; Palotie, Aarno] Helsinki Univ Hosp, Helsinki 00290, Finland. [De Witte, Anniek; Giles, Shane] Agilent Technol, Santa Clara, CA 95051 USA. [Marth, Gabor T.; Garrison, Erik P.; Indap, Amit; Kural, Deniz; Lee, Wan-Ping; Leong, Wen Fung; Stewart, Chip; Ward, Alistair N.; Wu, Jiantao] Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA. [Huang, Weichun] US Natl Inst Hlth, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Quinlan, Aaron R.] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Stromberg, Michael P.] Illumina, San Diego, CA 92121 USA. [Lee, Charles; Mills, Ryan E.; Shi, Xinghua; Altshuler, David L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Shi, Xinghua; Altshuler, David L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Browning, Brian L.] Univ Washington, Dept Med, Div Gen Med, Seattle, WA 98195 USA. [Grossman, Sharon R.; Sabeti, Pardis C.; Shlyakhter, Ilya A.] Harvard Univ, Ctr Syst Biol, Dept Organism & Evolut Biol, Cambridge, MA 02138 USA. [Price, Alkes] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cooper, David N.; Ball, Edward V.; Mort, Matthew; Phillips, Andrew D.; Stenson, Peter D.] Cardiff Univ, Inst Med Genet, Cardiff CF14 4XN, Wales. [Sebat, Jonathan] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Makarov, Vladimir] Mt Sinai Sch Med, Seaver Autism Ctr, New York, NY 10029 USA. [Makarov, Vladimir] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Ye, Kenny] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Yoon, Seungtai C.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Bustamante, Carlos D.; Boyko, Adam; Gravel, Simon; Kaganovich, Mark; Lacroute, Phil; Du, Jiang; Lam, Hugo Y. K.; Urban, Alexander E.; Kidd, Jeffrey M.; Snyder, Michael; Grubert, Fabian; Lam, Hugo Y. K.; Urban, Alexander E.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Gutenkunst, Ryan N.] Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA. [Korbel, Jan O.; Stuetz, Adrian M.] Genome Biol Res Unit, European Mol Biol Lab, D-69117 Heidelberg, Germany. [Ye, Kai] Leiden Univ Med Ctr, Mol Epidemiol Sect, NL-2333 ZA Leiden, Netherlands. [Batzer, Mark A.; Konkel, Miriam K.; Walker, Jerilyn A.] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Craig, David W.; Beckstrom-Sternberg, Steve M.; Christoforides, Alexis; Kurdoglu, Ahmet A.; Pearson, Johnv.; Sinari, Shripad A.; Tembe, Waibhav D.] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Haussler, David; Hinrichs, Angie S.; Katzman, Sol J.; Kern, Andrew; Kuhn, Robert M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Przeworski, Molly] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Przeworski, Molly] Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA. [Hernandez, Ryan D.; Howie, Bryan; Kelley, Joanna L.; Melton, S. Cord] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Cookson, William O.; Moffatt, Miriam F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2, England. [Lathrop, Mark] Ctr Natl Genotypage, F-91000 Evry, France. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Scheet, Paul] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Awadalla, Philip] Univ Montreal, Fac Med, Dept Pediat, Ste Justine Hosp Res Ctr, Montreal, PQ H3T IC5, Canada. [Casals, Ferran; Idaghdour, Youssef; Keebler, John; Stone, Eric A.; Zilversmit, Martine] Univ Montreal, Dept Med, Ctr Hosp, Univ Montreal Res Ctr, Montreal, PQ H2L 2W5, Canada. [Jorde, Lynn; Xing, Jinchuan; Xing, Jinchuan; Jorde, Lynn] Univ Utah, Sch Med, Eccles Inst Human Genet, Salt Lake City, UT 84112 USA. [Eichler, Evan E.; Alkan, Can; Alkan, Can] Univ Washington, Sch Med, Depat Genome Sci, Seattle, WA 98195 USA. [Eichler, Evan E.; Alkan, Can; Alkan, Can] Howard Hughes Med Inst, Seattle, WA 98195 USA. [Hajirasouliha, Iman; Hormozdiari, Fereydoun; Sahinalp, S. Cenk; Hajirasouliha, Iman; Hormozdiari, Fereydoun] Simon Fraser Univ, Dept Comp Sci, Burnaby, BC V5A 1S6, Canada. [Albers, Cornelis A.] Univ Cambridge, Dept Haematol, Cambridge CB2 1TN, England. [Albers, Cornelis A.] Natl Hlth Serv Blood & Transplant, Cambridge CB2 1TN, England. [Dermitzakis, Emmanouil T.; Montgomery, Stephen B.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Jin, Hanjun] Korea Natl Inst Hlth, Ctr Genome Sci, Seoul 122701, South Korea. [Abyzov, Alexej; Habegger, Lukas; Haraksingh, Rajini; Gerstein, Mark B.; Abyzov, Alexej; Haraksingh, Rajini; Jee, Justin; Leng, Jing; Mu, Xinmeng Jasmine] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Balasubramanian, Suganthi; Bjornson, Robert; Gerstein, Mark B.; Du, Jiang] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA. [Abyzov, Alexej; Khurana, Ekta; Urban, Alexander E.; Zhang, Zhengdong; Balasubramanian, Suganthi] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Urban, Alexander E.; Urban, Alexander E.] Stanford Univ, Dept Psychiat & Behav Studies, Stanford, CA 94305 USA. [Gharani, Neda; Toji, Lorraine H.] Corell Inst, Camden, NJ 08103 USA. [Kaye, Jane S.] Univ Oxford, Ctr Hlth Law & Emerging Technol, Oxford OX3 7LF, England. [Kent, Alastair] Genet Alliance, London N1 3QP, England. [McGuire, Amy L.] Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Ossorio, Pilar N.] Univ Wisconsin Madison, Dept Med Hist & Bioeth, Madison, WI 53706 USA. [Rotimi, Charles N.] US Natl Inst Hlth, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Brooks, Lisa D.; Felsenfeld, Adam L.; McEwen, Jean E.; Clemm, Nicholas C.; Green, Eric D.; Guyer, Mark S.; Peterson, Jane L.; Brooks, Lisa D.] US Natl Inst Hlth, NHGRI, Bethesda, MD 20892 USA. [Abdallah, Assya] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. [Juenger, Christopher R.] US FDA, Rockville, MD 20857 USA. RP Durbin, RM (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. RI Casals, Ferran/H-4347-2015; Wang, Jun/C-8434-2016; Lunter, Gerton/H-4939-2016; Pearson, John/F-2249-2011; Mu, Xinmeng/P-2562-2016; Stone, Eric/Q-7840-2016; Mills, Ryan/A-1979-2011; Dahl, Andreas/E-3783-2017; Ye, Kai/B-3640-2012; Cartwright, Reed/A-9707-2009; Wendl, Michael/A-2741-2008; Rosenstiel, Philip/A-5137-2009; Korbel, Jan/G-6470-2012; Kelley, Joanna/H-1693-2012; Dermitzakis, Emmanouil/B-7687-2013; Khurana, Ekta/C-4933-2013; Abyzov, Alexej/M-4284-2013; Le, Quang/A-4861-2012; Myers, Simon/A-6792-2015; Tumian, Afidalina/J-4404-2014; Li, Yingrui/K-1064-2015; Albers, Kees/A-4170-2015; Cooper, David/H-4384-2011; Xing, Jinchuan/A-2489-2012; Sincan, Murat /A-3794-2010; Alkan, Can/D-2982-2009; Abecasis, Goncalo/B-7840-2010; Chen, Ken/A-1074-2009; Altshuler, David/A-4476-2009; MacArthur, Daniel/E-3275-2010; Browning, Brian/A-1178-2010; Schreiber, Stefan/B-6748-2008; Schaffner, Stephen/D-1189-2011; Ding, Jun/G-3918-2011; Li, Heng/D-9344-2011; De La Vega, Francisco/H-3832-2011; Wang, Jun/B-9503-2016; OI Casals, Ferran/0000-0002-8941-0369; Wang, Jun/0000-0002-8540-8931; Pearson, John/0000-0003-0904-4598; Mu, Xinmeng/0000-0002-8079-0828; Mills, Ryan/0000-0003-3425-6998; Dahl, Andreas/0000-0002-2668-8371; Stuetz, Adrian/0000-0001-7650-3470; Cunningham, Fiona/0000-0002-7445-2419; Quinlan, Aaron/0000-0003-1756-0859; Durbin, Richard/0000-0002-9130-1006; Rosenstiel, Philip/0000-0002-9692-8828; Korbel, Jan/0000-0002-2798-3794; Le, Quang/0000-0002-3715-210X; Myers, Simon/0000-0002-2585-9626; Tumian, Afidalina/0000-0003-2763-6677; Albers, Kees/0000-0003-4115-3727; Cooper, David/0000-0002-8943-8484; Alkan, Can/0000-0002-5443-0706; Altshuler, David/0000-0002-7250-4107; Browning, Brian/0000-0001-6454-6633; Schreiber, Stefan/0000-0003-2254-7771; Li, Heng/0000-0003-4874-2874; Zheng Bradley, Xiangqun/0000-0002-9324-2708; Abyzov, Alexej/0000-0001-5405-6729; Ayub, Qasim/0000-0003-3291-0917; Keenan, Stephen/0000-0002-9141-7690; Sebat, Jonathan/0000-0002-9087-526X; Sudmant, Peter/0000-0002-9573-8248; Kidd, Jeffrey/0000-0002-9631-1465; Radhakrishnan, Rajesh/0000-0001-7170-699X; Sidore, Carlo/0000-0001-7504-7477; Lindsay, Sarah/0000-0002-0965-3070; Wang, Jun/0000-0002-2113-5874; Leinonen, Rasko/0000-0002-2639-7187; Haraksingh, Rajini/0000-0002-6644-8874; Zalunin, Vadim/0000-0002-7722-1958; Kelley, Joanna/0000-0002-7731-605X; Abecasis, Goncalo/0000-0003-1509-1825; Herrero, Javier/0000-0001-7313-717X; Clarke, Laura/0000-0002-5989-6898; Yu, Jin/0000-0002-2990-6602; Flicek, Paul/0000-0002-3897-7955; McLaren, William/0000-0001-6218-1116; Walter, Klaudia/0000-0003-4448-0301; Hinrichs, Angie/0000-0002-1697-1130; Lunter, Gerton/0000-0002-3798-2058; Iqbal, Zamin/0000-0001-8466-7547; Keane, Thomas/0000-0001-7532-6898; Kulesha, Eugene/0000-0002-4285-6232 FU Wellcome Trust [WT089088/Z/09/Z, WT085532AIA, WT086084/Z/08/Z, WT081407/Z/06/Z, WT075491/Z/04, WT077009]; Medical Research Council [G0801823]; British Heart Foundation [RG/09/012/28096]; The Leverhulme Trust; EPSRC; Louis-Jeantet Foundation; Swiss National Science Foundation; NGI/EBI [050-72-436]; National Basic Research Program of China (973 program) [2011CB809200]; National Natural Science Foundation of China [30725008, 30890032, 30811130531, 30221004]; Chinese 863 program [2006AA02Z177, 2006AA02Z334, 2006AA02A302, 2009AA022707]; Shenzhen Municipal Government of China [JC200903190767A, JC200903190772A, CXB200903110066A, ZYC200903240077A, ZYC200903240076A, ZYC200903240080A]; Danish Natural Science Research Council; German Research Foundation (Deutsche Forschungsgemeinschaft); BMBF [01GS08201, PREDICT 0315428A]; BMBF NGFN PLUS; EU [242257]; Max Planck Society; Genome Quebec; Ministry of Economic Development, Innovation and Trade [PSR-SIIRI-195]; National Library of Medicine; National Institute of Environmental Health Sciences; NIH [P41HG4221, U01HG5209, P41HG4222, R01GM59290, R01GM72861, R01HG2651, R01MH84698, U01HG5214, P01HG4120, U54HG2750, U54HG2757, U01HG5210, U01HG5208, U01HG5211, R01HG3698, R01HG4719, RC2HG5552, R01HG3229, P50HG2357, R01HG4960, P41HG2371, U41HG4568, R01HG4333]; BWF and Packard Foundation; Pew Charitable Trust; NSF; [S10RR025056] FX We thank many people who contributed to this project: K. Beal, S. Fitzgerald, G. Cochrane, V. Silventoinen, P. Jokinen, E. Birney and J. Ahringer for comments on the manuscript; T. Hunkapiller and Q. Doan for their advice and coordination; N. Kalin, F. Laplace, J. Wilde, S. Paturej, I. Kuhndahl, J. Knight, C. Kodira and M. Boehnke for valuable discussions; Z. Cheng, S. Sajjadian and F. Hormozdiari for assistance in managing data sets; and D. Leja for help with the figures. We thank the Yoruba in Ibadan, Nigeria, the Han Chinese in Beijing, China, the Japanese in Tokyo, Japan, the Utah CEPH community, the Luhya in Webuye, Kenya, the Toscani in Italia, and the Chinese in Denver, Colorado, for contributing samples for research. This research was supported in part by Wellcome Trust grants WT089088/Z/09/Z to R. M. D.; WT085532AIA to P. F.; WT086084/Z/08/Z to G. A. M.; WT081407/Z/06/Z to J. S. K.; WT075491/Z/04 to G. L.; WT077009 to C.T.-S.; Medical Research Council grant G0801823 to J. L. M.; British Heart Foundation grant RG/09/012/28096 to C. A.; The Leverhulme Trust and EPSRC studentships to L. M. and A. T.; the Louis-Jeantet Foundation and Swiss National Science Foundation in support of E. T. D. and S. B. M.; NGI/EBI fellowship 050-72-436 to K.Y.; a National Basic Research Program of China (973 program no. 2011CB809200); the National Natural Science Foundation of China (30725008, 30890032, 30811130531, 30221004); the Chinese 863 program (2006AA02Z177, 2006AA02Z334, 2006AA02A302, 2009AA022707); the Shenzhen Municipal Government of China (grants JC200903190767A, JC200903190772A, ZYC200903240076A, CXB200903110066A, ZYC200903240077A, ZYC200903240076A and ZYC200903240080A); the Ole Romer grant from the Danish Natural Science Research Council; an Emmy Noether Fellowship of the German Research Foundation (Deutsche Forschungsgemeinschaft) to J.O.K.; BMBF grant 01GS08201; BMBF grant PREDICT 0315428A to R. H.; BMBF NGFN PLUS and EU 6th framework READNA to S. S.; EU 7th framework 242257 to A. V. S.; the Max Planck Society; a grant from Genome Quebec and the Ministry of Economic Development, Innovation and Trade, PSR-SIIRI-195 to P. A.; the Intramural Research Program of the NIH; the National Library of Medicine; the National Institute of Environmental Health Sciences; and NIH grants P41HG4221 and U01HG5209 to C. L.; P41HG4222 to J. S.; R01GM59290 to L. B. J. and M. A. B.; R01GM72861 to M. P.; R01HG2651 and R01MH84698 to G. R. A.; U01HG5214 to G. R. A. and A. C.; P01HG4120 to E. E. E.; U54HG2750 to D. L. A.; U54HG2757 to A. C.; U01HG5210 to D. C.; U01HG5208 to M. J. D.; U01HG5211 to R. A. G.; R01HG3698, R01HG4719 and RC2HG5552 to G. T. M.; R01HG3229 to C. D. B. and A. G. C.; P50HG2357 to M. S.; R01HG4960 to B. L. B; P41HG2371 and U41HG4568 to D. H.; R01HG4333 to A. M. L.; U54HG3273 to R. A. G.; U54HG3067 to E. S. L.; U54HG3079 to R. K. W.; N01HG62088 to the Coriell Institute; S10RR025056 to the Translational Genomics Research Institute; Al Williams Professorship funds for M. B. G.; the BWF and Packard Foundation support for P. C. S.; the Pew Charitable Trusts support for G. R. A.; and an NSF Minority Postdoctoral Fellowship in support of R. D. H. E. E. E. is an HHMI investigator, M. P. is an HHMI Early Career Scientist, and D. M. A. is Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. NR 50 TC 3000 Z9 3055 U1 68 U2 582 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 28 PY 2010 VL 467 IS 7319 BP 1061 EP 1073 DI 10.1038/nature09534 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 671XW UT WOS:000283548600039 ER PT J AU Miller, FG Kaptchuk, TJ AF Miller, Franklin G. Kaptchuk, Ted J. TI Acupuncture for Chronic Low Back Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Miller, Franklin G.] NIH, Bethesda, MD 20892 USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Boston, MA USA. RP Miller, FG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 3 TC 3 Z9 3 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 28 PY 2010 VL 363 IS 18 BP 1776 EP 1776 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 671XF UT WOS:000283546400037 PM 21038518 ER PT J AU Gravitt, PE Paul, P Katki, HA Vendantham, H Ramakrishna, G Sudula, M Kalpana, B Ronnett, BM Vijayaraghavan, K Shah, KV AF Gravitt, Patti E. Paul, Proma Katki, Hormuzd A. Vendantham, Haripriya Ramakrishna, Gayatri Sudula, Mrudula Kalpana, Basany Ronnett, Brigitte M. Vijayaraghavan, K. Shah, Keerti V. CA CATCH Study Team TI Effectiveness of VIA, Pap, and HPV DNA Testing in a Cervical Cancer Screening Program in a Peri-Urban Community in Andhra Pradesh, India SO PLOS ONE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; LOW-RESOURCE SETTINGS; LUGOLS IODINE VILI; VISUAL INSPECTION; ACETIC-ACID; HUMAN-PAPILLOMAVIRUS; DEVELOPING-COUNTRIES; RURAL INDIA; CYTOLOGY; ACCURACY AB Background: While many studies have compared the efficacy of Pap cytology, visual inspection with acetic acid (VIA) and human papillomavirus (HPV) DNA assays for the detection cervical intraepithelial neoplasia and cancer, few have evaluated the program effectiveness. Methods and Findings: A population-based sample of 5603 women from Medchal Mandal in Andhra Pradesh, India were invited to participate in a study comparing Pap cytology, VIA, and HPV DNA screening for the detection of CIN3+. Participation in primary screening and all subsequent follow-up visits was rigorously tracked. A 20% random sample of all women screened, in addition to all women with a positive screening test result underwent colposcopy with directed biopsy for final diagnosis. Sensitivity, specificity, positive and negative predictive values were adjusted for verification bias. HPV testing had a higher sensitivity (100%) and specificity (90.6%) compared to Pap cytology (sensitivity = 78.2%; specificity = 86.0%) and VIA (sensitivity = 31.6%; specificity = 87.5%). Since 58% of the sample refused involvement and another 28% refused colposcopy or biopsy, we estimated that potentially 87.6% of the total underlying cases of CIN3 and cancer may have been missed due to program failures. Conclusions: We conclude that despite our use of available resources, infrastructure, and guidelines for cervical cancer screening implementation in resource limited areas, community participation and non-compliance remain the major obstacles to successful reduction in cervical cancer mortality in this Indian population. HPV DNA testing was both more sensitive and specific than Pap cytology and VIA. The use of a less invasive and more user-friendly primary screening strategy (such as self-collected swabs for HPV DNA testing) may be required to achieve the coverage necessary for effective reduction in cervical cancer mortality. C1 [Gravitt, Patti E.; Paul, Proma] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti E.; Shah, Keerti V.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Katki, Hormuzd A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vendantham, Haripriya; Sudula, Mrudula; Kalpana, Basany; Vijayaraghavan, K.] Mediciti Inst Med Sci, SHARE INDIA, Ghanpur, India. [Ramakrishna, Gayatri] Ctr DNA Fingerprinting & Diagnost, Hyderabad, Andhra Pradesh, India. [Ronnett, Brigitte M.] Johns Hopkins Univ, Sch Med & Hosp, Dept Pathol, Baltimore, MD USA. [Ronnett, Brigitte M.] Johns Hopkins Univ, Sch Med & Hosp, Dept Gynecol & Obstet, Baltimore, MD USA. RP Gravitt, PE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. EM pgravitt@jhsph.edu RI Katki, Hormuzd/B-4003-2015 FU Department of Biotechnology, Ministry of Science and Technology, Government of India; NIH, USA [BT/IN/US/CRHR/PP/2002]; Research Excellence (SPORE) in Cervical Cancer [P50 CA98252] FX INDO-US collaborative program of Department of Biotechnology, Ministry of Science and Technology, Government of India and the NIH, USA (BT/IN/US/CRHR/PP/2002). NIH Specialized Programs of Research Excellence (SPORE) in Cervical Cancer P50 CA98252. Reagent discounts from Qiagen Corp (formerly Digene) and reagent gifts from Roche Molecular Systems. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 25 Z9 25 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 28 PY 2010 VL 5 IS 10 AR e13711 DI 10.1371/journal.pone.0013711 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 672HN UT WOS:000283573800011 PM 21060889 ER PT J AU Hinton, DM AF Hinton, Deborah M. TI Transcriptional control in the prereplicative phase of T4 development SO VIROLOGY JOURNAL LA English DT Review ID COLI RNA-POLYMERASE; BACTERIOPHAGE-T4 ASIA PROTEIN; SIGMA FACTOR ASIA; TERMINATION FACTOR-RHO; ACTIVATOR MOTA INTERACTS; AMINO-ACID CONTACTS; DNA-BINDING DOMAIN; PROMOTERS IN-VIVO; ESCHERICHIA-COLI; ALPHA-SUBUNIT AB Control of transcription is crucial for correct gene expression and orderly development. For many years, bacteriophage T4 has provided a simple model system to investigate mechanisms that regulate this process. Development of T4 requires the transcription of early, middle and late RNAs. Because T4 does not encode its own RNA polymerase, it must redirect the polymerase of its host, E. coli, to the correct class of genes at the correct time. T4 accomplishes this through the action of phage-encoded factors. Here I review recent studies investigating the transcription of T4 prereplicative genes, which are expressed as early and middle transcripts. Early RNAs are generated immediately after infection from T4 promoters that contain excellent recognition sequences for host polymerase. Consequently, the early promoters compete extremely well with host promoters for the available polymerase. T4 early promoter activity is further enhanced by the action of the T4 Alt protein, a component of the phage head that is injected into E. coli along with the phage DNA. Alt modifies Arg265 on one of the two alpha subunits of RNA polymerase. Although work with host promoters predicts that this modification should decrease promoter activity, transcription from some T4 early promoters increases when RNA polymerase is modified by Alt. Transcription of T4 middle genes begins about 1 minute after infection and proceeds by two pathways: 1) extension of early transcripts into downstream middle genes and 2) activation of T4 middle promoters through a process called sigma appropriation. In this activation, the T4 co-activator AsiA binds to Region 4 of sigma(70), the specificity subunit of RNA polymerase. This binding dramatically remodels this portion of sigma(70), which then allows the T4 activator MotA to also interact with sigma(70). In addition, AsiA restructuring of sigma(70) prevents Region 4 from forming its normal contacts with the -35 region of promoter DNA, which in turn allows MotA to interact with its DNA binding site, a MotA box, centered at the -30 region of middle promoter DNA. T4 sigma appropriation reveals how a specific domain within RNA polymerase can be remolded and then exploited to alter promoter specificity. C1 NIDDKD, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Hinton, DM (reprint author), NIDDKD, Lab Mol & Cellular Biol, NIH, Bldg 8,Room 2A-13, Bethesda, MD 20892 USA. EM dhinton@helix.nih.gov FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX I thank T. James, K. Decker, L. Knipling, R. Bonocora, M. Hsieh, and C. Philpott for helpful discussions and R. Bonocora for help with the design of Figure 3. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 150 TC 19 Z9 19 U1 1 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD OCT 28 PY 2010 VL 7 AR 289 DI 10.1186/1743-422X-7-289 PG 16 WC Virology SC Virology GA 683RB UT WOS:000284491800002 PM 21029433 ER PT J AU White, VB Leib, JR Farmer, JM Biesecker, BB AF White, V. Brook Leib, Jennifer R. Farmer, Jennifer M. Biesecker, Barbara B. TI Exploration of transitional life events in individuals with Friedreich ataxia: Implications for genetic counseling SO BEHAVIORAL AND BRAIN FUNCTIONS LA English DT Article ID QUALITY-OF-LIFE; MUSCULAR-DYSTROPHY; CHRONIC ILLNESS; TURNING-POINTS; IDENTITY; DISEASE; PERSPECTIVES; ADOLESCENTS; EXPERIENCE; SCLEROSIS AB Background: Human development is a process of change, adaptation and growth. Throughout this process, transitional events mark important points in time when one's life course is significantly altered. This study captures transitional life events brought about or altered by Friedreich ataxia, a progressive chronic illness leading to disability, and the impact of these events on an affected individual's life course. Methods: Forty-two adults with Friedreich ataxia (18-65y) were interviewed regarding their perceptions of transitional life events. Data from the interviews were coded and analyzed thematically using an iterative process. Results: Identified transitions were either a direct outcome of Friedreich ataxia, or a developmental event altered by having the condition. Specifically, an awareness of symptoms, fear of falling and changes in mobility status were the most salient themes from the experience of living with Friedreich ataxia. Developmental events primarily influenced by the condition were one's relationships and life's work. Conclusions: Friedreich ataxia increased the complexity and magnitude of transitional events for study participants. Transitional events commonly represented significant loss and presented challenges to self-esteem and identity. Findings from this study help alert professionals of potentially challenging times in patients' lives, which are influenced by chronic illness or disability. Implications for developmental counseling approaches are suggested for genetic counseling. C1 [White, V. Brook] Carolinas Med Ctr, Charlotte, NC 28232 USA. [Leib, Jennifer R.] HealthFutures, Washington, DC USA. [Farmer, Jennifer M.] Friedreichs Ataxia Res Alliance, Exton, PA USA. [Biesecker, Barbara B.] NHGRI, NIH, Bethesda, MD 20892 USA. RP White, VB (reprint author), Carolinas Med Ctr, POB 32861, Charlotte, NC 28232 USA. EM Brook.White@carolinas.org FU National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 49 TC 2 Z9 2 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-9081 J9 BEHAV BRAIN FUNCT JI Behav. Brain Funct. PD OCT 27 PY 2010 VL 6 AR 65 DI 10.1186/1744-9081-6-65 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 682JC UT WOS:000284396900001 PM 20979606 ER PT J AU Huang, EP Fridlyand, J Lewin-Koh, N Yue, P Shi, XY Dornan, D Burington, B AF Huang, Erich P. Fridlyand, Jane Lewin-Koh, Nicholas Yue, Peng Shi, Xiaoyan Dornan, David Burington, Bart TI Statistical techniques to construct assays for identifying likely responders to a treatment under evaluation from cell line genomic data SO BMC CANCER LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; GENE-EXPRESSION; BREAST-CANCER; LYMPHOMA; CHEMOTHERAPY; PATTERNS; EFFICACY; SUBTYPES; DISEASE; PROTEIN AB Background: Developing the right drugs for the right patients has become a mantra of drug development. In practice, it is very difficult to identify subsets of patients who will respond to a drug under evaluation. Most of the time, no single diagnostic will be available, and more complex decision rules will be required to define a sensitive population, using, for instance, mRNA expression, protein expression or DNA copy number. Moreover, diagnostic development will often begin with in-vitro cell-line data and a high-dimensional exploratory platform, only later to be transferred to a diagnostic assay for use with patient samples. In this manuscript, we present a novel approach to developing robust genomic predictors that are not only capable of generalizing from in-vitro to patient, but are also amenable to clinically validated assays such as qRT-PCR. Methods: Using our approach, we constructed a predictor of sensitivity to dacetuzumab, an investigational drug for CD40-expressing malignancies such as lymphoma using genomic measurements of cell lines treated with dacetuzumab. Additionally, we evaluated several state-of-the-art prediction methods by independently pairing the feature selection and classification components of the predictor. In this way, we constructed several predictors that we validated on an independent DLBCL patient dataset. Similar analyses were performed on genomic measurements of breast cancer cell lines and patients to construct a predictor of estrogen receptor (ER) status. Results: The best dacetuzumab sensitivity predictors involved ten or fewer genes and accurately classified lymphoma patients by their survival and known prognostic subtypes. The best ER status classifiers involved one or two genes and led to accurate ER status predictions more than 85% of the time. The novel method we proposed performed as well or better than other methods evaluated. Conclusions: We demonstrated the feasibility of combining feature selection techniques with classification methods to develop assays using cell line genomic measurements that performed well in patient data. In both case studies, we constructed parsimonious models that generalized well from cell lines to patients. C1 [Fridlyand, Jane; Lewin-Koh, Nicholas; Yue, Peng; Shi, Xiaoyan; Dornan, David; Burington, Bart] Genentech Inc, San Francisco, CA 94080 USA. [Huang, Erich P.] NCI, Biometr Res Branch, Dept Canc Treatment & Diag, NIH, Rockville, MD 20852 USA. RP Burington, B (reprint author), Genentech Inc, San Francisco, CA 94080 USA. EM burington.bart@gene.com FU Genentech, Inc., South San Francisco, CA, USA FX The authors would like to thank Gracie Lieberman (Genentech, Inc., South San Francisco, CA, USA) for supporting the project. NR 34 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 27 PY 2010 VL 10 AR 586 DI 10.1186/1471-2407-10-586 PG 17 WC Oncology SC Oncology GA 678WR UT WOS:000284114300001 PM 20979617 ER PT J AU Migueles, SA Connors, M AF Migueles, Stephen A. Connors, Mark TI Long-term Nonprogressive Disease Among Individuals With Untreated HIV Infection Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID HEPATITIS-C INFECTION; SUPPRESSORS; IMMUNOBLOTS C1 [Migueles, Stephen A.; Connors, Mark] NIAID, NIH, Bethesda, MD 20892 USA. RP Migueles, SA (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mconnors@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 27 PY 2010 VL 304 IS 16 BP 1785 EP 1786 DI 10.1001/jama.2010.1477 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 671JZ UT WOS:000283501300016 ER PT J AU Wang, J Carnicella, S Ahmadiantehrani, S He, DY Barak, S Kharazia, V Ben Hamida, S Zapata, A Shippenberg, TS Ron, D AF Wang, Jun Carnicella, Sebastien Ahmadiantehrani, Somayeh He, Dao-Yao Barak, Segev Kharazia, Viktor Ben Hamida, Sami Zapata, Agustin Shippenberg, Toni S. Ron, Dorit TI Nucleus Accumbens-Derived Glial Cell Line-Derived Neurotrophic Factor Is a Retrograde Enhancer of Dopaminergic Tone in the Mesocorticolimbic System SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; FACTOR EXPRESSION; BASAL GANGLIA; NEURONS; GDNF; ADULT; CHANNELS; DRUG; RAT; DEPRESSION AB Spontaneous firing of ventral tegmental area (VIA) dopamine (DA) neurons provides ambient levels of DA in target areas such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC). Here we report that the glial cell line-derived neurotrophic factor (GDNF), produced in one target region, the NAc, is retrogradely transported by DA neurons to the VIA where the growth factor positively regulates the spontaneous firing activity of both NAc- and PFC-projecting DA neurons in a mechanism that requires the activation of the mitogen-activated protein kinase (MAPK) pathway. We also show that the consequence of GDNF-mediated activation of the MAPK signaling cascade in the VIA is an increase in DA overflow in the NAc. Together, these results demonstrate that NAc-produced GDNF serves as a retrograde enhancer that upregulates the activity of the mesocorticolimbic DA system. C1 [Wang, Jun; Carnicella, Sebastien; Ahmadiantehrani, Somayeh; He, Dao-Yao; Barak, Segev; Kharazia, Viktor; Ben Hamida, Sami; Ron, Dorit] Gallo Res Ctr, Emeryville, CA 94608 USA. [Ahmadiantehrani, Somayeh; Ron, Dorit] Univ Calif San Francisco, Grad Program Pharmaceut Sci & Pharmacogenom, San Francisco, CA 94143 USA. [Carnicella, Sebastien; Ron, Dorit] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Zapata, Agustin; Shippenberg, Toni S.] Natl Inst Drug Abuse, Integrat Neurosci Sect, Baltimore, MD 21224 USA. RP Ron, D (reprint author), 5858 Horton St,Suite 200, Emeryville, CA 94608 USA. EM dron@gallo.ucsf.edu RI Wang, Jun/N-8472-2015; Wang, Jun/M-2337-2016; OI Wang, Jun/0000-0002-0085-4722; Wang, Jun/0000-0002-0085-4722; Barak, Segev/0000-0002-3143-6777 FU National Institutes of Health (NIH)-National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R01 AA014366]; State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco; NIH; NIAAA [F31 AA017801]; Merck Scholar Award; Department of the Army [W81XWH-07-1-0079] FX This work was supported by National Institutes of Health (NIH)-National Institute on Alcohol Abuse and Alcoholism (NIAAA) Grant R01 AA014366 (DR.); the State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco (D.R.);the NIH National Institute on Drug Abuse Intramural Research Program (T.S.S..); National Research Service Award-NIAAA Grant F31 AA017801 (S.A.); the Merck Scholar Award (S.A.); and Department of the Army Grant W81XWH-07-1-0079 (DR.), for which the U.S. Army Medical Research Acquisition Activity (Fort Detrick, MD) is the awarding and administering acquisition office. The content of the information represented does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. We thank Wenheng Zhu for technical support; Dr. Elyssa Margolis for technical support, helpful discussions, and critical review of this manuscript; Drs. Billy Chen, Robert Froemke, and Patricia Janak for critical review of this manuscript; and Drs. Howard Fields and Greg Hjelmstad for helpful discussions. NR 53 TC 19 Z9 20 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 OCT 27 PY 2010 VL 30 IS 43 BP 14502 EP 14512 DI 10.1523/JNEUROSCI.3909-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 674ZA UT WOS:000283790800027 PM 20980608 ER PT J AU Patti, GJ Shriver, LP Wassif, CA Woo, HK Uritboonthai, W Apon, J Manchester, M Porter, FD Siuzdak, G AF Patti, G. J. Shriver, L. P. Wassif, C. A. Woo, H. K. Uritboonthai, W. Apon, J. Manchester, M. Porter, F. D. Siuzdak, G. TI NANOSTRUCTURE-INITIATOR MASS SPECTROMETRY (NIMS) IMAGING OF BRAIN CHOLESTEROL METABOLITES IN SMITH-LEMLI-OPITZ SYNDROME SO NEUROSCIENCE LA English DT Article DE Smith-Lemli-Opitz syndrome; brain imaging; nanostructure-initiator mass spectrometry; cholesterol; metabolism; mass spectrometry ID DHCR7 NULL MICE; STEROL BIOSYNTHESIS; NEONATAL LETHALITY; REDUCTASE GENE; INBORN-ERRORS; MOUSE MODEL; AUTISM; 7-DEHYDROCHOLESTEROL; DISORDERS; MUTATIONS AB Cholesterol is an essential component of cellular membranes that is required for normal lipid organization and cell signaling. While the mechanisms associated with maintaining cholesterol homeostasis in the plasma and peripheral tissues have been well studied, the role and regulation of cholesterol biosynthesis in normal brain function and development have proven much more challenging to investigate. Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis characterized by mutations of 7-dehydrocholesterol reductase (DHCR7) that impair the reduction of 7dehydrocholesterol (7DHC) to cholesterol and lead to neurocognitive deficits, including cerebellar hypoplasia and austism behaviors. Here we have used a novel mass spectrometry-based imaging technique called cation-enhanced nanostructure-initiator mass spectrometry (NIMS) for the in situ detection of intact cholesterol molecules from biological tissues. We provide the first images of brain sterol localization in a mouse model for SLOS (Dhcr7(-/-)). In SLOS mice, there is a striking localization of both 7DHC and residual cholesterol in the abnormally developing cerebellum and brainstem. In contrast, the distribution of cholesterol in 1-day old healthy pups was diffuse throughout the cerebrum and comparable to that of adult mice. This study represents the first application of NIMS to localize perturbations in metabolism within pathological tissues and demonstrates that abnormal cholesterol biosynthesis may be particularly important for the development of these brain regions. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Patti, G. J.; Woo, H. K.; Uritboonthai, W.; Apon, J.; Siuzdak, G.] Scripps Res Inst, Scripps Ctr Mass Spectrometry, Dept Mol Biol, La Jolla, CA 92037 USA. [Shriver, L. P.; Manchester, M.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92037 USA. [Wassif, C. A.; Porter, F. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Sect Mol Dysmorphol, Program Dev Endocrinol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Siuzdak, G (reprint author), Scripps Res Inst, Scripps Ctr Mass Spectrometry, Dept Mol Biol, La Jolla, CA 92037 USA. EM siuzdak@scripps.edu OI Manchester, Marianne/0000-0002-7143-5744; Wassif, Christopher/0000-0002-2524-1420 FU California Institute of Regenerative Medicine [TR1-01219]; National Institutes of Health [R24 EY017540-04, P30 MH062261-10, P01 DA026146-02]; NIH/NCRR/STSI [UL1 RR025774]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH/NINDS [1 F32 NS068015-01A1] FX This work was supported by the California Institute of Regenerative Medicine (TR1-01219), the National Institutes of Health (R24 EY017540-04, P30 MH062261-10, and P01 DA026146-02), NIH/NCRR/STSI UL1 RR025774, the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and NIH/NINDS 1 F32 NS068015-01A1 (LPS). NR 44 TC 28 Z9 28 U1 5 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 27 PY 2010 VL 170 IS 3 BP 858 EP 864 DI 10.1016/j.neuroscience.2010.07.038 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 675KZ UT WOS:000283830900019 PM 20670678 ER PT J AU Peiperl, L Morgan, C Moodie, Z Li, HL Russell, N Graham, BS Tomaras, GD De Rosa, SC McElrath, MJ AF Peiperl, Laurence Morgan, Cecilia Moodie, Zoe Li, Hongli Russell, Nina Graham, Barney S. Tomaras, Georgia D. De Rosa, Stephen C. McElrath, M. Juliana CA NIAID HIV Vaccine Trials Network TI Safety and Immunogenicity of a Replication-Defective Adenovirus Type 5 HIV Vaccine in Ad5-Seronegative Persons: A Randomized Clinical Trial (HVTN 054) SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; NEUTRALIZING ANTIBODIES; CANDIDATE VACCINE; HEALTHY-ADULTS; PHASE-1 SAFETY; GAG VACCINES; VIRUS; DNA; VECTOR; IMMUNITY AB Background: Individuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses. Methodology/Principal Findings: Volunteers received one dose of vaccine at either 10(10) or 10(11) adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-gamma ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients. Conclusions/Significance: This vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector. C1 [Peiperl, Laurence] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Morgan, Cecilia; Moodie, Zoe; Li, Hongli; De Rosa, Stephen C.; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Russell, Nina] Bill & Melinda Gates Fdn, Seattle, WA USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Tomaras, Georgia D.] Duke Univ, Durham, NC USA. [De Rosa, Stephen C.; McElrath, M. Juliana] Univ Washington, Seattle, WA 98195 USA. RP Peiperl, L (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM jmcelrat@fhcrc.org RI Tomaras, Georgia/J-5041-2016; OI Peiperl, Laurence/0000-0003-1237-4846 FU Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), United States National Institutes of Health (NIH); NIAID FX The study was sponsored by the Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), United States National Institutes of Health (NIH) and conducted through the NIAID-funded HIV Vaccine Trials Network (HVTN). Study vaccine and placebo were provided by the Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH. VRC and HVTN both contributed to the study design, decision to publish, and preparation of the manuscript. The clinical trial and data analyses were conducted by HVTN and the Statistical Center for HIV/AIDS Research and Prevention (SCHARP). NR 45 TC 34 Z9 35 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2010 VL 5 IS 10 AR e13579 DI 10.1371/journal.pone.0013579 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 671UN UT WOS:000283537000011 PM 21048953 ER PT J AU Hurst, FP Jindal, RM Graham, LJ Falta, EM Elster, EA Stackhouse, GB Agodoa, LY Lentine, KL Salifu, MO Abbott, KC AF Hurst, Frank P. Jindal, Rahul M. Graham, Lindsey J. Falta, Edward M. Elster, Eric A. Stackhouse, George B. Agodoa, Lawrence Y. Lentine, Krista L. Salifu, Moro O. Abbott, Kevin C. TI Incidence, Predictors, Costs, and Outcome of Renal Cell Carcinoma After Kidney Transplantation: USRDS Experience SO TRANSPLANTATION LA English DT Article DE Renal cell carcinoma; Kidney cysts; Cost of screening; Risk of renal cell carcinoma ID UNITED-STATES; DISEASE; RECIPIENTS; CANCER AB Introduction. We carried out an analysis of the United States Renal Data System to determine the incidence, risk factors, prognosis, and costs associated with the diagnosis of renal cell carcinoma (RCC) after kidney transplantation. Methods. This is a retrospective cohort of 40,821 Medicare primary renal transplant recipients transplanted from January 1, 2000, to July 1, 2005, and followed up till December 31, 2005, excluding those with prior RCC or nephrectomy. Kaplan-Meier analysis was performed to determine the time of occurrence of RCC, and Cox regression was used to determine factors associated with RCC. Results. Three hundred sixty-eight patients were diagnosed with RCC within 3 years after transplant (incidence of 3.16 per 1000 person years). The 3-year incidence of RCC posttransplant was 9.29 per 1000 person years (2.3%) for those with pretransplant cysts and 3.08 per 1000 person years (0.7%) without pretransplant cysts. RCC was diagnosed disproportionately early posttransplant in patients with cysts. Cysts were independently associated with increased risk of RCC, as was male gender, older recipient, donor age, African American recipient, increased time on dialysis and acute rejection within first year posttransplant. RCC was associated with increased risk of mortality with a higher risk with pretransplant cysts. Patients who developed RCC had higher cumulative median costs ($55,456 at 2 years) than those who did not develop RCC ($40,369). There was no "clustering" of RCC in individual states or centers more than would be expected by chance. Conclusion. RCC was diagnosed disproportionately early in patients with pretransplant renal cysts and was associated with a worse prognosis and increased costs. C1 [Jindal, Rahul M.] Walter Reed Army Med Ctr, Dept Organ Transplantat, Organ Transplant Serv, Washington, DC 20307 USA. [Hurst, Frank P.; Graham, Lindsey J.; Elster, Eric A.; Abbott, Kevin C.] Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. [Hurst, Frank P.; Jindal, Rahul M.; Graham, Lindsey J.; Falta, Edward M.; Elster, Eric A.; Abbott, Kevin C.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Nephrol & Surg, Bethesda, MD 20814 USA. [Jindal, Rahul M.] George Washington Univ, Dept Med, Washington, DC USA. [Stackhouse, George B.] Walter Reed Army Med Ctr, Urol Serv, Washington, DC 20307 USA. [Agodoa, Lawrence Y.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Lentine, Krista L.] St Louis Univ, Sch Med, Ctr Outcomes Res, St Louis, MO USA. [Salifu, Moro O.] Suny Downstate Med Ctr, Dept Med, Div Nephrol, Brooklyn, NY 11203 USA. RP Jindal, RM (reprint author), Walter Reed Army Med Ctr, Dept Organ Transplantat, Organ Transplant Serv, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM jindalr@msn.com OI Abbott, Kevin/0000-0003-2111-7112 NR 16 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD OCT 27 PY 2010 VL 90 IS 8 BP 898 EP 904 DI 10.1097/TP.0b013e3181f30479 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 668JD UT WOS:000283263700015 PM 21248500 ER PT J AU Bobe, G Murphy, G Albert, PS Sansbury, LB Lanza, E Schatzkin, A Colburn, NH Cross, AJ AF Bobe, G. Murphy, G. Albert, P. S. Sansbury, L. B. Lanza, E. Schatzkin, A. Colburn, N. H. Cross, A. J. TI Serum cytokine concentrations, flavonol intake and colorectal adenoma recurrence in the Polyp Prevention Trial SO BRITISH JOURNAL OF CANCER LA English DT Article DE cancer prevention; colorectal adenoma; colorectal cancer; cytokines; flavonols ID QUERCETIN-INDUCED APOPTOSIS; ENDOTHELIAL-CELL-ADHESION; COLONY-STIMULATING FACTOR; PROSTATE-CANCER CELLS; NF-KAPPA-B; GENE-EXPRESSION; DIETARY FLAVONOIDS; IN-VITRO; ANTIINFLAMMATORY ACTIVITY; PROGNOSTIC-SIGNIFICANCE AB BACKGROUND: Serum cytokine concentrations may reflect inflammatory processes occurring during the development of colorectal neoplasms. Flavonols, bioactive compounds found in plant-based foods and beverages, may inhibit colorectal neoplasms partly by attenuating inflammation. METHODS: Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to investigate the association between serum concentrations of interleukin (IL) 1 beta, 2, 8, 10, 12p70, granulocyte macrophage colony stimulating factor, interferon-gamma, and tumour necrosis factor-alpha, measured over time, flavonol intake, estimated from a flavonol database used in conjunction with a food frequency questionnaire, and adenoma recurrence in 872 participants from the intervention arm of the Polyp Prevention Trial. RESULTS: Decreased IL-2 concentration during the trial increased the risk of any adenoma recurrence (4th vs 1st quartile, OR = 1.68, 95% CI = 1.13-2.49), whereas decreased IL-1 beta or IL-10 reduced the risk of advanced adenoma recurrence (OR = 0.37, 95% CI = 0.15-0.94; OR = 0.39, 95% CI = 0.15-0.98, respectively). Individuals with flavonol intake above the median (29.7 mg per day) and decreased cytokine concentrations had the lowest risk of advanced adenoma recurrence. CONCLUSION: Overall, no consistent associations were observed between serum cytokine profile and colorectal adenoma recurrence; however, decreased cytokine concentrations during high flavonol consumption may indicate prevention of colorectal neoplasms. British Journal of Cancer (2010) 103, 1453-1461. doi: 10.1038/sj.bjc.6605915 www.bjcancer.com Published online 5 October 2010 (C) 2010 Cancer Research UK C1 [Bobe, G.; Lanza, E.; Colburn, N. H.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH,Dept Hlth & Human Serv, Frederick, MD 21702 USA. [Murphy, G.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Albert, P. S.] NICHHD, Biostat & Bioinformat Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Sansbury, L. B.] NCI, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. [Schatzkin, A.; Cross, A. J.] NCI, Nutr Epidemiol Branch, DCEG, NIH,DHHS, Bethesda, MD 20892 USA. RP Bobe, G (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, NIH,Dept Hlth & Human Serv, Bldg 576,Room 101,1050 Boyles St, Frederick, MD 21702 USA. EM gerd.bobe@oregonstate.edu FU Office of Dietary Supplements; National Cancer Institute, NIH, DHHS, Bethesda, MD, USA FX We thank the Polyp Prevention Trial Study Group for their outstanding contribution to this project. We thank Helen Rager and Yanyu Wang from the Clinical Support Laboratory of SAIC Frederick, Inc. (Frederick, MD, USA) for cytokine analysis of the serum samples. This study was funded by the Office of Dietary Supplements and the Intramural Research Program, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA. NR 80 TC 14 Z9 14 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 26 PY 2010 VL 103 IS 9 BP 1453 EP 1461 DI 10.1038/sj.bjc.6605915 PG 9 WC Oncology SC Oncology GA 671VU UT WOS:000283540300020 PM 20924374 ER PT J AU Lerro, CC McGlynn, KA Cook, MB AF Lerro, C. C. McGlynn, K. A. Cook, M. B. TI A systematic review and meta-analysis of the relationship between body size and testicular cancer SO BRITISH JOURNAL OF CANCER LA English DT Review DE body height; body mass index; body weight; meta-analysis; review; systematic; testicular neoplasms ID GERM-CELL TUMORS; UNITED-STATES; MASS INDEX; YOUNG MEN; UNDESCENDED TESTES; EUROPEAN COUNTRIES; PHYSICAL-ACTIVITY; DIETARY PRACTICES; ADOLESCENT MILK; SECULAR TRENDS AB BACKGROUND: Studies assessing the relationships of anthropometry and testicular germ-cell tumour (TGCT) have reported heterogeneous findings. METHODS: We undertook a systematic review and meta-analysis of the associations between adult height, weight, body mass index (BMI), and testicular cancer. Search strategies were conducted in PubMed, EMBASE, Scopus, and Web of Science on 26 May 2009. Studies that met our inclusion criteria were included in meta-analytic models using STATA 11. RESULTS: A total of 3255 references were retrieved, of which 14 met the inclusion criteria. Random effects meta-analysis found adult height (odds ratio (OR) per 5-cm increase 1.13, 95% confidence interval (CI) 1.07-1.19, P<0.001) and weight (OR overweight vs normal 0.92, 95% CI 0.86-0.98, P = 0.011) to be associated with TGCT. The meta-analysis of weight and TGCT produced a summary estimate, which indicated no association, although an analysis restricted studies to North American was suggestive of association (OR per 1-kg increase 1.01, 95% CI 1.00-1.01, P<0.001). CONCLUSIONS: This systematic review and meta-analysis has found evidence for a positive association of adult height and TGCT, and tentative evidence for an inverse association of BMI and TGCT. British Journal of Cancer (2010) 103, 1467-1474. doi: 10.1038/sj.bjc.6605934 www.bjcancer.com (C) 2010 Cancer Research UK C1 [Lerro, C. C.; McGlynn, K. A.; Cook, M. B.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Lerro, C. C.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU National Cancer Institute, NIH FX We thank Cindy Clark of the NIH Library for her help with designing the search strategies, and the following scientists for their kind provision of supplementary data: Dr Tone Bjorge (University of Bergen, Germany); Dr Clair Chilvers and Dr Carol Coupland (University of Nottingham, UK); Dr Klaus-Peter Dieckmann (Department of Urology, Albertinen-Hospital, Germany); Dr Lennart Hardell (University Hospital, Orebro, Sweden); Saiyi Pan (Centre for Chronic Disease Prevention and Control, Public Health Agency of Canada); Dr Lorenzo Richiardi (University of Turin, Italy); Dr Alice Sigurdson (National Cancer Institute, Division of Cancer Epidemiology and Genetics, MD, USA); and Dr Andreas Stang (Institute of Clinical Epidemiology, Martin-Luther-University of Halle-Wittenberg, Germany). We would also like to thank Dr Michael Bracken and Dr Yawei Zhang for their contributions. This study was supported by the Intramural Research Program of the National Cancer Institute, NIH. NR 62 TC 27 Z9 27 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 26 PY 2010 VL 103 IS 9 BP 1467 EP 1474 DI 10.1038/sj.bjc.6605934 PG 8 WC Oncology SC Oncology GA 671VU UT WOS:000283540300022 PM 20978513 ER PT J AU Velagaleti, RS Gona, P Larson, MG Wang, TJ Levy, D Benjamin, EJ Selhub, J Jacques, PF Meigs, JB Tofler, GH Vasan, RS AF Velagaleti, Raghava S. Gona, Philimon Larson, Martin G. Wang, Thomas J. Levy, Daniel Benjamin, Emelia J. Selhub, Jacob Jacques, Paul F. Meigs, James B. Tofler, Geoffrey H. Vasan, Ramachandran S. TI Multimarker Approach for the Prediction of Heart Failure Incidence in the Community SO CIRCULATION LA English DT Article DE biomarkers; epidemiology; heart failure; natriuretic peptides; risk; prediction ID C-REACTIVE PROTEIN; PLASMA NATRIURETIC PEPTIDE; PLASMINOGEN-ACTIVATOR INHIBITOR-1; PRIOR MYOCARDIAL-INFARCTION; METABOLIC RISK-FACTORS; CARDIOVASCULAR EVENTS; DIABETES-MELLITUS; BLOOD-PRESSURE; DIASTOLIC DYSFUNCTION; HOMOCYSTEINE LEVELS AB Background-Several biological pathways are activated in ventricular remodeling and in overt heart failure (HF). There are no data, however, on the incremental utility of a parsimonious set of biomarkers (reflecting pathways implicated in HF) for predicting HF risk in the community. Methods and Results-We related a multibiomarker panel to the incidence of a first HF event in 2754 Framingham Heart Study participants (mean age, 58 years; 54% women) who were free of HF and underwent routine assays for 6 biomarkers (C-reactive protein, plasminogen activator inhibitor-1, homocysteine, aldosterone-to-renin ratio, B-type natriuretic peptide, and urinary albumin-to-creatinine ratio). We estimated model c statistic, calibration, and net reclassification improvement to assess the incremental predictive usefulness of biomarkers. We also related biomarkers to the incidence of nonischemic HF in participants without prevalent coronary heart disease. On follow-up (mean, 9.4 years), 95 first HF events occurred (54 in men). In multivariable-adjusted models, the biomarker panel was significantly related to HF risk (P=0.00005). On backward elimination, B-type natriuretic peptide and urinary albumin-to-creatinine ratio emerged as key biomarkers predicting HF risk; hazards ratios per 1-SD increment in log marker were 1.52 (95% confidence interval, 1.24 to 1.87) and 1.35 (95% confidence interval, 1.11 to 1.66), respectively. B-type natriuretic peptide and urinary albumin-to-creatinine ratio significantly improved the model c statistic from 0.84 (95% confidence interval, 0.80 to 0.88) in standard models to 0.86 (95% confidence interval, 0.83 to 0.90), enhanced risk reclassification (net reclassification improvement=0.13; P=0.002), and were independently associated with nonischemic HF risk. Conclusion-Using a multimarker strategy, we identified B-type natriuretic peptide and urinary albumin-to-creatinine ratio as key risk factors for new-onset HF with incremental predictive utility over standard risk factors. (Circulation. 2010;122:1700-1706.) C1 [Velagaleti, Raghava S.; Gona, Philimon; Larson, Martin G.; Wang, Thomas J.; Levy, Daniel; Benjamin, Emelia J.; Meigs, James B.; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Gona, Philimon; Larson, Martin G.] Boston Univ, Sch Med, Dept Math & Stat, Boston, MA 02118 USA. [Gona, Philimon; Larson, Martin G.] Boston Univ, Sch Med, Prevent Med & Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Selhub, Jacob; Jacques, Paul F.] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Tofler, Geoffrey H.] Royal N Shore Hosp, Dept Cardiol, Sydney, NSW, Australia. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM vasan@bu.edu RI Max, Mad/E-5238-2010; OI Max, Mad/0000-0001-6966-6829; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute [N01-HC-25195]; National Institutes of Health [RO1HL67288, HL080124, K24-HL04334]; American Diabetes Association; National Institute of Diabetes and Digestive and Kidney Diseases [K24DK080140] FX This work was supported by the National Heart, Lung and Blood Institute (contract N01-HC-25195); National Institutes of Health grants RO1HL67288, HL080124, and K24-HL04334 (Dr Vasan); and an American Diabetes Association clinical research grant. Dr Meigs is supported by National Institute of Diabetes and Digestive and Kidney Diseases K24DK080140. NR 55 TC 56 Z9 57 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 26 PY 2010 VL 122 IS 17 BP 1700 EP + DI 10.1161/CIRCULATIONAHA.109.929661 PG 19 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 670PU UT WOS:000283440600014 PM 20937976 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Risk Stratification for Sudden Cardiac Death A Puzzle Beyond p Values SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cardiorespiratory fitness; exercise testing; sudden cardiac death C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 7 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 26 PY 2010 VL 56 IS 18 BP 1484 EP 1485 DI 10.1016/j.jacc.2010.05.047 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 665VZ UT WOS:000283065300008 PM 20951324 ER PT J AU Li, YX Kurlander, RJ AF Li, Yixin Kurlander, Roger J. TI Comparison of anti-CD3 and anti-CD28-coated beads with soluble anti-CD3 for expanding human T cells: Differing impact on CD8 T cell phenotype and responsiveness to restimulation SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID EX-VIVO; LYMPHOCYTE-CULTURES; CD28 COSTIMULATION; EFFECTOR FUNCTIONS; ADOPTIVE TRANSFER; MEMORY; ANTIGEN; DIFFERENTIATION; PROLIFERATION; EXPRESSION AB Background: The ability to expand virus-or tumor-specific T cells without damaging their functional capabilities is critical for success adoptive transfer immunotherapy of patients with opportunistic infection or tumor. Careful comparisons can help identify expansion methods better suited for particular clinical settings and identify recurrent deficiencies requiring new innovation. Methods: We compared the efficacy of magnetic beads coated with anti-CD3 and anti-CD28 (anti-CD3/CD28 beads), and soluble anti-CD3 plus mixed mononuclear cells (designated a rapid expansion protocol or REP) in expanding normal human T cells. Results: Both anti-CD3/CD28 beads and soluble anti-CD3 promoted extensive expansion. Beads stimulated greater CD4 cell growth (geometric mean of 56-versus 27-fold (p < 0.01) at day 21) but both stimulated similar CD8 expansion (189-versus 186-fold). Phenotypically, bead-treated CD4 and CD8 T cells and anti-CD3-treated CD4 cells typically assumed an effector/effector memory phenotype by day 14. By comparison, a subset of anti-CD3-treated CD8 cells, derived from naive cells, retained much greater expression of CD45RA, CD27 and CCR7, than matched bead-treated cells despite comparable expansion. These cells were clearly distinguishable from CD45RA+ terminally differentiated effector cells by the presence of CD27, the absence of CD57 and their inability to produce cytokines after stimulation. When used to expand previously stimulated cells, anti-CD3 plus autologous MNCs produced much less antigen-induced cell death of CD8 cells and significantly more CD8 expansion than beads. Conclusions: Anti-CD3/CD28 beads are highly effective for expanding CD4 cells, but soluble anti-CD3 has significant potential advantages for expanding CD8 T cells, particularly where preservation of phenotypically "young" CD8 cells would be desirable, or where the T cells of interest have been antigen-stimulated in vitro or in vivo in the recent past. C1 [Li, Yixin; Kurlander, Roger J.] Natl Inst Hlth, Dept Lab Med, NIH Clin Ctr, Bethesda, MD 20892 USA. RP Kurlander, RJ (reprint author), Natl Inst Hlth, Dept Lab Med, NIH Clin Ctr, Bethesda, MD 20892 USA. EM rkurlander@mail.cc.nih.gov FU NIH; Clinical Center FX We wish to acknowledge Fran Hakim for her many helpful suggestions and for reviewing the manuscript. This research was supported by the Intramural Research Program of the NIH and the Clinical Center NR 43 TC 23 Z9 27 U1 1 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 OCT 26 PY 2010 VL 8 AR 104 DI 10.1186/1479-5876-8-104 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 682AG UT WOS:000284367000001 PM 20977748 ER PT J AU Neal, RE Lin, C Isom, R Vaishnav, K Zigler, JS AF Neal, R. E. Lin, C. Isom, R. Vaishnav, K. Zigler, J. S., Jr. TI Opacification of lenses cultured in the presence of Pb SO MOLECULAR VISION LA English DT Article ID ALPHA-B-CRYSTALLIN; AGE-RELATED-CHANGES; BLOOD LEAD LEVELS; 2-DIMENSIONAL ELECTROPHORESIS; OXIDATIVE STRESS; ORGAN-CULTURE; A-CRYSTALLIN; RAT LENSES; MASS-SPECTROMETRY; EXPOSURE ALTERS AB Purpose: Occupational and environmental Pb-exposure is associated with protein aggregation diseases which typically present in elderly populations (Parkinsons and cataract). Post-translational processing of crystallins, the major structural proteins of the lens, is altered with short-term Pb-exposure in Fisher 344 rats. In addition, lenses from aged rats become opaque upon long-term exposure to Pb in organ culture. To explore the route to lens opacification in the presence of Pb, cultured lenses from young rats which exhibit higher metabolic activity in lens culture and are more susceptible to experimental cataract in vivo and in vitro were exposed to Pb and evaluated for morphological and biochemical alterations. Methods: Following culture in Pb (as lead nitrate) for four days (in the presence/absence of oxidative challenge), lenses were examined for clarity, integrity of epithelial layer, and molecular stability including crystallin post-translational modification and choline transport. Clarity of lenses cultured with/without Pb for up to 8 days was assessed to determine if Pb exposure would accelerate opacification. Results: Lenses cultured in Pb for four days exhibited epithelial abnormalities including epithelial cell multilayering and nuclei abnormalities with extension of the nucleated epithelial cells past the bow region. Alterations in crystallin post-translational modifications and decreased membrane transport of choline were noted without corresponding lens opacification or altered a-crystallin chaperone activity. Lenses treated with Pb according to the same exposure protocol with subsequent challenge by hydrogen peroxide became opaque while the contralateral control lenses did not. Lenses which were cultured in the presence of Pb for longer periods with no subsequent oxidative insult exhibited lens failure at earlier time points than did the controls. Conclusions: These data indicate that Pb-exposure can accelerate the degradation of the cultured lens through induction of epithelial cell abnormalities, induce structural protein modifications before opacity, and predispose the lens to opacification with subsequent oxidant challenge. C1 [Neal, R. E.] Univ Louisville, Dept Environm & Occupat Hlth Sci, Sch Publ Hlth & Informat Sci, Louisville, KY 40292 USA. [Neal, R. E.; Lin, C.; Isom, R.; Vaishnav, K.; Zigler, J. S., Jr.] NEI, NIH, Bethesda, MD 20892 USA. RP Neal, RE (reprint author), Univ Louisville, Dept Environm & Occupat Hlth Sci, Sch Publ Hlth & Informat Sci, 485 E Gray St, Louisville, KY 40292 USA. EM rachel.neal@louisville.edu NR 43 TC 5 Z9 5 U1 1 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD OCT 26 PY 2010 VL 16 IS 229-31 BP 2137 EP 2145 PG 9 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 674EV UT WOS:000283717900001 PM 21139692 ER PT J AU Zeuner, KE Knutzen, A Al-Ali, A Hallett, M Deuschl, G Bergmann, TO Siebner, HR AF Zeuner, Kirsten E. Knutzen, Arne Al-Ali, Asmaa Hallett, Mark Deuschl, Guenther Bergmann, Til O. Siebner, Hartwig R. TI Associative Stimulation of the Supraorbital Nerve Fails to Induce Timing-Specific Plasticity in the Human Blink Reflex SO PLOS ONE LA English DT Article ID HUMAN MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; HOMEOSTATIC PLASTICITY; HAND DYSTONIA; BLEPHAROSPASM; METAPLASTICITY; INTERNEURONS; HIPPOCAMPUS AB Background: Associative high-frequency electrical stimulation (HFS) of the supraorbital nerve in five healthy individuals induced long-term potentiation (LTP)-like or depression (LTD)-like changes in the human blink reflex circuit according to the rules of spike timing-dependent plasticity (Mao and Evinger, 2001). HFS given at the onset of the R2 component of the blink reflex (HFS(LTP)) produced a lasting facilitation of the R2, whereas HFS given shortly before R2 (HFS(LTD)) caused a lasting suppression of the R2. In patients with benign essential blepharospasm (BEB), a focal dystonia affecting the orbicularis oculi muscles, HFS(LTP) induced excessive LTP-like associative plasticity relative to healthy controls, which was normalized after botulinum toxin (BTX) injections (Quartarone et al, 2006). Methodology/Principal Findings: We used HFS conditioning of the supraorbital nerve to study homeostatic metaplasticity of the blink reflex circuit in healthy subjects and dystonic patients. On separate days, we tested the conditioning effects on the R2 response and paired-pulse R2 inhibition after (i) HFS(LTP), (ii) HFS(LTP) followed by HFS(LTP), and (iii) HFS(LTP) followed by HFS(LTD). Controls also received (iv) HFS(LTD) alone and (v) a non-intervention protocol. In BEB patients, HFS(LTP) followed by HFS(LTD) was given before and after BTX treatment. We were not able to replicate the bidirectional timing-dependent effects of HFS(LTP) and HFS(LTD) alone. All HFS protocols produced a non-specific reduction of the R2 response and a relative decrease in paired-pulse inhibition. These R2 changes also occurred in controls when no HFS was applied. There was also no trace of a homeostatic response pattern in BEB patients before or after BTX treatment. Conclusion/Significance: Our data challenge the efficacy of associative HFS to produce bidirectional plasticity in the human blink reflex circuit. The non-specific decrease of the R2 response might indicate habituation of the blink reflex following repeated electrical supraorbital stimulation. The increase of inhibition after paired pulse stimulation might reflect homeostatic behaviour to prevent further down regulation of the R2 response to preserve the protection of this adverse-effects reflex. C1 [Zeuner, Kirsten E.; Knutzen, Arne; Al-Ali, Asmaa; Deuschl, Guenther; Bergmann, Til O.; Siebner, Hartwig R.] Univ Kiel, Dept Neurol, D-2300 Kiel, Germany. [Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD USA. [Siebner, Hartwig R.] Copenhagen Univ Hosp Hvidovre, Danish Res Ctr Magnet Resonance, Hvidovre, Denmark. [Siebner, Hartwig R.] Univ Copenhagen, Inst Neurol Psychiat & Senses, Fac Med, Copenhagen, Denmark. RP Zeuner, KE (reprint author), Univ Kiel, Dept Neurol, D-2300 Kiel, Germany. EM k.zeuner@neurologie.uni-kiel.de RI Bergmann, Til/F-9453-2010; Deuschl, Gunther/A-7986-2010; Siebner, Hartwig/G-4052-2016 OI Bergmann, Til/0000-0002-2282-6618; FU Benign Essential Blepharospasm Foundation, USA; Deutsche Forschungsgemeinschaft [DE 438/7-1, 7-2]; National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) FX This work has been supported by Benign Essential Blepharospasm Foundation, USA to K.E.Z., G.D. and H.S. and a grant from the Deutsche Forschungsgemeinschaft to G.D. and H.S. (DE 438/7-1 and 7-2). M.H. is supported by the Intramural Program of the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 5 Z9 5 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 26 PY 2010 VL 5 IS 10 AR e13602 DI 10.1371/journal.pone.0013602 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 671GB UT WOS:000283487400009 PM 21049057 ER PT J AU Trask, SD Taraporewala, ZF Boehme, KW Dermody, TS Patton, JT AF Trask, Shane D. Taraporewala, Zenobia F. Boehme, Karl W. Dermody, Terence S. Patton, John T. TI Dual selection mechanisms drive efficient single-gene reverse genetics for rotavirus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE recombinant virus; Reoviridae; NSP2; RNAi; temperature-sensitive virus ID TEMPERATURE-SENSITIVE MUTANTS; NONSTRUCTURAL PROTEIN NSP2; STRANDED-RNA VIRUSES; GENOME REPLICATION; SIMIAN ROTAVIRUS-SA11; GEL-ELECTROPHORESIS; BLUETONGUE VIRUS; MIXED INFECTION; SYSTEM; SEGMENTS AB Current methods for engineering the segmented double-stranded RNA genome of rotavirus (RV) are limited by inefficient recovery of the recombinant virus. In an effort to expand the utility of RV reverse genetics, we developed a method to recover recombinant viruses in which independent selection strategies are used to engineer single-gene replacements. We coupled a mutant SA11 RV encoding a temperature-sensitive (ts) defect in the NSP2 protein with RNAi-mediated degradation of NSP2 mRNAs to isolate a virus containing a single recombinant gene that evades both selection mechanisms. Recovery is rapid and simple; after two rounds of selective passage the recombinant virus reaches titers of >= 10(4) pfu/mL. We used this reverse genetics method to generate a panel of viruses with chimeric NSP2 genes. For one of the chimeric viruses, the introduced NSP2 sequence was obtained from a pathogenic, noncultivated human RV isolate, demonstrating that this reverse genetics system can be used to study the molecular biology of circulating RVs. Combining characterized RV ts mutants and validated siRNA targets should permit the extension of this "two-hit" reverse genetics methodology to other RV genes. Furthermore, application of a dual selection strategy to previously reported reverse genetics methods for RV may enhance the efficiency of recombinant virus recovery. C1 [Trask, Shane D.; Taraporewala, Zenobia F.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Boehme, Karl W.; Dermody, Terence S.] Vanderbilt Univ, Dept Pediat, Sch Med, Nashville, TN 37232 USA. [Dermody, Terence S.] Vanderbilt Univ, Dept Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA. [Boehme, Karl W.; Dermody, Terence S.] Vanderbilt Univ, Elizabeth B Lamb Ctr Pediat Res, Sch Med, Nashville, TN 37232 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU National Institutes of Allergy and Infectious Diseases, National Institutes of Health [Z01 AI000788]; National Institutes of Allergy and Infectious Diseases [T32 CA09385, F32 AI075776, R01 AI32539, R37 AI38296] FX We thank Christine Rippinger for technical assistance and Michelle Arnold, Kristen Guglielmi, Sarah McDonald, and Aitor Navarro for helpful discussions. We also thank Koji Ishii and Tatsuo Miyamura (National Institute of Infectious Diseases, Tokyo), Carl Kirkwood (University of Melbourne, Parkville, VIC, Australia), Eric Poeschla (College of Medicine, Mayo Clinic, Rochester, MN), and Frank Ramig (Baylor College of Medicine, Houston) for providing invaluable reagents and Bishop Hague, Kevin Holmes, and David Stephany for assistance with flow cytometry. S. D. T., Z.F.T., and J.T.P. were supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health (Z01 AI000788); K. W. B. was supported by Public Health Service awards T32 CA09385 and F32 AI075776 from the National Institutes of Allergy and Infectious Diseases; and T. S. D. was supported by Public Health Service awards R01 AI32539 and R37 AI38296 from the National Institutes of Allergy and Infectious Diseases. Additional support was provided by the Elizabeth B. Lamb Center for Pediatric Research. NR 37 TC 30 Z9 34 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 26 PY 2010 VL 107 IS 43 BP 18652 EP 18657 DI 10.1073/pnas.1011948107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 673QG UT WOS:000283677400077 PM 20937889 ER PT J AU Navarro, G Moreno, E Aymerich, M Marcellino, D McCormick, PJ Mallol, J Cortes, A Casado, V Canela, EI Ortiz, J Fuxe, K Lluis, C Ferre, S Franco, R AF Navarro, Gemma Moreno, Estefania Aymerich, Marisol Marcellino, Daniel McCormick, Peter J. Mallol, Josefa Cortes, Antoni Casado, Vicent Canela, Enric I. Ortiz, Jordi Fuxe, Kjell Lluis, Carmen Ferre, Sergi Franco, Rafael TI Direct involvement of sigma-1 receptors in the dopamine D-1 receptor-mediated effects of cocaine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE receptor heteromer; drug addiction ID MICE; TRANSPORTER; HETEROMERIZATION; ADDICTION; PROTEINS; SYSTEM; REWARD AB It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D-1 receptors (D(1)Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to sigma-1 receptors, the physiological role of which is largely unknown. In the present study, D1R and sigma R-1 were found to heteromerize in transfected cells, where cocaine robustly potentiated D1R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D1R stimulation in a dopamine transporter-independent and sigma R-1-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in sigma R-1 KO mice, providing evidence for the existence of sigma R-1-D1R heteromers in the brain. Therefore, these results provide a molecular explanation for which D1R plays a more significant role in the behavioral effects of cocaine, through sigma R-1-D1R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction. C1 [Navarro, Gemma; Moreno, Estefania; McCormick, Peter J.; Mallol, Josefa; Cortes, Antoni; Casado, Vicent; Canela, Enric I.; Lluis, Carmen; Franco, Rafael] Univ Barcelona, Fac Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain. [Navarro, Gemma; Moreno, Estefania; McCormick, Peter J.; Mallol, Josefa; Cortes, Antoni; Casado, Vicent; Canela, Enric I.; Lluis, Carmen; Franco, Rafael] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. [Aymerich, Marisol; Franco, Rafael] Univ Navarra, Ctr Invest Med Aplicada, Pamplona 31008, Spain. [Marcellino, Daniel; Fuxe, Kjell] Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. [Ortiz, Jordi] Univ Autonoma Barcelona, Fac Med, Inst Neurosci, Bellaterra 08193, Spain. [Ortiz, Jordi] Univ Autonoma Barcelona, Fac Med, Dept Biochem & Mol Biol, Bellaterra 08193, Spain. [Ferre, Sergi] NIDA, Intramural Res Program, Nihon Univ, US Dept HHS, Baltimore, MD 21224 USA. RP Ferre, S (reprint author), Univ Barcelona, Fac Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain. EM sferre@intra.nida.nih.gov RI Ortiz, Jordi/E-9018-2011; Canela, Enric I./M-8726-2013; McCormick, Peter/E-7387-2012; Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; OI Ortiz, Jordi/0000-0002-9748-2290; Canela, Enric I./0000-0003-4992-7440; McCormick, Peter/0000-0002-2225-5181; Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Marcellino, Daniel/0000-0002-4618-7267; Moreno, Estefania/0000-0002-2491-5753 FU Spanish Ministerio de Ciencia y Tecnologia [SAF2008-00146, SAF2008-03229-E, SAF2009-07276]; Fundacio La Marato de TV3 [060110]; National Institute on Drug Abuse FX We thank Hanna Hoffmann (Universitat Autonoma de Barcelona) for assistance with brain striatal slices and Jasmina Jimenez (University of Barcelona) for technical assistance. Brains from sigma1R KO and wild-type littermates CD1 albino Swiss male mice were generously provided by Laboratorios Esteve (Barcelona, Spain). This study was supported by Grants SAF2008-00146, SAF2008-03229-E, and SAF2009-07276 from Spanish Ministerio de Ciencia y Tecnologia, Grant 060110 from Fundacio La Marato de TV3, and by Intramural Funds of the National Institute on Drug Abuse. NR 28 TC 60 Z9 60 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 26 PY 2010 VL 107 IS 43 BP 18676 EP 18681 DI 10.1073/pnas.1008911107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 673QG UT WOS:000283677400081 PM 20956312 ER PT J AU Lo, SC Pripuzova, N Li, BJ Komaroff, AL Hung, GC Wang, R Alter, HJ AF Lo, Shyh-Ching Pripuzova, Natalia Li, Bingjie Komaroff, Anthony L. Hung, Guo-Chiuan Wang, Richard Alter, Harvey J. TI Reply to Erlwein et al. and Martin: On detection of murine leukemia virus-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Lo, Shyh-Ching; Pripuzova, Natalia; Li, Bingjie; Hung, Guo-Chiuan] US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. [Lo, Shyh-Ching; Pripuzova, Natalia; Li, Bingjie; Hung, Guo-Chiuan] US FDA, Div Human Tissues, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Komaroff, Anthony L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Wang, Richard; Alter, Harvey J.] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Lo, SC (reprint author), US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. EM shyhching.lo@fda.hhs.gov NR 5 TC 1 Z9 1 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 26 PY 2010 VL 107 IS 43 BP E163 EP E164 DI 10.1073/pnas.1012780107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 673QG UT WOS:000283677400003 ER PT J AU Gambardella, L Hemberger, M Hughes, B Zudaire, E Andrews, S Vermeren, S AF Gambardella, Laure Hemberger, Myriam Hughes, Bethany Zudaire, Enrique Andrews, Simon Vermeren, Sonja TI PI3K Signaling Through the Dual GTPase-Activating Protein ARAP3 Is Essential for Developmental Angiogenesis SO SCIENCE SIGNALING LA English DT Article ID TRANSGENIC MOUSE STRAIN; PATHOLOGICAL ANGIOGENESIS; DOWNSTREAM ACTIVATION; CELL MIGRATION; IN-VIVO; ARF6; GROWTH; P110-ALPHA; PROMOTES; MOTILITY AB One function of phosphoinositide 3-kinase a (PI3K alpha), which generates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)], is its regulation of angiogenesis in the developing embryo and in pathological situations. ARAP3 is a PtdIns(3,4,5)P(3)- and Rap-activated guanosine triphosphatase (GTPase)-activating protein (GAP) for the small GTPases RhoA and Arf6. Here, we show that deleting Arap3 in the mouse caused embryonic death in mid-gestation due to an endothelial cell-autonomous defect in sprouting angiogenesis. Explants taken at a developmental stage at which no defect was yet present reproduced this phenotype ex vivo, demonstrating that the defect was not secondary to hypoxia, placental defects, or organ failure. In addition, knock-in mice expressing an ARAP3 point mutant that cannot be activated by PtdIns(3,4,5)P(3) had angiogenesis defects similar to those of Arap3(-/-) embryos. Our work delineates a previously unknown signaling pathway that controls angiogenesis immediately downstream of PI3Ka through ARAP3 to the Rho and Arf family of small GTPases. C1 [Gambardella, Laure; Hughes, Bethany; Vermeren, Sonja] Babraham Inst, Inositide Lab, Cambridge CB22 3AT, England. [Hemberger, Myriam] Babraham Inst, Epigenet & Dev Lab, Cambridge CB22 3AT, England. [Hemberger, Myriam] Univ Cambridge, Ctr Trophoblast Res, Cambridge CB2 3EG, England. [Zudaire, Enrique] NCI, Angiogenesis Core Facil, NIH, Gaithersburg, MD 20892 USA. RP Vermeren, S (reprint author), Babraham Inst, Inositide Lab, Cambridge CB22 3AT, England. EM sonja.vermeren@bbsrc.ac.uk OI Vermeren, Sonja/0000-0002-8460-0884 FU Cancer Research UK [C1485/A2636]; Medical Research Council [G0700740]; [BB/C520712] FX The first year of this work was supported by a Cancer Research UK grant (C1485/A2636) to L. Stephens, P. Hawkins, and R. Williams. The following years were funded by a Medical Research Council grant (G0700740) to S.V.S.V. is a Biotechnology and Biological Sciences Research Council David Phillips Fellow (BB/C520712). Author contributions: L.G., M.H., S.A., and S.V. designed the experiments. L.G., M.H., B.H., and S.V. performed the experiments. L.G., M.H., E.Z., and S.V. analyzed the data. S.V., L.G., and M. H. wrote the paper. Competing interests: The authors declare that they have no competing interests. The following mouse strains require a materials transfer agreement (MTA) from The Babraham Institute: Arap3fl/fl and Arap3R302,303A. NR 40 TC 17 Z9 17 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD OCT 26 PY 2010 VL 3 IS 145 AR ra76 DI 10.1126/scisignal.2001026 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 674IP UT WOS:000283733600003 PM 20978237 ER PT J AU Grainger, JR Smith, KA Hewitson, JP McSorley, HJ Harcus, Y Filbey, KJ Finney, CAM Greenwood, EJD Knox, DP Wilson, MS Belkaid, Y Rudensky, AY Maizels, RM AF Grainger, John R. Smith, Katie A. Hewitson, James P. McSorley, Henry J. Harcus, Yvonne Filbey, Kara J. Finney, Constance A. M. Greenwood, Edward J. D. Knox, David P. Wilson, Mark S. Belkaid, Yasmine Rudensky, Alexander Y. Maizels, Rick M. TI Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; IN-VIVO; AIRWAY INFLAMMATION; PROTECTIVE IMMUNITY; POLYGYRUS INFECTION; AUTOIMMUNE-DISEASE; NEMATODE INFECTION; TH2 RESPONSES; ORAL ANTIGEN; B-CELLS AB Foxp3-expressing regulatory T (T reg) cells have been implicated in parasite-driven inhibition of host immunity during chronic infection. We addressed whether parasites can directly induce T reg cells. Foxp3 expression was stimulated in naive Foxp3(-) T cells in mice infected with the intestinal helminth Heligmosomoides polygyrus. In vitro, parasite-secreted proteins (termed H. polygyrus excretory-secretory antigen [HES]) induced de novo Foxp3 expression in fluorescence-sorted Foxp3(-) splenocytes from Foxp3-green fluorescent protein reporter mice. HES-induced T reg cells suppressed both in vitro effector cell proliferation and in vivo allergic airway inflammation. HES ligated the transforming growth factor (TGF) beta receptor and promoted Smad2/3 phosphorylation. Foxp3 induction by HES was lost in dominant-negative TGF-beta RII cells and was abolished by the TGF-beta signaling inhibitor SB431542. This inhibitor also reduced worm burdens in H. polygyrus-infected mice. HES induced IL-17 in the presence of IL-6 but did not promote Th1 or Th2 development under any conditions. Importantly, antibody to mammalian TGF-beta did not recognize HES, whereas antisera that inhibited HES did not affect TGF-beta. Foxp3 was also induced by secreted products of Teladorsagia circumcincta, a related nematode which is widespread in ruminant animals. We have therefore identified a novel pathway through which helminth parasites may stimulate T reg cells, which is likely to be a key part of the parasite's immunological relationship with the host. C1 [Grainger, John R.; Smith, Katie A.; Hewitson, James P.; McSorley, Henry J.; Harcus, Yvonne; Filbey, Kara J.; Finney, Constance A. M.; Greenwood, Edward J. D.; Maizels, Rick M.] Univ Edinburgh, Inst Immunol & Infect Res, Edinburgh EH9 3JT, Midlothian, Scotland. [Knox, David P.] Moredun Res Inst, Midlothian EH26 0PZ, Scotland. [Wilson, Mark S.; Belkaid, Yasmine] NIH, Bethesda, MD 20892 USA. [Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA. RP Maizels, RM (reprint author), Univ Edinburgh, Inst Immunol & Infect Res, Edinburgh EH9 3JT, Midlothian, Scotland. EM r.maizels@ed.ac.uk RI Smith, Katherine/D-8092-2015 OI Smith, Katherine/0000-0001-8150-5702 FU Wellcome Trust; Medical Research Council; National Institutes of Health FX J.R. Grainger thanks the Wellcome Trust for studentship support through the 4-year PhD Program, H.J. McSorley, K.J. Filbey, and C.A.M. Finney thank the Medical Research Council for studentship support, E.J.D. Greenwood thanks the Wellcome Trust for an undergraduate summer studentship, and K.A. Smith, J.P. Hewitson, Y. Harcus, and R.M. Maizels thank the Wellcome Trust for Programme Grant support. A.Y. Rudensky is a Howard Hughes Medical Institute Investigator and is supported by a National Institutes of Health grant. NR 56 TC 212 Z9 216 U1 6 U2 35 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 25 PY 2010 VL 207 IS 11 BP 2331 EP 2341 DI 10.1084/jem.20101074 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 697HW UT WOS:000285504900006 PM 20876311 ER PT J AU Miletic, AV Anzelon-Mills, AN Mills, DM Omori, SA Pedersen, IM Shin, DM Ravetch, JV Bolland, S Morse, HC Rickert, RC AF Miletic, Ana V. Anzelon-Mills, Amy N. Mills, David M. Omori, Sidne A. Pedersen, Irene M. Shin, Dong-Mi Ravetch, Jeffrey V. Bolland, Silvia Morse, Herbert C., III Rickert, Robert C. TI Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SPLENIC MARGINAL ZONE; DOMAIN-CONTAINING INOSITOL-5-PHOSPHATASE; 5-PHOSPHATASE SHIP; BINDING PROTEIN; PI3K PATHWAY; MICE; SURVIVAL; GENE; ACTIVATION AB The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain-containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)-mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP(-/-)) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP(-/-) B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27(kip1) and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP(-/-) B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP(-/-) B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway. C1 [Miletic, Ana V.; Anzelon-Mills, Amy N.; Mills, David M.; Omori, Sidne A.; Rickert, Robert C.] Sanford Burnham Med Res Inst, Ctr Canc, Infect & Inflammatory Dis Ctr, Program Inflammatory Dis Res, La Jolla, CA 92037 USA. [Pedersen, Irene M.] Univ Calif San Diego, Mol Biol Sect, Div Biol Sci, La Jolla, CA 92093 USA. [Pedersen, Irene M.] Univ Calif San Diego, Univ Calif San Diego Canc Ctr, La Jolla, CA 92093 USA. [Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. [Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Ravetch, Jeffrey V.] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10065 USA. RP Rickert, RC (reprint author), Sanford Burnham Med Res Inst, Ctr Canc, Infect & Inflammatory Dis Ctr, Program Inflammatory Dis Res, La Jolla, CA 92037 USA. EM robert@sanfordburnham.org OI Morse, Herbert/0000-0002-9331-3705 FU National Institutes of Health [HL088686, CA135531, F32CA132350, K01CA122192]; Arthritis Foundation; Irvington Institute for the Cancer Research Institute; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health Grants HL088686 and CA135531 (R.C. Rickert), F32CA132350 (A.V. Miletic), and K01CA122192 (I.M. Pedersen). D.M. Mills was supported by an Arthritis Foundation Postdoctoral Fellowship. A.V. Miletic was supported by an Irvington Institute for the Cancer Research Institute Postdoctoral Fellowship. This work was also supported, in part, by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (H.C. Morse, D-M. Shin, and S. Bolland). NR 56 TC 37 Z9 39 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 25 PY 2010 VL 207 IS 11 BP 2407 EP 2420 DI 10.1084/jem.20091962 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 697HW UT WOS:000285504900012 PM 20956547 ER PT J AU Weiss, JM Ridnour, LA Back, T Hussain, SP He, PJ Maciag, AE Keefer, LK Murphy, WJ Harris, CC Wink, DA Wiltrout, RH AF Weiss, Jonathan M. Ridnour, Lisa A. Back, Tim Hussain, S. Perwez He, Peijun Maciag, Anna E. Keefer, Larry K. Murphy, William J. Harris, Curtis C. Wink, David A. Wiltrout, Robert H. TI Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID E-CADHERIN; IN-VIVO; JS-K; RELATIVE EXPRESSION; TISSUE INHIBITOR; CARCINOMA-CELLS; CANCER; GROWTH; ANGIOGENESIS; INTERLEUKIN-12 AB Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or alpha-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/alpha-CD40, but not IL-2 or alpha-CD40, induced significant nitric oxide synthase ( NOS) 2 expression in tumor-associated macrophages. In control-treated mice ( low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy ( high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/alpha-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/alpha-CD40 induced the IFN-gamma- and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase ( TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/alpha-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/alpha-CD40-mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease. C1 [Weiss, Jonathan M.; Back, Tim; Wiltrout, Robert H.] Natl Canc Inst, Canc & Inflammat Program, Frederick, MD 21702 USA. [Keefer, Larry K.] Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Maciag, Anna E.] Natl Canc Inst, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Ridnour, Lisa A.; Wink, David A.] NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. [Hussain, S. Perwez; He, Peijun; Harris, Curtis C.] NIH, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Murphy, William J.] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95816 USA. RP Wiltrout, RH (reprint author), Natl Canc Inst, Canc & Inflammat Program, Frederick, MD 21702 USA. EM wiltrour@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Institutes of Health (NIH)/NCI [R01-CA-95572]; SAIC [HHSN261200800001E] FX This project was funded in whole or part by the Intramural Research Program of National Institutes of Health (NIH)/NCI and with Federal funds from the NCI, NIH under R01-CA-95572 (W.J. Murphy) and SAIC Contract # HHSN261200800001E. NR 47 TC 41 Z9 43 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 25 PY 2010 VL 207 IS 11 BP 2455 EP 2467 DI 10.1084/jem.20100670 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 697HW UT WOS:000285504900015 PM 20921282 ER PT J AU Pareek, TK Lam, E Zheng, XJ Askew, D Kulkarni, AB Chance, MR Huang, AY Cooke, KR Letterio, JJ AF Pareek, Tej K. Lam, Eric Zheng, Xiaojing Askew, David Kulkarni, Ashok B. Chance, Mark R. Huang, Alex Y. Cooke, Kenneth R. Letterio, John J. TI Cyclin-dependent kinase 5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; DOUBLE-EDGED-SWORD; MULTIPLE-SCLEROSIS; ACTIN CYTOSKELETON; ALZHEIMERS-DISEASE; TYROSINE KINASES; P35/CDK5 KINASE; MONOCYTIC CELLS; CANCER CELLS; CDK5 AB Cyclin-dependent kinase 5 (Cdk5) is a ubiquitously expressed serine/threonine kinase. However, a requirement for Cdk5 has been demonstrated only in postmitotic neurons where there is abundant expression of its activating partners p35 and/or p39. Although hyperactivation of the Cdk5-p35 complex has been found in a variety of inflammatory neurodegenerative disorders, the potential contribution of nonneuronal Cdk5-p35 activity has not been explored in this context. We describe a previously unknown function of the Cdk5-p35 complex in T cells that is required for induction of experimental autoimmune encephalomyelitis (EAE). T cell receptor (TCR) stimulation leads to a rapid induction of Cdk5-p35 expression that is required for T lymphocyte activation. Chimeric mice lacking Cdk5 gene expression in hematopoietic tissues (Cdk5(-/-C)) are resistant to induction of EAE, and adoptive transfer of either Cdk5(-/-C) or p35(-/-) encephalitogenic lymphocytes fails to transfer disease. Moreover, our data reveal a novel mechanism involving Cdk5-mediated phosphorylation of the actin modulator coronin 1a on threonine 418. Cdk5-deficient lymphocytes lack this posttranslational modification of coronin 1a and exhibit defective TCR-induced actin polarization and reduced migration toward CCL-19. These data define a distinct role for Cdk5 in lymphocyte biology and suggest that inhibition of this kinase may be beneficial in the treatment of T cell-mediated inflammatory disorders. C1 [Pareek, Tej K.; Lam, Eric; Askew, David; Huang, Alex Y.; Cooke, Kenneth R.; Letterio, John J.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Dept Pediat, Div Pediat Hematol Oncol, Cleveland, OH 44106 USA. [Pareek, Tej K.; Lam, Eric; Askew, David; Huang, Alex Y.; Cooke, Kenneth R.; Letterio, John J.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Zheng, Xiaojing; Chance, Mark R.] Case Western Reserve Univ, Case Ctr Prote & Bioinformat, Cleveland, OH 44106 USA. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Letterio, JJ (reprint author), Case Western Reserve Univ, Univ Hosp Case Med Ctr, Dept Pediat, Div Pediat Hematol Oncol, Cleveland, OH 44106 USA. EM John.Letterio@uhhospitals.org OI Pareek, Tej/0000-0001-5134-1647; Huang, Alex/0000-0002-5701-4521 FU Jane and Lee Seidman Chair in Pediatric Cancer Innovation; The Case Research Institute FX We would like to acknowledge the support from the Jane and Lee Seidman Chair in Pediatric Cancer Innovation and The Case Research Institute. NR 60 TC 24 Z9 24 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 25 PY 2010 VL 207 IS 11 BP 2507 EP 2519 DI 10.1084/jem.20100876 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 697HW UT WOS:000285504900019 PM 20937706 ER PT J AU Flomerfelt, FA El Kassar, N Gurunathan, C Chua, KS League, SC Schmitz, S Gershon, TR Kapoor, V Yan, XY Schwartz, RH Gress, RE AF Flomerfelt, Francis A. El Kassar, Nahed Gurunathan, Chandra Chua, Kevin S. League, Stacy C. Schmitz, Sabrina Gershon, Timothy R. Kapoor, Veena Yan, Xiao-Yi Schwartz, Ronald H. Gress, Ronald E. TI Tbata modulates thymic stromal cell proliferation and thymus function SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NEDD8 CONJUGATION PATHWAY; MOUSE SPERMATOGENESIS; DEVELOPING CEREBELLUM; CYCLE PROGRESSION; EPITHELIAL-CELLS; MAMMALIAN-CELLS; EXPRESSION; DEGRADATION; UBIQUITIN; PROTEIN AB Niche availability provided by stromal cells is critical to thymus function. Thymi with diminished function contain fewer stromal cells, whereas thymi with robust function contain proliferating stromal cell populations. Here, we show that the thymus, brain, and testes-associated gene (Tbata; also known as SPATIAL) regulates thymic epithelial cell (TEC) proliferation and thymus size. Tbata is expressed in thymic stromal cells and interacts with the enzyme Uba3, thereby inhibiting the Nedd8 pathway and cell proliferation. Thymi from aged Tbata-deficient mice are larger and contain more dividing TECs than wild-type littermate controls. In addition, thymic reconstitution after bone marrow transplantation occurred more rapidly in Rag2(-/-)Tbata(-/-) mice than in Rag2(-/-)Tbata(+/+) littermate controls. These findings suggest that Tbata modulates thymus function by regulating stromal cell proliferation via the Nedd8 pathway. C1 [Flomerfelt, Francis A.; El Kassar, Nahed; Gurunathan, Chandra; Chua, Kevin S.; League, Stacy C.; Schmitz, Sabrina; Kapoor, Veena; Yan, Xiao-Yi; Gress, Ronald E.] NCI, Experimental Transplantat Immunol Branch, NIH, Bethesda, MD 20892 USA. [Gershon, Timothy R.] Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. [Schwartz, Ronald H.] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Flomerfelt, FA (reprint author), NCI, Experimental Transplantat Immunol Branch, NIH, Bethesda, MD 20892 USA. EM flomerff@mail.nih.gov OI Gershon, Timothy/0000-0001-7034-6400 NR 47 TC 10 Z9 13 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 25 PY 2010 VL 207 IS 11 BP 2521 EP 2532 DI 10.1084/jem.20092759 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 697HW UT WOS:000285504900020 PM 20937703 ER PT J AU Hanley, LL McGivern, DR Teng, MN Djang, R Collins, PL Fearns, R AF Hanley, Laura L. McGivern, David R. Teng, Michael N. Djang, Robin Collins, Peter L. Fearns, Rachel TI Roles of the respiratory syncytial virus trailer region: Effects of mutations on genome production and stress granule formation SO VIROLOGY LA English DT Article DE Respiratory syncytial virus; Paramyxovirus; Promoter; Genome replication; Stress granules; TIAR ID MINUS-STRAND RNA; MESSENGER-RNA; GENE-EXPRESSION; WEST-NILE; NUCLEOTIDE-SEQUENCES; VACCINE CANDIDATE; REPLICATION; TRANSCRIPTION; POLYMERASE; PROTEIN AB The 5' extragenic trailer region of respiratory syncytial virus (RSV) is known to be necessary for genome replication, but is more than three times the length of the 3' leader replication promoter, raising the possibility that trailer might play an additional role in viral replication. To examine this, mutant recombinant viruses were constructed in which the trailer region was truncated or substituted with leader-complement sequence. This analysis showed that the complete trailer increased promoter activity, facilitating genome production and viral multiplication. In addition, trailer-containing viruses did not induce stress granules, whereas the leader-complement virus mutant did, resulting in poor multi-cycle viral growth. These data demonstrate that although the RSV trailer does not contain a unique essential sequence, it augments virus growth by enabling optimal genome production. In addition, a sequence at the 5' terminal end of the trailer region allows RSV to subvert stress granule formation. (C) 2010 Elsevier Inc. All rights reserved. C1 [Hanley, Laura L.; Djang, Robin; Fearns, Rachel] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [McGivern, David R.; Fearns, Rachel] Univ Dundee, Div Pathol & Neurosci, Dundee DD1 9SY, Scotland. [Teng, Michael N.; Collins, Peter L.; Fearns, Rachel] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Fearns, R (reprint author), Boston Univ, Sch Med, Dept Microbiol, 72 E Concord St,R512, Boston, MA 02118 USA. EM rfearns@bu.edu RI Teng, Michael/I-5006-2012; OI Teng, Michael/0000-0002-0722-3659; Dickey, Laura/0000-0001-9943-9598; Fearns, Rachel/0000-0003-0783-7498; McGivern, David/0000-0003-3497-5087 FU Wellcome Trust [065568]; NIAID, NIH [R01AI074903]; Boston University FX We thank Kim Tran and Myron Hill for assistance in performing the mouse study, Bernard Moss for providing MVA-T7 and Paul Anderson for providing the TIAR +/+ and TIAR -/- mouse embryonic fibroblasts. This research was supported by grants from the Wellcome Trust (065568) and NIAID, NIH (R01AI074903) to RF, the Intramural Research Program of NIAID, NIH, and Boston University. NR 41 TC 30 Z9 30 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 OCT 25 PY 2010 VL 406 IS 2 BP 241 EP 252 DI 10.1016/j.virol.2010.07.006 PG 12 WC Virology SC Virology GA 652TX UT WOS:000282034000008 PM 20701943 ER PT J AU Chiba, Y Tanabe, M Sakai, H Kimura, S Misawa, M AF Chiba, Yoshihiko Tanabe, Miki Sakai, Hiroyasu Kimura, Shioko Misawa, Miwa TI A functional interaction between CPI-17 and RACK1 proteins in bronchial smooth muscle cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Yeast two-hybrid system; CPI-17; RACK1; Ca(2+) sensitization ID ACETYLCHOLINE-INDUCED PHOSPHORYLATION; KINASE-C; ENDOTHELIN-1-INDUCED PHOSPHORYLATION; POSSIBLE INVOLVEMENT; INHIBITORY PROTEIN; RHO-KINASE; RATS; LOCALIZATION; CONTRACTION; CLONING AB CPI-17 is a phosphorylation-dependent inhibitor of smooth muscle myosin light chain. Using yeast two-hybrid system, we have identified the receptor for activated C kinase 1 (RACK1) as a novel interaction partner of CPI-17. The direct interaction and co-localization of CPI-17 with RACK1 were confirmed by immunoprecipitation and confocal microscopy analysis, respectively. An in vitro assay system using recombinant/purified proteins revealed that the PKC-mediated phosphorylation of CPI-17 was augmented in the presence of RACK1. These results suggest that RACK1 may play a role in PKC/CPI-17 signaling pathway. (C) 2010 Elsevier Inc. All rights reserved. C1 [Chiba, Yoshihiko] Hoshi Univ, Dept Pharmacol, Sch Pharm, Shinagawa Ku, Tokyo 1428501, Japan. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Chiba, Y (reprint author), Hoshi Univ, Dept Pharmacol, Sch Pharm, Shinagawa Ku, 2-4-41 Ebara, Tokyo 1428501, Japan. EM chiba@hoshi.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan FX We thank Ms. Emi Yamaguchi and Ms. Mariko Mori for their technical assistance. This work was partly supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 18 TC 1 Z9 1 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 22 PY 2010 VL 401 IS 3 BP 487 EP 490 DI 10.1016/j.bbrc.2010.09.086 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 676CR UT WOS:000283888200030 PM 20875397 ER PT J AU Kimura, A Martin, C Robinson, GW Simone, JM Chen, WP Wickre, MC O'Shea, JJ Hennighausen, L AF Kimura, Akiko Martin, Cyril Robinson, Gertraud W. Simone, James M. Chen, Weiping Wickre, Mark C. O'Shea, John J. Hennighausen, Lothar TI The Gene Encoding the Hematopoietic Stem Cell Regulator CCN3/NOV Is under Direct Cytokine Control through the Transcription Factors STAT5A/B SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING ACTIVITY; SELF-RENEWAL; PROGENITOR CELLS; STEM/PROGENITOR CELLS; LYMPHOID DEVELOPMENT; EXPRESSION; ACTIVATION; DIFFERENTIATION; BCR/ABL; GROWTH AB Cytokines control the biology of hematopoietic stem cells (HSCs) and progenitor cells in part through the transcription factors STAT5A/B. To investigate the target genes of STAT5A/B activated by cytokines in HSCs and progenitors, we performed microarray analyses using Lineage(-) Sca-1(+) c-Kit(+) (KSL) cells in the presence and absence of STAT5A/B. Stimulation with a mixture containing IL-3, IL-6, stem cell factor, thrombopoietin, and Flt3 ligand induced Ccn3/Nov mRNA over 100-fold in WT (control) but not Stat5a/b-null KSL cells. CCN3/NOV is a positive regulator of human HSC self-renewal and development of committed blood cells. Without stimulation, the Ccn3/Nov signal level was low in control KSL cells similar to Stat5a/b-null KSL cells. To determine which cytokine activates the Ccn3/Nov gene, we analyzed Lineage(-) c-Kit(+) (KL) and 32D cells using quantitative PCR and ChIP assays. Although stimulation with a mixture lacking IL-3 prevented the induction of Ccn3/Nov in control KL cells, IL-3 alone could induce Ccn3/Nov mRNA in control KL and 32D cells. ChIP assays using 32D cells revealed IL-3-induced binding of STAT5A/B to a gamma-interferon-activated sequences site in the Ccn3/Nov gene promoter. This is the first report that Ccn3/Nov is directly induced by cytokines through STAT5A/B. C1 [Kimura, Akiko; Martin, Cyril; Robinson, Gertraud W.; Wickre, Mark C.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, Bethesda, MD 20892 USA. [Simone, James M.] NIAMS, Flow Cytometry Sect, Off Sci & Technol, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDK, Microarray Core Facil Genom Core Lab, Bethesda, MD 20892 USA. [O'Shea, John J.] NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Kimura, A (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 37,Rm 3016, Bethesda, MD 20892 USA. EM kimuraa@mail.nih.gov RI Robinson, Gertraud/I-2136-2012 FU NIDDK/National Institutes of Health FX This work was supported, in whole or in part, by the intramural program of the NIDDK/National Institutes of Health. L. H. is a participant in the WCU program (R33-10059) at Chonnam National University, Republic of Korea. NR 34 TC 8 Z9 9 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 OCT 22 PY 2010 VL 285 IS 43 BP 32704 EP 32709 DI 10.1074/jbc.M110.141804 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 665PP UT WOS:000283048200005 PM 20720003 ER PT J AU Daniels, SI Davis, DA Soule, EE Stahl, SJ Tebbs, IR Wingfield, P Yarchoan, R AF Daniels, Sarah I. Davis, David A. Soule, Erin E. Stahl, Stephen J. Tebbs, Irene R. Wingfield, Paul Yarchoan, Robert TI The Initial Step in Human Immunodeficiency Virus Type 1 GagProPol Processing Can Be Regulated by Reversible Oxidation SO PLOS ONE LA English DT Article ID NF-KAPPA-B; HIV-1 PROTEASE; VIRAL INFECTIVITY; SEQUENTIAL STEPS; GAGPOL PRECURSOR; CLEAVAGE SITES; IN-VITRO; ACTIVATION; DIMERIZATION; INHIBITION AB Background: Maturation of human immunodeficiency virus type 1 (HIV-1) occurs upon activation of HIV-1 protease embedded within GagProPol precursors and cleavage of Gag and GagProPol polyproteins. Although reversible oxidation can regulate mature protease activity as well as retrovirus maturation, it is possible that the effects of oxidation on viral maturation are mediated in whole, or part, through effects on the initial intramolecular cleavage event of GagProPol. In order assess the effect of reversible oxidation on this event, we developed a system to isolate the first step in protease activation involving GagProPol. Methodology/Principal Findings: To determine if oxidation influences this step, we created a GagProPol plasmid construct (pGPfs-1C) that encoded mutations at all cleavage sites except p2/NC, the initial cleavage site in GagProPol. pGPfs-1C was used in an in vitro translation assay to observe the behavior of this initial step without interference from subsequent processing events. Diamide, a sulfhydral oxidizing agent, inhibited processing at p2/NC by >60% for pGPfs-1C and was readily reversed with the reductant, dithiothreitol. The ability to regulate processing by reversible oxidation was lost when the cysteines of the embedded protease were mutated to alanine. Unlike mature protease, which requires only oxidation of cys95 for inhibition, both cysteines of the embedded protease contributed to this inhibition. Conclusions/Significance: We developed a system that can be used to study the first step in the cascade of HIV-1 GagProPol processing and show that reversible oxidation of cysteines of HIV-1 protease embedded in GagProPol can block this initial GagProPol autoprocessing. This type of regulation may be broadly applied to the majority of retroviruses. C1 [Daniels, Sarah I.; Davis, David A.; Soule, Erin E.; Tebbs, Irene R.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stahl, Stephen J.; Wingfield, Paul] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. RP Daniels, SI (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dadavis@helix.nih.gov NR 35 TC 3 Z9 3 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 22 PY 2010 VL 5 IS 10 AR e13595 DI 10.1371/journal.pone.0013595 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 670KA UT WOS:000283419100021 PM 21042582 ER PT J AU Sun, GH Hasebe, T Fujimoto, K Lu, R Fu, LZ Matsuda, H Kajita, M Ishizuya-Oka, A Shi, YB AF Sun, Guihong Hasebe, Takashi Fujimoto, Kenta Lu, Rosemary Fu, Liezhen Matsuda, Hiroki Kajita, Mitsuko Ishizuya-Oka, Atsuko Shi, Yun-Bo TI Spatio-Temporal Expression Profile of Stem Cell-Associated Gene LGR5 in the Intestine during Thyroid Hormone-Dependent Metamorphosis in Xenopus laevis SO PLOS ONE LA English DT Article ID AMPHIBIAN METAMORPHOSIS; PROTEIN; EPITHELIUM; RECEPTORS; IDENTIFICATION; PROLIFERATION; RENEWAL; RELAXIN; CANCER; REGION AB Background: The intestinal epithelium undergoes constant self-renewal throughout adult life across vertebrates. This is accomplished through the proliferation and subsequent differentiation of the adult stem cells. This self-renewal system is established in the so-called postembryonic developmental period in mammals when endogenous thyroid hormone (T3) levels are high. Methodology/Principal Findings: The T3-dependent metamorphosis in anurans like Xenopus laevis resembles the mammalian postembryonic development and offers a unique opportunity to study how the adult stem cells are developed. The tadpole intestine is predominantly a monolayer of larval epithelial cells. During metamorphosis, the larval epithelial cells undergo apoptosis and, concurrently, adult epithelial stem/progenitor cells develop de novo, rapidly proliferate, and then differentiate to establish a trough-crest axis of the epithelial fold, resembling the crypt-villus axis in the adult mammalian intestine. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a well-established stem cell marker in the adult mouse intestinal crypt. Here we have cloned and analyzed the spatiotemporal expression profile of LGR5 gene during frog metamorphosis. We show that the two duplicated LGR5 genes in Xenopus laevis and the LGR5 gene in Xenopus tropicalis are highly homologous to the LGR5 in other vertebrates. The expression of LGR5 is induced in the limb, tail, and intestine by T3 during metamorphosis. More importantly, LGR5 mRNA is localized to the developing adult epithelial stem cells of the intestine. Conclusions/Significance: These results suggest that LGR5-expressing cells are the stem/progenitor cells of the adult intestine and that LGR5 plays a role in the development and/or maintenance of the adult intestinal stem cells during postembryonic development in vertebrates. C1 [Sun, Guihong; Fujimoto, Kenta; Lu, Rosemary; Fu, Liezhen; Matsuda, Hiroki; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bethesda, MD USA. [Hasebe, Takashi; Ishizuya-Oka, Atsuko] Nippon Med Sch, Dept Biol, Kawasaki Ku, Kanagawa, Japan. [Kajita, Mitsuko; Ishizuya-Oka, Atsuko] Nippon Med Sch, Inst Dev & Aging Sci, Dept Mol Biol, Kawasaki Ku, Kanagawa, Japan. RP Sun, GH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bethesda, MD USA. EM Shi@helix.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health; Narishige Zoological Science Award FX This research was supported in part by the Intramural Research Program of National Institute of Child Health and Human Development, National Institutes of Health and in part by Narishige Zoological Science Award to T.H. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 16 Z9 17 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 22 PY 2010 VL 5 IS 10 AR e13605 DI 10.1371/journal.pone.0013605 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 670KA UT WOS:000283419100024 PM 21042589 ER PT J AU Satyanarayana, A Gudmundsson, KO Chen, X Coppola, V Tessarollo, L Keller, JR Hou, SX AF Satyanarayana, Ande Gudmundsson, Kristbjorn Orri Chen, Xiu Coppola, Vincenzo Tessarollo, Lino Keller, Jonathan R. Hou, Steven X. TI RapGEF2 is essential for embryonic hematopoiesis but dispensable for adult hematopoiesis SO BLOOD LA English DT Article ID SIGNAL-REGULATED KINASE; MEDIATED CELL-ADHESION; B-RAF; DEFINITIVE HEMATOPOIESIS; TRANSCRIPTION FACTORS; MICE LACKING; RAP1 ACTIVATION; MAP KINASE; T-CELLS; EXPRESSION AB RapGEF2 is one of many guanine nucleotide exchange factors (GEFs) that specifically activate Rap1. Here, we generated RapGEF2 conditional knockout mice and studied its role in embryogenesis and fetal as well as adult hematopoietic stem cell (HSC) regulation. RapGEF2 deficiency led to embryonic lethality at similar to E11.5 due to severe yolk sac vascular defects. However, a similar number of Flk1(+) cells were present in RapGEF2(+/+) and RapGEF2(-/-) yolk sacs indicating that the bipotential early progenitors were in fact generated in the absence of RapGEF2. Further analysis of yolk sacs and embryos revealed a significant reduction of CD41 expressing cells in RapGEF2(-/-) genotype, suggesting a defect in the maintenance of definitive hematopoiesis. RapGEF2(-/-) cells displayed defects in proliferation and migration, and the in vitro colony formation ability of hematopoietic progenitors was also impaired. At the molecular level, Rap1 activation was impaired in RapGEF2(-/-) cells that in turn lead to defective B-raf/ERK signaling. Scl/Gata transcription factor expression was significantly reduced, indicating that the defects observed in RapGEF2(-/-) cells could be mediated through Scl/Gata deregulation. Inducible deletion of RapGEF2 during late embryogenesis in RapGEF2(cko/cko)ER(cre) mice leads to defective fetal liver erythropoiesis. Conversely, inducible deletion in the adult bone marrow, or specific deletion in B cells, T cells, HSCs, and endothelial cells has no impact on hematopoiesis. (Blood.2010;116(16):2921-2931) C1 [Satyanarayana, Ande; Chen, Xiu; Coppola, Vincenzo; Tessarollo, Lino; Hou, Steven X.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Gudmundsson, Kristbjorn Orri; Keller, Jonathan R.] NCI, Basic Res Program, SAIC Frederick, Ctr Canc Res, Frederick, MD 21702 USA. RP Hou, SX (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560-12-70,1050 Boyles St, Frederick, MD 21702 USA. EM kellerjo@mail.nih.gov; hous@mail.nih.gov RI Coppola, Vincenzo/E-2917-2011 OI Coppola, Vincenzo/0000-0001-6163-1779 FU National Institutes of Health (NIH), NCI, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. NR 50 TC 13 Z9 13 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 OCT 21 PY 2010 VL 116 IS 16 BP 2921 EP 2931 DI 10.1182/blood-2010-01-262964 PG 11 WC Hematology SC Hematology GA 668VJ UT WOS:000283299500014 PM 20595512 ER PT J AU Narazaki, M Segarra, M Hou, X Tanaka, T Li, XR Tosato, G AF Narazaki, Masashi Segarra, Marta Hou, Xu Tanaka, Toshio Li, Xuri Tosato, Giovanna TI Oligo-guanosine nucleotide induces neuropilin-1 internalization in endothelial cells and inhibits angiogenesis SO BLOOD LA English DT Article ID SCAVENGER RECEPTORS; GROWTH-FACTOR; VASCULAR-PERMEABILITY; SEMAPHORIN-III; BINDING; VEGF; EXPRESSION; LIGAND; GROWTH-FACTOR-165; INTERLEUKIN-6 AB Ligand interaction with cognate cell-surface receptor often promotes receptor internalization, protecting cells from prolonged or excessive signaling from extracellular ligands. Compounds that induce internalization of surface receptors prevent ligand binding to cognate cell-surface receptors serving as inhibitors. Here, we show that synthetic polyriboguanosine (poly G) and oligo-deoxyriboguanosine (oligo G) reduce endothelial levels of surface neuropilin-1 (NRP1), a receptor shared by semaphorin 3A and vascular endothelial growth factor (VEGF), which plays critical roles in angiogenesis. Oligo G also reduces levels of cell-surface scavenger receptor expressed by endothelial cells I (SREC-I), but not levels of NRP2, gp130, CD31, VEGFR-1, or VEGFR-2. Poly or oligo A, T, and C do not promote NRP1 or SREC-I internalization. We find that oligo G binds to NRP1 with high affinity (Kd: 1.3 +/- 0.16nM), bridges the extracellular domain of NRP1 to that of SREC-I, and induces coordinate internalization of NRP1 and SREC-I. In vitro, oligo G blocks the binding and function of VEGF(165) in endothelial cells. In vivo, intravitreal administration of oligo G reduces choroidal neovascularization in mice. These results demonstrate that synthetic oligo G is an inhibitor of pathologic angiogenenesis that reduces cell-surface levels and function of NRP1 acting as an internalization inducer. (Blood.2010;116(16):3099-3107) C1 [Narazaki, Masashi; Segarra, Marta; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Narazaki, Masashi; Tanaka, Toshio] Osaka Univ, Dept Resp Med Allergy & Rheumat Dis, Grad Sch Med, Osaka, Japan. [Hou, Xu; Li, Xuri] NEI, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 4124, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov OI narazaki, masashi/0000-0002-5613-4409 FU NIH, National Cancer Institute, Center for Cancer Research; Osaka Foundation for Promotion of Clinical Immunology; Japan Society for the Promotion of Science [20590399]; National Eye Institute FX This work was supported by the intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the National Eye Institute, the Japan Society for the Promotion of Science KAKENHI (20590399), and by the Osaka Foundation for Promotion of Clinical Immunology. NR 40 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 21 PY 2010 VL 116 IS 16 BP 3099 EP 3107 DI 10.1182/blood-2010-01-265801 PG 9 WC Hematology SC Hematology GA 668VJ UT WOS:000283299500034 PM 20606164 ER PT J AU Pawelczyk, E Nowicki, BJ Izban, MG Pratap, S Sashti, NA Sanderson, M Nowicki, S AF Pawelczyk, Edyta Nowicki, Bogdan J. Izban, Michael G. Pratap, Siddharth Sashti, Nupur A. Sanderson, Maureen Nowicki, Stella TI Spontaneous preterm labor is associated with an increase in the proinflammatory signal transducer TLR4 receptor on maternal blood monocytes SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article ID TOLL-LIKE RECEPTOR-4; HISTOLOGIC CHORIOAMNIONITIS; INFLAMMATORY RESPONSE; PERIPHERAL-BLOOD; EXPRESSION; RECOGNITION; ACTIVATION; DELIVERY; TERM; EPIDEMIOLOGY AB Background: Localized inflammation and increased expression of TLR4 receptors within the uterus has been implicated in the pathogenesis of preterm labor. It remains unclear whether intrauterine inflammatory responses activate the maternal peripheral circulatory system. Therefore we determined whether increased TLR4 expression is present in the peripheral maternal white blood cells of women with spontaneous preterm labor. Methods: This is a cross-sectional study of 41 preterm labor cases and 41 non-preterm controls. For each case and control sample, RNA was purified from white blood cells and TLR4 mRNA pool size was evaluated by quantitative PCR. Protein expression levels were determined by flow cytometry. Statistical evaluation using multiple linear regressions was used to determine any significant differences between the cases and controls. The purpose was to determine association prevalence of TLR4 levels and preterm labor. Results: Adjusted mean TLR4 mRNA levels of 0.788 +/- 0.037 (standard error) for preterm labor and 0.348 +/- 0.038 for the corresponding pregnant control women were statistically significantly different (P = 0.002). Using the lower 95% confidence interval of the mean expression level in PTL subjects (0.7) as a cutoff value for elevated TLR4 mRNA levels, 25/41 (60.9%) of PTL patients expressed elevated TLR4 mRNA as compared to 0/41 (0%) in control subjects. The TLR4 receptor levels in the granulocyte fraction of white blood cells from preterm labor and pregnant controls were similar. However, TLR4(+)/CD14(+) monocytes were 2.3 times more frequent (70% vs. 30%) and TLR4 also had a 2.6-fold higher density (750 vs. 280 molecules per cell) in preterm labor women compared with pregnant controls. There was no difference in the levels of TLR4 in patients at term. Conclusions: Patients with preterm labor exhibited elevated levels of CD14(+) maternal blood monocytes each bearing enhanced expression of TLR4, indicating that the peripheral circulatory system is activated in patients with preterm labor. Elevated leukocyte TLR4 levels may be a useful biomarker associated with preterm labor. C1 [Nowicki, Bogdan J.; Sanderson, Maureen; Nowicki, Stella] Meharry Med Coll, Dept Obstet, Nashville, TN 37208 USA. [Nowicki, Bogdan J.; Sanderson, Maureen; Nowicki, Stella] Meharry Med Coll, Dept Gynecol, Nashville, TN 37208 USA. [Pawelczyk, Edyta] NIH, Bethesda, MD 20892 USA. [Nowicki, Bogdan J.; Izban, Michael G.; Pratap, Siddharth; Nowicki, Stella] Meharry Med Coll, Dept Microbiol & Immunol, Nashville, TN 37208 USA. [Sashti, Nupur A.] Tennessee Dept Hlth, Communicable Dis Serv, Nashville, TN USA. [Sashti, Nupur A.] Tennessee Dept Hlth, Environm Dis Serv, Nashville, TN USA. RP Nowicki, S (reprint author), Meharry Med Coll, Dept Obstet, Nashville, TN 37208 USA. EM snowicki@mmc.edu OI Pratap, Siddharth/0000-0003-2200-0848 FU National Institute of Child Health and Human Development [HD41687]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK42029]; Clinical Research Center of Meharry Medical College, National Institutes of Health [P20RR011792]; RCMI Clinical Research Infrastructure Initiative; Meharry Medical College Microarray and Bioinformatics Core [U54HD044315]; NIH [P20RR011792, G12RR03032-19] FX This study was supported by Public Health Service grant HD41687 from the National Institute of Child Health and Human Development to S. Nowicki and B.J. Nowicki, and in part, by grant DK42029 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Clinical Research Center of Meharry Medical College grant P20RR011792 from the National Institutes of Health and RCMI Clinical Research Infrastructure Initiative and U54HD044315 to B.J. Nowicki. Data analyses were performed through the use of the Meharry Medical College Microarray and Bioinformatics Core, which is supported in part by NIH grants G12RR03032-19 and P20RR011792. [http://www.mmc.edu/bioinformatics] NR 30 TC 12 Z9 13 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD OCT 21 PY 2010 VL 10 AR 66 DI 10.1186/1471-2393-10-66 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 840PE UT WOS:000296451900001 PM 20964862 ER PT J AU Ghoreschi, K Laurence, A Yang, XP Tato, CM McGeachy, MJ Konkel, JE Ramos, HL Wei, L Davidson, TS Bouladoux, N Grainger, JR Chen, QA Kanno, Y Watford, WT Sun, HW Eberl, G Shevach, E Belkaid, Y Cua, DJ Chen, WJ O'Shea, JJ AF Ghoreschi, Kamran Laurence, Arian Yang, Xiang-Ping Tato, Cristina M. McGeachy, Mandy J. Konkel, Joanne E. Ramos, Haydee L. Wei, Lai Davidson, Todd S. Bouladoux, Nicolas Grainger, John R. Chen, Qian Kanno, Yuka Watford, Wendy T. Sun, Hong-Wei Eberl, GerRard Shevach, EthanM. Belkaid, Yasmine Cua, Daniel J. Chen, WanJun O'Shea, John J. TI Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling SO NATURE LA English DT Article ID REGULATORY T-CELLS; GROWTH-FACTOR-BETA; HELPER-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; PROINFLAMMATORY IL-17(+); TH17 CELLS; IN-VIVO; DIFFERENTIATION; LINEAGE; INFLAMMATION AB CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity(1-4). Although crucial for T(H)17 cells in vivo(5,6), IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-beta 1 have been proposed to be the factors responsible for initiating specification(7-10). Here we show that T(H)17 differentiation can occur in the absence of TGF-beta signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1 beta effectively induced IL-17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-beta 1, allowing the generation of cells that co-expressed ROR gamma t (encoded by Rorc) and T-bet. T-bet(+)ROR gamma t(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-beta 1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications. C1 [Ghoreschi, Kamran; Laurence, Arian; Yang, Xiang-Ping; Ramos, Haydee L.; Wei, Lai; Kanno, Yuka; Watford, Wendy T.; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Tato, Cristina M.; McGeachy, Mandy J.; Cua, Daniel J.] Merck Res Labs, Palo Alto, CA 94304 USA. [Konkel, Joanne E.; Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Davidson, Todd S.; Chen, Qian; Shevach, EthanM.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Grainger, John R.; Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Sun, Hong-Wei] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Eberl, GerRard] Inst Pasteur, Lymphoid Tissue Dev Unit, F-75724 Paris, France. RP Ghoreschi, K (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM ghoreschik@mail.nih.gov; osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009; Yang, Xiangping/B-4833-2011; Eberl, Gerard/A-1160-2013; Kanno, Yuka/B-5802-2013; Wei, Lai/D-1088-2014 OI Laurence, Arian/0000-0003-0942-8292; FU NIAMS; NIDCR; NIAID FX We thank J. Simone, J. Lay (Flow Cytometry Section, NIAMS) and the NIAMS LACU staff for technical support. This work has been supported by the Intramural Research Programs of NIAMS, NIDCR and NIAID. NR 34 TC 546 Z9 565 U1 8 U2 52 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 21 PY 2010 VL 467 IS 7318 BP 967 EP U144 DI 10.1038/nature09447 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 668FT UT WOS:000283254700039 PM 20962846 ER PT J AU Traynor, BJ Singleton, AB AF Traynor, Bryan J. Singleton, Andrew B. TI Nature versus Nurture: Death of a Dogma, and the Road Ahead SO NEURON LA English DT Article ID GENOME-WIDE ASSOCIATION; LIFE-STYLE; MYOCARDIAL-INFARCTION; PARKINSONS-DISEASE; PRIMARY PREVENTION; ALZHEIMER-DISEASE; RISK; HEIGHT; LOCI; VARIANTS AB Interaction between the genome and the environment has been widely discussed in the literature, but has the importance ascribed to understanding these interactions been overstated? In this opinion piece, we critically discuss gene-environment interactions and attempt to answer three key questions. First, is it likely that gene-environment interactions actually exist? Second, what is the realistic value of trying to unravel these interactions, both in terms of understanding disease pathogenesis and as a means of ameliorating disease? Finally, and most importantly, do the technologies and methodologies exist to facilitate an unbiased search for gene-environment interactions? Addressing these questions highlights key areas of feasibility that must be considered in this area of research. C1 [Traynor, Bryan J.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Traynor, Bryan/G-5690-2010 FU NIH; National Institute on Aging [Z01-AG000949-02] FX This research was supported entirely by the Intramural Research Program of the NIH and the National Institute on Aging (Z01-AG000949-02). NR 44 TC 13 Z9 13 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD OCT 21 PY 2010 VL 68 IS 2 BP 196 EP 200 DI 10.1016/j.neuron.2010.10.002 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 681IJ UT WOS:000284304300008 PM 20955927 ER PT J AU Tewari, K Flynn, BJ Boscardin, SB Kastenmueller, K Salazar, AM Anderson, CA Soundarapandian, V Ahumada, A Keler, T Hoffman, SL Nussenzweig, MC Steinman, RM Seder, RA AF Tewari, Kavita Flynn, Barbara J. Boscardin, Silvia B. Kastenmueller, Kathrin Salazar, Andres M. Anderson, Charles A. Soundarapandian, Velmurugan Ahumada, Adriana Keler, Tibor Hoffman, Stephen L. Nussenzweig, Michel C. Steinman, Ralph M. Seder, Robert A. TI Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and alpha DEC-CSP in non human primates SO VACCINE LA English DT Article DE Pre-erythrocytic vaccines; Poly(I:C); Circumsporozoite protein (CSP) ID MALARIA VACCINE; DENDRITIC CELLS; IRRADIATED SPOROZOITES; DIRECT STIMULATION; CUTTING EDGE; I INTERFERON; LIVER-STAGES; IMMUNITY; PROTECTION; CD4(+) AB Development of a fully effective vaccine against the pre-erythrocytic stage of malaria infection will likely require induction of both humoral and cellular immune responses. Protein based vaccines can elicit such broad-based immunity depending on the adjuvant and how the protein is formulated. Here to assess these variables, non human primates (NHP) were immunized three times with Plasmodium falciparum (Pf) circumsporozoite protein (CSP) or CSP cloned into MG38, a monoclonal antibody that targets DEC-205 (alpha DEC-CSP), an endocytic receptor on dendritic cells (DCs). Both vaccines were administered with or without poly(I:C) as adjuvant. Following three immunizations, the magnitude and quality of cytokine secreting CD4+ T cells were comparable between CSP + poly(I:C) and alpha DEC-CSP + poly(I:C) groups with both regimens eliciting multi-functional cytokine responses. However, NHP immunized with CSP + poly(I:C) had significantly higher serum titers of CSP-specific IgG antibodies and indirect immunofluorescent antibody (IFA) titers against Pf sporozoites. Furthermore, sera from both CSP or alpha DEC-CSP + poly(I:C) immunized animals limited sporozoite invasion of a hepatocyte cell line (HC04) in vitro. To determine whether CSP-specific responses could be enhanced, all NHP primed with CSP or alpha DEC-CSP + poly(I:C) were boosted with a single dose of 150,000 irradiated Pf sporozoites (PfSPZ) intravenously. Remarkably, boosting had no effect on the CSP-specific immunity. Finally, immunization with CSP + poly-ICLC reduced malaria parasite burden in the liver in an experimental mouse model. Taken together, these data showing that poly(I:C) is an effective adjuvant for inducing potent antibody and Th1 immunity with CSP based vaccines offers a potential alternative to the existing protein based pre-erythrocytic vaccines. Published by Elsevier Ltd. C1 [Seder, Robert A.] NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Boscardin, Silvia B.; Nussenzweig, Michel C.; Steinman, Ralph M.] Rockefeller Univ, New York, NY 10065 USA. [Salazar, Andres M.] Oncovir Inc, Washington, DC 20008 USA. [Anderson, Charles A.; Soundarapandian, Velmurugan; Ahumada, Adriana; Hoffman, Stephen L.] Sanaria Inc, Rockville, MD 20850 USA. [Keler, Tibor] Celldex Therapeut, Phillipsburg, NJ 08865 USA. RP Seder, RA (reprint author), NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 3512, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Boscardin, Silvia Beatriz/C-3397-2012; Steinman, Ralph/F-7729-2012; Vacinas, Inct/J-9431-2013 OI Boscardin, Silvia Beatriz/0000-0002-7845-7110; NR 48 TC 59 Z9 59 U1 1 U2 9 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 OCT 21 PY 2010 VL 28 IS 45 BP 7256 EP 7266 DI 10.1016/j.vaccine.2010.08.098 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 677WY UT WOS:000284026600005 PM 20846528 ER PT J AU Nanda, H Datta, SAK Heinrich, F Losche, M Rein, A Krueger, S Curtis, JE AF Nanda, Hirsh Datta, Siddhartha A. K. Heinrich, Frank Loesche, Mathias Rein, Alan Krueger, Susan Curtis, Joseph E. TI Electrostatic Interactions and Binding Orientation of HIV-1 Matrix Studied by Neutron Reflectivity SO BIOPHYSICAL JOURNAL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BILAYER-LIPID MEMBRANES; ROUS-SARCOMA-VIRUS; VIRAL LIFE-CYCLE; TYPE-1 MATRIX; PLASMA-MEMBRANE; PROTEIN; GAG; DOMAIN; PHOSPHATIDYLINOSITOL-(4,5)-BISPHOSPHATE AB The N-terminal matrix (MA) domain of the HIV-1 Gag protein is responsible for binding to the plasma membrane of host cells during viral assembly. The putative membrane-binding interface of MA was previously mapped by means of mutagenesis and analysis of its trimeric crystal structure. However, the orientation of MA on membranes has not been directly determined by experimental measurements. We present neutron reflectivity measurements that resolve the one-dimensional scattering length density profile of MA bound to a biomimetic of the native viral membrane. A molecular refinement procedure was developed using atomic structures of MA to determine the orientation of the protein on the membrane. The orientation defines a lipid-binding interface consistent with previous mutagenesis results. The MA protein maintains this orientation without the presence of a myristate group, driven only by electrostatic interactions. Furthermore, MA is found to penetrate the membrane headgroup region peripherally such that only the side chains of specific Lys and Arg residues interact with the surface. The results suggest that electrostatic interactions are sufficient to favorably orient MA on viral membrane mimics. The spatial determination of the membrane-bound protein demonstrates the ability of neutron reflectivity to discern orientation and penetration under physiologically relevant conditions. C1 [Nanda, Hirsh; Heinrich, Frank; Loesche, Mathias; Krueger, Susan; Curtis, Joseph E.] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Datta, Siddhartha A. K.; Rein, Alan] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Heinrich, Frank; Loesche, Mathias] Carnegie Mellon Univ, Dept Phys, Biol Phys Grp, Pittsburgh, PA 15213 USA. RP Nanda, H (reprint author), NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. EM hirsh.nanda@nist.gov RI Heinrich, Frank/A-5339-2010; Losche, Mathias/J-2986-2013; OI Heinrich, Frank/0000-0002-8579-553X; Losche, Mathias/0000-0001-6666-916X; Datta, Siddhartha/0000-0002-4098-7490 FU U.S. Department of Commerce [70NANB8H8009]; National Institutes of Health [NIH; 1P01 AG032131]; American Health Assistance Foundation [A2008-307]; Center for Cancer Research, National Cancer Institute, NIH FX This work was supported by the U.S. Department of Commerce through the MSE program (70NANB8H8009), the National Institutes of Health (NIH; 1P01 AG032131), and the American Health Assistance Foundation (A2008-307). It was also supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (http://biowulf.nih.gov). NR 45 TC 22 Z9 22 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT 20 PY 2010 VL 99 IS 8 BP 2516 EP 2524 DI 10.1016/j.bpj.2010.07.062 PG 9 WC Biophysics SC Biophysics GA 670HT UT WOS:000283412500018 PM 20959092 ER PT J AU Yang, ST Zaitseva, E Chernomordik, LV Melikov, K AF Yang, Sung-Tae Zaitseva, Elena Chernomordik, Leonid V. Melikov, Kamran TI Cell-Penetrating Peptide Induces Leaky Fusion of Liposomes Containing Late Endosome-Specific Anionic Lipid SO BIOPHYSICAL JOURNAL LA English DT Article ID HEMAGGLUTININ-MEDIATED FUSION; PROTEIN TRANSDUCTION DOMAINS; BIOLOGICAL MEMBRANE-FUSION; TAT PEPTIDE; HIV-1 TAT; BINDING MECHANISM; NUCLEAR DELIVERY; HEPARAN-SULFATE; RICH PEPTIDES; TRANSLOCATION AB Cationic cell-penetrating peptides (CPPs) are a promising vehicle for the delivery of macromolecular drugs. Although many studies have indicated that CPPs enter cells by endocytosis, the mechanisms by which they cross endosomal membranes remain elusive. On the basis of experiments with liposomes, we propose that CPP escape into the cytosol is based on leaky fusion (i.e., fusion associated with the permeabilization of membranes) of the bis(monoacylglycero)phosphate (BMP)-enriched membranes of late endosomes. In our experiments, prototypic CPP HIV-1 TAT peptide did not interact with liposomes mimicking the outer leaflet of the plasma membrane, but it did induce lipid mixing and membrane leakage as it translocated into liposomes mimicking the lipid composition of late endosome. Both membrane leakage and lipid mixing depended on the BMP content and were promoted at acidic pH, which is characteristic of late endosomes. Substitution of BMP with its structural isomer, phosphatidylglycerol (PG), significantly reduced both leakage of the aqueous probe from liposomes and lipid mixing between liposomes. Although affinity of binding to TAT was similar for BMP and PG, BMP exhibited a higher tendency to support the inverted hexagonal phase than PG. Finally, membrane leakage and peptide translocation were both inhibited by inhibitors of lipid mixing, further substantiating the hypothesis that cationic peptides cross BMP-enriched membranes by inducing leaky fusion between them. C1 [Yang, Sung-Tae; Zaitseva, Elena; Chernomordik, Leonid V.; Melikov, Kamran] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. RP Melikov, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. EM melikovk@mail.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health (L.V.C.). NR 52 TC 54 Z9 54 U1 3 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT 20 PY 2010 VL 99 IS 8 BP 2525 EP 2533 DI 10.1016/j.bpj.2010.08.029 PG 9 WC Biophysics SC Biophysics GA 670HT UT WOS:000283412500019 PM 20959093 ER PT J AU DeRouchey, J Parsegian, VA Rau, DC AF DeRouchey, Jason Parsegian, V. Adrian Rau, Donald C. TI Cation Charge Dependence of the Forces Driving DNA Assembly SO BIOPHYSICAL JOURNAL LA English DT Article ID X-RAY-DIFFRACTION; HYDRATION FORCES; RODLIKE POLYELECTROLYTES; INTERMOLECULAR FORCES; MULTIVALENT CATIONS; BIOGENIC POLYAMINES; CHROMATIN-STRUCTURE; GENE-EXPRESSION; DOUBLE HELICES; ATTRACTION AB Understanding the strength and specificity of interactions among biologically important macromolecules that control cellular functions requires quantitative knowledge of intermolecular forces. Controlled DNA condensation and assembly are particularly critical for biology, with separate repulsive and attractive intermolecular forces determining the extent of DNA compaction. How these forces depend on the charge of the condensing ion has not been determined, but such knowledge is fundamental for understanding the basis of DNA-DNA interactions. Here, we measure DNA force-distance curves for a homologous set of arginine peptides. All forces are well fit as the sum of two exponentials with 2.4- and 4.8-angstrom decay lengths. The shorter-decay-length force is always repulsive, with an amplitude that varies slightly with length or charge. The longer-decay-length force varies strongly with cation charge, changing from repulsion with Arg(1) to attraction with Arg(2). Force curves for a series of homologous polyamines and the heterogeneous protein protamine are quite similar, demonstrating the universality of these forces for DNA assembly. Repulsive amplitudes of the shorter-decay-length force are species-dependent but nearly independent of charge within each species. A striking observation was that the attractive force amplitudes for all samples collapse to a single curve, varying linearly with the inverse of the cation charge. C1 [DeRouchey, Jason; Rau, Donald C.] NICHHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Parsegian, V. Adrian] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. RP DeRouchey, J (reprint author), Univ Kentucky, Dept Chem, 125 Chem Phys Bldg, Lexington, KY 40506 USA. EM derouchey@uky.edu; raud@mail.nih.gov RI DeRouchey, Jason/C-5907-2011 OI DeRouchey, Jason/0000-0002-3624-4432 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 52 TC 26 Z9 26 U1 1 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT 20 PY 2010 VL 99 IS 8 BP 2608 EP 2615 DI 10.1016/j.bpj.2010.08.028 PG 8 WC Biophysics SC Biophysics GA 670HT UT WOS:000283412500028 PM 20959102 ER PT J AU Berezhkovskii, AM Sample, C Shvartsman, SY AF Berezhkovskii, Alexander M. Sample, Christine Shvartsman, Stanislav Y. TI How Long Does It Take to Establish a Morphogen Gradient? SO BIOPHYSICAL JOURNAL LA English DT Article ID DIFFUSION AB A morphogen gradient is defined as a concentration field of a molecule that acts as a dose-dependent regulator of cell differentiation. One of the key questions in studies of morphogen gradients is whether they reach steady states on time-scales relevant for developmental patterning. We propose a systematic approach for addressing this question and illustrate it by analyzing several models that account for diffusion and degradation of locally produced chemical signals. C1 [Sample, Christine; Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. [Sample, Christine; Shvartsman, Stanislav Y.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Shvartsman, SY (reprint author), Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. EM stas@princeton.edu FU National Institutes of Health, Center for Information Technology; National Institutes of Health [HHSN266200500021C, N01-AI-50021] FX The authors were partially supported by the Intramural Research Program of the National Institutes of Health, Center for Information Technology (A.M.B.), and the National Institutes of Health under contract No. HHSN266200500021C and ADB grant No. N01-AI-50021 (S.Y.S. and C.S.). NR 11 TC 31 Z9 31 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT 20 PY 2010 VL 99 IS 8 BP L59 EP L61 DI 10.1016/j.bpj.2010.07.045 PG 3 WC Biophysics SC Biophysics GA 670HT UT WOS:000283412500001 PM 20959075 ER PT J AU Bratlie, MS Johansen, J Sherman, BT Huang, DW Lempicki, RA Drablos, F AF Bratlie, Marit S. Johansen, Jostein Sherman, Brad T. Huang, Da Wei Lempicki, Richard A. Drablos, Finn TI Gene duplications in prokaryotes can be associated with environmental adaptation SO BMC GENOMICS LA English DT Article ID COMPLETE GENOME SEQUENCE; DNA ADENINE METHYLATION; ORYZAE PV. ORYZAE; BACTEROIDES-THETAIOTAOMICRON; RALSTONIA-METALLIDURANS; METHANOSARCINA-BARKERI; BACTERIAL GENOMES; DATABASE; PARALOGS; TOOLS AB Background: Gene duplication is a normal evolutionary process. If there is no selective advantage in keeping the duplicated gene, it is usually reduced to a pseudogene and disappears from the genome. However, some paralogs are retained. These gene products are likely to be beneficial to the organism, e.g. in adaptation to new environmental conditions. The aim of our analysis is to investigate the properties of paralog-forming genes in prokaryotes, and to analyse the role of these retained paralogs by relating gene properties to life style of the corresponding prokaryotes. Results: Paralogs were identified in a number of prokaryotes, and these paralogs were compared to singletons of persistent orthologs based on functional classification. This showed that the paralogs were associated with for example energy production, cell motility, ion transport, and defence mechanisms. A statistical overrepresentation analysis of gene and protein annotations was based on paralogs of the 200 prokaryotes with the highest fraction of paralog-forming genes. Biclustering of overrepresented gene ontology terms versus species was used to identify clusters of properties associated with clusters of species. The clusters were classified using similarity scores on properties and species to identify interesting clusters, and a subset of clusters were analysed by comparison to literature data. This analysis showed that paralogs often are associated with properties that are important for survival and proliferation of the specific organisms. This includes processes like ion transport, locomotion, chemotaxis and photosynthesis. However, the analysis also showed that the gene ontology terms sometimes were too general, imprecise or even misleading for automatic analysis. Conclusions: Properties described by gene ontology terms identified in the overrepresentation analysis are often consistent with individual prokaryote lifestyles and are likely to give a competitive advantage to the organism. Paralogs and singletons dominate different categories of functional classification, where paralogs in particular seem to be associated with processes involving interaction with the environment. C1 [Bratlie, Marit S.; Johansen, Jostein; Drablos, Finn] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7006 Trondheim, Norway. [Sherman, Brad T.; Huang, Da Wei; Lempicki, Richard A.] NCI, Lab Immunopathogenesis & Bioinformat, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Drablos, F (reprint author), Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7006 Trondheim, Norway. EM finn.drablos@ntnu.no RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU Research Council of Norway FX The project has been supported by The National Programme for Research in Functional Genomics in Norway (FUGF) in The Research Council of Norway. NR 68 TC 23 Z9 25 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 20 PY 2010 VL 11 AR 588 DI 10.1186/1471-2164-11-588 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 673LD UT WOS:000283662500001 PM 20961426 ER PT J AU Hill, BJ Skerry, JC Smith, TJ Arnon, SS Douek, DC AF Hill, Brenna J. Skerry, Janet C. Smith, Theresa J. Arnon, Stephen S. Douek, Daniel C. TI Universal and specific quantitative detection of botulinum neurotoxin genes SO BMC MICROBIOLOGY LA English DT Article ID REAL-TIME PCR; LINKED-IMMUNOSORBENT-ASSAY; POLYMERASE-CHAIN-REACTION; CLOSTRIDIUM-BOTULINUM; NEUROTRANSMITTER RELEASE; IMMUNE GLOBULIN; INFANT BOTULISM; WOUND BOTULISM; TOXIN GENE; A TOXIN AB Background: Clostridium botulinum, an obligate anaerobic spore-forming bacterium, produces seven antigenic variants of botulinum toxin that are distinguished serologically and termed "serotypes". Botulinum toxin blocks the release of acetylcholine at neuromuscular junctions resulting in flaccid paralysis. The potential lethality of the disease warrants a fast and accurate means of diagnosing suspected instances of food contamination or human intoxication. Currently, the Food and Drug Administration (FDA)-accepted assay to detect and type botulinum neurotoxins (BoNTs) is the mouse protection bioassay. While specific and sensitive, this assay requires the use of laboratory animals, may take up to four days to achieve a diagnosis, and is unsuitable for high-throughput analysis. We report here a two-step PCR assay that identifies all toxin types, that achieves the specificity of the mouse bioassay while surpassing it in equivalent sensitivity, that has capability for high-throughput analysis, and that provides quantitative results within hours. The first step of our assay consists of a conventional PCR that detects the presence of C. botulinum regardless of the neurotoxin type. The second step uses quantitative PCR (qPCR) technology to determine the specific serotype of the neurotoxin. Results: We assayed purified C. botulinum DNA and crude toxin preparations, as well as food and stool from healthy individuals spiked with purified BoNT DNA, and one stool sample from a case of infant botulism for the presence of the NTNH gene, which is part of the BoNT gene cluster, and for the presence of serotype-specific BoNT genes. The PCR surpassed the mouse bioassay both in specificity and sensitivity, detecting positive signals in BoNT preparations containing well below the 1 LD50 required for detection via the mouse bioassay. These results were type-specific and we were reliably able to quantify as few as 10 genomic copies. Conclusions: While other studies have reported conventional or quantitative PCR-based assays for the detection of C. botulinum genes, our procedure's high-throughput capability and its portability allows most laboratories to quickly assess the possible presence of BoNTs either in food processing samples or in suspected cases of botulism. Thus, this assay provides rapid and specific detection of BoNT and toxin complex genes and would enable the targeting of appropriate therapeutics to infected individuals in a timely manner. C1 [Hill, Brenna J.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Skerry, Janet C.; Smith, Theresa J.] USAMRIID, Integrated Toxicol Div, Ft Detrick, MD 21702 USA. [Arnon, Stephen S.] Calif Dept Publ Hlth, Infant Botulism Treatment & Prevent Program, Richmond, CA 94804 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov NR 57 TC 18 Z9 18 U1 3 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD OCT 20 PY 2010 VL 10 AR 267 DI 10.1186/1471-2180-10-267 PG 16 WC Microbiology SC Microbiology GA 675UO UT WOS:000283864300001 PM 20961439 ER PT J AU Kadam, Y Singh, K Marangoni, DG Ma, JH Aswal, VK Bahadur, P AF Kadam, Y. Singh, K. Marangoni, D. G. Ma, J. H. Aswal, V. K. Bahadur, P. TI Thermodynamic of micelle formation of nonlinear block co-polymer Tetronic (R) T904 in aqueous salt solution SO COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS LA English DT Article DE Tetronic (R); Micellization; Thermodynamic parameters; Isothermal calorimetry (ITC) ID ISOTHERMAL TITRATION CALORIMETRY; DIFFERENTIAL SCANNING CALORIMETRY; ANGLE NEUTRON-SCATTERING; OXIDE TRIBLOCK COPOLYMER; AGGREGATION BEHAVIOR; POLY(PROPYLENE OXIDE); INDUCED MICELLIZATION; ASSOCIATIVE BEHAVIOR; FTIR SPECTROSCOPY; IONIC-STRENGTH AB Calorimetric and spectroscopic studies have been carried out to investigate the thermodynamics of temperature-induced micellization of Tetronic (R) T904 [(EO(15)PO(17))(2)NCH(2)CH(2)N (PO(17)EO(15))(2)] in aqueous salt solutions. High-sensitivity differential scanning calorimetry (HSDSC), nuclear magnetic resonance (NMR) and Fourier transfer infrared (FTIR) measurements were used to evaluate the critical micellization temperature (CMT). The critical micellization concentration (CMC) and the thermodynamic parameters of micelle formations, namely enthalpy (Delta H(mic)), Gibbs energy (Delta G(mic)), and entropy (Delta S(mic)) of micellization were determined as a function of temperature and salt concentration using isothermal calorimetry (ITC). These measurements indicated spontaneous micellization with substantial enthalpy-entropy compensation of 1904 micellization. (C) 2010 Elsevier B.V. All rights reserved. C1 [Kadam, Y.; Bahadur, P.] VN S Gujarat Univ, Dept Chem, Surat 395007, Gujarat, India. [Singh, K.; Marangoni, D. G.] StFX Univ, Dept Chem, Antigonish, NS, Canada. [Ma, J. H.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Aswal, V. K.] Bhabha Atom Res Ctr, Div Solid State Phys, Bombay 400085, Maharashtra, India. RP Kadam, Y (reprint author), VN S Gujarat Univ, Dept Chem, Udhana Magdalla Rd, Surat 395007, Gujarat, India. EM yogeshkadam2010@yahoo.com; ksingh@stfx.ca; gmarango@stfx.ca; jhma1980@yahoo.com.cn; vkaswal@barc.gov.in; pbahadur2002@yahoo.com RI Marangoni, Gerrard/G-3438-2011; OI Kadam, Yogesh/0000-0002-3522-4659; singh, kulbir/0000-0003-3152-1119 FU StFX University; NSERC FX PB is grateful to St. Francis Xavier University, Antigonish, Canada for a James Chair Visiting Professorship. DGM and KS thank StFX University and NSERC for the provision of research funding. NR 49 TC 29 Z9 29 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7757 J9 COLLOID SURFACE A JI Colloid Surf. A-Physicochem. Eng. Asp. PD OCT 20 PY 2010 VL 369 IS 1-3 BP 121 EP 127 DI 10.1016/j.colsurfa.2010.08.010 PG 7 WC Chemistry, Physical SC Chemistry GA 670BN UT WOS:000283395600017 ER PT J AU Cha, SS An, YJ Lee, CR Lee, HS Kim, YG Kim, SJ Kwon, KK De Donatis, GM Lee, JH Maurizi, MR Kang, SG AF Cha, Sun-Shin An, Young Jun Lee, Chang Ro Lee, Hyun Sook Kim, Yeon-Gil Kim, Sang Jin Kwon, Kae Kyoung De Donatis, Gian Marco Lee, Jung-Hyun Maurizi, Michael R. Kang, Sung Gyun TI Crystal structure of Lon protease: molecular architecture of gated entry to a sequestered degradation chamber SO EMBO JOURNAL LA English DT Article DE AAA plus protein; ATP-dependent protease; compartmentalized protease; protein quality control; TonLon ID ESCHERICHIA-COLI LON; ATP HYDROLYSIS; ANGSTROM RESOLUTION; PROTEOLYTIC DOMAIN; 20S PROTEASOME; ACTIVE-SITE; AAA; SUBSTRATE; TRANSLOCATION; PROTEINS AB Lon proteases are distributed in all kingdoms of life and are required for survival of cells under stress. Lon is a tandem fusion of an AAA + molecular chaperone and a protease with a serine-lysine catalytic dyad. We report the 2.0-angstrom resolution crystal structure of Thermococcus onnurineus NA1 Lon (TonLon). The structure is a three-tiered hexagonal cylinder with a large sequestered chamber accessible through an axial channel. Conserved loops extending from the AAA + domain combine with an insertion domain containing the membrane anchor to form an apical domain that serves as a gate governing substrate access to an internal unfolding and degradation chamber. Alternating AAA + domains are in tight- and weak-binding nucleotide states with different domain orientations and intersubunit contacts, reflecting intramolecular dynamics during ATP-driven protein unfolding and translocation. The bowl-shaped proteolytic chamber is contiguous with the chaperone chamber allowing internalized proteins direct access to the proteolytic sites without further gating restrictions. The EMBO Journal (2010) 29, 3520-3530. doi:10.1038/emboj.2010.226; Published online 10 September 2010 Subject Categories: proteins; structural biology C1 [De Donatis, Gian Marco; Maurizi, Michael R.] NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Cha, Sun-Shin; An, Young Jun; Lee, Chang Ro; Lee, Hyun Sook; Kim, Sang Jin; Kwon, Kae Kyoung; Lee, Jung-Hyun; Kang, Sung Gyun] Korea Ocean Res & Dev Inst, Marine Biotechnol Res Ctr, Ansan 426744, South Korea. [Cha, Sun-Shin; Kim, Sang Jin; Kwon, Kae Kyoung; Lee, Jung-Hyun; Kang, Sung Gyun] Univ Sci & Technol, Dept Marine Biotechnol, Taejon, South Korea. [Kim, Yeon-Gil] Pohang Inst Sci & Technol, Pohang Accelerator Lab, Beamline Div, Pohang 790600, Kyungbuk, South Korea. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, 37 Convent Dr,Bldg 37 Room 2128, Bethesda, MD 20892 USA. EM chajung@kordi.re.kr; mmaurizi@helix.nih.gov; sgkang@kordi.re.kr FU KORDI [PE98513]; Marine and Extreme Genome Research Center; Ministry of Land, Transport, and Maritime Affairs, Republic of Korea; Center for Cancer Research, NCI, NIH Bethesda, MD FX We thank the staff of beamline 17A at Photon Factory for help with data collection. We are grateful to H-Y Kim and WC Lee at Korea Basic Science Institute (KBSI) for the use of Rigaku MicroMax-007HF X-ray generator and to Susan Gottesman and Matthew Humbard (National Cancer Institute, Bethesda, MD) for comments on the manuscript. This work was supported by KORDI in-house programme (PE98513), the Marine and Extreme Genome Research Center programme, and the Development of Biohydrogen Production Technology Using Hyperthermophilic Archaea programme of the Ministry of Land, Transport, and Maritime Affairs, Republic of Korea. MRM and GMDD are supported by the intramural research programme of the Center for Cancer Research, NCI, NIH Bethesda, MD. The atomic coordinates have been deposited in the Protein Data Bank (accession code 3K1J). NR 55 TC 47 Z9 47 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 20 PY 2010 VL 29 IS 20 BP 3520 EP 3530 DI 10.1038/emboj.2010.226 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 680NG UT WOS:000284239900009 PM 20834233 ER PT J AU Niida, H Murata, K Shimada, M Ogawa, K Ohta, K Suzuki, K Fujigaki, H Khaw, AK Banerjee, B Hande, MP Miyamoto, T Miyoshi, I Shirai, T Motoyama, N Delhase, M Appella, E Nakanishi, M AF Niida, Hiroyuki Murata, Kazuhiro Shimada, Midori Ogawa, Kumiko Ohta, Kumiko Suzuki, Kyoko Fujigaki, Hidetsugu Khaw, Aik Kia Banerjee, Birendranath Hande, M. Prakash Miyamoto, Tomomi Miyoshi, Ichiro Shirai, Tomoyuki Motoyama, Noboru Delhase, Mireille Appella, Ettore Nakanishi, Makoto TI Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo SO EMBO JOURNAL LA English DT Article DE apoptosis; cancer; checkpoint; DNA damage; senescence ID ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE CHECKPOINT; BREAST-CANCER; P53; KINASE; PHOSPHORYLATION; ACTIVATION; TUMORIGENESIS; PROTEIN; CELLS AB Although the linkage of Chk1 and Chk2 to important cancer signalling suggests that these kinases have functions as tumour suppressors, neither Chk1(+/-) nor Chk2(-/-) mice show a predisposition to cancer under unperturbed conditions. We show here that Chk1(+/-) Chk2(-/-) and Chk1(+/-) Chk2(+/-) mice have a progressive cancer-prone phenotype. Deletion of a single Chk1 allele compromises G2/M checkpoint function that is not further affected by Chk2 depletion, whereas Chk1 and Chk2 cooperatively affect G1/S and intra-S phase checkpoints. Either or both of the kinases are required for DNA repair depending on the type of DNA damage. Mouse embryonic fibroblasts from the double-mutant mice showed a higher level of p53 with spontaneous DNA damage under unperturbed conditions, but failed to phosphorylate p53 at S23 and further induce p53 expression upon additional DNA damage. Neither Chk1 nor Chk2 is apparently essential for p53- or Rb-dependent oncogene-induced senescence. Our results suggest that the double Chk mutation leads to a high level of spontaneous DNA damage, but fails to eliminate cells with damaged DNA, which may ultimately increase cancer susceptibility independently of senescence. The EMBO Journal (2010) 29, 3558-3570. doi:10.1038/emboj.2010.218; Published online 10 September 2010Subject Categories: genome stability & dyanamics; molecular biology of disease C1 [Nakanishi, Makoto] Nagoya City Univ, Dept Cell Biol, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Ogawa, Kumiko; Shirai, Tomoyuki] Nagoya City Univ, Dept Expt Pathol & Tumor Biol, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Ohta, Kumiko; Suzuki, Kyoko; Motoyama, Noboru] Natl Ctr Geriatr & Gerontol, Dept Cognit Brain Sci, Aichi, Japan. [Fujigaki, Hidetsugu; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Khaw, Aik Kia; Banerjee, Birendranath; Hande, M. Prakash] Natl Univ Singapore, Dept Physiol, Yong Loo Lin Sch Med, Singapore 117548, Singapore. [Miyamoto, Tomomi; Miyoshi, Ichiro] Nagoya City Univ, Dept Comparat & Expt Med, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Miyamoto, Tomomi; Miyoshi, Ichiro] Nagoya City Univ, Ctr Anim Sci, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Niida, Hiroyuki] Hamamatsu Univ Sch Med, Dept Biochem, Higashi Ku, Shizuoka, Japan. RP Nakanishi, M (reprint author), Nagoya City Univ, Dept Cell Biol, Grad Sch Med Sci, Mizuho Ku, 1 Kawasumi,Mizuho Cho, Nagoya, Aichi 4678601, Japan. EM mkt-naka@med.nagoya-cu.ac.jp RI Hande, M. Prakash/B-1645-2008 OI Hande, M. Prakash/0000-0002-4511-6256 FU Ministry of Education, Science, Sports and Culture of Japan; MEXT; Mitsubishi Foundation; Naito Memorial Foundation; Toyoaki Foundation; Takeda Foundation; Uehara Foundation; NIH, National Cancer Institute FX We thank Drs Nakayama and Nishiyama for analysis of E7.5 embryos, Drs Hayashi and Sakai for anti-Cdc25A antibodies, Dr Yamada-Namikawa, Miss Morimoto, Miss Kojima, Mr Seeni_mohamed and Mr Tang for technical assistance. This work was supported in part by the Ministry of Education, Science, Sports and Culture of Japan through a Grant-in-Aid for Scientific Research on Priority Area (A), a grant for Scientific Research (B), the project for realization of regenerative medicine of MEXT and by the Mitsubishi Foundation, the Naito Memorial Foundation, the Toyoaki Foundation, the Takeda Foundation and the Uehara Foundation awarded to MN. The study was also partially supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 61 TC 29 Z9 33 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD OCT 20 PY 2010 VL 29 IS 20 BP 3558 EP 3570 DI 10.1038/emboj.2010.218 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 680NG UT WOS:000284239900012 PM 20834228 ER PT J AU Yan, ZH Khadra, A Li, S Tomic, M Sherman, A Stojilkovic, SS AF Yan, Zonghe Khadra, Anmar Li, Shuo Tomic, Melanija Sherman, Arthur Stojilkovic, Stanko S. TI Experimental Characterization and Mathematical Modeling of P2X7 Receptor Channel Gating SO JOURNAL OF NEUROSCIENCE LA English DT Article ID P2X(7) RECEPTOR; PURINERGIC RECEPTOR; AGONIST BINDING; XENOPUS OOCYTES; PORE FORMATION; EXPRESSION; LYMPHOCYTES; ACTIVATION; PHYSIOLOGY; KINETICS AB The P2X7 receptor is a trimeric channel with three binding sites for ATP, but how the occupancy of these sites affects gating is still not understood. Here we show that naive receptors activated and deactivated monophasically at low and biphasically at higher agonist concentrations. Both phases of response were abolished by application of Az10606120, a P2X7R-specific antagonist. The slow secondary growth of current in the biphasic response coincided temporally with pore dilation. Repetitive stimulation with the same agonist concentration caused sensitization of receptors, which manifested as a progressive increase in the current amplitude, accompanied by a slower deactivation rate. Once a steady level of the secondary current was reached, responses at high agonist concentrations were no longer biphasic but monophasic. Sensitization of receptors was independent of Na+ and Ca2+ influx and similar to 30 min washout was needed to reestablish the initial gating properties. T15E- and T15K-P2X7 mutants showed increased sensitivity for agonists, responded with monophasic currents at all agonist concentrations, activated immediately with dilated pores, and deactivated slowly. The complex pattern of gating exhibited by wild-type channels can be accounted for by a Markov state model that includes negative cooperativity of agonist binding to unsensitized receptors caused by the occupancy of one or two binding sites, opening of the channel pore to a low conductance state when two sites are bound, and sensitization with pore dilation to a high conductance state when three sites are occupied. C1 [Yan, Zonghe; Li, Shuo; Tomic, Melanija; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, Bethesda, MD 20892 USA. [Khadra, Anmar; Sherman, Arthur] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, Program Dev Neurosci, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Tomic, Melanija/C-3371-2016 FU National Institutes of Health; National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases FX We were supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development (Z.Y., S. L., S. S. S.), and National Institute of Diabetes and Digestive and Kidney Diseases (A. K., A. S.). Z.Y. performed the bulk of the experiments and A. K. did the modeling. NR 32 TC 58 Z9 58 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 20 PY 2010 VL 30 IS 42 BP 14213 EP 14224 DI 10.1523/JNEUROSCI.2390-10.2010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 674YM UT WOS:000283788000030 PM 20962242 ER PT J AU Anastos, K Hoover, DR Burk, RD Cajigas, A Shi, QH Singh, DK Cohen, MH Mutimura, E Sturgis, C Banzhaf, WC Castle, PE AF Anastos, Kathryn Hoover, Donald R. Burk, Robert D. Cajigas, Antonio Shi, Qiuhu Singh, Diljeet K. Cohen, Mardge H. Mutimura, Eugene Sturgis, Charles Banzhaf, William C. Castle, Philip E. TI Risk Factors for Cervical Precancer and Cancer in HIV-Infected, HPV-Positive Rwandan Women SO PLOS ONE LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; ASCUS-LSIL TRIAGE; NATURAL-HISTORY; NEOPLASIA; POPULATION; DIAGNOSIS; DNA; BIOPSY; ALTS AB Background: Although cervical cancer is an AIDS-defining condition, infection with human immunodeficiency virus (HIV) may only modestly increase the risk of cervical cancer. There is a paucity of information regarding factors that influence the natural history of human papillomavirus (HPV) in HIV-infected women. We examined factors associated with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in Rwandan women infected with both HIV and HPV (HIV+/HPV+). Methods: In 2005, 710 HIV+ Rwandan women >= 25 years enrolled in an observational cohort study; 476 (67%) tested HPV+. Each woman provided sociodemographic data, CD4 count, a cervical cytology specimen and cervicovaginal lavage (CVL), which was tested for >40 HPV genotypes by MY09/MY11 PCR assay. Logistic regression models calculated odds ratios (OR) and 95% confidence intervals (CI) of associations of potential risk factors for CIN3+ among HIV+/HPV+ women. Results: Of the 476 HIV+/HPV+ women 42 (8.8%) were diagnosed with CIN3+. Factors associated with CIN3+ included >= 7 (vs. 0-2) pregnancies, malarial infection in the previous six months (vs. never), and >= 7 (vs. 0-2) lifetime sexual partners. Compared to women infected by non-HPV16 carcinogenic HPV genotypes, HPV16 infection was positively associated and non-carcinogenic HPV infection was inversely associated with CIN3+. CD4 count was significantly associated with CIN3+ only in analyses of women with non-HPV16 carcinogenic HPV (OR = 0.62 per 100 cells/mm(3), CI = 0.40-0.97). Conclusions: In this HIV+/HPV+ population, lower CD4 was significantly associated with CIN3+ only in women infected with carcinogenic non-HPV16. We found a trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection; this association should be investigated in a larger group of HIV+/HPV+ women. C1 [Anastos, Kathryn] Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. [Anastos, Kathryn] Montefiore Med Ctr, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Hoover, Donald R.] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [Hoover, Donald R.] Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, Piscataway, NJ USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Div Genet, Bronx, NY 10467 USA. [Cajigas, Antonio] Montefiore Med Ctr, Dept Pathol, Bronx, NY 10467 USA. [Shi, Qiuhu] New York Med Coll, Dept Epidemiol & Community Hlth, Valhalla, NY 10595 USA. [Singh, Diljeet K.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Cohen, Mardge H.] John Stroger Hosp, Chicago, IL USA. [Cohen, Mardge H.] Rush Univ, Chicago, IL 60612 USA. [Mutimura, Eugene] Womens Equ Access Care & Treatment, Kigali, Rwanda. [Sturgis, Charles] Providence Reg Med Ctr, Everett, WA USA. [Banzhaf, William C.] Univ Chicago, Pritzker Sch Med, Evanston, IL USA. [Castle, Philip E.] NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Anastos, K (reprint author), Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. EM kanastos@verizon.net RI Banzhaf, Wolfgang/A-7992-2008 OI Banzhaf, Wolfgang/0000-0002-6382-3245 FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004]; AIDS International Training and Research Program (Fogarty International Center) [NIH D43-TW001403]; National Institutes of Health (NIH) [AI-51519]; National Institute of Diabetes and Digestive and Kidney Disease [DK54615]; NIH, National Cancer Institute FX This study was supported by supplements from the National Institute of Allergy and Infectious Diseases and the National Cancer Institute to the Bronx/Manhattan Women's Interagency HIV Study (WIHS) funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004). This work was also supported in part by the AIDS International Training and Research Program (Fogarty International Center, NIH D43-TW001403) and the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center funded by the National Institutes of Health (NIH AI-51519) and by the National Institute of Diabetes and Digestive and Kidney Disease (DK54615). Dr. Castle was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 9 Z9 9 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 20 PY 2010 VL 5 IS 10 AR e13525 DI 10.1371/journal.pone.0013525 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 667TI UT WOS:000283216400027 PM 20976000 ER PT J AU Caceres, A Shang, F Wawrousek, E Liu, Q Avidan, O Cvekl, A Yang, Y Haririnia, A Storaska, A Fushman, D Kuszak, J Dudek, E Smith, D Taylor, A AF Caceres, Andrea Shang, Fu Wawrousek, Eric Liu, Qing Avidan, Orna Cvekl, Ales Yang, Ying Haririnia, Aydin Storaska, Andrew Fushman, David Kuszak, Jer Dudek, Edward Smith, Donald Taylor, Allen TI Perturbing the Ubiquitin Pathway Reveals How Mitosis Is Hijacked to Denucleate and Regulate Cell Proliferation and Differentiation In Vivo SO PLOS ONE LA English DT Article ID ANAPHASE-PROMOTING COMPLEX; LENS EPITHELIAL-CELLS; ALPHA-A-CRYSTALLIN; PROTEIN-DEGRADATION; MOUSE LENS; CHAINS; NEURODEGENERATION; EXPRESSION; PROTEOMICS; DISEASES AB Background: The eye lens presents a unique opportunity to explore roles for specific molecules in cell proliferation, differentiation and development because cells remain in place throughout life and, like red blood cells and keratinocytes, they go through the most extreme differentiation, including removal of nuclei and cessation of protein synthesis. Ubiquitination controls many critical cellular processes, most of which require specific lysines on ubiquitin (Ub). Of the 7 lysines (K) least is known about effects of modification of K6. Methodology and Principal Findings: We replaced K6 with tryptophan (W) because K6 is the most readily modified K and W is the most structurally similar residue to biotin. The backbone of K6W-Ub is indistinguishable from that of Wt-Ub. K6W-Ub is effectively conjugated and deconjugated but the conjugates are not degraded via the ubiquitin proteasome pathways (UPP). Expression of K6W-ubiquitin in the lens and lens cells results in accumulation of intracellular aggregates and also slows cell proliferation and the differentiation program, including expression of lens specific proteins, differentiation of epithelial cells into fibers, achieving proper fiber cell morphology, and removal of nuclei. The latter is critical for transparency, but the mechanism by which cell nuclei are removed has remained an age old enigma. This was also solved by expressing K6W-Ub. p27(kip), a UPP substrate accumulates in lenses which express K6W-Ub. This precludes phosphorylation of nuclear lamin by the mitotic kinase, a prerequisite for disassembly of the nuclear membrane. Thus the nucleus remains intact and DNAseII beta neither gains entry to the nucleus nor degrades the DNA. These results could not be obtained using chemical proteasome inhibitors that cannot be directed to specific tissues. Conclusions and Significance: K6W-Ub provides a novel, genetic means to study functions of the UPP because it can be targeted to specific cells and tissues. A fully functional UPP is required to execute most stages of lens differentiation, specifically removal of cell nuclei. In the absence of a functional UPP, small aggregate prone, cataractous lenses are formed. C1 [Caceres, Andrea; Shang, Fu; Liu, Qing; Avidan, Orna; Dudek, Edward; Smith, Donald; Taylor, Allen] Tufts Univ, Lab Nutr & Vis Res, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Wawrousek, Eric] NEI, Mol & Dev Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cvekl, Ales; Yang, Ying] Albert Einstein Coll Med, Dept Ophthalmol, Bronx, NY 10467 USA. [Cvekl, Ales; Yang, Ying] Albert Einstein Coll Med, Dept Visual Sci & Genet, Bronx, NY 10467 USA. [Haririnia, Aydin; Storaska, Andrew; Fushman, David] Univ Maryland, Dept Chem & Biochem, Ctr Biomol Struct & Org, College Pk, MD 20742 USA. [Kuszak, Jer] Rush Univ, Med Ctr, Dept Ophthalmol, Chicago, IL 60612 USA. [Kuszak, Jer] Rush Univ, Med Ctr, Dept Pathol, Chicago, IL 60612 USA. RP Caceres, A (reprint author), Tufts Univ, Lab Nutr & Vis Res, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM allen.taylor@tufts.edu RI Cvekl, Ales/B-2427-2013 FU NIH [GM065334]; American Health Assistant Foundation [RO1 13250]; Johnson and Johnson FX The work was supported by NIH grant GM065334 (to D. F.) and to AT NEI RO1 13250, American Health Assistant Foundation, Johnson and Johnson Focused Giving Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 16 Z9 16 U1 3 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 OCT 20 PY 2010 VL 5 IS 10 AR e13331 DI 10.1371/journal.pone.0013331 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 667TI UT WOS:000283216400002 PM 20975996 ER PT J AU Pigati, L Yaddanapudi, SCS Iyengar, R Kim, DJ Hearn, SA Danforth, D Hastings, ML Duelli, DM AF Pigati, Lucy Yaddanapudi, Sree C. S. Iyengar, Ravi Kim, Dong-Ja Hearn, Steven A. Danforth, David Hastings, Michelle L. Duelli, Dominik M. TI Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells SO PLOS ONE LA English DT Article ID BREAST-CANCER CELLS; STEM-CELLS; GENE-EXPRESSION; MESSENGER-RNA; TUMOR-GROWTH; MESENCHYMAL TRANSITION; CIRCULATING MICRORNAS; DIAGNOSTIC BIOMARKERS; TAMOXIFEN RESISTANCE; PANCREATIC-CANCER AB MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease. C1 [Pigati, Lucy; Iyengar, Ravi; Kim, Dong-Ja; Duelli, Dominik M.] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Pathol, N Chicago, IL 60064 USA. [Yaddanapudi, Sree C. S.; Hastings, Michelle L.; Duelli, Dominik M.] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell Biol & Anat, N Chicago, IL USA. [Yaddanapudi, Sree C. S.] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Bligh Canc Res Ctr, N Chicago, IL USA. [Hearn, Steven A.] Cold Spring Harbor Lab, Microscopy Facil, Cold Spring Harbor, NY 11724 USA. [Danforth, David] NCI, Surg Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Pigati, L (reprint author), Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Pathol, N Chicago, IL 60064 USA. EM Dominik.Duelli@Rosalindfranklin.edu FU United States Department of Defense [W81XWH-08-1-0641]; American Cancer Society [08-29]; Rosalind Franklin University of Medicine and Science; Bligh Cancer Research Center; NIH NCRR [S10 RR19325]; HRSA [C76 HF03610-01-00] FX This work was supported by the United States Department of Defense grant W81XWH-08-1-0641, and an American Cancer Society of Illinois Research Grant 08-29 to DMD, Rosalind Franklin University of Medicine and Science start-up funds and support of the Bligh Cancer Research Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge the Midwest Proteome Center, funded by NIH NCRR S10 RR19325, and HRSA C76 HF03610-01-00 for services rendered. NR 105 TC 241 Z9 262 U1 3 U2 27 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 OCT 20 PY 2010 VL 5 IS 10 AR e13515 DI 10.1371/journal.pone.0013515 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 667TI UT WOS:000283216400020 PM 20976003 ER PT J AU Andersen, JB Factor, VM Marquardt, JU Raggi, C Lee, YH Seo, D Conner, EA Thorgeirsson, SS AF Andersen, Jesper B. Factor, Valentina M. Marquardt, Jens U. Raggi, Chiara Lee, Yun-Han Seo, Daekwan Conner, Elizabeth A. Thorgeirsson, Snorri S. TI An Integrated Genomic and Epigenomic Approach Predicts Therapeutic Response to Zebularine in Human Liver Cancer SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID DNA METHYLTRANSFERASE INHIBITOR; HUMAN HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; EPIGENETIC THERAPY; CPG-ISLANDS; METHYLATION; CELLS; CLASSIFICATION; MODEL; DECITABINE AB Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome. C1 [Andersen, Jesper B.; Factor, Valentina M.; Marquardt, Jens U.; Raggi, Chiara; Lee, Yun-Han; Seo, Daekwan; Conner, Elizabeth A.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244; RAGGI, Chiara/0000-0003-2473-3535 FU NIH, NCI, Center for Cancer Research FX Supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 46 TC 37 Z9 38 U1 1 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 20 PY 2010 VL 2 IS 54 AR 54ra77 DI 10.1126/scitranslmed.3001338 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735TC UT WOS:000288439700006 PM 20962331 ER PT J AU Williams, RJ Tse, T Harlan, WR Zarin, DA AF Williams, Rebecca J. Tse, Tony Harlan, William R. Zarin, Deborah A. TI Registration of observational studies: Is it time? SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Article ID HYPOTHESIS-GENERATING RESEARCH; EPIDEMIOLOGIC RESEARCH; SUBMITTING PAPERS; PUBLICATION; QUALITY; TRIALS C1 [Williams, Rebecca J.] NIH, Natl Lib Med, US Dept HHS, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Williams, RJ (reprint author), NIH, Natl Lib Med, US Dept HHS, Lister Hill Natl Ctr Biomed Commun, Bldg 38A,Rm 7N711,8600 Rockville Pike, Bethesda, MD 20894 USA. EM williamsre@mail.nih.gov FU National Institutes of Health, National Library of Medicine FX Financial support for this article was received from the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 26 TC 41 Z9 42 U1 1 U2 1 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD OCT 19 PY 2010 VL 182 IS 15 BP 1638 EP 1642 DI 10.1503/cmaj.092252 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 660KG UT WOS:000282640000019 PM 20643833 ER PT J AU Pichiorri, F Suh, SS Rocci, A De Luca, L Taccioli, C Santhanam, R Zhou, WC Benson, DM Hofmainster, C Alder, H Garofalo, M Di Leva, G Volinia, S Lin, HJ Perrotti, D Kuehl, M Aqeilan, RI Palumbo, A Croce, CM AF Pichiorri, Flavia Suh, Sung-Suk Rocci, Alberto De Luca, Luciana Taccioli, Cristian Santhanam, Ramasamy Zhou, Wenchao Benson, Don M., Jr. Hofmainster, Craig Alder, Hansjuerg Garofalo, Michela Di Leva, Gianpiero Volinia, Stefano Lin, Huey-Jen Perrotti, Danilo Kuehl, Michael Aqeilan, Rami I. Palumbo, Antonio Croce, Carlo M. TI Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development SO CANCER CELL LA English DT Article ID PHARMACOLOGICAL ACTIVATION; HEMATOLOGICAL MALIGNANCIES; P53; CELLS; PROLIFERATION; EXPRESSION; CANCER; RESTORATION; MIGRATION; SURVIVAL AB In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development. C1 [Pichiorri, Flavia; Suh, Sung-Suk; Taccioli, Cristian; Santhanam, Ramasamy; Alder, Hansjuerg; Garofalo, Michela; Di Leva, Gianpiero; Volinia, Stefano; Perrotti, Danilo; Aqeilan, Rami I.; Croce, Carlo M.] Ohio State Univ, Dept Mol Virol, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Pichiorri, Flavia; Suh, Sung-Suk; Taccioli, Cristian; Santhanam, Ramasamy; Alder, Hansjuerg; Garofalo, Michela; Di Leva, Gianpiero; Volinia, Stefano; Perrotti, Danilo; Aqeilan, Rami I.; Croce, Carlo M.] Ohio State Univ, Dept Immunol, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Pichiorri, Flavia; Suh, Sung-Suk; Taccioli, Cristian; Santhanam, Ramasamy; Alder, Hansjuerg; Garofalo, Michela; Di Leva, Gianpiero; Volinia, Stefano; Perrotti, Danilo; Aqeilan, Rami I.; Croce, Carlo M.] Ohio State Univ, Dept Human Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Pichiorri, Flavia; Suh, Sung-Suk; Aqeilan, Rami I.] Hebrew Univ Hadassah Med Sch, IMRIC Lautenberg Ctr Immunol & Canc Res, IL-91120 Jerusalem, Israel. [Rocci, Alberto; Palumbo, Antonio] Univ Turin, Div Hematol, I-10149 Turin, Italy. [De Luca, Luciana] Referral Canc Ctr Basilicata Crob, IRCCS, Mol Oncol Unit, I-85028 Rionero In Vulture, PZ, Italy. [Taccioli, Cristian] UCL, Inst Canc, London WC1E, England. [Zhou, Wenchao; Lin, Huey-Jen] Ohio State Univ, Sch Allied Med Profess, Med Technol Div, Columbus, OH 43210 USA. [Benson, Don M., Jr.; Hofmainster, Craig] Ohio State Univ, Div Hematol & Oncol, Dept Med, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Volinia, Stefano] Univ Ferrara, Telethon Facil Data Min Anal DNA Microarrays, Dept Morphol & Embryol, I-44100 Ferrara, Italy. [Kuehl, Michael] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. RP Pichiorri, F (reprint author), Ohio State Univ, Dept Mol Virol, Ctr Comprehens Canc, Columbus, OH 43210 USA. EM flavia.pichiorri@osumc.edu; carlo.croce@osumc.edu RI Lin, Huey-Jen/E-3514-2011; Taccioli, Cristian/F-8801-2010; Volinia, Stefano/A-3029-2010; Perrotti, Danilo/E-3852-2011; De Luca, Luciana/K-6478-2016; Aqeilan, Rami/R-4443-2016 OI Taccioli, Cristian/0000-0003-2995-5612; Volinia, Stefano/0000-0003-0910-3893; De Luca, Luciana/0000-0002-2332-3086; Aqeilan, Rami/0000-0002-6034-023X FU Ohio State University; Kimmel Foundation; Fondazione Telethon FX We thank Kay Huebner for careful reading of the draft MS, Nicola Zanesi for helping with the animal procedures, Dorothee Wernicke for helpful scientific discussion, Michele Morara for statistical advice, Yuri Pekarsky for scientific advice, Guido Marcucci and Ramiro Garzon for scientific advice, and Sharon Palko for administrative support. We also thank Dr. Shaomeng Wang's laboratory for supplying MI-219 compound and Dr. Irene M. Ghobrial for providing MM1s GFP+/Luc+ cells. We are grateful for research support from the Ohio State University Targeted Investment in Excellence Award and the Kimmel Foundation award (F.P.). NR 41 TC 221 Z9 240 U1 1 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 19 PY 2010 VL 18 IS 4 BP 367 EP 381 DI 10.1016/j.ccr.2010.09.005 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 673XJ UT WOS:000283697200010 PM 20951946 ER PT J AU Kranz, G Shamim, EA Lin, PT Kranz, GS Hallett, M AF Kranz, G. Shamim, E. A. Lin, P. T. Kranz, G. S. Hallett, M. TI Transcranial magnetic brain stimulation modulates blepharospasm A randomized controlled study SO NEUROLOGY LA English DT Article ID WRITERS CRAMP; MOTOR AREAS; EXCITABILITY; DYSTONIA; NUCLEUS; REGIONS; COIL AB Background: Benign essential blepharospasm (BEN is a common form of focal dystonia. Besides pathology in the basal ganglia, accumulating evidence suggests pathologic changes in the anterior cingulate cortex (ACC). Methods: This is a randomized, sham-controlled, observer-blinded prospective study. In 12 patients with BEB, we evaluated the effects of a 15-minute session of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the ACC with stimulation intensities at 100% active motor threshold with 3 stimulation coils: a conventional circular coil (C-coil), a sham coil (S-coil), and a Hesed coil (H-coil, which allows stimulation of deeper brain regions. Primary outcome was the clinical effects on BEB (blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after, and 1 hour after stimulation); secondary outcome was the blink reflex recovery curve. Results: Subjective stimulation comfort was similar for each coil with no stimulation-associated adverse events. Stimulation with the H- and C-coils resulted in a significant improvement in all 3 outcome measures and was still detectable in physician rating and patient rating 1 hour after stimulation. S-coil stimulation had no effects. The active motor threshold was significantly lower for the H-coil compared to the other 2 coils. Conclusions: rTMS could be used as a therapeutic tool in BEB. Further studies will be necessary to show whether repeated stimulation applications result in lasting clinical effects. Classification of evidence: This study provides Class II evidence that for patients with BEB, Hand C-coil rTMS is safe and improves clinical symptoms of BEB immediately and 1 hour after stimulation. Neurology 2010;75:1465-1471 C1 [Kranz, G.] Med Univ Vienna, Dept Neurol, A-1090 Vienna, Austria. [Kranz, G.; Shamim, E. A.; Lin, P. T.; Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD USA. [Kranz, G. S.] Med Univ Vienna, Dept Biol Psychiat, A-1090 Vienna, Austria. [Shamim, E. A.] Kaiser Permanente, Dept Neurol, Suitland, MD USA. [Lin, P. T.] Santa Clara Valley Med Ctr, Dept Neurol, San Jose, CA 95128 USA. RP Kranz, G (reprint author), Med Univ Vienna, Dept Neurol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM gottfried.kranz@meduniwien.ac.at FU NIH/NINDS Human Motor Control Section; Max Kade Foundation, New York; NIH/NINDS; Ipsen; Neurotoxin Institute; Ariston Pharmaceuticals; US Department of Defense (Army); NIH; Blackwell Publisher; Cambridge University Press; Springer Verlag; Taylor Francis Group; Oxford University Press; John Wiley Sons; Elsevier FX Supported by the NIH/NINDS Human Motor Control Section and the Max Kade Foundation, New York (G.K.); Dr. Kranz has received funding for travel from the NIH/NINDS and Ipsen; has received speaker honoraria from Allergan, Inc., Ipsen, and Merz Pharmaceuticals, LLC; and has received research support from the Max Kade Foundation and the NIH/NINDS (Intramural Grant). Dr. Shamim receives research support from the NIH/NINDS (Intramural Grant) and holds stock in Amgen, Pfizer Inc., and Medtronic, Inc. Dr. Lin has received research support from the NIH/NINDS (Intramural Grant). G.S. Kranz reports no disclosures. Dr. Hallett serves as Chair of the Medical Advisory Board for and receives funding for travel from the Neurotoxin Institute; serves as Chair of the Medical Advisory Board of the Benign Essential Blepharospasm Foundation; serves on editorial advisory boards for Clinical Neurophysiology (Editor-in-Chief), Western Hemisphere, Brain, Acta Neurologica Scandinavica, Journal of Clinical Neurophysiology, Italian Journal of Neurological Sciences, Medical Problems of Performing Artists, Annals of Neurology, Neurology and Clinical Neurophysiology, The Cerebellum, NeuroRx, Current Trends in Neurology, Faculty of 1000 Biology, European Neurology, Faculty of 1000 Medicine, Brain Stimulation, Journal of Movement Disorders (Korea), and World Neurology; may accrue revenue on patents re: Immunotoxin (MAB-Ricin) for the treatment of focal movement disorders and Coil for magnetic stimulation and methods for using the same; receives royalties from publishing from Blackwell Publisher, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, and Elsevier; receives research support from Ariston Pharmaceuticals, NIH/NINDS (Intramural Program), and the US Department of Defense (Army); has received license fee payments from the NIH (from Brainsway) for licensing the parent for the H-coil; and with his spouse held stock in Agilent Technologies, Amgen, Amylin Pharmaceuticals, Merck & Co., Monsanto Co. New Del, Sanofi-Aventis, Coventry Health Care Inc., Sigma Aldrich Corp., Warner Chilcott Ltd., Pfizer Inc., Genentech, Inc., United Health Group, St. Jude Medical, and Eli Lilly and Company. NR 23 TC 22 Z9 25 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 19 PY 2010 VL 75 IS 16 BP 1465 EP 1471 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 671TF UT WOS:000283533200013 PM 20956792 ER PT J AU Ofek, G Guenaga, FJ Schief, WR Skinner, J Baker, D Wyatt, R Kwong, PD AF Ofek, Gilad Guenaga, F. Javier Schief, William R. Skinner, Jeff Baker, David Wyatt, Richard Kwong, Peter D. TI Elicitation of structure-specific antibodies by epitope scaffolds SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE computational design; epitope transplantation; structural mimicry ID COMPLEMENTARITY-DETERMINING REGION; VIRUS TYPE-1 HIV-1; CRYSTAL-STRUCTURES; NEUTRALIZING ANTIBODIES; ECTODOMAIN REGION; RIBONUCLEASE-S; HEAVY-CHAIN; GP41; PROTEIN; MEMBRANE AB Elicitation of antibodies against targets that are immunorecessive, cryptic, or transient in their native context has been a challenge for vaccine design. Here we demonstrate the elicitation of structure-specific antibodies against the HIV-1 gp41 epitope of the broadly neutralizing antibody 2F5. This conformationally flexible region of gp41 assumes mostly helical conformations but adopts a kinked, extended structure when bound by antibody 2F5. Computational techniques were employed to transplant the 2F5 epitope into select acceptor scaffolds. The resultant "2F5-epitope scaffolds" possessed nanomolar affinity for antibody 2F5 and a range of epitope flexibilities and antigenic specificities. Crystallographic characterization of the epitope scaffold with highest affinity and antigenic discrimination confirmed good to near perfect attainment of the target conformation for the gp41 molecular graft in free and 2F5-bound states, respectively. Animals immunized with 2F5-epitope scaffolds showed levels of graft-specific immune responses that correlated with graft flexibility (p < 0.04), while antibody responses against the graft-as dissected residue-by-residue with alanine substitutions-resembled more closely those of 2F5 than sera elicited with flexible or cyclized peptides, a resemblance heightened by heterologous prime-boost. Lastly, crystal structures of a gp41 peptide in complex with monoclonal antibodies elicited by the 2F5-epitope scaffolds revealed that the elicited antibodies induce gp41 to assume its 2F5-recognized shape. Epitope scaffolds thus provide a means to elicit antibodies that recognize a predetermined target shape and sequence, even if that shape is transient in nature, and a means by which to dissect factors influencing such elicitation. C1 [Ofek, Gilad; Guenaga, F. Javier; Wyatt, Richard; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Schief, William R.; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Skinner, Jeff] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Baker, David/K-8941-2012; OI Baker, David/0000-0001-7896-6217; Skinner, Jeff/0000-0001-5697-0442 FU National Institutes of Health; International AIDS Vaccine Initiative and its Neutralizing Antibody Consortium; U.S. Department of Energy, Basic Energy Sciences, Office of Science FX We thank B.K. Chakrabarti and G.J. Nabel for sera generated from placing the 2F5 epitope into the flexible V3 loop of gp120; Y. Geng and V. Savich (ProSci) for assistance for monoclonal antibody elicitation; H. Katinger for antibody 2F5; J.R. Mascola and K. McKee for neutralization analysis; G.J. Nabel, J.R. Mascola, L. Shapiro, I. Wilson, and members of the Structural Bioinformatics and Biology Sections, Vaccine Research Center, for discussions and comments on the manuscript; J. Stuckey for assistance with figures; and GlaxoSmithKline for AS01B adjuvant. Support for this work was provided by the Intramural Research Program of the National Institutes of Health and by the International AIDS Vaccine Initiative and its Neutralizing Antibody Consortium. Use of SER-CAT at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science. NR 41 TC 161 Z9 163 U1 2 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 19 PY 2010 VL 107 IS 42 BP 17880 EP 17887 DI 10.1073/pnas.1004728107 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 667HV UT WOS:000283184800010 PM 20876137 ER PT J AU Redon, CE Dickey, JS Nakamura, AJ Kareva, IG Naf, D Nowsheen, S Kryston, TB Bonner, WM Georgakilas, AG Sedelnikova, OA AF Redon, Christophe E. Dickey, Jennifer S. Nakamura, Asako J. Kareva, Irina G. Naf, Dieter Nowsheen, Somaira Kryston, Thomas B. Bonner, William M. Georgakilas, Alexandros G. Sedelnikova, Olga A. TI Tumors induce complex DNA damage in distant proliferative tissues in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumor-induced bystander effect; oxidative DNA damage; cytokines ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; DOUBLE-STRAND BREAKS; BYSTANDER CELLS; CANCER; LESIONS; INFLAMMATION; GAMMA-H2AX; EXPRESSION; STRESS; MODELS AB That tumors cause changes in surrounding tissues is well documented, but whether they also affect distant tissues is uncertain. Such knowledge may be important in understanding the relationship between cancer and overall patient health. To address this question, we examined tissues distant to sites of implanted tumors for genomic damage using cohorts of C57BL/6 and BALB/c mice with early-stage subcutaneous syngeneic grafts, specifically, B16 melanoma, MO5076 sarcoma, and COLON26 carcinoma. Here we report that levels of two serious types of DNA damage, double-strand breaks (DSBs) measured by gamma-H2AX focus formation and oxidatively induced non-DSB clustered DNA lesions (OCDLs), were elevated in tissues distant from the tumor site in tumor-bearing mice compared with their age-and sex-matched controls. Most affected were crypts in the gastrointestinal tract organs and skin, both highly proliferative tissues. Further investigation revealed that, compared with controls, tumor-bearing mice contained elevated amounts of activated macrophages in the distant gastrointestinal tissues, as well as elevated serum levels of several cytokines. One of these cytokines, CCL2/MCP-1, has been linked to several inflammation-related conditions and macrophage recruitment, and strikingly, CCL2-deficient mice lacked increased levels of DSBs and OCDLs in tissues distant from implanted tumors. Thus, this study is unique in being a direct demonstration that the presence of a tumor may induce a chronic inflammatory response in vivo, leading to increased systemic levels of DNA damage. Importantly, these findings suggest that tumors may have more profound effects on their hosts than heretofore expected. C1 [Redon, Christophe E.; Dickey, Jennifer S.; Nakamura, Asako J.; Kareva, Irina G.; Bonner, William M.; Sedelnikova, Olga A.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Naf, Dieter] NCI, Lab Anim Sci Program, Frederick, MD 21702 USA. [Nowsheen, Somaira; Kryston, Thomas B.; Georgakilas, Alexandros G.] E Carolina Univ, Dept Biol, Thomas Harriot Coll Arts & Sci, Greenville, NC 27858 USA. RP Sedelnikova, OA (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM sedelnio@mail.nih.gov FU National Cancer Institute; Center for Cancer Research; National Institutes of Health; Biology Department of East Carolina University FX We thank the Laboratory Animal Sciences Program and Pathology Histotechnology Laboratory staff (National Cancer Institute-Frederick) for help with animal maintenance and histological analysis and C. Richardson, P. Kalogerinis, B. Flood, and T. Santangelo (East Carolina University) for technical assistance. We thank Drs. M. Potter and G. Trinchieri (NCI) for critical reading of the manuscript. This work was funded by a National Cancer Institute Career Development Award (to C. E. R. and O.A.S.), the Intramural Research Program of the National Cancer Institute, the Center for Cancer Research, the National Institutes of Health, and a Research/Creative Activity grant and a College Research award from the Biology Department of East Carolina University (to A.G.G.). NR 42 TC 74 Z9 78 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 OCT 19 PY 2010 VL 107 IS 42 BP 17992 EP 17997 DI 10.1073/pnas.1008260107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 667HV UT WOS:000283184800029 PM 20855610 ER PT J AU Kreisel, D Nava, RG Li, WJ Zinselmeyer, BH Wang, BM Lai, JM Pless, R Gelman, AE Krupnick, AS Miller, MJ AF Kreisel, Daniel Nava, Ruben G. Li, Wenjun Zinselmeyer, Bernd H. Wang, Baomei Lai, Jiaming Pless, Robert Gelman, Andrew E. Krupnick, Alexander S. Miller, Mark J. TI In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE lung; two-photon microscopy; transendothelial migration; ischemia; transplant ID LUNG TRANSPLANTATION; INTRAVASCULAR MACROPHAGES; INJURY; MICE; CCR2; RECRUITMENT; INFECTION; MIGRATION; DYNAMICS; DISEASE AB Immune-mediated pulmonary diseases are a significant public health concern. Analysis of leukocyte behavior in the lung is essential for understanding cellular mechanisms that contribute to normal and diseased states. Here, we used two-photon imaging to study neutrophil extravasation from pulmonary vessels and subsequent interstitial migration. We found that the lungs contained a significant pool of tissue-resident neutrophils in the steady state. In response to inflammation produced by bacterial challenge or transplant-mediated, ischemia-reperfusion injury, neutrophils were rapidly recruited from the circulation and patrolled the interstitium and airspaces of the lung. Motile neutrophils often aggregated in dynamic clusters that formed and dispersed over tens of minutes. These clusters were associated with CD115(+) F4/80(+) Ly6C(+) cells that had recently entered the lung. The depletion of blood monocytes with clodronate liposomes reduced neutrophil clustering in the lung, but acted by inhibiting neutrophil transendothelial migration upstream of interstitial migration. Our results suggest that a subset of monocytes serve as key regulators of neutrophil extravasation in the lung and may be an attractive target for the treatment of inflammatory pulmonary diseases. C1 [Kreisel, Daniel; Zinselmeyer, Bernd H.; Wang, Baomei; Gelman, Andrew E.; Miller, Mark J.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Kreisel, Daniel; Nava, Ruben G.; Li, Wenjun; Lai, Jiaming; Gelman, Andrew E.; Krupnick, Alexander S.] Washington Univ, Dept Surg, St Louis, MO 63110 USA. [Pless, Robert] Washington Univ, Dept Comp Sci & Engn, St Louis, MO 63110 USA. [Zinselmeyer, Bernd H.] Nat Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20824 USA. RP Miller, MJ (reprint author), Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA. EM miller@pathology.wustl.edu RI Pless, Robert/I-4698-2013 FU National Heart, Lung, and Blood Institute [1R01HL094601, 1K08HL083983]; Thoracic Surgery Foundation for Research and Education; National Institute of Allergy and Infectious Diseases [AI077600] FX We thank A. P. Gieselman for animal care. D. K. and A. E. G. are supported by National Heart, Lung, and Blood Institute Grant 1R01HL094601 and D. K. by Grant 1K08HL083983, jointly sponsored by the National Heart, Lung, and Blood Institute and the Thoracic Surgery Foundation for Research and Education. M.J.M. is supported by the National Institute of Allergy and Infectious Diseases Grant AI077600. NR 38 TC 148 Z9 150 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 19 PY 2010 VL 107 IS 42 BP 18073 EP 18078 DI 10.1073/pnas.1008737107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 667HV UT WOS:000283184800043 PM 20923880 ER PT J AU Merkel, TJ Perera, PY Kelly, VK Verma, A Llewellyn, ZN Waldmann, TA Mosca, JD Perera, LP AF Merkel, Tod J. Perera, Pin-Yu Kelly, Vanessa K. Verma, Anita Llewellyn, Zara N. Waldmann, Thomas A. Mosca, Joseph D. Perera, Liyanage P. TI Development of a highly efficacious vaccinia-based dual vaccine against smallpox and anthrax, two important bioterror entities SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE biodefense; IL-15; bioterrorism ID BACILLUS-ANTHRACIS; PROTECTIVE ANTIGEN; T-CELLS; SPORES; MICE; INTERLEUKIN-15; ANTIBODIES; CHALLENGE; CORRELATE; IMMUNITY AB Bioterrorism poses a daunting challenge to global security and public health in the 21st century. Variola major virus, the etiological agent of smallpox, and Bacillus anthracis, the bacterial pathogen responsible for anthrax, remain at the apex of potential pathogens that could be used in a bioterror attack to inflict mass casualties. Although licensed vaccines are available for both smallpox and anthrax, because of inadequacies associated with each of these vaccines, serious concerns remain as to the deployability of these vaccines, especially in the aftermath of a bioterror attack involving these pathogens. We have developed a single vaccine (Wyeth/IL15/PA) using the licensed Wyeth smallpox vaccine strain that is efficacious against both smallpox and anthrax due to the integration of immune-enhancing cytokine IL-15 and the protective antigen (PA) of B. anthracis into the Wyeth vaccinia virus. Integration of IL-15 renders Wyeth vaccinia avirulent in immunodeficient mice and enhances anti-vaccinia immune responses. Wyeth/IL-15/PA conferred sterile protection against a lethal challenge of B. anthracis Ames strain spores in rabbits. A single dose of Wyeth/IL-15/PA protected 33% of the vaccinated A/J mice against a lethal spore challenge 72 h later whereas a single dose of licensed anthrax vaccine protected only 10%. Our dual vaccine Wyeth/IL-15/PA remedies the inadequacies associated with the licensed vaccines, and the inherent ability of Wyeth vaccinia virus to be lyophilized without loss of potency makes it cold-chain independent, thus simplifying the logistics of storage, stockpiling, and field delivery in the event of a bioterror attack involving smallpox or anthrax. C1 [Waldmann, Thomas A.; Perera, Liyanage P.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merkel, Tod J.; Kelly, Vanessa K.; Verma, Anita] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Perera, Pin-Yu] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Llewellyn, Zara N.] So Res Inst, Birmingham, AL 35255 USA. [Mosca, Joseph D.] JDM Technol, Ellicott City, MD 21042 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov; pereral@mail.nih.gov FU National Cancer Institute; Trans-National Institutes of Health/Food and Drug Administration; Center for Cancer Research; National Institutes of Health FX We thank Dr. Toyoko Hiroi for assistance with the graphics and Ms. Jean R. Decker for contractual administrative support. We gratefully acknowledge the receipt of reagents from the Biodefense and Emerging Infections Research Resources Repository (BEI Resources, National Institute of Allergy and Infectious Diseases) for this study. This work was supported in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health, and by a 3-y competitive research funding award (to L. P. P.) from the Trans-National Institutes of Health/Food and Drug Administration Intramural Biodefense Program. NR 35 TC 14 Z9 15 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 19 PY 2010 VL 107 IS 42 BP 18091 EP 18096 DI 10.1073/pnas.1013083107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 667HV UT WOS:000283184800046 PM 20921397 ER PT J AU McVey, D Zuber, M EttyReddy, D Reiter, CD Brough, DE Nabel, GJ King, CR Gall, JGD AF McVey, Duncan Zuber, Mohammed EttyReddy, Damodar Reiter, Christopher D. Brough, Douglas E. Nabel, Gary J. King, C. Richter Gall, Jason G. D. TI Characterization of human adenovirus 35 and derivation of complex vectors SO VIROLOGY JOURNAL LA English DT Article ID GENE-TRANSFER; VACCINE VECTORS; ANTI-AD5 IMMUNITY; SUBGROUP-B; IMMUNOGENICITY; TYPE-35; EXPRESSION; CELLS; SEROPREVALENCE; MODULATION AB Background: Replication-deficient recombinant adenoviral vectors based on human serotype 35 (Ad35) are desirable due to the relatively low prevalence of neutralizing antibodies in the human population. The structure of the viral genome and life cycle of Ad35 differs from the better characterized Ad5 and these differences require differences in the strategies for the generation of vectors for gene delivery. Results: Sequences essential for E1 and E4 function were identified and removed and the effects of the deletions on viral gene transcription were determined. In addition, the non-essential E3 region was deleted from rAd35 vectors and a sequence was found that did not have an effect on viability but reduced viral fitness. The packaging capacity of rAd35 was dependent on pIX and vectors were generated with stable genome sizes of up to 104% of the wild type genome size. These data were used to make an E1-, E3-, E4-deleted rAd35 vector. This rAd35 vector with multiple gene deletions has the advantages of multiple blocks to viral replication (i.e., E1 and E4 deletions) and a transgene packaging capacity of 7.6 Kb, comparable to rAd5 vectors. Conclusions: The results reported here allow the generation of larger capacity rAd35 vectors and will guide the derivation of adenovirus vectors from other serotypes. C1 [McVey, Duncan; Zuber, Mohammed; EttyReddy, Damodar; Reiter, Christopher D.; Brough, Douglas E.; King, C. Richter; Gall, Jason G. D.] GenVec Inc, Dept Res, Gaithersburg, MD 20874 USA. [Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Gall, JGD (reprint author), GenVec Inc, Dept Res, 65 W Watkins Mill Rd, Gaithersburg, MD 20874 USA. EM jgall@genvec.com NR 27 TC 8 Z9 8 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD OCT 19 PY 2010 VL 7 AR 276 DI 10.1186/1743-422X-7-276 PG 15 WC Virology SC Virology GA 680YE UT WOS:000284272600001 PM 20959004 ER PT J AU Hu, N Clifford, RJ Yang, HH Wang, CY Goldstein, AM Ding, T Taylor, PR Lee, MP AF Hu, Nan Clifford, Robert J. Yang, Howard H. Wang, Chaoyu Goldstein, Alisa M. Ding, Ti Taylor, Philip R. Lee, Maxwell P. TI Genome wide analysis of DNA copy number neutral loss of heterozygosity (CNNLOH) and its relation to gene expression in esophageal squamous cell carcinoma SO BMC GENOMICS LA English DT Article ID NUCLEOTIDE POLYMORPHISM ARRAYS; ACUTE MYELOID LEUKEMIAS; UNIPARENTAL DISOMY; ALLELIC LOSS; COMPREHENSIVE ANALYSIS; FAMILY-HISTORY; NORMALIZATION; ASSOCIATION; POPULATION; MUTATION AB Background: Genomic instability plays an important role in human cancers. We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors using the Affymetrix GeneChip Human Mapping 500K array in 30 cases from a high-risk region of China. In the current study we focused on copy number neutral (CN = 2) LOH (CNNLOH) and its relation to gene expression in ESCC. Results: Overall we found that 70% of all LOH observed was CNNLOH. Ninety percent of ESCCs showed CNNLOH (median frequency in cases = 60%) and this was the most common type of LOH in two-thirds of cases. CNNLOH occurred on all 39 autosomal chromosome arms, with highest frequencies on 19p (100%), 5p (96%), 2p (95%), and 20q (95%). In contrast, LOH with CN loss represented 19% of all LOH, occurred in just half of ESCCs (median frequency in cases = 0%), and was most frequent on 3p (56%), 5q (47%), and 21q (41%). LOH with CN gain was 11% of all LOH, occurred in 93% of ESCCs (median frequency in cases = 13%), and was most common on 20p (82%), 8q (74%), and 3q (42%). To examine the effect of genomic instability on gene expression, we evaluated RNA profiles from 17 pairs of matched normal and tumor samples (a subset of the 30 ESCCs) using Affymetrix U133A 2.0 arrays. In CN neutral regions, expression of 168 genes (containing 1976 SNPs) differed significantly in tumors with LOH versus tumors without LOH, including 101 genes that were up-regulated and 67 that were down-regulated. Conclusion: Our results indicate that CNNLOH has a profound impact on gene expression in ESCC, which in turn may affect tumor development. C1 [Hu, Nan; Wang, Chaoyu; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Clifford, Robert J.; Yang, Howard H.; Lee, Maxwell P.] NCI, Lab Populat Genet, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. [Ding, Ti] Shanxi Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. RP Taylor, PR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov; leemax@mail.nih.gov FU NIH; National Cancer Institute; Division of Cancer Epidemiology and Genetics; Center for Cancer Research; PRT FX This research was supported by the Intramural Research Program of the NIH, the National Cancer Institute, the Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research.; NH, AMG, TD, and PRT designed, conducted, and supervised the field and clinical studies; PRT obtained funding for the project; NH and CW designed and performed the laboratory analyses; NH, RJC, HHY, and MPL conducted the statistical analyses; NH and ML drafted the manuscript; NH, RJC, AMG, PRT, and MPL conceptualized the data analyses and revised and edited the manuscript. All authors read and approved the final manuscript. NR 36 TC 52 Z9 54 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 18 PY 2010 VL 11 AR 576 DI 10.1186/1471-2164-11-576 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 674ZI UT WOS:000283791900001 PM 20955586 ER PT J AU Wittekindt, NE Padhi, A Schuster, SC Qi, J Zhao, FQ Tomsho, LP Kasson, LR Packard, M Cross, P Poss, M AF Wittekindt, Nicola E. Padhi, Abinash Schuster, Stephan C. Qi, Ji Zhao, Fangqing Tomsho, Lynn P. Kasson, Lindsay R. Packard, Michael Cross, Paul Poss, Mary TI Nodeomics: Pathogen Detection in Vertebrate Lymph Nodes Using Meta-Transcriptomics SO PLOS ONE LA English DT Article ID PROVENTRICULAR DILATATION DISEASE; EMERGING INFECTIOUS-DISEASES; MICROBIAL COMMUNITIES; GARDNERELLA-VAGINALIS; HELICOBACTER-PYLORI; VIRAL REPLICATION; GENE-EXPRESSION; GUT MICROBIOME; RNA; IDENTIFICATION AB The ongoing emergence of human infections originating from wildlife highlights the need for better knowledge of the microbial community in wildlife species where traditional diagnostic approaches are limited. Here we evaluate the microbial biota in healthy mule deer (Odocoileus hemionus) by analyses of lymph node meta-transcriptomes. cDNA libraries from five individuals and two pools of samples were prepared from retropharyngeal lymph node RNA enriched for polyadenylated RNA and sequenced using Roche-454 Life Sciences technology. Protein-coding and 16S ribosomal RNA ( rRNA) sequences were taxonomically profiled using protein and rRNA specific databases. Representatives of all bacterial phyla were detected in the seven libraries based on protein-coding transcripts indicating that viable microbiota were present in lymph nodes. Residents of skin and rumen, and those ubiquitous in mule deer habitat dominated classifiable bacterial species. Based on detection of both rRNA and protein-coding transcripts, we identified two new proteobacterial species; a Helicobacter closely related to Helicobacter cetorum in the Helicobacter pylori/Helicobacter acinonychis complex and an Acinetobacter related to Acinetobacter schindleri. Among viruses, a novel gamma retrovirus and other members of the Poxviridae and Retroviridae were identified. We additionally evaluated bacterial diversity by amplicon sequencing the hypervariable V6 region of 16S rRNA and demonstrate that overall taxonomic diversity is higher with the meta-transcriptomic approach. These data provide the most complete picture to date of the microbial diversity within a wildlife host. Our research advances the use of meta-transcriptomics to study microbiota in wildlife tissues, which will facilitate detection of novel organisms with pathogenic potential to human and animals. C1 [Wittekindt, Nicola E.; Schuster, Stephan C.; Qi, Ji; Zhao, Fangqing; Tomsho, Lynn P.; Kasson, Lindsay R.; Packard, Michael] Penn State Univ, Ctr Comparat Genom & Bioinformat, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Padhi, Abinash; Schuster, Stephan C.; Poss, Mary] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Cross, Paul] US Geol Survey, No Rocky Mt Sci Ctr, Bozeman, MT USA. [Poss, Mary] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Wittekindt, NE (reprint author), Penn State Univ, Ctr Comparat Genom & Bioinformat, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. EM mposs@bx.psu.edu RI Wittekindt, Nicola/G-3469-2013; QI, JI/E-2797-2016 OI Wittekindt, Nicola/0000-0002-3310-0919; FU United States Geological Service [06HQAG0141, 06131HS001]; Science & Technology Directorate, Department of Homeland Security,; Fogarty International Center, National Institutes of Health; Gordon and Betty Moore Foundation FX This work was supported by United States Geological Service 06HQAG0141, subcontract 06131HS001. MP was supported, in part, by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. S. C. S. was supported by the Gordon and Betty Moore Foundation. Any use of trade, product, or firm names is for descriptive purposes only and does not imply endorsement by the U. S. Government. Field data collection was partially funded by the sale of hunting and fishing licenses in Montana, and matching Federal Aid in Wildlife Restoration grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 9 Z9 9 U1 1 U2 13 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 OCT 18 PY 2010 VL 5 IS 10 AR e13432 DI 10.1371/journal.pone.0013432 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 665ON UT WOS:000283045300015 PM 20976145 ER PT J AU Chu, C Lugovtsev, V Lewis, A Betenbaugh, M Shiloach, J AF Chu, Chia Lugovtsev, Vladimir Lewis, Andrew Betenbaugh, Michael Shiloach, Joseph TI Production and antigenic properties of influenza virus from suspension MDCK-siat7e cells in a bench-scale bioreactor SO VACCINE LA English DT Article DE Hemagglutinin; Mammalian cell line; Anchorage-independent; Vaccine ID PANDEMIC INFLUENZA; VACCINES; CULTURE; GROWTH; REPLICATION; SERUM; VERO; EGG AB In efforts to overcome limitations associated with egg-based influenza vaccines, mammalian cell substrates have gradually emerged as potential production platforms. Recently, a suspension Madin Darby canine kidney (MDCK) cell line for influenza virus production was created by expressing the human siat7e gene. To examine the broad susceptibility of this novel cell line, the scalability of the production process, and the antigenic stability of cell-derived progeny viruses, infection experiments using four current influenza vaccine strains (A/California/07/2009 X-179A H1N1, A/Brisbane/59/2007 IVR-148 H1N1, A/Uruguay/716/2007 X-175C H3N2, and B/Brisbane/60/2008) were performed. In small-scale experiments, this cell line was found to support high-titer replication of all four virus strains. Subsequently, production in a bench-scale bioreactor and the antigenic characteristics of progeny viruses were assessed. High titers of hemagglutinin (at least 1:512) were produced in a 2-L bench-scale bioreactor with all four strains. Immunoblot results demonstrated higher yields in the cells than those obtained in chicken embryonated eggs with three of the four tested strains. Progeny viruses collected after serial passages in this cell line exhibited minimal mutations in the HA-encoding gene. Hemagglutination inhibition (HAI) assays using ferret antiserum confirmed the antigenic stability. As a proof-of-concept this work demonstrates that by using a proper strategy, high yields of biologically active hemagglutinin can be produced from scalable cultures of suspension MDCK-siat7e cells. Published by Elsevier Ltd. C1 [Chu, Chia; Shiloach, Joseph] NIDDK, NIH, Bethesda, MD 20892 USA. [Chu, Chia; Betenbaugh, Michael] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Lugovtsev, Vladimir; Lewis, Andrew] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), 9000 Rockville Pike Bldg 14A Rm 173, Bethesda, MD 20892 USA. EM chuchia@mail.nih.gov; vladimir.lugovtsev@fda.hhs.gov; andrew.lewis@fda.hhs.gov; beten@jhu.edu; yossi@nih.gov RI Betenbaugh, Michael J./A-3252-2010 OI Betenbaugh, Michael J./0000-0002-6336-4659 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding was provided by the Intramural program at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The authors would like to thank Gideon Foseh for his assistance in the characterization of the MDCK cell tumorigenic phenotype Dr. Alejandro Negrete for his assistance with bioreactor setups, and Mrs. D. Livnat for critical proof reading of the manuscript. NR 26 TC 6 Z9 7 U1 3 U2 18 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 OCT 18 PY 2010 VL 28 IS 44 BP 7193 EP 7201 DI 10.1016/j.vaccine.2010.08.059 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 677HT UT WOS:000283980400009 PM 20800699 ER PT J AU Leviton, A Allred, E Kuban, KCK Dammann, O O'Shea, TM Hirtz, D Schreiber, MD Paneth, N AF Leviton, Alan Allred, Elizabeth Kuban, Karl C. K. Dammann, Olaf O'Shea, T. Michael Hirtz, Deborah Schreiber, Michael D. Paneth, Nigel CA ELGAN Study Investigators TI Early Blood Gas Abnormalities and the Preterm Brain SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE blood gas analysis; brain; infant; newborn; leukomalacia; periventricular; premature birth ID LOW-BIRTH-WEIGHT; RISK-FACTORS; PERIVENTRICULAR LEUKOMALACIA; INTRAVENTRICULAR HEMORRHAGE; PREMATURE-INFANTS; GESTATIONAL-AGE; CEREBRAL-PALSY; CELL-DEATH; 28TH WEEK; INJURY AB The authors explored associations between blood gas abnormalities in more than 1,000 preterm infants during the first postnatal days and indicators of neonatal brain damage. During 2002-2004, women delivering infants before 28 weeks' gestation at one of 14 participating institutions in 5 US states were asked to enroll in the study. The authors compared infants with blood gas values in the highest or lowest quintile for gestational age and postnatal day (extreme value) on at least 1 of the first 3 postnatal days with the remainder of the subjects, with separate analyses for blood gas abnormalities on multiple days and for partial pressure of oxygen in the alveolar gas of < 35. Outcomes analyzed were ventriculomegaly and an echolucent lesion on an ultrasound scan in the neonatal intensive care unit, and cerebral palsy, microcephaly, and a low score on a Bayley Scale of Infant Development at 24 months. Every blood gas derangement (hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidosis) was associated with multiple indicators of brain damage. However, for some, the associations were seen with only 1 day of exposure; others were evident with 2 or more days' exposure. Findings suggest that individual blood gas derangements do not increase brain damage risk. Rather, the multiple derangements associated with indicators of brain damage might be indicators of immaturity/vulnerability and illness severity. C1 [Leviton, Alan; Allred, Elizabeth] Childrens Hosp Boston, Neuroepidemiol Unit, Dept Neurol, Boston, MA 02215 USA. [Leviton, Alan; Allred, Elizabeth] Harvard Univ, Sch Med, Boston, MA USA. [Kuban, Karl C. K.] Boston Univ, Boston Med Ctr, Dept Pediat, Div Pediat Neurol, Boston, MA 02215 USA. [Dammann, Olaf] Tufts Univ, Sackler Sch Grad Biomed Sci, Floating Hosp Children, Tufts Med Ctr, Boston, MA 02111 USA. [O'Shea, T. Michael] Wake Forest Univ, Dept Pediat, Winston Salem, NC 27109 USA. [Hirtz, Deborah] Natl Inst Neurol Disorders & Stroke, Div Extramural Res, Bethesda, MD USA. [Schreiber, Michael D.] Univ Chicago, Dept Pediat, Comer Childrens Hosp, Chicago, IL 60637 USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. RP Leviton, A (reprint author), Childrens Hosp Boston, Neuroepidemiol Unit 720, 1 Autumn St, Boston, MA 02215 USA. EM alan.leviton@childrens.harvard.edu OI Kuban, Karl/0000-0001-5299-3567 FU National Institute of Neurological Disorders and Stroke [5U01NS040069-05]; National Institute of Child Health and Human Development, Bethesda, Maryland [NIH-P30-HD-18655] FX This study was supported by a cooperative agreement with the National Institute of Neurological Disorders and Stroke (5U01NS040069-05) and a program project grant from the National Institute of Child Health and Human Development (NIH-P30-HD-18655), Bethesda, Maryland. NR 40 TC 16 Z9 17 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2010 VL 172 IS 8 BP 907 EP 916 DI 10.1093/aje/kwq222 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 666CW UT WOS:000283089700005 PM 20807736 ER PT J AU Boyles, AL DeRoo, LA Lie, RT Taylor, JA Jugessur, A Murray, JC Wilcox, AJ AF Boyles, Abee L. DeRoo, Lisa A. Lie, Rolv T. Taylor, Jack A. Jugessur, Astanand Murray, Jeffrey C. Wilcox, Allen J. TI Maternal Alcohol Consumption, Alcohol Metabolism Genes, and the Risk of Oral Clefts: A Population-based Case-Control Study in Norway, 1996-2001 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; alcoholic beverages; cleft lip; cleft palate; genetic research; maternal exposure; pregnancy ID FETAL ALCOHOL; BIRTH-DEFECTS; DEHYDROGENASE GENES; ADH1C POLYMORPHISM; OROFACIAL CLEFTS; BINGE-DRINKING; PREGNANCY; ASSOCIATION; MORPHOLOGY; GENOTYPES AB Heavy maternal alcohol consumption during early pregnancy increases the risk of oral clefts, but little is known about how genetic variation in alcohol metabolism affects this association. Variants in the alcohol dehydrogenase 1C (ADH1C) gene may modify the association between alcohol and clefts. In a population-based case-control study carried out in Norway (1996-2001), the authors examined the association between maternal alcohol consumption and risk of oral clefts according to mother and infant ADH1C haplotypes encoding fast or slow alcohol-metabolizing phenotypes. Subjects were 483 infants with oral cleft malformations and 503 control infants and their mothers, randomly selected from all other livebirths taking place during the same period. Mothers who consumed 5 or more alcoholic drinks per sitting during the first trimester of pregnancy had an elevated risk of oral cleft in their offspring (odds ratio (OR) = 2.6, 95% confidence interval (CI): 1.4, 4.7). This increased risk was evident only in mothers or children who carried the ADH1C haplotype associated with reduced alcohol metabolism (OR= 3.0, 95% CI: 1.4, 6.8). There was no evidence of alcohol-related risk when both mother and infant carried only the rapid-metabolism ADH1C variant (OR = 0.9, 95% CI: 0.2, 4.1). The teratogenic effect of alcohol may depend on the genetic capacity of the mother and fetus to metabolize alcohol. C1 [Boyles, Abee L.; DeRoo, Lisa A.; Taylor, Jack A.; Wilcox, Allen J.] NIEHS, Epidemiol Branch, Durham, NC 27709 USA. [Lie, Rolv T.] Univ Bergen, Sect Epidemiol & Med Stat, Dept Publ Hlth & Primary Hlth Care, Fac Med & Dent, Bergen, Norway. [Jugessur, Astanand] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway. [Jugessur, Astanand] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Coll Publ Hlth, Iowa City, IA 52242 USA. [Murray, Jeffrey C.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Murray, Jeffrey C.] Univ Iowa, Dept Biol Sci, Coll Publ Hlth, Iowa City, IA USA. RP Boyles, AL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,MD A3 05, Durham, NC 27709 USA. EM boylesa@niehs.nih.gov OI Boyles, Abee/0000-0002-8711-2077; Wilcox, Allen/0000-0002-3376-1311; taylor, jack/0000-0001-5303-6398 FU US National Institutes of Health (NIH) [DE085592, RO1 DE-11948-04]; NIH [N01-HG-65403]; US National Institute of Environmental Health Sciences [Z01 ES049027-11, Z01 ES040007]; Research Council of Norway [166026/V50] FX This research was supported by the US National Institutes of Health (NIH) (grants DE085592 and RO1 DE-11948-04), the Intramural Research Program of the NIH, the US National Institute of Environmental Health Sciences (grants Z01 ES049027-11 and Z01 ES040007), and the Research Council of Norway (grant 166026/V50). Genotyping services were provided by the Center for Inherited Disease Research, which is funded through a federal contract from the NIH to the Johns Hopkins University (grant N01-HG-65403). NR 36 TC 27 Z9 28 U1 2 U2 7 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 OCT 15 PY 2010 VL 172 IS 8 BP 924 EP 931 DI 10.1093/aje/kwq226 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 666CW UT WOS:000283089700007 PM 20810466 ER PT J AU Milbrandt, EB Eldadah, B Nayfield, S Hadley, E Angus, DC AF Milbrandt, Eric B. Eldadah, Basil Nayfield, Susan Hadley, Evan Angus, Derek C. TI Toward an Integrated Research Agenda for Critical Illness in Aging SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE critical care; elderly; aging ID INTENSIVE-CARE-UNIT; MECHANICALLY VENTILATED PATIENTS; RESPIRATORY-DISTRESS-SYNDROME; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; HEALTHY OLDER-ADULTS; ACUTE KIDNEY INJURY; ILL PATIENTS; CLINICAL-OUTCOMES; ELDERLY-PATIENTS AB Aging brings an increased predisposition to critical illness. Patients older than 65 years of age account for approximately half of all intensive care unit (ICU) admissions in the United States, a proportion that is expected to increase considerably with the aging of the population. Emerging research suggests that elderly survivors of intensive care suffer significant long-term sequelae, including accelerated age-related functional decline. Existing evidence-based interventions are frequently underused and their efficacy untested in older subjects. Improving ICU outcomes in the elderly will require not only better methods for translating sound science into improved ICU practice but also an enhanced understanding of the underlying molecular, physiological, and pathophysiological interactions of critical illness with the aging process itself. Yet, significant barriers to research for critical illness in aging exist. We review the state of knowledge and identify gaps in knowledge, research opportunities, and barriers to research, with the goal of promoting an integrated research agenda for critical illness in aging. C1 [Milbrandt, Eric B.; Angus, Derek C.] Univ Pittsburgh, CRISMA Ctr Clin Res Invest & Syst Modeling Acute, Dept Crit Care Med, Pittsburgh, PA 15261 USA. [Eldadah, Basil; Nayfield, Susan; Hadley, Evan] NIA, Div Geriatr & Clin Gerontol, NIH, Bethesda, MD 20892 USA. RP Angus, DC (reprint author), Univ Pittsburgh, CRISMA Ctr, Dept Crit Care Med, 614 Scaife Hall, Pittsburgh, PA 15261 USA. RI Angus, Derek/E-9671-2012 FU National Institute on Aging; NIH/NIA; NIH FX Supported by the National Institute on Aging; E B M does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript B E does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript S N received $10,001-$50,000 from the NIH/NIA for serving as a scientific advisor for anemia clinical trials and more than 5100,001 from the NIH in sponsored grants for investigator-initiated clinical research E H does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript D C A does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript NR 97 TC 16 Z9 16 U1 1 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD OCT 15 PY 2010 VL 182 IS 8 BP 995 EP 1003 DI 10.1164/rccm.200904-0630CP PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 669XR UT WOS:000283384000005 PM 20558632 ER PT J AU Kang, N Ro, H Park, Y Kim, HT Huh, TL Rhee, M AF Kang, Nami Ro, Hyunju Park, Yonghoon Kim, Hyun-taek Huh, Tae-Lin Rhee, Myungchull TI Seson, a novel zinc finger protein, controls cilia integrity for the LR patterning during zebrafish embryogenesis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE LR asymmetry; Kupffer's vesicle; Cilia; C(2)H(2) zinc finger domain; Zebrafish ID LEFT-RIGHT ASYMMETRY; GENE SOUTHPAW; EXPRESSION; LATERALITY; REGULATOR; ENCODES; XENOPUS; EMBRYO; ORGAN; HEART AB In zebrafish embryos, bilateral symmetry is broken by asymmetric nodal flow generated in Kupffer's vesicle (KV), the transient cilia-rich organ, analogous to the mouse node. Asymmetric nodal flow induces the asymmetric expression of several genes, which are critical for the determination of correct LR body patterning. seson encoding three consecutive C(2)H(2) zinc finger protein is predominantly expressed in the cilia-rich organs including KV. Inhibition of its function by the injection of a seson-specific MO inhibited the left-side biased expression of spaw, and resulted in randomization of the heart, gut looping and brain laterality. Disruption of the LR patterning in seson morphants appeared to be due to severe cilia defects in KV. Seson function was also required for ciliogenesis in other tissues such as the pronephros and olfactory organs. Collectively, our data suggest that Seson has critical roles in ciliogenesis and LR body axis patterning. (C) 2010 Elsevier Inc. All rights reserved. C1 [Kang, Nami; Park, Yonghoon; Kim, Hyun-taek; Rhee, Myungchull] Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. [Ro, Hyunju] NICHHD, Mol Genet Lab, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Huh, Tae-Lin] Kyungpook Natl Univ, Dept Genet Engn, Taegu 702701, South Korea. RP Rhee, M (reprint author), Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. EM mrhee@cnu.ac.kr FU Korean Government [2009-0074496]; MOE HRD [KRF-2005-070-C00118] FX We thank Dr. Choi, S-Y for helpful comments. This research was supported by National Research Foundation of Korea Grants funded by the Korean Government (2009-0074496); MOE HRD (KRF-2005-070-C00118). We thank the Korea zebrafish Organogenesis Mutant Bank (ZOMB) for maintenance and providing zebrafish lines. NR 31 TC 2 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 15 PY 2010 VL 401 IS 2 BP 169 EP 174 DI 10.1016/j.bbrc.2010.08.124 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 672GT UT WOS:000283571700001 PM 20816938 ER PT J AU Volkow, ND AF Volkow, Nora D. TI Opioid-Dopamine Interactions: Implications for Substance Use Disorders and Their Treatment SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID COCAINE-SEEKING; DRUG-ADDICTION; NALTREXONE; RELEASE; BRAIN; RATS C1 NIDA, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd,Mail Stop Code 9581,Suite 5, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 14 TC 9 Z9 9 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2010 VL 68 IS 8 BP 685 EP 686 DI 10.1016/j.biopsych.2010.08.002 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 664XJ UT WOS:000282997000001 PM 20888455 ER PT J AU Ghitza, UE Preston, KL Epstein, DH Kuwabara, H Endres, CJ Bencherif, B Boyd, SJ Copersino, ML Frost, JJ Gorelick, DA AF Ghitza, Udi E. Preston, Kenzie L. Epstein, David H. Kuwabara, Hiroto Endres, Christopher J. Bencherif, Badreddine Boyd, Susan J. Copersino, Marc L. Frost, J. James Gorelick, David A. TI Brain Mu-Opioid Receptor Binding Predicts Treatment Outcome in Cocaine-Abusing Outpatients SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Addiction; cocaine; dependence; mu-opioid receptor; positron emission tomography (PET); treatment ID SEEKING BEHAVIOR; DEPENDENCE; ADDICTION; RELAPSE; PET; REINSTATEMENT; NALTREXONE; SMOKING; DENSITY; INSULA AB Background: Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown. Methods: We determined whether regional brain mOR binding before treatment correlates with outcome and compared it with standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine abstinence reinforcement, whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography with [(11)C]-carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment; and 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology. Results: Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sublobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use. Conclusions: Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction. C1 [Ghitza, Udi E.] NIDA, Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, NIH,Dept Hlth & Human Serv,Ctr Clin Trials Networ, Bethesda, MD 20892 USA. [Gorelick, David A.] NIDA, Off Sci Director, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Kuwabara, Hiroto; Endres, Christopher J.; Bencherif, Badreddine; Frost, J. James] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Kuwabara, Hiroto; Endres, Christopher J.; Bencherif, Badreddine; Frost, J. James] Johns Hopkins Univ, Sch Med, Dept Radiol Sci & Neurosci, Baltimore, MD 21205 USA. RP Ghitza, UE (reprint author), NIDA, Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, NIH,Dept Hlth & Human Serv,Ctr Clin Trials Networ, 6001 Execut Blvd,Room 3109,MSC 9557, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU National Institutes of Health, National Institute on Drug Abuse; National Institutes of Health [R01 DA-09479] FX This study was supported in pail by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse and in part by National Institutes of Health Grant R01 DA-09479 to JIF. NR 41 TC 30 Z9 32 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2010 VL 68 IS 8 BP 697 EP 703 DI 10.1016/j.biopsych.2010.05.003 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 664XJ UT WOS:000282997000004 PM 20579973 ER PT J AU Roos, D Kuhns, DB Maddalena, A Roesler, J Lopez, JA Ariga, T Avcin, T de Boer, M Bustamante, J Condino-Neto, A Di Matteo, G He, JX Hill, HR Holland, SM Kannengiesser, C Koker, MY Kondratenko, I van Leeuwen, K Malech, HL Marodi, L Nunoi, H Stasia, MJ Ventura, AM Witwer, CT Wolach, B Gallin, JI AF Roos, Dirk Kuhns, Douglas B. Maddalena, Anne Roesler, Joachim Alvaro Lopez, Juan Ariga, Tadashi Avcin, Tadej de Boer, Martin Bustamante, Jacinta Condino-Neto, Antonio Di Matteo, Gigliola He, Jianxin Hill, Harry R. Holland, Steven M. Kannengiesser, Caroline Koker, M. Yavuz Kondratenko, Irina van Leeuwen, Karin Malech, Harry L. Marodi, Laszlo Nunoi, Hiroyuki Stasia, Marie-Jose Ventura, Anna Maria Witwer, Carl T. Wolach, Baruch Gallin, John I. TI Hematologically important mutations: X-linked chronic granulomatous disease (third update) SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE gp91(phox); Chronic granulomatous disease; Mutation; CYBB; NADPH oxidase; X-linked disease ID HEAVY-CHAIN GENE; HUMAN NADPH OXIDASE; AUTOSOMAL RECESSIVE FORMS; CYBB GENE; CYTOCHROME B(558); GP91-PHOX GENE; MOLECULAR ANALYSIS; POINT MUTATION; MISSENSE MUTATION; PROMOTER REGION AB Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations. (C) 2010 Elsevier Inc. All rights reserved. C1 [Roos, Dirk; de Boer, Martin; van Leeuwen, Karin] Sanquin Res, NL-1066 CX Amsterdam, Netherlands. [Roos, Dirk; de Boer, Martin; van Leeuwen, Karin] Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1066 CX Amsterdam, Netherlands. [Kuhns, Douglas B.] SAIC Frederick Inc, NCI Frederick, Frederick, MD USA. [Maddalena, Anne] GeneDx, Gaithersburg, MD USA. [Roesler, Joachim] Univ Hosp Carl Gustav Carus, Dept Pediat, Dresden, Germany. [Alvaro Lopez, Juan] Univ Antioquia, Sch Microbiol, Medellin, Colombia. [Ariga, Tadashi] Hokkaido Univ, Grad Sch Med, Dept Pediat, Sapporo, Hokkaido, Japan. [Avcin, Tadej] Univ Childrens Hosp, Dept Allergol Rheumatol & Clin Immunol, Ljubljana, Slovenia. [Bustamante, Jacinta] INSERM, U550, Lab Human Genet Infect Dis, Paris, France. [Bustamante, Jacinta] Univ Paris 05, Necker Med Sch, Paris, France. [Condino-Neto, Antonio] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, Brazil. [Di Matteo, Gigliola] Univ Roma Tor Vergata, Dept Publ Hlth & Cellular Biol, Rome, Italy. [He, Jianxin] Capital Med Univ, Beijing Childrens Hosp, Pediat Res Inst, Lung Funct Lab, Beijing, Peoples R China. [Hill, Harry R.; Witwer, Carl T.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Hill, Harry R.; Witwer, Carl T.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Hill, Harry R.; Witwer, Carl T.] Univ Utah, Dept Med, Salt Lake City, UT USA. [Hill, Harry R.; Witwer, Carl T.] ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Kannengiesser, Caroline] Univ Paris 07, INSERM, Biomed Res Ctr Bichat Beaujon, F-75018 Paris, France. [Kannengiesser, Caroline] Bichat Claude Bernard Hosp, AP HP, Hormonal Biochem & Genet Serv, F-75018 Paris, France. [Koker, M. Yavuz] Erciyes Univ, Immunol Lab, Kayseri, Turkey. [Koker, M. Yavuz] Erciyes Univ, Cappadocia Transplant Ctr, Kayseri, Turkey. [Kondratenko, Irina] Russian Childrens Clin Hosp, Dept Clin Immunol, Moscow, Russia. [Malech, Harry L.; Gallin, John I.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Marodi, Laszlo] Univ Debrecen, Med & Hlth Sci Ctr, Dept Infectiol & Pediat Immunol, Debrecen, Hungary. [Nunoi, Hiroyuki] Miyazaki Univ, Fac Med, Div Pediat, Dept Reprod & Dev Med, Miyazaki, Japan. [Stasia, Marie-Jose] Univ J Fourrier, CNRS, Univ Hosp Grenoble,Therex TIMC Imag UMR 5525, Chron Granulomatous Dis Diag & Res Ctr, Grenoble, France. [Ventura, Anna Maria] Univ Bari, Dept Biomed & Dev Age, Bari, Italy. [Wolach, Baruch] Meir Med Ctr, Dept Pediat, Kefar Sava, Israel. [Wolach, Baruch] Meir Med Ctr, Lab Leukocyte Funct, Kefar Sava, Israel. RP Roos, D (reprint author), Sanquin Res, Plesmanlaan 125, NL-1066 CX Amsterdam, Netherlands. EM d.roos@sanquin.nl; HMALECH@niaid.nih.gov RI Ariga, Tadashi/A-4252-2012; STASIA, Marie Jose/M-7165-2014; koker, Mustafa Yavuz/A-7296-2012; OI koker, Mustafa Yavuz/0000-0001-7061-8525; Malech, Harry/0000-0001-5874-5775 FU CGD Research Trust, London, UK; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2005/59568]; Slovenian Research Agency [L3-0624]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank the CGD Research Trust, London, UK, for the financial support. LM thanks B. Toth (Debrecen) for the helpful contribution to this work. ACN thanks Edgar Borges de Oliveira Jr, PhD, for the excellent work, and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo for the financial support (FAPESP, Grant 2005/59568). This work was supported in part by the Slovenian Research Agency (Grant L3-0624). CK thanks Prof. M.A. Gougerot-Pocidalo for performing the Western blot analysis of NADPH oxidase subunits and measurement of respiratory burst in patients' polymorphonuclear neutrophils. DR thanks Dr. Paul Heyworth for providing information on unpublished mutations.; This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 113 TC 69 Z9 73 U1 0 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD OCT 15 PY 2010 VL 45 IS 3 BP 246 EP 265 DI 10.1016/j.bcmd.2010.07.012 PG 20 WC Hematology SC Hematology GA 657IO UT WOS:000282406600014 PM 20729109 ER PT J AU Zucali, PA Petrini, I Lorenzi, E Merino, M Cao, LA Di Tommaso, L Lee, HS Incarbone, M Walter, BA Simonelli, M Roncalli, M Santoro, A Giaccone, G AF Zucali, Paolo A. Petrini, Iacopo Lorenzi, Elena Merino, Maria Cao, Liang Di Tommaso, Luca Lee, Hye Seung Incarbone, Matteo Walter, Beatriz A. Simonelli, Matteo Roncalli, Massimo Santoro, Armando Giaccone, Giuseppe TI Insulin-Like Growth Factor-1 Receptor and Phosphorylated AKT-Serine 473 Expression in 132 Resected Thymomas and Thymic Carcinomas SO CANCER LA English DT Article DE thymoma; insulin-like growth factor-1 receptor; expression; immunohistochemistry; prognosis ID DISEASE-FREE SURVIVAL; EPITHELIAL TUMORS; CANCER; THERAPY; CLASSIFICATION; TRANSFORMATION; TUMORIGENESIS; INSTITUTION; SPECTRUM; ANTIBODY AB BACKGROUND: Thymic malignancies are rare tumors. The insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) system is involved in the development of the thymus. IGF-1R expression in thymic epithelial malignancies is unknown. METHODS: The authors investigated the expression of IGF-1R and phosphorylated AKT serine 473 (p-AKT) by using immunohistochemistry and examined the clinicopathologic correlations in a retrospective, single-institution surgical series of 132 patients with thymic epithelial malignancies. RESULTS: Earlier disease stage, less aggressive histologic types, and complete resection were significant positive prognostic factors for disease-related survival and progression-free survival, and being a woman was a better prognostic factor for disease-related survival. IGF-1R and p-AKT protein levels were expressed in 20% and 36% of thymic tumors, respectively. Both markers were expressed more commonly in recurrent disease than in primary tumors, in more aggressive subtypes, and in more advanced disease stages. There was a trend toward better survival and progression-free survival in patients who were negative for IGF1R or p-AKT expression in the whole series. When only the 91 primary tumors, IGF1R expression was associated with worse progression-free survival (P<.001). CONCLUSIONS: The current retrospective analysis demonstrated that disease stage, tumor histology, sex, and resection type were major prognostic factors in the survival of patients with thymic malignancies. The expression levels of IGF-1R and p-AKT in thymic tumors suggested that IGF-1R is a potential target for treatment. Cancer 2010; 116: 4686-95. Published 2010 by the American Cancer Society. C1 [Petrini, Iacopo; Lee, Hye Seung; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Zucali, Paolo A.; Lorenzi, Elena; Simonelli, Matteo; Santoro, Armando] IRCCS, Humanitas Clin Inst, Dept Oncol, Milan, Italy. [Merino, Maria; Walter, Beatriz A.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Cao, Liang] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Di Tommaso, Luca; Roncalli, Massimo] IRCCS, Humanitas Clin Inst, Dept Pathol, Milan, Italy. [Incarbone, Matteo] IRCCS, Humanitas Clin Inst, Dept Thorac Surg, Milan, Italy. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Lee, Hye Seung/G-6419-2011; Petrini, Iacopo/K-7316-2016; Giaccone, Giuseppe/E-8297-2017; OI Lee, Hye Seung/0000-0002-1667-7986; Petrini, Iacopo/0000-0002-7752-6866; Giaccone, Giuseppe/0000-0002-5023-7562; di tommaso, luca/0000-0002-9013-4728; Roncalli, Massimo/0000-0002-7901-8910; Simonelli, Matteo/0000-0002-5264-1251 FU National Institutes of Health/National Cancer Institute FX This work was funded by the National Institutes of Health/National Cancer Institute intramural program. NR 41 TC 23 Z9 24 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2010 VL 116 IS 20 BP 4686 EP 4695 DI 10.1002/cncr.25367 PG 10 WC Oncology SC Oncology GA 663SS UT WOS:000282910800008 PM 20597130 ER PT J AU Fairfield, KM Lucas, FL Earle, CC Small, L Trimble, EL Warren, JL AF Fairfield, Kathleen M. Lucas, F. Lee Earle, Craig C. Small, Laurie Trimble, Edward L. Warren, Joan L. TI Regional Variation in Cancer-Directed Surgery and Mortality Among Women With Epithelial Ovarian Cancer in the Medicare Population SO CANCER LA English DT Article; Proceedings Paper CT 4th International Meeting on Shared Decision Making CY JUN 14-17, 2009 CL Boston, MA DE ovarian cancer; disparities; regional variation; epidemiology; chemotherapy ID UNITED-STATES; CARE; CHEMOTHERAPY; CARCINOMA; SPECIALTY; PATTERNS; OUTCOMES; IMPACT AB BACKGROUND: Regional differences in health services can point to disparities in access to healthcare. The authors performed a population-based cohort study to examine differences in ovarian cancer treatment and mortality according to geographic region. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify 4589 women aged >= 65 years with ovarian cancer diagnosed between 1998 and 2002 who had Medicare claims filed from 1998 to 2005. Hospital Referral Region (HRR) was assigned according to patient zip code. The authors calculated the proportion of women in each HRR who underwent cancer-directed surgery. With HRR as the predictor of interest, mortality and the receipt of cancer-directed surgery were described in multivariate analyses. RESULTS: Among 4589 women with ovarian cancer, 3286 underwent cancer-directed surgery. The receipt of cancer-directed surgery varied by HRR (range, 53%-88%). Women were less likely to undergo cancer-directed surgery if they were older, nonwhite, had higher stage disease, or had more comorbidities. For example, white women were more likely to undergo such surgery (odds ratio, 1.41; 95% confidence interval, 1.10-1.82) compared with all nonwhite women. HRR was a significant predictor of cancer-directed surgery (P = .01). A significant correlation was observed between HRR and all-cause mortality (P = .02); however, after adjusting for cancer-directed surgery, that correlation was no longer significant (P = .10). CONCLUSIONS: There was regional variation in mortality among Medicare recipients with ovarian cancer, and access to cancer-directed surgery explained some of that variation. Improving access to high-quality cancer surgery for ovarian cancer may improve outcomes, particularly for minorities and for older women. Cancer 2010; 116: 4840-8. (C) 2010 American Cancer Society. C1 [Fairfield, Kathleen M.; Lucas, F. Lee] Maine Med Ctr, Ctr Outcomes Res Evaluat, Res Inst, Portland, ME 04102 USA. [Earle, Craig C.] Sunnybrook Hlth Sci Ctr, Inst Clin Evaluat Sci, Toronto, ON M4N 3M5, Canada. [Small, Laurie] Maine Med Ctr, Dept Gynecol Oncol, Portland, ME 04102 USA. [Trimble, Edward L.] Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. [Warren, Joan L.] Natl Canc Inst, Appl Res Program, Bethesda, MD USA. RP Fairfield, KM (reprint author), Maine Med Ctr, Ctr Outcomes Res Evaluat, Res Inst, 22 Bramhall St, Portland, ME 04102 USA. EM fairfk@mmc.org FU NCI NIH HHS [N01-PC-35136, N01-PC-35139, N02-PC-15105]; PHS HHS [U55/CCR921930-02] NR 23 TC 27 Z9 27 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2010 VL 116 IS 20 BP 4840 EP 4848 DI 10.1002/cncr.25242 PG 9 WC Oncology SC Oncology GA 663SS UT WOS:000282910800027 PM 20578182 ER PT J AU Swan, J Breen, N Graubard, BI McNeel, TS Blackman, D Tangka, FK Ballard-Barbash, R AF Swan, Judith Breen, Nancy Graubard, Barry I. McNeel, Timothy S. Blackman, Donald Tangka, Florence K. Ballard-Barbash, Rachel TI Data and Trends in Cancer Screening in the United States SO CANCER LA English DT Article DE National Health Interview Survey; cancer screening; mammography; Papanicolaou test; prostate-specific antigen; colorectal screening ID HEALTH INTERVIEW SURVEY; COLORECTAL-CANCER; SOCIETY GUIDELINES; PROSTATE-CANCER; CERVICAL-CANCER; CARE SERVICES; ANTIGEN TEST; WOMEN; RECOMMENDATION; MAMMOGRAPHY AB BACKGROUND: This paper examines the prevalence of cancer screening use as reported in 2005 among US adults, focusing on differences among historically underserved subgroups. We also examine trends from 1992 through 2005 to determine whether differences in screening use are increasing, staying the same, or decreasing. METHODS: Data from the National Health Interview Surveys between 1992 and 2005 were analyzed to describe patterns and trends in cancer screening practices, including Papanicolaou test, mammography, prostate-specific antigen, and colorectal screening. Logistic regression was used to report 2005 data for population subgroups defined by several demographic and socioeconomic characteristics. RESULTS: Rates of use for cancer tests are rising only for colorectal cancer, due largely to the increase in colorectal endoscopy screening. Use of all the modalities was strongly influenced by contact with a physician and by having health insurance coverage. CONCLUSIONS: There remain large gaps in use for all screening modalities by education, income, usual source of care, health insurance, and recent physician contact. These specific populations would benefit from interventions to overcome these barriers to screening. Cancer 2010; 116: 4872-81. Published 2010 by the American Cancer Society. C1 [Swan, Judith; Breen, Nancy; Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Silver Spring, MD USA. [Blackman, Donald; Tangka, Florence K.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Breen, N (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6130 Executive Blvd,EPN 4005, Rockville, MD 20852 USA. EM Breenn@mail.nih.gov NR 35 TC 75 Z9 76 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2010 VL 116 IS 20 BP 4872 EP 4881 DI 10.1002/cncr.25215 PG 10 WC Oncology SC Oncology GA 663SS UT WOS:000282910800030 PM 20597133 ER PT J AU Matrone, MA Whipple, RA Balzer, EM Martin, SS AF Matrone, Michael A. Whipple, Rebecca A. Balzer, Eric M. Martin, Stuart S. TI Microtentacles Tip the Balance of Cytoskeletal Forces in Circulating Tumor Cells SO CANCER RESEARCH LA English DT Review ID BREAST-CANCER; TUBULIN CARBOXYPEPTIDASE; IN-VIVO; MICROTUBULES; METASTASIS; PROTEIN; TAU; DETYROSINATION; REATTACHMENT; ENDOTHELIUM AB Detection of circulating tumor cells (CTC) is advancing as an effective predictor of patient outcome and therapeutic response. Unfortunately, our knowledge of CTC biology remains limited, and the impact of drug treatments on CTC metastatic potential is currently unclear. Improved CTC imaging in vivo and analysis of free-floating tumor cells now show that cytoskeletal regulation in CTCs contrasts starkly with tumor cells attached to extracellular matrix. In this review, we examine how persistent microtubule stabilization promotes the formation of microtentacles on the surface of detached breast tumor cells and enhances metastatic potential. Cancer Res; 70(20); 7737-41. (C) 2010 AACR. C1 [Whipple, Rebecca A.; Balzer, Eric M.; Martin, Stuart S.] Univ Maryland, Sch Med, Dept Physiol, Greenebaum NCI Canc Ctr, Baltimore, MD 21201 USA. [Matrone, Michael A.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. RP Martin, SS (reprint author), Univ Maryland, Sch Med, Marlene & Stewart Greenebaum NCI Canc Ctr, 655 W Baltimore St,BRB 10-029, Baltimore, MD 21201 USA. EM ssmartin@som.umaryland.edu FU National Cancer Institute [R01-CA124704]; USA Medical Research and Materiel Command [BC061047]; MD Stem Cell Exploratory Award [MSCRFE-0081]; Flight Attendant Medical Research Institute [CIA-062497] FX S.S. Martin: R01-CA124704, National Cancer Institute; Breast Cancer Idea Award, USA Medical Research and Materiel Command (BC061047); MD Stem Cell Exploratory Award (MSCRFE-0081); Clinical Innovator Award, Flight Attendant Medical Research Institute (CIA-062497). NR 30 TC 25 Z9 27 U1 1 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 OCT 15 PY 2010 VL 70 IS 20 BP 7737 EP 7741 DI 10.1158/0008-5472.CAN-10-1569 PG 5 WC Oncology SC Oncology GA 663JG UT WOS:000282879900001 PM 20924109 ER PT J AU Sangaletti, S Tripodo, C Ratti, C Piconese, S Porcasi, R Salcedo, R Trinchieri, G Colombo, MP Chiodoni, C AF Sangaletti, Sabina Tripodo, Claudio Ratti, Chiara Piconese, Silvia Porcasi, Rossana Salcedo, Rosalba Trinchieri, Giorgio Colombo, Mario P. Chiodoni, Claudia TI Oncogene-Driven Intrinsic Inflammation Induces Leukocyte Production of Tumor Necrosis Factor That Critically Contributes to Mammary Carcinogenesis SO CANCER RESEARCH LA English DT Article ID VASCULAR ENDOTHELIAL-CELLS; FACTOR-ALPHA INHIBITOR; NF-KAPPA-B; TNF-ALPHA; TRANSGENIC MICE; OVARIAN-CANCER; PHASE-II; IN-VIVO; GROWTH; EXPRESSION AB Oncogene activation promotes an intrinsic inflammatory pathway that is crucial for cancer development. Here, we have investigated the actual effect of the inflammatory cytokine tumor necrosis factor (TNF) on the natural history of spontaneous mammary cancer in the HER2/neuT (NeuT) transgenic mouse model. Bone marrow transplantation from TNF knockout mice into NeuT recipients significantly impaired tumor growth, indicating that the source of TNF fostering tumor development was of bone marrow origin. We show that the absence of leukocyte-derived TNF disarranged the tumor vasculature, which lacked pericyte coverage and structural integrity, leading to diffuse vascular hemorrhage and stromal necrosis. In addition, tumor-associated Tie2-expressing monocytes were reduced and cytokine expression skewed from Th2 to Th1 type. Treatment of NeuT mice with anti-TNF antibody partially phenocopied the antitumor effect of TNF-deficient bone marrow cell transplantation, providing a strong preclinical background and rationale for the introduction of TNF antagonists in the treatment of human breast cancer, including basal-like samples for which consolidated targeted therapies do not exist. Cancer Res; 70(20); 7764-75. (C) 2010 AACR. C1 [Sangaletti, Sabina; Ratti, Chiara; Piconese, Silvia; Colombo, Mario P.; Chiodoni, Claudia] Fdn IRCCS Ist Nazl Tumori, Mol Immunol Unit, Dept Expt Oncol & Mol Med, I-20133 Milan, Italy. [Tripodo, Claudio; Porcasi, Rossana] Univ Palermo, Dept Human Pathol, Palermo, Italy. [Salcedo, Rosalba; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD USA. RP Colombo, MP (reprint author), Fdn IRCCS Ist Nazl Tumori, Mol Immunol Unit, Dept Expt Oncol & Mol Med, Via Venezian 1, I-20133 Milan, Italy. EM mario.colombo@istitutotumori.mi.it RI Tripodo, Claudio/O-4536-2016; Chiodoni, Claudia/C-2172-2017; Sangaletti, Sabina/C-4495-2017 OI Colombo, Mario Paolo/0000-0003-0042-7955; Tripodo, Claudio/0000-0002-0821-6231; Chiodoni, Claudia/0000-0002-7644-9969; Sangaletti, Sabina/0000-0001-7047-287X FU Associazione Italiana Ricerca sul Cancro; Italian Ministry of Health FX Associazione Italiana Ricerca sul Cancro and the Italian Ministry of Health. NR 43 TC 20 Z9 20 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2010 VL 70 IS 20 BP 7764 EP 7775 DI 10.1158/0008-5472.CAN-10-0471 PG 12 WC Oncology SC Oncology GA 663JG UT WOS:000282879900005 PM 20924115 ER PT J AU Yang, DZ Kedei, N Li, LW Tao, JA Velasquez, JF Michalowski, AM Toth, BI Marincsak, R Varga, A Biro, T Yuspa, SH Blumberg, PM AF Yang, Dazhi Kedei, Noemi Li, Luowei Tao, Juan Velasquez, Julia F. Michalowski, Aleksandra M. Toth, Balazs I. Marincsak, Rita Varga, Attila Biro, Tamas Yuspa, Stuart H. Blumberg, Peter M. TI RasGRP3 Contributes to Formation and Maintenance of the Prostate Cancer Phenotype SO CANCER RESEARCH LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; CELL-LINE; PHORBOL ESTERS; IN-VITRO; DEPENDENT PHOSPHORYLATION; SIGNALING SYSTEMS; RAS; ACTIVATION; RECEPTOR; PROTEIN AB RasGRP3 mediates the activation of the Ras signaling pathway that is present in many human cancers. Here, we explored the involvement of RasGRP3 in the formation and maintenance of the prostate cancer phenotype. RasGRP3 expression was elevated in multiple human prostate tumor tissue samples and in the human androgen-independent prostate cancer cell lines PC-3 and DU 145 compared with the androgen-dependent prostate cancer cell line LNCaP. Downregulation of endogenous RasGRP3 in PC-3 and DU 145 cells reduced Ras-GTP formation, inhibited cell proliferation, impeded cell migration, and induced apoptosis. Anchorage-independent growth of the PC-3 cells and tumor formation in mouse xenografts of both cell lines were likewise inhibited. Inhibition of RasGRP3 expression reduced AKT and extracellular signal-regulated kinase 1/2 phosphorylation and sensitized the cells to killing by carboplatin. Conversely, exogenous RasGRP3 elevated Ras-GTP, stimulated proliferation, and provided resistance to phorbol 12-myristate 13-acetate-induced apoptosis in LNCaP cells. RasGRP3-overexpressing LNCaP cells displayed a markedly enhanced rate of xenograft tumor formation in both male and female mice compared with the parental line. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses, caused the cells to resume the LNCaP morphology, and suppressed growth, confirming the functional role of RasGRP3 in the altered behavior of these cells. We conclude that RasGRP3 contributes to the malignant phenotype of the prostate cancer cells and may constitute a novel therapeutic target for human prostate cancer. Cancer Res; 70(20); 7905-17. (C) 2010 AACR. C1 [Yang, Dazhi; Kedei, Noemi; Li, Luowei; Tao, Juan; Velasquez, Julia F.; Michalowski, Aleksandra M.; Yuspa, Stuart H.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Toth, Balazs I.; Marincsak, Rita; Biro, Tamas] Univ Debrecen, Dept Physiol, Med & Hlth Sci Ctr, Res Ctr Mol Med, H-4012 Debrecen, Hungary. [Varga, Attila] Univ Debrecen, Dept Urol, Med & Hlth Sci Ctr, Res Ctr Mol Med, H-4012 Debrecen, Hungary. RP Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Room 4048,Bldg 37,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov RI Toth, Balazs/K-1214-2013 FU NIH, National Cancer Institute, Center for Cancer Research; OTKA [K63153]; Hungarian Academy of Sciences FX The research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in part by OTKA K63153 (T. Biro). T. Biro is a recipient of the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. NR 50 TC 18 Z9 19 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2010 VL 70 IS 20 BP 7905 EP 7917 DI 10.1158/0008-5472.CAN-09-4729 PG 13 WC Oncology SC Oncology GA 663JG UT WOS:000282879900018 PM 20876802 ER PT J AU Mi, YJ Liang, YJ Huang, HB Zhao, HY Wu, CP Wang, F Tao, LY Zhang, CZ Dai, CL Tiwari, AK Ma, XX To, KKW Ambudkar, SV Chen, ZS Fu, LW AF Mi, Yan-jun Liang, Yong-ju Huang, Hong-bing Zhao, Hong-yun Wu, Chung-Pu Wang, Fang Tao, Li-yang Zhang, Chuan-zhao Dai, Chun-Ling Tiwari, Amit K. Ma, Xiao-xu To, Kenneth Kin Wah Ambudkar, Suresh V. Chen, Zhe-Sheng Fu, Li-wu TI Apatinib (YN968D1) Reverses Multidrug Resistance by Inhibiting the Efflux Function of Multiple ATP-Binding Cassette Transporters SO CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITOR; ENDOTHELIAL GROWTH-FACTOR; SUBFAMILY-B MEMBER-1; BREAST-CANCER CELLS; P-GLYCOPROTEIN; IN-VIVO; DRUG-RESISTANCE; SIDE POPULATION; ABCG2; PROTEIN AB Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non-small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK2930/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [(125)I] iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1-and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs. Cancer Res; 70(20); 7981-91. (C) 2010 AACR. C1 [Mi, Yan-jun; Liang, Yong-ju; Huang, Hong-bing; Zhao, Hong-yun; Wang, Fang; Tao, Li-yang; Zhang, Chuan-zhao; Dai, Chun-Ling; Ma, Xiao-xu; Fu, Li-wu] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol S China, Guangzhou 510060, Guangdong, Peoples R China. [Wu, Chung-Pu; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dai, Chun-Ling; Tiwari, Amit K.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. [To, Kenneth Kin Wah] Chinese Univ Hong Kong, Sch Pharm, Hong Kong, Hong Kong, Peoples R China. RP Fu, LW (reprint author), Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol S China, Guangzhou 510060, Guangdong, Peoples R China. EM Fulw@mail.sysu.edu.cn RI Tiwari, Amit/A-3667-2012; To, Kenneth /M-4500-2013 OI Tiwari, Amit/0000-0002-7427-7155; To, Kenneth /0000-0003-2755-0283 FU China National Natural Sciences Foundation [30672407, 81072669]; Key Subject Project Foundation of State Key Laboratory of Oncology in Southern China; St. John's University [582-2082-7601]; National Cancer Institute, NIH, Center for Cancer Research FX China National Natural Sciences Foundation grants 30672407 (L-w. Fu) and 81072669 (L-w. Fu), the Key Subject Project Foundation of State Key Laboratory of Oncology in Southern China, and St. John's University Seed Grant no. 582-2082-7601 (Z-S. Chen). Drs. C-P. Wu and S. V. Ambudkar were supported by the Intramural Research Program of the National Cancer Institute, NIH, Center for Cancer Research. NR 50 TC 93 Z9 105 U1 5 U2 27 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2010 VL 70 IS 20 BP 7981 EP 7991 DI 10.1158/0008-5472.CAN-10-0111 PG 11 WC Oncology SC Oncology GA 663JG UT WOS:000282879900025 PM 20876799 ER PT J AU Easwaran, HP van Neste, L Cope, L Sen, S Mohammad, HP Pageau, GJ Lawrence, JB Herman, JG Schuebel, KE Baylin, SB AF Easwaran, Hariharan P. van Neste, Leander Cope, Leslie Sen, Subhojit Mohammad, Helai P. Pageau, Gayle J. Lawrence, Jeanne B. Herman, James G. Schuebel, Kornel E. Baylin, Stephen B. TI Aberrant Silencing of Cancer-Related Genes by CpG Hypermethylation Occurs Independently of Their Spatial Organization in the Nucleus SO CANCER RESEARCH LA English DT Article ID HISTONE LYSINE METHYLATION; HUMAN COLORECTAL-CANCER; DNA METHYLATION; SC-35 DOMAINS; INHIBITION; EXPRESSION; LOCUS; CELLS; DENSITY; DEMETHYLATION AB Aberrant promoter DNA-hypermethylation and repressive chromatin constitutes a frequent mechanism of gene inactivation in cancer. There is great interest in dissecting the mechanisms underlying this abnormal silencing. Studies have shown changes in the nuclear organization of chromatin in tumor cells as well as the association of aberrant methylation with long-range silencing of neighboring genes. Furthermore, certain tumors show a high incidence of promoter methylation termed as the CpG island methylator phenotype. Here, we have analyzed the role of nuclear chromatin architecture for genes in hypermethylated inactive versus nonmethylated active states and its relation with long-range silencing and CpG island methylator phenotype. Using combined immunostaining for active/repressive chromatin marks and fluorescence in situ hybridization in colorectal cancer cell lines, we show that aberrant silencing of these genes occurs without requirement for their being positioned at heterochromatic domains. Importantly, hypermethylation, even when associated with long-range epigenetic silencing of neighboring genes, occurs independent of their euchromatic or heterochromatic location. Together, these results indicate that, in cancer, extensive changes around promoter chromatin of individual genes or gene clusters could potentially occur locally without preference for nuclear position and/or causing repositioning. These findings have important implications for understanding relationships between nuclear organization and gene expression patterns in cancer. Cancer Res; 70( 20); 8015-24. (C) 2010 AACR. C1 [Easwaran, Hariharan P.; Sen, Subhojit; Mohammad, Helai P.; Herman, James G.; Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [van Neste, Leander] Univ Ghent, Dept Mol Biotechnol, Fac Biosci Engn, B-9000 Ghent, Belgium. [Cope, Leslie] Johns Hopkins Kimmel Canc Ctr, Baltimore, MD USA. [Pageau, Gayle J.; Lawrence, Jeanne B.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Schuebel, Kornel E.] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Baylin, SB (reprint author), Johns Hopkins Univ, Sch Med, Bunting Blaustein Canc Ctr, 1650 Orleans St,Suite 541, Baltimore, MD 21231 USA. EM sbaylin@jhmi.edu RI Sen, Subhojit/I-9033-2012; easwaran, hariharan/D-7480-2015 OI Sen, Subhojit/0000-0001-8457-915X; easwaran, hariharan/0000-0002-5517-2972 FU National Institute of Environmental Health Sciences [ES011858]; National Cancer Institute [CA043318]; Hodson Foundation FX National Institute of Environmental Health Sciences grant ES011858; National Cancer Institute Grant CA043318. H. Easwaran was supported by the Hodson Foundation postdoctoral fellowship. NR 45 TC 18 Z9 20 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2010 VL 70 IS 20 BP 8015 EP 8024 DI 10.1158/0008-5472.CAN-10-0765 PG 10 WC Oncology SC Oncology GA 663JG UT WOS:000282879900028 PM 20736368 ER PT J AU Solier, S Barb, J Zeeberg, BR Varma, S Ryan, MC Kohn, KW Weinstein, JN Munson, PJ Pommier, Y AF Solier, Stephanie Barb, Jennifer Zeeberg, Barry R. Varma, Sudhir Ryan, Mike C. Kohn, Kurt W. Weinstein, John N. Munson, Peter J. Pommier, Yves TI Genome-wide Analysis of Novel Splice Variants Induced by Topoisomerase I Poisoning Shows Preferential Occurrence in Genes Encoding Splicing Factors SO CANCER RESEARCH LA English DT Article ID RNA-POLYMERASE-II; DNA TOPOISOMERASES; MAMMALIAN-CELLS; TRANSCRIPTION; PHOSPHORYLATION; INHIBITION; EXPRESSION; PROTEINS; VIVO; IDENTIFICATION AB RNA splicing is required to remove introns from pre-mRNA, and alternative splicing generates protein diversity. Topoisomerase I (Top1) has been shown to be coupled with splicing by regulating serine/arginine-rich splicing proteins. Prior studies on isolated genes also showed that Top1 poisoning by camptothecin (CPT), which traps Top1 cleavage complexes (Top1cc), can alter RNA splicing. Here, we tested the effect of Top1 inhibition on splicing at the genome-wide level in human colon carcinoma HCT116 and breast carcinoma MCF7 cells. The RNA of HCT116 cells treated with CPT for various times was analyzed with ExonHit Human Splice Array. Unlike other exon array platforms, the ExonHit arrays include junction probes that allow the detection of splice variants with high sensitivity and specificity. We report that CPT treatment preferentially affects the splicing of splicing-related factors, such as RBM8A, and generates transcripts coding for inactive proteins lacking key functional domains. The splicing alterations induced by CPT are not observed with cisplatin or vinblastine and are not simply due to reduced Top1 activity, as Top1 downregulation by short interfering RNA did not alter splicing like CPT treatment. Inhibition of RNA polymerase II (Pol II) hyperphosphorylation by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) blocked the splicing alteration induced by CPT, which suggests that the rapid Pol II hyperphosphorylation induced by CPT interferes with normal splicing. The preferential effect of CPT on genes encoding splicing factors may explain the abnormal splicing of a large number of genes in response to Top1cc. Cancer Res; 70(20); 8055-65. (C) 2010 AACR. C1 [Barb, Jennifer; Munson, Peter J.; Pommier, Yves] Ctr Informat Technol, Math & Stat Comp Lab, Div Computat Biosci, NIH, Bethesda, MD 20892 USA. [Solier, Stephanie; Zeeberg, Barry R.; Varma, Sudhir; Ryan, Mike C.; Kohn, Kurt W.; Weinstein, John N.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), Ctr Informat Technol, Math & Stat Comp Lab, Div Computat Biosci, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU NIH, Center for Cancer Research, National Cancer Institute [Z01BC006161-17LMP] FX NIH Intramural Program, Center for Cancer Research, National Cancer Institute (Z01BC006161-17LMP). NR 50 TC 33 Z9 34 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2010 VL 70 IS 20 BP 8055 EP 8065 DI 10.1158/0008-5472.CAN-10-2491 PG 11 WC Oncology SC Oncology GA 663JG UT WOS:000282879900032 PM 20817775 ER PT J AU Faucz, FR Stratakis, CA AF Faucz, Fabio Rueda Stratakis, Constantine A. TI Adrenal cortex and micro-RNAs An update SO CELL CYCLE LA English DT Editorial Material ID ADRENOCORTICAL DISEASE; BREAST-CANCER; HYPERPLASIAS; TUMORS; EXPRESSION; SIGNATURE C1 [Faucz, Fabio Rueda; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol Genet, Sect Endocrinol Genet, Bethesda, MD USA. [Stratakis, Constantine A.] NIH, Pediat Endocrinol Inter Inst, Training Program, Bethesda, MD 20892 USA. RP Faucz, FR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol Genet, Sect Endocrinol Genet, Bethesda, MD USA. EM fabio.faucz@pucpr.br FU Intramural NIH HHS NR 14 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2010 VL 9 IS 20 BP 4039 EP 4040 DI 10.4161/cc.9.20.13626 PG 2 WC Cell Biology SC Cell Biology GA 665TL UT WOS:000283058300004 PM 21058423 ER PT J AU Wu, YL Brosh, RM AF Wu, Yuliang Brosh, Robert M., Jr. TI Helicase-inactivating mutations as a basis for dominant negative phenotypes SO CELL CYCLE LA English DT Article DE helicase; dominant negative; dominant lethal; DNA repair; replication; genomic stability; human disease; Fanconi anemia; FANCJ; G-quadruplex ID WERNER-SYNDROME PROTEIN; NUCLEOTIDE EXCISION-REPAIR; ESCHERICHIA-COLI UVRD; BLOOM-SYNDROME CELLS; TELOMERIC-D-LOOPS; DNA HELICASE; FANCONI-ANEMIA; SACCHAROMYCES-CEREVISIAE; WRN HELICASE; GENOME STABILITY AB There is ample evidence from studies of both unicellular and multicellular organisms that helicase-inactivating mutations lead to cellular dysfunction and disease phenotypes. In this review, we will discuss the mechanisms underlying the basis for abnormal phenotypes linked to mutations in genes encoding DNA helicases. Recent evidence demonstrates that a clinically relevant patient missense mutation in Fanconi Anemia Complementation Group J exerts detrimental effects on the biochemical activities of the FANCJ helicase, and these molecular defects are responsible for aberrant genomic stability and a poor DNA damage response. The ability of FANCJ to use the energy from ATP hydrolysis to produce the force required to unwind duplex or G-quadruplex DNA structures or destabilize protein bound to DNA is required for its DNA repair functions in vivo. Strikingly, helicase-inactivating mutations can exert a spectrum of dominant negative phenotypes, indicating that expression of the mutant helicase protein potentially interferes with normal DNA metabolism and has an effect on basic cellular processes such as DNA replication, the DNA damage response and protein trafficking. This review emphasizes that future studies of clinically relevant mutations in helicase genes will be important to understand the molecular pathologies of the associated diseases and their impact on heterozygote carriers. C1 [Wu, Yuliang; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. EM BroshR@mail.nih.gov FU NIH; National Institute on Aging; Fanconi Anemia Research Fund FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the Fanconi Anemia Research Fund (R.M.B.). We wish to thank Drs. Suhasini Avvaru and Brian Berquist (Laboratory of Molecular Gerontology, NIA-NIH) for critical reading of the manuscript and Mr. Jimmy Burril (Visual Media Services, NIA-NIH) for assistance with artwork. NR 111 TC 14 Z9 14 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2010 VL 9 IS 20 BP 4080 EP 4090 DI 10.4161/cc.9.20.13667 PG 11 WC Cell Biology SC Cell Biology GA 665TL UT WOS:000283058300018 PM 20980836 ER PT J AU Sourbier, C Valera-Romero, V Giubellino, A Yang, YF Sudarshan, S Neckers, L Linehan, WM AF Sourbier, Carole Valera-Romero, Vladimir Giubellino, Alessio Yang, Youfeng Sudarshan, Sunil Neckers, Len Linehan, W. Marston TI Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma SO CELL CYCLE LA English DT Article DE HLRCC; bortezomib; cisplatin; ROS; kidney cancer; FH ID PROTEASOME INHIBITOR BORTEZOMIB; MULTIPLE-MYELOMA CELLS; OXIDATIVE STRESS; MITOCHONDRIAL-DNA; INNATE IMMUNITY; CANCER; APOPTOSIS; FIBROBLASTS; DISEASE; INJURY AB Hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated renal tumors are aggressive and tend to metastasize early. There are currently no effective forms of therapy for patients with advanced HLRCC-associated kidney cancer. We have previously shown that HLRCC cells express a high level of reactive oxygen species (ROS). In the present study we investigated the cytotoxiceffects of increasing ROS level using bortezomib in combination with cisplatin on HLRCC cells in vitro and in an in vivo xenograft model. The cytotoxic effect of several ROS inducers on FH-deficient cells was assessed by synthetic lethality. ROS inducers had a pronounced impact on the viability of FH-deficient cells. Because of its high potency, the proteasome inhibitor bortezomib was further investigated. Bortezomib induced apoptosis in vitro in HLRCC cells and inhibited HLRCC tumour growth in vivo. Bortezomib-associated cytotoxicity was highly correlated with cellular ROS level: combining bortezomib with other ROS inducers enhanced cytotoxicity, while combining bortezomib with a ROS scavenger inhibited its cytotoxic effect. Finally, HLRCC murine xenografts were treated with bortezomib and cisplatin, another ROS inducer. This regimen induced HLRCC tumour regression in vivo. These findings suggest that increasing ROS level in HLRCC above a certain threshold can induce HLRCC-tumor cell death. Increasing tumor ROS with bortezomib in combination with cisplatin represents a novel targeted therapeutic approach to treat advanced HLRCC-associated renal tumors. C1 [Sourbier, Carole; Valera-Romero, Vladimir; Giubellino, Alessio; Yang, Youfeng; Neckers, Len; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sudarshan, Sunil] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM WML@nih.gov RI Bell, Tiffany/F-4403-2010; OI Giubellino, Alessio/0000-0002-5352-0662 FU NIH, National Cancer Institute, Center for Cancer Research FX We wish to thank Dr. B. T. Scroggins for helpful discussions, Ms. Catherine Wells for technical assistance and Ms. G. Shaw for editorial assistance. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 29 TC 16 Z9 16 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2010 VL 9 IS 20 BP 4183 EP 4189 DI 10.4161/cc.9.20.13458 PG 7 WC Cell Biology SC Cell Biology GA 665TL UT WOS:000283058300029 PM 20953139 ER PT J AU Iwasaki, H Kovacic, JC Olive, M Beers, JK Yoshimoto, T Crook, MF Tonelli, LH Nabel, EG AF Iwasaki, Hiroaki Kovacic, Jason C. Olive, Michelle Beers, Jeanette K. Yoshimoto, Takanobu Crook, Martin F. Tonelli, Leonardo H. Nabel, Elizabeth G. TI Disruption of Protein Arginine N-Methyltransferase 2 Regulates Leptin Signaling and Produces Leanness In Vivo Through Loss of STAT3 Methylation SO CIRCULATION RESEARCH LA English DT Article DE PRMT2; leptin; methylation; STAT3 ID TYROSINE-PHOSPHATASE 1B; POMC NEURONS; TARGET NEURONS; MICE LACKING; OB/OB MICE; OBESITY; RECEPTOR; PROOPIOMELANOCORTIN; IDENTIFICATION; TRANSCRIPTION-3 AB Rationale: Arginine methylation by protein N-arginine methyltransferases (PRMTs) is an important posttranslational modification in the regulation of protein signaling. PRMT2 contains a highly conserved catalytic Ado-Met binding domain, but the enzymatic function of PRMT2 with respect to methylation is unknown. The JAK-STAT pathway is proposed to be regulated through direct arginine methylation of STAT transcription factors, and STAT3 signaling is known to be required for leptin regulation of energy balance. Objective: To identify the potential role of STAT3 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis. Methods and Results: We identified that PRMT2(-/-) mice are hypophagic, lean, and have significantly reduced serum leptin levels. This lean phenotype is accompanied by resistance to food-dependent obesity and an increased sensitivity to exogenous leptin administration. PRMT2 colocalizes with STAT3 in hypothalamic nuclei, where it binds and methylates STAT3 through its Ado-Met binding domain. In vitro studies further clarified that the Ado-Met binding domain of PRMT2 induces STAT3 methylation at the Arg31 residue. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic STAT3, which was associated with increased expression of hypothalamic proopiomelanocortin following leptin stimulation. Conclusions: These data elucidate a molecular pathway that directly links arginine methylation of STAT3 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes. (Circ Res. 2010;107:992-1001.) C1 [Iwasaki, Hiroaki; Olive, Michelle; Beers, Jeanette K.; Yoshimoto, Takanobu; Crook, Martin F.; Nabel, Elizabeth G.] NHLBI, Vasc Biol Sect, NIH, Bethesda, MD 20892 USA. [Kovacic, Jason C.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Tonelli, Leonardo H.] Univ Maryland, Mood & Anxiety Program, Dept Psychiat, Baltimore, MD 21201 USA. RP Nabel, EG (reprint author), Brigham & Womens Hosp, 75 Francis St,PB408, Boston, MA 02115 USA. EM enabel@partners.org FU Division of Intramural Research at the National Heart, Lung, and Blood Institute, NIH FX This work was supported by the Division of Intramural Research at the National Heart, Lung, and Blood Institute, NIH. NR 42 TC 27 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD OCT 15 PY 2010 VL 107 IS 8 BP 992 EP 1001 DI 10.1161/CIRCRESAHA.110.225326 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 664MM UT WOS:000282965300008 PM 20798359 ER PT J AU Simard, EP Engels, EA AF Simard, Edgar P. Engels, Eric A. TI Cancer as a Cause of Death among People with AIDS in the United States SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; NON-HODGKIN-LYMPHOMA; LUNG-CANCER; MORTALITY; DIAGNOSIS; INCREASE; TRENDS; EPOCH AB Background. People with human immunodeficiency virus (HIV) infection and AIDS have an elevated risk for cancer. Highly active antiretroviral therapy (HAART), which has been widely available since 1996, has resulted in dramatic decreases in AIDS-related deaths. Methods. We evaluated cancer as a cause of death in a US registry-based cohort of 83,282 people with AIDS (1980-2006). Causes of death due to AIDS-defining cancers (ADCs) and non-ADCs (NADCs) were assessed. We evaluated mortality rates and the fraction of deaths due to cancer. Poisson regression assessed rates according to calendar year of AIDS onset. Results. Overall mortality decreased from 302 deaths per 1000 person-years in 1980-1989, to 140 deaths per 1000 person-years in 1990-1995, and to 29 deaths per 1000 person-years in 1996-2006. ADC-related mortality decreased from 2.95 deaths per 1000 person-years in 1980-1989 to 0.65 deaths per 1000 person-years in 19962006 (P<.01), but the fraction of ADC-related deaths increased from 1.05% to 2.47% in association with decreases in other AIDS-related deaths. Non-Hodgkin lymphoma was the most common cancer-related cause of death (36% of deaths during 1996-2006). Likewise, NADC-related mortality decreased from 2.21 to 0.84 deaths per 1000 person-years from the period 1980-1989 to the period 1996-2006 (P<.05), but the fraction of NADC-deaths increased to 3.16% during 1996-2006. Lung cancer was the most common NADC cause of death (21% of cancer-related deaths in 1996-2006). Conclusions. Cancer-related mortality decreased in the HAART era, but because of decreasing mortality due to AIDS, cancers account for a growing fraction of deaths. Improved cancer prevention and treatment, particularly for non-Hodgkin lymphoma and lung cancer, would reduce mortality among people with AIDS. C1 [Simard, Edgar P.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7076, Rockville, MD 20892 USA. EM engelse@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX Financial support. The Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 31 TC 69 Z9 70 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2010 VL 51 IS 8 BP 957 EP 962 DI 10.1086/656416 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 652UU UT WOS:000282036700013 PM 20825305 ER PT J AU Richards, JS Stanisic, DI Fowkes, FJI Tavul, L Dabod, E Thompson, JK Kumar, S Chitnis, CE Narum, DL Michon, P Siba, PM Cowman, AF Mueller, I Beeson, JG AF Richards, Jack S. Stanisic, Danielle I. Fowkes, Freya J. I. Tavul, Livingstone Dabod, Elijah Thompson, Jennifer K. Kumar, Sanjeev Chitnis, Chetan E. Narum, David L. Michon, Pascal Siba, Peter M. Cowman, Alan F. Mueller, Ivo Beeson, James G. TI Association between Naturally Acquired Antibodies to Erythrocyte-Binding Antigens of Plasmodium falciparum and Protection from Malaria and High-Density Parasitemia SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INVASION PATHWAYS; REGION-II; INHIBITORY ANTIBODIES; RECEPTOR SPECIFICITY; TARGETED DISRUPTION; MEROZOITE ANTIGENS; CLINICAL MALARIA; EBA-175; LIGAND; RESPONSES AB Background. Antibodies targeting blood stage antigens are important in protection against malaria, but the principle targets remain unclear. Erythrocyte-binding antigens (EBAs) are important erythrocyte invasion ligands used by merozoites and may be targets of protective immunity, but there are limited data examining their potential importance. Methods. We examined antibodies among 206 Papua New Guinean children who were treated with antimalarials at enrolment and observed prospectively for 6 months for reinfection and malaria. Immunoglobulin (Ig) G, IgG subclasses, and IgM to different regions of EBA175, EBA140, and EBA181 expressed as recombinant proteins were assessed in comparison with several other merozoite antigens. Results. High levels of IgG to each of the EBAs were strongly associated with protection from symptomatic malaria and high density parasitemia, but not with risk of reinfection per se. The predominant IgG subclasses were either IgG1 or IgG3, depending on the antigen. The predominance of IgG1 versus IgG3 reflected structural features of specific regions of the proteins. IgG3 was most strongly associated with protection, even for those antigens that had an IgG1 predominant response. Conclusions. The EBAs appear important targets of acquired protective immunity. These findings support their further development as vaccine candidates. C1 [Richards, Jack S.; Stanisic, Danielle I.; Fowkes, Freya J. I.; Thompson, Jennifer K.; Cowman, Alan F.; Beeson, James G.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [Richards, Jack S.] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3010, Australia. [Stanisic, Danielle I.; Tavul, Livingstone; Dabod, Elijah; Michon, Pascal; Siba, Peter M.; Mueller, Ivo] Papua New Guinea Inst Med Res, Madang, Papua N Guinea. [Kumar, Sanjeev; Chitnis, Chetan E.] Int Ctr Genet Engn & Biotechnol, New Delhi, India. [Narum, David L.] NIAID, Malaria Vaccine Dev Branch, Bethesda, MD 20892 USA. RP Beeson, JG (reprint author), Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Parkville, Vic 3050, Australia. EM beeson@wehi.edu.au RI Mueller, Ivo/C-7251-2013; Cowman, Alan/C-7642-2013; OI Mueller, Ivo/0000-0001-6554-6889; Cowman, Alan/0000-0001-5145-9004; Richards, Jack/0000-0001-5786-6989; Fowkes, Freya/0000-0001-5832-9464 FU National Health and Medical Research Council of Australia [361646]; Department of Innovation, Industry, Science, and Research, Australian Government; Australian Research Council; Victorian State Government Operational Infrastructure; IRIISS [361646] FX The National Health and Medical Research Council of Australia (project grant and career development award to J.G.B., postgraduate research fellowship to J.S.R., and training award to F.J.F. [IRIISS grant 361646]), the Australia-India Strategic Research Fund (Department of Innovation, Industry, Science, and Research, Australian Government), Australian Research Council (Future Fellowship to J.G.B.), and the Victorian State Government Operational Infrastructure Support grant. NR 40 TC 75 Z9 75 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2010 VL 51 IS 8 BP E50 EP E60 DI 10.1086/656413 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 652UU UT WOS:000282036700027 PM 20843207 ER PT J AU Stybayeva, G Kairova, M Ramanculov, E Simonian, AL Revzin, A AF Stybayeva, Gulnaz Kairova, Markhabat Ramanculov, Erlan Simonian, Aleksandr L. Revzin, Alexander TI Detecting interferon-gamma release from human CD4 T-cells using surface plasmon resonance SO COLLOIDS AND SURFACES B-BIOINTERFACES LA English DT Article DE CD4 T-cells; Antibody-antigen interactions; Immunoassay; SPR; Cytokine biosensors ID BIOSENSORS; CYTOKINES AB Cytokine secretion by leukocytes is an important indicator of immune response to pathogens and therefore has significant implications in disease diagnostics. Given heterogeneity of leukocyte subsets and the ability of multiple cell subsets to secrete the same cytokines, connecting cytokine production to a specific leukocyte subset is a distinct challenge. In the present paper we describe a strategy combining antibody (Ab)-based affinity cell separation and surface plasmon resonance (SPR) for capturing human CD4 T-cells and for label-free detection of cell-secreted interferon (IFN)-gamma - an important inflammatory cytokine. Human blood was introduced into a flow chamber modified with anti-CD4 Abs resulting in capture of CD4(+) T-cells. After mitogenic activation of cells inside the flow chamber, culture medium was routed onto an SPR chip modified with monoclonal IFN-gamma Abs. SPR signal observed in this experiment correlated with cytokine production by T-cells. The strategy of combining SPR detection with cell purification may be used in the future for label-free, sensitive detection of multiple cytokines or proteins secreted by the desired cell subset. (C) 2010 Elsevier B.V. All rights reserved. C1 [Stybayeva, Gulnaz; Revzin, Alexander] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Kairova, Markhabat; Simonian, Aleksandr L.] Auburn Univ, Dept Mat Engn, Auburn, AL 36849 USA. [Stybayeva, Gulnaz; Kairova, Markhabat; Ramanculov, Erlan] Natl Biotechnol Ctr, Astana, Kazakhstan. RP Revzin, A (reprint author), Univ Calif Davis, Dept Biomed Engn, 451 Hlth Sci Dr 2519, Davis, CA 95616 USA. EM als@eng.auburn.edu; arevzin@ucdavis.edu RI Ramanculov, Erlan/E-2823-2013; OI Kairova, Markhabat/0000-0002-6858-663X FU National Center for Biotechnology, Republic of Kazakhstan; NSF [0937997] FX The authors would like to thank Profs. Louie and Marcu for use of their microscopes. GS and MK were supported in part by the fellowship from the National Center for Biotechnology, Republic of Kazakhstan. This study was also supported in part by the NSF EFRI grant (#0937997) awarded to AR. ALS acknowledges working at the National Science Foundation during the time this study was carried out. The views expressed in this article are those of the authors and do not reflect the views of the National Science Foundation. NR 17 TC 27 Z9 27 U1 1 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7765 J9 COLLOID SURFACE B JI Colloid Surf. B-Biointerfaces PD OCT 15 PY 2010 VL 80 IS 2 BP 251 EP 255 DI 10.1016/j.colsurfb.2010.06.015 PG 5 WC Biophysics; Chemistry, Physical; Materials Science, Biomaterials SC Biophysics; Chemistry; Materials Science GA 640UA UT WOS:000281077500022 PM 20634047 ER PT J AU Matsuda, M Chitnis, AB AF Matsuda, Miho Chitnis, Ajay B. TI Atoh1a expression must be restricted by Notch signaling for effective morphogenesis of the posterior lateral line primordium in zebrafish SO DEVELOPMENT LA English DT Article DE mind bomb; Posterior lateral line; Neuromasts; Morphogenesis; Zebrafish; Cadherins; FGF signaling; Lateral inhibition ID UBIQUITIN LIGASE; CELL-MIGRATION; MIND-BOMB; TISSUE MIGRATION; CRANIAL GANGLIA; FGF; SYSTEM; NEUROGENESIS; ACTIVATION; LIGANDS AB The posterior lateral line primordium (pLLp) migrates caudally, depositing neuromasts to establish the posterior lateral line system in zebrafish. A Wnt-dependent FGF signaling center at the leading end of the pLLp initiates the formation of 'proneuromasts' by facilitating the reorganization of cells into epithelial rosettes and by initiating atoh1a expression. Expression of atoh1a gives proneuromast cells the potential to become sensory hair cells, and lateral inhibition mediated by Delta-Notch signaling restricts atoh1a expression to a central cell. We show that as atoh1a expression becomes established in the central cell, it drives expression of fgf10 and of the Notch ligand deltaD, while it inhibits expression of fgfr1. As a source of Fgf10, the central cell activates the FGF pathway in neighboring cells, ensuring that they form stable epithelial rosettes. At the same time, DeltaD activates Notch in neighboring cells, inhibiting atoh1a expression and ensuring that they are specified as supporting cells. When Notch signaling fails, unregulated atoh1a expression reduces Fgfr1 expression, eventually resulting in attenuated FGF signaling, which prevents effective maturation of epithelial rosettes in the pLLp. In addition, atoh1a inhibits e-cadherin expression, which is likely to reduce cohesion and contribute to fragmentation of the pLLp. Together, our observations reveal a genetic regulatory network that explains why atoh1a expression must be restricted by Notch signaling for effective morphogenesis of the pLLp. C1 [Matsuda, Miho; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, Sect Neural Dev Dynam, NIH, Bethesda, MD 20892 USA. RP Chitnis, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, Sect Neural Dev Dynam, NIH, Bethesda, MD 20892 USA. EM chitnisa@mail.nih.gov RI Matsuda, Miho/G-1616-2011 FU NIH/NICHD FX We thank James Hudspeth, Rockefeller University, NY, USA, for providing anti-Claudin b antibody, Motoyuki Itoh for preliminary exploration of these questions, and all members of the A. B. C. laboratory for their comments. This work was supported by the Intramural Research Program of the NIH/NICHD. Deposited in PMC for immediate release. This article is freely accessible online from the date of publication. NR 33 TC 39 Z9 39 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT 15 PY 2010 VL 137 IS 20 BP 3477 EP 3487 DI 10.1242/dev.052761 PG 11 WC Developmental Biology SC Developmental Biology GA 655AN UT WOS:000282213100015 PM 20876657 ER PT J AU Bao, JJ Scott, I Lu, ZP Pang, LY Dimond, CC Gius, D Sack, MN AF Bao, Jianjun Scott, Iain Lu, Zhongping Pang, Liyan Dimond, Christopher C. Gius, David Sack, Michael N. TI SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE SIRT3; Lipotoxicity; Electron transfer chain; Reactive oxygen species; Palmitate; Free radicals ID LYSINE ACETYLATION; MITOCHONDRIAL-FUNCTION; DIABETES-MELLITUS; SKELETAL-MUSCLE; DEACETYLATION; METABOLISM; SIRTUINS; OBESITY; STRESS; LIVER AB SIRT3 is the primary mitochondrial deacetylase that modulates mitochondrial metabolic and oxidative stress regulatory pathways. However, its role in response to nutrient excess remains unknown. Thus, we investigated SIRT3 regulation of the electron transfer chain and evaluated the role of SIRT3 in hepatic lipotoxic stress. SIRT3-depleted HepG2 cells show diffuse disruption in mitochondrial electron transfer chain functioning, a concurrent reduction in the mitochondrial membrane potential, and excess basal reactive oxygen species levels. As this phenotype may predispose to increased lipotoxic hepatic susceptibility we evaluated the expression of SIRT3 in murine liver after chronic high-fat feeding. In this nutrient-excess model SIRT3 transcript and protein levels are downregulated in parallel with increased hepatic fat storage and oxidative stress. Palmitate was used to investigate lipotoxic susceptibility in SIRT3 knockout mouse primary hepatocytes and SIRT3-siRNA-transfected HepG2 cells. Under SIRT3-deficient conditions palmitate enhances reactive oxygen species and increases hepatocyte death. Reconstitution of SIRT3 levels and/or treatment with N-acetylcysteine ameliorates these adverse effects. In conclusion SIRT3 functions to ameliorate hepatic lipotoxicity, although paradoxically, exposure to high fat downregulates this adaptive program in the liver. This SIRT3-dependent lipotoxic susceptibility is possibly modulated, in part, by SIRT3-mediated control of electron transfer chain flux. Published by Elsevier Inc. C1 [Bao, Jianjun; Scott, Iain; Lu, Zhongping; Pang, Liyan; Dimond, Christopher C.; Sack, Michael N.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Gius, David] Vanderbilt Univ, Dept Radiat Oncol & Pediat, Sch Med, Nashville, TN 37232 USA. RP Sack, MN (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov FU NHLBI Division of Intramural Research FX This study was funded by the NHLBI Division of Intramural Research. We acknowledge with appreciation the technical assistance obtained from the NHLBI Intramural flow cytometry and light microscopy core facilities. NR 24 TC 68 Z9 71 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT 15 PY 2010 VL 49 IS 7 BP 1230 EP 1237 DI 10.1016/j.freeradbiomed.2010.07.009 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 647MX UT WOS:000281623700010 PM 20647045 ER PT J AU Bartkowiak, B Liu, PD Phatnani, HP Fuda, NJ Cooper, JJ Price, DH Adelman, K Lis, JT Greenleaf, AL AF Bartkowiak, Bartlomiej Liu, Pengda Phatnani, Hemali P. Fuda, Nicholas J. Cooper, Jeffrey J. Price, David H. Adelman, Karen Lis, John T. Greenleaf, Arno L. TI CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1 SO GENES & DEVELOPMENT LA English DT Article DE CTD kinase; transcription; RNA polymerase II; C-terminal repeat domain; P-TEFb ID RNA-POLYMERASE-II; CYCLIN-DEPENDENT KINASE; TERMINAL REPEAT DOMAIN; IN-VIVO; P-TEFB; LARGEST SUBUNIT; PROCESSING FACTORS; PROTEIN-KINASE; HEAT-SHOCK; PHOSPHORYLATION AB Drosophila contains one (dCDK12) and humans contain two (hCDK12 and hCDK13) proteins that are the closest evolutionary relatives of yeast Ctk1, the catalytic subunit of the major elongation-phase C-terminal repeat domain (CTD) kinase in Saccharomyces cerevisiae, CTDK-I. However, until now, neither CDK12 nor CDK13 has been demonstrated to be a bona fide CTD kinase. Using Drosophila, we demonstrate that dCDK12 (CG7597) is a transcription-associated CTD kinase, the ortholog of yCtk1. Fluorescence microscopy reveals that the distribution of dCDK12 on formaldehyde-fixed polytene chromosomes is virtually identical to that of hyper-phosphorylated RNA polymerase II (RNAPII), but is distinct from that of P-TEFb (dCDK9 + dCyclin T). Chromatin immunoprecipitation (ChIP) experiments confirm that dCDK12 is present on the transcribed regions of active Drosophila genes. Compared with P-TEFb, dCDK12 amounts are lower at the 5' end and higher in the middle and at the 39 end of genes (both normalized to RNAPII). Appropriately, Drosophila dCDK12 purified from nuclear extracts manifests CTD kinase activity in vitro. Intriguingly, we find that cyclin K is associated with purified dCDK12, implicating it as the cyclin subunit of this CTD kinase. Most importantly, we demonstrate that RNAi knockdown of dCDK12 in S2 cells alters the phosphorylation state of the CTD, reducing its Ser2 phosphorylation levels. Similarly, in human HeLa cells, we show that hCDK13 purified from nuclear extracts displays CTD kinase activity in vitro, as anticipated. Also, we find that chimeric (yeast/human) versions of Ctk1 containing the kinase homology domains of hCDK12/13 (or hCDK9) are functional in yeast cells (and also in vitro); using this system, we show that a bur1(ts) mutant is rescued more efficiently by a hCDK9 chimera than by a hCDK13 chimera, suggesting the following orthology relationships: Bur1 <-> CDK9 and Ctk1 <-> CDK12/13. Finally, we show that siRNA knockdown of hCDK12 in HeLa cells results in alterations in the CTD phosphorylation state. Our findings demonstrate that metazoan CDK12 and CDK13 are CTD kinases, and that CDK12 is orthologous to yeast Ctk1. C1 [Bartkowiak, Bartlomiej; Liu, Pengda; Phatnani, Hemali P.; Greenleaf, Arno L.] Duke Univ, Med Ctr, Duke Ctr RNA Biol, Dept Biochem, Durham, NC 27710 USA. [Fuda, Nicholas J.; Lis, John T.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14850 USA. [Cooper, Jeffrey J.; Price, David H.] Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA. [Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Greenleaf, AL (reprint author), Duke Univ, Med Ctr, Duke Ctr RNA Biol, Dept Biochem, Durham, NC 27710 USA. EM arno@duke.edu FU NIH [GM040505, GM025232, GM035500]; NIH, National Institute of Environmental Health Sciences [Z01 ES101987] FX We thank Craig B. Bennett and April MacKellar for insights and helpful discussions, Janis Werner for performing the polytene staining experiments, Daniel A. Gilchrist for an introduction to S2 cells, Dirk Eick for the kind gift of mAb 3E10, and Greg Prelich for the bur1-8 strain. This research was supported by grants from the NIH to A.L.G. (GM040505), J.T.L. (GM025232), and D.H.P. (GM035500), and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, to K.A. (Z01 ES101987). NR 58 TC 135 Z9 140 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD OCT 15 PY 2010 VL 24 IS 20 BP 2303 EP 2316 DI 10.1101/gad.1968210 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 665QJ UT WOS:000283050200009 PM 20952539 ER PT J AU Ambartsumyan, G Gill, RK Perez, SD Conway, D Vincent, J Dalal, Y Clark, AT AF Ambartsumyan, Gayane Gill, Rajbir K. Perez, Silvia Diaz Conway, Deirdre Vincent, John Dalal, Yamini Clark, Amander T. TI Centromere protein A dynamics in human pluripotent stem cell self-renewal, differentiation and DNA damage SO HUMAN MOLECULAR GENETICS LA English DT Article ID HUMAN PREIMPLANTATION DEVELOPMENT; CENP-A; CHROMOSOME SEGREGATION; HUMAN OOCYTES; HISTONE H3; ES CELLS; CHROMATIN; TRANSCRIPTOME; ORGANIZATION; TRANSLATION AB Human pluripotent stem cells (hPSCs) hold significant promise for use in regenerative medicine, or as a model to understand human embryo development. However, the basic mechanisms required for proliferation and self-renewal of hPSCs have not been fully uncovered. Proliferation in all eukaryotes is dependent upon highly regulated expression of the histone H3 variant Centromere protein A (CENP-A). In the current study, we demonstrate that hPSCs have a unique messenger ribonucleic acid (mRNA) reserve of CENP-A not found in somatic fibroblasts. Using short hairpin RNA technology to reduce but not ablate CENP-A, we show that CENP-A-depleted hPSCs are still capable of maintaining a functional centromeric mark, whereas fibroblasts are not. However, upon induction of differentiation or DNA damage, hPSCs with depleted CENP-A arrest in G2/M and undergo apoptosis. Analysis of CENP-A dynamics following DNA damage in hPSCs reveals that 60 min after irradiation, CENP-A is found in multiple small nuclear foci that are mutually exclusive to gamma H2AX as well as CENP-C. Furthermore, following irradiation, hPSCs with depleted CENP-A mount a normal apoptotic response at 6 h; however at 24 h, apoptosis is significantly increased in CENP-A-depleted hPSCs relative to control. Taken together, our results indicate that hPSCs exhibit a unique mechanism for maintaining genomic integrity by possessing the flexibility to reduce the amount of CENP-A required to maintain a functional centromere under self-renewing conditions, and maintaining a reserve of CENP-A mRNA to rebuild the centromere following differentiation or DNA damage. C1 [Ambartsumyan, Gayane; Perez, Silvia Diaz; Conway, Deirdre; Vincent, John; Clark, Amander T.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Ambartsumyan, Gayane; Conway, Deirdre] Univ Calif Los Angeles, Dept OB GYN, Los Angeles, CA 90095 USA. [Perez, Silvia Diaz; Vincent, John; Clark, Amander T.] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA. [Vincent, John; Clark, Amander T.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Gill, Rajbir K.; Dalal, Yamini] NCI, Chromatin Struct & Epigenet Mech Unit, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. RP Clark, AT (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, 621 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM clarka@ucla.edu OI Dalal, Yamini/0000-0002-7655-6182 FU NIH/NICHD [R01 1R01HD058047-01]; NIH/NIGMS [P01 P01GM081621]; Fuller Foundation; NIH/NCI; NIH/NICHHD UCLA Women's Reproductive Health Research Center [5 K12 HD001281]; UCLA Clinical Fellows California Institute for Regenerative Medicine (CIRM); CIRM; NIH-NCRR [CJX1-443835-WS-29646]; NSF [CHE-0722519]; UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research FX This work was supported by an R01 grant from the NIH/NICHD (R01 1R01HD058047-01), P01 funds from the NIH/NIGMS (P01 P01GM081621), funds from the Fuller Foundation (A. T. C.) and intramural research funding NIH/NCI (Y.D., R. K. G.). G. A. was supported by a training grant from the NIH/NICHHD UCLA Women's Reproductive Health Research Center (5 K12 HD001281) and a UCLA Clinical Fellows California Institute for Regenerative Medicine (CIRM) training grant. J.V. is supported by a graduate student training grant from CIRM. Fluorescence microscopy for some experiments was performed at the California Nano-Systems Institute Advanced Light Microscopy/Spectroscopy Shared Facility at UCLA, directed by Dr Laurent Bentolila and supported with funding from NIH-NCRR shared resources grant (CJX1-443835-WS-29646) and NSF Major Research Instrumentation grant (CHE-0722519). Funding to pay the Open Access Charge was provided by UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. NR 56 TC 11 Z9 11 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2010 VL 19 IS 20 BP 3970 EP 3982 DI 10.1093/hmg/ddq312 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 657UF UT WOS:000282439700007 PM 20650959 ER PT J AU Teer, JK Mullikin, JC AF Teer, Jamie K. Mullikin, James C. TI Exome sequencing: the sweet spot before whole genomes SO HUMAN MOLECULAR GENETICS LA English DT Article ID MULTIPLEX AMPLIFICATION; HYBRID SELECTION; DNA METHYLATION; HIGH-ALTITUDE; CAPTURE; ENRICHMENT; GENE; EXONS; HYBRIDIZATION; ADAPTATION AB The development of massively parallel sequencing technologies, coupled with new massively parallel DNA enrichment technologies (genomic capture), has allowed the sequencing of targeted regions of the human genome in rapidly increasing numbers of samples. Genomic capture can target specific areas in the genome, including genes of interest and linkage regions, but this limits the study to what is already known. Exome capture allows an unbiased investigation of the complete protein-coding regions in the genome. Researchers can use exome capture to focus on a critical part of the human genome, allowing larger numbers of samples than are currently practical with whole-genome sequencing. In this review, we briefly describe some of the methodologies currently used for genomic and exome capture and highlight recent applications of this technology. C1 [Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Teer, Jamie K.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Mullikin, JC (reprint author), 5625 Fishers Lane,Rm 5N-01Q,MSC 9400, Bethesda, MD 20892 USA. EM mullikin@mail.nih.gov RI Sincan, Murat /A-3794-2010 FU National Human Genome Research Institute, National Institutes of Health FX The authors are supported by the Intramural Research Program of the National Human Genome Research Institute. Funding to pay the Open Access Charge was provided by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 45 TC 142 Z9 146 U1 3 U2 32 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2010 VL 19 SI 2 BP R145 EP R151 DI 10.1093/hmg/ddq333 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 683FC UT WOS:000284456100005 PM 20705737 ER PT J AU Yue, W Wang, JP Li, YB Fan, P Liu, GJ Zhang, N Conaway, M Wang, HK Korach, KS Bocchinfuso, W Santen, R AF Yue, Wei Wang, Ji-Ping Li, Yuebai Fan, Ping Liu, Guijian Zhang, Nan Conaway, Mark Wang, Hongkun Korach, Kenneth S. Bocchinfuso, Wayne Santen, Richard TI Effects of estrogen on breast cancer development: role of estrogen receptor independent mechanisms SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; Wnt-1; estrogen receptor alpha knockout ID MAMMARY-GLAND HYPERPLASIA; BRCA2 MUTATION CARRIERS; ESTRADIOL HYPERSENSITIVITY; AROMATASE INHIBITORS; POSTMENOPAUSAL WOMEN; COMBINATION TRIAL; EPITHELIAL-CELLS; RANDOMIZED-TRIAL; TRANSGENIC MICE; ATAC ARIMIDEX AB Development of breast cancer involves genetic factors as well as lifetime exposure to estrogen. The precise molecular mechanisms whereby estrogens influence breast tumor formation are poorly understood. While estrogen receptor alpha (ER alpha) is certainly involved, nonreceptor mediated effects of estradiol (E-2) may also play an important role in facilitating breast tumor development. A "reductionist'' strategy allowed us to examine the role of ER alpha independent effects of E-2 on mammary tumor development in ER alpha knockout (ERKO) mice bearing the Wnt-1 oncogene. Exogenous E-2 "clamped'' at early follicular and midluteal phase levels (i.e., 80 and 240 pg/ml) accelerated tumor formation in a dose-related fashion in ERKO/Wnt-1 animals (p = 0.0002). Reduction of endogenous E-2 by oophorectomy (p < 0.001) or an aromatase inhibitor (AI) (p = 0.055) in intact ERKO/Wnt-1 animals delayed tumorigenesis as further evidence for an ER-independent effect. The effects of residual ER alpha or beta were not involved since enhancement of tumor formation could not be blocked by the antiestrogen fulvestrant. 17 alpha-OH-E-2, a metabolizable but ER-impeded analogue of E-2 stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER-independent actions of E-2 can influence breast tumor development in concert with ER dependent effects. These observations suggest 1 mechanism whereby AIs, which block E-2 synthesis, would be more effective for breast cancer prevention than use of antiestrogens, which only block ER-mediated effects. C1 [Yue, Wei; Wang, Ji-Ping; Li, Yuebai; Fan, Ping; Liu, Guijian; Zhang, Nan; Santen, Richard] Univ Virginia Hlth Syst, Dept Med, Charlottesville, VA USA. [Conaway, Mark; Wang, Hongkun] Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA. [Korach, Kenneth S.; Bocchinfuso, Wayne] NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Yue, W (reprint author), Univ Virginia, Div Endocrinol & Metab, POB 801416, Charlottesville, VA 22908 USA. EM wy9c@virginia.edu OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS [Z01 ES070065-31] NR 70 TC 24 Z9 24 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2010 VL 127 IS 8 BP 1748 EP 1757 DI 10.1002/ijc.25207 PG 10 WC Oncology SC Oncology GA 657HX UT WOS:000282404900002 PM 20104523 ER PT J AU Hou, LF Wang, H Sartori, S Gawron, A Lissowska, J Bollati, V Tarantini, L Zhang, FF Zatonski, W Chow, WH Baccarelli, A AF Hou, Lifang Wang, Hao Sartori, Samantha Gawron, Andrew Lissowska, Jolanta Bollati, Valentina Tarantini, Letizia Zhang, Fang Fang Zatonski, Witold Chow, Wong-Ho Baccarelli, Andrea TI Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE gastric cancer; methylation; global hypomethylation; gastric cancer risk ID CPG ISLAND HYPERMETHYLATION; CELL LUNG-CANCER; HELICOBACTER-PYLORI INFECTION; STOMACH-CANCER; PROMOTER METHYLATION; PROSTATE-CANCER; SERUM; INSTABILITY; BIOMARKER; ALCOHOL AB Global hypomethylation has been shown to increase genome instability potentially leading to increased cancer risk. We determined whether global methylation in blood leukocyte DNA was associated with gastric cancer in a population-based study on 302 gastric cancer cases and 421 age-and sex-matched controls in Warsaw, Poland, between 1994 and 1996. Using PCR-pyrosequencing, we analyzed methylation levels of Alu and LINE-1, 2 CG-rich repetitive elements, to measure global methylation levels. Gastric cancer risk was highest among those with lowest level of methylation in either Alu (OR = 1.3, 95% CI = 0.9-1.9) or LINE-1 (OR = 1.4, 95% CI = 0.9-2.0) relative to those with the highest levels, although the trends were not statistically significant. For Alu, the association was stronger among those aged 70 or older (OR = 2.6, 95% CI = 1.3-5.5, p for interaction = 0.02). We did not observe meaningful differences in the associations by other risk factors and polymorphisms examined. For LINE-1, the association tended to be stronger among individuals with a family history of cancer (OR = 3.1, 95% CI = 1.4-7.0, p for interaction = 0.01), current alcohol drinkers (OR = 1.9, 95% CI = 1.0-3.6, p for interaction = 0.05), current smokers (OR = 2.3, 95% CI = 1.1-4.6, p for interaction = 0.02), those who rarely or never consumed fruit (OR = 3.1, 95% CI = 1.2-8.1, p for interaction = 0.03), CC carriers for the MTRR Ex5 + 123C>T polymorphism (OR = 2.3, 95% CI = 1.2-4.4, p for interaction = 0.01) and TT carriers for the MTRR Ex15 + 572T>C polymorphism (OR = 1.7, 95% CI = 1.0-2.8, p for interaction = 0.06). The association was not different by sex, Helicobacter pylori infection, intake of folate, vitamin B6 and total protein and the remaining polymorphisms examined. Our results indicate that interactions between blood leukocyte DNA hypomethylation and host characteristics may determine gastric cancer risk. C1 [Hou, Lifang; Gawron, Andrew] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Wang, Hao] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sartori, Samantha] Univ Milan, Inst Med Stat & Biometr GA Maccacaro, Milan, Italy. [Sartori, Samantha; Bollati, Valentina; Tarantini, Letizia; Baccarelli, Andrea] Univ Milan, Dept Environm & Occupat Hlth, Mangiagalli & Regina Elena IRCCS Fdn, Ctr Mol & Genet Epidemiol,Maggiore Policlin Hosp, Milan, Italy. [Gawron, Andrew] Northwestern Univ, Feinberg Sch Med, Dept Internal Med, Div Gastroenterol, Chicago, IL 60611 USA. [Lissowska, Jolanta; Zatonski, Witold] M Sklosowska Curie Inst Oncol, Warsaw, Poland. [Lissowska, Jolanta; Zatonski, Witold] Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. [Zhang, Fang Fang] Univ N Texas, Hlth Sci Ctr, Sch Publ Hlth, Dept Epidemiol, Ft Worth, TX USA. [Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. RP Hou, LF (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM l-hou@northwestern.edu RI Gawron, Andrew/H-4479-2013; Sartori, Samantha/E-6396-2015; Mendez, Pedro /J-8955-2016; Sartori, Stefano/K-9498-2016; OI Sartori, Samantha/0000-0003-0618-9409; Mendez, Pedro /0000-0001-6713-7907; Sartori, Stefano/0000-0002-0012-6848; Baccarelli, Andrea/0000-0002-3436-0640; Lissowska, Jolanta/0000-0003-2695-5799; Bollati, Valentina/0000-0002-0370-9598 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH FX Grant sponsor: Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH NR 50 TC 62 Z9 64 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2010 VL 127 IS 8 BP 1866 EP 1874 DI 10.1002/ijc.25190 PG 9 WC Oncology SC Oncology GA 657HX UT WOS:000282404900013 PM 20099281 ER PT J AU Coley, W Van Duyne, R Carpio, L Guendel, I Kehn-Hall, K Chevalier, S Narayanan, A Luu, T Lee, N Klase, Z Kashanchi, F AF Coley, William Van Duyne, Rachel Carpio, Lawrence Guendel, Irene Kehn-Hall, Kylene Chevalier, Sebastien Narayanan, Aarthi Luu, Truong Lee, Norman Klase, Zachary Kashanchi, Fatah TI Absence of DICER in Monocytes and Its Regulation by HIV-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; STEM-CELLS; SILENCING PATHWAY; HUMAN MACROPHAGES; GENE-EXPRESSION; TAR ELEMENT; INFECTION; RNA AB MicroRNAs (miRNAs) are a class of small RNA molecules that function to control gene expression and restrict viral replication in host cells. The production of miRNAs is believed to be dependent upon the DICER enzyme. Available evidence suggests that in T lymphocytes, HIV-1 can both suppress and co-opt the host's miRNA pathway for its own benefit. In this study, we examined the state of miRNA production in monocytes and macrophages as well as the consequences of viral infection upon the production of miRNA. Monocytes in general express low amounts of miRNA-related proteins, and DICER in particular could not be detected until after monocytes were differentiated into macrophages. In the case where HIV-1 was present prior to differentiation, the expression of DICER was suppressed. MicroRNA chip results for RNA isolated from transfected and treated cells indicated that a drop in miRNA production coincided with DICER protein suppression in macrophages. We found that the expression of DICER in monocytes is restricted by miR-106a, but HIV-1 suppressed DICER expression via the viral gene Vpr. Additionally, analysis of miRNA expression in monocytes and macrophages revealed evidence that some miRNAs can be processed by both DICER and PIWIL4. Results presented here have implications for both the pathology of viral infections in macrophages and the biogenesis of miRNAs. First, HIV-1 suppresses the expression and function of DICER in macrophages via a previously unknown mechanism. Second, the presence of miRNAs in monocytes lacking DICER indicates that some miRNAs can be generated by proteins other than DICER. C1 [Coley, William; Van Duyne, Rachel; Carpio, Lawrence; Guendel, Irene; Kehn-Hall, Kylene; Narayanan, Aarthi; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodefense & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. [Klase, Zachary] NIAID, Bethesda, MD 20892 USA. [Chevalier, Sebastien] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Luu, Truong; Lee, Norman] George Washington Univ, Sch Med, Dept Physiol & Pharmacol, Washington, DC 20037 USA. RP Kashanchi, F (reprint author), George Mason Univ, Natl Ctr Biodefense & Infect Dis, Dept Mol & Microbiol, Discovery Hall,Rm 306,10900 Univ Blvd,MS 1H8, Manassas, VA 20110 USA. EM fkashanc@gmu.edu RI Kehn-Hall, Kylene/I-5752-2013 FU National Institutes of Health [AI078859, AI074410, AI043894] FX This work was supported, in whole or in part, by National Institutes of Health Grants AI078859, AI074410, and AI043894. NR 56 TC 51 Z9 52 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2010 VL 285 IS 42 BP 31930 EP 31943 DI 10.1074/jbc.M110.101709 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 660XZ UT WOS:000282683000006 PM 20584909 ER PT J AU Soetandyo, N Ye, YH AF Soetandyo, Nia Ye, Yihong TI The p97 ATPase Dislocates MHC Class I Heavy Chain in US2-expressing Cells via a Ufd1-Npl4-independent Mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETICULUM-ASSOCIATED DEGRADATION; ENDOPLASMIC-RETICULUM; MEMBRANE-PROTEIN; RETRO-TRANSLOCATION; DEUBIQUITINATING ENZYME; MISFOLDED PROTEINS; LIGASE MK3; ER; COMPLEX; CYTOSOL AB The human cytomegalovirus (HCMV) protein US2 hijacks the endoplasmic reticulum (ER)-associated degradation machinery to dispose of MHC class I heavy chain (HC) at the ER. This process requires retrotranslocation of newly synthesized HC molecules from the ER membrane into the cytosol, but the mechanism underlying the dislocation reaction has been elusive. Here we establish an in vitro permeabilized cell assay that recapitulates the retrotranslocation of MHC HC in US2-expressing cells. Using this assay, we demonstrate that the dislocation process requires ATP and ubiquitin, as expected. The retrotranslocation also involves the p97 ATPase. However, the mechanism by which p97 dislocates MHC class I HC in US2 cells is distinct from that in US11 cells: the dislocation reaction in US2 cells is independent of the p97 cofactor Ufd1-Npl4. Our results suggest that different retrotranslocation mechanisms can employ distinct p97 ATPase complexes to dislocate substrates. C1 [Soetandyo, Nia; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), 5 Ctr Dr, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU National Institutes of Health, NIDDK FX This work was supported, in whole or in part, by a National Institutes of Health grant from the Intramural Research Program, NIDDK. NR 44 TC 17 Z9 17 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2010 VL 285 IS 42 BP 32352 EP 32359 DI 10.1074/jbc.M110.131649 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 660XZ UT WOS:000282683000048 PM 20702414 ER PT J AU Varkey, J Isas, JM Mizuno, N Jensen, MB Bhatia, VK Jao, CC Petrlova, J Voss, JC Stamou, DG Steven, AC Langen, R AF Varkey, Jobin Isas, Jose Mario Mizuno, Naoko Jensen, Martin Borch Bhatia, Vikram Kjoller Jao, Christine C. Petrlova, Jitka Voss, John C. Stamou, Dimitrios G. Steven, Alasdair C. Langen, Ralf TI Membrane Curvature Induction and Tubulation Are Common Features of Synucleins and Apolipoproteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMPHIPATHIC-ALPHA-HELICES; N-BAR DOMAIN; HIGH-DENSITY-LIPOPROTEINS; FIBRILLIZATION IN-VITRO; PARKINSONS-DISEASE; A-I; SECONDARY STRUCTURE; HIPPOCAMPAL-NEURONS; ELECTRON-MICROSCOPY; GAMMA-SYNUCLEIN AB Synucleins and apolipoproteins have been implicated in a number of membrane and lipid trafficking events. Lipid interaction for both types of proteins is mediated by 11 amino acid repeats that form amphipathic helices. This similarity suggests that synucleins and apolipoproteins might have comparable effects on lipid membranes, but this has not been shown directly. Here, we find that alpha-synuclein, beta-synuclein, and apolipoprotein A-1 have the conserved functional ability to induce membrane curvature and to convert large vesicles into highly curved membrane tubules and vesicles. The resulting structures are morphologically similar to those generated by amphiphysin, a curvature-inducing protein involved in endocytosis. Unlike amphiphysin, however, synucleins and apolipoproteins do not require any scaffolding domains and curvature induction is mediated by the membrane insertion and wedging of amphipathic helices alone. Moreover, we frequently observed that alpha-synuclein caused membrane structures that had the appearance of nascent budding vesicles. The ability to function as a minimal machinery for vesicle budding agrees well with recent findings that alpha-synuclein plays a role in vesicle trafficking and enhances endocytosis. Induction of membrane curvature must be under strict regulation in vivo; however, as we find it can also cause disruption of membrane integrity. Because the degree of membrane curvature induction depends on the concerted action of multiple proteins, controlling the local protein density of tubulating proteins may be important. How cellular safeguarding mechanisms prevent such potentially toxic events and whether they go awry in disease remains to be determined. C1 [Langen, Ralf] Univ So Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Mizuno, Naoko; Steven, Alasdair C.] NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Jensen, Martin Borch; Bhatia, Vikram Kjoller; Stamou, Dimitrios G.] Univ Copenhagen, Bionanotechnol Lab, Dept Neurosci & Pharmacol, Lundbeck Fdn Ctr Biomembranes Nanomed, DK-2100 Copenhagen, Denmark. [Petrlova, Jitka; Voss, John C.] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA. RP Langen, R (reprint author), Univ So Calif, Zilkha Neurogenet Inst, 1501 San Pablo St,121 ZNI, Los Angeles, CA 90033 USA. EM langen@usc.edu RI Stamou, Dimitrios/D-5042-2016; OI Stamou, Dimitrios/0000-0001-8456-8995; Voss, John/0000-0001-9279-209X FU National Institutes of Health [GM063915, R01 AG029246]; NIAMS; Larry L. Hillblom foundation; Danish Research Councils; University of Copenhagen; Lundbeck foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants GM063915 (to R.L.), R01 AG029246 (to J.C.V.), and the Intramural Research Program of NIAMS (to A.C.S.). This work was also supported by the Larry L. Hillblom foundation (to R.L.) and the Danish Research Councils, the University of Copenhagen and the Lundbeck foundation (to D.G.S.). NR 76 TC 88 Z9 88 U1 3 U2 29 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2010 VL 285 IS 42 BP 32486 EP 32493 DI 10.1074/jbc.M110.139576 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 660XZ UT WOS:000282683000062 PM 20693280 ER PT J AU Chang, CR Manlandro, CM Arnoult, D Stadler, J Posey, AE Hill, RB Blackstone, C AF Chang, Chuang-Rung Manlandro, Cara Marie Arnoult, Damien Stadler, Julia Posey, Ammon E. Hill, R. Blake Blackstone, Craig TI A Lethal de Novo Mutation in the Middle Domain of the Dynamin-related GTPase Drp1 Impairs Higher Order Assembly and Mitochondrial Division SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIZE-EXCLUSION CHROMATOGRAPHY; LIGHT-SCATTERING; PROTEIN DLP1; CELLULAR SENESCENCE; FUSION MEDIATORS; MAMMALIAN-CELLS; FISSION; APOPTOSIS; MORPHOLOGY; BINDING AB Mitochondria dynamically fuse and divide within cells, and the proper balance of fusion and fission is necessary for normal mitochondrial function, morphology, and distribution. Drp1 is a dynamin-related GTPase required for mitochondrial fission in mammalian cells. It harbors four distinct domains: GTP-binding, middle, insert B, and GTPase effector. A lethal mutation (A395D) within the Drp1 middle domain was reported in a neonate with microcephaly, abnormal brain development, optic atrophy, and lactic acidemia (Waterham, H. R., Koster, J., van Roermund, C. W., Mooyer, P. A., Wanders, R. J., and Leonard, J. V. (2007) N. Engl. J. Med. 356, 1736-1741). Mitochondria within patient-derived fibroblasts were markedly elongated, but the molecular mechanisms underlying these findings were not demonstrated. Because the middle domain is particularly important for the self-assembly of some dynamin superfamily proteins, we tested the hypothesis that this A395D mutation, and two other middle domain mutations (G350D, G363D) were important for Drp1 tetramerization, higher order assembly, and function. Although tetramerization appeared largely intact, each of these mutations compromised higher order assembly and assembly-dependent stimulation of Drp1 GTPase activity. Moreover, mutant Drp1 proteins exhibited impaired localization to mitochondria, indicating that this higher order assembly is important for mitochondrial recruitment, retention, or both. Overexpression of these middle domain mutants markedly inhibited mitochondrial division in cells. Thus, the Drp1 A395D lethal defect likely resulted in impaired higher order assembly of Drp1 at mitochondria, leading to decreased fission, elongated mitochondria, and altered cellular distribution of mitochondria. C1 [Manlandro, Cara Marie; Posey, Ammon E.; Hill, R. Blake] Johns Hopkins Univ, Dept Biol & Chem, Baltimore, MD 21218 USA. [Chang, Chuang-Rung] Natl Tsing Hua Univ, Inst Biotechnol, Hsinchu 30013, Taiwan. [Chang, Chuang-Rung] Natl Tsing Hua Univ, Dept Life Sci, Hsinchu 30013, Taiwan. [Arnoult, Damien] INSERM, U542, F-94807 Villejuif, France. [Arnoult, Damien] Univ Paris Sud, Hop Paul Brousse, F-94807 Villejuif, France. [Stadler, Julia; Blackstone, Craig] NINDS, Cellular Neurol Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Hill, RB (reprint author), Johns Hopkins Univ, Dept Biol & Chem, Baltimore, MD 21218 USA. EM hill@jhu.edu; blackstc@ninds.nih.gov RI Chang, Chuang-Rung /C-1815-2012; Posey, Ammon/H-6505-2013 FU National Institutes of Health Intramural Research Program of the NINDS [5T32GM080189, 5T32GM008403, RO1GM067180] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NINDS (to C.-R.C., J.S., and C.B.), Training Grant 5T32GM080189 (to C.M.M.), Training Grant 5T32GM008403 (to A.E.P.), and Grant RO1GM067180 (to R.B.H.). NR 46 TC 66 Z9 67 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 15 PY 2010 VL 285 IS 42 BP 32494 EP 32503 DI 10.1074/jbc.M110.142430 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 660XZ UT WOS:000282683000063 PM 20696759 ER PT J AU Wei, Y Du, SJ Ito, Y AF Wei, Yun Du, Shijuan Ito, Yoichiro TI Enantioseparation of lomefloxacin hydrochloride by high-speed counter-current chromatography using sulfated-beta-cyclodextrin as a chiral selector SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE High-speed counter-current chromatography; Enantioseparation; Lomefloxacin hydrochloride; Sulfated-beta-cyclodextrin ID CENTRIFUGAL PARTITION CHROMATOGRAPHY; SEPARATION AB Enantiomers of lomefloxacin hydrochloride were separated by high-speed counter-current chromatography (HSCCC) using sulfated-beta-cyclodextrin as a chiral selector (CS). The separation was performed with a two-phase solvent system composed of ethyl acetate-methanol-water (10:1:10, v/v) containing CS at 0-60 mmol/l in a head-to-tail elution mode, while obtained fractions were identified by polarimeter and spectropolarimeter. The results show that the concentration of the CS in the system strongly affects the peak resolution (Rs). As the concentration of CS increases, the Rs first increases reaching the maximum at 50 mmol/l and then decreases. When the CS concentration is kept constant in the solvent systems, the Rs decreases as the concentration of the lomefloxacin hydrochloride increases. The overall results of our studies indicated that sulfated-beta-cyclodextrin is very useful for the chiral separation by HSCCC. (C) 2010 Elsevier B.V. All rights reserved. C1 [Wei, Yun; Du, Shijuan] Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Wei, Y (reprint author), Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, 15 Beisanhuan E Rd, Beijing 100029, Peoples R China. EM weiyun@mail.buct.edu.cn FU Natural Science Foundation of China [21075007]; Beijing Natural Science Foundation [2073028] FX The financial support of this work is supported by the Natural Science Foundation of China (Project 21075007) and Beijing Natural Science Foundation (Project 2073028). NR 21 TC 13 Z9 15 U1 2 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD OCT 15 PY 2010 VL 878 IS 28 BP 2937 EP 2941 DI 10.1016/j.jchromb.2010.08.030 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 673TX UT WOS:000283687200043 PM 20837406 ER PT J AU Ruckwardt, TJ Luongo, C Malloy, AMW Liu, J Chen, M Collins, PL Graham, BS AF Ruckwardt, Tracy J. Luongo, Cindy Malloy, Allison M. W. Liu, Jie Chen, Man Collins, Peter L. Graham, Barney S. TI Responses against a Subdominant CD8(+) T Cell Epitope Protect against Immunopathology Caused by a Dominant Epitope SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; INFLUENZA-VIRUS; IMMUNODOMINANT EPITOPE; LYMPHOCYTE-RESPONSES; INFECTION; MICE; IMMUNIZATION; PEPTIDE; IDENTIFICATION; REPLICATION AB CD8(+) T cell responses are critical for the control of virus infections. Following infection, epitope-specific responses establish an unpredictable but reproducible pattern of dominance that is dictated by a large number of both positive and negative factors. Immunodomination, or diminution of subdominant epitope-specific responses by dominant epitopes, can play a substantial role in the establishment of epitope hierarchy. To determine the role of a dominant (K(d)M2(82-90)) and a subdominant ((DM187-195)-M-b) epitope of respiratory syncytial virus in viral control and immunodomination, MHC-binding anchor residues in the two epitopes were mutated individually in recombinant infectious viruses, greatly reducing or deleting the epitope-specific CD8(+) T cell responses. Neither mutation negatively affected viral clearance in mice, and compensation by the unmutated epitope was seen in both cases, whereas compensation by five other subdominant epitopes was minimal. Mutation of the dominant K(d)M2(82-90) response resulted in effective viral clearance by the subdominant epitope with less illness, whereas mutation of the subdominant (DM187-195)-M-b response resulted in overcompensation of the already dominant K(d)M2(82-90) epitope, and increased severity of illness. Increased illness was associated with poor functionality of the abundant population of CD8(+) T cells specific to the dominant KdM2(82-90) epitope, as measured by the percentage and magnitude of IFN-gamma production. These data demonstrate efficient viral clearance, and a protective effect of subdominant CD8(+) T cell responses. The Journal of Immunology, 2010, 185: 4673-4680. C1 [Ruckwardt, Tracy J.; Malloy, Allison M. W.; Liu, Jie; Chen, Man; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Luongo, Cindy; Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 2502, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU National Institute of Allergy and Infectious Disease FX This work was supported by the National Institute of Allergy and Infectious Disease Intramural Research Program. NR 44 TC 27 Z9 28 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 OCT 15 PY 2010 VL 185 IS 8 BP 4673 EP 4680 DI 10.4049/jimmunol.1001606 PG 8 WC Immunology SC Immunology GA 658WU UT WOS:000282525900019 PM 20833834 ER PT J AU Das, A Long, EO AF Das, Asmita Long, Eric O. TI Lytic Granule Polarization, Rather than Degranulation, Is the Preferred Target of Inhibitory Receptors in NK Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL CYTOTOXICITY; IMMUNE SYNAPSES; CUTTING EDGE; IMMUNOLOGICAL SYNAPSE; GRANZYME-B; HLA-C; ACTIVATION; BINDING; LIGAND; SIGNAL AB Natural cytotoxicity is achieved by polarized release of perforin and granzymes at the NK cell-target cell immunological synapse. Signals for granule polarization and degranulation can be uncoupled in NK cells, which raises the question of their respective sensitivity to inhibitory receptors. Expression of either HLA-C or HLA-E on the human cell line 721.221 blocked granule polarization, degranulation, and CD16-dependent MIP-1 alpha secretion by NK cell clones that expressed inhibitory receptors of matching HLA specificity. To test inhibition of signals for polarization and degranulation separately, Drosophila S2 cells expressing ICAM-1 with either HLA-C or HLA-E were used. CD16-dependent degranulation and MIP-1 alpha secretion were not fully inhibited, suggesting that other receptor-ligand interactions, which occur with 721.221 cells, contribute to inhibition. In contrast, HLA-C or HLA-E on S2 cells coexpressing ICAM-1 or ULBP1 were sufficient to block granule polarization induced by either LFA-1 or NKG2D, even during concomitant CD16-dependent degranulation. Similarly, expression of a ligand for NKR-P1A on S2 cells inhibited granule polarization but not CD16-induced degranulation. Therefore, granule polarization, rather than degranulation, is the preferred target of inhibitory receptors in NK cells. The Journal of Immunology, 2010, 185: 4698-4704. C1 [Das, Asmita; Long, Eric O.] 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 National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 30 TC 15 Z9 15 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 OCT 15 PY 2010 VL 185 IS 8 BP 4698 EP 4704 DI 10.4049/jimmunol.1001220 PG 7 WC Immunology SC Immunology GA 658WU UT WOS:000282525900022 PM 20833835 ER PT J AU Vaudaux, JD Muccioli, C James, ER Silveira, C Magargal, SL Jung, C Dubey, JP Jones, JL Doymaz, MZ Bruckner, DA Belfort, R Holland, GN Grigg, ME AF Vaudaux, Jean D. Muccioli, Cristina James, Erick R. Silveira, Claudio Magargal, Spencer L. Jung, Calvin Dubey, J. P. Jones, Jeffrey L. Doymaz, Mehmet Z. Bruckner, David A. Belfort, Rubens, Jr. Holland, Gary N. Grigg, Michael E. TI Identification of an Atypical Strain of Toxoplasma gondii as the Cause of a Waterborne Outbreak of Toxoplasmosis in Santa Isabel do Ivai, Brazil SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID FREE-RANGE CHICKENS; CONGENITAL TOXOPLASMOSIS; OCULAR TOXOPLASMOSIS; INFECTIONS; DISEASE; PCR; GENOTYPE; SAMPLES; PARANA; STATE AB Multilocus DNA sequencing has identified a nonarchetypal strain of Toxoplasma gondii as the causal agent of a waterborne outbreak in Brazil in 2001. The strain, isolated from a water supply epidemiologically linked to the outbreak, was virulent to mice, and it has previously been identified as BrI. Using a serologic assay that detects strain-specific antibodies, we found that 13 (65%) of 20 individuals who were immunoglobulin (Ig) M positive during the outbreak possessed the same serotype as mice infected with the purported epidemic strain. The remaining 7 individuals, plus additional IgM-negative, IgG-positive individuals, possessed 1 of 4 novel serotypes, the most common of which matched the serotype of mice infected with strains isolated from chickens foraging near the outbreak site. The latter strains likely reflect the genetic diversity of T. gondii circulating in highly endemic regions of Brazil. The serotyping assay proved a useful tool for identification of specific individuals infected with the outbreak agent. C1 [Magargal, Spencer L.; Grigg, Michael E.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Vaudaux, Jean D.; Holland, Gary N.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Ocular Inflammatory Dis Ctr, Los Angeles, CA 90095 USA. [Vaudaux, Jean D.; Holland, Gary N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Doymaz, Mehmet Z.; Bruckner, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Dubey, J. P.] ARS, Anim Parasit Dis Lab, Anim & Nat Resources Inst, USDA, Beltsville, MD USA. [Jones, Jeffrey L.] United States Ctr Dis Control & Prevent, Div Parasit Dis, Natl Ctr Zoonot Vector Borne & Enter Infect, Atlanta, GA USA. [Muccioli, Cristina; Silveira, Claudio; Belfort, Rubens, Jr.] Univ Fed Sao Paulo, Dept Ophthalmol, Sao Paulo, Brazil. [James, Erick R.; Jung, Calvin] Univ British Columbia, Dept Med, Vancouver, BC, Canada. RP Grigg, ME (reprint author), NIAID, Parasit Dis Lab, 4 Ctr Dr,Rm B1-06, Bethesda, MD 20892 USA. EM uveitis@jsei.ucla.edu; griggm@niaid.nih.gov RI James, Erick/D-4725-2012; Belfort Jr, Rubens/E-2252-2012; Muccioli, Cristina/C-3419-2013 OI Belfort Jr, Rubens/0000-0002-8422-3898; FU National Institutes of Health; National Institute of Allergy and Infectious Diseases [AI001018]; US Department of Agriculture [1265-32000-076]; US Centers for Disease Control and Prevention; Fonds National Suisse pour la Recherche Scientifique [PBLA33102339]; Research to Prevent Blindness (RPB); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Skirball Foundation; Jack H. Skirball Endowed Professorship FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (grant AI001018 to M. E. G.), the US Department of Agriculture (Agricultural Research Service, Current Research Information System [CRIS] Project 1265-32000-076 to J.P.D.), the US Centers for Disease Control and Prevention (contract to J.D.V., G.N.H., and J.L.J.), Fonds National Suisse pour la Recherche Scientifique (PBLA33102339 to J.D.V.), Research to Prevent Blindness (RPB; support to G.N.H.), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq I-A Investigator Grant to C. M., C. S., and R. B.), the Skirball Foundation, (support to G.N.H.), and the Jack H. Skirball Endowed Professorship (to G.N.H.). G.N.H. is the recipient of an RPB Physician-Scientist Award. M.E.G. is a scholar of the Michael Smith Foundation for Health Research and the Canadian Institute for Advanced Research Program for Integrated Microbial Biodiversity. NR 22 TC 48 Z9 48 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2010 VL 202 IS 8 BP 1226 EP 1233 DI 10.1086/656397 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 733GJ UT WOS:000288250900012 PM 20836703 ER PT J AU Mackelprang, RD Carrington, M John-Stewart, G Lohman-Payne, B Richardson, BA Wamalwa, D Gao, XJ Majiwa, M Mbori-Ngacha, D Farquhar, C AF Mackelprang, Romel D. Carrington, Mary John-Stewart, Grace Lohman-Payne, Barbara Richardson, Barbra A. Wamalwa, Dalton Gao, Xiaojiang Majiwa, Maxwel Mbori-Ngacha, Dorothy Farquhar, Carey TI Maternal Human Leukocyte Antigen A*2301 Is Associated with Increased Mother-to-Child HIV-1 Transmission SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TYPE-1 TRANSMISSION; KAPOSIS-SARCOMA; HLA; INFECTION AB We examined associations between maternal human leukocyte antigen (HLA) and vertical human immunodeficiency virus type 1 (HIV-1) transmission in a perinatal cohort of 277 HIV-infected women in Nairobi. HLA class I genes were amplified by using sequence-specific oligonucleotide probes, and analyses were performed using logistic regression. Maternal HLA-A*2301 was associated with increased transmission risk before and after adjusting for maternal viral load (unadjusted: odds ratio [OR], 3.21; 95% confidence interval [CI], 1.42-7.27; P = .005; P(corr) = 0.04; adjusted: OR, 3.07; 95% CI, 1.26-7.51; P = .01; P(corr) is not significant). That macorr ternal HLA-A*2301 was associated with transmission independent of plasma HIV-1 RNA levels suggests that HLA may alter infectivity through mechanisms other than influencing HIV-1 load. C1 [Mackelprang, Romel D.; John-Stewart, Grace; Farquhar, Carey] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [John-Stewart, Grace; Lohman-Payne, Barbara; Farquhar, Carey] Univ Washington, Dept Med, Seattle, WA 98104 USA. [John-Stewart, Grace; Farquhar, Carey] Univ Washington, Dept Global Hlth, Seattle, WA 98104 USA. [Carrington, Mary; Richardson, Barbra A.] Univ Washington, Dept Biostat, Seattle, WA 98104 USA. [Gao, Xiaojiang] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Lohman-Payne, Barbara; Wamalwa, Dalton; Majiwa, Maxwel; Mbori-Ngacha, Dorothy] Univ Nairobi, Dept Paediat, Nairobi, Kenya. RP Mackelprang, RD (reprint author), Univ Washington, Dept Epidemiol, 325 9th Ave,POB 359909, Seattle, WA 98104 USA. EM romelm@u.washington.edu FU US National Institute of Child Health and Development (NICHD) [HD23412]; National Institutes of Health (NIH) [K23 HD41879, K01 TW06080]; Fogarty International Center (NIH) [D43 TW000007]; NIH National Cancer Institute [N01-C0-12400]; National Cancer Institute Center for Cancer Research FX Research was funded by the US National Institute of Child Health and Development (NICHD) (grant HD23412) and by support from the National Institutes of Health (NIH) (grants K23 HD41879 to C. F. and K01 TW06080 to B.L.-P.). D.W. and M.M. were trainees in the International AIDS Research and Training Program, supported by the Fogarty International Center (NIH research grant D43 TW000007). This project has been funded in whole or in part with federal funds from the NIH National Cancer Institute (contract N01-C0-12400).; The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the National Cancer Institute Center for Cancer Research. NR 15 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2010 VL 202 IS 8 BP 1273 EP 1277 DI 10.1086/656318 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 733GJ UT WOS:000288250900017 PM 20812845 ER PT J AU D'Souza, MP Axten, KL Hecht, FM Altfeld, M AF D'Souza, M. Patricia Axten, Karen L. Hecht, Frederick M. Altfeld, Marcus TI Acute HIV-1 Infection: What's New? Where Are We Going? INTRODUCTION SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID IMMUNITY; VACCINE; STEP AB This supplemental issue of the Journal of Infectious Diseases is devoted to the important topic of primary human immunodeficiency virus type 1 (HIV-1) infection. It was prompted by the planning of the Acute HIV-1 Infection Meeting in Boston in September 2009, at which leading scientists and practitioners gathered to discuss new insights into the early, critical events of HIV-1 infection. The reviews that follow underline the current state of the field with regard to transmission biology of HIV-1; the clinical presentation, diagnosis, and management of primary HIV-1 infection; the pathogenesis of primary HIV-1 infection; and innate and adaptive immune responses to the virus. We trust that these findings have the potential to influence the development of effective vaccine strategies. C1 [D'Souza, M. Patricia] NIAID, Vaccine Clin Res Branch, Div Aids, NIH, Bethesda, MD 20892 USA. [Hecht, Frederick M.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA. [Axten, Karen L.; Altfeld, Marcus] Ragon Inst MGH MIT & Harvard, Boston, MA USA. RP Altfeld, M (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Bldg 149,13th St,6th Floor, Charlestown Navy Yard, MA 02129 USA. EM maltfeld@partners.org NR 13 TC 4 Z9 4 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2010 VL 202 SU 2 BP S267 EP S269 DI 10.1086/655650 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 651FJ UT WOS:000281911000001 PM 20846032 ER PT J AU Kong, L Sheppard, NC Stewart-Jones, GBE Robson, CL Chen, HY Xu, XD Krashias, G Bonomelli, C Scanlan, CN Kwong, PD Jeffs, SA Jones, IM Sattentau, QJ AF Kong, Leopold Sheppard, Neil C. Stewart-Jones, Guillaume B. E. Robson, Cynthia L. Chen, Hongying Xu, Xiaodong Krashias, George Bonomelli, Camille Scanlan, Christopher N. Kwong, Peter D. Jeffs, Simon A. Jones, Ian M. Sattentau, Quentin J. TI Expression-System-Dependent Modulation of HIV-1 Envelope Glycoprotein Antigenicity and Immunogenicity SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE computational modeling; HIV-1 gp120; mass spectrometry; B-cell immunogenicity; glycan type ID HUMAN-IMMUNODEFICIENCY-VIRUS; SITE-SPECIFIC ANALYSIS; INFECTED INSECT CELLS; HAMSTER OVARY CELLS; COMPLEX N-GLYCANS; MONOCLONAL-ANTIBODIES; HTLV-III; GLYCOSYLATION SITES; LINKED GLYCANS; NMR SYSTEM AB Recombinant expression systems differ in the type of glycosylation they impart on expressed antigens such as the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins, potentially affecting their biological properties. We performed head-to-head antigenic, immunogenic and molecular profiling of two distantly related Env surface (gp120) antigens produced in different systems: (a) mammalian (293 FreeStyle (TM) cells; 293F) cells in the presence of kifunensine, which impart only high-mannose glycans; (b) insect cells (Spodoptera frugiperda, Sf9), which confer mainly paucimannosidic glycans; (c) Sf9 cells recombinant for mammalian glycosylation enzymes (Sf9 Mimic (TM)), which impart high-mannose, hybrid and complex glycans without sialic acid; and (d) 293F cells, which impart high-mannose, hybrid and complex glycans with sialic acid. Molecular models revealed a significant difference in gp120 glycan coverage between the Sf9-derived and wild-type mammalian-cell-derived material that is predicted to affect ligand binding sites proximal to glycans. Modeling of solvent-exposed surface electrostatic potentials showed that sialic acid imparts a significant negative surface charge that may influence gp120 antigenicity and immunogenicity. Gp120 expressed in systems that do not incorporate sialic acid displayed increased ligand binding to the CD4 binding and CD4-induced sites compared to those expressed in the system that do, and imparted other more subtle differences in antigenicity in a gp120 subtype-specific manner. Non-sialic-acid-containing gp120 was significantly more immunogenic than the sialylated version when administered in two different adjuvants, and induced higher titers of antibodies competing for CD4 binding site ligand-gp120 interaction These findings suggest that non-sialic-acid-imparting systems yield gp120 immunogens with modified antigenic and immunogenic properties, considerations that should be considered when selecting expression systems for glycosylated antigens to be used for structure-function studies and for vaccine use. (C) 2010 Elsevier Ltd All rights reserved C1 [Kong, Leopold; Sheppard, Neil C.; Robson, Cynthia L.; Krashias, George; Sattentau, Quentin J.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Kong, Leopold; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Stewart-Jones, Guillaume B. E.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Chen, Hongying; Xu, Xiaodong; Jones, Ian M.] Univ Reading, Sch Biol Sci, Reading RG6 6UR, Berks, England. [Bonomelli, Camille; Scanlan, Christopher N.] Univ Oxford, Dept Biochem, Glycobiol Inst, Oxford OX1 3QU, England. [Jeffs, Simon A.] Univ London Imperial Coll Sci Technol & Med, Div Med, Wright Fleming Inst, London W2 1PG, England. RP Sattentau, QJ (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM quentin.sattentau@path.ox.ac.uk RI Stewart-Jones, Guillaume/E-7013-2013 FU UK Medical Research Council [G0000635]; IAVI NAC; Fondation Dormeur FX We thank). E. Robinson, D. R. Burton, D. Katinger, S. Zolla-Pazner, D. Corti and A Lanzavecchia for their generous gifts of mAbs, and the NIBSC CFAR, NIH AIDS Reagent Program and the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium (NAC) repository for reagent supply. We acknowledge the support of the UK Medical Research Council (grant G0000635), the IAVI NAC and Fondation Dormeur. Q.J.S. is a Jenner Institute fellow. The authors have no conflicting commercial interests relevant to the work published herein. NR 65 TC 34 Z9 34 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 15 PY 2010 VL 403 IS 1 BP 131 EP 147 DI 10.1016/j.jmb.2010.08.033 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673WK UT WOS:000283694700011 PM 20800070 ER PT J AU Salgaller, ML Marincola, FM AF Salgaller, Michael L. Marincola, Francesco M. TI Biotechnology entrepreneurship - where no research has gone before SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Salgaller, Michael L.] ThinkBiotech LLC, Washington, DC 20009 USA. [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Salgaller, ML (reprint author), ThinkBiotech LLC, Washington, DC 20009 USA. EM mlsalgaller@yahoo.com NR 5 TC 2 Z9 2 U1 0 U2 2 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 OCT 15 PY 2010 VL 8 AR 102 DI 10.1186/1479-5876-8-102 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 674HN UT WOS:000283728400001 PM 20950465 ER PT J AU Zheng, YL Li, BS Rudrabhatla, P Shukla, V Amin, ND Maric, D Kesavapany, S Kanungo, J Pareek, TK Takahashi, S Grant, P Kulkarni, AB Pant, HC AF Zheng, Ya-Li Li, Bing-Sheng Rudrabhatla, Parvathi Shukla, Varsha Amin, Niranjana D. Maric, Dragan Kesavapany, Sashi Kanungo, Jyotshnabala Pareek, Tej K. Takahashi, Satoru Grant, Philip Kulkarni, Ashok B. Pant, Harish C. TI Phosphorylation of p27(Kip1) at Thr187 by Cyclin-dependent Kinase 5 Modulates Neural Stem Cell Differentiation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; CDK5 INHIBITORY PEPTIDE; NEURONAL DIFFERENTIATION; PROGENITOR CELLS; NERVOUS-SYSTEM; ACTIVATOR; XENOPUS; P27; MIGRATION; P27(XIC1) AB Cyclin-dependent kinase 5 (Cdk5) plays a key role in the development of the mammalian nervous system; it phosphorylates a number of targeted proteins involved in neuronal migration during development to synaptic activity in the mature nervous system. Its role in the initial stages of neuronal commitment and differentiation of neural stem cells (NSCs), however, is poorly understood. In this study, we show that Cdk5 phosphorylation of p27(Kip1) at Thr187 is crucial to neural differentiation because 1) neurogenesis is specifically suppressed by transfection of p27Kip1 siRNA into Cdk5(+/+) NSCs; 2) reduced neuronal differentiation in Cdk5(+/+) compared with Cdk5(+/+) NSCs; 3) Cdk5(+/+) NSCs, whose differentiation is inhibited by a nonphosphorylatable mutant, p27/Thr187A, are rescued by cotransfection of a phosphorylation-mimicking mutant, p27/Thr187D; and 4) transfection of mutant p27(Kip1) (p27/187A) into Cdk5(+/+) NSCs inhibits differentiation. These data suggest that Cdk5 regulates the neural differentiation of NSCs by phosphorylation of p27(Kip1) at theThr187 site. Additional experiments exploring the role of Ser10 phosphorylation by Cdk5 suggest that together with Thr187 phosphorylation, Ser10 phosphorylation by Cdk5 promotes neurite outgrowth as neurons differentiate. Cdk5 phosphorylation of p27(Kip1), a modular molecule, may regulate the progress of neuronal differentiation from cell cycle arrest through differentiation, neurite outgrowth, and migration. C1 [Zheng, Ya-Li; Li, Bing-Sheng; Rudrabhatla, Parvathi; Shukla, Varsha; Amin, Niranjana D.; Kanungo, Jyotshnabala; Grant, Philip; Pant, Harish C.] NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Zheng, Ya-Li] Ningxia Peoples Hosp, Dept Nephrol, Yinchuan 750021, Ningxia, Peoples R China. [Maric, Dragan] NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. [Pareek, Tej K.; Takahashi, Satoru; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. [Kesavapany, Sashi] Natl Univ Singapore, Dept Biochem, Ctr Life Sci, Neurobiol Programme, Singapore 117597, Singapore. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov RI Shukla, Varsha/G-5136-2010; OI Pareek, Tej/0000-0001-5134-1647 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This work was supported by intramural funds from the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 52 TC 18 Z9 19 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT 15 PY 2010 VL 21 IS 20 BP 3601 EP 3614 PG 14 WC Cell Biology SC Cell Biology GA 663GD UT WOS:000282870300010 PM 20810788 ER PT J AU Kang, SY Wasaka, T Shamim, EA Auh, S Ueki, Y Lopez, GJ Kida, T Jin, SH Dang, N Hallett, M AF Kang, Suk Yun Wasaka, Toshiaki Shamim, Ejaz A. Auh, Sungyoung Ueki, Yoshino Lopez, Grisel J. Kida, Tetsuo Jin, Seung-Hyun Dang, Nguyet Hallett, Mark TI Characteristics of the Sequence Effect in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; sequence effect; fatigue; rTMS; levodopa; pegboard test ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; LEVODOPA-INDUCED DYSKINESIAS; TERM-FOLLOW-UP; BASAL GANGLIA; ARM MOVEMENTS; REACTION-TIME; L-DOPA; FATIGUE; HANDEDNESS AB The sequence effect (SE) in Parkinson's disease (PD) is progressive slowing of sequential movements. It is a feature of bradykinesia, but is separate from a general slowness without deterioration over time. It is commonly seen in PD, but its physiology is unclear. We measured general slowness and the SE separately with a computer-based, modified Purdue pegboard in 11 patients with advanced PD. We conducted a placebo-controlled, four-way crossover study to learn whether levodopa and repetitive transcranial magnetic stimulation (rTMS) could improve general slowness or the SE. We also examined the correlation between the SE and clinical fatigue. Levodopa alone and rTMS alone improved general slowness, but rTMS showed no additive effect on levodopa. Levodopa alone, rTMS alone, and their combination did not alleviate the SE. There was no correlation between the SE and fatigue. This study suggests that dopaminergic dysfunction and abnormal motor cortex excitability are not the relevant mechanisms for the SE. Additionally, the SE is not a component of clinical fatigue. Further work is needed to establish the physiology and clinical relevance of the SE. (C) 2010 Movement Disorder Society C1 [Kang, Suk Yun; Wasaka, Toshiaki; Shamim, Ejaz A.; Ueki, Yoshino; Lopez, Grisel J.; Kida, Tetsuo; Jin, Seung-Hyun; Dang, Nguyet; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Kang, Suk Yun] Hallym Univ, Coll Med, Kang Nam Sacred Heart Hosp, Dept Neurol, Seoul, South Korea. [Shamim, Ejaz A.] Kaiser Permanente Midatlantic Permanente Med Grp, Suitland, MD USA. [Auh, Sungyoung] Natl Inst Neurol Disorders & Stroke, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, 10 Ctr Dr MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU NINDS at the NIH and the American Parkinson Disease Association; Kinetics Foundation; Neurotoxin Institute; Ariston Pharmaceuticals; US Department of Defense (Army); NIH (from Brainsway); US Army via the Henry Jackson Foundation; Ariston Pharmaceutical Company via a Cooperative Research and Development Agreement (CRADA); Kinetics Foundation via a Clinical Trials Agreement (CTA) FX This work was supported by the intramural research program of the NINDS at the NIH and the American Parkinson Disease Association. We appreciate the Kinetics Foundation (Ken Kubota, BS) and Intel Inc. (William DeLeeuw, BSEE and David Wolff, BS) for providing the at-home testing device and technical support. We thank two anonymous reviewers for their valuable comments and suggestions, and Devera G. Schoenberg, MSc, and B. J. Hessie, BSc, ELS, for skillful editing.; Suk Yun Kang, Toshiaki Wasaka, Sungyoung Auh, Yoshino Ueki, Grisel J. Lopez, Tetsuo Kida, Seung-Hyun Jin, Nguyet Dang: None. Ejaz A. Shamim has medically related stocks, Amgen, Pfizer, and Medtronics; serves on the speakers bureau of Allergan; has received financial support from the Kinetics Foundation. Mark Hallett serves as Chair of the Medical Advisory Board for and receives funding for travel from the Neurotoxin Institute; serves as Chair of the Medical Advisory Board of the Benign Essential Blepharospasm Foundation and Chair of the Medical Advisory Board of the International Essential Tremor Foundation; has received honoraria and/or funding for travel for lectures or educational activities not funded by industry; serves on Editorial Advisory Boards for Clinical Neurophysiology, Brain, Acta Neurologica Scandinavica, Journal of Clinical Neurophysiology, Italian Journal of Neurological Sciences, Medical Problems of Performing Artists, Annals of Neurology, Neurology and Clinical Neurophysiology, The Cerebellum, NeuroRx, Current Trends in Neurology, Faculty of 1000 Biology, European Neurology, Faculty of 1000 Medicine, Brain Stimulation, Journal of Movement Disorders (Korea), and World Neurology; may accrue revenue on US Patent #6,780,413 B2 (issued: August 24, 2004): immunotoxin (MAB-Ricin) for the treatment of focal movement disorders; US Patent #7,407,478 (issued: August 5, 2008): coil for magnetic stimulation and methods for using the same; receives royalties from publishing from Blackwell Publisher, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, and Elsevier; receives research support from Ariston Pharmaceuticals, NIH/NINDS (Intramural Program) and the US Department of Defense (Army); has received license fee payments from the NIH (from Brainsway) for licensing the patent for the H-coil; and with his spouse held stock in Agilent Technologies, Amgen, Amylin Pharmaceuticals, Merck & Co., Monsanto Co New Del, Sanofi-aventis, Coventry Health Care Inc., Sigma Aldrich Corp., Warner Chilcott Ltd., Pfizer Inc., Genentech, Inc., United Health Group, St. Jude Medical, and Eli Lilly and Company. Dr. Hallett's research at the NIH is largely supported by the NIH Intramural Program. Supplemental research funds come from the US Army via the Henry Jackson Foundation, Ariston Pharmaceutical Company via a Cooperative Research and Development Agreement (CRADA) with the NIH, and the Kinetics Foundation via a Clinical Trials Agreement (CTA) with the NIH. NR 57 TC 18 Z9 19 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD OCT 15 PY 2010 VL 25 IS 13 BP 2148 EP 2155 DI 10.1002/mds.23251 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 665HV UT WOS:000283026900020 PM 20669182 ER PT J AU Djamshidian, A Jha, A O'Sullivan, SS Silveira-Moriyama, L Jacobson, C Brown, P Lees, A Averbeck, BB AF Djamshidian, Atbin Jha, Ashwani O'Sullivan, Sean S. Silveira-Moriyama, Laura Jacobson, Clare Brown, Peter Lees, Andrew Averbeck, Bruno B. TI Risk and Learning in Impulsive and Nonimpulsive Patients With Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; impulse control disorder; risk and learning; memory ID DOPAMINE REPLACEMENT THERAPY; DECISION-MAKING; WORKING-MEMORY; COGNITIVE FUNCTION; CONTROL DISORDERS; REWARD; PERSONALITY; PREVALENCE; MODULATION; BEHAVIORS AB Relatively little is known about the interaction between behavioral changes, medication, and cognitive function in Parkinson's disease (PD). We examined working memory, learning and risk aversion in PD patients with and without impulsive or compulsive behavior (ICB) and compared the results with those in a group of age-matched control subjects. Parkinson patients with PD+ICB had poorer working memory performance than either controls or PD patients without ICB. PD+ICB patients also showed decreased learning from negative feedback and increased learning from positive feedback in off compared with on dopaminergic medication. This interaction between medication status and learning was the opposite of that found in the PD patients without a diagnosis of ICB. Finally, the PD group showed increased risk preference on medication relative to controls, and the subgroup of PD+ICB patients with pathological gambling were overall more risk prone than the PD group. Thus, medication status and an impulsive behavioral diagnosis differentially affect several behaviors in PD. (C) 2010 Movement Disorder Society C1 [Djamshidian, Atbin; O'Sullivan, Sean S.; Silveira-Moriyama, Laura; Lees, Andrew] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Djamshidian, Atbin; O'Sullivan, Sean S.; Silveira-Moriyama, Laura; Lees, Andrew] UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, London, England. [Djamshidian, Atbin] Gen Hosp Hietzing Neurol Ctr Rosenhuegel, Dept Neurol 2, Vienna, Austria. [Jha, Ashwani; Brown, Peter; Averbeck, Bruno B.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London, England. [Jacobson, Clare] UCL, Inst Neurol, Dept Neuropsychol, London, England. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. EM averbeckbb@mail.nih.gov RI O'Sullivan, Sean/C-9333-2012; Lees, Andrew/A-6605-2009; Brown, Peter/J-4307-2016; Silveira-Moriyama, Laura/G-4592-2014; OI O'Sullivan, Sean/0000-0002-0583-7956; Brown, Peter/0000-0002-5201-3044; Djamshidian, Atbin/0000-0001-7174-6000; Silveira-Moriyama, Laura/0000-0002-8267-0977; Silveira Moriyama, Laura/0000-0003-2184-626X FU Department of Health's NIHR Biomedical Research Centres; Atbin Djamshidian-none; Ashwani Jha-UK Parkinson's Disease Society; Sean O'Sullivan-UK Parkinson's Disease Society; Laura Silveira-Moriyama-none; Clare Jacobson-none; Peter Brown-none; Andrew Lees-PSP Association Weston Trust, The Reta Lila Howard Foundation; National Institute of Mental Health; Intellectual Property Rights FX This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. We thank Karen Shaw for advice with the ethics amendment for this study. We also thank all patients and their partners who participated on this study.; Stock Ownership in medically-related fields: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none; Consultancies: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none; Advisory Boards: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira- Moriyama; Clare Jacobson-none, Peter Brown-Medtronic, Andrew Lees-Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan; Orion; Bruno Averbeck-none; Partnerships: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none; Honoraria: Atbin Djamshidian-none, Ashwani Jha-none, Sean O'Sullivan-Britannia Pharmaceuticals, Laura Silveira-Moriyama- Britannia Pharmaceuticals; Clare Jacobson-none, Peter Brown-Medtronic, Andrew Lees-Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan; Orion; Bruno Averbeck-none; Grants: Atbin Djamshidian-none, Ashwani Jha-UK Parkinson's Disease Society; Sean O'Sullivan-UK Parkinson's Disease Society; Laura Silveira-Moriyama-none; Clare Jacobson-none; Peter Brown-none; Andrew Lees-PSP Association Weston Trust, The Reta Lila Howard Foundation; Bruno Averbeck-Wellcome, Intramural research program of the National Institute of Mental Health; Intellectual Property Rights: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none; Expert Testimony: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none; Employment: Atbin Djamshidian-Reta Lila Weston Foundation, Ashwani Jha-UCL/UCLH, Sean O'Sullivan-Barts and the London NHS Trust, UK; Laura Silveira-Moriyama-Reta Lila Weston Foundation; Clare Jacobson-UCL/UCLH, Peter Brown-UCL/UCLH, Andrew Lees-UCL/UCLH, Bruno Averbeck-UCL/UCLH; Contracts: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none; Royalties: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none; Others: Atbin Djamshidian, Ashwani Jha, Sean O'Sullivan, Laura Silveira-Moriyama; Clare Jacobson, Peter Brown, Andrew Lees, Bruno Averbeck-none. NR 36 TC 41 Z9 42 U1 4 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD OCT 15 PY 2010 VL 25 IS 13 BP 2203 EP 2210 DI 10.1002/mds.23247 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 665HV UT WOS:000283026900028 PM 20721918 ER PT J AU Voon, V Butler, TR Ekanayake, V Gallea, C Ameli, R Murphy, DL Hallett, M AF Voon, Valerie Butler, Tracy R. Ekanayake, Vindhya Gallea, Cecile Ameli, Rezvan Murphy, Dennis L. Hallett, Mark TI Psychiatric Symptoms Associated with Focal Hand Dystonia SO MOVEMENT DISORDERS LA English DT Article DE obsessive compulsive disorder; depression; dystonia; striatum; obsession; compulsion ID OBSESSIVE-COMPULSIVE DISORDER; MYOCLONUS-DYSTONIA; ALCOHOL DEPENDENCE; MUTATION CARRIERS; PUTAMEN AB Myoclonus dystonia and idiopathic dystonia are associated with a greater frequency of obsessive compulsive disorder (OCD) and major depression. We investigated the frequency of OCD in 39 patients with primary focal hand dystonia (FHD) using a semistructured interview. OCD and subsyndromal OCD was diagnosed in 5 of 39 (12.82%) patients with FHD, whereas OCD occurs in 2.3% of the general population. Recurrent depression occurred in (7 of 39) 17.95% of patients with FHD along with a family history of depression in (16 of 39) 41.02%. Overlapping mechanisms manifesting as FHD may also predispose to OC symptoms and likely implicates a common striatal dysfunction. (C) 2010 Movement Disorder Society C1 [Voon, Valerie; Butler, Tracy R.; Ekanayake, Vindhya; Gallea, Cecile; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Voon, Valerie] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. [Ameli, Rezvan; Murphy, Dennis L.] NIMH, NIH, Bethesda, MD 20892 USA. RP Voon, V (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, 10 Ctr Dr,Bldg 10-Rm 7D37, Bethesda, MD USA. EM voonv@gmail.com OI Butler, Tracy/0000-0002-3849-7951 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health; National Institutes of Health FX The study was supported and conducted at the National Institute of Neurological Disorders and Stroke, National Institutes of Health. We thank Elaine Considine for her assistance in contacting patients.; Dr. Voon has received travel expenses from MOTAC in the last year. Dr. Hallett has received personal compensation or travel expenses for activities with Neurotoxin Institute, John Templeton Foundation, Parkinson's and Ageing Research Foundation, University of Pennsylvania, Thomas Jefferson University, Baylor College of Medicine, American Academy of Neurology, Medical University of South Carolina, Northshore-Long Island Jewish Hospital, American Clinical Neurophysiology Society, Columbia University, University of Alabama, Blackwell Publisher, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, Inc., and Elsevier as an advisory board member, an editor, a writer, or a speaker. Dr. Hallett has received license fee payments from the National Institutes of Health for the H-coil, a type of coil for magnetic stimulation. Dr. Hallett and his wife held or holds stock and/or stock options in Agilent Technologies, Amgen, Amylin Pharmaceuticals, Merck & Co., Monsanto Co New Del, Sanofi Aventis Adr., Coventry Health Care Inc., Sigma Aldrich Corp., Warner Chilcott Ltd., Pfizer Inc, Genentech, Inc., United Health Group, St. Jude Medical, and Eli Lilly & Company. Dr. Hallett's wife received personal compensation or travel expenses from Bolchazy-Carducci, US Naval Academy, Charles County Public Schools, College of Notre Dame, Oxford University Press, Classical Association of New England Summer Institute, Princeton University, Trinity University, and Johns Hopkins University for writing, editing, or speaking. NR 16 TC 15 Z9 15 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD OCT 15 PY 2010 VL 25 IS 13 BP 2249 EP 2252 DI 10.1002/mds.23250 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 665HV UT WOS:000283026900036 PM 20737548 ER PT J AU Misaki, M Kim, Y Bandettini, PA Kriegeskorte, N AF Misaki, Masaya Kim, Youn Bandettini, Peter A. Kriegeskorte, Nikolaus TI Comparison of multivariate classifiers and response normalizations for pattern-information fMRI SO NEUROIMAGE LA English DT Article DE Multi-voxel pattern analysis; decoding; classification analysis; fMRI; normalization; pattern-information analysis ID SUPPORT VECTOR MACHINES; HUMAN BRAIN ACTIVITY; TEMPORAL CORTEX; VISUAL-CORTEX; CLASSIFICATION; STATES; REPRESENTATIONS; RECOGNITION; ALGORITHMS; ACTIVATION AB A popular method for investigating whether stimulus information is present in fMRI response patterns is to attempt to "decode" the stimuli from the response patterns with a multivariate classifier. The sensitivity for detecting the information depends on the particular classifier used. However, little is known about the relative performance of different classifiers on fMRI data. Here we compared six multivariate classifiers and investigated how the response-amplitude estimate used (beta- or t-value) and different pattern normalizations affect classification performance. The compared classifiers were a pattern-correlation classifier, a k-nearest-neighbors classifier, Fisher's linear discriminant, Gaussian naive Bayes, and linear and nonlinear (radial-basis-function kernel) support vector machines. We compared these classifiers' accuracy at decoding the category of visual objects from response patterns in human early visual and inferior temporal cortex acquired in an event-related design with BOLD fMRI at 3 T using SENSE and isotropic voxels of about 2-mm width. Overall, Fisher's linear discriminant (with an optimal-shrinkage covariance estimator) and the linear support vector machine performed best. The pattern-correlation classifier often performed similarly as those two classifiers. The nonlinear classifiers never performed better and sometimes significantly worse than the linear classifiers, suggesting overfitting. Defining response patterns by t-values (or in error-standard-deviation units) rather than by beta estimates (in % signal change) to define the patterns appeared advantageous. Cross-validation by a leave-one-stimulus-pair-out method gave higher accuracies than a leave-one-run-out method, suggesting that generalization to independent runs (which more safely ensures independence of the test set) is more challenging than generalization to novel stimuli within the same category. Independent selection of fewer more visually responsive voxels tended to yield better decoding performance for all classifiers. Normalizing mean and standard deviation of the response patterns either across stimuli or across voxels had no significant effect on decoding performance. Overall our results suggest that linear decoders based on t-value patterns may perform best in the present scenario of visual object representations measured for about 60 min per subject with 3T fMRI. Published by Elsevier Inc. C1 [Misaki, Masaya; Kim, Youn; Bandettini, Peter A.; Kriegeskorte, Nikolaus] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Kim, Youn] Univ Calif San Diego, Dept Elect Engn, San Diego, CA 92103 USA. [Kriegeskorte, Nikolaus] MRC, Cognit & Brain Sci Unit, Cambridge CB2 7EF, England. RP Misaki, M (reprint author), NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr MSC 1148, Bethesda, MD 20892 USA. EM misakim@mail.nih.gov; nikolaus.kriegeskorte@mrc-cbu.cam.ac.uk OI Kriegeskorte, Nikolaus/0000-0001-7433-9005 FU NIMH FX This work was supported by the NIMH Intramural Research Program. This study utilized the high performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 44 TC 147 Z9 151 U1 6 U2 25 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2010 VL 53 IS 1 BP 103 EP 118 DI 10.1016/j.neuroimage.2010.05.051 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 637LJ UT WOS:000280818900012 PM 20580933 ER PT J AU Londin, ER Keller, MA Maista, C Smith, G Mamounas, LA Zhang, R Madore, SJ Gwinn, K Corriveau, RA AF Londin, Eric R. Keller, Margaret A. Maista, Cathleen Smith, Gretchen Mamounas, Laura A. Zhang, Ran Madore, Steven J. Gwinn, Katrina Corriveau, Roderick A. TI CoAIMs: A Cost-Effective Panel of Ancestry Informative Markers for Determining Continental Origins SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; MULTILOCUS GENOTYPE DATA; SELF-REPORTED RACE; POPULATION-STRUCTURE; ADMIXTURE PROPORTIONS; GENETIC ASSOCIATION; EUROPEAN AMERICANS; LATINO POPULATIONS; PARKINSON-DISEASE; HEPATITIS-C AB Background: Genetic ancestry is known to impact outcomes of genotype-phenotype studies that are designed to identify risk for common diseases in human populations. Failure to control for population stratification due to genetic ancestry can significantly confound results of disease association studies. Moreover, ancestry is a critical factor in assessing lifetime risk of disease, and can play an important role in optimizing treatment. As modern medicine moves towards using personal genetic information for clinical applications, it is important to determine genetic ancestry in an accurate, cost-effective and efficient manner. Self-identified race is a common method used to track and control for population stratification; however, social constructs of race are not necessarily informative for genetic applications. The use of ancestry informative markers (AIMs) is a more accurate method for determining genetic ancestry for the purposes of population stratification. Methodology/Principal Findings: Here we introduce a novel panel of 36 microsatellite (MSAT) AIMs that determines continental admixture proportions. This panel, which we have named Continental Ancestry Informative Markers or CoAIMs, consists of MSAT AIMs that were chosen based upon their measure of genetic variance (F(st)), allele frequencies and their suitability for efficient genotyping. Genotype analysis using CoAIMs along with a Bayesian clustering method (STRUCTURE) is able to discern continental origins including Europe/Middle East (Caucasians), East Asia, Africa, Native America, and Oceania. In addition to determining continental ancestry for individuals without significant admixture, we applied CoAIMs to ascertain admixture proportions of individuals of self declared race. Conclusion/Significance: CoAIMs can be used to efficiently and effectively determine continental admixture proportions in a sample set. The CoAIMs panel is a valuable resource for genetic researchers performing case-control genetic association studies, as it can control for the confounding effects of population stratification. The MSAT-based approach used here has potential for broad applicability as a cost effective tool toward determining admixture proportions. C1 [Londin, Eric R.; Keller, Margaret A.; Maista, Cathleen; Smith, Gretchen; Madore, Steven J.; Corriveau, Roderick A.] Coriell Inst Med Res, Camden, NJ USA. [Mamounas, Laura A.; Zhang, Ran; Gwinn, Katrina] NINDS, Bethesda, MD 20892 USA. RP Londin, ER (reprint author), Coriell Inst Med Res, Camden, NJ USA. EM elondin@coriell.org OI Gwinn, Katrina/0000-0002-8277-651X FU National Institute of Neurological Disorders and Stroke Repository [HH271200800033C] FX This study was funded as part of National Institute of Neurological Disorders and Stroke Repository contract HH271200800033C. The funder had no role in study design, data collection and analysis, decision to publish, or preperation of the manuscript. NR 59 TC 12 Z9 13 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 15 PY 2010 VL 5 IS 10 AR e13443 DI 10.1371/journal.pone.0013443 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 665NX UT WOS:000283043700028 PM 20976178 ER PT J AU Moaddel, R Venkata, SLV Tanga, MJ Bupp, JE Green, CE Iyer, L Furimsky, A Goldberg, ME Torjman, MC Wainer, IW AF Moaddel, Ruin Venkata, Swarajya Lakshmi Vattem Tanga, Mary J. Bupp, James E. Green, Carol E. Iyer, Lalitha Furimsky, Anna Goldberg, Michael E. Torjman, Marc C. Wainer, Irving W. TI A parallel chiral-achiral liquid chromatographic method for the determination of the stereoisomers of ketamine and ketamine metabolites in the plasma and urine of patients with complex regional pain syndrome SO TALANTA LA English DT Article DE Ketamine metabolites; Pain management; Chiral separation; Metabolism ID LIVER MICROSOMAL PREPARATIONS; STEREOSELECTIVE PHARMACOKINETICS; MASS-SPECTROMETRY; RACEMIC KETAMINE; SHETLAND PONIES; S-KETAMINE; NORKETAMINE; ENANTIOMERS; INFUSION; RAT AB A parallel chiral/achiral LC-MS/MS assay has been developed and validated to measure the plasma and urine concentrations of the enantiomers of ketamine,(R)- and (S)-Ket, in complex regional pain syndrome (CRPS) patients receiving a 5-day continuous infusion of a sub-anesthetic dose of (R,S)-Ket. The method was also validated for the determination of the enantiomers of the Ket metabolites norketamine, (R)and (S)-norKet and dehydronorketamine, (R)- and (S)-DHNK, as well as the diastereomeric metabolites hydroxynorketamine, (2S,6S)-/(2R,6R)-HNK and two hydroxyketamines, (2S,6S)-HKet and (2S,6R)-Hket. In this method, (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK and the diastereomeric hydroxyl-metabolites were separated and quantified using a C(18) stationary phase and the relative enantiomeric concentrations of (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK were determined using an AGP-CSP. The analysis of the results of microsomal incubations of (R)- and (S)-Ket and a plasma and urine sample from a CRPS patient indicated the presence of 10 additional compounds and glucuronides. The data from the analysis of the patient sample also demonstrated that a series of HNK metabolites were the primary metabolites in plasma and (R)- and (S)-DHNK were the major metabolites found in urine. The results suggest that norKet is the initial, but not the primary metabolite and that downstream norKet metabolites play a role in (R,S)-Ket-related pain relief in CRPS patients. Published by Elsevier B.V. C1 [Wainer, Irving W.] NIA, Clin Invest Lab, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Tanga, Mary J.; Bupp, James E.; Green, Carol E.; Iyer, Lalitha; Furimsky, Anna] SRI Int, Menlo Pk, CA 94025 USA. [Goldberg, Michael E.; Torjman, Marc C.] UMDNJ Robert Wood Johnson Med Sch, Cooper Univ Hosp, Camden, NJ USA. RP Wainer, IW (reprint author), NIA, Clin Invest Lab, Biomed Res Ctr, NIH, 8B133,251 Bayview Blvd, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov FU National Institute on Aging/NIH; National Institutes on Aging [N01AG-3-1008] FX This research was supported in part by the Intramural Research Program of the National Institute on Aging/NIH and by the National Institutes on Aging under contract number N01AG-3-1008. NR 24 TC 26 Z9 26 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0039-9140 J9 TALANTA JI Talanta PD OCT 15 PY 2010 VL 82 IS 5 BP 1892 EP 1904 DI 10.1016/j.talanta.2010.08.005 PG 13 WC Chemistry, Analytical SC Chemistry GA 676ID UT WOS:000283903300039 PM 20875593 ER PT J AU Hickstein, DD West, RR AF Hickstein, Dennis D. West, Robert R. TI A WHIM-sical zebrafish SO BLOOD LA English DT Editorial Material ID CELL-MIGRATION; DISEASE; CXCR4 C1 [Hickstein, Dennis D.; West, Robert R.] Natl Canc Inst, Bethesda, MD 20892 USA. RP Hickstein, DD (reprint author), Natl Canc Inst, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 14 PY 2010 VL 116 IS 15 BP 2621 EP 2622 PG 2 WC Hematology SC Hematology GA 664JR UT WOS:000282956700004 PM 20947686 ER PT J AU Kristinsson, SY Tang, M Pfeiffer, RM Bjorkholm, M Blimark, C Mellqvist, UH Wahlin, A Turesson, I Landgren, O AF Kristinsson, Sigurdur Y. Tang, Min Pfeiffer, Ruth M. Bjorkholm, Magnus Blimark, Cecilie Mellqvist, Ulf-Henrik Wahlin, Anders Turesson, Ingemar Landgren, Ola TI Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study SO BLOOD LA English DT Article ID BONE-MINERAL DENSITY; MULTIPLE-MYELOMA; OSTEOPOROTIC PATIENTS; VERTEBRAL FRACTURES; SIGNIFICANCE MGUS; RESORPTION; COLLAGEN; MARKERS; TELOPEPTIDE; PREVALENCE AB Patients with multiple myeloma (MM) have an increased risk of fractures. On the basis of small numbers, patients with monoclonal gammopathy of undetermined significance (MGUS) have been reported to have an increased fracture risk. Using population-based data from Sweden, we assessed the risks of fractures in 5326 MGUS patients diagnosed from 1958 to 2006, compared with 20 161 matched controls. MGUS patients had an increased risk of any fracture at 5 (hazard ratio [HR] = 1.74; 95% confidence interval [CI], 1.58-1.92) and 10 (HR = 1.61; 95% CI, 1.49-1.74) years. The risk was significantly higher for axial (skull, vertebral/pelvis, and sternum/costae) compared with distal (arm and leg) fractures (P < .001). On the basis of 10 years of follow-up, there was an increased risk of vertebral/pelvic (HR = 2.37; 95% CI, 2.02-2.78), sternal/costae (HR = 1.93; 95% CI, 1.5-2.48), arm (HR = 1.23; 95% CI, 1.06-1.43), leg (HR = 1.40; 95% CI, 1.26-1.56), and other/multiple fractures (HR = 4.25; 95% CI, 3.29-5.51). Risks for fractures did not differ by isotype or M protein concentration at diagnosis. MGUS patients with (versus without) fractures had no excess risk of MM or Waldenstrom macroglobulinemia. Our results suggest that bone alterations are present in early myelomagenesis. Our findings may have implications for the development of better prophylaxis for bone disease in MGUS, and they provide novel clues on pathogenesis of MM bone disease. (Blood. 2010;116(15):2651-2655) C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Inst, Stockholm, Sweden. [Tang, Min; Pfeiffer, Ruth M.; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Blimark, Cecilie; Mellqvist, Ulf-Henrik] Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Med, Gothenburg, Sweden. [Wahlin, Anders] Umea Univ Hosp, Sect Hematol, Ctr Canc, S-90185 Umea, Sweden. [Turesson, Ingemar] Skane Univ Hosp, Dept Hematol, Malmo, Sweden. [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Pfeiffer, Ruth /F-4748-2011; Tang, Min/A-9311-2012; Wahlin, Anders/F-6043-2013; Kristinsson, Sigurdur /M-2910-2015 OI Wahlin, Anders/0000-0001-6402-0463; Kristinsson, Sigurdur /0000-0002-4964-7476 FU NIH; National Cancer Institute; Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; Roche FX This work was supported by the Intramural Research Program of the NIH and the National Cancer Institute; by grants from the Swedish Cancer Society, Stockholm County Council, and the Karolinska Institutet Foundations; and by an unrestricted grant from Roche. NR 28 TC 29 Z9 29 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 OCT 14 PY 2010 VL 116 IS 15 BP 2651 EP 2655 DI 10.1182/blood-2010-04-282848 PG 5 WC Hematology SC Hematology GA 664JR UT WOS:000282956700011 PM 20610813 ER PT J AU Jun, HS Lee, YM Cheung, YY McDermott, DH Murphy, PM De Ravin, SS Mansfield, BC Chou, JY AF Jun, Hyun Sik Lee, Young Mok Cheung, Yuk Yin McDermott, David H. Murphy, Philip M. De Ravin, Suk See Mansfield, Brian C. Chou, Janice Y. TI Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-beta-deficient neutrophils in a congenital neutropenia syndrome SO BLOOD LA English DT Article ID PHOSPHOHISTIDINE-ENZYME INTERMEDIATE; STORAGE-DISEASE TYPE-1A; NADPH OXIDASE; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; HEXOSE-6-PHOSPHATE DEHYDROGENASE; GLUCOSE-6-PHOSPHATE TRANSPORTER; RESPIRATORY BURST; SKELETAL-MUSCLE; MICE LACKING; BONE-MARROW AB G6PC3 deficiency, characterized by neutropenia and neutrophil dysfunction, is caused by deficiencies in the endoplasmic reticulum (ER) enzyme glucose-6-phosphatase-beta(G6Pase-beta or G6PC3) that converts glucose-6-phosphate (G6P) into glucose, the primary energy source of neutrophils. Enhanced neutrophil ER stress and apoptosis underlie neutropenia in G6PC3 deficiency, but the exact functional role of G6Pase-beta in neutrophils remains unknown. We hypothesized that the ER recycles G6Pase-beta-generated glucose to the cytoplasm, thus regulating the amount of available cytoplasmic glucose/G6P in neutrophils. Accordingly, a G6Pase-beta deficiency would impair glycolysis and hexose monophosphate shunt activities leading to reductions in lactate production, adenosine-5'-triphosphate (ATP) production, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Using annexin V-depleted neutrophils, we show that glucose transporter-1 translocation is impaired in neutrophils from G6pc3(-/-) mice and G6PC3-deficient patients along with impaired glucose uptake in G6pc3(-/-) neutrophils. Moreover, levels of G6P, lactate, and ATP are markedly lower in murine and human G6PC3-deficient neutrophils, compared with their respective controls. In parallel, the expression of NADPH oxidase subunits and membrane translocation of p47(phox) are down-regulated in murine and human G6PC3-deficient neutrophils. The results establish that in nonapoptotic neutrophils, G6Pase-beta is essential for normal energy homeostasis. A G6Pase-beta deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil dysfunction. (Blood.2010;116(15):2783-2792) C1 [Jun, Hyun Sik; Lee, Young Mok; Cheung, Yuk Yin; Mansfield, Brian C.; Chou, Janice Y.] NICHHD, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [McDermott, David H.; Murphy, Philip M.] NIAID, Lab Mol Immunol, Bethesda, MD 20892 USA. [De Ravin, Suk See] NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHHD, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bldg 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov RI Jun, Hyun Sik/C-6799-2013; OI McDermott, David/0000-0001-6978-0867; Mansfield, Brian/0000-0002-8533-2789 FU National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Institute of Child Health and Human Development and the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 56 TC 29 Z9 30 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 14 PY 2010 VL 116 IS 15 BP 2783 EP 2792 DI 10.1182/blood-2009-12-258491 PG 10 WC Hematology SC Hematology GA 664JR UT WOS:000282956700027 PM 20498302 ER PT J AU McDermott, DH De Ravin, SS Jun, HS Liu, QA Priel, DAL Noel, P Takemoto, CM Ojode, T Paul, SM Dunsmore, KP Hilligoss, D Marquesen, M Ulrick, J Kuhns, DB Chou, JY Malech, HL Murphy, PM AF McDermott, David H. De Ravin, Suk See Jun, Hyun Sik Liu, Qian Priel, Debra A. Long Noel, Pierre Takemoto, Clifford M. Ojode, Teresa Paul, Scott M. Dunsmore, Kimberly P. Hilligoss, Dianne Marquesen, Martha Ulrick, Jean Kuhns, Douglas B. Chou, Janice Y. Malech, Harry L. Murphy, Philip M. TI Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis SO BLOOD LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; G-CSF; BONE-MARROW; MUTATIONS; PROTEIN; GENE; MOBILIZATION; CELLS; ELA2; ELASTASE AB Mutations in more than 15 genes are now known to cause severe congenital neutropenia (SCN); however, the pathologic mechanisms of most genetic defects are not fully defined. Deficiency of G6PC3, a glucose-6-phosphatase, causes a rare multisystem syndrome with SCN first described in 2009. We identified a family with 2 children with homozygous G6PC3 G260R mutations, a loss of enzymatic function, and typical syndrome features with the exception that their bone marrow biopsy pathology revealed abundant neutrophils consistent with myelokathexis. This pathologic finding is a hallmark of another type of SCN, WHIM syndrome, which is caused by gain-of-function mutations in CXCR4, a chemokine receptor and known neutrophil bone marrow retention factor. We found markedly increased CXCR4 expression on neutrophils from both our G6PC3-deficient patients and G6pc3(-/-) mice. In both patients, granulocyte colony-stimulating factor treatment normalized CXCR4 expression and neutrophil counts. In G6pc3(-/-) mice, the specific CXCR4 antagonist AMD3100 rapidly reversed neutropenia. Thus, myelokathexis associated with abnormally high neutrophil CXCR4 expression may contribute to neutropenia in G6PC3 deficiency and responds well to granulocyte colony-stimulating factor. (Blood.2010;116(15):2793-2802) C1 [McDermott, David H.; Liu, Qian; Ojode, Teresa; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [De Ravin, Suk See; Hilligoss, Dianne; Marquesen, Martha; Ulrick, Jean; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Jun, Hyun Sik; Chou, Janice Y.] NICHHD, Sect Cellular Differentiat, NIH, Bethesda, MD 20892 USA. [Priel, Debra A. Long; Kuhns, Douglas B.] NCI, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Noel, Pierre] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Takemoto, Clifford M.] Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Baltimore, MD USA. [Paul, Scott M.] NIH, Dept Phys Med & Rehabil, Ctr Clin, Bethesda, MD 20892 USA. [Dunsmore, Kimberly P.] Univ Virginia, Hlth Sci Ctr, Div Hematol Oncol, Dept Pediat, Charlottesville, VA USA. RP McDermott, DH (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Rm 11N107, Bethesda, MD 20892 USA. EM dmcdermott@niaid.nih.gov RI Jun, Hyun Sik/C-6799-2013; OI Malech, Harry/0000-0001-5874-5775; McDermott, David/0000-0001-6978-0867; Paul, Scott/0000-0003-1274-6670 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 36 TC 35 Z9 36 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 14 PY 2010 VL 116 IS 15 BP 2793 EP 2802 DI 10.1182/blood-2010-01-265942 PG 10 WC Hematology SC Hematology GA 664JR UT WOS:000282956700028 PM 20616219 ER PT J AU Devlin, EE DaCosta, L Mohandas, N Elliott, G Bodine, DM AF Devlin, Emily E. DaCosta, Lydie Mohandas, Narla Elliott, Gene Bodine, David M. TI A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia SO BLOOD LA English DT Article ID RIBOSOMAL-PROTEIN S19; ERYTHROID-DIFFERENTIATION; MESSENGER-RNA; CLEFT-PALATE; DEFICIENCY; EXPRESSION; CELLS; LEADS; ERYTHROPOIESIS; IDENTIFICATION AB Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation. (Blood.2010;116(15):2826-2835) C1 [Devlin, Emily E.; Bodine, David M.] NHGRI, Genet & Mol Biol Branch, Hematopoiesis Sect, Bethesda, MD 20892 USA. [DaCosta, Lydie] INSERM, U1009, Villejuif, France. [DaCosta, Lydie] R Debre Hosp, Hematol Lab, Paris, France. [DaCosta, Lydie] Paris VII Denis Diderot Univ, Paris, France. [Mohandas, Narla] New York Blood Ctr, New York, NY 10021 USA. [Elliott, Gene] NHGRI, Embryon Stem Cell & Transgen Mouse Core Facil, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), NHGRI, Genet & Mol Biol Branch, Hematopoiesis Sect, 49 Convent Dr,Rm 4A04,MSC 4442, Bethesda, MD 20892 USA. EM tedyaz@mail.nih.gov FU NHGRI; National Institutes of Health [HL79565]; Fondation Medicale pour la Recherche, Agence Nationale de la Recherche; Daniella Arturi Foundation; Diamond Blackfan Anemia Foundation; American Society of Hematology FX This work was supported by the NHGRI intramural funds (D.M.B.), National Institutes of Health (grant HL79565; N.M.), Fondation Medicale pour la Recherche, Agence Nationale de la Recherche ("maladies rares" RIBODBA; L.D.C.), the Daniella Arturi Foundation (L.D.C.), and the Diamond Blackfan Anemia Foundation (E.E.D.).; E.E.D. is the recipient of 2008 American Society of Hematology Merit Award. NR 50 TC 44 Z9 44 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 OCT 14 PY 2010 VL 116 IS 15 BP 2826 EP 2835 DI 10.1182/blood-2010-03-275776 PG 10 WC Hematology SC Hematology GA 664JR UT WOS:000282956700032 PM 20606162 ER PT J AU Fasano, RM Monaco, A Meier, ER Pary, P Lee-Stroka, AH Otridge, J Klein, HG Marincola, FM Kamani, NR Luban, NLC Stroncek, D Flegel, WA AF Fasano, Ross M. Monaco, Alessandro Meier, Emily Riehm Pary, Philippe Lee-Stroka, A. Hallie Otridge, John Klein, Harvey G. Marincola, Francesco M. Kamani, Naynesh R. Luban, Naomi L. C. Stroncek, David Flegel, Willy A. TI RH genotyping in a sickle cell disease patient contributing to hematopoietic stem cell transplantation donor selection and management SO BLOOD LA English DT Article AB African individuals harbor molecular RH variants, which permit alloantibody formation to high-prevalence Rh antigens after transfusions. Genotyping identifies such RH variants, which are often missed by serologic blood group typing. Comprehensive molecular blood group analysis using 3 genotyping platforms, nucleotide sequencing, and serologic evaluation was performed on a 7-year-old African male with sickle cell disease who developed an "e-like" antibody shortly after initiating monthly red blood cell (RBC) transfusions for silent stroke. Genotyping of the RH variant predicted a severe shortage of compatible RBCs for long-term transfusion support, which contributed to the decision for hematopoetic stem cell transplantation. RH genotyping confirmed the RH variant in the human leukocyte antigen-matched sibling donor. The patient's (C)ce(s) type 1 haplotype occurs in up to 11% of African American sickle cell disease patients; however, haplotypematched RBCs were serologically incompatible. This case documents that blood unit selection should be based on genotype rather than one matching haplotype. (Blood. 2010;116(15):2836-2838) C1 Childrens Natl Med Ctr, Washington, DC USA. Natl Inst Hlth, Clin Cntr, Dept Transfus Med, Lab Serv Sect, Bethesda, MD 20892 USA. Progenika, Cambridge, MA USA. RP Flegel, WA (reprint author), Childrens Natl Med Ctr, Washington, DC USA. EM flegelwa@cc.nih.gov RI Monaco, Alessandro/O-5338-2015 OI Monaco, Alessandro/0000-0002-9941-7003 NR 0 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 14 PY 2010 VL 116 IS 15 BP 2836 EP 2838 PG 3 WC Hematology SC Hematology GA 664JR UT WOS:000282956700039 PM 20644109 ER PT J AU Agemy, L Sugahara, KN Kotamraju, VR Gujraty, K Girard, OM Kono, Y Mattrey, RF Park, JH Sailor, MJ Jimenez, AI Cativiela, C Zanuy, D Sayago, FJ Aleman, C Nussinov, R Ruoslahti, E AF Agemy, Lilach Sugahara, Kazuki N. Kotamraju, Venkata Ramana Gujraty, Kunal Girard, Olivier M. Kono, Yuko Mattrey, Robert F. Park, Ji-Ho Sailor, Michael J. Jimenez, Ana I. Cativiela, Carlos Zanuy, David Sayago, Francisco J. Aleman, Carlos Nussinov, Ruth Ruoslahti, Erkki TI Nanoparticle-induced vascular blockade in human prostate cancer SO BLOOD LA English DT Article ID TISSUE FACTOR; TUMOR VASCULATURE; HISTOLOGICAL GRADE; CELL CARCINOMA; ANGIOGENESIS; MICE; INFARCTION; DELIVERY; PEPTIDE; GROWTH AB The tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) specifically homes to tumors by binding to fibrin and fibrin-associated clotted plasma proteins in tumor vessels. Previous results show that CREKA-coated superparamagnetic iron oxide particles can cause additional clotting in tumor vessels, which creates more binding sites for the peptide. We have used this self-amplifying homing system to develop theranostic nanoparticles that simultaneously serve as an imaging agent and inhibit tumor growth by obstructing tumor circulation through blood clotting. The CREKA nanoparticles were combined with nanoparticles coated with another tumor-homing peptide, CRKDKC, and nanoparticles with an elongated shape (nanoworms) were used for improved binding efficacy. The efficacy of the CREKA peptide was then increased by replacing some residues with nonproteinogenic counterparts, which increased the stability of the peptide in the circulation. Treatment of mice bearing orthotopic human prostate cancer tumors with the targeted nanoworms caused extensive clotting in tumor vessels, whereas no clotting was observed in the vessels of normal tissues. Optical and magnetic resonance imaging confirmed tumor-specific targeting of the nanoworms, and ultrasound imaging showed reduced blood flow in tumor vessels. Treatment of mice with prostate cancer with multiple doses of the nanoworms induced tumor necrosis and a highly significant reduction in tumor growth. (Blood.2010;116(15):2847-2856) C1 [Agemy, Lilach; Sugahara, Kazuki N.; Kotamraju, Venkata Ramana; Gujraty, Kunal; Ruoslahti, Erkki] Univ Calif Santa Barbara, Ctr Nanomed, Vasc Mapping Lab, Sanford Burnham Med Res Inst, Santa Barbara, CA 92037 USA. [Park, Ji-Ho; Sailor, Michael J.] Univ Calif San Diego, Mat Sci & Engn Program, San Diego, CA 92103 USA. [Park, Ji-Ho; Sailor, Michael J.] Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92103 USA. [Girard, Olivier M.; Kono, Yuko; Mattrey, Robert F.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Jimenez, Ana I.; Cativiela, Carlos; Sayago, Francisco J.] Univ Zaragoza, Dept Organ Chem, Inst Ciencia Mat Aragon, Inst Carboquim CSIC, Zaragoza, Spain. [Zanuy, David; Aleman, Carlos] Univ Politecn Cataluna, ETSEIB, Dept Chem Engn, Barcelona, Spain. [Nussinov, Ruth] NCI, Basis Sci Program, Ctr Canc Res Nanobiol Program, SAIC Frederick, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, Tel Aviv, Israel. [Ruoslahti, Erkki] Sanford Burnham Med Res Inst, Canc Res Ctr, La Jolla, CA USA. RP Ruoslahti, E (reprint author), Univ Calif Santa Barbara, Ctr Nanomed, Vasc Mapping Lab, Sanford Burnham Med Res Inst, Santa Barbara, CA 92037 USA. EM ruoslahti@burnham.org RI Park, Ji Ho/C-1832-2011; Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 FU National Cancer Institute [P01-CA104898, P01-CA124427, P01-CA119335]; Cancer Center [CA 30199, P50-CA128346]; Spanish Ministerio de Ciencia e Innovacion [CTQ2008-00423-E/BQU, CTQ2007-62245]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by National Cancer Institute grants (P01-CA104898 [E. R.], P01-CA124427 [M.J.S., E. R.], and P01-CA119335 [R. F. M., M.J.S., E. R.]); Cancer Center support grant CA 30199, P50-CA128346 to the University of California at San Diego In Vivo Cancer Molecular Imaging Center; and grants CTQ2008-00423-E/BQU and CTQ2007-62245 (A.I.J., C.C., C.A.) from the Spanish Ministerio de Ciencia e Innovacion. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 34 TC 65 Z9 66 U1 1 U2 55 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 14 PY 2010 VL 116 IS 15 BP 2847 EP 2856 DI 10.1182/blood-2010-03-274258 PG 10 WC Hematology SC Hematology GA 664JR UT WOS:000282956700034 PM 20587786 ER PT J AU Yokoyama, H Lundqvist, A Su, S Childs, R AF Yokoyama, Hisayuki Lundqvist, Andreas Su, Su Childs, Richard TI Toxic effects of sorafenib when given early after allogeneic hematopoietic stem cell transplantation SO BLOOD LA English DT Letter C1 [Lundqvist, Andreas; Su, Su; Childs, Richard] NHLBI, NIH, Bethesda, MD 20892 USA. [Yokoyama, Hisayuki] Tohoku Univ, Sch Med, Sendai, Miyagi 980, Japan. RP Childs, R (reprint author), NHLBI, NIH, 10 Ctr Dr,Bldg 10,CRC Rm 35330, Bethesda, MD 20892 USA. EM childsr@nih.gov OI Lundqvist, Andreas/0000-0002-9709-2970 NR 1 TC 9 Z9 11 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 14 PY 2010 VL 116 IS 15 BP 2858 EP 2859 DI 10.1182/blood-2010-06-291104 PG 4 WC Hematology SC Hematology GA 664JR UT WOS:000282956700036 PM 20947691 ER PT J AU Takaku, T Malide, D Chen, JC Calado, RT Kajigaya, S Young, NS AF Takaku, Tomoiku Malide, Daniela Chen, Jichun Calado, Rodrigo T. Kajigaya, Sachiko Young, Neal S. TI Hematopoiesis in 3 dimensions: human and murine bone marrow architecture visualized by confocal microscopy SO BLOOD LA English DT Article ID STEM-CELL NICHE; PROGENITOR CELLS; MOUSE MODEL; INFUSION; MICROENVIRONMENT; LOCALIZATION; EXPRESSION; CRYSTALS; DYNAMICS; FAILURE AB In many animals, blood cell production occurs in the bone marrow. Hematopoiesis is complex, requiring self-renewing and pluripotent stem cells, differentiated progenitor and precursor cells, and supportive stroma, adipose tissue, vascular structures, and extracellular matrix. Although imaging is a vital tool in hematology research, the 3-dimensional architecture of the bone marrow tissue in situ remains largely uncharacterized. The major hindrance to imaging the intact marrow is the surrounding bone structures are almost impossible to cut/image through. We have overcome these obstacles and describe a method whereby whole-mounts of bone marrow tissue were immunostained and imaged in 3 dimensions by confocal fluorescence and reflection microscopy. We have successfully mapped by multicolor immunofluorescence the localization pattern of as many as 4 cell features simultaneously over large tiled views and to depths of approximately 150 mu m. Three-dimensional images can be assessed qualitatively and quantitatively to appreciate the distribution of cell types and their interrelationships, with minimal perturbations of the tissue. We demonstrate its application to normal mouse and human marrow, to murine models of marrow failure, and to patients with aplastic anemia, myeloid, and lymphoid cell malignancies. The technique should be generally adaptable for basic laboratory investigation and for clinical diagnosis of hematologic diseases. (Blood.2010;116(15):e41-e55) C1 [Takaku, Tomoiku; Chen, Jichun; Calado, Rodrigo T.; Kajigaya, Sachiko; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Malide, Daniela] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Takaku, T (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 CRC,Rm 3E-5216,9000 Rockville Pike, Bethesda, MD 20892 USA. EM takakut@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 FU NIH FX This work was supported by the NIH Intramural Research Program. NR 36 TC 55 Z9 56 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 14 PY 2010 VL 116 IS 15 BP E41 EP E55 DI 10.1182/blood-2010-02-268466 PG 15 WC Hematology SC Hematology GA 664JR UT WOS:000282956700001 PM 20647571 ER PT J AU Das, S Radtke, A Choi, YJ Mendes, AM Valenzuela, JG Dimopoulos, G AF Das, Suchismita Radtke, Andrea Choi, Young-Jun Mendes, Antonio M. Valenzuela, Jesus G. Dimopoulos, George TI Transcriptomic and functional analysis of the Anopheles gambiae salivary gland in relation to blood feeding SO BMC GENOMICS LA English DT Article ID ADULT FEMALE MOSQUITO; MALARIA VECTOR MOSQUITO; AEDES-AEGYPTI; LIFE-CYCLE; PLASMODIUM INVASION; BINDING-PROTEIN; IMMUNE-SYSTEM; FAMILY; GENES; SIALOME AB Background: The Anopheles gambiae salivary glands play a major role in malaria transmission and express a variety of bioactive components that facilitate blood-feeding by preventing platelet aggregation, blood clotting, vasodilatation, and inflammatory and other reactions at the probing site on the vertebrate host. Results: We have performed a global transcriptome analysis of the A. gambiae salivary gland response to blood-feeding, to identify candidate genes that are involved in hematophagy. A total of 4,978 genes were found to be transcribed in this tissue. A comparison of salivary gland transcriptomes prior to and after blood-feeding identified 52 and 41 transcripts that were significantly up-regulated and down-regulated, respectively. Ten genes were further selected to assess their role in the blood-feeding process using RNAi-mediated gene silencing methodology. Depletion of the salivary gland genes encoding D7L2, anophelin, peroxidase, the SG2 precursor, and a 5'nucleotidase gene significantly increased probing time of A. gambiae mosquitoes and thereby their capacity to blood-feed. Conclusions: The salivary gland transcriptome comprises approximately 38% of the total mosquito transcriptome and a small proportion of it is dynamically changing already at two hours in response to blood feeding. A better understanding of the salivary gland transcriptome and its function can contribute to the development of pathogen transmission control strategies and the identification of medically relevant bioactive compounds. C1 [Das, Suchismita; Radtke, Andrea; Mendes, Antonio M.; Dimopoulos, George] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Choi, Young-Jun] Univ Wisconsin Madison, Dept Pathobiol Sci, Madison, WI 53706 USA. [Mendes, Antonio M.] Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, Fac Nat Sci, London, England. [Valenzuela, Jesus G.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Dimopoulos, G (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM gdimopou@jhsph.edu RI Choi, Young-Jun/B-9848-2013; OI M. Mendes, Antonio/0000-0001-6562-5325; Dimopoulos, George/0000-0001-6755-8111 FU Ellison Medical Foundation; National Institutes of Health/National Institute for Allergy and Infectious Disease [1R01AI061576]; United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases; Johns Hopkins School of Public Health FX We thank the microarray core facility and the insectary personnel at the Johns Hopkins Malaria Research Institute. We also thank Dr. Fotis C. Kafatos and Dr. Jose M. Ribeiro for their discussions and fruitful suggestions and Dr. Deborah McClellan for editorial assistance. This work was supported by the Ellison Medical Foundation, the National Institutes of Health/National Institute for Allergy and Infectious Disease 1R01AI061576, the United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases, and the Johns Hopkins School of Public Health. NR 73 TC 38 Z9 40 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 14 PY 2010 VL 11 AR 566 DI 10.1186/1471-2164-11-566 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 671ZR UT WOS:000283553300001 PM 20946652 ER PT J AU Xu, R Hong, J Morse, CL Pike, VW AF Xu, Rong Hong, Jinsoo Morse, Cheryl L. Pike, Victor W. TI Synthesis, Structure-Affinity Relationships, and Radiolabeling of Selective High-Affinity 5-HT4 Receptor Ligands as Prospective Imaging Probes for Positron Emission Tomography SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VIVO; ARYL ETHERS; GUINEA-PIG; BRAIN; ANTAGONIST; PET; HYDROCHLORIDE; RADIOLIGANDS; DEALKYLATION; POSTMORTEM AB In a search for.high-affinity, receptor ligands that might serve for development as radioligands for the imaging of brain 5-HT4 receptors in vivo with positron emission tomography (PET), structural modifications were made to the high-affinity 5-HT4 antagonist (1-butylpiperidin-4-yl)methyl 8-amino-7-iodo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate (1. SB 207710). These modifications were made mainly on the aryl side of the ester bond to permit possible rapid labeling of the carboxylic acid component with a positron emitter, either carbon-III 4,2 = 20.4 min) or fluorine-18 (4,2= 109.7 min), and included (i) replacement of the iodine atom with a small substituent such as nitrile, methyl, or fluoro. (ii) methylation of the S-amino group, (iii) opening of the dioxan ring, and (iv) alteration of the length of the N-alkyl goup. I Ugh-affinity ligands were discovered for recombinant human 5-HT4 receptors with amenability to labeling with a positron emitter and potential for development as imaging probes. The ring-opened radioligand, (([methoxy-C-11]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [C-11]13), showed an especially favorable array of properties for future evaluation as a PET radioligand for brain 5-HT4 receptors. C1 [Xu, Rong; Hong, Jinsoo; Morse, Cheryl L.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU National Institutes of Health (NIH); National Institute of Mental Health (NIMH) [NO1MH32004] FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), specifically the National Institute of Mental Health (NIMH). We thank the NIH PET Department for radioisotope production and the NIMH Psychoactive Screening Program (PDSP) for performing assays. The PDSP is directed by Bryan L. Roth. PhD., with project officer Jamie Driscol (NIMH), at the University of North Carolina at Chapel Hill (Contract No. NO1MH32004). We thank our colleagues. Drs. Lisheng Cat and Joong-Hyun Chun for useful suggestions and technical assistance in some areas of this work. NR 54 TC 10 Z9 11 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 14 PY 2010 VL 53 IS 19 BP 7035 EP 7047 DI 10.1021/jm100668r PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 659CO UT WOS:000282544800020 PM 20812727 ER PT J AU Burbelo, PD Seam, N Groot, S Ching, KH Han, BL Meduri, GU Iadarola, MJ Suffredini, AF AF Burbelo, Peter D. Seam, Nitin Groot, Sandra Ching, Kathryn H. Han, Brian L. Meduri, G. Umberto Iadarola, Michael J. Suffredini, Anthony F. TI Rapid induction of autoantibodies during ARDS and septic shock SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; IFN-GAMMA; MEDICAL PROGRESS; SEPSIS; AUTOIMMUNITY; RESPONSES; IMMUNOPRECIPITATION; AUTOANTIGEN; INFECTIONS; ANTIBODIES AB Background: Little is known about the induction of humoral responses directed against human autoantigens during acute inflammation. We utilized a highly sensitive antibody profiling technology to study autoantibodies in patients with acute respiratory distress syndrome (ARDS) and severe sepsis, conditions characterized by intensive immune activation leading to multiple organ dysfunction. Methods: Using Luciferase Immunoprecipitation Systems (LIPS), a cohort of control, ARDS and sepsis patients were tested for antibodies to a panel of autoantigens. Autoantibody titers greater than the mean plus 3 SD of the 24 control samples were used to identify seropositive samples. Available longitudinal samples from different seropositive ARDS and sepsis patient samples, starting from within the first two days after admission to the intensive care, were then analyzed for changes in autoantibody over time. Results: From screening patient plasma, 57% of ARDS and 46% of septic patients without ARDS demonstrated at least one statistically significant elevated autoantibody compared to the controls. Frequent high titer antibodies were detected against a spectrum of autoantigens including potassium channel regulator, gastric ATPase, glutamic decarboxylase-65 and several cytokines. Analysis of serial samples revealed that several seropositive patients had low autoantibodies at early time points that often rose precipitously and peaked between days 7-14. Further, the use of therapeutic doses of corticosteroids did not diminish the rise in autoantibody titers. In some cases, the patient autoantibody titers remained elevated through the last serum sample collected. Conclusion: The rapid induction of autoantibodies in ARDS and severe sepsis suggests that ongoing systemic inflammation and associated tissue destruction mediate the break in tolerance against these self proteins. C1 [Burbelo, Peter D.; Groot, Sandra; Ching, Kathryn H.; Han, Brian L.; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. [Seam, Nitin; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Seam, Nitin] Vet Affairs Med Ctr, Dept Pulm & Crit Care Med, Washington, DC 20422 USA. [Meduri, G. Umberto] Vet Affairs Med Ctr, Div Pulm Crit Care & Sleep Med, Memphis, TN 38163 USA. RP Burbelo, PD (reprint author), Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU NIH; National Institute of Dental and Craniofacial Research; NIH Clinical Center; Biomarker subsection of the Center for Neuroscience and Regenerative Medicine FX The authors thank the patients who volunteered for these studies. This work was supported by in part by the Intramural Research Program of the NIH, the National Institute of Dental and Craniofacial Research, the NIH Clinical Center and in part a grant from the Biomarker subsection of the Center for Neuroscience and Regenerative Medicine. NR 35 TC 9 Z9 11 U1 0 U2 1 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 OCT 14 PY 2010 VL 8 AR 97 DI 10.1186/1479-5876-8-97 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 674HM UT WOS:000283728300001 PM 20946647 ER PT J AU Allen, HL Estrada, K Lettre, G Berndt, SI Weedon, MN Rivadeneira, F Willer, CJ Jackson, AU Vedantam, S Raychaudhuri, S Ferreira, T Wood, AR Weyant, RJ Segre, AV Speliotes, EK Wheeler, E Soranzo, N Park, JH Yang, J Gudbjartsson, D Heard-Costa, NL Randall, JC Qi, L Smith, AV Magi, R Pastinen, T Liang, L Heid, IM Luan, J Thorleifsson, G Winkler, TW Goddard, ME Lo, KS Palmer, C Workalemahu, T Aulchenko, YS Johansson, A Zillikens, MC Feitosa, MF Esko, T Johnson, T Ketkar, S Kraft, P Mangino, M Prokopenko, I Absher, D Albrecht, E Ernst, F Glazer, NL Hayward, C Hottenga, JJ Jacobs, KB Knowles, JW Kutalik, Z Monda, KL Polasek, O Preuss, M Rayner, NW Robertson, NR Steinthorsdottir, V Tyrer, JP Voight, BF Wiklund, F Xu, JF Zhao, JH Nyholt, DR Pellikka, N Perola, M Perry, JRB Surakka, I Tammesoo, ML Altmaier, EL Amin, N Aspelund, T Bhangale, T Boucher, G Chasman, DI Chen, C Coin, L Cooper, MN Dixon, AL Gibson, Q Grundberg, E Hao, K Junttila, MJ Kaplan, LM Kettunen, J Konig, IR Kwan, T Lawrence, RW Levinson, DF Lorentzon, M McKnight, B Morris, AP Muller, M Ngwa, JS Purcell, S Rafelt, S Salem, RM Salvi, E Sanna, S Shi, JX Sovio, U Thompson, JR Turchin, MC Vandenput, L Verlaan, DJ Vitart, V White, CC Ziegler, A Almgren, P Balmforth, AJ Campbell, H Citterio, L De Grandi, A Dominiczak, A Duan, J Elliott, P Elosua, R Eriksson, JG Freimer, NB Geus, EJC Glorioso, N Haiqing, S Hartikainen, AL Havulinna, AS Hicks, AA Hui, JN Igl, W Illig, T Jula, A Kajantie, E Kilpelaeinen, TO Koiranen, M Kolcic, I Koskinen, S Kovacs, P Laitinen, J Liu, JJ Lokki, ML Marusic, A Maschio, A Meitinger, T Mulas, A Pare, G Parker, AN Peden, JF Petersmann, A Pichler, I Pietilainen, KH Pouta, A Riddertrale, M Rotter, JI Sambrook, JG Sanders, AR Schmidt, CO Sinisalo, J Smit, JH Stringham, HM Walters, GB Widen, E Wild, SH Willemsen, G Zagato, L Zgaga, L Zitting, P Alavere, H Farrall, M McArdle, WL Nelis, M Peters, MJ Ripatti, S Meurs, JBJ Aben, KK Ardlie, KG Beckmann, JS Beilby, JP Bergman, RN Bergmann, S Collins, FS Cusi, D den Heijer, M Eiriksdottir, G Gejman, PV Hall, AS Hamsten, A Huikuri, HV Iribarren, C Kahonen, M Kaprio, J Kathiresan, S Kiemeney, L Kocher, T Launer, LJ Lehtimaki, T Melander, O Mosley, TH Musk, AW Nieminen, MS O'Donnell, CJ Ohlsson, C Oostra, B Palmer, LJ Raitakari, O Ridker, PM Rioux, JD Rissanen, A Rivolta, C Schunkert, H Shuldiner, AR Siscovick, DS Stumvoll, M Tonjes, A Tuomilehto, J van Ommen, GJ Viikari, J Heath, AC Martin, NG Montgomery, GW Province, MA Kayser, M Arnold, AM Atwood, LD Boerwinkle, E Chanock, SJ Deloukas, P Gieger, C Gronberg, H Hall, P Hattersley, AT Hengstenberg, C Hoffman, W Lathrop, GM Salomaa, V Schreiber, S Uda, M Waterworth, D Wright, AF Assimes, TL Barroso, I Hofman, A Mohlke, KL Boomsma, DI Caulfield, MJ Cupples, LA Erdmann, J Fox, CS Gudnason, V Gyllensten, U Harris, TB Hayes, RB Jarvelin, MR Mooser, V Munroe, PB Ouwehand, WH Penninx, BW Pramstaller, PP Quertermous, T Rudan, I Samani, NJ Spector, TD Volzke, H Watkins, H Wilson, JF Groop, LC Haritunians, T Hu, FB Kaplan, RC Metspalu, A North, KE Schlessinger, D Wareham, NJ Hunter, DJ O'Connell, JR Strachan, DP Schadt, HE Thorsteinsdottir, U Peltonen, L Uitterlinden, AG Visscher, PM Chatterjee, N Loos, RJF Boehnke, M McCarthy, MI Ingelsson, E Lindgren, CM Abecasis, GR Stefansson, K Frayling, TM Hirschhorn, JN AF Allen, Hana Lango Estrada, Karol Lettre, Guillaume Berndt, Sonja I. Weedon, Michael N. Rivadeneira, Fernando Willer, Cristen J. Jackson, Anne U. Vedantam, Sailaja Raychaudhuri, Soumya Ferreira, Teresa Wood, Andrew R. Weyant, Robert J. Segre, Ayellet V. Speliotes, Elizabeth K. Wheeler, Eleanor Soranzo, Nicole Park, Ju-Hyun Yang, Jian Gudbjartsson, Daniel Heard-Costa, Nancy L. Randall, Joshua C. Qi, Lu Smith, Albert Vernon Maegi, Reedik Pastinen, Tomi Liang, Liming Heid, Iris M. Luan, Jian'an Thorleifsson, Gudmar Winkler, Thomas W. Goddard, Michael E. Lo, Ken Sin Palmer, Cameron Workalemahu, Tsegaselassie Aulchenko, Yurii S. Johansson, Asa Zillikens, M. Carola Feitosa, Mary F. Esko, Tonu Johnson, Toby Ketkar, Shamika Kraft, Peter Mangino, Massimo Prokopenko, Inga Absher, Devin Albrecht, Eva Ernst, Florian Glazer, Nicole L. Hayward, Caroline Hottenga, Jouke-Jan Jacobs, Kevin B. Knowles, Joshua W. Kutalik, Zoltan Monda, Keri L. Polasek, Ozren Preuss, Michael Rayner, Nigel W. Robertson, Neil R. Steinthorsdottir, Valgerdur Tyrer, Jonathan P. Voight, Benjamin F. Wiklund, Fredrik Xu, Jianfeng Zhao, Jing Hua Nyholt, Dale R. Pellikka, Niina Perola, Markus Perry, John R. B. Surakka, Ida Tammesoo, Mari-Liis Altmaier, Elizabeth L. Amin, Najaf Aspelund, Thor Bhangale, Tushar Boucher, Gabrielle Chasman, Daniel I. Chen, Constance Coin, Lachlan Cooper, Matthew N. Dixon, Anna L. Gibson, Quince Grundberg, Elin Hao, Ke Junttila, M. Juhani Kaplan, Lee M. Kettunen, Johannes Koenig, Inke R. Kwan, Tony Lawrence, Robert W. Levinson, Douglas F. Lorentzon, Mattias McKnight, Barbara Morris, Andrew P. Mueller, Martina Ngwa, Julius Suh Purcell, Shaun Rafelt, Suzanne Salem, Rany M. Salvi, Erika Sanna, Serena Shi, Jianxin Sovio, Ulla Thompson, John R. Turchin, Michael C. Vandenput, Liesbeth Verlaan, Dominique J. Vitart, Veronique White, Charles C. Ziegler, Andreas Almgren, Peter Balmforth, Anthony J. Campbell, Harry Citterio, Lorena De Grandi, Alessandro Dominiczak, Anna Duan, Jubao Elliott, Paul Elosua, Roberto Eriksson, Johan G. Freimer, Nelson B. Geus, Eco J. C. Glorioso, Nicola Haiqing, Shen Hartikainen, Anna-Liisa Havulinna, Aki S. Hicks, Andrew A. Hui, Jennie Igl, Wilmar Illig, Thomas Jula, Antti Kajantie, Eero Kilpelaeinen, Tuomas O. Koiranen, Markku Kolcic, Ivana Koskinen, Seppo Kovacs, Peter Laitinen, Jaana Liu, Jianjun Lokki, Marja-Liisa Marusic, Ana Maschio, Andrea Meitinger, Thomas Mulas, Antonella Pare, Guillaume Parker, Alex N. Peden, John F. Petersmann, Astrid Pichler, Irene Pietilainen, Kirsi H. Pouta, Anneli Riddertrale, Martin Rotter, Jerome I. Sambrook, Jennifer G. Sanders, Alan R. Schmidt, Carsten Oliver Sinisalo, Juha Smit, Jan H. Stringham, Heather M. Walters, G. Bragi Widen, Elisabeth Wild, Sarah H. Willemsen, Gonneke Zagato, Laura Zgaga, Lina Zitting, Paavo Alavere, Helene Farrall, Martin McArdle, Wendy L. Nelis, Mari Peters, Marjolein J. Ripatti, Samuli vVan Meurs, Joyce B. J. Aben, Katja K. Ardlie, Kristin G. Beckmann, Jacques S. Beilby, John P. Bergman, Richard N. Bergmann, Sven Collins, Francis S. Cusi, Daniele den Heijer, Martin Eiriksdottir, Gudny Gejman, Pablo V. Hall, Alistair S. Hamsten, Anders Huikuri, Heikki V. Iribarren, Carlos Kahonen, Mika Kaprio, Jaakko Kathiresan, Sekar Kiemeney, Lambertus Kocher, Thomas Launer, Lenore J. Lehtimaki, Terho Melander, Olle Mosley, Tom H., Jr. Musk, Arthur W. Nieminen, Markku S. O'Donnell, Christopher J. Ohlsson, Claes Oostra, Ben Palmer, Lyle J. Raitakari, Olli Ridker, Paul M. Rioux, John D. Rissanen, Aila Rivolta, Carlo Schunkert, Heribert Shuldiner, Alan R. Siscovick, David S. Stumvoll, Michael Toenjes, Anke Tuomilehto, Jaakko van Ommen, Gert-Jan Viikari, Jorma Heath, Andrew C. Martin, Nicholas G. Montgomery, Grant W. Province, Michael A. Kayser, Manfred Arnold, Alice M. Atwood, Larry D. Boerwinkle, Eric Chanock, Stephen J. Deloukas, Panos Gieger, Christian Gronberg, Henrik Hall, Per Hattersley, Andrew T. Hengstenberg, Christian Hoffman, Wolfgang Lathrop, G. Mark Salomaa, Veikko Schreiber, Stefan Uda, Manuela Waterworth, Dawn Wright, Alan F. Assimes, Themistocles L. Barroso, Ines Hofman, Albert Mohlke, Karen L. Boomsma, Dorret I. Caulfield, Mark J. Cupples, L. Adrienne Erdmann, Jeanette Fox, Caroline S. Gudnason, Vilmundur Gyllensten, Ulf Harris, Tamara B. Hayes, Richard B. Jarvelin, Marjo-Ritta Mooser, Vincent Munroe, Patricia B. Ouwehand, Willem H. Penninx, Brenda W. Pramstaller, Peter P. Quertermous, Thomas Rudan, Igor Samani, Nilesh J. Spector, Timothy D. Voelzke, Henry Watkins, Hugh Wilson, James F. Groop, Leif C. Haritunians, Talin Hu, Frank B. Kaplan, Robert C. Metspalu, Andres North, Kari E. Schlessinger, David Wareham, Nicholas J. Hunter, David J. O'Connell, Jeffrey R. Strachan, David P. Schadt, H. -Erich Thorsteinsdottir, Unnur Peltonen, Leena Uitterlinden, Andre G. Visscher, Peter M. Chatterjee, Nilanjan Loos, Ruth J. F. Boehnke, Michael McCarthy, Mark I. Ingelsson, Erik Lindgren, Cecilia M. Abecasis, Goncalo R. Stefansson, Kari Frayling, Timothy M. Hirschhorn, Joel N. CA Procardis Consortium TI Hundreds of variants clustered in genomic loci and biological pathways affect human height SO NATURE LA English DT Article ID WIDE ASSOCIATION ANALYSIS; COMMON VARIANTS; HERITABILITY; POPULATION; ADULT; STRATIFICATION; DISEASES; TRAITS; GROWTH; SNPS AB Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways. C1 [Allen, Hana Lango; Weedon, Michael N.; Wood, Andrew R.; Perry, John R. B.; Hattersley, Andrew T.; Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Exeter EX1 2LU, Devon, England. [Estrada, Karol; Rivadeneira, Fernando; Aulchenko, Yurii S.; Amin, Najaf; vVan Meurs, Joyce B. 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[Hayes, Richard B.] NYU, Med Ctr, New York, NY 10016 USA. [Jarvelin, Marjo-Ritta] Univ Oulu, Bioctr Oulu, Oulu 90014, Finland. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, NL-2300 RC Leiden, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 GZ Groningen, Netherlands. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [North, Kari E.] Univ N Carolina, Sch Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC 27514 USA. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Strachan, David P.] St Georges Univ London, Div Community Hlth Sci, London SW17 0RE, England. [Schadt, H. -Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Eriksson, Johan G.] Pacific Biosci, Menlo Pk, CA 94025 USA. Sage Bionetworks, Seattle, WA 98109 USA. [Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Peltonen, Leena] Univ Helsinki, Dept Med Genet, Helsinki 00014, Finland. [McCarthy, Mark I.] Churchill Hosp, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LJ, England. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Allen, HL (reprint author), Univ Exeter, Peninsula Coll Med & Dent, Exeter EX1 2LU, Devon, England. RI Coin, Lachlan/A-9001-2014; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Ziegler, Andreas/G-4246-2012; Aben, Katja/G-9686-2016; Yang, Jian/A-5852-2010; Smith, Albert/K-5150-2015; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Deloukas, Panos/B-2922-2013; Nyholt, Dale/C-8384-2013; Marusic, Ana/E-7683-2013; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Kiemeney, Lambertus/D-3357-2009; Pramstaller, Peter/C-2357-2008; Cooper, Matthew/J-4420-2014; Johansson, Asa/G-5270-2011; Palmer, Lyle/K-3196-2014; Salvi, Erika/C-1033-2015; Rioux, John/A-9599-2015; Kaplan, Robert/A-2526-2011; Abecasis, Goncalo/B-7840-2010; Polasek, Ozren/B-6002-2011; Schreiber, Stefan/B-6748-2008; Beckmann, Jacques S /A-9772-2008; Voight, Benjamin/F-1775-2011; Aspelund, Thor/F-4826-2011; Segre, Ayellet/E-9800-2010; Aspelund, Thor/C-5983-2008; Spector, Tim/F-6533-2012; Ridderstrale, Martin/F-7678-2012; Kilpelainen, Tuomas/F-8569-2012; Rudan, Igor/I-1467-2012; Erdmann, Jeanette/P-7513-2014; OI Coin, Lachlan/0000-0002-4300-455X; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Pichler, Irene/0000-0001-8251-0757; Heard-Costa, Nancy/0000-0001-9730-0306; Cupples, L. Adrienne/0000-0003-0273-7965; Mulas, Antonella/0000-0002-6856-1483; Lango Allen, Hana/0000-0002-7803-8688; Magi, Reedik/0000-0002-2964-6011; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Ziegler, Andreas/0000-0002-8386-5397; Aben, Katja/0000-0002-0214-2147; Yang, Jian/0000-0003-2001-2474; Smith, Albert/0000-0003-1942-5845; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Deloukas, Panos/0000-0001-9251-070X; Marusic, Ana/0000-0001-6272-0917; Aulchenko, Yurii/0000-0002-7899-1575; Kiemeney, Lambertus/0000-0002-2368-1326; Cooper, Matthew/0000-0003-1139-3682; Johansson, Asa/0000-0002-2915-4498; Palmer, Lyle/0000-0002-1628-3055; Salvi, Erika/0000-0002-2724-2291; Rioux, John/0000-0001-7560-8326; Polasek, Ozren/0000-0002-5765-1862; Schreiber, Stefan/0000-0003-2254-7771; Beckmann, Jacques S /0000-0002-9741-1900; Aspelund, Thor/0000-0002-7998-5433; Rudan, Igor/0000-0001-6993-6884; Soranzo, Nicole/0000-0003-1095-3852; Zgaga, Lina/0000-0003-4089-9703; Esko, Tonu/0000-0003-1982-6569; Willer, Cristen/0000-0001-5645-4966; ELOSUA, ROBERTO/0000-0001-8235-0095; Goddard, Michael/0000-0001-9917-7946; sanna, serena/0000-0002-3768-1749; Gudbjartsson, Daniel/0000-0002-5222-9857; Johnson, Toby/0000-0002-5998-3270; Abecasis, Goncalo/0000-0003-1509-1825; Peters, Marjolein/0000-0003-3167-9063; Erdmann, Jeanette/0000-0002-4486-6231; Gieger, Christian/0000-0001-6986-9554; Hayes, Richard/0000-0002-0918-661X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Vandenput, Liesbeth/0000-0002-1712-6131; Watkins, Hugh/0000-0002-5287-9016; Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Ouwehand, Willem/0000-0002-7744-1790; Kaprio, Jaakko/0000-0002-3716-2455; Rivolta, Carlo/0000-0002-0733-9950; Bergmann, Sven/0000-0002-6785-9034; Sinisalo, Juha/0000-0002-0169-5137; de Geus, Eco/0000-0001-6022-2666; Martin, Nicholas/0000-0003-4069-8020 FU Academy of Finland [104781, 117797, 120315, 121584, 126925, 129269, 129494, 129680, 213506]; Affymetrix for genotyping services [N02-HL-6-4278]; Agency for Science, Technology and Research of Singapore; ALF/LUA Gothenburg; Althingi (the Icelandic Parliament); Amgen; AstraZeneca AB; Australian National Health and Medical Research Council [241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672]; Australian Research Council [DP0770096]; Biocentrum Helsinki; Boston Obesity Nutrition Research Center [DK46200]; British Diabetes Association; British Heart Foundation [PG/02/128]; British Heart Foundation Centre for Research Excellence, Oxford; CamStrad; Cancer Research UK; Centre for Neurogenomics and Cognitive Research; Chief Scientist Office of the Scottish Government [CZB/4/279]; Council of Health of the Academy of Finland; German Network of Diabetes; Diabetes UK; Donald W. Reynolds Foundation; Emil and Vera Cornell Foundation; Erasmus MC; Estonian Government [SF0180142s08]; European Commission [201413, ECOGENE:205419, BBMRI:212111, OPENGENE:245536, ENGAGE:HEALTH-F4-2007-201413, EURODIA:LSHG-CT-2004-518153, EU/WLRT-2001-01254, HEALTH-F2-2008-ENGAGE, HEALTH-F4-2007-201550, LSH-2006-037593, LSHG-CT-2006-018947, LSHG-CT-2006-01947, Procardis:LSHM-CT-2007-037273, POLYGENE:LSHC-CT-2005, QLG1-CT-2000-01643, QLG2-CT-2002-01254]; Eve Appeal; Finnish Ministry of Education; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Cardiovascular Research; Finnish Medical Society; Finska Lakaresallskapet; Folkhalsan Research Foundation; Fondation LeDucq; Foundation for Life and Health in Finland; Foundation for Strategic Research; GEN-AU; Genetic Association Information Network; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]; German Federal Ministry of Education and Research [01GS0831]; German Ministry for Health, Welfare and Sports; German Ministry of Cultural Affairs; German Ministry of Education, Culture and Science; German National Genome Research Net [01GS0823, 01ZZ0103, 01ZZ0403, 01ZZ9603, 03ZIK012]; German Research Council [KFO-152]; GlaxoSmithKline; Goteborg Medical Society; Gyllenberg Foundation; Helmholtz Center Munich; Juvenile Diabetes Research Foundation International [U01 DK062418]; Karolinska Institute; Knut and Alice Wallenberg Foundation; Lundberg Foundation; March of Dimes [6-FY-09-507]; MC Health; Medical Research Council UK [G0000649, G0000934, G0500539, G0600331, G0601261, G9521010D]; Microarray Core Facility of the Interdisciplinary Centre for Clinical Research [B27]; Mid-Atlantic Nutrition and Obesity Research Center of Maryland [P30 DK072488]; Ministry of Health and Department of Educational Assistance (South Tyrol, Italy); Ministry of Science, Education and Sport of the Republic of Croatia [216-1080315-0302]; Montreal Heart Institute Foundation; Narpes Health Care Foundation; National Cancer Institute; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute for Health Research Oxford Biomedical Research Centre; National Institute for Health Research Comprehensive Biomedical Research Centre; National Institutes of Health [263-MA-410953, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, CA047988, CA49449, CA50385, CA65725, CA67262, CA87969, DA12854, DK062370, DK063491, DK072193, DK079466, DK080145, DK58845, HG002651, HG005214, HG005581, HL043851, HL084729, HL69757, HL71981, K08-AR055688]; ADA; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging [050-060-810]; Netherlands Organisation for Scientific Research [175.010.2005.011, 911-03-012]; Netherlands Organization for the Health Research and Development [10-000-1002]; Netherlands Scientific Organization [904-61-090, 904-61-193, 480-04-004, 400-05-717, SPI 56-464-1419]; NIA; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Queensland Institute of Medical Research; Radboud University Nijmegen Medical Centre; Research Institute for Diseases in the Elderly [014-93-015]; Royal Swedish Academy of Science; Sahlgrenska Center for Cardiovascular and Metabolic Research [A305:188]; Siemens Healthcare, Erlangen, Germany; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; Social Ministry of the Federal State of Mecklenburg-West Pomerania; South Tyrolean Sparkasse Foundation; Stockholm County Council; Support for Science Funding programme; Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Medical Research Council; Swedish National Cancer Institute; Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation; Torsten and Ragnar Soderberg's Foundation; Vandervell Foundation; Vastra Gotaland Foundation; Wellcome Trust [072960, 075491, 079557, 079895, 083270, 068545/Z/02, 076113/B/04/Z, 076113/C/04/Z, 077016/Z/05/Z, 081682/Z/06/Z, 084183/Z/07/Z, 085301/Z/08/Z, 086596/Z/08/Z, 091746/Z/10/Z]; Wellcome Trust; Western Australian Genetic Epidemiology Resource; Western Australian DNA Bank; [560183]; [K2007-66X-20270-01-3]; [8691]; [33CSCO-122661] FX Several participating studies are members of the CHARGE and ENGAGE consortia. We acknowledge funding from the following organizations: the Academy of Finland (104781, 117797, 120315, 121584, 126925, 129269, 129494, 129680, 213506); Affymetrix for genotyping services (N02-HL-6-4278); Agency for Science, Technology and Research of Singapore; ALF/LUA Gothenburg; Althingi (the Icelandic Parliament); Amgen; AstraZeneca AB; Australian National Health and Medical Research Council (241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672); Australian Research Council (DP0770096); Biocentrum Helsinki; Boston Obesity Nutrition Research Center (DK46200); British Diabetes Association; British Heart Foundation (PG/02/128); British Heart Foundation Centre for Research Excellence, Oxford; CamStrad; Cancer Research UK; Centre for Neurogenomics and Cognitive Research; Chief Scientist Office of the Scottish Government (CZB/4/279); Council of Health of the Academy of Finland; DIAB Core project of the German Network of Diabetes; Diabetes UK; Donald W.; Reynolds Foundation; Emil and Vera Cornell Foundation; Erasmus MC; Estonian Government (SF0180142s08); European Commission (201413, ECOGENE:205419, BBMRI:212111, OPENGENE:245536, ENGAGE:HEALTH-F4-2007-201413, EURODIA:LSHG-CT-2004-518153, EU/WLRT-2001-01254, HEALTH-F2-2008-ENGAGE, HEALTH-F4-2007-201550, LSH-2006-037593, LSHG-CT-2006-018947, LSHG-CT-2006-01947, Procardis:LSHM-CT-2007-037273, POLYGENE:LSHC-CT-2005, QLG1-CT-2000-01643, QLG2-CT-2002-01254, DG XII, Marie Curie Intra-European Fellowship); Eve Appeal; Finnish Ministry of Education; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Cardiovascular Research; Finnish Medical Society; Finska Lakaresallskapet; Folkhalsan Research Foundation; Fondation LeDucq; Foundation for Life and Health in Finland; Foundation for Strategic Research; GEN-AU-Programme 'GOLD'; Genetic Association Information Network; German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H, 01 IG 07015 G); German Federal Ministry of Education and Research (01GS0831); German Ministry for Health, Welfare and Sports; German Ministry of Cultural Affairs; German Ministry of Education, Culture and Science; German National Genome Research Net (01GS0823, 01ZZ0103, 01ZZ0403, 01ZZ9603, 03ZIK012); German Research Council (KFO-152); GlaxoSmithKline; Goteborg Medical Society; Gyllenberg Foundation; Helmholtz Center Munich; Juvenile Diabetes Research Foundation International (U01 DK062418); Karolinska Institute; Knut and Alice Wallenberg Foundation; Lundberg Foundation; March of Dimes (6-FY-09-507); MC Health; Medical Research Council UK (G0000649, G0000934, G0500539, G0600331, G0601261, G9521010D, PrevMetSyn); Microarray Core Facility of the Interdisciplinary Centre for Clinical Research (B27); Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488); Ministry of Health and Department of Educational Assistance (South Tyrol, Italy); Ministry of Science, Education and Sport of the Republic of Croatia (216-1080315-0302); Montreal Heart Institute Foundation; Narpes Health Care Foundation; National Cancer Institute; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute for Health Research Oxford Biomedical Research Centre; National Institute for Health Research Comprehensive Biomedical Research Centre; National Institutes of Health (263-MA-410953, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, CA047988, CA49449, CA50385, CA65725, CA67262, CA87969, A12854, DK062370, DK063491, DK072193, DK079466, DK080145, DK58845, HG002651, HG005214, HG005581, HL043851, HL084729, HL69757, HL71981, K08-AR055688, K23-DK080145, K99-HL094535, M01-RR00425, MH084698, N01-AG12100, N01-AG12109, N01-HC15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55015, N01-HC55016, N01-HC55018N01-HC55022, N01-HC55222, N01-HC75150, N01-HC85079-N01-HC85086, N01-HG65403, R01-AG031890, R01 CA104021, R01-DK068336, R01-DK073490, R01-DK075681, R01-DK075787, R01-HL086694, R01-HL087641, R01-HL087647, R01-HL087652, R01-HL087676, R01-HL087679, R01-HL087700, R01-HL088119, R01-HL59367, R01-MH059160, R01-MH59565, R01-MH59566, R01-MH59571, R01-MH59586, R01-MH59587, R01-MH59588, R01-MH60870, R01-MH60879, R01-MH61675, R01-MH63706, R01-MH67257, R01-MH79469, R01-MH81800, RL1-MH083268, T32-HG00040, U01-CA098233, U01-GM074518, U01-HG004399, U01-HG004402, U01-HL080295, U01-HL084756, U01-HL72515, U01-MH79469, U01-MH79470, U54-RR020278, UL1-RR025005, Z01-AG00675, Z01-AG007380, Z01-HG000024; contract HHSN268200625226C; ADA Mentor-Based Postdoctoral Fellowship; Pew S; holarship for the Biomedical Sciences); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (investment number 175.010.2005.011, 911-03-012); Netherlands Organization for the Health Research and Development (10-000-1002); Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05-717, Center for Medical Systems Biology (NOW Genomics), SPI 56-464-1419); NIA Intramural Research Program; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Queensland Institute of Medical Research; Radboud University Nijmegen Medical Centre; Research Institute for Diseases in the Elderly (014-93-015); Royal Swedish Academy of Science; Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Siemens Healthcare, Erlangen, Germany; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; Social Ministry of the Federal State of Mecklenburg-West Pomerania; South Tyrolean Sparkasse Foundation; Stockholm County Council (560183); Support for Science Funding programme; Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Medical Research Council (K2007-66X-20270-01-3, 8691); Swedish National Cancer Institute; Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation (33CSCO-122661); Torsten and Ragnar Soderberg's Foundation; Vandervell Foundation; Vastra Gotaland Foundation; Wellcome Trust (072960, 075491, 079557, 079895, 083270, 068545/Z/02, 076113/B/04/Z, 076113/C/04/Z, 076113/C/04/Z, 077016/Z/05/Z, 081682/Z/06/Z, 084183/Z/07/Z, 085301/Z/08/Z, 086596/Z/ 08/Z, 091746/Z/10/Z; Wellcome Trust Research Career Development Fellowship); Western Australian Genetic Epidemiology Resource and the Western Australian DNA Bank (both National Health and Medical Research Council of Australia Enabling Facilities). A detailed list of acknowledgements by study is given in the Supplementary Information. NR 28 TC 530 Z9 539 U1 13 U2 150 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 14 PY 2010 VL 467 IS 7317 BP 832 EP 838 DI 10.1038/nature09410 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 663PB UT WOS:000282898700065 ER PT J AU Lockman, S Hughes, MD McIntyre, J Zheng, Y Chipato, T Conradie, F Sawe, F Asmelash, A Hosseinipour, MC Mohapi, L Stringer, E Mngqibisa, R Siika, A Atwine, D Hakim, J Shaffer, D Kanyama, C Wools-Kaloustian, K Salata, RA Hogg, E Alston-Smith, B Walawander, A Purcelle-Smith, E Eshleman, S Rooney, J Rahim, S Mellors, JW Schooley, RT Currier, JS AF Lockman, S. Hughes, M. D. McIntyre, J. Zheng, Y. Chipato, T. Conradie, F. Sawe, F. Asmelash, A. Hosseinipour, M. C. Mohapi, L. Stringer, E. Mngqibisa, R. Siika, A. Atwine, D. Hakim, J. Shaffer, D. Kanyama, C. Wools-Kaloustian, K. Salata, R. A. Hogg, E. Alston-Smith, B. Walawander, A. Purcelle-Smith, E. Eshleman, S. Rooney, J. Rahim, S. Mellors, J. W. Schooley, R. T. Currier, J. S. CA OCTANE A5208 Study Team TI Antiretroviral Therapies in Women after Single-Dose Nevirapine Exposure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NAIVE HIV-1-INFECTED PATIENTS; TO-CHILD TRANSMISSION; SUBTYPE-A; RESISTANCE MUTATIONS; DRUG-RESISTANCE; HIV-1 VARIANTS; INITIAL TREATMENT; PREVENTION; K103N; HIVNET-012 AB BACKGROUND Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus. METHODS In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir-emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death. RESULTS A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopin-avir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P = 0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died. CONCLUSIONS In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir-emtricitabine was superior to nevirapine plus tenofovir-emtricitabine for initial antiretroviral therapy. C1 [Lockman, S.] Harvard Univ, Sch Publ Hlth, IID, FXB 406, Boston, MA 02115 USA. [Lockman, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lockman, S.; Asmelash, A.] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [McIntyre, J.] Anova Hlth Inst, Johannesburg, South Africa. [Conradie, F.] Univ Witwatersrand, Johannesburg, South Africa. [Mohapi, L.] Chris Hani Baragwaneth Hosp, Johannesburg, South Africa. [Chipato, T.; Hakim, J.] Univ Zimbabwe, Harare, Zimbabwe. [Sawe, F.; Shaffer, D.] Kenya Govt Med Res Ctr, Walter Reed Project, Kericho, Kenya. [Sawe, F.; Shaffer, D.] US Mil HIV Res Program, Kericho, Kenya. [Hosseinipour, M. C.; Kanyama, C.] Univ N Carolina Project, Kamuzu Cent Hosp, Lilongwe, Malawi. [Stringer, E.] Univ Alabama, Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Mngqibisa, R.] Univ KwaZulu Natal, Durban, South Africa. [Siika, A.] Moi Univ, Fac Hlth Sci, Eldoret, Kenya. [Atwine, D.] Joint Clin Res Ctr, Kampala, Uganda. [Wools-Kaloustian, K.] Indiana Univ Sch Med, Indianapolis, IN USA. [Salata, R. A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Hogg, E.] Social & Sci Syst, Clin Trials Grp Operat Ctr, Silver Spring, MD USA. [Alston-Smith, B.; Purcelle-Smith, E.] NIH, Bethesda, MD 20892 USA. [Walawander, A.] Frontier Sci & Technol Res Fdn Inc, Chestnut Hill, MA USA. [Eshleman, S.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Rooney, J.] Gilead Sci Inc, Foster City, CA 94404 USA. [Rahim, S.] Abbott Labs, Abbott Pk, IL 60064 USA. [Mellors, J. W.] Univ Pittsburgh, Med Ctr, UPMC Presbyterian Hosp, Pittsburgh, PA USA. [Schooley, R. T.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Currier, J. S.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. RP Lockman, S (reprint author), Harvard Univ, Sch Publ Hlth, IID, FXB 406, 651 Huntington Ave, Boston, MA 02115 USA. EM slockman@hsph.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636, AI38838, SDMC AI68634]; National Center for Research; National Institutes of Health [K24 AI56933, 5401A1068636-04]; Boehringer Ingelheim; Medicines Development; Pfizer; Tibotec; Virionyx; Schering-Plough; Merck; Abbott Speakers Bureau; Abbott Virology; Gilead Sciences; Idenix Pharmaceuticals; Chimerix; RFS Pharmaceuticals,; Panacos Pharmaceuticals; Abbott Laboratories FX Supported in part by grants (U01AI068636, AI38838, and SDMC AI68634) from the National Institute of Allergy and Infectious Diseases to the AIDS Clinical Trials Group, by grants from the National Center for Research to the General Clinical Research Center Units, and by grants (K24 AI56933, to Dr. Currier, and 5401A1068636-04, to the Virology Support Laboratory for Adult AIDS Clinical Trials Group) from the National Institutes of Health. Study drugs were provided by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, and GlaxoSmithKline.; Dr. Hughes reports receiving fees as a member of the data and safety monitoring boards for Boehringer Ingelheim, Medicines Development, Pfizer, Tibotec, and Virionyx and the receipt by his department of financial support from Schering-Plough and Merck for an annual educational workshop; Dr. McIntyre, receiving financial support from the Abbott Speakers Bureau; Dr. Hosseinipour, receiving financial support from Abbott Virology for educational presentations; Dr. Mohapi, receiving reimbursement for travel expenses from Pfizer Laboratories; Dr. Wools-Kaloustian, receiving grant support from Gilead Sciences; Dr. Rooney, being a full-time employee of (and having stock options in) Gilead Sciences; Dr. Rahim, being a full-time employee of (and having stock options in) Abbott Laboratories at the time the study was conducted; Dr. Mellors, serving on the scientific advisory board for Gilead Sciences, receiving consulting fees from Merck, Idenix Pharmaceuticals, Chimerix, RFS Pharmaceuticals, Panacos Pharmaceuticals, and Abbott Laboratories, receiving grant support from Merck, having stock options in RFS Pharmaceuticals, and receiving reimbursement for travel expenses from Gilead Sciences, Merck, Chimerix, Idenix Pharmaceuticals, RFS Pharmaceuticals, and Panacos Pharmaceuticals; Dr. Schooley, receiving consulting fees from GlaxoSmithKline and Abbott Laboratories and reimbursement for travel expenses from Abbott Laboratories; and Dr. Currier, receiving consulting fees from GlaxoSmithKline and grant support from Merck and Tibotec. No other potential conflict of interest relevant to this article was reported. NR 38 TC 70 Z9 72 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 OCT 14 PY 2010 VL 363 IS 16 BP 1499 EP 1509 DI 10.1056/NEJMoa0906626 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 663KP UT WOS:000282887100004 PM 20942666 ER PT J AU Palumbo, P Lindsey, JC Hughes, MD Cotton, MF Bobat, R Meyers, T Bwakura-Dangarembizi, M Chi, BH Musoke, P Kamthunzi, P Schimana, W Purdue, L Eshleman, SH Abrams, EJ Millar, L Petzold, E Mofenson, LM Jean-Philippe, P Violari, A AF Palumbo, Paul Lindsey, Jane C. Hughes, Michael D. Cotton, Mark F. Bobat, Raziya Meyers, Tammy Bwakura-Dangarembizi, Mutsawashe Chi, Benjamin H. Musoke, Philippa Kamthunzi, Portia Schimana, Werner Purdue, Lynette Eshleman, Susan H. Abrams, Elaine J. Millar, Linda Petzold, Elizabeth Mofenson, Lynne M. Jean-Philippe, Patrick Violari, Avy TI Antiretroviral Treatment for Children with Peripartum Nevirapine Exposure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SINGLE-DOSE NEVIRAPINE; HIV-1 VERTICAL TRANSMISSION; K103N RESISTANCE MUTATION; INFECTED CHILDREN; RECEIVING NEVIRAPINE; UGANDAN WOMEN; THERAPY; PREVENTION; ZIDOVUDINE; GROWTH AB BACKGROUND Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. METHODS We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. RESULTS are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. Results A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P = 0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. CONCLUSIONS Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. C1 [Palumbo, Paul] Dartmouth Med Sch, Dept Med, Lebanon, NH 03765 USA. [Lindsey, Jane C.; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cotton, Mark F.] Univ Stellenbosch, Tygerberg Childrens Hosp, ZA-7505 Tygerberg, South Africa. [Bobat, Raziya] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Durban, South Africa. [Meyers, Tammy] Univ Witwatersrand, Chris Hani Baragwanath Hosp, Harriet Shezi Childrens Clin, Johannesburg, South Africa. [Violari, Avy] Perinatal HIV Res Unit, Johannesburg, South Africa. [Bwakura-Dangarembizi, Mutsawashe] Univ Zimbabwe, Coll Hlth Sci, Dept Paediat & Child Hlth, Harare, Zimbabwe. [Chi, Benjamin H.] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Musoke, Philippa] Johns Hopkins Univ, Res Collaborat, Makerere Univ, Kampala, Uganda. [Kamthunzi, Portia] Univ N Carolina Project, Lilongwe, Malawi. [Schimana, Werner] Duke Univ, KCMC Collaborat, Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Schimana, Werner] NIAID, Pharmaceut Affairs Branch, Div Aids, NIH, Bethesda, MD 20892 USA. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn, Div Aids, NIH, Bethesda, MD 20892 USA. [Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Abrams, Elaine J.] Columbia Univ, Mailman Sch Publ Hlth, Int Ctr AIDS Care & Treatment Programs, New York, NY USA. [Petzold, Elizabeth] Social & Sci Syst, Silver Spring, MD USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. [Millar, Linda] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. RP Palumbo, P (reprint author), Dartmouth Med Sch, Dept Med, Borwell C330W,1 Med Ctr Dr, Lebanon, NH 03765 USA. EM paul.e.palumbo@dartmouth.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632, 5 U01 AI41110, 1 U01 AI068616, HHSN272200800014C]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health; PACTG [5 U01 AI41110]; IMPAACT Group [1 U01 AI068616] FX Funded by the National Institutes of Health; Supported by grants to the Pediatric AIDS Clinical Trials Group (PACTG) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group from the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health. The Statistical and Data Analysis Center at the Harvard School of Public Health was supported by NIAID cooperative agreements with the PACTG (5 U01 AI41110) and the IMPAACT Group (1 U01 AI068616). Support of the sites was provided by the NIAID. Additional support was provided by the NIAID (contract no. HHSN272200800014C). NR 22 TC 122 Z9 125 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 14 PY 2010 VL 363 IS 16 BP 1510 EP 1520 DI 10.1056/NEJMoa1000931 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 663KP UT WOS:000282887100005 PM 20942667 ER PT J AU Rotimi, CN Jorde, LB AF Rotimi, Charles N. Jorde, Lynn B. TI GENOMIC MEDICINE Ancestry and Disease in the Age of Genomic Medicine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID CANCER RISK VARIANTS; STAGE RENAL-DISEASE; HEPATITIS-C VIRUS; GENETIC-VARIATION; AFRICAN-AMERICANS; PROSTATE-CANCER; ADMIXTURE PROPORTIONS; HUMAN-POPULATIONS; COPY-NUMBER; LINKAGE DISEQUILIBRIUM C1 [Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20851 USA. [Jorde, Lynn B.] Univ Utah, Hlth Sci Ctr, Dept Human Genet, Salt Lake City, UT 84132 USA. RP Rotimi, CN (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, 12 South Dr,MSC 5635, Bethesda, MD 20851 USA. EM rotimic@mail.nih.gov FU Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health; National Science Foundation; National Institutes of Health FX Supported by the Intramural Research Program of the Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health (Dr. Rotimi), and by grants from the National Science Foundation and the National Institutes of Health (to Dr. Jorde). NR 86 TC 75 Z9 78 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 14 PY 2010 VL 363 IS 16 BP 1551 EP 1558 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 663KP UT WOS:000282887100009 PM 20942671 ER PT J AU Swartz, CD King, LC Nesnow, S Umbach, DM Kumar, S Sikka, H DeMarini, DM AF Swartz, Carol D. King, Leon C. Nesnow, Stephen Umbach, David M. Kumar, Subodh Sikka, Harish DeMarini, David M. TI Mutagenicity, stable DNA adducts, and abasic sites induced in Salmonella by phenanthro[3,4-b]- and phenanthro[4,3-b] thiophenes, sulfur analogs of benzo[c]phenanthrene (vol 661, pg 47, 2009) SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Correction C1 [Swartz, Carol D.] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [King, Leon C.; Nesnow, Stephen; DeMarini, David M.] US EPA, Div Environm Carcinogenesis, Res Triangle Pk, NC 27711 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Kumar, Subodh; Sikka, Harish] SUNY Coll Buffalo, Environm Toxicol & Chem Lab, Great Lakes Ctr, Buffalo, NY 14222 USA. RP Swartz, CD (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD OCT 13 PY 2010 VL 692 IS 1-2 BP 66 EP 66 DI 10.1016/j.mrfmmm.2010.06.005 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 676FF UT WOS:000283894800012 ER PT J AU Gu, XL AF Gu, Xing-Long TI Deciphering the Corelease of Glutamate from Dopaminergic Terminals Derived from the Ventral Tegmental Area SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID NUCLEUS-ACCUMBENS; IN-VITRO; NEURONS; SYNAPSES C1 [Gu, Xing-Long] NIA, Unit Transgenesis, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Gu, XL (reprint author), 35 Convent Dr,Bldg 35,Room 1A1006, Bethesda, MD 20892 USA. EM xlgu2007@gmail.com RI gu, xinglong/A-3054-2011 OI gu, xinglong/0000-0002-0437-5606 FU Intramural NIH HHS [ZIA AG000959-06] NR 12 TC 1 Z9 1 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 13 PY 2010 VL 30 IS 41 BP 13549 EP 13551 DI 10.1523/JNEUROSCI.3802-10.2010 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 663HS UT WOS:000282874600001 PM 20943895 ER PT J AU Whittle, N Hauschild, M Lubec, G Holmes, A Singewald, N AF Whittle, Nigel Hauschild, Markus Lubec, Gert Holmes, Andrew Singewald, Nicolas TI Rescue of Impaired Fear Extinction and Normalization of Cortico-Amygdala Circuit Dysfunction in a Genetic Mouse Model by Dietary Zinc Restriction SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; C-FOS EXPRESSION; LONG-TERM POTENTIATION; CONDITIONED FEAR; FACILITATES EXTINCTION; INTERCALATED NEURONS; LEARNED FEAR; D-CYCLOSERINE; INFRALIMBIC CORTEX; GABA(A) RECEPTORS AB Fear extinction is impaired in neuropsychiatric disorders, including posttraumatic stress disorder. Identifying drugs that facilitate fear extinction in animal models provides leads for novel pharmacological treatments for these disorders. Zinc (Zn) is expressed in neurons in a cortico-amygdala circuit mediating fear extinction, and modulates neurotransmitter systems regulating extinction. We previously found that the 129S1/SvImJ mouse strain (S1) exhibited a profound impairment in fear extinction, coupled with abnormalities in the activation of the extinction circuit. Here, we tested the role of Zn in fear extinction in S1 and C57BL/6N reference strain (B6) by feeding the mice a Zn-restricted diet (ZnR) and testing for fear extinction, as well as neuronal activation of the extinction circuit via quantification of the immediate-early genes c-Fos and Zif268. Results showed that (preconditioning or postconditioning) ZnR completely rescued deficient extinction learning and long-term extinction retrieval in S1 and expedited extinction learning in B6, without affecting fear acquisition or fear expression. The extinction-facilitating effects of ZnR were associated with the normalization of Zif268 and/or c-Fos expression in cortico-amygdala regions of S1. Specifically, ZnR increased activity in infralimbic cortex, lateral and basolateral amygdala nuclei, and lateral central amygdala nucleus, and decreased activity in prelimbic and insular cortices and medial central amygdala nucleus. ZnR also increased activation in the main intercalated nucleus and decreased activation of the medial paracapsular intercalated mass in S1. Our findings reveal a novel role for Zn in fear extinction and further support the utility of the S1 model for identifying extinction facilitating drugs. C1 [Whittle, Nigel; Hauschild, Markus; Singewald, Nicolas] Univ Innsbruck, Dept Pharmacol & Toxicol, Inst Pharm, Ctr Mol Biosci Innsbruck, A-6020 Innsbruck, Austria. [Lubec, Gert] Med Univ Vienna, Dept Pediat, A-1090 Vienna, Austria. [Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. RP Singewald, N (reprint author), Univ Innsbruck, Dept Pharmacol & Toxicol, Inst Pharm, Ctr Mol Biosci Innsbruck, A-6020 Innsbruck, Austria. EM nicolas.singewald@uibk.ac.at OI , Markus/0000-0003-3539-7661; Lubec, Gert/0000-0002-6333-9461 FU Fonds zur Forderung der Wissenschaftlichen Forschung; National Institute on Alcohol Abuse and Alcoholism [Z01-AA000411] FX This work was supported by the Fonds zur Forderung der Wissenschaftlichen Forschung and National Institute on Alcohol Abuse and Alcoholism Intramural Research Program Grant Z01-AA000411. NR 76 TC 41 Z9 41 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 13 PY 2010 VL 30 IS 41 BP 13586 EP 13596 DI 10.1523/JNEUROSCI.0849-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 663HS UT WOS:000282874600006 PM 20943900 ER PT J AU Ablin, RJ Marincola, FM Natali, PG AF Ablin, Richard J. Marincola, Francesco M. Natali, Pier Giorgio TI The "Excellence in Translational Medicine" and "Bedside-to-Bench" Awards 2008-09 SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Ablin, Richard J.] Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85724 USA. [Ablin, Richard J.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. [Ablin, Richard J.] BIO5 Inst, Tucson, AZ 85724 USA. [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Natali, Pier Giorgio] Univ G DAnnunzio, CINBO Labs, Chieti, Italy. RP Ablin, RJ (reprint author), Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85724 USA. EM ablinrj@email.arizona.edu NR 4 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 13 PY 2010 VL 8 AR 95 DI 10.1186/1479-5876-8-95 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 670UO UT WOS:000283453000001 PM 20942919 ER PT J AU Galanis, J Nossal, R Losert, W Harries, D AF Galanis, Jennifer Nossal, Ralph Losert, Wolfgang Harries, Daniel TI Nematic Order in Small Systems: Measuring the Elastic and Wall-Anchoring Constants in Vibrofluidized Granular Rods SO PHYSICAL REVIEW LETTERS LA English DT Article ID LIQUID-CRYSTALS; HARD; TACTOIDS AB We investigate nematic order in vibrated granular rods confined to a small quasi-2D container less than 10 rod lengths in diameter. As rod density rho increases, patterning shifts from bipolar to uniform alignment. We find that a continuum liquid crystal free energy functional captures key patterning features down to almost the particle size. By fitting theory to experiments, we estimate the relative values of bend and splay elastic constants and wall anchoring. We find that splay is softer than bend for all rho and rod lengths tested, while the ratio of the average elastic constant to wall anchoring increases with rho. C1 [Galanis, Jennifer; Harries, Daniel] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Galanis, Jennifer; Harries, Daniel] Hebrew Univ Jerusalem, Fritz Haber Ctr, IL-91904 Jerusalem, Israel. [Nossal, Ralph] NICHHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Losert, Wolfgang] Univ Maryland, Dept Phys, IPST, College Pk, MD 20742 USA. [Losert, Wolfgang] Univ Maryland, IREAP, College Pk, MD 20742 USA. RP Galanis, J (reprint author), Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. RI Harries, Daniel/F-7016-2012 OI Harries, Daniel/0000-0002-3057-9485 FU ISF [1011/07, 1012/07]; NSF [NSF-DMR0907146]; Eunice Kennedy Shriver NICHD FX This research was supported by ISF Grants No. 1011/07 and No. 1012/07 (D. H.), NSF Grant No. NSF-DMR0907146 (W. L.), intramural funds from the Eunice Kennedy Shriver NICHD, and used the Biowulf computer cluster, NIH. NR 19 TC 14 Z9 15 U1 0 U2 8 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD OCT 13 PY 2010 VL 105 IS 16 AR 168001 DI 10.1103/PhysRevLett.105.168001 PG 4 WC Physics, Multidisciplinary SC Physics GA 663IE UT WOS:000282875800003 PM 21231016 ER PT J AU Wang, ZM Hildesheim, A Wang, SS Herrero, R Gonzalez, P Burdette, L Hutchinson, A Thomas, G Chanock, SJ Yu, K AF Wang, Zhaoming Hildesheim, Allan Wang, Sophia S. Herrero, Rolando Gonzalez, Paula Burdette, Laurie Hutchinson, Amy Thomas, Gilles Chanock, Stephen J. Yu, Kai TI Genetic Admixture and Population Substructure in Guanacaste Costa Rica SO PLOS ONE LA English DT Article ID MULTILOCUS GENOTYPE DATA; GENOME-WIDE ASSOCIATION; CENTRAL VALLEY; X-CHROMOSOME; PIGMENTATION; INFERENCE; PROGRAM; SLC24A5; MARKERS; CANCER AB The population of Costa Rica (CR) represents an admixture of major continental populations. An investigation of the CR population structure would provide an important foundation for mapping genetic variants underlying common diseases and traits. We conducted an analysis of 1,301 women from the Guanacaste region of CR using 27,904 single nucleotide polymorphisms (SNPs) genotyped on a custom Illumina InfiniumII iSelect chip. The program STRUCTURE was used to compare the CR Guanacaste sample with four continental reference samples, including HapMap Europeans (CEU), East Asians (JPT+CHB), West African Yoruba (YRI), as well as Native Americans (NA) from the Illumina iControl database. Our results show that the CR Guanacaste sample comprises a three-way admixture estimated to be 43% European, 38% Native American and 15% West African. An estimated 4% residual Asian ancestry may be within the error range. Results from principal components analysis reveal a correlation between genetic and geographic distance. The magnitude of linkage disequilibrium (LD) measured by the number of tagging SNPs required to cover the same region in the genome in the CR Guanacaste sample appeared to be weaker than that observed in CEU, JPT+CHB and NA reference samples but stronger than that of the HapMap YRI sample. Based on the clustering pattern observed in both STRUCTURE and principal components analysis, two subpopulations were identified that differ by approximately 20% in LD block size averaged over all LD blocks identified by Haploview. We also show in a simulated association study conducted within the two subpopulations, that the failure to account for population stratification (PS) could lead to a noticeable inflation in the false positive rate. However, we further demonstrate that existing PS adjustment approaches can reduce the inflation to an acceptable level for gene discovery. C1 [Wang, Zhaoming; Hildesheim, Allan; Wang, Sophia S.; Burdette, Laurie; Hutchinson, Amy; Chanock, Stephen J.; Yu, Kai] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Wang, Zhaoming; Burdette, Laurie; Hutchinson, Amy] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Etiol, Duarte, CA 91010 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Duarte, CA USA. [Herrero, Rolando; Gonzalez, Paula] Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Thomas, Gilles] Univ Lyon 1, Lyon, France. RP Wang, ZM (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM yuka@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 8 Z9 8 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 OCT 13 PY 2010 VL 5 IS 10 AR e13336 DI 10.1371/journal.pone.0013336 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 663FZ UT WOS:000282869800031 PM 20967209 ER PT J AU Xiao, XD Zhu, ZY Dankmeyer, JL Wormald, MM Fast, RL Worsham, PL Cote, CK Amemiya, K Dimitrov, DS AF Xiao, Xiaodong Zhu, Zhongyu Dankmeyer, Jennifer L. Wormald, Michael M. Fast, Randy L. Worsham, Patricia L. Cote, Christopher K. Amemiya, Kei Dimitrov, Dimiter S. TI Human Anti-Plague Monoclonal Antibodies Protect Mice from Yersinia pestis in a Bubonic Plague Model SO PLOS ONE LA English DT Article ID V-ANTIGEN; PNEUMONIC PLAGUE; PASTEURELLA-PESTIS; FUSION PROTEIN; VIRULENCE; VACCINE; F1; PHAGOCYTOSIS; PLASMID; LCRV AB Yersinia pestis is the etiologic agent of plague that has killed more than 200 million people throughout the recorded history of mankind. Antibiotics may provide little immediate relief to patients who have a high bacteremia or to patients infected with an antibiotic resistant strain of plague. Two virulent factors of Y. pestis are the capsid F1 protein and the low-calcium response (Lcr) V-protein or V-antigen that have been proven to be the targets for both active and passive immunization. There are mouse monoclonal antibodies (mAbs) against the F1- and V-antigens that can passively protect mice in a murine model of plague; however, there are no anti-Yersinia pestis monoclonal antibodies available for prophylactic or therapeutic treatment in humans. We identified one anti-F1-specific human mAb (m252) and two anti-V-specific human mAb (m253, m254) by panning a naive phage-displayed Fab library against the F1- and V-antigens. The Fabs were converted to IgG1s and their binding and protective activities were evaluated. M252 bound weakly to peptides located at the F1 N-terminus where a protective mouse anti-F1 mAb also binds. M253 bound strongly to a V-antigen peptide indicating a linear epitope; m254 did not bind to any peptide from a panel of 53 peptides suggesting that its epitope may be conformational. M252 showed better protection than m253 and m254 against a Y, pestis challenge in a plague mouse model. A synergistic effect was observed when the three antibodies were combined. Incomplete to complete protection was achieved when m252 was given at different times post-challenge. These antibodies can be further studied to determine their potential as therapeutics or prophylactics in Y. pestis infection in humans. C1 [Xiao, Xiaodong; Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21701 USA. [Zhu, Zhongyu] NCI, BSP, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Dankmeyer, Jennifer L.; Wormald, Michael M.; Fast, Randy L.; Worsham, Patricia L.; Cote, Christopher K.; Amemiya, Kei] USA, Med Res Inst Infect Dis, Bacteriol Div, Frederick, MD USA. RP Xiao, XD (reprint author), Medimmune LLC, Gaithersburg, MD USA. EM kei.amemiya@us.army.mil; dimiter.dimitrov@nih.gov FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [N01-CO-12400]; National Institute of Allergy and Infectious Diseases; Joint Science and Technology Office Defense Threat Reduction Agency (JUSTO/DTRA) [1.1A0018_07_RD_B]; SAIC-Frederick, Inc.; U.S. Government FX This project was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400, by the National Institute of Allergy and Infectious Diseases Biodefense Program to Dimiter S. Dimitrov and agency Joint Science and Technology Office Defense Threat Reduction Agency (JUSTO/DTRA) proposal no. 1.1A0018_07_RD_B to Kei Amemiya. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. SAIC-Frederick, Inc., as one of the funders of this study, had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; SAIC-Fredereick, Inc. is a wholly owned subsidiary of Science Applications International Corporation and operates exclusively under a single, long-term contract to the National Cancer Institute, part of the U.S. National Institutes of Health. All funding is derived from the U.S. Government. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 37 TC 10 Z9 12 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 13 PY 2010 VL 5 IS 10 AR e13047 DI 10.1371/journal.pone.0013047 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 663FZ UT WOS:000282869800002 PM 20976274 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI Prizes and Heroes: Lagging and leading indicators SO RETROVIROLOGY LA English DT Editorial Material ID RETROVIROLOGY-PRIZE AB What are the purposes of prizes and recognitions? Are they lagging indicators of past achievements or leading indicators of things to come? C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 6 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD OCT 13 PY 2010 VL 7 AR 87 DI 10.1186/1742-4690-7-87 PG 1 WC Virology SC Virology GA 670KD UT WOS:000283419400002 PM 20942941 ER PT J AU Huo, YW Hu, ZJ Zhang, K Wang, L Zhai, YJ Zhou, QJ Lander, G Zhu, JA He, YZ Pang, XY Xu, W Bartlam, M Dong, ZY Sun, F AF Huo, Yanwu Hu, Zhongjun Zhang, Kai Wang, Li Zhai, Yujia Zhou, Qiangjun Lander, Gabe Zhu, Jiang He, Yongzhi Pang, Xiaoyun Xu, Wei Bartlam, Mark Dong, Zhiyang Sun, Fei TI Crystal Structure of Group II Chaperonin in the Open State SO STRUCTURE LA English DT Article ID ELECTRON-MICROSCOPY; ARCHAEAL CHAPERONIN; UCSF CHIMERA; NMR SYSTEM; COMPLEX; MECHANISM; SOFTWARE; BINDING; CRYSTALLOGRAPHY; VISUALIZATION AB Thermosomes are group II chaperonins responsible for protein refolding in an ATP-dependent manner. Little is known regarding the conformational changes of thermosomes during their functional cycle due to a lack of high-resolution structure in the open state. Here, we report the first complete crystal structure of thermosome (rATcpn beta) in the open state from Acidianus tengchongensis. There is a 300 rotation of the apical and lid domains compared with the previous closed structure. Besides, the structure reveals a conspicuous hydrophobic patch in the lid domain, and residues locating in this patch are conserved across species. Both the closed and open forms of rATcpn beta were also reconstructed by electron microscopy (EM). Structural fitting revealed the detailed conformational change from the open to the closed state. Structural comparison as well as protease K digestion indicated only ATP binding without hydrolysis does not induce chamber closure of thermosome. C1 [Wang, Li; He, Yongzhi; Dong, Zhiyang] Chinese Acad Sci, Inst Microbiol, State Key Lab Microbial Resources, Beijing 100101, Peoples R China. [Huo, Yanwu; Hu, Zhongjun; Zhang, Kai; Zhai, Yujia; Zhou, Qiangjun; Pang, Xiaoyun; Xu, Wei; Sun, Fei] Chinese Acad Sci, Inst Biophys IBP, Natl Lab Biomacromol, Beijing 100101, Peoples R China. [Hu, Zhongjun] Logist Engn Univ, Dept Phys, Chongqing 401311, Peoples R China. [Lander, Gabe] Scripps Res Inst, La Jolla, CA 92037 USA. [Zhu, Jiang] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bartlam, Mark] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China. RP Dong, ZY (reprint author), Chinese Acad Sci, Inst Microbiol, State Key Lab Microbial Resources, Beijing 100101, Peoples R China. EM dongzy@sun.im.ac.cn; feisun@ibp.ac.cn OI Bartlam, Mark/0000-0001-5173-5080; hu, zhongjun/0000-0003-0431-0834 FU NSFC [30770496, 30721003]; "973" project [2006CB806506, 2006CB911001]; Chinese Academy of Sciences [KGCX1-YW-13]; "863" project [2007AA100604]; K.C. Wong Education Foundation, Hong Kong; National Institute of Health through the National Center for Research Resources [RR17573] FX We thank Lingpeng Cheng (Institute of Biophysics, Chinese Academy of Sciences) for his help with UCSF Chimera and Ruigang Su (F.S. group) for his help preparing carbon-coated grids. We also thank Xudong Zhao, Ruimin Zheng, and Su liu (Core Facilities for Protein Sciences, CAS) for their help on maintaining the instruments of F.S.'s lab. This work was supported by NSFC grant (30770496, 30721003), "973" project (2006CB806506, 2006CB911001), Chinese Academy of Sciences (KGCX1-YW-13) and "863" project (2007AA100604 to Z.D.). The author gratefully acknowledges the support of K.C. Wong Education Foundation, Hong Kong (to F.S.). CryoEM data sets were collected at the National Resource for Automated Molecular Microscopy, which is supported by the National Institute of Health through the National Center for Research Resources' P41 program (RR17573). NR 50 TC 24 Z9 24 U1 0 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT 13 PY 2010 VL 18 IS 10 BP 1270 EP 1279 DI 10.1016/j.str.2010.07.009 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 668KS UT WOS:000283268500011 PM 20947016 ER PT J AU Matsuoka, T Adair, JE Lih, FB Hsi, LC Rubino, M Eling, TE Tomer, KB Yashiro, M Hirakawa, K Olden, K Roberts, JD AF Matsuoka, T. Adair, J. E. Lih, F. B. Hsi, L. C. Rubino, M. Eling, T. E. Tomer, K. B. Yashiro, M. Hirakawa, K. Olden, K. Roberts, J. D. TI Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice SO BRITISH JOURNAL OF CANCER LA English DT Article DE gastric carcinoma; dietary fatty acid; cyclooxygenase; metastasis; invasion ID POLYUNSATURATED FATTY-ACIDS; PROTEIN-KINASE-C; BREAST-CANCER CELLS; NUDE-MICE; TUMOR-CELLS; DOCOSAHEXAENOIC ACID; IV COLLAGEN; IN-VITRO; GROWTH; ADHESION AB BACKGROUND: Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma. METHODS: We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo. RESULTS: Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53%; HLA: 89%; VHLA: 100%; P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM-2MD3 cells in the mouse model. CONCLUSION: Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention. British Journal of Cancer (2010) 103, 1182-1191. doi:10.1038/sj.bjc.6605881 www.bjcancer.com Published online 14 September 2010 (C) 2010 Cancer Research UK C1 [Matsuoka, T.; Adair, J. E.; Hsi, L. C.; Rubino, M.; Eling, T. E.; Olden, K.; Roberts, J. D.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Matsuoka, T.; Yashiro, M.; Hirakawa, K.] Osaka City Univ, Grad Sch Med, Dept Surg Oncol, Abeno Ku, Osaka 5458585, Japan. [Lih, F. B.; Tomer, K. B.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Matsuoka, T (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. EM tskmtsk@aol.com RI Tomer, Kenneth/E-8018-2013 FU NIH; NIEHS FX We thank Drs Ron Cannon, Robert Langenbach and Rajendra Chhabra of NIEHS for a critical analysis of the paper and Dr Shyamal D Peddada for help with statistical analysis. This study was supported by the Intramural Research Program of the NIH and NIEHS. NR 54 TC 11 Z9 12 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 12 PY 2010 VL 103 IS 8 BP 1182 EP 1191 DI 10.1038/sj.bjc.6605881 PG 10 WC Oncology SC Oncology GA 671WL UT WOS:000283542900007 PM 20842125 ER PT J AU Rughani, RV Branco, MC Pochan, D Schneider, JP AF Rughani, Ronak V. Branco, Monica C. Pochan, Darrin Schneider, Joel P. TI De Novo Design of a Shear-Thin Recoverable Peptide-Based Hydrogel Capable of Intrafibrillar Photopolymerization SO MACROMOLECULES LA English DT Article ID TISSUE ENGINEERING APPLICATIONS; BETA-SHEET PEPTIDES; RESPONSIVE BIOMATERIALS; BIOMEDICAL APPLICATIONS; PROTEIN DELIVERY; SCAFFOLDS; POLYMERIZATION; ENCAPSULATION; RELEASE; MATRIX AB A de novo designed peptide-based eel has been prepared whose mechanical rigidity can be modulated after shear-thin recovery. The photopolymerizable beta-hairpin peptide named MLD undergoes temperature-induced folding and self-assembly to afford a network of beta-sheet-rich fibrils that constitutes a moderately rigid hydrogel (G ' = 220 +/- 50 Pa, 1 wt %). The MLD hydrogel can be shear-thinned into a low-viscosity gel upon application of shear stress and immediately recovers its mechanical rigidity upon termination of stress. ml peptides contain non-natural sorbamide derivatives of lysine that allow the mechanical rigidity of its hydrogels to be enhanced through polymerization of dienes displayed alone the surface of the fibrils constituting the gel. Irradiation of the gel network increases its mechanical rigidity similar to 2.5-fold. Circular dichroism (CD) spectroscopy shows that MLD folds and self-assembles into beta-sheet-rich fibrils and that photo-cross-linking does not influence the secondary structure contained within the assembly. The M LID hydrogel shows potential as an injectable material whose mechanical properties can be modulated after delivery. C1 [Branco, Monica C.; Schneider, Joel P.] NCI, Ctr Canc Res, Chem Biol Lab, Frederick, MD 21701 USA. [Rughani, Ronak V.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Pochan, Darrin] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. RP Schneider, JP (reprint author), NCI, Ctr Canc Res, Chem Biol Lab, Frederick, MD 21701 USA. EM schneiderjp@mail.nih.gov RI rughani, ronak/F-4978-2011; Schneider, Joel/N-2610-2014 FU NSF [CHE0348323, DMR 0348147] FX This work was supported by NSF CHE0348323 and NSF Career DMR 0348147 while J.P.S. was at the University of Delaware. We thank Dr. Daphne A. Salick for her thoughtful suggestions. We also thank Daniel Sanborn (Anton Paar USA) for providing the Advanced UV Cell and Omnicure system for the rheology experiments. NR 70 TC 31 Z9 33 U1 4 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0024-9297 EI 1520-5835 J9 MACROMOLECULES JI Macromolecules PD OCT 12 PY 2010 VL 43 IS 19 BP 7924 EP 7930 DI 10.1021/ma1014808 PG 7 WC Polymer Science SC Polymer Science GA 658GM UT WOS:000282478500011 ER PT J AU Jeyabalan, A Powers, RW Clifton, RG Van Dorsten, P Hauth, JC Klebanoff, MA Lindheimer, MD Sibai, B Landon, M Miodovnik, M AF Jeyabalan, Arun Powers, Robert W. Clifton, Rebecca G. Van Dorsten, Peter Hauth, John C. Klebanoff, Mark A. Lindheimer, Marshall D. Sibai, Baha Landon, Mark Miodovnik, Menachem CA Eunice Kennedy Shriver Natl Inst C Human Dev Maternal-Fetal Med Units TI Effect of Smoking on Circulating Angiogenic Factors in High Risk Pregnancies SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CIGARETTE-SMOKING; MATERNAL SMOKING; SOLUBLE ENDOGLIN; PREECLAMPSIA; WOMEN; OUTCOMES; SMOKERS; HYPERTENSION; NONSMOKERS AB Objective: Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia. Study Design: We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0-22.6 weeks']). Smoking status was determined by self-report. Results: sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4-337.3] vs 95.9 [48.5-180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1-486.0] vs 152.2 [73.6-253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6-6.5] vs 6.8 [5.5-8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8-5.6] vs 5.3 [4.3-6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups. Conclusions: In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort. C1 [Jeyabalan, Arun; Powers, Robert W.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Womens Hlth, Pittsburgh, PA 15260 USA. [Clifton, Rebecca G.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Van Dorsten, Peter] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Hauth, John C.] Univ Alabama, Dept Obstet & Gynecol, Med Sch Birmingham, Birmingham, AL 35294 USA. [Klebanoff, Mark A.] Eunice Kennedy Shriver NICHHD, Bethesda, MD USA. [Lindheimer, Marshall D.] Univ Chicago, Sch Med, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Sibai, Baha] Univ Tennessee, Sch Med, Dept Obstet & Gynecol, Memphis, TN USA. [Landon, Mark] Ohio State Univ, Sch Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Miodovnik, Menachem] Univ Cincinnati, Sch Med, Dept Obstet & Gynecol, Cincinnati, OH USA. RP Jeyabalan, A (reprint author), Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Womens Hlth, Pittsburgh, PA 15260 USA. EM ajeyabalan@mail.magee.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD19897, HD36801, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917, NIH-2P01-HD30367] FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD19897, HD36801, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, and HD27917) and NIH-2P01-HD30367. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 7 Z9 8 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 12 PY 2010 VL 5 IS 10 AR e13270 DI 10.1371/journal.pone.0013270 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 662KX UT WOS:000282807300012 PM 20967275 ER PT J AU Larrea, AA Lujan, SA McElhinny, SAN Mieczkowski, PA Resnick, MA Gordenin, DA Kunkel, TA AF Larrea, Andres A. Lujan, Scott A. McElhinny, Stephanie A. Nick Mieczkowski, Piotr A. Resnick, Michael A. Gordenin, Dmitry A. Kunkel, Thomas A. TI Genome-wide model for the normal eukaryotic DNA replication fork SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA polymerase delta; lagging strand replication; mutational hotspot; replication fidelity; mutator ID SACCHAROMYCES-CEREVISIAE; MISMATCH REPAIR; CANCER; DATABASE AB To investigate DNA replication enzymology across the nuclear genome of budding yeast, deep sequencing was used to establish the pattern of uncorrected replication errors generated by an asymmetric mutator variant of DNA polymerase delta (Pol delta). Sequencing of 16 genomes identified 1,206-bp substitutions generated over 33 generations by L612M Pol delta in a mismatch repair defective strain. Alignment of sequences flanking these substitutions identified "hotspot" motifs for Pol delta replication errors. The substitutions were distributed evenly across all 16 chromosomes. The vast majority were transitions that occurred with a strand bias that varied in a predictable manner relative to known functional origins of replication. This strand bias strongly supports the idea that Pol delta is primarily a lagging strand polymerase during replication across the entire nuclear genome. C1 [Larrea, Andres A.; Lujan, Scott A.; McElhinny, Stephanie A. Nick; Resnick, Michael A.; Gordenin, Dmitry A.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Larrea, Andres A.; Lujan, Scott A.; McElhinny, Stephanie A. Nick; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. [Mieczkowski, Piotr A.] Univ N Carolina, Dept Genet, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU Division of Intramural Research of the National Institutes of Health; National Institute on Environmental Health Sciences [Z01 ES065089, ES065073-19]; National Institutes of Health [RC1 ES018091-02]; University Cancer Research Fund FX We thank Karen Adelman, Jessica Williams, and Steven Roberts for their thoughtful comments on this manuscript. This work was supported by Division of Intramural Research of the National Institutes of Health, National Institute on Environmental Health Sciences Project Z01 ES065089 (to T. A. K.) and Project ES065073-19 (to M. A. R.); and by National Institutes of Health Grant RC1 ES018091-02 and the University Cancer Research Fund (both to P.A.M.). NR 18 TC 45 Z9 45 U1 3 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 12 PY 2010 VL 107 IS 41 BP 17674 EP 17679 DI 10.1073/pnas.1010178107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 662LV UT WOS:000282809700043 PM 20876092 ER PT J AU Knodler, LA Vallance, BA Celli, J Winfree, S Hansen, B Montero, M Steele-Mortimer, O AF Knodler, Leigh A. Vallance, Bruce A. Celli, Jean Winfree, Seth Hansen, Bryan Montero, Marinieve Steele-Mortimer, Olivia TI Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE caspase-1; epithelial cells; flagella; IL-18; type III secretion ID GENE-EXPRESSION; SMALL-INTESTINE; CELL-DEATH; TYPHIMURIUM; INDUCTION; INFECTION; MECHANISM; APOPTOSIS; PROTEIN; INTERLEUKIN-18 AB Salmonella enterica is an intracellular bacterial pathogen that resides and proliferates within amembrane-bound vacuole in epithelial cells of the gut and gallbladder. Although essential to disease, how Salmonella escapes from its intracellular niche and spreads to secondary cells within the same host, or to a new host, is not known. Here, we demonstrate that a subpopulation of Salmonella hyperreplicating in the cytosol of epithelial cells serves as a reservoir for dissemination. These bacteria are transcriptionally distinct from intravacuolar Salmonella. They are induced for the invasion-associated type III secretion system and possess flagella; hence, they are primed for invasion. Epithelial cells laden with these cytosolic bacteria are extruded out of the monolayer, releasing invasion-primed and -competent Salmonella into the lumen. This extrusion mechanism is morphologically similar to the process of cell shedding required for turnover of the intestinal epithelium. In contrast to the homeostatic mechanism, however, bacterial-induced extrusion is accompanied by an inflammatory cell death characterized by caspase-1 activation and the apical release of IL-18, an important cytokine regulator of gut inflammation. Although epithelial extrusion is obviously beneficial to Salmonella for completion of its life cycle, it also provides a mechanistic explanation for the mucosal inflammation that is triggered during Salmonella infection of the gastrointestinal and biliary tracts. C1 [Knodler, Leigh A.; Celli, Jean; Winfree, Seth; Steele-Mortimer, Olivia] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Hansen, Bryan] NIAID, Res Technol Branch, Microscopy Unit, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Vallance, Bruce A.; Montero, Marinieve] Univ British Columbia, British Columbia Childrens Hosp, Dept Paediat, Div Gastroenterol, Vancouver, BC V6H 3V4, Canada. RP Knodler, LA (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM lknodler@niaid.nih.gov OI Vallance, Bruce/0000-0003-1345-6747 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; Canadian Institutes of Health; Crohn's and Colitis Foundation FX We thank Caixia Ma and Tina Huang for their expert technical assistance; Anita Mora for graphics assistance; the Genomics Core Facility at Rocky Mountain Laboratories for DNA sequence analysis; and Rey Carabeo, Ed Miao, Staffan Svard, and members of the Steele-Mortimer lab-oratory for discussion and critique of this manuscript. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (O.S.-M. and J.C.) and by grants from the Canadian Institutes of Health Research and the Crohn's and Colitis Foundation (to B.A.V.). M.M. was supported by the Canadian Institute of Gastroenterology/Crohn's and Colitis Foundation of Canada/Canadian Institutes of Health Research Fellowship. B.A.V. is the Canada Research Chair in Pediatric Gastroenterology and the Children with Intestinal and Liver Disorders (CHILD) Foundation Research Scholar. NR 44 TC 108 Z9 108 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 12 PY 2010 VL 107 IS 41 BP 17733 EP 17738 DI 10.1073/pnas.1006098107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 662LV UT WOS:000282809700053 PM 20876119 ER PT J AU Peterson, JH Tian, P Ieva, R Dautin, N Bernstein, HD AF Peterson, Janine H. Tian, Pu Ieva, Raffaele Dautin, Nathalie Bernstein, Harris D. TI Secretion of a bacterial virulence factor is driven by the folding of a C-terminal segment SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autotransporters; Bam complex; outer membrane; protein folding; protein translocation ID OUTER-MEMBRANE; ESCHERICHIA-COLI; PASSENGER DOMAIN; PROTEIN SECRETION; CRYSTAL-STRUCTURE; BETA-HELIX; AUTOTRANSPORTER; TRANSLOCATION; BIOGENESIS; MECHANISM AB Autotransporters are bacterial virulence factors consisting of an N-terminal "passenger domain" that is secreted in a C-to-N-terminal direction and a C-terminal "beta domain" that resides in the outer membrane (OM). Although passenger domain secretion does not appear to use ATP, the energy source for this reaction is unknown. Here, we show that efficient secretion of the passenger domain of the Escherichia coli O157:H7 autotransporter EspP requires the stable folding of a C-terminal approximate to 17-kDa passenger domain segment. We found that mutations that perturb the folding of this segment do not affect its translocation across the OM but impair the secretion of the remainder of the passenger domain. Interestingly, an examination of kinetic folding mutants strongly suggested that the approximate to 17-kDa segment folds in the extracellular space. By mutagenizing the approximate to 17-kDa segment, we also fortuitously isolated a unique translocation intermediate. Analysis of this intermediate suggests that a heterooligomer that facilitates the membrane integration of OM proteins (the Bam complex) also promotes the surface exposure of the approximate to 17-kDa segment. Our results provide direct evidence that protein folding can drive translocation and help to clarify the mechanism of autotransporter secretion. C1 [Peterson, Janine H.; Tian, Pu; Ieva, Raffaele; Dautin, Nathalie; Bernstein, Harris D.] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov RI TIAN, PU/F-5739-2012; Ieva, Raffaele/J-9207-2014 OI Ieva, Raffaele/0000-0002-3405-0650 FU National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Travis Barnard for helping to construct Fig. 1 and Susan Buchanan for providing valuable comments on the manuscript. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. NR 27 TC 55 Z9 57 U1 2 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 12 PY 2010 VL 107 IS 41 BP 17739 EP 17744 DI 10.1073/pnas.1009491107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 662LV UT WOS:000282809700054 PM 20876094 ER PT J AU Feng, JY Petersen, CD Coy, DH Jiang, JK Thomas, CJ Pollak, MR Wank, SA AF Feng, Jianying Petersen, Clark D. Coy, David H. Jiang, Jian-Kang Thomas, Craig J. Pollak, Martin R. Wank, Stephen A. TI Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemosensation; multimodal sensor; peptide hormone; calcilytic; calcimimetic ID EXTRACELLULAR CA2+-SENSING RECEPTOR; L-AMINO-ACIDS; PARATHYROID-HORMONE; SECONDARY HYPERPARATHYROIDISM; HYPOCALCIURIC HYPERCALCEMIA; SOMATOSTATIN SECRETION; GASTROINTESTINAL-TRACT; RAT STOMACH; EXPRESSION; STIMULATION AB The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR. C1 [Feng, Jianying; Petersen, Clark D.; Wank, Stephen A.] NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Coy, David H.] Tulane Hlth Sci Ctr, Dept Med, Peptide Res Labs, New Orleans, LA 70112 USA. [Jiang, Jian-Kang; Thomas, Craig J.] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Pollak, Martin R.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. RP Wank, SA (reprint author), NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. EM stevew@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institutes of Health [P01-0707056] FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and by Program Project Grant P01-0707056 from the National Institutes of Health. NR 54 TC 55 Z9 55 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 12 PY 2010 VL 107 IS 41 BP 17791 EP 17796 DI 10.1073/pnas.1009078107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 662LV UT WOS:000282809700063 PM 20876097 ER PT J AU Debas, K Carrier, J Orban, P Barakat, M Lungu, O Vandewalle, G Tahar, AH Bellec, P Karni, A Ungerleider, LG Benali, H Doyon, J AF Debas, Karen Carrier, Julie Orban, Pierre Barakat, Marc Lungu, Ovidiu Vandewalle, Gilles Tahar, Abdallah Hadj Bellec, Pierre Karni, Avi Ungerleider, Leslie G. Benali, Habib Doyon, Julien TI Brain plasticity related to the consolidation of motor sequence learning and motor adaptation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE functional MRI; memory consolidation; motor learning; sleep; wakefulness ID EXPERIENCE-DEPENDENT CHANGES; BIMANUAL COORDINATION TASK; MEMORY CONSOLIDATION; VISUOMOTOR ADAPTATION; SLEEP; ACQUISITION; ACTIVATION; REACTIVATION; MOVEMENTS; STRIATUM AB This study aimed to investigate, through functional MRI (fMRI), the neuronal substrates associated with the consolidation process of two motor skills: motor sequence learning (MSL) and motor adaptation (MA). Four groups of young healthy individuals were assigned to either (i) a night/sleep condition, in which they were scanned while practicing a finger sequence learning task or an eight-target adaptation pointing task in the evening (test) and were scanned again 12 h later in the morning (retest) or (ii) a day/awake condition, in which they were scanned on the MSL or the MA tasks in the morning and were rescanned 12 h later in the evening. As expected and consistent with the behavioral results, the functional data revealed increased test-retest changes of activity in the striatum for the night/sleep group compared with the day/awake group in the MSL task. By contrast, the results of the MA task did not show any difference in test-retest activity between the night/sleep and day/awake groups. When the two MA task groups were combined, however, increased test-retest activity was found in lobule VI of the cerebellar cortex. Together, these findings highlight the presence of both functional and structural dissociations reflecting the off-line consolidation processes of MSL and MA. They suggest that MSL consolidation is sleep dependent and reflected by a differential increase of neural activity within the corticostriatal system, whereas MA consolidation necessitates either a period of daytime or sleep and is associated with increased neuronal activity within the corticocerebellar system. C1 [Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Debas, Karen; Carrier, Julie; Orban, Pierre; Barakat, Marc; Lungu, Ovidiu; Vandewalle, Gilles; Tahar, Abdallah Hadj; Bellec, Pierre; Doyon, Julien] Univ Montreal, Ctr Rech, Inst Geriatr, Funct Neuroimaging Unit, Montreal, PQ H3W 1W5, Canada. [Debas, Karen; Carrier, Julie; Barakat, Marc; Doyon, Julien] Univ Montreal, Dept Psychol, Ctr Rech Neuropsychol & Cognit, Montreal, PQ H3C 3J7, Canada. [Carrier, Julie; Vandewalle, Gilles] Hop Sacre Coeur, Ctr Etud Sommeil & Rythmes Biol, Montreal, PQ H4J 1C5, Canada. [Karni, Avi] Univ Haifa, Brain Behav Ctr, Lab Funct Brain Imaging & Learning Res, IL-31905 Haifa, Israel. [Benali, Habib; Doyon, Julien] Univ Paris 06, INSERM, UMR S 678, CHU Pitie Salpetriere, F-75634 Paris, France. RP Ungerleider, LG (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM ungerlel@mail.nih.gov; julien.doyon@umontreal.ca OI Bellec, Pierre/0000-0002-9111-0699 FU Canadian Institutes of Health; Fonds de Recherche en Sante du Quebec FX We thank Vo An Nguyen, Estelle Breton, and Laurence Girouard for their help in data acquisition. Support for this research was provided by a Canadian Institutes of Health Research grant (to J.D., J.C., A.H.T., A.K., H.B., and L.G.U.) and a fellowship from the Fonds de Recherche en Sante du Quebec (to K.D.). NR 39 TC 94 Z9 95 U1 3 U2 22 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 12 PY 2010 VL 107 IS 41 BP 17839 EP 17844 DI 10.1073/pnas.1013176107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 662LV UT WOS:000282809700071 PM 20876115 ER PT J AU Duma, D Collins, JB Chou, JW Cidlowski, JA AF Duma, Danielle Collins, Jennifer B. Chou, Jeff W. Cidlowski, John A. TI Sexually Dimorphic Actions of Glucocorticoids Provide a Link to Inflammatory Diseases with Gender Differences in Prevalence SO SCIENCE SIGNALING LA English DT Article ID LIVER GENE-EXPRESSION; NF-KAPPA-B; GROWTH-HORMONE; RAT-LIVER; TRANSCRIPTION FACTORS; SEX; RECEPTOR; MECHANISMS; CYTOCHROME; INDUCTION AB Males and females show differences in the prevalence of many major diseases that have important inflammatory components to their etiology. These gender-specific diseases, which include autoimmune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, are largely considered to reflect the actions of sex hormones on the susceptibility to inflammatory stimuli. However, inflammation reflects a balance between pro-and anti-inflammatory signals, and investigation of gender-specific responses to the latter has been neglected. Glucocorticoids are the primary physiological anti-inflammatory hormones in mammals, and synthetic derivatives of these hormones are prescribed as anti-inflammatory agents, irrespective of patient gender. We explored the possibility that sexually dimorphic actions of glucocorticoid regulation of gene expression may contribute to the dimorphic basis of inflammatory disease by evaluating the rat liver, a classic glucocorticoid-responsive organ. Surprisingly, glucocorticoid administration expanded the set of hepatic sexually dimorphic genes. Eight distinct patterns of glucocorticoid-regulated gene expression were identified, which included sex-specific genes. Our experiments also defined specific genes with altered expression in response to glucocorticoid treatment in both sexes, but in opposite directions. Pathway analysis identified sex-specific glucocorticoid-regulated gene expression in several canonical pathways involved in susceptibility to and progression of diseases with gender differences in prevalence. Moreover, a comparison of the number of genes involved in inflammatory disorders between sexes revealed 84 additional glucocorticoid-responsive genes in the male, suggesting that the anti-inflammatory actions of glucocorticoids are more effective in males. These gender-specific actions of glucocorticoids in liver were substantiated in vivo with a sepsis model of systemic inflammation. C1 [Duma, Danielle; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Collins, Jennifer B.] NIEHS, Microarray Facil, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Chou, Jeff W.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES090057-12, Z01 ES090057-13] NR 48 TC 40 Z9 41 U1 0 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD OCT 12 PY 2010 VL 3 IS 143 AR ra74 DI 10.1126/scisignal.2001077 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 662LH UT WOS:000282808300001 PM 20940427 ER PT J AU Dimitrakakis, C Zava, D Marinopoulos, S Tsigginou, A Antsaklis, A Glaser, R AF Dimitrakakis, Constantine Zava, David Marinopoulos, Spyros Tsigginou, Alexandra Antsaklis, Aris Glaser, Rebecca TI Low salivary testosterone levels in patients with breast cancer SO BMC CANCER LA English DT Article ID HORMONE REPLACEMENT THERAPY; POSTMENOPAUSAL WOMEN; ANDROGEN RECEPTOR; BINDING GLOBULIN; RISK; ESTROGEN; CARCINOGENESIS; STIMULATION; CARCINOMA; REGIMENS AB Background: Correlation between circulating sex steroid levels and breast cancer has been controversial, with measurement of free, or bioavailable hormone rarely available. Salivary hormone levels represent the bioavailable fraction. To further elucidate the role of endogenous hormones in breast cancer, we aimed to assess correlation between salivary sex steroid levels and breast cancer prevalence. Methods: Salivary hormone levels of testosterone (T), Estradiol (E2), Progesterone (P), Estriol (E3), Estrone (E1), DHEAS and Cortisol (C) were measured by Enzyme Immunoassay (EIA) in 357 women with histologically verified breast cancer and 184 age-matched control women. Results: Salivary T and DHEAS levels were significantly lower in breast cancer cases vs. controls (27.2+13.9 vs. 32.2+17.5 pg/ml, p < 0.001 for T and 5.3+4.3 vs. 6.4+4.5 ng/ml, p = 0.007 for DHEAS). E2 and E1 levels were elevated and E3 levels were lowered in cases vs. controls. Conclusions: Salivary T levels, representing the bioavailable hormone, are significantly lower in women with breast cancer compared to age-matched control women. These findings support the protective role of biovailable testosterone in counteracting the proliferative effects of estrogens on mammary tissue. C1 [Dimitrakakis, Constantine] NICHD, DEB, NIH, CRC, Bethesda, MD USA. [Dimitrakakis, Constantine; Marinopoulos, Spyros; Tsigginou, Alexandra; Antsaklis, Aris] Univ Athens, Sch Med, Athens 11528, Greece. [Zava, David] ZRT Lab, Beaverton, OR USA. [Glaser, Rebecca] Wright State Univ, Boonshoft Sch Med, Dayton, OH 45435 USA. RP Dimitrakakis, C (reprint author), NICHD, DEB, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD USA. EM dimitrac@mail.nih.gov NR 32 TC 5 Z9 5 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 11 PY 2010 VL 10 AR 547 DI 10.1186/1471-2407-10-547 PG 8 WC Oncology SC Oncology GA 669EX UT WOS:000283330500003 PM 20937135 ER PT J AU Laeyendecker, O Church, JD Oliver, AE Mwatha, A Owen, SM Donnell, D Brookmeyer, R Musoke, P Jackson, JB Guay, L Nakabiito, C Quinn, TC Eshleman, SH AF Laeyendecker, Oliver Church, Jessica D. Oliver, Amy E. Mwatha, Anthony Owen, S. Michele Donnell, Deborah Brookmeyer, Ron Musoke, Philippa Jackson, J. Brooks Guay, Laura Nakabiito, Clemesia Quinn, Thomas C. Eshleman, Susan H. TI Pregnancy Does Not Affect HIV Incidence Test Results Obtained Using the BED Capture Enzyme Immunoassay or an Antibody Avidity Assay SO PLOS ONE LA English DT Article ID SINGLE-DOSE NEVIRAPINE; UNITED-STATES; WOMEN; SEROCONVERSION; INFECTIONS; ALGORITHM AB Background: Accurate incidence estimates are needed for surveillance of the HIV epidemic. HIV surveillance occurs at maternal-child health clinics, but it is not known if pregnancy affects HIV incidence testing. Methods: We used the BED capture immunoassay (BED) and an antibody avidity assay to test longitudinal samples from 51 HIV-infected Ugandan women infected with subtype A, C, D and intersubtype recombinant HIV who were enrolled in the HIVNET 012 trial (37 baseline samples collected near the time of delivery and 135 follow-up samples collected 3, 4 or 5 years later). Nineteen of 51 women were also pregnant at the time of one or more of the follow-up visits. The BED assay was performed according to the manufacturer's instructions. The avidity assay was performed using a Genetic Systems HIV-1/HIV-2 + O EIA using 0.1M diethylamine as the chaotropic agent. Results: During the HIVNET 012 follow-up study, there was no difference in normalized optical density values (OD-n) obtained with the BED assay or in the avidity test results (%) when women were pregnant (n = 20 results) compared to those obtained when women were not pregnant (n = 115; for BED: p = 0.9, generalized estimating equations model; for avidity: p = 0.7, Wilcoxon rank sum). In addition, BED and avidity results were almost exactly the same in longitudinal samples from the 18 women who were pregnant at only one study visit during the follow-up study (p = 0.6, paired t-test). Conclusions: These results from 51 Ugandan women suggest that any changes in the antibody response to HIV infection that occur during pregnancy are not sufficient to alter results obtained with the BED and avidity assays. Confirmation with larger studies and with other HIV subtypes is needed. C1 [Laeyendecker, Oliver; Church, Jessica D.; Oliver, Amy E.; Jackson, J. Brooks; Guay, Laura; Quinn, Thomas C.; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Mwatha, Anthony; Donnell, Deborah] Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. [Owen, S. Michele] Ctr Dis Control & Prevent, Atlanta, GA USA. [Brookmeyer, Ron] Univ Calif Los Angeles, Los Angeles, CA USA. [Musoke, Philippa; Nakabiito, Clemesia] MUJHU Res Collaborat, Kampala, Uganda. [Musoke, Philippa; Nakabiito, Clemesia] Makerere Univ, Sch Med, Kampala, Uganda. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Laeyendecker, O (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. EM olaeyen1@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760; Donnell, Deborah/0000-0002-0587-7480 FU U.S. National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Dept. of Health and Human Services (DHHS) through Family Health International [N01-AI-35173]; Fred Hutchinson Cancer Research Center [N01-AI-45200]; Johns Hopkins Univ. [NOI-AI-35173-417]; NIAID; National Institutes of Child Health and Human Development (NICH/HD); National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research of NIH, DHHS [U01-AI-46745, U01-AI-48054, U01-AI-068613]; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group Network Laboratory [U01 AI068632] FX This work was supported by (1) the HIV Network for Prevention Trials (HIVNET) and sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Dept. of Health and Human Services (DHHS), through contracts with Family Health International (N01-AI-35173), Fred Hutchinson Cancer Research Center (N01-AI-45200), and Johns Hopkins Univ. (NOI-AI-35173-417), (2) the HIV Prevention Trials Network (HPTN) sponsored by the NIAID, National Institutes of Child Health and Human Development (NICH/HD), National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, DHHS (U01-AI-46745, U01-AI-48054, and U01-AI-068613), and (3) the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group Network Laboratory (U01 AI068632). Additional support was provided by the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 6 Z9 6 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 11 PY 2010 VL 5 IS 10 AR e13259 DI 10.1371/journal.pone.0013259 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 661SK UT WOS:000282748100009 PM 20949006 ER PT J AU Powers, RW Jeyabalan, A Clifton, RG Van Dorsten, P Hauth, JC Klebanoff, MA Lindheimer, MD Sibai, B Landon, M Miodovnik, M AF Powers, Robert W. Jeyabalan, Arun Clifton, Rebecca G. Van Dorsten, Peter Hauth, John C. Klebanoff, Mark A. Lindheimer, Marshall D. Sibai, Baha Landon, Mark Miodovnik, Menachem CA Eunice Kennedy Shriver Natl Inst TI Soluble fms-Like Tyrosine Kinase 1 (sFlt1), Endoglin and Placental Growth Factor (PlGF) in Preeclampsia among High Risk Pregnancies SO PLOS ONE LA English DT Article ID ANTIANGIOGENIC FACTORS; DEVELOP PREECLAMPSIA; WOMEN; PREVENTION AB Background: Differences in circulating concentrations of antiangiogenic factors sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are reported to precede the onset of preeclampsia weeks to months in low-risk pregnant women. The objective of this study was to investigate whether similar changes can be detected in pregnant women at high-risk to develop the syndrome. Methods: This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies. Serum samples were available from 194 women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and PlGF. Results: The odds of developing preeclampsia were significantly increased among women with multiple fetuses for each 2-fold elevation in sFlt1, sEng and the ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82) between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic factors across gestation showed significant differences during the third trimester in women who develop preeclampsia compared with appropriate controls in all high-risk groups. However, when data were examined in relation to the gestational week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia. Conclusions: The pattern of elevated concentrations of sFlt1 and sEng, and low PlGF in high-risk pregnant subjects who develop preeclampsia is similar to that reported in low-risk pregnant women. However, differences in these factors among high-risk women who do and do not develop preeclampsia are modest, and do not appear to be clinically useful predictors in these high-risk pregnant women. C1 [Powers, Robert W.; Jeyabalan, Arun] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Womens Hlth, Pittsburgh, PA 15260 USA. [Clifton, Rebecca G.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Van Dorsten, Peter] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Hauth, John C.] Univ Alabama, Sch Med, Dept Obstet & Gynecol, Birmingham, AL USA. [Klebanoff, Mark A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Lindheimer, Marshall D.] Univ Chicago, Sch Med, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Sibai, Baha] Univ Tennessee, Dept Obstet & Gynecol, Sch Med, Memphis, TN 38103 USA. [Landon, Mark] Ohio State Univ, Sch Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Miodovnik, Menachem] Univ Cincinnati, Sch Med, Dept Obstet & Gynecol, Cincinnati, OH USA. RP Powers, RW (reprint author), Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Womens Hlth, Pittsburgh, PA 15260 USA. EM powersrw@upmc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD19897, HD36801, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917, NIH-2P01-HD30367] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD19897, HD36801, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, and HD27917) and NIH-2P01-HD30367. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 16 TC 60 Z9 63 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 11 PY 2010 VL 5 IS 10 AR e13263 DI 10.1371/journal.pone.0013263 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 661SK UT WOS:000282748100012 PM 20948996 ER PT J AU Ramalingam, SS Kummar, S Sarantopoulos, J Shibata, S LoRusso, P Yerk, M Holleran, J Lin, Y Beumer, JH Harvey, RD Ivy, SP Belani, CP Egorin, MJ AF Ramalingam, Suresh S. Kummar, Shivaani Sarantopoulos, John Shibata, Stephen LoRusso, Patricia Yerk, Mara Holleran, Julianne Lin, Yan Beumer, Jan H. Harvey, R. Donald Ivy, S. Percy Belani, Chandra P. Egorin, Merrill J. TI Phase I Study of Vorinostat in Patients With Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SUBEROYLANILIDE HYDROXAMIC ACID; ADVANCED MALIGNANCIES; IMATINIB MESYLATE; RENAL DYSFUNCTION; VARYING DEGREES; PHARMACOKINETICS; TRIAL AB Purpose Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. Patients and Methods Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally. Results Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. Conclusion Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered. J Clin Oncol 28:4507-4512. (C) 2010 by American Society of Clinical Oncology C1 [Ramalingam, Suresh S.] Emory Univ, Winship Canc Ctr, Atlanta, GA 30322 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. City Hope Canc Ctr, Duarte, CA USA. Karmanos Canc Inst, Detroit, MI USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Penn State Hershey Canc Inst, Hershey, PA USA. RP Ramalingam, SS (reprint author), Emory Univ, Winship Canc Ctr, 1365 Clifton Rd NE,Room C-3090, Atlanta, GA 30322 USA. EM Suresh.ramalingam@emory.edu OI Belani, Chandra/0000-0001-5049-5329; Beumer, Jan/0000-0002-8978-9401 FU National Institutes of Health [NO1 CM-62208, NO1-CO-124001]; National Institutes of Health/General Clinical Research Center (University of Pittsburgh) [5M01 RR 00056]; California Cancer Consortium [U01 CA-062505]; Karmanos Cancer Institute [UO1 CA-062487] FX Supported by National Institutes of Health Grants No. NO1 CM-62208 (Southeast Phase 2 Consortium); NO1-CO-124001, subcontract 25XS115-Task Order 2, UO1-CA099168, P30CA47904, and National Institutes of Health/General Clinical Research Center 5M01 RR 00056 (University of Pittsburgh); U01 CA-062505 (California Cancer Consortium); and UO1 CA-062487 (Karmanos Cancer Institute). NR 10 TC 38 Z9 38 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2010 VL 28 IS 29 BP 4507 EP 4512 DI 10.1200/JCO.2010.30.2307 PG 6 WC Oncology SC Oncology GA 660LG UT WOS:000282643600041 PM 20837947 ER PT J AU Cheng, J Shah, YM Ma, XC Pang, XY Tanaka, T Kodama, T Krausz, KW Gonzalez, FJ AF Cheng, Jie Shah, Yatrik M. Ma, Xiaochao Pang, Xiaoyan Tanaka, Toshiya Kodama, Tatsuhiko Krausz, Kristopher W. Gonzalez, Frank J. TI Therapeutic Role of Rifaximin in Inflammatory Bowel Disease: Clinical Implication of Human Pregnane X Receptor Activation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NF-KAPPA-B; XENOBIOTIC RECEPTOR; GENE-EXPRESSION; COLITIS; INHIBITION; INDUCTION; RIFAMPIN; PATHWAY AB Human pregnane X receptor (PXR) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Rifaximin, a human PXR activator, is in clinical trials for treatment of IBD and has demonstrated efficacy in Crohn's disease and active ulcerative colitis. In the current study, the protective and therapeutic role of rifaximin in IBD and its respective mechanism were investigated. PXR-humanized (hPXR), wild-type, and Pxr-null mice were treated with rifaximin in the dextran sulfate sodium (DSS)-induced and trinitrobenzene sulfonic acid (TNBS)-induced IBD models to determine the protective function of human PXR activation in IBD. The therapeutic role of rifaximin was further evaluated in DSS-treated hPXR and Pxr-null mice. Results demonstrated that preadministration of rifaximin ameliorated the clinical hallmarks of colitis in DSS-and TNBS-treated hPXR mice as determined by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. In addition, higher survival rates and recovery from colitis symptoms were observed in hPXR mice, but not in Pxr-null mice, when rifaximin was administered after the onset of symptoms. Nuclear factor kappa B (NF-kappa B) target genes were markedly down-regulated in hPXR mice by rifaximin treatment. In vitro NF-kappa B reporter assays demonstrated inhibition of NF-kappa B activity after rifaximin treatment in colon-derived cell lines expressing hPXR. These findings demonstrated the preventive and therapeutic role of rifaximin on IBD through human PXR-mediated inhibition of the NF-kappa B signaling cascade, thus suggesting that human PXR may be an effective target for the treatment of IBD. C1 [Cheng, Jie; Pang, Xiaoyan; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Div Gastroenterol, Ann Arbor, MI USA. [Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Ma, Xiaochao] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. [Tanaka, Toshiya; Kodama, Tatsuhiko] Univ Tokyo, Lab Syst Biol & Med, Tokyo, Japan. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU National Institutes of Health National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute. NR 36 TC 73 Z9 73 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT 10 PY 2010 VL 335 IS 1 BP 32 EP 41 DI 10.1124/jpet.110.170225 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 652KM UT WOS:000282005300004 PM 20627999 ER PT J AU Rousset, X Vaisman, B Auerbach, B Krause, BR Homan, R Stonik, J Csako, G Shamburek, R Remaley, AT AF Rousset, Xavier Vaisman, Boris Auerbach, Bruce Krause, Brian R. Homan, Reyn Stonik, John Csako, Gyorgy Shamburek, Robert Remaley, Alan T. TI Effect of Recombinant Human Lecithin Cholesterol Acyltransferase Infusion on Lipoprotein Metabolism in Mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; TRANSGENIC MICE; FAMILIAL LECITHIN; PLASMA LECITHIN; APOA-I; SR-BI; ATHEROSCLEROSIS; DEFICIENCY; OVEREXPRESSION AB Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly increased HDL-cholesterol (C) and lowered cholesterol in fractions containing very-low-density lipoprotein (VLDL) and Lp-X. rLCAT was produced in a stably transfected human embryonic kidney 293f cell line and purified to homogeneity, with a specific activity of 1850 nmol/mg/h. Infusion of rLCAT intravenously, subcutaneously, or intramuscularly into human apoA-I transgenic mice showed a nearly identical effect in increasing HDL-C approximately 2-fold. When rLCAT was intravenously injected into LCAT-KO mice, it showed a similar effect as plasma from human LCAT transgenic mice in correcting the abnormal lipoprotein profile, but it had a considerably shorter half-life of approximately 1.23 +/- 0.63 versus 8.29 +/- 1.82 h for the plasma infusion. rLCAT intravenously injected in LCAT-KO mice crossed with human apolipoprotein (apo) A-I transgenic mice had a half-life of 7.39 +/- 2.1 h and increased HDL-C more than 8-fold. rLCAT treatment of LCAT-KO mice was found to increase cholesterol efflux to HDL isolated from mice when added to cells transfected with either ATP-binding cassette (ABC) transporter A1 or ABCG1. In summary, rLCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-KO mice and increased cholesterol efflux, suggesting the possibility of using rLCAT as an enzyme replacement therapy agent for LCAT deficiency. C1 [Rousset, Xavier; Vaisman, Boris; Stonik, John; Shamburek, Robert; Remaley, Alan T.] NHLBI, NIH, Pulm & Vasc Med Branch, Lipoprot Metab Sect, Bethesda, MD 20892 USA. [Auerbach, Bruce; Krause, Brian R.; Homan, Reyn] AlphaCore Pharma, Ann Arbor, MI USA. [Csako, Gyorgy; Remaley, Alan T.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Rousset, X (reprint author), NHLBI, NIH, Pulm & Vasc Med Branch, Lipoprot Metab Sect, Bldg 10,Room 8N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM roussetx@mail.nih.gov RI Rousset, Xavier/B-3352-2008; Rousset, Xavier/H-5490-2015 OI Rousset, Xavier/0000-0002-5830-6577; Rousset, Xavier/0000-0002-5830-6577 FU National Institutes of Health National Heart, Lung, and Blood Institute [HL09265601] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health National Heart, Lung, and Blood Institute and the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL09265601]. NR 41 TC 34 Z9 35 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT 10 PY 2010 VL 335 IS 1 BP 140 EP 148 DI 10.1124/jpet.110.169540 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 652KM UT WOS:000282005300016 PM 20605907 ER PT J AU Koek, W France, CP Cheng, KJ Rice, KC AF Koek, Wouter France, Charles P. Cheng, Kejun Rice, Kenner C. TI GABA(B) Receptor-Positive Modulators: Enhancement of GABA(B) Receptor Agonist Effects In Vivo SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ALCOHOL-PREFERRING RATS; PRECURSOR GAMMA-BUTYROLACTONE; ALLOSTERIC MODULATOR; DIFFERENTIAL ANTAGONISM; MOTIVATIONAL PROPERTIES; HYDROXYBUTYRIC ACID; BINDING-SITES; BACLOFEN; CGP7930; GS39783 AB In vivo effects of GABA(B) receptor-positive modulators suggest that they have therapeutic potential for treating central nervous system disorders such as anxiety, depression, and drug abuse. Although these effects generally are thought to be mediated by positive modulation of GABA(B) receptors, such modulation has been examined primarily in vitro. The present study was aimed at further examining the in vivo positive modulatory properties of the GABA(B) receptor-positive modulators, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R, S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). Both compounds enhanced loss of righting induced by baclofen in mice. However, CGP7930 was less effective and rac-BHFF was less potent for enhancing loss of righting induced by gamma-hydroxybutyrate (GHB), which, like baclofen, has GABA(B) receptor agonist properties. In contrast with baclofen- and GHB-induced loss of righting, the hypothermic effects of baclofen and GHB were not enhanced by rac-BHFF but were enhanced by CGP7930 only at doses that produced hypothermia when given alone. CGP7930-induced hypothermia was not attenuated by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348), at doses that blocked baclofen-induced hypothermia, and was not increased by the nitric-oxide synthase inhibitor N-omega-nitro-L-arginine methyl ester, at doses that increased the hypothermic effects of baclofen and GHB. The results provide evidence that CGP7930 and rac-BHFF act in vivo as positive modulators at GABA(B) receptors mediating loss of righting, but not at GABA(B) receptors mediating hypothermia. Conceivably, CGP7930, but not rac-BHFF, acts as an allosteric agonist at these latter receptors. Taken together, the results provide further evidence of pharmacologically distinct GABA(B) receptor subtypes, possibly allowing for a more selective therapeutic interference with the GABA(B) system. C1 [Koek, Wouter; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Koek, Wouter; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Koek, W (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7703 Floyd Curl Dr,Mail Code 7792, San Antonio, TX 78229 USA. EM koek@uthscsa.edu FU National Institutes of Health National Institute on Drug Abuse [DA15692, DA17918]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA15692, DA17918] and the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 47 TC 21 Z9 21 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT 10 PY 2010 VL 335 IS 1 BP 163 EP 171 DI 10.1124/jpet.110.171116 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 652KM UT WOS:000282005300019 PM 20628000 ER PT J AU Sun, Y Santra, S Buzby, AP Mascola, JR Nabel, GJ Letvin, NL AF Sun, Yue Santra, Sampa Buzby, Adam P. Mascola, John R. Nabel, Gary J. Letvin, Norman L. TI Recombinant vector-induced HIV/SIV-specific CD4(+) T lymphocyte responses in rhesus monkeys SO VIROLOGY LA English DT Article DE HIV vaccine; CD4(+) T cell responses; Rhesus monkey; SHIV-89.6P ID IMMUNODEFICIENCY VIRUS CHALLENGE; CELL RESPONSES; MEMORY; INFECTION; REPLICATION; PROTECTION; SURVIVAL; HELP; GAG AB The recently reported modest success of the RV144 Thai trial vaccine regimen in preventing HIV-1 acquisition has focused interest on the potential contribution to that protection of vaccine-elicited CD4(+) T cell responses. We evaluated the induction of virus-specific CD4(+) T cell responses in rhesus monkeys using a series of diverse vaccine vectors. We assessed both the magnitudes and functional profiles of the antigen-specific CD4+ T cells by measuring cytokine production, memory differentiation, and the expression of mucosal homing molecules. We found that DNA prime/recombinant MVA boost immunizations induced particularly high-frequency virus-specific CD4(+) T cell responses with polyfunctional repertoires, and these responses were partially preserved following SHIV-89.6P challenge. The majority of the vaccine-elicited CD4(+) T cells were CD28(+) memory T cells that expressed low levels of beta 7. Neither the magnitudes nor the functional profiles of the virus-specific CD4(+) T cells generated by vaccination were associated with a preservation of CD4(+) T cells or control of viral replication following SHIV-89.6P challenge. Interestingly, monkeys primed with recombinant Ad5 immunogens showed a dramatic expansion of both the magnitude and polyfunctionality of the vaccine-elicited CD4(+) T cell responses following envelope protein boost. These results demonstrate that vaccine strategies that include recombinant MVA or recombinant Ad5 vectors can elicit robust CD4(+) T cell responses. Published by Elsevier Inc. C1 [Letvin, Norman L.] Harvard Univ, Div Viral Pathogenesis, Beth Israel Deaconess Med Ctr, Sch Med,Dept Med,Ctr Life Sci, Boston, MA 02115 USA. [Mascola, John R.; Nabel, Gary J.; Letvin, Norman L.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Letvin, NL (reprint author), Harvard Univ, Div Viral Pathogenesis, Beth Israel Deaconess Med Ctr, Sch Med,Dept Med,Ctr Life Sci, 330 Brookline Ave, Boston, MA 02115 USA. EM nletvin@bidmc.harvard.edu FU Vaccine Research Center, NIAID, NIH; Harvard Medical School CFAR [AI060354]; NIH [N01-AI30033] FX We are grateful to Mario Roederer for helpful conversations and Michelle Lifton for technical assistance. The protein and adjuvant were provided by Dr. Susan Barnett (Novartis). This work was supported in part by funds from the intramural research program of the Vaccine Research Center, NIAID, NIH, the Harvard Medical School CFAR grant AI060354, and the NIH grant N01-AI30033. NR 23 TC 8 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 10 PY 2010 VL 406 IS 1 BP 48 EP 55 DI 10.1016/j.virol.2010.07.004 PG 8 WC Virology SC Virology GA 647BA UT WOS:000281589400006 PM 20667574 ER PT J AU Schaap-Nutt, A D'Angelo, C Amaro-Carambot, E Nolan, SM Davis, S Wise, SM Higgins, C Bradley, K Kim, O Mayor, R Skiadopoulos, MH Collins, PL Murphy, BR Schmidt, AC AF Schaap-Nutt, Anne D'Angelo, Christopher Amaro-Carambot, Emerito Nolan, Sheila M. Davis, Stephanie Wise, Shenelle-Marie Higgins, Caraline Bradley, Konrad Kim, Olivia Mayor, Reina Skiadopoulos, Mario H. Collins, Peter L. Murphy, Brian R. Schmidt, Alexander C. TI Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates SO VIROLOGY LA English DT Article DE Parainfluenza virus; HPIV2; V protein; Interferon; STAT; Non-human primates ID RESPIRATORY SYNCYTIAL VIRUS; UBIQUITIN LIGASE COMPLEXES; STAT PROTEIN-DEGRADATION; CYSTEINE-RICH DOMAIN; L-POLYMERASE PROTEIN; PARAMYXOVIRUS SV5 V; VACCINE CANDIDATES; ALPHA/BETA-INTERFERON; REVERSE GENETICS; I INTERFERON AB The HPIV2 V protein inhibits type I interferon (IFN) induction and signaling. To manipulate the V protein, whose coding sequence overlaps that of the polymerase-associated phosphoprotein (P), without altering the P protein, we generated an HPIV2 virus in which P and V are expressed from separate genes (rHPIV2-P+V). rHPIV2-P+V replicated like HPIV2-WT in vitro and in non-human primates. HPIV2-P+V was modified by introducing two separate mutations into the V protein to create rHPIV2-L101E/L102E and rHPIV2-Delta 122-127. In contrast to HPIV2-WT, both mutant viruses were unable to degrade STAT2, leaving virus-infected cells susceptible to IFN. Neither mutant, nor HPIV2-WT, induced significant amounts of IFN-beta in infected cells. Surprisingly, neither rHPIV2-L101E/L102E nor rHPIV2-Delta 122-127 was attenuated in two species of non-human primates. This indicates that loss of HPIV2's ability to inhibit IFN signaling is insufficient to attenuate virus replication in vivo as long as IFN induction is still inhibited. Published by Elsevier Inc. C1 [Schaap-Nutt, Anne; D'Angelo, Christopher; Amaro-Carambot, Emerito; Nolan, Sheila M.; Davis, Stephanie; Wise, Shenelle-Marie; Higgins, Caraline; Bradley, Konrad; Kim, Olivia; Mayor, Reina; Skiadopoulos, Mario H.; Collins, Peter L.; Murphy, Brian R.; Schmidt, Alexander C.] NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Schaap-Nutt, A (reprint author), NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,Dept Hlth & Human Serv, 50 South Dr,Bldg 50,Room 6515,MSC 8007, Bethesda, MD 20892 USA. EM schaapa@niaid.nih.gov FU National Institute of Allergy and Infectious Disease, National Institutes of Health; NIAID; MedImmune, LLC [AI-5114] FX We thank Bradley Finneyfrock of Bioqual, Inc., for performing nonhuman primate studies. Antibodies to HPIV2 P and V proteins were kindly provided by Machiko Nishio of Mie University Graduate School of Medicine in Japan. John Hiscott, McGill University, kindly provided the VSV-GFP virus. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, and was partly performed under a cooperative research and development agreement (CRADA) between NIAID and MedImmune, LLC (CRADA #AI-5114) for the development of live attenuated virus vaccines for respiratory syncytial viruses, parainfluenza viruses, and human metapneumovirus. NR 82 TC 7 Z9 7 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 10 PY 2010 VL 406 IS 1 BP 65 EP 79 DI 10.1016/j.virol.2010.07.011 PG 15 WC Virology SC Virology GA 647BA UT WOS:000281589400008 PM 20667570 ER PT J AU Lau, YF Tang, LH Ooi, EE Subbarao, K AF Lau, Yuk-Fai Tang, Lay-Hoon Ooi, Eng-Eong Subbarao, Kanta TI Activation of the innate immune system provides broad-spectrum protection against influenza A viruses with pandemic potential in mice SO VIROLOGY LA English DT Article DE TLR3; Influenza; Immunoprophylaxis ID NEURAMINIDASE INHIBITOR OSELTAMIVIR; PLASMACYTOID DENDRITIC CELLS; DOUBLE-STRANDED-RNA; H5N1 VIRUS; ALVEOLAR MACROPHAGES; PULMONARY INFECTION; ALPHA-INTERFERON; GUINEA-PIGS; NEUTROPHILS; CHILDREN AB The efficacy of a stabilized chemical analog of double-stranded ribonucleic acid (RNA). PIKA, as prophylaxis against infection with 5 different influenza A virus subtypes, including the 2009 swine-origin pandemic H1N1 virus, was evaluated in mice. Intranasal treatment with PIKA resulted in a significant reduction of viral replication in the respiratory tract. The inhibitory effect was mediated by rapid infiltration of immune cells into the lungs, and production of inflammatory cytokines. While TLR3 is important for the optimal production of these inflammatory cytokines, inhibition of viral replication was still observed in TLR3(-/-) mice. In addition, a significant synergistic effect in inhibiting H5N1 virus replication was observed when PIKA was coadministered with oseltamivir. The broad-spectrum protection provided by PIKA makes it an attractive option for prophylaxis from infection with influenza A viruses. Published by Elsevier Inc. C1 [Lau, Yuk-Fai; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Lau, Yuk-Fai; Tang, Lay-Hoon; Ooi, Eng-Eong] DSO Natl Labs, Med Countermeasures Biol Lab, DMERI, Singapore 117510, Singapore. RP Subbarao, K (reprint author), Bldg 33,Room 3E13C1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov OI Ooi, Eng Eong/0000-0002-0520-1544 FU NIAID, NIH; Future Systems Directorate, Ministry of Defence, Republic of Singapore FX We thank Jadon Jackson and Amber McCall for their excellent technical assistance. This research was supported by funds from the Intramural Research Program of the NIAID, NIH and the Future Systems Directorate, Ministry of Defence, Republic of Singapore. NR 62 TC 19 Z9 20 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 10 PY 2010 VL 406 IS 1 BP 80 EP 87 DI 10.1016/j.virol.2010.07.008 PG 8 WC Virology SC Virology GA 647BA UT WOS:000281589400009 PM 20667572 ER PT J AU Riazuddin, SA Shahzadi, A Zeitz, C Ahmed, ZM Ayyagari, R Chavali, VRM Ponferrada, VG Audo, I Michiels, C Lancelot, ME Nasir, IA Zafar, AU Khan, SN Husnain, T Jiao, XD MacDonald, IM Riazuddin, S Sieving, PA Katsanis, N Hejtmancik, JF AF Riazuddin, S. Amer Shahzadi, Amber Zeitz, Christina Ahmed, Zubair M. Ayyagari, Radha Chavali, Venkata R. M. Ponferrada, Virgilio G. Audo, Isabelle Michiels, Christelle Lancelot, Marie-Elise Nasir, Idrees A. Zafar, Ahmad U. Khan, Shaheen N. Husnain, Tayyab Jiao, Xiaodong MacDonald, Ian M. Riazuddin, Sheikh Sieving, Paul A. Katsanis, Nicholas Hejtmancik, J. Fielding TI A Mutation in SLC24A1 Implicated in Autosomal-Recessive Congenital Stationary Night Blindness SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RHODOPSIN MUTATION; MISSENSE MUTATION; PAKISTANI FAMILY; GENE; EXCHANGER; ROD; ELECTRORETINOGRAM; IDENTIFICATION; MEMBRANE; PROTEIN AB Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6 53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily Sequencing of all the coding exons identified a 2 bp deletion in exon 2. c 1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p 17538Cf5X23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7 In situ and immunohistological studies localized both SLC24A1 and S1c24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans. C1 [Riazuddin, S. Amer; Shahzadi, Amber; Nasir, Idrees A.; Zafar, Ahmad U.; Khan, Shaheen N.; Husnain, Tayyab; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Riazuddin, S. Amer; Katsanis, Nicholas] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Zeitz, Christina; Audo, Isabelle; Michiels, Christelle; Lancelot, Marie-Elise] INSERM, U968, F-75012 Paris, France. [Zeitz, Christina; Audo, Isabelle; Michiels, Christelle; Lancelot, Marie-Elise] CNRS, UMR_7210, F-75012 Paris, France. [Zeitz, Christina; Audo, Isabelle; Michiels, Christelle; Lancelot, Marie-Elise] Univ Paris 06, UMR S 968, Dept Genet, Inst Vis, F-75012 Paris, France. [Ahmed, Zubair M.; Ponferrada, Virgilio G.] Cincinnati Childrens Hosp, Med Ctr, Div Pediat Ophthalmol, Cincinnati, OH 45229 USA. [Ahmed, Zubair M.] Coll Med, Dept Ophthalmol, Cincinnati, OH 45229 USA. [Ayyagari, Radha; Chavali, Venkata R. M.] Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92037 USA. [Audo, Isabelle] INSERM DHOS CIC 503, Ctr Hosp Natl Ophtalmol Quinze Vingts, F-75012 Paris, France. [Audo, Isabelle] Inst Ophthalmol, Dept Mol Genet, London EC1V 9EL, England. [Jiao, Xiaodong; MacDonald, Ian M.; Sieving, Paul A.; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 21850 USA. [MacDonald, Ian M.] Univ Alberta, Dept Ophthalmol, Edmonton, AB T5H 3V9, Canada. [Riazuddin, Sheikh] Allama Iqbal Med Coll, Lahore 54550, Pakistan. [Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC 27710 USA. RP Riazuddin, SA (reprint author), Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. RI Katsanis, Nicholas/E-1837-2012; Nasim Khan, Shaheen/F-2135-2015; Husnain, Tayyab/G-3805-2015; Zeitz, Christina/F-2757-2017; OI MacDonald, Ian/0000-0001-7472-8385; Katsanis, Nicholas/0000-0002-2480-0171 FU Higher Education Commission (H E.C.), Islamabad, Pakistan; Ministry of Science and Technology, Islamabad, Pakistan; Foundation Fighting Blindness, USA; Research to Prevent Blindness; [NIH-R00-DC009287-03]; [NIH-EY013198] FX The authors are grateful to all family members for their participation in this study None of the contributing authors have any financial interest related to this work This work was supported in part by Higher Education Commission (H E.C.), Islamabad, Pakistan, Ministry of Science and Technology, Islamabad, Pakistan, NIH-R00-DC009287-03 (Z A.); Research to Prevent Blindness (Z A), Foundation Fighting Blindness, USA (PA), Research to prevent blindness (R A) and NIH-EY013198 (R.A.) N K is a Distinguished George W. Brumley Professor. NR 32 TC 26 Z9 27 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 8 PY 2010 VL 87 IS 4 BP 523 EP 531 DI 10.1016/j.ajhg.2010.08.013 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 665LU UT WOS:000283037600008 PM 20850105 ER PT J AU McLaughlin, HM Sakaguchi, R Liu, CP Igarashi, T Pehlivan, D Chu, K Iyer, R Cruz, P Cherukuri, PF Hansen, NF Mullikin, JC Biesecker, LG Wilson, TE Ionasescu, V Nicholson, G Searby, C Talbot, K Vance, JM Zuchner, S Szigeti, K Lupski, JR Hou, YM Green, ED Antonellis, A AF McLaughlin, Heather M. Sakaguchi, Reiko Liu, Cuiping Igarashi, Takao Pehlivan, Davut Chu, Kristine Iyer, Ram Cruz, Pedro Cherukuri, Praveen F. Hansen, Nancy F. Mullikin, James C. Biesecker, Leslie G. Wilson, Thomas E. Ionasescu, Victor Nicholson, Garth Searby, Charles Talbot, Kevin Vance, Jeffrey M. Zuchner, Stephan Szigeti, Kinga Lupski, James R. Hou, Ya-Ming Green, Eric D. Antonellis, Anthony CA NISC Comparative Sequencing TI Compound Heterozygosity for Loss-of-Function Lysyl-tRNA Synthetase Mutations in a Patient with Peripheral Neuropathy SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MARIE-TOOTH-DISEASE; HEREDITARY NEUROPATHY; MISSENSE MUTATIONS; MUSCULAR-ATROPHY; GENE; FORM; LIABILITY; ENZYMES; SERVER; 2D AB Charcot-Mane-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by unpaired distal motor and sensory function Mutations in three genes encoding ammoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology ARSs are ubiquitously expressed, essential enzymes responsible for charging tRNA molecules with their cognate amino acids To further explore the role of ARSs in CMT disease, we performed a large-scale mutation screen of the 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT Here we describe three variants (p.Leu133His, p Tyr173SerfsX7, and p Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort Functional analyses revealed that two of these mutations (pLeu133His and p Tyr173SerfsX7) severely affect enzyme activity. Interestingly, both functional variants were found in a single patient with CMT disease and additional neurological and non-neurological sequelae Based on these data, KARS becomes the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function. C1 [McLaughlin, Heather M.; Antonellis, Anthony] Univ Michigan, Dept Human Genet, Sch Med, Ann Arbor, MI 48109 USA. [Sakaguchi, Reiko; Liu, Cuiping; Igarashi, Takao; Hou, Ya-Ming] Thomas Jefferson Univ, Dept Biochem & Mol Pharmacol, Philadelphia, PA 19107 USA. [Pehlivan, Davut; Szigeti, Kinga; Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Chu, Kristine; Cruz, Pedro; Cherukuri, Praveen F.; Hansen, Nancy F.; Mullikin, James C.; Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Iyer, Ram; Wilson, Thomas E.] Univ Michigan, Dept Pathol, Sch Med, Ann Arbor, MI 48109 USA. [Mullikin, James C.; Green, Eric D.; NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Ionasescu, Victor; Searby, Charles] Univ Iowa, Div Med Genet, Dept Pediat, Iowa City, IA 52242 USA. [Nicholson, Garth] Concord Hosp, Northcott Neurosci Lab, ANZAC Res Inst, Concord, NSW 2139, Australia. [Nicholson, Garth] Concord Hosp, Mol Med Lab, Concord, NSW 2139, Australia. [Nicholson, Garth] Univ Sydney, Fac Med, Camperdown, NSW 2006, Australia. [Talbot, Kevin] Univ Oxford, Dept Clin Neurol, Oxford OX1 3QX, England. [Vance, Jeffrey M.; Zuchner, Stephan] Univ Miami, Miller Sch Med, Hussman Inst Human Genom, Miami, FL 33136 USA. [Szigeti, Kinga] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Lupski, James R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Lupski, James R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Antonellis, Anthony] Univ Michigan, Dept Neurol, Sch Med, Ann Arbor, MI 48109 USA. RP Antonellis, A (reprint author), Univ Michigan, Dept Human Genet, Sch Med, Ann Arbor, MI 48109 USA. RI Talbot, Kevin /F-7361-2011; OI Pehlivan, Davut/0000-0001-5788-0270; Hou, Ya-Ming/0000-0001-6546-2597; Searby, Charles/0000-0002-8108-8782 FU National Institute of Neurological Diseases and Stroke [R00NS060983]; National Human Genome Research Institute (NIH); National Human Genome Research Institute; NIH [T32 GM007544-32]; Muscular Dystrophy Association [157681] FX We are indebted to the patients and their families for their participation in this study We thank Ellen Pederson, Bob Lyons, and the University of Michigan DNA Sequencing Core for sequencing and genotyping assistance, Jeffrey Innis and the Michigan Medical Genetics Laboratory for anonymized DNA samples, Giovanni Manfredi and Kiyotaka Shiba for KARS cDNA constructs, and Jiqiang Ling and Dieter Soil for sharing unpublished data We are also very grateful to the two anonymous reviewers for their helpful comments and suggestions, which dramatically improved the study. This work was supported in part by grant R00NS060983 from the National Institute of Neurological Diseases and Stroke (AA) and by the Intramural Research Program of the National Human Genome Research Institute (NIH). The ClinSeq cohort and sequencing were also supported by Intramural Funding from the National Human Genome Research Institute H M M was supported by the Rackham Merit Fellowship and the NIH Genetics Training Grant T32 GM007544-32 Y.-M H. and R.S were supported by a grant from the Muscular Dystrophy Association (157681 to Y-M H). NR 33 TC 80 Z9 81 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 8 PY 2010 VL 87 IS 4 BP 560 EP 566 DI 10.1016/j.ajhg.2010.09.008 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 665LU UT WOS:000283037600013 PM 20920668 ER PT J AU Johnson, JO Gibbs, JR Van Maldergem, L Houlden, H Singleton, AB AF Johnson, Janel O. Gibbs, J. Raphael Van Maldergem, Lionel Houlden, Henry Singleton, Andrew B. TI Exome Sequencing in Brown-Vialetto-Van Laere Syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter C1 [Johnson, Janel O.; Gibbs, J. Raphael; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Johnson, Janel O.; Gibbs, J. Raphael] UCL, Dept Mol Neurosci, London WC1N 3BG, England. [Johnson, Janel O.; Gibbs, J. Raphael] UCL, Reta Lila Weston Labs, Inst Neurol, London WC1N 3BG, England. [Van Maldergem, Lionel] Univ Liege, Ctr Genet Humaine, CHU Sart Tilman, B-4000 Liege, Belgium. [Houlden, Henry] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Houlden, Henry] Inst Neurol, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 FU Intramural NIH HHS; Medical Research Council [G0802760]; NIA NIH HHS [Z01 AG000958, Z01 AG000958-07] NR 5 TC 32 Z9 34 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 8 PY 2010 VL 87 IS 4 BP 567 EP 569 DI 10.1016/j.ajhg.2010.05.021 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 665LU UT WOS:000283037600014 PM 20920669 ER PT J AU Taylor, W Mathias, A Ali, A Ke, HN Stoynev, N Shilkaitis, A Green, A Kiyokawa, H Christov, K AF Taylor, Winna Mathias, Amanda Ali, Arshia Ke, Hengning Stoynev, Nikolay Shilkaitis, Anne Green, Albert Kiyokawa, Hiroaki Christov, Konstantin TI p27(Kip1) deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process SO BMC CANCER LA English DT Article ID INTRAEPITHELIAL NEOPLASIA; TUMOR-SUPPRESSOR; NOBLE RATS; P27(KIP1)-DEFICIENT MICE; 9-CIS-RETINOIC ACID; CANCER PROGRESSION; CELL-PROLIFERATION; P27; GROWTH; CHEMOPREVENTION AB Background: p27 is a cell cycle suppressor gene, whose protein is a negative regulator of cyclin/cdk complexes. p27 is also a potential target of retinoids in cancer prevention studies. In benign prostate hyperplasia (BPH), and in most carcinomas, p27(Kip1) is down-regulated, suggesting its potential resistance to retinoids. To test this hypothesis, we examined the efficacy of 9-cis retinoic acid (9cRA) to suppress prostate cell proliferation (PECP) and carcinogenesis in p27(Kip1) deficient mice. Methods: p27(Kip1) deficient (-/-), heterozygous (+/-) and homozygous (+/+) mice were treated for 7 days with testosterone, 9cRA, or with both, and cell proliferation in dorsolateral prostate (DLP) was determined by BrdU labeling. Prostate carcinogenesis was induced by N-Methyl-N-Nitrosourea (MNU) and hormone stimulation. Results: PECP in DLP of two-month-old mice of all genotypes was similar but significantly increased in old p27-/- mice only. Testosterone treatment increased PECP in all three p27 genotypes with the highest values in p27-/- mice. p27(Kip1) deficiency did not affect the response of PEC to 9cRA and to 9cRA+testosterone. The decrease of p27(Kip1) in p27+/- and p27-/- mice progressively increased the incidence and frequency of PIN and tumors. 9cRA suppressed PIN in all three p27 genotypes and this was associated with decreased PECP and increased cellular senescence. Conclusions: This data indicates that p27(Kip1) deficiency promotes prostate cell proliferation and carcinogenesis but does not affect 9cRA's potential to suppress prostate carcinogenesis, suggesting that patients with PIN and carcinomas lacking or having a low level of p27(Kip1) expression may also benefit from clinical trials with retinoids. C1 [Taylor, Winna; Mathias, Amanda; Ali, Arshia; Shilkaitis, Anne; Green, Albert; Christov, Konstantin] Univ Illinois, Dept Surg, Div Surg Oncol, Chicago, IL 60612 USA. [Ke, Hengning] NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Stoynev, Nikolay] Med Univ Sofia, Dept Endocrinol, Sofia, Bulgaria. [Kiyokawa, Hiroaki] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. RP Christov, K (reprint author), Univ Illinois, Dept Surg, Div Surg Oncol, 840 S Wood St, Chicago, IL 60612 USA. EM christov@uic.edu FU NIH [CA095712, CN-35112] FX This study was supported by CA095712 and CN-35112 from NIH. We are thankful to Dr. Vernon Steele, Ph.D., MPH, from NIH for supporting this study and to Dr. Clinton Grubbs from University of Alabama, Birmingham, AL, for providing the 9cRA mixed in the diet. The authors also thank Scott Kennedy for his editorial work. NR 41 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 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 8 PY 2010 VL 10 AR 541 DI 10.1186/1471-2407-10-541 PG 12 WC Oncology SC Oncology GA 669EV UT WOS:000283330300001 PM 20932324 ER PT J AU Palacios, D Mozzetta, C Consalvi, S Caretti, G Saccone, V Proserpio, V Marquez, VE Valente, S Mai, A Forcales, SV Sartorelli, V Puri, PL AF Palacios, Daniela Mozzetta, Chiara Consalvi, Silvia Caretti, Giuseppina Saccone, Valentina Proserpio, Valentina Marquez, Victor E. Valente, Sergio Mai, Antonello Forcales, Sonia V. Sartorelli, Vittorio Puri, Pier Lorenzo TI TNF/p38 alpha/Polycomb Signaling to Pax7 Locus in Satellite Cells Links Inflammation to the Epigenetic Control of Muscle Regeneration SO CELL STEM CELL LA English DT Article ID EMBRYONIC STEM-CELLS; TUMOR-SUPPRESSOR ACTIVITY; POLYCOMB GROUP PROTEINS; SKELETAL-MUSCLE; SELF-RENEWAL; GENE-EXPRESSION; PROGENITOR CELLS; TARGET GENES; MYOGENIC DIFFERENTIATION; DEVELOPMENTAL REGULATORS AB How regeneration cues are converted into the epigenetic information that controls gene expression in adult stem cells is currently unknown. We identified an inflammation-activated signaling in muscle stem (satellite) cells, by which the polycomb repressive complex 2 (PRC2) represses Pax7 expression during muscle regeneration. TNF-activated p38 alpha kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzymatic subunit of the complex, leading to the formation of repressive chromatin on Pax7 promoter. TNF-alpha antibodies stimulate satellite cell proliferation in regenerating muscles of dystrophic or normal mice. Genetic knockdown or pharmacological inhibition of the enzymatic components of the p38/PRC2 signaling-p38 alpha and EZH2-invariably promote Pax7 expression and expansion of satellite cells that retain their differentiation potential upon signaling resumption. Genetic knockdown of Pax7 impaired satellite cell proliferation in response to p38 inhibition, thereby establishing the biological link between p38/PRC2 signaling to Pax7 and satellite cell decision to proliferate or differentiate. C1 [Palacios, Daniela; Mozzetta, Chiara; Consalvi, Silvia; Saccone, Valentina; Puri, Pier Lorenzo] IRCCS Fdn Santa Lucia, DTI, I-00143 Rome, Italy. [Palacios, Daniela; Mozzetta, Chiara; Consalvi, Silvia; Saccone, Valentina; Puri, Pier Lorenzo] European Brain Res Inst, I-00143 Rome, Italy. [Palacios, Daniela; Mozzetta, Chiara; Consalvi, Silvia; Saccone, Valentina; Puri, Pier Lorenzo] Sanford Burnham Inst Med Res, La Jolla, CA 92037 USA. [Caretti, Giuseppina; Proserpio, Valentina; Sartorelli, Vittorio] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Caretti, Giuseppina; Proserpio, Valentina] Univ Milan, Dept Biomol Sci & Biotechnol, I-20133 Milan, Italy. [Marquez, Victor E.] NCI, Med Chem Lab, Frederick, MD 21720 USA. [Valente, Sergio; Mai, Antonello] Univ Roma La Sapienza, Dept Chem & Drug Technol, Inst Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. RP Puri, PL (reprint author), IRCCS Fdn Santa Lucia, DTI, I-00143 Rome, Italy. EM plpuri@dti.telethon.it RI Forcales, Sonia/B-2157-2013; Valente, Sergio/K-2198-2016; Palacios, Daniela/K-4698-2016; OI Valente, Sergio/0000-0002-2241-607X; Palacios, Daniela/0000-0002-2207-2369; Proserpio, Valentina/0000-0003-2071-4206; Mozzetta, Chiara/0000-0002-7147-7266; Forcales, Sonia/0000-0002-7111-4959 FU National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMSD) [R01 AR053779]; European Community [241440]; Sanford Children's Health Research Center; Association Francaise contre les Myopathies (AFM) [14767]; Associazione Italiana Ricerca sul Cancro (AIRC); Parent Project Onlus; AIRC MFAG; Marie Curie Reintegration Grant; AFM; National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the NIH; Fondazione Telethon FX P.L.P. is an Associate Telethon Scientist of the Dulbecco Telethon Institute (DTI) and Associate Investigator of Sanford Children's Health Research Center. This work has been supported by the following grants to P.L.P.: R01 AR053779 from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMSD); research funding from the European Community's Seventh Framework Programme in the project ENDOSTEM (Activation of vasculature associated stem cells and muscle stem cells for the repair and maintenance of muscle tissue; grant agreement number 241440); Sanford Children's Health Research Center grant; Association Francaise contre les Myopathies (AFM, Pharmacological treatment of muscular dystrophy: insight into deacetylase inhibitor-mediated regeneration and synergistic cooperation with anti-inflammatoryagents" code # 14767); Associazione Italiana Ricerca sul Cancro (AIRC); and Parent Project Onlus.; G.C. is supported by AIRC MFAG and Marie Curie Reintegration Grant. C.M. is a recipient of AFM fellowship. This work was also supported in part by the Intramural Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the NIH to V.S. NR 79 TC 167 Z9 169 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 8 PY 2010 VL 7 IS 4 BP 455 EP 469 DI 10.1016/j.stem.2010.08.013 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 668LJ UT WOS:000283270600008 PM 20887952 ER PT J AU Shiels, A Bennett, TM Hejtmancik, JF AF Shiels, Alan Bennett, Thomas M. Hejtmancik, J. Fielding TI Cat-Map: putting cataract on the map SO MOLECULAR VISION LA English DT Article ID AGE-RELATED CATARACT; SIGNIFICANT FAMILIAL AGGREGATION; RECESSIVE CONGENITAL CATARACTS; IDIOPATHIC PRESENILE CATARACT; SHARED ENVIRONMENTAL-FACTORS; AUTOSOMAL-DOMINANT CATARACT; TARGETED GENOMIC DELETION; NANCE-HORAN-SYNDROME; S-TRANSFERASE M1; NUCLEAR CATARACT AB Lens opacities, or cataract(s), may be inherited as a classic Mendelian disorder usually with early-onset or, more commonly, acquired with age as a multi-factorial or complex trait. Many genetic forms of cataract have been described in mice and other animal models. Considerable progress has been made in mapping and identifying the genes and mutations responsible for inherited forms of cataract, and genetic determinants of age-related cataract are beginning to be discovered. To provide a convenient and accurate summary of current information focused on the increasing genetic complexity of Mendelian and age-related cataract we have created an online chromosome map and reference database for cataract in humans and mice (Cat-Map). C1 [Shiels, Alan; Bennett, Thomas M.] Washington Univ, Dept Ophthalmol & Visual Sci, Sch Med, St Louis, MO 63110 USA. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Shiels, A (reprint author), Washington Univ, Dept Ophthalmol & Visual Sci, Sch Med, Campus Box 8096,660 S Euclid Ave, St Louis, MO 63110 USA. EM shiels@vision.wustl.edu FU NIH/NEI [EY012284, EY02687]; Research to Prevent Blindness FX We thank Frank Schottler for website assistance and an anonymous reviewer for insightful comments. This work was supported by NIH/NEI grants EY012284 (to A.S.) and EY02687 (Core grant for vision research), and by an unrestricted grant to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness. NR 112 TC 86 Z9 86 U1 1 U2 7 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD OCT 8 PY 2010 VL 16 IS 215-19 BP 2007 EP 2015 PG 9 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 674ED UT WOS:000283716000002 PM 21042563 ER PT J AU Keiser, PB Gibbs, BT Coster, TS Moran, EE Stoddard, MB Labrie, JE Schmiel, DH Pinto, V Chen, P Zollinger, WD AF Keiser, Paul B. Gibbs, Barnett T. Coster, Trinka S. Moran, E. Ellen Stoddard, Mark B. Labrie, Joseph E., III Schmiel, Deborah H. Pinto, Valerian Chen, Ping Zollinger, Wendell D. TI A phase 1 study of a group B meningococcal native outer membrane vesicle vaccine made from a strain with deleted lpxL2 and synX and stable expression of opcA SO VACCINE LA English DT Article DE Neisseria; NOMV; lpxL2; Lipooligosaccharide; OpcA ID NEISSERIA-MENINGITIDIS; UNITED-STATES; ANTIBODIES; MICE; DISEASE AB This phase 1 clinical trial assessed the safety and immunogenicity of a native outer membrane vesicle (NOMV) vaccine prepared from a IpxL2(-)synX(-)mutant of strain 44/76 with opcA expression stabilized. Thirty-four volunteers were assigned to one of the three dose groups (25 mcg, 25 mcg with aluminum hydroxide adjuvant, and 50 mcg) to receive three intramuscular injections at 0, 6 and 24 weeks. Specific local and systemic adverse events (AEs) were solicited by diary and at visits on days 1, 2, 7 and 14 after each vaccination and at the end of the study at 30 weeks. Blood chemistries, complete blood count, and coagulation studies were measured on each vaccination day and again two days later. Blood for antibody measurements and bactericidal assays were drawn 0, 14, and 42 days after each vaccination. The proportion of volunteers who developed a fourfold or greater increase in serum bactericidal activity (SBA) to the wild-type parent of the vaccine strain with high opcA expression at 6 weeks after the third dose was 12/26 (0.46, 95% confidence interval 0.27-0.65). Antibody levels to OpcA were significantly higher in vaccine responders than in non-responders (p = 0.008), and there was a trend for higher antibody levels to the lipooligosaccharide (LOS) (p = 0.059). Bactericidal depletion assays on sera from volunteers with high-titer responses also indicate a major contribution of anti-OpcA and anti-LOS antibodies to the bactericidal response. These results suggest that genetically modified NOMV vaccines can induce protection against group B meningococcus. Published by Elsevier Ltd. C1 [Keiser, Paul B.; Moran, E. Ellen; Labrie, Joseph E., III; Schmiel, Deborah H.; Pinto, Valerian; Zollinger, Wendell D.] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Gibbs, Barnett T.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Coster, Trinka S.] USA, Off Surg Gen, Silver Spring, MD USA. [Stoddard, Mark B.] Univ Alabama, Sch Med, Birmingham, AL USA. [Chen, Ping] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Keiser, PB (reprint author), Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. EM paul.keiser@us.army.mil RI Schmiel, Deborah/B-2875-2011; Zollinger, Wendell/B-2887-2011 FU Military Infectious Disease Research Program FX This study was funded by the Military Infectious Disease Research Program, Fort Detrick, MD. Disclosure: Presented in part as a poster at the International Pathogenic Neisseria Conference, September 2008 in Rotterdam, Netherlands. NR 27 TC 28 Z9 28 U1 2 U2 4 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 OCT 8 PY 2010 VL 28 IS 43 BP 6970 EP 6976 DI 10.1016/j.vaccine.2010.08.048 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 677DW UT WOS:000283970300004 PM 20732470 ER PT J AU Zielinski, RJ Smedley, JV Perera, PY Silvera, PM Waldmann, TA Capala, J Perera, LP AF Zielinski, Rafal J. Smedley, Jeremy V. Perera, Pin-Yu Silvera, Peter M. Waldmann, Thomas A. Capala, Jacek Perera, Liyanage P. TI Smallpox vaccine with integrated IL-15 demonstrates enhanced in vivo viral clearance in immunodeficient mice and confers long term protection against a lethal monkeypox challenge in cynomolgus monkeys SO VACCINE LA English DT Article DE Smallpox vaccine; IL-15; Monkeypox ID HUMAN INTERLEUKIN-2; EXPRESSING IL-2; VIRUS; IMMUNITY; IMMUNOGENICITY; INFECTION; RESPONSES; IMMUNIZATION; EFFICACY; STRAIN AB Despite the eradication of smallpox, there is heightened concern that it could be reintroduced as a result of intentional release of Variola major virus through an act of bioterrorism. The live vaccine that was pivotal in the eradication of smallpox though considered a gold standard for its efficacy still retains sufficient residual virulence that can cause life-threatening sequelae especially in immune deficient individuals. Therefore, a safer smallpox vaccine that can match the efficacy of first generation vaccines is urgently needed. We previously reported that the integration of human IL-15 cytokine into the genome of Wyeth strain of vaccinia (Wyeth/IL-15), the same strain as the licensed vaccine, generates a vaccine with superior immunogenicity and efficacy in a mouse model. We now demonstrate that Wyeth/IL-15 is non-lethal to athymic nude mice when administered intravenously at a dose of 107 plaque forming units and it undergoes enhanced in vivo clearance in these immune deficient mice. Furthermore, a majority of cynomolgus monkeys vaccinated with vaccinia viruses with integrated IL-15, when challenged 3 years later with a lethal dose of monkeypox virus displayed milder clinical manifestations with complete recovery supporting the utility of Wyeth/IL-15 for contemporary populations as a safer and efficacious smallpox vaccine. Published by Elsevier Ltd. C1 [Waldmann, Thomas A.; Perera, Liyanage P.] NCI, Ctr Canc Res, Metab Branch, Bethesda, MD 20892 USA. [Zielinski, Rafal J.; Capala, Jacek] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Smedley, Jeremy V.] NCI, Vet Resources Program, Bethesda, MD 20892 USA. [Perera, Pin-Yu] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Silvera, Peter M.] So Res Inst, Frederick, MD 21701 USA. RP Perera, LP (reprint author), NCI, Ctr Canc Res, Metab Branch, Bldg10,Room 4B40, Bethesda, MD 20892 USA. EM pereral@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Cancer Institute, Center for Cancer Research, NIH; Trans-NIH/FDA Intramural Biodefense Program FX This work was in part supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH and by a 3-year competitive research funding award to L.P.P. from the Trans-NIH/FDA Intramural Biodefense Program. NR 36 TC 11 Z9 11 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 OCT 8 PY 2010 VL 28 IS 43 BP 7081 EP 7091 DI 10.1016/j.vaccine.2010.08.008 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 677DW UT WOS:000283970300018 PM 20728526 ER PT J AU Milner, JD Orekov, T Ward, JM Cheng, L Torres-Velez, F Junttila, I Sun, GP Buller, M Morris, SC Finkelman, FD Paul, WE AF Milner, Joshua D. Orekov, Tatyana Ward, Jerrold M. Cheng, Lily Torres-Velez, Fernando Junttila, Ilkka Sun, Guangping Buller, Mark Morris, Suzanne C. Finkelman, Fred D. Paul, William E. TI Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation SO BLOOD LA English DT Article ID LYMPHOHISTIOCYTOSIS HLH; EXPRESSION; MODEL; CELLS; GAMMA; MICE; CYTOKINES; RESPONSES; MURINE; YM1 AB Erythrophagocytosis and inflammation from activated macrophages occur in distinct clinical scenarios. The presence of CD8(+) T cells and interferon-gamma (IFN-gamma) production is required to induce disease in mouse models of hemophagocytic lymphohistiocytosis. We investigated the roles of a different class of proinflammatory cytokines, interleukin-4 (IL-4) and IL-13, in the induction of inflammatory tissue macrophage accumulation and/or hemophagocytosis. We found that large amounts of IL-4, but not IL-13, delivered via an implanted mini-pump or IL-4/anti-IL-4 complexes, lead to substantial YM1(+) tissue macrophage accumulation, erythrophagocytosis within the liver, spleen, and bone marrow, decreased hemoglobin and platelet levels, and acute weight loss. This effect is not dependent on the presence of antibody or T cells, as treatment of Rag2(-/-) mice leads to similar disease, and IFN-gamma neutralization during IL-4 treatment had no effect. IL-4 treatment results in suppression of IL-12, elevation of serum IFN-gamma, IL-10, and the murine IL-8 homolog KC, but not IL-6, IL-1 beta, or tumor necrosis factor-alpha. Finally, mice transgenic for IL-4 production developed tissue macrophage accumulation, disruption of splenic architecture, bone marrow hypocellularity, and extramedullary hematopoiesis. These data describe a novel pathophysiologic pathway for erythrophagocytosis in the context of tissue macrophage accumulation and inflammation involving elevations in IL-4 and alternative macrophage activation. (Blood. 2010;116(14):2476-2483) C1 [Milner, Joshua D.; Junttila, Ilkka; Paul, William E.] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Milner, Joshua D.; Sun, Guangping] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. [Orekov, Tatyana; Morris, Suzanne C.; Finkelman, Fred D.] Univ Cincinnati, Coll Med, Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. [Orekov, Tatyana; Morris, Suzanne C.; Finkelman, Fred D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Buller, Mark] St Louis Univ, Sch Med, Dept Mol Microbiol, St Louis, MO USA. RP Milner, JD (reprint author), NIAID, Immunol Lab, 9000 Rockville Pike,NIH Bldg 10,Rm 12S236A, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU National Institutes of Health [R01AI070300]; NIAID; US Department of Veterans Affairs FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, NIAID, the US Department of Veterans Affairs (merit award), and the National Institutes of Health (grant R01AI070300). NR 20 TC 37 Z9 38 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 OCT 7 PY 2010 VL 116 IS 14 BP 2476 EP 2483 DI 10.1182/blood-2009-11-255174 PG 8 WC Hematology SC Hematology GA 660MA UT WOS:000282645900015 PM 20570861 ER PT J AU Oliveira, JB Bleesing, JJ Dianzani, U Fleisher, TA Jaffe, ES Lenardo, MJ Rieux-Laucat, F Siegel, RM Su, HC Teachey, DT Rao, VK AF Oliveira, Joao B. Bleesing, Jack J. Dianzani, Umberto Fleisher, Thomas A. Jaffe, Elaine S. Lenardo, Michael J. Rieux-Laucat, Frederic Siegel, Richard M. Su, Helen C. Teachey, David T. Rao, V. Koneti TI Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop SO BLOOD LA English DT Article ID FAS GENE-MUTATIONS; LYMPHOCYTE APOPTOSIS; EVANS-SYNDROME; DISORDER; DISEASE; CONSEQUENCES; DEFICIENCY; ACTIVATION; CASPASE-8; FEATURES AB Lymphadenopathy in children for which no infectious or malignant cause can be ascertained constitutes a challenging diagnostic dilemma. Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosis resulting in an accumulation of lymphocytes and childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, and an increased risk of B-cell lymphoma. In 1999, investigators at the National Institutes of Health (NIH) suggested criteria to establish the diagnosis of ALPS. Since then, with approximately 500 patients with ALPS studied worldwide, significant advances in our understanding of the disease have prompted the need for revisions to the existing diagnostic criteria and classification scheme. The rationale and recommendations outlined here stem from an international workshop held at NIH on September 21 and 22, 2009, attended by investigators from the United States, Europe, and Australia engaged in clinical and basic science research on ALPS and related disorders. It is hoped that harmonizing the diagnosis and classification of ALPS will foster collaborative research and better understanding of the pathogenesis of autoimmune cytopenias and B-cell lymphomas. (Blood. 2010;116(14): e35-e40) C1 [Rao, V. Koneti] NIAID, ALPS Unit, LCID, NIH, Bethesda, MD 20892 USA. [Oliveira, Joao B.; Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Bleesing, Jack J.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH USA. [Dianzani, Umberto] Univ Piemonte Orientale, Novara, Italy. [Dianzani, Umberto] Interdisciplinary Res Ctr Autoimmune Dis, Novara, Italy. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Rieux-Laucat, Frederic] Univ Paris 05, INSERM, U768, Paris, France. [Siegel, Richard M.] NIAMSD, Immunoregulat Unit, Autoimmun Branch, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Teachey, David T.] Childrens Hosp Philadelphia, Div Hematol & Oncol, Dept Pediat, Philadelphia, PA USA. RP Rao, VK (reprint author), NIAID, ALPS Unit, LCID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM oliveirajb@cc.nih.gov; krao@niaid.nih.gov RI Su, Helen/H-9541-2015; Dianzani, Umberto/K-1952-2016; Rieux-Laucat, Frederic/A-7916-2017; OI Su, Helen/0000-0002-5582-9110; Rieux-Laucat, Frederic/0000-0001-7858-7866; Oliveira, Joao/0000-0001-9388-8173; Jaffe, Elaine/0000-0003-4632-0301 FU NIH (National Cancer Institute, National Institute of Allergy and Infectious Diseases, Clinical Center); NIH Office of the Rare Diseases; Division of Intramural Research, NIAID FX This research was supported by the Intramural Research Program of the NIH (National Cancer Institute, National Institute of Allergy and Infectious Diseases, Clinical Center), and funding for the ALPS Workshop was provided by NIH Office of the Rare Diseases and Division of Intramural Research, NIAID. NR 37 TC 116 Z9 122 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 7 PY 2010 VL 116 IS 14 BP E35 EP E40 DI 10.1182/blood-2010-04-280347 PG 6 WC Hematology SC Hematology GA 660MA UT WOS:000282645900001 PM 20538792 ER PT J AU Simon, R AF Simon, Richard TI Translational research in oncology: key bottlenecks and new paradigms SO EXPERT REVIEWS IN MOLECULAR MEDICINE LA English DT Review ID CLINICAL-TRIAL DESIGNS; ADAPTIVE SIGNATURE DESIGN; HUMAN BREAST-CANCER; PHARMACOGENOMIC PREDICTOR; ONCOGENE ADDICTION; VALIDATION; CHALLENGES; CARCINOGENESIS; BIOMARKERS; PERSPECTIVES AB Translational research is about transforming progress in basic research into products that benefit patients. Here I discuss some of the key obstacles to effective translational research in oncology that have previously received limited attention. Basic research often does not go far enough for straightforward clinical translation, and long-term, high-risk endeavours to fill these key gaps have not been adequately addressed either by industry or by the culture of investigator-initiated research. These key gaps include the identification of causative oncogenic mutations and new approaches to regulating currently undruggable targets such as tumour suppressor genes. Even where an inhibitor of a key target has been identified, new approaches to clinical development are needed. The current approach of treating broad populations of patients based primarily on primary cancer site is not well suited to the development of molecularly targeted drugs. Although developing drugs with predictive diagnostics makes drug development more complex, it can improve the success rate of development, as well as provide benefit to patients and the economics of healthcare. I review here some prospective Phase III designs that have been developed for transition from the era of correlative science to one of reliable predictive and personalised oncology. C1 NCI, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rsimon@nih.gov NR 47 TC 9 Z9 9 U1 1 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1462-3994 J9 EXPERT REV MOL MED JI Expert Rev. Mol. Med. PD OCT 7 PY 2010 VL 12 AR e32 DI 10.1017/S1462399410001638 PG 11 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 674TV UT WOS:000283773800001 PM 20929594 ER PT J AU Hennessy, E Hughes, SO Goldberg, JP Hyatt, RR Economos, CD AF Hennessy, Erin Hughes, Sheryl O. Goldberg, Jeanne P. Hyatt, Raymond R. Economos, Christina D. TI Parent-child interactions and objectively measured child physical activity: a cross-sectional study SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article ID UNITED-STATES; OBESITY; ADOLESCENTS; STYLE; ACCELEROMETER; POPULATION; OVERWEIGHT; BEHAVIORS; SOCIALIZATION; PERSPECTIVE AB Background: Parents influence their children's behaviors directly through specific parenting practices and indirectly through their parenting style. Some practices such as logistical and emotional support have been shown to be positively associated with child physical activity (PA) levels, while for others (e. g. monitoring) the relationship is not clear. The objectives of this study were to determine the relationship between parent's PA-related practices, general parenting style, and children's PA level. Methods: During the spring of 2007 a diverse group of 99 parent-child dyads (29% White, 49% Black, 22% Hispanic; 89% mothers) living in low-income rural areas of the US participated in a cross-sectional study. Using validated questionnaires, parents self-reported their parenting style (authoritative, authoritarian, permissive, and uninvolved) and activity-related parenting practices. Height and weight were measured for each dyad and parents reported demographic information. Child PA was measured objectively through accelerometers and expressed as absolute counts and minutes engaged in intensity-specific activity. Results: Seventy-six children had valid accelerometer data. Children engaged in 113.4 +/- 37.0 min. of moderate-vigorous physical activity (MVPA) per day. Children of permissive parents accumulated more minutes of MVPA than those of uninvolved parents (127.5 vs. 97.1, p < 0.05), while parents who provided above average levels of support had children who participated in more minutes of MVPA (114.2 vs. 98.3, p = 0.03). While controlling for known covariates, an uninvolved parenting style was the only parenting behavior associated with child physical activity. Parenting style moderated the association between two parenting practices - reinforcement and monitoring - and child physical activity. Specifically, post-hoc analyses revealed that for the permissive parenting style group, higher levels of parental reinforcement or monitoring were associated with higher levels of child physical activity. Conclusions: This work extends the current literature by demonstrating the potential moderating role of parenting style on the relationship between activity-related parenting practices and children's objectively measured physical activity, while controlling for known covariates. Future studies in this area are warranted and, if confirmed, may help to identify the mechanism by which parents influence their child's physical activity behavior. C1 [Hennessy, Erin] NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [Hughes, Sheryl O.] Baylor Coll Med, USDA ARS Childrens Nutr Res Ctr, Dept Pediat, Houston, TX 77030 USA. [Goldberg, Jeanne P.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Hyatt, Raymond R.] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Economos, Christina D.] Tufts Univ, Friedman Sch Nutr Sci & Policy, John Hancock Res Ctr Phys Act Nutr & Obes Prevent, Boston, MA 02111 USA. RP Hennessy, E (reprint author), NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. EM hennessye@mail.nih.gov FU Centers for Disease Control and Prevention [1R36DP001325-01]; New Balance Foundation; Save the Children, US Programs; Robert Wood Johnson Foundation [59458] FX This research was supported by awards from the Centers for Disease Control and Prevention (Public Health Dissertation Research Award, Grant 1R36DP001325-01) and New Balance Foundation with additional funding provided by Save the Children, US Programs and the Robert Wood Johnson Foundation (Grant 59458). NR 65 TC 46 Z9 46 U1 0 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD OCT 7 PY 2010 VL 7 AR 71 DI 10.1186/1479-5868-7-71 PG 14 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 671NG UT WOS:000283512200001 PM 20929570 ER PT J AU Oshinski, JN Delfino, JG Sharma, P Gharib, AM Pettigrew, RI AF Oshinski, John N. Delfino, Jana G. Sharma, Puneet Gharib, Ahmed M. Pettigrew, Roderic I. TI Cardiovascular magnetic resonance at 3.0T: Current state of the art SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Review ID MYOCARDIAL-PERFUSION MR; TO-NOISE RATIO; 3 TESLA; FREE PRECESSION; FIELD-STRENGTH; IN-VIVO; CLINICAL-APPLICATIONS; CORONARY-ARTERIES; CAROTID-ARTERY; K-SPACE AB There are advantages to conducting cardiovascular magnetic resonance (CMR) studies at a field strength of 3.0 Telsa, including the increase in bulk magnetization, the increase in frequency separation of off-resonance spins, and the increase in T1 of many tissues. However, there are significant challenges to routinely performing CMR at 3.0T, including the reduction in main magnetic field homogeneity, the increase in RF power deposition, and the increase in susceptibility-based artifacts. In this review, we outline the underlying physical effects that occur when imaging at higher fields, examine the practical results these effects have on the CMR applications, and examine methods used to compensate for these effects. Specifically, we will review cine imaging, MR coronary angiography, myocardial perfusion imaging, late gadolinium enhancement, and vascular wall imaging. C1 [Oshinski, John N.; Delfino, Jana G.; Sharma, Puneet] Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. [Oshinski, John N.] Emory Univ, Dept Biomed Engn, Atlanta, GA 30322 USA. [Oshinski, John N.] Georgia Inst Technol, Atlanta, GA 30322 USA. [Gharib, Ahmed M.; Pettigrew, Roderic I.] NIDDKD, Lab Integrat Cardiovasc Imaging, Dept Radiol, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. RP Oshinski, JN (reprint author), Emory Univ, Sch Med, Dept Radiol, 1364 Clifton Rd,Room AG34, Atlanta, GA 30322 USA. EM jnoshin@emory.edu RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X FU American Heart Association [08553863E]; National Institutes of Health [HL089160]; Wallace Coulter Foundation; Philips Medical Systems; Siemens Medical Solutions FX The authors would like to acknowledge funding from the American Heart Association (Grant-in-aid no. 08553863E), the National Institutes of Health (HL089160), and the Wallace Coulter Foundation.; John Oshinski has received research funding from Philips Medical Systems and Siemens Medical Solutions. NR 93 TC 32 Z9 34 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD OCT 7 PY 2010 VL 12 AR 55 DI 10.1186/1532-429X-12-55 PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 671NN UT WOS:000283512900001 PM 20929538 ER PT J AU Berezhkovskii, AM Dagdug, L AF Berezhkovskii, Alexander M. Dagdug, Leonardo TI Biased diffusion in tubes formed by spherical compartments SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID PERIODIC POROUS MATERIALS; NARROW ESCAPE; TRANSPORT AB We study the effect of the driving force on Brownian motion of a point particle in a tube formed by identical spherical compartments, which create periodic entropy potential for the motion along the tube axis. The focus is on (i) the effective mobility and diffusion coefficient of the particle as functions of the driving force, (ii) localization of the particle in the central part of the tube induced by the driving force, and (iii) transit time of the particle between the openings connecting neighboring compartments. Some of the results at very small and large driving force are obtained analytically, while the majority of the results are obtained from Brownian dynamics simulations. (C) 2010 American Institute of Physics. [doi:10.1063/1.3489375] C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM dll@xanum.uam.mx FU NIH, Center for Information Technology FX We are grateful to Sergey Bezrukov, Yurii Makhnovskii, and Vladimir Zitserman for numerous illuminating discussions of different aspects of transport in the presence of entropy barriers. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 43 TC 23 Z9 23 U1 0 U2 5 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 OCT 7 PY 2010 VL 133 IS 13 AR 134102 DI 10.1063/1.3489375 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 661CE UT WOS:000282699800005 PM 20942518 ER PT J AU Venable, RM Hatcher, E Guvench, O MacKerell, AD Pastor, RW AF Venable, Richard M. Hatcher, Elizabeth Guvench, Olgun MacKerell, Alexander D., Jr. Pastor, Richard W. TI Comparing Simulated and Experimental Translation and Rotation Constants: Range of Validity for Viscosity Scaling SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; AQUEOUS CARBOHYDRATE SOLUTIONS; PARTICLE MESH EWALD; C-13 NMR RELAXATION; DIFFUSION-COEFFICIENTS; TRANSPORT-PROPERTIES; WATER; DEPENDENCE; HYDRATION; MALTOSE AB Proper simulation of dynamic properties, including molecular diffusion, is an important goal of empirical force fields. However, the widely used TIP3P water model does not reproduce the experimental viscosity of water. Consequently, scaling of simulated diffusion constants of solutes in aqueous solutions is required to effectively compare them with experiment. It is proposed that scaling by the ratio of viscosities of model and real water is appropriate in the regime where the concentration dependence of simulated and experimental solution viscosities is parallel. With this ansatz, viscosity scaling can be carried out for glucose and trehalose Lip to 20 wt % for simulations carried out with the CHARMM additive carbohydrate force field C35 and TIP3P water; above this value, the concentration dependence of simulated viscosities lags that of experiment, and scaling is not advised. Scaled translational diffusion constants for glucose and the disaccharides trehalose, maltose, and melibiose at low concentration agree nearly quantitatively with experiment, as do NMR (13)C T(1)'s for glucose, trehalose, and maltose; these results support the use of C35 for simulations of sugar transport properties at low concentration. At high concentrations the scaled diffusion constants for glucose and trehalose underestimate and overestimate experiment, respectively. Hydrodynamic bead model calculations indicate a hydration level of approximately I water/hydroxyl for glucose. Patterns for the disaccharides are more complicated, though trehalose binds 0.5 to 1 more water than does maltose depending on the analysis. C1 [Venable, Richard M.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Hatcher, Elizabeth; Guvench, Olgun; MacKerell, Alexander D., Jr.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Guvench, Olgun] Univ New England, Coll Pharm, Dept Pharmaceut Sci, Portland, ME 04103 USA. RP Pastor, RW (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov OI MacKerell, Alex/0000-0001-8287-6804 FU NIH, National Heart, Lung and Blood Institute [GM070855] FX This research was supported in part by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, by NIH Grant GM070855 to ADM Jr., and utilized the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (NHLBI LoBoS cluster). NR 42 TC 25 Z9 25 U1 1 U2 18 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 OCT 7 PY 2010 VL 114 IS 39 BP 12501 EP 12507 DI 10.1021/jp105549s PG 7 WC Chemistry, Physical SC Chemistry GA 654ZK UT WOS:000282209900009 PM 20831149 ER PT J AU Mathews, LA Hurt, EM Zhang, XH Farrar, WL AF Mathews, Lesley A. Hurt, Elaine M. Zhang, Xiaohu Farrar, William L. TI Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells SO MOLECULAR CANCER LA English DT Article ID BMX TYROSINE KINASE; EPITHELIAL-MESENCHYMAL TRANSITION; EMBRYONIC STEM-CELLS; ENDOTHELIAL GROWTH-FACTOR; STAT3 ACTIVATION; BREAST-CANCER; METASTATIC PROGRESSION; COLORECTAL-CANCER; SIGNALING PATHWAY; GENE-EXPRESSION AB Background: Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs) that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation. Results: Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1. Conclusions: Using this method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub-populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis. C1 [Mathews, Lesley A.; Hurt, Elaine M.; Farrar, William L.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Zhang, Xiaohu] NCI, Canc Stem Cell Sect, Lab Canc Prevent, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Farrar, WL (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. EM farrarw@mail.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research 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, and supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 71 TC 22 Z9 22 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD OCT 7 PY 2010 VL 9 AR 267 DI 10.1186/1476-4598-9-267 PG 17 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 669WK UT WOS:000283380700001 PM 20929579 ER PT J AU Cai, QA Lu, L Tian, JH Zhu, YB Qiao, HF Sheng, ZH AF Cai, Qian Lu, Li Tian, Jin-Hua Zhu, Yi-Bing Qiao, Haifa Sheng, Zu-Hang TI Snapin-Regulated Late Endosomal Transport Is Critical for Efficient Autophagy-Lysosomal Function in Neurons SO NEURON LA English DT Article ID RETROGRADE TRANSPORT; NERVOUS-SYSTEM; CELLS; PROTEIN; DYNEIN; DEGENERATION; ORGANELLES; FUSION; MICE; NEURODEGENERATION AB Neuron maintenance and survival require late endocytic transport from distal processes to the soma where lysosomes are predominantly localized. Here, we report a role for Snapin in attaching dynein to late endosomes through its intermediate chain (DIC). snapin(-/-) neurons exhibit aberrant accumulation of immature lysosomes, clustering and impaired retrograde transport of late endosomes along processes, reduced lysosomal proteolysis due to impaired delivery of internalized proteins and hydrolase precursors from late endosomes to lysosomes, and impaired clearance of autolysosomes, combined with reduced neuron viability and neurodegeneration. The phenotypes are rescued by expressing the snapin transgene, but not the DIC-binding-defective Snapin-L99K mutant. Snapin overexpression in wild-type neurons enhances late endocytic transport and lysosomal function, whereas expressing the mutant defective in Snapin-DIC coupling shows a dominant-negative effect. Altogether, our study highlights new mechanistic insights into "how Snapin-DIC coordinates retrograde transport and late endosomal-lysosomal trafficking critical for autophagy-lysosomal function, and thus neuronal homeostasis. C1 [Cai, Qian; Lu, Li; Tian, Jin-Hua; Zhu, Yi-Bing; Qiao, Haifa; Sheng, Zu-Hang] Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Cai, QA (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Room 2B-215,35 Convent Dr, Bethesda, MD 20892 USA. EM caiq@ninds.nih.gov; shengz@ninds.nih.gov FU NINDS, NIH; NIH FX We thank R. Youle, H Arnheiter, and members of the Sheng lab for helpful discussions, D. Glazer-Schoenberg, M Davis, and J Tokita for editing; B Zhou for mouse maintenance and genotyping; X Zhuang, B. Firestein, P.D. Stahl, W Li, and N Raben for reagents; and NINDS Facility for Electron Microscopy, DNA Sequencing, and Protein Sequencing. L.L. and Y.-B.Z. are graduate students of the NIH-Shanghai Jiao-Tong University Joint Ph D. Program. This work was supported by the Intramural Research Program of NINDS, NIH (Z-H S.) and the NIH Pathway to Independence Award K99 (Q.C.). The authors declare no competing financial interests NR 42 TC 75 Z9 76 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD OCT 7 PY 2010 VL 68 IS 1 BP 73 EP 86 DI 10.1016/j.neuron.2010.09.022 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 674AA UT WOS:000283704200009 PM 20920792 ER PT J AU Appelbaum, L Wang, G Yokogawa, T Skariah, GM Smith, SJ Mourrain, P Mignot, E AF Appelbaum, Lior Wang, Gordon Yokogawa, Tohei Skariah, Gemini M. Smith, Stephen J. Mourrain, Philippe Mignot, Emmanuel TI Circadian and Homeostatic Regulation of Structural Synaptic Plasticity in Hypocretin Neurons SO NEURON LA English DT Article ID DEVELOPING VISUAL-SYSTEM; IN-VIVO; GENE-EXPRESSION; OREXIN NEURONS; AMPA RECEPTORS; SLEEP; ZEBRAFISH; PENTRAXIN; NARP; WAKEFULNESS AB Neurons exhibit rhythmic activity that ultimately affects behavior such as sleep. In living zebrafish larvae, we used time-lapse two-photon imaging of the presynaptic marker synaptophysin in hypocretin/orexin (HCRT) neurons to determine the dynamics of synaptic modifications during the day and night. We observed circadian rhythmicity in synapse number in HCRT axons. This rhythm is regulated primarily by the circadian clock but is also-affected by sleep deprivation. Furthermore, NPTX2, a protein implicated in AMPA receptor clustering, modulates circadian synaptic changes. In zebrafish, nptx2b is a rhythmic gene that is mostly expressed in hypothalamic and pineal gland cells. Arrhythmic transgenic nptx2b overexpression (hcrt:NPTX2b) increases synapse number and abolishes rhythmicity in HCRT axons. Finally, hcrt:NPTX2b fish are resistant to the sleep-promoting effects of melatonin. This behavioral effect is consistent with NPTX2b-mediated increased activity of HCRT circuitry. These data provide real-time in vivo evidence of circadian and homeostatic regulation of structural synaptic plasticity. C1 [Appelbaum, Lior; Yokogawa, Tohei; Mignot, Emmanuel] Stanford Univ, Howard Hughes Med Inst, Palo Alto, CA 94305 USA. [Wang, Gordon; Smith, Stephen J.] Stanford Univ, Beckman Ctr, Dept Mol & Cellular Physiol, Palo Alto, CA 94305 USA. [Yokogawa, Tohei] NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Mourrain, Philippe] INSERM, U784, F-75005 Paris, France. [Appelbaum, Lior; Yokogawa, Tohei; Skariah, Gemini M.; Mourrain, Philippe; Mignot, Emmanuel] Stanford Univ, Dept Psychiat & Behav Sci, Ctr Narcolepsy, Stanford, CA 94305 USA. RP Appelbaum, L (reprint author), Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. EM mourrain@stanford.edu FU McKnight Foundation; NIH [NS23724, NS062798]; Howard Hughes Medical Research Institute; Vincent Coates Foundation FX We thank Laura Alexandere and Wilfredo Mann for assistance in fish maintenance and experiments We thank Dr Geraldine Maro for her expertise and assistance in confocal microscopy We also thank Dr Jamie Zeitzer and Dr Oren levy for helping in statistical analysis and Dr Matthew E Carter. Dr Brian Grone, Dr Juliette Faraco, Dr Simon Warby, Dr Yoav Gothilf, and Dr Luis de Lecea for helpful comments on the manuscript This research was supported by the McKnight Foundation. the NIH (NS23724, NS062798), the Howard Hughes Medical Research Institute (E M), and the Vincent Coates Foundation (S J S) NR 65 TC 75 Z9 78 U1 4 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD OCT 7 PY 2010 VL 68 IS 1 BP 87 EP 98 DI 10.1016/j.neuron.2010.09.006 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 674AA UT WOS:000283704200010 PM 20920793 ER PT J AU Le Floc'h, S Cloutier, G Finet, G Tracqui, P Pettigrew, RI Ohayon, J AF Le Floc'h, Simon Cloutier, Guy Finet, Gerard Tracqui, Philippe Pettigrew, Roderic I. Ohayon, Jacques TI On the potential of a new IVUS elasticity modulus imaging approach for detecting vulnerable atherosclerotic coronary plaques: in vitro vessel phantom study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; POLYVINYL-ALCOHOL HYDROGEL; SPECKLE MODEL ESTIMATOR; INTRAVASCULAR ULTRASOUND; ENDOVASCULAR ELASTOGRAPHY; CIRCUMFERENTIAL STRESS; MECHANICAL-PROPERTIES; CAP THICKNESS; PART I; RUPTURE AB Peak cap stress amplitude is recognized as a good indicator of vulnerable plaque (VP) rupture. However, such stress evaluation strongly relies on a precise, but still lacking, knowledge of the mechanical properties exhibited by the plaque components. As a first response to this limitation, our group recently developed, in a previous theoretical study, an original approach, called iMOD (imaging modulography), which reconstructs elasticity maps (or modulograms) of atheroma plaques from the estimation of strain fields. In the present in vitro experimental study, conducted on polyvinyl alcohol cryogel arterial phantoms, we investigate the benefit of coupling the iMOD procedure with the acquisition of intravascular ultrasound (IVUS) measurements for detection of VP. Our results show that the combined iMOD-IVUS strategy: (1) successfully detected and quantified soft inclusion contours with high positive predictive and sensitivity values of 89.7 +/- 3.9% and 81.5 +/- 8.8%, respectively, (2) estimated reasonably cap thicknesses larger than similar to 300 mu m, but underestimated thinner caps, and (3) quantified satisfactorily Young's modulus of hard medium (mean value of 109.7 +/- 23.7 kPa instead of 145.4 +/- 31.8 kPa), but overestimated the stiffness of soft inclusions (mean Young's moduli of 31.4 +/- 9.7 kPa instead of 17.6 +/- 3.4 kPa). All together, these results demonstrate a promising benefit of the new iMOD-IVUS clinical imaging method for in vivo VP detection. C1 [Le Floc'h, Simon; Cloutier, Guy] Univ Montreal Hosp CRCHUM, Lab Biorheol & Med Ultrason, Res Ctr, Montreal, PQ, Canada. [Le Floc'h, Simon; Tracqui, Philippe; Ohayon, Jacques] CNRS, Lab TIMC DynaCell, UJF, UMR 5525,In3S, Grenoble, France. [Cloutier, Guy] Univ Montreal, Dept Radiol Radio Oncol & Nucl Med, Montreal, PQ, Canada. [Cloutier, Guy] Univ Montreal, Inst Biomed Engn, Montreal, PQ, Canada. [Finet, Gerard] Hosp Civils Lyon, Dept Hemodynam & Intervent Cardiol, Lyon, France. [Finet, Gerard] Univ Lyon 1, INSERM Unit 886, F-69365 Lyon, France. [Pettigrew, Roderic I.; Ohayon, Jacques] NIDDKD, Lab Integrat Cardiovasc Imaging Sci, NIH, Bethesda, MD 20892 USA. [Ohayon, Jacques] Univ Savoie, Engn Sch Polytech, Savoie, France. RP Cloutier, G (reprint author), Univ Montreal Hosp CRCHUM, Lab Biorheol & Med Ultrason, Res Ctr, Montreal, PQ, Canada. EM Guy.Cloutier@umontreal.ca; Jacques.Ohayon@imag.fr RI Ohayon, Jacques/M-6576-2014 FU Agence Nationale de la Recherche (ANR), France [06-BLAN-0263, 09-BLAN-0423]; Natural Sciences and Engineering Research Council of Canada (NSERC) [323405-06, STPGP-381136-09]; Canadian Institutes of Health Research (CIHR) [CPG-80085]; University Joseph Fourier (UJF), France; Floralis-France; Rhone-Alpes (France) FX The authors thank Professor Denis Favier (L3SR Laboratory, Grenoble, France) for the DMA experiment. Acknowledgements are also addressed to Dr Jeremie Fromageau and Mr Cedric Schmitt of the Laboratory of Biorheology and Medical Ultrasonics, University of Montreal Hospital Research Center, for their experimental supports during in vitro phantom experiments. Grant supports were provided by the Agence Nationale de la Recherche (ANR), France (ATHEBIOMECH project 06-BLAN-0263), and by the collaborative health research joint program of the Natural Sciences and Engineering Research Council of Canada (NSERC 323405-06) and Canadian Institutes of Health Research (CIHR CPG-80085). This research is now supported by a joint international program of the ANR (MELANII project 09-BLAN-0423) and NSERC strategic grant STPGP-381136-09. Financial support was also provided by a post-doctoral appointment (S Le Floc'h) from a valorization research program of the University Joseph Fourier (UJF), France, in partnership with Floralis-France. Funding was also obtained from the Rhone-Alpes (France) research cluster (I3M: Medical Images and Multiscale Models). NR 62 TC 23 Z9 23 U1 0 U2 9 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 7 PY 2010 VL 55 IS 19 BP 5701 EP 5721 DI 10.1088/0031-9155/55/19/006 PG 21 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 653CP UT WOS:000282061800006 PM 20826899 ER PT J AU Bulger, EM May, S Brasel, KJ Schreiber, M Kerby, JD Tisherman, SA Newgard, C Slutsky, A Coimbra, R Emerson, S Minei, JP Bardarson, B Kudenchuk, P Baker, A Christenson, J Idris, A Davis, D Fabian, TC Aufderheide, TP Callaway, C Williams, C Banek, J Vaillancourt, C van Heest, R Sopko, G Hata, JS Hoyt, DB AF Bulger, Eileen M. May, Susanne Brasel, Karen J. Schreiber, Martin Kerby, Jeffrey D. Tisherman, Samuel A. Newgard, Craig Slutsky, Arthur Coimbra, Raul Emerson, Scott Minei, Joseph P. Bardarson, Berit Kudenchuk, Peter Baker, Andrew Christenson, Jim Idris, Ahamed Davis, Daniel Fabian, Timothy C. Aufderheide, Tom P. Callaway, Clifton Williams, Carolyn Banek, Jane Vaillancourt, Christian van Heest, Rardi Sopko, George Hata, J. Steven Hoyt, David B. CA ROC Investigators TI Out-of-Hospital Hypertonic Resuscitation Following Severe Traumatic Brain Injury A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GLASGOW OUTCOME SCALE; RAPID-SEQUENCE INTUBATION; DISABILITY RATING-SCALE; SEVERE HEAD-INJURY; INTRACRANIAL-PRESSURE; SALINE RESUSCITATION; CONSENSUS CONFERENCE; PROSTAGLANDIN E(2); SEPSIS; SCORE AB Context Hypertonic fluids restore cerebral perfusion with reduced cerebral edema and modulate inflammatory response to reduce subsequent neuronal injury and thus have potential benefit in resuscitation of patients with traumatic brain injury (TBI). Objective To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI. Design, Setting, and Participants Multicenter, double-blind, randomized, placebo-controlled clinical trial involving 114 North American emergency medical services agencies within the Resuscitation Outcomes Consortium, conducted between May 2006 and May 2009 among patients 15 years or older with blunt trauma and a prehospital Glasgow Coma Scale score of 8 or less who did not meet criteria for hypovolemic shock. Planned enrollment was 2122 patients. Intervention A single 250-mL bolus of 7.5% saline/6% dextran 70 (hypertonic saline/dextran), 7.5% saline (hypertonic saline), or 0.9% saline (normal saline) initiated in the out-of-hospital setting. Main Outcome Measure Six-month neurologic outcome based on the Extended Glasgow Outcome Scale (GOSE) (dichotomized as >4 or <= 4). Results The study was terminated by the data and safety monitoring board after randomization of 1331 patients, having met prespecified futility criteria. Among the 1282 patients enrolled, 6-month outcomes data were available for 1087 (85%). Baseline characteristics of the groups were equivalent. There was no difference in 6-month neurologic outcome among groups with regard to proportions of patients with severe TBI (GOSE <= 4) (hypertonic saline/dextran vs normal saline: 53.7% vs 51.5%; difference, 2.2% [95% CI, -4.5% to 9.0%]; hypertonic saline vs normal saline: 54.3% vs 51.5%; difference, 2.9% [95% CI, -4.0% to 9.7%]; P=.67). There were no statistically significant differences in distribution of GOSE category or Disability Rating Score by treatment group. Survival at 28 days was 74.3% with hypertonic saline/dextran, 75.7% with hypertonic saline, and 75.1% with normal saline (P=.88). Conclusion Among patients with severe TBI not in hypovolemic shock, initial resuscitation with either hypertonic saline or hypertonic saline/dextran, compared with normal saline, did not result in superior 6-month neurologic outcome or survival. C1 [Bulger, Eileen M.] Univ Washington, Harborview Med Ctr, Dept Surg, Seattle, WA 98104 USA. [May, Susanne; Emerson, Scott] Univ Washington, Dept Biostat, Seattle, WA 98104 USA. [Kudenchuk, Peter] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Bardarson, Berit] Univ Washington, Clin Trials Ctr, Seattle, WA 98104 USA. [Brasel, Karen J.] Med Coll Wisconsin, Dept Surg, Milwaukee, WI 53226 USA. [Aufderheide, Tom P.] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Schreiber, Martin] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Newgard, Craig] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Newgard, Craig] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Kerby, Jeffrey D.; Williams, Carolyn] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. [Tisherman, Samuel A.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Callaway, Clifton] Univ Pittsburgh, Dept Emergency Med, Pittsburgh, PA USA. [Slutsky, Arthur] Univ Toronto, Dept Med, Toronto, ON, Canada. [Baker, Andrew] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Baker, Andrew] Univ Toronto, Dept Anesthesia, Toronto, ON, Canada. [Coimbra, Raul] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. [Davis, Daniel] Univ Calif San Diego, Dept Emergency Med, San Diego, CA 92103 USA. [Minei, Joseph P.; Idris, Ahamed] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA. [Christenson, Jim] Emergency & Hlth Serv Commiss, Vancouver, BC, Canada. [Fabian, Timothy C.] Univ Tennessee, Dept Surg, Memphis, TN USA. [Banek, Jane; Vaillancourt, Christian] Ottawa Res Inst, Dept Emergency Med, Ottawa, ON, Canada. [van Heest, Rardi] Royal Columbia Hosp, Trauma Serv, New Westminster, BC, Canada. [Sopko, George] NHLBI, NIH, Bethesda, MD 20892 USA. [Hata, J. Steven] Univ Iowa, Div Crit Care, Iowa City, IA USA. [Hoyt, David B.] Amer Coll Surg, Chicago, IL USA. RP Bulger, EM (reprint author), Univ Washington, Harborview Med Ctr, Dept Surg, 325 9th Ave,POB 359796, Seattle, WA 98104 USA. EM ebulger@u.washington.edu FU National Heart, Lung, and Blood Institute [5U01 HL077863, HL077881, HL077871, HL077872, HL077866, HL077908, HL077867, HL077885, HL077887, HL077873, HL077865]; National Institute of Neurological Disorders and Stroke; US Army Medical Research and Materiel Command; Canadian Institutes of Health Research (CIHR) Institute of Circulatory and Respiratory Health; Defence Research and Development Canada; Heart and Stroke Foundation of Canada FX The Resuscitation Outcome Consortium is supported by a series of cooperative agreements with 10 regional clinical centers and 1 data coordinating center (5U01 HL077863, HL077881, HL077871, HL077872, HL077866, HL077908, HL077867, HL077885, HL077887, HL077873, HL077865) from the National Heart, Lung, and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke, US Army Medical Research and Materiel Command, the Canadian Institutes of Health Research (CIHR) Institute of Circulatory and Respiratory Health, Defence Research and Development Canada, and the Heart and Stroke Foundation of Canada. NR 41 TC 95 Z9 105 U1 1 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 6 PY 2010 VL 304 IS 13 BP 1455 EP 1464 DI 10.1001/jama.2010.1405 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 658SO UT WOS:000282509900021 PM 20924011 ER PT J AU Rid, A Emanuel, EJ Wendler, D AF Rid, Annette Emanuel, Ezekiel J. Wendler, David TI Evaluating the Risks of Clinical Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PERCUTANEOUS LIVER-BIOPSY; HEALTH UTILITIES INDEX; QUALITY-OF-LIFE; PEDIATRIC RESEARCH; OPTIMAL NUMBER; MINIMAL RISK; IMMUNOTHERAPY; COMPLICATIONS; BENEFIT; ETHICS AB The ethical appropriateness of clinical research depends on protecting participants from excessive risks. Yet no systematic framework has been developed to assess research risks, and as a result, investigators, funders, and review boards rely only on their intuitive judgments. Because intuitive judgments of risk are subject to well-documented cognitive biases, this approach raises concern that research participants are not being adequately protected. To address this situation, we delineate a method called the systematic evaluation of research risks (SERR), which evaluates the risks of research interventions by comparing these interventions with the risks of comparator activities that have been deemed acceptable. This method involves a 4-step process: (1) identify the potential harms posed by the proposed research intervention; (2) categorize the magnitude of the potential harms into 1 of 7 harm levels on a harm scale; (3) quantify or estimate the likelihood of each potential harm; and (4) compare the likelihood of each potential harm from the research intervention with the likelihood of harms of the same magnitude occurring as a result of an appropriate comparator activity. By explicitly delineating, quantifying, and comparing the risks of research interventions with the risks posed by appropriate comparator activities, SERR offers a way to minimize the influence of cognitive biases on the evaluation of research risks and thereby better protect research participants from excessive risks. JAMA. 2010; 304(13): 1472-1479 C1 [Rid, Annette; Emanuel, Ezekiel J.; Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Rid, Annette] Univ Zurich, Inst Biomed Eth, Zurich, Switzerland. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU Department of Bioethics at the National Institutes of Health (NIH) Clinical Center; Swiss National Science Foundation FX This study was funded by the Department of Bioethics at the National Institutes of Health (NIH) Clinical Center. Dr Rid reports receipt of support by a grant from the Swiss National Science Foundation. NR 70 TC 40 Z9 42 U1 5 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 6 PY 2010 VL 304 IS 13 BP 1472 EP 1479 DI 10.1001/jama.2010.1414 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 658SO UT WOS:000282509900023 PM 20924013 ER PT J AU Litton, P Miller, FG AF Litton, Paul Miller, Franklin G. TI What Physician-Investigators Owe Patients Who Participate in Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CLINICAL-RESEARCH; ETHICS; TRIALS C1 [Litton, Paul] Univ Missouri, Sch Law, Columbia, MO 65211 USA. [Miller, Franklin G.] NIH, Bethesda, MD 20892 USA. RP Litton, P (reprint author), Univ Missouri, Sch Law, 203 Hulston Hall, Columbia, MO 65211 USA. EM littonp@missouri.edu NR 8 TC 8 Z9 8 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 6 PY 2010 VL 304 IS 13 BP 1491 EP 1492 DI 10.1001/jama.2010.1409 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 658SO UT WOS:000282509900028 PM 20924018 ER PT J AU Budhu, A Ji, JF Wang, XW AF Budhu, Anuradha Ji, Junfang Wang, Xin W. TI The clinical potential of microRNAs SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Review ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SMALL INTERFERING RNA; NON-TUMOROUS TISSUES; BREAST-CANCER CELLS; HUMAN LUNG CANCERS; REAL-TIME PCR; HEPATOCELLULAR-CARCINOMA; IN-VIVO; EXPRESSION PROFILES; OVARIAN-CANCER AB MicroRNAs are small noncoding RNAs that function to control gene expression. These small RNAs have been shown to contribute to the control of cell growth, differentiation and apoptosis, important features related to cancer development and progression. In fact, recent studies have shown the utility of microRNAs as cancer-related biomarkers. This is due to the finding that microRNAs display altered expression profiles in cancers versus normal tissue. In addition, microRNAs have been associated with cancer progression. In this review, the mechanisms to alter microRNA expression and their relation to cancer will be addressed. Moreover, the potential application of microRNAs in clinical settings will also be highlighted. Finally, the challenges regarding the translation of research involving microRNAs to the clinical realm will be discussed. C1 [Budhu, Anuradha; Ji, Junfang; Wang, Xin W.] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Budhu, A (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM budhua@mail.nih.gov RI Wang, Xin/B-6162-2009 FU Center for Cancer Research, the US National Cancer Institute FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, the US National Cancer Institute. NR 99 TC 49 Z9 59 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD OCT 6 PY 2010 VL 3 AR 37 DI 10.1186/1756-8722-3-37 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 668SX UT WOS:000283291400002 PM 20925959 ER PT J AU Zhang, H Lin, SC Nicolelis, MAL AF Zhang, Hao Lin, Shih-Chieh Nicolelis, Miguel A. L. TI Spatiotemporal Coupling between Hippocampal Acetylcholine Release and Theta Oscillations In Vivo SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; MEDIAL SEPTAL NEURONS; RAT CEREBRAL-CORTEX; CHOLINERGIC SYSTEM; ELECTROPHYSIOLOGICAL CHARACTERISTICS; NONCHOLINERGIC NEURONS; MUSCARINIC RECEPTORS; MEMORY CONSOLIDATION; CORTICAL PLASTICITY; GABAERGIC NEURONS AB Both acetylcholine (ACh) and theta oscillations are important for learning and memory, but the dynamic interaction between these two processes remains unclear. Recent advances in amperometry techniques have revealed phasic ACh releases in vivo. However, it is unknown whether phasic ACh release co-occurs with theta oscillations. We investigated this issue in the CA1 region of urethane-anesthetized male rats using amperometric and electrophysiological recordings. We found that ACh release was highly correlated with the appearance of both spontaneous and induced theta oscillations. Moreover, the maximal ACh release was observed around or slightly above the pyramidal layer. Interestingly, such release lagged behind theta initiation by 25-60 s. The slow ACh release profile was matched by the slow firing rate increase of a subset of medial-septal low-firing-rate neurons. Together, these results establish, for the first time, the in vivo coupling between phasic ACh release and theta oscillations on spatiotemporal scales much finer than previously known. These findings also suggest that phasic ACh is not required for theta initiation and may instead operate synergistically with theta oscillations to promote neural plasticity in the service of learning and memory. C1 [Zhang, Hao; Lin, Shih-Chieh; Nicolelis, Miguel A. L.] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. [Lin, Shih-Chieh; Nicolelis, Miguel A. L.] Duke Univ, Ctr Neuroengn, Durham, NC 27710 USA. [Nicolelis, Miguel A. L.] Duke Univ, Dept Biomed Engn, Durham, NC 27710 USA. [Nicolelis, Miguel A. L.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27710 USA. [Lin, Shih-Chieh] NIA, NIH, Baltimore, MD 21224 USA. [Nicolelis, Miguel A. L.] Edmond & Lily Safra Int Inst Neurosci Natal, BR-59066060 Natal, RN, Brazil. RP Zhang, H (reprint author), Duke Univ, Med Ctr, Dept Neurobiol, 101 Bryan Res Bldg,311 Res Dr, Durham, NC 27710 USA. EM zhanghao@neuro.duke.edu RI Incemaq, Inct/J-8752-2013; Zhang, Hao/D-7270-2013; OI Zhang, Hao/0000-0003-1833-7069; Lin, Shih-Chieh/0000-0003-3693-5476 FU National Institutes of Health (NIH) [5R01 DE011451-11]; NIH-National Institute of Neurological Disorders and Stroke [R33NS049534]; National Alliance for Research on Schizophrenia and Depression 2008 Young Investigator Award; National Institute on Aging (NIH) FX This research was supported by National Institutes of Health (NIH) Grant 5R01 DE011451-11 and NIH-National Institute of Neurological Disorders and Stroke Grant R33NS049534 to M.A.L.N. and by the National Alliance for Research on Schizophrenia and Depression 2008 Young Investigator Award and the Intramural Research Program of the National Institute on Aging (NIH) to S.-C. L. We thank Dr. Georgia Alexander for critical discussions and comments on this manuscript, G. Lehew and J. Meloy for technical assistance, and Susan Halkiotis for proofreading this manuscript. NR 79 TC 35 Z9 35 U1 1 U2 17 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 6 PY 2010 VL 30 IS 40 BP 13431 EP 13440 DI 10.1523/JNEUROSCI.1144-10.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 659MQ UT WOS:000282571000023 PM 20926669 ER PT J AU Altshuler, JS Balogh, E Barker, AD Eck, SL Friend, SH Ginsburg, GS Herbst, RS Nass, SJ Streeter, CM Wagner, JA AF Altshuler, Jill S. Balogh, Erin Barker, Anna D. Eck, Stephen L. Friend, Stephen H. Ginsburg, Geoffrey S. Herbst, Roy S. Nass, Sharyl J. Streeter, Christopher M. Wagner, John A. TI Opening Up to Precompetitive Collaboration SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID RESEARCH-AND-DEVELOPMENT; PHARMACEUTICAL INNOVATION; INDUSTRY AB In order to enhance biomedical research and development efficiency and innovation, nontraditional research collaborations have emerged that feature the sharing of information, resources, and capabilities. Although many of these so-called precompetitive collaborations are in the field of oncology, the lessons they offer are broadly applicable to other subfields of translational medicine. C1 [Friend, Stephen H.] Sage Bionetworks, Seattle, WA 98109 USA. [Altshuler, Jill S.; Streeter, Christopher M.] AltshulerGray, Brookline, MA 02445 USA. [Balogh, Erin; Nass, Sharyl J.] Inst Med, Washington, DC 20001 USA. [Barker, Anna D.] NCI, NIH, Bethesda, MD 20892 USA. [Eck, Stephen L.] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Ginsburg, Geoffrey S.] Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC 27708 USA. [Herbst, Roy S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wagner, John A.] Merck & Co Inc, Merck Res Labs, Rahway, NJ 07065 USA. RP Friend, SH (reprint author), Sage Bionetworks, Seattle, WA 98109 USA. EM friend@sagebase.org FU National Cancer Institute; Centers for Disease Control and Prevention, Food and Drug Administration; American Cancer Society; American Society of Clinical Oncology; Association of American Cancer Institutes; C-Change; CEO Roundtable on Cancer FX The responsibility for the content of this article rests with the authors and does not necessarily represent the views of the Institute of Medicine, its committees, or its convening activities. The activities of the National Cancer Policy Forum of the Institute of Medicine are supported by its sponsoring members, which include the National Cancer Institute, Centers for Disease Control and Prevention, Food and Drug Administration, American Cancer Society, American Society of Clinical Oncology, Association of American Cancer Institutes, C-Change, and the CEO Roundtable on Cancer. We thank the workshop speakers and participants. NR 23 TC 22 Z9 22 U1 3 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 6 PY 2010 VL 2 IS 52 AR 52cm26 DI 10.1126/scitranslmed.3001515 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735SV UT WOS:000288438800001 PM 20926831 ER PT J AU Shiels, MS Pfeiffer, RM Engels, EA AF Shiels, Meredith S. Pfeiffer, Ruth M. Engels, Eric A. TI Age at Cancer Diagnosis Among Persons With AIDS in the United States SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTED INDIVIDUALS; HODGKIN LYMPHOMA; CROHNS-DISEASE; HEPATOCELLULAR-CARCINOMA; GENETIC ANTICIPATION; LUNG-CANCER; RISK; PEOPLE AB Background: Studies have reported young ages at cancer diagnosis in HIV-infected persons and have suggested that HIV accelerates carcinogenesis. However, these comparisons did not account for differences in population age structures. Objective: To compare ages at diagnosis for non-AIDS-defining types of cancer that occur in both the AIDS and general populations, after adjustment for differences in age and other demographic characteristics between these populations. Design: Registry linkage study. Setting: 15 HIV/AIDS and cancer registry databases in the United States. Participants: 212 055 persons with AIDS enrolled in the U. S. HIV/AIDS Cancer Match Study from 1996 to 2007. Measurements: Comparison of age-at-diagnosis distributions for various types of cancer in both the AIDS and general populations, after adjustment for age and other demographic characteristics. Results: The proportion of person-time contributed by older persons (age >= 65 years) was far smaller in the AIDS population (1.5%) than in the general population (12.5%). Reflecting this difference, the ages at diagnosis for most types of cancer were approximately 20 years younger among persons with AIDS. However, after adjustment for differences in the populations at risk, the median ages at diagnosis in the AIDS and general populations did not differ for most types of cancer (for example, colon, prostate, or breast cancer; all P > 0.100). In contrast, ages at diagnosis of lung (median, 50 vs. 54 years) and anal cancer (median, 42 vs. 45 years) were significantly younger in persons with AIDS than expected in the general population (P < 0.001), and the age at diagnosis of Hodgkin lymphoma was significantly older (median, 42 vs. 40 years; P < 0.001). Limitations: Information on other cancer risk factors, including cigarette smoking, was not available. Analysis was restricted to non-Hispanic white and black persons who had AIDS, which could limit the generalizability of the findings to other racial and ethnic groups or to persons with HIV but not AIDS. Conclusion: For most types of cancer, the age at diagnosis is similar in the AIDS and general populations, after adjustment for the ages of the populations at risk. Modest age differences remained for a few types of cancer, which may indicate either acceleration of carcinogenesis by HIV or earlier exposure to cancer risk factors. C1 [Shiels, Meredith S.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. RP Shiels, MS (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7059, Rockville, MD 20892 USA. EM shielsms@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU National Cancer Institute FX Grant Support: By the intramural research program of the National Cancer Institute. NR 39 TC 102 Z9 102 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 5 PY 2010 VL 153 IS 7 BP 452 EP + DI 10.7326/0003-4819-153-7-201010050-00008 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 658VG UT WOS:000282517000004 PM 20921544 ER PT J AU Labay, V Weichert, RM Makishima, T Griffith, AJ AF Labay, Valentina Weichert, Rachel M. Makishima, Tomoko Griffith, Andrew J. TI Topology of Transmembrane Channel-like Gene 1 Protein SO BIOCHEMISTRY LA English DT Article ID HEARING-LOSS; EPIDERMODYSPLASIA-VERRUCIFORMIS; MEMBRANE TOPOLOGY; PREDICTION; CELLS; ER; MODEL; LOCALIZATION; MUTATIONS; DOMINANT AB Mutations of transmembrane channel-like gene 1 (TMC1) cause hearing loss in humans and mice. TMC1 is the founding member of a family of genes encoding proteins of unknown function that are predicted to contain multiple transmembrane domains. The goal of our study was to define the topology of mouse TMC1 expressed heterologously in tissue culture cells. TMC1 was retained in the endoplasmic reticulum (ER) membrane of five tissue culture cell lines that we tested. We used anti-TMC1 and anti-HA antibodies to probe the topologic orientation of three native epitopes and seven HA epitope tags along full-length TMC1 after selective or complete permeabilization of transfected cells with digitonin or Triton X-100, respectively. TMC1 was present within the ER as an integral membrane protein containing six transmembrane domains and cytosolic N- and C-termini. There is a large cytoplasmic loop, between the fourth and fifth transmembrane domains, with two highly conserved hydrophobic regions that might associate with or penetrate, but do not span, the plasma membrane. Our study is the first to demonstrate that TMC1 is a transmembrane protein. The topologic organization revealed by this study shares some features with that of the shaker-TRP superfamily of ion channels. C1 [Labay, Valentina; Weichert, Rachel M.; Makishima, Tomoko; Griffith, Andrew J.] NIDCD, Mol Biol & Genet Sect, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), 5 Res Ct,Room 2B28, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov FU National Institutes of Health [Z01-DC-000060] FX This work was supported by National Institutes of Health Intramural Research Fund Z01-DC-000060. NR 29 TC 25 Z9 26 U1 4 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 5 PY 2010 VL 49 IS 39 BP 8592 EP 8598 DI 10.1021/bi1004377 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 654BZ UT WOS:000282144400015 PM 20672865 ER PT J AU Berezhkovskii, AM Pustovoit, MA Bezrukov, SM AF Berezhkovskii, Alexander M. Pustovoit, Mark A. Bezrukov, Sergey M. TI Fluxes of non-interacting and strongly repelling particles through a single conical channel: Analytical results and their numerical tests SO CHEMICAL PHYSICS LA English DT Article DE Stochastic processes; Diffusion in confined geometries; Entropic effects; Channel-facilitated transport ID FACILITATED MEMBRANE-TRANSPORT; FILE PORES; DIFFUSION AB Using a diffusion model of particle dynamics in the channel, we study entropic effects in channel-facilitated transport. We derive general expressions for the fluxes of non-interacting particles and particles that strongly repel each other through the channel of varying cross section area, assuming that the transport is driven by the difference in particle concentrations on the two sides of the membrane. For a special case of a right truncated cone expanding in the left-to-right direction, we show how the fluxes depend on the geometric parameters of the channel and on the particle concentrations. For non-interacting particles the flux is direction-independent in the sense that inversion of the concentration difference leads to the inversion of the direction of the flux without changing its magnitude. This symmetry is broken for repelling particles: the flux in the left-to-right direction exceeds its right-to-left counterpart. Our theoretical predictions are supported by three-dimensional Brownian dynamics simulations. Published by Elsevier B.V. C1 [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Pustovoit, Mark A.] St Petersburg Nucl Phys Inst, Gatchina 188300, Russia. RP Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM bezrukos@mail.nih.gov FU NIH, Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development; Russian Foundation for Basic Research [08-02-00314a]; Quantum Macrophysics; Strongly Correlated Electrons in Metals, Superconductors, Semiconductors and Magnetic Materials; Neutron studies of matter FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development. M.A.P. also thanks the Russian Foundation for Basic Research (Project 08-02-00314a) and the State Programs "Quantum Macrophysics", "Strongly Correlated Electrons in Metals, Superconductors, Semiconductors and Magnetic Materials", and "Neutron studies of matter" for partial support. NR 36 TC 9 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD OCT 5 PY 2010 VL 375 IS 2-3 BP 523 EP 528 DI 10.1016/j.chemphys.2010.04.040 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 659VH UT WOS:000282594600053 PM 21057663 ER PT J AU Mitchell, GF Wang, N Palmisano, JN Larson, MG Hamburg, NM Vita, JA Levy, D Benjamin, EJ Vasan, RS AF Mitchell, Gary F. Wang, Na Palmisano, Joseph N. Larson, Martin G. Hamburg, Naomi M. Vita, Joseph A. Levy, Daniel Benjamin, Emelia J. Vasan, Ramachandran S. TI Hemodynamic Correlates of Blood Pressure Across the Adult Age Spectrum Noninvasive Evaluation in the Framingham Heart Study SO CIRCULATION LA English DT Article DE aorta; blood pressure; epidemiology; hemodynamics ID ISOLATED SYSTOLIC HYPERTENSION; NUTRITION EXAMINATION SURVEY; AORTIC INPUT IMPEDANCE; PULSE-WAVE VELOCITY; NATIONAL-HEALTH; REFLECTION; STIFFNESS; DIAMETER; WOMEN; MEN AB Background-Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial. Methods and Results-We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing, and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53% women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: In younger participants, pulse pressure was lower and wave reflection was higher with advancing age, whereas in older participants, pulse pressure was higher and wave reflection was lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80% (central) and 66% (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90% and 84% in the older participants (>= 50 years; all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered. Conclusions-Higher pulse pressure at any age and higher pulse pressure with advancing age is associated predominantly with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor. (Circulation. 2010;122:1379-1386.) C1 [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA 02062 USA. [Wang, Na; Palmisano, Joseph N.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBIs Framingham Study, Framingham, MA USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Med, 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. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edgewater Dr,Ste 201A, Norwood, MA 02062 USA. EM GaryFMitchell@mindspring.com OI Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute [N01-HC-25195]; Donald W. Reynolds Foundation; [HL076784]; [AG028321]; [HL070100]; [HL060040]; [HL080124]; [HL071039]; [HL077447]; [2-K24-HL04334] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and by HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, and 2-K24-HL04334 and a grant from the Donald W. Reynolds Foundation. NR 22 TC 106 Z9 107 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 5 PY 2010 VL 122 IS 14 BP 1379 EP + DI 10.1161/CIRCULATIONAHA.109.914507 PG 19 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 658RM UT WOS:000282507100011 PM 20855656 ER PT J AU Canugovi, C Maynard, S Bayne, ACV Sykora, P Tian, JY de Souza-Pinto, NC Croteau, DL Bohr, VA AF Canugovi, Chandrika Maynard, Scott Bayne, Anne-Cecile V. Sykora, Peter Tian, Jingyan de Souza-Pinto, Nadja C. Croteau, Deborah L. Bohr, Vilhelm A. TI The mitochondrial transcription factor A functions in mitochondrial base excision repair SO DNA REPAIR LA English DT Article DE TFAM; BER; Tumor suppressor; ROS (reactive oxygen species); 8oxoG; OGG1 ID FACTOR-A; DNA MUTATIONS; DAMAGED DNA; HUMAN-CELLS; BINDING; TFAM; P53; DELETIONS; PROTEINS; REPLICATION AB Mitochondrial transcription factor A (TFAM) is an essential component of mitochondrial nucleoids TFAM plays an important role in mitochondrial transcription and replication TFAM has been previously reported to inhibit nucleotide excision repair (NER) in vitro but NER has not yet been detected in mitochondria, whereas base excision repair (BER) has been comprehensively characterized in these organelles The BER proteins are associated with the inner membrane in mitochondria and thus with the mitochondrial nucleoid, where TFAM is also situated However, a function for TFAM in BER has not yet been investigated This study examines the role of TFAM in BER In vitro studies with purified recombinant TFAM indicate that it preferentially binds to DNA containing 8-oxoguanines, but not to abasic sites, uracils, or a gap in the sequence TFAM inhibited the in vitro incision activity of 8-oxoguanine DNA glycosylase (OGG1), uracil-DNA glycosylase (UDG), apurinic endonuclease 1 (APE1), and nucleotide incorporation by DNA polymerase gamma (pol gamma) On the other hand, a DNA binding-defective TFAM mutant, L58A, showed less inhibition of BER in vitro Characterization of TFAM knockdown (KD) cells revealed that these lysates had higher 8oxoG incision activity without changes in alpha OGG1 protein levels TFAM KD cells had mild resistance to menadione and increased damage accumulation in the mtDNA when compared to the control cells In addition, we found that the tumor suppressor p53, which has been shown to interact with and alter the DNA binding activity of TFAM, alleviates TFAM-Induced inhibition of BER proteins Together, the results suggest that TFAM modulates BER in mitochondria by virtue of its DNA binding activity and protein interactions Published by Elsevier B V C1 [Canugovi, Chandrika; Maynard, Scott; Bayne, Anne-Cecile V.; Sykora, Peter; Tian, Jingyan; de Souza-Pinto, Nadja C.; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [de Souza-Pinto, Nadja C.] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508 Sao Paulo, Brazil. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; OI Souza-Pinto, Nadja/0000-0003-4206-964X; Maynard, Scott/0000-0001-5625-936X FU National Institute on Aging [Z01-AG000733-14] FX We greatly appreciate the gift of purified pol gamma from Dr William C Copeland, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, USA We would like to thank David M Wilson, III (Laboratory of Molecular Gerontology, NIA, NIH) for hAPE1 protein We would like to thank Dr DK Singh and Dr M Ramamoorthy for critically reading this manuscript This work was supported by the National Institutes of Health Intramural Program of the National Institute on Aging (Z01-AG000733-14) NR 37 TC 46 Z9 49 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD OCT 5 PY 2010 VL 9 IS 10 BP 1080 EP 1089 DI 10.1016/j.dnarep.2010.07.009 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 674OH UT WOS:000283756100009 PM 20739229 ER PT J AU Mukherjee, S Roth, MJ Dawsey, SM Yan, WS Rodriguez-Canales, J Erickson, HS Hu, N Goldstein, AM Taylor, PR Richardson, AM Tangrea, MA Chuaqui, RF Emmert-Buck, MR AF Mukherjee, Sumana Roth, Mark J. Dawsey, Sanford M. Yan, Wusheng Rodriguez-Canales, Jaime Erickson, Heidi S. Hu, Nan Goldstein, Alisa M. Taylor, Philip R. Richardson, Annely M. Tangrea, Michael A. Chuaqui, Rodrigo F. Emmert-Buck, Michael R. TI Increased matrix metalloproteinase activation in esophageal squamous cell carcinoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID EXPRESSION; CANCER; BEHAVIOR; MMP-9 AB Background: Esophageal squamous cell carcinomas (ESCC) are usually asymptomatic and go undetected until they are incurable. Cytological screening is one strategy to detect ESCC at an early stage and has shown promise in previous studies, although improvement in sensitivity and specificity are needed. Proteases modulate cancer progression by facilitating tumor invasion and metastasis. In the current study, matrix metalloproteinases (MMPs) were studied in a search for new early detection markers for ESCC. Methods: Protein expression levels of MMPs were measured using zymography in 24 cases of paired normal esophagus and ESCC, and in the tumor-associated stroma and tumor epithelium in one sample after laser capture microdissection (LCM). MMP-3 and MMP-10 transcripts in both the epithelium and stroma in five cases were further analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Results: Gelatin zymography showed bands corresponding in size to MMP-2, MMP-3, MMP-9, and MMP-10 enzymes in each of the 24 cancer cases. MMP levels tended to be higher in tumors than paired normal tissue; however, only the 45 kDa band that corresponds to the activated form of MMP-3 and MMP-10 was strongly expressed in all 24 tumors with little or no expression in the paired normal foci. LCM-based analysis showed the 45 kDA band to be present in both the stromal and epithelial components of the tumor microenvironment, and that MMP-3 and MMP-10 mRNA levels were higher in tumors than paired normal tissues for each compartment. Conclusions: Increased levels of MMPs occur in ESCC suggesting their up-regulation is important in esophageal tumorigenesis. The up-regulated gene products have the potential to serve as early detection markers in the clinic. C1 [Mukherjee, Sumana; Yan, Wusheng; Rodriguez-Canales, Jaime; Erickson, Heidi S.; Richardson, Annely M.; Tangrea, Michael A.; Chuaqui, Rodrigo F.; Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Roth, Mark J.; Dawsey, Sanford M.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hu, Nan; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Emmert-Buck, MR (reprint author), NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM buckm@mail.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 24 TC 23 Z9 26 U1 0 U2 7 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 OCT 5 PY 2010 VL 8 AR 91 DI 10.1186/1479-5876-8-91 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 668JA UT WOS:000283263400001 PM 20920372 ER PT J AU Tost, H Meyer-Lindenberg, A AF Tost, Heike Meyer-Lindenberg, Andreas TI I fear for you: A role for serotonin in moral behavior SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PREFRONTAL CORTEX; SOCIAL COGNITION; NEURAL CIRCUITRY; AMYGDALA; HUMANS; JUDGMENTS; TRUST C1 [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-68159 Mannheim, Germany. [Tost, Heike] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Meyer-Lindenberg, A (reprint author), Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-68159 Mannheim, Germany. EM a.meyer-lindenberg@zi-mannheim.de RI Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Intramural NIH HHS NR 19 TC 7 Z9 7 U1 2 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 5 PY 2010 VL 107 IS 40 BP 17071 EP 17072 DI 10.1073/pnas.1012545107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 658TJ UT WOS:000282512000007 PM 20876090 ER PT J AU Fields, RD Ni, YC AF Fields, R. Douglas Ni, Yingchun TI Nonsynaptic Communication Through ATP Release from Volume-Activated Anion Channels in Axons SO SCIENCE SIGNALING LA English DT Article ID AMINO-ACID RELEASE; GLUTAMATE RELEASE; ADENOSINE-TRIPHOSPHATE; MECHANICAL CHANGES; CHLORIDE CHANNELS; ACTION-POTENTIALS; WHITE-MATTER; GLIAL-CELLS; PHARMACOLOGICAL CHARACTERIZATION; MOUSE ASTROCYTES AB The release of neuronal messengers outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We identify a mechanism for nonsynaptic, nonvesicular release of adenosine triphosphate (ATP) from axons through volume-activated anion channels (VAACs) activated by microscopic axon swelling during action potential firing. We used a combination of single-photon imaging of ATP release, together with imaging for intrinsic optical signals, intracellular calcium ions (Ca(2+)), time-lapse video, and confocal microscopy, to investigate action potential-induced nonsynaptic release of this neurotransmitter. ATP release from cultured embryonic dorsal root ganglion axons persisted when bafilomycin or botulinum toxin was used to block vesicular release, whereas pharmacological inhibition of VAACs or prevention of action potential-induced axon swelling inhibited ATP release and disrupted activity-dependent signaling between axons and astrocytes. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease. C1 [Fields, R. Douglas; Ni, Yingchun] NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bldg 35,Room 2A211,MSC 3713,35 Lincoln Dr, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU Intramural NIH HHS [Z01 HD000713-13] NR 71 TC 64 Z9 65 U1 1 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD OCT 5 PY 2010 VL 3 IS 142 AR ra73 DI 10.1126/scisignal.2001128 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 658WN UT WOS:000282524700003 PM 20923934 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI An introduction to standardized clinical nomenclature for dysmorphic features: the Elements of Morphology project SO BMC MEDICINE LA English DT Editorial Material ID TERMINOLOGY; LANGUAGE; REGION AB Human structural malformations (anomalies or birth defects) have an enormous and complex range of manifestations and severity. The description of these findings can be challenging because the variation of many of the features is continuous and only some of them can be objectively assessed (that is, measured), among other factors. An international group of clinicians resolved to develop a set of terms that could be used to describe human structural malformations, under the general project name 'Elements of Morphology'. Here, the background to the project, progress to date, and the practical implementation of the terminology in research reporting is discussed. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov FU Intramural NIH HHS NR 11 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 4 PY 2010 VL 8 AR 56 DI 10.1186/1741-7015-8-56 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 668ZZ UT WOS:000283317400001 PM 20920337 ER PT J AU Anderson, LA Engels, EA AF Anderson, Lesley A. Engels, Eric A. TI Autoimmune conditions and hairy cell leukemia: an exploratory case-control study SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article ID CHRONIC INFLAMMATION; ASSOCIATION AB Background: Case reports suggest that hairy cell leukemia (HCL) may be associated with autoimmune conditions, however no systematic investigations in this area have been undertaken. Methods: Using the United States Surveillance, Epidemiology, and End Results Medicare linked database, we conducted an exploratory study comparing autoimmune conditions in 418 HCL cases (aged >= 65 years) and 160,086 controls. Results: Overall, the proportion with autoimmune conditions was similar between HCL cases and controls (n = 79 (18.9%) and n = 29,284 (18.3%), respectively). Before diagnosis/selection, there was no overall difference in the prevalence of autoimmune conditions in HCL cases (n = 37, 8.9%) compared with controls (n = 14,085, 8.8%), p = 0.969. However, compared with controls, HCL cases more frequently had sarcoidosis (OR 9.6, 95%CI 2.4-39.5), Sjogren syndrome (OR 6.1, 95% CI 2.0-19.3) and erythema nodosum (OR 37, 95% CI 4.9-284) before diagnosis. Autoimmune conditions were also more common in HCL cases than controls around the time of diagnosis/selection (p < 0.001) but not subsequently. Conclusions: The findings do not support an overall relationship between autoimmune conditions and HCL, although the association with some autoimmune conditions prior to HCL diagnosis may warrant further investigation. Our findings also suggest that autoimmune conditions in HCL patients may be detected around the time of diagnosis. C1 [Anderson, Lesley A.] Queens Univ Belfast, Canc Epidemiol & Hlth Serv, Res Grp, Ctr Publ Hlth,Sch Med Dent & Biomed Sci, Belfast BT7 1NN, Antrim, North Ireland. [Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Anderson, LA (reprint author), Queens Univ Belfast, Canc Epidemiol & Hlth Serv, Res Grp, Ctr Publ Hlth,Sch Med Dent & Biomed Sci, Belfast BT7 1NN, Antrim, North Ireland. EM l.anderson@qub.ac.uk OI Anderson, Lesley/0000-0002-1000-3649 FU National Cancer Institute; Research and Development Office, Northern Ireland FX This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. The authors thank Winnie Ricker and Ruth Parsons, Information Management Services, Rockville, MD for constructing the dataset, and our colleagues on the SMAHRT Study, who provided advice and assistance with the SEER-Medicare dataset. This research was supported by the Intramural Research Program of the National Cancer Institute. The Research and Development Office, Northern Ireland, funded Dr. Lesley Anderson to participate in the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute. The authors reported no potential conflicts of interest. NR 15 TC 7 Z9 8 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD OCT 4 PY 2010 VL 3 AR 35 DI 10.1186/1756-8722-3-35 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 664LJ UT WOS:000282961200001 PM 20920342 ER PT J AU Jonsson, H Helgadottir, GP Sverrisdottir, JE Eiriksdottir, G Launer, L Harris, T Gudnason, V AF Jonsson, H. Helgadottir, G. P. Sverrisdottir, J. E. Eiriksdottir, G. Launer, L. Harris, T. Gudnason, V. TI PHOTOGRAPHIC SCORING IS INSENSITIVE FOR MONITORING PROGRESS OF HAND OSTEOARTHRITIS, BUT SIDE BY SIDE COMPARISON OF PHOTOGRAPHS DETECTS PROGRESS AT 5 YEAR INTERVALS IN THE ELDERLY. THE AGES-REYKJAVIK STUDY SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the OsteoArthritis-Research-Society-International CY SEP 23-26, 2010 CL Brussels, BELGIUM SP OsteoArthritis Res Soc Int C1 [Jonsson, H.] Univ Iceland, Landspitalinn, Reykjavik, Iceland. [Sverrisdottir, J. E.; Eiriksdottir, G.; Gudnason, V.] Icelandic Heart Assoc, Kopavogur, Iceland. [Launer, L.; Harris, T.] NIA, Bethesda, MD 20892 USA. RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2010 VL 18 SU 2 BP S183 EP S184 PG 2 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 670UN UT WOS:000283452900437 ER PT J AU Yamashita, T Honda, M Nakamoto, Y Yamashita, T Arai, K Takatori, H Nio, K Hara, Y Ikeda, H Zen, Y Wang, XW Kaneko, S AF Yamashita, Taro Honda, Masao Nakamoto, Yasunari Yamashita, Tatsuya Arai, Kuniaki Takatori, Hajime Nio, Kouki Hara, Yasumasa Ikeda, Hiroko Zen, Yoh Wang, Xin W. Kaneko, Shuichi TI HETEROGENEITY AND HIERARCHY OF CANCER STEM CELLS IN HUMAN LIVER CANCER SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Yamashita, Taro; Honda, Masao; Nakamoto, Yasunari; Yamashita, Tatsuya; Arai, Kuniaki; Takatori, Hajime; Nio, Kouki; Hara, Yasumasa; Ikeda, Hiroko; Zen, Yoh; Kaneko, Shuichi] Kanazawa Univ Hosp, Ctr Liver Dis, Kanazawa, Ishikawa, Japan. [Wang, Xin W.] NCI, Human Carcinogenesis Lab, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 13 BP 325A EP 326A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600014 ER PT J AU Zhang, XZ Murphy, AA Yang, J Lempicki, RA Masur, H Polis, MA Kottilil, S AF Zhang, Xiaozhen Murphy, Alison A. Yang, Jun Lempicki, Richard A. Masur, Henry Polis, Michael A. Kottilil, Shyam TI DIFFERENTIAL TRANSCRIPTOSOME PROFILES AND ANTIVIRAL EFFECT OF IL28B AND INTERFeRON alpha ON HCV-INFECTED AND UNINFECTED HEPATOMA CELLS SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Zhang, Xiaozhen; Murphy, Alison A.; Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Masur, Henry] NIH, CCMD, CC, Bethesda, MD USA. [Yang, Jun; Lempicki, Richard A.] SAIC Frederick Inc, Frederick, MD USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 38 BP 339A EP 339A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600039 ER PT J AU Li, QS Krishnamurthy, S Lan, KH Liang, TJ AF Li, Qisheng Krishnamurthy, Siddharth Lan, Keng-Hsin Liang, T. Jake TI A NOVEL NF-KAPPAB-INDEPENDENT FUNCTION OF IKKALPHA IN HEPATITIS C VIRUS ASSEMBLY SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Li, Qisheng; Krishnamurthy, Siddharth; Lan, Keng-Hsin; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. RI Li, Qisheng/K-1909-2013 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 41 BP 340A EP 340A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600042 ER PT J AU Yang, JD Seol, SY Leem, SH Kim, YH Sun, ZF Lee, JS Thorgeirsson, SS Chu, IS Kang, KJ Roberts, LR AF Yang, Ju Dong Seol, So-Young Leem, Sun-Hee Kim, Yong Hoon Sun, Zhifu Lee, Ju-Seog Thorgeirsson, Snorri S. Chu, In-Sun Kang, Koo Jeong Roberts, Lewis R. TI GENES ASSOCIATED WITH RECURRENCE OF HEPATOCELLULAR CARCINOMA: INTEGRATED ANALYSIS BY GENE EXPRESSION AND METHYLATION PROFILING SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Yang, Ju Dong; Kang, Koo Jeong; Roberts, Lewis R.] Mayo Clin, GI Basic Res, Rochester, MN USA. [Seol, So-Young; Leem, Sun-Hee] Dong A Univ, Dept Biol Sci, Pusan, South Korea. [Kim, Yong Hoon; Kang, Koo Jeong] Keimyung Univ, Sch Med, Dept Surg, Taegu, South Korea. [Sun, Zhifu] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Rochester, MN USA. [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. [Chu, In-Sun] Korea Res Inst Biosci & Biotechnol, Korean Bioinformat Ctr, Taejon, South Korea. 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 49 BP 344A EP 344A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600050 ER PT J AU Marquardt, JU Uchida, K Seo, D Conner, EA Factor, VM Thorgeirsson, SS AF Marquardt, Jens U. Uchida, Koichi Seo, Deakwan Conner, Elizabeth A. Factor, Valentina M. Thorgeirsson, Snorri S. TI LOSS OF HGF/C-MET SIGNALING IN HEPATOCYTES POTENTIATES THE ACTIVATION OF HEPATIC STELLATE CELLS AND AGGRAVATES THE PROGRESSION OF CHRONIC LIVER FIBROSIS SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Marquardt, Jens U.; Uchida, Koichi; Seo, Deakwan; Conner, Elizabeth A.; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, LEC, NIH, Bethesda, MD 20892 USA. [Uchida, Koichi] Yamaguchi Univ, Div Gastroenterol, Yamaguchi, Japan. 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 158 BP 398A EP 398A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600159 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, Constance E. Everhart, James E. TI DEFINING UPPER LIMITS OF NORMAL (ULN) FOR ALANINE AMINOTRANSFERASE ACTIVITY (ALT) IN THE UNITED STATES POPULATION SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Ruhl, Constance E.] Social & Sci Syst Inc, Silver Spring, MD USA. [Everhart, James E.] NIDDK, 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 171 BP 409A EP 409A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600178 ER PT J AU Hoofs, JC Shiffman, ML Goodman, Z Kleiner, DE Stoddard, AM Dienstag, JL AF Hoofs, John C. Shiffman, Mitchell L. Goodman, Zachary Kleiner, David E. Stoddard, Anne M. Dienstag, Jules L. TI RATE OF PROGRESSION OF HEPATIC FIBROSIS IN PATIENT WITH CHRONIC HEPATITIS C (CHC) PREDICTS NON-HCC AND HCC OUTCOMES: RESULTS FROM THE HALT-C TRIAL SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Hoofs, John C.] Univ Calif Irvine, Orange, CA 92668 USA. [Shiffman, Mitchell L.] Bon Secours Hlth Syst, Liver Inst Virginia, Newport News, VA USA. [Goodman, Zachary] Inova Fairfax Hosp, Ctr Liver Dis, Falls Church, VA USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Stoddard, Anne M.] New England Res Inst Inc, Watertown, MA USA. [Dienstag, Jules L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 178 BP 412A EP 412A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600184 ER PT J AU Lok, AS Everhart, JE Wright, EC Morgan, TR Di Bisceglie, AM Kim, HY AF Lok, Anna S. Everhart, James E. Wright, Elizabeth C. Morgan, Timothy R. Di Bisceglie, Adrian M. Kim, Hae-Young TI MAINTENANCE PEGINTERFERON (PEGIFN) THERAPY TO PREVENT HEPATOCELLULAR CARCINOMA (HCC) IN PATIENTS (PTS) WITH ADVANCED CHRONIC HEPATITIS C (CHC): EXTENDED FOLLOW-UP RESULTS FROM THE HALT-C TRIAL SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Everhart, James E.; Wright, Elizabeth C.] NIDDK, NIH, Bethesda, MD USA. [Morgan, Timothy R.] VA Med Ctr, Long Beach, CA USA. [Di Bisceglie, Adrian M.] St Louis Univ, St Louis, MO 63103 USA. [Kim, Hae-Young] NERI, Watertown, MA USA. NR 0 TC 0 Z9 1 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 OCT PY 2010 VL 52 IS 4 SU S MA 214 BP 428A EP 429A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600220 ER PT J AU Freedman, ND Curto, TM Lindsay, K Wright, EC Sinha, R Everhart, JE AF Freedman, Neal D. Curto, Teresa M. Lindsay, Karen Wright, Elizabeth C. Sinha, Rashmi Everhart, James E. TI COFFEE IS ASSOCIATED WITH VIROLOGIC RESPONSE IN CHRONIC HEPATITIS C (CHC): FINDINGS FROM THE HEPATITIS C LONG-TERM TREATMENT AGAINST CIRRHOSIS TRIAL (HALT-C) SO HEPATOLOGY LA English DT Meeting Abstract CT 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 29-NOV 02, 2010 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Freedman, Neal D.; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Curto, Teresa M.] New England Res Inst, Watertown, MA 02172 USA. [Lindsay, Karen] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Everhart, James E.] NIDDK, Div Digest Dis & Nutr, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2010 VL 52 IS 4 SU S MA 224 BP 434A EP 435A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740EY UT WOS:000288775600230 ER EF